GU Guidelines Update Meeting: M0 Castrate Resistant Prostate Cancer. Dr. Simon Yu Nov 18, 2017

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1 GU Guidelines Update Meeting: M0 Castrate Resistant Prostate Cancer Dr. Simon Yu Nov 18, 2017

2 Faculty/Presenter Disclosure Faculty: Dr. Simon Yu Relationships with commercial interests: Grants/Research Support: N/A Speakers Bureau/Honoraria: Amgen, BMS, Roche, Merck, Novartis, Pfizer, Astra Zeneca, Celgene, Astellas, Janssen Consulting Fees: N/A Other: N/A

3 Current BCCA Guidelines on M0 CRPC

4 M0 CRPC - Definitions No detectable metastatic disease by conventional imaging technetium-99m scintigraphy (bone scan) and CT of chest/abdo/pelvis Castrate level = serum testosterone < 50ng/dL PCWG2 definition of PSA progression: 25% increase from nadir, with a minimum rise of 2 ng/ml

5 Current Available Guidelines for M0 CRPC ASCO (Virgo et al: JCO April 2017) castrate state should be maintained indefinitely No data support the use of second-line hormonal therapies for chemotherapy-naïve men with M0 CRPC who are at low risk of developing metastases (low risk is defined as low prostate-specific antigen [PSA] and slow PSA doubling time) high risk of developing metastases (rapid PSA doubling time or velocity), secondline hormonal therapies that lower PSA values or slow the rate of rise may be offered, preferably in a clinical trial setting where available AUA (Cookson et al: AUA 2015) Clinicians should recommend observation with continued androgen deprivation may offer treatment with first generation anti-androgens or first generation androgen synthesis inhibitors to patients unwilling to accept observation should not offer chemotherapy or immunotherapy outside the context of a clinical trial

6 Current Clinical Evidence for M0 CRPC There are no FDA-approved agents currently in this setting Baseline PSA levels and PSA doubling time are independently associated with metastasisfree survival and overall survival Smith et al JCO 2005 Hormonal manipulation beyond androgen deprivation therapy has not shown survival benefit and limited evidence from phase 2 studies efficacy only measured in PSA response Adding first generation anti-androgen 14% Anti-androgen withdrawl 21% Switching anti-androgen 35-45% Ketoconazole 27-56% Steroids 14-61% Estrogen derivatives 12-54%

7 What s New in M0 CRPC? Denosumab vs placebo in delaying bone-metastasis free survival Smith et al: Lancet 2012 Patient population high risk M0 CRPC as defined by baseline PSA > 8 ng/ml and/or PSA doubling time of < 10 months 120 mg of SC denosumab monthly vs placebo Bone scan q 4 months Delay in bone-metastasis free survival from 25 to 29 months (HR 0.85, p = 0.028), no improvement in OS ONJ rate = 5% Denosumab did not receive FDA approve for this indication

8 What s New in M0 CRPC? 2 negative phase 3 RCT s for selective endothelin-a receptor antagonists Atrasentan Nelson et al: Cancer 2008 Zibotentan Miller et al: Prostate Cancer Prostatic Dis 2013 Primary endpoints were metastasis-free and/or overall survival Studies done in metastatic CRPC alone or in combination with docetaxel were also negative

9 What s New in M0 CRPC? Other agents that have been studied in phase 2 trials Bevacizumab no impact on time to PSA progression Ogita et al: ISRN Oncology 2012 PSA-TRICOM (vaccine) no improvement PFS and OS compared to nilutamide Bilusic et al: JCO 2011 Orteronel single arm phase 2 study, time to metastasis = 25.4 months Saad et al: Lancet 2015 IMMAGEN: Abiraterone and prednisone single arm phase 2 study, time to PSA progression = 28.7 months - Ryan et al: JCO 2015 STRIVE (M0 subgroup) Enzalutamide vs bicalutamide rpfs benefit (HR 0.24, median not yet reached for E) Penson et al: J Urol 2015

10 Coming Soon To An Ad Board Meeting Near You PROSPER Phase 3 RCT of high-risk M0 CRPC (PSA DT < 10 months or PSA > 2 ng/ml) 1440 patients randomized 2:1 enzalutamide vs placebo Primary endpoint is metastasis-free survival SPARTAN Phase 3 RCT of high-risk M0 CRPC (PSA DT < 10 months) Apalutamide is a next-generation oral androgen receptor inhibitor 1200 patients randomized 2:1 apalutamide vs placebo Primary endpoint is metastasis-free survival

12 Surveillance Guidelines for M0 CRPC? No evidence provides guidance about optimal frequency of PSA monitoring ASCO guidelines suggest PSA q 4-6 months for low-risk, q 3 months for high-risk Bone scan and CT or MRI of abdomen/pelvis considered appropriate imaging modalities (PCWG3 criteria) Other modalities such FDG, PSMA or NaF-PET still considered investigational Routine radiographic imaging not recommended, unless PSA is unreliable or findings could alter treatment selection/management Virgo et al: JCO 2017

13 My Suggestions for GU Guidelines M0 CRPC Definition of M0 CRPC Define high-risk vs low-risk population and anticipated time to first metastasis PSA and imaging monitoring guidelines Systemic Therapy Maintain castrate levels of testosterone indefinitely Secondary hormone therapy considered for high-risk population based on physician discretion/experience and after discussion with patient re: benefit/toxicities No role for chemotherapy, immunotherapy, or bone-targeted therapy (specifically for improving metastasis-free survival)

Updates in Prostate Cancer Treatment 2018

Updates in Prostate Cancer Treatment 2018 Mountain States Cancer Conference Elaine T. Lam, MD November 3, 2018 Learning Objectives Understand the difference between hormone sensitive and castration resistant