1. CALGB 90401: A randomized double-blind placebo controlled phase III trial comparing docetaxel, prednisone and placebo with docetaxel, prednisone and bevacizumab in men with metastatic castrate resistant prostate cancer (mCRPC). Wm. Kevin Kelly, Susan Halabi, Michael Carducci, Daniel George, John F. Mahoney, Walter M. Stadler, Michael Morris, Philip Kantoff, Paul Monk, Eric J. Small for the Cancer and Leukemia Group B (CALGB) and Eastern Cooperative Oncology Group (ECOG)

2. Role of Vascular Endothelial Growth Factor (VEGF) in CRPC Lower baseline urinary VEGF levels are associated with improved survival (P = 0.024). (Bok, R. A. et al. Cancer Res 2001;61:2533-2536) Multivariate model of plasma VEGF levels predicting survival time among 197 CRPC patients (George DJ, et al. Clin Cancer Res. 2001 7:1932-6) FactorHRP VEGF (>260 vs ≤260) 2.42.006 Measurable disease ( Y vs N) 2.01<.001 Alkakine phosphatase (>170 vs ≤170) 1.60.030 Baseline PSA (>150 vs ≤150) 1.48.050

3. Cancer and Leukemia Group B: Phase II Studies in CRPC AuthorsNObjective Response 50% PSA Decline TTP- PSA (Months) Median Survival (Months) Savarese et al. 1 Estramustine Docetaxel 4750%68%720 Oh et al. 2 Estramustine Docetaxel Carboplatin 4055%68%918 Picus et al. 3 Estramustine Docetaxel Bevacizumab 7759%75%824 1 J Clin Oncol. 2001 May 1;19(9):2509-16 2 Cancer. 2003 Dec 15;98(12):2592-8 3 Picus et al. Cancer in press

4. CALGB 90401 Primary Objective –To determine if the addition of bevacizumab to docetaxel and prednisone increases overall survival compared to docetaxel and prednisone alone in patients with CRPC. Secondary Objectives –To compare the PFS of these two regimens in patients with CRPC. –To compare the proportion of patients who experience 50% post-therapy PSA decline from baseline. –To compare proportion of patients who have grade 3 or higher toxicities

5. CALGB 90401: Eligibility Criteria Progressive adenocarcinoma of the prostate by consensus criteria No prior cytotoxic chemotherapy or anti- angiogenic agents Four or more weeks since major surgery or radiation therapy Eight or more weeks from radio-isotope therapy ECOG performance status of 0-2 Signed Informed Consent Patient with HTN were to be well controlled (< 160/90) No significant history of bleeding within 6 months of registration No GI perforation or arterial thrombotic event within 12 months of registration

6. Required initial laboratory values: –Absolute neutrophil count:≥ 1500/ µL –Platelet count≥ 100,000/ µL –Creatinine≤ 1.5 x ULN –Bilirubin*≤ 1.5 x ULN –AST≤ 1.5 x ULN –PSA≥ 5 ng/ml (non-measurable ds.) –UPC ratio< 1.0 –Serum Testosterone≤ 50 ng/dl *Patient with Gilbert’s Disease, ≤ 2.5 x ULN is allowed CALGB 90401: Eligibility Criteria

7. CALGB 90401: Stratification Factors 1.Predicted 24 month survival probability using the nomogram developed by Halabi et al*. Group 1: < 10% Group 2: 10-29.9% Group 3:≥ 30% 2.Age < 65 years ≥ 65 years 3.Prior history of arterial events (cardiac ischemia/infarction, cerebral ischemia, peripheral arterial ischemia or CNS hemorrhage. Yes No *Halabi et al JCO.2:1232-7, 2003

8. CALGB 90410: Treatment Schema RANDOMIZE (1:1) Arm 2 Dexamethasone8 mg po x 3 doses Docetaxel75 mg/m 2 on day 1 q 21 days Prednisone10 mg po daily Placebo 1 IV on day 1 q 21 days Arm 1 Dexamethasone8 mg po x 3 doses Docetaxel75 mg/m 2 on day 1 q 21 days Prednisone10 mg po daily Bevacizumab 1 15 mg/kg IV on day 1 q 21 days ASA 325 mg encouraged in all patients that can tolerate 1 In the event of intolerable toxicity to Docetaxel the Bevacizumab\placebo may be continued alone until POD

9. CALGB 90410: Study Evaluation Baseline Frequency Physical exam Toxicity assessment Routine chemistry, CBC, Urine protein\creatinine ratio Prostate specific antigen (PSA) Testosterone Chest x-ray Bone Scan CT or MRI of abdomen\pelvis q cycle *q cycle *Every 3 cycles *Every 3 months until evidence of progression or relapse for a maximum of 5 years from the time of registration

10. Primary endpoint: Overall Survival (OS) Secondary endpoint: –50% decline in PSA 1 –Progression Free Survival (PFS) 1 –Toxicity 1050 men randomized 86% power to detect a hazard ratio (HR) of 1.26 (assume an increase in median OS from 19 mo. in DP to 24 mo. with DP+B) –Final analysis was based on 748 deaths Primary analysis an intent-to-treat approach using the stratified log-rank statistic adjusting for the stratification factors Trial was monitored for efficacy and safety by the CALGB DSMB 1 PSAWG Criteria, J.Clin.Oncol. 22:537-556, 2004 CALGB 90401:Trial Design and Data Analysis

11. Baseline Clinical Characteristics (N =1050) May 2005 – December 2007 Arm 1 DP + B N=524 Arm 2 DP N=526 Race White88%87% Age <65 65+ years 34% 66% 33% 67% Prior history of arterial events Yes No 7% 93% 8% 92% 24-Month Predicted Survival Probability <10% 10%-29.9% 30%+ 18% 34% 47% 18% 35% 47% ECOG PS 0, 1 2 96% 4% 95% 5% Measurable Disease48%52% Percent on opioid pain medication35%

12. Median Number of Treatment Cycles Range (0-40) (0-38) (0-37)

13. Median DP = 21.5 (20.0-23.0) Median DPB=22.6 (21.1-24.5) HR= 0.91 (0.78-1.05)

14. Median DP = 7.5 (6.7-8.0) Median DPB=9.9 (9.1-10.6) HR= 0.77 (0.68-0.88)

15. Secondary Endpoints: Objective Response and 50% Decline in PSA Clinical Endpoint Arm 1 DP+B (N=524) Arm 2 DP (N=526) p-value ≥50% decline in PSA (95% CI) 69.5% (65.2-73.5) 57.9% (53.3-62.3) 0.0002 Objective Response (95% CI) (# with measurable disease) 53.2% (46.8-59.6) (248) 42.1% (36.2-48.2) (273) 0.0113

16. Forest Plot of Overall Survival in Select Subgroups

18. Significant Grade ≥ 3 Adverse Events ARM 1 DP +B ARM 2 DP Neutrophils30%24% Fatigue18%10% Leukocytes17%13% Febrile Neutropenia7%4% Hypertension7%1% Hemorrhage, GI6%2% GI, Perforation4%0% Mucositis\stomatitis3%0% Pneumonitis2%0% Thrombosis\embolism4%7%

19. Adverse Events Summary ArmGrade 3 # (%) Grade 4 # (%) *Grade 5 # (%) Maximum Hematologic AEDP + B DP 11% 12% 24% 17% 0% Maximum non-Hematologic AEDP + B DP 53% 35% 11% 10% 3.8% 1.1% Maximum Overall AEDP + B DP 41% 31% 30% 23% 3.8% 1.1% * Infection major cause of treatment related deaths

20. Conclusions The addition of bevacizumab to docetaxel/prednisone did not significantly prolong survival in men with metastatic CRPC, although a trend towards improved survival was observed (22.6 vs 21.5 m, p = 0.18). The addition of bevacizumab to docetaxel/prednisone DID have a significant impact on: PFS 9.9 mo. vs. 7.5 mo. p < 0.0001 Objective RR 53.2% vs. 42.1% p= 0.0113 PSA decline ≥ 50%69.5% vs. 57.9% p= 0.0002

21. Conclusions OS with docetaxel/prednisone is longer than previously reported (21.5 mos vs 19.2 mos in TAX327) and may be due to: Stage migration A good risk population (47% of pts had a 24 mo predicted survival of > 30%) Discrepancy between OS and other markers of clinical benefit such as PFS and RR may be due to: Impact of longer-than-expected survival in the control group on power calculations Impact of subsequent therapy on OS True disconnect between PFS/RR and OS Discordance between OS and PFS\overall response

22. The addition of bevacizumab to docetaxel/prednisone resulted in more severe toxicities. The role of anti-angiogenic therapeutics in metastatic CRPC remains to be defined. Exploratory analysis of patient subsets that may have a clinical benefit from bevacizumab are underway. Conclusions

23. Acknowledgements Patients and families that participated in the study All colleagues and investigators that contributed to the success of CALGB 90401. Cancer and Leukemia Group B central office and statistical staff –Eleanor Leung, Ellen Kaplan, Jennifer Williams, John Taylor

24. Thank You