Urologic Cancers FOCUS ON. Current advances, future directions S UPPLEMENT. Biomarkers for bladder cancer: Current and future

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1 APRIL 15, 2017 S UPPLEMENT FOCUS ON Urologic Cancers Current advances, future directions What s new in prostate cancer tests: Markers, imaging Immunotherapy for GU Ca: A primer for urologists Biomarkers for bladder cancer: Current and future Guidelines update: Bladder, kidney, prostate cancer

2 S2 Focus on Urologic Cancers: Current advances, future directions APRIL 15, 2017 Urology Times SUPPLEMENT What s new in prostate Ca tests: Markers, imaging New diagnostic modalities aid clinical decisions, but challenges remain By Cheryl Guttman Krader UT Contributing Editor Men in the United States have about a 1 in 7 lifetime chance of being diagnosed with prostate cancer, but many of these men will have indolent disease that has a low likelihood of ever causing clinical symptoms. Now a number of diagnostic modalities are available that provide prognostic information to aid urologists and patients with decisions about biopsy and management of prostate cancer. These tools include a variety of urine-, blood-, and tissue-based laboratory tests assaying various prostate cancer biomarkers along with magnetic resonance imaging (MRI), with many additional diagnostics emerging. In this article, urologists Scott E. Eggener, MD, and Stacy Loeb, MD, MSc, discuss the current applications for biomarkers and MRI, their impact on clinical practice, and future developments. Biomarker tests The biomarkers for prostate cancer with direct relevance to practicing urologists fall into several categories defined by the clinical scenario where they are used. They include tests for early detection to help the decision about having an KEY TAKEAWAYS Percent free PSA, 4Kscore, and phi can help men with an elevated PSA decide about undergoing biopsy or repeat biopsy. PCA3 and ConfirmMDx are additional options for men who have had at least one prior negative biopsy and are thought to be at higher risk. Urologists should consider MRI in men with a previous negative biopsy while taking into account quality of the test and expertise of the radiologist. MiPS and SelectMDx are other promising new markers that may help with biopsy decisions. Prolaris, Oncotype DX, and Decipher Score analyzing genomic markers provide risk stratification that can help select patients with clinically localized prostate cancer decide on management. initial or repeat biopsy after a previously negative result, tests providing information for risk stratification to guide initial management decisions in men newly diagnosed with clinically localized prostate cancer, and tests to help inform decisions about adjuvant radiation following radical prostatectomy. Not discussed in this article are prostate cancer biomarker tests used by medical oncologists to help with targeted treatment selection for existing metastatic disease. The NCCN Guidelines Version for Prostate Cancer Early Detection recommends consideration of percent free PSA, Prostate Health Index (phi), and 4Kscore in men with a PSA >3.0 ng/ml who have not yet had a biopsy. Mi-Prostate Score (MiPS) and SelectMDx are other new tests that can be used to assist the decision of whether or not to perform an initial biopsy in men with an elevated PSA. The current NCCN guidelines state percent free PSA, phi, 4Kscore, PCA3, and ConfirmMDx may also be considered for men who have had at least one prior negative biopsy and are thought to be at higher risk. SelectMDx, MiPS, or MRI of the prostate can also be used in this setting. A greater percent of PSA circulating in the free form indicates a lower risk of prostate cancer and aggressive disease. The percent free PSA test has been around since the 1990s and is a widely available second-line testing option. phi is a blood test that reports probability of having prostate cancer detected on biopsy based on measurement of total, free, and p2psa ([-2]proPSA). Nomograms are available combining phi with other risk factors to predict aggressive prostate cancer. Continued on page S8 INSIDE Immunotherapy for GU cancer S10 Bladder cancer biomarkers S14 Guidelines update S18 Cover: Magic mine/shutterstock.com

3 For previously treated locally advanced or metastatic urothelial carcinoma TECENTRIQ : THE FIRST AND ONLY FDA-APPROVED ANTI-PDL1 CANCER IMMUNOTHERAPY THE NEXT ERA OF TREATMENT Indication TECENTRIQ (atezolizumab) is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who: Have disease progression during or following platinum-containing chemotherapy Have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Important Safety Information Serious Adverse Reactions Please refer to the full Prescribing Information for important dose management information specific to adverse reactions. Immune-Related Pneumonitis Immune-mediated pneumonitis or interstitial lung disease, including 2 fatal cases, occurred with TECENTRIQ treatment Across clinical trials, 2.6% of patients developed pneumonitis Monitor patients for signs with radiographic imaging and symptoms of pneumonitis. Administer steroids for Grade 2 pneumonitis. Withhold TECENTRIQ until resolution of Grade 2 pneumonitis. Permanently discontinue for Grade 3 or 4 pneumonitis Immune-Related Hepatitis Immune-mediated hepatitis, including a fatal case, and liver test abnormalities have occurred with TECENTRIQ treatment Across clinical trials, Grade 3 or 4 elevation occurred in ALT (2.5%), AST (2.3%), and total bilirubin (1.6%). In patients with urothelial carcinoma (UC), immune-mediated hepatitis occurred in 1.3% of patients Monitor patients for signs and symptoms of hepatitis. Monitor AST, ALT, and bilirubin prior to and periodically during treatment Administer corticosteroids for Grade 2 transaminase elevations, with or without concomitant elevation in total bilirubin. Withhold TECENTRIQ for Grade 2 and permanently discontinue for Grade 3 or 4 immune-mediated hepatitis PD-L1=programmed death-ligand 1. Please see additional Important Safety Information and Brief Summary of Prescribing Information on adjacent pages.

4 TECENTRIQ DELIVERED DURABLE RESPONSES Durable responses demonstrated across all patients (median follow-up: 14.4 months) 1 ORR DoR (14.4-month median follow-up) 14.8% ORR (n=46/310*; 95% CI, 11.1, 19.3) 5.5% 9.4% CR PR MEDIAN DoR NOT REACHED (range: 2.1+, 13.8+) 22% ORR in patients with disease progression following prior neoadjuvant or adjuvant therapy (n=13/59; 95% CI, 12.3, 34.7) PD-L1 testing is not required to prescribe TECENTRIQ IMvigor210 was a Phase II, multicenter, open-label, 2-cohort trial that included a cohort of 310 patients with locally advanced or metastatic urothelial carcinoma who had disease progression during or following a platinum-containing regimen, or within 12 months of treatment with a platinum-containing neoadjuvant or adjuvant regimen. Patients were treated with TECENTRIQ 1200 mg IV q3w. Major efficacy endpoints included ORR as assessed by IRF using RECIST v1.1 and DoR. 1,2 CI=confidence interval; CR=complete response; DoR=duration of response; IRF=independent review facility; IV=intravenous; ORR=objective response rate; PR=partial response; q3w=every 3 weeks; RECIST=Response Evaluation Criteria In Solid Tumors. + denotes censored value. *Number of IRF-assessed confirmed responders. Important Safety Information (cont d) Immune-Related Colitis Immune-mediated colitis or diarrhea, including a fatal case of diarrheaassociated renal failure, have occurred with TECENTRIQ treatment Across clinical trials, colitis or diarrhea occurred in 19.7% of patients. In UC, immune-mediated colitis or diarrhea occurred in 0.8% of patients Monitor patients for signs and symptoms of diarrhea or colitis. Withhold TECENTRIQ for Grade 2 or Grade 3 diarrhea or colitis. Permanently discontinue for Grade 4 diarrhea or colitis Immune-Related Endocrinopathies Immune-related thyroid disorders, adrenal insufficiency, hypophysitis, and type 1 diabetes mellitus, including diabetic ketoacidosis, have occurred in patients receiving TECENTRIQ. Monitor patients for clinical signs and symptoms of endocrinopathies Across clinical trials hypo- and hyperthyroidism occurred in 3.9% and 1.0% of patients, respectively. For symptomatic hypothyroidism, withhold TECENTRIQ and initiate hormone replacement as needed. Manage isolated hypothyroidism with replacement therapy and without corticosteroids. For symptomatic hyperthyroidism, withhold TECENTRIQ and initiate an anti-thyroid drug as needed Across clinical trials, adrenal insufficiency occurred in 0.4% of patients. For symptomatic adrenal insufficiency, withhold TECENTRIQ and administer corticosteroids 2016 Genentech USA, Inc. All rights reserved. PDL/101215/0083 Hypophysitis occurred in 0.2% of patients with UC. Administer corticosteroids and hormone replacement as clinically indicated. Withhold for Grade 2 or Grade 3, and permanently discontinue for Grade 4 hypophysitis New onset diabetes with ketoacidosis occurred in patients. Diabetes mellitus without an alternative etiology occurred in 0.2% of patients with urothelial carcinoma. Initiate treatment with insulin for type 1 diabetes mellitus. For Grade 3 hyperglycemia (fasting glucose > mg/dl), withhold TECENTRIQ Other Immune-Related Adverse Reactions Other immune-related adverse reactions, including meningoencephalitis, myasthenic syndrome/myasthenia gravis, Guillain-Barré syndrome, ocular inflammatory toxicity, and pancreatitis, including increases in serum amylase and lipase levels, have occurred in 1.0% of patients treated with TECENTRIQ Symptomatic pancreatitis without an alternative etiology occurred in 0.1% of patients across clinical trials Monitor patients for clinical signs and symptoms of meningitis or encephalitis, as well as symptoms of motor and sensory neuropathy. Permanently discontinue TECENTRIQ for any grade of meningitis or encephalitis or any grade of myasthenic syndrome/myasthenia gravis or Guillain-Barré syndrome Monitor patients for signs and symptoms of acute pancreatitis. Withhold TECENTRIQ for Grade 3 serum amylase or lipase levels (>2.0 ULN), or Grade 2 or 3 pancreatitis. Permanently discontinue for Grade 4 or any grade of recurrent pancreatitis

5 ONE FIXED DOSE, ONCE EVERY 3 WEEKS Recommended dosing and administration 1 IF TOLERATED FIXED DOSE 1200 MG IV 60-MINUTE INITIAL INFUSION 30-MINUTE SUBSEQUENT INFUSIONS EVERY 3 WEEKS UNTIL DISEASE PROGRESSION OR UNACCEPTABLE TOXICITY Do not administer as an IV push or bolus Do not co-administer other drugs through the same IV line Most common adverse events 1 The most common adverse events ( 20%) included fatigue (52%), decreased appetite (26%), nausea (25%), urinary tract infection (22%), pyrexia (21%), and constipation (21%) Incidence of grade 3 to 4 adverse events included fatigue (6%), decreased appetite (1%), nausea (2%), urinary tract infection (9%), pyrexia (1%), and constipation (0.3%) Learn more at TECENTRIQ.com/info Important Safety Information (cont d) Infection Severe infections, including sepsis, herpes encephalitis, and mycobacterial infection leading to retroperitoneal hemorrhage occurred in patients receiving TECENTRIQ Across clinical trials, infections occurred in 38.4% of patients In urothelial carcinoma, infection occurred in 37.7% of patients. Grade 3 or 4 infection occurred in 11.5% of patients, while 3 patients died due to infections. Urinary tract infections were the most common cause of Grade 3 or higher infection, occurring in 7.1% of patients Monitor patients for signs and symptoms of infection and treat with antibiotics for suspected or confirmed bacterial infections. Withhold TECENTRIQ for Grade 3 infection Infusion-Related Reactions Severe infusion reactions have occurred in patients in clinical trials of TECENTRIQ. Infusion-related reactions occurred in 1.7% in UC Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions. Permanently discontinue TECENTRIQ in patients with Grade 3 or 4 infusion reactions Embryo-Fetal Toxicity Based on its mechanism of action, TECENTRIQ can cause fetal harm when administered to a pregnant woman. Advise pregnant women or women planning to become pregnant of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with TECENTRIQ and for at least 5 months after the last dose of TECENTRIQ Nursing Mothers Because of the potential for serious adverse reactions in breastfed infants from TECENTRIQ, advise female patients not to breastfeed while taking TECENTRIQ and for at least 5 months after the last dose Most Common Adverse Reactions The most common adverse reactions (rate 20%) in UC included fatigue (52%), decreased appetite (26%), nausea (25%), urinary tract infection (22%), pyrexia (21%), and constipation (21%). You may report side effects to the FDA at FDA-1088 or You may also report side effects to Genentech at Please see Brief Summary of Prescribing Information on adjacent pages. References: 1. TECENTRIQ Prescribing Information. Genentech, Inc. May US National Institutes of Health. ClinicalTrials.gov. ct2/show/nct Accessed August 26, 2016.

6 TECENTRIQ (atezolizumab) Initial U.S. Approval: 2016 This is a brief summary of information about TECENTRIQ. Before prescribing, please see full Prescribing Information. 1 INDICATIONS AND USAGE TECENTRIQ (atezolizumab) is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who: Have disease progression during or following platinum-containing chemotherapy Have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinumcontaining chemotherapy This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials [see Clinical Studies (14.1)]. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Immune-Related Pneumonitis Immune-mediated pneumonitis or interstitial lung disease, defined as requiring use of corticosteroids and with no clear alternate etiology, occurred in patients receiving TECENTRIQ. Across clinical trials, 2.6% (51/1978) of patients developed pneumonitis. Fatal pneumonitis occurred in two patients. In 523 patients with urothelial carcinoma who received TECENTRIQ, pneumonitis occurred in 6 (1.1%) patients. Of these patients, there was one patient with fatal pneumonitis, one patient with Grade 3, three patients with Grade 2, and one patient with Grade 1 pneumonitis. TECENTRIQ was held in all cases and five patients were treated with corticosteroids. Pneumonitis resolved in three patients. The median time to onset was 2.6 months (range: 15 days to 4.2 months). The median duration was 15 days (range: 6 days to 3.1+ months). Monitor patients for signs with radiographic imaging and symptoms of pneumonitis. Administer steroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for Grade 2 or greater pneumonitis, followed by corticosteroid taper. Withhold TECENTRIQ until resolution for Grade 2 pneumonitis. Permanently discontinue TECENTRIQ for Grade 3 or 4 pneumonitis [see Dosage and Administration (2.2)]. 5.2 Immune-Related Hepatitis Immune-mediated hepatitis, defined as requiring use of corticosteroids and with no clear alternate etiology, occurred in patients receiving TECENTRIQ. Liver test abnormalities occurred in patients who received TECENTRIQ. Across clinical trials (n=1978), Grade 3 or 4 elevation occurred in ALT (2.5%), AST (2.3%), and total bilirubin (1.6%). In patients with urothelial carcinoma (n=523) Grade 3 or 4 elevation occurred in ALT (2.5%), AST (2.5%), and total bilirubin (2.1%). Immune-mediated hepatitis occurred in 1.3% of patients. Of these cases, one patient died from hepatitis, five patients had Grade 3, and one patient had Grade 2 hepatitis. The median time to onset was 1.1 months (range: 0.4 to 7.7 months). Of the seven patients with immune-mediated hepatitis, TECENTRIQ was temporarily interrupted in four patients; none of these patients developed recurrence of hepatitis after resuming TECENTRIQ. Monitor patients for signs and symptoms of hepatitis. Monitor AST, ALT, and bilirubin prior to and periodically during treatment with TECENTRIQ. Administer corticosteroids at a dose of 1-2 mg/kg/day prednisone equivalents for Grade 2 or greater transaminase elevations, with or without concomitant elevation in total bilirubin, followed by corticosteroid taper. Withhold TECENTRIQ for Grade 2 and permanently discontinue TECENTRIQ for Grade 3 or 4 immune-mediated hepatitis [see Dosage and Administration (2.2) and Adverse Reactions (6.1)]. 5.3 Immune-Related Colitis Immune-mediated colitis or diarrhea, defined as requiring use of corticosteroids and with no clear alternate etiology, occurred in patients receiving TECENTRIQ. Across clinical trials, colitis or diarrhea occurred in 19.7% (389/1978) of all patients and in 18.7% (98/523) of patients with urothelial carcinoma. Ten patients (1.9%) developed Grade 3 or 4 diarrhea. Four patients (0.8%) had immune-mediated colitis or diarrhea with a median time to onset of 1.7 months (range: 1.1 to 3.1 months). Immune-mediated colitis resolved with corticosteroid administration in three of these patients, while the other patient died without resolution of colitis in the setting of diarrhea-associated renal failure. Monitor patients for signs and symptoms of diarrhea or colitis. Withhold treatment with TECENTRIQ for Grade 2 diarrhea or colitis. If symptoms persist for longer than 5 days or recur, administer 1 2 mg/kg prednisone or equivalent per day. Withhold treatment with TECENTRIQ for Grade 3 diarrhea or colitis. Treat with IV methylprednisolone 1 2 mg/kg per day and convert to oral steroids once the patient has improved. For both Grade 2 and Grade 3 diarrhea or colitis, when symptoms improve to Grade 0 or Grade 1, taper steroids over 1 month. Resume treatment with TECENTRIQ if the event improves to Grade 0 or 1 within 12 weeks and corticosteroids have been reduced to the equivalent of 10 mg oral prednisone per day. Permanently discontinue TECENTRIQ for Grade 4 diarrhea or colitis [see Dosage and Administration (2.2) and Adverse Reactions (6.1)]. 5.4 Immune-Related Endocrinopathies Immune-related thyroid disorders, adrenal insufficiency, hypophysitis, and type 1 diabetes mellitus, including diabetic ketoacidosis, have occurred in patients receiving TECENTRIQ. Monitor patients for clinical signs and symptoms of endocrinopathies. Hypophysitis Hypophysitis occurred in 0.2% (1/523) of patients with urothelial cancer receiving TECENTRIQ. Monitor for signs and symptoms of hypophysitis. Administer corticosteroids and hormone replacement as clinically indicated. Withhold TECENTRIQ for Grade 2 or Grade 3 and permanently discontinue for Grade 4 hypophysitis [see Dosage and Administration (2.2) and Adverse Reactions (6.1)]. Thyroid Disorders Thyroid function was assessed routinely only at baseline and the end of the study. Across clinical trials, hypothyroidism occurred in 3.9% (77/1978) of patients and in 2.5% (13/523) of patients with urothelial carcinoma. One patient had Grade 3 and twelve patients had Grade 1 2 hypothyroidism. The median time to first onset was 5.4 months (range: 21 days to 11.3 months). Thyroid stimulating hormone (TSH) was elevated and above the patient s baseline in 16% (21/131) of patients with a follow-up measurement. Hyperthyroidism occurred in 1.0% (20/1978) of patients across clinical trials and in 0.6% (3/523) of patients with urothelial carcinoma. Of the three urothelial carcinoma patients, one patient had Grade 2 and two patients had Grade 1 hyperthyroidism. The median time to onset was 3.2 months (range: 1.4 to 5.8 months). TSH was decreased and below the patient s baseline in 3.8% (5/131) of patients with a follow-up measurement. Monitor thyroid function prior to and periodically during treatment with TECENTRIQ. Asymptomatic patients with abnormal thyroid function tests can receive TECENTRIQ. For symptomatic hypothyroidism, withhold TECENTRIQ and initiate thyroid hormone replacement as needed. Manage isolated hypothyroidism with replacement therapy and without corticosteroids. For symptomatic hyperthyroidism, withhold TECENTRIQ and initiate an anti-thyroid drug as needed. Resume treatment with TECENTRIQ when symptoms of hypothyroidism or hyperthyroidism are controlled and thyroid function is improving [see Dosage and Administration (2.2) and Adverse Reactions (6.1)]. Adrenal Insufficiency Adrenal insufficiency occurred in 0.4% (7/1978) of patients across clinical trials, including two patients with Grade 3, four patients with Grade 2, and one patient with Grade 1. Adrenal insufficiency resolved in two patients. For symptomatic adrenal insufficiency, withhold TECENTRIQ and administer methylprednisolone 1 2 mg/kg per day IV followed by oral prednisone 1 2 mg/kg per day or equivalent once symptoms improve. Start steroid taper when symptoms improve to Grade 1 and taper steroids over 1 month. Resume treatment with TECENTRIQ if the event improves to Grade 1 within 12 weeks and corticosteroids have been reduced to the equivalent of 10 mg oral prednisone per day and the patient is stable on replacement therapy, if required [see Dosage and Administration (2.2) and Adverse Reactions (6.1)]. Diabetes Mellitus New onset diabetes with ketoacidosis has occurred in patients receiving TECENTRIQ. Diabetes mellitus without an alternative etiology occurred in one (0.2%) patient with urothelial carcinoma. Initiate treatment with insulin for type 1 diabetes mellitus. For Grade 3 hyperglycemia (fasting glucose > mg/dl), withhold TECENTRIQ. Resume treatment with TECENTRIQ when metabolic control is achieved on insulin replacement therapy [see Dosage and Administration (2.2) and Adverse Reactions (6.1)]. 5.5 Other Immune-Related Adverse Reactions Other immune-related adverse reactions including meningoencephalitis, myasthenic syndrome/ myasthenia gravis, Guillain-Barré, ocular inflammatory toxicity, and pancreatitis, including increases in serum amylase and lipase levels, have occurred in 1.0% of patients treated with TECENTRIQ. Meningitis / Encephalitis Monitor patients for clinical signs and symptoms of meningitis or encephalitis. Permanently discontinue TECENTRIQ for any grade of meningitis or encephalitis. Treat with IV steroids (1 2 mg/kg/day methylprednisolone or equivalent) and convert to oral steroids (prednisone 60 mg/day or equivalent) once the patient has improved. When symptoms improve to Grade 1, taper steroids over 1 month [see Dosage and Administration (2.2) and Adverse Reactions (6.1)]. Motor and Sensory Neuropathy Monitor patients for symptoms of motor and sensory neuropathy. Permanently discontinue TECENTRIQ for any grade of myasthenic syndrome/myasthenia gravis or Guillain-Barré syndrome. Institute medical intervention as appropriate. Consider initiation of systemic corticosteroids at a dose of 1 2 mg/kg/day prednisone [see Dosage and Administration (2.2) and Adverse Reactions (6.1)]. Pancreatitis Symptomatic pancreatitis without an alternative etiology occurred in 0.1% (2/1978) of patients across clinical trials. Monitor patients for signs and symptoms of acute pancreatitis. Withhold TECENTRIQ for Grade 3 serum amylase or lipase levels (> 2.0 ULN), or Grade 2 or 3 pancreatitis. Treat with 1 2 mg/kg IV methylprednisolone or equivalent per day. Once symptoms improve, follow with 1 2 mg/kg of oral prednisone or equivalent per day. Resume treatment with TECENTRIQ if serum amylase and lipase levels improve to Grade 1 within 12 weeks, symptoms of pancreatitis have resolved, and corticosteroids have been reduced to 10 mg oral prednisone or equivalent per day. Permanently discontinue TECENTRIQ for Grade 4 or any grade of recurrent pancreatitis [see Dosage and Administration (2.2) and Adverse Reactions (6.1)]. 5.6 Infection Severe infections, including sepsis, herpes encephalitis, and mycobacterial infection leading to retroperitoneal hemorrhage occurred in patients receiving TECENTRIQ. Across clinical trials, infections occurred in 38.4% (759/1978) of patients. In 523 patients with urothelial carcinoma who received TECENTRIQ, infection occurred in 197 (37.7%) patients. Grade 3 or 4 infection occurred in 60 (11.5%) patients, while three patients died due to infections. Urinary tract infections were the most common cause of Grade 3 or higher infection, occurring in 37 (7.1%) patients. In a randomized trial in patients with non-small cell lung cancer, infections were more common in patients treated with TECENTRIQ (42%) compared with those treated with docetaxel (33%). Grade 3 or 4 infections occurred in 9.2% of patients treated with TECENTRIQ compared with 2.2% in patients treated with docetaxel. One patient (0.7%) treated with TECENTRIQ died due to infection, compared to two patients (1.5%) treated with docetaxel. Pneumonia was the most common cause of Grade 3 or higher infection, occurring in 6.3% of patients treated with TECENTRIQ. Monitor patients for signs and symptoms of infection and treat with antibiotics for suspected or confirmed bacterial infections. Withhold TECENTRIQ for Grade 3 infection [see Dosage and Administration (2.2) and Adverse Reactions (6.1)]. 5.7 Infusion-Related Reactions Severe infusion reactions have occurred in patients in clinical trials of TECENTRIQ. Infusion-related reactions occurred in 1.3% (25/1978) of patients across clinical trials and in 1.7% (9/523) of patients with urothelial carcinoma. Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions. Permanently discontinue TECENTRIQ in patients with Grade 3 or 4 infusion reactions [see Dosage and Administration (2.2) and Adverse Reactions (6.1)]. 5.8 Embryo-Fetal Toxicity Based on its mechanism of action, TECENTRIQ can cause fetal harm when administered to a pregnant woman. Animal studies have demonstrated that inhibition of the PD-L1/PD-1 pathway can lead to increased risk of immune-related rejection of the developing fetus resulting in fetal death. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TECENTRIQ and for at least 5 months after the last dose [see Use in Specific Populations (8.1, 8.3)]. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: Immune-Related Pneumonitis [see Warnings and Precautions (5.1)] Immune-Related Hepatitis [see Warnings and Precautions (5.2)] Immune-Related Colitis [see Warnings and Precautions (5.3)] Immune-Related Endocrinopathies [see Warnings and Precautions (5.4)] Other Immune-Related Adverse Reactions [see Warnings and Precautions (5.5)] Infection [see Warnings and Precautions (5.6)] Infusion-Related Reactions [see Warnings and Precautions (5.7)] 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. The data described in Table 1 reflects exposure to TECENTRIQ in Cohort 2 of Study 1. This cohort enrolled 310 patients in a single arm trial with locally advanced or metastatic urothelial carcinoma who had disease progression during or following at least one platinum-containing chemotherapy regimen or who had disease progression within 12 months of treatment with a platinum-containing neoadjuvant or adjuvant chemotherapy regimen [see Clinical Studies (14.1)]. Patients received 1200 mg of TECENTRIQ intravenously every 3 weeks until unacceptable toxicity or either radiographic or clinical progression. The median duration of exposure was 12.3 weeks (range: 0.1, 46 weeks). The most common adverse reactions ( 20%) were fatigue (52%), decreased appetite (26%), nausea (25%), urinary tract infection (22%), pyrexia (21%), and constipation (21%). The most

7 common Grade 3 4 adverse reactions ( 2%) were urinary tract infection, anemia, fatigue, dehydration, intestinal obstruction, urinary obstruction, hematuria, dyspnea, acute kidney injury, abdominal pain, venous thromboembolism, sepsis, and pneumonia. Three patients (0.9%) who were treated with TECENTRIQ experienced either sepsis, pneumonitis, or intestinal obstruction which led to death. TECENTRIQ was discontinued for adverse reactions in 3.2% (10/310) of the 310 patients. Sepsis led to discontinuation in 0.6% (2/310) of patients. Adverse reactions leading to interruption of TECENTRIQ occurred in 27% of patients; the most common (> 1%) were liver enzyme increase, urinary tract infection, diarrhea, fatigue, confusional state, urinary obstruction, pyrexia, dyspnea, venous thromboembolism, and pneumonitis. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions (> 2%) were urinary tract infection, hematuria, acute kidney injury, intestinal obstruction, pyrexia, venous thromboembolism, urinary obstruction, pneumonia, dyspnea, abdominal pain, sepsis, and confusional state. Table 1 summarizes the adverse reactions that occurred in 10% of patients while Table 2 summarizes Grade 3 4 selected laboratory abnormalities that occurred in 1% of patients treated with TECENTRIQ in Cohort 2 of Study 1. Table 1: All Grade Adverse Reactions in 10% of Patients with Urothelial Carcinoma in Study 1 TECENTRIQ N = 310 Adverse Reaction All Grades (%) Grades 3 4 (%) All Adverse Reactions Gastrointestinal Disorders Nausea 25 2 Constipation Diarrhea 18 1 Abdominal pain 17 4 Vomiting 17 1 General Disorders and Administration Fatigue 52 6 Pyrexia 21 1 Peripheral edema 18 1 Infections and Infestations Urinary tract infection 22 9 Metabolism and Nutrition Disorders Decreased appetite 26 1 Musculoskeletal and Connective Tissue Disorders Back/Neck pain 15 2 Arthralgia 14 1 Renal and urinary disorders Hematuria 14 3 Respiratory, Thoracic, and Mediastinal Disorders Dyspnea 16 4 Cough Skin and Subcutaneous Tissue Disorders Rash Pruritus Table 2: Grade 3 4 Laboratory Abnormalities in Patients with Urothelial Carcinoma in Study 1 in 1% of Patients Laboratory Test Grades 3 4 (%) Lymphopenia 10 Hyponatremia 10 Anemia 8 Hyperglycemia 5 Increased Alkaline phosphatase 4 Increased Creatinine 3 Increased ALT 2 Increased AST 2 Hypoalbuminemia Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. Among 275 patients in Study 1, 114 patients (41.5%) tested positive for treatment-emergent (treatment-induced or treatment-enhanced) anti-therapeutic antibodies (ATA) at one or more post-dose time points. In Study 1, the presence of ATAs did not appear to have a clinically significant impact on pharmacokinetics, safety or efficacy. Immunogenicity assay results are highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of incidence of ATAs to TECENTRIQ with the incidence of antibodies to other products may be misleading. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on its mechanism of action, TECENTRIQ can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on the use of TECENTRIQ in pregnant women. Animal studies have demonstrated that inhibition of the PD-L1/PD-1 pathway can lead to increased risk of immune-related rejection of the developing fetus resulting in fetal death [see Data]. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Animal reproduction studies have not been conducted with TECENTRIQ to evaluate its effect on reproduction and fetal development. A literature-based assessment of the effects on reproduction demonstrated that a central function of the PD-L1/PD-1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to a fetus. Blockage of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to a fetus and to result in an increase in fetal loss; therefore, potential risks of administering TECENTRIQ during pregnancy include increased rates of abortion or stillbirth. As reported in the literature, there were no malformations related to the blockade of PD-L1/PD-1 signaling in the offspring of these animals; however, immune-mediated disorders occurred in PD-1 and PD-L1 knockout mice. Based on its mechanism of action, fetal exposure to atezolizumab may increase the risk of developing immune-mediated disorders or altering the normal immune response. 8.2 Lactation Risk Summary There is no information regarding the presence of atezolizumab in human milk, the effects on the breastfed infant, or the effects on milk production. As human IgG is excreted in human milk, the potential for absorption and harm to the infant is unknown. Because of the potential for serious adverse reactions in breastfed infants from TECENTRIQ, advise a lactating woman not to breastfeed during treatment and for at least 5 months after the last dose. 8.3 Females and Males of Reproductive Potential Contraception Females Based on its mechanism of action, TECENTRIQ can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with TECENTRIQ and for at least 5 months following the last dose. Infertility Females Based on animal studies, TECENTRIQ may impair fertility in females of reproductive potential while receiving treatment [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use The safety and effectiveness of TECENTRIQ have not been established in pediatric patients. 8.5 Geriatric Use Of the 310 patients with urothelial carcinoma treated with TECENTRIQ in Study 1, 59% were 65 years or older. No overall differences in safety or efficacy were observed between patients 65 years of age and younger patients. 8.6 Renal Impairment Based on a population pharmacokinetic analysis, no dose adjustment of TECENTRIQ is recommended for patients with renal impairment [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment Based on a population pharmacokinetic analysis, no dose adjustment of TECENTRIQ is recommended for patients with mild hepatic impairment. TECENTRIQ has not been studied in patients with moderate or severe hepatic impairment [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE There is no information on overdose with TECENTRIQ. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Inform patients of the risk of immune-related adverse reactions that may require corticosteroid treatment and interruption or discontinuation of TECENTRIQ, including: Pneumonitis: Advise patients to contact their healthcare provider immediately for any new or worsening cough, chest pain, or shortness of breath [see Warnings and Precautions (5.1)]. Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, pain on the right side of abdomen, lethargy, or easy bruising or bleeding [see Warnings and Precautions (5.2)]. Colitis: Advise patients to contact their healthcare provider immediately for diarrhea or severe abdominal pain [see Warnings and Precautions (5.3)]. Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypophysitis, hyperthyroidism, hypothyroidism, adrenal insufficiency, or type 1 diabetes mellitus, including diabetic ketoacidosis [see Warnings and Precautions (5.4)] Meningoencephalitis, myasthenic syndrome/myasthenia gravis, and Guillain-Barré syndrome: Advise patients to contact their healthcare provider immediately for signs or symptoms of meningitis, myasthenic syndrome/myasthenia gravis, or Guillain-Barré syndrome [see Warnings and Precautions (5.5)]. Ocular Inflammatory Toxicity: Advise patients to contact their healthcare provider immediately for signs or symptoms of ocular inflammatory toxicity [see Warnings and Precautions (5.5)]. Pancreatitis: Advise patients to contact their healthcare provider immediately for signs and symptoms of pancreatitis [see Warnings and Precautions (5.5)]. Infection: Advise patients to contact their healthcare provider immediately for signs or symptoms of infection [see Warnings and Precautions (5.6)]. Infusion-Related Reactions: Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion-related reactions [see Warnings and Precautions (5.7)]. Rash: Advise patients to contact their healthcare provider immediately for signs or symptoms of rash [see Dosage and Administration (2.2)]. Embryo-Fetal Toxicity Advise female patients that TECENTRIQ can cause fetal harm. Instruct females of reproductive potential to use effective contraception during treatment and for at least 5 months after the last dose of TECENTRIQ [see Use in Specific Populations (8.1, 8.3)]. Lactation Advise female patients not to breastfeed while taking TECENTRIQ and for at least 5 months after the last dose [see Use in Specific Populations (8.2)]. TECENTRIQ (atezolizumab) Manufactured by: PDL/121615/0161 Genentech, Inc. Initial U.S. Approval: May 2016 A Member of the Roche Group 1 DNA Way TECENTRIQ is a trademark of Genentech, Inc. South San Francisco, CA Genentech, Inc.

8 S8 Focus on Urologic Cancers: Current advances, future directions APRIL 15, 2017 Urology Times SUPPLEMENT Continued from page S2 4Kscore, also a blood test, measures free, total, and intact PSA along with human kallikrein 2 and takes into account age, digital rectal exam results, and prior biopsy status to calculate a percent likelihood of finding high-grade (Gleason 7) cancer on biopsy. Prostate Cancer Antigen 3 (PCA3) is a urine test that assays for a noncoding, prostate tissue-specific RNA that is overexpressed in prostate cancer. It generates a score reflecting likelihood of a positive biopsy. MiPS analyzes serum PSA plus PCA3 and the TMPRSS2:ERG gene in urine. It provides a quantitative risk of having prostate cancer detected on biopsy and of having potentially aggressive prostate cancer detected on biopsy. SelectMDx is a urinary assay measuring mrna levels of two genetic biomarkers that are associated with increased probability for high-grade prostate cancer. It reports the likelihood of detecting prostate cancer on biopsy and the probability for high- versus lowgrade disease. ConfirmMDx is an epigenetic test that analyzes prostate biopsy tissue from a previous biopsy for prostate cancer-associated DNA methylation changes in three genes and addresses the possibility of sampling error and cancer in the prostate missed by the biopsy needle. For men diagnosed with prostate cancer who are deciding whether to choose treatment or active surveillance, there are three tissue-based tests available that can help inform management decisions. They are Prolaris, Oncotype DX, and Decipher Score. Prolaris analyzes 46 cell cycle progression genes and also takes into account clinical parameters. It reports probability of 10-year mortality with conservative management or biochemical recurrence risk following treatment. Oncotype DX analyzes 17 cancerrelated genes and generates a categorical result of risk for unfavorable pathology, defined as primary Gleason pattern 4 or higher or extracapsular extension. Decipher analyzes 22 genes corresponding to RNAs from coding and nonprotein-coding regions of the genome and gives a score relating to likelihood of developing metastasis within 5 years after surgery. Decipher can also be used to help inform decisions about adjuvant versus salvage radiation therapy following radical prostatectomy. Clinical impact Dr. Loeb, assistant professor of urology and population health at NYU School of Medicine, New York, said she considers the laboratory biomarkers that are used to refine initial biopsy decisions very helpful because they provide additional information and have higher specificity than total PSA. Undoubtedly, there are situations when the biomarkers are so powerful that it makes the decision relatively simple and easy. However, a significant proportion of men are left with the same uncertainty they had before the biomarker results were available. Scott E. Eggener, MD Dr. Eggener, who is associate professor of surgery at the University of Chicago Medicine, concurred. The introduction of PSA screening led to a dramatic reduction in the number of men dying from prostate cancer, but also a large number of men diagnosed with cancers unlikely to ever cause problems and unlikely to benefit from immediate treatment, he said. These new screening biomarkers outperform PSA as they capture all or nearly all cancers that are destined to cause problems while limiting the proportion of men who undergo biopsy. Dr. Eggener noted that biomarker testing has also been helpful for limiting unnecessary repeat biopsies. Whereas in the past, biopsy would be done routinely in a patient with a previous negative biopsy and ongoing clinical suspicion for prostate cancer, these newer biomarker tests provide risk stratification that can help determine if repeat biopsy is warranted, he said. Even though there is strong scientific rationale underlying all of the biomarker tests and solid clinical data to support their use, there are economic challenges for their integration into clinical practice, Dr. Eggener said. If the biomarker tests were cheap and easy, then they would be considered for nearly every patient. But such routine use does not seem appropriate because some of these tests are expensive and for many patients the results may not influence the decision one way or another, he said. Undoubtedly, there are situations when the biomarkers are so powerful that it makes the decision relatively simple and easy. However, a significant proportion of men are left with the same uncertainty they had before the biomarker results were available. Individual differences in risk tolerance help explain why the biomarker tests do not have a more definitive influence on management decisions, said Dr. Eggener, offering the following example to illustrate this point: A healthy 60-year-old man with a normal prostate exam and no family his-

9 Urology Times SUPPLEMENT APRIL 15, 2017 Focus on Urologic Cancers: Current advances, future directions S9 tory of prostate cancer has a PSA of 5.0 ng/ml. The patient is told the probability of finding prostate cancer on biopsy is probably 30% to 40%, and the likelihood of finding high-risk disease is significantly lower. The 4Kscore is ordered. If the result shows the man has a 1% chance of high-grade disease, he would probably be confident foregoing biopsy while he probably would not hesitate to choose biopsy if the 4Kscore indicated a 60% chance of finding high-grade cancer. However, the threshold at which an individual might choose or decline biopsy will vary, Dr. Eggener said. When the 4Kscore shows there is a 7% chance of having high-grade prostate cancer, some men will definitely want a biopsy, some will be certain they do not need it, and others will still hem and haw. Role of MRI MRI to identify suspicious areas in the prostate is another option for supplementing decisions on whether to repeat a biopsy. According to a 2016 joint consensus statement from the AUA and Society of Abdominal Radiology, MRI should be strongly considered in a patient who is undergoing a repeat biopsy because of persistent clinical suspicion for prostate cancer. However, the decision whether to perform MRI must also take into account the results of other biomarkers, cost, and the availability of high-quality MRI images and interpretation. Dr. Eggener, who was a member of the workgroup that developed the consensus statement, noted there are numerous studies showing the value of prostate MRI and MRI-targeted cores for improving the detection of clinically significant disease. In referring patients for MRI, however, urologists must keep in mind that high-quality MRI and MRI interpretation is essential to optimize the value of the information. When it comes to prostate imaging, an MRI is not an MRI is not an MRI. Quality of the imaging depends on the quality of the equipment, how the test is done, and the experience and expertise of For a patient who has a rising PSA with a previous negative biopsy, MRI along with blood, urine, and tissue tests are all options, but we don t know which should come first and how best to integrate the markers with MRI. Stacy Loeb, MD, MSc the interpreting radiologist. Many centers have looked at their targeted biopsy results and published data for external review. An overwhelming majority of centers that do MRI of the prostate, however, do not know their internal quality and outcomes, Dr. Eggener said. Dr. Loeb noted that at NYU Langone, MRI is used routinely to provide a roadmap for targeting suspicious areas in men undergoing biopsy. She described its role as transformative, but she also cautioned that urologists need to consider the quality of the test and whether the institution where the MRI will be done has a quality assurance program for data tracking. MRI is also being used fairly often to guide repeat biopsy in men with favorable-risk prostate cancer who are considering active surveillance, with data showing it improves detection of more aggressive cancers that might exclude a man from proceeding with active surveillance. In addition, some data suggest a role for MRI prior to initial biopsy. Ongoing clinical trials will determine whether the use of MRI prior to considering a first biopsy is worthwhile. Currently it is not standard of care and should not be done routinely, Dr. Eggener said. Future tools and further insights Research to develop additional biomarkers for prostate cancer is continuing. The ExoDx Prostate IntelliScore, a novel urine exosome gene expression assay, is a newer test demonstrating utility for identifying high-grade prostate cancer. The Stockholm-3 Model (STHLM3) has shown promise for helping men to decide whether or not to undergo biopsy. It combines six plasma protein biomarkers, genetic polymorphisms, and clinical variables to estimate the risk of a Gleason Score 7 prostate cancer on biopsy. Looking ahead, Dr. Loeb said she hopes growing experience and forthcoming data from clinical studies will provide insights for refining biomarker options in various clinical scenarios and in what order they might be done. For a patient who has a rising PSA with a previous negative biopsy, MRI along with blood, urine, and tissue tests are all options, but we don t know which should come first and how best to integrate the markers with MRI, she explained. She pointed out there have also been very few head-to-head studies comparing the markers. Results from head-tohead studies show the phi test and 4Kscore have similar performance, and phi is better than PCA3 for predicting clinically significant disease. However, there is a lack of evidence about the relative performance of most other biomarkers. Hopefully we will see results from more comparative studies in the future that will help better guide our care, Dr. Loeb said. UT Disclosures: Dr. Eggener has been a consultant, speaker, or investigator for OPKO, MDxHealth, Myriad Genetics, and Genomic Health. Dr. Loeb has received honoraria from Boehringer Ingelheim and MDxHealth, consulting fees from Lilly, and travel reimbursement from Minomic.

10 S10 Focus on Urologic Cancers: Current advances, future directions APRIL 15, 2017 Urology Times SUPPLEMENT Immunotherapy for GU Ca: A primer for urologists Modern agents show impressive survival in advanced RCC, bladder cancer KEY TAKEAWAYS Immunotherapies are approved for the treatment of the three major genitourinary cancers prostate, kidney, and bladder based on results from clinical trials demonstrating an overall survival. Sipuleucel-T, a cell-based vaccine, is approved for treatment of men with asymptomatic or minimally symptomatic castration-resistant prostate cancer. Anti-PD-1/PD-L1 checkpoint inhibitors that are licensed for treatment of metastatic renal cell carcinoma and/or metastatic or advanced urothelial carcinoma have indications for use as secondline therapies. Immunotherapy agents appear to be more effective when the tumor burden is lower. Many other studies of immunotherapy are ongoing and include trials evaluating: investigational agents targeting other checkpoints or pathways regulating immunotherapy resistance; combination approaches using immunotherapy; sequencing of immunotherapy; and markers for predicting response. By Cheryl Guttman Krader UT Contributing Editor Immunotherapy for genitourinary malignancies is not new, as highdose interleukin-2 (IL-2 [Proleukin]) for metastatic renal cell carcinoma (mrcc) and intravesical bacillus Calmette-Guérin for high-grade bladder cancer have been used since the 1990s. However, the modern era of immunotherapy for bladder, renal, and prostate cancer began in 2010 with the approval of sipuleucel-t (Provenge), the autologous, dendritic cell-based vaccine for treatment of asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mcrpc), and it is a rapidly evolving landscape. Since then, multiple checkpoint inhibitors (CPIs) have been approved for mrcc and metastatic urothelial carcinoma (UC), and numerous trials of immunotherapy for prostate cancer, UC, and RCC are ongoing. This article discusses the current status and potential future developments in immunotherapy for genitourinary malignancies with insights from urologic oncology specialists Hyung L. Kim, MD, and Daniel P. Petrylak, MD. Mechanism of action Sipuleucel-T, which is the first therapeutic cancer vaccine approved by the FDA, stimulates an anti-tumor T-cell response using the patient s own antigen-presenting cells that are removed, activated, and educated against tumor antigen ex vivo, and then reinfused. Rather than inducing an immune response, CPIs release inhibitory mechanisms and restore the body s natural T-cell-mediated antitumor response. The T-cell-mediated immune response is regulated by a system involving stimulatory and inhibitory molecules. The inhibitory molecules, which are known as immune checkpoints, regulate activation of cytotoxic lymphocytes and their effector function to maintain selftolerance and minimize damage to normal collateral tissue during an immune response. The development of CPI immunotherapy for cancer was initiated by the finding that some tumors highly express immune checkpoint molecules. The two CPIs currently approved for treatment of genitourinary cancers, The development of checkpoint inhibitor immunotherapy was initiated by the finding that some tumors highly express immune checkpoint molecules.

11 Urology Times SUPPLEMENT APRIL 15, 2017 Focus on Urologic Cancers: Current advances, future directions S11 nivolumab (Opdivo) and atezolizumab (Tecentriq), are monoclonal antibodies targeting the programmed death receptor-1 (PD-1) protein that is expressed on T cells or its ligand, programmed deathligand 1 (PD-L1). Nivolumab, which targets PD-1, was approved in 2015 for patients with mrcc who progressed on prior anti-angiogenic therapy with an anti-vegfr TKI agent. In February 2017, nivolumab received FDA approval for use as second-line therapy for patients with locally advanced or metastatic UC. Atezolizumab is an anti-pd-l1 antibody that was approved in 2016 for use as second-line therapy in patients with locally advanced or metastatic UC. A February 2017 article published online in the New England Journal of Medicine reported positive results from the randomized, phase III KEYNOTE-045 clinical trial that investigated the anti- PD-1 antibody pembrolizumab (Keytruda) as second-line therapy in patients with platinum-refractory advanced UC. Compared with the control, which was standard of care treatment using the investigator s choice of chemotherapy, pembrolizumab significantly improved median overall survival and was associated with a lower rate of treatmentrelated adverse events. The objective response rate was also significantly higher with pembrolizumab and the responses were more durable. Compared with vaccines that work by pressing the accelerator on the immune system, the CPIs work by releasing the brakes on the immune system. CPIs have produced some very exciting results in terms of improving overall survival and producing durable responses in patients with advanced renal and bladder cancer, said Dr. Kim, co-medical director of the Urologic Oncology Center, Cedars-Sinai, Los Angeles. Not only can the CPIs shrink the tumor, but it has been suggested that immunotherapy can alter the long-term growth kinetics. In other words, tumor growth may occur at a slower rate, and that too can translate into improved survival. Dr. Kim also pointed out some unique pharmacodynamics characteristics of the immunotherapies. For example, improved survival with sipuleucel-t is not accompanied by a PSA response, and early imaging in patients with UC or RCC treated with a CPI may show the tumor size is increased. However, the change may not be a sign of tumor progression. Instead, it may represent a pseudoresponse in which immune cells have infiltrated the tumor, Dr. Kim explained. In addition, whereas the effect of chemotherapy persists only as long as the drug is in the body, the anti-tumor effect of immunotherapy may continue after the treatment is stopped, mediated by the activity of memory T cells. Safety The modern immunotherapy agents have a different and better safety profile than that of chemotherapy and with IL-2. Interleukin-2 has good clinical activity as treatment for mrcc in selected patients, particularly those with pulmonary metastases, but it can be fairly toxic with the potential to cause shock and hypotension, said Dr. Petrylak, professor of medicine and urology, Yale School of Medicine, New Haven, CT. Among the immunotherapy agents approved for genitourinary malignancies, sipuleucel-t is probably the best tolerated. Its most common adverse events are chills, fatigue, fever, back pain, nausea, joint ache, and headache. The adverse events most commonly associated with CPIs arise from activation of the host immune system and include immune-mediated colitis, dermatitis, hepatotoxicity, hypophysitis, and hypothyroidism. With prompt recognition and timely management using immunosuppression and temporary dose modification or treatment interruption, Checkpoint inhibitors have produced some very exciting results in terms of improving overall survival and producing durable responses in patients with advanced renal and bladder cancer. Hyung L. Kim, MD the severity of these toxicities can be limited, and they are usually reversible. It is important to monitor patients for the immune-related adverse events, but it is interesting that some studies of immunotherapy found that development of autoimmune toxicity corresponded with a better anti-tumor response, Dr. Kim said. Adverse events associated with the CPIs targeting the PD-1/PD-L1 axis appear to be less severe than those occurring with anti-ctla-4 antibodies. Future directions Immunotherapy for the genitourinary cancers is a very active area of research. For prostate cancer, the investigational pipeline of immunotherapies includes other therapeutic vaccines, and CPIs are also being studied in clinical trials. The relative lag in development of CPI treatment for prostate cancer may be explained in part by an early finding that PD-L1 was not highly expressed on CRPC specimens. Therefore, it was reasoned that antibodies targeting the PD-1/PD-L1 axis would not be effec- Continued on page S12

12 S12 Focus on Urologic Cancers: Current advances, future directions APRIL 15, 2017 Urology Times SUPPLEMENT Continued from page S11 tive, said Dr. Petrylak. In an early pilot study investigating nivolumab as treatment for mcrpc, there were no objective responses observed among the 17 enrolled patients who were all heavily pretreated. The commercially available CTLA-4 antibody, ipilimumab (Yervoy), was also investigated as treatment for mcrpc in two phase III trials, one enrolling patients prior to docetaxel (Taxotere) As second-line treatment for bladder cancer, immunotherapy has survival benefits compared with chemotherapy. Now, ongoing trials are comparing these two categories as front-line therapy. Daniel P. Petrylak, MD and the other after docetaxel failure, but no survival benefit was seen. In a post hoc analysis in the post-docetaxel chemotherapy trial, however, improved survival was seen with ipilimumab versus placebo in men who had boney, non-visceral metastases. Benefit was also observed in men with enzalutamide (XTANDI)-resistant mcrpc in a study investigating pembrolizumab, which is an anti-pd-1 antibody like nivolumab. Upregulation of PD-L1 expression by enzalutamide is one possible explanation for the antitumor activity that was observed with pembrolizumab, Dr. Petrylak said. Ongoing trials for mcrpc are investigating CPIs as single agents and in combination with available treatments (eg, radium 223 [Xofigo] or enzalutamide). There are also trials evaluating sipuleucel-t combined with approved drugs (eg, abiraterone acetate [Zytiga], enzalutamide, radium 223) or with a CPI. Similarly, studies are evaluating a CPI combined with agents from another therapeutic class (eg, chemotherapy, investigational molecules targeting pathways regulating immunotherapy resistance, targeted small molecules) as treatment for UC and RCC. Studies of combination approaches using immunotherapy for UC and RCC include those exploring what appears to be an interesting interplay between angiogenesis and immunotherapy, Dr. Petrylak said. Combinations of CPIs that target different checkpoint axes are also being investigated for mrcc and prostate cancer. The combination of ipilimumab and nivolumab is already approved for the treatment of metastatic melanoma, Dr. Kim said. CPIs targeting novel checkpoints, such as lymphocyte activation gene- 3, are also in clinical trials for UC and RCC. In addition, ongoing research with the available immunotherapies for genitourinary malignancies is examining genomic and other potential predictors for response. Sequencing and earlier use Other studies are investigating optimal sequencing of immunotherapy and other treatments. The question of the preferred sequence of agents for treatment of patients with minimally or asymptomatic mcrpc was addressed by a consensus panel of members of the Society for Immunotherapy of Cancer, of which Dr. Petrylak was a member. Based on a review of the available evidence, nearly all (90%) of the panel members recommended using sipuleucel-t before an androgen receptor-targeted agent. They were unanimous in recommending the of sipuleucel-t or an androgen receptortargeted agent prior to radium and chemotherapy. A role for immunotherapy earlier in the disease course is also an area of research interest. As second-line treatment for bladder cancer, immunotherapy has survival benefits compared with chemotherapy. Now, ongoing trials are comparing these two categories as front-line therapy, said Dr. Petrylak. There is good rationale for investigating earlier use of immunotherapy, as available evidence shows that it tends to be more effective when the tumor burden is lower. This phenomenon may be explained by the fact that the tumor itself causes immune suppression, Dr. Kim said. We have entered into an exciting time when there is a whole new class of therapies available for patients who develop metastatic disease, he said. The next step will be testing them as neoadjuvant and adjuvant therapies for patients with high-risk localized disease, and the studies of neoadjuvant treatment will need to determine whether preoperative use of immunotherapy creates any safety issues for subsequent surgery. Dr. Kim noted that while immunotherapy for genitourinary cancers is currently in the realm of medical oncologists, urologists should be familiar with these agents and stay tuned for results from clinical trials investigating them as earlier intervention. UT Disclosures: Dr. Kim holds a patent on a novel approach for checkpoint inhibition. Dr. Petrylak has received consultant fees from Bayer, Bellicum, Dendreon, Sanofi, Johnson & Johnson, Exelixis, Ferring, Millenium, Medivation, Pfizer, and Roche Laboratories. He has received grant support from Oncogenix, Progenics, Johnson & Johnson, Merck, Millineum, Dendreon, Sanofi, Agensys, Eli Lilly, and Roche Laboratories, and has an ownership interest/investment in Bellicum and Tyme Technologies.

13 IMFINZI is a trademark of the AstraZeneca group of companies AstraZeneca. All rights reserved /17

14 S14 Focus on Urologic Cancers: Current advances, future directions APRIL 15, 2017 Urology Times SUPPLEMENT Biomarkers for bladder cancer: Current and future Uptake of protein-, cell-based tests likely to rise with AUA/SUO guidance KEY TAKEAWAYS The AUA/SUO NMIBC guideline statements incorporate a role for using urinary biomarkers to assess response to intravesical BCG and adjudicate equivocal cytology. The sensitivity of FDA-approved urinary biomarkers ranges from 47% to 85% for diagnosis and from 55% to 75% for surveillance; specificity ranges from 53% to 95% for diagnosis and from 71% to 83% for surveillance. The overall specificity of urine cytology ranges from 90% to 100% and sensitivity from 50% to 60%. The FISH assay has been reported to yield an anticipatory positive test. New tests analyzing methylation profiles or genetic changes are forthcoming and may hold promise for better performance in NMIBC diagnosis in surveillance. By Cheryl Guttman Krader UT Contributing Editor The role of protein- and cellbased urinary biomarkers for bladder cancer detection and surveillance is controversial, and in 2017 these assays have yet to come into widespread use among urologists. Their uptake is expected to increase, however, considering that the American Urological Association/Society of Urologic Oncology Guideline on Diagnosis and Treatment of Non-Muscle Invasive Bladder Cancer (NMIBC) that was released in 2016 identifies situations for using urinary biomarkers, according to Badrinath R. Konety, MD. According to the guideline, clinicians may use select urinary biomarkers to assess response to intravesical chemotherapy with bacillus Calmette-Guérin (UroVysion Bladder Cancer Kit) and to adjudicate equivocal cytology (UroVysion and ImmunoCyt). It also states, however, that urinary biomarkers should not be used in place of cystoscopic evaluation for surveillance of NMIBC. In addition, the guideline states that neither urinary biomarkers nor cytology should be routinely used during surveillance of a patient with a history of low-risk cancer and a normal cystoscopy. Several urinary biomarkers have been approved by the FDA for use in bladder cancer detection and/or surveillance (table). These include fluorescence in situ hybridization (FISH [UroVysion]), nuclear matrix protein 22 (NMP22 [NMP22 and NMP22BladderChek]), bladder tumor antigen (BTA [BTA stat and BTA TRAK]), and fluorescent immunohistochemistry (ImmunoCyt/uCyt+). Other urine-based tests marketed by clinical laboratories that meet Clinical Improvement Act standards include CertNDx and Cxbladder Triage, Cxbladder Detect, and Cxbladder Monitor. CertNDx assesses mutations in fibroblast growth factor receptor 3, which may be associated with lower grade bladder tumors that have a good prognosis, and is used in combination with cytology. The Cxbladder tests measure five genes (CDC2, HOXA13, MDK, AGFBP5, CXCR2). Cxbladder Triage also analyzes phenotypic and clinical risk factors and is intended for primary evaluation of patients with hematuria to reduce the need for an invasive workup in patients who have a low probability of having bladder cancer. Cxbladder Detect is intended for evaluation of patients presenting with hematuria as an adjunct to cystoscopy. Cxbladder Monitor combines the genomic biomarkers with patient-specific clinical factors and is used to monitor for bladder cancer recurrence. Cytology vs. biomarkers Voided urine cytology has been the mainstay for urine-based bladder can-

15 Urology Times SUPPLEMENT APRIL 15, 2017 Focus on Urologic Cancers: Current advances, future directions S15 cer detection, and it has the advantage of having very high specificity. If the cytology comes back positive, then there is a greater than 90% chance that cancer is present. However, a negative result is not that helpful because the majority of low-grade tumors have negative cytology, and that limitation of cytology is the gap that the newer biomarkers are trying to fill, said Dr. Konety, professor and chair of urology at the University of Minnesota, Minneapolis. As another drawback, there is a turnaround delay of several days for cytolo- Continued on page S16 TABLE. FDA-approved urinary biomarkers for bladder cancer Test (manufacturer) Description and intended use* Sensitivity 1 Specificity 1 PROTEIN-BASED TESTS BTA stat/bta TRAK Identifies bladder tumor associated antigen (BTA), a human complement factor H-related protein produced by human bladder cell lines. Intended as an aid in the management of bladder cancer patients. BTA stat (qualitative) Overall Diagnosis Surveillance BTA TRAK (quantitative) Overall Diagnosis Surveillance 58% 47% 70% 69% 67% 61% NMP22BladderChek/NMP22 Identifies NMP22, a nuclear mitotic apparatus protein that is thought to be released from the nucleus of tumor cells during apoptosis. NMP22BladderChek is intended for professional and prescription home use as an aid in monitoring bladder cancer patients. NMP22 is intended as an aid in the diagnosis of persons with symptoms or risk factors for transitional cell cancer (TCC) of the bladder and in the management of patients after surgical treatment to identify patients with occult or rapidly recurrent TCC. NMP22BladderChek (qualitative) Overall Diagnosis Surveillance NMP22 (quantitative) Overall Diagnosis Surveillance CELL-BASED TESTS 64% 76% 60% 65% 76% 58% UroVysion Bladder Cancer Kit Fluorescence in situ hybridization DNA probe technology detects chromosomal abnormalities. Intended as an aid for initial diagnosis of bladder carcinoma in patients with hematuria and subsequent monitoring for tumor recurrence after diagnosis. Overall Diagnosis Surveillance 63% 73% 55% Immunocyt/uCyt+ Uses fluorescence immunohistochemistry with monoclonal antibodies to a mucin glycoprotein found on epithelial cell surfaces in malignancy and a carcinoembryonic antigen expressed by bladder tumor cells. Intended as an aid in the management of bladder cancer for use in conjunction with cytology to increase the overall sensitivity for detection of tumor cells in patients previously diagnosed with bladder cancer. Overall Diagnosis Surveillance CYTOLOGY 35% to 55% 94% to 99% *All tests are intended for use in conjunction with cystoscopy/other current standard diagnostic procedures. 1 Source: Data range for cytology from Urol Int 2015; 94:1 24. Sensitivity and specificity data for other tests extracted from J Urol 2016; 196: % 85% 75% 88% 93% 83% 77% 84% 71% 77% 78% 76% 74% 53% 79% 87% 95% 80% 78% 83% 76%

16 S16 Focus on Urologic Cancers: Current advances, future directions APRIL 15, 2017 Urology Times SUPPLEMENT Continued from page S15 gy, whereas some of the other biomarkers (BTA stat, NMP22BladderChek) are point-of-care tests that generate immediate results. In addition, the results of cytology can be variable because there are at least five official values for the results, and the interpretation is reader dependent. In contrast, some of the second- and third-generation biomarker tests provide a result that is cut and dry the test is either positive or negative. Slow uptake Consistent with the AUA/SUO guideline, Dr. Konety observed that the biomarkers seem to be finding the greatest application in the follow-up of patients diagnosed with bladder cancer and particularly as a second-level test in the setting of atypical urine cytology. It appears they are being used less often for initial diagnosis in patients with hematuria. In order to investigate the uptake of the newer urinary biomarker tests for bladder cancer surveillance, Dr. Konety and colleagues conducted an analysis using Medicare data. Their methods did not include analyses of any individual assays, but the results showed that overall use of biomarkers by urologists increased from 11% in 2000 to 26% in Commenting on the findings, Dr. Konety described the uptake as stagnated and said he does not believe that the new urinary markers have led to a change in approach to management of bladder cancer. The lament of people who have been doing research with the new urinary biomarkers is that these diagnostic tools have not been adopted to the extent that might be expected considering their specificity is in the 50% to 80% range. This reluctance is difficult to reconcile when juxtaposed against the high reliance on PSA for prostate cancer screening and monitoring, taking into account that as a stand-alone marker, PSA has a specificity of only about 25%, Dr. Konety said. He suggested multiple factors to explain the limited utilization of the bladder cancer biomarkers. Cost may be an issue, although the protein-based markers are covered by insurance and not that expensive, which may explain why the qualitative NMP22 assay may have the greatest use overall. And while the FISH assay was initially very expensive, costing thousands of dollars, it has now come down in price, he said. When patients with bladder cancer were asked about the level of performance a urine test should provide before they would be willing to stop undergoing cystoscopic monitoring, they wanted 95% sensitivity and specificity. Badrinath R. Konety, MD Logistics is another consideration, but uncertainty of how to apply the results clinically likely plays a major role. Because guidelines have not definitively advocated for or against biomarkers for diagnosis or surveillance, urologists have not been compelled to use them. In fact, the current AUA guideline on diagnosis, evaluation, and follow-up of asymptomatic microhematuria in adults, which is from 2012, doesn t even advocate for cytology in the workup. That creates a high bar for justifying the use of these newer, more expensive markers, Dr. Konety said. Performance and advantages Dr. Konety said there is good evidence to show that use of urinary biomarkers to adjudicate equivocal cytology helps to avoid unnecessary additional workup. There is also research that demonstrates including urinary biomarker testing in a surveillance paradigm increases the detection rate for recurrences, said Dr. Konety, citing a study by van der Aa et al (J Urol 2010; 183:76-80) looking at how knowledge of results of a microsatellite marker urine test (not FDA approved) influenced the accuracy of cystoscopy performed as follow-up in patients with low-grade NMIBC. The randomized study compared the number of histologically proven bladder cancer recurrences in patients who underwent cystoscopy on the basis of the urologist knowing that the urine test was positive and a control arm in which cystoscopy was performed routinely at 3, 12, and 24 months. During a median follow-up of 34 months, the number of detected recurrences was significantly greater in the group where the urologist performed cystoscopy based on the assay results, and in that arm, a recurrence was detected in almost one-third of the 131 cystoscopies done. A total of 120 cystoscopies were performed in the control arm, of which only six detected a recurrence. The recurrence rate for patients who did not undergo cystoscopy because they had a negative test result was 7% and almost identical to that of the control arm. Perhaps the awareness of a positive urine test result improves detection of recurrence using cystoscopy because it leads to heightened awareness of subtle changes in the cystoscopic appearance of the bladder, or maybe it lowers the threshold for triggering the biopsy, Dr. Konety said. There are also data from studies sup-

17 Urology Times SUPPLEMENT APRIL 15, 2017 Focus on Urologic Cancers: Current advances, future directions S17 porting a role for biomarkers in evaluating response to intravesical BCG. Most of that evidence exists for the FISH assay, and it comes from large studies that are both manufacturer sponsored and conducted by independent investigators. All of the available studies reported that if a patient had a positive FISH before starting BCG and the assay turned negative after 6 weeks of BCG induction, the patient was likely to have a positive response to BCG, decreased likelihood of recurrence, and decreased disease progression. The proportion of patients who did not demonstrate disease progression after the FISH turned negative varied from study to study, but the basic outcome was consistent across all of the studies, Dr. Konety said. It is also possible that the urinary markers can detect changes at the cellular level prior to the development of endoscopically visible lesions. This phenomenon, which is referred to as an anticipatory positive result, has been described with FISH as well as with cytology. The false-positive rate with all of these markers can be as high as 30% to 50%, although it is generally in the 20% to 25% range. Not everybody, however, believes that all false-positive findings are truly false, Dr. Konety explained. Data with FISH show that about 30% to 40% of patients who have a false-positive result will develop a tumor over the next few years. Whether the tumor developed subsequent to the test or the assay predicted its development is hard to say. However, those who argue in favor of the anticipatory positive result contend there must be an association with the earlier positive test if it remained positive until the tumor ultimately appeared. Further study is needed to establish that the FISH assay offers such increased sensitivity for early detection. [Tests in development] have the potential to not only determine whether or not a patient has or is likely to develop cancer, but they might also give clues about the tumor biology and its response to various treatments that could be used to guide treatment decisions. Badrinath R. Konety, MD The false-positive conundrum The relatively high rate of false-positive results with the newer biomarkers compared to cytology is likely also a factor limiting their use. For example, I often receive calls from urologists who are unsure what to do when the FISH is positive and the patient undergoes a thorough workup with a complete upper tract evaluation and biopsy with negative findings, Dr. Konety said. This false-positive conundrum also occurs with routine cytology, although considering the high specificity of cytology, some urologists would treat empirically with intravesical BCG until the cytology became negative. It may be more difficult to argue in favor of using that same approach based on a positive FISH considering that FISH tests for genetic changes. Unless there is evidence of a phenotypic change, urologists may not be comfortable being aggressive with treatment. The future Ongoing research with biomarkers includes a focus on developing tests that identify genomic alterations in cells found in the urinary sediment of patients with microhematuria in order to provide a tool that could accurately detect existing cancer or predict its subsequent development. In the area of recurrence monitoring, the ability to reliably detect or rule out cancer using a urine assay remains the holy grail for diagnostic evaluation as it would potentially eliminate the burdens of a more extensive workup, Dr. Konety said. Cystoscopy in the office is generally well tolerated, but avoiding repeated biopsies, upper tract studies, and CT scans would be an important advantage. It is interesting, however, that when patients with bladder cancer were asked about the level of performance a urine test should provide before they would be willing to stop undergoing cystoscopic monitoring, they wanted 95% sensitivity and specificity. With this information in mind, it is unlikely that patients or urologists would be willing to accept replacing cystoscopy with follow-up biomarker assays either in the initial diagnosis or surveillance paradigms for bladder cancer. The tests in development are characterizing methylation profiles of the genes, genetic mutations, or both. Companies working in this area include MDxHealth, Genomic Health, GenomeDx, Foundation Medicine, and Cepheid. These types of tests have the potential to not only determine whether or not a patient has or is likely to develop cancer, but they might also give clues about the tumor biology and its response to various treatments that could be used to guide treatment decisions, Dr. Konety said. By identifying specific genomic and epigenomic markers, these tests might also be useful for personalized prediction of recurrence risk. UT Disclosures: Dr. Konety is an investigator in a clinical trial for Genomic Health.

18 S18 Focus on Urologic Cancers: Current advances, future directions APRIL 15, 2017 Urology Times SUPPLEMENT Guidelines update: Bladder, kidney, prostate cancer Recent statements reflect rapid pace of diagnostic, treatment advances By Aine Cryts UT Correspondent In a 2012 paper, researchers from RAND Corp. called clinical practice guidelines one of the foundations of efforts to improve health care (Implement Sci 2012; 7:62). The pace of modern medical advances underscores the importance of published clinical guidance, and has in fact led to an increase in the speed of guideline development and updates. The field of genitourinary cancer is no stranger to this trend. This article highlights the key points of two urologic cancer guidelines (which provide evidence-based guidance) and two consensus statements (which provide consensus recommendations by a multidisciplinary panel of experts) that have been published in the past year. The guidelines discuss nonmuscle-invasive bladder cancer and small renal masses, while the consensus statements examine immunotherapy for renal cell carcinoma and prostate cancer. Nonmuscle-invasive bladder cancer (AUA/SUO) The 2016 American Urological Association/Society of Urologic Oncology guideline on the diagnosis and treatment of nonmuscle-invasive bladder cancer (NMIBC) provides clinicians with a risk-stratification approach to treating this condition. The full guideline was The NMIBC guideline s treatment algorithm incorporates the tumor s characteristics while factoring in the individual patient s response to therapy. published in The Journal of Urology (2016; 196:1021 9). Depending on the patient s unique experience with NMIBC, sometimes more follow-up and surveillance are warranted, whereas with other patients, their clinical teams should be mindful about when it s more appropriate to back off, says Sam Dr. Chang S. Chang, MD, professor of urologic surgery and urologic surgeon/oncologist at Vanderbilt University, Nashville, TN, who helped develop the guideline. Leveraging a risk-stratified approach, the guideline puts patients into one of three categories: low, intermediate, and high risk. The guideline s treatment algorithm incorporates the tumor s characteristics while factoring in the individual patient s response to therapy. Attempting to help clinicians evaluate and treat individual patients, the guideline includes 38 statements, which rely on a variety of evidence. During diagnosis, specifically, the guideline recommends that clinicians perform a thorough cystoscopic examination of the patient s entire urethra and bladder, in addition to evaluating and documenting the size, location, configuration, number, and mucosal abnormalities of the tumor. Experts also recommend that during the initial diagnosis, a complete visual resection of the bladder tumor(s) should be performed, in addition to imaging of the patient s upper urinary tract. For a patient who has been treated for NMIBC in the past and has normal cystoscopy and positive cytology, prostatic urethral biopsies and upper tract imaging, in addition to enhanced cystoscopic techniques, such as blue light cystoscopy, should be considered. Also, in a patient with suspected or known low- or intermediate-risk bladder cancer, a single postoperative instillation of intravesical chemotherapy, such as mitomycin C or epirubicin, should be considered within 24 hours of transure-

19 Urology Times SUPPLEMENT APRIL 15, 2017 Focus on Urologic Cancers: Current advances, future directions S19 theral resection of a bladder tumor. For patients at intermediate risk those who completely respond to induction bacillus Calmette-Guerin (BCG) their clinical team should consider maintenance BCG for 1 year, as tolerated by the patient. In addition to recommendations on BCG relapse, salvage regimens, and other aspects of management, the document also provides risk-adjusted surveillance and follow-up strategies. Small renal masses (ASCO) It wasn t until the 1990s that kidney preservation in patients with small renal masses started to take hold, largely at Memorial Sloan Kettering Cancer Center, Mayo Clinic, and Cleveland Clinic in the United States and by health care providers in Europe. At Memorial Sloan Kettering in New York, urologic surgeon Paul Russo, MD, contrasts Dr. Russo the number of kidneysparing operations his team did each year when he was a fellow in the late 1980s three total with the three he performed on a recent day. That s when a consensus started to develop around the positive outcomes patients could experience if only the tumor was removed and the kidney was spared, a decision that s predicated by the size of the tumor and its location in the kidney, Dr. Russo says. He notes that 70% of cancerous masses found in the kidney are considered small 4 cm or less and the vast majority of these are amenable to partial nephrectomy. Even a stage T1b tumor at 7 cm or less is still relatively small, adds Dr. Russo, who helped develop the American Society of Clinical Oncology s clinical practice guideline on management of small renal masses, which was published earlier this year (J Clin Oncol 2017; 35:668 80). (Approximately 30% of cancerous masses found in the kidney are considered large and/or metastatic.) Partial nephrectomy is the recommended treatment in patients whose tumor measures 4 cm or less. The guideline recommends radical nephrectomy only in instances where the tumor is significantly complex and not technically amenable to a kidney-sparing approach. Further, patients who develop progressive chronic kidney disease in particular, proteinuria and/or a glomerular filtration rate of less than 60 ml/ min/1.73 m 2 should receive a referral to a nephrologist. Biopsy is best utilized in patients with a small renal mass when the results could alter management. In contrast, patients with significant comorbidities and limited life expectancy with a small renal mass are better candidates for active surveillance, and biopsy in that The guideline recommends radical nephrectomy only in instances where the tumor is significantly complex and not technically amenable to a kidneysparing approach. setting can be omitted. The guideline authors note that for patients with significant comorbidities and limited life expectancy, active surveillance is the appropriate response for initial treatment. The reasoning behind this recommendation is many of the asymptomatic masses found in patients over 70 years of age are often relatively indolent with limited metastatic potential and unlikely to threaten the patient during their remaining lifetime. In addition, the competing comorbidities, taken alone or together, are far more life threatening in the near term. Immunotherapy for treatment of RCC (Society for Immunotherapy of Cancer) A subset of patients with metastatic kidney cancer may not need immediate treatment, says Brian Rini, MD, medical oncologist at the Cleveland Clinic Taussig Cancer Institute and professor of medicine at the Cleveland Clinic Lerner College of Medicine. That point, along with recommendations on the use of Dr. Rini newer immunotherapy agents and older drugs, is outlined in the Society for Immunotherapy of Cancer s consensus statement on immunotherapy for the treatment of renal cell carcinoma (RCC), which was published last year in the Journal for ImmunoTherapy of Cancer (2016; 4:81). Since clinicians are trying to provide patients with the most benefit with the least amount of risk, that sometimes means not treating RCC patients or certainly not treating them immediately, says Dr. Rini, the consensus statement s first author. This is the appropriate treatment approach for patients who The resection of oligometastases is supported, but it s unclear how novel immunotherapy could impact these surgical approaches. Continued on page S20

20 S20 Focus on Urologic Cancers: Current advances, future directions APRIL 15, 2017 Urology Times SUPPLEMENT Continued from page S19 have very indolent disease that s not bothering them. An additional benefit of this approach is that sometimes simply watching patients for a period of time can delay side effects while not compromising the benefit of ultimate treatment, he adds. While interferon-alpha and interleukin-2 have been used for decades with positive results, new immunotherapy agents for the treatment of renal cell carcinoma have been approved, according to the consensus statement. These new agents prevent tumor growth by preventing vascular endothelial growth factors in addition to tumor metabolism. Immune checkpoint inhibitors, the newest class of immunotherapy agents, should also have an impact on patients with RCC. According to the consensus statement, observation or enrollment in a clinical trial based on Level A evidence for cytokines and Level A evidence from the ASSURE clinical trial are the most appropriate treatment paths for patients with resected stage II and III renal cell cancer. Members of the task force that developed the statement agreed that nephrectomy is an important component of managing patients with renal cell carcinoma; further, the resection of oligometastases is supported, but it s unclear how novel immunotherapy could impact these surgical approaches. There was division among task force members on the role of high-dose interleukin-2 in treating metastatic RCC. The overall opinion was that appropriate patients who have undergone a nephrectomy should discuss interleukin-2 with their clinicians and then receive a referral to a center of excellence for further discussion of treatment options. Sixtyseven percent of the experts agreed that a discussion about interleukin-2 was appropriate, while the remaining members said it was more appropriate for clinicians to select patients for these types of conversations. In addition to outlining new therapeutic agents and different approaches to patients, and incorporating immunotherapy into the routine management of kidney cancer, which is only just starting, Dr. Rini says this guideline is really setting the stage for what s to come as much as it is about taking care of patients now. Immunotherapy for treatment of prostate carcinoma (Society for Immunotherapy of Cancer) The Society for Immunotherapy of Cancer s consensus 2016 statement on immunotherapy for the treatment of prostate carcinoma provides a framework to inform clinicians about which Dr. Gulley patients are most appropriate for immunotherapy and which patients are not appropriate for such a treatment path, says James L. Gulley, MD, PhD, director of the Medical Oncology Service with the National Institutes for Health s Center for Cancer Research, who contributed to the consensus statement. The consensus statement was published in the Journal for ImmunoTherapy of Cancer (2016; 4:92). Still, Dr. Gulley points out that the consensus statement doesn t say specifically which immunotherapy will work for individual patients. Rather, it provides guidance for the type of patients that he and other prostate cancer experts believe are most likely to benefit. Thus, not every patient is going to be an appropriate candidate for immunotherapy, he says. According to the consensus statement, immunotherapy is indicated for metastatic castration-prone cancer in patients with minimal or no symptoms. After reviewing the available studies, the experts found that the quartile of patients who received sipuleucel-t (Provenge) versus placebo earliest in the disease process lived an average of 13 months longer and experienced a 50% decrease in the chance of death. Patients in more advanced stages of the disease who received sipuleucel-t versus placebo gained an increase of 2 months and experienced a 20% reduction in the chance of death. As a group, the consensus panel experts state a reluctance to treat patients with rapidly progressing disease or significant visceral disease, such as liver metastasis. That s because there was no dramatic decrease in the volume of the After reviewing the available studies, the experts found that the quartile of patients who received sipuleucel-t versus placebo earliest in the disease process lived an average of 13 months longer and experienced a 50% decrease in the chance of death. tumor or a decrease in prostatic ductal adenocarcinoma with sipuleucel-t treatment. Dr. Gulley says that s likely because of the long-term effect of developing an adequate immune response during earlier stages of the disease. If clinicians believe they will run into problems earlier clinically, then they should pursue other treatments; a plurality of the experts said they would use agents like enzalutamide (XTANDI) in addition to sipuleucel-t, according to Dr. Gulley. UT Disclosures: Full disclosure of the guideline and consensus panel members conflicts of interest is provided in the published versions of the statements: bit.ly/nmibcstatement, bit.ly/ Renalmassesstatement, bit.ly/rccimmunotherapy, and bit.ly/ PCaimmunotherapy.

21 XTANDI (enzalutamide) capsules for oral use Initial U.S. Approval: 2012 BRIEF SUMMARY OF PRESCRIBING INFORMATION The following is a brief summary. Please see the package insert for full prescribing information. INDICATIONS AND USAGE XTANDI is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC). CONTRAINDICATIONS Pregnancy XTANDI can cause fetal harm and potential loss of pregnancy WARNINGS AND PRECAUTIONS Seizure Seizure occurred in 0.5% of patients receiving XTANDI in clinical studies. In placebo-controlled studies, 8 of 1671 (0.5%) patients treated with XTANDI and 1 of 1243 (0.1%) patients treated with placebo experienced a seizure. In patients who previously received docetaxel, 7 of 800 (0.9%) patients treated with XTANDI experienced a seizure and no patients treated with placebo experienced a seizure. Seizure occurred from 31 to 603 days after initiation of XTANDI. In a placebo-controlled study in chemotherapy-naïve patients, 1 of 871 (0.1%) treated with XTANDI and 1 of 844 (0.1%) patients treated with placebo experienced a seizure. In bicalutamide-controlled studies conducted in chemotherapy-naïve patients, 3 of 380 (0.8%) patients treated with XTANDI and 1 of 387 (0.3%) patients treated with bicalutamide experienced a seizure. Patients experiencing seizure were permanently discontinued from therapy and all seizure events resolved. There is no clinical trial experience re-administering XTANDI to patients who experienced seizure. Limited safety data are available in patients with predisposing factors for seizure because these patients were generally excluded from the trials. These exclusion criteria included a history of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, and brain arteriovenous malformation. Study 1 excluded the use of concomitant medications that may lower the seizure threshold, whereas Study 2 permitted the use of these medications. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment. Posterior Reversible Encephalopathy Syndrome (PRES) There have been reports of posterior reversible encephalopathy syndrome (PRES) in patients receiving XTANDI. PRES is a neurological disorder which can present with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably magnetic resonance imaging (MRI). Discontinue XTANDI in patients who develop PRES. ADVERSE REACTIONS 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 practice. Three randomized clinical trials enrolled patients with metastatic prostate cancer that has progressed on androgen deprivation therapy (GnRH therapy or bilateral orchiectomy), a disease setting that is also defined as metastatic CRPC. Two trials were placebo-controlled (Studies 1 and 2), and one trial was bicalutamidecontrolled (Study 3). In Studies 1 and 2, patients received XTANDI 160 mg or placebo orally once daily. In Study 3, patients received XTANDI 160 mg or bicalutamide 50 mg orally once daily. All patients continued androgen deprivation therapy. Patients were allowed, but not required, to take glucocorticoids. The most common adverse reactions ( 10%) that occurred more commonly ( 2% over placebo) in the XTANDI-treated patients from the two randomized placebo-controlled clinical trials were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo. Study 1: XTANDI versus Placebo in Metastatic CRPC Following Chemotherapy Study 1 enrolled 1199 patients with metastatic CRPC who had previously received docetaxel. The median duration of treatment was 8.3 months with XTANDI and 3.0 months with placebo. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids. Grade 3 and higher adverse reactions were reported among 47% of XTANDI-treated patients and 53% of placebo-treated patients. Discontinuations due to adverse events were reported for 16% of XTANDI-treated patients and 18% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the XTANDI-treated patients compared to none (0%) of the placebo-treated patients. Table 1 shows adverse reactions reported in Study 1 that occurred at a 2% higher frequency in the XTANDI arm compared to the placebo arm. Table 1. Adverse Reactions in Study 1 XTANDI Placebo Grade 1-4 a (%) N = 800 Grade 3-4 (%) Grade 1-4 (%) N = 399 Grade 3-4 (%) General Disorders Asthenic Conditions b Peripheral Edema Musculoskeletal And Connective Tissue Disorders Back Pain Arthralgia Musculoskeletal Pain Muscular Weakness Musculoskeletal Stiffness Gastrointestinal Disorders Diarrhea Vascular Disorders Hot Flush Hypertension Nervous System Disorders Headache Dizziness c Spinal Cord Compression and Cauda Equina Syndrome Paresthesia Mental Impairment Disorders d Hypoesthesia Infections And Infestations Upper Respiratory 10.9 Tract Infection e Lower Respiratory Tract And Lung Infection f Psychiatric Disorders Insomnia Anxiety Renal And Urinary Disorders Hematuria Pollakiuria Injury, Poisoning And Procedural Complications Fall Non-pathologic Fractures Skin And Subcutaneous Tissue Disorders Pruritus Dry Skin Respiratory Disorders Epistaxis a CTCAE v4. b Includes asthenia and fatigue. c Includes dizziness and vertigo. d Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. e Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. f Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection. Study 2: XTANDI versus Placebo in Chemotherapynaïve Metastatic CRPC Study 2 enrolled 1717 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy, of whom 1715 received at least one dose of study drug. The median duration of treatment was 17.5 months with XTANDI and 4.6 months with placebo. Grade 3-4 adverse reactions were reported in 44% of XTANDI-treated patients and 37% of placebo-treated patients. Discontinuations due to adverse events were reported for 6% of XTANDI-treated patients and 6% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was fatigue/asthenia, which occurred in 1% of patients on each treatment arm. Table 2 includes adverse reactions reported in Study 2 that occurred at a 2% higher frequency in the XTANDI arm compared to the placebo arm. Table 2. Adverse Reactions in Study 2 XTANDI Placebo Grade 1-4 a (%) N = 871 Grade 3-4 (%) Grade 1-4 (%) N = 844 Grade 3-4 (%) General Disorders Asthenic Conditions b Peripheral Edema Musculoskeletal And Connective Tissue Disorders Back Pain Arthralgia Gastrointestinal Disorders Constipation Diarrhea Vascular Disorders Hot Flush Hypertension Nervous System Disorders Dizziness c Headache Dysgeusia Mental Impairment Disorders d Restless Legs Syndrome Respiratory Disorders Dyspnea e Infections And Infestations Upper Respiratory 16.4 Tract Infection f Lower Respiratory Tract And Lung Infection g Psychiatric Disorders Insomnia Renal And Urinary Disorders Hematuria Injury, Poisoning And Procedural Complications Fall Non-Pathological Fracture Metabolism and Nutrition Disorders Decreased Appetite Investigations Weight Decreased Reproductive System and Breast Disorders Gynecomastia a CTCAE v4. b Includes asthenia and fatigue. c Includes dizziness and vertigo. d Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. e Includes dyspnea, exertional dyspnea, and dyspnea at rest. f Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. g Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection. Study 3: XTANDI versus Bicalutamide in Chemotherapynaïve Metastatic CRPC Study 3 enrolled 375 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy, of whom 372 received at least one dose of study drug. The median duration of treatment was 11.6 months with XTANDI and

22 5.8 months with bicalutamide. Discontinuations with an adverse event as the primary reason were reported for 7.6% of XTANDI-treated patients and 6.3% of bicalutamidetreated patients. The most common adverse reactions leading to treatment discontinuation were back pain and pathological fracture, which occurred in 3.8% of XTANDItreated patients for each event and in 2.1% and 1.6% of bicalutamide-treated patients, respectively. Table 3 shows overall and common adverse reactions ( 10%) in XTANDItreated patients. Table 3. Adverse Reactions in Study 3 XTANDI Bicalutamide Grade 1-4 a (%) N = 183 Grade 3-4 (%) Grade 1-4 a (%) N = 189 Grade 3-4 (%) Overall General Disorders Asthenic Conditions b Musculoskeletal And Connective Tissue Disorders Back Pain Musculoskeletal Pain c Vascular Disorders Hot Flush Hypertension Gastrointestinal Disorders Nausea Constipation Diarrhea Infections And Infestations Upper Respiratory Tract Infection d Investigational Weight Loss a CTCAE v 4. b Including asthenia and fatigue. c Including musculoskeletal pain and pain in extremity. d Including nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. Laboratory Abnormalities In the two randomized placebo-controlled clinical trials, Grade 1-4 neutropenia occurred in 15% of patients treated with XTANDI (1% Grade 3-4) and in 6% of patients treated with placebo (0.5% Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was 6% of patients treated with XTANDI (0.3% Grade 3-4) and 5% of patients treated with placebo (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of patients treated with XTANDI (0.2% Grade 3-4) and 16% of patients treated with placebo (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of patients treated with XTANDI (0.1% Grade 3-4) and 2% of patients treated with placebo (no Grade 3-4). Infections In Study 1, 1% of patients treated with XTANDI compared to 0.3% of patients treated with placebo died from infections or sepsis. In Study 2, 1 patient in each treatment group (0.1%) had an infection resulting in death. Falls and Fall-related Injuries In the two randomized placebo-controlled clinical trials, falls including fall-related injuries, occurred in 9% of patients treated with XTANDI compared to 4% of patients treated with placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in patients treated with XTANDI and included non-pathologic fractures, joint injuries, and hematomas. Hypertension In the two randomized placebo-controlled trials, hypertension was reported in 11% of patients receiving XTANDI and 4% of patients receiving placebo. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of patients in each arm. Post-Marketing Experience The following additional adverse reactions have been identified during post approval use of XTANDI. Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Neurological Disorders: posterior reversible encephalopathy syndrome (PRES) DRUG INTERACTIONS Drugs that Inhibit CYP2C8 Co-administration of a strong CYP2C8 inhibitor (gemfibrozil) increased the composite area under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl enzalutamide by 2.2-fold. Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI with a strong CYP2C8 inhibitor cannot be avoided, reduce the dose of XTANDI. Drugs that Induce CYP3A4 Co-administration of rifampin (strong CYP3A4 inducer and moderate CYP2C8 inducer) decreased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 37%. Co-administration of strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) with XTANDI should be avoided if possible. St John s wort may decrease enzalutamide exposure and should be avoided. If co-administration of a strong CYP3A4 inducer with XTANDI cannot be avoided, increase the dose of XTANDI. Effect of XTANDI on Drug Metabolizing Enzymes Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. At steady state, XTANDI reduced the plasma exposure to midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Concomitant use of XTANDI with narrow therapeutic index drugs that are metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (e.g., phenytoin, warfarin) and CYP2C19 (e.g., S-mephenytoin) should be avoided, as enzalutamide may decrease their exposure. If co-administration with warfarin cannot be avoided, conduct additional INR monitoring. USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary XTANDI is contraindicated for use in pregnant women because the drug can cause fetal harm and potential loss of pregnancy. XTANDI is not indicated for use in females. There are no human data on the use of XTANDI in pregnant women. In animal reproduction studies, oral administration of enzalutamide in pregnant mice during organogenesis caused adverse developmental effects at doses lower than the maximum recommended human dose. Animal Data In an embryo-fetal developmental toxicity study in mice, enzalutamide caused developmental toxicity when administered at oral doses of 10 or 30 mg/kg/day throughout the period of organogenesis (gestational days 6-15). Findings included embryo-fetal lethality (increased post-implantation loss and resorptions) and decreased anogenital distance at 10 mg/kg/day, and cleft palate and absent palatine bone at 30 mg/kg/day. Doses of 30 mg/kg/day caused maternal toxicity. The doses tested in mice (1, 10 and 30 mg/kg/day) resulted in systemic exposures (AUC) approximately 0.04, 0.4 and 1.1 times, respectively, the exposures in patients. Enzalutamide did not cause developmental toxicity in rabbits when administered throughout the period of organogenesis (gestational days 6-18) at dose levels up to 10 mg/kg/day (approximately 0.4 times the exposures in patients based on AUC). Lactation Risk Summary XTANDI is not indicated for use in females. There is no information available on the presence of XTANDI in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Females and Males of Reproductive Potential Contraception Males Based on findings in animal reproduction studies, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the final dose of XTANDI. Infertility Based on animal studies, XTANDI may impair fertility in males of reproductive potential. Pediatric Use Safety and effectiveness of XTANDI in pediatric patients have not been established. Geriatric Use Of 1671 patients who received XTANDI in the two randomized placebo-controlled clinical trials, 75% were 65 and over, while 31% were 75 and over. No overall differences in safety or effectiveness were observed between these 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. Patients with Renal Impairment A dedicated renal impairment trial for XTANDI has not been conducted. Based on the population pharmacokinetic analysis using data from clinical trials in patients with metastatic CRPC and healthy volunteers, no significant difference in enzalutamide clearance was observed in patients with pre-existing mild to moderate renal impairment (30 ml/min creatinine clearance [CrCL] 89 ml/min) compared to patients and volunteers with baseline normal renal function (CrCL 90 ml/min). No initial dosage adjustment is necessary for patients with mild to moderate renal impairment. Severe renal impairment (CrCL < 30 ml/min) and end-stage renal disease have not been assessed. Patients with Hepatic Impairment Dedicated hepatic impairment trials compared the composite systemic exposure of enzalutamide plus N-desmethyl enzalutamide in volunteers with baseline mild, moderate, or severe hepatic impairment (Child- Pugh Class A, B, or C, respectively) versus healthy controls with normal hepatic function. The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild, moderate, or severe baseline hepatic impairment compared to volunteers with normal hepatic function. No initial dosage adjustment is necessary for patients with baseline mild, moderate, or severe hepatic impairment. OVERDOSAGE In the event of an overdose, stop treatment with XTANDI and initiate general supportive measures taking into consideration the half-life of 5.8 days. In a dose escalation study, no seizures were reported at 240 mg daily, whereas 3 seizures were reported, 1 each at 360 mg, 480 mg, and 600 mg daily. Patients may be at increased risk of seizure following an overdose. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been conducted to evaluate the carcinogenic potential of enzalutamide. Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the in vitro mouse lymphoma thymidine kinase (Tk) gene mutation assay or the in vivo mouse micronucleus assay. Based on nonclinical findings in repeat-dose toxicology studies, which were consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with XTANDI. In a 26-week study in rats, atrophy of the prostate and seminal vesicles was observed at 30 mg/kg/day (equal to the human exposure based on AUC). In 4-, 13-, and 39-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides were observed at 4 mg/kg/day (0.3 times the human exposure based on AUC). Manufactured for and Distributed by: Astellas Pharma US, Inc., Northbrook, IL Marketed by: Astellas Pharma US, Inc., Northbrook, IL Medivation, Inc., San Francisco, CA Revised: October I074-XTA Rx Only 2016 Astellas Pharma US, Inc. XTANDI is a registered trademark of Astellas Pharma Inc PM

23 Indication and Important Safety Information Indication XTANDI (enzalutamide) capsules is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC). Important Safety Information Contraindications XTANDI is not indicated for women. XTANDI can cause fetal harm and potential loss of pregnancy. Warnings and Precautions Seizure occurred in 0.5% of patients receiving XTANDI in clinical studies. In placebo-controlled studies, 8 of 1671 (0.5%) patients treated with XTANDI and 1 of 1243 (0.1%) patients treated with placebo experienced a seizure. In patients who previously received docetaxel, 7 of 800 (0.9%) patients treated with XTANDI experienced a seizure and no patients treated with placebo experienced a seizure. In a placebo-controlled study in chemotherapy-naïve patients, 1 of 871 (0.1%) patients treated with XTANDI and 1 of 844 (0.1%) patients treated with placebo experienced a seizure. In bicalutamidecontrolled studies conducted in chemotherapy-naïve patients, 3 of 380 (0.8%) patients treated with XTANDI and 1 of 387 (0.3%) patients treated with bicalutamide experienced a seizure. Permanently discontinue XTANDI in patients who develop a seizure during treatment. Posterior Reversible Encephalopathy Syndrome (PRES) In post approval use, there have been reports of PRES in patients receiving XTANDI. PRES is a neurological disorder which can present with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably MRI. Discontinue XTANDI in patients who develop PRES. Adverse Reactions The most common adverse reactions ( 10%) that occurred more commonly ( 2% over placebo) in the XTANDI patients from the two placebo-controlled clinical trials were asthenia/ fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo. In the bicalutamide-controlled study of chemotherapy-naïve patients, the most common adverse reactions ( 10%) reported in XTANDI patients were asthenia/fatigue, back pain, musculoskeletal pain, hot flush, hypertension, nausea, constipation, upper respiratory tract infection, diarrhea, and weight loss. In the study of patients taking XTANDI who previously received docetaxel, Grade 3 and higher adverse reactions were reported among 47% of XTANDI patients and 53% of placebo patients. Discontinuations due to adverse events were reported for 16% of XTANDI patients and 18% of placebo patients. In the placebo-controlled study of chemotherapy-naïve patients, Grade 3-4 adverse reactions were reported in 44% of XTANDI patients and 37% of placebo patients. Discontinuations due to adverse events were reported for 6% of both study groups. In the bicalutamide-controlled study of chemotherapy-naïve patients, Grade 3-4 adverse reactions were reported in 38.8% of XTANDI patients and 37.6% of bicalutamide patients. Discontinuations due to adverse events were reported for 7.6% of XTANDI patients and 6.3% of bicalutamide patients. Lab Abnormalities: In the two placebo-controlled trials, Grade 1-4 neutropenia occurred in 15% of XTANDI patients (1% Grade 3-4) and 6% of placebo patients (0.5% Grade 3-4). Grade 1-4 thrombocytopenia occurred in 6% of XTANDI patients (0.3% Grade 3-4) and 5% of placebo patients (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of XTANDI patients (0.2% Grade 3-4) and 16% of placebo patients (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of XTANDI patients (0.1% Grade 3-4) and 2% of placebo patients (no Grade 3-4). Infections: In a study of patients taking XTANDI who previously received docetaxel, 1% of XTANDI patients compared to 0.3% of placebo patients died from infections or sepsis. In the placebo-controlled study of chemotherapy-naïve patients, 1 patient in each treatment group (0.1%) had an infection resulting in death. Falls (including fall-related injuries) occurred in 9% of XTANDI patients and 4% of placebo patients in the two placebocontrolled trials. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in XTANDI patients, and included non-pathologic fractures, joint injuries, and hematomas. Hypertension occurred in 11% of XTANDI patients and 4% of placebo patients in the two placebo-controlled trials. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of patients in each arm. Drug Interactions Effect of Other Drugs on XTANDI Avoid strong CYP2C8 inhibitors, as they can increase the plasma exposure to XTANDI. If co-administration is necessary, reduce the dose of XTANDI. Avoid strong CYP3A4 inducers as they can decrease the plasma exposure to XTANDI. If co-administration is necessary, increase the dose of XTANDI. Effect of XTANDI on Other Drugs Avoid CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring. Please see adjacent pages for Brief Summary of Full Prescribing Information. References: 1. XTANDI [package insert]. Northbrook, IL: Astellas, Inc. 2. Shore ND, Chowdhury S, Villers A, et al. Efficacy and safety of enzalutamide versus bicalutamide for patients with metastatic prostate cancer (TERRAIN): a randomised, double-blind, phase 2 study. Lancet Oncol 2016;17(2): Beer TM, Armstrong AJ, Rathkopf DE, et al., for the PREVAIL Investigators. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014;371(5): Astellas Pharma US, Inc. All rights reserved. Printed in USA PM 2/17 XTANDI, Astellas, and the flying star logo are registered trademarks of Astellas Pharma Inc.

24 Data vs bicalutamide Median rpfs* was 19.5 months (95% CI, 11.8-NR) for patients receiving XTANDI + GnRH therapy vs 13.4 months (95% CI, ) for patients receiving bicalutamide + GnRH therapy (HR = 0.60 [95% CI, ]) 1 Upon progression on GnRH therapy in mcrpc1 TO EXTEND SURVIVAL1 23% reduction in risk of death with XTANDI + GnRH therapy vs placebo + GnRH therapy in PREVAIL 1 Co-primary endpoint, OS: (HR = 0.77 [95% CI, ])1 Median OS was 35.3 months (95% CI, 32.2-NR) with XTANDI vs 31.3 months (95% CI, ) with placebo1 Co-primary endpoint, rpfs*: (HR = 0.17 [95% CI, ]; P < )1 CONVENIENT DOSING1 Administer XTANDI as 160 mg (four 40 mg capsules) orally, once daily Each capsule should be swallowed whole and should not be chewed, dissolved, or opened. If a patient experiences a Grade 3 toxicity or an intolerable side effect, withhold dosing for one week or until symptoms improve to Grade 2, then resume at the same or a reduced dose (120 mg or 80 mg), if warranted. For additional dosing information, see Drug Interactions and Full Prescribing Information. Learn more about XTANDI at StartXtandi.com Indication XTANDI (enzalutamide) capsules is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC). Select Safety Information XTANDI is not indicated for use in women. XTANDI can cause fetal harm and potential loss of pregnancy. Seizure occurred in 0.5% of patients receiving XTANDI in clinical studies. Permanently discontinue XTANDI in patients who develop a seizure during treatment. There have been post approval reports of posterior reversible encephalopathy syndrome (PRES), a neurological disorder that can present with rapidly evolving symptoms and requires confirmation by brain imaging. Discontinue XTANDI in patients who develop PRES. CI, confidence interval; HR, hazard ratio; mcrpc, metastatic castration-resistant prostate cancer; NR, not reached; OS, overall survival; rpfs, radiographic progression-free survival. *Radiographic progression-free survival was defined as the time from randomization until first objective evidence of radiographic disease progression based on the assessments by Independent Central Review (ICR) or death, whichever occurred first.1 Or after bilateral orchiectomy.1 As seen in the TERRAIN trial (Study 3): an additional trial in metastatic CRPC. TERRAIN was a multinational, double-blind, randomized trial that enrolled 375 patients and compared XTANDI + GnRH therapy, or after bilateral orchiectomy with bicalutamide + GnRH therapy, or after bilateral orchiectomy in patients who were asymptomatic or mildly symptomatic.1,2 Radiographic disease progression was assessed by ICR using the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria and/or Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria for progression of soft tissue lesions.1 llas seen in the PREVAIL trial (Study 2): a multinational, double-blind, randomized, phase 3 trial that enrolled 1717 patients with metastatic CRPC who progressed on GnRH therapy, or after bilateral orchiectomy, and who had not received prior cytotoxic chemotherapy. All patients continued on GnRH therapy.1,3 An updated survival analysis was conducted when 784 deaths were observed. The median follow-up time was 31 months. Results from this analysis were consistent with those from the prespecified interim analysis.1 Please see reverse for Important Safety Information and for Brief Summary of Full Prescribing Information.