# Presentation: 859523

## 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)**

## RTOG 92-02

**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.**

## RTOG 9202 Prostate Cancer Survival by PSA-DT

**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

**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

**N = 341**

## PSA DT (continuous)	AHR: 0.86 [0.8, 0.9]	  p < 0.001

- <date/time>

- 0

- 5

- 10

- 15

- 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**

## 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****	****	****< 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**

## <footer>

- <date/time>

## Slide 18

## 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]**

## 68/224 ~ 30%

**68/224 ~ 30%**

## 103/416 ~25%

**103/416 ~25%**

## 126/557~ 22%

**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**