Bone-targeted therapies for prostate cancer in Institut Gustave Roussy Villejuif, France

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1 Bone-targeted therapies for prostate cancer in 2012 Pr Karim Fizazi, MD, PhD Institut Gustave Roussy Villejuif, France

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

3 Prostate cancer is the most frequent solid tumour associated with bone metastasis in Europe No. of patient ts (thousands) Bone mets Incidence (%): Median survival (months): Pts with active disease Pts with stage III IV disease Pts with bone mets Prostate Breast NSCLC Myeloma Kidney NSCLC, non-small cell lung cancer Data Sources: Mattson Jack Cancer METRIC Active Disease 2006, % of BP-treated BM pts from IMS onco DB MATQ3/05, IMS MIDAS MATQ3/05 MM Active disease Pts from Globocan

4 Osteolytic and osteoblastic bone metastases: presence of osteoclasts irrespective of radiology Osteolysis Osteoblastosis PC Osteolysis 1 Osteoblastosis 2 Black arrows = osteoclasts 1. Roodman GD. N Engl J Med 2004;350: Amgen, data on file

5 The prognostic importance of bone-related factors in CRPC Alkaline Phosphatase Urinary N-telopeptide Bone pain Previous SRE ASCO 2012, Abstr 4642

6 Defining Skeletal Related Events (SRE) Pain requiring Radiation to Bone Pathologic Fracture Spinal Cord Compression Surgery to Bone 33% 25% 8% 4% Saad, et al. J Urol 2003;169(Suppl).

7 Bone targeting before 2011 Bisphosphonates Zoledronic acic Clodronate Radio-pharmaceuticals Strontium-89 Samarium-153

8 Zoledronic acid for prevention of SRE in patients with metastatic CRPC Reduced proportion of patients with 1 SRE Increased time to first SRE Saad et al. Nat Cancer Inst 2002; 94 :

9 Prostate Cancer: ZEUS Key endpoints Primary: Time to bone metastases Others: Overall survival, PSA doubling time, substudies on bone markers 1,433 patients Prostate cancer, M0 +/- previous local curative treatment, +/- ADT High risk PCa with at least one of the following criteria: Gleason Score 8-10 pn+ PSA 20 at diagnosis R Zoledronic acid 4 mg q 3 months No Zoledronic acid* Treatment duration 4 years

10 Overall survival Clodronate in hormone-sensitive prostate cancer Metastatic disease (PR05 trial, n=278) HR: 0.77 ( ), p= Non-metastatic disease (PR04 trial, n=471) Dearnaley D, Lancet Oncol 2009, 10: 872-6

11 Radiopharmaceuticals Phase III Strontium-89 vs placebo after radiotherapy: Improvement in time to pain (n=126) (Porter 1993) No improvement (n=95) (Smeland 2003) Phase III Strontium-89 vs radiotherapy: Similar pain control (n=284) (Quilty 1994) Better OS: 7 months vs 11 months (p<0.05) (n=101) (Oosterhof 2003) Phase III Samarium-153 vs placebo: Better pain control (n=118) (Serafini 1998); (n=152) (Sartor 2004)

12 New data in 2012 with bone-targeted agents 1 bad news: Zibotentan 3 good news: Denosumab: Prevention SRE Prevention bone metastases Cabozantinib Alpharadin

13 Zibotentan Phase III (14): Overall Survival zibotentan 10 mg vs placebo: HR= %CI=(0.69, 1.10); P= Proportion Alive ITT population Number of deaths, n %1yr survival Medians (months) zibotentan 10 mg n= % 24.5 placebo n= % Time to Overall Survival (months) Randomised Treatment zibotentan 10mg placebo 22.5 Number of Patients at Risk Months zibotentan 10mg placebo Nelson J, ASCO GU 2011

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

15 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 OSB OSB + OSB + 2b + 2a LNCaP + PC3 CTR OPG RANKL Fizazi et al., Clin Cancer Res 2003;9: Fizazi et al., J Clin Oncol 2009; 27:

16 Key Inclusion Phase III trial of Denosumab in bone metastases from castrateresistant prostate cancer (103) 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

17 Denosumab: Time to First SRE Proportion of Subj jects 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 Subjects at risk: Study Month Zoledronic Acid Denosumab Fizazi et al. Lancet 2011; 377:

18 Time to First and Subsequent SRE Cumulative Mea an Number of SREs per Patient Rate Ratio = 0.82 (95% CI: 0.71, 0.94) P = Study Month 18% Risk Reduction Events Denosumab 494 Zoledronic acid *Events occurring at least 21 days apart Fizazi et al. Lancet 2011; 377:

19 Preventing the onset of the worse 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 F, J Natl Cancer Inst 2004;96: Fizazi K, Lancet 2011; 377:

20 Bone-targeted agents: Are they worth using? Significantly reduce morbidity Prevention vs treatment of bone morbidity Overall good tolerance No demonstrated role on survival 1-2% risk of ONJ

21 Bone-targeted agents: Price? Much cheaper than new cancer drugs Avoid SRE-related costs Dmab: avoids IV related costs Europe: Premium Dmab/Zol: % Cost-effectiveness depends on your country model US: Premium Dmab/Zol: +80%

22 Can Denosumab prevent the onset of bone metastases? The 147 trial Castrate-resistant prostate cancer at high risk for development of bone metastasis Denosumab 120 mg SC every 4 weeks (N = 716) Calcium and Vitamin D Supplementation Placebo 120 mg SC every 4 weeks (N = 716) PSA value 8.0 ng/ml within 3 mo before randomization AND/OR PSA doubling time 10.0 mo Primary Endpoint: Bone Metastasis-Free Survival Time to first bone metastasis (symptomatic or asymptomatic) or death on study

23 Denosumab significantly prolonged bone metastasis-free survival vs placebo 1.0 Primary endpoint was met Proportion of pa atients Placebo (n = 716) Denosumab (n = 716) HR = 0.85 (95% CI, ) P = Median: 25.2 months 29.5 months Study month Events: Smith MR, et al. Lancet 2012;379:39 46.

24 Bone metastasis-free survival in patients with PSA DT 6 months 1.0 HR = 0.77 (95% CI, ) P = Proportion of patients with bone metastasis s-free survival Placebo Denosumab 23% Placebo Denosumab Study month Median months Risk reduction Delay (months) %of study population Smith MR, et al. J Clin Oncol 2012;30(Suppl 5): [Abstract 6].

25 Time to Symptomatic Bone Metastasis 1.0 Proportio on of Patients Placebo Denosumab HR = 0.67 (95% CI 0.49, 0.92) P = % Placebo Denosumab Risk Reduction Events 96 (13%) 69 (10%) Study Month Oudard S, et al., ECCO-ESMO 2011

26 Overall Survival 1.0 HR = 1.01 (95% CI 0.85, 1.20) P = 0.91 Proportion of Patients Survived Placebo Denosumab Placebo Denosumab Study Month

27 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

28 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 to (cancer) cells Limited hematological toxicity

29 ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) Phase III Study Design TREATMENT PATIENTS STRATIFICATION Confirmed symptomatic CRPC 2 bone metastases No known visceral metastases Total ALP: < 220 U/L vs 220 U/L Bisphosphonate use: Yes vs No Prior docetaxel: Yes vs No Post-docetaxel or unfit for docetaxel R A N D O M I S E D 2:1 N = 922 Planned follow-up is 3 years Clinicaltrials.gov identifier: NCT injections at 4-week intervals Radium-223 (50 kbq/kg) + Best standard of care Placebo (saline) + Best standard of care

30 Radium-223 Phase III trial (ALSYMPCA): Overall Survival 100 n= HR = % CI, 0.581, P = % 50 Radium-223, n = 614 Median OS: 14.9 months Placebo, n = 307 Median OS: 11.3 months 10 0 Month Radium Placebo Parker C, ASCO 2012

31 Additional informations from the Alsympca final analysis? ECCO ASCO

Role for HGF and VEGF in Tumor-Bone Interactions HGF is highly expressed in bone metastases Stroma Angiogenesis VEGF Osteoblasts and osteoclasts express MET and VEGFRs respond to HGF and VEGF

32 Role for HGF and VEGF in Tumor-Bone Interactions HGF is highly expressed in bone metastases Stroma Angiogenesis VEGF Osteoblasts and osteoclasts express MET and VEGFRs respond to HGF and VEGF Proliferation Differentiation Survival HGF Osteoblast HGF VEGF HGF HGF and VEGF promote angiogenesis VEGF NP-1 MET HGF Migration Proliferation Survival Migration Proliferation Survival VEGF Osteoclast HGF and VEGF may be key factors mediating cross-talk between tumor cells, osteoblasts, and osteoclasts Tumor Cell

33 Bone Scan Effects of Cabozantinib Baseline Week 12 Docetaxel-pretreated Baseline Week 12 Docetaxel-pretreated Baseline Week 12 Docetaxel-pretreated Baseline Week 12 Docetaxel-naïve Each Patient had Pain Improvement Hussain M, ASCO 2011, Abstr 4516

34 Cabozantinib: ASCO 2011 vs ASCO 2012 n=171 Primary endpoint: Recist progression-free: 68% (vs hypothesis: 35%) Response (Recist): 4% PSA response not reported No PSA changes /imaging correlation Impressive bone scan improvement (post-hoc) Pain effect: Opioids decrease: 68% vs 33% (post-hoc) Activity on bone markers (ALP and CTx) TKI profile of toxicity Hussain M., ASCO 2011 n=93 Primary endpoint: Bone scan response (Computed Assisted Detection): 67% (Hypothesis?) Not reported CTC conversion: 39% (56%) Smith M, ASCO 2012, Abst 4513

35 Cabozantinib Phase 3 Trials in CRPC Key Eligibility Criteria CRPC with bone metastases Prior treatment with docetaxel + abiraterone and/or enzalutamide No limit on the number of prior therapies COMET--1 COMET COMET--2 COMET Primary Endpoint: Overall Survival Primary Endpoint: Confirmed Pain Response CRPC (N = 960) Randomization Cabozantinib (60 mg qd) CRPC with bone pain (N = 246) Randomization Prednisone Cabozantinib (60 mg qd) Mitoxantrone + Prednisone

36 Conclusion Bone targeting in 2012 Denosumab (Rank-L) Delays Skeletal-Related Events better than Zoledronic Acid Delays the onset bone metastases in non-metastatic CRPC Better but not much better ONJ, hypocalcemia with both agents Alpharadin (Rx-pharm) Improves OS and SRE in pts with CRPC and bone metastases Cabozantinib (Met, VEGF-R and others) Very promising phase II results Exact target? Planned phase III

37 Conclusion: Toward multi-drug treatment for bone metastases

Castrate-resistant prostate cancer: Bone-targeted agents. Pr Karim Fizazi, MD, PhD Institut Gustave Roussy Villejuif, France

Castrate-resistant prostate cancer: Bone-targeted agents Pr Karim Fizazi, MD, PhD Institut Gustave Roussy Villejuif, France Disclosure Participation in advisory boards or as a speaker for: Amgen, Astellas,