CD-1 Second-line Chemotherapy for Hormone Refractory Prostate Cancer Disease Background Nicholas J. Vogelzang, MD Director Nevada Cancer Institute CD-1 QC

CD-2 Prostate Cancer Mortality in the United States In ,050 US men will die from metastatic prostate cancer –Second leading cause of cancer death among US men –~ 90% with bone metastases –Painful and debilitating illness American Cancer Society: CD-35 QC

CD-3 Treatment of Prostate Cancer Local therapies highly curative A subset of patients develop or present with metastatic disease Initial response to androgen deprivation therapy of 2 to 3 years followed by progression to hormone-refractory state Chemotherapy for men with hormone refractory metastatic prostate cancer QC

CD-4 Three Approved Chemotherapy Drugs for Hormone Refractory Prostate Cancer 1981: Estramustine 1996: Mitoxantrone 2004: Docetaxel CD-38 QC

CD-5 HRPC: Docetaxel Therapy Is Not a Cure SWOG 9916 a Median PFS –Docetaxel + estramustine: 6.3 months –Mitoxantrone + prednisone: 3.2 months –HR = 0.73 (0.63, 0.86) TAX 327 b Median PFS –Docetaxel + prednisone: 6.7 months c a Petrylak D, et al. N Engl J Med. 2004;351: b Tannock I, et al. N Engl J Med. 2004;351; C Unpublished; used by permission of M. Eisenberger. QC

CD-6 No Established Second-Line Chemotherapy in HRPC Logical extension of clinical research Unmet medical need for a rapidly progressing and debilitating disease (median survival = 12 months) No effective regimen in this setting Less than half of patients receive second-line chemotherapy a a IntrinsiQ and Decision Resources, QC

CD-7 No Established Second-line Chemotherapy in HRPC Mitoxantrone and weekly docetaxel most commonly used agents Limited clinical evidence in second-line setting Open field for investigation of new agents Effective and well-tolerated second-line chemotherapy the standard in breast, colon, and lung cancers Second-line regimen in HRPC is an unmet medical need QC

CD-8 Challenges in Second-line Trials in HRPC No prior phase III trials Frail and elderly population with multiple comorbidities Rapidly progressing and debilitating disease Majority of patients with difficult to measure and painful bone lesions Need for composite endpoint including clinically-relevant and objective measures of disease progression, pain, and functional status QC

CD-9 CALGB Composite PFS Endpoint Three widely used measures of clinical benefit 1. Disease progression 2. Pain control and opioid analgesic use 3. Weight loss or performance status decline Applied to 9 large CALGB trials (first-line) Predictive of overall survival –22 months vs 9 months, HR = 0.52, p < CD-43 Halabi S, et al. ASCO QC

CD-10 Pain Predicts Overall Survival in Men With HRPC CALGB database ~600 patients –17.6 months (low pain) vs 10.2 months (high pain); p < TAX 327 database of 414 patients – 21.1 months (pain response) vs 12.7 months (no pain response); p < Halabi S, et al. ASCO. Prostate Cancer Symposium Berthold D, et al. ASCO QC

CD-11 Pain in Hormone Refractory Prostate Cancer Moyad et al. (ASCO 2006) Survey of 409 HRPC patients: Experienced bone pain all the time or every day 60% “Can't do the things I would like”50% Need daily medication to manage pain47% Feel depressed32% Moyad et al. ASCO. 2006, # QC

CD-12 In Summary—HRPC Progressing After First-line Chemotherapy An unmet medical need A rapidly progressing, debilitating, and ultimately fatal disease Urgent need for effective and well-tolerated therapies Optimal evaluation requires a composite endpoint including measures of pain and tumor progression QC