Medical Officer's Primary Review of Efficacy and Safety

Oncology Drugs Advisory Committee Meeting of December 18, 2002

**NDA** 20-498/s012

**Applicant** AstraZeneca Pharmaceuticals LP\
PO Box 8355\
Wilmington, DE 19803-8355

**Submission Type** Efficacy supplement

**Drug**

**Established name** Bicalutamide

**Trade name** Casodex

**Drug Class** Nonsteroidal anti-androgen

**Proposed Indication** *Original Indication (Submitted 20 December 2001
with NDA)*\
Immediate hormonal therapy or adjuvant therapy to treatment of curative
intent in patients with non-metastatic prostate cancer

*First Revision of Indication (Submitted 10 May 2002)*\
Part 1: 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

Part 2: Immediate treatment of non-metastatic prostate cancer in
patients for whom therapy of curative intent is not indicated

*Second Revision of Indication (Submitted 22 October 2002)*\
Part 1: (Unchanged from 10 May 2002 submission)

Part 2: Immediate treatment of [localized]{.underline} non-metastatic
prostate cancer in patients for whom therapy of curative intent is not
indicated

**Dosing Regimen** One 150 mg tablet daily

**Medical Reviewer** Scott E. Monroe MD\
Division of Reproductive and\
Urologic Drug Products

**November 19, 2002**

**TABLE OF CONTENTS**

EXECUTIVE SUMMARY

1 Brief Overview of Clinical Program
[9](#brief-overview-of-clinical-program)

1.1 Drug [9](#drug)

1.2 Design of the Clinical Program [9](#design-of-the-clinical-program)

2 Efficacy [9](#efficacy)

2.1 Proposed Label Claim [9](#proposed-label-claim)

2.2 Primary Efficacy Endpoints [9](#primary-efficacy-endpoints)

2.3 Efficacy Population and Efficacy Results (Primary Endpoints and
Analyses)
[10](#efficacy-population-and-efficacy-results-primary-endpoints-and-analyses)

2.3.1 Demographics [10](#demographics)

2.3.2 Sponsor's Preferred Endpoints and Analyses
[10](#sponsors-preferred-endpoints-and-analyses)

2.3.3 FDA Requested Endpoints and Analyses
[10](#fda-requested-endpoints-and-analyses)

2.3.4 Deaths [11](#deaths)

2.4 Unresolved Efficacy Issues [12](#unresolved-efficacy-issues)

3 Safety [12](#safety)

3.1 Adequacy of Safety Testing [12](#adequacy-of-safety-testing)

3.2 Overview of Safety Findings [12](#overview-of-safety-findings)

3.2.1 Common Adverse Events. [13](#common-adverse-events.)

3.2.2 Potentially Serious or Life-Threatening Adverse Events
[13](#potentially-serious-or-life-threatening-adverse-events)

3.2.3 Deaths [13](#deaths-1)

4 Dosing REgimen [14](#dosing-regimen)

CLINICAL REVIEW

1 INTRODUCTION AND BACKGROUND [15](#introduction-and-background)

1.1 General Information [15](#general-information)

1.2 Carcinoma of the Prostate [15](#carcinoma-of-the-prostate)

1.2.1 Epidemiology [15](#epidemiology)

1.2.2 Treatment of Prostate Cancer [16](#treatment-of-prostate-cancer)

1.2.3 Rationale for the Use of Androgen Ablation Therapy
[16](#rationale-for-the-use-of-androgen-ablation-therapy)

1.2.4 Pharmacology of Casodex and Other Nonsteroidal Anti-androgens
[17](#pharmacology-of-casodex-and-other-nonsteroidal-anti-androgens)

1.3 Other Relevant Information [17](#other-relevant-information)

1.3.1 Earlier Submission (NDA 20-498/s006)
[17](#earlier-submission-nda-20-498s006)

1.3.2 Regulatory and Marketing Status
[18](#regulatory-and-marketing-status)

1.3.2.1 Casodex 50 mg Tablets [18](#casodex-50-mg-tablets)

1.3.2.2 Casodex 150 mg Monotherapy [18](#casodex-150-mg-monotherapy)

1.3.2.3 Postmarketing Experience [19](#postmarketing-experience)

1.4 Important Issues with Pharmacologically Related Agents
[19](#important-issues-with-pharmacologically-related-agents)

2 HUMAN PHARMACOKINETICS AND PHARMACODYNAMICS
[20](#human-pharmacokinetics-and-pharmacodynamics)

2.1 Pharmacokinetics [20](#pharmacokinetics)

2.1.1 Pharmacokinetics [20](#pharmacokinetics-1)

2.1.2 Potential for Interactions as Substrate, Inhibitor, or Inducer
[20](#potential-for-interactions-as-substrate-inhibitor-or-inducer)

2.1.3 Effects of Renal or Hepatic Insufficiency and Age
[20](#effects-of-renal-or-hepatic-insufficiency-and-age)

2.2 Pharmacodynamics [20](#pharmacodynamics)

3 Description of clinical data and sources
[21](#description-of-clinical-data-and-sources)

3.1 Sources of Clinical Data [21](#sources-of-clinical-data)

3.1.1 Clinical Trials [21](#clinical-trials)

3.2 Overview of Clinical Trials [22](#overview-of-clinical-trials)

4 Integrated Review of Efficacy [24](#integrated-review-of-efficacy)

4.1 Brief Statement about Efficacy [24](#brief-statement-about-efficacy)

4.2 General Approach to the Review of the Efficacy of the Drug
[24](#general-approach-to-the-review-of-the-efficacy-of-the-drug)

4.3 Clinical Trials to Support Sponsor's Efficacy Claim
[24](#clinical-trials-to-support-sponsors-efficacy-claim)

4.3.1 Overall Study Design [24](#overall-study-design)

4.3.2 Study Objectives [25](#study-objectives)

4.3.3 Study Patients and Enrollment Criteria
[26](#study-patients-and-enrollment-criteria)

4.3.4 Study Drugs [27](#study-drugs)

4.3.4.1 Rationale for Choice of Comparator
[27](#rationale-for-choice-of-comparator)

4.3.4.2 Rationale for Dose Selection of Casodex
[27](#rationale-for-dose-selection-of-casodex)

4.3.4.3 Assignment to Study Drug and Treatment Schedules
[28](#assignment-to-study-drug-and-treatment-schedules)

4.4 Study Procedures and Study Conduct
[29](#study-procedures-and-study-conduct)

4.4.1 Schedule of Study Assessments and Procedures
[29](#schedule-of-study-assessments-and-procedures)

4.4.2 Efficacy Assessments [31](#efficacy-assessments)

4.4.2.1 Objective Progression [31](#objective-progression)

4.4.2.2 Non-objective Progression [32](#non-objective-progression)

4.4.2.3 Bone Scans [32](#bone-scans)

4.5 Efficacy Endpoints and Analyses
[33](#efficacy-endpoints-and-analyses)

4.5.1 Primary Efficacy Endpoints and Analyses
[33](#primary-efficacy-endpoints-and-analyses)

4.5.2 Secondary Efficacy Endpoints and Analyses
[34](#secondary-efficacy-endpoints-and-analyses)

4.5.3 Overview of Statistical Analyses
[34](#overview-of-statistical-analyses)

4.5.3.1 Efficacy Population [34](#efficacy-population)

4.5.3.2 Sponsor's Analyses of Primary Efficacy Endpoints
[35](#sponsors-analyses-of-primary-efficacy-endpoints)

4.5.3.3 FDA Requested Analyses [35](#fda-requested-analyses)

4.6 Results [36](#results)

4.6.1 Enrollment and Patient Disposition
[36](#enrollment-and-patient-disposition)

4.6.2 Demographics and Baseline Disease Characteristics
[38](#demographics-and-baseline-disease-characteristics)

4.6.2.1 Baseline Demographics [38](#baseline-demographics)

4.6.2.2 Baseline Disease Characteristics
[39](#baseline-disease-characteristics)

4.6.3 Primary Efficacy Outcomes [41](#primary-efficacy-outcomes)

4.6.3.1 Objective Disease Progression or Death in Absence of Progression
(Sponsor's Preferred Endpoints and Analyses)
[42](#objective-disease-progression-or-death-in-absence-of-progression-sponsors-preferred-endpoints-and-analyses)

4.6.3.2 Efficacy Outcomes (FDA-Requested Endpoints and Analyses)
[46](#efficacy-outcomes-fda-requested-endpoints-and-analyses)

4.6.3.3 Additional Subset Analyses to Support Adjuvant Use of Casodex
[52](#additional-subset-analyses-to-support-adjuvant-use-of-casodex)

4.6.3.4 First Revision by Sponsor to Proposed Label Claims
[56](#first-revision-by-sponsor-to-proposed-label-claims)

4.6.3.5 Additional Subset Analyses to Support Immediate or Monotherapy
Indication
[56](#additional-subset-analyses-to-support-immediate-or-monotherapy-indication)

4.6.3.6 Second Revision by Sponsor to Proposed Label Claims
[58](#second-revision-by-sponsor-to-proposed-label-claims)

4.6.3.7 Additional Subset Analyses by Baseline Disease Characteristics
[59](#additional-subset-analyses-by-baseline-disease-characteristics)

4.6.3.8 Central Reread of Bone Scans [60](#central-reread-of-bone-scans)

4.6.3.9 Survival [62](#survival)

4.6.4 Secondary Efficacy Endpoints [63](#secondary-efficacy-endpoints)

4.6.4.1 Time to Treatment Failure [63](#time-to-treatment-failure)

4.6.4.2 Time to PSA Doubling [64](#time-to-psa-doubling)

4.7 Consultations [66](#consultations)

4.8 Conclusions Regarding Demonstrated Efficacy
[66](#conclusions-regarding-demonstrated-efficacy)

4.8.1 Achievement of Protocol-Defined Primary Efficacy Endpoints
[66](#achievement-of-protocol-defined-primary-efficacy-endpoints)

4.8.2 Support of Label Efficacy Claims
[66](#support-of-label-efficacy-claims)

4.9 Statistician's Assessment of Efficacy
[67](#statisticians-assessment-of-efficacy)

4.10 Medical Reviewer's Overall Assessment of Efficacy (Statistical and
Clinical Significance)
[68](#medical-reviewers-overall-assessment-of-efficacy-statistical-and-clinical-significance)

4.10.1 Demonstrated Efficacy of Casodex in Non-US Clinical Trials
(Trials 24 and 25)
[69](#demonstrated-efficacy-of-casodex-in-non-us-clinical-trials-trials-24-and-25)

4.10.2 Lack of Casodex Efficacy in US Clinical Trial (Trial 23)
[69](#lack-of-casodex-efficacy-in-us-clinical-trial-trial-23)

4.10.3 Relevance of Watchful Waiting (Immediate Therapy) Subgroups in
Trials 24 and 25\
to Prostate Cancer Patients in the US Managed by Watchful Waiting
[70](#relevance-of-watchful-waiting-immediate-therapy-subgroups-in-trials-24-and-25-to-prostate-cancer-patients-in-the-us-managed-by-watchful-waiting)

4.10.4 Lack of Improved Survival in Casodex-Treated Patients
[71](#lack-of-improved-survival-in-casodex-treated-patients)

5 Integrated Review of Safety [72](#integrated-review-of-safety)

5.1 Brief Statement of Conclusions [72](#brief-statement-of-conclusions)

5.2 Overview of Controlled Safety Studies (Trials 23, 24, and 25)
[72](#overview-of-controlled-safety-studies-trials-23-24-and-25)

5.3 Protocol Defined Safety Assessments
[73](#protocol-defined-safety-assessments)

5.3.1 Adverse Events and Survival [73](#adverse-events-and-survival)

5.3.2 Clinical Laboratory Tests [74](#clinical-laboratory-tests)

5.3.3 Assessment of Sexual Function (Trial 25 Only)
[74](#assessment-of-sexual-function-trial-25-only)

5.4 Demographics and Other Baseline Characteristics (Safety Population)
[75](#demographics-and-other-baseline-characteristics-safety-population)

5.4.1 Exposure and Duration of Treatment in the Controlled Clinical
Trials
[75](#exposure-and-duration-of-treatment-in-the-controlled-clinical-trials)

5.5 Patient Disposition [76](#patient-disposition)

5.6 Adverse Events [77](#adverse-events)

5.6.1 Overview of Adverse Events [78](#overview-of-adverse-events)

5.6.2 Adverse Events (All Intensities and All Relationships to Study
Drug)
[79](#adverse-events-all-intensities-and-all-relationships-to-study-drug)

5.6.3 Treatment-Related Adverse Events
[81](#treatment-related-adverse-events)

5.6.4 Adverse Events Resulting in Patient Withdrawal
[82](#adverse-events-resulting-in-patient-withdrawal)

5.6.5 Serious Adverse Events during the Treatment Period
[84](#serious-adverse-events-during-the-treatment-period)

5.7 Deaths [86](#deaths-2)

5.8 Laboratory Assessments [92](#laboratory-assessments)

5.8.1 Mean LFT Values and Mean Changes from Baseline Values
[92](#mean-lft-values-and-mean-changes-from-baseline-values)

5.8.2 Shifts in LFT Laboratory Values to Above the Normal Range
[93](#shifts-in-lft-laboratory-values-to-above-the-normal-range)

5.8.3 Clinically Relevant Changes in LFT Laboratory Values
[94](#clinically-relevant-changes-in-lft-laboratory-values)

5.8.4 Non-hepatic Laboratory Safety Assessments
[96](#non-hepatic-laboratory-safety-assessments)

5.9 Safety Issues of Special Interest or Concern
[97](#safety-issues-of-special-interest-or-concern)

5.9.1 Pharmacological Adverse Events
[97](#pharmacological-adverse-events)

5.9.1.1 Gynecomastia and Breast Pain during the Treatment Period
[98](#gynecomastia-and-breast-pain-during-the-treatment-period)

5.9.1.2 Resolution of Breast Pain and Gynecomastia after Withdrawal of
Treatment
[100](#resolution-of-breast-pain-and-gynecomastia-after-withdrawal-of-treatment)

5.9.2 Sexual Dysfunction [101](#sexual-dysfunction)

5.9.3 Liver Toxicity [102](#liver-toxicity)

5.9.3.1 Abnormal Liver Function Test (LFT) Values Reported as Adverse
Events
[102](#abnormal-liver-function-test-lft-values-reported-as-adverse-events)

5.9.3.2 Hepatic-related Adverse Events during the Treatment Period
[103](#hepatic-related-adverse-events-during-the-treatment-period)

5.9.3.3 Deaths Related to Hepatic Failure or Primary Hepatic Neoplasms
[105](#deaths-related-to-hepatic-failure-or-primary-hepatic-neoplasms)

5.9.4 Cardiovascular Morbidity and Mortality
[107](#cardiovascular-morbidity-and-mortality)

5.9.4.1 Cardiovascular Adverse Events during the Treatment Period
[107](#cardiovascular-adverse-events-during-the-treatment-period)

5.9.4.2 Cardiovascular Mortality [107](#cardiovascular-mortality)

5.9.5 Second Tumors [110](#second-tumors)

5.9.5.1 Gastrointestinal Tumors [110](#gastrointestinal-tumors)

5.9.5.2 Myelodysplasia and Leukemia [111](#myelodysplasia-and-leukemia)

5.10 Adequacy of Patient Exposure and Safety Assessments
[112](#adequacy-of-patient-exposure-and-safety-assessments)

6 Dosing Regimen [113](#dosing-regimen-1)

6.1 Dosing Regimen [113](#dosing-regimen-2)

6.2 Effects of Renal or Hepatic Impairment on Casodex Pharmacokinetics
[113](#effects-of-renal-or-hepatic-impairment-on-casodex-pharmacokinetics)

7 Conclusions and Recommendations
[113](#conclusions-and-recommendations)

7.1 Conclusions [113](#conclusions)

7.1.1 Benefits of Treatment with Casodex
[113](#benefits-of-treatment-with-casodex)

7.1.2 Risks of Treatment with Casodex
[114](#risks-of-treatment-with-casodex)

7.1.3 Summary of Risk-Benefit Analysis
[115](#summary-of-risk-benefit-analysis)

7.2 Recommendations [116](#recommendations)

7.2.1 Recommendations Regarding Approvability (Based on Indications
Submitted on\
10 May 2002)
[116](#recommendations-regarding-approvability-based-on-indications-submitted-on-10-may-2002)

8 References [118](#references)

**APPENDIX (Supplemental Efficacy Analyses)**
...........................................**119**

TABLE OF TABLES

Table 1. Studies Supporting Safety and Efficacy of Casodex for Localized
or Locally Advanced Prostate Cancer. [23](#__RefHeading___Toc25309661)

Table 2 Overview of Phase III Clinical Trials (Similarities and
Differences) [25](#__RefHeading___Toc25309662)

Table 3 Primary and Secondary Objectives of the Clinical Trials
[26](#__RefHeading___Toc25309663)

Table 4 Schedule of Study Assessments and Procedures
[30](#__RefHeading___Toc25309664)

Table 5 Summary of Primary and Secondary Endpoints and Analyses
[33](#__RefHeading___Toc25309665)

Table 6 Patient Enrollment and Treatment Status as of June 2, 2000 ^1^
[38](#__RefHeading___Toc25309666)

Table 7 Patient Years of Exposure to Study Drug and Follow-up ^1^
[38](#__RefHeading___Toc25309667)

Table 8 Baseline Demographic Characteristics (Trials 23, 24, and 25)
[39](#__RefHeading___Toc25309668)

Table 9 Disease Characteristics at Baseline
[40](#__RefHeading___Toc25309669)

Table 10 Serum PSA (Prior to Prostatectomy or Radiotherapy and/or at
Randomization) [41](#__RefHeading___Toc25309670)

Table 11 Objective Disease Progression or Death in Trials 23, 24, and 25
[42](#__RefHeading___Toc25309671)

Table 12 Time to Objective Progression or Death in Absence of
Progression [43](#__RefHeading___Toc25309672)

Table 13 Objective Disease Progression or Death in Absence of
Progression Based on Pre-randomization Treatment (Data for Trials 23,
24, and 25 Combined) [44](#__RefHeading___Toc25309673)

Table 14 Time to Objective Progression or Death (Trials 23, 24, and 25
Combined) [44](#__RefHeading___Toc25309674)

Table 15 Objective Disease Progression or Death in Absence of
Progression in Subgroups Based on Pre-randomization Treatment (Trial 24)
[45](#__RefHeading___Toc25309675)

Table 16 Objective Disease Progression or Death in Absence of
Progression in Subgroups Based on Pre-randomization Treatment (Trial 25)
[45](#__RefHeading___Toc25309676)

Table 17 Hazard Ratios for Objective Disease Progression or Death (Any
Cause) in Subgroups based on Pre-randomization Treatment (Trials 24 and
25) [46](#__RefHeading___Toc25309677)

Table 18 Bone Scan Confirmed Disease Progression or Death in the Absence
of Progression within 2.5 Years after Randomization
[47](#__RefHeading___Toc25309678)

Table 19 Odds Ratios for Bone Scan Confirmed Progression or Death in
Absence of Progression within 2.5 Years after Randomization
[48](#__RefHeading___Toc25309679)

Table 20 Bone Scan Confirmed Disease Progression or Death within 2.5
Years after Randomization (Trial 23: Prior Treatment Subgroups)
[49](#__RefHeading___Toc25309680)

Table 21 Bone Scan Confirmed Disease Progression or Death within 2.5
Years after Randomization (Trial 24: Prior Treatment Subgroups)
[49](#__RefHeading___Toc25309681)

Table 22 Bone Scan Confirmed Disease Progression or Death within 2.5
Years after Randomization (Trial 25: Prior Treatment Subgroups)
[49](#__RefHeading___Toc25309682)

Table 23 Odds Ratios for Bone Scan Confirmed Progression or Death from
Any Cause within 2.5 Years after Randomization in Treatment Subgroups
[51](#__RefHeading___Toc25309683)

Table 24 Disease Progression in Patients with Locally Advanced
(Stage T~3~/T~4~), M~0~ Prostate Cancer and Post Prostatectomy PSA
Values \> 0.2 ng/mL [55](#__RefHeading___Toc25309684)

Table 25 Patients with Bone Scan Progression or Death from Any Cause
within 2.5 Years of Randomization in Watchful Waiting Group (Trial 24)
[57](#__RefHeading___Toc25309685)

Table 26 Patients with Bone Scan Progression or Death from Any Cause
within 2.5 Years of Randomization in Watchful Waiting Group (Trial 25)
[57](#__RefHeading___Toc25309686)

Table 27 Patients with Bone Scan Progression or Death from Prostate
Cancer within 2.5 Years of Randomization in Watchful Waiting Group
(Trials 24 and 25) [59](#__RefHeading___Toc25309687)

Table 28 Comparison of Local Read and Central Reread (Data from Trials
23, 24, and 25 Combined) [61](#__RefHeading___Toc25309688)

Table 29 Comparison of Results of Local Read and Central Reread
including only Scans Reread as Positive or Negative
[62](#__RefHeading___Toc25309689)

Table 30 Number and Percentage of Deaths in Trials 23, 24, and 25
[63](#__RefHeading___Toc25309690)

Table 31 Reasons for Treatment Failure (Trials 23, 24, and 25)
[64](#__RefHeading___Toc25309691)

Table 32 Analyses of Time to Treatment Failure (Trials 23, 24, and 25)
[64](#__RefHeading___Toc25309692)

Table 33 Number (%) of Patients with a PSA Doubling Event
[65](#__RefHeading___Toc25309693)

Table 34 Analyses of Time to a PSA Doubling Event in Trials 23, 24, and
25 [65](#__RefHeading___Toc25309694)

Table 35 Years of Exposure to Study Drug (Trials 23, 24, and 25
Combined) [75](#__RefHeading___Toc25309695)

Table 36 Duration of Treatment (Trials 23, 24, and 25 Combined)
[76](#__RefHeading___Toc25309696)

Table 37 Disposition of Patients in Trials 23, 24, and 25 as of 23
February 2001 [77](#__RefHeading___Toc25309697)

Table 38 Overview of Adverse Events during Treatment (Trials 23, 24, and
25) [78](#__RefHeading___Toc25309698)

Table 39 Overview of Adverse Events by Clinical Trial during Randomized\
Treatment [79](#__RefHeading___Toc25309699)

Table 40 Adverse Events with an Incidence 5% (Combined Data from Trials
23, 24, and 25) [80](#__RefHeading___Toc25309700)

Table 41. Treatment-Related Adverse Events Occurring in  0.5% of
Patients (Combined Data from Trials 23, 24, and 25)
[82](#__RefHeading___Toc25309701)

Table 42 Adverse Events with an Incidence  0.3% Leading to Withdrawal
(Combined Data from Trials 23, 24, and 25)
[83](#__RefHeading___Toc25309702)

Table 43 Serious Adverse Events with Incidence  0.5% during Treatment
Period [85](#__RefHeading___Toc25309703)

Table 44 Number and Percentage of Deaths in Trials 23, 24, and 25
(Combined Data) [86](#__RefHeading___Toc25309704)

Table 45 Number and percentages of Deaths in Each of Trials 23, 24, and
25 [86](#__RefHeading___Toc25309705)

Table 46 Primary Causes of Death due to Drug-Related Adverse Events
[87](#__RefHeading___Toc25309706)

Table 47 Number (%) of Patients with Primary Cause of Death Classified
by COSTART Body System Term and Treatment Period (All Trials)
[88](#__RefHeading___Toc25309707)

Table 48 Primary Causes of Death (Other than Prostate Cancer) during the
Treatment Period (Trials 23, 24, and 25 Combined)
[90](#__RefHeading___Toc25309708)

Table 49 Mean Serum ALT Values (U/L) and Mean of Percent Changes from
Baseline during Treatment (Data Combined from Trials 23, 24, and 25)
[92](#__RefHeading___Toc25309709)

Table 50 ALT Shifts from Within the Normal Range at Baseline to Above
the Normal Range (High) during Treatment in Each of Trials 23, 24, and
25 [93](#__RefHeading___Toc25309710)

Table 51 Bilirubin Shifts from Within the Normal Range at Baseline to
Above the Normal Range (High) during Treatment in each of Trials 23, 24,
and 25 [94](#__RefHeading___Toc25309711)

Table 52 Clinically Relevant Changes in ALT, AST, and Total Bilirubin
Values during Treatment in Trials 23, 24, and 25 (Combined Analysis)
[95](#__RefHeading___Toc25309712)

Table 53 Resolution of Clinically Relevant Changes in ALT, AST, and
Total\
Bilirubin Values in Trials 23, 23, and 25 (Combined Analyses)
[96](#__RefHeading___Toc25309713)

Table 54 Adverse Events Reported as Anemia or Erythrocyte Disorder
during the Treatment Period (Combined Data from Trials 23, 24, and 25)
[97](#__RefHeading___Toc25309714)

Table 55 Pharmacological-Related (Anti-androgenic and Estrogenic)
Adverse Events (Combined Data from Trials 23, 24, and 25)
[97](#__RefHeading___Toc25309715)

Table 56 Incidence of and Withdrawals due to Gynecomastia and Breast
Pain within the Treatment Period (Combined Data from Trials 23, 24, and
25) [98](#__RefHeading___Toc25309716)

Table 57 Incidence of and Withdrawals due to Gynecomastia and Breast
Pain within the Treatment Period in Each of Trials 23, 24, and 25
[100](#__RefHeading___Toc25309717)

Table 58 Percentage of Patients with Resolution of Gynecomastia and
Breast Pain after Withdrawal of Treatment
[101](#__RefHeading___Toc25309718)

Table 59 Maintenance of Sexual Function Relative to Baseline
[102](#__RefHeading___Toc25309719)

Table 60 Number (%) of Patients with Increased Liver Function Test
Values Reported as Adverse Events (Trials 23, 24, and 25)
[103](#__RefHeading___Toc25309720)

Table 61 Hepatic-related Adverse Events during Treatment (Trials 23, 24,
and 25) [104](#__RefHeading___Toc25309721)

Table 62 Deaths Related to Hepatic Failure or Primary Hepatic Neoplasms
[105](#__RefHeading___Toc25309722)

Table 63 Serious Cardiovascular Adverse Events with Incidence  0.2%
during Treatment Period (Combined Data from Trials 23, 24, and 25)
[107](#__RefHeading___Toc25309723)

Table 64 Patients with a Cardiovascular-related Primary Cause of Death
(Combined Data from Trials 23, 24, and 25)
[108](#__RefHeading___Toc25309724)

Table 65 Primary Causes of Cardiovascular Deaths with Incidence 0.05%
(Combined Data from Trials 23, 24, and 25)
[109](#__RefHeading___Toc25309725)

Table 66 Solid Tumors Reported as Adverse Events within the Treatment
Period in  0.2% Patients (Data Combined for Trials 23, 24, and 25)
[110](#__RefHeading___Toc25309726)

Table 67 Incidence of Gastrointestinal Tumors (Trials 23, 24, and 25)
[111](#__RefHeading___Toc25309727)

Table 68 Patients Who Developed Myelodysplasia Syndrome or Leukemia
[112](#__RefHeading___Toc25309728)

TABLE OF FIGURES

Figure 1 Efficacy Analysis Population and Treatment Status at Time of
Data\
Cutoff [37](#__RefHeading___Toc25232678)

Figure 2 Overview of Safety Patient Population
[73](#__RefHeading___Toc25232679)

Figure 3 Time to First Occurrence of Gynecomastia within the Treatment
Period [99](#__RefHeading___Toc25232680)

EXECUTIVE SUMMARY

# Brief Overview of Clinical Program

## Drug

Casodex (bicalutamide) is a nonsteroidal anti-androgen with no other
known endocrine activity. It competitively inhibits the action of
androgens by binding to cytosol androgen receptors in the target tissue.

## Design of the Clinical Program

The Sponsor submitted data from 3 placebo-controlled, randomized,
double-blind, parallel-group clinical trials that enrolled men with
local or locally advanced non-metastatic prostate cancer. The trials
were conducted in (1) North America, predominantly the US \[Trial 23\],
(2) Europe (other than Scandinavia), South Africa, Israel, Mexico, and
Australia \[Trial 24\], and (3) Scandinavia \[Trial 25\]. Patients were
randomized in a 1:1 ratio to treatment with either Casodex 150 mg per
day or matching placebo. In all 3 trials, Casodex was investigated as
adjuvant therapy in patients who had had previous therapy for their
prostate cancer (i.e., radical prostatectomy or radiation therapy). In
Trials 24 and 25 (but not Trial 23), Casodex also was investigated as
monotherapy (i.e., in patients who had had no prior therapy and whose
prostate cancer would otherwise be managed by watchful waiting or
surveillance). In Trial 23, treatment was limited to a maximum of
2 years or until objective disease progression (whichever occurred
first). In Trials 24 and 25, patients were to be treated for 5 years
(adjuvant group in Trial 24) or indefinitely (all other groups) or until
progression of disease (all patients).

# Efficacy

## Proposed Label Claim

The Sponsor has proposed (revised indication of 10 May 2002) that
Casodex 150 mg per day is indicated as (1) 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 and (2) immediate treatment of non-metastatic
prostate cancer in patients for whom therapy of curative intent is not
indicated.

## Primary Efficacy Endpoints

The protocol-defined primary efficacy endpoints were (1) *objective
disease progression* defined as local or distant progression of disease
confirmed by bone scan, x‑ray, CT scan, magnetic resonance imaging,
ultrasonography, or biopsy and (2) *death* due to any cause in the
absence of objectively confirmed progression. The protocol-defined
primary efficacy analyses were *time to objective progression or death*.
Because of the potential for assessment bias (the side effects of
Casodex treatment were likely to unblind patient treatment assignments
in many instances), the Division of Reproductive and Urologic Drug
Products (DRUDP) requested that the primary efficacy endpoints be
limited to (1) the events of (a) *bone scan documented disease
progression* and (b) *death* due to any cause in the absence of bone
scan confirmed progression and (2) events that occurred within 2 years
of randomization.

## Efficacy Population and Efficacy Results (Primary Endpoints and Analyses)

### Demographics

A total of 8,113 patients were randomized to therapy (the
intent-to-treat population) with 3292, 3603, and 1218 patients
randomized to Trials 23, 24, and 25, respectively. Median patient-years
of follow up for disease progression and survival (efficacy analyses)
were 3.2 years (Trial 23), 2.6 years (Trial 24) and 3.0 years
(Trial 25). Within each of the individual trials, baseline demographic
and disease characteristics were well balanced across the Casodex and
placebo treatment groups. In general, baseline patient characteristics
across Trials 24 and 25 were similar but differed somewhat from those in
Trial 23 in that patients in Trial 23 tended to be younger by several
years, weighed slightly more, and had lower serum PSA values.

### Sponsor's Preferred Endpoints and Analyses

The percentages of patients with disease progression or death in the
absence of disease progression in each of the trials (based on the
Sponsor's preferred protocol-defined endpoints) are summarized in Table
A. The percentage of patients with disease progression in each of Trials
24 and 25 was numerically lower in the Casodex-treated patients. Based
on this endpoint and a time to event analysis, there was a statistically
significant reduction in the time to disease progression in Trial 24
(hazard ratio \[HR\] = 0.574, 95% confidence interval \[CI\]: 0.477 to
0.692) and Trial 25 (HR = 0.430, 95% CI: 0.336 to 0.552). There was no
evidence of benefit from Casodex treatment in Trial 23 (the only trial
conducted in the US).

Table A Disease Progression or Death (Based on Sponsor's Preferred
Endpoints)

  -------------- ---------- -------- ---- ----------- ---------- -------- ----------- ---------- ------------ --------- ---------- ------------ -------- ---------- ------------ --------- ---------- ------------
                 Number                                                                                                                                                                               
                 (per cent)                                                                                                                                                                           
                 of                                                                                                                                                                                   
                 patients                                                                                                                                                                             
                 with event                                                                                                                                                                           

  Event          Study 23                                                             Study 24                                                           Study 25                                     

                 Casodex\                             Placebo\                        Casodex\                          Placebo\                         Casodex\                          Placebo\   
                 (N = 1647)                           (N = 1645)                      (N = 1798)                        (N = 1805)                       (N = 607)                         N = 611)   

  Positive bone             21            (1.3)                  15       (0.9)       60         (3.3)        116                  (6.4)        32                  (5.3)        95                   (15.5)
  scan                                                                                                                                                                                                

  Other                              10   (0.6)                  17       (1.0)       25         (1.4)        85                   (4.7)        19                  (3.1)        40                   (6.5)
  objective                                                                                                                                                                                           
  events ^1^                                                                                                                                                                                          

  Death in                  52            (3.2)                  55       (3.3)       96         (5.3)        92                   (5.1)        48                  (7.9)        44                   (7.2)
  absence of                                                                                                                                                                                          
  progression                                                                                                                                                                                         

  **Total (%)               **83**        **(5.0)**              **87**   **(5.3)**   **181**    **(10.1)**   **293**              **(16.2)**   **99**              **(16.3)**   **179**              **(29.3)**
  Patients**                                                                                                                                                                                          
  -------------- ---------- -------- ---- ----------- ---------- -------- ----------- ---------- ------------ --------- ---------- ------------ -------- ---------- ------------ --------- ---------- ------------

^1^ Documented by magnetic resonance imaging, computerized tomography,
sonography, or biopsy.

Exploratory subset analyses for Trial 24 (based on the sponsor's
preferred endpoints) indicated a reduction in disease progression in the
Casodex-treated patients in both the adjuvant therapy subgroups
(patients treated by prior prostatectomy or radiotherapy) and the
watchful waiting (immediate or monotherapy) subgroup. Results for the
watchful waiting subgroup in Trial 25 (the only subgroup with more than
250 patients in this trial) also showed a numeric reduction in disease
progression in Casodex-treated patients. The estimates of the hazard
ratios and 95% CIs for the watchful waiting subgroups were 0.674 (Trial
24, 95% CI = 0.518 to 0.878) and 0.423 (Trial 25, 95% CI = 0.321 to
0.557).

### FDA Requested Endpoints and Analyses

The percentages of patients with objective disease progression or death
in the absence of objective progression within 2.5 years of
randomization are presented in Table B. For Trials 24 and 25, the
estimates of the odds ratios (OR) and 95% CIs were 0.645 (Trial 24, 95%
CI = 0.500 to 0.832 and 0.515 (Trial 25, 95% CI = 0.365 to 0.729).

Table B Disease Progression or Death (Based on FDA Requested Endpoints)

  -------------- ---- --------------- -------- ----------- ---------- -------- ----------- --------- ---------- ----------- --------- ---------- ----------- -------- ---------- ------------ --------- ---------- ------------
                      Number (per                                                                                                                                                                                  
                      cent) of                                                                                                                                                                                     
                      patients with                                                                                                                                                                                
                      event within                                                                                                                                                                                 
                      2.5 yr. of                                                                                                                                                                                   
                      randomization                                                                                                                                                                                

  Event               Study 23                                                                       Study 24                                                         Study 25                                     

                      Casodex\                             Placebo\                                  Casodex\                         Placebo\                        Casodex\                          Placebo\   
                      (N = 1647)                           (N = 1645)                                (N = 1798)                       (N = 1805)                      (N = 607)                         N = 611)   

  Positive bone  14                            (0.9)                  11       (0.7)       42                   (2.3)       98                   (5.4)       22                  (3.6)        72                   (11.8)
  scan                                                                                                                                                                                                             

  Death in       25                            (1.5)                  37       (2.2)       70                   (3.9)       70                   (3.9)       41                  (6.8)        33                   (5.4)
  absence of                                                                                                                                                                                                       
  progression                                                                                                                                                                                                      

  **Total (%) of                      **39**   **(2.4)**              **48**   **(2.9)**   **112**              **(6.2)**   **168**              **(9.3)**   **63**              **(10.4)**   **105**              **(17.2)**
  patients**                                                                                                                                                                                                       
  -------------- ---- --------------- -------- ----------- ---------- -------- ----------- --------- ---------- ----------- --------- ---------- ----------- -------- ---------- ------------ --------- ---------- ------------

Exploratory subset analyses for Trial 24 indicated that the proportions
of Casodex-treated patients with disease progression were numerically
lower in both the adjuvant therapy subgroups (patients treated by prior
prostatectomy or radiotherapy) and the watchful waiting subgroup (Table
C). The estimates of the odds ratios and 95% CIs for the subgroups were
0.616 (radical prostatectomy, 95% CI = 0.379 to 1.003), 0.625
(radiotherapy, 95% CI = 0.361 to 1.081), and 0.674 (watchful waiting,
95% CI = 0.471 to 0.964).

Table C Disease Progression or Death by Pre-randomization Treatment in
Trial 24 (FDA Requested Endpoints)

  -------------- ----------------- -------- ---- ----------- -------- ---------- ---- ----------- ------------------ ----------- ---------- -------- ------------ -------- ------------ ----------- ---------- ------------
                 Number (per cent)                                                                                                                                                                             
                 of patients with                                                                                                                                                                              
                 event within 2.5                                                                                                                                                                              
                 yr. of                                                                                                                                                                                        
                 randomization                                                                                                                                                                                 

  **Event**      **Radical                                                                        **Radiotherapy**                                                         **Watchful                          
                 Prostatectomy**                                                                                                                                           Waiting**                           

                 Casodex\                                             Placebo\                    Casodex\                       Placebo\                                  Casodex\                 Placebo\   
                 (N = 835)                                            (N = 813)                   (N = 335)                      (N = 325)                                 (N = 628)                (N = 666)  

  Positive bone                    12            (1.4)                           27   (3.3)       11                 (3.3)                  28       (8.6)        19                    (3.0)       43         (6.5)
  scan                                                                                                                                                                                                         

  Death (any                                17   (2.0)       16                       (2.0)       13                 (3.9)                  8        (2.5)        40                    (6.4)       46         (6.9)
  cause) in                                                                                                                                                                                                    
  absence of                                                                                                                                                                                                   
  progression                                                                                                                                                                                                  

  **Total (%)                      **29**        **(3.5)**   **43**                   **(5.3)**   **24**             **(7.2)**              **36**   **(11.1)**   **59**                **(9.4)**   **89**     **(13.4)**
  Patients**                                                                                                                                                                                                   
  -------------- ----------------- -------- ---- ----------- -------- ---------- ---- ----------- ------------------ ----------- ---------- -------- ------------ -------- ------------ ----------- ---------- ------------

Results for the watchful waiting subgroup in Trial 25 (the only subgroup
with more than 250 patients in this trial) also showed a numeric
reduction in disease progression in Casodex-treated patients. The
estimate of the odds ratio and 95% CI for this subgroup was 0.498,
95% CI = 0.338 to 0.734.

### Deaths

The total number and percentage of deaths due to prostate cancer or
other causes in each of the trials at the data cutoff for the efficacy
analyses (2 June 2000) and the data cutoff for the safety update
(28 September 2001) are listed in Table D. There were no significant
differences in the percentage of patients who died, either of prostate
cancer or of other causes, in the Casodex and placebo groups within each
of the trials. There were, however, differences across the trials.

Table D Total Number and (%) of Deaths due to Prostate Cancer or Other
Causes

  ------------ ---------- ----------- --------- ----------- -- ---------- ------------ --------- ------------ -- ---------- ------------ ---------- ------------
  Cause of\    Study 23                                        Study 24                                          Study 25                           
  Death                                                                                                                                             

               Casodex\               Placebo                  Casodex\                Placebo                   Casodex\                Placebo\   
               N= 1647                N=1645                   N= 1798                 N=1805                    N= 607                  N= 611     

               n          (%)         n         (%)            n          (%)          n         (%)             n          (%)          n          (%)

  Prostate     8          (0.5)       3         (0.2)          26         (1.4)        38        (2.1)           24         (4.0)        28         (4.6)
  cancer                                                                                                                                            

  Other        54         (3.3)       58        (3.5)          97         (5.4)        99        (5.5)           45         (7.4)        42         (6.9)

  **Total      **62**     **(3.8)**   **61**    **(3.7)**      **123**    **(6.8)**    **137**   **(7.6)**       **69**     **(11.4)**   **70**     **(11.5)**
  ^1^**                                                                                                                                             

  Prostate     14         (0.9)       6         (0.4)          56         (3.1)        66        (3.7)           49         (8.1)        56         (9.2)
  cancer                                                                                                                                            

  Other        91         (5.6)       93        (5.7)          168        (9.4)        161       (9.0)           67         (11.1)       50         (8.2)

  **Total      **105**    **(6.5)**   **99**    **(6.1)**      **224**    **(12.5)**   **227**   **(12.7)**      **116**    **(19.2)**   **106**    **(17.4)**
  ^2^**                                                                                                                                             
  ------------ ---------- ----------- --------- ----------- -- ---------- ------------ --------- ------------ -- ---------- ------------ ---------- ------------

> 1\. Data cutoff of 2 June 2000 (efficacy population). 2. Data cutoff
> of 28 September 2001 (safety population).

## Unresolved Efficacy Issues

The relevance of the findings in Trials 24 and 25 to men with prostate
cancer in the US who would be treated with Casodex (either adjuvant
therapy or monotherapy) is unclear.

**Adjuvant Therapy**. *Based on the data submitted by the Sponsor,
patients similar to those enrolled in Trial 230 who are initially
treated by radical prostatectomy or radiotherapy in the US would derive
no benefit from Casodex adjuvant therapy.* A supplemental analysis by
the Sponsor, based on a subset of patients in Trial 23, also did not
show convincing evidence of efficacy for Casodex adjuvant therapy. In
addition, it was not possible (1) to adequately characterize the
patients in Trials 24 and 25 because of lack of standardized Gleason
scores and (2) to extrapolate the data from patients in Trials 24 and 25
to Trial 23 to identify US patients who might benefit from Casodex
adjuvant therapy.

**Immediate Treatment or Monotherapy.** A watchful waiting subgroup was
not included in Trial 23. The proposed indication does not adequately
identify the population of prostate cancer patients in the US who might
derive sufficient benefit from Casodex monotherapy to warrant the risks
of treatment.

-   **For local or early disease**. The Sponsor has not shown that
    patients presently managed by watchful waiting in the US would
    experience disease progression of sufficient magnitude to warrant
    treatment with Casodex and the side effects associated with such
    treatment.

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-   **For locally advanced disease.** Since the comparator in these
    trials was placebo and not active therapy (i.e., medical or surgical
    castration), it is not possible to adequately address the efficacy
    of Casodex monotherapy. This is a critical issue since survival may
    be shortened in patients treated with Casodex monotherapy instead of
    by medical or surgical castration (the present standard of care in
    the US for such patients).

# Safety

## Adequacy of Safety Testing

The database from Trials 23, 24, and 25 supporting the safety of Casodex
150 mg per day was large. It included 4,022 Casodex-treated patients,
representing 9,387 patient-years of exposure. Patient exposure to
Casodex in the controlled clinical trials was adequate to assess the
likely safety profile of Casodex 150 mg per day in men with prostate
cancer.

## Overview of Safety Findings

Most patients in the controlled clinical trials (97.4% Casodex group,
88.2% placebo group) had at least 1 adverse event. The number of
patients with at least 1 drug-related adverse event was approximately
3-fold higher in the Casodex group (90.5%) than the placebo group
(31.4%). A greater number of patients in the Casodex group also were
withdrawn from treatment as a result of an adverse event (27.7% compared
with 9.2% of placebo-treated patients). The number of patients who had
at least 1 serious adverse event was similar across the treatment groups
(33.6% Casodex group, 32.5% placebo group). Much of the difference
between the Casodex and placebo treatment groups in each of the
categories of (a) any adverse event, (b) drug-related adverse events,
and (c) adverse events leading to withdrawal was due to the
pharmacological (anti-androgenic and compensatory estrogenic) actions of
Casodex.

Side effects associated with Casodex treatment can be classified for the
most part into one of 2 categories: (1) those of a generally non-serious
and non-life threatening nature that are due to the pharmacological
actions of Casodex and which occur with a high incidence and (2) those
that occur in a few percent of patients and which may be serious or
life-threatening (primarily liver toxicity).

### Common Adverse Events. 

The most commonly reported adverse events that occurred more frequently
in Casodex-treated patients and the percentage of Casodex-treated
patients that experienced these adverse events were breast pain (73%),
gynecomastia (67%), asthenia (11%), vasodilatation (9%), impotence (9%),
alopecia (6%), and weight gain (6%). All of these adverse events (other
than perhaps asthenia and weight gain) are likely to be due to the
pharmacological actions of Casodex.

Most Casodex-treated patients (86.2%) reported gynecomastia or breast
pain. Of these patients, 16.1% withdrew from Casodex therapy because of
these adverse events. Gynecomastia or breast pain was reported as severe
in 8.6% of Casodex-treated patients. Breast pain was reversible in
\> 90% of patients after cessation of Casodex therapy. Gynecomastia,
however, resolved in only 50% of patients after discontinuation of
treatment. In the placebo-treated patients, only 12.4% patients reported
gynecomastia or breast pain, and only 0.6% withdrew from treatment
because of these adverse events.

### Potentially Serious or Life-Threatening Adverse Events

Treatment with all nonsteroidal anti-androgens is associated with
hepatotoxicity that can be serious and occasionally fatal.
Hepatotoxicity appears to occur more frequently in patients being
treated with flutamide than other nonsteroidal anti-androgens. In the
combined findings from Trials 23, 24, and 25, patient withdrawals due to
increased serum ALT and AST values or increased bilirubin values were
higher in Casodex-treated patients (1.2% and 0.4%, respectively) than in
placebo-treated patients (0.5% and 0.2%, respectively). Similarly,
adverse events classified as serious due to increased serum ALT and AST
values or increased bilirubin values were more frequent in
Casodex-treated patients (0.3% and 0.2%, respectively) than in
placebo-treated patients (0.0% and \<0.1%, respectively). However, the
number of patients reported to have died from hepatic failure or a
primary hepatic neoplasm was similar in the 2 treatment groups (5 of
4,022 Casodex-treated patients and 5 or 6 of 4,031 placebo-treated
patients).

Twelve (12) Casodex-treated patients and 5 placebo-treated patients
developed myelodysplasia syndrome or leukemia (relative incidence
Casodex/placebo = 2.4). Of these patients, 8 of the Casodex-treated
patients and 4 of the placebo-treated patients have died as a direct or
indirect result of their underlying hematologic disorder. The
significance of this numeric imbalance and its possible relationship to
treatment with Casodex are not known at this time.

### Deaths

As of the data cutoff date for the Safety Update (28 September 2001),
445 of 4,022 patients (11.1%) who received Casodex and 432 of 4,031
patients (10.7%) who received placebo had died. Prostate cancer was the
listed cause of death in 2.96% and 3.18% of patients in the Casodex- and
placebo-treatment groups, respectively. Among non-prostate cancer causes
of death, cardiovascular events were the major cause of death with 77
cases reported in Casodex-treated patients and 66 cases reported in
placebo-treated patients. Deaths that linked to the respiratory system
were the second most frequent in both treatment groups, occurring in 29
Casodex-treated and 36 placebo-treated patients. Deaths that linked to
the digestive system were the third most frequent, affecting 24
Casodex-treated patients and 17 placebo-treated patients. Among this
group, gastrointestinal carcinoma was the most common single cause of
death, affecting 18 Casodex-treated patients and 10 placebo-treated
patients.

# Dosing REgimen

The proposed dosing-regimen is Casodex 150 mg per day for at least 2
years or until disease progression. The proposed dose appears to be
appropriate based on dose-ranging data concerning suppression of serum
PSA values in men with prostate cancer that were provided in an earlier
submission (NDA 20-498/s006). The basis for the recommendation that
treatment should continue for at least 2 years is unclear since
treatment in Trial 24 and Trial 25 was to be for at least 5 years or
until disease progression.

CLINICAL REVIEW

# INTRODUCTION AND BACKGROUND

## General Information

-   **NDA** 20-498/s012

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-   Applicant AstraZeneca Pharmaceuticals Lupron\
    PO Box 8355\
    Wilmington, DE 19803-8355

-   Submission Type Efficacy supplement

-   Drug

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-   Established name Bicalutamide

-   Trade name Casodex

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-   Drug Class Nonsteroidal anti-androgen

-   Proposed Indication *[Original Indication]{.underline}*\
    Immediate hormonal therapy or adjuvant therapy to treatment of
    curative intent in patients with non-metastatic prostate cancer

*[First Revision of Indication (Submitted 10 May 2002)]{.underline}*\
(1) 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

\(2\) Immediate treatment of non-metastatic prostate cancer in patients
for whom therapy of curative intent is not indicated

*[Second Revision of Indication (Submitted 22 October
2002)]{.underline}*\
(1) (Unchanged from 10 May 2002 submission).

\(2\) Immediate treatment of [localized]{.underline} non-metastatic
prostate cancer in patients for whom therapy of curative intent is not
indicated

-   Dosing Regimen One 150 mg tablet daily

## Carcinoma of the Prostate 

### Epidemiology

Cancer of the prostate is the most frequent noncutaneous malignancy in
men, and after lung cancer, the second most frequent cause of death from
cancer in men over 50 years of age. It is estimated that approximately
200,000 new cases of prostate cancer were diagnosed and that 30,000
deaths occurred from the disease in the year 2001. Prostate cancer is a
major social, economic, and health issue.

### Treatment of Prostate Cancer

Treatment options for prostate cancer include radical prostatectomy,
radiotherapy, androgen ablation or deprivation therapy (achieved by
surgical castration, GnRH analogs, or nonsteroidal antiandrogens), and
no active therapy (watchful waiting or surveillance). Selection of the
most appropriate treatment depends on many factors that include the
clinical stage of the tumor (localized to the prostate, local extension
beyond the prostate, or distant or bony metastases), status of regional
lymph nodes, degree of tumor differentiation (generally assessed as
Gleason grade), serum prostate specific antigen (PSA) concentration, and
the patient's likely life expectancy due to the presence of other
co-morbid conditions.

Patients with tumors that are localized to the prostate gland may be
cured of their disease by a radical prostatectomy or radiation therapy.
Patients with local extension of their tumor beyond the prostate gland
also may be candidates for a curative procedure (radical prostatectomy
or radiotherapy) in some instances, particularly if the tumor is well-
or moderately well-differentiated and is associated with a serum PSA of
\< 10 ng/mL at the time of diagnosis. Patients with extensive local
disease generally are not candidates for a curative procedure,
particularly if the tumor is poorly differentiated and the serum PSA is
\> 10 ng/mL. Such patients are often managed by androgen ablation
therapy alone or androgen ablation therapy plus radiotherapy. Patients
with bony metastases or non-local soft tissue metastases are generally
treated with androgen ablation therapy alone.

A minority of patients in the US (perhaps 10% of newly diagnosed cases)
are initially managed by watchful waiting or surveillance. In the US,
men who initially receive no active therapy tend to be older (generally
\> 75 years of age at diagnosis), have low grade and localized tumors,
have no symptoms from their prostate cancer, and often have a life
expectancy of \< 10 years. The rationale for management by watchful
waiting or surveillance is the expectation that prostate cancer will
remain asymptomatic in the majority of these men, and they will likely
die from a disorder unrelated to prostate cancer.

### Rationale for the Use of Androgen Ablation Therapy

Growth of prostate glandular tissue is regulated by a complex of growth
factors of which androgens play a pivotal role. In most men, prostate
cancer is at least partially an androgen-dependent tumor at the time of
initial presentation. Prostate cancer also is partially
androgen-dependent in most men at the time of initial progression
(either local or metastatic) if the patient has not been treated
previously with androgen ablation or deprivation therapy.

Because of the androgen-dependence of prostate cancer and the
availability of GnRH analogs and nonsteroidal antiandrogens, androgen
ablation therapy has been used as adjuvant therapy in conjunction with
radical prostatectomy and radiation therapy. There are limited data on
the benefits of androgen deprivation adjuvant therapy following radical
prostatectomy, particularly in men with lymph node negative disease.^1^
A report demonstrating the benefit of androgen deprivation adjuvant
therapy in men with positive lymph nodes was that of Messing et al.^2^
In this study, 98 men with positive lymph nodes at the time of radical
prostatectomy were randomized to receive either immediate androgen
deprivation therapy (with either a GnRH analog or surgical castration)
or placebo therapy. After 7.1 median years of follow up, 7 of 47 men who
received immediate androgen deprivation therapy had died as compared
with 18 of 51 men in the placebo group (p \< 0.02).

The potential benefit of androgen ablation therapy in conjunction with
radiotherapy, generally for locally advanced or high-grade prostate
carcinoma, has been investigated in several clinical trials. In one such
trial (Bolla et al ^3^), 415 men with locally advanced prostate cancer
were treated with external beam radiotherapy alone or radiotherapy plus
a GnRH analog. At a median follow up of 45 months, estimates of overall
survival at 5 years were 79% and 62% for patients treated with adjuvant
GnRH analog compared to placebo (p = 0.001). Other studies in which men
were treated with radiotherapy and adjuvant androgen ablation therapy
have shown improvement in local control of disease or improved survival
in subgroups (Hellerstedt BA and Pienta KJ ^4^).

Based in part on these findings in men with prostate cancer and the
demonstrated benefits of adjuvant anti-estrogen therapy in women with
carcinoma of the breast, AstraZeneca initiated 3 clinical trials (the
pivotal trials in support this supplemental NDA) in men with
non-metastatic prostate cancer. In each of the trials, the potential
benefit of adjuvant therapy with Casodex immediately following either
radical prostatectomy or radiotherapy was compared to placebo. In 2 of
the trials, the potential benefit of Casodex monotherapy (compared to
placebo) was investigated in men with non-metastatic prostate cancer who
otherwise would be managed by watchful waiting or surveillance.

### Pharmacology of Casodex and Other Nonsteroidal Anti-androgens

Nonsteroidal anti-androgens (NSAAs) currently available for clinical use
in the US include flutamide (Eulexin), nilutamide (Nilandron), and
bicalutamide (Casodex). All three are approved for use in the US in
combined androgen blockade therapies: Casodex (50 mg per day ) and
flutamide in combination with a GnRH agonist and nilutamide in
combination with surgical castration are approved for the treatment of
advanced prostate cancer. No NSAA is presently licensed in the US as
single agent monotherapy.

The mode of action of NSAAs such as Casodex differs from that of medical
(i.e., GnRH-induced) or surgical castration. Whereas castration causes a
reduction in circulating levels of androgens, Casodex is a competitive
antagonist of testosterone and dihydrotestosterone action at the level
of the intracellular androgen receptor. Casodex binds competitively and
reversibly to the androgen receptor without activating gene expression,
and thus inhibits the stimulatory effect of androgens. This action of
Casodex and other NSAAs markedly reduces the effects of circulating
androgens on prostate cancer cells.

## Other Relevant Information

### Earlier Submission (NDA 20-498/s006)

In February 2000, AstraZeneca submitted an efficacy supplement (NDA
20-498/s006) for the treatment of locally advanced, non-metastatic
(Stages T3-T4, NX, M0) prostate cancer with Casodex monotherapy (150
mg/d). Two pivotal trials (Trials 0306 and 0307) were submitted in
support of the application. The trials were similar in design but
conducted in different geographic locales. Neither study was conducted
in North America. Both were open-label, active comparator trials that
compared Casodex monotherapy to medical or surgical castration. The
studies originally included patients with metastatic disease (Stage M1)
as well as non-metastatic (M0) disease. Based on an interim analysis of
survival, the Data Safety Monitoring Board (DSMB) recommended that
Casodex treatment be discontinued in M1 patients. The data at the time
of their recommendation indicated that the risk of death was 25% and 31%
higher in the Casodex M1 groups compared to the castration M1 groups in
Trails 0306 and 0307, respectively. The trials continued thereafter with
only patients who had Stage M0 disease at the time of entry.

Survival in the Casodex-treated MO patients, compared to that in the
patients treated by castration, differed across Trials 0306 and 0307. In
Trial 0306 (n = 140 M0 patients), the risk of death was calculated as
36% lower in the Casodex group while in Trial 0307 (n = 352 M0
patients), the risk of death was calculated as 25% higher in the Casodex
group. Both the primary medical reviewer and statistical reviewer
recommended that the application not be approved for several reasons
that included (1) the conflicting trial results with the larger trial
demonstrating a survival disadvantage in the Casodex treatment group for
M0 patients, (2) a survival disadvantage for M1 patients treated with
Casodex in both clinical trials, and (3) a combined statistical analysis
that (a) did not fully meet the Sponsor's original definition of
noninferiority and (b) was considered to be statistically inappropriate.
Upon learning that the application would not be approved, AstraZeneca
withdrew the supplemental NDA in December 2000.

### Regulatory and Marketing Status

#### Casodex 50 mg Tablets

Casodex at a daily dose of 50 mg in combination with medical or surgical
castration is registered world-wide for the treatment of advanced
prostate cancer. In some markets, the mode of castration is limited to
one or the other method. The product was approved in the US in 1995 for
the treatment of metastatic prostate cancer (Stage D2) in combination
with GnRH analog therapy.

#### Casodex 150 mg Monotherapy

Casodex and other NSAAs are not approved as monotherapy in the US.

**Locally advanced prostate cancer.** The applicant stated that "Product
Licences have been granted for the use of Casodex 150 mg monotherapy in
the treatment of locally advanced, non-metastatic prostate cancer in 35
countries. Applications are currently under review in a number of other
countries." Representative approved labeling for Casodex 150 mg
monotherapy for locally advanced non-metastatic prostate cancer is
presented below:

> *[Sweden]{.underline}: Casodex 150 mg per day monotherapy is indicated
> for the treatment of patients with locally advanced, non-metastatic
> prostate cancer, for whom hormonal treatment is indicated, but
> surgical or medical castration is considered inappropriate.*
>
> *[UK]{.underline}:  Casodex 150 mg is also indicated for the
> management of patients with locally advanced, non-metastatic prostate
> cancer for whom surgical castration or other medical intervention is
> not appropriate or acceptable.*

A supplemental NDA (20-498/s006) was submitted to the FDA in February
2000 seeking approval for Casodex monotherapy (150 mg per day) for the
treatment of locally advanced non-metastatic prostate cancer. The
application was withdrawn in December 2000 after the applicant learned
that the sNDA would not be approved (see Section 1.3.1).

**Localized or locally advanced prostate cancer.** Following submission
of additional data regarding the use of Casodex in men with early
prostate cancer (Clinical Trials 7054IL/0023, 7054IL/0024, and
7054IL/0025 \[the pivotal trials in sNDA 20-498/s012 as well\]), the
Product Licenses for Casodex monotherapy were broadened in several
countries. As of 1 March 2002 according to the Sponsor, Casodex (150 mg
per day) had been approved in 12 countries as therapy for men with
localized or locally advanced prostate cancer, either alone as
monotherapy or as adjuvant therapy to radical prostatectomy or radiation
therapy of curative intent. These 12 countries are (in order of approval
date) Slovakia, Italy, UK, Greece, Austria, Portugal, Belgium and
Luxembourg, Czech Republic, Mexico, Norway, and Hungary.

##### Medical Officer's Comments {#medical-officers-comments .unnumbered}

-   All of the 12 countries listed above in which Casodex monotherapy
    has been approved for localized prostate cancer had previously
    approved Casodex monotherapy for locally advanced prostate cancer
    based on the results of clinical trials 0306 and 0307. These were
    the pivotal clinical trials in NDA 20-498/s006 that was withdrawn by
    the Sponsor in December 2000.

-   The approved indication of treatment of men with Casodex for
    localized or locally advanced prostate cancer differs slightly
    across the 12 countries. The most significant difference appears to
    be in the approved indications for patients the United Kingdom,
    Greece, Austria, and Portugal. In these latter countries, Casodex
    150 mg per is approved as immediate therapy for patients with
    localized prostate cancer only if they are not being treated by
    radical prostatectomy or radiation therapy (i.e., patients being
    managed by watchful waiting). In these markets, it has not been
    approved as adjuvant therapy for patients with local disease if they
    have previously received therapy of curative intent.

-   In response to a request for additional information regarding the
    approval of Casodex monotherapy in markets outside of the US, the
    Sponsor informed DRUDP in their submission of 22 May 2002 that
    Casodex monotherapy had been recommended for approval by the
    Australian Drug Evaluation Committee (ADEC) for the treatment of
    local and locally advanced prostate cancer. This Committee had
    previously rejected the Sponsor's application for treatment with
    Casodex monotherapy for locally advanced non-metastatic prostate
    cancer based solely on the results of Trials 0306 and 0307.

#### Postmarketing Experience

According to the Sponsor, the estimated postmarketing worldwide exposure
to Casodex (50 mg or 150 mg) from 1995 until 28 September 2001 was
approximately 687,000 patient years. Approximately 9,800 patient-years
of the total exposure was to Casodex 150 mg.

## Important Issues with Pharmacologically Related Agents

Two other nonsteroidal anti-androgens, flutamide and nilutamide, are
approved for use in men with prostate cancer. All of the nonsteroidal
anti-androgens have similar pharmacologically-related side effects.
Pharmacologically-related adverse events are secondary to either the
direct anti-androgenic actions of the drugs (e, g, increased incidence
of erectile dysfunction, decreased libido, and anemia) or indirect
compensatory estrogenic effects of the drugs (increased incidence of
breast pain and gynecomastia).

All nonsteroidal anti-androgens are hepatotoxic to varying degrees.
Treatment with nilutamide (but not flutamide or Casodex ) also has been
reported to be associated with an increased incidence of interstitial
pneumonia.

##### Medical Officer's Comment {#medical-officers-comment .unnumbered}

-   Hepatotoxicity is a common adverse event associated with the use of
    flutamide. It can be serious and even fatal in patients being
    treated with flutamide. The incidence of significant
    flutamide-related hepatotoxicity has been estimated to be 2.5 per
    100000 prescriptions in the US (Wysowski 1996 ^5^) against a
    background incidence in a similar US population of 0.2 per 100000
    prescriptions in patients not exposed to drugs. Serious adverse
    events related to hepatic toxicity (primarily increased serum
    transaminase levels) and withdrawals due to hepatic toxicity were
    2-3 fold greater in Casodex-treated patients compared to
    placebo-treated patients in the controlled trials in NDA
    20-498/s012. However, fatal events related to hepatotoxicity appear
    to be rare in Casodex-treated patients ( Section 5.8.3 and Section
    5.9.3).

# HUMAN PHARMACOKINETICS AND PHARMACODYNAMICS

## Pharmacokinetics

### Pharmacokinetics

Casodex is a racemate with the anti-androgenic activity almost
exclusively in the (R)-enantiomer; the (S)-enantiomer is essentially
inactive. Casodex is well absorbed following oral administration,
although the absolute bioavailability is unknown. The pharmacokinetics
of Casodex were dose proportional over the range of 10 mg to 150 mg
doses. Co-administration of Casodex with food had no clinically
significant effect on rate or extent of absorption. Casodex is highly
protein-bound (\>90%) and may displace other highly protein bound drug
substances, thus increasing their free plasma concentrations.

### Potential for Interactions as Substrate, Inhibitor, or Inducer

R-Casodex significantly inhibited CYP 3A4, 2C9, 2C19, 2D6, and 1A2, in
vitro, while no significant inhibition was noted with S-Casodex.

### Effects of Renal or Hepatic Insufficiency and Age

Renal impairment (as measured by creatinine clearance) had no
significant effect on the elimination of total bicalutamide or the
active R-enantiomer in doses up to 450 mg. No clinically significant
difference in the pharmacokinetics of either enantiomer of bicalutamide
was noted in patients with mild-to-moderate hepatic disease as compared
to healthy controls. However, the half-life of the R-enantiomer was
increased approximately 76% (5.9 and 10.4 days for normal and impaired
patients, respectively) in patients with severe liver disease (n=4). In
studies in patients given up to 450 mg daily, no significant
relationship between age and steady-state levels of total bicalutamide,
or the active R-enantiomer has been shown.

## Pharmacodynamics

Casodex is a nonsteroidal anti-androgen with no other known endocrine
activity. It competitively inhibits the action of androgens by binding
to androgen receptors in the target tissue. No pharmacodynamic data were
submitted with the present efficacy supplement. At the request of the
medical reviewer, the Sponsor submitted information on the effects of
treatment with Casodex on serum concentrations of testosterone,
dihydrotestosterone (DHT), and estradiol obtained from a clinical study
that was not included in the present application.

In this study, mean serum concentrations of testosterone during
treatment with 150 mg Casodex increased from 3.15 nmol/L at baseline
(n=23) to a maximum of 6.00 nmol/L at Month 2 (n=21). At Month 6 of
treatment, mean serum concentrations of testosterone were 5.22 nmol/L
(n=21). Mean serum concentrations of DHT in these patients were 0.29
ng/mL (baseline), 0.35 ng/mL (Month 2) and 0.34 ng/mL (Month 6). Mean
serum concentrations of free testosterone in these patients were 8.77
\[no units provided\] at baseline, 13.47 at Month 2, and 13.55 at Month
6. Mean serum concentration of estradiol in these patients increased
from 34.4 pmol/L at baseline to 55.8 pmol/L at Month 6.

##### Medical Officer\'s Comments {#medical-officers-comments-1 .unnumbered}

-   Based on the numeric values for serum concentrations of testosterone
    and the values and units for DHT (ng/mL), the correct units for
    serum testosterone concentrations are probably also ng/mL and not
    nmol/L as reported by the Sponsor.

-   During treatment with Casodex and other NSAAs, there is an increase
    in serum concentrations of testicular androgens and estradiol
    because of partial inhibition of gonadal steroid negative feedback
    at the level of the hypothalamus and/or pituitary gland and a
    compensatory increase in the secretion of pituitary gonadotropins.
    It is likely that the reduction in effective androgen levels at the
    level of the prostate cancer cells (i.e., reduction in stimulation
    of androgen receptors in prostate cancer cells) is less than that
    which follows treatment with a GnRH analog or surgical castration.
    This is supported by the previously described observations from
    Clinical Trials 0306 and 0307 in which median survival in men with
    metastatic prostate cancer (Stage M1 disease) treated with Casodex
    was less than that in men treated with a GnRH analog or surgical
    castration.

-   The increase in serum estradiol, perhaps further compounded by the
    reduction in effective androgen levels, is responsible for the most
    common side effects associated with Casodex treatment in men,
    namely, gynecomastia and breast pain.

# Description of clinical data and sources

## Sources of Clinical Data

### Clinical Trials

The sponsor submitted efficacy and safety data from 3 Phase III clinical
trials (Trials 7054IL/0023, 7054IL/0024, and 7054IL/0025, hereafter
referred to as Trials 23, 24, and 25, respectively) on 20 December 2001.
The trials were conducted in (1) North America, predominantly the US
\[Trial 23\], (2) Europe (other than Scandinavia), South Africa, Israel,
Mexico, and Australia \[Trial 24\], and (3) Scandinavia \[Trial 25\]. On
18 April 2002, the sponsor provided an integrated, comprehensive 4-month
Safety Update for Trials 23, 24, and 25. Throughout the review process,
the sponsor submitted additional data and analyses in response to
requests from DRUDP.

## Overview of Clinical Trials

Complete Final Study Reports for 3 Phase III clinical trials were
submitted with NDA 20‑498/s012 to support the safety and efficacy of
Casodex 150 mg tablets for the treatment of men with localized and
locally advanced prostate cancer. Enrollment in the 3 clinical trials
was initiated in August 1995 (Trial 23), September 1995 (Trial 24), and
October 1995 (Trial 25). The last patients were enrollment in August
1997 (Trial 23) and July 1998 (Trials 24 and 25). The data cutoff date
for each of the Final Study Reports was 2 June 2000. The applicant also
submitted a separate safety addendum for each of the clinical trials
(data cut-off date of 23 February 2001 for each addendum). The study
number and title of each of the trials are listed below.

1.  Trial Number 7054IL/0023. "A Randomized Double-Blind Comparative
    Trial of Bicalutamide (CASODEX) Versus Placebo in Patients with
    Early Prostate Cancer."\
    (First patient recruited: 01 August 1995; last patient recruited: 29
    August 1997).

2.  Trial Number 7054IL/0024. "A Randomised, Double-Blind,
    Parallel-Group Trial Comparing CASODEX 150 mg Once Daily with
    Placebo in Patients with Non-metastatic Prostate Cancer." (First
    patient recruited: 21 September 1995; last patient recruited: 27
    July 1998).

3.  Trial Number 7054IL/0025. "A Randomised, Double-Blind,
    Parallel-Group Trial Comparing CASODEX 150 mg Once Daily with
    Placebo in Patients with Non-metastatic Prostate Cancer (SPCG-6)."
    (First patient recruited: 4 October 1995; last patient recruited: 30
    July 1998).

Each of the clinical trials was a comparative, randomized, double blind,
parallel-group, multicenter trial. In each trial, the efficacy and
safety of Casodex (150 mg per day) was compared to that of placebo.
Additional information concerning each of the clinical trials is
provided in Table 1.

[]{#__RefHeading___Toc25309661 .anchor}Table 1. Studies Supporting
Safety and Efficacy of Casodex for Localized or Locally Advanced
Prostate Cancer.

+--------------+----------+---------+-----------------+--------------+
| **Study      | **Study  | **No.   | **Total No. of  | **Treatment\ |
| No.**        | Design** | of      | Sites**         | Study Drug:  |
|              |          | Pat     |                 | number       |
| **Study      | **Study  | ients** | **Country and   | patients ^1^ |
| Title**      | Status** | ^1^     | (No. Pt. per    | Duration of  |
|              |          |         | country**)      | Treatment**  |
|              |          | **Age   |                 |              |
|              |          | of      |                 |              |
|              |          | Pt**.\  |                 |              |
|              |          | Mean    |                 |              |
|              |          | (range) |                 |              |
|              |          |         |                 |              |
|              |          | *       |                 |              |
|              |          | *Racial |                 |              |
|              |          | Distrib |                 |              |
|              |          | ution** |                 |              |
+==============+==========+=========+=================+==============+
| **7          | Phase 3, | 3292    | 96 Sites        | Treatment\   |
| 054IL/0023** | ran      | men     |                 | Casodex:     |
|              | domized, |         | United States   | 1647         |
| "A           | blinded, | 64.5    | (n=2974),\      | patients\    |
| Randomized   | placebo  | years\  | Canada (n=318). | Placebo:     |
| Double-Blind | con      | (38-85  |                 | 1645         |
| Comparative  | trolled, | years)  |                 | patients     |
| Trial of     | and      |         |                 |              |
| Bicalutamide | mult     | White   |                 | Duration\    |
| (CASODEX)    | icenter. | 2760\   |                 | All          |
| Versus       |          | Black   |                 | patients\    |
| Placebo in   | T        | 379\    |                 | 2 years or   |
| Patients     | reatment | H       |                 | until        |
| with Early   | com      | ispanic |                 | objective\   |
| Prostate     | pleted;\ | 106\    |                 | progression  |
| Cancer       | follow   | Other   |                 |              |
|              | up for   | 47      |                 |              |
|              | survival |         |                 |              |
|              | ongoing. |         |                 |              |
+--------------+----------+---------+-----------------+--------------+
|              |          |         |                 |              |
+--------------+----------+---------+-----------------+--------------+
| **7          | Phase 3, | 3603    | 191 Sites       | Treatment\   |
| 054IL/0024** | ran      | men     |                 | Casodex:     |
|              | domized, |         | Australia       | 1798         |
| "A           | blinded, | 68.7    | (n=14), Austria | patients\    |
| Randomized,  | placebo  | years\  | (n=62), Belgium | Placebo:     |
| D            | con      | (42-93  | (n=236), Czech  | 1805         |
| ouble-Blind, | trolled, | years)  | Rep (n=184),    | patients     |
| Pa           | and      |         | France (n=348), |              |
| rallel-Group | mult     | White   | Germany         | Duration\    |
| Trial        | icenter. | 3423\   | (n=107),        | Adjuvant     |
| Comparing    |          | H       | Holland         | patients\    |
| CASODEX 150  | T        | ispanic | (n=220),        | 5 years or   |
| mg Once      | reatment | 62\     | Hungary (n=70), | until        |
| Daily with   | ongoing. | Mixed   | Ireland (n=23), | progression  |
| Placebo in   |          | 61\     | Israel          |              |
| Patients     |          | Afro-\  | (n=193),\       | Non-adjuvant |
| with         |          | Ca      | Italy (n=94),   | patients\    |
| No           |          | ribbean | Mexico (n=77),\ | Until        |
| n-metastatic |          | 30\     | Poland (n=7),   | progression  |
| Prostate     |          | Other   | Portugal        |              |
| Cancer."     |          | 27      | (n=170),\       |              |
|              |          |         | South Africa    |              |
|              |          |         | (n=394), Spain  |              |
|              |          |         | (n=506), and UK |              |
|              |          |         | (n=898).        |              |
+--------------+----------+---------+-----------------+--------------+
|              |          |         |                 |              |
+--------------+----------+---------+-----------------+--------------+
| **7          | Phase 3, | 1218    | 62 Sites        | Treatment\   |
| 054IL/0025** | ran      | men     |                 | Casodex: 607 |
|              | domized, |         | Denmark         | patients\    |
| "A           | blinded, | 68.5    | (n=173),        | Placebo: 611 |
| Randomized,  | placebo  | years\  | Finland         | patients     |
| D            | con      | (46-87  | (n=277), Norway |              |
| ouble-Blind, | trolled, | years)  | (n=509), and    | Duration\    |
| Pa           | and      |         | Sweden (n=259). | All          |
| rallel-Group | mult     | White   |                 | patients\    |
| Trial        | icenter. | 1213\   |                 | Until        |
| Comparing    |          | H       |                 | progression  |
| CASODEX 150  | T        | ispanic |                 |              |
| mg Once      | reatment | 3\      |                 |              |
| Daily with   | ongoing. | Other 2 |                 |              |
| Placebo in   |          |         |                 |              |
| Patients     |          |         |                 |              |
| with         |          |         |                 |              |
| No           |          |         |                 |              |
| n-metastatic |          |         |                 |              |
| Prostate     |          |         |                 |              |
| Cancer       |          |         |                 |              |
| (SPCG-6)."   |          |         |                 |              |
+--------------+----------+---------+-----------------+--------------+

> 1\. Number of patients randomized (i.e., the efficacy population). Not
> all patients received study drug.\
> Source: Prepared by Medical Officer from various sources.

# Integrated Review of Efficacy

## Brief Statement about Efficacy

The Sponsor has provided statistically significant evidence in two
non-US clinical trials (Trials 24 and 25) that treatment with Casodex
150 mg per day, compared to treatment with placebo, in men with
non-metastatic prostate cancer at entry delayed progression of disease
as assessed by (1) bone scan confirmed metastases or (2) death from any
cause in the absence of disease progression. In these trials, Casodex
was studied as (1) adjuvant therapy in men previously treated by radical
prostatectomy or radiotherapy or (2) monotherapy in men who would
otherwise be managed by watchful waiting. In Trial 23 (the only trial
conducted in the US and the trial most relevant to patients in the US),
there was no evidence that treatment with Casodex delayed disease
progression. The relevance of benefit from treatment with Casodex in the
2 non-US trials for men with prostate cancer in the US who might be
treated with Casodex adjuvant therapy or Casodex monotherapy is unknown.

There was no evidence that treatment with Casodex improved survival in
any of the trials or in the combined analysis. Evidence of improved
survival, however, was not anticipated by the cut-off date for efficacy
data (2 June 2000) or the cut-off for the Safety Update (28 September
2001) as the survival data were expected to be immature.

## General Approach to the Review of the Efficacy of the Drug

The clinical component of NDA 20-498/s012 consisted of 3 pivotal Phase
III clinical trials (Trials 23, 24, and 25). Efficacy data from each of
the Phase III clinical trials were reviewed separately and collectively.
The 3 clinical trials were very similar in design. Efficacy assessments
were identical across studies, and each trial had nearly identical
primary and secondary efficacy endpoints; consequently, the 3 pivotal
efficacy trials are presented, for the most part, in an integrated
manner in the review that follows.

## Clinical Trials to Support Sponsor's Efficacy Claim

### Overall Study Design

The 3 Phase III clinical trials were comparative, multicenter,
randomized, double-blind, parallel-group trials. Table 1 provides an
overview of these trials. The trials were conducted in (1) North America
(Trial 23), (2) Europe (other than Scandinavia), South Africa, Israel,
Mexico, and Australia (Trial 24), and (3) Scandinavia (Trial 25). All
patients who qualified for enrollment were randomized in a 1:1 ratio to
treatment with either Casodex 150 mg per day or matching placebo. Table
2 provides a comparison of the similarities and differences across the 3
trials. All trials excluded the enrollment of patients with metastatic
disease beyond that of positive regional lymph nodes; however, in Trial
23, patients with positive regional lymph nodes also were not eligible.
All 3 trials investigated Casodex as adjuvant therapy in patients who
had had previous therapy for their prostate cancer (i.e., radical
prostatectomy or radiation therapy). Trials 24 and 25 (but not Trial 23)
also investigated Casodex monotherapy (patients who had had no prior
therapy and whose prostate cancer would otherwise be managed by watchful
waiting or surveillance). The maximal period of treatment with study
drug varied in each of the studies. In Trial 23, treatment was limited
to a maximum of 2 years or until objective disease progression
(whichever occurred first). In Trial 25, patients were to be treated
indefinitely or until progression of disease. In Study 24, patients with
prior therapy (adjuvant patients) were to be treated for a maximum of
5 years. Patients in each of the clinical trials were to have a bone
scan at 2 years after enrollment unless objective progression of their
disease had been confirmed prior to this time.

[]{#__RefHeading___Toc25309662 .anchor}Table 2 Overview of Phase III
Clinical Trials (Similarities and Differences)

  ----------------------------- ------------ ------------- ------------- ------------- ------------
  **Design Element**            **Trial 23**               **Trial 24**  **Trial 25**  

                                North                      Europe, South Scandinavia   
                                America                    Africa,                     
                                                           Israel,                     
                                                           Mexico,                     
                                                           Australia                   

  Double-blind, placebo         Yes                        Yes           Yes           
  controlled                                                                           

  Number of patients randomized 3292                       3603          1218          

  Tumor staging criteria        T1b-T4, N0                 T1b-T4,\      Same as 0024  
                                or NX (N+                  any N, M0                   
                                excluded),                                             
                                M0                                                     

  Permitted standard care                                                              

  Radical prostatectomy or      Yes                        Yes           Yes           
  radiotherapy                                                                         

  Watchful waiting              No                         Yes           Yes           

  Intended period of randomized 2 yr.                      5 yr. for     Until         
  treatment                                                adjuvant      progression   
                                                           patients      for all       
                                                                         patients      

                                             Until                                     
                                             progression                               
                                             in non                                    
                                             adjuvant                                  
                                             patients                                  

  2-yr. bone scan to determine  Yes                        Yes           Yes           
  progression                                                                          

  Follow-up for progression and Yes ^1^                    Yes           Yes           
  survival                                                                             
  ----------------------------- ------------ ------------- ------------- ------------- ------------

1 Monitored only for survival and serum PSA. Bone scans to be obtained
at discretion of Investigator.

### Study Objectives 

The primary and secondary objectives of the 3 clinical trials are listed
in Table 3. They were very similar across the 3 trials with some
exceptions. Survival was a secondary objective in Trial 24 instead of a
primary objective as in Trials 23 and 25. Sexual satisfaction was
assessed only in Study 25.

[]{#__RefHeading___Toc25309663 .anchor}Table 3 Primary and Secondary
Objectives of the Clinical Trials

+-----------------------------------------------------------------------+
| **Primary Objectives**:                                               |
+-----------------------------------------------------------------------+
| -   To compare Casodex 150 mg once daily with placebo in terms of     |
|     time to objective progression                                     |
+-----------------------------------------------------------------------+
| -   To compare Casodex 150 mg once daily with placebo in terms of     |
|     overall survival ^1^                                              |
+-----------------------------------------------------------------------+
| -   To evaluate the tolerability of Casodex 150 mg compared with      |
|     placebo ^2^                                                       |
+-----------------------------------------------------------------------+
| **Secondary objectives:**                                             |
+-----------------------------------------------------------------------+
| -   To compare Casodex 150 mg once daily with placebo in terms of     |
|     time to treatment failure                                         |
+-----------------------------------------------------------------------+
| -   To compare Casodex 150 mg once daily with placebo in terms of the |
|     time for prostate specific antigen (PSA) to double                |
+-----------------------------------------------------------------------+
| -   To assess sexual function using the Golombok Rust Inventory ^3^   |
+-----------------------------------------------------------------------+

^1^ Secondary objective in Study 24.\
^2^ Secondary objective in Study 23.\
^3^ Included only in Study 25.

### Study Patients and Enrollment Criteria

Only patients with non-metastatic prostate cancer (Stage M0) were
potentially eligible for enrollment in the clinical trials. Entry
criteria were generally similar across the 3 clinical trials although
there were some significant differences, particularly in the entry
criteria for Trial 23 compared to those for Trials 24 and 25. These
differences included exclusion of patients from Trial 23 who (1) had
positive local or regional lymph nodes and (2) had not undergone either
a radical prostatectomy or radiation therapy with the expectation that
the procedure would be curative. Thus patients who had not received
active therapy for their prostate cancer (patients initially managed by
watchful waiting) were excluded from Trial 23.

> Inclusion Criteria Included

-   Histologically or cytologically confirmed adenocarcinoma of the
    prostate gland

-   Clinical or pathological stage T1b, T1c, T2, T3, or T4 disease

-   No distant metastases (Stage M0) as confirmed by a negative bone
    scan

-   Any N (local nodal status) for Studies 24 and 25; only N0 for Study
    23

-   For Study 23 only, patient must have received one of the following:

> **--** a radical prostatectomy (nerve or non-nerve sparing) defined as
> the total extirpation of the prostate including the seminal vesicles
> performed within 16 weeks before randomization
>
> **--** radiation to the prostate initiated within 16 weeks before
> randomization

-   At least 18 years of age

-   Informed consent to participate in the trial

> Exclusion Criteria Included

-   Previous systemic therapy for prostate cancer other than neoadjuvant
    therapy prior to primary therapy of curative intent or therapy with
    5-alpha-reductase inhibitors

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-   History or presence of another malignancy within the last 5 years,
    other than prostate cancer or treated squamous/basal cell carcinoma
    of the skin

```{=html}
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```
-   A serum bilirubin, aspartate aminotransferase (AST) or alanine
    aminotransferase (ALT) concentration \>2.5x the upper limit of
    normal (World Health Organization grade 2 toxicity)

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```
-   Any physical or mental condition which, in the opinion of the
    investigator, might interfere with the patient's ability to comply
    with scheduled visits and assessments

-   For Study 23 only:

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```
-   A patient whose prostate cancer was not confined to the surgical
    specimen

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-   For Study 25 only:

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```
-   Patients for whom long-term therapy was considered inappropriate
    because of their expected survival times (i.e., patients with
    undetectable PSA levels and negative margins following radical
    prostatectomy or radiotherapy to the prostate bed)

##### Medical Officer's Comments {#medical-officers-comments-2 .unnumbered}

-   Although the inclusion and exclusion criteria were identical for the
    most part, the few differences across studies had the potential to
    have a significant effect on the outcomes of the respective studies.

-   In Trial 25, exclusion of patients with negative PSA values or
    negative tissue specimen margins after prostatectomy would likely
    have excluded virtually all surgically treated patients with early
    or localized prostate cancer. In contrast, patients with early or
    localized disease comprised the majority of patients enrolled into
    Trial 23.

### Study Drugs 

#### Rationale for Choice of Comparator

According to the Sponsor, it was not common clinical practice or
established policy at the time that these trials were initiated, to use
immediate rather than deferred therapy in patients with localized
disease. There also was not a consensus of opinion on the use of
hormonal therapy as adjuvant therapy following radical prostatectomy or
radiation treatment for localized disease. The Sponsor therefore chose
to compare the effects of treatment with Casodex to those of treatment
with placebo.

##### Medical Officer's Comments {#medical-officers-comments-3 .unnumbered}

-   Use of placebo therapy as the comparator for patients with localized
    disease, treated by either prostatectomy or radiation therapy, was a
    reasonable decision as no therapy has been shown to be of benefit in
    this population.

-   The use of placebo for locally advanced disease in patients who were
    to receive no active therapy is more controversial as such patients
    are not generally managed by watchful waiting in the US. However,
    watchful waiting as initial management for such patients outside of
    the US, particularly in Scandinavia, is not uncommon.

#### Rationale for Dose Selection of Casodex

The applicant had previously conducted a series of dose-ranging trials
with Casodex (Trials 0002, 0003, and 0005) to identify the lowest dose
of Casodex that appeared to exert maximal anti-androgenic effects. In
these studies, the percentage inhibition of PSA was used as a measure of
the anti-androgenic effect of Casodex. Following 3 months of
administration, Casodex doses of 100 to 200 mg produced the maximal
suppression of serum PSA. Doses of 100 mg and 150 mg were subsequently
selected for comparison with castration in a Phase III clinical program
(Trails 0306 and 0307) that were conducted in support of an earlier
application (NDA 20-498/s006). Based on a planned, early evaluation of
these 2 doses, Casodex 150 mg per day was selected for (1) continued
evaluation in these latter 2 trials and (2) the early prostate cancer
program (Trials 23, 24, and 25 in the present application).

##### Medical Officer's Comments {#medical-officers-comments-4 .unnumbered}

-   Based on the results of these earlier trials, the use of Casodex 150
    mg per day is a reasonable dose for Clinical Trials 23, 24, and 25.

#### Assignment to Study Drug and Treatment Schedules

Randomized study drugs were administered in tablet form as a once daily
oral dose and were supplied as white tablets containing either 150 mg of
Casodex or placebo. Patients were randomly assigned in a 1:1 ratio to
treatment with either Casodex or placebo. Treatment was to be initiated
as soon as possible after randomization, but in no case was this period
to exceed 2 weeks. Treatment with study drug initially was to be for 2
years in all 3 of the clinical trials. Prior to the first patient
completing 2 years of treatment, the Data and Safety Monitoring
Committee (DSMC) reviewed the blinded patient safety data across the
whole program. The DSMC concluded that both treatments (Casodex and
placebo) were well tolerated and that there were no safety concerns to
prevent treatment of patients beyond 2 years (96 weeks) in any of the
trials. However, the final decisions regarding extending treatment
beyond 2 years differed for each of the 3 trials. These differences were
based, according to the Sponsor, upon investigator preferences.

> **Trial 23**. It was decided that treatment would not extend beyond 2
> years as the investigators thought this treatment period was
> sufficient for the study population.
>
> **Trial 24**. It was decided that adjuvant patients (patients who had
> initially received primary treatment by either radical prostatectomy
> or radiation therapy would continue to receive blinded treatment for a
> total of 5 years. However, therapy in these patients could continue
> treatment beyond 5 years based at the individual investigator's
> discretion. For other patients (i.e., those initially managed by
> watchful waiting), there would be no limit on the duration of
> treatment. For both groups of patients, it also was recommended that
> treatment with study drug be discontinued if objective disease
> progression was documented or if a patient reached any treatment
> failure endpoint as defined in Section 4.5.2.
>
> **Study 25.** It was decided that all patients would continue to
> receive randomized treatment until they had reached a treatment
> failure endpoint.

Until such time as objective disease progression had been documented,
patients were not to receive any systemic treatment other than
randomized study therapy. If the investigator considered that it was in
the patient's best interest to initiate alternative systemic therapy for
prostate cancer before progression had been documented, this was
considered a treatment failure, and the patient's randomized therapy was
to be discontinued.

##### Medical Officer's Comment {#medical-officers-comment-1 .unnumbered}

-   Although assignment to treatment was randomized and blinded, it was
    unlikely that treatment assignments were actually blinded because of
    the pharmacological actions of Casodex. Patients receiving Casodex
    were much more likely to development gynecomastia and/or breast pain
    in contrast to placebo-treated patients. In addition,
    Casodex-treated patients (but not placebo-treated patients) who had
    detectable PSA values at randomization were likely to show a
    decrease in PSA values.

## Study Procedures and Study Conduct

### Schedule of Study Assessments and Procedures

The schedule for study assessments and procedures is summarized in Table
4. During the baseline or screening period, a potential patient's
eligibility for participation was determined according to the inclusion
and exclusion criteria described in Section 4.3.3). Baseline assessments
included a physical examination and medical history, a bone scan if not
previously performed within the prior 24 weeks (later amended to 30
weeks), measurements of serum PSA and liver transaminases, and
completion of the Golombok Rust Inventory of Sexual Satisfaction (GRISS)
questionnaire (Trial 25 only).

**Study Weeks 1-96**

During the first 96 weeks of each clinical trial, patients were to be
assessed every 12 weeks for clinical evidence of disease progression and
monitoring of liver function and adverse events. A bone scan to detect
distant metastases of prostate cancer was to be performed at Week 96 in
all patients (regardless of treatment status) unless the patient
previously had had a positive on-treatment bone scan. Patients in Trial
25 also completed the GRISS questionnaire at Weeks 12, 24, 36, and 48.
Patients who terminated treatment prior to Week 96 for a reason other
than objective disease progression were to continue with clinical visits
every 12 weeks for monitoring for clinical disease progression and
measurement of serum PSA. Following documentation of objective disease
progression, patients were to be assessed every 24 weeks for survival.

[]{#__RefHeading___Toc25309664 .anchor}Table 4 Schedule of Study
Assessments and Procedures

  --------------- ----------------- --- ---- ---- ---- ---- ---- ---- ---- ------ ------------- -------
  **Procedure**   **Weeks after                                                                 
                  randomization**                                                               

                  Baseline              Wk   Wk   Wk   Wk   Wk   Wk   Wk   Wk 96  After Early   Post\
                                        12   24   36   48   60   72   84          Termination   Wk 96
                                                                                  ^1^           ^1a^

  Physical        X ^2^                 X    X    X    X    X    X    X    X      X             
  examination                                                                                   

  Bone scan       X ^3^                                                    X ^3a^               X ^4^

  PSA ^5^         X                     X    X    X    X    X    X    X    X      X             X ^5^

  ALT, AST,       X                     X    X    X    X    X    X    X    X                    
  bilirubin                                                                                     

  Assess for                            X    X    X    X    X    X    X    X      X             X
  clinical                                                                                      
  progression ^6^                                                                               

  GRISS           X                     X    X    X    X                                        
  questionnaire                                                                                 
  ^7^                                                                                           

  Adverse events                        X    X    X    X    X    X    X    X      X             

  Concomitant     X                     X    X    X    X    X    X    X    X                    
  therapy                                                                                       

  Daily dosing                          X    X    X    X    X    X    X    X                    X
  with Study Drug                                                                               
  ^8^                                                                                           
  --------------- ----------------- --- ---- ---- ---- ---- ---- ---- ---- ------ ------------- -------

1\. Patients were to be assessed every 12 weeks until progression
irrespective of whether they had stopped randomized treatment; following
progression, patients were to be assessed every 24 weeks.

1a In Trial 23, patients were to have clinical visits very 6 months
through 4 years post randomization and annually thereafter until death.
In Trials 24 and 25, patients were to continue to have a clinic visit
every 12 weeks while continuing to receive randomized treatment.
Following discontinuation of randomized treatment or documentation of
disease progression, patients were to have a clinic visit every 6 months
until death.

2\. Included demographic and medical history at baseline visit.

3\. To be performed within 24 weeks (Trials 24 and 25) or 30 weeks
(Trail 23) before randomization.

3a. All patients were to have a bone scan at Week 96 unless they
previously had had an on-treatment positive bone scan documenting
progression of disease.

4\. Additional assessments performed every 96 weeks thereafter for
Trials 24 and 25 only.

5\. PSA measurements were to be obtained (1) at each 12-week clinical
visit until disease progression in Trials 24 and 25 or (2) at each
6-month or annual clinical visit until disease progression in Trial 23.

6\. Patients were assessed, as warranted by clinical symptoms and
findings, for local and regional disease and distant metastases at each
clinical visit until objective progression was documented.

7\. Golombok Rust Inventory of Sexual Satisfaction (GRISS). Performed
only in Trial 25.

8\. In all trials, dosing with blinded study drug was to continue
through Week 96 or until objective progression of disease. Dosing in
Trial 23 was limited to a maximum of 2 years. In Trials 24 and 25,
dosing was to continue through 5 years (adjuvant group in Trial 24) or
indefinitely (all other groups) or until objective disease progression.

**After Study Week 96**

**Trial 23.** Treatment with study drug was limited to 96 weeks in Trial
23. Subjects who completed 96 weeks of treatment without documented
evidence of clinical progression were to be contacted every 3 months
thereafter. In addition, they were to have a clinical visit every 6
months for a physical examination and PSA assessment, up to and
including Month 48 and annually thereafter. A bone scan also was to be
performed at the discretion of the investigator if progression was
suspected. Subjects who had documented evidence of clinical progression
were to be contacted every 3 months to determine their survival status.

**Trials 24 and 25.** Treatment with study drug was to continue for at
least 5 years or until disease progression in Trials 24 and 25 (See
Section 4.3.4.3 for further details). During treatment with randomized
therapy, patients were to continue to have clinical visits every
12 weeks. At each visit, they were to be assessed for clinical
progression of disease and adverse events. A blood specimen for the
measurement of PSA, ALT, AST, and bilirubin concentrations was to be
collected. In addition to the assessments performed every 12 weeks, a
repeat bone scan was to be performed every 96 weeks, or earlier, if
warranted by clinical findings until objective progression of disease
was documented.

Following discontinuation of treatment with study drug, patients were to
be seen in the clinic every 24 weeks until objective disease progression
and/or death. Patients who had gynecomastia or breast pain at
termination of treatment with study drug, were to be assessed for
improvement or resolution of these signs or symptoms at each post
treatment visit.

##### Medical Officer\'s Comment {#medical-officers-comment-2 .unnumbered}

-   Not requiring bone scans at 2 year intervals after Week 96 in Trial
    23, is a significant problem in the design of this Trial. Since
    these patients had minimal disease at entry and have shown a very
    low rate of disease progression (see Section 4.6.3.1), failure to
    require bone scans at 2-year intervals as in Trials 24 and 25
    markedly limits the likelihood that a benefit for treatment with
    Casodex will be demonstrated.

### Efficacy Assessments

At each clinical visit, patients were assessed for signs of disease
progression. These assessments included a physical examination and
measurement of serum PSA concentration. These assessments were performed
every 12 to 24 weeks in accordance with the schedule of assessments
listed in Table 4. In addition, bone scans were to be performed at Study
Week 96 if objective disease progression (as defined below) had not been
documented previously. Evidence of disease progression (either local or
distant progression) was classified by the Sponsor as either objective
or non-objective depending upon the clinical or laboratory method of
documentation.

#### Objective Progression

**Imaging procedures or biopsy**. Objective progression required
confirmation of disease progression by either an imaging procedure
(e.g., bone scan, x-ray, magnetic resonance imaging, computerized
tomography, or ultrasonography) or biopsy.

##### Medical Officer's Comment {#medical-officers-comment-3 .unnumbered}

-   With the exception of death due to prostate cancer, disease
    progression documented by bone scan was considered by this reviewer
    and other Medical Officers both within DRUDP and the Division of
    Oncology Drug Products to be the most clinically significant
    evidence of disease progression.

#### Non-objective Progression

**Signs and Symptoms.** Non-objective progression included signs or
symptoms that were compatible with disease progression (e.g., ureteral
obstruction, lymphedema of the lower extremities, vesical obstruction)
but which were not confirmed by an imaging procedure or biopsy.
Investigators were instructed to confirm non-objective progressive
events by an objective procedure whenever possible.

**Serum PSA.** Increases in serum PSA values by themselves were not
considered to be objective evidence of disease progression. PSA samples
obtained at baseline (immediately prior to randomization) and following
randomization were, for the most part, measured at one of two central
laboratories using the Hybritech Assay. For Trial 23, PSA assays were
performed at Quest Diagnostics (formerly SmithKline Beecham
Laboratories), Clinical Trials Center, Van Nuys, CA. For Trials 24 and
25, PSA assays were performed at AstraZeneca's Central Laboratory,
Mereside, Alderley Park, Cheshire, UK. PSA samples obtained prior to
radical prostatectomy or radiation therapy (i. e., prior to screening
for enrollment into the clinical trials) may have been analyzed by other
assay procedures at the respective study site.

#### Bone Scans

In each of the clinical trials, a bone scan was to obtained at Study
Week 96 or sooner if warranted by the patient's symptoms or clinical
findings. If a bone scan was obtained prior to Week 96 for clinical
reasons and was found to be negative, the bone scan was to be repeated
at Study Week 96. All bone scans were performed at the study sites and
read locally.

##### Medical Officer's Comments {#medical-officers-comments-5 .unnumbered}

-   It was likely that blinding of treatment assignment would not be
    maintained for many patients because of the high incidence of
    gynecomastia and breast pain and decrease in serum PSA
    concentrations in Casodex-treated patients; consequently, there was
    concern that local readings of bone scans could be biased. The
    Division requested that the bone scans be reread by a group of
    blinded reviewers at a central facility.

-   Based on this request, the sponsor proposed that all positive scans
    and a representative subset of negative scans would each be reread
    by at least 2 blinded reviewers at a central facility (Columbia
    Presbyterian Medical Center, New York). The objective of the
    blinded, central reread would be to assess the potential for bias in
    the Sponsor's primary analysis of time to objective disease
    progression. The procedures employed and the outcome of the central
    reread are described in Section 4.6.3.8.

-   Details of the conduct of the central reread are provided in the
    separate review of Robert Yaes MD, Medical Officer, Division of
    Medical Imaging and Radiological Drug Products (HFD 160).

## Efficacy Endpoints and Analyses

The primary and secondary efficacy endpoints in each of the 3 clinical
trials and in the sponsor's combined analysis are listed in Table 5.
They were identical in each of the trials with one exception, time to
death was a secondary endpoint in Trial 24 but a primary endpoint in
Trials 23 and 25 as well as in the combined analysis. Each of these
endpoints is described further in Sections 4.5.1 and 4.5.2. The Sponsor
chose a data cutoff date of 2 June 2000 for efficacy data, which allowed
(according to the Sponsor) for at least 2 years of follow up after
randomization for each patient in each clinical trial.

[]{#__RefHeading___Toc25309665 .anchor}Table 5 Summary of Primary and
Secondary Endpoints and Analyses

+---------------+-----------------------------------+---+---+---+-----+
| **Endpoint**  | **Definition**                    | * |   |   | *   |
|               |                                   | * |   |   | *Co |
|               |                                   | T |   |   | m-\ |
|               |                                   | r |   |   | bi  |
|               |                                   | i |   |   | ned |
|               |                                   | a |   |   | ^1  |
|               |                                   | l |   |   | ^** |
|               |                                   | * |   |   |     |
|               |                                   | * |   |   |     |
+---------------+-----------------------------------+---+---+---+-----+
|               |                                   | * | * | * |     |
|               |                                   | * | * | * |     |
|               |                                   | 2 | 2 | 2 |     |
|               |                                   | 3 | 4 | 5 |     |
|               |                                   | * | * | * |     |
|               |                                   | * | * | * |     |
+---------------+-----------------------------------+---+---+---+-----+
|               |                                   | * |   |   |     |
|               |                                   | * |   |   |     |
|               |                                   | P |   |   |     |
|               |                                   | r |   |   |     |
|               |                                   | i |   |   |     |
|               |                                   | m |   |   |     |
|               |                                   | a |   |   |     |
|               |                                   | r |   |   |     |
|               |                                   | y |   |   |     |
|               |                                   | o |   |   |     |
|               |                                   | r |   |   |     |
|               |                                   | S |   |   |     |
|               |                                   | e |   |   |     |
|               |                                   | c |   |   |     |
|               |                                   | o |   |   |     |
|               |                                   | n |   |   |     |
|               |                                   | d |   |   |     |
|               |                                   | a |   |   |     |
|               |                                   | r |   |   |     |
|               |                                   | y |   |   |     |
|               |                                   | ^ |   |   |     |
|               |                                   | 2 |   |   |     |
|               |                                   | ^ |   |   |     |
|               |                                   | * |   |   |     |
|               |                                   | * |   |   |     |
+---------------+-----------------------------------+---+---+---+-----+
| **Time to     | > Time from randomization to:\    | 1 | 1 | 1 | 1   |
| objective     | > 1. Objectively confirmed        |   |   |   |     |
| progression   | > progression\                    |   |   |   |     |
| ^3^**         | > 2. Death in the absence of      |   |   |   |     |
|               | > objectively confirmed           |   |   |   |     |
|               | > progression                     |   |   |   |     |
+---------------+-----------------------------------+---+---+---+-----+
|               |                                   |   |   |   |     |
+---------------+-----------------------------------+---+---+---+-----+
| **Time to     | > Time from randomization to      | 1 | 2 | 1 | 1   |
| death         | > death from any cause            |   |   |   |     |
| (overall      |                                   |   |   |   |     |
| survival)**   |                                   |   |   |   |     |
+---------------+-----------------------------------+---+---+---+-----+
|               |                                   |   |   |   |     |
+---------------+-----------------------------------+---+---+---+-----+
| **Time to     | > Time from randomization to the  | 2 | 2 | 2 | 2   |
| treatment     | > first of:\                      |   |   |   |     |
| failure**     | > 1. Additional systemic therapy  |   |   |   |     |
|               | > or radiotherapy 2. Withdrawal   |   |   |   |     |
|               | > of trial therapy\               |   |   |   |     |
|               | > 3. Objective progression\       |   |   |   |     |
|               | > 4. Death from any cause         |   |   |   |     |
+---------------+-----------------------------------+---+---+---+-----+
|               |                                   |   |   |   |     |
+---------------+-----------------------------------+---+---+---+-----+
| **Time to PSA | > Time from randomization to the  | 2 | 2 | 2 | 2   |
| doubling**    | > first of:\                      |   |   |   |     |
|               | > 1. An increase of serum PSA to  |   |   |   |     |
|               | > twice that at randomization\    |   |   |   |     |
|               | > 2. Objectively confirmed        |   |   |   |     |
|               | > progression\                    |   |   |   |     |
|               | > 3. Death from any cause         |   |   |   |     |
+---------------+-----------------------------------+---+---+---+-----+

^1^ Sponsor's combined analysis for Trials 23 + 24 + 25.

^2^ 1 = primary endpoint; 2 = secondary endpoint.

^3^ Objectively confirmed progression = local or distant progression of
disease confirmed by bone scan, x-ray, CT scan, magnetic resonance
imaging, ultrasonography, or biopsy.

### Primary Efficacy Endpoints and Analyses

**Objective progression**. Objective progression, as defined previously
in Section 4.4.2.1, was examined in each of the clinical trials and in
the combined analyses. Time to objective progression (TTP) was defined
as the number of days between randomization and the documented date of
objective progression or death (by any cause in the absence of objective
disease progression).

**Overall survival (time to death).** Time to death (TTD) was a primary
efficacy endpoint in 2 of the 3 clinical trials (Trials 23 and 25) and
in the Sponsor's combined analysis. Time to death was defined as the
number of days between randomization and the documented date of the
*patient's death from **any cause***.

##### Medical Officer's Comments {#medical-officers-comments-6 .unnumbered}

-   Although treatment assignment was to be blinded, it was recognized
    by both the Sponsor and the Division that there could be assessment
    bias in a time-to-event analysis. The basis for this potential bias
    was related to the high incidence of gynecomastia and breast pain
    and lower serum PSA values in Casodex-treated patients. Because of
    this concern, the Division requested, and the Sponsor provided,
    additional binary analyses for objective progression based on the
    incidence of bone scan confirmed progression or death in the absence
    of progression within 2 years of randomization. The 2-year time
    point was selected because all patients were to have a bone scan at
    2 years per protocol unless objective progression had previously
    been documented.

-   The Study Protocols did not provide specific criteria by which to
    judge whether local progression had occurred. No instances of
    progression, with the exception of selected bone scans that were
    reviewed centrally, were reviewed by a central, blinded panel. The
    possibility of local bias in these other assessments of disease
    progression cannot be excluded.

### Secondary Efficacy Endpoints and Analyses

Secondary efficacy endpoints were time to treatment failure and time to
a PSA doubling event.

**Time to treatment failure (TTF).** Time to treatment failure was
defined as the number of days from the date of randomization until the
earliest of the following events:

-   death from any cause

-   objective progression of disease

-   withdrawal of trial therapy

-   administration of an additional systemic therapy or radiotherapy for
    prostate cancer

The reason for treatment failure was defined as the first of these
events to occur.

**Time to a PSA doubling event (TTPSAd).** Time to a PSA doubling event
was defined as the number of days from the date of randomization until
the earliest of the following events:

-   PSA sample time at which PSA had doubled compared with the value
    recorded immediately prior to randomization

-   time of objective disease progression

-   time of death.

### Overview of Statistical Analyses 

#### Efficacy Population

Efficacy data were analyzed on an intent-to-treat (ITT) basis (analyzed
as randomized). Therefore, all randomized patients with data were
included in the efficacy analyses regardless of whether the patient had
met all the entry criteria (protocol violations), had departed from the
protocol design or procedures after entry into the trial (protocol
deviations), had not received randomized therapy, or had received
subsequent non-randomized prostate cancer therapy.

#### Sponsor's Analyses of Primary Efficacy Endpoints

**Time to objective progression** was analyzed for each individual trial
and for pooled data from all 3 contributing trials. The analyses were
achieved by fitting a Cox proportional hazards regression model to the
data. Terms were fitted allowing for the effects of randomized treatment
and the following covariates:

-   Trial

-   PSA concentrations

-   Stage of prostate cancer

-   Previous therapy of curative intent

-   Gleason category

From the model including these main effects, the hazard ratio
(Casodex/placebo) was estimated together with its associated 95%
confidence interval and p-value. Data also were displayed graphically
using Kaplan-Meier plots. For the purpose of the analyses, only patients
with objectively confirmed disease progression (positive bone scan or
other objective event) or who had died (from any cause) in the absence
of objective progression were considered to have had disease
progression.

##### Medical Officer's Comments {#medical-officers-comments-7 .unnumbered}

-   The Sponsor claimed that a combined analysis of all 3 contributing
    trials was justified for the following reasons: (1) the trials were
    of similar statistical design; (2) they recruited patients with
    overlapping demographic characteristics via similar
    inclusion/exclusion criteria, and (3) they assessed
    identically-defined efficacy endpoints of time to objective
    progression, survival, and time to treatment failure.

-   Although the inclusion/exclusion criteria were similar across the 3
    clinical trials, review of the demographic and baseline disease
    characteristics disclosed significant differences between Trial 23
    (North American Trial) and Trials 24 and 25; consequently, both the
    medical and statistical reviewers do not believe that a combined
    efficacy analysis that includes Trials 23, 24, and 25 is
    appropriate. Specific differences among the study populations are
    described in Section 4.6.2.

#### FDA Requested Analyses

The FDA requested that the primary analyses for disease progression
utilize only the results of (1) bone scans obtained at the
protocol-mandated 2-year time point and (2) death in the absence of
progression within 2 years of randomization as these endpoints were
least likely to be influenced by potential bias. The results the
FDA-requested analyses (i.e., the proportion of patients with disease
progression or death ***at 2 years after randomization**)* as well as
analyses based on bone scan documented progression or death in the
absence of objective progression ***within 2 years of randomization***
were provided. The Sponsor stated in the Application that the within 2
years of randomization was the more appropriate analysis. The rationale
for the Sponsor's position was that in accordance with the protocol,
bone-scans could be taken at times prior to the 2-year time point if
clinically indicated. If the bone scan was positive, these patients were
not required to have another bone scan at the 2-year time point. Such
patients would therefore be incorrectly classified in the analyses as
not having had objective progression of disease if a strict definition
of "at 2 years after randomization" was employed.

The results of these analyses were expressed in terms of an odds ratio
of Casodex relative to placebo, together with the associated 95%
confidence limits and p-value. Results also were expressed in terms of
relative risk and simple incidence rates. Confidence intervals for
relative risks also were calculated.

##### Medical Officer's Comments {#medical-officers-comments-8 .unnumbered}

-   This Medical Officer concurs with the Sponsor that the more
    appropriate analysis is that which included events that occurred
    **within 2 years of randomization** and not only those events that
    were based on the protocol mandated bone scan at 2 years post
    randomization.

-   The actual statistical analyses employed by the Sponsor used a
    window of 2 years plus 6 months both for bone scan documented
    progression and death. The rationale for this window was that some
    protocol mandated 2-year bone-scans were actually obtained a short
    time after 2 years from randomization. For consistency, deaths in
    the absence of bone-scan progression occurring within 2 years plus 6
    months of randomization also were included in the analyses. This
    reviewer believes that the Sponsor's rationale for extending the
    period of assessment from 2 years to 2 years plus 6 months is
    acceptable.

## Results

### Enrollment and Patient Disposition

A total of 8113 patients were randomized to treatment in the 3 clinical
trials that were submitted in support of this Application. Of these,
4052 patients were randomized to receive Casodex 150 mg per day and 4061
patients were randomized to receive placebo. The disposition of the
patients at the time of the efficacy data cutoff (2 June 2000) is shown
in Figure 1.

[]{#__RefHeading___Toc25232678 .anchor}Figure 1 Efficacy Analysis
Population and Treatment Status at Time of Data Cutoff

![](media/image1.png){width="6.238888888888889in"
height="2.9305555555555554in"}

A total of 3292, 3603, and 1218 patients were randomized to treatment in
Trial 23, Trial 24, and Trial 25, respectively. The first patients were
enrolled in August 1995 (Trial 23), September 1995 (Trial 24), and
October 1995 (Trial 25). The last patients were enrolled in August 1997
(Trial 23) and July 1998 (Trials 24 and 25). The clinical trials
included a total of 349 investigative sites (Trial 23: 96 sites; Trial
24: 191 sites; and Trial 25: 62 sites). Each of the trials was conducted
in a different geographic area. Trial 23 was conducted in North America,
with approximately 90% of patients from the United States and the
remainder from Canada. Trial 24 was conducted in Europe (other than
Scandinavia), South Africa, Israel, Mexico, and Australia. Trial 25 was
conducted in Scandinavia (Denmark, Finland, Norway, and Sweden). Table 1
lists the number of patients enrolled in each country in each of the
clinical trials.

Patient enrollment and patient status (i.e., terminated treatment
prematurely, completed treatment, or continuing treatment) in each of
the 3 trials as of 2 June 2000 (efficacy data cutoff date) is summarized
in Table 6. In Trial 23, treatment was limited to a maximum of 2 years
and the maximum treatment period for all patients had been reached by 2
June 2000. Thirty eight percent (38%) of patients in the Casodex group
and 20.2% of patients in the placebo group terminated treatment before
completing 2 years. In Trials 24 and 25, treatment was on going at the
time of data cutoff. In Trial 24, 40.3% and 37.2% of the patients in the
Casodex and placebo treatment groups had terminated treatment as of 2
June 2000. In Trial 25, 31.9% and 47.0% of the patients in the Casodex
and placebo treatment groups had terminated treatment as of 2 June 2000.

[]{#__RefHeading___Toc25309666 .anchor}Table 6 Patient Enrollment and
Treatment Status as of June 2, 2000 ^1^

+--------------------------+------+------+------+------+------+------+
|                          | T    |      | T    |      | T    |      |
|                          | rial |      | rial |      | rial |      |
|                          | 23   |      | 24   |      | 25   |      |
+--------------------------+------+------+------+------+------+------+
|                          | Cas  | Pla  | Cas  | Pla  | Cas  | Pla  |
|                          | odex | cebo | odex | cebo | odex | cebo |
+--------------------------+------+------+------+------+------+------+
| Number of patients       | 1647 | 1645 | 1798 | 1805 | 605  | 611  |
| randomized               |      |      |      |      |      |      |
+--------------------------+------+------+------+------+------+------+
| Number of patients       | 1627 | 1627 | 1790 | 1795 | 605  | 609  |
| treated                  |      |      |      |      |      |      |
+--------------------------+------+------+------+------+------+------+
| Patient disposition      |      |      |      |      |      |      |
+--------------------------+------+------+------+------+------+------+
| > Terminated prematurely | 3    | 2    | 4    | 3    | 3    | 4    |
| > (% of pt.) ^2,\ 4^     | 8.0% | 0.2% | 0.3% | 7.2% | 1.9% | 7.0% |
+--------------------------+------+------+------+------+------+------+
| > Completed treatment    | 6    | 7    | 5    | 6    | 6    | 5    |
| > (Trial 23 only) or     | 2.0% | 9.8% | 9.7% | 2.8% | 8.1% | 3.0% |
| > treatment ongoing (%   |      |      |      |      |      |      |
| > of pt.) ^3,\ 4^        |      |      |      |      |      |      |
+--------------------------+------+------+------+------+------+------+

1\. June 2, 2000 was the efficacy data cutoff date.

2\. Includes patients withdrawn from treatment because of disease
progression, adverse events, need for prohibited therapy and other
reasons.

3\. Treatment period in Study 23 was up to a maximum of 2 years;
treatment period in Trial 23 completed prior to June 2, 2000.

4\. Percentages based on number of patients treated (i.e., those who
received study drug).

Source: Text Table T3.8 (Final Study Reports for Trials 23, 24, and 25).

Patient exposure to randomized study drugs and follow up times for
disease progression in each of the clinical trials is summarized in
Table 7. Median patient exposure to study drug ranged from 1.8 years in
Trial 23 (Casodex and placebo treatment groups) to 2.5 years in Trial 25
(Casodex treatment group). Median patient years of follow up for disease
progression and survival (efficacy analyses) were 3.2 years (Trial 23),
2.6 years (Trial 24) and 3.0 years (Trial 25).

[]{#__RefHeading___Toc25309667
.anchor}^Table\ 7\ Patient\ Years\ of\ Exposure\ to\ Study\ Drug\ and\ Follow-up^
1

  ------------------- --------- --- --------- ------ -- --------- --------- -- --------- ---------
                      **Trial                           **Trial                **Trial   
                      23**                              24**                   25**      

                      Casodex       Placebo             Casodex   Placebo      Casodex   Placebo

  Patient exposure to                                                                    
  study drug                                                                             

  Total pt yr.        2276          2660                3820      4024         1531      1419

  Median pt yr.       1.8           1.8                 2.2       2.3          2.5       2.3

  Follow up for                                                                          
  progression and                                                                        
  survival                                                                               

  Total pt yr.        5430          5428                4817      4811         1807      1794

  Median pt yr.       3.2           3.2                 2.6       2.6          3.0       3.0
  ------------------- --------- --- --------- ------ -- --------- --------- -- --------- ---------

1\. As of efficacy data cutoff date of June 2, 2000.

Source: Tables T5.1.1 and T5.2.1 from Final Study Reports for Trials 23,
24, and 25.

### Demographics and Baseline Disease Characteristics

#### Baseline Demographics 

Baseline demographic characteristics for each of the 3 trials are
summarized in Table 8. Mean treatment group ages at enrollment ranged
from 64.4 and 64.5 years (Trial 23) to 68.6 and 68.7 years (Trial 24).
Individual patient ages ranged from 38 years to 93 years. Mean treatment
group weights ranged from 77.3 and 78.1 kg in Trial 24 to 85.4 and 84.6
kg in Trial 23.

##### Medical Officer\'s Comments {#medical-officers-comments-9 .unnumbered}

-   Within each trial, demographic characteristics in the Casodex and
    placebo treatment groups were well balanced. In general, demographic
    characteristics across Trials 24 and 25 were very similar but
    differed somewhat from those in Trial 23.

-   Patients in Trial 23 tended to be younger (mean difference about 4
    years) than those in Trials 24 and 25. Approximately 45% of patients
    in Trial 23 were less than 65 years old compared to approximately
    25% of patients (Trial 24) or \<20% of patients (Trial 25).

-   The mean weights of patients in Trial 23 were approximately 4-6 kg
    greater than those of patients in Trials 24 and 25.

-   Approximately 11.5% of patients in Trial 23 were black in contrast
    to \< 1% and 0% in Trials 24 and 25, respectively.

[]{#__RefHeading___Toc25309668 .anchor}Table 8 Baseline Demographic
Characteristics (Trials 23, 24, and 25)

  ------------------ ------------ -- -------- ------------ -------- ------------ -------- ------------ -------- ------------ -------- ------------ --------
  **Demographic      **Trial 23**                                   **Trial 24**                                **Trial 25**                       
  Characteristic**                                                                                                                                 

                     **Casodex\               **Placebo\            **Casodex\            **Placebo\            **Casodex\            **Placebo\   
                     **(N=1647)               **(N=1645)            **(N=1798)            **(N=1805)            **(N=607)             **(N=611)    

  Age (yr.)                                                                                                                                        

  Mean               64.5                     64.4                  68.6                  68.7                  68.5                  68.5         

  Range              42 to 85                 38 to 83              42 to 93              46 to 93              46 to 87              52 to 77     

  Age Distribution                                                                                                                                 
  (n,%)                                                                                                                                            

  \<55 yr.           151             (9.2)    155          (9.4)    62           (3.4)    51           (2.8)    10           (1.6)    4            (0.7)

  55 to \< 65 yr.    614             (37.3)   607          (36.9)   422          (23.5)   432          (23.9)   99           (16.3)   113          (18.5)

  65 to \<75 yr.     780             (47.4)   785          (47.7)   936          (52.1)   934          (51.7)   475          (78.3)   468          (76.6)

  75 yr.             102             (6.2)    98           (6.0)    378          (21.0)   388          (21.5)   23           (3.8)    26           (4.3)

  Weight (kg)                                                                                                                                      

  Mean               85.38                    84.60                 77.28                 78.08                 79.31                 80.61        

  Range              49 to 166                46 to 160             45 to 132             40 to 135             46 to 143             48 to 125    

  Race (n, %)                                                                                                                                      

  White              1369            (83.1)   1391         (84.6)   1714         (95.3)   1709         (94.7)   606          (99.8)   607          (99.3)

  Black              191             (11.6)   188          (11.4)   17           (0.9)    13           (0.7)    0                     0            

  Other              87              (5.3)    66           (4.0)    67           (3.7)    83           (4.6)    1            (0.2)    4            (0.7)
  ------------------ ------------ -- -------- ------------ -------- ------------ -------- ------------ -------- ------------ -------- ------------ --------

Source: Text table 4, pg. 29, ISE.

#### Baseline Disease Characteristics

Baseline disease characteristics (other than serum PSA values) in each
of the 3 trials are summarized in Table 9. The distribution of disease
characteristics is expressed in terms of percentage of patients with the
specific characteristic in each category. Within each of the individual
trials, baseline disease characteristics were well balanced across the
Casodex and placebo treatment groups. In each of the trials, more than
50% of patients had Stage T1/T2 disease (early or localized disease). A
slightly greater percentage of patients in Trial 24 (approximately 35%)
and Trial 25 (approximately 40%) had Stage T3/T4 disease (locally
advanced disease) than in Trial 23 (less than 30%). Based on reported
Gleason scores, a greater percentage of patients in Trial 23 (47-48%)
had poorly differentiated tumors (Gleason scores of 7-10) than in either
Trial 24 (26-27%) or Trial 25 (11-12%). In accordance with the inclusion
criteria for Trial 23, all patients had received prior therapy of
curative intent with approximately 80% of patients having had a radical
prostatectomy. In contrast, 35-37% of patients in Trial 24 and 80-83% of
patients in Trial 25 were being managed by watchful waiting (i.e., had
not had therapy) prior to randomization.

[]{#__RefHeading___Toc25309669 .anchor}Table 9 Disease Characteristics
at Baseline

  ---------------------- ------------ ---------- ---------- ---------- --------- ---------
                         Percentage                                              
                         of patients                                             
                         within each                                             
                         category                                                

  **Characteristic**     Study 23                Study 24              Study 25  

                         Casodex      Placebo    Casodex    Placebo    Casodex   Placebo

                         (N=1647)     (N=1645)   (N=1798)   (N=1805)   (N=607)   (N=611)

  **Tumor stage: T                                                               
  category**                                                                     

  T1                     9.6          9.7        25.5       25.2       19.8      22.4

  T2                     62.7         63.2       38.8       41.1       39.7      38.1

  T3                     27.4         26.9       33.2       31.2       38.9      37.0

  T4                     0.2          0.2        2.6        2.5        1.5       2.3

  **Gleason score**                                                              

  Well differentiated    4.2          4.8        31.0       31.2       42.7      43.2
  (2,3,4)                                                                        

  Moderately             47.9         48.5       40.5       41.1       43.7      45.2
  differentiated (5,6)                                                           

  Poorly differentiated  47.9         46.7       26.7       26.1       11.9      11.1
  (7,8,9,10)                                                                     

  **Lymph node                                                                   
  category**                                                                     

  N-                     72.0         71.2       61.3       60.4       21.7      20.0

  N+                     0.1          0.0        2.6        2.7        4.6       4.3

  NX                     27.9         28.8       36.0       36.9       73.6      75.8

  **Previous therapy**                                                           

  Radical prostatectomy  80.3         80.5       46.4       45.0       13.0      13.1

  Radiotherapy only      19.7         19.5       18.6       18.0       6.4       4.3

  Watchful waiting       0.0          0.0        34.9       36.9       80.1      82.7
  ---------------------- ------------ ---------- ---------- ---------- --------- ---------

> Source: Text table 5, pg. 30, ISE

Median serum PSA concentrations, both prior to prostatectomy or
radiation therapy in patients who had had prior active therapy and at
the time of randomization in all patients, are listed in Table 10 for
each of the trials. Median serum PSA values prior to prostatectomy or
radiation ranged from 7.1 g/L in Trial 23 to 17.0 g/L in Trial 25.
Median pre-randomization serum PSA values were lowest in patients who
had been treated by radical prostatectomy (median range: below the limit
of detection \[NQ, Trials 23 and 24\] to 1.2 g/L \[Trial 25\]) and
highest in patients managed by watchful waiting (median range: 11.0 g/L
\[Trial 24\] to 17.8 g/L \[Trial 25\]). Within each initial treatment
group, median serum PSA concentrations at randomization tended to be
lowest in Trial 23 (or Trial 24 for watchful waiting patients) and
highest in Trial 25.

[]{#__RefHeading___Toc25309670 .anchor}Table 10 Serum PSA (Prior to
Prostatectomy or Radiotherapy and/or at Randomization)

+--------------------+-------+-------+-------+-------+-------+-------+
| > Time of          | **    |       | **    |       | **    |       |
| > Measurement or   | Trial |       | Trial |       | Trial |       |
| >                  | 23**  |       | 24**  |       | 25**  |       |
|  Pre-randomization |       |       |       |       |       |       |
| > Group            |       |       |       |       |       |       |
+--------------------+-------+-------+-------+-------+-------+-------+
|                    | Ca    | Pl    | Ca    | Pl    | Ca    | Pl    |
|                    | sodex | acebo | sodex | acebo | sodex | acebo |
+--------------------+-------+-------+-------+-------+-------+-------+
| ***PSA (g/L) prior |       |       |       |       |       |       |
| to prostatectomy   |       |       |       |       |       |       |
| or radiation       |       |       |       |       |       |       |
| therapy***         |       |       |       |       |       |       |
+--------------------+-------+-------+-------+-------+-------+-------+
| > Number patients  | 1578  | 1581  | 1152  | 1122  | 109   | 99    |
| > ^1^              |       |       |       |       |       |       |
+--------------------+-------+-------+-------+-------+-------+-------+
| > ***Median PSA*** | ***7  | ***7  | ***12 | ***11 | ***17 | ***16 |
|                    | .1*** | .1*** | .0*** | .5*** | .0*** | .0*** |
+--------------------+-------+-------+-------+-------+-------+-------+
| ***PSA (g/L) at    |       |       |       |       |       |       |
| time of            |       |       |       |       |       |       |
| randomization***   |       |       |       |       |       |       |
+--------------------+-------+-------+-------+-------+-------+-------+
| > Prostatectomy    |       |       |       |       |       |       |
| > patients         |       |       |       |       |       |       |
+--------------------+-------+-------+-------+-------+-------+-------+
| > Number patients  | 1312  | 1316  | 800   | 795   | 78    | 78    |
+--------------------+-------+-------+-------+-------+-------+-------+
| > ***Median PSA*** | ***NQ | ***   | ***   | ***   | ***1  | ***1  |
|                    | ^     | NQ*** | NQ*** | NQ*** | .2*** | .1*** |
|                    | 2^*** |       |       |       |       |       |
+--------------------+-------+-------+-------+-------+-------+-------+
| > Radiotherapy     |       |       |       |       |       |       |
| > patients         |       |       |       |       |       |       |
+--------------------+-------+-------+-------+-------+-------+-------+
| > Number patients  | 323   | 317   | 330   | 310   | 39    | 25    |
+--------------------+-------+-------+-------+-------+-------+-------+
| > ***Median PSA*** | ***2  | ***3  | ***3  | ***3  | ***8  | ***8  |
|                    | .9*** | .0*** | .5*** | .4*** | .2*** | .0*** |
+--------------------+-------+-------+-------+-------+-------+-------+
| > Watchful waiting |       |       |       |       |       |       |
| > patients         |       |       |       |       |       |       |
+--------------------+-------+-------+-------+-------+-------+-------+
| > Number patients  | 0     | 0     | 604   | 642   | 483   | 497   |
+--------------------+-------+-------+-------+-------+-------+-------+
| > ***Median PSA*** | ***\  | ***\  | ***11 | ***11 | ***16 | ***17 |
|                    | --*** | --*** | .0*** | .6*** | .6*** | .8*** |
+--------------------+-------+-------+-------+-------+-------+-------+
| > All treatments   |       |       |       |       |       |       |
| > (all patients)   |       |       |       |       |       |       |
+--------------------+-------+-------+-------+-------+-------+-------+
| > Number patients  | 1635  | 1633  | 1734  | 1748  | 603   | 600   |
+--------------------+-------+-------+-------+-------+-------+-------+
| > ***Median PSA*** | ***   | ***   | ***1  | ***1  | ***12 | ***13 |
|                    | NQ*** | NQ*** | .3*** | .3*** | .6*** | .8*** |
+--------------------+-------+-------+-------+-------+-------+-------+

1\. Number of patients for whom PSA values were available.

2\. NQ = non quantifiable (i.e., below the minimal detectable value).

Source: Text table 7, pg. 32, ISE.

##### Medical Officer\'s Comments {#medical-officers-comments-10 .unnumbered}

-   Within each of the individual trials, baseline disease
    characteristics were well balanced across the Casodex and placebo
    treatment groups although there were significant differences across
    the 3 trials, particularly between Trial 23 and Trials 24 and 25.

-   The most surprising difference between Trial 23 and Trials 24 and 25
    was the low percentage of patients in Trials 24 and 25 with poorly
    differentiated tumors (Gleason grades of 7-10). Based on the
    observed incidence of positive bone scans at Study Year 2 (higher in
    Trials 24 and 25 than in Trial 23), one would have anticipated a
    higher percentage of poorly differentiated tumors in Trials 24 and
    25 than in Trials 23.

-   Trials 24 and 25, but not Trial 23, allowed the enrollment of
    patients who were being managed by watchful waiting. Although it is
    estimated that 10% or less of men with prostate cancer in the United
    States are managed by watchful waiting, this is a more frequently
    employed therapeutic option in other countries. In Trials 24 and 25,
    approximately 35% and 80% of patients, respectively, were initially
    managed by watchful waiting and received only Casodex monotherapy
    for treatment of their prostate cancer.

### Primary Efficacy Outcomes

In the following Section on primary efficacy outcomes, the Sponsor's
preferred endpoints and the outcomes related to these endpoints are
first presented and reviewed. This is followed by presentation and
review of the efficacy outcomes based on the FDA-requested endpoints and
analyses. The FDA-requested analyses were performed, for the most part,
by the Sponsor.

#### Objective Disease Progression or Death in Absence of Progression (Sponsor's Preferred Endpoints and Analyses)

Objective disease progression or death in the absence of objective
progression in each of the clinical trials is summarized in Table 11.
This Table lists by trial and treatment group the total number (%) of
patients with (1) a positive bone, (2) other objective events classified
as disease progression by the Sponsor, and (3) death in the absence of
objective progression. The percentage of patients with bone scan
confirmed objective evidence of disease progression was lowest in Trial
23, intermediate in Trial 24, and highest in Trial 25. In each of Trials
24 and 25, the percentage of patients with either (1) a positive bone
scan or (2) other objective events of disease progression was
numerically lower in the Casodex treatment group compared to the placebo
group. In Trial 23, there were no differences between the Casodex and
placebo treatment groups in the proportions of patients with disease
progression.

[]{#__RefHeading___Toc25309671 .anchor}Table 11 Objective Disease
Progression or Death in Trials 23, 24, and 25

  -------------- ---------- -------- ---- ----------- ---------- -------- ----------- ---------- ------------ --------- ---------- ------------ -------- ---------- ------------ --------- ---------- ------------
                 Number                                                                                                                                                                               
                 (per cent)                                                                                                                                                                           
                 of                                                                                                                                                                                   
                 patients                                                                                                                                                                             
                 with event                                                                                                                                                                           
                 ^1^                                                                                                                                                                                  

  Event          Study 23                                                             Study 24                                                           Study 25                                     

                 Casodex\                             Placebo\                        Casodex\                          Placebo\                         Casodex\                          Placebo\   
                 (N = 1647)                           (N = 1645)                      (N = 1798)                        (N = 1805)                       (N = 607)                         N = 611)   

  Positive bone             21            (1.3)                  15       (0.9)       60         (3.3)        116                  (6.4)        32                  (5.3)        95                   (15.5)
  scan                                                                                                                                                                                                

  Other                              10   (0.6)                  17       (1.0)       25         (1.4)        85                   (4.7)        19                  (3.1)        40                   (6.5)
  objective                                                                                                                                                                                           
  events ^2^                                                                                                                                                                                          

  Death in                  52            (3.2)                  55       (3.3)       96         (5.3)        92                   (5.1)        48                  (7.9)        44                   (7.2)
  absence of                                                                                                                                                                                          
  progression                                                                                                                                                                                         

  **Total (%)               **83**        **(5.0)**              **87**   **(5.3)**   **181**    **(10.1)**   **293**              **(16.2)**   **99**              **(16.3)**   **179**              **(29.3)**
  Patients**                                                                                                                                                                                          
  -------------- ---------- -------- ---- ----------- ---------- -------- ----------- ---------- ------------ --------- ---------- ------------ -------- ---------- ------------ --------- ---------- ------------

1\. Based on Sponsor's preferred endpoints.

2\. Other objectively confirmed progression (documented by magnetic
resonance imaging, computerized tomography, sonography, or biopsy).

Source: Table T4.1, ISE.

##### Medical Officer\'s Comments {#medical-officers-comments-11 .unnumbered}

-   Disease progression documented by a positive bone scan in a patient
    with a bone scan that was previously negative is a more reliable
    indicator of clinically significant disease progression than the
    category of "other objective events." This latter category includes
    objectively confirmed local events that may have less significance
    as a prognostic sign than the appearance of new bone metastases.

-   In Trial 23, the proportion of patients with events considered to
    reflect progression of disease or death in the absence of
    progression was very low in both the Casodex and placebo treatment
    groups. There was no evidence that treatment with Casodex offered
    any clinical benefit in this Trial.

-   The Sponsor stated that the low incidence of progressive disease
    events in Trial 23 was not surprising based on the baseline disease
    characteristics of the patients. The Sponsor noted that patients in
    Trial 23, compared to those in Trials 24 and 25, were younger by
    about 4 years, weighed more (5-7 kg), had lower preprocedure serum
    PSA values, and all had had prior therapy of curative intent.
    However, a higher proportion of patients in Trials 24 and 25 had
    Stage T1 disease and well differentiated tumors (based on Gleason
    scores) than patients in Trial 23.

-   Although Casodex treatment reduced the proportion of patients with
    positive bone scans and other objective events of progression in
    Trials 24 and 25, it did not reduce the proportion of patients who
    died of any cause in the absence of progression. Overall survival
    and death specifically due to prostate cancer in each of the trials
    is discussed in Section 4.6.3.9 .

The Sponsor's primary analyses of time to disease progression (TTP) for
each of the individual trials and the trials combined are presented in
Table 12. Hazard ratios were 0.933 (Trial 23), 0.477 (Trial 24), 0.430
(Trial 25), and 0.509 (combined analysis). All hazard ratios, other than
that for Trial 23 were highly statistically significant (p \< 0.0001).

[]{#__RefHeading___Toc25309672 .anchor}Table 12 Time to Objective
Progression or Death in Absence of Progression

  ------------- ------------- -------- ---------- -------- ---------- ------------ ----------
  **Study**     **Number (%)                               **Hazard   **95%        **P
                of patients                                ratio      confidence   value**
                with event\                                ^1^**      interval**   
                (objective                                                         
                progression                                                        
                or death)**                                                        

                Casodex                Placebo                                     

                Number        (%)      Number     (%)                              

  23            83/1647       (5.0)    87/1645    (5.3)    0.933      0.691 to     0.653
                                                                      1.261        

  24            181/1798      (10.1)   293/1805   (16.2)   0.574      0.477 to     \<0.0001
                                                                      0.692        

  25            99/607        (16.3)   179/611    (29.3)   0.430      0.336 to     \<0.0001
                                                                      0.552        

  Combined      363/4052      (9.0)    559/4061   (13.8)   0.581      0.509 to     \<0.0001
  Data\                                                               0.663        
  (Trials                                                                          
  23+24+25)                                                                        
  ------------- ------------- -------- ---------- -------- ---------- ------------ ----------

1\. Based on Sponsor's preferred endpoints and analyses.

Source: Table T4.2, ISE.

##### Medical Officer's Comments {#medical-officers-comments-12 .unnumbered}

-   Combining data from Trial 23 with that from Trials 24 and 25 is not
    appropriate. Based on the baseline disease characteristics for the
    patients in each of the 3 trials, the study population in Trial 23
    was clearly different from those in Trials 24 and 25.

-   The Sponsor attributes the apparent absence of a beneficial effect
    of treatment with Casodex in Trial 23 to (1) the immaturity of the
    data for this trial and (2) the relatively better prognostic factors
    for these patients at the time of randomization into the Trial.

Objective disease progression or death in the absence of progression
based on pre-randomization treatment (radical prostatectomy, radiation
therapy, or watchful waiting) is summarized in Table 13. Data have been
combined across the 3 clinical trials in the sponsor's analysis that is
presented in the Table. Based on this combined analysis, the proportions
of patients exhibiting progression based on either a positive bone scan
or other objective events were numerically lower both in patients who
had had prior therapy and in those who had not had prior therapy
(watchful waiting treatment group). There was no effect of treatment on
the proportion of patients who experienced death in the absence of
disease progression.

[]{#__RefHeading___Toc25309673 .anchor}Table 13 Objective Disease
Progression or Death in Absence of Progression Based on
Pre-randomization Treatment (Data for Trials 23, 24, and 25 Combined)

  -------------- --------------- --------- ---- ----------- --------- ---------- ---- ----------- -------------- ------------ ---------- --------- ------------ --------- ---------- ------------ ---------- ------------
                 Number (per                                                                                                                                                                                 
                 cent) of                                                                                                                                                                                    
                 patients with                                                                                                                                                                               
                 event ^1^                                                                                                                                                                                   

  Event          Radical                                                                          Radiotherapy                                                            Watchful                           
                 Prostatectomy                                                                                                                                            Waiting                            

                 Casodex\                                             Placebo\                    Casodex\                    Placebo\                                    Casodex\                Placebo\   
                 (N = 2236)                                           (N = 2218)                  (N = 699)                   (N = 671)                                   (N = 1114)              N = 1171)  

  Positive bone                  33             (1.5)                            58   (2.6)       28             (4.0)                   45        (6.7)        51                   (4.6)        123        (10.5)
  scan                                                                                                                                                                                                       

  Other                                    22   (1.0)       58                        (2.6)       11             (1.6)                   20        (3.0)        21                   (1.9)        64         (5.5)
  objective                                                                                                                                                                                                  
  events ^2^                                                                                                                                                                                                 

  Death in                       60             (2.7)       54                        (2.4)       36             (5.2)                   38        (5.7)        100                  (9.0)        99         (8.5)
  absence of                                                                                                                                                                                                 
  progression                                                                                                                                                                                                

  **Total (%)                    **115**        **(5.1)**   **170**                   **(7.7)**   **75**         **(10.7)**              **103**   **(15.4)**   **172**              **(15.4)**   **286**    **(24.4)**
  Patients**                                                                                                                                                                                                 
  -------------- --------------- --------- ---- ----------- --------- ---------- ---- ----------- -------------- ------------ ---------- --------- ------------ --------- ---------- ------------ ---------- ------------

1\. Based on Sponsor's preferred endpoints.

2\. Other objectively confirmed progression (documented by magnetic
resonance imaging, computerized tomography, sonography, or biopsy).

Source: Table T4.4, ISE.

The Sponsor's analyses of time to progression in the radical
prostatectomy, radiation therapy, and watchful waiting treatment groups
(data combined across the 3 trials) are summarized in Table 14. Hazard
ratios ranged from 0.53 (watchful waiting group) to 0.63 (adjuvant
treatment groups).

[]{#__RefHeading___Toc25309674 .anchor}Table 14 Time to Objective
Progression or Death (Trials 23, 24, and 25 Combined)

+-------------------+-------+------+--------+------+-----+---------+
| **Patient         | **N   |      |        |      | **  | **95%   |
| Subgroup**        | umber |      |        |      | Haz | con     |
|                   | (%)   |      |        |      | ard | fidence |
|                   | of    |      |        |      | ra  | int     |
|                   | pat   |      |        |      | tio | erval** |
|                   | ients |      |        |      | ^1  |         |
|                   | with  |      |        |      | ^** |         |
|                   | e     |      |        |      |     |         |
|                   | vent\ |      |        |      |     |         |
|                   | (obje |      |        |      |     |         |
|                   | ctive |      |        |      |     |         |
|                   | p     |      |        |      |     |         |
|                   | rogre |      |        |      |     |         |
|                   | ssion |      |        |      |     |         |
|                   | or    |      |        |      |     |         |
|                   | dea   |      |        |      |     |         |
|                   | th)** |      |        |      |     |         |
+-------------------+-------+------+--------+------+-----+---------+
|                   | Ca    |      | P      |      |     |         |
|                   | sodex |      | lacebo |      |     |         |
+-------------------+-------+------+--------+------+-----+---------+
|                   | N     | (%)  | Number | (%)  |     |         |
|                   | umber |      |        |      |     |         |
+-------------------+-------+------+--------+------+-----+---------+
| All adjuvant      | 190   | (    | 27     | (    | 0   | 0.52 to |
| patients          | /2935 | 6.5) | 3/2889 | 9.4) | .63 | 0.76    |
+-------------------+-------+------+--------+------+-----+---------+
| > Radical         | 115   | (    | 17     | (    | 0   | 0.50 to |
| > prostatectomy   | /2236 | 5.1) | 0/2218 | 7.7) | .63 | 0.80    |
| > patients        |       |      |        |      |     |         |
+-------------------+-------+------+--------+------+-----+---------+
| > Radiotherapy    | 7     | (1   | 1      | (1   | 0   | 0.46 to |
| > patients        | 5/699 | 0.7) | 03/671 | 5.4) | .63 | 0.85    |
+-------------------+-------+------+--------+------+-----+---------+
| All watchful      | 172   | (1   | 28     | (2   | 0   | 0.44 to |
| waiting           | /1114 | 5.4) | 6/1171 | 4.4) | .53 | 0.64    |
| patients^2^       |       |      |        |      |     |         |
+-------------------+-------+------+--------+------+-----+---------+

1\. Based on Sponsor's preferred endpoints and analyses.

2\. Includes only patients from Trials 24 and 25.

Source: Table T4.13, ISE.

##### Medical Officer's Comments {#medical-officers-comments-13 .unnumbered}

-   Combined analyses that merge data from Trial 23 with that from
    Trials 24 and 25 are not appropriate because of clinically
    significant differences in baseline disease characteristics.
    However, certain conclusions can still be made from these analyses.

-   Based on all objective events of disease progression (as defined by
    the Sponsor's protocol), treatment with Casodex appears to have
    statistically reduced the proportion of patients who had disease
    progression in both the adjuvant and watchful waiting treatment
    groups in Trials 24 and 25. This observation, however, cannot be
    extrapolated to patients in Trial 23. In Trial 23, there was no
    evidence that treatment with Casodex offered any clinical benefit.

At the request of the Medical Reviewer, the Sponsor provided additional
subset analyses for Trial 24 (Table 15) and Trial 25 (Table 16). In each
of the subgroups (radical prostatectomy, radiotherapy, and watchful
waiting) in Trial 24 and Trial 25, the proportion of patients with
disease progression was numerically lower in the Casodex-treated
patients.

[]{#__RefHeading___Toc25309675 .anchor}Table 15 Objective Disease
Progression or Death in Absence of Progression in Subgroups Based on
Pre-randomization Treatment (Trial 24)

  -------------- --------------- -------- ---- ----------- -------- ---------- ---- ------------ -------------- ------------ ---------- -------- ------------ -------- ---------- ------------ ---------- ------------
                 Number (per                                                                                                                                                                              
                 cent) of                                                                                                                                                                                 
                 patients with                                                                                                                                                                            
                 event ^1^                                                                                                                                                                                

  Event          Radical                                                                         Radiotherapy                                                          Watchful                           
                 Prostatectomy                                                                                                                                         Waiting                            

                 Casodex\                                           Placebo\                     Casodex\                    Placebo\                                  Casodex\                Placebo\   
                 (N = 835)                                          (N = 813)                    (N = 335)                   (N = 325)                                 (N = 628)               (N = 666)  

  Positive bone                  17            (2.0)                           36   (4.4)        17             (5.1)                   32       (9.8)        26                  (4.1)        48         (7.2)
  scan                                                                                                                                                                                                    

  Other                                   14   (1.7)       42                       (5.2)        4              (1.2)                   15       (4.6)        7                   (1.1)        28         (4.2)
  objective                                                                                                                                                                                               
  events ^2^                                                                                                                                                                                              

  Death in                       21            (2.5)       21                       (2.6)        14             (4.2)                   12       (3.7)        61                  (9.7)        59         (8.9)
  absence of                                                                                                                                                                                              
  progression                                                                                                                                                                                             

  **Total (%)                    **52**        **(6.2)**   **99**                   **(12.2)**   **35**         **(10.4)**              **59**   **(18.2)**   **94**              **(15.0)**   **135**    **(20.3)**
  Patients**                                                                                                                                                                                              
  -------------- --------------- -------- ---- ----------- -------- ---------- ---- ------------ -------------- ------------ ---------- -------- ------------ -------- ---------- ------------ ---------- ------------

1\. Based on Sponsor's preferred endpoints

2\. Other objectively confirmed progression (documented by magnetic
resonance imaging, computerized tomography, sonography, or biopsy).

Source: Submission of April 3, 2002, Appendix 1.

[]{#__RefHeading___Toc25309676 .anchor}Table 16 Objective Disease
Progression or Death in Absence of Progression in Subgroups Based on
Pre-randomization Treatment (Trial 25)

  -------------- --------------- ------- --- ------------ -------- ---------- ---- ------------ -------------- ------------ ---------- -------- ------------ -------- ---------- ------------ ---------- ------------
                 Number (per                                                                                                                                                                             
                 cent) of                                                                                                                                                                                
                 patients with                                                                                                                                                                           
                 event ^1^                                                                                                                                                                               

  Event          Radical                                                                        Radiotherapy                                                          Watchful                           
                 Prostatectomy                                                                                                                                        Waiting                            

                 Casodex\                                          Placebo\                     Casodex\                    Placebo\                                  Casodex\                Placebo\   
                 (N = 79)                                          (N = 80)                     (N = 39)                    (N = 26)                                  (N = 486)               (N = 505)  

  Positive bone                  2           (2.5)                            11   (13.8)       4              (10.3)                  9        (34.6)       25                  (5.1)        75         (14.9)
  scan                                                                                                                                                                                                   

  Other                                  1   (1.3)        3                        (3.8)        4              (10.3)                  1        (3.8)        14                  (2.9)        36         (7.1)
  objective                                                                                                                                                                                              
  events ^2^                                                                                                                                                                                             

  Death in                       5           (6.3)        1                        (1.3)        4              (10.3)                  3        (11.5)       39                  (8.0)        40         (7.9)
  absence of                                                                                                                                                                                             
  progression                                                                                                                                                                                            

  **Total (%)                    **8**       **(10.1)**   **15**                   **(18.8)**   **12**         **(30.8)**              **13**   **(50.0)**   **78**              **(16.0)**   **151**    **(29.9)**
  Patients**                                                                                                                                                                                             
  -------------- --------------- ------- --- ------------ -------- ---------- ---- ------------ -------------- ------------ ---------- -------- ------------ -------- ---------- ------------ ---------- ------------

1\. Based on Sponsor's preferred endpoints.

2\. Other objectively confirmed progression (documented by magnetic
resonance imaging, computerized tomography, sonography, or biopsy).

Source: Submission of April 3, 2002, Appendix 1.

Estimates of the hazard ratios (and 95% confidence limits) for the
differences between the time to disease progression in the
Casodex-treated and placebo-treated patients are provided in Table 17.
Hazard ratios ranged from 0.423 (watchful waiting patients in Trial 25)
to 0.674 (watchful waiting patients in Trial 24).

[]{#__RefHeading___Toc25309677 .anchor}Table 17 Hazard Ratios for
Objective Disease Progression or Death (Any Cause) in Subgroups based on
Pre-randomization Treatment (Trials 24 and 25)

  -------- --------------- ------------ -------- ---------- ---------- ---------- ------- ------------
  Trial    Previous        Randomized   Number   Number of  \%         Estimate           95%\
  Number   Treatment       Treatment    of       patients   patients   of hazard          confidence
                                        events              with event ratio ^1^          limits

  24       Radical         Casodex      52       835        6.2%                          
           prostatectomy                                                                  

                           Placebo      99       814        12.2%      0.463      0.331   
                                                                                  to      
                                                                                  0.649   

           Radiotherapy    Casodex      35       335        10.4%                         

                           Placebo      59       325        18.2%      0.564      0.370   
                                                                                  to      
                                                                                  0.860   

           Watchful        Casodex      94       628        15.0%                         
           waiting                                                                        

                           Placebo      135      666        20.3%      0.674      0.518   
                                                                                  to      
                                                                                  0.878   

  25       Radical         Casodex      9        82         11.0%                         
           prostatectomy                                                                  

                           Placebo      15       80         18.8%      0.530      0.230   
                                                                                  to      
                                                                                  1.220   

           Radiotherapy    Casodex      12       39         30.8%                         

                           Placebo      13       26         50.0%      0.436      0.194   
                                                                                  to      
                                                                                  0.979   

           Watchful        Casodex      78       486        16.0%                         
           waiting                                                                        

                           Placebo      151      505        29.9%      0.423      0.321   
                                                                                  to      
                                                                                  0.557   
  -------- --------------- ------------ -------- ---------- ---------- ---------- ------- ------------

1\. Based on Sponsor's preferred endpoints and analyses.

Source: Submission of 3 April 2002 Appendix 2.

##### Medical Officer\'s Comments {#medical-officers-comments-14 .unnumbered}

-   Although these were exploratory subgroup analyses, the outcomes were
    consistent in that all of them suggested that treatment with Casodex
    reduced the proportion of patients with disease progression (as
    defined by the Sponsor) and delayed disease progression. However,
    there was no suggestion that treatment with Casodex improved
    disease-specific survival or overall survival (see Section 4.6.3.9).

-   These subgroup analyses support the sponsor's contention that the
    overall positive treatment effect of Casodex in Trial 24 and Trial
    25 was not entirely dependent on the findings in the watchful
    waiting patients.

-   These positive finding, however, do not address the questions of (1)
    relevance of these findings to US patients, (2) the clinical
    significance of "objective progression" that was not documented by a
    positive bone scan, and (3) potential assessment bias due to the
    likely unblinding of treatment assignment in many patients.

#### Efficacy Outcomes (FDA-Requested Endpoints and Analyses)

As discussed earlier in Section 4.5.3.3, the Division of Reproductive
and Urologic Drug Products (DRUDP) was concerned about the possibility
of assessment bias in a time-to-event analysis because treatment
blinding could not assured; consequently, DRUDP requested that the
efficacy outcomes be evaluated by means of a binary analysis based on
the proportion of patients with bone scan confirmed progression ***at 2
years*** or death in the absence of disease progression. The Sponsor
provided the requested analyses as well as a slightly modified analysis
bone scan confirmed progression or death in the absence of progression
***within 2.5 years of randomization***. Findings based on this latter
analysis are presented in the remainder of this section.

Table 18 lists the number and percentage of patients with bone scan
confirmed progression or death in the absence of progression within 2.5
years of randomization in each of the trials. In Trial 23, there was no
evidence of a significant reduction in the proportion of patients with
disease progression or death in the Casodex group (2.4%) compared to the
placebo group (2.9%). In each of Trials 24 and 25, the proportion of
patients with disease progression or death was lower in the Casodex
group compared to the placebo group (Trial 24: 6.2% vs. 9.3%; Trial 25:
10.4% vs. 17.2%).

[]{#__RefHeading___Toc25309678 .anchor}Table 18 Bone Scan Confirmed
Disease Progression or Death in the Absence of Progression within 2.5
Years after Randomization

  -------------- ---- ---------- -------- ----------- ---------- -------- ----------- --------- ---------- ----------- --------- ---------- ----------- -------- ---------- ------------ --------- ---------- ------------
                      Number                                                                                                                                                                                  
                      (per cent)                                                                                                                                                                              
                      of                                                                                                                                                                                      
                      patients                                                                                                                                                                                
                      with event                                                                                                                                                                              
                      ^1^                                                                                                                                                                                     

  Event               Study 23                                                                  Study 24                                                         Study 25                                     

                      Casodex\                        Placebo\                                  Casodex\                         Placebo\                        Casodex\                          Placebo\   
                      (N = 1647)                      (N = 1645)                                (N = 1798)                       (N = 1805)                      (N = 607)                         N = 611)   

  Positive bone  14                       (0.9)                  11       (0.7)       42                   (2.3)       98                   (5.4)       22                  (3.6)        72                   (11.8)
  scan                                                                                                                                                                                                        

  Death in       25                       (1.5)                  37       (2.2)       70                   (3.9)       70                   (3.9)       41                  (6.8)        33                   (5.4)
  absence of                                                                                                                                                                                                  
  progression                                                                                                                                                                                                 

  **Total (%) of                 **39**   **(2.4)**              **48**   **(2.9)**   **112**              **(6.2)**   **168**              **(9.3)**   **63**              **(10.4)**   **105**              **(17.2)**
  patients**                                                                                                                                                                                                  
  -------------- ---- ---------- -------- ----------- ---------- -------- ----------- --------- ---------- ----------- --------- ---------- ----------- -------- ---------- ------------ --------- ---------- ------------

1\. Based on FDA-requested endpoints.

Source: Table A4, pg. A56-A58, ISE.

##### Medical Officer\'s Comments {#medical-officers-comments-15 .unnumbered}

-   This medical reviewer concurs with the Sponsor's rationale for
    recommending the use of the analysis based on events that occurred
    within 2.5 years of randomization and not just those that occurred
    at 2 years. (See Section 4.5.3.3 for the basis for this opinion).

-   The findings summarized in Table 18 are based on the FDA-requested
    endpoints and binary analysis and are less likely to be affected by
    assessment bias than a time-to-event analysis. The events listed in
    the Table also do not include disease progression based on local
    changes or non-osseous findings that may be of limited clinical
    significance.

The estimates of the odds ratio (and 95% confidence limit) for disease
progression in Casodex-treated patients compared to placebo-treated
patients for each of Trials 23, 24, and 25, based on the requested FDA
analysis, are listed in Table 19.

[]{#__RefHeading___Toc25309679
.anchor}^Table\ 19\ Odds\ Ratios\ for\ Bone\ Scan\ Confirmed\ Progression\ or\ Death\ in\
Absence\ of\ Progression\ within\ 2.5\ Years\ after\ Randomization^

  --------- ----------- -------- ---------- ---------- ---------- -----------------
  Trial     Treatment   No. of   No. of     \%         Estimate   95% confidence
                        events   patients   patients   of Odds    limit
                                            with event Ratio^1^   

  23        Casodex     39       1647       2.4%                  

            Placebo     48       1645       2.9%       0.81 ^2^   0.52 to 1.24 ^1^

  24        Casodex     112      1798       6.2%                  

            Placebo     168      1803       9.3%       0.645      0.500 to 0.832

  25        Casodex     63       607        10.4%                 

            Placebo     105      611        17.2%      0.515      0.365 to 0.729
  --------- ----------- -------- ---------- ---------- ---------- -----------------

1 Based in FDA-requested endpoints and analyses.

2 Values for Trial 23 calculated by FDA statistician. Values for Trials
24 and 25 calculated by Sponsor.

Source: Submission of 17 May 2002, Appendix 2.

##### Medical Officer\'s Comments {#medical-officers-comments-16 .unnumbered}

-   Based on these analyses, it appears that the reductions in the
    proportion of patients with bone scan confirmed disease progression
    or death in the Casodex treatment groups in Trials 24 and 25 were
    statistically significant.

-   The actual reductions in the proportion of patients with disease
    progression or death, however, were relatively small and were 3.1%
    (Trial 24) and 6.8% (Trial 25).

-   The differences between the treatment groups are a result of a
    reduction in bone scan confirmed disease progression and not
    improved survival as shown by the data in Table 18 and Table 30 as
    discussed later in this review.

-   Because the studies are immature relative to anticipated survival
    with a median follow up of approximately 3 years, the long-term
    clinical significance of these modest reductions in bone scan
    confirmed disease progression is unknown at this time.

To obtain a more complete picture of which treatment subgroup(s) may
have derived benefit from treatment with Casodex, the Sponsor was asked
to provide additional subgroup analyses based on the patient's treatment
prior to randomization (i.e., radical prostatectomy, radiotherapy, or
management by watchful waiting). The descriptive analyses for each of
the trials are summarized in Table 20, Table 21, and Table 22. For each
of the trials, the proportion of patients with bone scan confirmed
disease progression or death from any cause in the absence of disease
progression was numerically lower in Casodex-treated patients in each of
the subgroups. For Trial 23, the reductions in total events in
Casodex-treated patients compared to placebo-treated patients were (1)
very small (0.3% in the prostatectomy subgroup; 1.6% in the radiotherapy
subgroup group), (2) based on a very small number of events, and (3)
were not related to a reduction in the proportion of patients with
positive bone scans.

[]{#__RefHeading___Toc25309680 .anchor}Table 20 Bone Scan Confirmed
Disease Progression or Death within 2.5 Years\
after Randomization (Trial 23: Prior Treatment Subgroups)

  ------------------- ----------------- -------- ---- ----------- -------- ---------- --- ----------- ------------------ ----------- ---------- -------- -----------
                      Number (per cent)                                                                                                                  
                      of patients with                                                                                                                   
                      event ^1,\ 2^                                                                                                                      

  **Event**           **Radical                                                                       **Radiotherapy**                                   
                      Prostatectomy**                                                                                                                    

                      Casodex\                                             Placebo\                   Casodex\                       Placebo\            
                      (N = 1322)                                           (N = 1325)                 (N = 325)                      (N = 320)           

  Positive bone scan                    10            (0.8)                           8   (0.6)       4                  (1.2)                  3        (0.9)

  Death (any cause)                              16   (1.2)       22                      (1.7)       9                  (2.8)                  15       (4.7)
  in absence of                                                                                                                                          
  progression                                                                                                                                            

  **Total (%)                           **26**        **(2.0)**   **30**                  **(2.3)**   **13**             **(4.0)**              **18**   **(5.6)**
  Patients**                                                                                                                                             
  ------------------- ----------------- -------- ---- ----------- -------- ---------- --- ----------- ------------------ ----------- ---------- -------- -----------

1\. Based on FDA-requested endpoints.

2\. Patients previously managed by watchful waiting were not eligible
for this Trial.

Source: Submission of 3 April 2002, Appendix 3.

[]{#__RefHeading___Toc25309681 .anchor}Table 21 Bone Scan Confirmed
Disease Progression or Death within 2.5 Years\
after Randomization (Trial 24: Prior Treatment Subgroups)

  -------------- ----------------- -------- ---- ----------- -------- ---------- ---- ----------- ------------------ ----------- ---------- -------- ------------ -------- ------------ ----------- ---------- ------------
                 Number (per cent)                                                                                                                                                                             
                 of patients with                                                                                                                                                                              
                 event ^1^                                                                                                                                                                                     

  **Event**      **Radical                                                                        **Radiotherapy**                                                         **Watchful                          
                 Prostatectomy**                                                                                                                                           Waiting**                           

                 Casodex\                                             Placebo\                    Casodex\                       Placebo\                                  Casodex\                 Placebo\   
                 (N = 835)                                            (N = 813)                   (N = 335)                      (N = 325)                                 (N = 628)                (N = 666)  

  Positive bone                    12            (1.4)                           27   (3.3)       11                 (3.3)                  28       (8.6)        19                    (3.0)       43         (6.5)
  scan                                                                                                                                                                                                         

  Death (any                                17   (2.0)       16                       (2.0)       13                 (3.9)                  8        (2.5)        40                    (6.4)       46         (6.9)
  cause) in                                                                                                                                                                                                    
  absence of                                                                                                                                                                                                   
  progression                                                                                                                                                                                                  

  **Total (%)                      **29**        **(3.5)**   **43**                   **(5.3)**   **24**             **(7.2)**              **36**   **(11.1)**   **59**                **(9.4)**   **89**     **(13.4)**
  Patients**                                                                                                                                                                                                   
  -------------- ----------------- -------- ---- ----------- -------- ---------- ---- ----------- ------------------ ----------- ---------- -------- ------------ -------- ------------ ----------- ---------- ------------

1\. Based on FDA-requested endpoints.

Source: Submission of 3 April 2002, Appendix 3.

[]{#__RefHeading___Toc25309682 .anchor}Table 22 Bone Scan Confirmed
Disease Progression or Death within 2.5 Years\
after Randomization (Trial 25: Prior Treatment Subgroups)

  -------------- ----------------- ------- --- ----------- ------- ---------- ------------ ------------------ ------------ ---------- ------- ------------ -------- ------------ ------------ ---------- ------------
                 Number (per cent)                                                                                                                                                                       
                 of patients with                                                                                                                                                                        
                 event ^1^                                                                                                                                                                               

  **Event**      **Radical                                                                 **Radiotherapy**                                                         **Watchful                           
                 Prostatectomy**                                                                                                                                    Waiting**                            

                 Casodex\                                          Placebo\                Casodex\                        Placebo\                                 Casodex\                  Placebo\   
                 (N = 79) ^2^                                      (N = 80)                (N = 39)                        (N = 26)                                 (N = 486)                 (N = 505)  

  Positive bone                    1           (1.3) ^3^           7          (8.8)        3                  (7.7)                   6       (23.1)       17                    (3.5)        59         (11.7)
  scan                                                                                                                                                                                                   

  Death (any                               5   (6.3)       1                  (1.3)        4                  (10.3)                  3       11.5)        32                    (6.6)        29         (5.7)
  cause) in                                                                                                                                                                                              
  absence of                                                                                                                                                                                             
  progression                                                                                                                                                                                            

  **Total (%)                      **6**       **(7.6)**   **8**              **(10.0)**   **7**              **(17.9)**              **9**   **(34.6)**   **49**                **(10.1)**   **88**     **(17.4)**
  Patients**                                                                                                                                                                                             
  -------------- ----------------- ------- --- ----------- ------- ---------- ------------ ------------------ ------------ ---------- ------- ------------ -------- ------------ ------------ ---------- ------------

1\. Based on FDA-requested endpoints.

2\. Does not include 3 patients who were initially treated by radical
prostatectomy followed by local radiotherapy.

3\. Does not include 1 patient who was initially treated by radical
prostatectomy followed by local radiotherapy.

Source: Submission of 3 April 2002, Appendix 3.

##### Medical Officer's Comments {#medical-officers-comments-17 .unnumbered}

-   The proportions of patients with bone scan confirmed disease
    progression in the placebo treatment groups in Trial 23 were \< 1%;
    consequently, there was no opportunity for Casodex to be of benefit
    as these patients, at the time of data cutoff, were essential free
    of metastatic disease.

-   Based on the findings in Trial 23, there are no data that suggest
    that patients with early or localized prostate cancer who are
    treated by either radical prostatectomy or radiation therapy would
    derive any benefit from adjuvant treatment with Casodex.

-   Each of the subgroups in Trial 24 had a sizable number of patients.
    In this Trial, the effect of treatment with Casodex was similar in
    each subgroup in that the proportion of patients with bone scan
    documented disease progression (excluding death in the absence of
    progression) was reduced by slightly more than 50%. The actual
    percent reductions in each subgroup, however, were relatively small
    and were 1.9% (radical prostatectomy), 3.5% (watchful waiting), and
    5.3% (radiotherapy).

-   The radical prostatectomy and radiotherapy subgroups in Trial 25
    contained only small numbers of patients and very few events. The
    subgroup of watchful waiting included almost 1000 patients. The
    proportion of patients with positive bone scans was reduced from 59
    of 505 patients (11.7%) in the placebo group to 17 of 486 patients
    (3.5%) in the Casodex group, a reduction of 8.2%.

The estimate of the odds ratio (and 95% confidence interval) for the
proportion of patients with bone scan confirmed disease progression or
death in each of the subgroups is listed in Table 23. In all instances
other than the subgroup of watchful waiting, the upper bound of the 95%
confidence limit exceeded 1.000. In Trial 24, however, the upper bound
of the 95% confidence limit for the radical prostatectomy and
radiotherapy subgroups barely crossed 1.000 and was 1.003 and 1.081,
respectively.

[]{#__RefHeading___Toc25309683 .anchor}Table 23 Odds Ratios for Bone
Scan Confirmed Progression or Death from Any Cause within 2.5 Years
after Randomization in Treatment Subgroups

  -------- ---------------- ------------ -------- ---------- ---------- ---------- ------- ------------
  Trial    Previous         Randomized   Number   Number of  \%         Estimate           95%\
  Number   Treatment        Treatment    of       patients   patients   of Odds            confidence
                                         events              with event Ratio ^1^          limits

  23       All treatments   Casodex      39       1647       2.4%                          

                            Placebo      48       1645       2.9%       0.81 ^2^   0.52 to 
                                                                                   1.24    
                                                                                   ^2^     

           Radical          Casodex      26       1322       2.0%                          
           prostatectomy                                                                   

                            Placebo      30       1325       2.3%       0.862      0.506   
                                                                                   to      
                                                                                   1.467   

           Radiotherapy     Casodex      13       325        4.0%                          

                            Placebo      18       320        5.6%       0.672      0.321   
                                                                                   to      
                                                                                   1.408   

  24       All treatments   Casodex      112      1798       6.2%                          

                            Placebo      168      1805       9.3%       0.645      0.500   
                                                                                   to      
                                                                                   0.832   

           Radical          Casodex      29       835        3.5%                          
           prostatectomy                                                                   

                            Placebo      43       814        5.3%       0.616      0.379   
                                                                                   to      
                                                                                   1.003   

           Radiotherapy     Casodex      24       335        7.2%                          

                            Placebo      36       325        11.1%      0.625      0.361   
                                                                                   to      
                                                                                   1.081   

           Prostatectomy or Casodex      53       1170       4.5%                          
           Radiotherapy                                                                    

                            Placebo      79       1139       6.9%       0.619      0.430   
                                                                                   to      
                                                                                   0.890   

           Watchful waiting Casodex      59       628        9.4%                          

                            Placebo      89       666        13.4%      0.674      0.471   
                                                                                   to      
                                                                                   0.964   

  25       All treatments   Casodex      63       607        10.4%                         

                            Placebo      105      611        17.2%      0.515      0.365   
                                                                                   to      
                                                                                   0.729   

           Radical          Casodex      7        82         8.5%                          
           prostatectomy                                                                   

                            Placebo      8        80         10.0%      0.836      0.282   
                                                                                   to      
                                                                                   2.480   

           Radiotherapy     Casodex      7        39         17.9%                         

                            Placebo      9        26         34.6%      0.397      0.123   
                                                                                   to      
                                                                                   1.285   

           Prostatectomy.   Casodex      14       121        11.6%                         
           or Radiotherapy                                                                 

                            Placebo      17       106        16.0%      0.584      0.264   
                                                                                   to      
                                                                                   1.292   

           Watchful waiting Casodex      49       486        10.1%                         

                            Placebo      88       505        17.4%      0.498      0.338   
                                                                                   to      
                                                                                   0.734   
  -------- ---------------- ------------ -------- ---------- ---------- ---------- ------- ------------

1\. Based on FDA-requested endpoints and analyses.

2 Values calculated by FDA statistician. Other values calculated by
Sponsor.

Source: Submission of 3 April 2002, Appendix 4 and Submission of 17 May
2002, Appendix 2.

##### Medical Officer's Comments {#medical-officers-comments-18 .unnumbered}

-   Although these were exploratory analyses, they support the Sponsor's
    claim that treatment with Casodex is of benefit to patients who
    would otherwise have their prostate cancer managed entirely by
    watchful waiting. However, it is not know at this time if this
    benefit (1) extends to patients in the US and (2) extends beyond
    that of delaying the development of osseous metastases. It also is
    not known if the benefit of treatment with Casodex in this
    population would be comparable to that of treatment with a GnRH
    agonist. GnRH therapy is often used in the US for patients who are
    not candidates for radical prostatectomy or who decline to have a
    radical prostatectomy or radiotherapy. Data from Clinical Trials
    0306 and 0307 previously submitted by the Sponsor in NDA 20-498/s006
    suggested that Casodex treatment for locally advanced non-metastatic
    prostate cancer may have been less effective than medical or
    surgical castration.

-   The exploratory subset analyses presented in Table 23 also suggest
    that in Trial 24 adjuvant treatment with Casodex reduced bone scan
    confirmed disease progression or death in the absence of progression
    in patients previously treated by radical prostatectomy. However, in
    Trial 23 (the North American trial and the trial of most relevance
    to men with prostate cancer in the United States) there was no
    apparent benefit of Casodex adjuvant therapy.

-   The proportion of placebo-treated patients with bone scan documented
    disease progression in the subgroups of radical prostatectomy and
    radiotherapy were several fold higher in Trial 24 compared to that
    in Trial 23. It thus appears that patients enrolled into Trial 24
    for adjuvant therapy either had less favorable baseline disease
    characteristics or underwent less effective primary therapies, or
    both.

-   A meaningful comparison of baseline disease characteristics in Trial
    23 to those in the non-North American trials (Trials 24 and 25) has
    not been possible, in part, because of failure by the Sponsor to
    require standardized criteria for assigning Gleason scores to tumor
    tissues. It is recommended that the Sponsor attempt to have the
    tumor specimens from the 3 clinical trials reread either centrally
    or by common criteria to facilitate meaningful cross study
    comparisons of the degree of tumor differentiation. Obtaining such
    information might help the Sponsor to identify the group of patients
    in the US who might benefit from adjuvant therapy with Casodex.

-   Based on the information in the present application, one can only
    identify those patients in the US who would not likely derive
    benefit from Casodex adjuvant therapy (i.e., those types of patients
    enrolled into Trial 23). The information in the present application
    does not identify patients with local or locally advanced prostate
    cancer in the US for whom adjuvant therapy might be of benefit. (See
    Section 4.6.3.3 for additional discussion).

#### Additional Subset Analyses to Support Adjuvant Use of Casodex

On 25 April 2002, a teleconference between the Sponsor and DRUDP was
held. The purpose of the teleconference was to provide the Sponsor with
an update as to the status of the review and to inform the Sponsor that
there were several unresolved review issues. Prior to the
teleconference, the Sponsor was provided with a list of questions that
included the following:

1.  How do you explain the disparity between the efficacy findings of
    Trial 23 (North American study) and those of Trials 24 and 25?

2.  Based on the findings in Trial 23 as of 2 June 2000 (data cutoff
    date), it appears that Casodex does not offer a significant benefit
    for men with early prostate cancer who initially are treated by
    radical prostatectomy or radiation therapy with a curative intent.
    In light of this observation, what population of patients with
    prostate cancer in the US, who are initially treated with radical
    prostatectomy or radiation therapy of curative intent, would benefit
    from adjuvant treatment with Casodex?

3.  Since there was not a watchful waiting group in Trial 23, can you
    tell us how men treated by watchful waiting in Trials 24 and 25
    compare to those that are likely to be treated by watchful waiting
    in the US. In particular, how do we know that such patients in the
    US would respond in a similar fashion as patients in Trials 24 and
    25?

4.  Please explain the criteria that were used to obtain Gleason scores
    for the tumors in each of the clinical trials. Did all pathologists
    use the same criteria?

5.  There appears to be a lack of correlation between Gleason scores and
    preprocedure PSA values. Patients in Trial 23 had higher Gleason
    scores (more severe disease) but lower PSA values. How do you
    explain this?

These questions initially were addressed by the Sponsor during the
teleconference and subsequently more completely in a written response of
10 May 2002. The Sponsor's written response included the following
information and explanations regarding the 5 questions listed above.

1.  "The disparity in efficacy findings between Trial 23 and Trials 24
    and 25 is related to the immaturity of Trial 23. At data cutoff,
    only 5.2% of patients had objective progression, with the majority
    of progression events being non-prostate cancer related deaths."

2.  ".... on closer examination of the data, by means of the
    multivariate analysis, several groups of patients were identified in
    which a clear and consistent benefit for Casodex was found. These
    patients were as follows:

-   patients who underwent prostatectomy with locally advanced disease
    and detectable postsurgical PSA levels and

-   patients who underwent radiotherapy with locally advanced disease
    and elevated preradiation PSA levels"

"AstraZeneca believes that patients with locally advanced non-metastatic
prostate cancer who undergo radical prostatectomy but are at high risk
for disease recurrence (e.g., patients with detectable postsurgical PSA
levels) would benefit from adjuvant treatment with Casodex."

3.  "These data and guidelines \[e.g., the American Urologic
    Association's Prostate Cancer Clinical Guidelines Panel Report\]
    clearly show that watchful waiting is a well-recognized and
    practiced treatment option in the US, with the guidelines also
    recognizing this treatment for the types of patients represented in
    the watchful waiting cohorts in Trials 24 and 25."

4.  "In the Casodex EPC program, the local pathologist assessed Gleason
    grade. In Trial 23, the actual numerical score was captured, but in
    Trials 24 and 25, the grade was captured only in terms of well,
    moderately, or poorly differentiated with guidance that 'well'
    represented a Gleason score of 2 to 4; moderate, a score of 5 or 6;
    and poorly, a grade of  7."

5.  "The reason for the lack of correlation between Gleason grade and
    PSA is unclear, but may relate to the fact that they measure
    different aspects of the tumor. Therefore, as noted in Question 2,
    AZ does not believe that conclusions can be drawn in this program on
    the basis of Gleason grade."

##### Medical Officer's Comment {#medical-officers-comment-4 .unnumbered}

-   The Sponsor's responses to questions 1, 4, and 5 did not provide new
    information but rather confirmed this reviewer's initial
    interpretation of previously submitted information. The Sponsor's
    confirmation that Gleason grades or scores were not assigned in
    accordance with specific guidelines is problematic. Most US
    physicians consider the Gleason grade of the tumor an important
    prognostic indicator. The lack of concordance between the US and
    non-US Gleason grades further limits one's ability to make
    comparisons between Trial 23 (the sole US study) and the 2 non-US
    trials.

With the written response of 10 May 2002, the Sponsor provided addition
information in support of their contention that patients who would
benefit from adjuvant Casodex therapy included those with locally
advanced disease (Stage T3/T4) prior to initial therapy and either (1) a
serum PSA concentration \> 0.2 ng/mL following radical prostatectomy or
(2) a serum PSA concentrations \> 10 ng/mL prior to radiotherapy. Table
24 summarizes objective disease progression or death in the absence of
progression for the subset of patients with Stage T3/T4 tumors and post
prostatectomy PSA values \> 0.2 ng/mL. Events represented in Table 24
are based on the Sponsor's preferred endpoints.

[]{#__RefHeading___Toc25309684 .anchor}Table 24 Disease Progression in
Patients with Locally Advanced (Stage T~3~/T~4~), M~0~ Prostate Cancer
and Post Prostatectomy PSA Values \> 0.2 ng/mL

  ----------- --------------- -- ---------- -- ----------- ------- --- -- -- ----------- ------------- ----------- ------------ -------- ------------- -- -- ------------- -------- ------------- --- --------------
                                                                                         **Number (%)                                                                                                 
                                                                                         of patients                                                                                                  
                                                                                         with event                                                                                                   
                                                                                         ^1,\ 2^**                                                                                                    

                                                                                         **Casodex**                                                         **Placebo**                              **Hazard
                                                                                                                                                                                                      Ratio**

  **Event**                                                                                            **Number                                              **Number                                 **(95% CL)**
                                                                                                       (%)**                                                 (%)**                                    

  **Trial                                                                                                                                                                                             
  23**                                                                                                                                                                                                

              **Total Pts                                                                              **83**^4^                                             **75**^4^                                
              Enrolled**                                                                                                                                                                              
              (158/2647                                                                                                                                                                               
              \[6.0%\])^3^                                                                                                                                                                            

                                 **Number                                                                                       **8**    **(9.6%)**                        **12**   **(16.0%)**       **0.53 (0.21,
                                 of Pts                                                                                                                                                               1.37)**
                                 with                                                                                                                                                                 
                                 Event**                                                                                                                                                              

                                               Bone Scan                                                                                                                   5                          
                                               Positive                                                                                                                                               

                                               Other                                                                                                                       2                          
                                               Objective                                                                                                                                              
                                               Events                                                                                                                                                 

                                               Deaths                                                                                    1                                          4                 
                                               ^5,\ 6^                                                                                                                                                

  **Trial                                                                                                                                                                                             
  24**                                                                                                                                                                                                

              **Total Pts                                                                                          **133^4^**                                **144^4^**                               
              Enrolled**                                                                                                                                                                              
              (277/1648                                                                                                                                                                               
              \[16.8%\])^3^                                                                                                                                                                           

                                 **Total                                                                                        **20**   **(15.0%)**                       **35**   **(24.3%)**       **0.55 (0.32,
                                 Events**                                                                                                                                                             0.96)**

                                               Bone Scan                                                                                 11                                         15                
                                               Positive                                                                                                                                               

                                               Other                                                                                     4                                          16                
                                               Objective                                                                                                                                              
                                               Events                                                                                                                                                 

                                               Deaths ^5^                                                                                5                                          4                 

  **Trial                                                                                                                                                                                             
  25**                                                                                                                                                                                                

              **Total Pts                                                    **33^4^**                                                                       **41^4^**                                
              Enrolled**                                                                                                                                                                              
              (74/159                                                                                                                                                                                 
              \[46.5%\])^3^                                                                                                                                                                           

                                 **Total                                                                                        **4**    **(12.1%)**                       **11**   **(26.8%)**       **0.49 (0.15,
                                 Events**                                                                                                                                                             1.58)**

                                               Bone Scan                                                                                 2                                          8                 
                                               Positive                                                                                                                                               

                                               Other                                                                                     1                                          2                 
                                               Objective                                                                                                                                              
                                               Events                                                                                                                                                 

                                               Deaths ^5^                                                                                1                                          1                 
  ----------- --------------- -- ---------- -- ----------- ------- --- -- -- ----------- ------------- ----------- ------------ -------- ------------- -- -- ------------- -------- ------------- --- --------------

1\. Based on Sponsor's preferred endpoints of positive bone, other
objective events, or death from any cause at any time
post-randomization.

2\. Values (other than for category of "Total Events") compiled by
medical reviewer from Submission of 22 May 2002.

3\. The value expressed as \[%\] represents the percentage of patients
in the Trial previously treated by radical prostatectomy who were
clinical stage T3 or T4 and had a postsurgical PSA value \> 0.2 ng/mL
relative to all patients previously treated by prostatectomy.

4\. Total number of patients enrolled in the Casodex or placebo
treatment group previously treated by radical prostatectomy who were
clinical stage T3 or T4 and had a postsurgical PSA value \> 0.2 ng/mL.

5\. Death from any cause.

6\. All deaths in Trial 23 (other than 1 case in the placebo group) were
due to causes other than prostate cancer.

Source: Submission of 10 May 2002, Table 2; Submission of 22 May 2002,
Appendix 3.

##### Medical Officer's Comments {#medical-officers-comments-19 .unnumbered}

-   The sponsor initially provided data only for "total events"
    expressed as percentages in each of the 3 trials. These data showed
    a numeric advantage for treatment with Casodex in terms of a
    reduction in the proportion of patients with objective disease
    progression or death. However, among the 3 trials, only the 95%
    confidence interval for the hazard ratio for Trial 24 did not cross
    1.00 (Hazard ratio: 0.55 \[95% CI: 0.32-0.96\]). Upon request, the
    Sponsor provided further details regarding disease progression each
    of the trials (i.e., numbers of patients with \[1\] a positive bone
    scan, \[2\] other objective progression, and \[3\] death from any
    cause in the absence of objective progression). Review of these
    additional data (represented in Table 24 in non-bold text) indicated
    that the excess of events in the placebo-treated patients in Trial
    23 was a result of (a) objective events other than positive bone
    scans and (b) deaths that were not due to prostate cancer. The data
    also indicated that most of the excess of events in the
    placebo-treated patients in Trial 24 was due to "other objective
    events."

#### First Revision by Sponsor to Proposed Label Claims

Based in part on the information provided in the written response of 10
May 2002, the Sponsor also submitted revised wording for the Casodex 150
mg label. The revised indication (also submitted on 10 May 2002) was:

> Casodex 150 mg is indicated as

-   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

```{=html}
<!-- -->
```
-   Immediate treatment of non-metastatic prostate cancer in patients
    for whom therapy of curative intent is not indicated.

##### Medical Officer\'s Comment {#medical-officers-comment-5 .unnumbered}

-   The revised proposed indication for the adjuvant use of Casodex is
    more reflective of the findings from the clinical trials. The
    revision acknowledges that there is little, if any, evidence (based
    primarily on the results from Trial 23) that adjuvant use of Casodex
    following radical prostatectomy or radiotherapy of curative intent
    in patients with localized prostate cancer is of clinical benefit.

#### Additional Subset Analyses to Support Immediate or Monotherapy Indication 

AstraZeneca was asked to provide additional information about the
disease characteristics of the watchful waiting patients in Trials 24
and 25 to allow DRUDP to assess further the relevance of these findings
in non-US patients to patients in the US who would otherwise be managed
by watchful waiting or surveillance. The Sponsor was asked to provide
the requested data in a manner that would allow DRUDP to determine if
the benefit of treatment with Casodex in the watchful waiting (immediate
treatment) subgroup also was observed in patients with minimal or early
disease. These data are summarized in Table 25 (Trial 24) and Table 26
(Trial 25). In these tables, patients with bone scan confirmed
progression or death from any cause in the absence of progression within
2.5 years after randomization (FDA-requested endpoints) are presented in
terms of baseline disease characteristics (clinical stage, Gleason
category, and pre-randomization serum PSA value).

[]{#__RefHeading___Toc25309685 .anchor}Table 25 Patients with Bone Scan
Progression or Death from Any Cause within 2.5 Years of Randomization in
Watchful Waiting Group (Trial 24)

  -------------------- ---------- --------- --- ------------- -------- -- ------------- --------
                       **All                    **Number (%)                            
                       patients                 of patients                             
                       in                       with event                              
                       category                 ^1^**                                   
                       ^2^**                                                            

  **Subgroup**                                  **Casodex**               **Placebo**   

                       N          \%            N             \%          N             \%

  All Patients         1294       \(100\)       59/628        (9.4)       89/666        (13.4)

  Tumor Stage                                                                           

  Localized (T1/T2)    996        \(77\)        35/475        (7.4)       52/521        (10.0)

  Locally advanced     298        \(23\)        24/153        (15.7)      37/145        (25.5)

                                                                                        

  Gleason category                                                                      

  Well differentiated  560        \(43\)        22/272        (8.1)       22/288        (7.6)

  Moderately           463        \(36\)        19/226        (8.4)       33/237        (13.9)
  differentiated                                                                        

  Poorly               239        \(19\)        18/115        (15.7)      31/124        (25.0)
  differentiated                                                                        

                                                                                        

  Prerandomization PSA                                                                  

  0.2 ng/mL            8          (\<1)         0/4           (0.0)       0/4           (0.0)

  \> 0.2 to 4 ng/mL    252        \(20\)        6/122         (4.9)       10/130        (7.7)

  \> 4 to 10 ng/mL     298        \(24\)        8/156         (5.1)       16/142        (11.3)

  \> 10 to 20 ng/mL    316        \(26\)        20/150        (13.3)      16/166        (9.6)

  \>20 ng/mL           370        \(30\)        20/170        (11.8)      44/200        (22.0)
  -------------------- ---------- --------- --- ------------- -------- -- ------------- --------

1\. Based on FDA-requested endpoints for disease progression.

2\. Includes all patients (both those who did and did not have disease
progression.

Source: Submission of 17 May 2002, Appendix 3.

[]{#__RefHeading___Toc25309686 .anchor}Table 26 Patients with Bone Scan
Progression or Death from Any Cause within 2.5 Years of Randomization in
Watchful Waiting Group (Trial 25)

  -------------------- ---------- --------- ---- ------------- -------- -- ------------- --------
                       **All                     **Number (%)                            
                       patients                  of patients                             
                       in                        with event                              
                       category                  ^1^**                                   
                       ^2^**                                                             

  **Subgroup**                                   **Casodex**               **Placebo**   

                       N          \%             N             \%          N             \%

  All patients         991        \(100\)        49/486        (10.1)      88/505        (17.4)

  Tumor Stage                                                                            

  Localized (T1/T2)    631        \(64\)         29/304        (9.5)       39/327        (11.9)

  Locally advanced     360        \(36\)         20/182        (11.0)      49/178        (27.5)

                                                                                         

  Gleason category                                                                       

  Well differentiated  462        \(47\)         16/229        (7.0)       24/233        (10.3)

  Moderately           415        \(42\)         15/198        (7.6)       44/217        (20.3)
  differentiated                                                                         

  Poorly               101        \(10\)         17/49         (34.7)      18/52         (34.6)
  differentiated                                                                         

                                                                                         

  Prerandomization PSA                                                                   

  0.2 ng/mL            2          (\<1)          1/2           (50.0)      0/0           (0.0)

  \> 0.2 to 4 ng/mL    98         \(10\)         4/39          (10.3)      3/59          (5.1)

  \> 4 to 10 ng/mL     209        \(21\)         11/111        (9.9)       10/98         (10.2)

  \> 10 to 20 ng/mL    237        \(24\)         7/125         (5.6)       12/112        (10.7)

  \> 20 ng/mL          434        \(44\)         26/206        (12.6)      61/228        (26.8)
  -------------------- ---------- --------- ---- ------------- -------- -- ------------- --------

1\. Based on FDA-requested endpoints for disease progression.

2\. Includes all patients (both those who did and did not have disease
progression.

Source: Submission of 17 May 2002, Appendix 3.

##### Medical Officer\'s Comments {#medical-officers-comments-20 .unnumbered}

-   In each of Trials 24 and 25, approximately two thirds of the
    watchful waiting patients had localized disease (stage T1 or T2) as
    would be expected in a US population. However, the effect of
    treatment with Casodex in this subset was numerically small
    (i.e., Trial 24: 7.4% progression \[Casodex group\] vs. 10.0%
    progression \[placebo group\] and Trial 25: 9.5% progression
    \[Casodex group\] vs. 11.9% progression \[placebo group\]). In
    contrast, patients with locally advanced disease (stage T3 or T4)
    had more events and the effect of treatment with Casodex was
    numerically greater (e.g. Trial 24: 15.7% progression \[Casodex
    group\] vs. 25.5% progression \[placebo group\]). Patients with
    locally advanced disease are not generally managed by watchful
    waiting in the US.

-   In Trials 24 and 25, 30% and 44% of patients had serum PSA values
    \> 20 ng/mL at randomization. These values suggest more than minimal
    disease and it is not likely that many of these patients would be
    managed by watchful waiting or surveillance in the US.

-   The majority of patients had tumor Gleason categories of well
    differentiated or moderately differentiated. These categories would
    be compatible with those likely to be observed in a US population.
    However, because of the lack of standardized criteria for assigning
    Gleason scores, they cannot be readily interpreted in these studies.

-   A comparison of Casodex-treatment to that of placebo-treatment is
    probably not appropriate for estimating the likely benefit of
    Casodex-therapy for patients with locally advanced disease (T3/T4)
    and PSA values \>20 ng. Such patients would most likely have
    received active therapy (e.g., GnRH analog therapy) in the US based
    on present standards of care.

#### Second Revision by Sponsor to Proposed Label Claims

After receiving comments from DRUDP concerning the reasons for the
non-approval of NDA 20-498/s012, AstraZeneca revised the claim for the
immediate use of Casodex. The modification limited the target population
to patients with *localized* disease, defined by the Sponsor as patients
with T~1~/T~2~, N~X~, M~0~ prostate cancer. According to this
modification, patients with locally advanced disease (i.e., T3/T4) would
no longer be appropriate candidates for Casodex immediate therapy.

##### Medical Officer\'s Comments {#medical-officers-comments-21 .unnumbered}

-   The primary objective of this proposed label change was presumably
    to address the concerns of DRUDP. Based on the findings from
    Clinical Trials 306 and 307 previously submitted under NDA
    20-498/s006, DRUDP was concerned that Casodex-treatment of locally
    advanced prostate cancer would be less effective than medical
    castration with a GnRH analog.

-   To be of benefit to patients with localized non-metastatic prostate
    cancer who are presently managed by watchful waiting or surveillance
    in the US, the Sponsor will need to provide data demonstrating that
    prostate cancer-related morbidity or mortality in such patients
    occurs with a sufficiently high incidence that the potential
    benefits of Casodex treatment will out weight the adverse effects of
    treatment (e.g., gynecomastia, breast pain, and possible liver
    toxicity).

-   Based on the data presented in Table 25 and Table 26, the proportion
    of patients with localized disease and disease progression within
    2.5 years of randomization was low.

Many elderly patients with prostate cancer die of causes unrelated to
their prostate disease. The sponsor was therefore asked to provide
information on the number of patients in the watchful waiting groups in
Trials 24 and 25 who had objective disease progression (i.e., a positive
bone scan) or death due only to prostate cancer in the absence of
objective progression. This information is presented in Table 27. For
patients with no prior treatment and localized disease in the placebo
treatment groups, only 3.6% of patients (Trial 24) and 7.3% of patients
(Trial 25) experienced disease progression.

[]{#__RefHeading___Toc25309687 .anchor}Table 27 Patients with Bone Scan
Progression or Death from Prostate Cancer within 2.5 Years of
Randomization in Watchful Waiting Group (Trials 24 and 25)

  -------------------- ---------- --------- ---- ------------- ------- -- ------------- --------
                       **All                     **Number (%)                           
                       patients                  of patients                            
                       in                        with event                             
                       category                  ^1^**                                  
                       ^2^**                                                            

  **Subgroup**                                   **Casodex**              **Placebo**   

                       N          \%             N             \%         N             \%

  *Trial 24*                                                                            

  All patients         1294       \(100\)        23/628        (3.7)      48/666        (7.2)

  Tumor Stage                                                                           

  Localized (T1/T2)    996        \(77\)         10/475        (2.1)      19/521        (3.6)

  Locally advanced     298        \(23\)         13/153        (8.5)      29/145        (20.0)

                                                                                        

  *Trial 25*                                                                            

  All patients         991        \(100\)        22/486        (4.5)      64/505        (12.7)

  Tumor Stage                                                                           

  Localized (T1/T2)    631        \(64\)         9/304         (3.0)      24/327        (7.3)

  Locally advanced     360        \(36\)         13/182        (7.1)      40/178        (22.5)
  -------------------- ---------- --------- ---- ------------- ------- -- ------------- --------

1\. Only deaths from prostate cancer or a positive bone scan are
considered to be an event.

2\. Includes all patients (both those who did and did not have disease
progression.

Source: Submission of 17 May 2002, Appendix 3.

##### Medical Officer\'s Comments {#medical-officers-comments-22 .unnumbered}

-   Based on the small number of events in these subgroups and the
    absence of any survival difference in the treatment groups, it is
    questionable if patients with localized disease would derive
    sufficient clinical benefit from Casodex treatment to justify the
    adverse effects of treatment. It is likely that up to 85% of
    Casodex-treated patients will experience gynecomastia and/or breast
    pain within 2 years of treatment onset (see Section 5.9.1.1 under
    Pharmacological Adverse Events). Although breast pain generally
    resolves after discontinuation of treatment, gynecomastia was
    reported to resolve in only 50% of patients.

-   A better assessment of the likely benefit of Casodex treatment could
    be obtained if the Sponsor were to provide efficacy data based on a
    data cutoff more current than June 2000 (i.e., data from a more
    mature study).

#### Additional Subset Analyses by Baseline Disease Characteristics

Although there were some differences in the inclusion and exclusion
criteria of each the 3 pivotal clinical trials (see Section 4.3.3),
patients with all stages of non-metastatic (M0) prostate disease
(i.e., stages T1-T4) were eligible for enrollment. In addition, patients
may have undergone active therapy (radical prostatectomy or
radiotherapy) or no therapy (except in Trial 23) prior to enrollment. To
allow DRUDP to investigate the effects of Casodex treatment in each of
these subgroups, the Sponsor was asked to provide additional descriptive
subset analyses based on patient disease characteristics prior to
enrollment. In these analyses, the proportions of patients with disease
progression in each Trial are presented based on (1) clinical stage
(T1-T4), (2) Gleason score, (3) PSA value at randomization, and (4) PSA
value prior to prostatectomy or radiotherapy for adjuvant patients. Data
for adjuvant patients are presented separately for the prostatectomy and
radiotherapy groups in the Appendix (Appendix Tables 1a-1c, pg.
120-123). Data for the "immediate therapy patients" (i.e., watchful
waiting group) are presented in Table 25 and Table 26 in the main body
of this review. In these descriptive analyses, disease progression is
defined as (1) a positive bone scan or (2) death from any cause in the
absence of a positive bone scan, both within 2.5 years of randomization
(FDA-preferred endpoints). A second set of descriptive subset analyses
for adjuvant patients is presented in Appendix Tables 2a-2c (pg.
124-127). In these later analyses, disease progression is defined as (1)
a positive bone scan or (2) death due to prostate cancer in the absence
of a positive bone scan, both within 2.5 years of randomization (a
modification of the FDA-preferred endpoints).

#### Central Reread of Bone Scans

The use of a binary primary efficacy endpoint, instead of a
time-to-event analysis, reduced one potential source of assessment bias
due to the likely unblinding of treatment assignments in some patients.
Another possible source of bias resulting from this unblinding of
treatment assignments concerned the reading of bone scans at the local
study centers. It was possible that bone scans from patients thought to
be on placebo therapy would be more likely to be read as positive than
scans from patients on Casodex therapy. To investigate this possible
source of bias, it was recommended by DRUDP that bone scans be reread by
blinded reviewers at a central facility. In response to this request,
the Sponsor designed and conducted a substudy in which all positive bone
scans and a representative sample of negative scans were to be reread by
at least 2 blinded reviewers at a central facility. The design and
outcome of this substudy are described in detail in the separate review
of Robert Yaes MD, Division of Medical Imaging and Radiopharmaceutical
Drug Products (DMIRDP), FDA. The following is a brief summary of the
findings from this substudy.

A total of 1,259 scans from among the 3 trials were identified for
review at the central facility. Of these, 1,032 were available for
review. Table 28 summarizes the comparative results from the original
local read and the central reread. Scans that were available for reread
were classified as positive, negative, or indeterminate. Approximately
15% of scans were not available for reread.

[]{#__RefHeading___Toc25309688 .anchor}Table 28 Comparison of Local Read
and Central Reread (Data from\
Trials 23, 24, and 25 Combined)

  ----------- ----------- ---------- ------- ---------- ------- --------------- ------- ----------- -------
  Treatment   Local       Central                                                                   
  Group       Result      Reread                                                                    
                          Result                                                                    

                          Number (%)                                                                
                          of scans                                                                  
                          in each                                                                   
                          category                                                                  

                          Positive           Negative           Indeterminate           Not         
                                                                                        Available   

  Casodex     Positive    73         (65%)   22         (19%)   5               (4%)    13          (12%)

                                                                                                    

              Negative    31         (5%)    443        (72%)   34              (6%)    107         (17%)

                                                                                                    

  Placebo     Positive    144        (63%)   36         (16%)   18              (8%)    28          (12%)

                                                                                                    

              Negative    22         (4%)    359        (71%)   45              (9%)    79          (16%)
  ----------- ----------- ---------- ------- ---------- ------- --------------- ------- ----------- -------

Source: Report on Bone Scan Reread Study, Table T9.2, pg. ST-66.

##### Medical Officer\'s Comments {#medical-officers-comments-23 .unnumbered}

-   The correlation between the original result and the reread was less
    than optimal. In this reviewer's opinion, it was surprisingly low,
    especially for positive scans. Excluding scans not available for
    reread, 73 of 100 scans locally read as positive from
    Casodex-treated patients were reread as positive. Twenty-two (22)
    and 5 were reread as negative and indeterminate, respectively. The
    findings were similar for scans originally read as positive from
    placebo-treated patients.

-   For scans locally read as negative in Casodex-treated patients and
    available for central review, 443 of 508 (87%) were reread as
    negative. Thirty-one (31) and 34 were reread as positive and
    indeterminate, respectively. The findings were similar for scans
    originally read as negative from placebo treated patients.

-   Although no systematic treatment-related reading bias was apparent,
    27% of scans read as positive by local readers (the readings used in
    the Sponsor's efficacy analyses), were read as negative or
    indeterminate at the central reread. This lack of correlation
    between the initial and central readings for positive scans raises
    some concern about assessing the efficacy of Casodex treatment based
    on the relatively small differences in the numbers of non-fatal
    events in these immature clinical trials.

Table 29 summarizes the comparative results from the original local read
and the central reread for each trial, considering only those scans
reread as positive or negative and excluding those that were reread as
indeterminate or those that were not available for reread.

[]{#__RefHeading___Toc25309689 .anchor}Table 29 Comparison of Results of
Local Read and Central Reread\
including only Scans Reread as Positive or Negative

  --------- ----------- ----------- ---------- --------- ---------- ------------
                                    Central                         
                                    Reread                          
                                    Result                          

  Trial     Treatment   Local\      Number (%)                      
            Group       Result      of scans                        
                                    in each                         
                                    category                        

                                    Positive             Negative   

  23        Casodex     Positive    13         (72%)     5          (23%)

                        Negative    10         (6%)      150        (94%)

            Placebo     Positive    8          (67%)     4          (33%)

                        Negative    7          (5%)      136        (95%)

                                                                    

  24        Casodex     Positive    33         (69%)     15         (31%)

                        Negative    12         (7%)      153        (93%)

            Placebo     Positive    70         (76%)     22         (24%)

                        Negative    10         (8%)      122        (92%)

                                                                    

  25        Casodex     Positive    27         (93%)     2          (7%)

                        Negative    9          (6%)      140        (94%)

            Placebo     Positive    66         (87%)     10         (13%)

                        Negative    5          (5%)      101        (95%)
  --------- ----------- ----------- ---------- --------- ---------- ------------

Source: Report on Bone Scan Reread Study, Table T9.3, pg. ST-67 to
ST-69.

##### Medical Officer's Comments {#medical-officers-comments-24 .unnumbered}

-   The results of the reread were consistent with there being no
    systematic treatment-related bias in the local readings of the bone
    scans between the Casodex and placebo treatment groups.

-   The percentage of negative scans reread as positive was
    comparatively small relative to the percentage of positive scans
    reread as negative. However, because more than 90% of the bone scans
    across the 3 clinical trials were read locally as negative, the
    impact of what appears to be a small misclassification error could
    be substantial if it were to occur more frequently in one of the 2
    treatment arms.

#### Survival 

At the time of the efficacy data cutoff date of 2 June 2000, the median
follow-up time for patients in each treatment group was 3.0 years, which
was equivalent to 12,053 and 12,033 total patient-years of follow-up for
the Casodex and placebo groups, respectively. Additional data on
survival were provided in the Safety Addendum Reports for each trial and
the 4‑Month Safety Update. The cumulative numbers and percentages of
deaths due to prostate cancer or other causes in each of the trials at
data cutoff dates of 2 June 2000, 23 February 2001 (Safety Addendum
Reports), and 28 September 2001 (4-Month Safety Update) are listed in
Table 30. At each of the data cutoff dates, there were no significant
differences in the percentage of patients who had died, either of
prostate cancer or of other causes, in the Casodex or placebo groups
within each of the trials. There were, however, significant differences
in the proportion of deaths across the trials, particularly for deaths
due to prostate cancer. The percentages of patients who died from all
causes was approximately 2-fold and 3-fold greater in Trial 24 and Trial
25, respectively, than in Trial 23 at each of the data cutoff times.

[]{#__RefHeading___Toc25309690 .anchor}Table 30 Number and Percentage of
Deaths in Trials 23, 24, and 25

  ------------ ---------- ----------- -------- --------- ----------- -- ---------- ------------ --------- ------------ -- ---------- ------------ ---------- ------------
  **Cause of\  **Study                                                  **Study                                           **Study                            
  Death**      23**                                                     24**                                              25**                               

               Casodex\                        Placebo                  Casodex\                Placebo                   Casodex\                Placebo\   
               N= 1647                         N=1645                   N= 1798                 N=1805                    N= 607                  N= 611     

               n          (%)         n                  (%)            n          (%)          n         (%)             n          (%)          n          (%)

  Prostate     8          (0.5)       3                  (0.2)          26         (1.4)        38        (2.1)           24         (4.0)        28         (4.6)
  cancer                                                                                                                                                     

  Other        54         (3.3)       58                 (3.5)          97         (5.4)        99        (5.5)           45         (7.4)        42         (6.9)

  **Total      **62**     **(3.8)**   **61**             **(3.7)**      **123**    **(6.8)**    **137**   **(7.6)**       **69**     **(11.4)**   **70**     **(11.5)**
  ^1^**                                                                                                                                                      

  Prostate     9          (0.6)       4                  (0.2)          47         (2.6)        53        (2.9)           35         (5.8)        42         (6.9)
  cancer                                                                                                                                                     

  Other        74         (4.6)       83                 (5.1)          132        (7.3)        131       (7.3)           54         (8.9)        43         (7.1)

  **Total      **83**     **(5.1)**   **87**             **(5.3)**      **179**    **(10.0)**   **184**   **(10.3)**      **89**     **(14.7)**   **85**     **(14.0)**
  ^2^**                                                                                                                                                      

  Prostate     14         (0.9)       6                  (0.4)          56         (3.1)        66        (3.7)           49         (8.1)        56         (9.2)
  cancer                                                                                                                                                     

  Other        91         (5.6)       93                 (5.7)          168        (9.4)        161       (9.0)           67         (11.1)       50         (8.2)

  **Total      **105**    **(6.5)**   **99**             **(6.1)**      **224**    **(12.5)**   **227**   **(12.7)**      **116**    **(19.2)**   **106**    **(17.4)**
  ^3^**                                                                                                                                                      
  ------------ ---------- ----------- -------- --------- ----------- -- ---------- ------------ --------- ------------ -- ---------- ------------ ---------- ------------

> 1\. Data cutoff date of 2 June 2000. Data based on efficacy
> population.
>
> 2\. Data cutoff date of 23 February 2001. Data based on safety
> population. (Calculated by medical reviewer).
>
> 3\. Data cutoff date of 28 September 2001. Data based on safety
> population. (Calculated by medical reviewer).
>
> Source: Table T5.1, ISE; Table T8.2 Safety Addendum for each of Trials
> 23, 24, and 25; Submission of 17 May 2002, Appendix 1.

##### Medical Officer's Comments {#medical-officers-comments-25 .unnumbered}

-   The proportion of patients who died from prostate cancer in the
    placebo treatment groups was approximately 9-fold and 23-fold
    greater in Trial 24 and Trial 25, respectively, compared to that in
    Trial 23. These observations are consistent with the higher
    proportions of patients with positive bone scans in Trials 24 and
    25.

-   There is no evidence that treatment with Casodex had a beneficial
    effect on overall survival in any of the trials based on presently
    available data.

-   There is a suggestion that the percentage of deaths due to prostate
    cancer may be reduced in the Casodex treatment arm in Trial 25.
    However, there is an opposite trend in deaths due to other causes in
    this Trial.

### Secondary Efficacy Endpoints

#### Time to Treatment Failure

The number and percentage of patients who failed treatment in each of
the trials, categorized by the reason for treatment failure, are
presented in Table 31. The proportion of patients who had a treatment
failure event ranged from 21.1% (Trial 23, placebo group) to 48.0%
(Trial 25, placebo group). The most common reason for treatment failure
in each of the trials was "withdrawal of therapy" in the absence of
objective disease progression or death. Withdrawal of therapy, as the
reason for treatment failure ranged from 18.5% of patients (Trial 23,
placebo group) to 36.5% (Trial 23, Casodex group). In Trial 23,
virtually all patients who failed treatment did so because of withdrawal
of therapy in the absence of objective disease progression or death.
Additional information as to the reasons for "withdrawal of therapy" in
the absence of disease progression is provided in Section 5.5 (Patient
Disposition).

[]{#__RefHeading___Toc25309691 .anchor}Table 31 Reasons for Treatment
Failure (Trials 23, 24, and 25)

  -------------- ---------- --------- ------------ --------- ---------- ------------ ---------- ------------ --------- ---------- ------------ --------- ---------- ------------ --------- ---------- ------------
                 Number                                                                                                                                                                               
                 (per cent)                                                                                                                                                                           
                 of                                                                                                                                                                                   
                 patients                                                                                                                                                                             
                 with event                                                                                                                                                                           

  **Reason for** Study 23                                                            Study 24                                                            Study 25                                     

  **treatment    Casodex\                                    Placebo\                Casodex\                          Placebo\                          Casodex\                          Placebo\   
  failure ^1^**  (N = 1647)                                  (N = 1645)              (N = 1798)                        (N = 1805)                        (N = 607)                         N = 611)   

  Objective                 5         (0.3)        8                    (0.5)        47         (2.6)        151                  (8.4)        32                   (5.3)        103                  (16.9)
  disease\                                                                                                                                                                                            
  progression                                                                                                                                                                                         

  Withdrawal of             601       (36.5)       304                  (18.5)       620        (34.5)       468                  (25.9)       133                  (21.9)       163                  (26.7)
  therapy^2^                                                                                                                                                                                          

  Death                     9         (0.5)        13                   (0.8)        48         (2.7)        36                   (2.0)        26                   (4.3)        18                   (2.9)

  Additional                3         (0.2)        4                    (0.2)        12         (0.7)        25                   (1.4)        3                    (0.5)        7                    (1.1)
  systemic\                                                                                                                                                                                           
  therapy given                                                                                                                                                                                       

  No trial                  20        (1.2)        18                   (1.1)        8          (0.4)        10                   (0.6)        2                    (0.3)        2                    (0.3)
  therapy\                                                                                                                                                                                            
  received                                                                                                                                                                                            

  **Total (%)               **638**   **(38.7)**   **347**              **(21.1)**   **735**    **(40.9)**   **690**              **(38.2)**   **196**              **(32.3)**   **293**              **(48.0)**
  Patients**                                                                                                                                                                                          
  -------------- ---------- --------- ------------ --------- ---------- ------------ ---------- ------------ --------- ---------- ------------ --------- ---------- ------------ --------- ---------- ------------

1\. Categories are mutually exclusive and hierarchical; the event that
occurred first was assigned as the reason for treatment failure.

2\. Withdrawal of therapy in the absence of disease progression or
death.

Source: Text Table 16, pg. 48, ISE.

The Sponsor's analyses of time to treatment failure are summarized in
Table 32. The hazard ratios for the time to treatment failure in the
Casodex versus placebo treatment groups showed statistical significance
in both Trial 23 and Trial 25 (albeit in opposite directions) with no
statistical significance for Trial 24.

[]{#__RefHeading___Toc25309692 .anchor}Table 32 Analyses of Time to
Treatment Failure (Trials 23, 24, and 25)

  ------- ----------- -------- --------- -------- ---------- -------------- ---------
  Trial   Number (%)                              Hazard     95% confidence p-value
          of patients                             ratio      interval       
          with event                                                        
          of                                                                
          treatment                                                         
          failure                                                           

          Casodex              Placebo                                      
          group                group                                        

  23      638         (38.7)   347       (21.1)   2.083      1.827 to 2.374 \<0.001

  24      735         (40.9)   690       (38.2)   1.095      0.986 to 1.215 0.089

  25      196         (32.3)   293       (48.0)   0.565      0.471 to 0.679 \<0.001
  ------- ----------- -------- --------- -------- ---------- -------------- ---------

Source: Table T6.2, ISE.

##### Medical Officer's Comment {#medical-officers-comment-6 .unnumbered}

-   In Trial 23, patients receiving Casodex were more likely to have a
    treatment failure event than those on placebo. In Trial 25, the
    converse was true. Patients receiving placebo in Trial 25 were more
    likely to have a treatment failure event than those receiving
    Casodex.

#### Time to PSA Doubling

A PSA doubling event was the earliest of (1) a doubling of serum PSA
concentrations relative to baseline, (2) objective progression of
disease, or (3) death from any cause. The number and proportion of
patients with a PSA doubling event in each of the trials is summarized
in Table 33. In each of the trials, the proportion of patients in whom
PSA doubled or with a PSA doubling event was lower in the
Casodex-treated patients compared to placebo-treated patients.

[]{#__RefHeading___Toc25309693 .anchor}Table 33 Number (%) of Patients
with a PSA Doubling Event

  ---------------- ---------- ------------ ---------- ------------ ---------- ------------ ---------- --------- ------------ --------- ---------- ------------ ---------- --------- ------------
                   Number                                                                                                                                                           
                   (per cent)                                                                                                                                                       
                   of                                                                                                                                                               
                   patients                                                                                                                                                         
                   with event                                                                                                                                                       

  **Earliest Event Study 23                                        Study 24                                                            Study 25                                     
  ^1^**                                                                                                                                                                             

                   Casodex\                Placebo\                Casodex\                Placebo\                                    Casodex\                Placebo\             
                   (N = 1647)              (N = 1645)              (N = 1798)              (N = 1805)                                  (N = 607)               N = 611)             

  PSA doubled      211        (12.8)       333        (20.2)       126        (7.0)                   440       (24.4)       48                   (7.9)                   243       (39.8)

  Objective        12         (0.7)        9          (0.5)        53         (2.9)                   80        (4.4)        37                   (6.1)                   56        (9.2)
  progression                                                                                                                                                                       

  Death            47         (2.9)        52         (3.2)        93         (5.2)                   80        (4.4)        46                   (7.6)                   36        (5.9)

  **Total (%) of   **270**    **(16.4)**   **394**    **(24.0)**   **272**    **(15.1)**              **600**   **(33.2)**   **131**              **(21.6)**              **335**   **(54.8)**
  patients**                                                                                                                                                                        
  ---------------- ---------- ------------ ---------- ------------ ---------- ------------ ---------- --------- ------------ --------- ---------- ------------ ---------- --------- ------------

1\. Categories are mutually exclusive and hierarchical; the event that
occurred first was assigned as the reason for PSA doubling.

Source: Text Table 19, pg. 51, ISE.

##### Medical Officer\'s Comment {#medical-officers-comment-7 .unnumbered}

-   The proportion of patients in the Casodex treatment arm in Trial 23
    with a PSA doubling event (16.4%) was similar to that in the Casodex
    treatment arm in Trial 24 (15.1%) and only somewhat lower than that
    in Trial 25 (21.6%). This is an unexpected finding since the
    proportion of patients with objective progression (Sponsor's
    definition of objective progression) was much lower in Trial 23
    (0.7%) compared to that in Trial 24 (2.9%) and Trial 25 (6.1%).

The results of the sponsor's analyses of time to PSA doubling (TTPSAd)
are presented in Table 34. Treatment with Casodex increased the time to
a PSA doubling event in each of the trials.

[]{#__RefHeading___Toc25309694 .anchor}Table 34 Analyses of Time to a
PSA Doubling Event in Trials 23, 24, and 25

  ------------ ---------- -------- ---------- -------- ---------- ------------ ----------
  **Trial**    **Number                                **Hazard   **95%        **P
               (%) of                                  ratio**    confidence   value**
               patients                                           interval**   
               with PSA\                                                       
               doubling                                                        
               event**                                                         

               Casodex             Placebo                                     
               Group               Group                                       

               Number     (%)      Number     (%)                              

  23           270/1647   (16.4)   394/1645   (24.0)   0.619      0.530 to     \<0.0001
                                                                  0.722        

  24           272/1798   (15.1)   600/1805   (33.2)   0.369      0.320 to     \<0.0001
                                                                  0.426        

  25           131/607    (21.6)   335/611    (54.8)   0.243      0.197 to     \<0.0001
                                                                  0.299        
  ------------ ---------- -------- ---------- -------- ---------- ------------ ----------

Source: Text Table 20, pg. 54, ISE.

##### Medical Officer's Comment {#medical-officers-comment-8 .unnumbered}

-   The Sponsor's analysis of time to a PSA doubling event is the only
    analysis provided in this Application that showed a potential
    benefit for treatment with Casodex in Trial 23. In Trial 23, there
    was no evidence that Casodex treatment was of benefit compared to
    placebo in terms of either of the 2 primary efficacy endpoints
    objective disease progression or survival (no difference from
    placebo) or the secondary endpoint of time to treatment failure
    (Casodex was statistically inferior to placebo).

## Consultations

The findings from Clinical Trials 23, 24, and 25 were presented to the
Oncology Coordinating Committee (OCC), FDA on 28 March 2002.
Recommendations from the OCC regarding the approvability of Casodex 150
mg for the Sponsor's originally proposed indication included the
following:

-   The primary efficacy endpoint based on bone scan confirmed disease
    progression is acceptable to evaluate the potential clinical benefit
    of treatment with Casodex 150 mg.

-   Demonstrating a statistically significant increase in survival is
    not necessary for approval if the efficacy and safety profiles are
    otherwise acceptable.

-   Because of the lack of efficacy in the US clinical trial (Trial 23),
    approval can not be recommended in the absence of (a) the Sponsor
    conducting a trial in the US that demonstrates efficacy for the
    proposed indication or (2) the Sponsor providing further evidence of
    the relevance of the efficacy findings from Trials 24 and 25 to
    patients in the US with prostate cancer.

## Conclusions Regarding Demonstrated Efficacy

### Achievement of Protocol-Defined Primary Efficacy Endpoints

Time to objective disease progression (Trials 23, 24, and 25) and time
to death (Trials 23 and 25 and the Sponsor's combined analysis) were the
protocol-defined primary efficacy endpoints. For two of the 3 clinical
trials (Trials 24 and 25), the Sponsor provided statistically
significant evidence that treatment with Casodex 150 mg per day,
compared to treatment with placebo, delayed disease progression as
assessed by the appearance of new bone metastases or death in the
absence disease progression. In Trial 23 (the only trial conducted in
the US and the trial most relevant to patients in the US), there was no
evidence that treatment with Casodex delayed disease progression.

There was no evidence that treatment with Casodex improved survival in
any of the trials or in the combined analysis. Evidence of improved
survival, however, was not anticipated by the cutoff date for efficacy
data (2 June 2000) as the data were expected to be immature.

### Support of Label Efficacy Claims

The Sponsor originally proposed the following efficacy claim:

> *CASODEX 150 mg tablets are indicated as immediate hormonal therapy or
> as adjuvant therapy to treatment of curative intent in patients with
> non-metastatic prostate cancer.*

On 10 May 2002, the Sponsor submitted the following revised efficacy
claim:

> *CASODEX 150 mg is indicated as (1) 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 (2) immediate treatment of non-metastatic
> prostate cancer in patients for whom therapy of curative intent is not
> indicated.*

The revised efficacy claim was submitted in response to questions
submitted to the Sponsor by the Division (DRUDP) concerning the
relevance of the non-US data to patients in the US, particularly in
light of the negative outcome of Trial 23 (see Section 4.6.3.3). An
exploratory subset analyses submitted by the Sponsor on 10 May 2002 from
Trials 24 and 25 was somewhat supportive of the revised indication.
However, a similar subset analysis for Trial 23, which included only
adjuvant treated patients, provided at best only minimal support for the
revised indication. Other data submitted by the Sponsor on 17 May 2002
were inconclusive as to the relevance of the efficacy findings for
patients in the immediate therapy groups in Trials 24 and 25 to patients
in the US presently managed by watchful waiting or surveillance (see
Section 4.6.3.5)

##### Medical Officer's Comment {#medical-officers-comment-9 .unnumbered}

-   Supplemental efficacy analyses submitted by the sponsor on 10 May
    2002 and 17 May 2002 were not sufficient to support the Sponsor's
    proposed label indications for either adjuvant or immediate therapy
    with Casodex for patients with prostate cancer in the US.

On 22 October 2002, the Sponsor revised the proposed claim for immediate
treatment with Casodex. The revised claim limited immediate treatment to
patients with localized (T1, T2), NX, M0 disease. This change was made,
according to the Sponsor, to address concerns by DRUDP regarding the
appropriateness of Casodex monotherapy for patients with locally
advanced (T3, T4) disease (see Section 1.3.1).

##### Medical Officer\'s Comments {#medical-officers-comments-26 .unnumbered}

-   To be of benefit to patients with localized non-metastatic prostate
    cancer who are presently managed by watchful waiting or surveillance
    in the US, the Sponsor will need to provide data demonstrating that
    prostate cancer-related morbidity or mortality in such patients
    occurs with a sufficiently high incidence that the potential
    benefits of Casodex treatment will out weight the adverse effects of
    treatment (e.g., gynecomastia, breast pain, and possible liver
    toxicity).

## Statistician's Assessment of Efficacy 

The following statements are the conclusion of Dr. Hoberman's
statistical review of the efficacy findings in NDA 20-498/s012. Dr.
Hoberman was the primary statistical reviewer for this application.

> "Each European trial provides statistically significant evidence that
> Casodex 150 mg delays or possibly prevents objective progression of
> early prostate cancer as measured by bone scans positive for
> metastases. However, the inclusion of disparate patient groups which
> received different background therapy (or lack thereof), complicates
> inference by inviting examination of treatment comparisons within
> subgroups of patients. Nevertheless, there is evidence in each
> European trial that patients who either underwent previous therapy
> (radiation and/or radical prostatectomy) or who underwent 'watchful
> waiting' derived some benefit from Casodex therapy. This evidence
> takes the form of (1) consistent direction of effect for Casodex in
> clinically relevant subgroups in both trials and of (although not
> rigorous statistical evidence) and (2) nominally low p-values in both
> trials separately comparing Casodex to placebo in each of these
> clinically relevant subgroups. However, based on Casodex labeling in
> other countries and the recent data searching by the sponsor, the
> revised version of the sponsor's indication now excludes patients who
> underwent RP with T1/T2 disease.
>
> However, there is no evidence that Casodex would be beneficial to
> patients who underwent previous therapy in the US (the only class of
> patients who were studied in the US). Moreover, the sponsor has not
> provided evidence that 'watchful waiting' patients would benefit from
> Casodex 150 mg in the US. In fact, there is reason to believe that
> patients who got 'watchful waiting ' in Europe are not the same
> patients who would receive 'watchful waiting' in the US. Although the
> sponsor claims that the patient population undergoing previous therapy
> in Europe and the US were quite different, adjusting for clinically
> relevant factors at baseline does not seem to account for the
> difference in incidence, a sign that baseline measurements may not be
> calibrated between the two regions, associations with progression are
> weak, and/or that there are some unrecorded factors which depressed
> "objectively confirmed progression" in the US. It is also possible
> that differences in clinical practice rendered the US study such that
> the prostatectomy patients were fated to get no benefit from Casodex.
> Only monitoring the current US trial can answer that question. Given
> the lack of sufficient information in the US at this time, one course
> is to request further data from the Trial 23 so that a decision does
> not rest solely on an extrapolation of results from Europe."

## Medical Reviewer's Overall Assessment of Efficacy (Statistical and Clinical Significance)

Interpretation of the overall body of data submitted by the Sponsor in
support of the efficacy of Casodex in delaying progression of disease in
men with non-metastatic prostate cancer and the relevance of these data
to US patients is problematic for several reasons.

1.  Each of the trials enrolled patients who had undergone different
    therapies prior to treatment with Casodex or placebo. Each of the
    trials, however, was powered only to show an overall treatment
    effect and the protocol-defined primary efficacy analysis for each
    study did not address the issue of varying degrees of efficacy in
    the different subsets of patients based on prior therapy.

2.  Although the enrollment criteria for the 3 pivotal trials were
    similar for the most part, there were significant differences. More
    importantly, review of the baseline disease characteristics of the
    patients enrolled into each of the 3 trials suggested that the
    extent or severity of disease at the time of randomization differed
    significantly in each of the trials.

3.  The Sponsor's protocol-defined primary efficacy assessments,
    endpoints, and analyses were never entirely accepted by DRUDP.

```{=html}
<!-- -->
```
a.  Whereas DRUDP felt that objective disease progression should be
    limited to the events of bone scan confirmed evidence of metastases
    or death in the absence of a positive bone scan, the Sponsor
    preferred a broader definition of objective disease progression. The
    Sponsor's protocol defined events of objective disease progression
    included not only events confirmed by bone scan but events (both
    local and distant) that were documented by magnetic resonance
    imaging, computerized tomography, sonography, or biopsy.

b.  The Sponsor preferred a time to event analysis in which all
    post-randomization "objective" events would be included in the
    analyses. Because of the potential for investigator assessment bias
    due to lack of adequate treatment blinding, DRUDP preferred an
    alternative binary analysis. DRUDP preferred an analysis based
    entirely on the proportion of patients with bone scan confirmed
    progress or death within 2 years of randomization. The 2-year time
    point was selected because all patients were to have a protocol
    mandated bone scan at Year 2 if objective disease progression had
    not been previously documented.

```{=html}
<!-- -->
```
4.  The outcomes of the 2 non-US trials (both supportive of efficacy)
    differed from the outcome of the single US trial (no evidence of
    efficacy).

Items 1 to 3 would have been less problematic to interpretation of the
overall body of efficacy data if the outcome of Trial 23 had not
differed from that of Trials 24 and 25 (Item 4).

In spite of the study design issues listed above, the Sponsor has
provided and statistically significant evidence in two of 3 clinical
trials (Trials 24 and 25) that treatment with Casodex 150 mg per day,
compared to treatment with placebo, delayed progression of prostate
cancer as assessed by the appearance of new bone scan documented
metastases or death in the absence of disease progression. The relevance
of these findings to US patients with prostate cancer, who might receive
Casodex as (1) adjuvant therapy following radical prostatectomy or
radiotherapy or (2) monotherapy instead of management by watchful
waiting or surveillance, is not clear.

### Demonstrated Efficacy of Casodex in Non-US Clinical Trials (Trials 24 and 25)

Efficacy analyses of the data in each of Trials 24 and 25 provided
statistically significant evidence that treatment with Casodex, compared
to treatment with placebo, delayed progression of prostate cancer.
Evidence of efficacy was provided using either (1) the Sponsor's
preferred endpoint of all "objective progressions" or death in the
absence of objective progression and a time-to-event analysis or (2) the
FDA-preferred endpoint of bone scan confirmed progression or death in
the absence of objective progression and a binary analysis based on
events within 2.0 years (or 2.5 years) of randomization.

Although none of the trials was designed or powered to demonstrate
statistically significant improvement within a subgroup, estimates of
the odds ratio for each subgroup in Trials 24 and 25 with a total of at
least 500 patients suggested a benefit of Casodex treatment based on the
FDA-requested endpoints and analyses. For the watchful waiting subgroups
in Trials 24 and 25, the estimates of the odds ratios (Casodex vs.
placebo) and the associated 95% confidence intervals were 0.674 (95% CI:
0.471 to 0.964; Trial 24) and 0.498 (95% CI: 0.338 to 0.734; Trial 25).
For adjuvant-treated patients in Trial 24, the estimates of the odds
ratios (Casodex vs. placebo) and the associated 95% confidence intervals
were 0.616 (95% CI: 0.379 to 1.003; radical prostatectomy subgroup) and
0.625 (95% CI: 0.361 to 1.081; radiotherapy subgroup). Too few
adjuvant-treated patients were studied in Trial 25 to draw any
conclusions about the efficacy of Casodex treatment.

### Lack of Casodex Efficacy in US Clinical Trial (Trial 23)

Data presented by the Sponsor from Trial 23 showed no evidence of
efficacy for adjuvant treatment with Casodex in patients previously
treated by radical prostatectomy or radiotherapy. Patients previously
managed by watchful waiting were not enrolled into Trial 23. Because the
incidence of objective disease progression (i.e., positive bone scans)
was very low in placebo-treated patients in Trial 23 (\<1.5%), there was
no opportunity for Casodex to demonstrate efficacy in the study
population. The Sponsor's explanation for the low incidence of disease
progression in this Trial, relative to that in Trial 24 and Trial 25,
was that patients enrolled into Trial 23 had less advanced disease at
entry and had derived greater benefit from their initial therapy. To
support this position, the Sponsor presented data from 2 subset analyses
across the 3 trials. These subsets consisted of:

-   patients who underwent prostatectomy with locally advanced disease
    (Stage T3/T4) and detectable postsurgical PSA levels (PSA
    \> 0.20 ng/mL) and

-   patients who underwent radiotherapy with locally advanced disease
    (Stage T3/T4) and elevated preradiation PSA levels (PSA
    \> 10 ng/mL).

The subset analysis for Casodex adjuvant treatment of patients initially
treated by radical prostatectomy appeared to be somewhat supportive of
the Sponsor's position. Upon further review of the of the analysis for
Trial 23, however, it was learned that the numeric difference in support
of the efficacy of Casodex was a result primarily of (1) objective
events other than bone metastases and (2) deaths unrelated to prostate
cancer. The subset analysis for Casodex adjuvant treatment of patients
initially treated by radiotherapy included very few patients from Trial
23 and was not supportive of the sponsor's position. Based on the
results from Trial 23, it is not possible to determine which patients
who are initially treated by radical prostatectomy or radiotherapy in
the US might derive benefit from adjuvant treatment with Casodex.

### Relevance of Watchful Waiting (Immediate Therapy) Subgroups in Trials 24 and 25 to Prostate Cancer Patients in the US Managed by Watchful Waiting

Patients managed by watchful waiting in the US generally are elderly men
( 75 years of age), have low grade (i.e., low Gleason Score), and
localized (stage T1/T2) tumors with serum PSA levels \< 20 ng/mL. It is
anticipated that most of these men will remain free of clinically
significant prostate cancer symptoms during their lifetime and will die
from causes other than prostate cancer. Based on demographic data,
baseline disease characteristics, and outcomes in the watchful waiting
patients, it appeared that many of the patients in Trials 24 and 25
would likely have received active therapy (radiotherapy or castration
\[medical or surgical\]) in the US in accordance with present standards
of care. It cannot be determined with a reasonable level of assurance
from the non-US data if patients in the US who are generally managed by
watchful waiting would have experienced a sufficient number of bone scan
confirmed events in the time frame of the clinical trials to have
derived clinically significant benefit from Casodex monotherapy.

The originally proposed indications and the first revision of the
proposed indications for Casodex 150 mg therapy indicated that the
Sponsor also was seeking approval for treatment of patients with locally
advanced, non-metastatic prostate cancer. This was a concern since the
efficacy of Casodex monotherapy in such patients was not compared to
that of castration (the generally accepted standard of care in the US)
in the trials submitted in support of this application. Data previously
submitted by the Sponsor from Trials 0306 and 0307 did not adequately
support the Sponsor's contention that Casodex treatment and castration
(medical or surgical) were equally efficacious (based on survival) for
the treatment of locally advanced non-metastatic prostate cancer.
Survival in the Casodex-treated MO patients, compared to that in the
patients treated by castration, differed across the 2 trials. In Trial
0306 (n = 140 M0 patients), the risk of death was calculated as 36%
lower in the Casodex group while in Trial 0307 (n = 352 M0 patients),
the risk of death was calculated as 25% higher in the Casodex group.
This concern has been addressed in part by the Sponsor's second revision
to the proposed indication for Casodex immediate therapy. The second
revision states that Casodex immediate treatment is indicated for the
treatment of "[localized]{.underline} non-metastatic prostate cancer in
patients for whom therapy of curative intent is not indicated."

### Lack of Improved Survival in Casodex-Treated Patients

Treatment with Casodex had no demonstrable effect on either
disease-specific or overall survival. This finding was anticipated
because of the short period of patient follow up subsequent to entry
into the trials (median of 3 years follow up) and immaturity of the
data.

# Integrated Review of Safety 

## Brief Statement of Conclusions

The database from Trials 23, 24, and 25 supporting the safety of Casodex
150 mg per day was large. It included 4,022 Casodex-treated patients,
representing 9,387 patient years of exposure. Overall, most patients
(97.4% Casodex group, 88.2% placebo group) had at least one adverse
event. The number of patients with at least 1 drug-related adverse event
was approximately 3-fold higher in the Casodex group (90.5%) than the
placebo group (31.4%). A greater number of patients in the Casodex group
also were withdrawn from treatment because of an adverse event (27.7%
compared with 9.2% of placebo-treated patients). The number of patients
who had at least 1 serious adverse event was similar across the
treatment groups (33.6% Casodex group, 32.5% placebo group). Much of the
difference between the Casodex and placebo treatment groups in each of
the categories of (1) any adverse event, (2) drug-related adverse
events, and (3) adverse events leading to withdrawal was due to the
pharmacological (anti-androgenic and compensatory estrogenic) actions of
Casodex.

Adverse events associated with Casodex treatment can be classified for
the most part into one of 2 categories: (1) those of a non-life
threatening nature that are due to the pharmacological actions of
Casodex and which occur with a high incidence (e.g., breast pain and
gynecomastia) and (2) those that occur in a few percent of patients and
which may be severe and rarely fatal (primarily hepatotoxicity). The
risks of treatment with Casodex 150 mg per day appear to be justified
and acceptable for patients who would derive significant benefit from
treatment with Casodex.

## Overview of Controlled Safety Studies (Trials 23, 24, and 25)

The sponsor submitted data from 3 randomized, double blind, placebo
controlled clinical trials that enrolled men with non-metastatic
prostate cancer. Enrollment criteria (with some exceptions), efficacy
assessments, and safety assessments were similar across the 3 trials.
Trial 23 (n = 3,254 safety patients) was conducted in North America,
primarily the United States. Trial 24 (n = 3,585 safety patients) was
conducted in Europe (other than Scandinavia), Israel, South Africa,
Mexico, and Australia. Trial 25 (n = 1,214 safety patients) was
conducted in Scandinavia. Of these patients, 4,022 received Casodex 150
mg per day and 4,031 received placebo tablets (Table 1 and Figure 2).

[]{#__RefHeading___Toc25232679 .anchor}Figure 2 Overview of Safety
Patient Population

![](media/image2.png)

## Protocol Defined Safety Assessments

Safety assessments in the controlled clinical trials consisted primarily
of (a) monitoring for and recording of adverse events and deaths and (b)
clinical laboratory measurements for signs of liver toxicity or
dysfunction. Table 4 lists the times at which the protocol-required
safety assessments were to be performed.

### Adverse Events and Survival

**Collection of adverse event data**

An adverse event was defined by the Sponsor as "any detrimental change
in the condition of the patient unrelated to prostate cancer,
irrespective of whether the investigator considered that this reported
change was related to trial therapy." Adverse events were identified by
spontaneous reporting by the patient and in response to a non-leading
question asked by the investigator. In addition, any clinical finding or
laboratory data considered by the investigator to be clinically
significant or warranting treatment also was to be reported as an
adverse event. All adverse events were to be reported if (1) they had an
onset date or worsened while a patients was on randomized treatment or
(2) they occurred within 28 days after termination of treatment or
within 28 days of the onset of initiating additional systemic therapy
for prostate therapy. On occasion, serious adverse events that had an
onset date outside of the 28-day follow-up period also were reported.

During the first 96 weeks after treatment onset in each of the clinical
trial, patients were to be monitored for adverse events and changes in
liver function every 12 weeks while receiving study drug. In Trial 23,
randomized treatment was limited to 96 weeks or until disease
progression, whichever occurred first. In Trials 24 and 25, treatment
with study drug was to continue for at least 5 years or until disease
progression. Following completion of, or withdrawal from randomized
treatment, patients were to be contacted every 3-12 months to collect
survival data. Progression of prostate cancer and the symptoms thereof
were not routinely recorded as adverse events.

**Analysis and presentation of adverse event data**

All patients receiving trial therapy were included in the assessment of
safety. Investigator's descriptions of adverse events were categorized
using an in-house dictionary of terms, based on the Food and Drug
Administration's Coding Symbols for Thesaurus of Adverse Reaction Terms
(COSTART) system. Consolidated COSTART terms were created to pool
together common COSTART preferred terms for descriptive analyses.
Adverse events were summarized by consolidated COSTART-preferred term.

Deaths were attributed to either prostate cancer alone or to other
causes. In contrast to adverse event data that was limited to
on-treatment events, deaths that occurred from any cause, either during
or after withdrawal of trial therapy, were included in the submission.

### Clinical Laboratory Tests

Protocol-required clinical laboratory tests were limited to the
assessment of liver toxicity and liver function and consisted of (1)
SGOT/AST, (2) SGPT/ALT, and (3) total bilirubin. Blood samples for these
measurements were collected at screening and every 12 weeks after the
start of treatment with study drug.

For the most part, all samples from the clinical trials were analyzed at
a central laboratory at either AstraZeneca Pharmaceuticals, Macclesfield
(Trials 24 and 25, European sites only) or Quest Diagnostics, Van Nuys,
CA (Trial 23) (formerly SmithKline Beecham Diagnostics). For Trial 24,
samples from Australia, Israeli, Mexican, and South African centers were
sent to a local laboratory in each country.

### Assessment of Sexual Function (Trial 25 Only)

In Trial 25, sexual function during the first 48 weeks of treatment was
monitored by a patient-completed shortened version of the Golombok Rust
Inventory of Sexual Satisfaction (GRISS) questionnaire. The
questionnaire was completed at the baseline (pre-randomization) visit
and at Weeks 12, 24, 36, and 48. The questionnaire consisted of the
following 6 questions:

1.  Do you have sexual intercourse more than twice a week?

2.  Do you become easily sexually aroused?

3.  Do you fail to get an erection?

4.  Do you get an erection during foreplay with your partner?

5.  Are there weeks in which you don't have sex at all?

6.  Do you lose your erection during intercourse?

From the scores obtained for the 6 questions, 2 measures (domains) of
sexual function were calculated: infrequency (based on the sum of the
scores of Questions 1 and 5) and impotence (based on the sum of the
scores of Questions 2, 3, 4 and 6).

## Demographics and Other Baseline Characteristics (Safety Population)

Virtually all (\>99%) of the patients randomized to treatment (the
efficacy population) received one or more doses of study drug. Baseline
demographic data and baseline disease characteristics for the efficacy
population were reviewed earlier in Section 4.6.2. Baseline demographic
data are summarized in Table 8 and baseline disease characteristics are
summarized in Table 9 and Table 10.

##### Medical Officer's Comment {#medical-officers-comment-10 .unnumbered}

-   The Casodex and placebo treatment groups were well balanced when
    data from the 3 clinical trials were combined as well as when
    assessed within each trial. However, there were significant
    differences across each of the trials. These differences do not
    affect pooling of data across the 3 trials for safety analyses, but
    preclude meaningful pooling of data for efficacy analyses as
    discussed earlier.

### Exposure and Duration of Treatment in the Controlled Clinical Trials

For the controlled trials, exposure was defined as the time from
starting therapy to the earlier of either withdrawal of study therapy or
addition of other systemic therapy for treatment of prostate cancer. If
a patient had not discontinued randomized study therapy or had not
received additional systemic therapy as of the date of the safety data
cutoff, the time of exposure was calculated up to the last time that the
patient was known to have taken study therapy.

Table 35 presents combined patient-years of exposure in the 3 controlled
trials as of the 4‑Month Safety Update data cutoff date of 28 September
2001. The mean and median duration of exposure to study drug was
slightly higher for placebo-treated patients than for Casodex-treated
patients.

[]{#__RefHeading___Toc25309695 .anchor}Table 35 Years of Exposure to
Study Drug (Trials 23, 24, and 25 Combined)

  --------------------------------- ------------------- ------------------
                                    Years of exposure   

                                    Casodex             Placebo

                                    (N=4022)            (N=4031)

  Total patient-years               9387                9778

  Mean patient years                2.33                2.43

  Median patient years              1.85                1.86

  Range (year)                      \<0.01 to 5.98      \<0.01 to 5.80
  --------------------------------- ------------------- ------------------

N = Number of patients who received randomized treatment

Source: Safety Update, Table T2.2.1.

Table 36 summarizes exposure to treatment by duration of treatment
across the 3 controlled trials. Approximately 42% of patients who
received Casodex (1680/4022) and placebo (1690/4031) remained on therapy
for at least 2 years. At the time of data cutoff for the Safety Update,
more than 50% of the patients in Trials 24 and 25 had received at least
3 years of Casodex therapy. Unlike Trials 24 and 25, the treatment
period in Trial 23 did not extend beyond 2 years.

> []{#__RefHeading___Toc25309696 .anchor}Table 36 Duration of Treatment
> (Trials 23, 24, and 25 Combined)

  ----------------------------- ------------- ---------- ------------- ----------
                                **Number (%)                           
                                of patients**                          

  **Duration of exposure**      **Casodex**              **Placebo**   

                                (N=4022)                 (N=4031)      

  \<6 months                    573           (14.2)     324           (8.0)

  6 months to \<12 months       384           (9.5)      309           (7.7)

  12 months to \<18 months      230           (5.7)      217           (5.4)

  18 months to \<24 months      1155          (28.7)     1491          (37.0)

  24 months to \<36 months      248           (6.2)      303           (7.5)

  36 months to \<48 months      706           (17.6)     708           (17.6)

  48 months +                   726           (18.1)     679           (16.8)
  ----------------------------- ------------- ---------- ------------- ----------

Source: Safety Update, Table T2.1.1.

##### Medical Officer\'s Comments {#medical-officers-comments-27 .unnumbered}

-   The database supporting the safety of Casodex 150 mg per day is
    large. More than 4,000 patients, representing more than 9,000
    patient years of exposure, were treated with Casodex 150 mg per day.

-   Patient exposure to Casodex in the controlled clinical trials was
    adequate to assess the likely safety profile of Casodex 150 per day
    in men with prostate cancer.

## Patient Disposition 

At the time of data cutoff for the ISS (23 February 2001), 1,532 of
4,022 patients (38.1%) in the Casodex-treated patients and 1,282 of
4,031 patients (31.8%) in the placebo-treated patients had withdrawn
prematurely from treatment with study drug. Patient disposition in each
of the clinical trials is summarized in Table 37.

In Trial 23, a total of 618 (38.0%) patients in the Casodex group and
329 (20.2%) patients in the placebo group were withdrawn from the trial.
Of patients withdrawing from Casodex treatment, 31.0% withdrew due to
adverse events, most notably gynecomastia and breast pain. In the
placebo group, 9.0% withdrew from treatment due to adverse events. In
Trial 24, 841 (47.0%) patients treated with Casodex and 801 (44.6%)
patients treated with placebo were withdrawn from the trial. The most
common reason for withdrawal from Casodex treatment was an adverse event
(27.0% of patients compared with 9.4% of placebo-treated patients).
Disease progression, either subjectively or objectively confirmed, was
the most common reason for withdrawal in placebo-treated patients (12.6%
compared with 3.7% of Casodex-treated patients). In Trial 25, 225
(37.2%) patients were withdrawn from Casodex treatment and 328 (53.9%)
were withdrawn from placebo treatment. The most common reason for
withdrawal from Casodex treatment was an adverse event (17.2% of
patients compared with 7.4% of placebo-treated patients). Disease
progression, either subjectively or objectively confirmed, was the most
common reason for withdrawal in placebo-treated patients (32.3% compared
with 10.7% of Casodex-treated patients).

[]{#__RefHeading___Toc25309697 .anchor}Table 37 Disposition of Patients
in Trials 23, 24, and 25 as of 23 February 2001

  ------------------------- -------------- ---------- -- ---------- ---------- -- ---------- ----------
                            **Percentage                                                     
                            of Patients**                                                    

  **Disposition**           **Trial 23**                 **Trial                  **Trial    
                                                         24**                     25**       

                            Casodex\       Placebo\      Casodex\   Placebo\      Casodex\   Placebo\
                            (N=1627)       (N=1627)      (N=1790)   (N=1795)      (N=605)    (N=609)

  Treatment completed or    62.0%          79.8%         53.0%      55.4%         62.8%      46.1%
  ongoing ^1^                                                                                

  Premature termination of  38.0%          20.2%         47.0%      44.6%         37.2%      53.9%
  treatment                                                                                  

  Death                     0.6%           0.8%          3.4%       2.6%          4.6%       3.3%

  Disease progression ^2^   0.3%           0.7%          3.7%       12.6%         10.7%      32.3%

  Adverse event             31.0%          9.0%          27.0%      9.4%          17.2%      7.4%

  Non-compliance            0.4%           0.6%          0.8%       0.9%          0.2%       0.2%

  Patient's decision        5.0%           5.4%          9.0%       7.6%          3.6%       5.3%

  Investigator decision     0.6%           3.6%          \--        \--           \--        \--

  Lost to follow up         \--            \--           0.8%       1.2%          0.2%       0.7%

  Other ^3^                 0.1%           0.1%          2.1%       10.3%         0.7%       4.8%
  ------------------------- -------------- ---------- -- ---------- ---------- -- ---------- ----------

1\. Treatment period in Trial 23 ended prior to 23 February 2001.
Treatment in Trials 24 and 25 is ongoing.

2\. Includes objective and subjective progression but not an increase in
PSA alone.

3\. Includes increase in PSA, need for other systemic therapy, and
investigator's decision (Trials 24 and 25).

Source: Text Table 2, Safety Addendum Report for each of Trials 23, 24,
and 25.

##### Medical Officer\'s Comments {#medical-officers-comments-28 .unnumbered}

-   In each of the clinical trials, the most common cause for premature
    termination of treatment with Casodex was an adverse event. Adverse
    events were responsible for premature termination in 31.0%, 27.0%,
    and 17.2% of Casodex-treated patients in Trials 23, 24, and 25,
    respectively. In each of the trials, the percentage of patients
    terminating prematurely due to an adverse event was higher in the
    Casodex-treated patients. In each of the trials, breast pain or
    gynecomastia was the most common adverse event leading to premature
    termination of treatment in these patients.

-   In placebo-treated patients, the most common cause for premature
    termination of treatment was either an adverse event (Trial 23) or
    disease progression (Trial 24 and Trial 25).

## Adverse Events

In this review, adverse events for Trials 23, 24, and 25 are presented
and discussed in the following manner. An overview of reported adverse
events, based on the numbers of patients reporting adverse events
summarized into broad categories, is first presented (Section 5.6.1).
This is followed by a summary and discussion of (1) the most commonly
reported adverse events (all degrees of severity and all relationships
to study drugs, Section 5.6.2), (2) the most commonly reported adverse
events possibly related to treatment with study drugs (Section 5.6.3),
(3) adverse events that resulted in withdrawal of patients from the
clinical trials (Section 5.6.4), and (4) serious adverse events reported
during the treatment period (Section 5.6.5). In these trials, clinical
signs or symptoms that were related to progression of prostate cancer
were not considered as adverse events and were not in general reported
or included in data summaries or listings.

Deaths from all causes other than prostate cancer are discussed in
Section 5.7. Adverse events of particular interest (e.g.,
pharmacological adverse events such as gynecomastia) or adverse events
of particular concern based on the reported safety data (e.g., liver
toxicity and blood dyscrasias) are reviewed separately in Section 5.9.

### Overview of Adverse Events 

Table 38 provides an overview of the proportion of patients who
experienced adverse events across the 3 clinical trials during treatment
with study drug. Overall, most patients (97.4% Casodex group, 88.2%
placebo group) had at least one adverse event. The number of patients
with at least 1 drug-related adverse event was approximately 3-fold
higher in the Casodex group (90.5%) than the placebo group (31.4%). A
greater number of patients in the Casodex group also were withdrawn from
treatment because of an adverse event (27.7% compared with 9.2% of
placebo-treated patients). The number of patients who had at least
1 serious adverse event was similar across the treatment groups (33.6%
Casodex group, 32.5% placebo group). The percentage of patients with an
adverse event leading to death (a non-prostate cancer related death that
occurred within the treatment period) was slightly higher in the Casodex
group (4.2% compared to 3.6% in placebo-treated patients).

[]{#__RefHeading___Toc25309698 .anchor}Table 38 Overview of Adverse
Events during Treatment (Trials 23, 24, and 25)

  ------------------------------------ ------------- -------- ---------- --------
                                       **Number (%)                      
                                       of patients**                     

  **Category ^1^**                     Casodex                Placebo    

                                       (N=4022)^2^            (N=4031)   

  Patients with at least 1 adverse     3916          (97.4)   3555       (88.2)
  event                                                                  

  Drug-related adverse events          3641          (90.5)   1267       (31.4)

  Adverse events leading to withdrawal 1116          (27.7)   369        (9.2)

  Serious adverse events               1350          (33.6)   1310       (32.5)

  Adverse events leading to death ^3^  168           (4.2)    145        (3.6)
  ------------------------------------ ------------- -------- ---------- --------

1\. Patients may appear in more than 1 category.

2\. N = number of patients who received randomized treatment.

3\. Does not include deaths attributed to prostate cancer.

Source: Safety Update. Data derived from Table T3.1.1.

##### Medical Officer's Comments {#medical-officers-comments-29 .unnumbered}

-   Much of the difference between the Casodex and placebo treatment
    groups in each of the categories of (1) patients with at least 1
    adverse event, (2) drug-related adverse events, and (3) adverse
    events leading to withdrawal was due to the pharmacological
    (anti-androgenic and compensatory estrogenic) actions of Casodex,
    particularly breast pain and gynecomastia, as shown in the Table
    below.

  ---------------------------------------- ------------- ---------- ----------- ----------
                                           ***Number (%)                        
                                           of                                   
                                           patients***                          

  ***Category***                           *Casodex                 *Placebo    
                                           (N=4022)*                (N=4031)*   

  *Any adverse event*                                                           

  *All Causes*                             *3916*        *(97.4)*   *3555*      *(88.2)*

  *Gynecomastia and breast pain excluded*  *3583*        *(89.1)*   *3517*      *(87.2)*

  *Drug-related adverse events*                                                 

  *All Causes*                             *3641*        *(90.5)*   *1267*      *(31.4)*

  *Gynecomastia and breast pain excluded*  *1700*        *(42.3)*   *962*       *(23.9)*

  *Adverse events leading to withdrawal*                                        

  *All Causes*                             *1116*        *(27.7)*   *369*       *(9.2)*

  *Gynecomastia and breast pain excluded*  *579*         *(14.4)*   *350*       *(8.7)*
  ---------------------------------------- ------------- ---------- ----------- ----------

*Source: Tables T3.1.1 and T3.1.8 from Safety Update*.

Table 39 provides an overview of the proportion of patients who
experienced adverse events within each of Trials 23, 24, and 25 during
treatment with study drug.

[]{#__RefHeading___Toc25309699 .anchor}Table 39 Overview of Adverse
Events by Clinical Trial during Randomized Treatment

  -------------------- -- -------------- --------- -- --------- --------- -- --------- ---------
                          **Percentage                                                 
                          of Patients                                                  
                          with Event**                                                 

  **Category ^1^**        **Trial 23**                **Trial                **Trial   
                                                      24**                   25**      

                          Casodex        Placebo      Casodex   Placebo      Casodex   Placebo

                          N=1627         N=1627       N=1790    N=1795       N=605     N=609

  Patients with 1         98.1           90.4         95.9      85.7         98.7      87.4
  adverse event                                                                        

  Drug related adverse    92.8           31.8         87.5      32.0         92.7      26.3
  event                                                                                

  AE leading to           31.0           9.0          27.3      9.4          17.2      7.1
  withdrawal                                                                           

  Serious adverse         17.8           18.6         38.2      37.3         50.4      44.3
  event                                                                                

  AE leading to death     1.2            1.5          4.7       4.3          6.9       4.4
  ^2^                                                                                  
  -------------------- -- -------------- --------- -- --------- --------- -- --------- ---------

1\. Patients may appear in more than 1 category.

2\. Does not include deaths attributed to prostate cancer.

N = number of patients who received randomized treatment.

Source: ISS, Table T3.1.2.

##### Medical Officer's Comments {#medical-officers-comments-30 .unnumbered}

-   The proportion of patients experiencing adverse events in each of
    the categories listed in Table 39 were similar across the 3 trials
    with the following exceptions:

```{=html}
<!-- -->
```
-   *In the Casodex-treatment groups, adverse events leading to
    withdrawal occurred most frequently in Trial 23 (31.0% of patients)
    and least frequently in Trial 25 (17.2% of patients).*

-   *The proportion of patients with serious adverse events was
    approximately 2-fold and 2.5-fold greater in Trials 24 and 25,
    respectively, compared to Trial 23.*

-   *The proportion of patients with adverse events leading to death was
    highest in Trial 25 and lowest in Trial 23.*

### Adverse Events (All Intensities and All Relationships to Study Drug)

The majority of patients enrolled in the clinical trials had at least 1
adverse event. In the Casodex treatment group, 3,916 of 4,022 patients
(97.4%) reported one or more adverse events compared with 3,555 of 4,031
patients (88.2%) in the placebo treatment group. Adverse events that
occurred in 5% or more of the patients in either of the treatment groups
are listed in Table 40 by decreasing incidence in the Casodex-treated
patients. Adverse events more common in the Casodex-treatment group than
in the placebo group included breast pain, gynecomastia, alopecia,
weight gain, vasodilatation, impotence, and asthenia. The majority of
these latter adverse events were considered by the investigator to be
related to study drug.

##### Medical Officer's Comments {#medical-officers-comments-31 .unnumbered}

-   Much of difference in the proportion of patients reporting the
    adverse events listed in Table 40 can be attributed to the
    pharmacological (anti-androgenic and compensatory estrogenic)
    effects of treatment with Casodex.

-   The observed incidence of non-pharmacological adverse events is not
    unexpected in a population of elderly men (mean age \>65 years) with
    prostate cancer.

-   Other adverse events of possible clinical importance that were
    reported with a frequency of \< 5% but which occurred more
    frequently in Casodex-treated patients were heart failure (2.1%
    Casodex, 1.4% placebo) and abnormal liver function tests
    (3.0% Casodex; 1.5% placebo). These are reviewed and discussed later
    in Section 5.9.

[]{#__RefHeading___Toc25309700 .anchor}Table 40 Adverse Events with an
Incidence 5% (Combined Data from\
Trials 23, 24, and 25)

+------------------------+-------+-------+---+---+-------+--------+---+--------+
| **Adverse Event**      | **N   |       |   |   |       |        |   | **Re   |
|                        | umber |       |   |   |       |        |   | lative |
|                        | of    |       |   |   |       |        |   | Incid  |
|                        | pat   |       |   |   |       |        |   | ence** |
|                        | ients |       |   |   |       |        |   |        |
|                        | repo  |       |   |   |       |        |   | [Cas   |
|                        | rting |       |   |   |       |        |   | odex]{ |
|                        | ad    |       |   |   |       |        |   | .under |
|                        | verse |       |   |   |       |        |   | line}\ |
|                        | ev    |       |   |   |       |        |   | p      |
|                        | ent** |       |   |   |       |        |   | lacebo |
+------------------------+-------+-------+---+---+-------+--------+---+--------+
|                        | Cas   |       |   |   | Pla   |        |   |        |
|                        | odex\ |       |   |   | cebo\ |        |   |        |
|                        | (N =  |       |   |   | (N =  |        |   |        |
|                        | 4022) |       |   |   | 4031) |        |   |        |
+------------------------+-------+-------+---+---+-------+--------+---+--------+
|                        | n ^1^ | (%)   |   |   | n ^1^ | (%)    |   |        |
+------------------------+-------+-------+---+---+-------+--------+---+--------+
| Breast pain            | 2937  | (     |   | 2 |       | (7.3)  | 9 |        |
|                        |       | 73.0) |   | 9 |       |        | . |        |
|                        |       |       |   | 6 |       |        | 9 |        |
|                        |       |       |   |   |       |        | 4 |        |
+------------------------+-------+-------+---+---+-------+--------+---+--------+
| Gynecomastia           | 2700  | (     |   | 3 |       | (8.1)  | 8 |        |
|                        |       | 67.1) |   | 2 |       |        | . |        |
|                        |       |       |   | 5 |       |        | 3 |        |
|                        |       |       |   |   |       |        | 3 |        |
+------------------------+-------+-------+---+---+-------+--------+---+--------+
| Asthenia               | 427   | (     |   | 3 |       | (7.5)  | 1 |        |
|                        |       | 10.6) |   | 0 |       |        | . |        |
|                        |       |       |   | 3 |       |        | 4 |        |
|                        |       |       |   |   |       |        | 1 |        |
+------------------------+-------+-------+---+---+-------+--------+---+--------+
| Pharyngitis            | 415   | (     |   | 4 |       | (10.9) | 0 |        |
|                        |       | 10.3) |   | 4 |       |        | . |        |
|                        |       |       |   | 1 |       |        | 9 |        |
|                        |       |       |   |   |       |        | 4 |        |
+------------------------+-------+-------+---+---+-------+--------+---+--------+
| Rash                   | 390   | (9.7) |   | 3 |       | (8.0)  | 1 |        |
|                        |       |       |   | 2 |       |        | . |        |
|                        |       |       |   | 4 |       |        | 2 |        |
|                        |       |       |   |   |       |        | 1 |        |
+------------------------+-------+-------+---+---+-------+--------+---+--------+
| Back pain              | 367   | (9.1) |   | 4 |       | (11.0) | 0 |        |
|                        |       |       |   | 4 |       |        | . |        |
|                        |       |       |   | 2 |       |        | 8 |        |
|                        |       |       |   |   |       |        | 3 |        |
+------------------------+-------+-------+---+---+-------+--------+---+--------+
| Vasodilatation         | 364   | (9.1) |   | 2 |       | (5.2)  | 1 |        |
|                        |       |       |   | 1 |       |        | . |        |
|                        |       |       |   | 1 |       |        | 7 |        |
|                        |       |       |   |   |       |        | 3 |        |
+------------------------+-------+-------+---+---+-------+--------+---+--------+
| Impotence              | 362   | (9.0) |   | 2 |       | (6.2)  | 1 |        |
|                        |       |       |   | 5 |       |        | . |        |
|                        |       |       |   | 0 |       |        | 4 |        |
|                        |       |       |   |   |       |        | 5 |        |
+------------------------+-------+-------+---+---+-------+--------+---+--------+
| Constipation           | 344   | (8.6) |   | 2 |       | (7.0)  | 1 |        |
|                        |       |       |   | 8 |       |        | . |        |
|                        |       |       |   | 3 |       |        | 2 |        |
|                        |       |       |   |   |       |        | 2 |        |
+------------------------+-------+-------+---+---+-------+--------+---+--------+
| Arthralgia             | 314   | (7.8) |   | 3 |       | (9.4)  | 0 |        |
|                        |       |       |   | 7 |       |        | . |        |
|                        |       |       |   | 8 |       |        | 8 |        |
|                        |       |       |   |   |       |        | 3 |        |
+------------------------+-------+-------+---+---+-------+--------+---+--------+
| Urinary tract          | 299   | (7.4) |   | 2 |       | (6.4)  | 1 |        |
| infection              |       |       |   | 5 |       |        | . |        |
|                        |       |       |   | 9 |       |        | 1 |        |
|                        |       |       |   |   |       |        | 6 |        |
+------------------------+-------+-------+---+---+-------+--------+---+--------+
| Flu syndrome           | 295   | (7.3) |   | 2 |       | (7.3)  | 1 |        |
|                        |       |       |   | 9 |       |        | . |        |
|                        |       |       |   | 6 |       |        | 0 |        |
|                        |       |       |   |   |       |        | 0 |        |
+------------------------+-------+-------+---+---+-------+--------+---+--------+
| Abdominal pain         | 275   | (6.8) |   | 2 |       | (6.9)  | 0 |        |
|                        |       |       |   | 7 |       |        | . |        |
|                        |       |       |   | 8 |       |        | 9 |        |
|                        |       |       |   |   |       |        | 9 |        |
+------------------------+-------+-------+---+---+-------+--------+---+--------+
| Hypertension           | 271   | (6.7) |   | 3 |       | (7.5)  | 0 |        |
|                        |       |       |   | 0 |       |        | . |        |
|                        |       |       |   | 3 |       |        | 9 |        |
|                        |       |       |   |   |       |        | 0 |        |
+------------------------+-------+-------+---+---+-------+--------+---+--------+
| Diarrhea               | 263   | (6.5) |   | 2 |       | (6.7)  | 0 |        |
|                        |       |       |   | 6 |       |        | . |        |
|                        |       |       |   | 8 |       |        | 9 |        |
|                        |       |       |   |   |       |        | 8 |        |
+------------------------+-------+-------+---+---+-------+--------+---+--------+
| Urinary incontinence   | 261   | (6.5) |   | 2 |       | (5.9)  | 1 |        |
|                        |       |       |   | 3 |       |        | . |        |
|                        |       |       |   | 7 |       |        | 1 |        |
|                        |       |       |   |   |       |        | 0 |        |
+------------------------+-------+-------+---+---+-------+--------+---+--------+
| Pain                   | 258   | (6.4) |   | 2 |       | (7.1)  | 0 |        |
|                        |       |       |   | 8 |       |        | . |        |
|                        |       |       |   | 6 |       |        | 9 |        |
|                        |       |       |   |   |       |        | 0 |        |
+------------------------+-------+-------+---+---+-------+--------+---+--------+
| Pelvic pain            | 258   | (6.4) |   | 2 |       | (6.5)  | 0 |        |
|                        |       |       |   | 6 |       |        | . |        |
|                        |       |       |   | 1 |       |        | 9 |        |
|                        |       |       |   |   |       |        | 9 |        |
+------------------------+-------+-------+---+---+-------+--------+---+--------+
| Alopecia               | 239   | (5.9) |   | 3 |       | (0.8)  | 7 |        |
|                        |       |       |   | 1 |       |        | . |        |
|                        |       |       |   |   |       |        | 7 |        |
|                        |       |       |   |   |       |        | 3 |        |
+------------------------+-------+-------+---+---+-------+--------+---+--------+
| Urinary tract disorder | 234   | (5.8) |   | 2 |       | (6.9)  | 0 |        |
|                        |       |       |   | 7 |       |        | . |        |
|                        |       |       |   | 7 |       |        | 8 |        |
|                        |       |       |   |   |       |        | 5 |        |
+------------------------+-------+-------+---+---+-------+--------+---+--------+
| Weight gain            | 231   | (5.7) |   | 1 |       | (2.9)  | 2 |        |
|                        |       |       |   | 1 |       |        | . |        |
|                        |       |       |   | 5 |       |        | 0 |        |
|                        |       |       |   |   |       |        | 1 |        |
+------------------------+-------+-------+---+---+-------+--------+---+--------+
| Edema                  | 226   | (5.6) |   | 2 |       | (5.1)  | 1 |        |
|                        |       |       |   | 0 |       |        | . |        |
|                        |       |       |   | 6 |       |        | 1 |        |
|                        |       |       |   |   |       |        | 0 |        |
+------------------------+-------+-------+---+---+-------+--------+---+--------+
| Hernia                 | 195   | (4.9) |   | 2 |       | (6.0)  | 0 |        |
|                        |       |       |   | 4 |       |        | . |        |
|                        |       |       |   | 2 |       |        | 8 |        |
|                        |       |       |   |   |       |        | 1 |        |
+------------------------+-------+-------+---+---+-------+--------+---+--------+
| Headache               | 191   | (4.8) |   | 2 |       | (5.1)  | 0 |        |
|                        |       |       |   | 0 |       |        | . |        |
|                        |       |       |   | 4 |       |        | 9 |        |
|                        |       |       |   |   |       |        | 4 |        |
+------------------------+-------+-------+---+---+-------+--------+---+--------+
| Hematuria              | 183   | (4.6) |   | 2 |       | (5.8)  | 0 |        |
|                        |       |       |   | 3 |       |        | . |        |
|                        |       |       |   | 5 |       |        | 7 |        |
|                        |       |       |   |   |       |        | 8 |        |
+------------------------+-------+-------+---+---+-------+--------+---+--------+
| Accidental injury      | 171   | (4.3) |   | 2 |       | (5.6)  | 0 |        |
|                        |       |       |   | 2 |       |        | . |        |
|                        |       |       |   | 5 |       |        | 7 |        |
|                        |       |       |   |   |       |        | 6 |        |
+------------------------+-------+-------+---+---+-------+--------+---+--------+

> ^1^ Number of patients reporting the respective adverse event.\
> Source: Modified from Text Table 12, ISS, pg. 32.

### Treatment-Related Adverse Events

Treatment-related adverse events were reported for 3,641 of 4,022
patients (90.5%) in the Casodex treatment group and 1,267 of 4,031
patients (31.4%) in the placebo treatment group. Treatment-related
adverse events that occurred in  0.5% of the patients in either of the
treatment groups are listed in Table 41 by decreasing incidence in the
Casodex-treated patients. Of the treatment-related adverse events listed
in Table 41, 28 of 29 occurred more frequently in Casodex-treated
patients. The most commonly reported treatment-related adverse events in
the Casodex treatment group were breast pain (72.3% of patients),
gynecomastia (66.7%), vasodilatation (8.5%), impotence (5.8%), asthenia
(5.1%), alopecia (4.7%), and weight gain (4.0%).

##### Medical Officer's Comments {#medical-officers-comments-32 .unnumbered}

-   Among the most commonly reported treatment-related adverse events,
    the increased incidence in the Casodex-treated patients was most
    likely a consequence of the pharmacological activity of the drug.
    These events are discussed further in Section 5.9.1.

-   When the adverse events of breast pain and gynecomastia were
    eliminated from consideration, the difference between the proportion
    of Casodex-treated and placebo-treated patients who experienced one
    or more treatment-related adverse events was reduced from 90.5%
    (Casodex) vs. 31.4% (placebo) to 42.3% (Casodex) vs.
    23.9% (placebo).

-   Drug-related adverse events of particular concern that occurred more
    frequently in the Casodex treated patients were abnormal liver
    function tests (Casodex group 2.5%; placebo group 1.0%) and jaundice
    (Casodex group 0.8%; placebo group 0.4%). These events are discussed
    further in Section 5.9.

[]{#__RefHeading___Toc25309701 .anchor}Table 41. Treatment-Related
Adverse Events Occurring in  0.5% of Patients (Combined Data from Trials
23, 24, and 25)

<table style="width:100%;">
<colgroup>
<col style="width: 34%" />
<col style="width: 1%" />
<col style="width: 0%" />
<col style="width: 10%" />
<col style="width: 0%" />
<col style="width: 12%" />
<col style="width: 0%" />
<col style="width: 2%" />
<col style="width: 0%" />
<col style="width: 9%" />
<col style="width: 0%" />
<col style="width: 12%" />
<col style="width: 1%" />
<col style="width: 11%" />
</colgroup>
<tbody>
<tr class="odd">
<td rowspan="3"><strong>Adverse Event</strong></td>
<td colspan="2" rowspan="3"></td>
<td colspan="9"><strong>Number of patients reporting adverse
event</strong></td>
<td></td>
<td rowspan="3"><p><strong>Relative Incidence</strong></p>
<p><u>Casodex</u><br />
placebo</p></td>
</tr>
<tr class="even">
<td colspan="4">Casodex<br />
(N = 4022)</td>
<td colspan="2"></td>
<td colspan="3">Placebo<br />
(N = 4031)</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2">n <sup>1</sup></td>
<td colspan="2">Percentage</td>
<td colspan="2"></td>
<td colspan="2">n <sup>1</sup></td>
<td>Percentage</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Breast pain</td>
<td colspan="2">2906</td>
<td colspan="2">72.3%</td>
<td colspan="2"></td>
<td colspan="2">282</td>
<td colspan="2">7.0%</td>
<td colspan="2">10.33</td>
</tr>
<tr class="odd">
<td colspan="2">Gynecomastia</td>
<td colspan="2">2681</td>
<td colspan="2">66.7%</td>
<td colspan="2"></td>
<td colspan="2">320</td>
<td colspan="2">7.9%</td>
<td colspan="2">8.40</td>
</tr>
<tr class="even">
<td colspan="2">Vasodilatation</td>
<td colspan="2">342</td>
<td colspan="2">8.5%</td>
<td colspan="2"></td>
<td colspan="2">185</td>
<td colspan="2">4.6%</td>
<td colspan="2">1.85</td>
</tr>
<tr class="odd">
<td colspan="2">Impotence</td>
<td colspan="2">233</td>
<td colspan="2">5.8%</td>
<td colspan="2"></td>
<td colspan="2">112</td>
<td colspan="2">2.8%</td>
<td colspan="2">2.09</td>
</tr>
<tr class="even">
<td colspan="2">Asthenia</td>
<td colspan="2">206</td>
<td colspan="2">5.1%</td>
<td colspan="2"></td>
<td colspan="2">105</td>
<td colspan="2">2.6%</td>
<td colspan="2">1.97</td>
</tr>
<tr class="odd">
<td colspan="2">Alopecia</td>
<td colspan="2">190</td>
<td colspan="2">4.7%</td>
<td colspan="2"></td>
<td colspan="2">19</td>
<td colspan="2">0.5%</td>
<td colspan="2">10.02</td>
</tr>
<tr class="even">
<td colspan="2">Weight gain</td>
<td colspan="2">161</td>
<td colspan="2">4.0%</td>
<td colspan="2"></td>
<td colspan="2">61</td>
<td colspan="2">1.5%</td>
<td colspan="2">2.65</td>
</tr>
<tr class="odd">
<td colspan="2">Rash</td>
<td colspan="2">141</td>
<td colspan="2">3.5%</td>
<td colspan="2"></td>
<td colspan="2">66</td>
<td colspan="2">1.6%</td>
<td colspan="2">2.14</td>
</tr>
<tr class="even">
<td colspan="2">Libido decreased</td>
<td colspan="2">122</td>
<td colspan="2">3.0%</td>
<td colspan="2"></td>
<td colspan="2">35</td>
<td colspan="2">0.9%</td>
<td colspan="2">3.49</td>
</tr>
<tr class="odd">
<td colspan="2">Constipation</td>
<td colspan="2">103</td>
<td colspan="2">2.6%</td>
<td colspan="2"></td>
<td colspan="2">49</td>
<td colspan="2">1.2%</td>
<td colspan="2">2.11</td>
</tr>
<tr class="even">
<td colspan="2">Diarrhea</td>
<td colspan="2">103</td>
<td colspan="2">2.6%</td>
<td colspan="2"></td>
<td colspan="2">82</td>
<td colspan="2">2.0%</td>
<td colspan="2">1.26</td>
</tr>
<tr class="odd">
<td colspan="2">Liver function tests abnormal</td>
<td colspan="2">99</td>
<td colspan="2">2.5%</td>
<td colspan="2"></td>
<td colspan="2">39</td>
<td colspan="2">1.0%</td>
<td colspan="2">2.54</td>
</tr>
<tr class="even">
<td colspan="2">Nausea</td>
<td colspan="2">88</td>
<td colspan="2">2.2%</td>
<td colspan="2"></td>
<td colspan="2">42</td>
<td colspan="2">1.0%</td>
<td colspan="2">2.10</td>
</tr>
<tr class="odd">
<td colspan="2">Somnolence</td>
<td colspan="2">78</td>
<td colspan="2">1.9%</td>
<td colspan="2"></td>
<td colspan="2">39</td>
<td colspan="2">1.0%</td>
<td colspan="2">2.00</td>
</tr>
<tr class="even">
<td colspan="2">Pruritus</td>
<td colspan="2">76</td>
<td colspan="2">1.9%</td>
<td colspan="2"></td>
<td colspan="2">30</td>
<td colspan="2">0.7%</td>
<td colspan="2">2.54</td>
</tr>
<tr class="odd">
<td colspan="2">Hirsutism</td>
<td colspan="2">46</td>
<td colspan="2">1.1%</td>
<td colspan="2"></td>
<td colspan="2">6</td>
<td colspan="2">0.1%</td>
<td colspan="2">7.68</td>
</tr>
<tr class="even">
<td colspan="2">Abdominal pain</td>
<td colspan="2">45</td>
<td colspan="2">1.1%</td>
<td colspan="2"></td>
<td colspan="2">24</td>
<td colspan="2">0.6%</td>
<td colspan="2">1.88</td>
</tr>
<tr class="odd">
<td colspan="2">Dizziness</td>
<td colspan="2">39</td>
<td colspan="2">1.0%</td>
<td colspan="2"></td>
<td colspan="2">18</td>
<td colspan="2">0.4%</td>
<td colspan="2">2.17</td>
</tr>
<tr class="even">
<td colspan="2">Headache</td>
<td colspan="2">37</td>
<td colspan="2">0.9%</td>
<td colspan="2"></td>
<td colspan="2">26</td>
<td colspan="2">0.6%</td>
<td colspan="2">1.43</td>
</tr>
<tr class="odd">
<td colspan="2">Edema</td>
<td colspan="2">37</td>
<td colspan="2">0.9%</td>
<td colspan="2"></td>
<td colspan="2">13</td>
<td colspan="2">0.3%</td>
<td colspan="2">2.85</td>
</tr>
<tr class="even">
<td colspan="2">Sweating</td>
<td colspan="2">36</td>
<td colspan="2">0.9%</td>
<td colspan="2"></td>
<td colspan="2">28</td>
<td colspan="2">0.7%</td>
<td colspan="2">1.29</td>
</tr>
<tr class="odd">
<td colspan="2">Dyspepsia</td>
<td colspan="2">31</td>
<td colspan="2">0.8%</td>
<td colspan="2"></td>
<td colspan="2">33</td>
<td colspan="2">0.8%</td>
<td colspan="2">0.94</td>
</tr>
<tr class="even">
<td colspan="2">Jaundice</td>
<td colspan="2">31</td>
<td colspan="2">0.8%</td>
<td colspan="2"></td>
<td colspan="2">16</td>
<td colspan="2">0.4%</td>
<td colspan="2">1.94</td>
</tr>
<tr class="odd">
<td colspan="2">Depression</td>
<td colspan="2">29</td>
<td colspan="2">0.7%</td>
<td colspan="2"></td>
<td colspan="2">8</td>
<td colspan="2">0.2%</td>
<td colspan="2">3.63</td>
</tr>
<tr class="even">
<td colspan="2">Pelvic pain</td>
<td colspan="2">27</td>
<td colspan="2">0.7%</td>
<td colspan="2"></td>
<td colspan="2">8</td>
<td colspan="2">0.2%</td>
<td colspan="2">3.38</td>
</tr>
<tr class="odd">
<td colspan="2">Chest pain</td>
<td colspan="2">24</td>
<td colspan="2">0.6%</td>
<td colspan="2"></td>
<td colspan="2">5</td>
<td colspan="2">0.1%</td>
<td colspan="2">4.81</td>
</tr>
<tr class="even">
<td colspan="2">Sleep disorder</td>
<td colspan="2">24</td>
<td colspan="2">0.6%</td>
<td colspan="2"></td>
<td colspan="2">8</td>
<td colspan="2">0.2%</td>
<td colspan="2">3.01</td>
</tr>
<tr class="odd">
<td colspan="2">Emotional lability</td>
<td colspan="2">21</td>
<td colspan="2">0.5%</td>
<td colspan="2"></td>
<td colspan="2">2</td>
<td colspan="2">&lt;0.1%</td>
<td colspan="2">10.52</td>
</tr>
<tr class="even">
<td colspan="2">Anxiety</td>
<td colspan="2">20</td>
<td colspan="2">0.5%</td>
<td colspan="2"></td>
<td colspan="2">5</td>
<td colspan="2">0.1%</td>
<td colspan="2">4.01</td>
</tr>
</tbody>
</table>

> ^1^ Number of patients reporting the event.\
> Source: Modified from ISS, Text Table 16, pg. 40.

### Adverse Events Resulting in Patient Withdrawal

Adverse events resulting in patient withdrawal were reported for 1,116
of 4,022 patients (27.7%) in the Casodex treatment group and 369 of
4,031 patients (9.2%) in the placebo treatment group. Adverse events
resulting in patient withdrawal that occurred in  0.3% of patients in
either of the treatment groups are listed in Table 42 by decreasing
incidence in the Casodex-treated patients. The most frequently reported
adverse events leading to withdrawal in the Casodex-treated patients
were breast pain (12.5% of patients), gynecomastia (10.6%), asthenia
(1.4%), abnormal liver function tests (1.2%), vasodilatation (0.9%), and
impotence (0.7%).

[]{#__RefHeading___Toc25309702 .anchor}Table 42 Adverse Events with an
Incidence  0.3% Leading to Withdrawal (Combined Data from Trials 23, 24,
and 25)

<table>
<colgroup>
<col style="width: 31%" />
<col style="width: 2%" />
<col style="width: 10%" />
<col style="width: 2%" />
<col style="width: 12%" />
<col style="width: 2%" />
<col style="width: 10%" />
<col style="width: 1%" />
<col style="width: 11%" />
<col style="width: 2%" />
<col style="width: 15%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="2" rowspan="2"><strong>Adverse Event</strong></td>
<td colspan="7"><strong>Number of patients reporting adverse
event</strong></td>
<td></td>
<td rowspan="3"><p><strong>Relative Incidence</strong></p>
<p><u>Casodex</u><br />
placebo</p></td>
</tr>
<tr class="even">
<td colspan="3">Casodex<br />
(N = 4022)</td>
<td rowspan="2"></td>
<td colspan="3">Placebo<br />
(N = 4031)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td></td>
<td>n <sup>1</sup></td>
<td colspan="2">Percentage</td>
<td>n <sup>1</sup></td>
<td colspan="2">Percentage</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">Breast pain</td>
<td colspan="2">504</td>
<td colspan="2">12.5%</td>
<td colspan="2">15</td>
<td>0.4%</td>
<td colspan="2">33.68</td>
</tr>
<tr class="odd">
<td colspan="2">Gynecomastia</td>
<td colspan="2">425</td>
<td colspan="2">10.6%</td>
<td colspan="2">16</td>
<td>0.4%</td>
<td colspan="2">26.62</td>
</tr>
<tr class="even">
<td colspan="2">Asthenia</td>
<td colspan="2">56</td>
<td colspan="2">1.4%</td>
<td colspan="2">18</td>
<td>0.5%</td>
<td colspan="2">3.12</td>
</tr>
<tr class="odd">
<td colspan="2">Liver function tests abnormal</td>
<td colspan="2">47</td>
<td colspan="2">1.2%</td>
<td colspan="2">18</td>
<td>0.5%</td>
<td colspan="2">2.62</td>
</tr>
<tr class="even">
<td colspan="2">Vasodilatation</td>
<td colspan="2">36</td>
<td colspan="2">0.9%</td>
<td colspan="2">14</td>
<td>0.4%</td>
<td colspan="2">2.58</td>
</tr>
<tr class="odd">
<td colspan="2">Impotence</td>
<td colspan="2">29</td>
<td colspan="2">0.7%</td>
<td colspan="2">6</td>
<td>0.2%</td>
<td colspan="2">4.84</td>
</tr>
<tr class="even">
<td colspan="2">Myocardial infarction</td>
<td colspan="2">27</td>
<td colspan="2">0.7%</td>
<td colspan="2">33</td>
<td>0.8%</td>
<td colspan="2">0.82</td>
</tr>
<tr class="odd">
<td colspan="2">Nausea</td>
<td colspan="2">26</td>
<td colspan="2">0.7%</td>
<td colspan="2">14</td>
<td>0.4%</td>
<td colspan="2">1.86</td>
</tr>
<tr class="even">
<td colspan="2">Rash</td>
<td colspan="2">26</td>
<td colspan="2">0.7%</td>
<td colspan="2">14</td>
<td>0.4%</td>
<td colspan="2">1.86</td>
</tr>
<tr class="odd">
<td colspan="2">Libido decreased</td>
<td colspan="2">25</td>
<td colspan="2">0.6%</td>
<td colspan="2">9</td>
<td>0.2%</td>
<td colspan="2">2.78</td>
</tr>
<tr class="even">
<td colspan="2">Abdominal pain</td>
<td colspan="2">23</td>
<td colspan="2">0.6%</td>
<td colspan="2">14</td>
<td>0.4%</td>
<td colspan="2">1.65</td>
</tr>
<tr class="odd">
<td colspan="2">Gastrointestinal carcinoma</td>
<td colspan="2">22</td>
<td colspan="2">0.6%</td>
<td colspan="2">18</td>
<td>0.5%</td>
<td colspan="2">1.22</td>
</tr>
<tr class="even">
<td colspan="2">Weight gain</td>
<td colspan="2">22</td>
<td colspan="2">0.6%</td>
<td colspan="2">6</td>
<td>0.2%</td>
<td colspan="2">3.67</td>
</tr>
<tr class="odd">
<td colspan="2">Diarrhea</td>
<td colspan="2">21</td>
<td colspan="2">0.5%</td>
<td colspan="2">20</td>
<td>0.5%</td>
<td colspan="2">1.05</td>
</tr>
<tr class="even">
<td colspan="2">Somnolence</td>
<td colspan="2">20</td>
<td colspan="2">0.5%</td>
<td colspan="2">5</td>
<td>0.1%</td>
<td colspan="2">4.01</td>
</tr>
<tr class="odd">
<td colspan="2">Heart failure</td>
<td colspan="2">17</td>
<td colspan="2">0.4%</td>
<td colspan="2">3</td>
<td>0.1%</td>
<td colspan="2">5.68</td>
</tr>
<tr class="even">
<td colspan="2">Jaundice</td>
<td colspan="2">17</td>
<td colspan="2">0.4%</td>
<td colspan="2">6</td>
<td>0.2%</td>
<td colspan="2">2.84</td>
</tr>
<tr class="odd">
<td colspan="2">Carcinoma of lung</td>
<td colspan="2">17</td>
<td colspan="2">0.4%</td>
<td colspan="2">20</td>
<td>0.5%</td>
<td colspan="2">0.85</td>
</tr>
<tr class="even">
<td colspan="2">Depression</td>
<td colspan="2">15</td>
<td colspan="2">0.4%</td>
<td colspan="2">6</td>
<td>0.2%</td>
<td colspan="2">2.51</td>
</tr>
<tr class="odd">
<td colspan="2">Cerebrovascular accident</td>
<td colspan="2">14</td>
<td colspan="2">0.4%</td>
<td colspan="2">30</td>
<td>0.7%</td>
<td colspan="2">0.47</td>
</tr>
<tr class="even">
<td colspan="2">Constipation</td>
<td colspan="2">14</td>
<td colspan="2">0.4%</td>
<td colspan="2">6</td>
<td>0.2%</td>
<td colspan="2">2.34</td>
</tr>
<tr class="odd">
<td colspan="2">Dizziness</td>
<td colspan="2">14</td>
<td colspan="2">0.4%</td>
<td colspan="2">10</td>
<td>0.3%</td>
<td colspan="2">1.40</td>
</tr>
<tr class="even">
<td colspan="2">Heart arrest</td>
<td colspan="2">13</td>
<td colspan="2">0.3%</td>
<td colspan="2">6</td>
<td>0.2%</td>
<td colspan="2">2.17</td>
</tr>
<tr class="odd">
<td colspan="2">Pruritus</td>
<td colspan="2">13</td>
<td colspan="2">0.3%</td>
<td colspan="2">3</td>
<td>0.1%</td>
<td colspan="2">4.34</td>
</tr>
<tr class="even">
<td colspan="2">Headache</td>
<td colspan="2">11</td>
<td colspan="2">0.3%</td>
<td colspan="2">4</td>
<td>0.1%</td>
<td colspan="2">2.76</td>
</tr>
<tr class="odd">
<td colspan="2">Chest pain</td>
<td colspan="2">10</td>
<td colspan="2">0.3%</td>
<td colspan="2">4</td>
<td>0.1%</td>
<td colspan="2">2.51</td>
</tr>
<tr class="even">
<td colspan="2">Angina pectoris</td>
<td colspan="2">10</td>
<td colspan="2">0.3%</td>
<td colspan="2">8</td>
<td>0.2%</td>
<td colspan="2">1.25</td>
</tr>
<tr class="odd">
<td colspan="2">Anxiety</td>
<td colspan="2">10</td>
<td colspan="2">0.3%</td>
<td colspan="2">3</td>
<td>0.1%</td>
<td colspan="2">3.34</td>
</tr>
<tr class="even">
<td colspan="2">Dyspnea</td>
<td colspan="2">10</td>
<td colspan="2">0.3%</td>
<td colspan="2">6</td>
<td>0.2%</td>
<td colspan="2">1.67</td>
</tr>
<tr class="odd">
<td colspan="2">Pneumonia</td>
<td colspan="2">5</td>
<td colspan="2">0.1%</td>
<td colspan="2">11</td>
<td>0.3%</td>
<td colspan="2">0.46</td>
</tr>
</tbody>
</table>

Source: Safety Update, Text Table 20, pg. 47.

#####  {#section .unnumbered}

##### Medical Officer\'s Comments {#medical-officers-comments-33 .unnumbered}

-   When the adverse events of breast pain and gynecomastia were
    eliminated from consideration, the difference between the proportion
    of Casodex-treated and placebo-treated patients who experienced one
    or more adverse events leading to withdrawal was reduced from 27.7%
    (Casodex) vs. 9.2% (placebo) to 14.4% (Casodex) vs. 8.7% (placebo).

-   Of the 23 adverse events listed in Table 42 that were not likely to
    be a direct result of the pharmacological activity of Casodex, 18 of
    the 23 events occurred in a higher proportion of Casodex-treated
    patients than placebo-treated patients (events with a relative
    incidence  1.2 \[Casodex vs. placebo\]).

-   Adverse events of particular concern, with an incidence at least
    2-fold greater in Casodex-treated patients, that lead to withdrawal
    of treatment involved the cardiovascular system and liver toxicity.
    These adverse events and their relative incidence (Casodex/placebo)
    included heart failure (5.68), heart arrest (2.17), abnormal liver
    function tests (2.62), and jaundice (2.84). Cardiovascular adverse
    events and liver toxicity are reviewed in Section 5.9.

### Serious Adverse Events during the Treatment Period

Adverse events classified as serious were reported for 1,350 of 4,022
patients (33.6%) in the Casodex treatment group and 1,310 of 4,031
patients (32.5%) in the placebo treatment group. Serious adverse events
that occurred in  0.5% of the patients during the treatment period in
either of the treatment groups are listed in Table 43, arranged by
decreasing incidence in the Casodex-treated patients.

##### Medical Officer's Comments {#medical-officers-comments-34 .unnumbered}

-   Serious adverse events were reported by approximately equal
    proportions of patients in the 2 treatment groups.

-   The types of reported serious adverse events were generally similar
    across the 2 treatment groups. Among the adverse events listed in
    Table 43, there were 16 instances in which the incidence of the
    adverse event in the Casodex group exceeded that in the placebo
    group by at least 20% (relative incidence \>1.2). Conversely, there
    were 16 instances in which the incidence of the adverse event in the
    placebo group exceeded that in the Casodex group by at least 20%
    (relative incidence Casodex/placebo  0.83).

-   Several serious cardiac-related adverse events were reported in a
    slightly higher proportion of Casodex-treated patients (heart
    failure: 1.5% vs. 0.9%; heart arrest: 0.5% vs. 0.2%; chest pain:
    1.4% vs. 0.7%). However, other serious cardiac-related adverse
    events were reported in a slightly higher proportion of
    placebo-treated patients (myocardial infarct: 1.8% \[Casodex\] vs.
    2.4% \[placebo\]; myocardial ischemia: 1.3% \[Casodex\] vs.
    1.6%\[placebo\]). Cardiac-related adverse events are discussed
    further in Section 5.9.

-   In general, the majority of the serious adverse events reported are
    compatible with the age and disease status of an elderly population
    of men with prostate cancer.

[]{#__RefHeading___Toc25309703 .anchor}Table 43 Serious Adverse Events
with Incidence  0.5% during Treatment Period

<table>
<colgroup>
<col style="width: 32%" />
<col style="width: 2%" />
<col style="width: 12%" />
<col style="width: 12%" />
<col style="width: 1%" />
<col style="width: 1%" />
<col style="width: 10%" />
<col style="width: 13%" />
<col style="width: 1%" />
<col style="width: 12%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="2" rowspan="2"><strong>Adverse Event</strong></td>
<td colspan="6"><strong>Number of patients reporting adverse
event</strong></td>
<td rowspan="3"></td>
<td rowspan="3"><p><strong>Relative Incidence</strong></p>
<p><u>Casodex</u><br />
placebo</p></td>
</tr>
<tr class="even">
<td colspan="2">Casodex<br />
(N = 4022)</td>
<td colspan="2" rowspan="2"></td>
<td colspan="2">Placebo<br />
(N = 4031)</td>
</tr>
<tr class="odd">
<td></td>
<td></td>
<td>n <sup>1</sup></td>
<td>Percentage</td>
<td>n <sup>1</sup></td>
<td>Percentage</td>
</tr>
<tr class="even">
<td colspan="2">Gynecomastia</td>
<td>109</td>
<td colspan="2">2.7%</td>
<td colspan="2">1</td>
<td>&lt;0.1%</td>
<td colspan="2">109.24</td>
</tr>
<tr class="odd">
<td colspan="2">Urinary tract disorder</td>
<td>103</td>
<td colspan="2">2.6%</td>
<td colspan="2">109</td>
<td>2.7%</td>
<td colspan="2">0.95</td>
</tr>
<tr class="even">
<td colspan="2">Hernia</td>
<td>87</td>
<td colspan="2">2.2%</td>
<td colspan="2">108</td>
<td>2.7%</td>
<td colspan="2">0.81</td>
</tr>
<tr class="odd">
<td colspan="2">Myocardial infarct</td>
<td>72</td>
<td colspan="2">1.8%</td>
<td colspan="2">97</td>
<td>2.4%</td>
<td colspan="2">0.74</td>
</tr>
<tr class="even">
<td colspan="2">Angina pectoris</td>
<td>71</td>
<td colspan="2">1.8%</td>
<td colspan="2">66</td>
<td>1.6%</td>
<td colspan="2">1.08</td>
</tr>
<tr class="odd">
<td colspan="2">Heart failure</td>
<td>61</td>
<td colspan="2">1.5%</td>
<td colspan="2">36</td>
<td>0.9%</td>
<td colspan="2">1.70</td>
</tr>
<tr class="even">
<td colspan="2">Pneumonia</td>
<td>60</td>
<td colspan="2">1.5%</td>
<td colspan="2">61</td>
<td>1.5%</td>
<td colspan="2">0.99</td>
</tr>
<tr class="odd">
<td colspan="2">Chest pain</td>
<td>56</td>
<td colspan="2">1.4%</td>
<td colspan="2">29</td>
<td>0.7%</td>
<td colspan="2">1.94</td>
</tr>
<tr class="even">
<td colspan="2">Myocardial ischemia</td>
<td>54</td>
<td colspan="2">1.3%</td>
<td colspan="2">64</td>
<td>1.6%</td>
<td colspan="2">0.85</td>
</tr>
<tr class="odd">
<td colspan="2">Infection</td>
<td>52</td>
<td colspan="2">1.3%</td>
<td colspan="2">30</td>
<td>0.7%</td>
<td colspan="2">1.74</td>
</tr>
<tr class="even">
<td colspan="2">Gastrointestinal carcinoma</td>
<td>45</td>
<td colspan="2">1.1%</td>
<td colspan="2">37</td>
<td>0.9%</td>
<td colspan="2">1.22</td>
</tr>
<tr class="odd">
<td colspan="2">Accidental injury</td>
<td>41</td>
<td colspan="2">1.0%</td>
<td colspan="2">65</td>
<td>1.6%</td>
<td colspan="2">0.63</td>
</tr>
<tr class="even">
<td colspan="2">Urinary retention</td>
<td>38</td>
<td colspan="2">0.9%</td>
<td colspan="2">68</td>
<td>1.7%</td>
<td colspan="2">0.56</td>
</tr>
<tr class="odd">
<td colspan="2">Cerebrovascular accident</td>
<td>37</td>
<td colspan="2">0.9%</td>
<td colspan="2">71</td>
<td>1.8%</td>
<td colspan="2">0.52</td>
</tr>
<tr class="even">
<td colspan="2">Dyspnea</td>
<td>33</td>
<td colspan="2">0.8%</td>
<td colspan="2">39</td>
<td>1.0%</td>
<td colspan="2">0.85</td>
</tr>
<tr class="odd">
<td colspan="2">Breast pain</td>
<td>30</td>
<td colspan="2">0.7%</td>
<td colspan="2">1</td>
<td>&lt;0.1%</td>
<td colspan="2">30.07</td>
</tr>
<tr class="even">
<td colspan="2">Abdominal pain</td>
<td>29</td>
<td colspan="2">0.7%</td>
<td colspan="2">19</td>
<td>0.5%</td>
<td colspan="2">1.53</td>
</tr>
<tr class="odd">
<td colspan="2">Urinary tract infection</td>
<td>29</td>
<td colspan="2">0.7%</td>
<td colspan="2">21</td>
<td>0.5%</td>
<td colspan="2">1.38</td>
</tr>
<tr class="even">
<td colspan="2">Cardiovascular disorder</td>
<td>28</td>
<td colspan="2">0.7%</td>
<td colspan="2">37</td>
<td>0.9%</td>
<td colspan="2">0.76</td>
</tr>
<tr class="odd">
<td colspan="2">Skin carcinoma</td>
<td>28</td>
<td colspan="2">0.7%</td>
<td colspan="2">24</td>
<td>0.6%</td>
<td colspan="2">1.17</td>
</tr>
<tr class="even">
<td colspan="2">Arthritis</td>
<td>26</td>
<td colspan="2">0.6%</td>
<td colspan="2">19</td>
<td>0.5%</td>
<td colspan="2">1.37</td>
</tr>
<tr class="odd">
<td colspan="2">Arthrosis</td>
<td>26</td>
<td colspan="2">0.6%</td>
<td colspan="2">25</td>
<td>0.6%</td>
<td colspan="2">1.04</td>
</tr>
<tr class="even">
<td colspan="2">Atrial arrhythmia</td>
<td>25</td>
<td colspan="2">0.6%</td>
<td colspan="2">35</td>
<td>0.9%</td>
<td colspan="2">0.72</td>
</tr>
<tr class="odd">
<td colspan="2">Cholelithiasis</td>
<td>25</td>
<td colspan="2">0.6%</td>
<td colspan="2">11</td>
<td>0.3%</td>
<td colspan="2">2.28</td>
</tr>
<tr class="even">
<td colspan="2">Carcinoma of lung</td>
<td>23</td>
<td colspan="2">0.6%</td>
<td colspan="2">27</td>
<td>0.7%</td>
<td colspan="2">0.85</td>
</tr>
<tr class="odd">
<td colspan="2">Hematuria</td>
<td>23</td>
<td colspan="2">0.6%</td>
<td colspan="2">33</td>
<td>0.8%</td>
<td colspan="2">0.70</td>
</tr>
<tr class="even">
<td colspan="2">Anemia</td>
<td>22</td>
<td colspan="2">0.5%</td>
<td colspan="2">16</td>
<td>0.4%</td>
<td colspan="2">1.38</td>
</tr>
<tr class="odd">
<td colspan="2">Cholecystitis</td>
<td>20</td>
<td colspan="2">0.5%</td>
<td colspan="2">15</td>
<td>0.4%</td>
<td colspan="2">1.34</td>
</tr>
<tr class="even">
<td colspan="2">Kidney calculus</td>
<td>20</td>
<td colspan="2">0.5%</td>
<td colspan="2">31</td>
<td>0.8%</td>
<td colspan="2">0.65</td>
</tr>
<tr class="odd">
<td colspan="2">Urinary incontinence</td>
<td>20</td>
<td colspan="2">0.5%</td>
<td colspan="2">11</td>
<td>0.3%</td>
<td colspan="2">1.82</td>
</tr>
<tr class="even">
<td colspan="2">Pain</td>
<td>19</td>
<td colspan="2">0.5%</td>
<td colspan="2">15</td>
<td>0.4%</td>
<td colspan="2">1.27</td>
</tr>
<tr class="odd">
<td colspan="2">Heart arrest</td>
<td>19</td>
<td colspan="2">0.5%</td>
<td colspan="2">7</td>
<td>0.2%</td>
<td colspan="2">2.72</td>
</tr>
<tr class="even">
<td colspan="2">Cataract specified</td>
<td>19</td>
<td colspan="2">0.5%</td>
<td colspan="2">32</td>
<td>0.8%</td>
<td colspan="2">0.60</td>
</tr>
<tr class="odd">
<td colspan="2">Back pain</td>
<td>18</td>
<td colspan="2">0.4%</td>
<td colspan="2">21</td>
<td>0.5%</td>
<td colspan="2">0.86</td>
</tr>
<tr class="even">
<td colspan="2">Syncope</td>
<td>18</td>
<td colspan="2">0.4%</td>
<td colspan="2">14</td>
<td>0.3%</td>
<td colspan="2">1.29</td>
</tr>
<tr class="odd">
<td colspan="2">Hypertension</td>
<td>15</td>
<td colspan="2">0.4%</td>
<td colspan="2">24</td>
<td>0.6%</td>
<td colspan="2">0.63</td>
</tr>
<tr class="even">
<td colspan="2">Sepsis</td>
<td>13</td>
<td colspan="2">0.3%</td>
<td colspan="2">19</td>
<td>0.5%</td>
<td colspan="2">0.69</td>
</tr>
<tr class="odd">
<td colspan="2">Rectal hemorrhage</td>
<td>13</td>
<td colspan="2">0.3%</td>
<td colspan="2">19</td>
<td>0.5%</td>
<td colspan="2">0.69</td>
</tr>
<tr class="even">
<td colspan="2">Pathological fracture</td>
<td>13</td>
<td colspan="2">0.3%</td>
<td colspan="2">21</td>
<td>0.5%</td>
<td colspan="2">0.62</td>
</tr>
<tr class="odd">
<td colspan="2">Vascular disorder</td>
<td>11</td>
<td colspan="2">0.3%</td>
<td colspan="2">27</td>
<td>0.7%</td>
<td colspan="2">0.41</td>
</tr>
<tr class="even">
<td colspan="2">Urination impaired</td>
<td>7</td>
<td colspan="2">0.2%</td>
<td colspan="2">19</td>
<td>0.5%</td>
<td colspan="2">0.37</td>
</tr>
</tbody>
</table>

Source: Safety Update, Text Table 22, pg. 51, and Table T5.2.3.

## Deaths

The number (and percentage) of patients in each treatment group who died
in Trials 23, 24, and 25 (data combined across trials) are listed in
Table 44. As of the data cutoff date for the Safety Update (28 September
2001), 445 of 4,022 patients (11.1%) who received Casodex and 432 of
4,031 patients (10.7%) who received placebo had died. The majority of
deaths in each of the treatment groups was due to reasons other than
prostate cancer.

[]{#__RefHeading___Toc25309704 .anchor}Table 44 Number and Percentage of
Deaths in Trials 23, 24, and 25 (Combined Data)

  -------------------------------------- ---------- -------- ---------- ---------
  Category                               Number (%)                     
                                         of                             
                                         patients                       

                                         Casodex             Placebo    

                                         (N=4022)            (N=4031)   

  Total deaths (number \[%\]) ^1^        445        (11.1)   432        (10.7)

  Deaths due to prostate cancer alone    119        (3.0)    128        (3.2)

  Deaths not due to prostate cancer      326        (8.1)    304        (7.5)

  Deaths due to adverse events ^2^       177        (4.4)    150        (3.7)

  Deaths due to drug-related adverse     7          (0.2)    1          (\<0.1)
  event                                                                 

  Deaths outside of treatment period     149        (3.7)    154        (3.8)
  -------------------------------------- ---------- -------- ---------- ---------

N = number of patients who received randomized treatment.

> ^1^ Two patients who received no therapy also died.
>
> ^2^ Includes deaths during the treatment period and deaths due to an
> adverse event that started during the treatment period.
>
> Source: Data derived from Tables T4.1 and T4.5 of Safety Update.

##### Medical Officer's Comment {#medical-officers-comment-11 .unnumbered}

-   The number of patients who were reported to have died due to
    prostate cancer alone was slightly higher in the placebo group.
    Conversely, the number of patients who were reported to have died
    due to causes other than prostate cancer was slightly higher in the
    Casodex group. The small numeric excess of deaths not due to
    prostate cancer appear to have occurred during the treatment period
    (i.e., deaths listed by the Sponsor as "deaths due to adverse
    events."

The number (and percentage) of patients in each treatment group who died
in each of Trials 23, 24, and 25 are listed in Table 45. Within each of
the trials, the number of deaths in the Casodex and placebo treatment
groups were similar. However, the proportions of patients who died from
prostate cancer or other causes varied across the 3 trials. Total deaths
across the trials ranged from approximately 6% (Trial 23) to 18% (Trial
25).

[]{#__RefHeading___Toc25309705 .anchor}Table 45 Number and percentages
of Deaths in Each of Trials 23, 24, and 25

  ------------ ---------- ----------- --------- ----------- -- ---------- ------------ --------- ------------ -- ---------- ------------ ---------- ------------
  **Cause of\  **Study                                         **Study                                           **Study                            
  Death**      23**                                            24**                                              25**                               

               Casodex\               Placebo                  Casodex\                Placebo                   Casodex\                Placebo\   
               N= 1647                N=1645                   N= 1798                 N=1805                    N= 607                  N= 611     

               n          (%)         n         (%)            n          (%)          n         (%)             n          (%)          n          (%)

  Prostate     14         (0.9)       6         (0.4)          56         (3.1)        66        (3.7)           49         (8.1)        56         (9.2)
  cancer                                                                                                                                            

  Other        91         (5.6)       93        (5.7)          168        (9.4)        161       (9.0)           67         (11.1)       50         (8.2)

  **Total**    **105**    **(6.5)**   **99**    **(6.1)**      **224**    **(12.5)**   **227**   **(12.7)**      **116**    **(19.2)**   **106**    **(17.4)**
  ------------ ---------- ----------- --------- ----------- -- ---------- ------------ --------- ------------ -- ---------- ------------ ---------- ------------

> Sources: Safety Update (SAS files) and submission of 17 May 2002.

##### Medical Officer's Comments {#medical-officers-comments-35 .unnumbered}

-   The proportion of patients who died of prostate cancer in the
    placebo treatment groups showed considerable variation across the 3
    trials and was approximately 9-fold and 23‑fold greater in Trial 24
    and Trial 25, respectively, than in Trial 23.

-   More patients also died of causes unrelated to prostate cancer in
    each of Trials 24 and 25 than in Trial 23. The proportions of
    patients who died of causes other than prostate cancer were slightly
    less than 2-fold greater in each of Trials 24 and 25 compared to
    Trial 23.

There were 8 instances in which a death was considered by the
investigator to be possibly related to treatment with study drug (Table
46). Seven (7) of these 8 deaths occurred in patients treated with
Casodex.

[]{#__RefHeading___Toc25309706 .anchor}Table 46 Primary Causes of Death
due to Drug-Related Adverse Events

  -------------------------------- -------------- ----------- -------------- -------------
  **Body system**                  **Number (%)                              
                                   of patients                               
                                   who died**                                

  **Consolidated COSTART term**    **Casodex**                **Placebo**    

                                   **(N=4022)**               **(N=4031)**   

  Cardiovascular system                                                      

  Cerebrovascular accident         1              (\<0.1)     0              

  Myocardial infarction            1              (\<0.1)     0              

  Myocardial ischemia              1              (\<0.1)     0              

  Pulmonary embolus                1              (\<0.1)     0              

  Digestive system                                                           

  Pancreas disorder                1              (\<0.1)     0              

  Hemic/lymphatic system                                                     

  Blood dyscrasia                  2              (0.1)       0              

  Urogenital system                                                          

  Kidney failure                   0                          1              (\<0.1)

  **Total**                        **7**          **(0.2)**   **1**          **(\<0.1)**
  -------------------------------- -------------- ----------- -------------- -------------

Source: Safety Update, Text Table 18, pg. 43.

##### Medical Officer's Comments {#medical-officers-comments-36 .unnumbered}

-   The observed imbalance in drug-related deaths should be viewed with
    reservation. Therapy in the clinical trials was not completely
    blinded due to the high incidence of pharmacological adverse events.
    It is unlikely that investigators would attribute a non-prostate
    cancer death to "placebo therapy."

-   Cardiac adverse events and acute myelogenous leukemia or
    myelodysplasia syndrome are reviewed in Section 5.9.4 and Section
    5.9.5.2.

The number (and percentage) of patients whose primary cause of death was
classified within each of the COSTART body systems are listed in Table
47. Deaths are further classified in terms of time of occurrence, i.e.,
during treatment with study drug or posttreatment. Patients whose
primary cause of death was prostate cancer are not included in the
Table. The body systems associated with the highest number of total
deaths (those occurring either during or following treatment) in the
Casodex treated patients were cardiovascular (n=143), respiratory
(n=62), digestive (n=42) and body as a whole (n=42). These 4 body
systems accounted for 289 of 326 (88.7%) of the non-prostate cancer
deaths. Total deaths in the placebo treated patients followed a similar
pattern with the cardiovascular (n=122), respiratory (n=72), digestive
(n=36) and body as a whole (n=44) body systems accounting for 274 of 304
(90.1%) of deaths.

[]{#__RefHeading___Toc25309707 .anchor}Table 47 Number (%) of Patients
with Primary Cause of Death Classified by COSTART Body System Term and
Treatment Period (All Trials)

<table style="width:100%;">
<colgroup>
<col style="width: 16%" />
<col style="width: 1%" />
<col style="width: 1%" />
<col style="width: 16%" />
<col style="width: 2%" />
<col style="width: 9%" />
<col style="width: 2%" />
<col style="width: 9%" />
<col style="width: 2%" />
<col style="width: 10%" />
<col style="width: 1%" />
<col style="width: 11%" />
<col style="width: 1%" />
<col style="width: 13%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td colspan="2" rowspan="3"></td>
<td></td>
<td colspan="8"><strong>Number (%) of patients with cause of death
<sup>1</sup></strong></td>
<td rowspan="3"></td>
<td rowspan="3"><p><strong>Relative Incidence</strong></p>
<p><u>Casodex</u><br />
placebo</p></td>
</tr>
<tr class="even">
<td><strong>Body<br />
System</strong></td>
<td><strong>Treatment<br />
Period</strong></td>
<td></td>
<td colspan="3">Casodex<br />
(N = 4022)</td>
<td rowspan="2"></td>
<td colspan="3">Placebo<br />
(N = 4031)</td>
</tr>
<tr class="odd">
<td></td>
<td></td>
<td></td>
<td>n</td>
<td colspan="2">Percentage</td>
<td>n</td>
<td colspan="2">Percentage</td>
</tr>
<tr class="even">
<td colspan="2"><blockquote>
<p>Body as a whole</p>
</blockquote></td>
<td colspan="3">During Treatment</td>
<td colspan="2">18</td>
<td colspan="2">0.45</td>
<td colspan="2">11</td>
<td>0.27</td>
<td colspan="2">1.64</td>
</tr>
<tr class="odd">
<td colspan="2"></td>
<td colspan="3">Post Treatment</td>
<td colspan="2">24</td>
<td colspan="2">0.60</td>
<td colspan="2">33</td>
<td>0.82</td>
<td colspan="2">0.73</td>
</tr>
<tr class="even">
<td colspan="2"></td>
<td colspan="3"><em>Total</em></td>
<td colspan="2"><em>42</em></td>
<td colspan="2"><em>1.04</em></td>
<td colspan="2"><em>44</em></td>
<td><em>1.09</em></td>
<td colspan="2"><em>0.96</em></td>
</tr>
<tr class="odd">
<td colspan="2"><blockquote>
<p>Cardiovascular</p>
</blockquote></td>
<td colspan="3">During Treatment</td>
<td colspan="2">77</td>
<td colspan="2">1.91</td>
<td colspan="2">66</td>
<td>1.64</td>
<td colspan="2">1.17</td>
</tr>
<tr class="even">
<td colspan="2"></td>
<td colspan="3">Post Treatment</td>
<td colspan="2">66</td>
<td colspan="2">1.64</td>
<td colspan="2">56</td>
<td>1.39</td>
<td colspan="2">1.18</td>
</tr>
<tr class="odd">
<td colspan="2"></td>
<td colspan="3"><em>Total</em></td>
<td colspan="2"><em>143</em></td>
<td colspan="2"><em>3.56</em></td>
<td colspan="2"><em>122</em></td>
<td><em>3.03</em></td>
<td colspan="2"><em>1.17</em></td>
</tr>
<tr class="even">
<td colspan="2"><blockquote>
<p>Digestive</p>
</blockquote></td>
<td colspan="3">During Treatment</td>
<td colspan="2">24</td>
<td colspan="2">0.60</td>
<td colspan="2">17</td>
<td>0.42</td>
<td colspan="2">1.41</td>
</tr>
<tr class="odd">
<td colspan="2"></td>
<td colspan="3">Post Treatment</td>
<td colspan="2">18</td>
<td colspan="2">0.45</td>
<td colspan="2">19</td>
<td>0.47</td>
<td colspan="2">0.95</td>
</tr>
<tr class="even">
<td colspan="2"></td>
<td colspan="3"><em>Total</em></td>
<td colspan="2"><em>42</em></td>
<td colspan="2"><em>1.04</em></td>
<td colspan="2"><em>36</em></td>
<td><em>0.89</em></td>
<td colspan="2"><em>1.17</em></td>
</tr>
<tr class="odd">
<td colspan="2"><blockquote>
<p>Endocrine</p>
</blockquote></td>
<td colspan="3">Post Treatment</td>
<td colspan="2">1</td>
<td colspan="2">0.02</td>
<td colspan="2">1</td>
<td>0.02</td>
<td colspan="2">1.00</td>
</tr>
<tr class="even">
<td colspan="2"></td>
<td colspan="3"><em>Total</em></td>
<td colspan="2"><em>1</em></td>
<td colspan="2"><em>0.02</em></td>
<td colspan="2"><em>1</em></td>
<td><em>0.02</em></td>
<td colspan="2"><em>1.00</em></td>
</tr>
<tr class="odd">
<td colspan="2" rowspan="2"><blockquote>
<p>Hematopoietic/<br />
lymphatic</p>
</blockquote></td>
<td colspan="3">During Treatment</td>
<td colspan="2">10</td>
<td colspan="2">0.25</td>
<td colspan="2">4</td>
<td>0.10</td>
<td colspan="2">2.51</td>
</tr>
<tr class="even">
<td colspan="3">Post Treatment</td>
<td colspan="2">3</td>
<td colspan="2">0.07</td>
<td colspan="2">2</td>
<td>0.05</td>
<td colspan="2">1.50</td>
</tr>
<tr class="odd">
<td colspan="2"></td>
<td colspan="3"><em>Total</em></td>
<td colspan="2"><em>13</em></td>
<td colspan="2"><em>0.32</em></td>
<td colspan="2"><em>6</em></td>
<td><em>0.15</em></td>
<td colspan="2"><em>2.17</em></td>
</tr>
<tr class="even">
<td colspan="2" rowspan="2"><blockquote>
<p>Metabolic and nutritional</p>
</blockquote></td>
<td colspan="3">During Treatment</td>
<td colspan="2">2</td>
<td colspan="2">0.05</td>
<td colspan="2">2</td>
<td>0.05</td>
<td colspan="2">1.00</td>
</tr>
<tr class="odd">
<td colspan="3">Post Treatment</td>
<td colspan="2">1</td>
<td colspan="2">0.02</td>
<td colspan="2">2</td>
<td>0.05</td>
<td colspan="2">0.50</td>
</tr>
<tr class="even">
<td colspan="2"></td>
<td colspan="3"><em>Total</em></td>
<td colspan="2"><em>3</em></td>
<td colspan="2"><em>0.07</em></td>
<td colspan="2"><em>4</em></td>
<td><em>0.10</em></td>
<td colspan="2"><em>0.75</em></td>
</tr>
<tr class="odd">
<td colspan="2"><blockquote>
<p>Musculoskeletal</p>
</blockquote></td>
<td colspan="3">During Treatment</td>
<td colspan="2">0</td>
<td colspan="2">0.00</td>
<td colspan="2">2</td>
<td>0.05</td>
<td colspan="2">0.00</td>
</tr>
<tr class="even">
<td colspan="2"></td>
<td colspan="3">Post Treatment</td>
<td colspan="2">1</td>
<td colspan="2">0.02</td>
<td colspan="2">1</td>
<td>0.02</td>
<td colspan="2">1.00</td>
</tr>
<tr class="odd">
<td colspan="2"></td>
<td colspan="3"><em>Total</em></td>
<td colspan="2"><em>1</em></td>
<td colspan="2"><em>0.02</em></td>
<td colspan="2"><em>3</em></td>
<td><em>0.07</em></td>
<td colspan="2"><em>0.33</em></td>
</tr>
<tr class="even">
<td colspan="2"><blockquote>
<p>Nervous</p>
</blockquote></td>
<td colspan="3">During Treatment</td>
<td colspan="2">4</td>
<td colspan="2">0.10</td>
<td colspan="2">4</td>
<td>0.10</td>
<td colspan="2">1.00</td>
</tr>
<tr class="odd">
<td colspan="2"></td>
<td colspan="3">Post Treatment</td>
<td colspan="2">3</td>
<td colspan="2">0.07</td>
<td colspan="2">3</td>
<td>0.07</td>
<td colspan="2">1.00</td>
</tr>
<tr class="even">
<td colspan="2"></td>
<td colspan="3"><em>Total</em></td>
<td colspan="2"><em>7</em></td>
<td colspan="2"><em>0.17</em></td>
<td colspan="2"><em>7</em></td>
<td><em>0.17</em></td>
<td colspan="2"><em>1.00</em></td>
</tr>
<tr class="odd">
<td colspan="2"><blockquote>
<p>Respiratory</p>
</blockquote></td>
<td colspan="3">During Treatment</td>
<td colspan="2">29</td>
<td colspan="2">0.72</td>
<td colspan="2">36</td>
<td>0.89</td>
<td colspan="2">0.81</td>
</tr>
<tr class="even">
<td colspan="2"></td>
<td colspan="3">Post Treatment</td>
<td colspan="2">33</td>
<td colspan="2">0.82</td>
<td colspan="2">36</td>
<td>0.89</td>
<td colspan="2">0.92</td>
</tr>
<tr class="odd">
<td colspan="2"></td>
<td colspan="3"><em>Total</em></td>
<td colspan="2"><em>62</em></td>
<td colspan="2"><em>1.54</em></td>
<td colspan="2"><em>72</em></td>
<td><em>1.79</em></td>
<td colspan="2"><em>0.86</em></td>
</tr>
<tr class="even">
<td colspan="2"><blockquote>
<p>Skin/appendages</p>
</blockquote></td>
<td colspan="3">During Treatment</td>
<td colspan="2">1</td>
<td colspan="2">0.02</td>
<td colspan="2">2</td>
<td>0.05</td>
<td colspan="2">0.50</td>
</tr>
<tr class="odd">
<td colspan="2"></td>
<td colspan="3">Post Treatment</td>
<td colspan="2">1</td>
<td colspan="2">0.02</td>
<td colspan="2">0</td>
<td>0.00</td>
<td colspan="2">NC</td>
</tr>
<tr class="even">
<td colspan="2"></td>
<td colspan="3"><em>Total</em></td>
<td colspan="2"><em>2</em></td>
<td colspan="2"><em>0.05</em></td>
<td colspan="2"><em>2</em></td>
<td><em>0.05</em></td>
<td colspan="2"><em>1.00</em></td>
</tr>
<tr class="odd">
<td colspan="2"><blockquote>
<p>Urogenital</p>
</blockquote></td>
<td colspan="3">During Treatment</td>
<td colspan="2">3</td>
<td colspan="2">0.07</td>
<td colspan="2">2</td>
<td>0.05</td>
<td colspan="2">1.50</td>
</tr>
<tr class="even">
<td colspan="2"></td>
<td colspan="3">Post Treatment</td>
<td colspan="2">4</td>
<td colspan="2">0.10</td>
<td colspan="2">5</td>
<td>0.12</td>
<td colspan="2">0.80</td>
</tr>
<tr class="odd">
<td colspan="2"></td>
<td colspan="3"><em>Total</em></td>
<td colspan="2"><em>7</em></td>
<td colspan="2"><em>0.17</em></td>
<td colspan="2"><em>7</em></td>
<td><em>0.17</em></td>
<td colspan="2"><em>1.00</em></td>
</tr>
</tbody>
</table>

^1^ Patients whose primary cause of death was prostate cancer are NOT
included in the listing.

Source: Safety Update, Table T4.4.

#####  {#section-1 .unnumbered}

##### Medical Officer's Comment {#medical-officers-comment-12 .unnumbered}

-   A greater percentage of patients treated with Casodex, compared to
    placebo-treated patients, died of primary causes that linked to the
    hematopoietic/lymphatic (0.32% vs. 0.15%; relative incidence 2.17),
    cardiovascular (3.56% vs. 3.03%; relative incidence 1.17), and
    digestive (1.04% vs. 0.89%; relative incidence 1.17) body systems.
    For the most part, these imbalances were a result of increased
    numbers of deaths that occurred during the period of treatment with
    study drug and not during the post treatment period.

The primary causes of death (other than that of prostate cancer) and the
number (%) of patients who died of these causes during the treatment
period are listed by COSTART body system and COSTART preferred term in
Table 48. Cardiovascular events were the major cause of death with 77
cases reported in Casodex-treated patients and 66 cases reported in
placebo-treated patients (relative incidence, Casodex/placebo: 1.17). Of
the cardiac-related deaths in Casodex-treated patients, deaths due to
myocardial infarction (n=24), heart failure (n=15), and heart arrest
(n=12) were the most commonly reported events. In the placebo-treated
patients, deaths due to myocardial infarction, heart failure, and heart
arrest were reported for 31, 1, and 5 patients, respectively.

Deaths that linked to the respiratory system were the second most
frequent in both treatment groups, occurring in 29 Casodex--treated and
36 placebo-treated patients.

Deaths that linked to the digestive system were the third most frequent,
affecting 24 Casodex-treated patients and 17 placebo-treated patients
(relative incidence, Casodex/placebo: 1.41). Among this group,
gastrointestinal carcinoma was the most common single cause of death,
affecting 18 Casodex-treated patients and 10 placebo-treated patients.

##### Medical Officer's Comments {#medical-officers-comments-37 .unnumbered}

-   As would be expected in a population of elderly men, cardiovascular
    events were the major cause of death unrelated to prostate cancer in
    both treatment groups. There was an excess of cardiovascular deaths
    due to myocardial infarction, heart failure, and heart arrest in the
    Casodex-treated patients (n=51) compared to the number of similarly
    classified deaths in the placebo-treated patients (n=37). This
    imbalance was partially offset by other causes of cardiovascular
    death in the placebo-treated patients and is discussed further in
    Section 5.9.4.1.

-   The imbalance in deaths related to the digestive system (greater in
    Casodex-treated patients) was due largely to the increased number of
    patients who died from a gastrointestinal malignancy in the
    Casodex-treated patients (n=18) compared to the number of similar
    deaths in the placebo-treated patients (n=10).

-   Deaths that linked to the hematopoietic/lymphatic body were 2.5-fold
    more common in Casodex-treated patients. These are discussed in
    Section 5.9.5.2.

[]{#__RefHeading___Toc25309708 .anchor}Table 48 Primary Causes of Death
(Other than Prostate Cancer) during the\
Treatment Period (Trials 23, 24, and 25 Combined)

<table>
<colgroup>
<col style="width: 32%" />
<col style="width: 2%" />
<col style="width: 12%" />
<col style="width: 12%" />
<col style="width: 1%" />
<col style="width: 1%" />
<col style="width: 10%" />
<col style="width: 13%" />
<col style="width: 1%" />
<col style="width: 12%" />
</colgroup>
<tbody>
<tr class="odd">
<td><strong>Body System</strong></td>
<td colspan="7"><strong>Number (%) of patients with cause of
death</strong></td>
<td rowspan="3"></td>
<td rowspan="3"><p><strong>Relative Incidence</strong></p>
<p><u>Casodex</u><br />
placebo</p></td>
</tr>
<tr class="even">
<td rowspan="2"><blockquote>
<p><strong>Cause of Death<br />
(COSTART term)</strong></p>
</blockquote></td>
<td></td>
<td colspan="2">Casodex<br />
(N = 4022)</td>
<td colspan="2" rowspan="2"></td>
<td colspan="2">Placebo<br />
(N = 4031)</td>
</tr>
<tr class="odd">
<td></td>
<td>n</td>
<td>Percentage</td>
<td>n</td>
<td>Percentage</td>
</tr>
<tr class="even">
<td colspan="2"><strong>Body as a whole</strong></td>
<td><strong>18</strong></td>
<td colspan="2"><strong>0.45</strong></td>
<td colspan="2"><strong>11</strong></td>
<td><strong>0.27</strong></td>
<td colspan="2"><strong>1.64</strong></td>
</tr>
<tr class="odd">
<td colspan="2">Accidental injury</td>
<td>2</td>
<td colspan="2">0.05</td>
<td colspan="2">2</td>
<td>0.05</td>
<td colspan="2">1.00</td>
</tr>
<tr class="even">
<td colspan="2">Ascites</td>
<td>1</td>
<td colspan="2">0.02</td>
<td colspan="2">0</td>
<td>0.00</td>
<td colspan="2">NC <sup>2</sup></td>
</tr>
<tr class="odd">
<td colspan="2">Carcinoma</td>
<td>2</td>
<td colspan="2">0.05</td>
<td colspan="2">1</td>
<td>0.02</td>
<td colspan="2">2.00</td>
</tr>
<tr class="even">
<td colspan="2">Death <sup>1</sup></td>
<td>7</td>
<td colspan="2">0.17</td>
<td colspan="2">0</td>
<td>0.00</td>
<td colspan="2">NC</td>
</tr>
<tr class="odd">
<td colspan="2">Gangrene</td>
<td>1</td>
<td colspan="2">0.02</td>
<td colspan="2">0</td>
<td>0.00</td>
<td colspan="2">NC</td>
</tr>
<tr class="even">
<td colspan="2">Neoplasm</td>
<td>1</td>
<td colspan="2">0.02</td>
<td colspan="2">3</td>
<td>0.07</td>
<td colspan="2">0.33</td>
</tr>
<tr class="odd">
<td colspan="2">Peritonitis</td>
<td>0</td>
<td colspan="2">0.00</td>
<td colspan="2">1</td>
<td>0.02</td>
<td colspan="2">0.00</td>
</tr>
<tr class="even">
<td colspan="2">Sarcoma</td>
<td>2</td>
<td colspan="2">0.05</td>
<td colspan="2">1</td>
<td>0.02</td>
<td colspan="2">2.00</td>
</tr>
<tr class="odd">
<td colspan="2">Sepsis</td>
<td>1</td>
<td colspan="2">0.02</td>
<td colspan="2">1</td>
<td>0.02</td>
<td colspan="2">1.00</td>
</tr>
<tr class="even">
<td colspan="2">Suicide</td>
<td>1</td>
<td colspan="2">0.02</td>
<td colspan="2">2</td>
<td>0.05</td>
<td colspan="2">0.50</td>
</tr>
<tr class="odd">
<td colspan="2"><strong>Cardiovascular</strong></td>
<td><strong>77</strong></td>
<td colspan="2"><strong>1.91</strong></td>
<td colspan="2"><strong>66</strong></td>
<td><strong>1.64</strong></td>
<td colspan="2"><strong>1.17</strong></td>
</tr>
<tr class="even">
<td colspan="2">Arrhythmia</td>
<td>0</td>
<td colspan="2">0.00</td>
<td colspan="2">2</td>
<td>0.05</td>
<td colspan="2">0.00</td>
</tr>
<tr class="odd">
<td colspan="2">Arteriosclerosis</td>
<td>2</td>
<td colspan="2">0.05</td>
<td colspan="2">0</td>
<td>0.00</td>
<td colspan="2">NC</td>
</tr>
<tr class="even">
<td colspan="2">Cardiomegaly</td>
<td>1</td>
<td colspan="2">0.02</td>
<td colspan="2">0</td>
<td>0.00</td>
<td colspan="2">NC</td>
</tr>
<tr class="odd">
<td colspan="2">Cardiomyopathy</td>
<td>1</td>
<td colspan="2">0.02</td>
<td colspan="2">2</td>
<td>0.05</td>
<td colspan="2">0.50</td>
</tr>
<tr class="even">
<td colspan="2">Cardiovascular disorder</td>
<td>2</td>
<td colspan="2">0.05</td>
<td colspan="2">2</td>
<td>0.05</td>
<td colspan="2">1.00</td>
</tr>
<tr class="odd">
<td colspan="2">Cerebrovascular accident</td>
<td>11</td>
<td colspan="2">0.27</td>
<td colspan="2">15</td>
<td>0.37</td>
<td colspan="2">0.73</td>
</tr>
<tr class="even">
<td colspan="2">Embolus</td>
<td>0</td>
<td colspan="2">0.00</td>
<td colspan="2">1</td>
<td>0.02</td>
<td colspan="2">0.00</td>
</tr>
<tr class="odd">
<td colspan="2">Heart arrest</td>
<td>12</td>
<td colspan="2">0.30</td>
<td colspan="2">5</td>
<td>0.12</td>
<td colspan="2">2.41</td>
</tr>
<tr class="even">
<td colspan="2">Heart failure</td>
<td>15</td>
<td colspan="2">0.37</td>
<td colspan="2">1</td>
<td>0.02</td>
<td colspan="2">15.03</td>
</tr>
<tr class="odd">
<td colspan="2">Intracranial hemorrhage</td>
<td>1</td>
<td colspan="2">0.02</td>
<td colspan="2">0</td>
<td>0.00</td>
<td colspan="2">NC</td>
</tr>
<tr class="even">
<td colspan="2">Myocardial infarction</td>
<td>24</td>
<td colspan="2">0.60</td>
<td colspan="2">31</td>
<td>0.77</td>
<td colspan="2">0.78</td>
</tr>
<tr class="odd">
<td colspan="2">Myocardial ischemia</td>
<td>4</td>
<td colspan="2">0.10</td>
<td colspan="2">5</td>
<td>0.12</td>
<td colspan="2">0.80</td>
</tr>
<tr class="even">
<td colspan="2">Pulmonary embolus</td>
<td>4</td>
<td colspan="2">0.10</td>
<td colspan="2">2</td>
<td>0.05</td>
<td colspan="2">2.00</td>
</tr>
<tr class="odd">
<td colspan="2"><strong>Digestive</strong></td>
<td><strong>24</strong></td>
<td colspan="2"><strong>0.60</strong></td>
<td colspan="2"><strong>17</strong></td>
<td><strong>0.42</strong></td>
<td colspan="2"><strong>1.41</strong></td>
</tr>
<tr class="even">
<td colspan="2">Cirrhosis of liver</td>
<td>0</td>
<td colspan="2">0.00</td>
<td colspan="2">1</td>
<td>0.02</td>
<td colspan="2">0.00</td>
</tr>
<tr class="odd">
<td colspan="2">Gastrointestinal carcinoma</td>
<td>18</td>
<td colspan="2">0.45</td>
<td colspan="2">10</td>
<td>0.25</td>
<td colspan="2">1.80</td>
</tr>
<tr class="even">
<td colspan="2">Gastrointestinal hemorrhage</td>
<td>1</td>
<td colspan="2">0.02</td>
<td colspan="2">2</td>
<td>0.05</td>
<td colspan="2">0.50</td>
</tr>
<tr class="odd">
<td colspan="2">GI neoplasia</td>
<td>2</td>
<td colspan="2">0.05</td>
<td colspan="2">1</td>
<td>0.02</td>
<td colspan="2">2.00</td>
</tr>
<tr class="even">
<td colspan="2">Hepatoma</td>
<td>1</td>
<td colspan="2">0.02</td>
<td colspan="2">2</td>
<td>0.05</td>
<td colspan="2">0.50</td>
</tr>
<tr class="odd">
<td colspan="2">Intestinal obstruction</td>
<td>1</td>
<td colspan="2">0.02</td>
<td colspan="2">0</td>
<td>0.00</td>
<td colspan="2">NC</td>
</tr>
<tr class="even">
<td colspan="2">Pancreas disorder</td>
<td>1</td>
<td colspan="2">0.02</td>
<td colspan="2">0</td>
<td>0.00</td>
<td colspan="2">NC</td>
</tr>
<tr class="odd">
<td colspan="2">Rectal hemorrhage</td>
<td>0</td>
<td colspan="2">0.00</td>
<td colspan="2">1</td>
<td>0.02</td>
<td colspan="2">0.00</td>
</tr>
</tbody>
</table>

^1^ Not otherwise specified. (Continued)\
^2^ Not calculated.

Source: Safety Update. Text Table 17, pg. 39 and Table T4.3.

Table 47 Primary Cause of Death (other than Prostate Cancer) during the\
Treatment Period (Trials 23, 24, and 25 Combined)

<table>
<colgroup>
<col style="width: 32%" />
<col style="width: 2%" />
<col style="width: 12%" />
<col style="width: 12%" />
<col style="width: 1%" />
<col style="width: 1%" />
<col style="width: 10%" />
<col style="width: 13%" />
<col style="width: 1%" />
<col style="width: 12%" />
</colgroup>
<tbody>
<tr class="odd">
<td><strong>Body System</strong></td>
<td colspan="7"><strong>Number (%) of patients with cause of
death</strong></td>
<td rowspan="3"></td>
<td rowspan="3"><p><strong>Relative Incidence</strong></p>
<p><u>Casodex</u><br />
placebo</p></td>
</tr>
<tr class="even">
<td rowspan="2"><blockquote>
<p><strong>Cause of Death<br />
(COSTART term)</strong></p>
</blockquote></td>
<td rowspan="2"></td>
<td colspan="2">Casodex<br />
(N = 4022)</td>
<td colspan="2" rowspan="2"></td>
<td colspan="2">Placebo<br />
(N = 4031)</td>
</tr>
<tr class="odd">
<td>n</td>
<td>Percentage</td>
<td>n</td>
<td>Percentage</td>
</tr>
<tr class="even">
<td colspan="2"><strong>Hematopoietic/lymphatic</strong></td>
<td><strong>10</strong></td>
<td colspan="2"><strong>0.25</strong></td>
<td colspan="2"><strong>4</strong></td>
<td><strong>0.10</strong></td>
<td colspan="2"><strong>2.50</strong></td>
</tr>
<tr class="odd">
<td colspan="2">Acute leukemia</td>
<td>2</td>
<td colspan="2">0.05</td>
<td colspan="2">1</td>
<td>0.02</td>
<td colspan="2">2.00</td>
</tr>
<tr class="even">
<td colspan="2">Blood dyscrasia</td>
<td>2</td>
<td colspan="2">0.05</td>
<td colspan="2">0</td>
<td>0.00</td>
<td colspan="2">NC <sup>2</sup></td>
</tr>
<tr class="odd">
<td colspan="2">Chronic myelocytic leukemia</td>
<td>1</td>
<td colspan="2">0.02</td>
<td colspan="2">1</td>
<td>0.02</td>
<td colspan="2">1.00</td>
</tr>
<tr class="even">
<td colspan="2">Leukemia</td>
<td>1</td>
<td colspan="2">0.02</td>
<td colspan="2">0</td>
<td>0.00</td>
<td colspan="2">NC</td>
</tr>
<tr class="odd">
<td colspan="2">Lymphoma like reaction</td>
<td>4</td>
<td colspan="2">0.10</td>
<td colspan="2">1</td>
<td>0.02</td>
<td colspan="2">4.01</td>
</tr>
<tr class="even">
<td colspan="2">Myeloma</td>
<td>0</td>
<td colspan="2">0.00</td>
<td colspan="2">1</td>
<td>0.02</td>
<td colspan="2">0.00</td>
</tr>
<tr class="odd">
<td colspan="2"><strong>Metabolic and nutritional</strong></td>
<td><strong>2</strong></td>
<td colspan="2"><strong>0.05</strong></td>
<td colspan="2"><strong>2</strong></td>
<td><strong>0.05</strong></td>
<td colspan="2"><strong>1.00</strong></td>
</tr>
<tr class="even">
<td colspan="2">Hypoxia</td>
<td>1</td>
<td colspan="2">0.02</td>
<td colspan="2">0</td>
<td>0.00</td>
<td colspan="2">NC</td>
</tr>
<tr class="odd">
<td colspan="2">Uremia</td>
<td>0</td>
<td colspan="2">0.00</td>
<td colspan="2">1</td>
<td>0.02</td>
<td colspan="2">0.00</td>
</tr>
<tr class="even">
<td colspan="2">Weight loss</td>
<td>1</td>
<td colspan="2">0.02</td>
<td colspan="2">1</td>
<td>0.02</td>
<td colspan="2">1.00</td>
</tr>
<tr class="odd">
<td colspan="2">Musculoskeletal</td>
<td></td>
<td colspan="2">0.00</td>
<td colspan="2"></td>
<td>0.00</td>
<td colspan="2">NC</td>
</tr>
<tr class="even">
<td colspan="2">Muscle atrophy</td>
<td>0</td>
<td colspan="2">0.00</td>
<td colspan="2">2</td>
<td>0.05</td>
<td colspan="2">0.00</td>
</tr>
<tr class="odd">
<td colspan="2"><strong>Nervous</strong></td>
<td><strong>4</strong></td>
<td colspan="2"><strong>0.10</strong></td>
<td colspan="2"><strong>4</strong></td>
<td><strong>0.10</strong></td>
<td colspan="2"><strong>1.00</strong></td>
</tr>
<tr class="even">
<td colspan="2">CNS neoplasia</td>
<td>1</td>
<td colspan="2">0.02</td>
<td colspan="2">3</td>
<td>0.07</td>
<td colspan="2">0.33</td>
</tr>
<tr class="odd">
<td colspan="2">Dementia</td>
<td>2</td>
<td colspan="2">0.05</td>
<td colspan="2">0</td>
<td>0.00</td>
<td colspan="2">NC</td>
</tr>
<tr class="even">
<td colspan="2">Extrapyramidal syndrome</td>
<td>0</td>
<td colspan="2">0.00</td>
<td colspan="2">1</td>
<td>0.02</td>
<td colspan="2">0.00</td>
</tr>
<tr class="odd">
<td colspan="2">Meningitis</td>
<td>1</td>
<td colspan="2">0.02</td>
<td colspan="2">0</td>
<td>0.00</td>
<td colspan="2">NC</td>
</tr>
<tr class="even">
<td colspan="2"><strong>Respiratory</strong></td>
<td><strong>29</strong></td>
<td colspan="2"><strong>0.72</strong></td>
<td colspan="2"><strong>36</strong></td>
<td><strong>0.89</strong></td>
<td colspan="2"><strong>0.81</strong></td>
</tr>
<tr class="odd">
<td colspan="2">Apnea</td>
<td>3</td>
<td colspan="2">0.07</td>
<td colspan="2">4</td>
<td>0.10</td>
<td colspan="2">0.75</td>
</tr>
<tr class="even">
<td colspan="2">Bronchitis</td>
<td>1</td>
<td colspan="2">0.02</td>
<td colspan="2">2</td>
<td>0.05</td>
<td colspan="2">0.50</td>
</tr>
<tr class="odd">
<td colspan="2">Carcinoma of larynx</td>
<td>0</td>
<td colspan="2">0.00</td>
<td colspan="2">1</td>
<td>0.02</td>
<td colspan="2">0.00</td>
</tr>
<tr class="even">
<td colspan="2">Carcinoma of lung</td>
<td>16</td>
<td colspan="2">0.40</td>
<td colspan="2">14</td>
<td>0.35</td>
<td colspan="2">1.15</td>
</tr>
<tr class="odd">
<td colspan="2">Emphysema</td>
<td>1</td>
<td colspan="2">0.02</td>
<td colspan="2">2</td>
<td>0.05</td>
<td colspan="2">0.50</td>
</tr>
<tr class="even">
<td colspan="2">Lung disorder</td>
<td>2</td>
<td colspan="2">0.05</td>
<td colspan="2">3</td>
<td>0.07</td>
<td colspan="2">0.67</td>
</tr>
<tr class="odd">
<td colspan="2">Pneumonia</td>
<td>4</td>
<td colspan="2">0.10</td>
<td colspan="2">10</td>
<td>0.25</td>
<td colspan="2">0.40</td>
</tr>
<tr class="even">
<td colspan="2">Respiratory disorder</td>
<td>2</td>
<td colspan="2">0.05</td>
<td colspan="2">0</td>
<td>0.00</td>
<td colspan="2">NC</td>
</tr>
<tr class="odd">
<td colspan="2"><strong>Skin/appendages</strong></td>
<td><strong>1</strong></td>
<td colspan="2"><strong>0.02</strong></td>
<td colspan="2"><strong>2</strong></td>
<td><strong>0.05</strong></td>
<td colspan="2"><strong>0.50</strong></td>
</tr>
<tr class="even">
<td colspan="2">Skin carcinoma</td>
<td>0</td>
<td colspan="2">0.00</td>
<td colspan="2">2</td>
<td>0.05</td>
<td colspan="2">0.00</td>
</tr>
<tr class="odd">
<td colspan="2">Skin melanoma</td>
<td>1</td>
<td colspan="2">0.02</td>
<td colspan="2">0</td>
<td>0.00</td>
<td colspan="2">NC</td>
</tr>
<tr class="even">
<td colspan="2"><strong>Urogenital</strong></td>
<td><strong>3</strong></td>
<td colspan="2"><strong>0.07</strong></td>
<td colspan="2"><strong>2</strong></td>
<td><strong>0.05</strong></td>
<td colspan="2"><strong>1.50</strong></td>
</tr>
<tr class="odd">
<td colspan="2">Bladder carcinoma</td>
<td>2</td>
<td colspan="2">0.05</td>
<td colspan="2">1</td>
<td>0.02</td>
<td colspan="2">2.00</td>
</tr>
<tr class="even">
<td colspan="2">Kidney failure</td>
<td>1</td>
<td colspan="2">0.02</td>
<td colspan="2">1</td>
<td>0.02</td>
<td colspan="2">1.00</td>
</tr>
</tbody>
</table>

^2^ Not calculated.

Source: Safety Update. Text Table 17, pg. 39 and Table T4.3.

## Laboratory Assessments

Protocol required laboratory assessments for safety were limited to
measurements of hepatic toxicity (ALT/SGPT, AST/SGOT) or hepatic
function (total bilirubin). Laboratory data for these assessments
(referred to as LFTs in this review) are presented as follows:

-   Mean values and mean changes from baseline values for each
    laboratory test at selected protocol-designated assessment times.

```{=html}
<!-- -->
```
-   Percentages of patients with laboratory values that shifted from
    within the normal range at baseline to above the normal range at
    selected protocol-designated assessment times.

```{=html}
<!-- -->
```
-   Clinically relevant laboratory values (values outside of the normal
    range that were considered to be of particular concern, based on the
    Sponsor's predefined criteria) that were observed during treatment.

### Mean LFT Values and Mean Changes from Baseline Values

Data for mean serum ALT values and mean of the percent changes from
baseline at 12-week intervals during the first year of treatment and
every 24 weeks thereafter through Week 144 in the Casodex-and
placebo-treatment groups are presented in Table 49. At baseline, the
treatment groups in each of the trials were well matched for mean and
median serum hepatic biochemistry values. During the first 6 months of
treatment, mean ALT values and the means of the changes from baseline
were numerically higher in the Casodex-treated patients. Thereafter,
mean serum ALT values and mean changes from baseline in the
Casodex-treated patients were comparable to or lower than those observed
in the placebo-treated patients.

[]{#__RefHeading___Toc25309709 .anchor}Table 49 Mean Serum ALT Values
(U/L) and Mean of Percent Changes from Baseline\
during Treatment (Data Combined from Trials 23, 24, and 25)

  ----------- ---------- ------- ------ -------- -------------- -- -- ----------- ---------- --------------
              Casodex\                                                Placebo\               
              (N=4022)                                                (N=4031)               
              ^1^                                                                            

  Study Week  n ^2^      Mean\                   Mean of %            Mean\       Mean of %  
                         ALT                     change from          ALT (U/L)   change\    
                         (U/L)                   baseline                         from       
                                                                                  baseline   

  Baseline    3942               21.5                                 21.2                   

  12          3817               22.8            25.9%                20.5                   6.7%

  24          3589               22.4            22.8%                20.7                   9.0%

  36          3422               20.8            14.7%                20.8                   9.6%

  48          3256               19.1            5.6%                 20.9                   10.5%

  72          3001               18.5            1.2%                 20.9                   12.5%

  96          2905               18.0            -2.5%                21.8                   16.9%

  120         1811 ^3^                  19.0     -1.5%                22.1                   16.1%

  144         1580               18.6            -2.8%                23.0                   15.6%
  ----------- ---------- ------- ------ -------- -------------- -- -- ----------- ---------- --------------

^1^ Number of patients who received at least one dose of study drug.

^2^ Number of patients upon which mean absolute values in Casodex
treatment group are based. The number of observations at each assessment
time is lower for the category of "mean of % change from baseline."

^3^ Decreased number of patients after Week 96 largely a result of
maximum 2-year treatment period in Trial 23.

Source: Table T7.2, ISS and Table 2, Appendix B of 3 May 2002
Submission.

##### Medical Officer\'s Comments {#medical-officers-comments-38 .unnumbered}

-   AST values (i.e., mean serum values and mean changes from baseline)
    in the Casodex- and placebo-treated patients showed a pattern of
    relative changes similar to that for ALT values.

-   There were no notable differences in mean serum bilirubin values or
    mean changes from baseline in the Casodex-treated patients compared
    to the placebo-treated patients.

-   In summary, although there were instances of large, clinically
    significant changes in LFT values in individual patients in both
    treatment groups, changes in mean and median serum values for ALT,
    AST, and total bilirubin were relatively small and did not appear to
    be of clinical significance.

### Shifts in LFT Laboratory Values to Above the Normal Range

The number and proportion of Casodex- and placebo-treated patients with
a normal ALT value at baseline and an ALT value above the normal range
at representative protocol-designated clinical visits are listed in
Table 50 for each of the 3 clinical trials. Similar data for changes in
bilirubin values in each of the trials are listed in Table 51.

[]{#__RefHeading___Toc25309710 .anchor}Table 50 ALT Shifts from Within
the Normal Range at Baseline to Above the Normal Range (High) during
Treatment in Each of Trials 23, 24, and 25

  --------- -- ---------- ------- ---------- ------- -- ---------- ------- ---------- ------- -- ---------- ------- ---------- -------
               **Number                                                                                                        
               (%) of                                                                                                          
               patients                                                                                                        
               with shift                                                                                                      
               to above                                                                                                        
               the normal                                                                                                      
               range**                                                                                                         

               **Trial                                  **Trial                                  **Trial                       
               23**                                     24**                                     25**                          

  **Study      Casodex\           Placebo\              Casodex\           Placebo\              Casodex\           Placebo\   
  Week**       N=1627             N=1627                N=1790             N=1795                N=605              N=609      

               n          (%) ^2^ n          (%)        n          (%)     n          (%)        n          (%)     n          (%)

  12           38         (2.6)   23         (1.5)      32         (2.2)   8          (0.5)      24         (4.3)   5          (0.9)

  24           48         (3.6)   16         (1.1)      39         (2.7)   14         (0.9)      24         (4.4)   5          (0.9)

  36           24         (2.0)   18         (1.3)      26         (1.8)   9          (0.6)      23         (4.3)   4          (0.8)

  48           14         (1.2)   15         (1.1)      22         (1.6)   14         (1.0)      13         (2.5)   2          (0.4)

  72           8          (0.8)   26         (2.0)      15         (1.2)   17         (1.3)      6          (1.2)   1          (0.2)

  96           8          (0.9)   26         (2.1)      15         (1.2)   18         (1.5)      5          (1.0)   7          (1.6)

  120          \-- ^1^            \--                   18         (1.5)   18         (1.5)      5          (1.1)   2          (0.5)

  144          \--                \--                   18         (1.7)   20         (2.0)      1          (0.2)   9          (2.6)
  --------- -- ---------- ------- ---------- ------- -- ---------- ------- ---------- ------- -- ---------- ------- ---------- -------

1\. Treatment period was limited to 96 weeks.

2\. Percentages based on both number of values above the normal range
and the total number of samples evaluate at each of the respective study
weeks.

Source: Safety Addendum for each of Trials 23, 24, and 25. Table T9.2.2.

##### Medical Officer\'s Comments {#medical-officers-comments-39 .unnumbered}

-   In both treatment groups, the proportion of patients who shifted to
    above the normal range for serum ALT values was relatively small and
    did not exceed 4.4% (Casodex-treatment group, Trial 25). However, a
    greater proportion of patients in the Casodex treatment groups
    shifted to above the normal range, most noticeable during the first
    36 weeks (Trial 23), first 48 weeks (Trial 24), and first 72 weeks
    (Trial 25) of treatment.

-   The largest numeric disparity between the Casodex and placebo
    treatment groups was observed in Trial 25.

-   Changes in AST values (not listed) were similar to those observed
    for ALT values.

[]{#__RefHeading___Toc25309711 .anchor}Table 51 Bilirubin Shifts from
Within the Normal Range at Baseline to Above the Normal Range (High)
during Treatment in each of Trials 23, 24, and 25

  --------- -- ---------- -------- ---------- ------- -- ---------- ------- ---------- ------- -- ---------- ------- ---------- -------
               **Number                                                                                                         
               (%) of                                                                                                           
               patients                                                                                                         
               with                                                                                                             
               shift**                                                                                                          

               **Trial                                   **Trial                                  **Trial                       
               23**                                      24**                                     25**                          

  **Study      Casodex\            Placebo\              Casodex\           Placebo\              Casodex\           Placebo\   
  Week**       N=1627              N=1627                N=1790             N=1795                N=605              N=609      

               n          (%)^2^   n          (%)        n          (%)     n          (%)        n          (%)     n          (%)

  12           27         (1.8)    30         (1.9)      24         (1.7)   31         (2.2)      4          (0.7)   8          (1.5)

  24           28         (2.0)    30         (2.0)      13         (1.0)   24         (1.8)      5          (1.0)   2          (0.4)

  36           21         (1.7)    28         (1.9)      14         (1.1)   28         (2.2)      5          (1.0)   4          (0.8)

  48           21         (1.8)    26         (1.9)      11         (0.9)   18         (1.4)      4          (0.8)   1          (0.2)

  72           20         (1.9)    27         (2.1)      15         (1.3)   20         (1.7)      3          (0.6)   4          (0.9)

  96           18         (1.9)    21         (1.7)      9          (0.8)   20         (1.8)      4          (0.9)   2          (0.5)

  120          \-- ^1^             \--                   9          (0.8)   18         (1.7)      2          (0.5)   1          (0.3)

  144          \--                 \--                   17         (1.8)   11         (1.2)      2          (0.5)   2          (0.6)
  --------- -- ---------- -------- ---------- ------- -- ---------- ------- ---------- ------- -- ---------- ------- ---------- -------

1\. Treatment period was limited to 96 weeks.

2\. Percentages based on both number of values above the normal range
and the total number of samples evaluate at each of the respective study
weeks.

Source: Safety Addendum for each of Trials 23, 24, and 25, Table T9.2.1.

##### Medical Officer\'s Comment {#medical-officers-comment-13 .unnumbered}

-   In both treatment groups, the proportion of patients who shifted to
    above the normal range for serum total bilirubin values was
    relatively small and did not exceed 2.2% at any specific assessment
    time. Within each trial, the proportion of patients in the Casodex
    and placebo treatment groups who shifted to above the normal range
    appeared to be comparable during the 96-week and 144-week treatment
    periods represented in the above Table.

### Clinically Relevant Changes in LFT Laboratory Values

Definitions for clinically relevant changes in hepatic laboratory values
(changes that were considered to be of particular concern) were
established by the Sponsor. For ALT and AST values, a clinically
relevant change was defined as an increase of (1) greater than or equal
to 3 times the upper reference range for that laboratory variable or (2)
greater than or equal to twice the upper reference range for that
laboratory variable on 2 or more consecutive occasions. For total
bilirubin values, a clinically relevant change was defined as an
increase from the pre-randomization value by greater than or equal to
100% of the upper reference range for that laboratory variable.

The number and percentage of patients with one or more clinically
relevant changes in each of ALT, AST, or total bilirubin values in
Trials 23, 24, and 25 (combined analysis) are listed in Table 52. For
each biochemistry variable, data are presented separately for patients
who had normal or abnormal baseline values. Among patients with normal
baseline values, a higher proportion of Casodex-treated patients showed
clinically relevant changes from baseline for AST (1.7%), ALT (1.6%),
and bilirubin (0.8%) than placebo-treated patients (0.7%, 0.4%, and
0.5%, respectively).

[]{#__RefHeading___Toc25309712 .anchor}Table 52 Clinically Relevant
Changes in ALT, AST, and Total Bilirubin Values during Treatment in
Trials 23, 24, and 25 (Combined Analysis)

  ----------- ----------- -- ------------ ------------ -------- --- ------------ ------------ -------
                             **Casodex                              **Placebo                 
                             (N=4022)**                             (N=4031)**                

  Parameter   Baseline\      Baseline     Patients                  Baseline     Patients     
              Value ^1^                   with                                   with         
                                          clinically                             clinically   
                                          relevant                               relevant     
                                          change                                 change       

                             N ^2^        n ^3^        (%)          N ^2^        n ^3^        (%)

  AST         Normal         3745         65           (1.7)        3770         27           (0.7)

              Abnormal       100          3            (3.0)        93           4            (4.3)

                                                                                              

  ALT         Normal         3660         60           (1.6)        3685         13           (0.4)

              Abnormal       186          9            (4.8)        179          8            (4.5)

                                                                                              

  Total       Normal         3530         29           (0.8)        3558         18           (0.5)
  bilirubin                                                                                   

              Abnormal       314          7            (2.2)        305          1            (0.3)
  ----------- ----------- -- ------------ ------------ -------- --- ------------ ------------ -------

^1^ Baseline value: normal = within reference range; abnormal = outside
reference range

^2^ N = number of patients with a baseline value and at least one
non-missing laboratory assessment post dose.

^3^ n = number of patients with a clinically relevant change in the
laboratory value.

Source: ISS, Text Table 24, pg. 62.

##### Medical Officer's Comments {#medical-officers-comments-40 .unnumbered}

-   The number of patients with normal baseline values that had
    clinically relevant changes in hepatic biochemistry values was
    generally very low. However, more patients treated with Casodex had
    clinically relevant changes from a baseline value of normal than
    placebo-treated patients.

-   In patients with abnormal baseline ALT or AST values, the proportion
    with clinically relevant changes during treatment was similar in
    both treatment groups. However, for patients with an abnormal
    bilirubin value at baseline, the proportion of patients with a
    clinically relevant change during treatment was greater in
    Casodex-treated patients.

The number of patients with resolution of their clinically relevant
change(s) in ALT, AST, or total bilirubin, either within the treatment
or post treatment period, is listed in Table 53. Resolution is presented
either as (1) return of the parameters to within the normal range or (2)
parameter no longer clinically relevant but not within the normal range.

[]{#__RefHeading___Toc25309713 .anchor}Table 53 Resolution of Clinically
Relevant Changes in ALT, AST, and Total Bilirubin Values in Trials 23,
23, and 25 (Combined Analyses)

  ------------------ -- ---------- --- -- -------- ---------- -------- -- ---------- -------- ---------- -------- -- ----------- -------- ---------- --------
                        AST                                               ALT                                        Bilirubin                       

  **Status of           Casodex\                   Placebo\               Casodex\            Placebo\               Casodex\             Placebo\   
  clinically\           N=68 ^1^                   N=31                   N=69                N=21                   N=36                 N=19       
  relevant (CR)                                                                                                                                      
  change**                                                                                                                                           

  Time of Resolution               n      (%)      n          (%)         n          (%)      n          (%)         n           (%)      n          (%)

  **Parameter within                                                                                                                                 
  normal range**                                                                                                                                     

  Within treatment      18                \(26\)   12         \(39\)      21         \(30\)   7          \(33\)      11          \(31\)   5          \(26\)
  period                                                                                                                                             

  Post treatment        23                \(34\)   7          \(23\)      23         \(33\)   5          \(24\)      3           \(8\)    0          \(0\)
  period                                                                                                                                             

  **Parameter no                                                                                                                                     
  longer CR**                                                                                                                                        

  Within treatment      5                 \(7\)    3          \(10\)      4          \(6\)    1          \(5\)       3           \(8\)    8          \(42\)
  period                                                                                                                                             

  Post treatment        2                 \(3\)    0          \(0\)       1          \(1\)    0          \(0\)       5           \(14\)   0          \(0\)
  period                                                                                                                                             

  **Not resolved**      3                 \(4\)    4          \(13\)      5          \(7\)    4          \(19\)      1           \(3\)    0          \(0\)

  **No further          17                \(25\)   5          \(16\)      15         \(22\)   4          \(19\)      13          \(36\)   6          \(32\)
  information**                                                                                                                                      
  ------------------ -- ---------- --- -- -------- ---------- -------- -- ---------- -------- ---------- -------- -- ----------- -------- ---------- --------

1 Total number of patients with the clinically relevant change.

Source: ISS, Tables T7.5.1, T7.5.2, and T7.5.3.

##### Medical Officer's Comments  {#medical-officers-comments-41 .unnumbered}

-   For those patients with follow up laboratory data (64-75% of
    patients in the Casodex group), more than 90% had resolution
    (complete or partial) of their clinically relevant changes. Among
    Casodex-treated patients with follow up data, 4% (AST), 7% (AST),
    and 3% (bilirubin) showed no improvement.

-   Overall, these changes in hepatic laboratory values do not raise
    concerns of sufficient magnitude to preclude the use of Casodex in
    the proposed population (men with prostate cancer) and are
    adequately addressed in proposed labeling. Previous labeling appears
    to have provided adequate guidance to physicians for the safe use of
    Casodex 50 mg per day in men with prostate cancer, based on post
    marketing safety reports.

-   The potential clinical significance of these changes in biochemistry
    measurements of hepatic toxicity or function is discussed further in
    Section 5.9.3.

### Non-hepatic Laboratory Safety Assessments 

Protocol required laboratory assessments for safety were limited to
measurements of hepatic toxicity (ALT/SGPT, AST/SGOT) and hepatic
function (total bilirubin). Androgens are known to affect
erythropoiesis; consequently, an increase in the number of
Casodex-treated patients, relative to placebo-treated patients, who
experienced reduced concentrations of hemoglobin and anemia, was not
unexpected. Since collection of hematological laboratory data was not a
component of these clinical trials, assessment of the effect of Casodex
on blood indices in these clinical trials is limited to reports of
hematological adverse events (see Table 54). A higher proportion of
Casodex-treated patients reported an adverse event classified as anemia
or erythrocyte disorder (2.9% vs. 1.9%). Adverse events of these types
classified as serious also occurred more frequently in Casodex-treated
patients (25 of 4022, 0.62%) than in placebo-treated patient s (19 of
4031, 0.47%).

[]{#__RefHeading___Toc25309714 .anchor}Table 54 Adverse Events Reported
as Anemia or Erythrocyte Disorder during the Treatment Period (Combined
Data from Trials 23, 24, and 25)

  ---------------------- ------------ ------- -------- ------ ----- ------------- -------- ---------- --------
                         **Number (%)                                                                 
                         of                                                                           
                         patients**                                                                   

  Treatment group        All\                 Deaths                Withdrawals            Serious\   
                         Adverse                                    ^2^                    Adverse    
                         events ^1^                                                        Events ^3^ 

                         n            \%               n      \%    n             \%       n          \%

  Casodex (N=4022)       115          (2.9)            0      \--   4             (0.10)   25         (0.62)

  Placebo (N=4031)       77           (1.9)            0      \--   2             (0.05)   19         (0.47)
  ---------------------- ------------ ------- -------- ------ ----- ------------- -------- ---------- --------

1\. All adverse events reported as anemia or erythrocyte disorder.\
2. All withdrawals due to an adverse event reported as anemia or
erythrocyte disorder.\
3. All serious adverse events reported as anemia or erythrocyte
disorder.

Source: ISS, Table T12.2

##### Medical Officer\'s Comment {#medical-officers-comment-14 .unnumbered}

-   The differences in the proportion of Casodex-treated and
    placebo-treated patients who experienced adverse events classified
    as anemia or erythrocyte disorders was to be expected. The magnitude
    of the differences, particularly for serious adverse events, was
    very small.

## Safety Issues of Special Interest or Concern

### Pharmacological Adverse Events

Adverse events that may have been a result of the anti-androgenic or
compensatory estrogenic activity of Casodex (i.e., pharmacological
adverse events) and the number of patients who experienced them are
summarized in Table 55. All occurred more frequently in Casodex-treated
patients than in placebo-treated patients. The most frequently reported
adverse events, occurring in 73% and 67% of patients in the Casodex
group were breast pain and gynecomastia, respectively. Other adverse
events occurring in 5-10% of Casodex treated patients were
vasodilatation, impotence, and alopecia.

[]{#__RefHeading___Toc25309715 .anchor}Table 55 Pharmacological-Related
(Anti-androgenic and Estrogenic)\
Adverse Events (Combined Data from Trials 23, 24, and 25)

  ------------------------- ------------ ----------- ----------- -----------
  **Adverse Event**         **Number (%)                         
                            of                                   
                            patients**                           

                            Casodex                  Placebo     

                            (N=4022)                 (N=4031)    

                            n            \%          n           \%

  Breast pain               2937         73.0%       296         7.3%

  Gynecomastia              2700         67.1%       325         8.1%

  Vasodilatation            364          9.1%        211         5.2%

  Impotence                 362          9.0%        250         6.2%

  Alopecia                  239          5.9%        31          0.8%

  Libido decreased          145          3.6%        45          1.1%
  ------------------------- ------------ ----------- ----------- -----------

Source: Modified from ISS, Text Table 30, pg. 74.

##### Medical Officer's Comment {#medical-officers-comment-15 .unnumbered}

-   The high incidence of gynecomastia and breast pain may be a direct
    consequence of the anti-androgenic activity of Casodex, a
    consequence of the compensatory increase in serum concentrations of
    estradiol that are observed during treatment with Casodex, or a
    combination of both.

#### Gynecomastia and Breast Pain during the Treatment Period

Most Casodex-treated patients (86.2%) reported gynecomastia or breast
pain. Of these, 649/4022 (16.1%) patients withdrew from Casodex therapy.
A total of 345/4,022 (8.6%) of these patients reported severe
gynecomastia or severe breast pain. In the placebo-treated patients,
only 12.4% patients reported gynecomastia or breast pain, and only 0.6%
withdrew from treatment because of these adverse events (Table 56).

[]{#__RefHeading___Toc25309716 .anchor}Table 56 Incidence of and
Withdrawals due to Gynecomastia and Breast Pain within the Treatment
Period (Combined Data from Trials 23, 24, and 25)

  ------------------------------------- ------------ ---------- ---------- ----------
                                        **Number (%)                       
                                        of                                 
                                        patients**                         

  **Category**                          Casodex                 Placebo    

                                        (N=4022)                (N=4031)   

                                        n            (%)        n          (%)

  **Number of patients with:**                                             

  Gynecomastia alone                    2700         (67.1)     325        (8.1)

  Male breast pain alone                2937         (73.0)     296        (7.3)

  Both gynecomastia and male breast     2170         (54.0)     120        (3.0)
  pain                                                                     

  *Either gynecomastia or male breast   *3467*       *(86.2)*   *501*      *(12.4)*
  pain*                                                                    

  **Number of patients with withdrawal                                     
  due to:**                                                                

  Gynecomastia                          418          (10.4)     15         (0.4)

  Male breast pain                      498          (12.4)     15         (0.4)

  Both gynecomastia and male breast     267          (6.6)      5          (0.1)
  pain                                                                     

  *Either gynecomastia or male breast   *649*        *(16.1)*   *25*       *(0.6)*
  pain*                                                                    
  ------------------------------------- ------------ ---------- ---------- ----------

Source: Text Table 31, pg. 75 of the ISS.

The time to occurrence of gynecomastia was estimated from Kaplan-Meier
plots (Figure 3). More than 50% of Casodex-treated patients who
developed gynecomastia did so within 200 days of treatment onset. Most
who developed gynecomastia did so within 24 months of starting
treatment.

[]{#__RefHeading___Toc25232680 .anchor}Figure 3 Time to First Occurrence
of Gynecomastia within the Treatment Period

![](media/image3.png)

Source: Figure 2, pg 76 of the ISS.

Table 57 summarizes the percentage of patients with gynecomastia and/or
breast pain within the treatment period and the percentage of patients
who withdrew because of these adverse events in each of Trials 23, 24,
and 25. The percentage of Casodex-treated patients reporting
gynecomastia was highest in Trial 23 (72.6%) and lowest in Trial 25
(55%). The percentage of Casodex-treated patients reporting either
gynecomastia or breast pain differed slightly across the 3 trials and
ranged from 90.1% (Trial 23) to 82.9% (Trial 24). The percentage of
patients reporting either of these adverse events was considerably lower
in the placebo treatment groups and ranged from 16.1% (Trial 23) to 6.6%
(Trial 25). The percentage of Casodex-treated patients who withdrew from
treatment because of either gynecomastia or breast pain also was highest
in Trial 23 (20.0%) and lowest in Trial 25 (4.5%). Less than 1% of
patients in any of the placebo groups withdrew because of either
gynecomastia or breast pain.

##### Medical Officer's Comments {#medical-officers-comments-42 .unnumbered}

-   Gynecomastia and/or breast pain are by far the most frequently
    reported adverse events in men treated with Casodex, occurring in
    86% of patients in the combined trials. In 8.6% of the patients,
    these adverse events were reported as severe. Across the 3 trials,
    16.1% of Casodex-treated patients withdrew because of these adverse
    events.

-   Patients in Trial 23 (primarily US patients) tolerated gynecomastia
    and/or breast pain least well. Twenty (20) percent of
    Casodex-treated patients in Trial 23 withdrew from treatment because
    of these adverse events while only 4.5% of Casodex-treated patients
    in Trial 25 withdrew for this reason. The high withdrawal rate
    because of gynecomastia and/or breast pain was clearly related to
    treatment with Casodex per se and not study participation in general
    in that \< 1% of patients in the placebo group in Trial 23 withdrew
    because of these adverse events.

-   The Sponsor performed subset analyses to determine if there were any
    associations other than Casodex that were related to the development
    of gynecomastia or breast pain. According to the Sponsor, there was
    no obvious relationship between age, race (Trial 23 only), tumor
    stage, weight, or body mass index and the incidence of gynecomastia
    or breast pain.

-   In Trial 25, some patients were offered breast irradiation prior to
    initiation of randomized therapy; however, the number of patients
    was too small to draw any conclusions about the benefit of the
    procedure.

[]{#__RefHeading___Toc25309717 .anchor}Table 57 Incidence of and
Withdrawals due to Gynecomastia and Breast Pain within the Treatment
Period in Each of Trials 23, 24, and 25

<table>
<colgroup>
<col style="width: 21%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 5%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 5%" />
<col style="width: 6%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 5%" />
<col style="width: 7%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td colspan="12"><strong>Number (per cent) of patients with
event</strong></td>
</tr>
<tr class="even">
<td rowspan="3"><strong>Category</strong></td>
<td colspan="4"><strong>Study 23</strong></td>
<td colspan="4"><strong>Study 24</strong></td>
<td colspan="4"><strong>Study 25</strong></td>
</tr>
<tr class="odd">
<td colspan="2">Casodex<br />
(N = 1627)</td>
<td colspan="2">Placebo<br />
(N = 1627)</td>
<td colspan="2">Casodex<br />
(N = 1790)</td>
<td colspan="2">Placebo<br />
(N = 1795)</td>
<td colspan="2">Casodex<br />
(N = 605)</td>
<td colspan="2">Placebo<br />
N = 609)</td>
</tr>
<tr class="even">
<td>n</td>
<td>(%)</td>
<td>n</td>
<td>(%)</td>
<td>n</td>
<td>(%)</td>
<td>n</td>
<td>(%)</td>
<td>n</td>
<td>(%)</td>
<td>n</td>
<td>(%)</td>
</tr>
<tr class="odd">
<td colspan="4"><em>Number of patients with adverse event</em></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td><blockquote>
<p>Gynecomastia</p>
</blockquote></td>
<td>1182</td>
<td>(72.6)</td>
<td>165</td>
<td>(10.1)</td>
<td>1185</td>
<td>(66.2)</td>
<td>141</td>
<td>(7.9)</td>
<td>333</td>
<td>(55.0)</td>
<td>19</td>
<td>(3.1)</td>
</tr>
<tr class="odd">
<td><blockquote>
<p>Breast pain</p>
</blockquote></td>
<td>1390</td>
<td>(85.4)</td>
<td>173</td>
<td>(10.6)</td>
<td>1173</td>
<td>(65.5)</td>
<td>98</td>
<td>(5.5)</td>
<td>374</td>
<td>(61.8)</td>
<td>25</td>
<td>(4.1)</td>
</tr>
<tr class="even">
<td><blockquote>
<p>Either gynecomastia or breast pain</p>
</blockquote></td>
<td>1466</td>
<td>(90.1)</td>
<td>262</td>
<td>(16.1)</td>
<td>1484</td>
<td>(82.9)</td>
<td>199</td>
<td>(11.1)</td>
<td>517</td>
<td>(85.5)</td>
<td>40</td>
<td>(6.6)</td>
</tr>
<tr class="odd">
<td colspan="7"><em>Number of patients withdrawing because of adverse
event</em></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td><blockquote>
<p>Gynecomastia</p>
</blockquote></td>
<td>190</td>
<td>(11.7)</td>
<td>6</td>
<td>(0.4)</td>
<td>212</td>
<td>(11.8)</td>
<td>8</td>
<td>(0.4)</td>
<td>16</td>
<td>(2.6)</td>
<td>1</td>
<td>(0.2)</td>
</tr>
<tr class="odd">
<td><blockquote>
<p>Breast pain</p>
</blockquote></td>
<td>285</td>
<td>(17.5)</td>
<td>8</td>
<td>(0.5)</td>
<td>195</td>
<td>(10.9)</td>
<td>7</td>
<td>(0.4)</td>
<td>18</td>
<td>(3.0)</td>
<td>0</td>
<td>(0.0)</td>
</tr>
<tr class="even">
<td><blockquote>
<p>Either gynecomastia or breast pain</p>
</blockquote></td>
<td>326</td>
<td>(20.0)</td>
<td>12</td>
<td>(0.7)</td>
<td>296</td>
<td>(16.5)</td>
<td>12</td>
<td>(0.7)</td>
<td>27</td>
<td>(4.5)</td>
<td>1</td>
<td>(0.2)</td>
</tr>
</tbody>
</table>

Source: ISS, Tables 9.3.2 and 9.3.3

#### Resolution of Breast Pain and Gynecomastia after Withdrawal of Treatment

Approximately 10% of all patients who withdrew from trial therapy with
ongoing gynecomastia or breast pain did not have any follow-up
information. For Casodex-treated patients who had gynecomastia ongoing
at the time of withdrawal and had at least 1 follow-up assessment as of
the 23 February 2001 data cutoff, 50.7% had resolution of their
gynecomastia (Table 58). The median time from withdrawal of trial
therapy to resolution of gynecomastia was approximately 101 weeks.
According to the Sponsor, the time to resolution of gynecomastia
appeared to be longer with increasing duration of trial therapy.

For Casodex-treated patients who had breast pain ongoing at the time of
withdrawal and had at least 1 follow-up assessment, 92.2% of patients
had resolution of breast pain by the date of data cutoff. The median
time from withdrawal of trial therapy to resolution of breast pain was
approximately 24 weeks.

[]{#__RefHeading___Toc25309718 .anchor}Table 58 Percentage of Patients
with Resolution of Gynecomastia and Breast\
Pain after Withdrawal of Treatment

+----------------------------------------------+----------+-----------+
|                                              | **Number |           |
|                                              | (%) of   |           |
|                                              | pa       |           |
|                                              | tients** |           |
+----------------------------------------------+----------+-----------+
| **Category**                                 | Casodex  |           |
|                                              | (N=4022) |           |
|                                              | ^1^      |           |
+----------------------------------------------+----------+-----------+
|                                              | n ^2^    | (%)       |
+----------------------------------------------+----------+-----------+
| Gynecomastia:                                |          |           |
+----------------------------------------------+----------+-----------+
| > Patients with event ongoing at withdrawal  | 1572     | (100.0)   |
| > and follow up information                  |          |           |
+----------------------------------------------+----------+-----------+
| > Patients with event ongoing at withdrawal  | 787      | (50.7)    |
| > and follow up information and resolution   |          |           |
+----------------------------------------------+----------+-----------+
| Breast pain                                  |          |           |
+----------------------------------------------+----------+-----------+
| > Patients with event ongoing at withdrawal  | 1729     | (100.0)   |
| > and follow up information                  |          |           |
+----------------------------------------------+----------+-----------+
| > Patients with event ongoing at withdrawal  | 1595     | (92.2)    |
| > and follow up information and resolution   |          |           |
+----------------------------------------------+----------+-----------+

> 1\. Total number of patients treated with Casodex.
>
> 2\. Number of patients with condition.
>
> Source: ISS, Summary Table T9.2.2.

##### Medical Officer's Comments {#medical-officers-comments-43 .unnumbered}

-   The high percentage of patients who developed gynecomastia during
    treatment (67%) and persistence of gynecomastia after
    discontinuation of Casodex treatment are significant problems and of
    concern. According to the Sponsor, only 50.7% of Casodex-treated
    patients with post treatment follow up data had resolution of
    gynecomastia by the date of data cutoff. For many men, particularly
    those with localized prostate disease who had undergone radical
    prostatectomy or radiation therapy of curative intent, permanent
    gynecomastia may be a significant quality of life consideration.

-   GnRH analogs were not compared to Casodex in the clinical trials
    included in this submission. However, in a prior submission (NDA
    20-498/s006), GnRH analogs were show to be at least as effective as
    Casodex in terms of a survival endpoint in men with locally advanced
    non-metastatic prostate cancer and superior to Casodex in men with
    metastatic (M1) prostate cancer. In the present application, the
    Sponsor argues that Casodex is likely to be better tolerated than
    GnRH analogs that induce a complete medical castration and more
    severe symptoms of androgen deprivation. GnRH analogs, however, do
    not induce gynecomastia or breast pain. It is therefore unclear as
    to which therapy would be associated with a better quality of life,
    particularly if long-term survival is anticipated.

### Sexual Dysfunction

In Trial 25, sexual function was assessed during the first 48 weeks of
treatment by a patient-completed shortened version of the GRISS
questionnaire. The questionnaire was completed and the responses were
collected at baseline and then at 12-week intervals until Week 48.
Maintenance of sexual function based on the GRISS questionnaire relative
to baseline during the first 48 weeks of treatment is summarized in
Table 59. Maintenance of sexual function was considered to be no loss of
potency or frequency. The findings summarized in Table 59 indicate that
Casodex therapy was associated with a reduction in the frequency of
sexual intercourse and an increase in impotence compared to treatment
with placebo. At Week 48, 31.4% of Casodex-treated patients and 47.6% of
placebo-treated patients were assessed as having had no significant
change in sexual frequency. Also at Week 48, 34.9% of Casodex-treated
patients and 53.4% of placebo-treated patients were assessed as having
had no significant change in sexual potency.

[]{#__RefHeading___Toc25309719 .anchor}Table 59 Maintenance of Sexual
Function Relative to Baseline

  -------------------- -- -------------------- -- ------- -------- -- ------- --------- -- ------- ------------
  Sexual function         Weeks                                                                    
  domain                  post-randomization                                                       

                          Wk 12                           Wk 24               Wk 36                Wk 48

                          Percentage of                                                            
                          patients who                                                             
                          maintained baseline                                                      
                          function                                                                 

  **Frequency**                                                                                    

  Casodex                 44.9%                   41.9%               36.1%                31.4%   

  Placebo                 61.5%                   55.1%               47.1%                47.6%   

  **Potency**                                                                                      

  Casodex                 49.8%                   43.7%               39.7%                34.9%   

  Placebo                 62.1%                   58.4%               60.1%                53.4%   
  -------------------- -- -------------------- -- ------- -------- -- ------- --------- -- ------- ------------

Source: Table 25, pg. 65, ISS.

##### Medical Officer\'s Comments {#medical-officers-comments-44 .unnumbered}

-   It is of interest that almost 40% of patients were assessed as
    having had a decrease in either sexual frequency or potency at 12
    weeks after the onset of placebo therapy.

-   Changes in sexual function based on the GRISS questionnaire were
    qualitatively consistent with the pattern of adverse events for
    decreased libido and impotence reported in Trial 25. Based on
    reported adverse events, Casodex-treated patients had higher rates
    of decreased libido (23/605 \[3.8%\]) and impotence (97/605
    \[16.0%\]) than placebo-treated patients (decreased libido: 7/609
    \[1.2%\] and impotence: 41/609 \[6.7%\]). These adverse events,
    however, appear to have been underreported since the proportion of
    patients with decreased sexual function based on the GRISS
    questionnaire was much higher.

### Liver Toxicity

#### Abnormal Liver Function Test (LFT) Values Reported as Adverse Events

Laboratory values outside of the normal range were not to be routinely
reported as adverse events unless the investigator believed that they
were clinically significant or required clinical intervention. The
number and proportion of patients for whom an increase in serum
concentrations of ALT, AST, or total bilirubin were reported as an
adverse event in each of the trials is listed in Table 60. Across the 3
trials, 138 of 4022 (3.4%) patients in the Casodex group and 94 of 4031
(2.3%) patients in the placebo group had one or more increased liver
function test values reported as an adverse event. In each of the
trials, the proportion of patients with a LFT-related adverse event (any
type) was numerically higher in the Casodex treatment group.

[]{#__RefHeading___Toc25309720 .anchor}Table 60 Number (%) of Patients
with Increased Liver Function Test Values Reported as Adverse Events
(Trials 23, 24, and 25)

<table>
<colgroup>
<col style="width: 21%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 5%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 5%" />
<col style="width: 6%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 4%" />
<col style="width: 8%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td colspan="12"><strong>Number (per cent) of patients with
event</strong></td>
</tr>
<tr class="even">
<td rowspan="3">Test Reported as Adverse Event</td>
<td colspan="4"><strong>Study 23</strong></td>
<td colspan="4"><strong>Study 24</strong></td>
<td colspan="4"><strong>Study 25</strong></td>
</tr>
<tr class="odd">
<td colspan="2">Casodex<br />
(N = 1627)</td>
<td colspan="2">Placebo<br />
(N = 1627)</td>
<td colspan="2">Casodex<br />
(N = 1790)</td>
<td colspan="2">Placebo<br />
(N = 1795)</td>
<td colspan="2">Casodex<br />
(N = 605)</td>
<td colspan="2">Placebo<br />
N = 609)</td>
</tr>
<tr class="even">
<td>n</td>
<td>(%)</td>
<td>n</td>
<td>(%)</td>
<td>n</td>
<td>(%)</td>
<td>n</td>
<td>(%)</td>
<td>n</td>
<td>(%)</td>
<td>n</td>
<td>(%)</td>
</tr>
<tr class="odd">
<td><blockquote>
<p>Any Increased Test <sup>1</sup></p>
</blockquote></td>
<td>68</td>
<td>(4.2)</td>
<td>60</td>
<td>(3.7)</td>
<td>50</td>
<td>(2.8)</td>
<td>14</td>
<td>(0.8)</td>
<td>20</td>
<td>(3.3)</td>
<td>6</td>
<td>(1.0)</td>
</tr>
<tr class="even">
<td><blockquote>
<p>Increased ALT</p>
</blockquote></td>
<td>52</td>
<td>(3.2)</td>
<td>44</td>
<td>(2.7)</td>
<td>41</td>
<td>(2.3)</td>
<td>11</td>
<td>(0.6)</td>
<td>19</td>
<td>(3.1)</td>
<td>2</td>
<td>(0.3)</td>
</tr>
<tr class="odd">
<td><blockquote>
<p>Increased AST</p>
</blockquote></td>
<td>43</td>
<td>(2.6)</td>
<td>25</td>
<td>(1.5)</td>
<td>39</td>
<td>(2.2)</td>
<td>12</td>
<td>(0.7)</td>
<td>18</td>
<td>(3.0)</td>
<td>3</td>
<td>(0.5)</td>
</tr>
<tr class="even">
<td><blockquote>
<p>Increased bilirubin</p>
</blockquote></td>
<td>20</td>
<td>(1.2)</td>
<td>19</td>
<td>(1.2)</td>
<td>8</td>
<td>(0.4)</td>
<td>3</td>
<td>(0.2)</td>
<td>4</td>
<td>(0.7)</td>
<td>3</td>
<td>(0.5)</td>
</tr>
</tbody>
</table>

1\. Total number (%) of patients with an increased ALT, AST, or
bilirubin value reported as an adverse event.

Source: Table 12, Safety Addendum Trial 23; Table 1 and Table 2 (Pg. 7)
of submission of May 3, 2002.

##### Medical Officer's Comments {#medical-officers-comments-45 .unnumbered}

-   For each of the 3 tests of liver toxicity or liver function, higher
    numbers of adverse events were reported for Casodex-treated patients
    in each of the trials with 2 exceptions (bilirubin values in Trials
    23 and 25). The absolute differences between the proportion of
    Casodex-treated and placebo-treated patients were in general small,
    particularly in Trial 23 ("any increased tests") and in all trials
    for "increased bilirubin."

-   Clinically relevant changes in LFT values and their likely clinical
    significance were previously reviewed (see Table 52 and Table 53).

#### Hepatic-related Adverse Events during the Treatment Period

**All adverse events.** A total of 220 (5.3%) of Casodex-treated
patients and 139 (3.3%) placebo-treated patients had at least one
hepatic-related adverse event. Table 61 summarizes all hepatic-related
adverse events reported during the treatment period in Trials 23, 24,
and 25 combined. In this Table, the category of Abnormal Liver Function
Test includes the COSTART preferred terms of "liver function tests
abnormal, AST/SGOT increased, and ALT/SGPT increased." The category of
jaundice includes the COSTART preferred terms of "cholestatic jaundice,
jaundice, bilirubinemia, and gamma glutamyl transpeptidase increased."
The incidence of hepatic-related adverse events was numerically greater
in the Casodex group for 7 of the 10 categories represented in Table 61.
However, only 3 categories of hepatic-related adverse events were
reported by 1% or more of the patients in either treatment group. These
were abnormal liver function test (3.0% Casodex group; 1.6% placebo
group), jaundice (1.0% Casodex group, 0.7% placebo group), and
cholelithiasis (1.0% Casodex group, 0.7% placebo group).

**Serious adverse events other than deaths.** The most frequently
reported serious hepatic-related adverse events were cholelithiasis
(0.6% Casodex-treated patients, 0.3% placebo-treated patients) and
cholecystitis (0.5% Casodex-treated patients; 0.4% placebo-treated
patients). Other categories in which the incidence of serious
hepatic-related adverse events exceeded 0.1% in Casodex-treated patients
were abnormal liver function tests (0.3%) and jaundice (0.2%).

[]{#__RefHeading___Toc25309721 .anchor}Table 61 Hepatic-related Adverse
Events during Treatment (Trials 23, 24, and 25)

  ---------------------- ----------- ----- --------- --- -------- --------- ------------- --------- ---------- ---------
  **Adverse Event**      **Number                                                                              
                         (%) of                                                                                
                         patients                                                                              
                         ^1,\ 2^**                                                                             

  Treatment group        All\                            Deaths             Withdrawals             Serious\   
                         Adverse                         ^3^                ^3^                     Adverse    
                         events ^3^                                                                 Events ^3^ 

                         n                 \%        n            \%        n             \%        n          \%

  **Abnormal Liver                                                                                             
  Function Test ^4^**                                                                                          

  Casodex                120               (3.0)     0                      47            (1.2)     10         (0.3)

  Placebo                63                (1.6)     0                      18            (0.5)     0          

  **Jaundice ^5^**                                                                                             

  Casodex                42                (1.0)     0                      17            (0.4)     6          (0.2)

  Placebo                30                (0.7)     0                      6             (0.2)     1          (\<0.1)

  **Cholelithiasis**                                                                                           

  Casodex                40                (1.0)     0                      1             (\<0.1)   23         (0.6)

  Placebo                28                (0.7)     0                      1             (\<0.1)   10         (0.3)

  **Cholecystitis**                                                                                            

  Casodex                22                (0.6)     0                      1             (\<0.1)   20         (0.5)

  Placebo                16                (0.4)     0                      1             (\<0.1)   14         (0.4)

  **Hepatitis**                                                                                                

  Casodex                8                 (0.2)     0                      4             (0.1)     4          (0.1)

  Placebo                1                 (\<0.1)   0                      0                       0          

  **Hepatic Neoplasia**                                                                                        

  Casodex                6                 (0.2)     1            (\<0.1)   1             (\<0.1)   3          (0.1)

  Placebo                5                 (0.1)     0                      1             (\<0.1)   4          (0.1)

  **Biliary Pain**                                                                                             

  Casodex                3                 (0.1)     0                      0                       0          

  Placebo                2                 (0.1)     0                      0                       1          (\<0.1)

  **Cirrhosis of Liver**                                                                                       

  Casodex                1                 (\<0.1)   0                      0                       0          

  Placebo                1                 (\<0.1)   1            (\<0.1)   1             (\<0.1)   1          (\<0.1)

  **Liver Fatty                                                                                                
  Deposit**                                                                                                    

  Casodex                1                 (\<0.1)   0                      0                       0          

  Placebo                6                 (0.2)     0                      0                       0          

  **Hepatomegaly**                                                                                             

  Casodex                0                           0                      0                       0          

  Placebo                3                 (0.1)     0                      1             (\<0.1)   0          
  ---------------------- ----------- ----- --------- --- -------- --------- ------------- --------- ---------- ---------

1\. Individual patients may have had more than 1 event and may be
represented in \> 1 category.

2\. 220 of 4022 (5.3%) Casodex-treated patients and 139 of 4031 (3.3%)
placebo-treated patients experienced one or more hepatic adverse events
during treatment.

3\. Includes all adverse events, deaths, withdrawals, or serious adverse
events in the respective category.

4\. Includes COSTART preferred terms of "liver function tests abnormal,
SGOT increased, and SGPT increased."

5\. Includes COSTART preferred terms of "cholestatic jaundice, jaundice,
bilirubinemia, and gamma glutamyl transpeptidase increased."

Source: Safety Update, Table T8.1.

##### Medical Officer's Comments {#medical-officers-comments-46 .unnumbered}

-   The majority of adverse events related to increased AST and ALT
    values appeared to have occurred within the first year of trial
    therapy in both treatment groups.

-   The incidences of abnormal LFTs and jaundice that led to withdrawal
    were higher in Casodex-treated patients (1.2% and 0.4%,
    respectively) than placebo-treated patients (0.5% and 0.2%,
    respectively). Of the patients with abnormal liver function tests,
    10 cases in Casodex-treated patients and 0 cases (none) in the
    placebo-treated patients were classified as serious.

#### Deaths Related to Hepatic Failure or Primary Hepatic Neoplasms

Deaths classified as related to hepatic failure or primary hepatic
neoplasms that occurred either during the treatment period or during the
post treatment follow up period are listed in Table 62. Five (5)
Casodex-treated patients and 6 placebo-treated patients were reported to
have died from one of these causes. One of the deaths in the placebo
group may have been associated with metastatic cancer to the liver and
not due to a primary hepatic tumor. One case in the Casodex treatment
group was classified by the investigator as possibly related to
treatment with study drug.

[]{#__RefHeading___Toc25309722 .anchor}Table 62 Deaths Related to
Hepatic Failure or Primary Hepatic Neoplasms

+---+------+---+--------------------+----+----+----------------------+
| T | Pat  | A | Cause of Death     | Le | S  | Comment              |
| r | ient | g |                    | ng | tu |                      |
| i | No.  | e | (Actual Wording of | th | dy |                      |
| a |      |   | Investigator)      | of | D  |                      |
| l |      |   |                    | Tx | ay |                      |
| N |      |   |                    | (D | of |                      |
| o |      |   |                    | ay | D  |                      |
| . |      |   |                    | s) | ea |                      |
|   |      |   |                    |    | th |                      |
+---+------+---+--------------------+----+----+----------------------+
| C |      |   |                    |    |    |                      |
| A |      |   |                    |    |    |                      |
| S |      |   |                    |    |    |                      |
| O |      |   |                    |    |    |                      |
| D |      |   |                    |    |    |                      |
| E |      |   |                    |    |    |                      |
| X |      |   |                    |    |    |                      |
+---+------+---+--------------------+----+----+----------------------+
| 2 | \    | 6 | Hepatic Coma ^1^   | 6  | 16 |                      |
| 3 | -\-- | 1 |                    | 73 | 41 |                      |
+---+------+---+--------------------+----+----+----------------------+
| 2 | \    | 7 | Hepatocarcinoma    | 17 | 18 | Poss. related to Tx  |
| 4 | -\-- | 6 |                    | 13 | 58 | per Investigator     |
+---+------+---+--------------------+----+----+----------------------+
| 2 | \    | 7 | Hepatic Cancer     | 17 | 17 |                      |
| 4 | -\-- | 5 | Death              | 02 | 49 |                      |
+---+------+---+--------------------+----+----+----------------------+
| 2 | \    | 5 | Liver Failure      | 12 | 13 | Pt received open     |
| 4 | -\-- | 7 |                    | 68 | 89 | label Casodex ^2^    |
+---+------+---+--------------------+----+----+----------------------+
| 2 | \    | 6 | Hepatocellular     | 2  | 18 |                      |
| 5 | -\-- | 7 | Cancer ^1^         | 48 | 49 |                      |
+---+------+---+--------------------+----+----+----------------------+
| P |      |   |                    |    |    |                      |
| L |      |   |                    |    |    |                      |
| A |      |   |                    |    |    |                      |
| C |      |   |                    |    |    |                      |
| E |      |   |                    |    |    |                      |
| B |      |   |                    |    |    |                      |
| O |      |   |                    |    |    |                      |
+---+------+---+--------------------+----+----+----------------------+
| 2 | \    | 6 | End Stage Liver    | 5  | 5  |                      |
| 3 | -\-- | 2 | Disease ^1^        | 05 | 47 |                      |
+---+------+---+--------------------+----+----+----------------------+
| 2 | \    | 5 | End-Stage          | 3  | 17 |                      |
| 3 | -\-- | 6 | Cirrhosis (Liver)  | 61 | 29 |                      |
+---+------+---+--------------------+----+----+----------------------+
| 2 | \    | 7 | Hepatic Cancer ^1^ | 6  | 7  |                      |
| 4 | -\-- | 2 |                    | 46 | 87 |                      |
+---+------+---+--------------------+----+----+----------------------+
| 2 | \    | 7 | Cirrhases Hepates  | 3  | 9  |                      |
| 5 | -\-- | 1 | ^1^                | 71 | 74 |                      |
+---+------+---+--------------------+----+----+----------------------+
| 2 | \    | 7 | Carcinoma          | 1  | 1  |                      |
| 5 | -\-- | 1 | Hepatocellulare    | 94 | 94 |                      |
+---+------+---+--------------------+----+----+----------------------+
| 2 | \    | 7 | Carcinoma Of Liver | 13 | 13 | May be metastatic    |
| 5 | -\-- | 1 |                    | 26 | 26 | cancer to liver      |
+---+------+---+--------------------+----+----+----------------------+

1\. Patient narrative not provided for review.

2\. Patient assigned to placebo treatment. Received open label Casodex
after code break.

Source: Prepared by medical reviewer from Sponsor's SAS transport file
for all deaths and Table G2, both in Safety Update.

##### Medical Officer's Comments {#medical-officers-comments-47 .unnumbered}

-   The distribution and causes of hepatic-related deaths appeared to be
    similar in the Casodex and placebo treatment groups.

-   There were 2 and 3 deaths in the Casodex and placebo treatment
    groups, respectively that were related to hepatic failure that was
    not associated with a primary hepatic tumor. Deaths due to a primary
    hepatic tumor were reported for 2 and 2 or 3 patients in the Casodex
    and placebo treatment groups, respectively.

##### Medical Officer's Summary Comments Regarding Hepatotoxicity {#medical-officers-summary-comments-regarding-hepatotoxicity .unnumbered}

-   The potential for drug-induced liver toxicity with all nonsteroidal
    anti-androgens is a concern, particularly if they are intended for
    long-term use. The safety data provided in this supplemental NDA
    includes 9,387 and 9,778 total patient-years of treatment in the
    Casodex and placebo treatment groups. This is an adequate sample
    size to assess the likely toxicity of Casodex 150 mg per day in men
    with localized and locally advanced non-metastatic cancer of the
    prostate. Since the 3 clinical trials that were conducted in support
    of this supplemental NDA were placebo controlled, safety comparisons
    across treatment groups are particularly useful.

-   The safety data provided in NDA 20-498/s012 indicate that treatment
    with Casodex is associated with an increase in the incidence of
    liver toxicity compared to treatment with placebo. The increase in
    liver-related toxicity is manifested primarily by an increase in the
    proportion of patients with an increase in serum transaminases and
    to a lesser extent an increase in serum total bilirubin levels.
    Patients withdrawals due to increased serum ALT or AST values and
    increased bilirubin values were higher in Casodex-treated patients
    (1.2% and 0.4%, respectively) than in placebo-treated patients (0.5%
    and 0.2%, respectively). Similarly, adverse events classified as
    serious due to increased serum ALT or AST values and increased
    bilirubin values were more frequent in Casodex-treated patients
    (0.3% and 0.2%, respectively) than in placebo-treated patients (0.0%
    and \<0.1%, respectively). However, the number of patients reported
    to have died from hepatic failure or a primary hepatic neoplasm was
    similar in the 2 treatment groups (5 of 4,022 Casodex-treated
    patients and 5 or 6 of 4,031 placebo-treated patients.

-   The current labeling for Casodex 50 mg and the proposed labeling for
    Casodex 150 mg indicate (under Warnings Section) that "serum
    transaminase levels should be measured prior to starting treatment
    with CASODEX, at regular intervals for the first 4 months of
    treatment, and periodically thereafter. If clinical symptoms or
    signs suggestive of liver dysfunction occur, (e.g., nausea,
    vomiting, abdominal pain, fatigue, anorexia, "flu-like" symptoms,
    dark urine, jaundice, or upper right quadrant tenderness), serum
    transaminases, in particular the serum ALT, should be measured
    immediately. If at any time a patient has jaundice, or the ALT level
    rises above 2 times the upper limit of normal, CASODEX should be
    discontinued, with appropriate follow-up of liver function."

-   The Sponsor also provided an analysis of liver toxicity for both
    flutamide and Casodex (50 mg per day) based on US post marketing
    safety data. According to the Sponsor, the incidence of significant
    flutamide-related hepatotoxicity has been estimated to be 2.5 per
    100,000 prescriptions in the US (Wysowski 1996 ^5^) against a
    background incidence in a similar US population of 0.2 per 100,000
    prescriptions in patients not exposed to drugs. Using the same
    criteria as Wysowski (cases from the USA only and number of
    prescriptions filled in the US), the Sponsor claims that the
    incidence of significant hepatic toxicity for Casodex using those US
    post-marketing cases considered by AstraZeneca Pharmaceuticals to be
    even possibly related to Casodex was 0.1 per 100,000 prescriptions.
    The estimated number of prescriptions for Casodex in the US since
    launch to May 2000 was 1,714,000 per the Sponsor. It is possible,
    however, that hepatotoxicity will be increased in patients receiving
    150 mg Casodex per day compared to those receiving 50 mg per day.

### Cardiovascular Morbidity and Mortality

#### Cardiovascular Adverse Events during the Treatment Period

Serious cardiovascular adverse events were reported less frequently in
Casodex-treated patients (351 of 4,022 patients \[8.73%\]) than
placebo-treated patients (386 of 4,031 patients \[9.58%\]) (Table 5.4,
submission of 3 May 2002). As noted earlier in this review, however,
some types of serious cardiovascular adverse events and deaths due to
cardiovascular causes (both based on COSTART preferred terms) were
reported more frequently in Casodex-treated patients. Serious
cardiovascular adverse events reported for 0.2% of patients in either
treatment group are listed in Table 63. Events are listed by decreasing
incidence in the Casodex-treated patients. Cardiac events of note that
occurred more frequently in Casodex-treated patients (relative incidence
of 1.2, Casodex/placebo) included heart failure, heart arrest, syncope,
and arrhythmia. Cardiac events that occurred more frequently in
placebo-treated patients (relative incidence of 0.85 included myocardial
infarction, myocardial ischemia, and atrial arrhythmia.

[]{#__RefHeading___Toc25309723 .anchor}Table 63 Serious Cardiovascular
Adverse Events with Incidence  0.2% during Treatment Period (Combined
Data from Trials 23, 24, and 25)

<table>
<colgroup>
<col style="width: 32%" />
<col style="width: 2%" />
<col style="width: 12%" />
<col style="width: 12%" />
<col style="width: 1%" />
<col style="width: 1%" />
<col style="width: 10%" />
<col style="width: 13%" />
<col style="width: 1%" />
<col style="width: 12%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="2" rowspan="2"><strong>Adverse Event</strong></td>
<td colspan="6"><strong>Number of patients reporting adverse
event</strong></td>
<td rowspan="3"></td>
<td rowspan="3"><p><strong>Relative Incidence</strong></p>
<p><u>Casodex</u><br />
placebo</p></td>
</tr>
<tr class="even">
<td colspan="2">Casodex<br />
(N = 4022)</td>
<td colspan="2" rowspan="2"></td>
<td colspan="2">Placebo<br />
(N = 4031)</td>
</tr>
<tr class="odd">
<td></td>
<td></td>
<td>n</td>
<td>Percentage</td>
<td>n</td>
<td>Percentage</td>
</tr>
<tr class="even">
<td colspan="2">Myocardial infarct</td>
<td>72</td>
<td colspan="2">1.8%</td>
<td colspan="2">97</td>
<td>2.4%</td>
<td colspan="2">0.74</td>
</tr>
<tr class="odd">
<td colspan="2">Angina pectoris</td>
<td>71</td>
<td colspan="2">1.8%</td>
<td colspan="2">66</td>
<td>1.6%</td>
<td colspan="2">1.08</td>
</tr>
<tr class="even">
<td colspan="2">Heart failure</td>
<td>61</td>
<td colspan="2">1.5%</td>
<td colspan="2">36</td>
<td>0.9%</td>
<td colspan="2">1.70</td>
</tr>
<tr class="odd">
<td colspan="2">Chest pain</td>
<td>56</td>
<td colspan="2">1.4%</td>
<td colspan="2">29</td>
<td>0.7%</td>
<td colspan="2">1.94</td>
</tr>
<tr class="even">
<td colspan="2">Myocardial ischemia</td>
<td>54</td>
<td colspan="2">1.3%</td>
<td colspan="2">64</td>
<td>1.6%</td>
<td colspan="2">0.85</td>
</tr>
<tr class="odd">
<td colspan="2">Cerebrovascular accident</td>
<td>37</td>
<td colspan="2">0.9%</td>
<td colspan="2">71</td>
<td>1.8%</td>
<td colspan="2">0.52</td>
</tr>
<tr class="even">
<td colspan="2">Cardiovascular disorder</td>
<td>28</td>
<td colspan="2">0.7%</td>
<td colspan="2">37</td>
<td>0.9%</td>
<td colspan="2">0.76</td>
</tr>
<tr class="odd">
<td colspan="2">Atrial arrhythmia</td>
<td>25</td>
<td colspan="2">0.6%</td>
<td colspan="2">35</td>
<td>0.9%</td>
<td colspan="2">0.72</td>
</tr>
<tr class="even">
<td colspan="2">Heart arrest</td>
<td>19</td>
<td colspan="2">0.5%</td>
<td colspan="2">7</td>
<td>0.2%</td>
<td colspan="2">2.72</td>
</tr>
<tr class="odd">
<td colspan="2">Syncope</td>
<td>18</td>
<td colspan="2">0.4%</td>
<td colspan="2">14</td>
<td>0.3%</td>
<td colspan="2">1.29</td>
</tr>
<tr class="even">
<td colspan="2">Cerebral Ischemia</td>
<td>16</td>
<td colspan="2">0.4%</td>
<td colspan="2">17</td>
<td>0.4%</td>
<td colspan="2">0.94</td>
</tr>
<tr class="odd">
<td colspan="2">Hypertension</td>
<td>15</td>
<td colspan="2">0.4%</td>
<td colspan="2">24</td>
<td>0.6%</td>
<td colspan="2">0.63</td>
</tr>
<tr class="even">
<td colspan="2">Arrhythmia</td>
<td>15</td>
<td colspan="2">0.4%</td>
<td colspan="2">11</td>
<td>0.3%</td>
<td colspan="2">1.37</td>
</tr>
<tr class="odd">
<td colspan="2">Vascular disorder</td>
<td>11</td>
<td colspan="2">0.3%</td>
<td colspan="2">27</td>
<td>0.7%</td>
<td colspan="2">0.41</td>
</tr>
<tr class="even">
<td colspan="2">Carotid occlusion</td>
<td>11</td>
<td colspan="2">0.3%</td>
<td colspan="2">14</td>
<td>0.4%</td>
<td colspan="2">0.97</td>
</tr>
<tr class="odd">
<td colspan="2">Arteriosclerosis</td>
<td>9</td>
<td colspan="2">0.2%</td>
<td colspan="2">8</td>
<td>0.2%</td>
<td colspan="2">1.13</td>
</tr>
<tr class="even">
<td colspan="2">Thrombosis</td>
<td>5</td>
<td colspan="2">0.1%</td>
<td colspan="2">9</td>
<td>0.2%</td>
<td colspan="2">0.56</td>
</tr>
</tbody>
</table>

Source: Safety Update, Text Table 22, pg. 51, and Table T5.2.3.

#### Cardiovascular Mortality

Cardiovascular-related events were the most common single cause of death
(other than prostate cancer), both during and following treatment with
study drug. The numbers (%) of patients whose primary cause of death was
classified as cardiovascular-related are listed in Table 64. A
numerically greater proportion of Casodex-treated patients was
classified as having died of a cardiovascular event, either during or
following treatment. Overall, the primary cause of death was considered
to be cardiovascular-related in 143 of 4,022 (3.56%) of Casodex-treated
patients and 122 of 4,031 (3.03%) of placebo-treated patients.

[]{#__RefHeading___Toc25309724 .anchor}Table 64 Patients with a
Cardiovascular-related Primary Cause of Death\
(Combined Data from Trials 23, 24, and 25)

<table>
<colgroup>
<col style="width: 22%" />
<col style="width: 1%" />
<col style="width: 12%" />
<col style="width: 1%" />
<col style="width: 14%" />
<col style="width: 1%" />
<col style="width: 11%" />
<col style="width: 1%" />
<col style="width: 13%" />
<col style="width: 1%" />
<col style="width: 18%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td colspan="8"><strong>Number (%) of patients</strong></td>
<td></td>
<td rowspan="3"><p><strong>Relative Incidence</strong></p>
<p><u>Casodex</u><br />
placebo</p></td>
</tr>
<tr class="even">
<td rowspan="2"><strong>Treatment Period</strong></td>
<td></td>
<td colspan="3">Casodex<br />
(N = 4022)</td>
<td></td>
<td colspan="3">Placebo<br />
(N = 4031)</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td>n</td>
<td colspan="2">Percentage</td>
<td></td>
<td>n</td>
<td colspan="2">Percentage</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">During Treatment</td>
<td colspan="2">77</td>
<td>1.91%</td>
<td colspan="3">66</td>
<td colspan="2">1.64%</td>
<td>1.17</td>
</tr>
<tr class="odd">
<td colspan="2">Post Treatment</td>
<td colspan="2">66</td>
<td>1.64%</td>
<td colspan="3">56</td>
<td colspan="2">1.39%</td>
<td>1.18</td>
</tr>
<tr class="even">
<td colspan="2"><em><strong>Total</strong></em></td>
<td colspan="2"><em><strong>143</strong></em></td>
<td><em><strong>3.56</strong></em></td>
<td colspan="3"><em><strong>122</strong></em></td>
<td colspan="2"><em><strong>3.03</strong></em></td>
<td><em><strong>1.17</strong></em></td>
</tr>
</tbody>
</table>

Source: Safety Update, Table T4.3.

The primary causes of cardiovascular-related deaths in each of the
treatment groups, both during and following treatment, are listed in
Table 65. The most common causes of deaths (treatment and post treatment
periods combined) in the Casodex-treated patients were myocardial
infarction (n=42), cerebrovascular accident (n=25), heart arrest (n=23),
and heart failure (n=21). In the placebo-treated patients, the most
common causes of death were myocardial infarction (n=52),
cerebrovascular accident (n=22), and heart arrest (n=12).

##### Medical Officer's Comments {#medical-officers-comments-48 .unnumbered}

-   Overall, there were 21 more deaths attributed to cardiovascular
    causes in the Casodex-treated patients than in the placebo treated
    patients. This difference can be accounted for almost entirely by
    the excess number of deaths due to heart arrest ( = 11) and heart
    failure ( = 16) in the Casodex-treated patient partially offset by
    an excess number of deaths due to myocardial infarction ( = 10) in
    the placebo-treated patients.

-   The Sponsor states the following in their analysis of
    cardiac-related deaths in the Integrated Summary of Efficacy.

```{=html}
<!-- -->
```
-   *"Across all 3 controlled studies, only 5 patients (3 CASODEX, 2
    placebo) experienced heart arrest in association with a cardiac
    condition which was not pre-existing at trial entry. These numbers
    of heart arrest events are too small to causally implicate
    CASODEX."*

-   "CASODEX does not cause heart failure in animals. Only 2 patients
    had unconfounded cases of heart failure (1 of which was deemed
    related to trial therapy by the investigator), a finding not
    unexpected in an elderly male population of 4,022 patients treated
    with CASODEX."

[]{#__RefHeading___Toc25309725
.anchor}^Table\ 65\ Primary\ Causes\ of\ Cardiovascular\ Deaths\ with\ Incidence\ 0.05%\ (Combined\ Data from\ Trials\ 23,\ 24,\ and\ 25)^

<table>
<colgroup>
<col style="width: 32%" />
<col style="width: 2%" />
<col style="width: 12%" />
<col style="width: 12%" />
<col style="width: 1%" />
<col style="width: 1%" />
<col style="width: 10%" />
<col style="width: 13%" />
<col style="width: 1%" />
<col style="width: 12%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td colspan="7"><strong>Number (%) of patients with cause of
death</strong></td>
<td rowspan="3"></td>
<td rowspan="3"><p><strong>Relative Incidence</strong></p>
<p><u>Casodex</u><br />
placebo</p></td>
</tr>
<tr class="even">
<td rowspan="2"><blockquote>
<p><strong>Cause of Death<br />
(COSTART term)</strong></p>
</blockquote></td>
<td></td>
<td colspan="2">Casodex<br />
(N = 4022)</td>
<td colspan="2" rowspan="2"></td>
<td colspan="2">Placebo<br />
(N = 4031)</td>
</tr>
<tr class="odd">
<td></td>
<td>n</td>
<td>Percentage</td>
<td>n</td>
<td>Percentage</td>
</tr>
<tr class="even">
<td colspan="2">Arrhythmia</td>
<td></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td colspan="2">On treatment</td>
<td>0</td>
<td colspan="2">0.00</td>
<td colspan="2">2</td>
<td>0.05</td>
<td colspan="2">0.00</td>
</tr>
<tr class="even">
<td colspan="2">Post treatment</td>
<td>0</td>
<td colspan="2">0.00</td>
<td colspan="2">0</td>
<td>0.00</td>
<td colspan="2">NC <sup>1</sup></td>
</tr>
<tr class="odd">
<td colspan="2">Total</td>
<td>0</td>
<td colspan="2">0.00</td>
<td colspan="2">2</td>
<td>0.05</td>
<td colspan="2">0.00</td>
</tr>
<tr class="even">
<td colspan="2">Arteriosclerosis</td>
<td></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td colspan="2">On treatment</td>
<td>2</td>
<td colspan="2">0.05</td>
<td colspan="2">0</td>
<td>0.00</td>
<td colspan="2">NC</td>
</tr>
<tr class="even">
<td colspan="2">Post treatment</td>
<td>5</td>
<td colspan="2">0.12</td>
<td colspan="2">3</td>
<td>0.07</td>
<td colspan="2">1.67</td>
</tr>
<tr class="odd">
<td colspan="2">Total</td>
<td>7</td>
<td colspan="2">0.17</td>
<td colspan="2">3</td>
<td>0.07</td>
<td colspan="2">2.34</td>
</tr>
<tr class="even">
<td colspan="2">Cardiomyopathy</td>
<td></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td colspan="2">On treatment</td>
<td>1</td>
<td colspan="2">0.02</td>
<td colspan="2">2</td>
<td>0.05</td>
<td colspan="2">0.50</td>
</tr>
<tr class="even">
<td colspan="2">Post treatment</td>
<td>0</td>
<td colspan="2">0.00</td>
<td colspan="2">2</td>
<td>0.05</td>
<td colspan="2">0.00</td>
</tr>
<tr class="odd">
<td colspan="2">Total</td>
<td>1</td>
<td colspan="2">0.02</td>
<td colspan="2">4</td>
<td>0.10</td>
<td colspan="2">0.25</td>
</tr>
<tr class="even">
<td colspan="2">Cardiovascular disorder</td>
<td></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td colspan="2">On treatment</td>
<td>2</td>
<td colspan="2">0.05</td>
<td colspan="2">2</td>
<td>0.05</td>
<td colspan="2">1.00</td>
</tr>
<tr class="even">
<td colspan="2">Post treatment</td>
<td>2</td>
<td colspan="2">0.05</td>
<td colspan="2">2</td>
<td>0.05</td>
<td colspan="2">1.00</td>
</tr>
<tr class="odd">
<td colspan="2">Total</td>
<td>4</td>
<td colspan="2">0.10</td>
<td colspan="2">4</td>
<td>0.10</td>
<td colspan="2">1.00</td>
</tr>
<tr class="even">
<td colspan="2">Cerebrovascular accident</td>
<td></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td colspan="2">On treatment</td>
<td>11</td>
<td colspan="2">0.27</td>
<td colspan="2">15</td>
<td>0.37</td>
<td colspan="2">0.73</td>
</tr>
<tr class="even">
<td colspan="2">Post treatment</td>
<td>14</td>
<td colspan="2">0.35</td>
<td colspan="2">7</td>
<td>0.17</td>
<td colspan="2">2.00</td>
</tr>
<tr class="odd">
<td colspan="2">Total</td>
<td>25</td>
<td colspan="2">0.62</td>
<td colspan="2">22</td>
<td>0.55</td>
<td colspan="2">1.14</td>
</tr>
<tr class="even">
<td colspan="2">Heart arrest</td>
<td></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td colspan="2">On treatment</td>
<td>12</td>
<td colspan="2">0.30</td>
<td colspan="2">5</td>
<td>0.12</td>
<td colspan="2">2.41</td>
</tr>
<tr class="even">
<td colspan="2">Post treatment</td>
<td>11</td>
<td colspan="2">0.27</td>
<td colspan="2">7</td>
<td>0.17</td>
<td colspan="2">1.57</td>
</tr>
<tr class="odd">
<td colspan="2">Total</td>
<td>23</td>
<td colspan="2">0.57</td>
<td colspan="2">12</td>
<td>0.30</td>
<td colspan="2">1.92</td>
</tr>
<tr class="even">
<td colspan="2">Heart failure</td>
<td></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td colspan="2">On treatment</td>
<td>15</td>
<td colspan="2">0.37</td>
<td colspan="2">1</td>
<td>0.02</td>
<td colspan="2">15.03</td>
</tr>
<tr class="even">
<td colspan="2">Post treatment</td>
<td>6</td>
<td colspan="2">0.15</td>
<td colspan="2">4</td>
<td>0.10</td>
<td colspan="2">1.50</td>
</tr>
<tr class="odd">
<td colspan="2">Total</td>
<td>21</td>
<td colspan="2">0.52</td>
<td colspan="2">5</td>
<td>0.12</td>
<td colspan="2">4.21</td>
</tr>
<tr class="even">
<td colspan="2">Myocardial infarction</td>
<td></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td colspan="2">On treatment</td>
<td>24</td>
<td colspan="2">0.60</td>
<td colspan="2">31</td>
<td>0.77</td>
<td colspan="2">0.78</td>
</tr>
<tr class="even">
<td colspan="2">Post treatment</td>
<td>18</td>
<td colspan="2">0.45</td>
<td colspan="2">21</td>
<td>0.52</td>
<td colspan="2">0.86</td>
</tr>
<tr class="odd">
<td colspan="2">Total</td>
<td>42</td>
<td colspan="2">1.04</td>
<td colspan="2">52</td>
<td>1.29</td>
<td colspan="2">0.81</td>
</tr>
<tr class="even">
<td colspan="2">Myocardial ischemia</td>
<td></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td colspan="2">On treatment</td>
<td>4</td>
<td colspan="2">0.10</td>
<td colspan="2">5</td>
<td>0.12</td>
<td colspan="2">0.80</td>
</tr>
<tr class="even">
<td colspan="2">Post treatment</td>
<td>4</td>
<td colspan="2">0.20</td>
<td colspan="2">3</td>
<td>0.07</td>
<td colspan="2">1.33</td>
</tr>
<tr class="odd">
<td colspan="2">Total</td>
<td>8</td>
<td colspan="2">0.20</td>
<td colspan="2">8</td>
<td>0.20</td>
<td colspan="2">1.00</td>
</tr>
<tr class="even">
<td colspan="2">Pulmonary embolus</td>
<td></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td colspan="2">On treatment</td>
<td>4</td>
<td colspan="2">0.10</td>
<td colspan="2">2</td>
<td>0.05</td>
<td colspan="2">2.00</td>
</tr>
<tr class="even">
<td colspan="2">Post treatment</td>
<td>1</td>
<td colspan="2">0.12</td>
<td colspan="2">4</td>
<td>0.10</td>
<td colspan="2">0.25</td>
</tr>
<tr class="odd">
<td colspan="2">Total</td>
<td>5</td>
<td colspan="2">0.12</td>
<td colspan="2">6</td>
<td>0.15</td>
<td colspan="2">0.84</td>
</tr>
</tbody>
</table>

1\. Unable to calculated as no events occurred in placebo group.

Source: Safety Update, Table T4.3.

### Second Tumors

The proportion of patients with solid second tumors during the treatment
period was similar in both treatment groups (312 of 4,022 \[7.76%\]
Casodex-treated patients; 315 of 4,031 \[7.81%\] placebo-treated
patients). Solid second tumors reported as an adverse event in  0.2% of
patients during the treatment period are summarized by body system and
COSTART preferred term in Table 66. The most common solid tumors in both
treatment groups were neoplasm (body as a whole), skin cancer, GI
neoplasia, gastrointestinal carcinoma, and carcinoma of the lung.

[]{#__RefHeading___Toc25309726 .anchor}Table 66 Solid Tumors Reported as
Adverse Events within the Treatment\
Period in  0.2% Patients (Data Combined for Trials 23, 24, and 25)

  --------------- --------------------- ---------- --------- -- ----- ---------- ---------
                                        Number (%)                               
                                        of                                       
                                        patients                                 
                                        with event                               

  COSTART\        COSTART preferred\    Casodex\                      Placebo\   
  body system     term                  (N=4022)                      (N=4031)   

                                        No. Pt     Percent      No.              Percent
                                                                Pt               

  Body as a whole Adenoma               9          0.22         14               0.35

                  Carcinoma             17         0.42         11               0.27

                  Neoplasm              67         1.67         60               1.49

  Digestive       Gastrointestinal      48         1.19         39               0.97
                  carcinoma                                                      

                  Gastrointestinal      65         1.62         75               1.86
                  neoplasm                                                       

  Respiratory     Carcinoma of lung     24         0.60         28               0.69

  Skin            Skin cancer           58         1.44         61               1.51

                  Skin melanoma         9          0.22         9                0.22

  Urogenital      Bladder carcinoma     13         0.32         9                0.22
  system                                                                         

                  Bladder neoplasm      9          0.22         7                0.17
  --------------- --------------------- ---------- --------- -- ----- ---------- ---------

Source: SAS File aeaf1 (calculated by medical reviewer) and Table T14.4,
both from Safety Update.

##### Medical Officer\'s Comments {#medical-officers-comments-49 .unnumbered}

-   Tumors listed as carcinoma under "body system as a whole" included a
    diverse number of tumor types for which descriptions were often
    vague, thus making more precise classification impossible in many
    instances. Included in this category were 5 cases of renal cell
    carcinoma or renal cancer (3 and 2 cases in the Casodex and placebo
    groups, respectively). Tumors listed as neoplasm under "body system
    as a whole" were predominantly benign neoplasms, often lipomas or
    merely described as 'lumps."

-   Tumors classified under the digestive body system included a greater
    number of tumors classified as gastrointestinal carcinoma in the
    Casodex-treated patients (n=48) than in placebo-treated patients
    (n=39). Conversely, tumors classified as gastrointestinal neoplasm
    were more common the placebo-treated patients (n=75) than in the
    Casodex-treated patients (n=65).

#### Gastrointestinal Tumors

The Sponsor provided a more detailed analysis of the incidence of
gastrointestinal tumors based on a somewhat broader review of the data
from the 3 clinical trials. The result of this analysis is presented in
Table 67.

[]{#__RefHeading___Toc25309727 .anchor}Table 67 Incidence of
Gastrointestinal Tumors (Trials 23, 24, and 25)

  ----------------------- --------------- --------------- ---------------
                          **Number of                     
                          patients with                   
                          event**                         

  **Gastrointestinal\     Casodex         Placebo\        Incidence\
  tumor site**            (N=4022)        (N=4031)        ratio ^1^

  Colorectal              30              27              1.11

  Colon                   21              23              0.91

  Rectal                  9               4               2.25

  CUP-abdominal ^2^       3               2               1.50

  Esophageal              5               3               1.67

  Gastric                 5               7               0.71

  Hepatic                 4               2               2.00

  Mouth                   1               2               0.50

  Pancreatic              5               5               1.00

  Parotid                 1               0               

  Small intestine         2               1               2.00

  **Total**               **56**          **49**          **1.14**
  ----------------------- --------------- --------------- ---------------

^1^ Casodex/placebo

^2^ CUP = cancer unknown primary

Source: Text Table 36 of Safety Update, pg. 80.

##### Medical Officer\'s Comments {#medical-officers-comments-50 .unnumbered}

-   Although the number of patients with a gastrointestinal tumor
    continued to be numerically higher in the Casodex-treated patients,
    the difference was relatively small (56 of 4,022 \[1.4%\]
    Casodex-treated patients; 49 of 4,031 \[1.2%\] placebo-treated
    patients.

#### Myelodysplasia and Leukemia

There was an increase in the number of Casodex-treated patients who
developed myelodysplasia syndrome or leukemia. The patients who were
identified by the Sponsor as having developed myelodysplasia syndrome or
leukemia or whose underlying cause of death was related to these
disorders are listed in Table 68. Twelve (12) Casodex-treated patients
and 5 placebo-treated patients are represented in the Table (relative
incidence Casodex/placebo = 2.4). Of these patients, 8 of 12
Casodex-treated patients and 4 of 5 placebo-treated patients have died
as a direct or indirect result of their underlying hematologic disorder.

[]{#__RefHeading___Toc25309728 .anchor}Table 68 Patients Who Developed
Myelodysplasia Syndrome or Leukemia

  ------------------ ---------- ----------- ------------ ------------ -------
  Patient number     Age at\    Diagnosis   Duration of  Time to      Death
                     Study      ^1^         Treatment\   Diagnosis\   (Y/N)
                     Entry                  (Days)       (Days)       

  **Casodex                                                           
  treatment group**                                                   

  \-\-\-\--          72         AML         321          1012         N

  \-\-\-\--          56         MDS         126          139          N

  \-\-\-\--          60         AML         666          1167         Y

  \-\-\-\--          68         MDS         658          496          Y

  \-\-\-\--          65         AML         283          1444         N

  \-\-\-\--          82         MDS         581          627          Y

  \-\-\-\--          70         AML         90           166          Y

  \-\-\-\--          74         AML         482          483          Y

  \-\-\-\--          64         AML         1084         1019         Y

  \-\-\-\--          73         MDS         1096         1024         N

  \-\-\-\--          74         MDS         90           113          Y

  \-\-\-\--          65         AML         1190         1168         Y

  **Placebo                                                           
  treatment group**                                                   

  \-\-\-\--          59         MDS         92           1012         Y

  \-\-\-\--          76         MDS         755          1335         Y

  \-\-\-\--          75         MDS         1776         1248         Y

  \-\-\-\--          66^2^      AML         1090         1139         N

  \-\-\-\--          72         AML         1253         1037         Y
  ------------------ ---------- ----------- ------------ ------------ -------

1 AML = acute myelogenous leukemia; MDS = myelodysplasia syndrome.

2 This patient was withdrawn from placebo therapy and began open-label
treatment with Casodex. AML was diagnosed 6-7 weeks after staring
Casodex.

Source: Text Table 35, pg. 78, of Safety Update.

##### Medical Officer's Comments {#medical-officers-comments-51 .unnumbered}

-   The basis for this numeric imbalance is unclear. Based on the
    preclinical toxicology of Casodex, one would not anticipate that
    treatment with this drug would cause the development of either
    myelodysplasia syndrome or leukemia.

-   The numeric imbalance (12 of 4022 Casodex-treated patients
    \[0.30%\]; and 5 of 4031 placebo-treated patients \[0.12%\]) was not
    statistically significant (p-value = 0.24, Fisher's exact test for a
    2-sided hypothesis, FDA calculation).

-   The significance of this numeric imbalance and its possible
    relationship to treatment with Casodex are not known at this time.

## Adequacy of Patient Exposure and Safety Assessments

The safety database for this application was large and included 4022
Casodex-treated patients and 4031 placebo-treated patients. At the time
of the data cutoff for the Safety Update, total exposure to study drug
was 9,387 patient-years in the Casodex treatment group and
9,778 patient-years in the placebo treatment group. Total patient
exposure to Casodex and safety monitoring in Trials 23, 24, and 25 was
adequate to assess the likely safety profile of Casodex 150 per day in
men with prostate cancer.

# Dosing Regimen

## Dosing Regimen

The proposed dosing-regimen is Casodex 150 mg per day for at least 2
years or until disease progression. The proposed dose appears to be
appropriate based on dose-ranging data provided in an earlier submission
(NDA 20-498/s006). The basis for the recommendation that treatment
should continue for at least 2 years is unclear since the protocols for
Trial 24 and Trial 25 recommended that treatment should continue for at
least 5 years or until disease progression.

## Effects of Renal or Hepatic Impairment on Casodex Pharmacokinetics

According to the Sponsor, renal impairment (as measured by creatinine
clearance) had no significant effect on the elimination of total
bicalutamide or the active R-enantiomer in doses up to 450 mg.

Casodex is extensively metabolized by the liver. Limited data in
subjects with severe hepatic impairment suggest that excretion of
Casodex may be delayed and could lead to further accumulation.

# Conclusions and Recommendations

## Conclusions

### Benefits of Treatment with Casodex 

The Sponsor has provided statistically significant findings from 2
non-US clinical trials in men with non-metastatic prostate cancer
(Clinical Trials 24 and 25) that treatment with Casodex 150 mg per day,
compared to treatment with placebo, delayed progression of disease.
Progression of disease was defined as (a) the appearance of new bone
scan confirmed metastases, (b) other objectively confirmed progression
of prostate cancer (as documented by magnetic resonance imaging,
computerized tomography, sonography, or biopsy), or (c) death due to any
cause in the absence of objectively documented progression of prostate
cancer. In these trials, Casodex was studied as (1) adjuvant therapy in
men previously treated by radical prostatectomy or radiotherapy or (2)
immediate therapy (monotherapy) in patients who otherwise were to be
managed by watchful waiting. In a third trial (Trial 23) that was
conducted primarily within the US, there was no evidence that treatment
with Casodex delayed disease progression. In this trial, Casodex was
studies only as an adjuvant therapy following radical prostatectomy or
radiotherapy. The relevance of the findings in the 2 non-US trials for
men with prostate cancer in the US who might be treated with Casodex
adjuvant therapy or Casodex monotherapy is uncertain at this time.

The actual reduction in the incidence of (a) objective disease
progression (based only on new bone scan confirmed metastases) and (b)
death from any cause in the absence of disease progression within 2.5
years after entry into Trial 24 or Trial 25 was modest. In Trial 24, the
proportion of patients with objective disease progression within
2.5 years of study entry decreased from 9.3% (placebo group) to 6.2%
(Casodex group). In Trial 25, the proportion of patients with objective
disease progression within 2.5 years of study entry decreased from 17.2%
(placebo group) to 10.4% (Casodex group). Based on the information
presented by the Sponsor, the short term clinical significance of this
decrease in disease progression in Casodex-treated patients is not known
as quality of life data (e.g., the proportion of symptomatic versus
asymptomatic bone metastases) and other assessments of quality of life
were not provided.

The long-term clinical benefit of treatment with Casodex is unknown.
There was no evidence of increased disease-specific survival or overall
survival for Casodex-treated men in any of the 3 clinical trials. Median
follow up time for disease progression was approximately 3 years, a
short period for assessing the long-term benefits of a medical therapy
for men with non-metastatic prostate cancer. It is possible, but
entirely unproved at this time, that treatment with Casodex might
improve disease-specific survival compared to placebo treatment.

**Medical therapy for early or locally advanced, non-metastatic prostate
cancer.** No medical therapy is presently approved by the FDA as
monotherapy for early or locally advanced, non-metastatic prostate
cancer. However, the present standard of care for patients with locally
advanced, non-metastatic prostate cancer generally includes androgen
deprivation therapy by medical or surgical castration.

Casodex adjuvant therapy or Casodex monotherapy for men with
non-metastatic prostate cancer may be equivalent to, but not superior
to, treatment with a GnRH analog in terms of reducing disease
progression. Both classes of drug (nonsteroidal anti-androgens and GnRH
analogs) are thought to be effective in the management of prostate
cancer by reducing androgen stimulation of cancer cells. However,
nonsteroidal anti-androgens compared to GnRH analogs are likely to be
less effective *in vivo* in blocking the effects of testosterone as
there is a compensatory increase in serum testosterone concentrations
during treatment with nonsteroidal anti-androgens. In some situation,
(e.g., men with metastatic prostate cancer), this difference in
pharmacological activity has important clinical consequences such as
reduced survival as was shown in Trials 0306 and 0307 (NDA 20-498/s006)
for patients with stage M1 disease. In other situations, efficacy may be
similar and the difference in side effect profiles may be an important
consideration in the choice of drug. Men treated with a GnRH analog are
likely to have more severe and more frequent vasomotor symptoms
(e.g., hot flashes), bone loss, and possibly more sexual dysfunction
(impotence and decreased libido). Conversely, a very high proportion of
men receiving 150 mg Casodex per day will develop gynecomastia and/or
breast pain and are at a slightly greater risk for clinically
significant hepatotoxicity.

### Risks of Treatment with Casodex

Adverse events associated with Casodex treatment can be classified for
the most part into one of 2 categories:

-   Those of a non-life threatening nature that are due to the
    pharmacological actions of Casodex and which occur with a high
    incidence (i.e., gynecomastia and breast pain)

-   Those that occur in a few percent of patients and which may be
    severe or life threatening (primarily hepatotoxicity)

**Gynecomastia and Breast Pain**. In Trials 23, 24, and 25, gynecomastia
alone was reported in 67.1% and 8.1% of Casodex-treated and
placebo-treated patients, respectively. Gynecomastia or breast pain was
reported to occur in 86.2% and 12.4% of Casodex-treated and
placebo-treated patients, respectively. Breast pain was reversible in
\> 90% of patients after cessation of Casodex therapy. Gynecomastia,
however, resolved in only 50% of patients with at least 1 or more follow
up visits.

**Hepatotoxicity**. The safety data provided in NDA 20-498/s012 indicate
that treatment with Casodex is associated with an increase in the
incidence of liver toxicity compared to treatment with placebo.
Liver-related toxicity is manifested primarily by an increase in the
proportion of Casodex-treated patients with elevated serum transaminase
levels, and to a lesser, elevated serum total bilirubin levels. Patient
withdrawals due to increased serum ALT or AST values or increased
bilirubin values were higher in Casodex-treated patients (1.2% and 0.4%,
respectively) than in placebo-treated patients (0.5% and 0.2%,
respectively). Similarly, adverse events due to increased serum ALT or
AST values or increased bilirubin values classified as serious were more
frequent in Casodex-treated patients (0.3% and 0.2%, respectively) than
in placebo-treated patients (0.0% and \<0.1%, respectively). However,
the number of patients reported to have died from hepatic failure or a
primary hepatic neoplasm was similar in the 2 treatment groups (5 of
4,022 Casodex-treated patients and 5 or 6 of 4,031 placebo-treated
patients.

The current labeling for Casodex 50 mg and the proposed labeling for
Casodex 150 mg state under the Warnings Section that "serum transaminase
levels should be measured prior to starting treatment with CASODEX, at
regular intervals for the first 4 months of treatment, and periodically
thereafter.....If at any time a patient has jaundice, or the ALT level
rises above 2 times the upper limit of normal, CASODEX should be
discontinued."

The risk of serious hepatotoxicity in Casodex-treated patients with
prostate cancer does not appear to be sufficient to preclude approval of
the drug if the benefits of therapy are clinically and statistical
significant.

### Summary of Risk-Benefit Analysis

The relevance of the findings in Trials 24 and 25 supporting the
efficacy of adjuvant treatment and monotherapy with Casodex 150 mg per
day to men with prostate cancer in the US is uncertain. Based on the
data submitted by the Sponsor, patients similar to those enrolled in
Trial 23 who are initially treated by radical prostatectomy or
radiotherapy, would derive no benefit from Casodex adjuvant therapy.
Such patients exhibited too few events of disease progression to warrant
treatment with Casodex. Whether patients who would be treated by Casodex
monotherapy, instead of watchful waiting in accordance with current
medical practices in the US, would derive significant benefit also is
uncertain. A watchful waiting subgroup was not included in Trial 23.
Review of the baseline disease characteristics of the watchful waiting
subgroups in Trials 24 and 25 indicated that many of these patients had
more advanced prostate cancer than patients likely to be managed by
watchful waiting alone in the US. The Sponsor has not show that patients
presently managed by watchful waiting in the US would experience disease
progression of sufficient magnitude to warrant treatment with Casodex
and the side effects associated with such treatment. The Sponsor also
has not shown that patients with locally advanced, non-metastatic
prostate cancer treated by Casodex monotherapy would derive comparable
benefit as patients treated by medical or surgical castration, the
present standard of care in the US. Data previously submitted by the
Sponsor from Trials 0306 and 0307 did not adequately support the
Sponsor's contention that Casodex treatment and castration (medical or
surgical) were equally efficacious (based on survival) for the treatment
of locally advanced non-metastatic prostate cancer. Patients with
locally advanced prostate cancer who are treated with Casodex
monotherapy may be at a slight survival disadvantage compared to men
treated by medical or surgical castration.

In summary, the risks of treatment with Casodex 150 mg per day are
justified and acceptable for patients who would derive significant
clinical benefit from treatment. Such patients may be similar to those
enrolled in Trials 24 and 25. However, based on data submitted to date
by the Sponsor, it is not clear as to which patients in the US would
derive significant clinical benefit from either adjuvant therapy or
immediate monotherapy with Casodex. In the absence of such data, the
risks of Casodex treatment for men in the US with non-metastatic
prostate cancer are not warranted.

## Recommendations

### Recommendations Regarding Approvability (Based on Indications Submitted on 10 May 2002)

**Indication No. 1:** "CASODEX 150 mg is indicated as 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."

-   **Approval for Indication No. 1 is not recommended at this time**

The Sponsor has not provided sufficient evidence (1) of efficacy for the
adjuvant use of Casodex in men with prostate cancer initially treated by
radical prostatectomy or radiotherapy in the US and (2) that the
findings in Trials 24 and 25 are relevant to prostate cancer patients in
the US. In particular, the data in the present application do not
identify the subset of men with prostate cancer in the US who are most
likely to benefit from Casodex adjuvant therapy.

**Indication No. 2:** "CASODEX 150 mg is indicated as immediate
treatment of non-metastatic prostate cancer in patients for whom therapy
of curative intent is not indicated."

-   **Approval for Indication No. 2 is not recommended at this tim**e.

The proposed indication does not adequately identify the population of
prostate cancer patients in the US who might derive sufficient benefit
from Casodex monotherapy to warrant the risks of treatment.

**For local or early disease.** The Sponsor has not provided sufficient
evidence that the findings in Trials 24 and 25 are relevant to prostate
cancer patients in the US who are currently managed by watchful waiting.
In addition, the Sponsor will need to provide data demonstrating that
prostate cancer-related morbidity or mortality in patients with
localized prostate cancer occurs with a sufficiently high incidence that
the potential benefits of Casodex treatment will out weight the adverse
effects of treatment (e.g., gynecomastia, breast pain, and possible
liver toxicity).

**For locally advanced disease**. Trials 24 and 25 were not conducted in
accordance with present standards of care for patients with locally
advanced, non-metastatic prostate cancer in the US. Since the comparator
in these trials was placebo and not active therapy (i.e., medical or
surgical castration), it is not possible to adequately address the
efficacy of Casodex monotherapy. This is a critical issue since survival
may be shortened in patients with locally advanced prostate cancer
treated with Casodex monotherapy instead of by medical or surgical
castration (the present standard of care in the US for such patients).

This concern has been addressed in part by the Sponsor's second revision
to the proposed indication for Casodex immediate therapy that was
submitted on 22 October 2002. The second revision states that Casodex
immediate treatment is indicated for the treatment of
"[localized]{.underline} non-metastatic prostate cancer in patients for
whom therapy of curative intent is not indicated."

# References

1.  Wirth MP and Froehner M. Perspectives in adjuvant treatment of
    prostate cancer. Urologia Internationalis 2002;68:1-5.

2.  Messing EM et al. Immediate hormonal therapy compared with
    observation after radical prostatectomy and pelvic lymphadenectomy
    in men with node-positive prostate cancer. N Engl J Med
    1999;341:1781-1788.

3.  Bolla M et al. Improved survival in patients with locally advanced
    prostate cancer treated with radiotherapy and goserelin. N Engl J
    Med 1997;337:295-300.

4.  Hellerstedt BA and Pienta KJ. The current state of hormonal therapy
    for prostate cancer. CA: A Cancer Journal for Clinicians
    2002;52:154-179.

5.  Wysowski DK and Fourcroy JL. Flutamide hepatotoxicity. J Urol
    1996;155:209-212.

Appendix

(Supplemental Efficacy Analyses)

Supplemental Efficacy Analyses (Set No. 1)

-   Proportion of Patients with (1) Bone Scan Documented Progression
    or (2) Death from Any Cause in the Absence of Progress within 2.5
    Years of Randomization as a Function of Baseline Disease
    Characteristics

Appendix Table 1a. Trial 23
........................................................... 121

Appendix Table 1b. Trial 24
........................................................... 122

Appendix Table 1c. Trial 25
........................................................... 123

> **Appendix Table 1a.** Proportion of Patients with (1) Bone Scan
> Documented Progression or (2) Death from Any Cause in the Absence of
> Progress within 2.5 Years of Randomization as a Function of Baseline
> Disease Characteristics
>
> **(Trial 23)**
>
> ![](media/image4.png){width="5.9944444444444445in" height="7.7in"}

**Appendix Table 1b.** Proportion of Patients with (1) Bone Scan
Documented Progression or (2) Death from Any Cause in the Absence of
Progress within 2.5 Years of Randomization as a Function of Baseline
Disease Characteristics

**(Trial 24)**

![](media/image5.png){width="5.998611111111111in" height="8.0in"}

**Appendix Table 1c.** Proportion of Patients with (1) Bone Scan
Documented Progression or (2) Death from Any Cause in the Absence of
Progress within 2.5 Years of Randomization as a Function of Baseline
Disease Characteristics

**(Trial 25)**

![](media/image6.png){width="5.993055555555555in"
height="7.813194444444444in"}

Supplemental Efficacy Analyses (Set No. 2)

-   Proportion of Patients with (1) Bone Scan Documented Progression
    or (2) Death only from Prostate Cancer in the Absence of Progress
    within 2.5 Years of Randomization as a Function of Baseline Disease
    Characteristics

Appendix Table 2a. Trial 23
........................................................... 125

Appendix Table 2b. Trial 24
........................................................... 126

Appendix Table 2c. Trial 25
........................................................... 127

**Appendix Table 2a** Proportion of Patients with (1) Bone Scan
Documented Progression or (2) Death only from Prostate Cancer in the
Absence of Progress within 2.5 Years of Randomization as a Function of
Baseline Disease Characteristics

**(Trial 23)**

![](media/image7.png){width="5.998611111111111in"
height="7.985416666666667in"}

**Appendix Table 2b** Proportion of Patients with (1) Bone Scan
Documented Progression or (2) Death only from Prostate Cancer in the
Absence of Progress within 2.5 Years of Randomization as a Function of
Baseline Disease Characteristics

**(Trial 24)**

![](media/image8.png){width="5.996527777777778in"
height="7.985416666666667in"}

**Appendix Table 2c** Proportion of Patients with (1) Bone Scan
Documented Progression or (2) Death only from Prostate Cancer in the
Absence of Progress within 2.5 Years of Randomization as a Function of
Baseline Disease Characteristics

**(Trial 25)**

![](media/image9.png){width="5.995138888888889in"
height="7.833333333333333in"}