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

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Presentation on theme: "The Role of the Medical Oncologist in the Treatment of Prostate Cancer Daniel P. Petrylak, MD Professor of Medicine Columbia University Medical Center."— Presentation transcript:

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

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

3 Natural History of Metastatic Prostate Cancer Tumor Volume and Activity Time Castration Secondary Hormonal Rx Chemo Rx

4 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

5 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

6 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

7 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

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9 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

10 AFFIRM AFFIRM Phase 3 Registration Trial of MDV3100 in Post-Chemotherapy CRPC Patients Scher, H. (North America) and De Bono, J. Co-PI, Medivation R 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

11 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

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

13 D+E M+P # at Risk # of Deaths Median in Months HR: 0.80 (95% CI 0.67, 0.97), p = 0.01 Overall Survival Petrylak et NEJM 2004

14 Months Median survival Hazard (mos) ratio P-value Combined: D 3 wkly: D wkly: Mitoxantrone16.4 –– Probability of Surviving Docetaxel 3 wkly Docetaxel wkly Mitoxantrone Overall Survival — TAX 327 Tannock et al. N Engl J Med 2004:351;

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17 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

18 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

19 CALGB 9040: Randomized Double Blinded Placebo controlled Phase III Trial Comparing Docetaxel + Prednisone with or without Bevacizumab in men with HRPC RANDOMIZE Eligibility Metastatic PC T <50 ng/ml No prior chemo Adequate hem, renal & liver function Stratification Halabi nomogram N = 1020 patients CALGB, ECOG, NCIC Arm A Dexamethasone8 mg po x 3 doses Docetaxel75 mg/m 2 on d1 q21d Prednisone10 mg po daily Placebo*IV on day 1 q 21 days Arm B Dexamethasone8 mg po x 3 doses Docetaxel75 mg/m 2 on d1 q 21d Prednisone10 mg po daily Bevacizumab*15 mg/kg IV on day 1q 21d

20 Structure of Thalidomide and the 2nd-Generation IMiDs

21 21 Best response by % change in PSA

22 22 MAINSAIL TRIAL CRPC Patients N= 1,015 Randomize 1:1 Docetaxel/Prednisone + Placebo Until Progression or Toxicity N ~ 500 Docetaxel/Prednisone + Lenalidomide Until Progression or Toxicity N ~ 500 Follow-Up: For Survival For Other Treatments Up to five years Metastatic CRPC Chemo-naïve Disease Progression Screening

23 23 TROPIC: Phase III Registration Study 146 Sites in 26 Countries 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 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. Stratification factors ECOG PS (0, 1 vs. 2) Measurable vs. non-measurable disease mCRPC patients who progressed during and after treatment with a docetaxel-based regimen (N=755)

24 24 Pre-Protocol Treatments MP (n=377) CBZP (n=378) Total prior docetaxel dose (mg/m²) Median Months from last docetaxel dose to progression Median Number of patients progressed (%) During last docetaxel treatment <3 months since last docetaxel dose ≥3 months since last docetaxel dose Radiation (%) Curative Palliative Chemotherapy (%) 1 regimen regimens ≥3 regimens

25 25 Primary Endpoint: Overall Survival (ITT Analysis) MP CBZP Number at risk Proportion of OS (%) months 6 months12 months18 months24 months30 months Median OS (months) 0.59–0.8395% CI <.0001 P-value 0.70 Hazard Ratio CBZPMP

26 26 On-Study Laboratory Abnormalities Safety Population MP (n=371) CBZP (n=371) All Grades (%)Grade ≥3 (%) All Grades (%)Grade ≥3 (%) Hematology Anemia Leukopenia Neutropenia Thrombocytopenia Biochemistry Alkaline Phosphatase ALAT ASAT Hyperbilirubinemia Creatinine

27 27 Total Deaths During Study Safety Population MP (n=371)CBZP (n=371) Total deaths during study275 (74.1%)227 (61.2%) Due to progression253 (68.2%)197 (53.1%) Due to AEs7 (1.9%)18 (4.9%) Due to other reasons15 (4.0%)12 (3.2%)

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

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

30 Proportion of Patients With SRE (-HCM) at Month 15 by Treatment (Intent-to-Treat Patients) Proportion of Patients With SRE * *P<.05 vs placebo ZOMETA 8/4 mg ZOMETA 4 mg Placebo 38% 34% 45%

31 Time to First SRE (–HCM) by Treatment % Patients Without the Event Time After the Start of Study Drug (Days) Median Time, Days* ZOMETA 4 mgNR Placebo321 *P=.011 ZOMETA 4 mg vs placebo

32 Study Design: International, Randomized, Double- Blind, Active-Controlled Study Zoledronic acid 4 mg IV* and Placebo SC every 4 weeks (N = 951) Denosumab 120 mg SC and Placebo IV* every 4 weeks (N = 950) Key Inclusion Hormone-refractory (castration resistant) prostate cancer and bone metastases Key Exclusion Current or prior IV bisphosphonate treatment *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. Calcium and Vitamin D supplemented in both treatment groups Accrual period from May 2006 to December 2008 Analysis cut-off date October 2009

33 Time to First On-Study SRE Zoledronic Acid Denosumab Subjects at risk: Proportion of Subjects Without SRE KM Estimate of Median Months Denosumab Zoledronic acid HR 0.82 (95% CI: 0.71, 0.95) P = (Non-inferiority) P = (Superiority) Study Month 18% Risk Reduction

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36 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

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

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


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