The document summarizes key information about prostate cancer including incidence, mortality rates, clinical stages, risk groups for localized prostate cancer, treatment options for advanced disease including hormone therapy and chemotherapy, and results from clinical trials of chemotherapy agents like docetaxel and cabazitaxel.

1. Prostate Cancer State of the art in Management Ali Shamseddine, MD Professor of Medicine Head, Hematology and Oncology Division American University of Beirut Medical Center Amman Oct.2011

2. Incidence and Mortality Crude annual incidence of prostate cancer in the European Union is 78.9/100 000 men Mortality in the EU is 30.6/100 000 men/year

3. Clinical States of Prostate Cancer Clinically localized Biochemically relapsed Non-metastatic, hormone- responsive Metastatic, hormone- responsive Non- metastatic CRPC Metastatic CRPC 10 -15 years + Death from co-morbidities Prostate cancer- specific death From George D. ASCO Prostate 2007

4. Risk Groups for Clinically Localized Prostate Cancer D’Amico A, et al. Oncology 2001; 15: 1049-1059; D’Amico A, et al. JAMA 1998; 280: 969-974. Risk group Characteristics Expected 10-yr PSA failure-free survival Low PSA < 10 and Gleason score < 7 and AJCC stage T1c, T2a 80 - 85% Intermediate PSA = 10 - 20 or Gleason score = 7 or AJCC stage T2b 50 - 60% High PSA > 20 or Gleason score > 7 or AJCC stage T2c, T3 30 - 40%

5. And When Hormone Therapy Fails? Possible strategies include: Adding an antiandrogen to castration 54% of patients obtain a >50% drop in PSA Adding castration to antiandrogen monotherapy 55% of patients obtain a >20% drop in PSA Antiandrogen withdrawal 15-20% PSA response for up to 5 months Lam JS et al. J Urol 2006;175: 27.

6. Secondary Hormonal Therapies? 1 Small EJ, et al. J Urol 1997; 157: 1204–1207. 2 Orlando M, et al. Ann Oncol 2000; 11: 177–181. 3 Weitzman AT, et al. J Urol 2000; 163: 834-837 4. Lucas A, Petrylak DP, et al. J Urol 2006; 176: S72 Secondary hormonal therapies have not been shown to improve survival 4 ↓ PSA >50% Ketoconazole (+HC) 62% 1 Estrogens 80% 2 Dexamethasone 61 - 0% 1,3

7. What Determines Whether a Patient Is Castration Resistant? Has an attempt been made to suppress the patient’s testosterone production through orchiectomy or hormone suppression therapy with an LHRH agonist with or without an antiandrogen (ie, ADT)? Is the patient’s testosterone level < 50 ng/mL? If the answer to both is yes, the patient is Hormone resistant

8. Definition of CRPC: Progression CRPC will develop in nearly all patients receiving ADT Definition: rising PSA with bone,nodal or visceral lesions or growth of measurable disease despite castrate testosterone levels [1] Prostate cancers that progress despite castrate levels of testosterone are classified as CRPC According to the 2008 guidelines published by the Prostate Cancer Clinical Trials Working Group, several criteria are used to define disease progression [2] ≥ 2 bone lesions Reappearance of primary prostate tumor in prostatic fossa after surgery New lesions at other sites of metastasis 1. Scher HI, et al. J Clin Oncol. 2005;23:8253-8261. 2. Scher HI, et al. J Clin Oncol. 2008;26:1148-1159 .

9. Beer T, modified Disease Burden Median Survival Chemotherapy Indicated Rising PSA only ~4 years ? ? Asymptomatic metastases (limited) ~18 to 24 months Individualize Asymptomatic metastases (extensive) ~18 months Yes Symptomatic metastases ~9 to 16 months Yes

10. Current Treatment Options

11. 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 1. Roodman GD, et al. N Engl J Med. 2004;15:1655-1664. The “vicious cycle” of bone metastases and tumor cell growth in the bone marrow microenvironment [1] RANKL Tumor Cells PTHrP IL-6 PGE 2 TNF M-CSF Osteoclast Bone BMP PDGF FGFs IGFs TGF- β Osteoblast

12. Time to 1st SRE in Prostate Cancer Patients: Zoledronic Acid vs Placebo Median, Days P Value Zoledronic acid , 4 mg 488 .009 Placebo 321 . Saad F, et al. J Natl Cancer Inst . 2004;96:879-882 No. at Risk Zoledronic Acid 4 mg 214 149 97 70 47 35 3 Placebo 208 128 78 44 32 20 3 Patients Without Event (%) 167 days 0 20 40 60 80 100 0 120 240 360 480 600 720 Days From Start of Treatment

13. Chemotherapy

14. When Is Chemotherapy Appropriate in the CRPC Patient? Yes, this patient should receive chemotherapy Nodal spread with no evidence of bone or visceral (liver, lung) disease Bone disease without nodal disease or visceral spread Visceral metastases with or without other metastatic sites No, this patient should not receive chemotherapy Locally progressing tumor without metastatic disease Rising PSA and no detectable metastatic disease (rising PSA-castrate)

15. In 1990s ≥ 50%  PSA response and pain response were introduced as surrogate endpoints 1 2 trials with mitoxantrone 2,3 relieves of pain due to metastasis in 29% of patients ≥ 50%  PSA in 33% of patients no survival improvement but not powered to test for a survival difference median survival 12 months Historical Data 1 Kelly et al J Clin Oncol. 1993 2 Tannock et al. J Clin Oncol. 1996; 14: 1756-1764 3 Kantoff et al. J Clin Oncol. 1999; 17: 2506-2513

16. Chemotherapy for mCRPC ? ? Experiences in 2003/2004 no standard cytotoxic regimen start chemotherapy for asymptomatic versus symptomatic progression no survival benefit for early initiation mono- versus combination therapy treatment in centres only Heidenreich A; Eur Urol 2003

17. Metastatic Castrate Resistant Prostate Cancer Taxane - based chemotherapy Two landmark Phase III trials with docetaxel-based therapy (TAX 327 and SWOG 9916) have shown a survival benefit with docetaxel chemotherapy for patients with metastatic CRPC Tannock I, N Engl J Med, 2004 Oct 7;351(15):1502-12 Petrylak D, N Engl J Med, 2004 Oct 7;351(15):1513-20

18. SWOG 9916 Overall Survival HR=0.80 (95% CI: 0.67–0.97); p=0.02 Taxotere® + estramustine Mitoxantrone + prednisone No. at risk 338 336 No. of deaths 217 235 Median OS (months) 17.5 15.6 Months 0 0.2 0.4 0.6 0.8 1.0 0 12 24 36 48 Taxotere® + estramustine Mitoxantrone + prednisone Probability of surviving 0 0.2 0.4 0.6 0.8 1.0 0 12 24 36 48 Petrylak et al, N Engl J Med 2004; 351: 1513-1520 HR: 0.80 (95% CI 0.67, 0.97), p = 0.01

19. Overall Survival Every 3 week Docetaxel Median survival Hazard (mos) ratio P-value Combined: 18.2 0.83 0.03 D 3 wkly: 18.9 0.76 0.009 D wkly: 17.3 0.91 0.3 Mitoxantrone 16.4 – – Months Probability of Surviving 0 6 12 18 24 30 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Docetaxel 3 wkly Docetaxel wkly Mitoxantrone Tannock I, N Engl J Med, 2004 Oct 7;351(15):1502-12 18.9 mos 16.4 mos

20. TAX 327 3-yr Updated Survival Analysis Berthold D et al. J. Clin. Oncol. 2008; 26:242-45 Median survival Hazard (mos) ratio P-value D 3 wkly: 19.3 0.79 0.005 D wkly: 17.8 0.87 0.10 Mitoxantrone 16.3 – –

21. Overall survival by 30% PSA decline Armstrong A J, et al. J Clin Oncol 2007, 26: 3965-3970

22. Overall survival by PSA normalization 0 0.25 0.50 0.75 1.00 0 5 10 15 20 25 30 35 40 45 50 PSA not normalized (n=743 ) PSA normalized (n=115) HR 0.30 (95% CI: 0.23–0.39) p<0.0001 Proportion surviving (%) Survival Time (months) Armstrong A J, et al. J Clin Oncol 2007, 26: 3965-3970

23. TAX 327 Survival by PSADT 0.25 0.50 0.75 1.00 Survival (%) 0 5 10 15 20 25 30 35 40 45 50 Survival (months) Log-rank p<0.001 0 Armstrong A J, et al. Clin Cancer Res 2007; 13 (21):6396-6403 PSADT <1 month PSADT 1–2 months PSADT 4–6 months PSADT >6 months PSADT 2–3 months

24. ITT Age < 65 Age ≥ 65 Age ≥ 75 Pain no Pain yes KPS ≥ 80 KPS ≤ 70 Docetaxel Mitoxantrone TAX 327: Survival Benefit Across All Subgroups Hazard ratio in favor of Improved survival in asymptomatic,symptomatic and elderly Berthold DR, et al. ASCO Prostate 2007 ; abstract # 147

25. Chemotherapy for mCRPC SWOG 99-16 TAX 327 update Docetaxel PSA Response Rate 50% 45.4% Mitoxantrone PSA Response Rate 27% 32% Docetaxel Overall Survival 18 mos 19.3 mos Improvement in Survival 2 mos 3 mos Hazard Ratio vs M+P 0.80 0.79 p value 0.01 0.005

26. What to do in PSA  following Docetaxel? all patients will progress mean progression-free survival 8 months what will be the standard approach?

27. Facing the Challenge of CRPC

28. Cabazitaxel: Tubulin-Targeting Drug Microtubule Inhibitor 1,2 Promotes assembly Stabilizes Inhibits cell transport Taxoid site ( b -tubulin) Docetaxel Cabazitaxel 1) Engels FK et al. Br J Cancer 2005;93:173-177; 2) Greenberger LM, Sampath D. Resistance to taxanes. In: Teicher BA, ed. Cancer Drug Discovery and Development: Cancer Drug Resistance . Totowa, New Jersey: Humana Press; 2006:329-358. Cabazitaxel Courtesy of sanofi-aventis Web site: http://www.oncology.sanofi-aventis.com/tcl/cp/en/layout.jsp?scat=4BF14C98-DE0C-4464-A2F1-6AA9C9D806A4 . Accessed March 22, 2010.

29. TROPIC: Randomized, Prospective, Open-Label, Multinational Phase III Trial Cabazitaxel* 25 mg/m 2 IV q3w + Prednisone 10 mg/day PO for 10 courses (n = 378) Mitoxantrone 12 mg/m 2 IV q3w + Prednisone 10 mg/day PO for 10 courses (n = 377) Patients with metastatic CRPC progressing on docetaxel (N = 755) * 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. Stratified by ECOG performance score (0,1 vs 2), and measurable vs nonmeasurable disease De Bono JS, et al. ASCO 2010. Abstract 4508.Lancet 2010;1147-54

30. TROPIC: Primary Endpoint—OS Updated ITT Analysis De Bono JS, et al. ASCO 2010. Abstract 4508. 100 OS (%) 80 60 40 20 0 0 6 12 18 24 30 Mos MP CBZP 377 299 195 94 31 9 378 321 241 137 60 19 Patients at Risk, n MP CBZP Censored Combined median follow-up: 13.7 mos 28% reduction in risk of death MP CBZP Median OS, Mos 12.7 15.1 HR 0.72 95% CI 0.61-0.84 P value < .0001

31. TROPIC: Progression-Free Survival De Bono JS, et al. ASCO 2010. Abstract 4508. PFS (%) 0 6 9 12 15 21 Mos MP CBZP 377 55 30 12 9 4 378 92 55 18 6 1 MP CBZP Censored Combined median follow-up: 13.7 mos 25% reduction in risk of progression 3 117 168 18 6 1 100 80 60 40 20 0 Patients at Risk, n MP CBZP Median PFS, Mos 1.4 2.8 HR 0.75 95% CI 0.65-0.87 P value .0002

32. TROPIC: Safety Deaths from AEs more common with cabazitaxel vs mitoxantrone (4.9% vs 1.9%) De Bono JS, et al. ASCO 2010. Abstract 4508 AE, % Cabazitaxel/Prednisone (n = 371) Mitoxantrone/Prednisone (n = 371) All Grade Grade ≥ 3 All Grade Grade ≥ 3 Anemia 97.3 10.5 81.4 4.9 Leukopenia 95.7 68.2 92.5 42.3 Neutropenia 93.5 81.7 87.6 58.0 Thrombocytopenia 47.4 4.0 43.1 1.6 Diarrhea 46.6 6.2 10.5 0.3 Fatigue 36.7 4.9 27.5 3 Nausea 34.2 1.9 22.9 0.3 Vomiting 22.6 1.9 10.2 0 Asthenia 20.5 4.6 12.4 2.4 Hematuria 16.7 1.9 3.8 0.5 Back pain 16.2 3.8 12.1 3 Abdominal pain 11.6 1.9 3.5 0 Febrile neutropenia 7.5 7.5 1.3 1.3

33. Warnings and Precautions Diarrhea Mortality related to diarrhea has been reported Rehydrate and treat with antiemetics and anti-diarrheals as needed If experiencing Grade ≥ 3 diarrhea, dosage should be modified Dose modification (Grade ≥ 3 diarrhea or persisting diarrhea despite appropriate medication, fluid and electrolytes replacement) Delay treatment until improvement or resolution, then reduce dosage of cabazitaxel to 20 mg/m 2 Cabazitaxel [prescribing information]. sanofi-aventis. Bridgewater, NJ. 2010.

34. Summary There is an unmet medical need for patients with mCRPC who have failed standard first-line therapy Cabazitaxel was approved for use in patients with mCRPC previously treated with a docetaxel-containing regimen on June 17, 2010 Most common (>5%) grade 3/4 AEs were neutropenia, leukopenia, anemia, febrile neutropenia, diarrhea, fatigue, and asthenia 2 Cabazitaxel demonstrated a significant OS improvement compared with mitoxantrone 1 15.1 months vs 12.7 months (HR=0.70, P < .0001) 1 ) Sartor AO, et al. Presented at the 2010 ASCO Genitourinary Cancers Symposium (abstract 9); 2) Cabazitaxel [prescribing information]. sanofi-aventis. Bridgewater, NJ. 2010.

35. Facing the Challenge of CRPC

37. Preparation

38. Mechansim of Action Courtesy of Provenge website: http://www.provenge.com/hcp/mechanism-of-action.aspx Accessed on August 15, 2011

39. Sipuleucel T Design: double-blind, placebo-controlled, multicenter phase 3 trial Population: metastatic CRPC 512 patients randomly assigned in a 2:1 ratio to receive either sipuleucel -T (341 patients) or placebo (171 patients) administered intravenously every 2 weeks, for a total of three infusions The primary end point : overall survival Kantoff PW et al N Engl J Med. 2010 Jul 29;363(5):411-22. ,

40. Sipuleucel T Efficacy Primary Efficacy Post Docetaxel Kantoff PW et al N Engl J Med. 2010 Jul 29;363(5):411-22. ,

41. Facing the Challenge of CRPC

42. Facing the Challenge of CRPC

44. Abiraterone 1195 patients who had previously received docetaxel were randomly assigned, in a 2:1 ratio, to receive 5 mg of prednisone twice daily with either 1000 mg of abiraterone acetate (797 patients) or placebo (398 patients). de Bono JS, N Engl J Med. 2011 May 26;364(21):1995-2005.

45. Results de Bono et al. N Engl J Med. 2011 May 26;364(21):1995-2005 . Overall Survival Time to PSA Progression Progression-free Survival

46. de Bono et al. N Engl J Med. 2011 May 26;364(21):1995-2005 de Bono et al. N Engl J Med. 2011 May 26;364(21):1995-2005

48. 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 Superior to zoledronic acid for preventing/delaying SREs in metastatic breast cancer [1] Noninferior to zoledronic acid for preventing/delaying SREs in solid tumors and multiple myeloma [2] 1. Stopeck A, et al. SABCS 2009. Abstract 22. 2. Henry D, et al. ECCO/ESMO 2009. Abstract 20LBA.

49. Denosumab vs Zoledronic Acid in Patients With CRPC and Bone Metastases Denosumab 120 mg SC + Placebo IV q4w (n = 950) Zoledronic Acid 4 mg IV + Placebo SC q4w (n = 951) Patients with CRPC and bone metastases, no current or previous IV treatment with bisphosphonate (N = 1901) Fizazi K, et al. ASCO 2010. Abstract LBA4507. Prospective, double-blind, placebo-controlled phase III trial

50. Denosumab vs Zoledronic Acid: Time to First On-Study SRE Fizazi K, et al. ASCO 2010. Abstract LBA4507. 1.00 0.75 0.50 0.25 0 0 3 6 9 12 15 18 21 24 27 Proportion of Subjects Without SRE Study Mo Denosumab Zoledronic acid HR: 0.82 (95% CI: 0.71-0.95; P = .0002 noninferiority; P = .008 superiority) KM Estimate of Median, Mos 20.7 17.1 Patients at Risk, n Zoledronic acid Denosumab 951 950 733 758 544 582 407 472 299 361 207 259 140 168 93 115 64 70 47 39

51. Denosumab vs Zoledronic Acid: Conclusions Denosumab superior to zoledronic acid in delaying or preventing SREs in patients with CRPC and bone metastases No significant difference between treatments in survival or disease progression High incidence of adverse events in both arms More patients who received zoledronic acid experienced acute phase reaction More patients who received denosumab experienced hypocalcemia ONJ rare but occurred in approximately twice as many patients with denosumab vs zoledronic acid Denosumab potential treatment option for patients with CRPC and bone metastases Fizazi K, et al. ASCO 2010. Abstract LBA4507.

52. CALGB 90401: Phase III Trial of Chemotherapy ± Bevacizumab in CRPC Dexamethasone 8 mg PO x 3 doses + Docetaxel 75 mg/m 2 on Day 1 of 21-day cycle + Prednisone 10 mg/day PO + Bevacizumab 15 mg/kg IV on Day 1 of 21-day cycle (n = 524) Patients with CRPC previously untreated with chemotherapy or biologic agents (N = 1050) Stratified by 24-mo survival probability (< 10%, 10% to 29.9%, ≥ 30%), age (< 65 yrs ≥ 65 yrs), previous history of arterial events Dexamethasone 8 mg PO x 3 doses + Docetaxel 75 mg/m 2 on Day 1 of 21-day cycle + Prednisone 10 mg/day PO + Placebo IV on Day 1 of 21-day cycle (n = 526) Kelly WK, et al. ASCO 2010. Abstract LBA4511 .

53. CALGB 90401: Overall and Progression-Free Survival Kelly WK, et al. ASCO 2010. Abstract LBA4511. Outcome, Mos (Range) Bevacizumab (n = 524) Placebo (n = 526) HR (95% CI) P Value Median OS 22.6 (21.1-24.5) 21.5 (20.0-23.0) 0.91 (0.78-1.05) .181 Median PFS 9.9 (9.1-10.6) 7.5 (6.7-8.0) 0.77 (0.68-0.88) < .0001

54. Addition of Bevacizumab Significantly Improved Other Clinical Endpoints Kelly WK, et al. ASCO 2010. Abstract LBA4511. Outcome, % (95% CI) Bevacizumab (n = 524) Placebo (n = 526) P Value ≥ 50% decline in PSA 69.5 (65.2-73.5) 57.9 (53.3-62.3) .0002 Objective response 53.2 (46.8-59.6) 42.1 (36.2-48.2) .0113

55. ASCENT2: Docetaxel + DN-101 (Calcitriol Formulation) in Patients With mCRPC ASCENT Arm DN-101 45 μ g PO on Days 1, 7, 14 + Docetaxel 36 mg/m 2 IV on Days 2, 8, 15 + Dexamethasone PO 12, 3, 1 hrs before docetaxel 28-day cycles (n = 477) Patients with progressive, metastatic CRPC (N = 953) Control Arm Prednisone 5 mg PO BID Docetaxel 75 mg/m 2 IV on Days 1, 22 Dexamethasone PO 12, 3, 1 hrs before docetaxel 21-day cycles (n = 476) 30 wks Scher HI, et al. ASCO 2010. Abstract 4509.

56. OS Shorter With ASCENT vs Control Treatment Scher HI, et al. ASCO 2010. Abstract 4509. 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 5 10 15 20 25 30 35 Mos From Enrollment Proportion Surviving Log rank P = .002 Control (n = 476; 137 died) ASCENT (n = 477; 174 died) Median follow-up for patients alive: 11.7 mos

57. Facing the Challenge of a Metastatic Disease in 2011 Metastatic Disease Docetaxel Resistant CRPC ADT resistant