Design of Clinical Trials for Select Patients With a Rising PSA following Primary Therapy

1
Design of Clinical Trials for Select Patients
With a Rising PSA following Primary Therapy

• Anthony V. DAmico, 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
RTOG 92-02
RANDOMIZE
Arm 1 goserelin and flutamide 2 mos before and
during standard RT (STAD)
T2c-T4 Pre Rx PSA
Arm 2 goserelin and flutamide 2 mos before and
during standard RT, followed by goserelin alone
for 24 mos (LTAD)
4
RTOG
P-Value
95 C.I.
Hazard Ratio
4.3, 8.9
6.2
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
Prostate Cancer Survival Rate
PSA DT Years since randomization
6
N 1451
7
CaPSURE/CPDR
P-Value
95 C.I.
Hazard Ratio
12.5, 30.9
19.6
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
PSA DT (continuous) AHR 0.86 0.8, 0.9 p 0.001
PSADT 15.0 months
1.0
0.75
PSADT 9.0 - 14.9 months
PSADT 3.0 - 8.9 months
0.50
Prostate Cancer Specific Survival
PSADT 0.25
p0.0
0
5
10
15
Years after Biochemical Recurrence
Number at risk 10 2 0 3.0-8.9 119
85 19 0 9.0-14.9
79 51 19
3 15 158 113
52 9
10
SUMMARYPatient Selection

• PSA DT is significantly associated with PCM
• RP
• RT
• RT short term H
• RT long term H
• PSA DT
• 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
• 18 months
• Johns Hopkins
• Patients with a PSA DT 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
• PSA level (continuous)
• 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

17
(No Transcript)
18
(No Transcript)
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)
• PSA DT (continuous) 0.002
• PSA level (continuous)
• 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

21
 
22
68/224 30
23
103/416 25
24
126/557 22
25
SUMMARY

• PSA DT
• 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