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2 Figure 1 Androgen action Harris W P et al. (2009) Nat Clin Pract Urol doi: /ncpuro1296

3 Figure 2 Mechanisms of castration resistance in prostate cancer Harris W P et al. (2009) Nat Clin Pract Urol doi: /ncpuro1296

4 Bone Metastasis in Prostate Cancer! Bone: most frequent site of prostate cancer metastasis! Favorable microenvironment for prostate tumor cells! Lesions first appear in axial skeleton, then appendicular skeleton! Main source of prostate cancer associated morbidity Tumor Cells The vicious cycle of bone metastases and tumor cell growth in the bone marrow microenvironment [1] PTHrP IL-6 PGE 2 TNF M-CSF Osteoblast RANKL Osteoclast BMP PDGF FGFs IGFs TGF-β Bone 1. Roodman GD, et al. N Engl J Med. 2004;15:

5 Time to 1st SRE in Prostate Cancer Patients: Zoledronic Acid vs Placebo Patients Without Event (%) Saad F. AUA Abstract Median, Days P Value Zoledronic acid, 4 mg Placebo days Days From Start of Treatment No. at Risk Zoledronic Acid 4 mg Placebo

6 Denosumab: Properties and Pivotal Clinical Investigation! High affinity human monoclonal antibody that binds RANKL! Administered via SC injection! Specific: does not bind to TNF-α, TNF-β, TRAIL, or CD40L! Inhibits formation and activation of osteoclasts 1. Stopeck A, et al. SABCS Abstract Henry D, et al. ECCO/ESMO Abstract 20LBA.

7 Denosumab vs Zoledronic Acid in Patients With CRPC and Bone Metastases Prospective, double-blind, placebo-controlled phase III trial Patients with CRPC and bone metastases, no current or previous IV treatment with bisphosphonate (N = 1901) Denosumab 120 mg SC + Placebo IV q4w (n = 950) Zoledronic Acid 4 mg IV + Placebo SC q4w (n = 951) Fizazi K, et al. ASCO Abstract LBA4507.

8 Denosumab vs Zoledronic Acid: Time to First On-Study SRE 1.00 HR: 0.82 (95% CI: ; P =.0002 noninferiority; P =.008 superiority) Proportion of Subjects Without SRE Patients at Risk, n Zoledronic acid Denosumab 0 Denosumab Zoledronic acid KM Estimate of Median, Mos Study Mo Fizazi K, et al. ASCO Abstract LBA4507. Reprinted with permission

9 Denosumab vs Zoledronic Acid: Safety Adverse Event, % Fizazi K, et al. ASCO Abstract LBA4507. Zoledronic Acid (n = 945) Denosumab (n = 943) Serious adverse events Adverse events causing treatment discontinuation Most common adverse events Anemia Back pain Decreased appetite Nausea Fatigue Acute-phase reactions (first 3 days) Renal adverse events ONJ Hypocalcemia

10 Advanced Prostate Cancer

11 SWOG 99-16: Docetaxel vs Mitoxantrone! Docetaxel/estramustine/dexamethasone produced superior PFS and OS vs mitoxantrone/prednisone in patients with androgenindependent prostate cancer (N = 674) 100 P = P <.001 OS (%) Docetaxel + estramustine (217 deaths; median: 17.5 mos) Mitoxantrone + prednisone (235 deaths; median: 15.6 mos) Mos After Enrollment 48 PFS (%) Docetaxel + estramustine (311 events; median: 6.3 mos) Mitoxantrone + prednisone (312 events; median: 3.2 mos) Mos After Enrollment 48 Petrylak D, et al. N Engl J Med. 2004;351: Copyright 2009 Massachusetts Medical Society. All rights reserved.

12 TROPIC: Randomized, Prospective, Open-Label, Multinational Phase III Stratified by ECOG performance score (0,1 vs 2), and measurable vs nonmeasurable disease Trial Patients with metastatic CRPC progressing on docetaxel (N = 755) Mitoxantrone 12 mg/m 2 IV q3w + Prednisone 10 mg/day PO for 10 courses (n = 377) Cabazitaxel* 25 mg/m 2 IV q3w + Prednisone 10 mg/day PO for 10 courses (n = 378) *Cabazitaxel group premedicated with antihistamine, steroid, and H 2 antagonist IV at least 30 min prior to each cabazitaxel dose. Antiemetic prophylaxis administered as necessary in either arm. De Bono JS, et al. ASCO Abstract 4508.

13 TROPIC: Primary Endpoint OS Updated ITT Analysis OS (%) % reduction in risk of death Mos Patients at Risk, n MP CBZP De Bono JS, et al. ASCO Abstract Reprinted with permission. MP Censored MP CBZP Combined median follow-up: 13.7 mos CBZP Median OS, Mos HR % CI P value <.0001

14 TROPIC: Progression-Free Survival PFS (%) % reduction in risk of progression Mos Patients at Risk, n MP CBZP De Bono JS, et al. ASCO Abstract Reprinted with permission. MP Censored MP CBZP Combined median follow-up: 13.7 mos CBZP Median PFS, Mos HR % CI P value.0002

15 TROPIC: Response Rates and Toxicity! Significantly higher response rates with cabazitaxel plus prednisone vs mitoxantrone plus prednisone! Tumor assessment: 14.4% response with cabazitaxel plus prednisone vs 4.4% with mitoxantrone plus prednisone (P =. 0005)! PSA assessment: 39.2% response with cabazitaxel plus prednisone vs 17.8% with mitoxantrone plus prednisone (P =.0002)! Toxicity profile generally manageable and similar between treatment arms! Higher incidence of febrile neutropenia, myelosuppression, and diarrhea with cabazitaxel plus prednisone vs mitoxantrone plus prednisone De Bono JS, et al. ASCO Abstract 4508.

16 Advanced Prostate Cancer

17 Angiogenesis

18 Advanced Prostate Cancer

19 Cell Cycle Inhibition

20 Docetaxel/Prednisone ± Dasatinib in CRPC: Phase III Study Patients with metastatic CRPC (Planned N = 1380) Docetaxel + Prednisone + Placebo daily Docetaxel + Prednisone + Dasatinib 100 mg PO daily Primary endpoint: OS Secondary endpoints: untx, time to first SRE, pain intensity, time to PSA progression, tumor response rate, SD, safety/tolerability Available at:

21 Advanced Prostate Cancer

22 Knudsen, K. E. et al. Clin Cancer Res 2009;15: Copyright 2009 American Association for Cancer Research

23 Abiraterone: Inhibit adrenal androgen synthesis LHRH Brain Pituitary Inhibitor LH ACTH Inhibitor Testis Adrenal Gland Testosterone Androgens Inhibitor? Prostate Cancer? De novo synthesis

24 ASCO 2008 Danila De Bono

25 Abiraterone Acetate in CRPC! Abiraterone inhibits CYP17! Targets androgen receptor signaling by inhibiting androgen synthesis! CTC decline associated with improved OS Study Phase I/II chemotherapy naive Patients with CTC Decline, % 5 CTCs at baseline 34 Decline from > 5 to < 5 CTCs 55 CTC decline by 30% 65 Phase II post-docetaxel 5 CTCs at baseline 76 Decline from > 5 to < 5 CTCs 50 CTCs decline by 30% 73 Reprinted with permission from de Bono JS, et al. ASCO Abstract Probability Time to PSA Progression Phase I/II study (chemo naive) Phase II study (post-docetaxel) Median TTP 399 days 0.25 Median TTP 231 days Days

26 Overexpressed AR in CRPC makes tumors sensitive to even castrate testosterone Testicular/Adrenal synthesis T T Testosterone T AR AR T AR T AR AR DNA binding T AR AR T AR cell nucleus T AR Androgen Receptors 1/11/11 26

27 Bicalutamide reduces AR binding but allows translocation/dna binding = partial agonist Testicular/Adrenal synthesis B T T T Testosterone T DNA binding B AR cell nucleus T AR AR AR B AR AR T AR B B AR AR T Androgen Receptors bicalutamide 1/11/11 27

28 Effects of MDV3100 on the AR are Distinct from Bicalutamide HSP 90 LBD HD Ligand 1 1. AR Binding Affinity DHT ~ 5nM Bicalutamide ~160 nm MDV3100 ~35 nm DBD NTD 2 2. Nuclear Import DHT: ++++ Bicalutamide: ++++ MDV3100: ++ 4 POL II 3. DNA Binding DHT: ++++ Bicalutamide: ++ MDV3100: Coactivator recruitment DHT: ++++ Bicalutamide: ++ MDV3100: - DNA

29 MDV3100 Induces Regression of Xenografts p<0.05; **p<0.01 by Nonparametric ANOVA with Kruskal Wallis Post Test n=7 per group, oral dosing

30 MDV3100! Blocks ability of cancer cell to respond to androgen! Phase 1/2 trial in CRPC (30 men):! 22 had PSA decline for at least 12 weeks! 13 had PSA decrease of more than 50%! Well tolerated Tran C et al. Science 324:787-90, 2009

31 MDV3100: Novel Androgen Receptor Antagonist! Phase I/II dose-escalation study in patients with progressive CRPC Scher HI, et al. Lancet 2010.

32 Metabolic Activity MDV3100 Scher HI, et al. Lancet 2010.

33 Advanced Prostate Cancer

34 Active Cellular Immunotherapy with Sipuleucel-T Recombinant PAP antigen combines with resting Antigen Presenting Cell (APC) APC takes up the antigen Antigen is processed and presented on surface of the APC Fully activated, the APC is now sipuleucel-t INFUSE PATIENT Active T- cell Inactive T-cell T-cells proliferate and attack cancer cells Sipuleucel-T activates T-cells in the body The precise mechanism of sipuleucel-t in prostate cancer has not been established.

35 Sipuleucel-T Immunotherapy for Castration-Resistant Prostate Cancer Kantoff PW et al. N Engl J Med 2010;363: The vaccine costs $93,000, which works out at $23,000 per month of survival advantage.

36 Patient Responses KB MS JF DR

37 Future Cancer Cell 2010

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