# Presentation: 697857

## NDA 21-801  Satraplatin Proposed Indication

- Satraplatin is indicated for the treatment of patients with androgen independent (hormone refractory) prostate cancer who  have failed prior chemotherapy

## Study Population

-  Hormone refractory metastatic prostate
-   cancer
-  Failed one prior chemotherapy regimen
-  No prior platinum drug
-  ECOG PS _<_ 2
-  Stable analgesic regimen

## Study Design

- Double-blind, randomized trial - satraplatin plus prednisone versus placebo plus prednisone
- Satraplatin 80 mg/m2 daily x 5 every 35 days
- Prednisone 5 mg bid daily
- 2:1 randomization
- Stratification: PS, PPI score, Type of Progression (Tumor Size vs PSA)
- At progression no crossover to satraplatin

## Study Endpoints

- Primary
-    - PFS
-    - OS
- Secondary
-    - Time to Pain Progression

## PFS

- 	Composite Endpoint
-    		- Radiologic progression
-    		- Pain progression
-    		- ECOG P.S.  (+2 units)
-    		- Weight loss  (>10%)
-  		- Skeletal related events
-   		- Clinical events
-  		- Death

## Partial Regulatory HistoryPFS Endpoint

- Oct. 2002-EOP2 - ? Appropriateness of PFS endpoint.
- May 2003-EOP2 - No agreement on PFS definition
- June 2005-pre-NDA – No experience with composite PFS endpoint
- March 2006 - PFS endpoint will be a review issue

## 
ODAC Question

Is the composite PFS endpoint, as defined, an acceptable endpoint for treatment evaluation in hormone refractory prostate cancer?  

- ODAC Question
- Is the composite PFS endpoint, as defined, an acceptable endpoint for treatment evaluation in hormone refractory prostate cancer?

## Sample Size Considerations

| Date | Endpoint | HR | Power | # Pts | # Events |
| --- | --- | --- | --- | --- | --- |
| 5/03 | OS | 1.3 | 80% | 792 |  |
| 7/03 | PFS/OS | 1.3 | 85% | 912 | 637 PFS
602 OS |
| 4/04 | OS | 1.3 | 85% | 912 | 602 OS |
| 6/05 | PFS/OS | 1.3 | 90% |  | 694 PFS
700 OS |
| 2/07 | PFS/OS |  |  | 950 | 802 PFS
463 (6/06) |

## Participant Countries

| Country | No. Pts | Country | No. Pts |
| --- | --- | --- | --- |
| U.S.A | 258 | Russia | 28 |
| France | 141 | Croatia | 24 |
| Argentina | 98 | Italy  | 23 |
| U.K. | 85 | Peru | 23 |
| Poland | 71 | Hungary | 22 |
| Germany | 61 | Israel | 14 |
| Belgium | 46 | Netherlands | 11 |
| Spain | 42 | Canada | 3 |

## Demographics

| Characteristic | Total n=950 |
| --- | --- |
| Age (median (min-max) | 70 (42-95) yrs |
| Race: Caucasian | 89% |
| ECOG 0-1 | 89% |
| Current bisphosphonates | 30% |
| PPI = 0 | 36% |
| Average analgesic score = 0 | 41% |
| Prior docetaxel | 51% |

## Progression Free Survival

## Interim Overall Survival66% Events

## ODAC Question

- Should the FDA wait for the final survival analysis before deciding whether this application is approvable?

## PFS Events

|  | Satraplatin
n=528 | Prednisone
n=274 | Total
n=802 |
| --- | --- | --- | --- |
| Radiologic | 36% | 37% | 36% |
| Pain | 35% | 43% | 37% |
| Death |   9% |   5% |   8% |
| PS/Weight |   6% |   6% |   6% |
| Other | 15% | 10% | 13% |

## Radiologic ProgressionIndependent Radiology Review

- Independent blinded review of all radiology studies by 2 radiologists
- If the two radiologists disagree as to the occurrence of progression or response or if they differ on the date of progression or  response a third radiologist (adjudicator) reviews the studies and agrees with either radiologist 1 or radiologist 2

## Adjudicated Radiology Progression

| Radiologic |  No. | Number Adjudicated | Percent Adjudicated |
| --- | --- | --- | --- |
| Progression | 290 | 116 | 40% |
| Not Progression | 660 | 220 | 33% |
| Total | 950 | 336 | 35% |

## ODAC Question

- As 336 of 950 study patients (35%) required adjudication to determine progression what does this indicate about the reliability of radiologic  progression assessment?

## Radiologic ProgressionImaging Methods

| Imaging Method | Total
N=290 |
| --- | --- |
| Bone scan only | 66% |
| Bone scan + other | 16% |

## Radiologic  Progression

## Time to Pain Progression

## Pain Progression Assessment

- Based on average weekly Present Pain Intensity (PPI) and Analgesic Scores (AS) recorded by patients on pain diaries
- Pain progression
- 	PPI Increase _>_ 1 point from baseline or            _>_ 2 points from nadir observed for _>_ 2       consecutive weeks
- Increase in average AS of >25% (narcotics only) observed for _>_ 2 consecutive weeks
- Independent blind review

## Baseline PPI

| Pain 
Score | Number of patients (%) |
| --- | --- |
| 0 (None) | 327 (35.9) |
| 1 (Mild) | 258 (28.3) |
| 2 (Discomforting) | 212 (23.3) |
| 3 (Distressing) | 97 (10.6) |
| 4 (Horrible) | 14  (1.5) |
| 5 (Excruciating) | 3 (0.1) |

## Baseline PPI 0, 1 or 2  Narcotic Use

| 
PPI | 
No. of patients | No. analgesic score = 0 | % analgesic score = 0 |
| --- | --- | --- | --- |
| 0 | 327 | 301 | 92 |
| 1 | 258 | 160 | 62 |
| 2 | 212 | 69 | 33 |

## Pain and/or Analgesic Progression

## Analgesic Score Progression % of Pain Progression

## ODAC Question

- Was pain progression reliably assessed in this trial?

## Objective Response Rate

|  | Satraplatin
N=274* | Placebo
N=134* |
| --- | --- | --- |
| CR + PR | 8% | 0.7% |
| * Number of patients with soft tissue lesions |  |  |

## Drug Exposure

|  | Satraplatin
+ Pred | Placebo
+ Pred |
| --- | --- | --- |
| Number of treatment cycles
Median (range) | 4
(1-32) | 2
(1-19) |
| % of  patients with
Dose reduction < 70 mg/m2
Dose delay > 7 days
Dose increase > 90 mg/m2 | 
21%
44%
8% | 
0.3%
11%
10% |

## Cycle 1 Hematologic Toxicity

|  | Satraplatin + Pred
n=629 | Placebo + Pred
n=313 |
| --- | --- | --- |
| Hemoglobin
All Grades
Grade 3-4 | 
96%
9% | 
90%
3% |
| Platelets
All Grades
Grade 3-4 | 
87%
22% | 
20%
1% |
| Neutrophils
All Grades
Grade 3-4 | 
67%
21% | 
5%
1% |

## Grade 3/4 Non-Hematologic TEAEs

|  | Satraplatin + Pred
n=629 | Placebo + Pred
n=313 |
| --- | --- | --- |
| Any TEAE | 55% | 30% |
| GI Disorders | 8% | 2% |
| Infections | 5% | 1% |

## ODAC Discussion Issues

- Is PFS, as defined, an acceptable endpoint for treatment evaluation in HRPC? 
Was radiologic progression reliably assessed?
Was pain progression reliably assessed?
Should FDA should wait for the final survival analysis before deciding whether this application is approvable? That analysis should be available by the end of 2007

- - Is PFS, as defined, an acceptable endpoint for treatment evaluation in HRPC?
- Was radiologic progression reliably assessed?
- Was pain progression reliably assessed?
- Should FDA should wait for the final survival analysis before deciding whether this application is approvable? That analysis should be available by the end of 2007