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

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

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

e

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

Sp

ecif

ic S

urv

iva

l

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

0.0

0.2

0.4

0.6

0.8

1.0

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mm

ula

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ea

th

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