Philip Kantoff, MD Dana-Farber Cancer Institute

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1 CHEMOTHERAPY FOR MCRPC Philip Kantoff, MD Dana-Farber Cancer Institute Harvard Medical School 1

2 Disclosure of Financial Relationships With Any Commercial Interest Name Nature of Financial Commercial Interests Relationships Philip Kantoff, MD Consultant Fees Amgen Inc., Bayer HealthCare Pharmaceuticals, Inc., BN ImmunoTherapeutics Inc., Dendreon Corporation, Exelixis, Inc., GTx, Inc., Janssen Pharmaceuticals, Inc. OncoCellMDX, Sanofi, SOTIO, LLC Scientific Advisory Board Bellicum Pharmaceuticals, Inc., BIND Biosciences, Inc., Metamark Genetics, Inc. Tokai Pharmaceuticals I do not plan to discuss the use of any off-label/unapproved use of drugs or devices.

3 Primary Chemotherapy Every 3-week docetaxel +/- prednisone has become the standard first line therapy for metastatic CRPC.

4 Phase 3 Trials of Docetaxel Combinations Docetaxel/Pred vs Docetaxel+/-Pred Combined With: Status Results DN-101 Terminated early Negative GVAX Terminated early Negative Bevacizumab Completed Negative Atrasentan Completed Negative ZD4054 Completed Negative Lenalidomide Terminated early Negative VEGF-Trap Completed Negative Dasatinib Completed Negative Custersin (OGX-011) Completed Pending 4

5 The Treatment Landscape in 2014 Standard Androgen Deprivation Therapy Denosumab, Zoledronic Acid Radium-223 Enzalutamide Local Therapy Androgen Deprivation Therapies After LHRH Agonists and Antiandrogens Abiraterone Chemotherapy Death Postchemotherapy Sipuleucel-T Docetaxel Cabazitaxel

6 IS THE ACTIVITY OF DOCETAXEL DIMINISHED AFTER ANDROGEN SIGNALING AGENTS? 6

7 7

8 Retrospective Analysis of Docetaxel Activity in Patients t Previously Treated with AA Of the 54 patients treated with AA, 35 subsequently received docetaxel. 9/35 (26%) patients treated with docetaxel had a PSA decline of 50% PSA declines 30% were achieved by 13/35 patients (37%, 95% CI 22% to 55%) All patients (n = 8) who failed to achieve a PSA fall on AA and were deemed AA-refractory were also docetaxelrefractory 8

9 Retrospective Analysis of Docetaxel Activity in Patients t Previously Treated with AA Of the 54 patients treated with AA, 35 subsequently received docetaxel. 9/35 (26%) patients treated with docetaxel had a PSA decline of 50% PSA declines 30% were achieved by 13/35 patients (37%, 95% CI 22% to 55%) All patients (n = 8) who failed to achieve a PSA fall on AA and were deemed AA-refractory were also docetaxel- refractory IT REMAINS UNKNOWN IF PRIOR TREATMENT WITH ANDROGEN BLOCKING AGENTS INTERFERES WITH EFFICACY OF DOCETAXEL 9

10 SECONDARY CHEMOTHERAPY 10

11 Cabazitaxel Semi-synthetic taxane Preclinical data As potent as docetaxel against sensitive cell lines and tumor models Activity against tumor cells and tumor models that are resistant to, or not sensitive to currently available taxanes Clinical data In Phase I trials, DLT was neutropenia Antitumor activity in mcrpc in Phase I trials including docetaxel- resistant disease

12 Proportion of OS (%) 100 Primary Endpoint: Overall Survival (ITT Analysis) Median OS (months) Hazard Ratio 95% CI P-value MP CBZP < months 6 months 12 months 18 months 24 months 30 months Number at risk MP CBZ DeBono et al Lancet 2010

13 Cabazitaxel Conclusions Cabazitaxel 30% risk reduction of death (HR = 0.70, P < ) Median OS improvement: 15.1 months vs 12.7 months Effective in both docetaxel sensitive and insensitive patients Granulocytopenia fever 7% Consider prophylactic growth factor support in those at higher risk (multiple risk factors) Alternatively consider lower dose

14 14 WHAT NEXT?

15 Firstana Trial Cabazitaxel 25mg/m2 mcrpc Cabazitaxel 20mg/m2 15 Endpoint-OS Fully accrued Docetaxel 75 mg/m2 plus prednisone

16 SHOULD CABAZITAXEL BE MOVED INTO EARLIER DISEASE 16

17 Proposed Trial Cabazitaxel 25mg/m2 mcrpc failing secondary hormone therapy Endpoint-PFS Abi if enza or enza if abi 17

18 Docetaxel in the Management of Metastatic HSPC 18

19 Metastatic HSPC: GETUG 15trial design n=385 pts Gravis G, Lancet Oncol 2013

20 Biochemical progression free survival Median PFS: ADT + D: 23 mo [ ] ADT: 13 mo [ ] 7] HR [95%CI]: 0.72 [ ] p= ADT+ docetaxel ADT ADT ADT+ docetaxel Gravis G, Lancet Oncol 2013

21 Clinical progression-free survival Median cpfs: ADT + D: 23 mo [ ] ADT: 15 mo [ ] 20] HR [95%CI]: 0.75 [ ] p= ADT+ docetaxel ADT ADT ADT+ docetaxel Gravis G, Lancet Oncol 2013

22 Overall Survival Median OS: ADT + D: 59 mo [51-69] ADT: 54 mo [42-NR] HR [95%CI]: 1.01 [ ] p= 0.95 ADT + docetaxel ADT ADT ADT + docetaxell Median follow-up: 50 months [49-54] Gravis G, Lancet Oncol 2013

23 Metastatic HSPC: CHAARTED Stratify Age > 70 vs < 70 ECOG - PS 0-1 vs 2 CAB > 30 DAYS Yes No Prior Adjuvant Hormonal Therapy > 12 months <12 months Bisphosphonate Yes No R A N D O M I Z E ECOG: CHAARTED Study; PI: Sweeney ARM A: Androgen Deprivation 3 plus Docetaxel 75 mg/m 2 every 21 days for maximum of 6 cycles ARM B: Androgen Deprivation 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 4 Follow for time to progression and overall survival. Chemotherapy at Investigator s discretion at progression 4

24 CHAARTED Statistical Considerations Enrollment: N= 780 pts High volume: visceral metastases and/or 4 or more bone metastases (with at least one beyond pelvis or vertebral column) Low volume: 3 or fewer bone mets and/or LN mets Primary endpoint: overall survival Powered to assess for a 33.3% 3% improvement in median OS (80% power and 1-sided alpha=2.5%).

25 NIH Press release 790 men with metastatic t ti HSPC between July 2006 and November 2012 randomized to ADT and ADT + docetaxel. A recent planned analysis showed that more men in the study who had received the combination of docetaxel and ADT were alive after three years (69 percent) than men who received only the ADT (52.5 percent). The benefit of the combination regimen was greatest (63.4 percent vs percent) for men with highly advanced prostate cancer.

26 TRIALS TESTING DOCETAXEL IN EARLY DISEASE 26

27 Lack of Success with Taxane-based Chemotherapy in Early High Risk Disease Neoadjuvant docetaxel-febbo Clin Cancer Res 2005 The 19 patients enrolled. Sixteen patients completed chemotherapy and had radical prostatectomy; none achieved pathologic complete response. Neoadjuvant ADT plus docetaxel, carbo, estramustine- Kelly J. Urol patients were treated with chemohormonal therapy The positive surgical margin rate was 22%. No CRs 27

28 DFCI High intermediate t and high risk prostate cancer N=340/350 ADT + XRT ADT + XRT + docetaxel q 3 week and then weekly PFS and OS D Amico and Kantoff 28

29 PEACE-2

30 Docetaxel in men with HSPC and Rising PSA Rising PSA following radical prostatectomy PSA doubling time of <9 months Minimum PSA of 1 Testosterone >100ng/ml N=420 RA ANDO OMIZ ZE Arm A Docetaxel 75 mg/m 2 q 3 weeks x 10 cycles GnRH agonist x 18 months Bicalutamide x 4 weeks Arm B GnRH agonist x 18 months Bicalutamide x 4 weeks The hypothesis of the study is that PFS probability will increase from 50% to 65% a minimum 36 months following randomization.

31 Conclusions Docetaxel +/- prednisone remains the standard d of care for men with mcrpc Use of sipuleucel-t, abiraterone and/or enzalutamide can be used before chemotherapy Some patients with mcrpc might benefit from earlier intervention with docetaxel-profile might include those with poor response to primary ADT, visceral disease etc. Cabazitaxel is effective in patients as second line chemotherapy whether or not they responded to docetaxel Docetaxel should be considered in men with mhspc along with ADT* 31

Early Chemotherapy for Metastatic Prostate Cancer

Early Chemotherapy for Metastatic Prostate Cancer Daniel P. Petrylak, MD Professor of Medicine and Urology Smilow Cancer Center Yale University Medical Center Disclosure Consultant: Sanofi Aventis, Celgene,