1. 1 NDA 20-498 / S012 CASODEX (bicalutamide) 150 mg FDA Review Division of Reproductive and Urologic Drug Products (DRUDP)

2. 2 Outline of FDA Presentation Background and Review Issues › Dan Shames, M.D., Director, DRUDP Review of Clinical Trial Data › Scott Monroe, M.D., Medical Team Leader, DRUDP Summary of Review Issues and Introduction of Questions › Dan Shames, M.D.

3. 3 Background Importance of current supplement on the public health Importance of adequate staging in the treatment of prostate cancer History of Casodex 150mg development

4. 4 Public Health Importance Would be first approved drug for non- metastatic prostate cancer Target population of hundreds of thousands Therapy not warranted in a proportion of patients › Variable natural history of prostate cancer › Side effects possible without drug benefit Drug could be used for years or decades

5. 5 Prediction of Prognoses of Prostate Cancer Subpopulations Definition of Prostate Cancer Subpopulation › Clinical/path stage › Gleason Score measure of differentiation Gleason score assigned by improper methodology in non US studies › PSA Partin, D’Amico, etc. › Gleason adds to precision of staging and prognosis

6. 6 History of CASODEX 150 Trials 306 & 307 Randomized, parallel studies in “Advanced” carcinoma of prostate (1992) › M 0 = T 3 /T 4, PSA = 5 x ULN (N=490) › M 1 = bone mets (N=960) Casodex 150 vs. castration (medical or surgical) Intent of study › to show survival non-inferiority of Casodex compared to castration › to show QOL advantage of Casodex compared to castration

7. 7 Trials 306 & 307 DSMB stopped the trials for M 1 patients › Casodex compared to castration decreased survival increased progression in both trials Trials continued with M 0 patients only › Trial 306 (N=128) › Trial 307 (N=352)

8. 8 Trials 306 & 307 (NDA 20-498 / S006) Submitted 2/25/00 “To compare in a combined analysis, the selected dose of Casodex 150mg with medical or surgical castration in terms of survival, time to progression and time to treatment failure, QOL and tolerability in patients with untreated, locally advanced prostate cancer (T 3-4, N x, M o )”

9. 9 Results of Trials 306 & 307 Hazard Ratios for Mortality (M 0 ) At 56% overall mortality, median of 6.3 yrs follow-up Trial 306 (N=128) › HR (Casodex/Castration) = 0.64 (0.39, 1.03) Trial 307 (N=352) › HR (Casodex/Castration) = 1.25 (0.92, 1.71) Combined Analysis › HR (Casodex/Castration) = 1.05 (0.81, 1.36) › Casodex failed to meet pre specified 1.25 to signify equivalence (Casodex could be no more than 25% worse than castration)

10. 10 Concerns Regarding Results of Trials 306 & 307 In M 1 patients, Casodex inferior to castration ( stopped by DSMB) In M 0 patients, Casodex had disparate results › data from larger trial indicated decreased survival and increase progression compared to castration

11. 11 Additional Information Regarding Long Term Use of Antiandrogens Ann Int Med, April 2000, Seidenfeld et al Issue of paradoxical antiandrogen stimulation › occurs with all anti androgens › receptor gene mutation?

12. 12 Review Issues for NDA 20-498 / S012 Efficacy Concerns › Duration of trials too short to demonstrate enduring benefit › Invalid Gleason Scores trials 24, 25 Gleason score assigned by improper methodology inconsistencies of clinical stage/outcomes and pathology between US and Non US trials › Data proposed to support efficacy in US patients based on retrospective subgroup analyses

13. 13 Review Issues for NDA 20-498 / S012 Safety Concerns › High discontinuation rates for adverse events › High incidence of gynecomastia/breast pain Irreversible gynecomastia › Liver toxicity

14. 14 Review Issues for NDA 20-498 / S012 Other issues › possible survival decrement with longer follow up paradoxical antiandrogen stimulation › QOL/Sexual › three trials with heterogeneous populations, and different treatments Non-US trials reflect different practice patterns › imprecision of bone scan readings

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16. 16 FDA Review of Efficacy and Safety NDA 20-498/s012 › Sponsor’s current indications for CASODEX 150 mg adjuvant therapy to radical prostatectomy and radiotherapy of curative intent in patients with locally advanced non-metastatic prostate cancer who have a high risk for disease recurrence or immediate treatment of localized non-metastatic prostate cancer in patients for whom therapy of curative intent is not indicated Medical Reviewer: Scott Monroe MD

17. 17 Overview of Clinical Program for “Early Prostate Cancer” Trial 23Trial 24Trial 25 N=3292 N=3603N=1218 N=8113 Casodex Pts n=4052 Placebo Pts n=4061 Withdrawn from Treatment n=1845 Treatment ongoing or completed n=2207 Treatment ongoing or completed n=2355 Withdrawn from Treatment n=1706

18. 18 Topics for Review and Presentation Presentation limited to › Significant Clinical Review Issues Differences between Sponsor and Division regarding –Study endpoints and data analyses –Interpretation of clinical findings Findings of concern to the Division

19. 19 Disease Characteristics at Baseline

20. 20 Discordance between Gleason Scores and Disease Progression Prostatectomy Patients

21. 21 Discordance between Gleason Scores and Disease Progression Radiotherapy Patients

22. 22 Primary Endpoints and Analysis Sponsor’s primary analysis and endpoints › Time to disease progression local or distant progression of disease confirmed by bone scan, x-ray, CT scan, MRI, ultrasonography, or biopsy death due to any cause in absence of progression FDA preferred analysis and endpoints › Proportion of patients with progression within 2 yrs post randomization positive bone scan death due to any cause in absence of progression

23. 23 Primary Endpoints and Analysis Rationale for FDA preferred endpoints and analysis › Blinding not maintained because of gynecomastia and decrease in PSA in Casodex treated patients › Specific criteria for local disease progression not provided in protocols › No central, blinded review of events classified as progression › All protocols mandated a bone scan at 2 yrs post randomization

24. 24 Disease Progression or Death (FDA Requested Analysis)

25. 25 Original Indication (submitted with NDA) for Treatment with Casodex 150 mg “Immediate hormonal therapy or adjuvant therapy to treatment of curative intent in patients with non- metastatic prostate cancer” T1 Clinical Stage of Prostate Ca M0 T2T3T4 Adjuvant Tx Immediate Tx Sponsor was asked to identify population treated by prostatectomy or radiotherapy in US who would benefit from adjuvant treatment Sponsor performed post hoc exploratory analyses that resulted in first of two changes to the proposed indication

26. 26 Sponsor’s First Revision to Proposed Indications for Treatment with Casodex 150 mg First revision of Indication (submitted May 2002) › Adjuvant therapy to radical prostatectomy and radiotherapy of curative intent in patients with locally advanced non-metastatic prostate cancer who have a high risk for disease recurrence or › Immediate treatment of non-metastatic prostate cancer in patients for whom therapy of curative intent is not indicated

27. 27 Disease Progression in “High Risk” Patients (T3/T4 and Detectable PSA Post-prostatectomy)

28. 28 Disease Progression in “High Risk” Patients (T3/T4 and Pre-radiation PSA >10 ng/mL

29. 29 Sponsor’s Revised Definition of High Risk for Disease Recurrence in Adjuvant Patients Sponsor’s original definition of high risk for recurrence › locally advanced (T3/T4) and one of the following – detectable postsurgical PSA or – preradiation PSA >10 ng/mL Sponsor’s revised definition of high risk for recurrence › locally advanced (T3/T4) and one of the following – detectable postsurgical PSA, or presurgical PSA >10 ng/mL, or Gleason score  7 or – preradiation PSA >4 ng/mL

30. 30 Disease Progression in “High and Low Risk” Adjuvant-Treated Patients (Revised Definition)

31. 31 Disease Progression in “High Risk” Prostatectomy Patients (Revised Definition of “High Risk”)

32. 32 Current (2nd) Revision to Proposed Indication for Casodex 150 mg Adjuvant usage (unchanged) › Adjuvant therapy to radical prostatectomy and radiotherapy of curative intent in patients with locally advanced non-metastatic prostate cancer who have a high risk for disease recurrence or Immediate or monotherapy usage (modified) › Immediate treatment of localized (T1/T2) non-metastatic prostate cancer in patients for whom therapy of curative intent is not indicated

33. 33 Disease Progression in Immediate Therapy (Monotherapy) T1/T2 (Localized Disease) Patients

34. 34 Disease Characteristics of Patients in Immediate Treatment (Monotherapy) Group

35. 35 Discordance between Local and Central Bone Scan Readings

36. 36 Number (%) of Deaths (Prostate Cancer-Related or Other Causes

37. 37 Summary of Unresolved Efficacy Issues Maturity of studies › Only 15.6% and 9.3% of pts had disease progression by Sponsor or FDA preferred analyses, respectively, across Trials 24 and 25 › Long-term benefit of treatment unclear in absence of survival and meaningful quality of life data Inability to identify those prostate cancer pts in US who would derive benefit from adjuvant therapy › Post hoc subset analyses by Sponsor were inconclusive or nonsupportive › Lack of valid Gleason scores in non-US trials What is the risk/benefit ratio for immediate therapy (monotherapy) in patients with localized disease

38. 38 Disposition of Patients

39. 39 Adverse Events with Incidence >5% and More Frequent in Casodex Patients

40. 40 Time to First Occurrence of Gynecomastia (All Trials)

41. 41 Incidence of and Withdrawals due to Gynecomastia or Breast Pain (All Trials)

42. 42 Persistence of Gynecomastia or Breast Pain Posttreatment in Casodex Patients

43. 43 Maintenance of Sexual Function Relative to Baseline (Trial 25)

44. 44 Clinically Relevant Changes in ALT, AST, and Bilirubin Values (Combined Data)

45. 45 Summary of Significant Safety Findings in NDA 20-498/012 A high percentage of patients reported antiandrogenic- or estrogenic-related adverse events › 86% Casodex patients vs. 12% placebo patients reported gynecomastia or breast pain › 16% Casodex patients vs. <1% placebo patients withdrew because of gynecomastia or breast pain › Gynecomastia persisted post-treatment in 50% patients Life-threatening or fatal hepatotoxicity - rare and similar in both groups › Clinically significant rises in ALT/AST and withdrawals due to hepatic AEs 2-3 fold greater in Casodex treated patients

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47. 47 Summary of Not Approvable Letter Division wanted submission of more mature trial data › Does progression advantage persist? › R/O survival disadvantage compared to placebo Perform Gleason scores on Trials 24 & 25 Choose well defined successful subgroup and perform well controlled prospective trial

48. 48 Review Issues for NDA 20-498 / S012 Efficacy Concerns › Duration of trials too short to demonstrate enduring benefit › Invalid Gleason Scores trials 24, 25 Gleason score assigned by improper methodology inconsistencies of clinical stage/outcomes and pathology between US and Non US trials › Data proposed to support efficacy in US patients based on retrospective subgroup analyses

49. 49 Review Issues for NDA 20-498 / S012 Safety Concerns › High discontinuation rates for adverse events › High incidence of gynecomastia/breast pain Irreversible gynecomastia › Liver toxicity

50. 50 Review Issues for NDA 20-498 / S012 Other issues › possible survival decrement with longer follow up paradoxical antiandrogen stimulation › QOL/Sexual › three trials with heterogeneous populations, and different treatments Non-US trials reflect different practice patterns › imprecision of bone scan readings

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