# Presentation: 184409

## Correlation of PSA Endpoints with Overall Survival in Men with Hormone-Naive D2 Prostate Cancer:  Southwest Oncology Group Study S8894 

- C. Tangen, M. Eisenberger, M. Hussain,
- D. Raghavan, J. Faulkner, Crawford ED

## Schema for SWOG 8894:

**Bilateral Orchiectomy + Flutamide**

**Bilateral Orchiectomy + Placebo**

**Schema for SWOG 8894:**

**** Blinded treatment assignment***

**A Phase III Clinical Trial in Patients with Histologically Confirmed Stage D2 Prostate Cancer**

## Eligibility Criteria

**Patients with histologically proven diagnosis of stage D2 adenocarcinoma of the prostate.  Measurable disease was not required.**
**Prior surgery and radiation therapy allowed, if metastatic disease evident.**
**No prior or planned hormonal therapy, chemotherapy, or biological response modifiers allowed**
**Patients with adequate hematologic, hepatic, and renal function**
**Patients with SWOG Performance Status of 0-3.  PS 3 allowed if due to pain only**

## Study Information

**Opened:  December 15, 1989**
**Closed:****	****  September 15, 1994**
**Accrual Goal: 1248 eligible patients.**
**Participants: SWOG and ECOG**
**Treatment results of trial: **
**	**Eisenberger MA, Blumenstein BA, Crawford ED, Miller G, McLeod DG, Loehrer PJ, et al.  Bilateral orchiectomy with or without flutamide for metastatic prostate cancer.  N Engl J Med 1998;339:1036-42.

## PSA Study Design Issues

- S8894 was not designed for the collection of PSA data (extracted from flow sheets)
- Not required to report assay method
-    (we only included those with ULN = 4.0 ng/ml)
- Schedule of follow-up PSA assessments was not rigid  (prestudy, week 1, month 1, every 3 months until progression)

## Sample Size for PSA Analyses

**      ****↓**
**1194  ****Patients alive at 9 months**
**      ↓**
**  ****742  **** 2 or more on-study PSA values                             ****	****   within the first 6 months and PSA            ****	****   assay method is specified and adequate**

**Sample Size for PSA Analyses**

**P=0.50 for survival comparison of those with PSA measurements (n=742) vs. those with incomplete PSA assessment**

## Patient Characteristics of n=742           at Study Entry

| Variable | Combined Arms  |
| --- | --- |
| Age (yrs.) mean (25%, 75%) | 69 (64,75) |
| Extensive vs. Minimal Disease | 78% |
| Performance Status 2-3 vs. 0-1 | 16% |
| Bone Pain Present | 52% |
| PSA mean (25%, 75%) | 586 (47, 563) |
| Prior Prostatectomy | 13% |
| African American vs. Other Race | 16% |

## Survival Curves by Treatment Arm

**For Those Assessable for PSA Endpoints at 9 Months**

**0%**

**20%**

**40%**

**60%**

**80%**

**100%**

**0**

**24**

**48**

**72**

**96**

**120**

**144**

**168**

**Months from Registration**

**Flutamide**

**Placebo**

_**At Risk**_

**379**

**363**

_**Death**_

**349**

**333**

**Median**

_**in Months**_

**39**

**32**

**P=0.48**

## Multivariate Analysis Results

**Multivariate Analysis Results**

| Potential PSA Surrogate | Definition |
| --- | --- |
| PSA Normalization | PSA ≤ 4.0 ng/ml |
| PSA Response  | A PSA decline from baseline of ≥ 50% |
| PSA Progression 
 | An increase of ≥ 50% over the nadir and at least 5 ng/ml |
| Slope of PSA  | The slope of the loge of PSA from baseline to cutoff |

**Potential PSA Surrogates for Survival**
**Using a Landmark Cutoff **
**Post-Randomization**

## N = 392

**For Patients with PSA Progression**

**0%**

**20%**

**40%**

**60%**

**80%**

**100%**

**0**

**12**

**24**

**36**

**48**

**Months After Registration**

**N = 392**

**Median = 11 mo**

## N = 551

**For Patients with PSA Normalization**

**0%**

**20%**

**40%**

**60%**

**80%**

**100%**

**0**

**3**

**6**

**9**

**12**

**15**

**18**

**Months After Registration**

**N = 551**

**Median = 2 months**

## Choosing a Landmark

- Evaluated cut points at 3, 6, and 9 months post-randomization
- Chose the cutoff that maximized the logrank statistic
- 9 months was chosen for both PSA normalization and PSA progression
- PSA response was not pursued since nearly everyone experienced it (50% by 1 mo.).

## Prevalence of Endpoints at 9 Months 

| PSA Intermediate Endpoint | Median Time to PSA Event | Prevalence of Event at 9 Months |
| --- | --- | --- |
| PSA Normalization | 2 Mo. | 72% |
| PSA Response | 1 Mo. | 98% |
| PSA Progression | 11 Mo. | 21% |

- Prevalence of Endpoints at 9 Months
- (n=742)

## Multivariate Analysis Results

**Multivariate Analysis Results**

**Potential PSA Surrogates for Survival**
**Using a Landmark of **_**9 Months**_**           Post-Randomization**

| Type of PSA Measure | Hazard Ratio* (p-value) |      R2
   (95% CI) |
| --- | --- | --- |
| Normalization | 0.52 (<0.0001) | 0.14 (.10, .20) |
| Progression | 4.45 (<0.0001) | 0.30 (.27, .37) |
| Slope of  ln PSA | 3.26 (<0.0001) | 0.16 (.11, .22) |

- * Adjusted for baseline PSA and prostatectomy status
-    R2 is the proportion of the variability that’s explained
-    by the model.

## Overall Survival

**By PSA Normalization Status at 9 Months**

**0%**

**20%**

**40%**

**60%**

**80%**

**100%**

**0**

**24**

**48**

**72**

**96**

**120**

**144**

**168**

**Months After Registration**

**Normalization**

**No Normalization**

_**At Risk**_

**531**

**211**

_**Failed**_

**476**

**206**

**Median**

_**in Months**_

**44**

**23**

## Overall Survival

**By PSA Progression Status at 9 Months**

**0%**

**20%**

**40%**

**60%**

**80%**

**100%**

**0**

**24**

**48**

**72**

**96**

**120**

**144**

**168**

**Months After Registration**

**No PSA Progression**

**PSA Progression**

_**At Risk**_

**584**

**158**

_**Failed**_

**525**

**157**

**Median**

_**in Months**_

**45**

**17**

## Progression-Free Survival

**Following PSA Progression**

**0%**

**20%**

**40%**

**60%**

**80%**

**100%**

**0**

**24**

**48**

**72**

**96**

**120**

**Months After PSA Progression**

_**At Risk**_

**392**

_**Failed**_

**390**

**Median**

_**in Months**_

**3**

## Summary of Analysis

**There are reasonable correlations of the PSA endpoints with survival.  PSA progression is the strongest.**
**We cannot evaluate surrogacy in this trial.  A significant treatment effect is needed.**
**PSA progression, for many patients, precedes objective progression by only a few months.**