Secondary Hormonal therapies in mcrpc

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1 Secondary Hormonal therapies in mcrpc Ravindran Kanesvaran Consultant,Division of Medical Oncology National Cancer Centre Singapore 1

2 Disclosures Research Support/P.I. Sanofi Consultant Major Stockholder Speakers Bureau Astellas, Bayer, Janssen, Pfizer, Mundipharma, Sanofi Honoraria Scientific Advisory Board Astellas, Bayer, Janssen, Pfizer, Mundipharma, Sanofi Astellas, Bayer, Janssen, Pfizer, Mundipharma, MSD, BMS 2

3 Outline Treatment landscape in 2016 Secondary hormonal therapies in mcrpc Sequencing Biomarkers in CRPC Summary 3

4 Outline Treatment landscape in 2016 Secondary hormonal therapies in mcrpc Sequencing Biomarkers in CRPC Summary 4

5 Slew of secondary hormonals Bicalutamide Ketoconazole Diethystilbestrol Dexamethasone/ Prednisolone Abiraterone acetate Enzalutamide 5

6 Abiraterone: Mechanism of action Cholesterol Pregnenolone CYP17 17α hydroxlase 17-OHpregnenolone Cortisol DHEA CYP17 17, 20-lyase Androstenedione Testosterone Estradiol 6 DHEA=dehydroepiandrosterone. Attard G, et al. J Clin Oncol2008;26:

7 Abiraterone: The COU-AA-301 trial Phase patients Progressive mcrpc postchemotherapy R A N D O M I S E D 2:1 Abiraterone 1000 mg QD + prednisone 5 mg BID (n=797) Placebo + prednisone 5 mg BID (n=398) Primary endpoint OS 7 BID=twice daily. Fizazi K, et al. Lancet Oncol 2012;13:

8 COU-AA-301: Overall survival 8 Median duration of treatment: 8 months and 4 months with abiraterone and placebo, respectively. P=prednisone. Fizazi K, et al. Lancet Oncol 2012;13:

9 9 Fizazi et al Lancet Oncol 2013

10 Enzalutamide: Mechanism of action Enzalutamide is an AR signalling inhibitor that directly targets three stages of the AR signalling pathway 10 A=androgen; AR=androgen receptor. Tran C, et al. Science 2009;324:

11 Enzalutamide: The AFFIRM trial Phase patients Progressive mcrpc postchemotherapy R A N D O M I S E D 2:1 Enzalutamide 160 mg QD (n=800) Placebo (n=399) Primary endpoint OS 11 Scher HI, et al. N Engl J Med 2012;367:

12 AFFIRM: Overall survival 12 NYR=not yet reached. Scher HI, et al. N Engl J Med 2012;367:

13 13 Scher et al NEJM 2012

Abiraterone: The COU-AA-302 trial (Chemo naïve) COU-AA-302 Phase 3 1088 patients with mcrpc Chemotherapynaïve No or mild symptoms R A N D O M I S E D Abiraterone 1000 mg QD +

14 Abiraterone: The COU-AA-302 trial (Chemo naïve) COU-AA-302 Phase patients with mcrpc Chemotherapynaïve No or mild symptoms R A N D O M I S E D Abiraterone 1000 mg QD + prednisone 5 mg BID (n=546) Placebo + prednisone 5 mg BID (n=542) Co-primary endpoints OS rpfs 1:1 14 rpfs=radiographic progression-free survival. Ryan CJ, et al. N Engl J Med 2013;368:

15 COU-AA-302: Efficacy outcomes 15 *Statistical significance did not cross the pre-specified significance level by O-Brien-Fleming boundary= Rathkopf DE, et al. Eur Urol 2014,

16 Enzalutamide: The PREVAIL trial (Chemo naïve) PREVAIL* Phase patients with mcrpc Chemotherapynaïve No or mild symptoms R A N D O M I S E D Enzalutamide 160 mg QD (n=872) Placebo (n=845) Co-primary endpoints OS rpfs 1:1 16 Beer TM, et al. N Engl J Med 2014;371:

17 PREVAIL*: Efficacy outcomes 17 Beer TM, et al. N Engl J Med 2014;371:

18 The PREVAIL Study (sub group analysis): Enzalutamide provided clinically significant benefit in mcrpc, with or without visceral disease, low or high volume disease 18 Evans CP et al. Eur Urol 2016;doi: /j.eururo

19 The PREVAIL Study: Specific Adverse Events of Interest All Grades, % Grade 3 Events, % Enzalutamide (n = 871) Placebo (n = 844) Enzalutamide (n = 871) Placebo (n = 844) Hypertension 13.4% 4.1% 6.8% 2.3% Any cardiac adverse event 10.1% 7.8% 2.8% 2.1% ALT increased 0.9% 0.6% 0.2% 0.1% Seizure 0.1% 0.1%^ 0.1% 0^ This seizure (n = 1) occurred after the data cutoff date ^Seizure in placebo arm was classified as grade 2 19 Beer TM, et al. NEJM 2014; 371(5)

20 Outline Treatment landscape in 2016 Secondary hormonal therapies in mcrpc Sequencing Biomarkers in CRPC Summary 20

21 Data on sequencing Scenario N Outcome Reference A after D and E 38 8% PSA 50% 18% PSA 30% PFS 2.7 mo Loriot 2013 A after D and E 30 No responses Noonan 2013 E after D and A % PSA 50% PFS 4.0 mo E after D and A 39 41% PSA 30% 13% PSA 50% CBZ after D and E/A 59 RR 14% Palliative benefit 24% 39% PSA 50% D after A 35 26% PSA 50% 37% PSA 30% All who failed A also failed D Schrader 2013 Bianchini 2013 Pezaro 2013 Mezynski A: abiraterone. E: enzalutamide. D: docetaxel. CBZ: cabazitaxel. Note: patients are more likely to be on opioid analgesia and have higher ALP and LDH later in course.

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23 Outline Treatment landscape in 2016 Secondary hormonal therapies in mcrpc Sequencing Biomarkers in CRPC Summary 23

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25 Predictor of resistance to treatment Detection of AR-V7 in CTC samples from patients with metastatic castration-resistant prostate cancer may predict resistance to enzalutamide and abiraterone Antonarakis E.S. et al. NEJM

26 Predictive Factors of Treatment Response 26

27 Best PSA Response (Enzalutamide) AR-V7(+) : 0/12 = 0% (95%CI: 0 26%) AR-V7( ) : 10/19 = 52.6% (95%CI: 29 76%) P = Antonarakis E.S. et al. NEJM

28 Best PSA Response (Abiraterone) AR-V7(+) : 0/6 = 0% 46%) (95%CI: 0 AR-V7( ) : 17/25 = 68.0% 46 85%) P = (95%CI: Antonarakis E.S. et al. NEJM

29 ARV7 + Responds to Chemotherapy 29

30 AR-V7 status can change with treatment 30

31 Outline Treatment landscape in 2016 Secondary hormonal therapies in mcrpc Sequencing Biomarkers in CRPC Summary 31

32 Conclusion Secondary hormonal therapies have a big role to play in the treatment of mcrpc Abiraterone acetate and enzalutamide have established roles in this area Important to understand the toxicities of the hormonal therapies Arv7 could be an important predictive biomarker 32

Singapore National Dental Centre Singapore National Heart Centre Singapore

33 THANK YOU 33 Members of the SingHealth Group Changi General Hospital KK Women s and Children s Hospital Singapore General Hospital National Cancer Centre Singapore National Dental Centre Singapore National Heart Centre Singapore National Neuroscience Institute Singapore National Eye Centre SingHealth Polyclinics

Second line hormone therapies. Dr Lisa Pickering Consultant Medical Oncologist ESMO Preceptorship Singapore 2017

Second line hormone therapies. Dr Lisa Pickering Consultant Medical Oncologist ESMO Preceptorship Singapore 2017 Second line hormone therapies Dr Lisa Pickering Consultant Medical Oncologist ESMO Preceptorship Singapore 2017 Disclosures Institutional Research Support/P.I. Employee Consultant Major Stockholder Speakers