First of its Kind: A Core Curriculum for Urologic Nursing

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1 EVERYDAY UROLOGY TM ONCOLOGY INSIGHTS A UROTODAY UBLICATION VOLUME 1, ISSUE 4 First of its Kind: A Core Curriculum for Urologic Nursing DIANE NEWMAN, DN, AN-BC, FAAN, BCB-MD mcrc Treatment: The Right Treatment for the Right atient at the Right Time CHARLES J. RYAN, MD The Multidisciplinary Cancer Clinic ALICIA K. MORGANS, MD, MH Spotlight: SUO 2016 Conference Highlights

2 For mcrc patients with symptomatic bone metastases1 Introduce Xofigo at the first sign of progression on hormonal therapy1* *In ALSYMCA, best standard of care (BSOC) was defined as antihormonal agents, local external beam radiation therapy (EBRT), ketoconazole, and treatment with glucocorticoids.2 XOFIGO IS INDICATED for the treatment of patients with castration-resistant prostate cancer (CRC), symptomatic bone metastases and no known visceral metastatic disease. with myelosuppression were observed in 1% of Xofigo-treated patients compared to 0.3% of patients treated with placebo. The incidence of infection-related deaths (2%), serious infections (10%), and febrile neutropenia (<1%) was similar for patients treated with Xofigo and placebo. Myelosuppression notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia has been reported in patients treated with Xofigo. Important Safety Information Monitor patients with evidence of compromised bone marrow Contraindications: Xofigo is contraindicated in women who reserve closely and provide supportive care measures when are or may become pregnant. Xofigo can cause fetal harm clinically indicated. Discontinue Xofigo in patients who when administered to a pregnant woman experience life-threatening complications despite supportive Bone Marrow Suppression: In the randomized trial, 2% of care for bone marrow failure patients in the Xofigo arm experienced bone marrow failure Hematological Evaluation: Monitor blood counts at baseline or ongoing pancytopenia, compared to no patients treated and prior to every dose of Xofigo. rior to first administering with placebo. There were two deaths due to bone marrow Xofigo, the absolute neutrophil count (ANC) should be failure. For 7 of 13 patients treated with Xofigo bone marrow failure was ongoing at the time of death. Among the 13 patients /L, the platelet count /L, and hemoglobin 10 g/dl. rior to subsequent administrations, the ANC should who experienced bone marrow failure, 54% required blood be 1 109/L and the platelet count /L. Discontinue transfusions. Four percent (4%) of patients in the Xofigo Xofigo if hematologic values do not recover within 6 to 8 weeks arm and 2% in the placebo arm permanently discontinued therapy due to bone marrow suppression. In the randomized after the last administration despite receiving supportive care trial, deaths related to vascular hemorrhage in association

3 S I G N I F I C A N T LY E X T E N D OV E R A L L S U R V I VA L ( OS ) 1,2a MME EDDI AI ANNOOSSWI INT HA NO RE XW ILTOHROAT U TO RC YO NA CNOA M LYIST A I SN1,2b T U S E O F A B I R AT E R O N E 9 a 100 HR=0.695 (95% CI: ) robability of survival (%) MONTHS lanned course of Xofigo treatment is 6 doses for Xofigo + BSOC (n=614) (95% CI: ) 30 % reduction in the risk of death vs placebo (HR=0.695)1, MONTHS 30 for placebo + BSOC (n=307) (95% CI: ) Time (months) Xofigo lacebo In the prespecified interim analysis.1 An exploratory updated OS analysis was performed before patient crossover, incorporating an additional 214 events, resulting in findings consistent with the interim analysis.1 a b respecified interim analysis: median OS was 14.0 months for Xofigo (95% Conf idence interval [CI]: ) vs 11.2 months for placebo (95% CI: )1 = ; Hazard ratio [HR]=0.695 (95% CI: ) Concomitant Use With Chemotherapy: Safety and efficacy of concomitant chemotherapy with Xofigo have not been established. Outside of a clinical trial, concomitant use of Xofigo in patients on chemotherapy is not recommended due to the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes, or hemibody external radiotherapy are administered during the treatment period, Xofigo should be discontinued Administration and Radiation rotection: Xofigo should be received, used, and administered only by authorized persons in designated clinical settings. The administration of Xofigo is associated with potential risks to other persons from radiation or contamination from spills of bodily fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in accordance with national and local regulations Adverse Reactions: The most common adverse reactions ( 10%) in the Xofigo arm vs the placebo arm, respectively, were nausea (36% vs 35%), diarrhea (25% vs 15%), vomiting (19% vs 14%), and 2016 Bayer. All rights reserved. BAYER, the Bayer Cross, and Xofigo are registered trademarks of Bayer US /16 rinted in USA peripheral edema (13% vs 10%). Grade 3 and 4 adverse events were reported in 57% of Xofigo-treated patients and 63% of placebo-treated patients. The most common hematologic laboratory abnormalities in the Xofigo arm ( 10%) vs the placebo arm, respectively, were anemia (93% vs 88%), lymphocytopenia (72% vs 53%), leukopenia (35% vs 10%), thrombocytopenia (31% vs 22%), and neutropenia (18% vs 5%) References: 1. Xofigo (radium Ra 223 dichloride) injection [prescribing information]. Whippany, NJ: Bayer HealthCare harmaceuticals Inc.; March arker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3): lease see following pages for brief summary of full rescribing Information. radium Ra 223 dichloride INJECTION Learn more about Xofigo at hcp.xofigo-us.com

4 XOFIGO (radium Ra 223 dichloride) Injection, for intravenous use Initial U.S. Approval: 2013 BRIEF SUMMARY of prescribing InFoRMAtIon consult package InSERt FoR FULL prescribing InFoRMAtIon 1 INDICATIONS AND USAGE Xofigo is indicated for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease. 2 DOSAGE AND ADMINISTRATION 2.3 Instructions for Use/Handling General warning Xofigo (an alpha particle-emitting pharmaceutical) should be received, used and administered only by authorized persons in designated clinical settings. The receipt, storage, use, transfer and disposal Xofigo are subject to the regulations and/or appropriate licenses of the competent official organization. Xofigo should be handled by the user in a manner which satisfies both radiation safety and pharmaceutical quality requirements. Appropriate aseptic precautions should be taken. Radiation protection The administration of Xofigo is associated with potential risks to other persons (e.g., medical staff, caregivers and patient s household members) from radiation or contamination from spills of bodily fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in accordance with national and local regulations. For drug handling Follow the normal working procedures for the handling of radiopharmaceuticals and use universal precautions for handling and administration such as gloves and barrier gowns when handling blood and bodily fluids to avoid contamination. In case of contact with skin or eyes, the affected area should be flushed immediately with water. In the event of spillage of Xofigo, the local radiation safety officer should be contacted immediately to initiate the necessary measurements and required procedures to decontaminate the area. A complexing agent such as 0.01 M ethylene-diamine-tetraacetic acid (EDTA) solution is recommended to remove contamination. For patient care Whenever possible, patients should use a toilet and the toilet should be flushed several times after each use. When handling bodily fluids, simply wearing gloves and hand washing will protect caregivers. Clothing soiled with Xofigo or patient fecal matter or urine should be washed promptly and separately from other clothing. Radium-223 is primarily an alpha emitter, with a 95.3% fraction of energy emitted as alpha-particles. The fraction emitted as beta-particles is 3.6%, and the fraction emitted as gamma-radiation is 1.1%. The external radiation exposure associated with handling of patient doses is expected to be low, because the typical treatment activity will be below 8,000 kbq (216 microcurie). In keeping with the As Low As Reasonably Achievable (ALARA) principle for minimization of radiation exposure, it is recommended to minimize the time spent in radiation areas, to maximize the distance to radiation sources, and to use adequate shielding. Any unused product or materials used in connection with the preparation or administration are to be treated as radioactive waste and should be disposed of in accordance with local regulations. The gamma radiation associated with the decay of radium-223 and its daughters allows for the radioactivity measurement of Xofigo and the detection of contamination with standard instruments. 4 CONTRAINDICATIONS Xofigo is contraindicated in pregnancy. Xofigo can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Xofigo is not indicated for use in women. Xofigo is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus [see Use in Specific opulations (8.1)]. 5 WARNINGS AND RECAUTIONS 5.1 Bone Marrow Suppression In the randomized trial, 2% of patients on the Xofigo arm experienced bone marrow failure or ongoing pancytopenia compared to no patients treated with placebo. There were two deaths due to bone marrow failure and for 7 of 13 patients treated with Xofigo, bone marrow failure was ongoing at the time of death. Among the 13 patients who experienced bone marrow failure, 54% required blood transfusions. Four percent (4%) of patients on the Xofigo arm and 2% on the placebo arm permanently discontinued therapy due to bone marrow suppression. In the randomized trial, deaths related to vascular hemorrhage in association with myelosuppression were observed in 1% of Xofigo-treated patients compared to 0.3% of patients treated with placebo. The incidence of infectionrelated deaths (2%), serious infections (10%), and febrile neutropenia (<1%) were similar for patients treated with Xofigo and placebo. Myelosuppression; notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia; has been reported in patients treated with Xofigo. In the randomized trial, complete blood counts (CBCs) were obtained every 4 weeks prior to each dose and the nadir CBCs and times of recovery were not well characterized. In a separate singledose phase 1 study of Xofigo, neutrophil and platelet count nadirs occurred 2 to 3 weeks after Xofigo administration at doses that were up to 1 to 5 times the recommended dose, and most patients recovered approximately 6 to 8 weeks after administration [see Adverse Reactions (6)]. Hematologic evaluation of patients must be performed at baseline and prior to every dose of Xofigo. Before the first administration of Xofigo, the absolute neutrophil count (ANC) should be 1.5 x 10 9 /L, the platelet count 100 x 10 9 /L and hemoglobin 10 g/dl. Before subsequent administrations of Xofigo, the ANC should be 1 x 10 9 /L and the platelet count 50 x 10 9 /L. If there is no recovery to these values within 6 to 8 weeks after the last administration of Xofigo, despite receiving supportive care, further treatment with Xofigo should be discontinued. atients with evidence of compromised bone marrow reserve should be monitored closely and provided with supportive care measures when clinically indicated. Discontinue Xofigo in patients who experience lifethreatening complications despite supportive care for bone marrow failure. The safety and efficacy of concomitant chemotherapy with Xofigo have not been established. Outside of a clinical trial, concomitant use with chemotherapy is not recommended due to the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes or hemibody external radiotherapy are administered during the treatment period, Xofigo should be discontinued. 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in another section of the label: Bone Marrow Suppression [see Warnings and recautions (5.1)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In the randomized clinical trial in patients with metastatic castration-resistant prostate cancer with bone metastases, 600 patients received intravenous injections of 55 kbq/kg (1.49 microcurie/kg) of Xofigo and best standard of care and 301 patients received placebo and best standard of care once every 4 weeks for up to 6 injections. rior to randomization, 58% and 57% of patients had received docetaxel in the Xofigo and placebo arms, respectively. The median duration of treatment was 20 weeks (6 cycles) for Xofigo and 18 weeks (5 cycles) for placebo. The most common adverse reactions ( 10%) in patients receiving Xofigo were nausea, diarrhea, vomiting, and peripheral edema (Table 3). Grade 3 and 4 adverse events were reported among 57% of Xofigo-treated patients and 63% of placebo-treated patients. The most common hematologic laboratory abnormalities in Xofigo-treated patients ( 10%) were anemia, lymphocytopenia, leukopenia, thrombocytopenia, and neutropenia (Table 4). Treatment discontinuations due to adverse events occurred in 17% of patients who received Xofigo and 21% of patients who received placebo. The most common hematologic laboratory abnormalities leading to discontinuation for Xofigo were anemia (2%) and thrombocytopenia (2%). Table 3 shows adverse reactions occurring in 2% of patients and for which the incidence for Xofigo exceeds the incidence for placebo. Table 3: Adverse Reactions in the Randomized Trial System/Organ Class Xofigo (n=600) lacebo (n=301) referred Term Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 % % % % Blood and lymphatic system disorders ancytopenia Gastrointestinal disorders Nausea Diarrhea Vomiting General disorders and administration site conditions eripheral edema Renal and urinary disorders Renal failure and impairment Laboratory Abnormalities Table 4 shows hematologic laboratory abnormalities occurring in > 10% of patients and for which the incidence for Xofigo exceeds the incidence for placebo. Table 4: Hematologic Laboratory Abnormalities Hematologic Xofigo (n=600) lacebo (n=301) Laboratory Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 Abnormalities % % % % Anemia Lymphocytopenia Leukopenia <1 Thrombocytopenia <1 Neutropenia <1 Laboratory values were obtained at baseline and prior to each 4-week cycle. As an adverse reaction, grade 3-4 thrombocytopenia was reported in 6% of patients on Xofigo and in 2% of patients on placebo. Among patients who received Xofigo, the laboratory abnormality grade 3-4 thrombocytopenia occurred in 1% of docetaxel naïve patients and in 4% of patients who had received prior docetaxel. Grade 3-4 neutropenia occurred in 1% of docetaxel naïve patients and in 3% of patients who have received prior docetaxel.

5 Fluid Status Dehydration occurred in 3% of patients on Xofigo and 1% of patients on placebo. Xofigo increases adverse reactions such as diarrhea, nausea, and vomiting which may result in dehydration. Monitor patients oral intake and fluid status carefully and promptly treat patients who display signs or symptoms of dehydration or hypovolemia. Injection Site Reactions Erythema, pain, and edema at the injection site were reported in 1% of patients on Xofigo. Secondary Malignant Neoplasms Xofigo contributes to a patient s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure may be associated with an increased risk of cancer and hereditary defects. Due to its mechanism of action and neoplastic changes, including osteosarcomas, in rats following administration of radium-223 dichloride, Xofigo may increase the risk of osteosarcoma or other secondary malignant neoplasms [see Nonclinical Toxicology (13.1)]. However, the overall incidence of new malignancies in the randomized trial was lower on the Xofigo arm compared to placebo (<1% vs. 2%; respectively), but the expected latency period for the development of secondary malignancies exceeds the duration of follow up for patients on the trial. Subsequent Treatment with Cytotoxic Chemotherapy In the randomized clinical trial, 16% patients in the Xofigo group and 18% patients in the placebo group received cytotoxic chemotherapy after completion of study treatments. Adequate safety monitoring and laboratory testing was not performed to assess how patients treated with Xofigo will tolerate subsequent cytotoxic chemotherapy. 7 DRUG INTERACTIONS No formal clinical drug interaction studies have been performed. Subgroup analyses indicated that the concurrent use of bisphosphonates or calcium channel blockers did not affect the safety and efficacy of Xofigo in the randomized clinical trial. 8 USE IN SECIFIC OULATIONS 8.1 regnancy Category X [see Contraindications (4)] Xofigo can cause fetal harm when administered to a pregnant woman based on its mechanism of action. While there are no human or animal data on the use of Xofigo in pregnancy and Xofigo is not indicated for use in women, maternal use of a radioactive therapeutic agent could affect development of a fetus. Xofigo is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with Xofigo. 8.3 Nursing Mothers Xofigo is not indicated for use in women. It is not known whether radium-223 dichloride is excreted in human milk. Because many drugs are excreted in human milk, and because of potential for serious adverse reactions in nursing infants from Xofigo, a decision should be made whether to discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. 8.4 ediatric Use The safety and efficacy of Xofigo in pediatric patients have not been established. In single- and repeat-dose toxicity studies in rats, findings in the bones (depletion of osteocytes, osteoblasts, osteoclasts, fibro-osseous lesions, disruption/ disorganization of the physis/growth line) and teeth (missing, irregular growth, fibro-osseous lesions in bone socket) correlated with a reduction of osteogenesis that occurred at clinically relevant doses beginning in the range of kbq ( microcurie) per kg body weight. 8.5 Geriatric Use Of the 600 patients treated with Xofigo in the randomized trial, 75% were 65 years of age and over and while 33% were 75 years of age and over. No dosage adjustment is considered necessary in elderly patients. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 atients with Hepatic Impairment No dedicated hepatic impairment trial for Xofigo has been conducted. Since radium-223 is neither metabolized by the liver nor eliminated via the bile, hepatic impairment is unlikely to affect the pharmacokinetics of radium-223 dichloride [see Clinical harmacology (12.3)]. Based on subgroup analyses in the randomized clinical trial, dose adjustment is not needed in patients with mild hepatic impairment. No dose adjustments can be recommended for patients with moderate or severe hepatic impairment due to lack of clinical data. 8.7 atients with Renal Impairment No dedicated renal impairment trial for Xofigo has been conducted. Based on subgroup analyses in the randomized clinical trial, dose adjustment is not needed in patients with existing mild (creatinine clearance [CrCl] 60 to 89 ml/min) or moderate (CrCl 30 to 59 ml/min) renal impairment. No dose adjustment can be recommended for patients with severe renal impairment (CrCl less than 30 ml/ min) due to limited data available (n = 2) [see Clinical harmacology (12.3)]. 8.8 Males of Reproductive otential Contraception Because of potential effects on spermatogenesis associated with radiation, advise men who are sexually active to use condoms and their female partners of reproductive potential to use a highly effective contraceptive method during and for 6 months after completing treatment with Xofigo. Infertility There are no data on the effects of Xofigo on human fertility. There is a potential risk that radiation by Xofigo could impair human fertility [see Nonclinical Toxicology (13.1)]. 10 OVERDOSAGE There have been no reports of inadvertent overdosing of Xofigo during clinical studies. There is no specific antidote. In the event of an inadvertent overdose of Xofigo, utilize general supportive measures, including monitoring for potential hematological and gastrointestinal toxicity, and consider using medical countermeasures such as aluminum hydroxide, barium sulfate, calcium carbonate, calcium gluconate, calcium phosphate, or sodium alginate. Single Xofigo doses up to 274 kbq (7.41 microcurie) per kg body weight were evaluated in a phase 1 clinical trial and no dose-limiting toxicities were observed. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Animal studies have not been conducted to evaluate the carcinogenic potential of radium-223 dichloride. However, in repeat-dose toxicity studies in rats, osteosarcomas, a known effect of bone-seeking radionuclides, were observed at clinically relevant doses 7 to 12 months after the start of treatment. The presence of other neoplastic changes, including lymphoma and mammary gland carcinoma, was also reported in 12- to 15-month repeat-dose toxicity studies in rats. Genetic toxicology studies have not been conducted with radium-223 dichloride. However, the mechanism of action of radium-223 dichloride involves induction of double-strand DNA breaks, which is a known effect of radiation. Animal studies have not been conducted to evaluate the effects of radium-223 dichloride on male or female fertility or reproductive function. Xofigo may impair fertility and reproductive function in humans based on its mechanism of action. 17 ATIENT COUNSELING INFORMATION Advise patients: To be compliant with blood cell count monitoring appointments while receiving Xofigo. Explain the importance of routine blood cell counts. Instruct patients to report signs of bleeding or infections. To stay well hydrated and to monitor oral intake, fluid status, and urine output while being treated with Xofigo. Instruct patients to report signs of dehydration, hypovolemia, urinary retention, or renal failure / insufficiency. There are no restrictions regarding contact with other people after receiving Xofigo. Follow good hygiene practices while receiving Xofigo and for at least 1 week after the last injection in order to minimize radiation exposure from bodily fluids to household members and caregivers. Whenever possible, patients should use a toilet and the toilet should be flushed several times after each use. Clothing soiled with patient fecal matter or urine should be washed promptly and separately from other clothing. Caregivers should use universal precautions for patient care such as gloves and barrier gowns when handling bodily fluids to avoid contamination. When handling bodily fluids, wearing gloves and hand washing will protect caregivers. Who are sexually active to use condoms and their female partners of reproductive potential to use a highly effective method of birth control during treatment and for 6 months following completion of Xofigo treatment. Manufactured for: Bayer HealthCare harmaceuticals Inc. Whippany, NJ Manufactured in Norway Xofigo is a trademark of Bayer Aktiengesellschaft. 2013, Bayer HealthCare harmaceuticals Inc. All rights reserved. Revised: March BS

6 EVERYDAY UROLOGY ONCOLOGY INSIGHTS A UROTODAY UBLICATION VOLUME 1, ISSUE 4 CONTENTS 10 COVER STORY First of its Kind: A Core Curriculum for Urologic Nursing DIANE NEWMAN, DN, AN-BC, FAAN, BCB-MD EXERT ERSECTIVE CLINICAL UDATE mcrc Treatment: The Right Treatment for the Right atient at the Right Time CHARLES J. RYAN, MD The Multidisciplinary Cancer Clinic ALICIA K. MORGANS, MD, MH

7 Everyday Urology ONCOLOGY INSIGHTS A UROTODAY UBLICATION Editorial Leadership EDITOR-IN-CHIEF Neal Shore, MD, FACS Atlantic Urology Clinics Myrtle Beach, South Carolina EDITOR-AT-LARGE E.David Crawford, MD University of Colorado Hospital Aurora, Coloradio SOTLIGHT 28 Spotlight: SUO 2016 Conference Highlights Editorial Board Bishoy Morris Faltas, MD Weill-Cornell Medical College New York, New York etros Grivas, MD, hd Cleveland Clinic Cleveland, Ohio Ashish M. Kamat, MD, MBBS, FACS The University of Texas, MD Anderson Cancer Center, Houston, Texas Thomas Keane, MBBCh, FRCHI, FACS Medical University of South Carolina Charleston, South Carolina Badrinath Konety, MD, MBA University of Minnesota Minneapolis, MN hillip Koo, MD Banner MD Anderson Cancer Center Gilbert, Arizona Alicia K. Morgans, MD Vanderbilt-Ingram Cancer Center Nashville, Tennessee Charles J. Ryan, MD University of California San Francisco San Francisco, California Evan Yu, MD Seattle Cancer Care Alliance Seattle, Washington Digital Science ress Inc. Founder and CEO Gina B. Carithers Director of Marketing Courtney Leonard resident Joseph alumbo Art Director Lisa Holmes, Yulan Studio About Digital Science ress Digital Science ress, Inc, has been publishing UroToday.com since 2003 and has developed OncToday.com, in Digital Science ress is committed to providing factually accurate, timely, evidence-based urological and oncology information to healthcare providers around the globe. In 2003 we recognized that there are a significant number of scientific publications and medical conferences and yet there was no single, easy to access platform that accommodates this content. UroToday.com became the reference platform that aggregates the relevant, unbiased urology disease and treatment-based content and is committed to assisting healthcare professionals in staying up-to-date. DISCLAIMER: The statements and opinions contained in the articles of Everyday Urology - Oncology Insights are solely those of the authors and contributors. The appearance of the advertisements in the publication is not a warranty, endorsement or approval of the products or services advertised or their effectiveness, quality or safety. The content of the publication may contain discussion of off-label uses of some of the agents mentioned. lease consult the prescribing information for full disclosure of approved uses. To the extent permissible under applicable laws, no responsibility is assumed by the publisher for any injury and/or damage as a result of any actual or alleged libelous statements, infringement of intellectual property, or privacy rights, or products liability whether resulting from negligence or otherwise, or for any use of operation, ideas, instructions, procedures, products, or methods contained within the material. Everyday Urology - Oncology Insights (ISSN ) is published four times a year by Digital Science ress, Inc., business office located at Deerfield Drive, Suite 2, Truckee, CA OSTMASTER: Send address changes to Everyday Urology - Oncology Insights Digital Science ress, Inc. Subscription Customer Service, Deerfield Drive, Suite 2, Truckee, CA CUSTOMER SERVICE: Customer service inquiries should be sent to publisher@urotoday.com Subscription inquiries should be sent to: cleonard@urotoday.com Access to this journal is online at Other correspondence for Digital Science ress, Inc. should be sent to: Attention: Digital Science ress, Inc Deerfield Drive, Suite 2 Truckee, CA COYRIGHT AND ERMISSIONS: Everyday Urology - Oncology Insights is published four times a year by Digital Science ress. No portion of the work(s) can be reproduced without written consent from the ublisher. ermission may be requested directly from the ublisher publisher@urotoday.com Copyright, 2016.

8 FROM THE DESK OF THE EDITOR Dear Colleagues: Over the past year, we ve been honored to provide you with the inaugural issues of Everyday Urology-Oncology Insights. This fourth issue completes our publications for 2016 a year highlighted by important developments in the optimal management and treatment of patients with genitourinary cancers. Everyday Urology-Oncology Insights has strived in our inaugural year of publication to provide our readership with timely articles, written by internationally renowned GU oncology experts. I d like to thank our editorial team and our advisory board for their dedication to selecting and reviewing the relevant content of interest for urologists, medical oncologists, radiation oncologists, and radiologists. As busy, practicing clinicians in the 21st century, we re deluged with written and web-based information, and thus, our aim has been to address and review meaningful and cutting edge topics which can contemporaneously optimize your patient care. In our first three issues, we ve addressed important unmet diagnostic and therapeutic needs as well as ongoing clinical controversies, including: the data concerning survival benefits, progression, and side effect and toxicity profiles of current therapies for metastatic castration-resistant prostate cancer (mcrc); the changing role of radiologists in imaging and managing GU cancers;- and emerging GU biomarkers and their role for the changing landscape of bladder cancer treatment strategies. Our cover story for this issue, authored by Diane Newman, DN, discusses the development of the ground-breaking Core Curriculum for Urological Nursing, to be published by the Society of Urologic Nurses and Associates in Dr. Newman details the vigorously researched content of this first-of-its-kind text four years in the making geared toward teaching best practices in urology nursing. Our Expert erspective, written by Charles Ryan, MD, is the second in a two-part series on recent mcrc therapies, discussing key treatment considerations for managing mcrc patients. In the first article of this series published in issue 2, Dr. Ryan reflected on the research journey and published results of the COU-AA-302 clinical trial, which led to the approval of abiraterone acetate plus prednisone therapy, the first novel oral hormonal therapy approved by both FDA and EMA for CRC patients. Our Clinical Update, written by Alicia Morgans, MD, reviews the benefits and challenges of establishing a multidisciplinary advanced prostate cancer clinic a clinical and administrative practice model that improves patient care and streamlines healthcare efficiencies. These clinics, which were unheard of five years ago, have revolutionized the clinical care paradigm within community practices, and thus will be further augmented by developing multidisciplinary clinics for advanced kidney and bladder cancer, as immuno-oncology options continue to burgeon. The Spotlight section features proceedings from the 17th Annual Meeting of the Society for Urology, and focuses on presentations with subjects such as immunotherapy, targeted therapy and robotic surgeries for GU cancer. The abstracts are written by Andres Correa, MD, Benjamin Ristau, MD, and Shreyas Joshi, MD, of the Fox Chase Cancer Center, Andrew Stephenson, MD, of the Cleveland Clinic Foundation, Stephen Williams, MD of the University of Texas Medical Branch, and Ashish Kamat, MD, of MD Anderson Cancer Center. In 2017 Everyday Urology-Oncology Insights and, UroToday. com will be launching a new program with tools that will facilitate understanding and implementation of state-of-the-art treatments for our GU oncology patients. UroToday s new up-to-date clinical trials portal will feature a unique and easily accessible registry initially focused solely on GU malignancies and sites actively enrolling patients. We welcome your feedback about the clinical trials portal, as well as the upcoming issues of Everyday Urology- Oncology Insights. Thank you for your time, feedback, and for reading our journal during this inaugural year. Sincerely, NEAL SHORE, MD, FACS Neal Shore, MD, FACS is an internationally recognized expert in systemic therapies for patients with advanced urologic cancers and innovative therapies to treat patients suffering from prostate enlargement symptoms. Dr. Shore was recently appointed resident-elect of the Large Urology Group ractice Association (LUGA), which seeks to provide urologists with all the tools they need to effectively care for patients. Neal D. Shore, MD, FACS, is the Medical Director of the Carolina Urologic Research Center. He practices with Atlantic Urology Clinics in Myrtle Beach, South Carolina. Dr. Shore has conducted more than 100 clinical trials, focusing mainly on prostate and bladder disease. 8 EVERYDAY UROLOGY TM

9 COMING SOON TO UROTODAY.COM Clinical Trials Section + Active, recruiting urology trials + Searchable by disease state + Featuring Editor in Chief, Dr. Evan Yu + Easy to use and up-to-date UroToday.com

10 COVER STORY First of its Kind: A Core Curriculum for Urologic Nursing By Diane Newman, DN, AN-BC, FAAN, BCB-MD 10 EVERYDAY UROLOGY TM

11 DR. DIANE NEWMAN, DN, AN-BC, FAAN, BCB-MD, is co-editor of the recently released 1st edition of the Core Curriculum for Urologic Nursing, published by the Society of Urologic Nurses and Associates. Dr. Newman is an Adjunct rofessor of Urology in Surgery and Research Investigator Senior at the erelman School of Medicine, University of ennsylvania in hiladelphia. She has more than 40 years of experience practicing in the field of urology. Dr Newman serves as co-director of the enn Center for Continence and elvic Health. Her urology expertise involves the evaluation, non-surgical treatment, and management of urinary incontinence and related pelvic disorders. The Core Curriculum is a first-of-its-kind textbook that can be used by nurses to study for specialty certification as a urology registered nurse, and is a source of material to support urology nursing instruction in academic programs. It has applicability to nurses in acute care, long term care, home care and rehab settings as all encounter patients with urologic problems. Dr. Newman collaborated with two co-editors on the Core Curriculum for Urologic Nursing: Dr. Jean Wyman, hd, CN, GN-BC, FAAN, a certified gerontology nurse practitioner with a subspecialization in incontinence care and Valre W. Welch, MSN, CN, a specialist in pediatric urology for more than 30 years. Dr. Wyman is rofessor and the Cora Meidl Siehl Chair in Nursing Research at the University of Minnesota School of Nursing, directs the Center for Aging Science and Care Innovation, and is the co-director of the Deborah E. owell Center of Women s Health in the Medical School. Ms. Welch is currently working in a private pediatric urology practice with two pediatric urologists Dr. Boyd H. Winslow and Dr. John D. Edmondson and has taught pediatric nursing in the Bachelor of Science in Nursing (BSN) program at Elmhurst College in Illinois. She has lectured extensively both nationally and internationally on pediatric urology, and has also served as a nursing consultant on a variety of industry nursing clinical boards. The Core Curriculum for Urologic Nursing is designed to be a thorough and evidence-based textbook for registered nurses, nurse practitioners, physician assistants, and healthcare providers involved in the care of urology patients. The material in the textbook is unique as it covers the urology across the lifespan. It is wide-ranging and has 51 chapters that cover pediatric urology; the assessment of adult urological conditions; urological management of genitourinary cancers; and interventions for acute and chronic adult urologic conditions, such as urinary stones, urinary tract infections, BH, and urinary incontinence. The text also addresses special populations, including geriatric patients; women with chronic urologic conditions, such as sexual dysfunction and pelvic organ prolapse; and men with common conditions such as benign prostate disease, male sexual dysfunction, and infertility. The book is also an important learning tool, since it provides a comprehensive view of embryology and genitourinary tract development and urologic health promotion. In addition, specialized assessments are covered, including radiological imaging, endoscopic evaluation, and cystoscopy. As nurses take on an expanding role in urologic practices, they need to be conversant in these diagnostic procedures and assessments. The Core Curriculum for Urologic Nursing also covers surgical interventions extensively, and provides a great deal of information about best practice standards in urologic surgery. The text delineates specific details about such surgeries, even the correct position for placing patients on the operating table! There are also special chapters on the most current expert advice for perioperative and post-operative care following urologic surgery. We wanted the text to be authoritative and comprehensive, so each chapter is written by an advanced practice registered nurse with a specialty in urology. One of the roadblocks we faced is the requirement that authors be experts in their field experts who could provide reliable and practical advice about caring for urology patients AND who were also proficient writers. This was a challenge! To ensure the material in the book included the latest scientific advances and practice standards, we also reviewed hundreds of scientific papers in urology, as well as treatment guidelines from the American Society of Clinical Oncology, the Association VOLUME 1, ISSUE 4 11

12 COVER STORY Table 1: Therapies for Metastatic Castrate Resistant Ca Drug Mechanism of Action Dosage Most Common Side Effects Nursing/ARN Considerations Abiraterone acetate with prednisone Inhibits 17 alphahydroxylase/cy 17 to block androgen biosynthesis by the tumor itself to decrease androgen sensitive tumor growth. Improves the control of mcrc and prolongs survival either before or after treatment with Docetaxel, the current reference standard chemotherapy. 1,000 mg daily (four 250 mg tablets once daily to equal 1,000 mg/day on empty stomach). Modify dosage as needed for hepatotoxicity. Do not crush or chew pills. Edema Hypokalemia Hepatotoxicity Hypertension Fatigue Arthralgia Increased hot flashes Low dose prednisone is administered with Abiraterone to limit overproduction of aldosterone and side effects of hypertension, hypokalemia, and fluid retention. Review for concomitant medications as has multiple drug/drug interactions. Must be taken on empty stomach 2 hours after and 1 hour before meals. Monitor ALT, AST and bilirubin labs every 2 weeks for the first 3 months, then monthly. Monitor K+ level for hypokalemia monthly. Monitor blood pressure every 2 weeks for 1st month then monthly. Assess for fluid retention monthly. Assess for medication side effects. Enzalutamide Oral androgen receptor antagonist that inhibits androgen receptor signaling in three different areas: 1) Blocks androgen from binding to androgen receptors through competitive inhibition. 2) Inhibits nuclear translocation of androgen receptors. 3) Interferes with the interaction between androgen receptors and DNA. Effective in controlling mcrc and prolonging survival. 160 mg daily (four-40 mg tabs once daily). Do not crush, chew, dissolve or open the capsule. Fatigue Diarrhea Upper respiratory infection Increase seizure risk Hot flashes Dizziness Headache Musculoskeletal pain Hypertension Contraindicated in patient at risk for seizure. FDA approved for use post docetaxel and predocetaxel. Monitor INR closely if on warfarin therapy. Monitor complete blood count (CBC) and basic metabolic profile routinely. Radium 223 Alpha particle radiation that is a calcium mimetic that bonds to bone stroma in regions of osteoblastic metastes. rolongs overall survival. rolongs time to symptomatic skeletal related events. 6 monthly treatments. Given IV in nuclear medicine. Dosed by weight. Diarrhea Myelosuppression eripheral edema Fatigue Nausea CBC will be checked 1 week before each treatment. Excreted in feces, < 5% in urine, counsel to sit to void, close toilet lid then flush toilet several times for the first week after treatment. Need to wear condoms for sexual activity during treatment and for 6 months after completed. No restrictions regarding contact with other individuals after injection. Sipuleucel-T Autologous cancer vaccine that stimulates the immune system through activation of T-cells to destroy Ca cells. rolongs overall survival. 3 doses of 50 million autologous activated CD54 cells in 250 ml Lactated Ringers IV at 2 weekly intervals. Mix gently before infusion. Infuse over 60 minutes. Do not use cell filter. May need to slow or stop infusion for acute infusion reactions. Acute transfusion reactions may occur within first 24 hours. Most are mild-moderate including: Chills Fever Fatigue Back pain Headache Nausea and vomiting Hypertension Tachycardia No markers at this time to evaluate effectiveness. Does not lower SA. If unable to place a 18 g IV may need vascular access device inserted for therapy. Undergo leukapheresis at American Red Cross, then 3 days later infused in office. remedicate with acetaminophen 650 mg orally and diphenhydramine 50 mg orally 30 minutes prior to infusion to decrease infusion reactions. Needs to be driven to and from infusion site. Observe during administration and for 30 minutes after completed.

13 of erioperative Registered Nurses, the American Urological Association, the National Comprehensive Cancer Network, and the National Cancer Institute, among others. Information discovered became an integral part of the book. We also reached out to many reviewers to critique all the chapters in the book, to make sure that the content met our exacting standards for scientific accuracy and reliability. The role of the urology nurse has continued to evolve and change over the last 10 years, as more urologists have retired and fewer young doctors enter the field. Thus, there s now a shortage of qualified urologists. Many urology practices particularly in rural areas have increasingly turned to advanced practice nurses to provide accessible, safe, high-quality care for patients with urologic disorders. An advanced practice registered nurse, when properly trained, can enable urologists to provide more, and improved, services within a practice. As a result, urologists can provide high-quality care in a more timely way. Advanced practice nurses in a urology practice can take on patient care tasks that are more complex than those usually delegated to registered nurses (RNs) and office assistants with less stringent training. In 2012, an American Urological Association survey revealed that 3,300 advanced practice RNs were practicing in urology departments and practices throughout the United States. Yet, there were no formalized training programs for generalized nurses or advanced practice nurses in urology who wanted to increase their knowledge and practice in the field. The Core Curriculum for Urologic Nursing helps provide that training as an adjunct to professional courses, enabling advanced practice nurses to take on more important roles within the urology practice. The development of this inaugural edition of the Core Curriculum for Urologic Nursing took four years, due to the scope and size of the text. Much of the content has not been published previously. There are no current urology nursing textbooks, and little information for the urology nurse about maintaining best practice standards. So, there is no blueprint for RNs who decide to practice in urology, and want to provide evidence-based care for patients with urologic disorders. This textbook serves as that blueprint, and will help expand the urology nurse s knowledge, and educate allied healthcare practitioners about the responsibilities of a urology nurse in different patient populations. The text includes unique chapters that discuss specialized and necessary skills in urology nursing, such as techniques for using urinary catheters, and hard-to-find information about procedures like bladder irrigation. We also discuss urologic interventional radiology, a field that is becoming increasingly important with the advent of medications such as radium-223 for the treatment of prostate cancer 1. (see Table 1) In addition, we included discussions of conditions that are increasingly prevalent in this country, such as urinary stones. We included a table on urinary stones that provides information on stone prevention and treatment. All the chapters are accompanied with many stellar illustrations by medical illustrator Robin Noel, as well as photos that can help the urology nurse truly understand the concepts discussed in the text. A related Society of Urologic Nurses and Associates supplement, titled Guide to Urologic Medications, was developed in conjunction with the Core Curriculum for Urologic Nursing textbook. The section on pediatric urology includes chapters on urogenital tumors in children and conditions such as Wilms tumor, one of the most common cancers affecting children. Urologic cancers are fairly rare in children, but can cause significant morbidity and mortality due to the age at which children are diagnosed, and to the increased toxicity of cancer therapies in children. There is really no book out there that has the depth and scope of information on pediatric urologic conditions that can be found in the Core Curriculum for Urologic Nursing. We even included several interesting chapters on the wide variety of pediatric urological congenital anomalies. Children can be born with two kidneys or two ureters or may have genitalia disorders disorders that are important for us to understand in an era of transgender surgeries. Congenital anomalies of the upper urinary tract in children include renal agenesis, in which children are born without kidneys, or genetic renal cystic disease, in which the kidneys develop abnormally. These are rare conditions, but can require extensive monitoring and follow-up, since treatment often revolves around controlling symptoms and slowing the onset of renal failure. The Core Curriculum for Urologic Nursing also provides significant guidance about the treatment of lower urinary tract symptoms (LUTS), including urinary retention, urinary incontinence, overactive bladder, pelvic pain, and interstitial cystitis. Although LUTS can have a significant effect on a patient s quality of life and self-esteem, in both men and women these conditions are often inadequately treated and poorly addressed by current urology practice. However, there s been tremendous growth in the use of advanced practice nurses and physician assistants to treat LUTS with nonsurgical and behavioral interventions. The Core Curriculum for Urologic Nursing offers guidelines about the assessment and treatments of LUTS, which can ideally be used in a multidisciplinary bladder and pelvic floor disorder center. The text discusses how to assess LUTS with a detailed history, and describes pelvic floor muscle training, which is often the firstline treatment in patients with LUTS. elvic floor muscle training is frequently used in patients who have symptoms of urinary incontinence, overactive bladder, urinary frequency and urgency, nocturia, pelvic floor muscle spasms, and incomplete bladder emptying. The textbook describes how to perform important assessments of the pelvic floor muscles and anal sphincter with digital exams prior to initiating pelvic floor muscle training. 1. Newman, DK, Wyman JF and Welch, eds. Core Curriculum for Urologic Nursing, 1st edition. itman NJ: Anthony J. Jannetti Inc. and Society of Urologic Nurses and Associates, Newman DK and Wein AJ. Office-based behavioral therapy for management of incontinence and other pelvic floor disorders. Urol Clin N Am. 2013; 40: VOLUME 1, ISSUE 4 13

14 EXERT ERSECTIVE ART TWO mcrc Treatment: The Right Treatment for the Right atient at the Right Time By Charles J. Ryan, MD 14 EVERYDAY UROLOGY TM

15 CHARLES J RYAN, MD is a prominent researcher and leading clinician in the treatment of prostate and other urologic cancers. Dr. Ryan was one of the leading researchers for the COU-AA-302 clinical trial, which led to the FDA approval of abiraterone acetate plus prednisone as the first oral therapy for treatment of chemotherapy-naïve metastatic castration-resistant prostate cancer (mcrc). Dr. Ryan is rofessor of Clinical Medicine and Urology and Thomas erkins Distinguished rofessor in Cancer Research, rogram Leader, Genitourinary Medical Oncology at the University of California-San Francisco Helen Diller Family Comprehensive Cancer Center in San Francisco, California. In the following article, he reflects on treatment considerations in using the newest treatments for mcrc, including patient characteristics and mechanisms of resistance. Metastatic castration-resistant prostate cancer (mcrc) presents with a wide spectrum of symptoms with varying effects on patient quality of life. It is estimated that more than 90% of patients with metastatic castrate resistant prostate cancer (mcrc) develop bone metastases that result in a significant increase in the risk of morbidity. 1 The extent of bone involvement in mcrc has also been found to be associated with patient survival. While most patients are clinically asymptomatic, those with symptoms may experience either pain and/or skeletal-related events (SREs). atients can have low-volume disease with very few symptoms and a good quality of life, but there are also patients who present with high-volume disease that causes significant and painful symptoms. So, the aim of therapy in patients with mcrc is to match the appropriate strength therapy to the appropriate level of patient symptoms and disease burden. In patients with mcrc with low disease burden and few symptoms or patients with slow-moving disease without visceral metastases and a fairly good prognosis it s reasonable to consider using sipuleucel-t immunotherapy as an initial therapy. In studies with sipuleucel-t, patients with a low disease burden who received the immunotherapy showed improved survival rates compared to patients who received placebo. As well as its survival benefit, sipuleucel-t s unique mechanism of action makes it a good choice for some mcrc patients with good performance status 2. For patients who have a good prognosis, it can also be wise to wait 2 to 3 months before starting therapy to get a sense of the pace of their disease. As long as patients remain in a good prognostic category, asymptomatic, and with less aggressive tumor biomarkers such as alkaline phosphatase and lactate dehydrogenase waiting 2 to 3 months is often not problematic. Once the clinician obtains additional information about the pace of the patient s cancer progression over several months, it becomes easier to choose the most appropriate therapy. Abiraterone and enzalutamide are novel androgen receptor oral therapies that provide comparable survival benefits in patients with mcrc. In choosing whether to treat a patient with mcrc with abiraterone and enzalutamide, a number of patient characteristics should be considered. In younger, healthier patients, either drug is fine. However, enzalutamide tends to have more central nervous system toxicity, so it is best to avoid this drug in older or frail patients, or in patients with a history of falls, because falls are a risk with enzalutamide. In the REVAIL study, patients on enzalutamide had a 12% risk of falls vs. a 6% risk of falls for patients on placebo 3. Other agents may be more appropriate in patients with baseline symptoms of fatigue, or in patients who are affected by confusion or gait imbalance. In addition, seizures are a known side effect of higher doses of enzalutamide. In the two major clinical trials on enzalutamide AFFIRM and REVAIL seizures were fairly rare, but this therapy should be avoided in patients with a history of seizures 3,4. For patients with mild baseline pain, abiraterone acetate plus prednisone therapy may be preferable instead. Since abiraterone is given with low-dose prednisone, patients may derive a significant treatment effect from taking the steroid. Approximately 25% of patients who received prednisone alone in the COU-AA-302 study showed a 50% or greater decline in SA, and patients who experienced this large a decline in SA survived longer than patients who did not 4. The steroid use in abiraterone acetate plus prednisone may also favor use of this treatment in older, frailer patients, who may already have signs of mild adrenal insufficiency 5,6. At the same time, abiraterone can cause fluid retention, and so it should be avoided in patients with a history of heart failure. If a patient has diabetes or renal failure, enzalutamide should also be strongly considered over abiraterone, since abiraterone can have mineralocorticoid-related or cardiotoxic effects. In the COU-AA-302 study, adverse events due to cardiac disorders occurred in 19% of the patients in the abiraterone-prednisone treatment group vs. 16% of patients in the prednisone-alone group. Hypertension was also more common in the VOLUME 1, ISSUE 4 15

16 EXERT ERSECTIVE abiraterone-prednisone treatment group (22% vs. 13%), as was fluid retention and edema (28% vs. 24%) and hypokalemia (17% vs. 13%) 5. The patient s age should not be the only factor one should weigh in choosing whether to treat a patient with enzalutamide or abiraterone. In the COU-AA-302 study, the magnitude of benefit of abiraterone-prednisone therapy was preserved in elderly men 75 years of age or older. The COU-AA-302 trial data showed that abiraterone plus prednisone did not induce harm, and conferred significant benefit in overall survival rates and radiographic progression-free survival rates in elderly men 2. In contrast, chemotherapy in elderly patients with prostate cancer has the potential to induce harm, and many elderly men cannot undergo chemotherapy 5,6,7. In the COU-AA-302 study, elderly men did have increased rates of liver toxicity and cardiac events, however. These findings reflect the fact that elderly men are generally more frail; thus, the fluid retention syndrome that abiraterone causes can negatively affect older men with less cardiac reserve. Elderly men also tend to take more medications and have more comorbid illnesses that can adversely affect liver toxicity 5,6. Still, choosing between enzalutamide and abiraterone can be challenging, even for clinicians with considerable expertise in using these medications. It s unlikely that a randomized clinical trial comparing these two medications will be performed, due to the impracticality of such an effort. Yet, patient-centered comparative effectiveness trials would be possible. Such studies could focus on the quality of life benefits, patient-reported outcomes, and patient-reported adverse events with the use of these medications 8. To complete these patient-centered outcome studies, researchers could use validated tools such as the RO-CTCAE, a patient-reported outcome measure developed to evaluate symptom toxicity in patients on cancer clinical trials, and many of the validated quality-of-life measure now available. As a result of such research, clinicians would be able to identify patients who are more likely to benefit or experience side effects from treatments such as abiraterone and enzalutamide therapy.8 One of the major challenges we face in treatment of mcrc is that resistance to abiraterone and enzalutamide typically develops after 11 to 18 months of beginning therapy. Although many responders to these drugs show an impressive decline in SA, along with radiographic disease control, other patients who respond present with a slowly rising SA. Thus, rising SA should not be the sole criteria used to decide whether to discontinue one of these medications. Instead, radiographic disease progression, clinical deterioration, and adverse events should be considered together in making decisions about stopping or switching treatments. (See Figure 1) In patients who are on abiraterone or enzalutamide therapy, and develop resistance but do not have significant symptoms, THE RO-CTCAE MEASUREMENT SYSTEM The NCI atient Reported Outcomes-Common Terminology Criteria for Adverse Events (RO-CTCAE) is a new patientreported outcome measurement system developed to characterize the frequency, severity and interference of 78 symptomatic treatment toxicities. These include symptomatic toxicities such as pain, fatigue, nausea, and cutaneous side effects such as rash and hand-foot syndrome, all toxicities that can be meaningfully reported from the patient perspective. The RO-CTCAE measurement system consists of an item library of adverse symptoms, and a prototype electronic platform with a variety of features designed to promote integration of the RO-CTCAE measurement system into clinical trials workflow. The system allows for data collection via the web, a hand-held computer, or an interactive voice-response system, and includes features that allow for customized RO-CTCAE questionnaires, tailoring the schedule for data collection, as well as patient reminders and clinician alerts for severe symptoms. Each of the 78 symptom terms included in the RO- CTCAE item library is assessed relative to one or more distinct attributes, including presence/absence, frequency, severity, and/or interference with usual or daily activities. Responses are provided on a 5-point Likert scale. The standard RO-CTCAE recall period is the past 7 days. RO-CTCAE is intended to enhance the quality of adverse event data reporting in clinical trials, provide data that complements and extends the information provided by clinician reporting using CTCAE, represent the patient perspective of the experience of symptomatic adverse events, and improve detection of potentially serious adverse events. 16 EVERYDAY UROLOGY TM

17 atient-reported Outcomes Version of the Common Terminology Criteria for Adverse Events RO-CTCAE TM ) Item Library (Version 1.0) ATTRIBUTES NEUROLOGICAL SLEE/WAKE F: Frequency S: Severity Numbness & tingling Dizziness SI SI Insomnia Fatigue SI SI I: Interference : resence/absence/amount CUTANEOUS Rash MOOD Anxious FSI ORAL Dry mouth Difficulty swallowing Mouth/throat sores Cracking at the corners of the mouth (cheilosis/cheilitis) Voice quality changes Hoarseness GASTROINTESTINAL Taste changes Decreased appetite Nausea Vomiting Heartburn Gas Bloating Hiccups Constipation Diarrhea Abdominal pain Fecal incontinence S S SI S S S SI FS FS FS FS FS S F FSI FI Skin dryness Acne Hair loss Itching Hives Hand-foot syndrome Nail loss Nail ridging Nail discoloration Sensitivity to sunlight Bed/pressure sores Radiation skin reaction Skin darkening Stretch marks VISUAL/ERCETUAL Blurred vision Flashing lights Visual floaters Watery eyes Ringing in ears ATTENTION/MEMORY S S S S S SI SI S Discouraged Sad GYNECOLOGIC/URINARY Irregular periods/vaginal bleeding Missed expected menstrual period Vaginal discharge Vaginal dryness ainful urination Urinary urgency Urinary frequency Change in usual urine color Urinary incontinence SEXUAL Achieve and maintain erection Ejaculation Decreased libido Delayed orgasm Unable to have orgasm ain w/sexual intercourse MISCELLANEOUS FSI FSI S S FI I FI S F S S RESIRATORY Shortness of breath Cough Wheezing Cardio/Circulatory Swelling Heart palpitations SI SI S FSI FS Concentration Memory AIN General pain Headache Muscle pain Joint pain SI SI FSI FSI FSI FSI Breast swelling and tenderness Bruising Chills Increased sweating Decreased sweating Hot flashes Nosebleed ain and swelling at injection site S FS FS FS FS Body odor S VOLUME 1, ISSUE 4 17

18 EXERT ERSECTIVE Figure 1: SA Response to AR-targeted Therapy % SA DECLINE FROM BASELINE Non-responder rimary Resistance BL wk 12 wk 24 wk 36 wk 48 wk 60 wk 72 A total of 3 consecutive SA declines following treatment (A) is associated with prolonged radiographic progression-free survival (RFS) (median not reached) relative to no sequential declines (B and C) median 23 weeks. Urologic Oncology: Seminars and Original Investigations , DOI: ( /j. urolonc ) it s often possible to switch the patient to another of these androgen-receptor targeted drugs. The clinician should keep in mind, however, that retrospective analyses suggest that the second agent is likely to have a more modest degree of activity in patients who do not respond to their first treatment with enzalutamide or abiraterone. As yet, there are few safety concerns with sequential treatment. Studies are also evaluating these agents in combination, in the hope of obtaining a response rate that is superior to that achieved with abiraterone or enzalutamide alone. The ALLIANCE phase III clinical trial is currently testing this approach in patients who have not had prior taxane-based chemotherapy or treatment with enzalutamide or abiraterone. Yet, since data from this trial will not be available for another two years, combining abiraterone and enzalutamide is not currently recommended in clinical practice. Recently, we were informed that a hase 4 clinical trial (LATO) investigating longer-term use of enzalutamide as a combination treatment for patients with metastatic castration-resistant prostate cancer (mcrc) did not reach its primary goal A N=30 B N=23 C N=33 Drifter Responder Acquired Resistance over time of improved progression-free survival. The trial is concluding, but data will continue to be evaluated, according to fizer and Astellas harma. Top-line results failed to show that continued treatment with enzalutamide in combination with the chemotherapy, abiraterone acetate and prednisone, improved progression-free survival (FS) in chemotherapy-naive mcrc patients whose SA levels had progressed despite previous enzalutamide therapy 9. The trial is a double-blind, placebo-controlled study, designed to assess the safety and efficacy of continued treatment with enzalutamide plus abiraterone acetate and prednisone following confirmed SA progression. The study enrolled 509 patients with mcrc who had never received chemotherapy treatment before, and was divided into two parts. In part one, patients received enzalutamide (160 mg/day) until an increase in their SA levels was confirmed. In the second part of the trial, patients were randomly assigned to either continue enzalutamide treatment, now combined with abiraterone acetate (1,000 mg/day orally) and prednisone (5 mg administered orally twice daily), or begin treatment with placebo plus abiraterone acetate and prednisone. Its primary goal was progression-free survival, defined by either radiographic progression, unequivocal clinical progression, or death 9. atients, who develop symptomatic disease and skeletal metastases while being treated with or following treatment of enzalutamide or abiraterone, should be considered for treatment with radium-223. Radium-223 has been shown to significantly delay the development of symptomatic skeletal events. More importantly, radium-223 is a life-prolongation therapy, as shown in the ALSYMCA (Alpharadin in Symptomatic rostate Cancer) hase III trial, which demonstrated a statistically significant improvement in overall survival for the radium-223 treatment arm 10. In this trial of 921 patients who had not received or could not receive docetaxel, radium-223 was compared to placebo. In the trial, patients who received six injections of radium-223 had 18 EVERYDAY UROLOGY TM

19 a median survival rate of 14.9 months vs months in patients receiving placebo (HR=.70, < ) In addition, the median time to the first symptomatic skeletal event was 15.6 months in the radium-223 group vs. 9.8 months in the placebo group (HR=.66, <0.001) 10. Radium-223 is approved as a course of therapy consisting of 6 cycles. It is not approved for any additional cycles, although this is being studied. Future trials may show that additional cycles or even higher dosages may be of further benefit. Ongoing studies are evaluating additional combination strategies. The only concomitant agents that are contraindicated in the labeled approval for radium-223 are taxane-based chemotherapies. In addition to investigating new treatments, researchers have begun to identify mechanisms of resistance to these treatments. These mechanisms of resistance are genetic mutations that affect androgen receptors or are related to DNA repair, and affect treatment outcomes. Recent genomic analyses have revealed that somatic inactivation or germline mutations in genes such as BRCA1, BRCA2, CKD12, and ATM occur in as many as 25% of advanced prostate cancers 10. AR inhibitors such as olaparib exploit defective DNA repair in BRCA1/BRCA2 tumors, including prostate cancer tumors. In the TOAR study, a phase II trial of olaparib in patients with advanced CRC, olaparib induced responses in tumors with mutations in other DNA repair genes, including ATM and CHEK2. According to recent research, platinum-based chemotherapy is also selective against DNA repair deficiencies 11. As we move into an era of molecularly targeted therapies, researchers and clinicians need to be mindful of the fact that empiric drug choices will not always be the right choice for every patient. Instead, we may need to perform more genomic sequencing on tumors to see if they contain mutations that can be addressed with a AR inhibitor or platinum-based chemotherapy. In the near future, we will also be doing androgen-receptor sequencing to determine whether a patient could be resistant to a given androgen receptor-targeted therapy. Thus, we might be able to do a biomarker genomic analysis that could tell us whether a patient will respond to abiraterone, and if not, then we would avoid using this medication. We are already moving into this era with a major effort by the Stand Up to Cancer rostate Dream Team 2 (SU2C-CF), which is exploring mechanisms of resistance to prostate cancer hormonal therapies. For instance, the Stand Up to Cancer rostate Dream Team is obtaining biopsies and genomic analyses from more than 300 patients with abiraterone-resistant disease. The Dream Team hopes to find the mechanisms of resistance as well as the histological changes that can occur in mcrc disease as it evolves. From there, the researchers will delve into the prognostic and therapeutic implications for these histological changes. So, a DNA repair defect, for example, might push clinicians toward using a AR inhibitor or platinum-based chemotherapy that may be selective against certain mutations. Treatment changes for mcrc is advancing at a rapid pace. A generation ago, many prostate cancer clinicians would not even begin therapy until after a patient had developed painful symptoms. We now know that this is unacceptable. It s crucial not to withhold a life-saving, disease-controlling therapy until a patient begins to experience painful symptoms. As we gain additional understanding in the treatment of mcrc, it s worthwhile for clinicians and patients to ask questions about whether genomic tissue analyses would be beneficial. Through such analyses, clinicians will gain important understanding into the optimal management of patients with mcrc. The challenge for clinicians in the community, of course, is to obtain the resources for performing tissue analyses. Yet, this effort should not be relegated just to research institutions. It s important for community clinics and clinicians to perform genomic analyses, so that these analyses become part of the standard management of prostate cancer. When treating bone metastases in CRC, it is crucial to understand the dynamic nature of the disease, and know that the site of prostate cancer evolves as do the patient s needs. Treatment approaches need to focus on treating the metastases. Clinical interventions in bone metastatic disease can significantly impact outcomes, including survival, skeletal-related events and patient quality of life. In this article, I have touched on many treatment strategies and clinical approaches some of which are still being developed. We must be vigilant to accurately assess patients disease burden, their symptomatology and quality of life. The goal should then be to target treatments to the right patients at the right time, and base these treatment decisions on patients disease burden, symptoms and characteristics. 1. Siegel R, Naishadham D, and Jemal A. Cancer statistics, CA Cancer J Clin. 2012; 62 (1): Kantoff W, Higano CS, Shore ND, et al.; the IMACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010; 363: Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014; 371 (5): Fizazi K, Sher HI, Miller K, et al. Effect of enzalutamide on time to first skeletal-related event, pain and quality of life in men with castration-resistant cancer: results from the randomised, phase 3 AFFIRM trial. Lancet Oncol. 2014; 15 (10): Ryan CJ, Smith MR, Fizazi K, et al; COU-AA-302 Investigators. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naïve men with metastatic prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2015; 16 (2): Smith MR, Rathkopf DE, Mulders F, et al. Efficacy and safety of abiraterone acetate in elderly ( 75 years) chemotherapy-naïve patients with metastatic castration-resistant prostate cancer. J Urol. 2015;194(5): Dhawan M, Ryan CJ. Utility of novel androgen receptor therapies in the real world: A nuanced approach. Urol Oncol. 2016; 34 (8): Kim W, Ryan CJ. Use of androgen receptor signaling-targeted therapies in chemotherapy-naïve metastatic castration-resistant prostate cancer: A call for patient-centered studies. J Comp Eff Res. 2016;5(1) fizer and Astellas announce top-line results from hase 4 LATO trial of XTANDI (enzalutamide) capsules in patients with metastatic castration-resistant prostate Cancer. Business Wire. December 14, http: /press.pfizer.com/press-release/ pfizer-and-astellas-announce-top-line-results-phase-4-plato-trial-xtandi-enzalutamide- 10. arker C, Nilsson S, Heinrich D, et al. Updated analysis of the phase III, double-blind, randomized multinational study of radium-223 chloride in castration-resistant prostate cancer (CRC) patients with bone metastases (ALSYMCA). J Clin Oncol. 2012; 30 (18 Suppl): Abstract LBA Dhawan M, Ryan CJ, Ashworth A. DNA repair deficiency is common in advanced prostate cancer: New therapeutic opportunities. Oncologist. 2016;21(8): VOLUME 1, ISSUE 4 19

20 CLINICAL UDATE The Multidisciplinary Cancer Clinic By Alicia K. Morgans, MD, MH 20 EVERYDAY UROLOGY TM

21 Dr. Morgans is an Assistant rofessor of Medicine in the Division of Hematology/Oncology at Vanderbilt University Medical Center. She is the Clinical Director of the Genitourinary Malignancy group, and the Co-Director of the Supportive Oncology rogram. She attended medical school at the University of ennsylvania School of Medicine, and residency in internal medicine at the Hospital of the University of ennsylvania in hiladelphia. Dr. Morgans completed a fellowship in Hematology/Oncology at Harvard s Dana Farber Cancer Institute and Massachusetts General Hospital Cancer Center in Boston, and earned a Master of ublic Health at Vanderbilt University. Dr. Morgans research assesses complications of advanced prostate cancer survivorship and treatment decision-making in advanced prostate cancer. Dr. Morgans is a member of the American Society of Clinical Oncology and the Eastern Cooperative Oncology Group. For cancer patients, it is often an overwhelming process to undergo diagnosis and treatment with different healthcare providers, who practice in different clinics, and even in different cities. A multidisciplinary prostate cancer clinic relieves some of the hassle and burden of traveling to numerous clinics, as well as the anxiety of having to wait for appointments with various providers, to find out about planned treatment. For cancer patients, it is often an overwhelming process to undergo diagnosis and treatment with different healthcare providers, who practice in different clinics, and even in different cities. A multidisciplinary prostate cancer clinic relieves some of the hassle and burden of traveling to numerous clinics, as well as the anxiety of having to wait for appointments with various providers, to find out about planned treatment. At a multidisciplinary prostate cancer clinic, all the providers are available on the same day, in the same place, and can work together to formulate a cohesive treatment plan. In contrast, when you have healthcare providers providing diagnosis and treatment in different practices, everyone works in a vacuum to some extent. roviders are not knowledgeable about all the possible implications of the patient s treatments. Thus, a medical oncologist may not see all the urology implications of certain cancer treatments, and a urologist may not be fully knowledgeable about the side effects of cancer treatments such as chemotherapy. Multidisciplinary clinics operate in different ways. Some are true multidisciplinary clinics; the providers are present in the same location on the same day, and work together on each patient s treatment plan. So, at the end of the day, the patient receives a multidisciplinary care plan that considers every health provider s expertise and perspective. Even when providers have different opinions, these differences can be discussed in front of patients, so that they understand all the pros and cons of a treatment plan. This type of communication between providers gives patients more faith in their treatment, as well as in the healthcare system. It can also be reassuring for patients to hear the same message about planned treatment from different specialists. It is very valuable from both the patient s and the provider s viewpoint to have good solid cohesive communication between the different providers in a multidisciplinary clinic. Other multidisciplinary clinics operate as virtual clinics: the providers communicate by or phone, but every provider s perspective is considered in a timely way when coming up with the patient s care plan. In contrast, a patient who receives care from various providers who are not in a multidisciplinary setting may be treated by physicians who do not communicate with each other, and whose electronic medical records (EMRs) are not even linked. It is very valuable from both the patient s and the provider s viewpoint to have good solid cohesive communication between the different providers in a multidisciplinary clinic. In our multidisciplinary advanced prostate cancer clinic, we have providers that include a participating urologist, medical oncologist, and a radiation oncologist. We also have dedicated support staff, including a clinic manager, advanced practice nurses, and physician assistants, as well as dedicated registered nurses (RNs). From the provider s standpoint, it is crucial to be able to talk to colleagues about challenging cases, and make treatment plans in close collaboration with providers in other disciplines. It (Continued on page 25) VOLUME 1, ISSUE 4 21

22 In the treatment of advanced prostate cancer IT DROS THAT FAST Start testosterone (T) suppression now with FIRMAGON (degarelix), the GnRH receptor antagonist that dropped by 88% on day 1 (N=207) 1,2 * FIRMAGON (N=207) dropped T by 88%, 94%, 96%, 97%, and 98% on day 1, 3, 7, 14, and 28, respectively 2 Leuprolide (N=201) increased T by 43%, 65%, and 8% on day 1, 3, and 7, respectively, and dropped T by 75% and 97% on day 14 and 28, respectively 2 By day 28, both FIRMAGON and leuprolide achieved similar testosterone levels 2 rostate-specific antigen (SA) reduction typically follows testosterone suppression FIRMAGON RESULTED IN A REDUCTION OF SA LEVELS, A SECONDARY ENDOINT 1 Median SA Levels (%) weeks 64% FIRMAGON (N=207) 1 month 3 months 85% 95% * The pivotal phase 3 trial (CS21) was a 3-armed, randomized (1:1:1), activecontrolled, open-label, parallel-group, 12-month clinical study of FIRMAGON compared to leuprolide. 3 Serum levels of testosterone were measured at screening, on days 0, 1, 3, 7, 14, and 28 in the first month, and then monthly until the end of the study. 2 FIRMAGON was shown to maintain testosterone suppression below castration level (50 ng/dl) over 12 months of treatment (primary endpoint). 3 SA is a nonspecific measurement that may indicate cancer progression. These SA results should be interpreted with caution because of the heterogeneity of the patient population studied. No evidence has shown that the rapidity of SA decline is related to clinical benefit. Therefore, SA data should not be viewed independently as evidence of the effectiveness of FIRMAGON. 1 GnRH = gonadotropin-releasing hormone. Indication FIRMAGON (degarelix for injection) is a GnRH receptor antagonist indicated for treatment of patients with advanced prostate cancer. Important Safety Information FIRMAGON is contraindicated in patients with a known hypersensitivity to degarelix or to any of the product components and in women who are or may become pregnant. FIRMAGON can cause fetal harm when administered to a pregnant woman. Hypersensitivity reactions, including anaphylaxis, urticaria and angioedema, have been reported post-marketing with FIRMAGON. In case of a serious hypersensitivity reaction, discontinue FIRMAGON immediately if the injection has not been completed, and manage as clinically indicated. atients with a known history of serious hypersensitivity reactions to FIRMAGON should not be re-challenged with FIRMAGON. Long-term androgen deprivation therapy (ADT) prolongs the QT interval. hysicians should consider whether the benefits of ADT outweigh the potential risks in patients with congenital long QT syndrome, electrolyte abnormalities, or congestive heart failure and in patients taking Class IA or Class III antiarrhythmic medications. lease see additional Important Safety Information and Brief Summary of full rescribing Information on adjacent pages.

23 Start testosterone suppression TODAY and reassess at SA nadir. Important Safety Information (continued) Therapy with FIRMAGON results in suppression of the pituitary gonadal system. Results of diagnostic tests of the pituitary gonadotropic and gonadal functions conducted during and after FIRMAGON may be affected. The therapeutic effect of FIRMAGON should be monitored by measuring serum concentrations of prostate-specific antigen (SA) periodically. If SA increases, serum concentrations of testosterone should be measured. The most common adverse reactions ( 10%) during FIRMAGON therapy included injection site reactions (eg, pain, erythema, swelling or induration), hot flashes, increased weight, fatigue, and increases in serum levels of transaminases and gammaglutamyltransferase. The majority of adverse reactions were Grade 1 or 2; 1% or less were Grade 3/4. Injection site reactions were mostly transient, of mild to moderate intensity, occurred primarily with the starting dose and led to few discontinuations (<1%). Learn more at REFERENCES: 1. FIRMAGON [package insert]. arsippany, NJ: Ferring harmaceuticals Inc. 2. Data on file. Ferring harmaceuticals Inc. 3. Klotz L, Boccon-Gibod L, Shore ND, et al. The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer. BJU Int. 2008;102(11): FIRMAGON is a registered trademark of Ferring B.V Ferring B.V. FN/014/2016/USe rinted in U.S.A. February 2016

24 FIRMAGON (degarelix for injection) BRIEF SUMMARY lease consult package insert for full rescribing Information. INDICATIONS AND USAGE FIRMAGON is a GnRH receptor antagonist indicated for treatment of patients with advanced prostate cancer. CONTRAINDICATIONS FIRMAGON is contraindicated in patients with known hypersensitivity to degarelix or to any of the product components. Degarelix is contraindicated in women who are or may become pregnant. Degarelix can cause fetal harm when administered to a pregnant woman. Degarelix given to rabbits during organogenesis at doses that were 0.02% of the clinical loading dose (240 mg) on a mg/m 2 basis caused embryo/fetal lethality and abortion. When degarelix was given to female rats during organogenesis, at doses that were just 0.036% of the clinical loading dose on a mg/m 2 basis, there was an increase post implantation loss and a decrease in the number of live fetuses. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. WARNINGS AND RECAUTIONS regnancy Category X Women who are or may become pregnant should not take FIRMAGON. Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis, urticaria and angioedema, have been reported post-marketing with FIRMAGON. In case of a serious hypersensitivity reaction, discontinue FIRMAGON immediately if the injection has not been completed, and manage as clinically indicated. atients with a known history of serious hypersensitivity reactions to FIRMAGON should not be re-challenged with FIRMAGON. Effect on QT/QTc Interval Androgen deprivation therapy may prolong the QT interval. roviders should consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients with congenital long QT syndrome, congestive heart failure, frequent electrolyte abnormalities, and in patients taking drugs known to prolong the QT interval. Electrolyte abnormalities should be corrected. Consider periodic monitoring of electrocardiograms and electrolytes. In the randomized, active-controlled trial comparing FIRMAGON to leuprolide, periodic electrocardiograms were performed. Seven patients, three (<1%) in the pooled degarelix group and four (2%) patients in the leuprolide 7.5 mg group, had a QTcF 500 msec. From baseline to end of study, the median change for FIRMAGON was 12.3 msec and for leuprolide was 16.7 msec. Laboratory Testing Therapy with FIRMAGON results in suppression of the pituitary gonadal system. Results of diagnostic tests of the pituitary gonadotropic and gonadal functions conducted during and after FIRMAGON may be affected. The therapeutic effect of FIRMAGON should be monitored by measuring serum concentrations of prostate-specific antigen (SA) periodically. If SA increases, serum concentrations of testosterone should be measured. ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. A total of 1325 patients with prostate cancer received FIRMAGON either as a monthly treatment ( mg) or as a single dose (up to 320 mg). A total of 1032 patients (78%) were treated for at least 6 months and 853 patients (64%) were treated for one year or more. The most commonly observed adverse reactions during FIRMAGON therapy included injection site reactions (e.g., pain, erythema, swelling or induration), hot flashes, increased weight, fatigue, and increases in serum levels of transaminases and gamma-glutamyltransferase (GGT). The majority of the adverse reactions were Grade 1 or 2, with Grade 3/4 adverse reaction incidences of 1% or less. FIRMAGON was studied in an active-controlled trial (N = 610) in which patients with prostate cancer were randomized to receive FIRMAGON (subcutaneous) or leuprolide (intramuscular) monthly for 12 months. Adverse reactions reported in 5% of patients or more are shown in Table 1. Table 1. Adverse Reactions Reported in 5% of atients in an Active Controlled Study FIRMAGON 240/160 mg (subcutaneous) N = 202 FIRMAGON 240/80 mg (subcutaneous) N = 207 Leuprolide 7.5 mg (intramuscular) N = 201 ercentage of subjects with adverse events 83% 79% 78% Body as a whole Injection site adverse events 44% 35% <1% Weight increase 11% 9% 12% Fatigue 6% 3% 6% Chills 4% 5% 0% Cardiovascular system Hot flash 26% 26% 21% Hypertension 7% 6% 4% Musculoskeletal system Back pain 6% 6% 8% Arthralgia 4% 5% 9% Urogenital system Urinary tract infection 2% 5% 9% Digestive system Increases in Transaminases and GGT 10% 10% 5% Constipation 3% 5% 5% The most frequently reported adverse reactions at the injection sites were pain (28%), erythema (17%), swelling (6%), induration (4%) and nodule (3%). These adverse reactions were mostly transient, of mild to moderate intensity, occurred primarily with the starting dose and led to few discontinuations (<1%). Grade 3 injection site reactions occurred in 2% or less of patients receiving degarelix. Hepatic laboratory abnormalities were primarily Grade 1 or 2 and were generally reversible. Grade 3 hepatic laboratory abnormalities occurred in less than 1% of patients. In 1-5% of patients the following adverse reactions, not already listed, were considered related to FIRMAGON by the investigator: Body as a whole: Asthenia, fever, night sweats; Digestive system: Nausea; Nervous system: Dizziness, headache, insomnia. The following adverse reactions, not already listed, were reported to be drug-related by the investigator in 1% of patients: erectile dysfunction, gynecomastia, hyperhidrosis, testicular atrophy, and diarrhea. The safety of FIRMAGON administered monthly was evaluated further in an extension study in 385 patients who completed the above active-controlled trial. Of the 385 patients, 251 patients continued treatment with FIRMAGON and 135 patients crossed over treatment from leuprolide to FIRMAGON. The median treatment duration on the extension study was approximately 43 months (range 1 to 58 months). The most common adverse reactions reported in 10% of the patients were injection site reactions (e.g., pain, erythema, swelling, induration or inflammation), pyrexia, hot flush, weight loss or gain, fatigue, increases in serum levels of hepatic transaminases and GGT. One percent of patients had injection site infections including abscess. Hepatic laboratory abnormalities in the extension study included the following: Grade 1/2 elevations in hepatic transaminases occurred in 47% of patients and Grade 3 elevations occurred in 1% of patients. Changes in bone density: Decreased bone density has been reported in the medical literature in men who have had orchiectomy or who have been treated with a GnRH agonist. It can be anticipated that long periods of medical castration in men will result in decreased bone density. Anti-degarelix antibody development has been observed in 10% of patients after treatment with FIRMAGON for 1 year. There is no indication that the efficacy or safety of FIRMAGON treatment is affected by antibody formation. DRUG INTERACTIONS No drug-drug interaction studies were conducted. Degarelix is not a substrate for the human CY450 system. Degarelix is not an inducer or inhibitor of the CY450 system in vitro. Therefore, clinically significant CY450 pharmacokinetic drug-drug interactions are unlikely. USE IN SECIFIC OULATIONS regnancy Category X Women who are or may become pregnant should not take FIRMAGON. When degarelix was given to rabbits during early organogenesis at doses of mg/kg/day (about 0.02% of the clinical loading dose on a mg/m 2 basis), there was an increase in early post-implantation loss. Degarelix given to rabbits during mid and late organogenesis at doses of mg/kg/day (about 0.05% of the clinical loading dose on a mg/m 2 basis) caused embryo/fetal lethality and abortion. When degarelix was given to female rats during early organogenesis, at doses of mg/kg/day (about 0.036% of the clinical loading dose on a mg/m 2 basis), there was an increase in early post-implantation loss. When degarelix was given to female rats during mid and late organogenesis, at doses of mg/kg/day (about 0.36% of the clinical loading dose on a mg/m 2 basis), there was an increase in the number of minor skeletal abnormalities and variants. Nursing Mothers FIRMAGON is not indicated for use in women and is contraindicated in women who are or who may become pregnant. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from degarelix, a decision should be made whether to discontinue nursing or discontinue the drug taking into account the importance of the drug to the mother. ediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Of the total number of subjects in clinical studies of FIRMAGON, 82% were age 65 and over, while 42% were age 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out. Renal Impairment No pharmacokinetic studies in renally impaired patients have been conducted. At least 20-30% of a given dose of degarelix is excreted unchanged in the urine. A population pharmacokinetic analysis of data from the randomized study demonstrated that there is no significant effect of mild renal impairment [creatinine clearance (CrCL) ml/min] on either the degarelix concentration or testosterone concentration. Data on patients with moderate or severe renal impairment is limited and therefore degarelix should be used with caution in patients with CrCL<50 ml/min. Hepatic Impairment atients with hepatic impairment were excluded from the randomized trial. A single dose of 1 mg degarelix administered as an intravenous infusion over 1 hour was studied in 16 non-prostate cancer patients with either mild (Child ugh A) or moderate (Child ugh B) hepatic impairment. Compared to non-prostate cancer patients with normal liver function, the exposure of degarelix decreased by 10% and 18% in patients with mild and moderate hepatic impairment, respectively. Therefore, dose adjustment is not necessary in patients with mild or moderate hepatic impairment. However, since hepatic impairment can lower degarelix exposure, it is recommended that in patients with hepatic impairment testosterone concentrations should be monitored on a monthly basis until medical castration is achieved. Once medical castration is achieved, an every-other-month testosterone monitoring approach could be considered. atients with severe hepatic dysfunction have not been studied and caution is therefore warranted in this group. OVERDOSAGE There have been no reports of overdose with FIRMAGON. In the case of overdose, however, discontinue FIRMAGON, treat the patient symptomatically, and institute supportive measures. As with all prescription drugs, this medicine should be kept out of the reach of children. SEE FIRMAGON ATIENT COUNSELING INFORMATION For more information, go to or call FERRING ( ) Manufactured for: Ferring harmaceuticals Inc., arsippany, NJ By: Rentschler Biotechnologie GmbH, Germany /2015 FIRMAGON is a registered trademark of Ferring B.V Ferring B.V. FN/224/2016/US

25 CLINICAL UDATE (Continued from page 21) increases their knowledge and education about a plan of care, and makes them better doctors at the end of the day. Having providers talk to each other about a case is not usually problematic, because as physicians, we love to get an answer from colleagues and get one quickly. Now that we have oral agents for treating advanced castration resistant prostate cancer (CRC) such as enzalutamide and abiraterone, questions often arise about treatment decisions, if one of these medications fail. The question that often faces urologists is whether a patient should be treated sequentially with another oral agent, or with chemotherapy. It s a real benefit to talk these complex decisions over with a doctor from another specialty. atients with metastatic CRC can also have urinary symptoms while undergoing oncology treatments, and it s important to have a urologist on board who can treat incontinence, blockages, and infections. On the other hand, you don t want to run into a urinary tract infection while a patient is on a cytotoxic agent, so having doctors available with both medical oncology and urology expertise is vital. There are challenges to running a multidisciplinary cancer clinic. One of the problems is having adequate support staff who can handle different types of treatment. A nurse trained in medical oncology does not necessarily have expertise in performing urologic procedures such as bladder scans. Yet, for a urology nurse, performing these procedures is second nature. A urology nurse may not have much experience dealing with the complications of systemic therapy, such as neutropenic fever or intractable nausea and vomiting. Having support staff that can cover all these specific areas of expertise is important, but it can be difficult to In a virtual clinic, cases may not be discussed in the same space, but everyone is on the phone at the same time to create a treatment plan for every patient. train people to be conversant in several different disciplines. hysical space can also be an issue. For a practice to be efficient, you must have multiple rooms running at the same time. With the additional providers required by a multidisciplinary clinic, you may need additional space and support staff to keep the clinic running smoothly. The idea is not to slow down the flow of patients seen by any of the clinic s doctors. In an era when doctors see increasing numbers of patients each day, and have increasing demands for documentation, the FIGURE 1: MULTIDISCILINARY AROACH TO TREATING ROSTATE CANCER RADIATION ONCOLOGIST MEDICAL ONCOLOGIST ROSTATE CANCER ATIENT UROLOGIST ALLIED HEALTHCARE ROFESSIONALS challenge is to remain efficient. When you have multiple providers in a multidisciplinary clinic, and you haven t worked out the spacing and support staff questions beforehand, it can be a daunting task to optimize everyone s time. You want to make sure that everyone s time is used in the most valuable way. Since it can be problematic to find sufficient space to run a multidisciplinary clinic under one roof, many clinics are maintained virtually. In a virtual clinic, cases may not be discussed in the same space, but everyone is on the phone at the same time to create a treatment plan for every patient. Virtual clinics can be clinics in which providers are in the same building, but on different floors, or even in different buildings throughout the community. At Vanderbilt, we have a multidisciplinary advanced prostate cancer clinic that takes place in one space on campus. In a community setting, however, having a virtual clinic is often the only way to operate a multidisciplinary cancer clinic. As more medical centers and clinics merge, however, it will also become easier for multidisciplinary community cancer clinics to take place in a central location. Thus, patients will obtain better care, and may be able to be seen sooner for problems such as treatment complications. For clinic managers, it can be a demanding task to put together schedules in a way that makes sense for all the providers, support staff and patients involved in a multidisciplinary clinic. Medical oncologists and radiation oncologists should be in the clinic on the same days that urology surgeons are available and not in the operating room. From a scheduling standpoint, you must VOLUME 1, ISSUE 4 25

26 CLINICAL UDATE make sure that nurse practitioners and physician assistants, who are well trained, are available to help pick up routine care when physicians cannot be present. These allied health professionals should also be up to date on every patient s care plan, and be part of making that plan, which takes time. It s helpful to encourage good communication about care plans and scheduling with regular phone calls and s to ensure that patients experience continuity of care. In an era of bundled payments, a multidisciplinary clinic can create efficiencies, because a patient can be seen by different Healthcare providers who start multidisciplinary clinics will find that patients will come out of the woodwork to attend these clinics. providers on the same day, and even at the same time, rather than having several different appointments with multiple providers. If providers can ask for opinions from other specialists, and get quick answers, it helps avoid additional physician visits and even errors. Due to the improved communication that takes place at a multidisciplinary prostate cancer clinic, lab tests are less likely to be repeated unnecessarily, and there s less risk that scans will be double-ordered, for instance. We re likely to see an increase in multidisciplinary localized prostate cancer clinics as well as advanced prostate cancer clinics in the near future. Studies have shown that establishing collaborative environments for treating localized prostate cancer is associated with triaging patients to higher rates of active surveillance, rather than treating patients with prostatectomy or radiation. Thus, a multidisciplinary localized prostate cancer clinic can be an advantage for payers, because it saves money by steering patients to less expensive interventions, and improves patient care. Eventually, multidisciplinary prostate cancer clinics will also include health professionals who provide psychosocial support, palliative care, and nutritional counseling as well as medical oncology, radiation oncology and urology. Having these support services within easy access will ensure earlier referrals and more comprehensive healthcare so there s less risk for patients to fall through the cracks. For patients, it can be a relief to be involved in a multidisciplinary prostate cancer clinic. As well as relieving the anxiety and emotional burden of having to visit providers in different offices, a multidisciplinary cancer clinic eases the physical burden of having to travel to different locations. It s also a benefit for caregivers, who can derive psychosocial benefits from having care delivered at just one clinic, where all the patient s healthcare providers collaborate on a treatment plan. Although staffing can be challenging for multidisciplinary cancer clinics, it is less of an issue for clinics that are in the same practice or under one roof. The use of physician assistants and nurse practitioners in a multidisciplinary clinic will depend on the scope of a practice, local regulations, as well as how a practice already uses these allied health professionals. Yet nurse practitioners and physician assistants can be very important additions to a multidisciplinary cancer clinic, because they can take on routine follow-up cares, and enable doctors to see more patients and provide improved quality care. An RN dedicated to a multidisciplinary clinic may also be useful, since they can help with the increased documentation and paperwork involved in running these clinics. Another issue that can be problematic for multidisciplinary cancer clinics is billing. So far, our multidisciplinary advanced prostate cancer clinic has not had problems billing for services provided by different members of our professional team, or billing for facility fees. That process has been made easier by the fact that we are all practicing at the same location. Billing for healthcare provided in a virtual multidisciplinary clinic in the community, however, may face more roadblocks, since urologists, medication oncologists and radiation oncologists all practice in different settings. In the future, however, billings by virtual multidisciplinary prostate cancer clinics in the community should become easier as payers recognize the efficiencies of these clinics. hysicians who decide to participate in a multidisciplinary prostate cancer clinic should be aware that their patient volume may increase dramatically, since each discipline will be involved in devising the patient s care plan in the early stages. So, a medical oncologist may contribute to the patient s care plan, even before that patient transitions to chemotherapy. As these multidisciplinary clinics become busier, the challenges of having sufficient space become more difficult. Thus, having enough space and the ability to expand is important. Healthcare providers who start multidisciplinary clinics will find that patients will come out of the woodwork to attend these clinics. atients are often eager to participate in multidisciplinary cancer clinics, because of the care coordination, quality treatment and psychosocial benefits offered there. atients who come to these clinics know that their doctors and other healthcare providers are working in concert to make the smartest treatment decisions possible. For healthcare providers, on the other hand, a multidisciplinary cancer clinic has the potential to improve patient satisfaction through cohesive treatment plans. Such clinics also offer easy access to collaborators who can help optimize your patient care. 26 EVERYDAY UROLOGY TM

27 Brought to you by the publishers of Everyday Urology and UroToday.com, a new site for medical oncologists that allows free, convenient access to daily aggregated content by tumor type. SIGN U TODAY TO RECEIVE NEWS AND UDATES VIA ERSONALIZED BASED ON YOUR REFERENCES OncToday.com

28 SOTLIGHT SUO 2016 Our Spotlight section in this issue presents proceedings and summaries of lectures from the 17th Annual Meeting of the Society of Urologic Oncology (SUO) from November 30 to December 2, 2016 in San Antonio, TX. The proceedings feature two State-of-the-Art lectures on treatment advances in metastatic renal cell carcinoma and the clinical implications of prostate cancer phenotypes. Written by fellows from leading medical and cancer centers, the summaries in this section discuss SUO meeting presentations on subjects such as targeted therapy for kidney cancer and controversies in the surgical management of this disease, immunotherapy for prostate cancer and open vs. radical prostatectomy, and treatment of bladder cancer in octogenerians. 28 EVERYDAY UROLOGY TM

29 State-of-the-Art Lecture: Advances in Management of Metastatic RCC The management of metastatic renal cell carcinoma (RCC) has rapidly changed in the last two years with the addition of several therapy options to the armamentarium available for advanced RCC treatment. One of the most exciting developments has been the approval of D-1 immunotherapy (nivolumab) by the FDA as a second line treatment for patients with advanced RCC. Recently research has begun in several clinical trials that include some of these novel treatments in the first-line setting, which may change the landscape of treatment for the disease. In this session, Dr. Choueiri from the Dana Faber Cancer Institute presented the current state-of-the-art management of metastatic RCC. The first-line management of advanced RCC has not changed significantly since the COMARZ trial which showed comparable survival in patients treated with sunitinib or pazopanib, with pazopanib having a better side effect profile. Most the current progress is taking place in the second-line setting with the addition of nivolumab, cabozantinib and lenvatinib as treatments. All these treatments show a significant difference in progression and overall survival in comparison to prior second-line treatments such as axitinib or everolimus. The publication of Checkmate-25 in 2015 showed a significant improved overall survival (OS) in patients treated with nivolumab compared to everolimus in the second-line setting. Surprisingly there was no difference in progression-free survival (FS) between the two groups. The expression of D-L1 was found to be prognostic but not predictive of response, which ratifies this discordance between the OS and FS. Given the significant difference in OS seen with checkpoint inhibitors, nivolumab plus ipilimumab is now being compared to sunitinib as first-line therapy in Checkmate 214. The combination of VEGF + mtor inhibitors in first-line therapy was associated with severe side effects and no improvement in survival. A recent study by Motzer and colleagues (Lancet Oncol, 2015), showed that the addition of a lenvatinib to everolimus as a second-line treatment showed a significant improvement in FS compared to lenvatinib or everolimus alone (14.6 months vs. 7.4 months vs. 5.5 months). Given this data, the CLEAR study has been launched to assess the effect of combining lenvatinib and everolimus in the first-line setting. Cabozantinib, a c-met inhibitor that targets the MET pathway, has produced good responses in patients who have failed VEGF treatments. The MET pathway appears to be upregulated with complete blockade of the VEGF pathway which may explain the increase invasiveness and metastatic potential of some tumors following VEGF blockade. The effect of cabozantinib as a second-line agent was then tested against everolimus, and showed a significant difference in both FS and OS. There is ongoing accrual of patients into a clinical trial that will assess cabozantinib as a first-line agent compared to sunitinib. How do these clinical trials translate to clinical practice? There are several limitations that clinical trials pose, such as tight selection criteria that leave out patients with poor performance status, older patients, patients in whom nephrectomy was not possible, patients with brain metastases, and those with renal and liver dysfunction. Dr. Choueiri has initiated an international multi-institutional database including 35 centers that seeks to finds the answers to these questions. Even with the known limitations associated with database research, the data was n able to provide answers to key questions. For example, the data was used to assess the progression-free survival (FS) of patients eligible for trials vs. patients found ineligible and treated with first-line therapy. The study showed that a significant number of patients (43%) would have been found ineligible for a clinical trial given current criteria. On evaluation of cohort FS, there was a clear difference between the groups with ineligible patients having a worse FS (5.2 months vs. 8.7 months, p>0.001). The database was also used to assess the impact of cytoreductive nephrectomy in the targeted area, given the slow accrual from the CARMENA trial. The data showed that cytoreductive nephrectomy is associated with a survival advantage. The database is currently being enriched with tumor and serum samples with the hope of being able to further the study with genetic profiling and biomarker discoveries. In summary, there is great excitement regarding the use of these novel agents in the primary setting along with potential combinations that may further improve the survival of patients with advanced RCC. Furthermore, the addition of biological samples to the multi-institution database has the potential to allow the study of unrepresented populations allowing a better translation of the survival data into the clinical setting. RESENTED BY: TONI CHOUEIRI, MD, DANA FABER CANCER INSTITUTE WRITTEN BY: ANDRES F. CORREA, MD, SOCIETY OF UROLOGIC ONCOLOGY FELLOW, FOX CHASE CANCER CENTER Novel redictive Biomarkers for Benefit of Immune Checkpoint Blockade William Kim, University of North Carolina, discussed biomarkers in the immune checkpoint blockade. The biomarkers currently explored are DL-1 and mutational load. DL-1 + is a biomarker of response, however, there are patients who are negative who also have a response to DL-1 inhibitors. Neoantigen burden correlates with response to immune checkpoint inhibition in other cancers. Mutational burden also correlates with response to inhibition in recent trials. Effector T-cell signature correlates with response to immune checkpoint inhibitors and specifically, a 25-gene signature on IFN-gamma has biological and clinical implications. Immune gene signature expression is highly correlated with response. Molecular subtypes have differential immune gene (Continued on page 30) VOLUME 1, ISSUE 4 29

30 SOTLIGHT: SUO 2016 (Continued from page 29) signature expression, mainly among basal and luminal subtypes, although others have been explored further. There are conflicting reports among subtypes in response to immune checkpoint blockade, which are illustrated by the IMvigor 210 and CheckMate 275 trials. The discrepancies among these trials may be due to differences in molecular subtyping methods, accuracy of subtyping and differences in the end targets of blockade (anti-d-1 vs. anti- D-L1). The field of immunology in bladder cancer is rapidly evolving with emerging trials. Further standardization of data reporting, in which patients are assessed based on molecular subtype, is needed to cohesively compare and understand how these inhibitors may benefit our patients. RESENTED BY: WILLIAM KIM, UNIVERSITY OF NORTH CAROLINA WRITTEN BY: STEHEN B. WILLIAMS, MD AND ASHISH M. KAMAT Immunotherapy for rostate Cancer: What is the Way Forward? Immunotherapy treatment for prostate cancer has been quite limited given that currently Sipuleucel-T is the only immunotherapy approved for the management of castration-resistant prostate cancer. With the introduction of checkpoint inhibitors, there has been a growing interest in these therapies in patients with advanced prostate cancer. In this session, Dr. Yu from the Seattle Cancer Care Alliance presented the current immunotherapy landscape for treatment of advanced prostate cancer. The use of immunotherapy for the management of advanced prostate cancer has been quite limited, due to the limited use of Sipuleucel-T in the clinical setting. Sipuleucel-T is only approved in a select cohort of patients with mildly symptomatic castration- resistant prostate cancer, which provides a very short window of opportunity. The effect of this treatment challenge is poor SA response to therapy, with no response on progression-free survival (FS) and 4-month improvement in overall survival (OS). A post-hoc analysis of the Sipuleucel-T clinical trial showed that for the immune system to be able to combat cancer, it requires a small tumor burden, and the best survival is seen in patients with SA levels < 25 ng/ml. Small trials on checkpoint inhibitors have not shown the improvements in OS seen in other GU malignancies, such as kidney or bladder, which has blunted the excitement about the use of checkpoint inhibitors in prostate cancer. Checkpoint inhibitors may lack effect because of low expression of D-L1 in prostate cancer along with the low tumor mutation rates. In further review of the available data, there appears to be an increased expression of D-L1 in high risk tumors, which appear to be diluted down in prior studies. A recent abstract presented at ESMO, showed improved responses, some durable, in patients treated with pembrolizumab who were found to have significant expression of the D-L1 ligand. A recent study from the University of British Columbia, looked at the expression of D-L1/2 in the dendritic cells of patients treated with enzalutamide. Interestingly, the dendritic expression of D-L1/2 appeared to increase in those patients treated with enzalutamide who were progressing on therapy. In a follow-up study, pembrolizumab was added to patients failing enzalutamide therapy, who showed a significant reduction in SA levels. Given the limited cohort of patients in whom immunotherapy appears to be effective, there are several ongoing trials looking at priming the immune system by using chemotherapy and radiation to release neo-antigens for dendritic cell priming. There is also some early work on combination therapy with pembrolizumab + docetaxel/ enzalutamide that may improve response. In summary, there are some encouraging early studies that show that immunotherapies may have benefits for a select group of patients with advanced prostate cancer that could be expanded with immune system priming and combination therapy. RESENTED BY: EVAN Y. YU, MD, SEATTLE CANCER CARE ALLIANCE WRITTEN BY: ANDRES F. CORREA, MD, SOCIETY OF UROLOGIC ONCOLOGY FELLOW, FOX CHASE CANCER CENTER Mechanisms of Resistance to AR: AR Variants and GR Dr. Arora presented original research demonstrating a new understanding of the resistance patterns to AR inhibition in castration-resistant metastatic prostate cancer (mcrc). Researchers at MSKCC and Washington University investigated the ways in which resistant tumor cells appear to bypass AR signaling and make them resistant to targeted AR blockade with enzalutamide. They identified the active role that the glucocorticoid receptor (GR) plays in this process. GR can functionally replace the activity of AR, due to similar structural properties. Thus, uninhibited GR can play the same role that AR plays in promoting cell proliferation. Worse, there appear to be subsets of cells that experience upregulation of GR after treatment with enzalutamide. Using xenograft mouse models with different prostate cancer cell lines, researchers were able to characterize this GR upregulation in enzalutamide-treated cells. AR pathways in normal cells appear to play a suppressive role with regard to GR expression. Investigators found that the GR enhancer/promoter region contains an AR-binding motif, and enzalutamide exposure removes this AR suppression and induces GR expression. In summary, there is a loss of AR-mediated repression at the GR enhancer with enzalutamide treatment. Additionally, there is another pathway (RC2) that produces a molecule that binds to and inhibits the GR enhancer. It appears that GR induction may also require loss of this second inhibitory pathway to gain full expression. By replacing the small molecule (JQ1) within enzalutamide-resistant cells, researchers were able to restore enzalutamide sensitivity by blocking GR expression and avoiding the 30 EVERYDAY UROLOGY TM

31 AR signaling bypass. There is currently a hase I trial underway to evaluate this modality as treatment. The more we understand the variant pathways that lead to resistant tumor cells, the more we will be able to identify drug targets that can enable early intervention. This research is one example of a promising step in that direction. RESENTED BY: VIVEK ARORA, MD, WASHINGTON UNIVERSITY WRITTEN BY: SHREYAS JOSHI, MD, FOX CHASE CANCER CENTER in the analysis. Also, while RC may provide a higher overall survival, it does not translate into a higher quality of life in elderly patients. An interesting question to consider would be whether cancer control with multimodal management provides a higher quality of life in patents for whom the estimated survival is usually less than 10 years. AUTHORS: WILLIAM BOYSEN, VIGNESH ACKIAM, JOSEH RODRIGUEZ III, MELANIE A. ADAMSKY, NORM SMITH AND GARY D. STEINBERG, UNIVERSITY OF CHICAGO WRITTEN BY: ANDRES F. CORREA, MD, SOCIETY OF UROLOGIC ONCOLOGY FELLOW, FOX CHASE CANCER CENTER Definite Treatment of Bladder Cancer in Octogenarians: Balancing Increased erioperative Mortality with Superior Overall Survival Radical cystectomy (RC) is the gold standard therapy for patient with muscle invasive bladder cancer (MIBC), and is the treatment associated with the best oncologic outcomes. However, RC causes great morbidity with an overall 90-day complication rate of approximately 30%. Thus, RC has seldom been performed in elderly patients, especially those in the later decades of life. In this study by Boysen and colleagues, the researchers sought to identify the perioperative risks of RC among octogenarians and analyze the survival benefit of available treatment modalities using the National Cancer Database. A total of 15,581 patients with MIBC between the ages of were identified in the database. Compared to younger patients, octogenarians were less likely to undergo RC (18.0% vs. 47.9%) and more likely to be treated with multimodal therapy chemotherapy/radiation (13.7% vs. 10.1%). The authors then performed a multivariate analysis, controlling for Charlson comorbidity index (CCI), race, and facility type, and assessing the risk of 30-day and 90-day mortality following RC. Age > 80 years was found to be an independent predictor of 30-day and 90-day mortality with an OR of 2.9 and 2.6, respectively. A Cox proportional multivariate analysis was then performed to assess overall survival associated with each treatment modality (RC, TURBT + chemotherapy, TURBT + radiation, TURBT + chemotherapy + radiation), showing that overall survival was highest among octogenarians treated with RC, and overall survival was sequentially worse for those treated with combination chemo/radiation, radiation and chemotherapy (HR 0.54 vs HR 0.60 vs HR 0.75 vs HR 0.77) compared to TURBT alone. This population-based study shows that octogenarians are less likely to receive RC compared to their younger counterparts although it is associated with improved overall survival compared to other treatment modalities. RC in octogenarians is associated with a higher 30-day and 90-day mortality compared to their younger counterparts even when the groups are controlled for comorbidities. The study must be considered carefully, since there is inherent selection bias in any population survey that is challenging to control SLCO2B1: Biology & Therapeutic Implications Dr. Harshman presented original research that studied the influence and manipulation of the SLCO2B1 transporter in prostate cancer treatment. SLCO2B1 is a gene that encodes a sodium-independent organic anionic transporter that is responsible for mediating the transport of a variety of hormones and drugs into cells. Studies have shown that expression of SLCO2B1 increases with progression from hormone-sensitive to castration-resistant prostate cancer. Interestingly, sophisticated gene analysis has demonstrated that this transporter is an important mediator of androgen metabolism. Higher risk SLCO2B1 alleles are associated with shorter prostate cancer survival, so understanding the functional role of this transporter is paramount. An important molecule that is transported is DHEAS (responsible for androgen entry into cells). Statins are a commonly used drug that also experience uptake with the SLCO2B1 transporter. Dr. Harshman presented retrospective data suggesting that statin use has an inverse relationship with prostate cancer incidence and mortality. Statin use appears to be beneficial for both of these outcomes. Investigators demonstrated that statins compete against and inhibit DHEAS uptake within tumor cells, and this effect is concentration-dependent and similar across multiple statin medications. They therefore hypothesized that statin use at the time of ADT initiation would improve prostate cancer outcomes, such as time to progression (TT). In a study of 1265 patients, they found patients on statins at ADT initiation did indeed have a significantly longer 10-month median TT on ADT: 27.5 vs months (p=0.0005). Abiraterone is a steroidal drug that could also be influenced by SLCOmediated transport, and work by Dr. Xiaodong Wang found that uptake of abiraterone is indeed SLCO-dependent. Dr. Harshman and colleagues predicted that statins may INHIBIT the effectiveness of abiraterone by competing for cellular uptake via SLCO transporters. Interestingly though, a retrospective analysis of 224 patients over 7 years found that among the 41% of patients taking statins, there was an opposite effect: There was a trend toward longer abiraterone duration in statin users. This would suggest that statins do not have a negative impact on abiraterone effectiveness. However, a (Continued on page 32) VOLUME 1, ISSUE 4 31

32 SOTLIGHT: SUO 2016 (Continued from page 31) subsequent analysis using patients with more advanced disease in the Hopkins database did not show a significant signal. As Dr. Harshman concludes, there is evidence that statins compete with DHEAS for uptake into tumor cells by SLCO2B1, which may decrease the tumor s available androgen pool. This may translate into improved outcomes for patients initiating ADT who use statins. Although it was feared that statin use may inhibit the effectiveness of abiraterone, research suggests that statin use does not appear to have a negative impact. Clearly, further prospective studies will help delineate the complete nature of these associations. RESENTED BY: LAUREN HARSHMAN, MD, DANA-FARBER CANCER INSTITUTE WRITTEN BY: SHREYAS JOSHI, MD, FOX CHASE CANCER CENTER Absence of Tumor on Repeat TURBT does not redict Final athologic T0 Stage in Muscle Invasive Bladder Cancer Treated with Radical Cystectomy For patients with muscle invasive bladder cancer (MIBC) who undergo neoadjuvant chemotherapy (NAC) the best predictor of response and prognosis is pt0 stage in the cystectomy specimen. There has been recent evidence that cystoscopy evidence of ct0 may be a good clinical surrogate for pt0 in the cystectomy specimen. Several groups are now looking into omitting radical cystectomy for patients with good response to NAC who appear to be ct0 on cystoscopic evaluation or following a repeat TURBT. Dr. Kukreja, from MD Anderson Cancer Center presented a retrospective institutional review of patients with MIBC who received a TURBT prior to cystectomy. The aim of the study was to assess the concordance rates between ct0 on TURBT and pt0 on cystectomy specimens. Secondary end-points were recurrence-free survival (RFS) and cancer-specific survival (CSS) in the cohort. On review of their prospectively collected bladder cancer database, they identified 159 patients who had evidence of ct0 on repeat TUBRBT immediately prior to cystectomy with 72 (45.3%) patients receiving NAC. On pathological evaluation of the cystectomy specimen, 66.7% of patients with ct0 showed evidence of residual tumor on the pathological specimen, and 41% showed pathological stage pt2 disease. Lymph node involvement was noted in 20 (12.6%) patients. On multivariate analysis that accounted for clinical stage, grade, NAC, lympho-vascular invasion (LVI), and CIS, only LVI and CIS were found to be predictive of residual disease in the cystectomy specimen. In the analysis, there was no statistical difference in achieving pt0 between patients who underwent TURBT alone compared to patients who received NAC + TUBRT. In controlling for pathological stage, there was no difference in RFS and CSS between those who achieve pt0 and those who did not. The authors conclude that complete tumor removal on TURBT does not predict pt0 at cystectomy. Furthermore, a notable number of patients though to be ct0 at TURBT were found to have locally advanced and/or lymph node positive disease. This study provides important information for clinicians who are hoping to use bladder presentation strategies in patients with a complete cystoscopic response following NAC. The study does have some limitations, including its retrospective nature, which adds selection bias. In addition, there was no standardization of the type of TURBT, which may range from an aggressive TURBT to a cold cup biopsy. Further trials should be performed that control for NAC and TURBT performed to further characterize these patients to find genomic markers that could be better surrogates for pt0. AUTHORS: JANET BAACK KUKREJA, SIMA ORTEN, VISHNUKAMAL GOLLA, GRACIELA NOGUERA-GONZALES, NEEMA NAVAI, ASHISH KAMAT, COLIN DINNEY, JAY SHAH; MD ANDERSON WRITTEN BY: ANDRES F. CORREA, MD, SOCIETY OF UROLOGIC ONCOLOGY FELLOW, FOX CHASE CANCER CENTER anel on Surgical Management for Advanced Kidney Cancer: Controversies in Case Management Moderated by Dr. Boorjian, this panel sought to explore challenges related to the surgical management of advanced kidney cancer. First, the panel addressed how best to approach patients with a venous tumor thrombus. In regards to the question of anticoagulation in patients with venous tumor thrombus, Dr. Leibovich offers anticoagulation during the interval between diagnosis and surgery to anyone with history of E or DVT, those with complete IVC occlusion, those with bland thrombus, and those with lower extremity edema or impending occlusion. He advised against placing an inferior vena cava (IVC) filter since it can induce harm. Regarding neoadjuvant systemic therapy, Dr. Jonasch considers a pre-surgical systemic therapy or radiation approach in patients with unresectable or borderline resectable tumors. Dr. Margulis countered that only rarely has neoadjuvant therapy influenced his surgical approach. In regards to the question of a minimally invasive vs. an open approach, Dr. Desai prefers a robotic approach if there is adequate clearance (2cm) from the main hepatic veins and no thrombus in the main IVC tributaries. Furthermore, he noted that obesity and bulky mesentery may be predictive of open conversion. In his mind, the volume of the tumor thrombus within the IVC is not the limiting factor for application of a minimally invasive approach. Rather, he uses clearance from the main hepatic veins when making the decision on surgical approach. Yet Dr. Leibovich vehemently disagrees. He supports minimally invasive approaches for freely mobile tumors. However, he strongly advocates open surgery for cases of complete/impended IVC occlusion, contralateral renal vein involvement, and lower extremity edema. (Continued on page 39) 32 EVERYDAY UROLOGY TM

33 For men with mcrc who have progressed on ADT Z Y T I G A & R E D N I S O N E LET S STRONG DO THIS TOGETHER INDICATION ZYTIGA (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mcrc). IMORTANT SAFETY INFORMATION Contraindications ZYTIGA is not indicated for use in women. ZYTIGA can cause fetal harm (regnancy Category X) when administered to a pregnant woman and is contraindicated in women who are or may become pregnant. Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in blood pressure, hypokalemia, or fluid retention. ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CY17 inhibition. Safety has not been established in patients with LVEF <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) because these patients were excluded from these randomized clinical trials. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly. Adrenocortical Insufficiency (AI) AI was reported in patients receiving ZYTIGA in combination with prednisone, after an interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. erform appropriate tests, if indicated, to confirm AI. Increased dosages of corticosteroids may be used before, during, and after stressful situations. mcrc = metastatic castration-resistant prostate cancer; ADT = androgen-deprivation therapy. lease see additional Important Safety Information on the next pages. lease see brief summary of full rescribing Information on subsequent pages.

34 For men with mcrc who have progressed on ADT ZYTIGA & REDNISONE: (abiraterone( acetate) ) For more than 5 years, ZYTIGA has been prescribed to men battling mcrc 1 5 years ZYTIGA was the #1 prescribed oral medication for mcrc in The median seating capacity of a professional football stadium is 69,000 ZYTIGA has been prescribed for more than 80,000 patients in the United States since its approval in April IMORTANT SAFETY INFORMATION Hepatotoxicity In postmarketing experience, there have been ZYTIGA -associated severe hepatic toxicities, including fulminant hepatitis, acute liver failure and deaths. Monitor liver function and modify, withhold, or discontinue ZYTIGA dosing as recommended (see rescribing Information for more information). Measure serum transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment, and monthly thereafter. romptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function. Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the patient s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN. ermanently discontinue ZYTIGA for patients who develop a concurrent elevation of ALT greater than 3X ULN and total bilirubin greater than 2X ULN in the absence of biliary obstruction or other causes responsible for the concurrent elevation. Janssen Biotech, Inc. Janssen Biotech, Inc / lease see brief summary of full rescribing Information on subsequent pages.

35 Let s do this Established safety profile Contraindicated in women who are or may become pregnant; Warnings and recautions include Mineralocorticoid Excess, Adrenocortical Insufficiency, and Hepatotoxicity The most common adverse reactions ( 10%) are fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection, and contusion The most common laboratory abnormalities (>20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT, and hypokalemia ZYTIGA in geriatric patients Of the total number of patients receiving ZYTIGA in phase 3 trials, 73% of patients were aged 65 years and over and 30% were aged 75 years and over No overall differences in safety or effectiveness were observed between these elderly patients and younger patients Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out IMORTANT SAFETY INFORMATION continued Drug Interactions Based on in vitro data, ZYTIGA is a substrate of CY3A4. In a drug interaction trial, co-administration of rifampin, a strong CY3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CY3A4 inducers during ZYTIGA treatment. If a strong CY3A4 inducer must be co-administered, increase the ZYTIGA dosing frequency only during the co-administration period [see Dosage and Administration (2.3)]. In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CY3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone. ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzymes CY2D6 and CY2C8. Avoid co-administration with CY2D6 substrates with a narrow therapeutic index. If alternative treatments cannot be used, exercise caution and consider a dose reduction of the CY2D6 substrate drug. In a CY2C8 drug interaction trial in healthy subjects, the AUC of pioglitazone, a CY2C8 substrate, was increased by 46% when administered with a single dose of ZYTIGA. atients should be monitored closely for signs of toxicity related to a CY2C8 substrate with a narrow therapeutic index if used concomitantly with ZYTIGA. Use in Specific opulations Do not use ZYTIGA in patients with baseline severe hepatic impairment (Child-ugh Class C) * Greater sensitivity of some older individuals cannot be ruled out. Reference: 1. Data on file. Janssen Biotech, Inc. Learn more today at STRONG TOGETHER

36 ZYTIGA (abiraterone acetate) Tablets Brief Summary of rescribing Information. INDICATIONS AND USAGE ZYTIGA is a CY17 inhibitor indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer. CONTRAINDICATIONS regnancy: ZYTIGA can cause fetal harm when administered to a pregnant woman. ZYTIGA is not indicated for use in women. ZYTIGA is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss [see Use in Specific opulations]. WARNINGS AND RECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CY17 inhibition [see Clinical harmacology (12.1) in full rescribing Information]. In the two randomized clinical trials, grade 3 to 4 hypertension occurred in 2% of patients, grade 3 to 4 hypokalemia in 4% of patients, and grade 3 to 4 edema in 1% of patients treated with ZYTIGA [see Adverse Reactions]. Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. Use ZYTIGA with caution in patients with a history of cardiovascular disease. The safety of ZYTIGA in patients with left ventricular ejection fraction <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) was not established because these patients were excluded from these randomized clinical trials [see Clinical Studies (14) in full rescribing Information]. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA. Adrenocortical Insufficiency: Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients taking ZYTIGA and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and recautions]. Hepatotoxicity: In postmarketing experience, there have been ZYTIGAassociated severe hepatic toxicity, including fulminant hepatitis, acute liver failure and deaths [see Adverse Reactions]. In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5X ULN) were reported in 4% of patients who received ZYTIGA, typically during the first 3 months after starting treatment. atients whose baseline ALT or AST were elevated were more likely to experience liver test elevation than those beginning with normal values. Treatment discontinuation due to liver enzyme increases occurred in 1% of patients taking ZYTIGA. No deaths clearly related to ZYTIGA were reported due to hepatotoxicity events. Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. romptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function. Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the patient s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration (2.2) in full rescribing Information]. ermanently discontinue ZYTIGA for patients who develop a concurrent elevation of ALT greater than 3 x ULN and total bilirubin greater than 2 x ULN in the absence of biliary obstruction or other causes responsible for the concurrent elevation [see Dosage and Administration (2.2) in full rescribing Information]. The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown. ZYTIGA (abiraterone acetate) Tablets ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Hypertension, Hypokalemia, and Fluid Retention due to Mineralocorticoid Excess [see Warnings and recautions]. Adrenocortical Insufficiency [see Warnings and recautions]. Hepatotoxicity [see Warnings and recautions]. Clinical Trial Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Two randomized placebo-controlled, multicenter clinical trials enrolled patients who had metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy. In both Study 1 and Study 2 ZYTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arms. lacebo plus prednisone 5 mg twice daily was given to control patients. The most common adverse reactions ( 10%) reported in the two randomized clinical trials that occurred more commonly (>2%) in the abiraterone acetate arm were fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion. The most common laboratory abnormalities (>20%) reported in the two randomized clinical trials that occurred more commonly ( 2%) in the abiraterone acetate arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypo phosphatemia, elevated ALT and hypokalemia. Study 1: Metastatic CRC Following Chemotherapy: Study 1 enrolled 1195 patients with metastatic CRC who had received prior docetaxel chemotherapy. atients were not eligible if AST and/or ALT 2.5X ULN in the absence of liver metastases. atients with liver metastases were excluded if AST and/or ALT >5X ULN. Table 1 shows adverse reactions on the ZYTIGA arm in Study 1 that occurred with a 2% absolute increase in frequency compared to placebo or were events of special interest. The median duration of treatment with ZYTIGA was 8 months. Table 1: Adverse Reactions due to ZYTIGA in Study 1 ZYTIGA with rednisone (N=791) lacebo with rednisone (N=394) System/Organ Class All Grades 1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Musculoskeletal and connective tissue disorders Joint swelling/ discomfort Muscle discomfort General disorders Edema Vascular disorders Hot flush Hypertension Gastrointestinal disorders Diarrhea Dyspepsia Infections and infestations Urinary tract infection Upper respiratory tract infection Respiratory, thoracic and mediastinal disorders Cough Renal and urinary disorders Urinary frequency Nocturia Injury, poisoning and procedural complications Fractures

37 ZYTIGA (abiraterone acetate) Tablets Table 1: Adverse Reactions due to ZYTIGA in Study 1 (continued) ZYTIGA with rednisone (N=791) lacebo with rednisone (N=394) System/Organ Class All Grades 1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Cardiac disorders Arrhythmia Chest pain or chest discomfort Cardiac failure Adverse events graded according to CTCAE version Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness. 3 Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness. 4 Includes terms Edema, Edema peripheral, itting edema, and Generalized edema. 5 Includes all fractures with the exception of pathological fracture. 6 Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia. 7 Includes terms Angina pectoris, Chest pain, and Angina unstable. Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively). 8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased. Table 2 shows laboratory abnormalities of interest from Study 1. Grade 3-4 low serum phosphorus (7%) and low potassium (5%) occurred at a greater than or equal to 5% rate in the ZYTIGA arm. Table 2: Laboratory Abnormalities of Interest in Study 1 Abiraterone (N=791) lacebo (N=394) Laboratory All Grades Grade 3-4 All Grades Grade 3-4 Abnormality (%) (%) (%) (%) Hypertriglyceridemia High AST Hypokalemia Hypophosphatemia High ALT High Total Bilirubin Study 2: Metastatic CRC rior to Chemotherapy: Study 2 enrolled 1088 patients with metastatic CRC who had not received prior cytotoxic chemotherapy. atients were ineligible if AST and/or ALT 2.5X ULN and patients were excluded if they had liver metastases. Table 3 shows adverse reactions on the ZYTIGA arm in Study 2 that occurred with a 2% absolute increase in frequency compared to placebo. The median duration of treatment with ZYTIGA was 13.8 months. Table 3: Adverse Reactions in 5% of atients on the ZYTIGA Arm in Study 2 ZYTIGA with rednisone (N=542) lacebo with rednisone (N=540) System/Organ Class All Grades 1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % General disorders Fatigue Edema yrexia Musculoskeletal and connective tissue disorders Joint swelling/ discomfort Groin pain Gastrointestinal disorders Constipation Diarrhea Dyspepsia Vascular disorders Hot flush Hypertension Respiratory, thoracic and mediastinal disorders Cough Dyspnea sychiatric disorders Insomnia ZYTIGA (abiraterone acetate) Tablets Table 3: Adverse Reactions in 5% of atients on the ZYTIGA Arm in Study 2 (continued) ZYTIGA with rednisone (N=542) lacebo with rednisone (N=540) System/Organ Class All Grades 1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Injury, poisoning and procedural complications Contusion Falls Infections and infestations Upper respiratory tract infection Nasopharyngitis Renal and urinary disorders Hematuria Skin and subcutaneous tissue disorders Rash Adverse events graded according to CTCAE version Includes terms Edema peripheral, itting edema, and Generalized edema. 3 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness. Table 4 shows laboratory abnormalities that occurred in greater than 15% of patients, and more frequently (>5%) in the ZYTIGA arm compared to placebo in Study 2. Grade 3-4 lymphopenia (9%), hyperglycemia (7%) and high alanine aminotransferase (6%) occurred at a greater than 5% rate in the ZYTIGA arm. Table 4: Laboratory Abnormalities in >15% of atients in the ZYTIGA Arm of Study 2 Abiraterone (N=542) Grade 1-4 Grade 3-4 % % lacebo (N=540) Laboratory Abnormality Grade 1-4 % Hematology Lymphopenia Chemistry Hyperglycemia High ALT High AST Hypernatremia Hypokalemia Based on non-fasting blood draws. Grade 3-4 % Cardiovascular Adverse Reactions: In the combined data for studies 1 and 2, cardiac failure occurred more commonly in patients treated with ZYTIGA compared to patients on the placebo arm (2.1% versus 0.7%). Grade 3-4 cardiac failure occurred in 1.6% of patients taking ZYTIGA and led to 5 treatment discontinuations and 2 deaths. Grade 3-4 cardiac failure occurred in 0.2% of patients taking placebo. There were no treatment discontinuations and one death due to cardiac failure in the placebo group. In Study 1 and 2, the majority of arrhythmias were grade 1 or 2. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arms and no deaths in the placebo arms. There were 7 (0.5%) deaths due to cardiorespiratory arrest in the ZYTIGA arms and 3 (0.3%) deaths in the placebo arms. Myocardial ischemia or myocardial infarction led to death in 3 patients in the placebo arms and 2 deaths in the ZYTIGA arms. ostmarketing Experience The following additional adverse reactions have been identified during post approval use of ZYTIGA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Respiratory, Thoracic and Mediastinal Disorders: non-infectious pneumonitis. Musculoskeletal and Connective Tissue Disorders: myopathy, including rhabdomyolysis. Hepatobiliary Disorders: fulminant hepatitis, including acute hepatic failure and death. DRUG INTERACTIONS Drugs that Inhibit or Induce CY3A4 Enzymes: Based on in vitro data, ZYTIGA is a substrate of CY3A4. In a dedicated drug interaction trial, co-administration of rifampin, a strong CY3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CY3A4 inducers during ZYTIGA treatment. If a strong CY3A4 inducer must be co-administered, increase the ZYTIGA dosing frequency [see Dosage and Administration (2.3) and Clinical harmacology (12.3) in full rescribing Information].

38 ZYTIGA (abiraterone acetate) Tablets In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CY3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone [see Clinical harmacology (12.3) in full rescribing Information]. Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzymes CY2D6 and CY2C8. In a CY2D6 drug-drug interaction trial, the C max and AUC of dextromethorphan (CY2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CY2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CY2D6 substrate drug [see Clinical harmacology (12.3) in full rescribing Information]. In a CY2C8 drug-drug interaction trial in healthy subjects, the AUC of pioglitazone (CY2C8 substrate) was increased by 46% when pioglitazone was given together with a single dose of 1,000 mg abiraterone acetate. Therefore, patients should be monitored closely for signs of toxicity related to a CY2C8 substrate with a narrow therapeutic index if used concomitantly with ZYTIGA [see Clinical harmacology (12.3) in full rescribing Information]. USE IN SECIFIC OULATIONS regnancy: regnancy Category X [see Contraindications].: ZYTIGA can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no adequate and well-controlled studies with ZYTIGA in pregnant women and ZYTIGA is not indicated for use in women, it is important to know that maternal use of a CY17 inhibitor could affect development of the fetus. Abiraterone acetate caused developmental toxicity in pregnant rats at exposures that were lower than in patients receiving the recommended dose. ZYTIGA is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with ZYTIGA. In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental toxicity when administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of organogenesis (gestational days 6-17). Findings included embryo-fetal lethality (increased post implantation loss and resorptions and decreased number of live fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter dilation) at doses 10 mg/kg/day, decreased fetal ano-genital distance at 30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/day. Doses 10 mg/kg/day caused maternal toxicity. The doses tested in rats resulted in systemic exposures (AUC) approximately 0.03, 0.1 and 0.3 times, respectively, the AUC in patients. Nursing Mothers: ZYTIGA is not indicated for use in women. It is not known if abiraterone acetate is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ZYTIGA, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. ediatric Use: Safety and effectiveness of ZYTIGA in pediatric patients have not been established. Geriatric Use: Of the total number of patients receiving ZYTIGA in hase 3 trials, 73% of patients were 65 years and over and 30% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. atients with Hepatic Impairment: The pharmacokinetics of abiraterone were examined in subjects with baseline mild (N=8) or moderate (N=8) hepatic impairment (Child-ugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of ZYTIGA increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function. In another trial, the pharmacokinetics of abiraterone were examined in subjects with baseline severe (N=8) hepatic impairment (Child-ugh Class C) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone increased by approximately 7-fold and the fraction of free drug increased 2-fold in subjects with severe baseline hepatic impairment compared to subjects with normal hepatic function. No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (Child- ugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once ZYTIGA (abiraterone acetate) Tablets daily. Do not use ZYTIGA in patients with baseline severe hepatic impairment (Child-ugh Class C). If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and Clinical harmacology (12.3) in full rescribing Information]. For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.2) in full rescribing Information, Warnings and recautions, and Clinical harmacology (12.3)] in full rescribing Information. atients with Renal Impairment: In a dedicated renal impairment trial, the mean K parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage adjustment is necessary for patients with renal impairment [see Dosage and Administration (2.1) and Clinical harmacology (12.3) in full rescribing Information]. OVERDOSAGE Human experience of overdose with ZYTIGA is limited. There is no specific antidote. In the event of an overdose, stop ZYTIGA, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function. Storage and Handling: Store at 20 C to 25 C (68 F to 77 F); excursions permitted in the range from 15 C to 30 C (59 F to 86 F) [see US controlled room temperature]. Based on its mechanism of action, ZYTIGA may harm a developing fetus. Therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Specific opulations]. ATIENT COUNSELING INFORMATION See FDA-approved patient labeling (atient Information) atients should be informed that ZYTIGA and prednisone are used together and that they should not interrupt or stop either of these medications without consulting their physician. atients receiving GnRH agonists should be informed that they need to maintain this treatment during the course of treatment with ZYTIGA and prednisone. atients should be informed that ZYTIGA should not be taken with food and that no food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. They should be informed that the tablets should be swallowed whole with water without crushing or chewing. atients should be informed that taking ZYTIGA with food causes increased exposure and this may result in adverse reactions. atients should be informed that ZYTIGA is taken once daily and prednisone is taken twice daily according to their physician s instructions. atients should be informed that in the event of a missed daily dose of ZYTIGA or prednisone, they should take their normal dose the following day. If more than one daily dose is skipped, patients should be told to inform their physician. atients should be apprised of the common side effects associated with ZYTIGA, including peripheral edema, hypokalemia, hypertension, elevated liver function tests, and urinary tract infection. Direct the patient to a complete list of adverse reactions in ATIENT INFORMATION. atients should be advised that their liver function will be monitored using blood tests. atients should be informed that ZYTIGA may harm a developing fetus; thus, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves. atients should also be informed that it is not known whether abiraterone or its metabolites are present in semen and they should use a condom if having sex with a pregnant woman. The patient should use a condom and another effective method of birth control if he is having sex with a woman of child-bearing potential. These measures are required during and for one week after treatment with ZYTIGA. Manufactured by: atheon Inc. Mississauga, Canada Manufactured for: Janssen Biotech, Inc. Horsham, A Janssen Biotech, Inc Revised: May

39 SOTLIGHT: SUO 2016 The panel then addressed the challenges associated with selecting patients for cytoreductive nephrectomy (CN) vs. systemic therapy along. Dr. Margulis bases his decision-making on the amount of debulking that can be provided and the patient s performance status/ overall comorbidities. In general, he would not offer CN to MSKCC poor risk patients. Dr. Jonasch prefers the litmus test approach. This consist of upfront systemic therapy followed by interval imaging. If there is no tumor growth for 6 to 9 months, patients are advised to move forward with cytoreduction. Most (~80%) of patients ultimately move forward to CN, but some of the bad actors are able to avoid surgery that is of questionable benefit. Dr. Leibovich concurred with this approach, and advocates CN in patients who are responders. The panelists agreed that for most TKIs, stopping therapy within a week of surgery and restarting therapy two weeks after surgery was an acceptable approach. Finally, the question of lymphadenectomy at the time of surgery was discussed. Dr. Leibovich has been a proponent of extended lymphadenectomy for much of his career. However, a recent paper looking at Mayo clinic cases demonstrated no benefit of lymphadenectomy, regardless of how the data was considered (J Urol 2016, MID: ). Due to this evidence, he has changed his practice to only perform lymphadenectomy in cases of clinical lymph node involvement. MODERATOR: STEHEN A. BOORJIAN, MD ANELISTS: MIHIR M. DESAI, MD, ERIC JONASCH, MD, BRADLEY C. LEIBOVICH, MD, AND VITALY MARGULIS, MD WRITTEN BY: BENJAMIN T. RISTAU, MD, SOCIETY OF UROLOGIC ONCOLOGY FELLOW, FOX CHASE CANCER CENTER rospective Multicenter Comparison of Open and Robotic Radical rostatectomy: the rost-qa/r2 Consortium eter Chang, Beth Israel Deaconess, presented their work from the rost-qa/r2 consortium. With rapid adoption of robotic prostatectomy (RAL) there is conflicting evidence regarding the superiority of RAL over open radical prostatectomy (R). This study was prospective and longitudinally powered to discern oncologic efficacy and quality of life (QOL) outcomes. atients from and were included with 1371 patients from the rost-qa cohort and 677 patients from the R2 cohort. QOL was assessed using multivariate GEE modeling with the EIC questionnaire. Surgical approach was not a significant predictor of longitudinal QOL change over time, regardless of nerve-sparing use. ositive surgical margin outcomes were not significantly different except in cases of extraprostatic extension (p=0.053), which approached significance. atients who underwent RAL were less likely to undergo lymphadenectomy, had decreased pain and shorter hospital stays (p<0.001) than R patients. RAL patients had decreased wound infections, unplanned catheterizations and fewer deep venous thrombosis episodes (<p<0.001) than R patients. Unfortunately, provider volume was not assessed; however, the cohorts were derived from high volume centers. These data support the recent level I evidence showing no difference among treatment approaches. However, there were inherent limitations in study design, including lymphadenectomy use and determining which patients were overtreated vs. undertreated. Given the surge in RAL along with the current evidence, it remains paramount that we as urologists do not entirely abandon R as a feasible treatment option. RESENTED BY: ETER CHANG, BETH ISRAEL DEACONESS WRITTEN BY: STEHEN B. WILLIAMS, MD AND ASHISH M. KAMAT Therapeutic Drug Trials in Kidney Cancer in the Immune-Oncology Era: Update on Current Status and Rationale for Combination Trials Immunotherapy and its application to advanced renal cell carcinoma (RCC) has begun to come of age over the past two to three years. Tumor cells (including renal cell carcinoma) are a lot like normal cells, since they have the ability to tell the immune system to go away using checkpoints. In order to reinvigorate the immune system, checkpoint inhibitors have been used. Interestingly, some tumors lack the ability to attract immune cells, while others have plenty of immune cells, but too many checkpoints. Moreover, there is evidence to suggest worse prognostic outcomes for tumors with higher proportions of immune infiltrate. Therefore, a major focus of ongoing trials is to determine specific subpopulations for whom immune checkpoint blockade will be most effective. Dr. Jonasch provided a nice overview of some of the clinical trials completed and developing in this space. Motzer and colleagues (NEJM 2015, 373: 1803) demonstrated improved overall survival for patients with advanced RCC receiving nivolumab vs. everolimus. While the trial met this primary endpoint, supplemental tables demonstrated a relatively high rate of progressive disease in the nivolumab arm compared to everolimus. Therefore, combination therapies are being increasingly explored, and there are a multitude of currently registered phase I to phase III trials in this space (RAID, IMmotion 151, Javelin Renal 100, Checkmate 214, etc.). One important component of all trials is defining biomarkers to better understand the subpopulations for whom the increasingly complex immunotherapy environment offers the highest efficacy. For example, D-L1 staining is not predictive of response to therapy. However, patients with long-term complete responses to anti-d1 therapy have trends towards increased CD98 infiltrate and increased expression of proinflammatory cytokines. Thus, a better (Continued on page 40) VOLUME 1, ISSUE 4 39

40 SOTLIGHT: SUO 2016 (Continued from page 39) understanding of appropriate clinical scenarios in which immune therapies can be applied is key to improving care in this challenging patient population. RESENTED BY: ERIC JONASCH, MD WRITTEN BY: BENJAMIN T. RISTAU, MD, SOCIETY OF UROLOGIC ONCOLOGY FELLOW, FOX CHASE CANCER CENTER Targeted Therapies and ersonalized Medicine in Kidney Cancer Renal cell carcinoma (RCC) is one of the most genetically understood malignancies starting with the identification of the VHL gene mutation in the early 1990s. This has led to several advances in the treatment of advanced RCC with the introduction of VEGF and mtor inhibitors. The current state of advanced RCC treatment is based on the setting in which the drug was approved (first-line vs. second-line) and matching side effect profiles with existing comorbidities. With new advances in gene profiling, it is now possible to further the field by providing individualized treatment based on tumor mutation profiles. In this session, Dr. Choueiri of the Dana-Faber Cancer Institute discussed advances in targeted therapy with a focus on individualized treatment based on gene profiling. Over the last 10 years there has been great excitement in the identification of several biomarkers (CA-IX, VHL, BRM1, D-L1) that would predict response to individual treatment strategies. Sadly, none of these biomarkers have been be able to be translated to the clinical setting. The genomic profiling of RCC by the TCGA has allowed researchers to find other pathways that may impact tumor progression and potential treatment targets such as chromatic regulation, metabolic shift in aggressive malignancies, and repeated mutations in the mtor pathway. Dr. Choueiri discussed the importance of genomic profiling of patients who present with advanced disease, since possible target sites can be identified that may improve response. At the Dana Faber Cancer Center, all patients are offered gene profiling, free of cost, to help guide treatment. With gene profiling, several key mutations can be identified, such as the TSC1 and TSC2 mutations in the mtor pathway that are exquisitely sensitive to mtor inhibitors. This was demonstrated by Dr. Kwiatkowski and colleagues (Clinical Cancer Res, 2016) of the MSKCC, who showed these mutations to be predictive of exceptional response. Similarly, patients treated with VEGF inhibitors patients harboring mutations in BRM1, T53 and KDM5C are more likely to be extreme responders. Similar studies have been performed on non-clear cell histologies, such as papillary RCC. Genomic profiling of patients with papillary RCC has shown that mutations in the MET pathway are more common in papillary type 1 compared to papillary type 2 RCC. Yet, this is not always the norm. The speaker gave an example of a patient with advanced high grade papillary type II RCC, who responded poorly to mtor inhibitor, but on gene profiling was found to harbor a mutation in the MET gene (METL1195F). The patient was the treated with savolitinib (a pure MET inhibitor) with a dramatic response. Gene profiling has also allowed identification of treatment targets for uncommon malignancies such as collecting duct carcinoma. Gene profiling of collecting duct carcinoma has shown mutations in NF2, which could be associated with everolimus sensitivity, and SMARCB1, which could be associated with EZH2 inhibitor sensitivity. In addition, gene profiling has allowed treatment crossover from malignancy type, such as the use of mtor inhibitors in patients with advanced urothelial carcinoma who have poor response to platinum-based chemotherapy, given the identification of tumor mutations in the mtor pathway. In conclusion, genomic profiling has the potential to further guide targeted therapy to improve responses and side effects profiles in patients with advanced RCC. RESENTED BY: TONI CHOUEIRI, MD, DANA FABER CANCER INSTITUTE WRITTEN BY: ANDRES F. CORREA, MD, SOCIETY OF UROLOGIC ONCOLOGY FELLOW, FOX CHASE CANCER CENTER Management of Residual Retroperitoneal Masses after Chemotherapy for Advanced Seminoma The management of advanced testicular seminoma is significantly different from that of non-seminoma germ cell tumors (NSGCT). Seminoma is exquisitely sensitive to both chemotherapy and radiation therapy with both showing 85% complete response following therapy. The management of post-chemotherapy residual masses in pure seminoma can be quite challenging, since there is a paucity of consensus in the management of these patients, especially those with masses >3 cm. In the session, Dr. Andrew J. Stephenson from the Cleveland Clinic Foundation, presented the management of post-chemotherapy residual masses in patients with pure seminoma. The use of post-chemotherapy retroperitoneal lymph-node dissection (C-RLND) for the management advanced seminoma is low with a rate of 5-10% in pure seminoma series, representing <10% of all C-RLND s performed. In comparison to NSGCT, the yield of viable tumor after a C-RLND in pure seminoma is <15%, and is associated with great morbidity due to the desmoplastic reaction seen following chemotherapy. In addition, regression of residual mass is common with >80% showing some evidence of regression and 50-60% showing complete resolution at a median follow-up of months. The two treatment paradigms in the management of residual masses >3 cm in size are immediate resection vs. observation with delayed surgical resection or salvage chemotherapy for progressive disease. A study from Rice and colleagues (J Urol 2014) looked the 40 EVERYDAY UROLOGY TM

41 survival outcomes of patients managed with C-RLND vs. salvage chemotherapy in patients with residual pure seminoma who failed initial observation. The study showed a significantly improved survival for patients undergoing C-RLND (75%) vs. those receiving salvage chemotherapy (25%). atient selection is imperative, given the morbidity with both C-RLND and salvage chemotherapy. atients presenting with masses <3 cm in size should be observed, since the risk of harboring viable cancer ranges from 0 to 4%. In masses >3cm, FDG-ET CT scan has been introduced as a screening tool to aid in patient selection. The SEMET trial, was a prospective multi-institutional evaluation of FDG-ET for residual masses >1 cm, which showed a specificity of 100%, a positive predictive value of 100% and negative predictive value of 96%. A retrospective validation of the SEMET trial was performed at the University of Indiana (Lewis et al, J Clin Onc 2006), and showed that no patients with ET negative scan relapsed, but found a 33% false positive rate in all patients, increasing to 66% in patients with <3 cm masses. In summary, the therapeutic evidence for C-RLND in advanced seminoma is less certain compared to NSGCT, mainly due to the increased morbidity associated with the procedure. Residual masses <3 cm should be observed, since the risk for occult viable tumor is low. atients with masses >3 cm should be further evaluated with FDG-ET scans, since patients with negative ET scan are very unlikely to recur and should be observed. For patient with positive ET scans, the available options are immediate C-RLND vs. observation with delayed resection/salvage chemotherapy. There is a paucity if data to guide best practices, but immediate C-RLND has been associated with improved survival relative to deferred surgery/chemotherapy in retrospective trials. RESENTED BY: ANDREW J. STEHENSON, MD, CLEVELAND CLINIC FOUNDATION WRITTEN BY: ANDRES F. CORREA, MD, SOCIETY OF UROLOGIC ONCOLOGY FELLOW, FOX CHASE CANCER CENTER State of the Art lecture: Genomic rofiling and Clinical Implications of Atypical Intermediate rostate Cancer henotype Our understanding of metastatic castration-resistant prostate cancer (mcrc) has grown dramatically over the past decade. Gene sequencing has begun to identify tumor changes that cause some patients to develop more aggressive and resistant tumors in the setting of androgen-receptor (AR) inhibition resistance. One of the more pernicious forms of these changes involves the trans-differentiation of prostate cancer into the neuroendocrine phenotype (t-nec) with extremely aggressive clinical features and poor survival. These tumors progress independently of AR activation, and we need a more thorough understanding of the biologic drivers of these tumors. Dr. Gleave and researchers from the various centers comprising the West Coast rostate Cancer Dream Team have sequenced and profiled many mcrc tumors, and have now identified three distinct entities along the degenerative pathway: Adenocarcinoma CRC, small cell t-nec, and intermediate atypical carcinoma (IAC). This last entity is thought to be an intermediary between adenocarcinoma and t-nec forms. The researchers have found a clear difference in survival in IAC, t-nec and adenocarcinoma CRC. IAC and t-nec have much poorer survival (11 months) than adenocarcinoma CRC (25 months). Beltran et al. has demonstrated that IAC and t-nec tumors express markers of NE lineage, but share enough genetic identity with adenocarcinoma CRC to be clones from a precursor adenocarcinoma cell type. Biopsies show that IAC is, in fact, quite common among men with mcrc. Researchers estimate that 29% of biopsies of mcrc men will have IAC, so it is important to understand these tumors more thoroughly. One of the most intriguing and promising discoveries in the field of genomic profiling is the identification of circulating tumor DNA (ctdna) derived from the plasma of patients with the disease. These liquid biopsies are ideal, because they can identify the full milieu of genetic entities present within the patient. This reduces heterogeneity based on temporal and spatial differences in tissue samples obtained at different times and at different sites. For example, plasma ctdna was used to track the AR genome in 62 patients with mcrc treated with abiraterone or enzalutamide. The researchers confirmed that plasma samples identified and characterized prostate cancer genomes that were identical to the genomes expressed from actual prostate tissue. Thus, plasma samples are an easier and more homogenous way to characterize the patient s tumor milieu than various tissue samples. The Dream Team group has more recently found that plasma samples not only have good concordance with metastatic tissue samples, but can identify additional genetic alterations that were not previously identified from tissue samples alone (full data to be presented at ASCO). This has already been used to treat patients with atypical agents not previously available as therapies for mcrc. The most pressing question to resolve concerns the drivers of transdifferentiation from adenocarcinoma CRC to t-nec. The answer is complicated, but there are a growing number of genes and pathway alterations that are now being mechanistically associated with this process. This research is exciting, since we are finding more targets for intervention with each new finding. An interesting takeaway from early research is that there is evidence that the baseline DNA sequence of transdifferentiated cells does not change. Instead, gene expression is radically changed by silencing adeno-markers and upregulating NE markers. This means transdifferentiation occurs by manipulating the phenotype from an identical genotype. Dr. Gleave concluded by discussing what we now know about the transdifferentiation process. A specific genome undergoes epigenetic changes, splicing, transcriptome manipulation, and further pathway (Continued on page 42) VOLUME 1, ISSUE 4 41

42 SOTLIGHT: SUO 2016 (Continued from page 41) derangements to ultimately form the t-nec phenotype. The intermediary forms comprising IAC are now being recognized as important for further understanding the genomic alterations responsible for transdifferentiation. Clearly, this will also open up more targets for future treatments. RESENTED BY: MARTIN E. GLEAVE, MD, FRCSC, FACS, VANCOUVER ROSTATE CENTER WRITTEN BY: SHREYAS JOSHI, M.D., FOX CHASE CANCER CENTER active investigation. From a practical standpoint, Dr. Twardowski currently recommends diffusion-weighted MRI of the spine and pelvis combined with 18F-fluciclovine ET/CT for patients with a rising SA after primary therapy. While SMA-based ET is exciting, its availability is currently restricted to clinical trials in the United States. Finally, Dr. Twardowski encouraged the development of clinical trials to assess the outcomes of salvage therapy based on guidance from these new imaging modalities. RESENTED BY: RZEMYSLAW W. TWARDOWSKI, MD WRITTEN BY: BENJAMIN T. RISTAU, MD, SOCIETY OF UROLOGIC ONCOLOGY FELLOW, FOX CHASE CANCER CENTER Imaging Modalities to Detect Metastatic Disease In this session, Dr. Twardowski discussed the role of various imaging modalities in detecting metastatic prostate cancer. Historically, a SA level of > 0.2ng/mL post-prostatectomy has been used as an indication of recurrence, and the success of salvage therapy is approximately 50% in this setting. Thus, roughly half of men with SA > 0.2ng/mL after prostatectomy harbor occult metastatic disease that traditional imaging modalities (e.g. computed tomography scan and bone scan) are unable to detect. Dr. Twardowski focused his discussion on magnetic resonance imaging (MRI) and positron emission tomography (ET). Diffusionweighted MRI techniques can identify 10-15% of metastatic prostate cancer over computed tomography (CT) scan and bone scan, and it has the advantage of not requiring gadolinium contrast agents. Thus, there is growing support for using MRI to detect metastatic disease in these patients. Most of the progress in detection of occult metastatic disease is occurring in ET scanning. ET scans use prostate cancer avid molecules such as choline, fluciclovine, and prostate-specific membrane antigen (SMA) analogues linked to a positron emitting tracer. Fluorodeoxyglucose (FDG) ET does not work well in prostate cancer, due its low glucose-metabolizing nature. Sodium fluoride ET is very sensitive, and results in an approximately 16.2% improvement over bone scan and CT scan, but has a low specificity with many false positives. Choline ET is based on choline kinase expression in prostate cancer. The major limitation to this approach is its modest performance at low prostate specific antigen (SA) levels. Fluciclovine ET was recently FDA-approved. It is slightly superior to choline ET, but its effectiveness in identifying metastatic disease is also limited at low SA levels. Lastly, SMA-based ET is gaining traction in Europe and is available in some clinical trials in the United States. It has improved performance characteristics at lower SA levels, and can identify greater than 50% of metastatic lesions at SA levels < 0.5ng/mL. In conclusion, new imaging modalities are more sensitive in visualizing metastatic prostate cancer than traditional CT and bone scan. Whether these new scans improve clinical outcomes is an area of Renal Dysfunction and the Kidney Cancer atient In patients presenting with localized renal cell carcinoma (RCC) 25% will have pre-existing chronic kidney disease (CKD) even in the presence of a normal serum creatinine level. In addition, 20% of patients undergoing nephron-sparing surgery will developed significant CKD within 5 years of surgery. It is well known that decreasing GFR has been correlated with risk of death, cardiovascular events and hospitalization. In this session, Dr. Dipen arekh of the University of Miami discussed modifiable factors that may impact the development of CKD in patients presenting with localized RCC. The pre-operative evaluation of these patients is crucial in the stratification of patients at high risk for developing significant CKD following renal surgery. Important factors in the pre-operative evaluation include proteinuria, hypertension, hyperlipidemia, and reduced GFR. atients at high risk for developing significant CKD should be considered for nephron-sparing surgery (NSS) and early referral to nephrology, since early referral to nephrology has been associated with improvement in overall survival in patients with diabetes and signs of CKD. Surgeons now can control the percentage of volume parenchyma spared and the ischemia time during a nephron-sparing procedure. In a study by Campbell and colleagues (Mir et al, Urology 2013), assessing predictive factors for CKD in patient with solitary rental units showed that the percentage of renal preservation was the most important factors in the developed of significant CKD. The study was validated in collaboration with the Mayo clinic (Thompson et al, Urology 2012) in which warm ischemia time (WIT) was added to the multivariate analysis model, showing that percentage of spared parenchyma was the only predictor associated with CKD. The speaker also focused on the effect of WIT on renal dysfunction by reviewing historical and contemporary studies on this subject. The first work regarding the effect of ischemia on renal damage was presented by Dr. Novick in the 1980s, and concluded that ischemia can be sustained with eventual recovery of renal function if ischemia is limited to 30 minutes. The speaker then presented a counter-argument by discussing a contemporary prospective randomized trial 42 EVERYDAY UROLOGY TM

43 assessing the effect of ischemia on functional biomarkers, structural biomarkers and electron microscopy structural changes during nephron sparing surgery (NSS). The study looked at serum samples and core biopsies of normal renal parenchyma prior to surgery, at 10-minute intervals and following renal ischemia during NSS. The study showed no difference in serum markers (Creatinine, Cystatin-C and egfr) between patients with WIT < 30 min compared to those with WIT up to 60 minutes. There was also no difference in structural biomarkers on immunohistochemical analysis that assessed several markers of cell integrity (Actin, Integrin, ptyr). In regards to intracellular changes, there was significant difference in mitochondria swelling as ischemia time increased; however, all the changes were reversed 5 minutes after reperfusion. The speaker concluded that pre-screening of patients at risk for developing significant CKD is of utmost importance for identifying patients in which maximal parenchymal preservation should be performed. In regards to ischemia, it appears to be safer than previously thought, and should not be a limiting factor for providing patients with the best oncologic control, parenchymal preservation and renal reconstruction. RESENTED BY: DIEN J. AREKH, MD, UNIVERSITY OF MIAMI MILLER SCHOOL OF MEDICINE WRITTEN BY: ANDRES F. CORREA, MD, SOCIETY OF UROLOGIC ONCOLOGY FELLOW, FOX CHASE CANCER CENTER Role of Chemotherapy in Oligometastatic Disease Chemotherapy in metastatic prostate cancer has assumed a new and important role in the setting of hormone-sensitive metastatic prostate cancer. Data from the CHAARTED and STAMEDE trials demonstrated a positive impact and improved survival for early chemotherapy in patients with hormone-sensitive prostate cancer. atients with oligometastatic disease (variably defined, but usually considered 1-3 metastatic sites) might be good candidates for systemic chemotherapy with the goal of eradicating disease from the few sites that currently harbor the tumor. However, the CHAARTED data clearly show that patients with higher disease burden appear to have the most benefit, so timing of patient selection is key. It is currently unclear if men who present initially with metastatic prostate cancer have a different disease than those who develop metastatic disease later. Indeed, other solid organ malignancies, such as colon cancer that metastasizes to the liver, can provide examples of how prostate cancers might sequentially progress. In the previous example, chemotherapy has been shown to play an important role in management. There are three schools of thought regarding the biology of metastatic C: 1) inherent CRC exists by the time there are metastases; 2) micrometastases ALWAYS exist beyond the metastases we initially see; or 3) micrometastases don t yet exist but may come from sequential progression of the primary tumor. Gundem et al. published an interesting report in Nature in 2015 demonstrating a clonal lineage for prostate cancer cells in a metastatic patient, and this can act as a launching point for understanding metastatic progression in these patients. Ultimately, we need to identify genomic signatures that can tell us who will have oligometastatic vs. systemic disease at presentation and follow-up. Further, what host-derived factors will provide the best environment for tumor treatment? As we study the use of chemotherapy in oligometastatic disease, we should try to develop a translational approach for defining genetic, clinical, and tumor burden characteristics that will lead to effective chemotherapeutic interventions in the right patients. RESENTED BY: TANYA B. DORFF, USC KECK SCHOOL OF MEDICINE WRITTEN BY: SHREYAS JOSHI, MD, FOX CHASE CANCER CENTER revalence and rognostic Significance of Circulating Tumor Cells in Clinically Localized rostate Cancer Simpa Salami, University of Michigan, discussed circulating tumor cells (CTC) in localized prostate cancer. There is potential to extend research beyond CTC numeration, and the objective of this study was to assess CTC significance in high risk prostate cancer. CTC counts were correlated with biochemical recurrence (BCR) using the Fisher s exact test. Serum samples underwent slide preparation, cell staining, scanning, biomarker analysis, and were correlated with pathology. CTCs were detected in 65% v 58% radical prostatectomy (R) and radiotherapy (XRT) patients respectively. BCR occurred more frequently in the R versus XRT group (14/26 vs. 1/19 respectively). More than 2.5 CTC/ml was significantly associated with BCR. High AR protein, unique CK and nuclear size were significantly associated with BCR. Multidimensional classifier used in the R cohort had a 33% and 95% sensitivity and specificity for predicting progression-free survival. Therefore, characterization of CTCs may provide additional prognostic information beyond numeration alone. At our institution, we are assessing the utility of this and other biomarkers in detecting biochemical recurrence. Equally important is cost-effectiveness research that discerns which biomarker detection is most appropriate with the highest sensitivity and specificity for improving the survival of our patients. RESENTED BY: SIMA SALAMI, UNIVERSITY OF MICHIGAN WRITTEN BY: STEHEN B. WILLIAMS, MD AND ASHISH M. KAMAT For complete SUO 2016 coverage, visit the Conference roceedings section on UroToday.com VOLUME 1, ISSUE 4 43

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