design of clinical trials for select patients with a rising psa following primary therapy anthony v....
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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
RANDOMIZE
RTOG 92-02
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.
0.0
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0 1 2 3 4 5 6 7 8
RTOG 9202 Prostate Cancer Survival by PSA-DT
Years since randomization
Pro
stat
e C
ance
r S
urv
ival
Rat
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PSA DT < 12 months
PSA DT 12 months
N = 1451
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.
N = 341
0 5 10 15
0.0
0.25
0.50
0.75
1.0
Years after Biochemical Recurrence
Pro
sta
te C
an
cer
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ecif
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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
SUMMARYPatient 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 < 0.0001– PSA level (continuous) < 0.0001– PSA DT > 3 months 0.03– Gleason score 0.40– pT2 0.40– Bone scan status 0.60
– 63 prostate cancer deaths
• Median cancer specific survival for patients with PSA nadir > 0.2– 4.8 [2.6, 7.1] years
0 1 2 3 4 5 6 7 8 9 10
Time (years) after 8 Months of ADT
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Detectable PSA Nadir (> 0.2 ng/ml) - DOC
Undetectable PSA Nadir (< 0.2 ng/ml) - DOC
Detectable PSA Nadir (> 0.2 ng/ml) - DOD
Undetectable PSA Nadir (< 0.2 ng/ml) - DOD
Patients with PSADT < 3 Months at the start of ADT
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) < 0.0001– PSA DT (continuous) 0.002– PSA level (continuous) < 0.0001– Gleason 8 to 10 0.01– Gleason 7 0.17– Interval to PSA failure (cont) 0.20– Initial Local rx 0.19– Age at PSA nadir 0.96
• 53 deaths – 28 Prostate Cancer Specific
• Adjusted HR for PCSM when PSA nadir > 0.2 • 20 [7, 61; p < 0.0001]
7-yr cumulative incidence estimates of PCSM with 95% CI
PSA nadir PSA DT < 3 mos PSA DT < 6 mos PSA DT < 9 mos
NptsNPC
deaths
7 yr PCSM[95%CI]
NptsNPC
deaths
7 yr PCSM[95%CI]
NptsNPC
deaths
7 yr PCSM[95%CI]
> 0.2 68 21 72 [45, 99]
103 23 55 [30, 80]
126 24 54 [28, 80]
0.2
156 3 4 [0.1, 9]
313 4 3 [0.1, 6]
431 4 2 [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