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

95% C.I. and P-value for the differenceProportionZol 4 mg Zol 8/4 mg

Placebo 92/20844%

-20.3%, -1.8%p=0.021

-15.1%, 3.6%p=0.222

4 mg 71/21433%

- (-3.7%, 14.3%),p=0.255

8/4 mg 85/22138%

- -

Time To First Event:FDA preferred Primary Endpoint

N Median TTE in days

(95% C.I.)

P-value (Log-rank)

Hazard Ratiovs placebo(95% C.I.)

Placebo 208 321(252, Not reached)

- -

Zol 4 mg 214 Not reached(383, Not reached)

0.009 0.66(0.48, 0.90)

Zol 8/4 mg 221 363(255, Not reached)

0.541 0.912(0.68, 1.23)

Time to to First SREHazard Ratios with 95% C.I.

Study 011

Study 039

4 mg

8 mg

4 mg

8 mg

HR = 1

Secondary Endpoints - 039

BPI scores

Analgesic scores

ECOG PS

FACT-G scores

TTP in bone

TTP

Overall survival

P value not significant for any endpoint at the end of 15 months

Exploratory analysis

Pooled analysis: Zometa vs. Placebo - 039exploratory analysis

Time to first SRE: Zometa 4 mg + 8/4 mg vs Placebo:p-value * = 0.06H.R. point estimate = 0.7895% C.I. = 0.60, 1.01Proportion of Patients with SRE: Zometa 4 mg + 8/4 mg vs Placebop-value * = 0.04Diff. In proportions = -0.0895% 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

Prop. Of patients with path fractures 4 mg vs placebo significant (p=0.015)

23

13

5 42

24

15

85

3

29

22

7 73

0

5

10

15

20

25

30

35

Radiation tobone

All fractures Change ofantineoplastic

therapy

Spinal cordcompression

Surgery to bone

Perc

ent o

f pat

ient

s

ZOMETA 4 mgZOMETA 8/4 mgPlacebo

N214221208

Proportions (%) of Patients with any SRE in Blastic Metastasis in Solid Tumor Trial-011

exploratory analysis - support for prostate cancer study

05

101520253035404550

4 mg8/4 mgPlacebo

Patients with blastic metastasis at baseline of Study 011

N=133

42 patients 51 patients 40 patients

26%29%

35%N=11

N=15

N=14

Perc

ent o

f pat

ient

s

No Baseline ImbalancesMultivariate 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 = 0.8795% CI = 0.67, 1.18

Early discontinuations were not the cause of inconsistency

Number of infusions and patients with SREs at 3 months of treatmentZol 4 mgN=213

Zol 8/4 mgN=219

PlaceboN=208

Discontinuations prior to15 months

62% 72% 69%

Infusions at 3 mos. 82% 81% 83%

SREs by 3 mos. 2512%

4822%

4723%

Summary of ResultsProstate 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 IndustryProviding 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 IndustryFDA 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?

Zometa for Bone Metastases of Solid Tumors other than Breast

Cancer and Prostate CancerProtocol 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

95% C.I. andP-value for the difference

Proportionof patients

4 mg 8/4 mgPlacebo 111/250

44%-15.2%,1.9%

p=0.127-18.2%,-1.4%

p=0.023

Zol 4 mg 97/25738%

- -11.4%,5.1%p=0.452

Zol 8/4 mg 92/26635%

- -

Time To First Event:FDA preferred Primary Endpoint

Treatmentarm

Median(days)

p value compared to placeboand 95% confidence limits

Placebo 163 -106-188 days

4 mg 230 0.026168 days - not reached

8/4 mg 219 0.035172 days - not reached

Pooled analysis: Zometa vs. Placebo - 011exploratory analysis

Time to first SRE Zometa: 4 mg + 8/4 mg vs Placebo:p-value * = 0.01H.R. point estimate = 0.7495% C.I. = 0.58, 0.935Proportion of Patients with SRE: Zometa 4 mg + 8/4 mg vs Placebop-value * = 0.03Diff. In proportions = -0.0895% 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

Tumor Types in Solid Tumor TrialCancer type Placebo Zol 4 mgNSCLC 121 124Renal 19 26Small cell lung cancer 22 19Colorectal 16 19Unknown 14 17Bladder 16 11GI (other) 12 10Head and neck 4 6GU 6 6Malignant melanoma 4 5hepatobiliary 4 3Thyroid 4 2Other 2 3Sarcoma 3 3Neuroendocrine/carcinoid 3 2Mesothelioma 0 1

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?