2014 Treatment Paradigms in mcrpc Docetaxel in hormone sensitive PC

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1 Ronald de Wit Erasmus MC Cancer Institute The Netherlands 2014 Treatment Paradigms in mcrpc Docetaxel in hormone sensitive PC

2 Disclosures Sanofi ; research grant support, consultancy and speaker fees Astellas; consultancy Janssen; consultancy and speaker fees Millenium/Takeda; research grant support, consultancy.

3 mcrpc; recent paradigm shift CRPC - failing LHRH (+ castrate level) or - failing MAB + AA withdrawal attempt further hormonal manipulations - including abiraterone/ enzalutamide Docetaxel/ Cabazitaxel - used only for true HRPC

4 Phase III clinical trials in mcrpc Study Agents N Indication HR OS TAX Docetaxel/P vs mito/p 1006 mcrpc IMPACT 2 Sipuleucel-T vs pbo 512 mcrpc (pre- Doc) COU-AA COU-AA Abiraterone/P vs P Abiraterone/P vs P mcrpc (pre- Doc) mcrpc (post- Doc) PREVAIL 5 AFFIRM 6 Enzalutamide vs pbo Enzalutamide vs pbo (or P) mcrpc (pre- Doc) mcrpc (post- Doc) (est) +4.8 TROPIC 7 Cabazitaxel/P vs mito/p 755 mcrpc (post- Doc) SAGB.CAB c 12/01/2015 ALSYMPC A 8 Radium-223 vs pbo 921 mcrpc ADT: Androgen Deprivation Therapy; P: Prednisone; Pbo: Placebo; Mito:Mitoxantrone; Doc: Docetaxel; CRPC: Castration-Resistant Prostate Cancer 1. Tannock IA et al, NEJM 2004; 2. Kantoff PW et al. NEJM 2010; 3. Ryan CJ et al. ESMO 2014 ; 4. Fizazi K et al. Lancet Oncol 2012; Beer TM et al. NEJM 2014; 6. Scher HI et al. NEJM. 2012,; 7. De Bono J et al. Lancet 2010; 8. Parker C et al. NEJM. 2013, 4

5 Available (approved) Choices in mcrpc in 2014 Both docetaxel, cabazitaxel, abiraterone and enzalutamide available, but which sequence? - docetaxel followed by; -> cabazitaxel or abiraterone/enzalutamide initially? -> abiraterone/enzalutamide predocetaxel? 2014; Sequence question applies for both the pre and for the post docetaxel setting; 2014; Use of docetaxel in hormone sensitive prostate cancer Sequence; Predictors for response?

6 Is baseline Gleason score predictive of response to therapies? Study Agent N Gleason HR for OS SAGB.CAB c 12/01/2015 TAX327 1 Pre-docetaxel COU-AA Doc/P vs Mito/P Abi/P vs Pbo/P PREVAIL 3 ENZ/P vs Pbo 1717 Post-docetaxel COU-AA Abi/P vs Pbo/P 1195 <7 7 <8 8 <8 8 < Post-hoc analyses of TAX327, COU-AA-201 and COU-AA-302 trials; planned subgroup analyses of PREVAIL 1. Tannock IA et al, NEJM 2004; 351: ; 2. Fizazi K et al. J Clin Oncol 2014;32(Suppl): abstract 20; 3. Beer TM et al. NEJM 2014; 371: (appendix) P: Prednisone; Abi: Abiraterone acetate; ENZ: Enzalutamide ; Mito: mitoxantrone 6

7 Initial Gleason score may guide treatment choice in chemo-naive mcrpc patients 1. van Soest R et al Eur Urol 2013 (epub ahead of print); 2. Fizazi K, J Clin Oncol 2014; 32 (suppl 4): abstract 20; Mo: months; P: prednisone

8 Duration of prior ADT & activity of ENZ in post-docetaxel (AFFIRM) Duration of prior LHRHa rpfs (months) ENZ n= mths mths >26.9 mths Pbo n=76 ENZ n=164 Pbo n=81 ENZ (n=171) Pbo (n=75) Median Difference HR (95% CI) 0.44 ( ) 0.42 ( ) 0.33( ) Overall survival Median (mths) NYR 14.7 NYR 15.5 HR (95% CI) 0.49 ( ) 0.69 ( ) 0.54 ( ) SAGB.CAB c 12/01/2015 Post-hoc analysis of AFFIRM study Duration of prior ADT prognostic for OS and predictive for Enza? de Bono JS, et al. ECC 2013; Poster presentation P369 8

associated with poor response to subsequent endocrine therapy (abiraterone or

9 Response to ADT and efficacy of secondary hormone therapy, docetaxel, and cabazitaxel in mcrpc Rapid progression on ADT has a poor prognosis and seems to associated with poor response to subsequent endocrine therapy (abiraterone or enzalutamide), but not chemotherapy Angelergues et al J Clin Oncol 32, 2014 (suppl 4; abstr 282))

10 TROPIC: cabazitaxel improves survival whatever the duration of prior ADT Oudard S et al. Poster 933P [ESMO 2012]: post-hoc analysis

11 Available (approved) Choices in mcrpc in 2014 Both docetaxel, cabazitaxel, abiraterone and enzalutamide available, but which sequence? - docetaxel followed by; -> cabazitaxel or abiraterone/enzalutamide initially? -> abiraterone/enzalutamide predocetaxel? 2014; Sequence question applies for both the pre and for the post docetaxel setting; Does exhaustion AR affects efficacy taxanes?

Cancer Res 2009; 69: 8386 94 2. Zhu ML et al.

12 Taxanes (at least in part) work by inhibiting AR nuclear transport and signaling 1. Gan L et al. Cancer Res 2009; 69: Zhu ML et al. Cancer Res 2010; 70; Darshan MS et al. Cancer Res 2011; 71;

13 Cabazitaxel is more effective than docetaxel in an in vivo model of CRPC with acquired resistance to enzalutamide Van Soest, de Wit et al. Eur Urol 2014 in press December 5

14 Choices in 2014 What is the optimal sequence of therapies? Does exhaustion of the AR clinically affects efficacy of the taxanes? Probably yes, but what is the magnitude of the effect?

Retrospective trials showing impaired efficacy of docetaxel post-abi (in chemonaive patients) VENICE is a prospective phase 3 trial evaluating docetaxel/prednisone ± aflibercept References 2-4 are

15 Retrospective trials showing impaired efficacy of docetaxel post-abi (in chemonaive patients) VENICE is a prospective phase 3 trial evaluating docetaxel/prednisone ± aflibercept References 2-4 are retrospective trials in a small number of patients 1. Tannock et al. Lancet Oncol 2013;14:760-8; 2. Mezinski & De Bono Annal Oncol 2012;23: ; 3. Schweizer MT et al. Eur Urol 2014 (epub ahead of print); 4. Azrad et al. ASCO GU 2014 (abstract 97)

16 Does prior abiraterone/enzalutamide decrease the efficacy of cabazitaxel? TROPIC 1-2 Pezzaro 3 Angelergues 4 Abiraterone or enzalutamide intake No (n=378) Before Caba (n=59) Before Caba (n=42) After Caba (n=27) PSA decrease 50% 39.2% 39% 42.9% 48.1% Partial response (RECIST) Median radiological or clinical PFS (months) 14.4% 14% 3.5 mo 5.1 mo 10.5 mo Median OS (mo) from - Docetaxel - Cabazitaxel 29.4 mo 15.1 mo NR 15.8 mo 38.2 mo 13.3 mo 66.2 mo 49 mo 1De Bono et al. Lancet 2010;; 2 Sartor et al. ASCO Pezzaro et al. Eur Urol 2013 ; 4Angelergues et al. ASCO

17 What is the optimal sequence of therapies in 2014? AR targeted agents may clinically affect the efficacy of the taxanes Most concern is with the use of these agents pre docetaxel. Use of docetaxel in castrate sensitive setting, prior to novel AR targeted therapies might produce a new opportunity

18 <br /><br />E3805<br />CHAARTED: ChemoHormonal Therapy versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer Presented By Christopher Sweeney at 2014 ASCO Annual Meeting

19 Early Chemo+ADT: A debate in one slide a need for randomized phase 3 trial Presented By Christopher Sweeney at 2014 ASCO Annual Meeting

20 E3805 CHAARTED Treatment Presented By Christopher Sweeney at 2014 ASCO Annual Meeting

21 Key Eligibility Criteria Presented By Christopher Sweeney at 2014 ASCO Annual Meeting

22 Study Endpoints Presented By Christopher Sweeney at 2014 ASCO Annual Meeting

23 Statistical Design: History of CHAARTED<br />Intent to treat analysis, 80% power 1-sided alpha=2.5% to detect 33% improvement in median OS (with all versions) Presented By Christopher Sweeney at 2014 ASCO Annual Meeting

24 Results: Presented By Christopher Sweeney at 2014 ASCO Annual Meeting

25 Patient characteristics Presented By Christopher Sweeney at 2014 ASCO Annual Meeting

26 Primary endpoint: Overall survival Presented By Christopher Sweeney at 2014 ASCO Annual Meeting

27 OS by extent of metastatic disease at start of ADT Presented By Christopher Sweeney at 2014 ASCO Annual Meeting

28 Causes of Death Presented By Christopher Sweeney at 2014 ASCO Annual Meeting

29 ADT + Docetaxel benefited all subgroups Presented By Christopher Sweeney at 2014 ASCO Annual Meeting

30 Secondary Endpoints Presented By Christopher Sweeney at 2014 ASCO Annual Meeting

31 Therapy beyond progression Presented By Christopher Sweeney at 2014 ASCO Annual Meeting

32 Non-Hematologic Toxicity (%) Presented By Christopher Sweeney at 2014 ASCO Annual Meeting

33 Hematologic Toxicity (%) Presented By Christopher Sweeney at 2014 ASCO Annual Meeting

34 Clinical interpretation Presented By Christopher Sweeney at 2014 ASCO Annual Meeting

35 A Decade s Promise and Progress: E3805 Presented By Michael Morris at 2014 ASCO Annual Meeting

36 Drugs that prolong OS for CRPC Presented By Michael Morris at 2014 ASCO Annual Meeting

37 Overall survival by volume of mets at start of ADT Presented By Michael Morris at 2014 ASCO Annual Meeting

38 Comparison to GETUG15 Presented By Michael Morris at 2014 ASCO Annual Meeting

39 Conclusions Presented By Michael Morris at 2014 ASCO Annual Meeting

40 Which treatment to choose; Conclusions Docetaxel remains first-line treatment in mcrpc Cabazitaxel second-line treatment option: Survival benefit whatever the initial Gleason score and duration of ADT Abiraterone (A) and Enzalutamide (E) are effective 2 nd /3 rd -line agents: A is an option pre-chemotherapy if Gleason <8 plus response to ADT > 1 yr AR-targeted agents in sequence; only modestly effective If a taxane is still an option this should be preferred Docetaxel may provide greatest benefit in castrate sensitive M1 disease

Sequencing Strategies in Metastatic Castration Resistant Prostate Cancer (MCRPC)

Sequencing Strategies in Metastatic Castration Resistant Prostate Cancer (MCRPC) Amit Bahl Consultant Oncologist Bristol Cancer Institute Clinical Director Spire Specialist Care Centre UK Disclosures Advisory