# Presentation: 671566

## Can Biochemical Failure (ASTRO Definition) Be Used As A Surrogate Endpoint For Prostate Cancer Survival In Phase III Localized Prostate Cancer Clinical Trials? Analysis Of RTOG Protocol 92-02

**Howard Sandler, Thomas Pajak, Gerald Hanks, Arthur Porter, Michelle DeSilvio, William Shipley**

## 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**
**PreRx PSA < 150 ng/ml**

**RANDOMIZE**

**RTOG 92-02**

## RTOG 92-02

**Study opened ****	****June 1992**
**Study closed ****	****April 1995**
**Total analyzable accrual ****	****1554**
**Median follow-up ****for this analysis****	****5.8 years**
**Total number of deaths****	****448**
**Deaths from prostate****cancer****	****142**

## Biochemical Failure (ASTRO Definition)

**3 consecutive rises**
**Time of failure backdated to halfway between first rise and last non-rising PSA**

## RTOG 92-02

**Survival data are just now maturing on this trial, which completed accrual 8 years ago**
**142 PCa deaths**
**However, PSA failure predates PCa death by many years and there are many more events**
**542 biochemical failures**

## RTOG 92-02

**RTOG 92-02 is a large, PSA-era trial that allows us to test whether PSA can be used as a surrogate endpoint**
**Design of the next generation of clinical trials would be greatly facilitated by the ability to use PSA-determined endpoints as surrogates for PCa-specific mortality**
**dramatically quicker**
**dramatically smaller**

## Prentice’s (1989) Operational Criteriafor a Surrogate Endpoint

**1.  Treatment is prognostic for true endpoint (e.g., overall or prostate cancer survival)**
**2.  Treatment is prognostic for surrogate endpoint (e.g., time to biochemical failure)**
**3.  Surrogate is prognostic for true endpoint**
**4.  The full effect of the treatment on the true endpoint is explained by surrogate**
**A. *****Is prostate cancer survival independent of treatment ******given that a patient failed biochemically*****?**
**B. *****Is prostate cancer survival independent of treatment ******given that a patient is biochemically free*****?**

## Criterion 1: Treatment Is Prognostic for True Endpoint RTOG 92-02 Prostate Cancer Survival

## Criterion 2: Treatment Is Prognostic for Surrogate Endpoint RTOG 92-02 Biochemical Failure

## Criterion 3: Surrogate Is Prognostic for True Endpoint

**Criterion 3:***** ******Surrogate****** Is Prognostic for True Endpoint***

## Criterion 3: Surrogate Is Prognostic for True Endpoint

**<0.0001**

**[6.2, 14.5]**

**9.49**

**P-Value**

**[95% C.I.]**

**Relative Risk**

**Hypothesis**
**Is biochemical failure prognostic for prostate cancer survival?**

**Conclusion**
**A patient who failed biochemically are 9.5 times at greater risk of prostate cancer death than those who did not fail biochemically.**

## Causes of Death byBiochemical Failure Status and Treatment

**143(93%)**

**107 (88%)**

**17 (29%)**

**31 (30%)**

**  ****Non-Prostate Cancer**

**11 (7%)**

**15 (12%)**

**42 (71%)**

**  ****72 (70%)**

**  ****Prostate Cancer**

**154**

**122**

**59**

**103**

**Dead**

**417**

**270**

**116**

**264**

**Alive**

**LTAD**
**(N=571)**

**STAD**
**(N=392)**

**LTAD**
**(N=175)**

**STAD**
**(N=367)**

**Survival Status**

**No**
**Biochemical Failure**

**Biochemical Failure**

## Criterion 4: Full effect of treatment on true endpoint is explained by surrogate

**0.05**

**[1.0, 2.1]**

**1.5**

**Hypothesis A**
**Is prostate cancer survival independent of treatment ****given that a patient failed biochemically?**

**Conclusion**
**A patient treated with LTAD is 1.5 times at greater risk of a prostate cancer death than a patient treated with STAD given that the patient failed biochemically.**

**P-Value**

**[95% C.I.]**

**Relative Risk**

## RTOG 92-02 Prostate Cancer Survival Given Biochemical Failure

## Criterion 4: Full effect of treatment on true endpoint is explained by surrogate

**0.17**

**[0.3, 1.2]**

**0.6**

**P-Value**

**[95% C.I.]**

**Relative Risk**

**Hypothesis B**
**Is prostate cancer survival independent of treatment ****given that a patient is biochemically free from recurrence?**

**Conclusion**
**A patient treated with LTAD is less likely or at the same risk of a prostate cancer death than a patient treated with STAD given that the patient did not fail biochemically.**

## RTOG 92-02 Prostate Cancer SurvivalGiven No Biochemical Failure

## Summary: Biochemical Failure Surrogate for Prostate Cancer Survival

**Met**

***    ******B. Prostate cancer survival independent of treatment ******given that a patient has not failed biochemically?***

**Not Met**

***     ******A. Prostate cancer survival independent of treatment ******given that a patient failed biochemically?***

**4. Full of effect of treatment on true endpoint is explained by surrogate**

**Met**

**3. ****Surrogate**** is prognostic for true endpoint**

**Met**

**2. ****Treatment**** is prognostic for surrogate endpoint**

**Met**

**1. ****Treatment**** is prognostic for true endpoint**

**Prentice’s Criteria**

## Conclusions (1)

**RTOG 92-02 demonstrates an advantage to long term androgen ablation**
**PSA failure is associated with an increased risk of prostate cancer death**

## Conclusions (2)

**Importantly, risk of death *****from the time of biochemical failure***** is increased in the LTAD arm**
**Presumably, some of the failures in the LTAD arm had HRPCa at the time of failure and were less responsive to salvage androgen ablation**

## Conclusions (3)

**Surrogate endpoints based on biochemical failure may not be appropriate for phase III localized prostate cancer trials, if the post-surrogate-failure clinical course is influenced by protocol treatment**

## Slide 21

## Prostate Cancer Deaths withoutBiochemical Failure