Timing of Androgen Deprivation: The Modern Debate Must be conducted in the following Contexts: 1. Clinical States Model

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1 Timing and Type of Androgen Deprivation Charles J. Ryan MD Associate Professor of Clinical Medicine UCSF Comprehensive Cancer Center Timing of Androgen Deprivation: The Modern Debate Must be conducted in the following Contexts: 1. Clinical States Model Homogeneous grouping, Uniform Outcome 2. Better risk assessments for Localized Disease Predicts micrometastatic Disease 3. Effective Secondary Rx (2 Hormones, Chemotherapy) Prolongs transition and Blurs distinction between Sensitive and Refractory disease Early Androgen Deprivation: For and Against Clinical States Model 1. Uniform grouping of pts 2. Outcome parameters based on state transitions For 1. Tumor Burden Low = Relatively higher Cell Kill 2. Disease exists on a continuum -if benefit for LD, and benefit for Mets, then why wouldn t there be a benefit in rpsa? Against 1. Selection Pressure: Early AD = Early HRPC. PCPT? AR Mutations? 2. Morbidity 3. No Prospective Survival advantage in rpsa pts No Cancer Localized Disease Scher and Heller, Urology 2000 Rising PSA 230,000 50,000 ADT When? Death From Non-Prostate Causes Hormone Naïve Metastatic Hormone Refractory Metastatic 29,000 Death From Disease

2 Timing of Androgen Deprivation: Issues to Consider 1. Pt risk for Bone Metastasis 2. Pt risk for Death 3. Comorbidities 4.??New Rx that may delay need for ADT. (What is the state of Clinical Trials in rpsa?) Approach to the Patient with a Rising PSA Question 1: Is the patient Still Curable? Age of patient Primary Rx Modality (RP or RT) Can do RP after RT RT after RP (more common) Question 2: Is the disease Systemic or Localized? Linear PSA doubling - Local Exponential PSA doubling - Systemic (is this true? ) Question 3: If We can deliver local Rx, should we do concomitent AD? UC SF PSA Doubling Time Is Predictive of Survival PSA Kinetics predict bone mets Rising PSA bone met Nomogram 12 months 3 months D Amico et al JCO 20: 4567, D Amico et al J. Urol Source Dotan et al JCO 2005

3 PSADT and Distant Mets post RT Dataset: 381 pts with T1-T3 rising PSA post RT, MSKCC Actuarial Mets probability Is Hormone Therapy Beneficial For those with a rising PSA? No definitive Prospective Data Extrapolations from studies in high risk localized disease Mets probability Retrospective Analyses from Databases. Zelefsky et al JCO 2005 Studies Demonstrating Benefits of Early AD - Based on Point of Initiation and Study Endpoint. Studies Demonstrating benefit to Early AD: Localized Disease Localized Disease Roach Rising PSA Metastasis Death Author Eligibility Therapy N= Followup TTP Benefit? DSS Benefit? OS Benefit? Bolla T 1,2 + high grade (9%) T 3,4, No AD vs. 3 yrs yrs NA 94% RT plus AD 78% RT low/int grade (91%) goserelin vs. 79% RT alone plus AD vs. (concurrent/adjuvant (p<.001) 62% RT with RT) alone (p<.001) EPC MRC Pilepich ct 1, T 2, N+ (28%) or ct 3 No AD vs. lifelong goserelin (adjuvant to RT) yrs NA 83% RT plus AD vs. 78% RT alone (p=.0053) 47% RT plus AD vs. 38% RT alone (p=.0043) Bolla, Pilepich, Messing Moul* Park Messing See N+ after Radical Prostatectomy S/P Radical Prostatectomy (55%) S/P Primary RT (17%) Watchful waiting (28%) No AD vs lifelong goserelin or orchiectomy Placebo or Bicalutamide 150 mg daily yrs NA 87.2% immediate AD vs. 56.9% at relapse (p=0.001) 8,113 3 yrs 9% objective NR progression vs. 13.8% (p<0.0001) 72.4% immediate AD vs. 49% at relapse (p=0.025) NR* *Benefit observed only for those with Gleason grade 7 in retrospective analysis D Amico PSA 10ng/mL Gleason Score 7 OR SVI or ECE 70 Gy 3D-CRT alone (N=104) or 70 Gy 3D- CRT plus LHRH analogue plus Flutamide (n=102) for 6 months years 21% AD plus RT versus 45% Rt alone (p<.001) Prostate cancer specific mortality 0% in RT plus AD group vs 6% for RT alone (p=.02) 88% RT plus AD versus 78% RT alone (p=.04)

4 Response of Rising PSA Pts to AD Prostate cancer-specific mortality after androgensuppression therapy stratified by a nadir prostate-specific antigen (PSA) level of more than 0.2 v 0.2 ng/ml or less Bianco et al PASCO 2004 Stewart, A. J. et al. J Clin Oncol; 23: Overall survival by prostate-specific antigen (PSA, ng/ml) status at end of induction Hussain, M. et al. J Clin Oncol; 24: Copyright American Society of Clinical Oncology Recommendations for ADT based on Post Primary Rx PSA: Where do we set the bar? PSADT < 6 months - CAB Consider IAB PSADT 6-12 months - Do Something IAB HD Casodex Flutamide/ Finasteride Clinical Trial PSADT >12 months - Do anything Consider Salvage RT Clinical Trial Nutrition Exercise etc. CAB OK if highly anxious

5 Hormone Therapy is changing: Treatment Options Combined Androgen Blockade Intermittent CAB Peripheral Androgen Blockade Antiandrogen / 5 Alpha Reductase Inhibitor HD Bicalutamide Meta-Analysis: 20 Randomized Trials of CAB vs Androgen Suppression Alone 5-Year Survival >6500 Men in 20 Trials (CAB with Nilutamide or Flutamide) Proportion Alive (%) % Treatment better by 2.9% (SE 1.3) % log rank P=.005 AS only AS + antiandrogen Time Since Randomization (Years) Prostate Cancer Trialists Collaborative Group. Lancet. 2000;355: Intermittent Androgen Deprivation: Rationale Progression of prostate cancer to androgen independence may be driven, in part, by AD Selection of androgen-independent clone activating mutations of the androgen receptor (AR) AD leads to activation of molecular pathways that mediate tumor progression Intermittent androgen replacement may delay progression to androgen independence in preclinical models 70% 60% 50% 40% 30% 20% 10% 0% PROSTATE CANCER Intermittent Androgen Deprivation: Time Off Treatment Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Grossfeld et al Urology 58: 240, 2001 On Off

6 Register AD SWOG 9346 Schema 8 months PSA 4 PSA > 4 study off Continuous AD until PD IAD (off AD until PSA > 20 or baseline) Once off Cycle is 3 mos Peripheral Androgen Blockade Flutamide 250 tid and Finasteride 5 mg day CALGB study (N=101) >80% PSA decline in (91/94) = 97% 64 Pts still on Study, Median f/u 33 months?effect on Survival and time to metastatic disease? Alternative to CAB? Continuous AD until PD Peripheral Androgen Blockade: HD Bicalutamide Adverse Events in > 10% of Men With Prostate Cancer Treated With Leuprolide Monotherapy or Bicalutamide Monotherapy Leup(n = 26) Bical (n = 25) P Anemia, % Breast enlargement, % <.001 Breast tenderness, % <.001 Fatigue, % Loss of sexual interest, % Vasomotor flushing, % 96 8 <.001 Peripheral Androgen Blockade: HD Bicalutamide preserves BMD LHRH Treated pts - 2.5% decrease in BMD Bicalutamide pts - 2.5% increase in BMD NOTE. All adverse events were Common Toxicity Criteria grade 1 or 2. Smith et al JCO 2004

7 Changing body morphology should be our highest priority Resistance Exercise in Prostate Cancer Patients Receiving ADT Pre ADT Post ADT 155 men on ADT Intervention 12 wk program: 9 exercises 3 x per week under supervision Control Segal J Clin Oncol 2003 Conclusions ADT is an effective but toxic anti-tumor therapy Most toxicity is cumulative, but much of it is preventable. The early use of ADT in prostate cancer means more men will be treated with this therapy for a longer time. Attention to these complications will help your patients!