Chemohormonal Therapy For Prostate Cancer. What is old, is new again!

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1 Chemohormonal Therapy For Prostate Cancer What is old, is new again! Mount Tremblant January 20, 2017 Kala S. Sridhar MD, MSc, FRCPC Medical Oncologist, Princess Margaret Hospital Head, GU Medical Oncology Site Group Associate Professor, University of Toronto Toronto, ON

2 Prostate Cancer Background Most common cancer in men 2 nd most frequent cancer related death 24, 600 new cases, 4,300 deaths (Can) 220,000 new cases, 32,050 deaths (US)

3 Prostate Cancer Disease Spectrum Localized Prostate Cancer Castration naive prostate cancer (CNPC) Castration resistant prostate cancer (CRPC) ADT Local Therapy ~ 200,000pts Salvage RT PSA rise M0 M1 ADT +/ Docetaxel M0 CRPC M1 CRPC Abiraterone Enzalutamide Docetaxel Cabazitaxel Radium 223 De Novo M1 5% ~ 10,000 pts (may increase with less PSA screening)

4 Hormone Sensitive Metastatic Prostate Cancer Most patients respond to androgen deprivation (ADT), standard of care for >70 yrs Some patients do well on ADT alone Presence of visceral disease or bone metastases beyond the axial skeleton is associated with poor outcomes Docetaxel was the first drug to offer a survival benefit (3.1 mo) in castration resistant disease 1 Huggins and Hodges Cancer Res, 1941; 2 Tangen J. Urol, 2012; 3 Millikan J.Clin Oncol, 2008; 4 Eisenberger NEJM, 1998; 5 Tannock NEJM, 2004; 6 Petrylak NEJM, 2004.

Rationale for ADT + Early Chemo+ADT Androgen

testosterone independent clones early allow ADT

the time of progression are too frail for chemo.

5 Rationale for ADT + Early Chemo+ADT Androgen Deprivation Therapy Pro Attack de novo testosterone independent clones early allow ADT to keep disease in remission Some patients at the time of progression are too frail for chemo. Re Regression emergence Con ADT will take cells out of cycle and be less responsive to cytotoxics Some patients respond for a long time and never need chemotherapy

6 E3805 CHAARTED Treatment Stratification Extent of Mets High vs Low Age 70 vs < 70y ECOG PS 0 1 vs 2 CAB> 30 days Yes vs No SRE Prevention Yes vs No Prior Adjuvant ADT 12 vs > 12 months R A N D O M I Z E ARM A: ADT + Docetaxel 75mg/m2 every 21 days for maximum 6 cycles ARM B: ADT (androgen deprivation therapy alone) Evaluate every 3 weeks while receiving docetaxel and at week 24 then every 12 weeks Evaluate every 12 weeks Follow for time to progression and overall survival Chemotherapy at investigator s discretion at progression ADT allowed up to 120 days prior to randomization. Intermittent ADT dosing was not allowed Standard dexamethasone premedication but no daily prednisone

7 Primary endpoint: Overall survival Update with median follow up: 53.7 months Sweeney et al ESMO 2016 Median (95% CI) ADT + D OS 57.6 (52.0, 63.9) ADT alone 47.2 (41.8, 52.8) p value (stratified* logrank)

8 Patient Demographics Median age of 64 y Caucasian: 88% High volume: 66% No prior localized therapy / de novo mets: 72% 5% prior adjuvant ADT So predominantly fit younger men with high volume de novo metastatic prostate cancer

9 Causes of Death ADT +Doc (N=397) ADT alone (N=393) N % N % Due to prostate Ca Due to protocol Rx Other cause Unknown Missing 0 2 Total Sweeney et al NEJM 2015

10 Outcome by Volume of Disease N Overall High volume Overall Survival and Number of Deaths by Subgroup ADT + D (Arm A) ADT alone (Arm B) p value Median (stratifie Median (95% Death Death (n) N (95% CI; d CI; months) (n) months) logrank) Low volume (52.0, 63.9) 51.2 (45.2, 58.1) 63.5 (58.3, 78.5) (41.8, 52.8) 34.4 (30.1, 42.1) NR (59.8, ) <

11 Long term CHAARTED data OS high volume OS - low volume Sweeney et al ESMO 2016

12 Secondary Endpoints ADT + Doc (N=397) ADT alone (N=393) P-value Hazard Ratio (95%CI*) PSA <0.2 ng/ml at 6 months PSA <0.2 ng/ml at 12 months Median time to CRPC - biochemical, symptoms, or radiographic (months) 27.5% 14.0% < % 11.7% < < (0.44, 0.70) Median time to clinical progression - symptoms or radiographic (months) *CI: confidence intervals < (0.37, 0.65) Sweeney et al NEJM 2015

13 CHAARTED Overall QOL on FACT P ADT plus docetaxel P<0.01 N=544 p=0.02 n = 706 ADT alone

14 CHAARTED Overall QOL on FACT P FACT P high volume FACT P low volume FACT Taxane high volume FACT Taxane low volume

15 Findings The combination of standard ADT and 6 cycles of docetaxel significantly improved OS compared to standard ADT alone in HSPC The benefit in patients with a high volume of metastases is clear and justifies the treatment burden Need to be chemo fit longer follow up for patients with low volume metastatic disease indicates no clear benefit possibly some who do but need better strategies to identify them

16 Some questions remain... Why is there benefit in high volume? 1) These patients have more events sooner and early chemo has an effect sooner? 2) Lower volume have less clonal evolution and more AR dependent and just need ADT alone? 3) Both 1 and 2?

17 GETUG Study

18 GETUG OS Results Median F/U 81.3 mo ( )

19 GETUG Summary GETUG accrued 385 patients, 1:1 randomized Average median follow up was 50 months Median survival 54.2 vs months Declared to be a negative study...

20 Comparison with GETUG The main differences were sample size, patient population and and subsequent treatments However, when GETUG was updated and prognostic criteria on GETUG and CHAARTED were aligned (HVD vs LVD) there were more similarities than differences between the trials and a trend to improved OS in GETUG15, but not enough power Gravis, G ASCO 2015

21 Align Definitions: ADT alone on CHAARTED and GETUG15 are Alike GETUG Median OS ADT alone: 35.1 [ ] ADT + D: 39 [ ] HR: 0.8 [ ] p=0.35 GETUG Median OS ADT alone: NR [61.8 NR] ADT + D: 83.1 [69.5 NR] HR: 1.0 [ ] p=0.87

22 STAMPEDE

23 Inclusion Criteria

24 Failure Free Survival

25 OS

26 Survival M1 Patients No stratification of M1 by volume of disease ADT alone arm looks very similar to CHAARTED? OS benefit driven by high volume pts Median OS SOC SOC+Doc 45m 60m HR (95%CI) 0.73 (0.59, 0.89) P value MRC STAMPEDE trial James et al Lancet 2015

27 So.what have we learnt? Early docetaxel works better in English speaking countries: No The CHAARTED and STAMPEDE investigators got lucky: No Therapies for CRPC subsequent to ADT and early docetaxel is key: Maybe.

28 Current Evidence M1 docetaxel: Failure free survival Results based on 2993 men / 2198 events Trial name CHAARTED GETUG 15 STAMPEDE (SOC +/ Doc) STAMPEDE (SOC+ZA +/ Doc) Overall Favours SOC + docetaxel.5 HR=0.64 (0.58, 0.70); p< Favours SOC 1 2 Heterogeneity:χ 2 =1.66, df=3, p=0.646, I 2 =0% ALL STUDIES GREATER DEBULKING OF THE DISEASE AND DELAYED PROGRESSION

29 Time to CRPC ADT + D Median (95% CI; months) ADT alone Median (95% CI; months) p value (stratified* logrank) Overall Chaarted 19.4 (16.8, 22.6) 11.7 (10.8, 14.4) <.0001 Overall GETUG 22.9 ( ) 12.9 CI, < HV Chaarted 14.9 (12.4, 17.2) 8.6 (6.8, 10.5) <.0001 HV GETUC 15.2 ( ( ) <0.001 LV Chaarted 31.0 (23.1, 51.1) 22.7 (18.9, 29.1) 0.03 LV Getug 40.9 ( ) 22.4 ( ) 0.16

30 GETUG 15 had Key Difference between GETUG15/STAMPEDE/CHAARTED Best OS on ADT alone arm overall Lowest % of patients with high volume disease Like CHAARTED Time to CRPC significantly longer in HV vs low volume Less access to subsequent life prolonging CRPC therapies Suggestion of OS benefit in HV and not a hint of benefit LV

31 Chance of Benefit with Early Docetaxel competing risks for death High Volume Low Volume Young Certain Likely not Life Expectancy (~5 yrs) Probably Likely not The availability of other well tolerated and effective treatment options cannot be ignored Patients need to be selected carefully regardless of the treatment

32 Ongoing randomized mhspc trials Control Arm Experimental Arm Acronyms Sponsor ADT + NSAA (+/ Docet) ADT + Enza (+/ Docet) EnzaMet ARCHES ANZUP Astellas ADT (No docet) Control + TAK700 SWOG ADT (PEACE 1: strat by docetaxel use) Control + Abiraterone PEACE1 Latitude STAMPEDE Arm G Uni/EORTC Janssen MRC ADT (strat by docet in last few) ADT +(+/ Docet) ADT + Docet ADT (strat by docet) ADT + abi + Enza STAMPEDE Arm J MRC ADT + Apalutamide (+/ Docet) ADT + Darolutamide +Docet TITAN ARASENS Janssen Bayer ADT + metformin STAMPEDE Arm K MRC ADT+Doc ADT+Doc+radium Proposals only MRC Alliance

33 Conclusion The use of chemotherapy for HSPC has shown significant benefits, esp. in high volume patients Overall chemo is well tolerated, and may offset the fact that many patients never end up getting docetaxel Trials are ongoing in HSPC, using other agents currently available in CRPC

34 Thank you for your attention.

Perspective on endocrine and chemotherapy agents. Cora N. Sternberg Department of Medical Oncology San Camillo & Forlanini Hospitals Rome, Italy

Perspective on endocrine and chemotherapy agents Cora N. Sternberg Department of Medical Oncology San Camillo & Forlanini Hospitals Rome, Italy Disclosures Dr. Sternberg has received research funding for