1. Hormone Refractory Prostate Cancer A Regulatory Perspective of End Points to Measure Safety and Efficacy of Drugs Hormone Refractory Prostate Cancer Bhupinder S. Mann, MBBS Medical Officer DODP CDER FDA

2. Objectives End points utilized for granting approval Comments on difficulties encountered in measuring safety and efficacy of drugs for treatment of advanced HRPC

3. Approval of a New Drug Substantial evidence of effectiveness Adequate and well-controlled clinical investigations

4. End Points (Before 1992) Required to represent clinical benefit Direct measures of benefit, e.g. Improvement in survival Improvement of symptoms Accepted surrogates for benefit, e.g. Durable complete responses in acute leukemia

5. Accelerated Approval (1992) Surrogate endpoints that are reasonably likely to predict clinical benefit The drug A benefit over available therapy Post-approval studies Demonstrate that the drug does provide clinical benefit

6. End points Accepted for drug approval Approved drugs for treatment of advanced HRPC Docetaxel (2004) Zoledronic acid (2003) Mitoxantrone(1996) Estramustine(1981)

7. Overall Survival (OS) Safety and efficacy Overall Survival A direct measure of efficacy A reassuring measure of safety

8. Docetaxel May 2004 Docetaxel in combination with prednisone is indicated for the treatment of patients with androgen independent (hormone refractory) metastatic prostate cancer Demonstration of efficacy Well controlled clinical trial Significant prolongation in OS

9. Docetaxel (TAX327) Docetaxel 75 mg/sqM IV q 3 weeks 10 cycles Cumulative dose = 750 mg/sqM Docetaxel 30 mg/sqM q w for 5 of 6 weeks 5 cycles Cumulative dose = 750 mg/sqM Mitoxantrone 12 mg/sqM q 3 weeks 10 cycles Prednisone 5 mg PO bid in each study arm

10. Docetaxel (TAX327) Patients=1,006 Primary efficacy end point Overall Survival Time from randomization to death from any cause

11. Docetaxel OS was significantly superior in the docetaxel q3w group compared with mitoxantrone q3w group OS was also significantly superior for the combined docetaxel group compared with mitoxantrone group OS for once weekly docetaxel arm was not statistically significantly different from that of mitoxantrone q 3 week group

12. Docetaxel Docetaxel + P, q3w Mitoxantrone + P, q3w Number of patients 335337 Median OS 95% CI 18.9 months (17.0-21.2) 16.5 months (14.4-18.6) Hazard Ratio 95% CI 0.761 (0.619-0.936) N/A P value0.0094N/A

13. Demonstration of efficacy Improvement in symptoms and other indices FDA accepted end points Symptom measures Non-survival morbidity indices Approvals based on non-survival end points Mitoxantrone Zoledronic acid

14. Mitoxantrone November 1996 For use in combination with corticosteroids as initial chemotherapy for treatment of patients with pain related to advanced hormone refractory prostate cancer

15. Mitoxantrone Pivotal trial- open label, Phase III 161 symptomatic patients End point- Palliative Response Prospectively defined A 2-point improvement on a 6-point pain intensity scale Accompanied by a stable analgesic score Duration- at least 6 weeks

16. Mitoxantrone M+PP p value Palliative response29%12%0.011 Median duration of palliative response 229 days53 days0.0001 Median time to disease progression 301 days133 days0.0001 Median survival time11.3 m10.8 m0.23 NS Decrease of ≥ 75% in PSA 27%5%0.011

17. Zoledronic acid 2003 Treatment of patients with progressive bone metastases from prostate cancer

18. Zoledronic acid End point used- Composite end point based on skeletal related events (SREs) Diverse disease manifestations Increased power Previously used in lytic bone disease in multiple myeloma and breast cancer

19. Zoledronic acid SRE included in the composite end point Pathological bone fractures Spinal cord compression Surgery to bone Radiation therapy to bone (including Radioactive Isotopes) A change in antineoplastic therapy due to increased pain Added for prostate cancer trial

20. Demonstration of efficacy SRE end point A decrease in the proportion of patients with at least one SRE 33% vs. 44% Difference 11%, p 0.021 An increase in the median time to first SRE NR vs. 321 days HR 0.67, p 0.011

21. Evaluating Treatments for Advanced Prostate Cancer Difficulties stem from several factors Disease characteristics Patient population Prevalent clinical practice

22. Advanced HRPC Disease of heterogeneous natural history  Variable clinical course  Diverse clinical manifestations  Difficult treatment decisions  Traditional efficacy end points  Limited utility

23. HRPC PSA only progression  Disease symptom  None  Bone scan  Negative  Survival  Relatively long

24. HRPC Symptomatic progressive disease Disease related symptoms Worsening of performance status Impaired quality of life Survival Shortened Clinical benefit of treatment Established

25. Patient Population Competing causes of mortality Advanced patient age Comorbid conditions

26. End points Problems confounding interpretation PSA driven treatment changes Missing clinical data

27. End points Problems confounding interpretation PSA based end points may be acceptable surrogates for anti-tumor activity, eg in Phase II clinical trials Reliable use of PSA based end points in Phase III comparative clinical trials remains to be defined

28. Acknowledgements Ramzi Dagher, MD Donna Griebel, MD John Johnson, MD Richard Pazdur, MD Dianne D Spillman Grant Williams, MD