Traitement médical du Cancer de la Prostate: du désert à la profusion. Prof. Karim Fizazi, MD, PhD Institut Gustave Roussy Villejuif, France

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1 Traitement médical du Cancer de la Prostate: du désert à la profusion Prof. Karim Fizazi, MD, PhD Institut Gustave Roussy Villejuif, France

2 Disclosure Participation in advisory boards or as a speaker for: Amgen, Astellas-Medivation, Astrazeneca, Bayer, BMS, Celgene, Dendreon, Exelixis, Ipsen, Janssen-Cougar, Keocyt, Millennium- Takeda, Novartis, Sanofi-Aventis

3 Advanced prostate cancer: Natural history (in the 2000s) Local Treatment PSA relapse (ADT) Castrate-resistant, M0 Docetaxel Zoledronate ADT Metastatic Castrate-Resistant Prostate Cancer Metastatic Hormone-Sensitive prostate cancer

4 A decade of research : No significant result in prostate cancer : - Sipuleucel-T - Cabazitaxel - Denosumab - Abiraterone - Alpharadin - MDV 3100

5 Endocrine therapies Adrenals Testis Androgen Receptor inhibitors: -Bicalutamide -Enzalutamide (MDV 3100) Abiraterone Castration (alhrh or surgery) Testosterone Autocrine secretion Abiraterone DNA Cell division

6 b CYP17 blockade inhibits androgen synthesis

7 Abiraterone acetate Phase III post-chemo study design Patients COU 301 Efficacy end points (ITT) 1195 patients with progressive mcrpc Failed 1 or 2 chemotherapy regimens, 1 of which contained docetaxel R A N D O M I Z E D 2:1 Abiraterone 1000mg daily Prednisone 5mg BID n=797 Placebo daily Prednisone 5mg BID n=398 Primary end point: OS (HR 0.8) Secondary end points: TTPP rpfs PSA response

8 COU-301: Abiraterone prolongs survival in post-docetaxel mcrpc patients Fizazi K, et al. Lancet Oncol. 2012;13:

9 Clinical benefit of abiraterone October 2008 January 2010 Images courtesy of Dr Fizazi.

10 Abiraterone in asymptomatic mcrpc: the COU-AA-302 Phase III study Co-primary endpoints Patients Progressive chemo-naïve mcrpc Asymptomatic or mildly symptomatic Randomisation 1:1 Abiraterone acetate + prednisone (n = 546) Placebo + prednisone (n = 542) Radiographic progression-free survival Overall survival Secondary Time to opiate use (cancer-related pain) Time to initiation of chemotherapy Time to ECOG-PS deterioration Time to PSA progression Stratification by ECOG performance status 0 vs. 1 Ryan C, et al. American Society of Clinical Oncology Congress 2012; Abstract LBA4518.

11 COU-AA-302: interim results Statistically significant radiographicallyevidenced progression-free survival (rpfs) HR 0.43 (95% CI: ; P < ) Abiraterone acetate Control AA + P PL + P Abiraterone acetate Placebo Data cut off: 20/12/2010 Ryan C, et al. ASCO 2012; Abstract LBA 4518.

12 COU-AA-302: interim results Overall survival HR 0.75 (95% CI: ); P = Abiraterone acetate Control Abiraterone acetate Placebo Data cut off: 20/12/2011 Ryan C, et al. ASCO 2012; Abstract LBA 4518.

13 AFFIRM: A Phase 3 Trial of MDV3100 vs. Placebo in Post-Chemotherapy Treated CRPC Patient Population: 1199 patients with progressive CRPC Failed docetaxel chemotherapy R A N D O M I Z E D 2:1 MDV mg daily n = 800 Placebo n = 399 Primary Endpoint: Overall Survival Clinicaltrials.gov identifier: NCT

14 MDV3100 Prolonged Survival by a Median of 4.8 Months in the Phase 3 AFFIRM Trial Scher H, N Engl J Med 2012 Survival (%) HR = (0.529, 0.752) P < % Reduction in Risk of Death Placebo: 13.6 months (95% CI: 11.3, 15.8) MDV3100: 18.4 months (95% CI: 17.3, NYR)

15 Taxanes for CRPC Docetaxel Well-established drug in Oncology Main toxicity: Peripheral neurotoxicity Nail Toxicity Cabazitaxel Crosses the blood-brain barrier in vivo (humans?) Active in some docetaxel-resistant models Main toxicity: Hemato (G-CSF) Diarrhea

16 Cabazitaxel in Second-line CRPC TROPIC Phase III Study mhrpc Progression after TXT Stratification factor : ECOG PS (0,1 vs 2) Mesurable/non_mesurable Primary Endpoint: Overall survival R A N D O M I Z E 360 pts Cabazitaxel 25mg/m2 q3w Prednisone 10mg qd Mitoxantrone 12mg/m2 q3w Prednisone 10mg qd 360 pts Secondary Endpoint: PSA response, PSA progression, PFS, RR, Pain progression, Safety, PK of cabazitaxel Enrolment closed: 745/720 pts Hypothesis: 25% Reduction in the risk of death or median OS=10.67 months for cabazitaxel vs 8 months 511 events, duration 36 months

17 Cabazitaxel vs Mitoxantrone: Overall Survival Proportion of Overall Survival MTX+PRED CBZ+PRED Median OS (months) MP CBZP Hazard ratio % CI P-value < % risk of death reduction Number at Risk MTX + PRED CBZ + PRED Time (months) Median FU: 13.7 mo De Bono et al., Lancet 2010;376:

18 Is prostate cancer a chemosensitive neoplasm? High response rate (>50%) in first-line Benefit in OS in first-line (Docetaxel) Second-line chemotherapy with demonstrated activity (Cabazitaxel) Chemotherapy improves PFS/OS when used in the localized setting to prevent relapse YES YES YES: OS! First answer in 2014?

19 Sipuleucel-T: Autologous APCs cultured with antigen fusion protein (PAP)

20 Sipuleucel-T autologous vaccine: Overall Survival Sipuleucel-T (n = 341) vs Placebo (n=171) Median OS: 25.8 vs 21.7 months 100 p = (Cox model) HR = 0.78 [95% CI: 0.61, 0.98] Percent Survival Survival (Months) Small EJ, J Clin Oncol 2009; 24: Kantoff PW, NEJM 2010, 363:

21 The vicious cycle of bone metastases Prostate cancer cells Cytokines and Growth Factors (ET-1, IL-6, IL-8, TNF-, PTHrP, etc) RANKL RANK RANKL Osteoblast lineage Direct effects on tumor? Osteoclast Growth Factors (TGF- IGFs, FGFs, PDGFs, BMPs) Bone Resorption Bone Ca 2+ Adapted from Roodman GD. N Engl J Med. 2004;350:

22 Targeting RANK-L: Proof of concept RANK-L overexpressed by osteoblasts in bone metastases Positive randomized Phase II: Denosumab decreases untx (biomarker for osteolysis) CTR OSB + 2b OSB + 2a OSB + LNCaP OSB + PC3 CTR OPG RANKL Fizazi et al., Clin Cancer Res 2003;9: Fizazi et al., J Clin Oncol 2009; 27:

23 Phase III trial of Denosumab in bone metastases from castrateresistant prostate cancer (103) Key Inclusion Castration-resistant prostate cancer and bone metastases Denosumab 120 mg SC and Placebo IV* every 4 weeks Key Exclusion SRE Current or prior intravenous bisphosphonate administration Zoledronic acid 4 mg IV* and Placebo SC every 4 weeks n= 1901 patients + Supplemental Calcium and Vitamin D

24 Denosumab: Time to First SRE Proportion of Subjects Without SRE HR 0.82 (95% CI: 0.71, 0.95) P = (Non-inferiority) P = (Superiority) Denosumab Zoledronic acid KM Estimate of Median Months % Risk Reduction Study Month Subjects at risk: Zoledronic Acid Denosumab Fizazi et al. Lancet 2011; 377:

25 Preventing the onset of the worst enemy: Spinal cord compression 9 8 8% 4% 2.7% 7 6 % Placebo Zoledronic acid Zoledronic acid Dmab ZA pivotal trial 103 trial Denosumab (120 mg Q4W) is not approved in the EU for use in patients with advanced cancer to delay SREs. Denosumab is investigational in that setting Saad, et al. J Natl Cancer Inst 2004;96:879 82; Fizazi et al. Lancet 2011; 377:

26 Radiopharmaceuticals: α versus β-emitters β-emitters: Strontium-89 Samarium-153 β-particles: 1 electron Relative mass: 1 α-emitter: Radium-223 α-particles: 2 neutrons + 2 protons Relative mass: 7000

27 Cell killing and marrow penetration: Two advantages of α-emitters Large molecule + High Linear Energy Transfer Low marrow penetration ( 100 μm ) More DNA double-strand breaks In (cancer) cells Limited hematological toxicity

28 ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) Phase III Study Design TREATMENT PATIENTS Confirmed symptomatic CRPC 2 bone metastases No known visceral metastases Postdocetaxel or unfit for docetaxel STRATIFICATION Total ALP: < 220 U/L vs 220 U/L Bisphosphonate use: Yes vs No Prior docetaxel: Yes vs No R A N D O M I Z E D 2:1 N = injections at 4-week intervals Radium-223 (50 kbq/kg) + Best standard of care Placebo (saline) + Best standard of care Planned follow-up is 3 years Clinicaltrials.gov identifier: NCT

29 Radium-223 Phase III trial (ALSYMPCA): Overall Survival n=921 HR = % CI, 0.581, P = % Placebo, n = 307 Median OS: 11.3 months Radium-223, n = 614 Median OS: 14.9 months 0 Month Radium Placebo Parker C, ASCO 2012

30 Systemic treatment for CRPC in Local Treatment PSA relapse (ADT) Castrate-resistant, M0 Abiraterone Abiraterone Enzalutamide Radium 223 Cabazitaxel Docetaxel Denosumab Zoledronate ADT Metastatic Castrate-Resistant Prostate Cancer Continuous ADT Metastatic Hormone-Sensitive prostate cancer

31 The cornucopia of new drugs for CRPC for in the CRPC future Endocrine agents ODM 201 (ESMO 12) ARN 509 (ASCO 12) Orteronel Immunotherapy Ipilimumab (2013?) Prostvac Tasquinimod Bone-targeting agents Cabozantinib (ASCO 12) Dasatinib (2013?) HSP-targeting drugs OGX 011, OGX 427 Endocrine agents Abiraterone Enzalutamide Immunotherapy Sipuleucel-T Chemotherapy Cabazitaxel Bone-targeting agents Denosumab Alpharadin