# Presentation: 190587

## Evidence Supporting a PSA (t) End Point as Proof of Clinical Efficacy 

**Anthony V. D’Amico, MD, PhD**
**Professor of Radiation Oncology**
**Harvard Medical School**

## Two Categories of Evidence

**Surrogate**
**Prognostic Factor**
**Prostate cancer-specific mortality**
**All cause mortality**

## PSA Time Dependent Parameters

**Surrogate**
**PSA doubling time following surgery or RT**
**PSA velocity for hormone refractory M0 state**
**PSA velocity for hormone refractory M1 state**
**SWOG**
**Prognostic Factor**
**PSA velocity prior to diagnosis**
**PSA slope ratio**
**Hormone sensitive**
**Hormone refractory**

## Prentice’s Criteria

**Prognostic factor**
**	****a. Rx**
**	****b. Surrogate**
**Treatment received should not affect time to death**
**Assess using Cox Regression**

## STATISTICAL METHODS

**PTE**
**Proportion of treatment effect explained by the proposed surrogate**
**Perfect Test: PTE = 1.0**
**pPVE**
**Partial proportion of the variation in the mortality data explained by the adding treatment to the Cox model containing the proposed surrogate**
**Perfect Test: pPVE = 0 **

## PSA Doubling Time Following Surgery or RT

## EVENT SAMPLE SIZE

**	****	**_**SURGERY **__**	**__**	**__**	**__**RADIATION**_
**	****	****N = 5918****	****	****	****N = 2751**
**N****PSA failure****	****  =   ****	****611****	****	****N****PSA failure****	****=   840**
**N****PC Deaths ****	****   ****=   ****	****26****	****	****N****PC Deaths**** ****	****=   84**
**N****other deaths**** =   ****	****10****	****	****N****other deaths****  =  34**

## RESULTSPSA DT < 3 mos

**Cox Regression**
**T****PCSD**
**PSA DT < 3 vs ******** 3 mos****	****	****	****p < 0.0001**
**RP vs RT (pts with PSA DT < 3 mos)****	****	****p = 0.37**
**T****ACD**
**PSA DT < 3 vs ******** 3 mos****	****	****	****p < 0.0001**
**RP vs RT (pts with PSA DT < 3 mos)****	****	****p = 0.67**
**Age (continuous)****	****	****	****	****p = 0.0002**

## Treatment Hazard RatioPSA DT < 3 months

| Model
 | HR [95% CI] |
| --- | --- |
| Treatment | 11.4 [ 7.8, 16.8 ] |
| Treatment + Confounders | 8.7 [ 5.6, 13.4 ] |
| Treatment + Confounders + Candidate Surrogate | 1.0 [ 0.6, 1.9 ] |

## Assessment of Prentice’s Criteria

**For a PSA DT < 3 months**
**PTE:****	**** ****	****0.91**
**pPVE: ****	****0.06**
**Given the proposed surrogate, initial Rx had little impact on time to PCSM following PSA failure**

## Slide 11

## Slide 12

## PSA Velocity in the Hormone Refractory M0 Patient

## EVENT SAMPLE SIZE

**	****	****RP + H****salvage****	****  ****	****RT + H****salvage**
**	****	****N = 560****	****	****	****	****N = 359**
**N****PC Deaths ****	****   ****=   ****	****8****	****	****N****PC Deaths**** ****	****=   18**
**N****other deaths**** =   ****	****25****	****	****N****other deaths****  =  14**

## RESULTSPSA velocity >  1.5 ng/ml/year

**Cox Regression**
**T****PCSD**
**PSA vel > 1.5 vs ******** 1.5 ng/ml/year ****	****p = 0.001**
**RP + H****salvage**** vs RT + H****salvage****	****	****p = 0.22**
**T****ACD**
**PSA vel > 1.5 vs ******** 1.5 ng/ml/year ****	****p = 0.01**
**RP + H****salvage**** vs RT + H****salvage****	****	****p = 0.93**

## Treatment Hazard RatioPSA velocity > 1.5 ng/ml/year

| Model
 | HR [95% CI] |
| --- | --- |
| Treatment | 4.3 [1.8, 10.4] |
| Treatment + Confounders | 3.8 [1.4, 10.0] |
| Treatment + Confounders + Candidate Surrogate | 1.8 [0.7, 4.8] |

## Slide 17

## Slide 18

## PSA Velocity Prior to Diagnosis

## Patient Selection

**1989 – 2002**
**1095 (Barnes Jewish Hospital)**
**RP for clinical category T1c, T2**
**Screening Study Patients**
**Median PSA = 4.3 (0.3 – 58.2) ng/ml**
**PSA obtained q 6-12 mos prior to dx**

## Database Descriptors

**Median Age at time of RP**
**65.4 (43.3 – 83.5)**
**Median Follow Up **
**5.1 (0.5 – 13.1) years**
**Mortality**
**PCSM ****	****	****n = 27**
**non–PCSM ****	****n = 57**

## Slide 22

## Slide 23

## PSA slope ratioHormone sensitive

## R = post/pre slope

**Time**

**PSA**

**Salvage Hormonal Therapy**

**Decreasing Hormone Insensitive Population and   R**

**R = post/pre slope**

**Decreasing Hormone Insensitive Population and   R**

**PSA Slope Ratio (R)**

## Interpretation of R

**Good PSA Response (R > 1)**
**Slow Rise**
**Quick Fall**
**Poor PSA Response (R < 1)**
**Fast Rise**
**Slow Fall**

## Patient Selection

**Rising PSA, Bone Scan (-)**
**Study Cohort (N = 199)**
**Radiation Managed**
**Single Institution**
**Validation Cohort (N = 1255)**
**Surgery and Radiation Managed**
**44 Institutions (CaPSURE, CPDR)**

## STUDY COHORT

## VALIDATION COHORT

## PSA slope ratioHormone refractory

## Time

**Time**

**PSA**

** ****Treatment (Cytocidal, Cytostatic,...)**

**PSA slope Ratio = post/pre PSA slope**

**Ratio > 0**

**Ratio = 0**

**Ratio < 0**

**Randomization**

**Progression**

**Response**

## METHODS

**Patient Selection**
**4 Randomized CALGB Trials**
**9181 (low vs. high dose megestrol)**
**9182 (Hct ******** Mitoxantrone)**
**9480 (3 doses of suramin)**
**9583 (AAW + Keto/HCT or AAW + keto at progression)**
**N = 911**
**Followed through progression and next Rx**
**3 pre- and 3-post chemotherapy PSA values**
** ****N = 153**
**Calculation of PSA slope Ratio (R)**
**First order kinetics**

## RESULTSCox Regression – multivariable

| Ratio | PCox | HR [95%CI] |
| --- | --- | --- |
| Best Tertile 
(< - 0.84) | 0.08* | 0.7 [0.5, 1.0] |
| Middle Tertile 
(- 0.84 to – 0.26) | 0.09* | 0.7 [0.5, 1.1] |
| Worse Tertile 
(> - 0.26) | - | 1.0 |

***Adjusted for pre-slope**

## Slide 34

## RESULTSPSA Response and PSA Slope ratio

| Ratio |  50% 
 in PSA | P-value |
| --- | --- | --- |
| Best  or Middle Tertile 
(< - 0.84 to – 0.26) | 33% | 
0.46 |
| Worse Tertile 
(> - 0.26) | 27% |  |

## RESULTSPSA Response and PSA Slope ratio

| Ratio |  50% 
 in PSA | P-value |
| --- | --- | --- |
| Best  or Middle Tertile 
(< - 0.84 to – 0.26) | 33% | 
0.46 |
| Worse Tertile 
(> - 0.26) | 27% |  |

## Slope = - 1

- <date/time>

**50% Decline**

**Slope = - 1**

**Slope = - 0.4**

**Best Tertile: ****	**** < - 0.84**
**Middle Tertile: ****	****– 0.84 to – 0.26**
**Worse Tertile:   ****	****> - 0.26**

## SUMMARY

**PSA Time Dependent Parameters**
**Surrogate for PCSM and ACM**
**PSA DT < 3 months**
**PSA velocity > 1.5 ng/ml/year**
**Prognostic Factors**
**PSA velocity > 2.0 ng/ml/year**
**PSA slope ratio**
**Hormone Sensitive**
**Hormone Refractory**