# Presentation: 006257

## Zometa for Prostate Cancer Bone Metastases

- Protocol 039
- Amna Ibrahim, M.D.
- Oncology Drug Products
- FDA

## Critical Questions: Study 039

- Considering both the 4 mg and 8/4 mg arms, how convincing is the Prostate Cancer Trial (039)?
- Can data from other studies provide support?

## Overview of Prostate Cancer Trial

- Study Results
- Exploratory analysis
- No baseline imbalances
- No impact of early discontinuations on primary endpoint
- Summary of issues of trial

## Proportions of Patients with SREs: Protocol defined Primary Endpoint

## Time To First Event:FDA preferred Primary Endpoint

## Time to to First SREHazard Ratios with 95% C.I.

- Study 011

- Study 039

- 4 mg

- 8 mg

- 4 mg

- 8 mg

- HR = 1

## Secondary Endpoints - 039

## Exploratory analysis

## Pooled analysis: Zometa vs. Placebo - 039exploratory analysis

- _Time to first SRE_: Zometa 4 mg + 8/4 mg vs Placebo:
- p-value * 			= 0.06
- H.R. point estimate 		= 0.78
- 95% C.I.			= 0.60, 1.01
- _Proportion of Patients with SRE_: Zometa 4 mg + 8/4 mg vs Placebo
- p-value * 			= 0.04
- Diff. In proportions 		= -0.08
- 95% C.I.			= -0.161, -0.001
-    * Should be interpreted with caution due to exploratory nature of the analysis.  is not adjusted for multiple testing

## Proportion of Patients with Individual SREs - 039exploratory analysis

## Proportions (%) of Patients with any SRE in Blastic Metastasis in Solid Tumor Trial-011exploratory analysis - support for prostate cancer study

- Patients with blastic metastasis at baseline of Study 011

**N=133**

- 42 patients

- 51 patients

- 40 patients

- 26%

- 9

- 29%

- 35%

- N=11

- N=15

- N=14

- Percent of patients

## No Baseline Imbalances

- 	**Multivariate Cox Regression model**
- 	- _4 mg arm vs. placebo_
- 			p-value = 0.02
- 			HR	   = 0.68
- 			95% CI = 0.49, 0.94
- 	- _8 /4 mg vs. placebo_ 		 		p-value = 0.37
- 			HR        = 0.87
- 			95% CI = 0.67, 1.18

## Early discontinuations were not the cause of inconsistency

## Summary of ResultsProstate Cancer Trial - 039

*Proportion of patients with SRE* and *Time to first SRE* for 4 mg arm were significantly better than placebo
*Proportion of patients with SRE* and* **Time to first SRE* for 8/4 mg arm show no difference compared to placebo

## FDA Guidance for IndustryProviding Clinical Evidence of Effectiveness for Human Drug and Biological Products

- 	*“**When considering whether to rely on a single multicenter trial, it is critical that the possibility of an incorrect outcome be considered and that **all the available data be examined** for their potential **to either support or undercut reliance on a single multicenter trial”*

## FDA Guidance for IndustryFDA approval of New Cancer Treatment Uses for Marketed Drug and Biological Products

*    “**If a product has already been shown to be safe and effective in the treatment of patients with a given type of cancer, **a single, adequate and well-controlled, multicenter study** **demonstrating acceptable safety and effectiveness in another biologically similar pattern of responsiveness** to chemotherapy may support labeling for that additional form of cancer”*

## Summary of Issues

- Considering both the 4 mg and 8/4 mg arms, how convincing is Study 039?
- This is a first indication of a bisphosphonate for a predominantly osteoblastic disease. Can support be drawn from other trials?
- Is there substantial evidence to support efficacy of the 4 mg arm?

## Slide 18

## Zometa for Bone Metastases of Solid Tumors other than Breast Cancer and Prostate Cancer

- Protocol 011

## Overview of the Solid Tumor Trial

- Study Results
- Heterogeneous population
- Response of bone metastases to chemotherapy
- Summary of issues

## Proportions of Patients with SREs: Protocol defined Primary Endpoint

## Time To First Event:FDA preferred Primary Endpoint

## Pooled analysis: Zometa vs. Placebo - 011exploratory analysis

- _Time to first SRE Zometa: 4 mg + 8/4 mg vs Placebo_:
- p-value * 			= 0.01
- H.R. point estimate 		= 0.74
- 95% C.I.			= 0.58, 0.935
- _Proportion of Patients with SRE: Zometa 4 mg + 8/4 mg vs Placebo_
- p-value * 			= 0.03
- Diff. In proportions 		= -0.08
- 95% C.I.			= -0.15, -0.01
-    *Should be interpreted with caution due to exploratory nature of the analysis.  is not adjusted for multiple testing

## Heterogeneous Population

- Varying predilection of different tumors to metastasize to bone.
- Variable tumor behavior in bone
- Potentially variable tumor response to Zometa in diverse tumor types

## Slide 25

## Response of bone metastases to chemotherapy

- Prior chemotherapy treatment not recorded
- The study was blinded and randomized, and likely will not impact on study results.

## Results Summary ‘Other Solid Tumor Trial’ - 011

- No statistical difference for 4 mg for *protocol-specified endpoint*
- Substantial evidence for 4 mg for *Time to First SRE*
- Substantial efficacy for 8 mg in both endpoints, i.e. *Proportions of Patients with any SRE* and *for Time to First Event*

## Issues of ‘Other Solid Tumors’ Trial

- Heterogeneous population
- Is there substantial evidence to support efficacy of the 4 mg arm?
- If yes, should Zometa be approved for all solid tumors?

## Slide 29