The Role of the Medical Oncologist in the Treatment of Prostate Cancer Daniel P. Petrylak, MD Professor of Medicine Columbia University Medical Center

When should you see an oncologist? High risk localized disease Rising PSA after local therapy Hormone sensitive disease Endocrine Resistant Disease

Natural History of Metastatic Prostate Cancer Tumor Volume and Activity Time Castration Secondary Hormonal Rx Chemo Rx This slide nicely illustrates the progression pattern over time. Although surgery and radiation are potentially curative in clinically localized disease, as many as a third of these patients will progress. At the time of disease progression, patients are offered hormonal therapy or ADT is often initiated earlier for high risk cases. Although the majority of patients respond initially to castration therapy, many will eventually progress to an androgen independent state. Treatment options at this stage are limited and transient.

Ligand activated androgen receptor signaling remains a ‘driver’ in CRPC Hypothesis: Hormone-refractory prostate cancer (HRPC) frequently remains driven by a ligand-activated androgen receptor (AR). This disease is not truly hormone refractory

Biological evidence for a continued hormone ‘driver’ in CRPC High intratumoral androgens despite castration Castration resistance: – AR amplification/ mutations in CRPC increase AR activity – ↑ AR mRNA expression alone → resistance in isogenic lines – Aberrant activation of the androgen receptor

Abiraterone: Response Response Parameter Untreated Prior Docetaxel PSA >50%: 38/54 (70%) 18/34(47%) >30%: 43/54 (80%) 22/34 (65%) TTP PSA 231 days 161 days RECIST 15/29(60%) NR

Abiraterone Clinical Trials Abiraterone vs placbo in patients with CRPC prior to docetaxel Abiraterone/prednisone vs placebo/prednisone in CPRC patients post chemotherapy. Close to accrual

Waterfall Plot of Best Percent PSA Change from Baseline Chemotherapy-Naïve (N=65) Post-Chemotherapy (N=75) 62% (40/65) >50% Decline 51% (38/75) >50% Decline

AFFIRM Phase 3 Registration Trial of MDV3100 in Post-Chemotherapy CRPC Patients MDV3100 – 240 mg QD Placebo QD 2 1 Primary Endpoint: 25% survival increase (12 to 15 months) Sample size: ~1170 (780 and 390) Statistics: 85% Power; p=0.05, two-sided Biomarkers: CTC enumeration and profiling with outcome Scher, H. (North America) and De Bono, J. Co-PI, Medivation

When is chemotherapy initiated? At first PSA rise in non metastatic patients At PSA rise in an asymptomatic patient At PSA rise and scan progression in an asymptomatic patient In a patient with symptomatic bone pain

Docetaxel HRPC Trials TAX 3271 N=1006 SWOG 99162 N=770 Randomize Mitoxantrone 12 mg/m2 Prednisone 10 mg q day Q 21 days up to 10 cycles Randomize Docetaxel 30 mg/m2/wk Prednisone 10 mg q day 5 on; 1 off x 6 cycles N=1006 Docetaxel 75 mg/m2 Prednisone 10 mg q day Q 21 days up to 10 cycles SWOG 99162 Mitoxantrone 12 mg/m2 Prednisone 5 mg bid Q 21 days N=770 Randomize Docetaxel 60 mg/m2 d 2 Estramustine 280 mg d1-5* Dexamethasone 20 mg, tid d 1 & 2 *Warfarin and aspirin 1. Tannock et al. N Engl J Med 2004:351;1502-1512. 2. Petrylak et al. N Engl J Med 2004;351:1513-1520.

Overall Survival HR: 0.80 (95% CI 0.67, 0.97), p = 0.01 # at Risk # of 0% 20% 40% 60% 80% 100% 12 24 36 48 Months # at Risk # of Deaths Median in Months D+E 338 217 18 M+P 336 235 16 HR: 0.80 (95% CI 0.67, 0.97), p = 0.01 Petrylak et NEJM 2004

Probability of Surviving Overall Survival — TAX 327 1.0 0.9 Docetaxel 3 wkly Docetaxel wkly 0.8 Mitoxantrone 0.7 0.6 Probability of Surviving 0.5 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 – – 0.4 Overall survival favors administration of docetaxel q3 weekly (p=0.009) compared to mitoxantrone arm 0.3 0.2 0.1 0.0 6 12 18 24 30 Months Tannock et al. N Engl J Med 2004:351;1502-1512.

Evidence for Angiongenis as a Target for Prostate Cancersis Microvessel density correlates with prognosis in radical prostatetectomy specimens Elevated levels of VEGF correlate with prognosis in CRPCa bFGF expresse in epithelial and stromal cells

CALGB Study Primary endpoint of improvement in median survival from 19 in docetaxel arm to 23 months in docetaxel/bevizcuzimab arm not met Press Release Roche 2010

CALGB 9040: Randomized Double Blinded Placebo controlled Phase III Trial Comparing Docetaxel + Prednisone with or without Bevacizumab in men with HRPC Arm A Dexamethasone 8 mg po x 3 doses Docetaxel 75 mg/m2 on d1 q21d Prednisone 10 mg po daily Placebo* IV on day 1 q 21 days Eligibility Metastatic PC T <50 ng/ml No prior chemo Adequate hem, renal & liver function RANDOMIZE Arm B Dexamethasone 8 mg po x 3 doses Docetaxel 75 mg/m2 on d1 q 21d Prednisone 10 mg po daily Bevacizumab* 15 mg/kg IV on day 1q 21d Stratification Halabi nomogram N = 1020 patients CALGB, ECOG, NCIC

Structure of Thalidomide and the 2nd-Generation IMiDs Immunomodulatory drugs (IMiDs) are synthetic analogs that were created based on thalidomide as a parent structure Various IMiDs have improved antitumor activities in vitro and different toxicity profiles compared with the parent compound

Best response by % change in PSA

MAINSAIL TRIAL Metastatic CRPC Chemo-naïve Disease Progression Screening CRPC Patients N= 1,015 Randomize 1:1 Docetaxel/Prednisone + Placebo Until Progression or Toxicity N ~ 500 Docetaxel/Prednisone + Lenalidomide Until Progression or Toxicity Follow-Up: For Survival For Other Treatments Up to five years

TROPIC: Phase III Registration Study 146 Sites in 26 Countries TROPIC slide deck. Slide6,10,13 mCRPC patients who progressed during and after treatment with a docetaxel-based regimen (N=755) Stratification factors ECOG PS (0, 1 vs. 2) • Measurable vs. non-measurable disease cabazitaxel 25 mg/m² q 3 wk + prednisone* for 10 cycles (n=378) mitoxantrone 12 mg/m² q 3 wk + prednisone* for 10 cycles (n=377) *Oral prednisone/prednisolone: 10 mg daily. Primary endpoint: OS Secondary endpoints: Progression-free survival (PFS), response rate, and safety Inclusion: Patients with measurable disease must have progressed by RECIST; otherwise must have had new lesions or PSA progression

Pre-Protocol Treatments TROPIC slide deck. Slide16,17,43 MP (n=377) CBZP (n=378) Total prior docetaxel dose (mg/m²) Median 529.2 576.6 Months from last docetaxel dose to progression 0.70 0.80 Number of patients progressed (%) During last docetaxel treatment 27.6 30.4 <3 months since last docetaxel dose 48.0 41.8 ≥3 months since last docetaxel dose 24.0 27.0 Radiation (%) Curative 29.7 25.9 Palliative 29.2 35.4 Chemotherapy (%) 1 regimen 71.1 68.8 2 regimens 21.0 24.9 ≥3 regimens 8.0 6.3

Primary Endpoint: Overall Survival (ITT Analysis) TROPIC slide deck. Slide21 Proportion of OS (%) 80 60 40 20 100 0 months 6 months 12 months 18 months 24 months 30 months 15.1 12.7 Median OS (months) 0.59–0.83 95% CI <.0001 P-value 0.70 Hazard Ratio CBZP MP Number at risk MP 377 300 188 67 11 1 CBZP 378 321 231 90 28 4

On-Study Laboratory Abnormalities Safety Population MP (n=371) CBZP (n=371) All Grades (%) Grade ≥3 (%) Hematology Anemia 81.4 4.9 97.3 10.5 Leukopenia 92.5 42.3 95.7 68.2 Neutropenia 87.6 58.0 93.5 81.7 Thrombocytopenia 43.1 1.6 47.4 4.0 Biochemistry Alkaline Phosphatase 57.7 9.7 53.6 7.3 ALAT 18.9 0.3 25.9 1.1 ASAT 28.0 0.5 27.8 0.8 Hyperbilirubinemia 4.6 3.8 Creatinine 11.6 15.6 1.3

Total Deaths During Study Safety Population TROPIC slide deck. Slide32 MP (n=371) CBZP (n=371) Total deaths during study 275 (74.1%) 227 (61.2%) Due to progression 253 (68.2%) 197 (53.1%) Due to AEs 7 (1.9%) 18 (4.9%) Due to other reasons 15 (4.0%) 12 (3.2%)

Zometa 039: Skeletal-Related Event (SRE) Prevention Study Bone metastases with progressive disease after ADT (N=639) Randomize Standard Care + ZOMETA Standard Care + Placebo Endpoint: SRE

Skeletal-Related Events Pathologic fracture Spinal cord compression/vertebral body collapse Radiation or surgery to bone Change in antineoplastic therapy

Proportionof Patients With SRE Proportion of Patients With SRE (-HCM) at Month 15 by Treatment (Intent-to-Treat Patients) 0.8 0.7 0.6 45% 0.5 Proportionof Patients With SRE * 38% 0.4 34% 0.3 0.2 0.1 ZOMETA 8/4 mg ZOMETA 4 mg Placebo *P<.05 vs placebo

Time to First SRE (–HCM) by Treatment Median Time, Days* ZOMETA 4 mg NR Placebo 321 110 100 90 80 70 60 50 40 30 20 10 % Patients Without the Event 0 50 100 150 200 250 300 350 400 450 500 550 Time After the Start of Study Drug (Days) *P=.011 ZOMETA 4 mg vs placebo

Study Design: International, Randomized, Double-Blind, Active-Controlled Study Key Inclusion Hormone-refractory (castration resistant) prostate cancer and bone metastases Key Exclusion Current or prior IV bisphosphonate treatment Denosumab 120 mg SC and Placebo IV* every 4 weeks (N = 950) Zoledronic acid 4 mg IV* and Placebo SC every 4 weeks (N = 951) This was a head-to-head comparison vs. active comparator, resulting in much higher sample size per arm (almost 1000) as compared to the historic zoledronic acid registration trial, which was placebo-controlled (about 220 per arm). The key inclusion criterion was that there was evidence of bone metastasis based on x-ray, CT, or MRI. The key exclusion criterion was no prior IV bisphosphonate. Prior oral bisphosphosphonate use for osteoporosis was allowed. Zoledronic acid (ZA) was administered per Zometa® prescribing information. IV product dose that was either zoledronic acid or placebo was calculated according to baseline creatinine clearance. Subsequent doses were withheld if there was elevation of the serum creatinine and the IV product was only reinstituted once the serum creatinine had returned to within 10% of baseline levels. This dose and schedule is per the Zometa® label. Subjects with creatinine clearance <30 mL/min were excluded per the Zometa® label. There was no modification of the subcutaneous product, which included denosumab or placebo either at baseline or on study. Subjects were stratified by previous SRE (YES/NO), current chemotherapy (within 6 weeks prior to randomization) (YES/NO), Baseline PSA (<10 vs. ≥10 ng/mL). All subjects were strongly recommended to take daily supplemental calcium (500 mg) and vitamin D (400 IU). Calcium and Vitamin D supplemented in both treatment groups Accrual period from May 2006 to December 2008 Analysis cut-off date October 2009 *Per protocol and Zometa® label, IV product dose adjusted for baseline creatinine clearance and subsequent dose intervals determined by serum creatinine. No SC dose adjustments made due to increased serum creatinine. 32

Time to First On-Study SRE HR 0.82 (95% CI: 0.71, 0.95) P = 0.0002 (Non-inferiority) P = 0.008 (Superiority) Risk Reduction 18% 1.00 0.75 Proportion of Subjects Without SRE 0.50 KM Estimate of Median Months Efficacy analyses are vs. the most potent bisphosphonate used in clinical practice, and the only one approved for use in prostate cancer bone metastasis. This is NOT a comparison vs. placebo, as has been done in Novartis registration trial The primary endpoint is represented on a Kaplan Meier curve. Denosumab was superior to zoledronic acid and reduced the risk of a first on-study SRE by 18% with a confidence interval from 0.71 to 0.95. The P value was equal to 0.0002 for noninferiority and equal to 0.008 for superiority. The median time to first on-study SRE was 20.7 months for denosumab and was 17.1 months for zoledronic acid, a 3.6 mo difference. The 2 most common components of SREs were fractures and radiation to bone. 727 subjects experienced a first on-study SRE; subject incidence was 341 (35.9%) in the denosumab arm and 386 (40.6%) in the zoledronic acid arm. 0.25 Denosumab 20.7 Zoledronic acid 17.1 3 6 9 12 15 18 21 24 27 Study Month Subjects at risk: Zoledronic Acid 951 733 544 407 299 207 140 93 64 47 Denosumab 950 758 582 472 361 259 168 115 70 39

Conclusions Standard of care for CRPCA is docetaxel/prednisone Novel phase IIII studies are combining docetaxel with novel targeted agents Carbazitaxel is approved as a second line therapy for castration resistant prostate cancer New biological approaches are being evaluated in the second line setting

Questions Prostate cancer after hormone ablation is Still hormone responsive Does not respond to chemotherapy Spreads to the bone in 90% of pateints A and C

Question 2 A significant complication of treatments targeting bone (bisphosphophonates and denosamab) is Osteonecrosis of the jaw Hand foot syndrome Rash Diarrhea