Celestia S. Higano MD, FACP Professor Medicine and Urology University of Washington Member, Fred Hutchison Cancer Research Center The Prostate Net Prostate Cancer Symposium Inaugural Meeting New York City October 6, 2009 Emerging Treatments on the Horizon

Many Potential New Therapeutic Agents on the Horizon  AR targeted hormonal therapy – Abiraterone – MDV3100  Immunotherapy – Provenge – Ipilimumab  Other emerging therapies

Prostate Cancer Clinical Disease States Rising PSA Clinical Metastases: Castration resistant 1st Line Docetaxel Clinical Metastases: Castration resistant Pre-chemo Clinically Localized Disease Rising PSA: Castration resistant Clinical Metastases: Hormone sensitive Clinical Metastases: Castration resistant Scher H et al. PCWG2. J Clin Oncol. 2008; 26:

4 Sipuleucel-T (Provenge ® ) Dendritic Cell Vaccine  Leukapheresis T cells attack tumor cells In vivo T cell activation Antigen Loading Antigen-loaded APC Antigen Processing Dendritic cell ~ 40 hours  Infusion  Culture Precursor APC Dendritic cell Tumor specific antigen

Phase III IMPACT Trial Primary endpoint:Overall Survival Secondary endpoint: Time to Objective Disease Progression Asymptomatic or Minimally Symptomatic Metastatic Castrate Resistant Prostate Cancer (N=512) Pre- chemotherapy Asymptomatic or Minimally Symptomatic Metastatic Castrate Resistant Prostate Cancer (N=512) Pre- chemotherapy Placebo Q 2 weeks x 3 Sipuleucel- T Q 2 weeks x 3 PROGRESSIONPROGRESSION PROGRESSIONPROGRESSION 2:1 SURVIVALSURVIVAL SURVIVALSURVIVAL Treated at Physician discretion and/or Salvage Protocol Placebo Q 2 weeks x 3 Treated at Physician discretion

IMPACT Overall Survival Percent Surviv al Survival (months) P = (Cox model) HR = [95% CI: 0.614, 0.979] Median Survival Benefit = 4.1 Mos. Sipuleucel-T (n = 341) Median Survival: 25.8 Mos. Placebo (n = 171) Median Survival: 21.7 Mos. Schellhammer, Higano, Berger et al, AUA Annual Meeting 2009.

Toxicity  Chills  Fever  Headache

Issue Surrounding Sipuleucel-T for FDA Review Pros  Overall survival benefit  Consistent data compared across studies  Favorable toxicity profile  Strong demand from patients Cons  No improvement of TTP  No pain palliative data  No effect on PSA  Administration issues  Cost  Other issues

CTLA-4 Blockade Activates Antigen Specific T-Cell Responses B7 T cell Activation CD28 MHC TCR T cell CTLA-4 APC 1. Co-stimulation via CD28 ligation transduces T cell activating signals MHC TCR Anti-CTLA4 mAb CD28 T cell CTLA-4 APC T cell Activation 3. Blocking CTLA-4 ligation enhances T cell responses MHC TCR T cell APC CD28 CTLA-4 T cell Inactivation B7 2. CTLA-4 ligation on activated T cells down-regulates T cell responses

Ipilimumab (Anti-CTLA 4 antibody)  Phase II Ipi alone and with single dose radiation  Phase III trial  Ipi and GVAX10

Radiation promotes cross-presentation of tumor associated antigens CTLA- 4 Anti-CTLA4 mAb Modified after: Demaria, et al, Int. J. Radiation Oncology Biol. Phys., Vol. 63, No. 3, pp. 655–666, 2005

Ipilimumab Phase II IPI 22 IPI 43 IPI 64 IPI (Days) (14 months) Or until PD -2 Screening 1 st Treatment Cycle Dosing q 3wk x 4 Follow Up or Additional Treatment Cycle(s); Assessments q 3 mos XRT Cohort 1 Mono Cohort 2 XRT in NoCHEMO Cohort 3 XRT in CHEMO 10 mg/kg IPI n =16 XRT + 10 mg/kg IPI Chemo naïve n = 16 XRT + 10 mg/kg IPI Chemo experienced n = 18 Slovin, Beer, Higano et al GU ASCO 2009

Immune-Related Adverse Events * Subjects are only counted once in each AE category. Mono N=16 ALL ≥ G3 XRT in NoCHEMO N=16 ALL >= ≥ G3 XRT in CHEMO N=18 ALL ≥ G3 Skin 9 (56.3%)4 (25.0%) GI 12 (75%) 6 (37.5%)4 (25.0%) 2 (12.5%)4 (22.2%) 3 (16.7%) Liver or Abnormal LFTs 4 (25.0%) 3 (18.9%)3 (16.7%) 2 (11.1%) Endocrine 4 (25.0%)2 (12.5%)

Best PSA Changes: Each Subject Mono XRT in NoCHEMO XRT in CHEMO

Summary of Objective Responses Treatment Group** RECIST Response 10 mg/kg monotherapy N=11 SD 5 (45.5%) PR* 1 (9.1%) CR 1 (9.1%) XRT in NoCHEMO N=13 SD 11 (84.6%) XRT in CHEMO N=6 SD 3 (50%) *Not confirmed ** Patients with measurable disease

Phase III Trial of Radiation plus Placebo or Ipilimumab  Must have received prior docetaxel  No more than 2 prior chemotherapy regimens  At least one bone lesion that has not been irradiated  Not eligible – Men with auto-immune diseases – Prior treatment with strontium or samarium16

Where is immunotherapy going?  Provenge likely to be approved – Who should get it?  GVAX is dead for now – Survival data for Vital 1 in progress in Seattle  Ipililumab just starting phase III – Can this type of agent be used in the community? – Stand by…17

ZD4054: ET A RET B R ET-1 Metastasis Disease progression Angiogenesis Osteoblast stimulation Invasion Vasodilatation Apoptosis Clearance of ET-1 ZD4054 specifically blocks ET A R, with no detectable activity at ET B R Morris CD et al. Br J Cancer 2005;92:2148–2152 a specific-ET A R antagonist

Randomized Phase II Trial Overall Survival Proportion of patients alive ZD mg versus placebo: HR= %CI=(0.49, 0.86); P=0.052 ZD mg versus placebo: HR= %CI=(0.41, 0.73); P=0.008 Time to death (days) *Patients receiving chemotherapy, including docetaxel after trial entry, 25 (23)28 (26)27 (28) Chemotherapy use*, n (%) Median OS, months Number of deaths, n Placebo n= mg n= mg n=98 ITT population ZD4054 ZD mg ZD mg Placebo

Enthuse Phase III Trials  Non-metastatic CRPC – 531 of 1500  Asymptomatic metastatic CRPC – Fully accrued, n=580 – Results Q2 2010, 2011 ASCO  Symptomatic metastatic CRPC – 591 of

Other On-going Phase III Trials in CRPC  CALGB docetaxel +/- bevacizumab (Avastin ® ) – Results 2010 ASCO  SWOG docetaxel +/- atrasentan – 694 of 930 accrued  Docetaxel +/- VEGF Trap – 800 of 1200 accrued  Docetaxel +/- ZD 4054 – 591 of

Take Home Messages  More active drugs  Many on-going and planned registration trials  Lots of potential!  Need patient participation to make progress!22

ARS ?

24 Baseline 3 months Ipilimumab and GVAX Gerritsen et al ASCO 2006 Patient 12 (5 mg/kg)

25 Baseline Patient 8 6 Months Bone Scan Improvement Patient 8 (3 mg/kg)

26 GVAX Cellular Vaccine Ward et al. Cancer Immunol Immunother. 2002:51:351. DCAntigen- loaded DC LNCaP PC3

GVAX Proposed Mechanism of Action Dendritic cell LNCaP / PC-3 cells GM-CSF Antigen(s) Lymphatics Antigen Lymph Node CD8 T Cell CD4 T Cell Skin B CELLS CTLS TUMOR IFN γ Antibodies

28 GVAX Immunotherapy  6 injections each leg or arm (12 injections each time)  Treatments every 3 weeks  Injection site redness and itching Data on file, Cell Genesys, Inc.

GVAX Phase III Trials  Vital 1  Vital 229

30 Phase III Vital 2 Trial  Primary end point: Overall survival  Secondary end points: Time to radiologic progression, time to progression of pain N=600 Symptomatic metastatic HRPC 1 prior chemotherapy permitted No prior taxanes RANDOMIZERANDOMIZE GVAX prostate* q21d + docetaxel 75 mg/m 2 q21d Docetaxel 75 mg/m 2 q21d + prednisone 10 mg/d Closed Aug 2008 by DSMB for excessive deaths in experimental arm, 67 vs 47

31 Phase III Vital 1 Trial  Primary end point: Overall survival  Secondary end points: Bone related events, progression of bone metastases, time to onset of bone pain N=60 0 Asymptomati c metastatic HRPC No prior chemotherapy RANDOMIZERANDOMIZE GVAX prostate q14d* Docetaxel 75 mg/m 2 q21d + prednisone 10 mg/d Terminated in October 2008 based on futility analysis showing that the trial had less than a 30 percent chance of meeting its predefined primary endpoint of an improvement in survival. Trial enrolled 627 patients

Intent-to-Treat Population (n=621) Vital 1 Kaplan-Meier Estimates of Survival Analysis Stratified by Randomization Factors (ECOG, Gleason Score, and Alkaline Phos.) Higano et al GU ASCO 2009

Patients with a Halabi Predicted Survival Time of ≥18 months (n=264) weeks ɩɩɩɩɩɩɩɩɩɩɩ ɩɩɩɩɩɩɩɩɩɩɩ Probability of Survival Arm D+P censored Arm G censored HR= 0.90 [95% CI: 0.61,1.33] Higano et al GU ASCO 2009 Vital 1 Kaplan-Meier Estimates of Survival Analysis Stratified by Randomization Factors (ECOG, Gleason Score, and Alkaline Phos.)

Patients with a Halabi Predicted Survival Time of <18 months (n=357) Vital 1 Kaplan-Meier Estimates of Survival Analysis Stratified by Randomization Factors (ECOG, Gleason Score, and Alkaline Phos.) Higano et al GU ASCO 2009

Celestia S. Higano MD, FACP Professor Medicine and Urology University of Washington Member, Fred Hutchison Cancer Research Center The Prostate Net Prostate Cancer Symposium Inaugural Meeting New York City October 6, 2009 Emerging Treatments on the Horizon

Emerging Treatment Protocols Eric Klein, MD

Phase III Chemoprevention Trials RRR = 22.5% RRR = 23.5% PCPT REDUCE

Prevention: What I Tell Patients Low calorie diet Exercise Vitamin E and Selenium don’t work Data on other dietary changes and supplements not proven 5-alpha reductase inhibitors are safe and effective, and the only intervention supported by results of Phase III controlled trials

5ARIs for Biochemical Recurrence Andriole et al, Urology 45:491, 1995

ARTS Study Design Multicenter, randomized, double-blind, placebo-controlled trial (n=276) Baseline Avodart (dutasteride) 0.5mg/day Placebo Screening Randomization Follow-up Treatment period 2 years -3 weeks +4 months Negative bone scan PSA nadir End of treatment Months

ARTS Endpoints Time to PSA doubling (primary) Time to disease progression and percentage of patients with disease progression Percentage of patients with treatment response (any PSA decrease or an increase  15%) Changes in PSA including: – Time to PSA rise and percentage of patients with a PSA rise – Time to PSA progression and percentage of patients with PSA progression – Absolute and percentage PSA change from baseline and nadir PSA Changes in PSA doubling time during treatment Disease-related patient anxiety (MAX-PC) Safety outcomes