mcrpc TREATMENT CONSIDERATIONS FOR GUIDANCE UROLOGY / RADIATION ONCOLOGY / MEDICAL ONCOLOGY

Transcription

1 GUIDANCE TREATMENT CONSIDERATIONS FOR mcrpc UROLOGY / RADIATION ONCOLOGY / MEDICAL ONCOLOGY TM info@careeducation.ca Community Academic Research

2 TREATMENT CONSIDERATIONS FOR mcrpc Castration-resistant prostate cancer (CRPC) is defined by disease progression despite castrate levels of testosterone, and may present as either a continuous rise in serum prostate-specific antigen (PSA) levels, the progression of pre-existing disease, and/or the appearance of new metastases. 1 A growing body of research has led to the development and approval of many agents in metastatic CRPC, and specialists face challenges regarding choice of therapy and sequencing of treatment options. Metastatic CRPC (mcrpc) has been a focus for the CARE Genitourinary Faculty since 2014, when they met at the American Society of Clinical Oncology (ASCO) annual meeting to discuss current challenges and considerations in the management of mcrpc. It was decided that multiple specialties (radiation oncology, urology, and medical oncology) needed to be involved in this discussion in order to provide their expertise and offer a variety of perspectives to the group. During the meeting at ASCO 2014, a CARE Treatment Guidance for mcrpc was developed. Since then, more data and agents have become available. Members of the CARE Faculty met at the Canadian Urological Association (CUA) Canadian Urologic Oncology Group (CUOG) Multidisciplinary Meeting 2015 (June 27, 2015) to further discuss treatment options and considerations in this disease category, with the ultimate goal of updating and augmenting the previous CARE guidance document. This document contains the updated CARE Treatment Guidance and provides additional details on the treatment options, including updated trial information on how the agent should be used, supporting recommendations from ASCO and Cancer Care Ontario (CCO), and supportive care issues. The development of this publication was led by CARE GU Faculty members Drs. Sebastien Hotte, Brita Danielson and Alan So, and includes insights/perspectives from other leading key opinion leaders from across Canada (please see guidance references for full details on specialists involved). CONTRIBUTING AUTHORS FOR THE CARE TREATMENT GUIDANCE: Dr. Sebastien Hotte (Juravinski Cancer Centre) Medical Oncology Chair Dr. Brita Danielson (Cross Cancer Institute) Radiation Oncology Chair Dr. Alan So (Vancouver Prostate Centre, BC Cancer Agency) Urology Chair Dr. Armen Aprikian (Montreal General Hospital) Urology Dr. Guila Delouya (CHUM) Radiation Oncology Dr. Neil Fleshner (Princess Margaret Cancer Centre) Urology Dr. Robert Hamilton (Princess Margaret Cancer Centre) Urology Dr. Anil Kapoor (St. Joseph s Healthcare) Urology Dr. Robyn MacFarlane (QEII) Medical Oncology Dr. Scott Morgan (The Ottawa Hospital) Radiation Oncology Dr. Srikala Sridhar (Princess Margaret Cancer Centre Medical Oncology) TM Genitourinary Cancer Oncology

3 TREATMENT OPTIONS FOR mcrpc The following section provides an overview of available mcrpc therapies in Canada, along with an assessment of each therapy (including their benefit, harm, evidence strength and recommendation strength). These assessments are based on the ASCO/CCO guidelines, and are augmented with insights from contributing Canadian specialists in order to best reflect recent data. ANDROGEN DEPRIVATION THERAPY (ADT) As prostate cancer is usually unable to propagate without androgens, androgen deprivation therapy works by decreasing the amount of testosterone in a man s body. Reducing the amount of testosterone has the potential to slow the progression of hormone sensitive prostate cancer. Continuous androgen deprivation (pharmaceutical or surgical) should be given indefinitely regardless of additional therapies. 2 Recommendation: Continuous androgen deprivation (pharmaceutical or surgical) should be continued indefinitely regardless of additional therapies. 3 Hot flashes and sweats, loss of libido, erectile dysfunction, gynecomastia Decreased muscle mass, decreased bone density Possible increased risk of cardiovascular disease and diabetes HARM: MODERATE EVIDENCE STRENGTH: WEAK RECOMMENDATION STRENGTH: MODERATE There are a number of therapies (in addition to ADT) that have demonstrated survival and quality of life benefits. These include: abiraterone, enzalutamide, radium-223, docetaxel, and cabazitaxel. ABIRATERONE ACETATE Abiraterone is approved in combination with prednisone for the first line treatment of mcrpc without symptoms prior to chemotherapy as well as post-chemotherapy for mcrpc patients with or without symptoms. Abiraterone acetate is an androgen biosynthesis inhibitor that works by decreasing circulating levels of testosterone. Abiraterone inhibits 17 α-hydroxylase/c17,20 lyase (CYP17A1), an enzyme expressed in testicular, adrenal, and prostatic tumour tissues, which prevents the formation of testosterone androgen precursors, DHEA and androstenedione. 4 The COU-AA-301 study showed safety, feasibility and survival benefit for the use of abiraterone in the post-chemotherapy setting, which led to the FDA approval for this agent. A second phase III randomized controlled trial (COU-AA-302) showed that abiraterone acetate also improved overall survival in chemotherapy naïve patients with mcrpc. 4 Abiraterone acetate must be accompanied by steroids (e.g. prednisone or dexamethasone). A steroid switch from prednisone to dexamethasone with abiraterone could also help to induce secondary responses. 5 Liver function tests and electrolytes should be periodically monitored after abiraterone and prednisone are initiated. Recommendation: Abiraterone acetate and prednisone should be offered. 3 Hypertension Hypokalemia Hepatotoxicity Fluid retention DRUG-DRUG INTERACTIONS: Multiple (see product monograph) FOOD INTERACTIONS No food should be eaten 2 hours before and 1 hour after taking abiraterone. Swallow tablets whole. Do not crush or chew tablets. Take tablets with water HARM: LOW RECOMMENDATION STRENGTH: STRONG

4 TREATMENT OPTIONS FOR mcrpc ENZALUTAMIDE Enzalutamide is an orally administered androgen receptor inhibitor approved for the first line treatment of mcrpc without symptoms, for patients with mcrpc post-docetaxel (based on the AFFIRM trial), as well as chemotherapy naïve patients (based on the PREVAIL trial). 6 This agent has OS benefit and appears to offer similar effects as abiraterone/prednisone. Recommendation: Enzalutamide should be offered. 3 SIDE EFFECTS TO BE AWARE OF: Seizure (rare) Hypertension DRUG-DRUG INTERACTIONS: Multiple (see product monograph) HARM: LOW RECOMMENDATION STRENGTH: STRONG RADIUM-223 Radium-223 is a first-in-class alpha-pharmaceutical approved for the treatment of patients with mcrpc with symptomatic bone metastases and no known visceral metastatic disease. It is intravenously administered and has to be given with nuclear medicine supervision. The short range of alpha particles spare surrounding healthy bone marrow and should thus limit side effects. 7 The Phase III ALSYMPCA trial randomized patients to receive either radium-223 with best standard of care (BSC) or placebo with BSC. Patients included in this study had progressive, symptomatic CRPC with two or more bone metastases on bone scintigraphy and no visceral metastases. They were receiving BSC and either previously received docetaxel, were docetaxel ineligible, or refused docetaxel. Results show that radium-223 significantly improves overall survival, delays the time to the first symptomatic skeletal event (SSE) and has a favourable safety profile. Bone marrow suppression (rare) Diarrhea Recommendation: Radium-223 should be offered to men with bone metastases. 3 HARM: LOW RECOMMENDATION STRENGTH: STRONG DOCETAXEL Docetaxel is approved in combination with prednisone for the first line treatment for mcrpc patients with symptoms, and the second line treatment of mcrpc without symptoms. The TAX 327 study was the basis of this approval, showing prolonged overall survival compared with mitoxantrone and prednisone, and improved palliation of disease-related symptoms versus prednisone alone. 8 Treatment with docetaxel and prednisone every three weeks was shown to produce superior survival and improved response rates in terms of pain, serum PSA level, and quality of life, compared to treatment with mitoxantrone and prednisone. 9 Recommendation: Docetaxel and prednisone should be offered. 3 HARM: MODERATE Anemia, neutropenia, infection, nausea, vomiting, anorexia, and fatigue FOOD INTERACTIONS: Grapefruit or grapefruit juice Recent data suggest there is a substantial survival benefit when adding a limited course of docetaxel to ADT for patients with newly diagnosed metastatic androgen-sensitive prostate cancer, primarily in men with a high burden of metastatic disease at presentation (visceral disease and/or > four bone metastatic lesions). The additive benefits or toxicities associated with subsequently retreating such patients with docetaxel in the castration-resistant setting are not known. 3 RECOMMENDATION STRENGTH: STRONG

5 CABAZITAXEL Cabazitaxel is a semi-synthetic derivative of a natural taxoid approved for and may be offered to men with mcrpc resistant to docetaxel. Results from the TROPIC trial identified that cabazitaxel with prednisone improves survival for patients who progressed on docetaxel. While this agent offers survival benefit, quality of life benefit is unclear. Recommendation: Cabazitaxel and prednisone may be offered to men who experience progression with docetaxel. 3 Neutropenia Hypersensitivity reactions Gastrointestinal symptoms Renal failure SHOULD NOT BE USED IN PATIENTS WITH: Hepatic dysfunction HARM: MODERATE TO HIGH FOOD INTERACTIONS: Grapefruit or grapefruit juice RECOMMENDATION STRENGTH: MODERATE MITOXANTRONE PLUS PREDNISONE Mitoxantrone plus prednisone has been shown to reduce pain and improve quality of life for men with advanced, hormone-refractory prostate cancer, but has not shown survival benefits. Mitoxantrone was approved in 1996 for use in patients with mcrpc, based on palliative benefits in a small phase III trial. Mitoxantrone plus prednisone was compared with prednisone alone among men with mcrpc after docetaxel therapy, and no significant survival advantage was observed. This is consistent with prior studies showing no survival benefit with mitoxantrone in the predocetaxel setting. Data also suggests that mitoxantrone may be associated with increased toxicity versus prednisone alone. 10 Recommendation: Mitoxantrone plus prednisone may be offered. 3 Genitourinary issues, including bladder pain, bloody or cloudy urine Fast, slow, or irregular heartbeat Swelling or inflammation of the mouth, ulcers or white spots in the mouth Mood changes, dizziness, anxiety SHOULD NOT BE USED IN PATIENTS WITH: Multiple sclerosis, heart problems or fungal infections anywhere in body BENEFIT: LOW EVIDENCE STRENGTH: WEAK HARM: MODERATE RECOMMENDATION STRENGTH: WEAK DRUG-DRUG INTERACTIONS WITH MITOXANTRONE: Cyclosporine (may increase risk of mitoxantrone's side effects) Trastuzumab (risk of its side effects may be increased) Digoxin or hydantoins (their effectiveness may be decreased) BEST SUPPORTIVE AND PALLIATIVE CARE Best supportive and palliative care should be provided throughout the treatment course of any patient with mcrpc. Palliative care teams (eg. nurses, doctors, social workers) can work with patients to improve communication by means of psychosocial counselling, as well as by helping reduce pain. Early involvement of best supportive care and palliative care can help to improve patient quality of life (QOL) by minimizing disease-related morbidity, treatment-related toxicity, and psychosocial distress. Recommendation: Palliative care should be offered to all patients, particularly to those exhibiting symptoms or quality-of-life (QOL) decrements, regardless of treatment type. 3 HARM: NONE EVIDENCE STRENGTH: MODERATE RECOMMENDATION STRENGTH: STRONG

6 mcrpc GUIDANCE Clinical Metastases (nodal or bone mets) YES Symptoms or Visceral Mets? NO Abiraterone Enzalutamide Progression YES Symptoms or Visceral Mets? NO BEST SUPPORTIVE CARE Palliative Radiation Therapy for Bone Pain * ** Docetaxel Docetaxel Radium-223 Radium No visceral or >3 cm lymph node metastases - Docetaxel refused or ineligible Progression Cabazitaxel Abiraterone Abiraterone Enzalutamide Enzalutamide Docetaxel Progression Docetaxel Radium-223 Cabazitaxel Abiraterone Enzalutamide * Consider clinical trial at any stage ** Consider multidisciplinary opinion

7 ADDITIONAL mcrpc MANAGEMENT CONSIDERATIONS 1. DEFINING SYMPTOMATIC DISEASE mcrpc typically begins as asymptomatic or mildly symptomatic disease. 11 Defining symptomatic disease has been a topic of debate in recent years with little consensus. In the ALSYMPCA trial, it was defined as regular use of opioid or non-opioid analgesic medication or treatment with external beam radiation therapy (EBRT) within the previous 12 weeks for cancer-related bone pain. 12 Some specialists feel that a patient is symptomatic as soon as they develop any increase in pain from baseline, while others consider it pain that requires analgesic medications. Symptomatic disease can be assessed using the Brief Pain Inventory (BPI) scale, a tool that assesses pain severity, location, and impact on everyday life. Mild pain is defined as a pain score of 1-4, moderate pain is defined as a score of 5-6, and severe pain is ranked In terms of defining symptomatic patients, asymptomatic patients have a score of 0-1, mildly symptomatic may range from 2-3, and symptomatic patients score 4 or higher out of PROGRESSION It is important to monitor mcrpc patients for symptomatic, clinical, and radiological progression. There is not a single accepted definition of clinically significant progression which warrants a change in therapy. The most common method of monitoring patients in treatment is with PSA. However, prognosis in mcrpc is associated with other factors, including performance status, presence of visceral metastases, presence of bone pain, extent of disease on bone scan, and serum lactate dehydrogenase (LDH) and alkaline phosphatase (ALP) levels. 1 The CUA recommends that PSA should not be used as the sole criteria for progression, and assessment of response should incorporate clinical and radiographic progression SEQUENCING Sequencing decisions are critical to optimizing overall survival in mcrpc. Though deciding on the best sequence in which to give therapies is important to providing the greatest benefit to patients, there is little guidance on treatment sequencing. Current research findings suggest that: Abiraterone and enzalutamide have shown benefit in docetaxel-naïve patients with mcrpc, but currently there are no head-to-head comparisons to guide treatment selection 14 Cross resistance is a potential issue between various treatments, especially for agents that target the androgen axis (eg. abiraterone and enzalutamide) If chemotherapy is being considered, docetaxel/ prednisone should be offered before cabazitaxel In a subgroup analysis, radium-223 had a positive survival benefit in both the pre- and post- chemotherapy setting (ALSYMPCA) Palliative care should be offered early to all patients Which agent should be used, when, and for how long, is still unclear. The management of mcrpc will continue to evolve as further trial results are available.

8 ABOUT THE ONCOLOGY FACULTY The CARE (Community, Academic, Research, Education) Oncology Faculty is a pan-canadian group of leaders in their field who gather, discuss and address gaps in knowledge, to develop education initiatives framing news from a Canadian perspective. The vision of the CARE Faculty is to share opinions and update Canadian specialists with news and developments from key conferences framed in a Canadian perspective. The mission of the CARE Faculty is to enhance medical education with the explicit goal of improving patient outcomes. REFERENCES 1. Fred Saad, Kim Chi, Antonio Finelli, Sebastien Hotte, Jonathan Izawa, Anil Kapoor, Wassim Kassouf, Andrew Loblaw, Scott North, Ricardo Rendon, Alan So, Nawaid Usmani, Eric Vigneault, Neil Fleshner. The 2015 CUA-CUOG Guidelines for the management of castration-resistant prostate cancer. 3-4, s.l. : Can Urol Assoc J, April 2015, Vol cua-cuog-guidelines.pdf. 2. Marc B. Garnick, M.D. Hormone therapy for prostate cancer. Harvard Medical School & Harvard Health Publications: Prostate Knowledge. [Online] hormone-therapy-for-prostate-cancer. 3. Ethan Basch et. al. Systemic Therapy in Men with Metastatic Castration-Resistant Prostate Cancer: American Society of Clinical Oncology and Cancer Care Ontario Clinical Practice Guideline. 30, s.l. : Journal of Clinical Oncology, 2014, Vol Ryan, C J, Smith, M R and de Bono, J S. Abiraterone in metastatic prostate cancer without previous chemotherapy. 6, s.l. : N Engl J Med., 2013, Vol. 368, p Lorente D, Omlin A, Ferraldeschi R, Pezaro C, Perez R, Mateo J, Altavilla A, Zafeirou Z, Tunariu N, Parker C, Dearnaley D,Gillessen S, de Bono J, Attard G. Tumour responses following a steroid switch from prednisone to dexamethasone in castration-resistant prostate cancer patients progressing on abiraterone. (12): , Br J Cancer, 2014, Vol Tomasz M. Beer, Andrew J. Armstrong, Cora N. Sternberg, Celestia S. Higano, Peter Iversen, Yohann Loriot, Dana E. Rathkopf, Suman Bhattacharya, Joan Carles, Johann S. De Bono, Christopher P. Evans, Anthony M. Joshua, Choung-Soo Kim, Go Kimura, Paul N. Mai. s.l. Enzalutamide in men with chemotherapy-naive metastatic prostate cancer (mcrpc): Results of phase III PREVAIL study. ASCO, LBA1. 7. Parker, Chris. Radium-223 in CRPC With Bone Metastases: Improving Survival and Delaying Skeletal-Related Events. ASCO. [Online] radium-223-crpc-bone-metastases-improving-survival-and-delaying-skeletal-related-events. 8. Armstrong, A J and George, D J. Optimizing the Use of Docetaxel in Men with Castration-resistant Metastatic Prostate Cancer. Medscape. [Online] Medscape, Tannock, Ian F et al. Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for Advanced Prostate Cancer. N Engl J Med, 2004, Vol. 351, pp Green, A K et al. Comparative effectiveness of mitoxantrone plus prednisone versus prednisone alone in metastatic castrate-resistant prostate cancer after docetaxel failure. Oncologist, 2015, Vol. 20, pp American Society of Clinical Oncology (ASCO). CancerNet. [Online] ASCO, [Cited: June 29, 2015.] asco-care-and-treatment-recommendations-patients/treatment-metastatic-castration-resistant-prostate-cancer. 12. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med, 2013, Vols. 369: Brief Pain Inventory. MD Anderson Cancer Center. [Online] [Cited: June 30, 2015.] Beer TM, Armstrong AJ, Sternberg, CN, et al. Enzalutamide in men with chemotherapy-naive metastatic prostate cancer (mcrpc): Results of phase III PREVAIL study. Genitourinary Cancers Symposium.. Presented January 30, Abstract LBA DailyMed. ZYTIGA (abiraterone acetate) tablet [Janssen Biotech, Inc.]. DailyMed. [Online] Janssen Biotech, Inc., September Sartor, O and Gillessen, S. Treatment sequencing in metastatic castrate-resistant prostate cancer. Asian J Androl., 2014, Vol. 16, pp This CARE PUBLICATION provides educational updates on current trends in medicine. Views expressed in this report are those of the faculty. All information is provided for general informational purposes only, on an as is basis, without any representations, warranties or conditions, whether express or implied, statutory or otherwise, including, without limitation, any representations, warranties or conditions as to quality, accuracy, completeness, currency, reliability, efficacy, or fitness for a particular purpose. This information is not a substitute for informed medical advice. Support for the distribution of this report was provided by Bayer Inc. and Sanofi Canada. Copyright 2015 by CARE. All rights reserved. This publication or any portion thereof, in print, electronic copy or any other form, cannot be reproduced without the express written consent of CARE. Any information, data, analysis, or results reproduced from another source remains the property of its authors.