# Presentation: 800603

## PSA Response A Surrogate for Overall Survival? Analysis of TAX 327 

- Martin Roessner M.S.
- Aventis, Bridgewater, NJ

## Study Design

**TXT qw (5 cycles)**

**TXT q3w (10 cycles)**

**MTZ q3w (10 cycles)**

**Taxotere 75 mg/m****2**** IV q3 weeks **
**Prednisone 5 mg PO BID**

**Taxotere 30 mg/m****2 ****IV weekly for 5 of 6 weeks**
**Prednisone 5 mg PO BID**

**Mitoxantrone 12 mg/m****2 ****IV q3 weeks **
**Prednisone 5 mg PO BID**

**R****A****N****D****O****M****I****Z****E**

**N = 1006  in 105 centers and  24 countries**

**Stratification: **
**Performance status & pain**

## Key Eligibility Criteria

**Androgen independent prostate cancer**
**S/P orchiectomy and/or LHRH agonist**
**Testosterone <50 ng/dL**
**Progressive disease**
**Stable pain scores and analgesia requirements**
**No prior chemotherapy (except estramustine)**

## Patient Characteristics

|  | TXT q3w | TXT qw | MTZ q3w |
| --- | --- | --- | --- |
| Randomized  | 335 | 334 | 337 |
| Median age (range) | 68(42-92) | 69(36-92) | 68(43-86) |
| Karnofsky PS ≥ 80 (%) | 88 | 87 | 86 |
| Prior treatment (%)
       Prostatectomy
       Radiotherapy
       Estramustine | 
19
52
19 | 
24
44
18 | 
21
51
21 |

## Overall Survival 

**0**

**6**

**12**

**18**

**24**

**30**

**0.0**

**0.1**

**0.2**

**0.3**

**0.4**

**0.5**

**0.6**

**0.7**

**0.8**

**0.9**

**1.0**

**TXT q3w**

**TXT qw**

**MTZ q3w**

**Months**

**Probability of Surviving**

**  ****Treatment   Median    Hazard  Nominal  P-value**
**	****      ****survival   ratio  sign.level**
**  ****TXT q3w:    18.92 mo  0.761   0.0175   0.0094**
**  ****TXT qw :    17.38 mo  0.912   0.0175   0.3624**
**  ****MTZ q3w:    16.49 mo     -****	****       -**

## Definition of PSA response and Tumor response

- PSA response
- Baseline PSA of at least 20 ng/ml
- Decrease from baseline of at least 50%
- Confirmed by a second value obtained at least 3 weeks later
- Response has to occur before progression
- Tumor response (WHO criteria)
- At least one measurable lesion at baseline
- Decrease by at least 50% of the sum of the products of the largest perpendicular diameters of all measurable lesions (if bi-dimensional)
- Decrease by at least 50% in the sum of the largest diameters of all lesions (if uni-dimensional)
- Confirmed Overall tumor response is defined as complete response or partial response at two assessments at least 28 days apart

## PSA and Tumor Response Rates

|  | TXT q3w | TXT qw | MTZ q3w |
| --- | --- | --- | --- |
| PSA Response Rate* |  |  |  |
| 	Number of subjects evaluable | 291 | 282 | 300 |
| 	PSA response rate (%) | 45.4 | 47.9 | 31.7 |
| 	P-value (vs. MTZ q3w) | 0.0005 | <0.0001 | ‒ |
| Tumor Response Rate* |  |  |  |
| 	Number of subjects evaluable | 141 | 134 | 137 |
| 	Tumor response rate (%) | 12.1 | 8.2 | 6.6 |
| 	P-value (vs. MTZ q3w) | 0.1112 | 0.5853 | ‒ |

**PSA and Tumor Response Rates**

- *	Determined only for subjects with baseline PSA 20 or measurable disease at baseline, respectively

## Questions

- Does change in PSA correlate with Overall Survival?
- IS change in PSA a surrogate for Overall Survival?
- Can change in PSA be used as primary endpoint in clinical trials?
- Information during development
- Phase I/II trials
- Regulatory decision making
- Confirmatory Phase III trials

## Prentice Criteria for Surrogate Endpoint

- Treatment must have a significant effect on overall survival.
- Treatment must have a significant effect on PSA change.
- There must be a significant association between PSA change and overall survival.
- The full effect of the treatment on overall survival must be explained by PSA change.

***Source: Prentice R.L., Surrogate endpoints in clinical trials: definition and operational criteria, *****Statistics in Medicine*****, **8**, 431-440 (1989)) **

## Background on PSA changes

- Several endpoints are used to validate PSA changes as a surrogate endpoint
- PSA Doubling Time
- Does not include the initial treatment effect
- Does not include patients with incomplete data
- PSA velocity
- Does not include patients with incomplete data
- Does not include the progression part if not on study
- Time to PSA progression
- Does not include the initial treatment effect
- Does not include patients with incomplete data
- PSA response
- Does not include the progression part
- Current datasets have limitations to the application of these approaches due to incomplete data

## PSA Profiles in TAX 327

## PSA response as surrogate endpoint in TAX 327

- Seems the most appropriate approach for TAX 327
- Not affected by missing data later during follow-up
- Censored in case of progression (tumor, pain, PSA)
- Accounts for the immediate effect of chemotherapy from baseline
- Does not ignore the initial effect (time to nadir)
- Includes all patients in the analysis with baseline PSA  20 ng/ml

## PSA results at baseline

|  | TXT q3w | TXT qw | MTZ q3w |
| --- | --- | --- | --- |
| Number of subjects | 335 | 333 | 336 |
| Baseline |  |  |  |
| Median (ng/ml) | 114.00 | 107.63 | 122.60 |
|  min - max(ng/ml) | 0.15 – 40740 | 0.0 -16709 | 0.30 – 8022 |
| < 20 ng/ml | 44 (13.1) | 52(15.6) | 37(11.0) |
| ≥ 20 ng/ml | 291(86.9) | 281(84.1) | 299(88.7) |
|  |  |  |  |
|  |  |  |  |
|  |  |  |  |

## PSA results post-baseline

|  | TXT q3w | TXT qw | MTZ q3w |
| --- | --- | --- | --- |
| Number of subjects | 335 | 333 | 336 |
| Nadir |  |  |  |
| Median (ng/ml) | 25.1 | 22.0 | 59.0 |
| Q1-Q3 |  
5.4-96.8
 | 3.3-91.7 | 14.0-216.1 |
|  |  |  |  |
| Occurring at baseline | 19% | 19% | 34% |
|  |  |  |  |
| Time to nadir (days) | 164 | 147 | 124 |
| Q1-Q3 | 85-214  | 85-209  | 63-211  |

## Treatment has a significant effect on Overall Survival and PSA Response Rate

**Overall survival**

**PSA response rate in %**

**p=0.0005**

| Hazard ratio
95% CI
Log-rank | 0.754
0.607;0.936
p=0.0103
 |
| --- | --- |
|  |  |
|  |  |
|  |  |

## Overall Survival by PSA Response

| Hazard ratio
95% CI
Cox model | 0.396
0.308;0.510
p<0.0001 |
| --- | --- |
|  |  |
|  |  |
|  |  |

- confirmed by Cox model with time dependent covariate for PSA response

## Treatment Effect on Overall Survival Explained by Effecton PSA Response for TXTq3w vs MTZ q3w

| Covariate | Hazard ratio  | 95% CI of hazard ratio  | p-value*  |
| --- | --- | --- | --- |
| Treatment effect | 0.865  | 0.695 – 1.078  | 0.1966  |
| PSA response status | 0.407  | 0.315 – 0.526  | < 0.0001  |

- Treatment Effect on Overall Survival Explained by Effecton PSA Response** for TXTq3w vs MTZ q3w**

- *Cox model with PSA Response Status as a time-dependent covariate and treatment as a fixed covariate

## Proportion of treatment effect on Overall Survival explained by PSA response for TXTq3w vs MTZ q3w

- PSA response is associated with the treatment effect on overall survival
- 49% * of the treatment effect is explained by PSA response
- PSA velocity shows similar results (66% explained)

- *Freedman LS, Graubard BI, Schatzkin A. ‘Statistical validation of intermediate end points within intervention trials or observational studies’, *Statistics in Medicine*, **11**, 167-178 (1992).** **

## TXT q3w has demonstrated a significant effect on PSA response and overall survival
There is a significant association between PSA response and overall survival 
The significant treatment effect on overall survival can be at least partially  (49%) explained by the positive effect on PSA response in TXTq3w
Proportion explaining the treatment effect is “too low” for a surrogate endpoint
Prentice criteria for surrogacy met(?)
But......

- There is a significant association between PSA response and overall survival
- The significant treatment effect on overall survival can be at least partially  (49%) explained by the positive effect on PSA response in TXTq3w
- Proportion explaining the treatment effect is “too low” for a surrogate endpoint
- Prentice criteria for surrogacy met(?)
- But......

- PSA response a surrogate for Overall Survival (1)

## PSA response a surrogate for Overall Survival (2)

- PSA response does not meet the Prentice criteria for TXT qw due to lack of survival benefit for TXT qw vs MTZq3w (HR=0.91, p=0.36)
- PSA response effect vs MTZq3w similar for  TXT q3w (45.4%) and TXT qw (47.9)
- Other response criteria (75% reduction in PSA) provide similar response rates for TXT q3w (33.7%) and TXT qw (33.0) vs MTZ q3w (18.3%)

## Conclusion

- PSA response can provide guidance in the development process of chemotherapeutic agents
- PSA response may be useful in a Phase I/II setting to demonstrate activity of chemotherapy
- PSA response alone can not replace Overall Survival  as primary endpoint in a Phase III metastatic setting to confirm ultimate clinical benefit

## Recommendations

- Need more complete datasets to assess the validity of PSA changes as a surrogate for Overall Survival
- Agree on the PSA endpoints used for validation
- Consider initial response effects as well as effects on progression
- Consider specific requirements depending on the clinical setting
- Agree on validation criteria
- Prentice
- R2
- Proportion of effect explained