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

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)

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

RTOG < [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.

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

N = 1451

CaPSURE/CPDR < [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.

N = 341

Years after Biochemical Recurrence Prostate Cancer Specific Survival Number at risk <3.0: : : > PSADT < 3.0 months PSADT months PSADT months PSADT > 15.0 months p<0.001, log-rank PSA DT (continuous)AHR: 0.86 [0.8, 0.9] p < 0.001

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

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

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

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?

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

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

RESULTS –PSA nadir < 0.2 ng/ml< –PSA level (continuous)< –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

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

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

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] > [45, 99] [30, 80] [28, 80]  [0.1, 9] [0.1, 6] [0.1, 5]

68/224 ~ 30%

103/416 ~25%

126/557~ 22%

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?

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