1. Design of Clinical Trials for Select Patients With a Rising PSA following Primary Therapy Anthony V. D’Amico, MD, PhD Professor of Radiation Oncology Harvard Medical School

2. Patient Selection PSA DT is significantly associated with time to cancer-specific death following PSA failure –Multi-institutional RTOG 9202 (RT + short vs. long-term H) CaPSURE/CPDR (RP or RT) –Single Institution Johns Hopkins (H Rx delayed until BS +) Barnes Jewish (Prospective Screening Study)

3. Arm 1: goserelin and flutamide 2 mos before and during standard RT (STAD) Arm 2: goserelin and flutamide 2 mos before and during standard RT, followed by goserelin alone for 24 mos (LTAD) T2c-T4 Pre Rx PSA < 150 ng/ml N = 1513 RANDOMIZERANDOMIZE RTOG 92-02

4. RTOG <0.0001 [4.3, 8.9]6.2 P-Value[95% C.I.]Hazard Ratio Interpretation Men whose PSA is doubling less than every 12 months are ~ 6 times at greater risk of prostate cancer death than those with a slower doubling time.

5. RTOG 9202 Prostate Cancer Survival by PSA-DT Years since randomization Prostate Cancer Survival Rate PSA DT < 12 months PSA DT  12 months

6. N = 1451

7. CaPSURE/CPDR <0.0001 [12.5, 30.9]19.6 P-Value[95% C.I.]Hazard Ratio Interpretation Men whose PSA is doubling less than every 3 months are ~ 20 times at greater risk of prostate cancer death than those with a slower doubling time.

8. N = 341

9. 051015 0.0 0.25 0.50 0.75 1.0 Years after Biochemical Recurrence Prostate Cancer Specific Survival Number at risk <3.0: 23 10 2 0 3.0-8.9: 119 85 19 0 9.0-14.9: 79 51 19 3 >15 158 113 52 9 PSADT < 3.0 months PSADT 9.0 - 14.9 months PSADT 3.0 - 8.9 months PSADT > 15.0 months p<0.001, log-rank PSA DT (continuous)AHR: 0.86 [0.8, 0.9] p < 0.001

10. SUMMARY Patient Selection PSA DT is significantly associated with PCM –RP –RT –RT + short term H –RT + long term H PSA DT < 3 months –Poor Prognostic Group 15-20% of PSA failure in general population 6-7% of PSA failure in a screened population

11. Clinical Practice In the US, for patients with a rising PSA, the rate of rise of PSA influences use of hormonal therapy –CaPSURE Median time to metastases following PSA failure in patients with a PSA DT < 3 months –18 months Johns Hopkins Patients with a PSA DT < 3 months are offered hormonal therapy

12. Treatment Arms Hormonal Therapy  Systemic Therapy –Taxotere Survival benefit in men with HRMPC –Other Agents

13. End Points Primary –Time to Bone Metastases Secondary –Time to Cancer-Specific Death –Time to all cause Death PSA –What is the evidence to suggest an association between a PSA nadir > 0.2 ng/ml and cancer-specific death in men treated with hormonal therapy for a rising PSA?

14. PSA Nadir > 0.2 Following Hormonal Therapy for a Rising PSA Multi-institutional –CaPSURE/CPDR Single Institutions –MSKCC –Harvard and Barnes Jewish

15. METHODOLOGY MSKCC –346 RP (81% BS negative) Cox Regression –End point Time to PCSM following 8 months of hormonal therapy –Covariates PSA level at initiation of hormonal therapy Pre-hormonal therapy PSA DT PSA nadir within 8 months of Hormonal therapy Prostatectomy T-category Gleason score Bone scan status

16. RESULTS –PSA nadir < 0.2 ng/ml< 0.0001 –PSA level (continuous)< 0.0001 –PSA DT > 3 months0.03 –Gleason score0.40 –pT20.40 –Bone scan status0.60 –63 prostate cancer deaths Median cancer specific survival for patients with PSA nadir > 0.2 –4.8 [2.6, 7.1] years

19. METHODOLOGY 44 Institutions – CPDR and CaPSURE –486 RP; 261 RT –Bone scan (-) Cox Regression –End point Time to PCSM following 8 months of hormonal therapy –Covariates PSA level at initiation of hormonal therapy Pre-hormonal therapy PSA DT PSA nadir within 8 months of Hormonal therapy Interval to PSA failure following RP or RT Gleason score Initial Local Therapy Age at time of PSA nadir

20. RESULTS –PSA nadir (continuous)< 0.0001 –PSA DT (continuous)0.002 –PSA level (continuous)< 0.0001 –Gleason 8 to 100.01 –Gleason 70.17 –Interval to PSA failure (cont)0.20 –Initial Local rx0.19 –Age at PSA nadir0.96 53 deaths –28 Prostate Cancer Specific Adjusted HR for PCSM when PSA nadir > 0.2 20 [7, 61; p < 0.0001]

21. 7-yr cumulative incidence estimates of PCSM with 95% CI PSA nadir PSA DT < 3 mos PSA DT < 6 mos PSA DT < 9 mos N pts N PC deaths 7 yr PCSM [95%CI] N pts N PC deaths 7 yr PCSM [95%CI] N pts N PC deaths 7 yr PCSM [95%CI] > 0.2 6821 72 [45, 99] 10323 55 [30, 80] 126 24 54 [28, 80]  0.2 1563 4 [0.1, 9] 3134 3 [0.1, 6] 431 4 2 [0.1, 5]

22. 68/224 ~ 30%

23. 103/416 ~25%

24. 126/557~ 22%

25. SUMMARY PSA DT < 3 months –30% did not nadir PSA on AST Hormone resistant –Accounted for nearly all PC death »Single institution data base »Multi-institutional data base –AST + Docetaxel If PSA nadir > 0.2 –Hormone and Docetaxel resistant ---  cancer death If PSA nadir > 0.2 decreased from 30% on AST to 10% on AST + Docetaxel, would this be likely to produce clinical benefit?

26. DISCUSSION Is PSA nadir > 0.2 following 8 months of AST (assuming castrate T) a clinically significant end point? In a phase III RCT if the proportion of men with a PSA nadir > 0.2 declined from 30% on AST to 10% on AST + Taxotere, would this be likely to provide clinical benefit? –Prolonged time to bone metastases –Prolonged time to cancer death