Clinical trial NCT02918968
Conditions: Prostate Cancer
Keywords: enzalutamide Xtandi Prostate Cancer
Sponsor: Astellas Pharma Inc
Start date: 2016-11-02; Completion date: 2020-03-27
Enrollment: 206 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of this study was to compare the efficacy and safety of the combination therapy with enzalutamide + androgen deprivation therapy (ADT) and the combination therapy with flutamide + ADT in patients with castration resistant prostate cancer who had relapsed during combined androgen blockade (CAB) therapy with bicalutamide and ADT. This study also investigated the order of alternative antiandrogen therapy (AAT) by changing the 1st line medication after relapse of prostate-specific antigen (PSA).

Detailed description:

Arms: arm 1: Participants received enzalutamide 160 mg capsules, orally once daily as 1st line of alternative antiandrogen therapy (AAT) until confirmed prostate-specific antigen (PSA) progression, other disease progression, or an intolerable adverse event. After confirmation of PSA progression, other disease progression, or an intolerable adverse event, participants received flutamide 125 mg tablets orally thrice daily after each meal as 2nd line of AAT. Treatment with each drug was continued until the participant met any of the discontinuation criteria or until 2 years from the enrollment of the last participant (approximately 38 months). arm 2: Participants received flutamide 125 mg tablets orally thrice daily after each meal as 1st line of AAT until confirmed PSA progression, other disease progression, or an intolerable adverse event. After confirmed PSA progression, other disease progression, or an intolerable adverse event. participants received enzalutamide 160 mg capsules orally once daily as 2nd line of AAT. Treatment with each drug was continued until the participant met any of the discontinuation criteria or until 2 years from the enrollment of the last participant (approximately 38 months).
Interventions: intervention 1: Enzalutamide intervention 2: Flutamide intervention 3: Androgen deprivation therapy
Intervention descriptions: intervention 1: Oral Capsule intervention 2: Oral tablet intervention 3: All subjects must undergo continuous Androgen deprivation therapy with GnRH agonist/antagonist or bilateral orchiectomy during the study period.

Protocol documents:
Prot_000.pdf: 
Sponsor: API 
ISN/Protocol 9785-MA-3051 
 
 
- CONFIDENTIAL - 
 
03 Aug 2016 
Astellas 
Page 1 of 109 
 
 
 
 
Protocol of Post-marketing Clinical Study on Enzalutamide  
—A Randomized Phase IV Study Comparing Enzalutamide versus Flutamide in CRPC Patients 
Who Have Failed Combined Androgen Blockade Therapy with Bicalutamide plus ADT— 
 
 
ISN/Protocol 9785-MA-3051 
Version 2.0/August 3, 2016 
 
 
 
 
Sponsor: Astellas Pharma Inc. (API) 
2-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo 
 
 
 
 
 
 
 
 
 
This confidential document is the property of the Sponsor. No unpublished information contained in this document 
may be disclosed without prior written approval of the Sponsor. 
 


Sponsor: API 
ISN/Protocol 9785-MA-3051 
 
 
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Table of Contents 
I. 
SIGNATURES ······················································································ 9
 
II. 
CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL ···························· 10
 
III. 
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS ·················· 11
 
IV. 
SYNOPSIS ·························································································· 15
 
V. 
FLOW CHART AND SCHEDULE OF ASSESSMENTS ································· 28
 
VI. 
ACCEPTABLE RANGE OF SCHEDULE OF ASSESSMENTS ························ 33
 
1 
INTRODUCTION ················································································· 36
 
1.1 
Background ···················································································· 36
 
1.2 
Non-clinical and Clinical Data ······························································ 36
 
1.2.1 
Non-clinical Studies ····································································· 36
 
1.2.2 
Clinical Data ············································································· 38
 
1.2.2.1 
Phase 1/2 Study in Japan [9785-CL-0111] ····································· 38
 
1.2.2.2 
Overseas Phase 3 Study [CRPC2] ··············································· 38
 
1.2.2.3 
Global Phase 3 Study [9785-CL-0231] ········································· 39
 
1.3 
Summary of Key Safety Information for Study Drugs ··································· 40
 
1.4 
Risk-Benefit Assessment ····································································· 40
 
1.4.1 
Risk Expected from Enzalutamide ···················································· 40
 
1.4.2 
Risks Expected from Flutamide ······················································· 42
 
1.4.3 
Expected Benefit ········································································ 43
 
2 
STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS ·································· 44
 
2.1 
Study Objectives ·············································································· 44
 
2.1.1 
Primary Objective ······································································· 44
 
2.1.2 
Secondary Objectives ··································································· 44
 
2.1.3 
Safety Objective ········································································· 44
 
2.1.4 
Exploratory Objectives ································································· 44
 
2.2 
Study Design and Dose Rationale ··························································· 45
 
2.2.1 
Study Design ············································································· 45
 
2.2.2 
Dose Rationale ··········································································· 46
 
2.3 
Endpoints ······················································································· 46
 
2.3.1 
Primary Endpoint ········································································ 46
 
2.3.2 
Secondary Endpoints ···································································· 46
 
2.3.3 
Safety Endpoints ········································································· 46
 


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2.3.4 
Exploratory Endpoints ·································································· 46
 
3 
STUDY POPULATION ·········································································· 47
 
3.1 
Selection of Study Population ······························································· 47
 
3.2 
Inclusion Criteria ·············································································· 47
 
3.3 
Exclusion Criteria ············································································· 48
 
3.4 
Criteria to Shift from 1st Line AAT to 2nd Line AAT ··································· 49
 
4 
TREATMENT(S) ·················································································· 50
 
4.1 
Identification of Investigational Product(s) ················································ 50
 
4.1.1 
Test Drug(s) ·············································································· 50
 
4.1.2 
Comparative Drug(s) ···································································· 50
 
4.2 
Packaging and Labeling ······································································ 50
 
4.3 
Study Drug Handling ········································································· 52
 
4.4 
Blinding ························································································ 52
 
4.5 
Assignment and Allocation ·································································· 52
 
5 
TREATMENTS AND EVALUATION ························································ 53
 
5.1 
Dosing and Administration of Study Drug(s) and Other Medication(s) ················ 53
 
5.1.1 
Dose/Dose Regimen and Administration Period ···································· 53
 
5.1.2 
Increase or Reduction in Dose of the Study Drug(s) ································ 53
 
5.1.3 
Previous and Concomitant Treatment (Medication and Non-Medication 
Therapy) ·················································································· 54
 
5.1.3.1 
Previous Treatment ································································ 54
 
5.1.3.2 
Concomitant Treatment ··························································· 54
 
5.1.3.3 
Required Concomitant Medications ············································· 54
 
5.1.3.4 
Prohibited Concomitant Treatment (Medication and Non-Medication 
Therapy) ············································································ 55
 
5.1.3.5 
Precautions for Concomitant Medication with Enzalutamide (Drug 
Interactions) ········································································ 55
 
5.1.4 
Treatment Compliance ·································································· 56
 
5.1.5 
Restrictions During the Study ·························································· 56
 
5.2 
Demographics and Baseline Characteristics ··············································· 56
 
5.2.1 
Demographics ············································································ 56
 
5.2.2 
Medical History ·········································································· 57
 
5.2.3 
Diagnosis of the Target Disease, Severity, and Duration of Disease ·············· 57
 
5.3 
Efficacy Assessment ·········································································· 57
 


Sponsor: API 
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5.3.1 
PSA ······················································································· 57
 
5.3.1.1 
Time to PSA Progression with 1st Line AAT (TTPP1) ······················· 57
 
5.3.1.2 
Time to PSA Progression with 1st Line AAT + 2nd Line AAT 
(TTPP2) ············································································· 58
 
5.3.1.3 
PSA Response Rate to 1st Line AAT (Decrease by at Least 50% or 
90% from Baseline) ······························································· 58
 
5.3.1.4 
PSA Response Rate to 1st Line AAT at Week 13 (Decrease by at 
Least 50% or 90% from Baseline) ··············································· 58
 
5.3.1.5 
Time to PSA Decrease by 50% from Baseline with 1st Line AAT ·········· 58
 
5.3.1.6 
Time to PSA Progression with 2nd Line AAT (2nd TTPP) ·················· 58
 
5.3.1.7 
PSA Response Rate to 2nd Line AAT (Decrease by at Least 50% or 
90% from Baseline) ······························································· 58
 
5.3.2 
CT/MRI and Bone Scintigraphy ······················································· 59
 
5.3.2.1 
Radiographic Progression-Free Survival (rPFS) ······························· 59
 
5.3.2.2 
Metastasis-Free Survival (MFS) ················································· 60
 
5.3.2.3 
Objective Response Rate (ORR) in Best Overall Soft Tissue Response 
of RECIST Guidelines with 1st Line AAT ····································· 60
 
5.3.3 
Time to Treatment Failure ······························································ 60
 
5.3.3.1 
Time to Treatment Failure of 1st Line AAT (TTF1) ·························· 61
 
5.3.3.2 
Time to Treatment Failure of 2nd Line AAT (TTF2) ························· 61
 
5.3.4 
Subject Reported Outcome ····························································· 61
 
5.3.4.1 
Functional Assessment of Cancer Therapy–Prostate (FACT–P) ············ 61
 
5.3.4.2 
European Quality of Life 5-Dimension-5 Level Instruments (EQ-5D-
5L) ··················································································· 61
 
5.3.4.3 
Brief Pain Inventory-Short Form (BPI-SF) ····································· 62
 
5.3.4.4 
Brief Fatigue Inventory (BFI) ···················································· 62
 
5.4 
Safety Assessment ············································································ 62
 
5.4.1 
Vital Signs (Blood Pressure and Pulse Rate) ········································· 62
 
5.4.2 
ECOG Performance Status ····························································· 62
 
5.4.3 
Adverse Events ·········································································· 62
 
5.4.3.1 
Adverse Events of Possible Hepatic Origin ···································· 63
 
5.4.4 
Laboratory Assessments ································································ 63
 
5.5 
Adverse Events and Other Safety Aspects ················································· 65
 
5.5.1 
Definition of Adverse Events (AEs) ·················································· 65
 
5.5.2 
Definition of Serious Adverse Events (SAEs) ······································· 65
 
5.5.3 
Criteria for Causal Relationship to the Study Drug ································· 66
 


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5.5.4 
Criteria for Defining the Severity of an Adverse Event ···························· 67
 
5.5.5 
Reporting of Serious Adverse Events (SAEs) ······································· 67
 
5.5.6 
Follow-up of Adverse Events ·························································· 67
 
5.5.7 
Procedure in Case of Pregnancy ······················································· 68
 
5.5.8 
Emergency Procedures and Management of Overdose ····························· 68
 
5.5.9 
Supply of New Information Affecting the Conduct of the Study ·················· 69
 
5.5.10 
Deviations from the Protocol and Other Actions Taken to Avoid Life-
Threatening Risks to Subjects ························································· 70
 
5.6 
Test Drug Concentration ····································································· 70
 
5.7 
Other Measurements, Assessments or Methods ··········································· 70
 
5.8 
Total Amount of Blood ······································································· 70
 
6 
DISCONTINUATION ············································································ 70
 
6.1 
Discontinuation of Individual Subject(s) ··················································· 70
 
6.2 
Discontinuation of the Site ··································································· 71
 
6.3 
Discontinuation of the Study ································································ 71
 
7 
STATISTICAL METHODOLOGY ··························································· 72
 
7.1 
Sample Size ···················································································· 72
 
7.2 
Analysis Set ···················································································· 73
 
7.2.1 
Intent-to-Treat (ITT) ···································································· 73
 
7.2.2 
Safety Analysis Set (SAF) ······························································ 73
 
7.2.3 
Pharmacokinetic Analysis Set (PKAS) ··············································· 74
 
7.2.4 
Pharmacodynamic Analysis Set (PDAS) ············································· 74
 
7.3 
Demographics and Other Baseline Characteristics ········································ 74
 
7.4 
Analysis of Efficacy ·········································································· 74
 
7.4.1 
Analysis of Primary Endpoint ························································· 74
 
7.4.1.1 
Primary Analysis··································································· 74
 
7.4.1.2 
Secondary Analysis ································································ 74
 
7.4.1.3 
Subgroup Analysis ································································· 75
 
7.4.2 
Analysis of Secondary Endpoints ····················································· 75
 
7.4.2.1 
Time to PSA Progression with 1st Line AAT + 2nd Line AAT 
(TTPP2) ············································································· 75
 
7.4.2.2 
PSA Response Rate to 1st Line AAT (Decrease by at Least 50% or 
90% from Baseline) ······························································· 75
 


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7.4.2.3 
PSA Response Rate to 1st Line AAT at Week 13 (Decrease by at 
Least 50% or 90% from Baseline) ··············································· 75
 
7.4.2.4 
Time to PSA Decrease by 50% from Baseline with 1st Line AAT ·········· 76
 
7.4.2.5 
Time to Treatment Failure of 1st Line AAT (TTF1) ·························· 76
 
7.4.2.6 
Time to Treatment Failure of 2nd Line AAT (TTF2) ························· 76
 
7.4.2.7 
Radiographic Progression-Free Survival (rPFS) ······························· 77
 
7.4.3 
Analysis of Exploratory Endpoints ···················································· 77
 
7.4.3.1 
Time to PSA Progression with 2nd Line AAT (2nd TTPP) ·················· 77
 
7.4.3.2 
PSA Response Rate to 2nd line AAT ··········································· 77
 
7.4.3.3 
Metastasis-Free Survival (MFS) ················································· 77
 
7.4.3.4 
FACT–P and EQ-5D-5L with 1st Line AAT and 2nd Line AAT ············ 77
 
7.4.3.5 
Brief Fatigue Inventory (BFI) with 1st Line AAT and 2nd Line AAT ······ 77  
7.4.3.6 
Objective Response Rate (ORR) in best Overall Soft Tissue Response 
of RECIST Guidelines with 1st Line AAT ····································· 77
 
7.5 
Analysis of Safety ············································································· 78
 
7.5.1 
Adverse Events ·········································································· 78
 
7.5.2 
Laboratory Assessments ································································ 78
 
7.5.3 
Vital Signs ················································································ 78
 
7.5.4 
ECOG Performance Status ····························································· 78
 
7.5.5 
Physical Examination ··································································· 78
 
7.5.6 
ECGs ······················································································ 79
 
7.5.7 
Imaging ··················································································· 79
 
7.6 
Analysis of Pharmacokinetics ······························································· 79
 
7.6.1 
Estimation of Pharmacokinetic Parameters ·········································· 79
 
7.6.2 
Statistical Analysis ······································································ 79
 
7.6.3 
Concentration-Response Relationship Analysis ····································· 79
 
7.7 
Analysis of Pharmacodynamics ····························································· 79
 
7.8 
Protocol Deviations and Other Analyses ··················································· 79
 
7.9 
Interim Analysis (and Early Discontinuation of the Clinical Study) ···················· 79
 
7.10 
Handling of Missing Data, Outliers, Visit Windows, and Other Information ········· 80  
8 
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS ···················· 84
 
8.1 
Procedure for Clinical Study Quality Control ············································· 84
 
8.1.1 
Data Collection ·········································································· 84
 
8.1.1.1 
Case Report Forms ································································ 84
 
8.1.1.2 
Subject Reported Outcome ······················································· 84
 


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8.1.1.3 
Examination Data ·································································· 84
 
8.1.2 
Specification of Source Documents ··················································· 84
 
8.1.3 
Clinical Study Monitoring ······························································ 85
 
8.1.4 
Direct Access to Source Data/Documents ············································ 86
 
8.1.5 
Data Management ······································································· 86
 
8.1.6 
End of Trial ·············································································· 86
 
8.2 
Ethics and Protection of Subject Confidentiality ·········································· 86
 
8.2.1 
Institutional Review Board (IRB) ····················································· 86
 
8.2.2 
Ethical Conduct of the Study··························································· 86
 
8.2.3 
Informed Consent of Subjects ························································· 87
 
8.2.3.1 
Subject Information and Consent ················································ 87
 
8.2.3.2 
Supply of New and Important Information Influencing the Subject’s 
Consent and Revision of the Written Information ····························· 87
 
8.2.4 
Subject Confidentiality ································································· 87
 
8.3 
Administrative Matters ······································································· 88
 
8.3.1 
Arrangement for Use of Information and Publication of the Clinical Study ····· 88  
8.3.2 
Documents and Records Related to the Clinical Study ····························· 88
 
8.3.3 
Protocol Amendment and/or Revision ················································ 90
 
8.3.4 
Insurance of Subjects and Others ······················································ 90
 
8.3.5 
Signatory Investigator for Clinical Study Report ···································· 91
 
9 
QUALITY ASSURANCE ········································································ 91
 
10 
STUDY ORGANIZATION ······································································ 91
 
10.1 
Independent Data-Monitoring Committee (IDMC) | Data and Safety Monitoring 
Board (DSMB) | Monitoring Committee | Other Evaluation Committee(s) ··········· 91
 
10.2 
Other Study Organization ···································································· 91
 
10.3 
Registration of Subjects ······································································ 91
 
11 
REFERENCES ···················································································· 94
 
12 
APPENDICES ····················································································· 95
 
12.1 
List of Excluded Concomitant Medications ··············································· 95
 
12.2 
Liver Safety Monitoring and Assessment ·················································· 96
 
12.3 
Always Serious Events ······································································· 99
 
12.4 
ECOG Performance Status ································································· 100
 
12.5 
FACT–P ······················································································ 101
 
12.6 
EQ-5D-5L ···················································································· 104
 


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12.7 
BPI-SF ························································································ 106
 
12.8 
BFI ···························································································· 108
 


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I. 
SIGNATURES 
1. AGREEMENT BETWEEN THE SPONSOR’S RESPONSIBLE PERSON AND THE 
INVESTIGATOR 
This clinical study will be conducted in adherence to GCP, ICH Guidelines and applicable 
laws and regulatory requirements, as well as this study protocol. As the evidence of the 
agreement, the investigator (CHIKEN SEKININ ISHI) and responsible person of the Sponsor 
(CHIKEN IRAI SEKININSHA) inscribe in the bipartite agreement. 
 
 


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II. 
CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL 
Contact Information for the Sponsor  
Corporate Name: Astellas Pharma Inc. 
Location: 2-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo 
Phone No.:
 
Fax: 
 
Sponsor’s personnel:
 
 
 
 
 
[Contact numbers during non-business hours and for emergency]:  
Phone No.: 
 
 
 
Contact Information for the Contract Research Organization (CRO) 
Corporate name: 
 
Location: 
 
Phone No.: 
 
Fax: 
 
CRO’s personnel: 
 
 
 
[Contact numbers during non-business hours and for emergency]:  
Phone No.: 
 
 


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III. 
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS 
 
List of Abbreviations 
Abbreviations 
Description of abbreviations 
AAT 
Alternative Antiandrogen Therapy 
ADT 
Androgen Deprivation Therapy 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AR 
Androgen Receptor 
AST 
Aspartate Aminotransferase 
BFI 
Brief Fatigue Inventory 
BPI-SF 
Brief Pain Inventory-Short Form 
BUN 
Blood Urea Nitrogen 
CAB 
Combined Androgen Blockade 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CRPC 
Castration-Resistant Prostate Cancer 
CSR 
Clinical Study Report 
CT 
Computerized Axial Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
DES 
Diethylstilbestrol 
DHEA 
Dihydroepiandrosterone 
DILI 
Drug-induced Liver Injury 
DNA 
Deoxyribonucleic Acid 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EQ-5D-5L 
European Quality of Life-5 Dimension-5 Level Instruments 
FACT–P 
Functional Assessment of Cancer Therapy–Prostate 
FDA 
Food and Drug Administration 
GABA 
Gamma Amino Butyric Acid 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practices 
GnRH 
Gonadotropin Releasing Hormone  
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IDMC 
Independent Data Monitoring Committee 
IRB 
Institutional Review Board 
ISN 
International Study Number 
ITT 
Intent-to-Treat 
IUD 
Intrauterine Device 
IUS 
Intrauterine System 
LA-CRF 
Liver Abnormality Case Report Form 
LDH 
Lactate Dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 


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Abbreviations 
Description of abbreviations 
MFS 
Metastasis-Free Survival 
MRI 
Magnetic Resonance Imaging 
NASH 
Non-Alcoholic Steatohepatitis 
NCI 
National Cancer Institute 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PCWG2 
Prostate Cancer Clinical Trials Working Group 2 
PDAS 
Pharmacodynamic Analysis Set 
P-gp 
P-glycoprotein 
PKAS 
Pharmacokinetic Analysis Set 
PSA 
Prostate-Specific Antigen 
QOL 
Quality of Life 
RECIST 
Response Evaluation Criteria in Solid Tumors 
rPFS 
Radiographic Progression-Free Survival 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SFL 
Screen Failure Log 
SOP 
Standard Operating Procedure 
t1/2 
Terminal Elimination Half-life 
TTF1 
Time to Treatment Failure 1 
TTF2 
Time to Treatment Failure 2 
TTPP1 
Time to PSA Progression 1 
TTPP2 
Time to PSA Progression 2 
2nd TTPP 
2nd Time to PSA Progression 
ULN 
Upper Limit of Normal 
WHODDE 
WHO Drug Dictionary Enhanced 
γ-GTP 
γ-gultamyltranspeptidase 
 
 


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Definition of Key Study Terms 
Terms 
Definition of terms 
Baseline  
Observed values/findings that are considered as observed starting point for 
comparison.  
The baseline of individual endpoints is defined as data from the following 
period: 
● 
Prostate-specific antigen (PSA), subject reported outcome, vital signs, 
laboratory test values, Eastern Cooperative Oncology Group (ECOG) 
Performance Status: Week 1 (Day 1) of 1st line AAT and 2nd line AAT 
● 
Diagnostic imaging: Screening period 
Enroll 
To register or enter into a clinical trial. NOTE: Once a subject has been 
enrolled, the clinical trial protocol applies to the subject. 
Intervention 
The drug, therapy or process under investigation in a clinical study that is 
believed to have an effect on outcomes of interest in a study. (e.g., health-
related quality of life, efficacy, safety, pharmacoeconomics). 
Investigational 
period 
Period of time where major interests of protocol objectives are observed, and 
where the test drug or comparative drug (sometimes without randomization) 
is usually given to a subject, and continues until the last assessment after 
completing administration of the test drug or comparative drug. 
Post investigational 
period 
Period of time after the last assessment of the protocol. Follow-up 
observations for sustained adverse events and/or survival are done in this 
period. 
Screening period 
Period of time before entering the investigational period, usually from the 
time of starting a subject signing the informed consent form until the initial 
administration of the test drug or comparative drug (sometimes without 
randomization) is given to a subject.  
Randomization 
The process of assigning trial subjects to treatment or control groups using 
an element of chance to determine assignments in order to reduce bias. 
Screening 
A process of active consideration of potential subjects for enrollment in a 
trial. 
Screen failure 
 
 
Potential subject who did not meet one or more criteria required for 
participation in a trial. 
1st line AAT 
period 
 
 
Period from starting the first study drug (test drug or comparative drug) after 
randomization to the end of last assessment at completion or discontinuation 
of treatment with 1st line AAT or to start the second study drug (test drug or 
comparative drug). 
2nd line AAT 
period 
 
Period from starting the second study drug (test drug or comparative drug) to 
the end of last assessment at completion or discontinuation of treatment with 
2nd line AAT. 
Safety follow-up 
period 
28 days from final administration of the study drug. 
Adverse Event 
Any untoward medical occurrence in a subject administered a study drug and 
which does not necessarily have a causal relationship with the study 
treatment. 
Subject 
An individual who participates in a clinical trial, and receives or is to receive 
the study drug. 
Subject Number, 
Subject ID Code 
A number given to an individual subject who agrees to participate in the 
study and signs an informed consent form. 


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Terms 
Definition of terms 
Study period 
Period of time from the first site initiation date to the last site completing the 
study. 
Variable 
Any quantity that varies; any attribute, phenomenon or event that can have 
different qualitative or quantitative values. 


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IV. 
SYNOPSIS 
Date and Version # of Protocol Synopsis:  
03 August, 2016, Version 2.0 
 
Sponsor:  
Astellas Pharma Inc (API)  
 
Protocol Number:  
9785-MA-3051 
Name of Study Drug:  
Enzalutamide 
Phase of Development:  
Phase 4 
Title of Study:  
Post-marketing clinical study on enzalutamide 
—A Randomized Phase IV Study Comparing Enzalutamide versus Flutamide in CRPC Patients 
Who Have Failed Combined Androgen Blockade Therapy with Bicalutamide plus ADT— 
Planned Study Period:  
From October 2016 to March 2020 
Study Objective(s):  
To compare the efficacy and safety of the combination therapy with enzalutamide + ADT and the 
combination therapy with flutamide + ADT in patients with castration resistant prostate cancer that 
relapsed during combined androgen blockade (CAB) therapy with bicalutamide and androgen 
deprivation therapy (ADT). To investigate the order of alternative antiandrogen therapy (AAT) by 
changing the 1st line medication after progression of prostate-specific antigen (PSA).  
 
Primary objective:  
● 
To determine the benefit of enzalutamide + ADT therapy as compared to flutamide + ADT 
therapy as assessed by time to PSA progression with 1st line AAT (time to PSA progression 1 
[TTPP1]).  
 
Secondary objectives:  
● 
To determine the order of AAT treatment as assessed by time to PSA progression with 1st line 
AAT + 2nd line AAT (time to PSA progression 2 [TTPP2]).  
● 
To determine the benefit of enzalutamide + ADT therapy as compared to flutamide + ADT 
therapy as assessed by PSA response rate to 1st line AAT (proportion of subjects with a 
decrease by at least 50% or 90% from baseline irrespective of the timing).  
● 
To determine the benefit of enzalutamide + ADT therapy as compared to flutamide + ADT 
therapy as assessed by PSA response rate to 1st line AAT at Week 13 (proportion of subjects 
with a decrease by at least 50% or 90% from baseline).  
● 
To determine the benefit of enzalutamide + ADT therapy as compared to flutamide + ADT 
therapy as assessed by time to PSA decrease by 50% from baseline with 1st line AAT.  
● 
To determine the benefit of enzalutamide + ADT therapy as compared to flutamide + ADT 
therapy as assessed by time to discontinuation of 1st line AAT (time to treatment failure 1 
[TTF1]).  
● 
To determine the order of AAT treatment as assessed by time to discontinuation of 2nd line 
AAT (time to treatment failure 2 [TTF2]).  
● 
To determine the benefit of enzalutamide + ADT therapy as compared to flutamide + ADT 
therapy as assessed by radiographic progression-free survival (rPFS).  
 


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Safety objective:  
● 
To determine the safety of enzalutamide + ADT therapy as compared to flutamide + ADT 
therapy.  
 
Exploratory objectives:  
● 
To evaluate time to PSA progression with 2nd line AAT (2nd time to PSA progression [2nd 
TTPP]).  
● 
To evaluate PSA response rate to 2nd line AAT.  
● 
To determine the benefit of enzalutamide + ADT therapy as compared to flutamide + ADT 
therapy as assessed by metastasis-free survival (MFS).  
● 
To evaluate Quality of Life (QOL) on 1st line AAT and 2nd line AAT using Functional 
Assessment of Cancer Therapy–Prostate (FACT–P) and European Quality of Life 5-
Dimension-5 Level instruments (EQ-5D-5L).  
● 
To evaluate Brief Pain Inventory-Short Form (BPI-SF) with 1st line AAT and 2nd line AAT.  
● 
To evaluate Brief Fatigue Inventory (BFI) with 1st line AAT and 2nd line AAT.  
● 
To determine the benefit of enzalutamide + ADT therapy as compared to flutamide + ADT 
therapy as assessed by objective response rate (ORR) in soft tissue with 1st line AAT based on 
the best overall response in RECIST guidelines.  
● 
To evaluate the efficacy in subgroups according to disease-related patient demographics.  
Planned Total Number of Study Centers and Location(s):  
Approximately 40 centers 
Japan 
Study Population:  
Patients with castration resistant prostate cancer that relapsed during CAB therapy with 
bicalutamide 
Number of Subjects to be Enrolled / Randomized:  
200 subjects (1st line AAT enzalutamide group: 100, 1st line AAT flutamide group: 100)  
Study Design Overview:  
This is a randomized, open-label, comparative study on enzalutamide and flutamide.  
Patients with M0 or M1 castration resistant prostate cancer that relapsed during CAB therapy with 
bicalutamide will be randomized to Groups A or B. Randomization will be stratified according to 
the stages shown below (M0/N0, M0/N1, or M1):  
● 
M0/N0: No distant metastasis, and no lymph node metastasis 
● 
M0/N1: Without distant metastasis, but with metastasis in lymph nodes distal to the 
aortic bifurcation 
● 
M1: With distant metastasis (including metastasis in lymph nodes proximal to the aortic 
bifurcation)  
For subjects in Group A, enzalutamide is administered as the 1st line AAT. After the confirmation 
of PSA progression, medication is changed from enzalutamide to flutamide as the 2nd line AAT. 
For subjects in Group B, flutamide is administered as the 1st line AAT. After the confirmation of 
PSA progression, medication is changed from flutamide to enzalutamide as the 2nd line AAT. The 
treatment period with each drug should not be more than 2 years from the enrollment of the last 
subjects.  
PSA progression will be defined according to the consensus guidelines of PCWG2. For patients 
with PSA declines at Week 13, the PSA progression date is defined as the date that a ≥ 25% 
increase and an absolute increase of ≥ 2 ng/mL above the nadir is documented, which is confirmed 
by a second consecutive value obtained 3 or more weeks later. For patients with no PSA decline at 


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Week 13, the PSA progression date is defined as the date that a ≥ 25% increase and an absolute 
increase of ≥ 2 ng/mL above the baseline is documented.  
Data for the analysis of primary endpoint TTPP1 will be cut-off if not less than 135 events of PSA 
progression occurred in association with the 1st line AAT.  
After the discontinuation of the 1st line AAT due to PSA progression or other reasons, the 2nd line 
AAT will be started. Subjects who discontinued the 1st line AAT due to PSA progression will start 
the 2nd line AAT within 6 weeks after the date of examination that identified PSA progression. 
Subjects who discontinued the 1st line AAT due to other reasons will start the 2nd line AAT within 
6 weeks from the day when the investigator or subinvestigator decided the discontinuation.  
A safety follow-up visit should be performed wherever possible in 28 days from the final study 
treatment, or before starting other study drugs, or before starting other treatment for prostate 
cancer, whichever comes first. If subjects do not show up on the safety follow-up visit, confirm 
adverse events by the telephone wherever possible.  
Inclusion/Exclusion Criteria:  
Inclusion:  
Subject is eligible for the study if all of the following apply: 
1. 
Subject must have submitted an informed consent form approved by the institutional review 
board (IRB) established at each study center prior to the study.  
2. 
Age ≥20 years at the time of signing the informed consent form.  
3. 
Subject is diagnosed with histologically or cytologically confirmed adenocarcinoma of the 
prostate without neuroendocrine differentiation or small-cell histology.  
4. 
Subject on continuous ADT with GnRH agonist/antagonist or bilateral orchiectomy (surgical 
or chemical castration).  
5. 
Subject for whom treatment with effective GnRH agonist/antagonist is to be continued during 
the study period if bilateral orchiectomy is not performed. 
6. 
Serum testosterone level ≤1.73 nmol/L (50 ng/dL or 0.5 ng/mL) at screening visit.  
7. 
Subject with no change in the dose of bisphosphonate preparation or denosumab for at least 4 
weeks if these drugs are used.  
8. 
Subject with asymptomatic or mildly symptomatic prostate cancer (BPI-SF score is <4 to 
Question 3 “the worst pain within 24 hours”).  
9. 
Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.  
10. Subject has an estimated life expectancy of ≥12 months.  
11. Subject is able to swallow the study drug, and comply with procedures required by the study.  
12. Subject has progression of the disease that falls under at least one of the following 3 criteria 
during CAB therapy in combination of bicalutamide and ADT.  
● 
PSA increase should be confirmed at least 2 timepoints with an interval of ≥1 week. In 
at least 6 weeks after the last dose of bicalutamide, PSA should be confirmed higher 
than the highest PSA measured after the nadir was confirmed during administration of 
bicalutamide. PSA at screening visit should be ≥2 ng/mL (2 μg/L).  
● 
Soft tissue disease progression defined by RECIST guidelines (version 1.1).  
● 
Progression of ≥2 bone lesions defined as new lesions in bone scintigraphy by PCWG2.  
13. A sexually active male subject and his female partner who is of childbearing potential must 
use 2 acceptable birth control methods shown below (1 of which must include a condom as a 
barrier method of contraception) from screening to 3 months after the last dose of the study 
drug.  


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● 
A male or female condom as a barrier method of contraception; 
● 
Consistent and correct usage of established, proper use of oral contraceptives; 
● 
Established intrauterine device or intrauterine system by the female partner; 
● 
Tubal ligation in the female partner performed at least 6 months prior to subject’s 
screening visit; 
● 
Vasectomy or other procedure resulting in infertility (e.g., bilateral orchiectomy) 
performed at least 6 months prior to screening; 
● 
Calendar-based contraceptive methods (Knaus-Ogino or rhythm method). 
14. Subject must use a condom throughout the study if engaging in sexual intercourse with a 
pregnant woman. 
15. Subject must agree not to donate sperm from screening to 3 months after the last dose of the 
study drug.  
16. Subject agrees not to participate in another interventional study while on treatment.  
 
Waivers to the inclusion criteria will NOT be allowed.  
 
Exclusion: 
Subject will be excluded from the study if any of the following apply: 
1. 
Subject with severe concurrent diseases, infections, or complications, which are considered 
inappropriate for enrollment by the investigator or subinvestigator.  
2. 
Subject with confirmed or suspected brain metastasis or active leptomeningeal metastasis.  
3. 
Subject with a history of malignant tumor other than prostate cancer in the past 5 years (except 
for non-melanoma skin cancer cured with radical therapy).  
4. 
Subject hypersensitive to the ingredients of enzalutamide capsules or flutamide tablets.  
5. 
Subject with a history of seizure, or any condition that may predispose to seizure.  
6. 
Subject with liver disorder such as viral hepatitis and hepatic cirrhosis, or subject with AST 
and ALT at screening visit higher than the upper limit of normal.  
7. 
Subject on warfarin.  
8. 
Subject received treatment for prostate cancer with cytocidal chemotherapy that includes 
anti-androgenic agents other than bicalutamide (e.g., enzalutamide, flutamide), abiraterone, or 
estramustine.  
9. 
Subject participated in a clinical trial on a drug other than GnRH agonist/antagonist in prostate 
cancer.  
10. Subject received treatment with herbal medications that may have hormonal anti-prostate 
cancer activity or herbal medications (saw palmetto) that may decrease PSA levels; subject 
received treatment for prostate cancer with systemic corticosteroids, or treatment for other 
diseases with systemic corticosteroids greater than the equivalent of 10 mg per day of 
prednisone (Decadron 1 mg/day) within 4 weeks prior to enrollment (Day 1).  
11. Subject received treatment with bicalutamide within 6 weeks prior to enrollment (Day 1).  
12. Subject received treatment with 5-α reductase inhibitors (finasteride, dutasteride), estrogens, 
or drugs with anti-tumor action other than GnRH agonists/antagonists within 4 weeks prior to 
enrollment (Day 1).  
13. Subject received treatment with opioid analgesic for pains associated with prostate cancer 


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within 4 weeks prior to enrollment (Day 1).  
14. Subject participated or is currently participating in a clinical trial or a post-marketing clinical 
study on other ethical drugs (excluding GnRH agonist/antagonist) or medical devices within 
12 weeks or 5 half lives (in case of ethical drugs), whichever is longer, prior to screening. 
15. Subject received treatment for primary or metastatic lesion with surgery or radiation therapy 
within 4 weeks prior to enrollment (Day 1).  
16. Subject with unstable psychiatric disease (e.g., schizophrenia, dementia, uncontrollable 
depression/bipolar disorder).  
17. Subject with a disease or reason unsuitable for participation in the study, which is considered 
by the investigator or subinvestigator to cause excessive risk to the subject or make the 
interpretation of safety data difficult.  
 
Waivers to the exclusion criteria will NOT be allowed.  
 
Criteria to shift from 1st line AAT to 2nd line AAT:  
If any of the following is satisfied, the study drug will be shifted to the 2nd line AAT after the 
discontinuation of the1st line AAT:  
1. 
PSA progression 
2. 
In case where the 1st line AAT is to be discontinued due to adverse events, but the investigator 
or subinvestigator considers that there is no problem in the subject tolerance to transition to 
the 2nd line AAT. 
3. 
In case where the 1st line AAT is to be discontinued due to progression of disease other than 
PSA progression, but the investigator or subinvestigator considers that there is no problem in 
the subject tolerance to transition to the 2nd line AAT. 
 
In any of the following cases, study treatment will be discontinued without shifting to the 2nd line 
AAT:  
1. 
In case of enzalutamide as 2nd line AAT, subjects with seizure as an adverse event 
2. 
In case of flutamide as 2nd line AAT, subjects with the latest AST or ALT exceeding the 
upper limit of normal 
3. 
Other cases that the investigator or subinvestigator considers unsuitable for study continuation 
 
Investigational Product(s):  
Enzalutamide capsule 40 mg 
Dose(s):  
160 mg once daily (160 mg/day)  
Mode of Administration:  
Oral 
Comparative Drug(s):  
Flutamide tablets 125 mg 
Dose(s):  
125 mg × 3 times daily (375 mg/day)  
Mode of Administration:  
Oral 
Drug(s) for Screening:  
Not applicable 


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Rescue Therapy:  
Not applicable 


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Enzalutamide Dose Reduction/Adjustment 
If a study drug associated adverse reaction occurs, is evaluated as Grade 3 or higher according to 
the National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0, and is not improved by proper medical intervention, stop the treatment for a week or 
until the severity of the adverse reaction improves to Grade 2 or lower. After the improvement, 
treatment may be restarted with the original or reduced dose at the discretion of the investigator or 
subinvestigator.  
If a strong CYP2C8 inhibitor (e.g., gemfibrozil) should be concurrently used, reduce the dose of 
enzalutamide to 80 mg once daily. When the CYP2C8 inhibitor is discontinued, return the dose of 
enzalutamide to the original dose.  
Flutamide Dose Reduction/Adjustment 
If a study drug associated adverse reaction occurs, is evaluated as Grade 3 or higher according to 
the NCI-CTCAE version 4.0, and is not improved by proper medical intervention, stop the 
treatment for a week or until the severity of the adverse reaction improves to Grade 2 or lower. 
After the improvement, treatment may be restarted with the original or reduced dose at the 
discretion of the investigator or subinvestigator.  
Concomitant Medication Restrictions or Requirements:  
Required concomitant medications:  
All subjects must undergo continuous ADT with GnRH agonist/antagonist or bilateral orchiectomy 
during the study period. GnRH agonist/antagonist will be prepared and administered by the study 
center. Do not change the medications in principle.  
 
Prohibited concomitant medications:  
The use of the following drugs and therapies are prohibited during the study treatment and in the 
period from the end of the 1st line AAT to the start of the 2nd line AAT:  
● 
anti-androgenic agents (steroid or non-steroid) other than study drugs such as chlormadinone 
and bicalutamide 
● 
CYP17 inhibitor (abiraterone)  
● 
cytocidal chemotherapy that includes estramustine 
● 
systemic corticosteroids for prostate cancer or systemic corticosteroids greater than the 
equivalent of 10 mg per day of prednisone (Decadron 1 mg/day) for other diseases 
● 
5-α reductase inhibitors (finasteride, dutasteride) 
● 
estrogen or progesterone agents such as medroxyprogesterone and diethylstilbestrol (DES) 
● 
biological agents or other drugs with anticancer activity to prostate cancer 
● 
herbal medications that may have hormonal anti-prostate cancer activity or herbal medications 
(saw palmetto) that may decrease serum PSA levels 
● 
androgen (e.g., testosterone, dehydroepiandrosterone [DHEA])  
● 
study drugs for prostate cancer 
● 
surgery or radiation therapy for primary lesion 
● 
warfarin 
 
Precautions for concomitant medication with enzalutamide (drug interactions):  
Enzalutamide may affect the exposure to other medications. Other medications may also affect the 
exposure to enzalutamide.  
● 
Concomitant use with strong CYP2C8 inhibitors (e.g., gemfibrozil) may elevate the plasma 
concentration of enzalutamide. Therefore, it is desirable to avoid the concomitant use. If the 
subject needs a strong CYP2C8 inhibitor, reduce the dose of enzalutamide to 80 mg once 


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daily, and return the dose of enzalutamide to the original dose when the combination use is 
discontinued. 
● 
Strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, and rifampicin) or 
moderate CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin, and 
hypericum erectum) may decrease the plasma concentration of enzalutamide. Therefore, it is 
desirable to avoid the concomitant use. It is recommended to select a drug that is less likely to 
induce CYP3A4, or minimizes the induction.  
● 
Enzalutamide is a strong inducer of CYP3A4, and moderate inducer of CYP2C9 and 
CYP2C19. Enzalutamide decreases the exposure to drugs of CYP3A4 substrate with a small 
therapeutic range (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, 
pimozide, quinidine, sirolimus, and tacrolimus), drugs of CYP2C9 substrate with a small 
therapeutic range (e.g., phenytoin and warfarin), drugs of CYP2C19 substrate with a small 
therapeutic range, and drugs of UGT1A1 substrate with a small therapeutic range (e.g., S-
mephenytoin). Therefore, it is desirable to avoid the concomitant use. 
● 
Enzalutamide is an inhibitor of human P-glycoprotein (P-gp) and may increase the exposure to 
drugs of P-gp substrate. Precaution is required for the combination use of drugs of P-gp 
substrate with a small therapeutic range (e.g., digoxin, colchicine, and dabigatran etexilate) 
with enzalutamide.  
 
Duration of Treatment:  
● 
The administration of the 1st line AAT will be continued until the case falls under the criteria 
for shifting from the1st line AAT to 2nd line AAT or the discontinuation criteria, or for 2 
years from the enrollment of the last subject.  
● 
After the discontinuation of the 1st line AAT due to PSA progression or other reasons, the 2nd 
line AAT will be started. Subjects who discontinued the 1st line AAT due to PSA progression 
will start the 2nd line AAT within 6 weeks after the date of examination that identified PSA 
progression. Subjects who discontinued the 1st line AAT due to other reasons will start the 
2nd line AAT within 6 weeks from the day when the investigator or subinvestigator decided 
the discontinuation.  
● 
The administration of the 2nd line AAT will be continued until PSA progression or until the 
case falls under the discontinuation criteria, or for 2 years from the enrollment of the last 
subject.  
 


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Discontinuation Criteria:  
The study will be discontinued in case of any of the following events:  
1. 
Adverse events (excluding events in the discontinuation criteria 2 and 3) that are intolerable 
for the subject, and are not improved by proper medical intervention or reduction of the study 
drug; or adverse events, which the investigator or subinvestigator considers that the 
continuation of the study drug may cause an excessive risk to subjects. 
2. 
Seizure during the treatment period of enzalutamide (subjects who had seizure on the1st line 
AAT may be shifted to the 2nd line AAT.)  
3. 
Liver disorder during the treatment period of flutamide (AST or ALT that exceeds 3 fold of 
the upper limit of normal) or interstitial pneumonia (subjects who had a case on the 1st line 
AAT may be shifted to the 2nd line AAT.)  
4. 
With or without PSA progression, the investigator or subinvestigator considers that the study 
should be discontinued due to the progression of the disease. 
5. 
Subject withdraws the informed consent. 
 
6. 
Observation cannot be continued (e.g., subject stops study visit; subject is lost to contact)  
7. 
The sponsor, investigator, or subinvestigator considers that the study should be discontinued 
due to deviation from the protocol (excluding the discontinuation criterion 8).  
8. 
It turns out after the enrollment that the subject did not satisfy the inclusion criteria at the time 
of enrollment, or met the exclusion criteria, and the continuation of the study is judged 
inappropriate. 
9. 
Other 
For reasons other than those mentioned above, the investigator or subinvestigator considers 
that the study should be discontinued.  
 
For discontinuation after the start of the study drug, a discontinuation examination/observation will 
be conducted wherever possible immediately after the decision of discontinuation.  
 
Endpoints for Evaluation:  
Primary:  
● 
Time to PSA progression with 1st line AAT (TTPP1)  
 
Secondary:  
● 
Time to PSA progression with 1st line AAT + 2nd line AAT (TTPP2)  
● 
PSA response rate to 1st line AAT (decrease by at least 50% or 90% from baseline)  
● 
PSA response rate to 1st line AAT at Week 13 (decrease by at least 50% or 90% from 
baseline)  
● 
Time to PSA decrease by 50% from baseline with 1st line AAT 
● 
Time to discontinuation of 1st line AAT (TTF1)  
● 
Time to discontinuation of 2nd line AAT (TTF2)  
● 
rPFS  
 
Safety:  
● 
Characteristics, frequency, and severity of adverse events 
● 
Safety-related laboratory tests (biochemistry and hematology)  
● 
Vital signs (blood pressure and pulse rate)  


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● 
ECOG Performance Status 
 
Exploratory:  
● 
Time to PSA progression with 2nd line AAT (2nd TTPP)  
● 
PSA response rate to 2nd line AAT (decrease by at least 50% or 90% from baseline)  
● 
MFS  
● 
QOL assessment with 1st line AAT and 2nd line AAT by FACT–P and EQ-5D-5L 
● 
BPI-SF with 1st line AAT and 2nd line AAT 
● 
BFI with 1st line AAT and 2nd line AAT 
● 
ORR in best overall soft tissue response of RECIST guidelines with 1st line AAT 
● 
Efficacy assessment by subgroups according to disease-related patient demographics 
 
Statistical Methods:  
Sample size justification:  
The sample size for evaluation will be approximately 200 subjects (1st line AAT enzalutamide 
group: 100, 1st line AAT flutamide group: 100).  
 
The sample size to evaluate the time to PSA progression with 1st line AAT (TTPP1) was calculated 
in consideration of the following points:  
● 
Median TTPP1 with enzalutamide: 10.5 months.  
 
 
 
  
● 
Median TTPP1 with flutamide: 6 months.  
Values reported in the literature: 5 months according to [Okihara et al., 2007]; 6.25 months 
according to [Narimoto et al., 2010].  
● 
The ratio of randomization of 1st line AAT enzalutamide and flutamide groups is 1:1.  
● 
Subject enrollment period is 12 months, and the observation period is 24 months from the 
enrollment of the last subject.  
● 
Type I error of the two-sided test is 0.05, and power is 90%.  
● 
A log-rank test with the TTPP1 parameters shown above requires 135 events. The necessary 
number of subjects calculated based on the required number of events is 74 subjects per group.  
● 
Considering the dropout rate of approximately 25%, 100 subjects are to be enrolled in each 
group.  
 


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Efficacy:  
Efficacy analysis will be performed on Intent-to-Treat (ITT) defined as all the randomized subjects.  
 
Primary endpoint:  
Time to PSA progression with 1st line AAT (TTPP1)  
● 
Time to PSA progression with 1st line AAT is defined as the period from randomization to the 
first day when PSA progression is objectively identified. Convention of censoring is specified 
in Section 7.10. 
● 
The benefit of enzalutamide as compared to flutamide will be assessed with stratified log-rank 
test as the primary efficacy analysis. The significance level is 0.05 (two-sided). The 
stratification factor will be the disease stages (M0/N0, M0/N1, or M1) used as stratification 
factor for allocation.  
● 
The benefit of enzalutamide as compared to flutamide will be also assessed with hazard ratio 
and its 95% CI based on Cox proportional hazards model. Disease stages (M0/N0, M0/N1, or 
M1) will be used as a covariate for adjustment.  
● 
Furthermore, the distribution of time to PSA progression will be estimated using the Kaplan–
Meier method. The median time to PSA progression will be estimated using the 50 percentile 
value of the Kaplan–Meier curve. The two-sided 95% CI will be calculated based on the 
estimation.  
 
Secondary endpoints:  
Time to PSA progression with 1st line AAT + 2nd line AAT (TTPP2)  
● 
Time to PSA progression with 2nd line AAT is defined as the period from Day 1 of 2nd line 
AAT to the date of PSA progression with 2nd line AAT. The total of time to PSA progression 
with 1st line AAT and time to PSA progression with 2nd line AAT will be evaluated. 
Convention of censoring is specified in Section 7.10.  
● 
The distribution of the period of TTPP2 will be estimated using the Kaplan–Meier method. 
The median period of TTPP2 will be estimated using the 50 percentile value of the Kaplan–
Meier curve. The two-sided 95% CI will be calculated based on the estimation. The benefit of 
enzalutamide as compared to flutamide will be descriptively assessed.  
 
PSA response rate to 1st line AAT (decrease by at least 50% or 90% from baseline)  
● 
PSA response rate decreasing by at least 50% will be calculated by treatment groups of 
subjects with baseline PSA value and PSA measured at least once after baseline. For the 
comparison of response rate between the enzalutamide and flutamide groups, the stratified 
Cochran–Mantel–Haenszel test will be used. The stratification factor will be the disease stages 
(M0/N0, M0/N1, or M1) used as stratification factor for allocation.  
● 
PSA decrease by at least 90% will also be compared at the 0.05 significance level (two-sided) 
between the enzalutamide and flutamide groups using stratified Cochran–Mantel–Haenszel 
test.  
 


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PSA response rate to 1st line AAT at Week 13 (decrease by at least 50% or 90% from baseline)  
● 
PSA response rate decreasing by at least 50% (or at least 90%) will be calculated by treatment 
groups of subjects with baseline PSA value and PSA measured at Week 13. Response rate 
between the enzalutamide and flutamide groups will be compared using the stratified 
Cochran–Mantel–Haenszel test. The stratification factor will be the disease stages (M0/N0, 
M0/N1, or M1) used as stratification factor for allocation.  
 
Time to PSA decrease by 50% from baseline with 1st line AAT  
● 
The time to PSA decrease by 50% with 1st line AAT is defined as the period from 
randomization to the day when the decrease of PSA from baseline by 50% is first identified. 
Convention of censoring is specified in Section 7.10.  
● 
The benefit of enzalutamide as compared to flutamide will be assessed by the stratified log-
rank test. The significance level is 0.05 (two-sided). The stratification factor will be the 
disease stages (M0/N0, M0/N1, or M1) used as stratification factor for allocation.  
● 
The distribution of the period where PSA decreases by 50% will be estimated using the 
Kaplan–Meier method. The median period where PSA decreases by 50% will be estimated 
using the 50 percentile value of the Kaplan–Meier curve. The two-sided 95% CI will be 
calculated based on the estimation.  
 
Time to discontinuation of 1st line AAT (TTF1)  
● 
The time to discontinuation of 1st line AAT will be calculated as the period from 
randomization to the date of discontinuation of 1st line AAT. Convention of censoring is 
specified in Section 7.10.  
● 
The benefit of enzalutamide as compared to flutamide will be assessed with the stratified log-
rank test. The significance level is 0.05 (two-sided). The stratification factor will be the 
disease stages (M0/N0, M0/N1, or M1) used as stratification factor for allocation.  
● 
The distribution of the time to discontinuation of 1st line AAT will be estimated using the 
Kaplan–Meier method. The median time to discontinuation of 1st line AAT will be estimated 
using the 50 percentile value of the Kaplan–Meier curve. The two-sided 95% CI will be 
calculated based on the estimation.  
 
Time to discontinuation of 2nd line AAT (TTF2)  
● 
The time to discontinuation of 2nd line AAT will be calculated as the period from 
randomization to the date of discontinuation of 2nd line AAT. Convention of censoring is 
specified in Section 7.10.  
● 
The distribution of the period of TTF2 will be estimated using the Kaplan–Meier method. The 
median period of TTF2 will be estimated using the 50 percentile value of the Kaplan–Meier 
curve. The two-sided 95% CI will be calculated based on the estimation. The benefit of 
enzalutamide as compared to flutamide will be descriptively assessed.  
 
Radiographic progression-free survival (rPFS)  
● 
rPFS will be assessed using the same method as that with the time to PSA progression with 1st 
line AAT (TTPP1) in subjects with distant metastasis confirmed at baseline.  


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Explorative endpoint:  
Time to PSA progression with 2nd line AAT (2nd TTPP)  
● 
Time to PSA progression with 2nd line AAT is defined as the period from the start of 2nd line 
AAT to the first day when PSA progression is objectively identified. Convention of censoring 
is specified in Section 7.10.  
● 
The distribution of the time to PSA progression with 2nd line AAT will be estimated using the 
Kaplan–Meier method. The median time to discontinuation of 2nd line AAT will be estimated 
using the 50 percentile value of the Kaplan–Meier curve. The two-sided 95% CI will be 
calculated based on the estimation. The benefit of enzalutamide as compared to flutamide will 
be descriptively assessed.  
 
PSA response rate to 2nd line AAT 
● 
PSA response rate to 2nd line AAT will be assessed using the same method as that with PSA 
response rate to 1st line AAT.  
 
Metastasis-free survival (MFS)  
● 
MFS will be assessed using the same method as that with 2nd TTPP in subjects without distant 
metastasis at baseline.  
 
FACT–P and EQ-5D-5L with 1st line AAT and 2nd line AAT 
● 
For FACT–P and EQ-5D-5L, summary statistics will be calculated at each assessment.  
 
Brief Pain Inventory-Short Form (BPI-SF) with 1st line AAT and 2nd line AAT 
● 
For BPI-SF, summary statistics will be calculated at each assessment.  
 
Brief Fatigue Inventory (BFI) with 1st line AAT and 2nd line AAT 
● 
For BFI, summary statistics will be calculated at each assessment.  
 
Objective response rate (ORR) in best overall soft tissue response of RECIST guidelines with 1st 
line AAT 
● 
ORR will be assessed using the same method as that with PSA response rate.  
 
Pharmacokinetics:  
Not applicable 
 
Pharmacodynamics:  
Not applicable 
 
Safety:  
For frequency and severity of adverse events, safety-related laboratory tests, and vital signs, 
summary statistics will be calculated. For ECOG Performance Status, frequency distribution will 
be calculated.  
 
Interim analyses:  
Not applicable 


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V. 
FLOW CHART AND SCHEDULE OF ASSESSMENTS 
Flow Chart 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*1: 28 days after final study treatment, or before starting other study drugs, or before starting other treatment for prostate cancer, whichever comes first 
*2: Subjects who discontinued the 1st line AAT due to PSA progression will start the 2nd line AAT within 6 weeks after the date of examination that identified 
PSA progression. Subjects who discontinued the 1st line AAT due to other reasons will start the 2nd line AAT within 6 weeks from the day when the 
investigator or subinvestigator decided the discontinuation. 
 
Group A 
Group B 
PSA progression 
PSA progression 
*2 
*2 
Flutamide 375 mg/day 
+ 
Androgen Deprivation Therapy 
Enzalutamide 160 mg/day 
+ 
Androgen Deprivation Therapy 
Flutamide 375 mg/day 
+ 
Androgen Deprivation Therapy 
Randomization 
Obtaining 
informed 
consent 
Enzalutamide 160 mg/day 
+ 
Androgen Deprivation Therapy 
Screening period 
Weeks −4 to −1 (Days −28 to −7) 
Confirmation 
of in/exclusion 
criteria 
1st line AAT 
(Every 4-week visit) 
2nd line AAT 
(Every 4-week visit) 
Safety follow-up 
(28 days after final study 
treatment*1) 
Safety follow-up 


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Table 1: Schedule of Assessments 
1st line AAT 
 
Screening period 
1st line AAT 
Unscheduled*a 
Visit Days 
Days −28 to −7 
1 
29 
57 
85 and every 
subsequent 84 days  
113 and every 
subsequent 28 days  
– 
Visit Weeks 
−4 to −1 
1 
5 
9 
13 and every 
subsequent 12 weeks  
17 and every 
subsequent 4 weeks  
– 
Allowed visit window (days) 
– 
– 
± 7 
± 7 
± 7 
± 7 
– 
Informed consent*b 
X *b 
 
 
 
 
 
 
Subject background survey 
X 
 
 
 
 
 
 
Confirmation of in/exclusion criteria 
X 
X 
 
 
 
 
 
Randomization/enrollment 
 
 X *c 
 
 
 
 
 
Vital signs*d 
X 
X 
X 
X 
X 
X 
X 
Height/body weight 
X 
 
 
 
 
 
 
Laboratory tests*e 
X 
X 
X 
X 
X 
X 
X 
PSA 
X 
X 
 
 
X 
X 
X 
Abdominopelvic CT/MRI and bone 
scintigraphy (every 3 months)  
X *f 
 
 
 
X 
 
X 
Chest CT 
X *f 
 
 
 
 X *g 
 
X 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
FACT–P 
 
X 
 
 
X 
 
 
EQ-5D-5L 
 
X 
 
 
X 
 
 
Brief Pain Inventory-Short Form  
(BPI-SF)*h 
X 
X 
 
 
X 
 
 
Brief Fatigue Inventory (BFI)  
X 
X 
 
 
X 
 
 
Adverse event survey*i 
 
X 
X 
X 
X 
X 
X 
Survey on previous/concomitant 
medication  
X 
X 
X 
X 
X 
X 
X 
Study drug prescription (every month)  
 
X 
X 
X 
X 
X 
 
CT: Computed Tomography, ECOG: Eastern Cooperative Oncology Group, FACT–P: Functional Assessment of Cancer Therapy–Prostate 
 
*a: Unscheduled visit may be made whenever adverse events should be assessed, or PSA progression and disease progression should be confirmed. Laboratory 
tests, PSA measurement, and diagnostic imaging will be performed when assessment is required.  
*b: Informed consent will be obtained within 42 days before enrollment (Day 1) and before initiating the scheduled study procedures.  
*c: Randomization should be performed on Day 1 after the confirmation of eligibility.  


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*d: Measure vital signs (blood pressure and pulse rate) at each visit.  
*e: Laboratory tests include hematology, biochemistry, blood glucose test, and urinalysis.  
*f: Imaging diagnosis performed before informed consent and within 42 days before randomization can be used as baseline data.  
*g: Not required if no chest metastasis is identified in the screening chest CT.  
*h: Instruct subjects to assess prostate cancer-related pains.  
*i: 
Collect all adverse events in the period from the start of study treatment to the date of safety follow-up visit.  


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2nd line AAT 
 
2nd line AAT 
 
Unscheduled*1 
At the end or 
discontinuation*2 
Safety 
follow-up 
Visit Days  
1 
29 
57 
85 and every 
subsequent 84 days  
113 and every 
subsequent 28 
days  
– 
– 
– 
Visit Weeks  
1 
5 
9 
13 and every 
subsequent 12 
weeks  
17 and every 
subsequent 4 
weeks  
– 
Final treatment 
28 days after 
final 
treatment*3 
Allowed visit window (days) 
– 
± 7 
± 7 
± 7 
± 7 
– 
Within 7 days 
after final 
treatment*11 
± 7 
Enrollment 
X 
 
 
 
 
 
X 
 
Vital signs*4 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory tests *5 
X 
X 
X 
X 
X 
X 
X 
X 
PSA 
X 
 
 
X 
X 
X 
X 
X 
Abdominopelvic CT/MRI and bone 
scintigraphy (every 3 months)  
 
 
 
X *6 
 
X 
X *12 
 
Chest CT 
 
 
 
X *6,7 
 
X 
X *12 
 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
FACT–P 
 
X *8 
 
 
X *8 
 
 
X *12 
 
EQ-5D-5L 
 
X *8 
 
 
X *8 
 
 
X *12 
 
Brief Pain Inventory-Short Form 
(BPI-SF) *9 
 
X *8 
 
 
X *8 
 
 
X *12 
 
Brief Fatigue Inventory (BFI)  
 
X *8 
 
 
X *8 
 
 
X *12 
 
Adverse event survey*10 
X 
X 
X 
X 
X 
X 
X 
X 
Previous/concomitant medication  
X 
X 
X 
X 
X 
X 
X 
X 
Study drug prescription (every month)  
X 
X 
X 
X 
X 
 
 
 
CT: Computed Tomography, ECOG: Eastern Cooperative Oncology Group, FACT–P: Functional Assessment of Cancer Therapy–Prostate 
 
*1: Unscheduled visit may be made during the study period whenever adverse events should be assessed, or PSA progression and disease progression should be 
confirmed. Laboratory tests, PSA measurement, and diagnostic imaging will be performed when assessment is required. If the study is discontinued at an 
unscheduled visit, perform laboratory tests, PSA measurement, and diagnostic imaging wherever possible.  
*2: For subjects who finished or discontinued the study with the 1st line AAT or 2nd line AAT, immediately perform examination/observation wherever 
possible.  


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*3: Conduct a visit for safety follow-up 28 days after the final study treatment, or before start of cytocidal chemotherapy, or before start of other new treatment 
for prostate cancer, whichever comes first.  
*4: Measure vital signs (blood pressure and pulse rate) at each visit.  
*5: Laboratory tests include hematology, biochemistry, blood glucose test, and urinalysis.  
*6: Perform diagnostic imaging every 12 weeks after Day 1 of 1st line AAT, independently from switching medications.  
*7: Not required if no chest metastasis is identified in screening chest CT.  
*8: Start the evaluation after switching the drugs on Day 1 of 2nd line AAT, and implement every subsequent 12 weeks.  
*9: Instruct subjects to assess prostate cancer-related pains.  
*10: Collect all adverse events until the date of safety follow-up visit. If there is no safety follow-up visit, collect adverse events until 28 days after the final study 
treatment. If subjects do not show up on the safety follow-up visit, confirm adverse events by the telephone wherever possible.  
*11: For subjects who discontinued the study treatment after the treatment interruption due to adverse events, adopt data within 7 days after the final study 
treatment as discontinuation data. If no data is available in the period within 7 days after the final study treatment, perform a discontinuation 
examination/observation immediately after the decision of discontinuation.  
*12: Not required if it occurs within 28 days from the latest measurement. 
 
 


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VI. 
ACCEPTABLE RANGE OF SCHEDULE OF ASSESSMENTS  
The acceptable time ranges of the examinations, observations, etc. specified in the schedule 
are as follows.  
[Acceptable Time Ranges of Efficacy Tests] 
(1) PSA 
1st line AAT 
Study Visit 
Reference Date 
Acceptable Range 
Screening visit 
−28 days to −7 days 
28 days to 7 days before 
randomization 
Week 1 (Day 1) 
1 
- 
Week 13 (Day 85) 
85 
Reference date ± 7 days 
Week 17 (Day 113) 
113 
Reference date ± 7 days 
Every subsequent 4 weeks 
Every subsequent 28 
days 
Reference date ± 7 days 
2nd line AAT 
Study Visit 
Reference Date 
Acceptable Range 
Week 1 (Day 1) 
1 
- 
Week 13 (Day 85) 
85 
Reference date ± 7 days 
Week 17 (Day 113) 
113 
Reference date ± 7 days 
Every subsequent 4 weeks 
Every subsequent 28 
days 
Reference date ± 7 days 
At completion or 
discontinuation 
Final study treatment 
Reference date + 7 days 
Safety follow-up 
Final study treatment 
+ 28 days 
Reference date ± 7 days 
 
(2) Abdominopelvic CT/MRI, Bone scintigraphy, Chest CT 
Study Visit 
Reference Date 
Acceptable Range 
Screening visit*1 
−28 days to −7 days 
28 days to 7 days before 
randomization 
Week 13 (Day 85) 
85 
Reference date ± 14 days 
Every subsequent 12 
weeks*2 
Every subsequent 84 
days 
Reference date ± 14 days 
At completion or 
discontinuation*3 
Final study treatment 
Reference date + 14 days 
*1: Images taken within 42 days before randomization as part of daily consultation before informed consent 
may be used as data in the screening period.  
*2: Perform every 12 weeks, irrespective of switching medications.  
*3: Not required if it occurs within 28 days from the latest measurement. 


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(3) FACT–P*1, EQ-5D-5L*1, BPI-SF, BFI 
1st line AAT 
Study Visit 
Reference Date 
Acceptable Range 
Screening visit 
−28 days to −7 days 
28 days to 7 days before 
randomization 
Week 1 (Day 1) 
1 
- 
Week 13 (Day 85) 
85 
78 days to 92 days 
Every subsequent 12 
weeks 
Every subsequent 84 
days 
Reference date ± 7 days 
2nd line AAT 
Study Visit 
Reference Date 
Acceptable Range 
Week 1 (Day 1) 
1 
- 
Week 13 (Day 85) 
85 
78 days to 92 days 
Every subsequent 12 
weeks 
Every subsequent 84 
days 
Reference date ± 7 days 
At completion or 
discontinuation*2 
Final study treatment 
Reference date + 7 days 
*1: Do not perform on screening visit. 
*2: Not required if it occurs within 28 days from the latest measurement. 
 
[Acceptable Time Ranges of Safety Tests] 
Laboratory test (biochemistry, hematology, and urinalysis), Vital signs (blood pressure and 
pulse rate), ECOG Performance Status 


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1st line AAT 
Study Visit 
Reference Date 
Acceptable Range 
Screening visit 
−28 days to −7 days 
28 days to 7 days before 
randomization 
Week 1 (Day 1) 
1 
- 
Week 5 (Day 29) 
29 
Reference date ± 7 days 
Week 9 (Day 57) 
57 
Reference date ± 7 days 
Week 13 (Day 85) 
85 
Reference date ± 7 days 
Every subsequent 4 weeks 
Every subsequent 28 
days 
Reference date ± 7 days 
2nd line AAT 
Study Visit 
Reference Date 
Acceptable Range 
Week 1 (Day 1) 
1 
- 
Week 5 (Day 29) 
29 
Reference date ± 7 days 
Week 9 (Day 57) 
57 
Reference date ± 7 days 
Week 13 (Day 85) 
85 
Reference date ± 7 days 
Every subsequent 4 weeks 
Every subsequent 28 
days 
Reference date ± 7 days 
At completion or 
discontinuation 
Final study treatment 
Reference date + 7 days 
Safety follow-up 
Final study treatment 
+ 28 days 
Reference date ± 7 days 
 
 


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1 
INTRODUCTION 
1.1 
Background 
Worldwide, prostate cancer ranks second in cancer incidence (2012) [Torre et al., 2015], and 
ranks second in Japan as well (2011) [Matsuda et al., 2013]. In 2020, prostate cancer is 
expected to be at the top in male cancer incidence [Sobue et al., 2012].  
Since prostate cancer exhibits androgen-dependent growth, androgen deprivation therapy 
(ADT) by surgical or chemical castration is widely conducted, and is positioned as a main 
therapy for prostate cancer. GnRH agonists/antagonists monotherapy or combined androgen 
blockade (CAB) therapy with concurrent anti-androgenic agents is the main stream androgen 
deprivation drug therapy in Japan [Japanese Urological Association, 2012].  
Castration-resistant prostate cancer (CRPC) is prostate cancer that progresses under 
endocrinotherapy with ADT. In an early ADT, serum prostate-specific antigen (PSA) level 
decreases and tumor partially regresses in most patients. Even during the resting period, 
tumor does not grow, and serum PSA remains low. However, some patients exhibit increased 
serum PSA and the course of radiographic disease progression in spite of the serum 
testosterone in the castration level. These patients are considered as castration-resistant. 
However, clinical researches and studies on the molecular profile of such progressive tumor 
demonstrate that the function of androgen receptor (AR) is maintained in CRPC, and tumor 
responds to treatment to lower the function of AR, such as blocking androgens and changing 
anti-androgenic agents. As a secondary endocrinotherapy, treatment can be selected from 
alternative antiandrogen therapy (AAT), estrogen therapy, corticosteroid therapy, and CYP17 
inhibitors. Chemotherapy is selected for metastatic CRPC resistant to existing 
endocrinotherapy.  
Enzalutamide is an anti-androgenic agent that inhibits AR signaling, and was jointly 
developed by Astellas Pharma Inc. and Medivation Inc. A clinical trial on enzalutamide 
targeting CRPC started in 2010 in Japan. In March 2014, marketing approval was obtained as 
the product name Xtandi® with an indication for castration-resistant prostate cancer.  
In order to further investigate combination therapy of ADT and anti-androgenic agents for 
CRPC, a post-marketing clinical study is to be conducted to compare the efficacy and safety 
of enzalutamide + ADT and flutamide + ADT. The order of treatment in AAT will also be 
investigated by switching the drugs for 1st line treatment after progression of PSA.  
 
1.2 
Non-clinical and Clinical Data 
1.2.1 
Non-clinical Studies 
In pharmacodynamic studies, enzalutamide exhibits inhibition of androgen binding to AR, 
inhibition of AR nuclear translocation, inhibition of AR binding to DNA, inhibition of AR-
dependent transcription, inhibition of cancer cell proliferation, induction of cell death, and 
tumor regression. Although enzalutamide is an AR inhibitor, it affects multiple steps in the 


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AR signaling pathway in the setting of AR overexpression, and is different from other 
anti-androgenic agents.  
A major human metabolite of enzalutamide, N-desmethyl enzalutamide, demonstrated 
pharmacological activity consistent with that demonstrated by enzalutamide. Enzalutamide 
and N-desmethyl enzalutamide bind to and antagonize the gamma amino butyric acid 
(GABA)-gated chloride channel. Enzalutamide given at high doses to mice induced dose-
dependent convulsions, an observation that parallels the clinical data showing that dose 
appears to be an important predictor of the risk of seizure in subjects. As some molecules that 
antagonize the GABA-gated chloride channel are associated with convulsions, enzalutamide 
and N-desmethyl enzalutamide may both contribute to the convulsions that were observed in 
non-clinical studies. Safety pharmacology studies evaluating the central nervous, respiratory, 
and cardiovascular systems did not identify any additional acute effects at exposures relevant 
to the human clinical dose of 160 mg/day.  
Following oral administration in animals, enzalutamide is eliminated slowly from plasma 
with a long terminal elimination half-life (t1/2) across species. In vitro studies showed that 
enzalutamide is metabolized by human recombinant cytochrome P450 (CYP) isoenzymes 
CYP2C8 and CYP3A4/5. Enzalutamide and/or its major human metabolites caused direct in 
vitro inhibition of multiple CYP enzymes including CYP2B6, CYP2C8, CYP2C9, CYP2C19, 
CYP2D6, and CYP3A4/5. In vitro, enzalutamide caused time-dependent inhibition of 
CYP1A2. Based on in vitro data, enzalutamide is an inducer of CYP3A4 but does not have a 
clinically problematic impact on CYP1A2.  
In vitro data show that enzalutamide and its active metabolite N-desmethyl enzalutamide are 
not substrates of the efflux transporter P-glycoprotein (P-gp), but are potential inhibitors.  
Overall, enzalutamide was generally well tolerated in non-clinical species with the most 
prominent effects occurring in reproductive and hormone-sensitive organs. In studies in rats 
(4 and 26 weeks) and dogs (4, 13, and 39 weeks), changes in the reproductive organs 
associated with enzalutamide were decreases in the organ weight with atrophy of the prostate 
and epididymis. Additional changes related to reproductive and hormone-sensitive organs 
included hypertrophy/hyperplasia of the pituitary gland and atrophy in seminal vesicles in 
rats and testicular hypospermia, seminiferous tubule degeneration, and 
hypertrophy/hyperplasia of the Leydig cells in dogs. Sex differences were noted in rat 
mammary glands (i.e., male atrophy and female lobular hyperplasia). Changes in the 
reproductive organs in both species were consistent with the pharmacological activity of 
enzalutamide and reversed or partially resolved after an 8-week recovery period. There were 
no other important changes in clinical pathology or histopathology in any other organ system, 
including the liver in either species.  
Electrocardiogram (ECG) and cardiovascular assessments in a toxicity study in dogs showed 
no enzalutamide-related effects. In vivo and in vitro safety pharmacology studies also 
demonstrated the absence of cardiovascular enzalutamide-related effects.  
Enzalutamide was non-mutagenic in bacteria and non-clastogenic in mammalian cells.  


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Enzalutamide was non-genotoxic in vivo in mice. The 2 major human metabolites (N-
desmethyl enzalutamide and an inactive carboxylic acid derivative) were negative for 
mutagenicity in the bacterial reverse mutation assay.  
 
1.2.2 
Clinical Data 
1.2.2.1 Phase 1/2 Study in Japan [9785-CL-0111] 
In phase 2 part, enzalutamide 160 mg/day was continuously administered to 38 patients with 
castration-resistant prostate cancer who had previously been treated with docetaxel. 
Radiographic response rate by Day 85, primary endpoint, was 5.3% (2/38 subjects, 90% CI: 
0.9% to 15.7%), and the lower limit of 90% CI was lower than the threshold response rate 
(5%). PSA response rate (the proportion of patients whose lowest PSA decreased by at least 
50% from baseline) was 28.9% (11/38 subjects, 90% CI: 17.2% to 43.3%).  
In phase 2 part, adverse reactions were observed in 63.2% (24/38 subjects). Most commonly 
reported adverse reactions included constipation (15.8%), electrocardiogram QT prolonged 
and weight decreased (13.2% respectively), fatigue, decreased appetite, and hypertension 
(10.5% respectively). Fourteen serious adverse reactions were observed in 4 subjects (10.5%), 
including fall, gait disturbance, dehydration, hypotension, acute respiratory distress syndrome, 
pulmonary oedema, anaemia, disseminated intravascular coagulation, acute renal failure, 
cellulitis, tumour pain, haematuria, urinary retention, and bladder tamponade.  
 
1.2.2.2 Overseas Phase 3 Study [CRPC2] 
With placebo as control, enzalutamide 160 mg/day was continuously administered to 800 
patients with castration-resistant prostate cancer who had previously been treated with 
docetaxel. For patients who had not undergone bilateral orchiectomy, concurrent castration 
treatment with GnRH agonists/antagonists was required.  
In the result of interim analysis (at the time when 520 events occurred, of the targeted 650 
events), the median overall survival (OS), which is the primary endpoint, was 18.4 months in 
enzalutamide group, and 13.6 months in placebo group. The OS of enzalutamide group was 
significantly longer than that of placebo group (hazard ratio: 0.631, 95% CI: 0.529 to 0.752, 
P value < 0.0001, stratified log-rank test).  
Adverse reactions were observed in 69.3% (554/800 subjects) of enzalutamide group, and 
66.7% (266/399 subjects) of placebo group. The most commonly reported adverse reactions 
in enzalutamide group included fatigue (21.5%), nausea (20.1%), and hot flush (15.0%).  
Serious adverse events (SAEs) were observed in 268 subjects (33.5%) of enzalutamide group, 
and 154 subjects (38.6%) of placebo group. The most commonly reported SAEs in 
enzalutamide group included spinal cord compression (6.0%), anaemia (2.6%), and general 
physical health deterioration (2.1%). Seizure-related SAEs were observed in 6 subjects 


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(seizure in 2 subjects, partial seizures in 2 subjects, status epilepticus in 1 subject, syncope in 
1 subject) in enzalutamide group, but were not observed in placebo group.  
 
1.2.2.3 Global Phase 3 Study [9785-CL-0231] 
With placebo as control, enzalutamide 160 mg/day was continuously administered to 871 
patients with asymptomatic castration-resistant prostate cancer or castration-resistant prostate 
cancer with mild symptoms who are chemotherapy-naive (872 subjects including 28 
Japanese were randomized). For patients who had not undergone bilateral orchiectomy, 
concurrent castration treatment with GnRH agonists/antagonists was required.  
In the result of interim analysis (at the time when 540 events occurred, of the targeted 765 
events), the median OS, one of 2 primary endpoints, was 32.4 months in enzalutamide group, 
and 30.2 months in placebo group. The OS in enzalutamide group was significantly longer 
than that in placebo group (hazard ratio: 0.706, 95% CI: 0.596 to 0.837, P value < 0.0001, 
non-stratified log-rank test). Radiographic progression-free survival (rPFS), the other primary 
endpoint, was defined as the period from randomization to the first radiographic evidence of 
disease progression, or to death within 168 days after treatment discontinuation irrespective 
of the cause, whichever occurred earlier. In 1633 subjects registered before the cut-off date, 
rPFS events judged by the central review facility as of the data cut-off were a total of 439 
events: 118 events (14.2%) in enzalutamide group, and 321 events (40.1%) in placebo group. 
The risk of rPFS or death was statistically significantly lower in enzalutamide group than in 
placebo group (hazard ratio: 0.186, 95% CI: 0.149 to 0.231, P value < 0.0001, non-stratified 
log-rank test). The median duration of rPFS was 3.9 months in placebo group while the 
number of events was not enough to estimate the median in enzalutamide group.  
The incidence of adverse reactions was higher in enzalutamide group at 65.0% than in 
placebo group at 49.9%. In enzalutamide group, adverse reactions with incidence ≥10% were 
nausea (13.3%), fatigue (25.3%), and hot flush (13.4%). The incidence of adverse reactions 
in Japanese patients was 46.4% in enzalutamide group, and 33.3% in placebo group. The 
incidence of adverse reactions in non-Japanese patients was 65.6% in enzalutamide group, 
and 50.6% in placebo group.  
The incidence of SAEs was 32.0% (279/871 subjects) in enzalutamide group, and 26.8% 
(226/844 subjects) in placebo group. In enzalutamide group, SAEs with incidence ≥1% were 
anaemia (1.6%), general physical health deterioration (1.6%), pneumonia (1.1%), 
pathological fracture (1.1%), metastatic pain (2.0%), spinal cord compression (3.2%), and 
urinary retention (1.1%).  
Seizure is the clinically most important adverse event (AE) reported on enzalutamide. In 
enzalutamide group in this study, seizure was observed in only 1 subject (0.1%) after data 
cut-off. In placebo group, seizure was observed in 1 subject (0.1%) before data cut-off.  
 


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1.3 
Summary of Key Safety Information for Study Drugs 
See package inserts of enzalutamide and flutamide.  
 
1.4 
Risk-Benefit Assessment 
1.4.1 
Risk Expected from Enzalutamide 
The following information on adverse reactions is an excerpt from the package insert of 
Xtandi® Capsules 40 mg (version 6, revised in November 2015).  
[Clinical study in Japan] 
In the phase 1/2 study in Japan in patients with castration-resistant prostate cancer, adverse 
reactions were observed in 31 subjects (66.0%) of 47 subjects who received enzalutamide. 
Most commonly reported adverse reactions included hypertension (14.9%), constipation 
(14.9%), fatigue (12.8%), decreased appetite (12.8%), weight decreased (10.6%), and 
electrocardiogram QT prolonged (10.6%). (At approval: March 2014) 
[Overseas clinical study] 
In the overseas phase 3 study in patients with castration-resistant prostate cancer who had 
previously been treated with docetaxel, adverse reactions were observed in 554 subjects 
(69.3%) of 800 subjects who received enzalutamide. Most commonly reported adverse 
reactions included fatigue (21.5%), nausea (20.1%), hot flush (15.0%), decreased appetite 
(12.6%), and asthenia (10.0%). (At approval: March 2014) 
[Global clinical study] 
In the global phase 3 study in chemotherapy-naive patients with castration-resistant prostate 
cancer, adverse reactions were observed in 566 subjects (65.0%) of 871 subjects (including 
28 Japanese subjects) who received enzalutamide. Most commonly reported adverse 
reactions included fatigue (25.3%), hot flush (13.4%), and nausea (13.3%). (At revision of 
Precautions for Indications: October 2014) 
The incidence of the following adverse reactions are calculated based on the patients who 
received enzalutamide in the phase 1/2 study in Japan, overseas phase 3 study, and global 
phase 3 study.  
(1) Significant adverse reactions 
1) Seizure (0.2%): Seizure such as convulsion, status epilepticus may occur. Patients 
should be carefully monitored, and if any abnormalities are observed, administration 
should be discontinued and appropriate measures should be taken. 
2) Platelets decreased (incidence unknown): Platelets decreased may occur. Patients 
should be carefully monitored, and if any abnormalities are observed, appropriate 
measures, such as discontinuing administration, should be taken.  


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(2) Other adverse reactions 
 
≥5% 
1% to 5% 
<1% 
Incidence 
unknown  
Blood 
 
Anaemia 
Haemoglobin 
decreased, 
leukopenia, 
neutropenia 
 
Heart 
 
 
Electrocardiogram 
QT prolonged 
 
Kidney 
 
 
Pollakiuria 
 
Ear 
 
 
Vertigo 
 
Eye 
 
 
Lacrimation 
increased 
 
Digestive organ 
Nausea, 
diarrhoea, 
constipation 
Vomiting, 
abdominal 
distension, 
abdominal pain 
upper, 
dyspepsia, 
flatulence 
Dry mouth, 
abdominal pain, 
gastritis, stomatitis, 
abdominal 
discomfort, 
gastrooesophageal 
reflux disease 
 
General and  
administration 
site 
Fatigue, 
asthenia 
Oedema 
peripheral, 
weight decreased 
Pain, chills, malaise, 
weight increased 
 
Liver 
 
 
 
Hepatic 
function 
abnormal 
Metabolism 
 
Decreased 
appetite 
 
Hypokalaemia, 
dehydration 
 
Musculoskeletal 
system 
 
Arthralgia, 
myalgia, back 
pain, muscular 
weakness, pain 
in extremity 
Musculoskeletal 
pain, muscle spasms, 
musculoskeletal 
stiffness 
 
Nervous system 
 
Headache, 
dizziness, 
dysgeusia, 
paraesthesia, 
lethargy 
Hypoaesthesia, 
memory impairment, 
somnolence, restless 
legs syndrome, 
neuropathy 
peripheral, cognitive 
disorder, disturbance 
in attention, syncope, 
amnesia 
 
Psychiatric 
 
Insomnia 
Anxiety, depression, 
confusional state, 
hallucination 
 


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≥5% 
1% to 5% 
<1% 
Incidence 
unknown  
Reproductive 
system and  
breast 
 
Gynaecomastia 
 
 
Respiratory 
organ 
 
Dyspnoea 
Cough, epistaxis 
 
Skin 
 
Dry skin, rash, 
hyperhidrosis 
Pruritus, night 
sweats, alopecia, 
erythema, rash 
maculo-papular 
 
Blood vessel 
Hot flush 
Hypertension, 
flushing 
 
 
Other 
 
 
Fall, spinal 
compression 
fracture, fracture 
(except for 
pathological fracture) 
 
The incidences of the adverse reactions above are calculated based on the updated data from 
the phase 1/2 study in Japan (47 subjects) and overseas phase 3 study (850 subjects), and the 
global phase 3 study (871 subjects).  
 
1.4.2 
Risks Expected from Flutamide 
The following information on adverse reactions is an excerpt from the package insert of 
Odyne® Tab. 125 mg (version 16, revised in August 2014).  
In the 6393 subjects in total (201 subjects at approval, 6192 subjects in post-marketing 
survey), the incidence of adverse reactions and abnormal laboratory test values was 29.0%. 
The most common adverse reactions included gynaecomastia (2.9%), inappetence (2.0%), 
diarrhoea (1.7%), nausea/vomiting (1.1%), AST increased (13.2%), ALT increased (13.2%), 
γ-GTP increased (5.9%), LDH increased (3.8%), ALP increased (3.1%), erythrocytes 
decreased (1.8%), haemoglobin decreased (1.5%), and haematocrit value decreased (1.5%). 
(At the end of re-examination) 
(1) Significant adverse reactions 
1) Serious liver disorder (0.5%): Hepatitis fulminant or other serious liver disorder 
(initial symptoms: inappetence, nausea/vomiting, general malaise, itching, rash, 
jaundice, etc.) may occur. Patients should be carefully monitored by regularly testing 
liver function (at least once a month). If any abnormalities are observed, 
administration should be discontinued and appropriate measures should be taken.  
2) Interstitial pneumonia (<0.1%): Interstitial pneumonia associated with such as pyrexia, 
cough, dyspnoea, chest X-ray abnormal, and eosinophilia may occur. Patients should 
be carefully monitored, and if any abnormalities are observed, administration should 


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be discontinued and appropriate measures, such as administration of corticosteroid, 
should be taken.  
3) Cardiac failure, myocardial infarction (incidence unknown): Cardiac failure and 
myocardial infarction may occur. Patients should be carefully monitored, and if any 
abnormalities are observed, appropriate measures, such as discontinuing 
administration, should be taken.  
(2) Other adverse reactions 
 
≥1% 
<1% 
Liver 
AST increased, ALT increased, γ-
GTP increased, LDH increased, 
ALP increased 
Bilirubin increased 
Endocrine 
Gynaecomastia 
Sexual desire decreased 
Digestive organ 
Nausea/vomiting, inappetence, 
diarrhoea 
Heartburn, gastralgia, stomach 
discomfort, thirst 
Blood 
anaemia 
White blood cell decreased, 
platelets decreased 
Kidney 
 
Creatinine increased, BUN 
increased, urinary protein positive 
Psychoneurotic 
system 
 
Dizziness, wobble, dizziness on 
standing up, headache, feelings of 
weakness, somnolence, 
sleeplessness, bewilderment, 
depressed state, feeling anxious, 
nervousness 
Hypersensitivity  
Rash, photosensitivity 
Skin 
 
Itching 
Other 
 
Oedema, general malaise, pyrexia, 
flushing, sweaty, taste 
disturbance, sugar blood level 
increased, urine sugar positive, 
serum total protein decreased 
 
1.4.3 
Expected Benefit 
Combination therapy of enzalutamide + ADT or combination therapy of flutamide + ADT 
may decrease PSA and improve symptoms.  
 
 


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2 
STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS 
2.1 
Study Objectives 
2.1.1 
Primary Objective 
● 
To determine the benefit of enzalutamide + ADT therapy as compared to flutamide + 
ADT therapy as assessed by time to PSA progression with 1st line AAT (time to PSA 
progression 1 [TTPP1]).  
 
2.1.2 
Secondary Objectives 
● 
To determine the order of AAT treatment as assessed by time to PSA progression with 
1st line AAT + 2nd line AAT (time to PSA progression 2 [TTPP2]).  
● 
To determine the benefit of enzalutamide + ADT therapy as compared to flutamide + 
ADT therapy as assessed by PSA response rate to 1st line AAT (proportion of subjects 
with a decrease by at least 50% or 90% from baseline irrespective of the timing).  
● 
To determine the benefit of enzalutamide + ADT therapy as compared to flutamide + 
ADT therapy as assessed by PSA response rate to 1st line AAT at Week 13 (proportion 
of subjects with a decrease by at least 50% or 90% from baseline).  
● 
To determine the benefit of enzalutamide + ADT therapy as compared to flutamide + 
ADT therapy as assessed by time to PSA decrease by 50% from baseline with 1st line 
AAT.  
● 
To determine the benefit of enzalutamide + ADT therapy as compared to flutamide + 
ADT therapy as assessed by time to treatment failure of 1st line AAT (time to treatment 
failure 1 [TTF1]).  
● 
To determine the order of AAT treatment as assessed by time to treatment failure of 2nd 
line AAT (time to treatment failure 2 [TTF2]).  
● 
To determine the benefit of enzalutamide + ADT therapy as compared to flutamide + 
ADT therapy as assessed by rPFS.  
 
2.1.3 
Safety Objective 
● 
To determine the safety of enzalutamide + ADT therapy as compared to flutamide + ADT 
therapy.  
 
2.1.4 
Exploratory Objectives 
● 
To evaluate time to PSA progression with 2nd line AAT (2nd time to PSA progression 
[2nd TTPP]).  
● 
To evaluate PSA response rate to 2nd line AAT.  
● 
To determine the benefit of enzalutamide + ADT therapy as compared to flutamide + 
ADT therapy as assessed by metastasis-free survival (MFS).  


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● 
To evaluate Quality of Life (QOL) on 1st line AAT and 2nd line AAT using Functional 
Assessment of Cancer Therapy–Prostate (FACT–P) and European Quality of Life 5-
Dimension-5 Level instruments (EQ-5D-5L). 
● 
To evaluate Brief Pain Inventory-Short Form (BPI-SF) with 1st line AAT and 2nd line 
AAT.  
● 
To evaluate Brief Fatigue Inventory (BFI) with 1st line AAT and 2nd line AAT.  
● 
To determine the benefit of enzalutamide + ADT therapy as compared to flutamide + 
ADT therapy as assessed by objective response rate (ORR) in soft tissue with 1st line 
AAT based on the best overall response in RECIST guidelines.  
● 
To evaluate the efficacy in subgroups according to disease-related patient demographics.  
 
2.2 
Study Design and Dose Rationale 
2.2.1 
Study Design 
This is a randomized, open-label, comparative study on enzalutamide and flutamide.  
Patients with M0 or M1 castration-resistant prostatic neoplasm that relapsed during CAB 
therapy with bicalutamide will be randomized to Group A or B. Dynamic allocation will be 
performed with minimization with biased coin technique. The following stages (M0/N0, 
M0/N1, or M1) will be used as allocation factors.  
● 
M0/N0: No distant metastasis, and no lymph node metastasis 
● 
M0/N1: Without distant metastasis, but with metastasis in lymph nodes distal to the 
aortic bifurcation 
● 
M1: With distant metastasis (including metastasis in lymph nodes proximal to the 
aortic bifurcation)  
For subjects in Group A, enzalutamide is administered as the 1st line AAT. After the 
confirmation of PSA progression, medication is changed from enzalutamide to flutamide as 
the 2nd line AAT. For subjects in Group B, flutamide is administered as the 1st line AAT. 
After the confirmation of PSA progression, medication is changed from flutamide to 
enzalutamide as the 2nd line AAT. The treatment period with each drug should not be more 
than 2 years from the enrollment of the last subjects.  
PSA progression will be defined according to the consensus guidelines of PCWG2. For 
patients with PSA declines at Week 13, the PSA progression date is defined as the date that a 
≥ 25% increase and an absolute increase of ≥ 2 ng/mL above the nadir is documented, which 
is confirmed by a second consecutive value obtained 3 or more weeks later. For patients with 
no PSA decline at Week 13, the PSA progression date is defined as the date that a ≥ 25% 
increase and an absolute increase of ≥ 2 ng/mL above the baseline is documented.  
Data for the analysis of primary endpoint TTPP1 will be cut-off if not less than 135 events of 
PSA progression occurred in association with the 1st line AAT.  
After the discontinuation of the 1st line AAT due to PSA progression or other reasons, the 
2nd line AAT will be started. Subjects who discontinued the 1st line AAT due to PSA 


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progression will start the 2nd line AAT within 6 weeks after the date of examination that 
identified PSA progression. Subjects who discontinued the 1st line AAT due to other reasons 
will start the 2nd line AAT within 6 weeks from the day when the investigator or sub-
investigator decided the discontinuation.  
A safety follow-up visit should be performed wherever possible in 28 days from the final 
study treatment, or before starting other study drugs, or before starting other treatment for 
prostate cancer, whichever comes first. If subjects do not show up on the safety follow-up 
visit, confirm AEs by the telephone wherever possible. 
 
2.2.2 
Dose Rationale 
This study targets adult patients with castration-resistant prostate cancer. As instructed on the 
package insert, enzalutamide 160 mg is to be administered orally once daily, and flutamide 
125 mg is to be administered orally thrice daily after meals.  
 
2.3 
Endpoints 
2.3.1 
Primary Endpoint 
● 
Time to PSA progression with 1st line AAT (TTPP1) 
 
2.3.2 
Secondary Endpoints 
● 
Time to PSA progression with 1st line AAT + 2nd line AAT (TTPP2) 
● 
PSA response rate to 1st line AAT (decrease by at least 50% or 90% from baseline) 
● 
PSA response rate to 1st line AAT at Week 13 (decrease by at least 50% or 90% from 
baseline) 
● 
Time to PSA decrease by 50% from baseline with 1st line AAT 
● 
Time to treatment failure of 1st line AAT (TTF1) 
● 
Time to treatment failure of 2nd line AAT (TTF2) 
● 
rPFS 
 
2.3.3 
Safety Endpoints 
● 
Characteristics, frequency, and severity of AEs 
● 
Safety-related laboratory tests (biochemistry and hematology) 
● 
Vital signs (blood pressure and pulse rate) 
● 
ECOG Performance Status 
 
2.3.4 
Exploratory Endpoints 
● 
Time to PSA progression with 2nd line AAT (2nd TTPP)  
● 
PSA response rate to 2nd line AAT (decrease by at least 50% or 90% from baseline)  


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● 
MFS  
● 
QOL assessment with 1st line AAT and 2nd line AAT by FACT–P) and EQ-5D-5L 
● 
BPI-SF with 1st line AAT and 2nd line AAT 
● 
BFI with 1st line AAT and 2nd line AAT 
● 
ORR in best overall soft tissue response of RECIST guidelines with 1st line AAT 
● 
Efficacy assessment by subgroups according to disease-related patient demographics 
 
3 
STUDY POPULATION 
3.1 
Selection of Study Population 
Patients with castration-resistant prostate cancer that relapsed during CAB therapy with 
bicalutamide.  
 
3.2 
Inclusion Criteria 
Subject is eligible for the study if all of the following apply:  
1. Subject must have submitted an informed consent form approved by the institutional 
review board (IRB) established at each study center prior to the study.  
2. Age ≥20 years at the time of signing the informed consent form.  
3. Subject is diagnosed with histologically or cytologically confirmed adenocarcinoma of 
the prostate without neuroendocrine differentiation or small-cell histology.  
4. Subject on continuous ADT with GnRH agonist/antagonist or bilateral orchiectomy 
(surgical or chemical castration).  
5. Subject for whom treatment with effective GnRH agonist/antagonist is to be continued 
during the study period if bilateral orchiectomy is not performed.  
6. Serum testosterone level ≤1.73 nmol/L (50 ng/dL or 0.5 ng/mL) at screening visit.  
7. Subject with no change in the dose of bisphosphonate preparation or denosumab for at 
least 4 weeks if these drugs are used.  
8. Subject with asymptomatic or mildly symptomatic prostate cancer (BFI-SF score is <4 to 
Question 3 “the worst pain within 24 hours”).  
9. Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 
1.  
10. Subject has an estimated life expectancy of ≥12 months.  
11. Subject is able to swallow the study drug and, comply with procedures required by the 
study.  
12. Subject has progression of the disease that falls under at least one of the following 3 
criteria during CAB therapy in combination of bicalutamide and ADT. 
● 
PSA increase should be confirmed at least 2 timepoints with an interval of ≥1 week. 
In at least 6 weeks after the last dose of bicalutamide, PSA should be confirmed 
higher than the highest PSA measured after the nadir was confirmed during 
administration of bicalutamide. PSA at screening visit should be ≥2 ng/mL (2 μg/L).  


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● 
Soft tissue disease progression defined by RECIST guidelines (version 1.1).  
● 
Progression of ≥2 bone lesions defined as new lesions in bone scintigraphy by 
PCWG2. 
13. A sexually active male subject and his female partner who is of childbearing potential 
must use 2 acceptable birth control methods shown below (1 of which must include a 
condom as a barrier method of contraception) from screening to 3 months after the last 
dose of the study drug.  
● 
A male or female condom as a barrier method of contraception; 
● 
Consistent and correct usage of established, proper use of oral contraceptives; 
● 
Established intrauterine device or intrauterine system by the female partner;  
● 
Tubal ligation in the female partner performed at least 6 months prior to subject’s 
screening visit; 
● 
Vasectomy or other procedure resulting in infertility (e.g., bilateral orchiectomy) 
performed at least 6 months prior to screening;  
● 
Calendar-based contraceptive methods (Knaus-Ogino or rhythm method). 
14. Subject must use a condom throughout the study if engaging in sexual intercourse with a 
pregnant woman. 
15. Subject must agree not to donate sperm from screening to 3 months after the last dose of 
the study drug.  
16. Subject agrees not to participate in another interventional study while on treatment. 
 
Waivers to the inclusion criteria will NOT be allowed. 
 
3.3 
Exclusion Criteria 
Subject will be excluded from the study if any of the following apply:  
1. Subject with severe concurrent diseases, infections, or complications, which are 
considered inappropriate for enrollment by the investigator or sub-investigator.  
2. Subject with confirmed or suspected brain metastasis or active leptomeningeal metastasis.  
3. Subject with a history of malignant tumor other than prostate cancer in the past 5 years 
(except for non-melanoma skin cancer cured with radical therapy).  
4. Subject hypersensitive to the ingredients of enzalutamide capsules or flutamide tablets.  
5. Subject with a history of seizure, or any condition that may predispose to seizure.  
6. Subject with liver disorder such as viral hepatitis and hepatic cirrhosis, or subject with 
AST and ALT at screening visit higher than the upper limit of normal.  
7. Subject on warfarin. 
8. Subject received treatment for prostate cancer with cytocidal chemotherapy that includes 
anti-androgenic agents other than bicalutamide (e.g., enzalutamide, flutamide), 
abiraterone, or estramustine. 
9. Subject participated in a clinical trial on a drug other than GnRH agonist/antagonist in 
prostate cancer.  


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10. Subject received treatment with herbal medications that may have hormonal anti-prostate 
cancer activity or herbal medications (saw palmetto) that may decrease PSA levels; 
subject received treatment for prostate cancer with systemic corticosteroids, or treatment 
for other diseases with systemic corticosteroids greater than the equivalent of 10 mg per 
day of prednisone (Decadron 1 mg/day) within 4 weeks prior to enrollment (Day 1).  
11. Subject received treatment with bicalutamide within 6 weeks prior to enrollment (Day 1).  
12. Subject received treatment with 5-α reductase inhibitors (finasteride, dutasteride), 
estrogens, or drugs with anti-tumor action other than GnRH agonists/antagonists within 
4 weeks prior to enrollment (Day 1). 
13. Subject received treatment with opioid analgesic for pains associated with prostate 
cancer within 4 weeks prior to enrollment (Day 1).  
14. Subject participated or is currently participating in a clinical trial or a post-marketing 
clinical study on other ethical drugs (excluding GnRH agonist/antagonist) or medical 
devices within 12 weeks or 5 half lives (in case of ethical drugs), whichever is longer, 
prior to screening.  
15. Subject received treatment for primary or metastatic lesion with surgery or radiation 
therapy within 4 weeks prior to enrollment (Day 1).  
16. Subject with unstable psychiatric disease (e.g., schizophrenia, dementia, uncontrollable 
depression/bipolar disorder).  
17. Subject with a disease or reason unsuitable for participation in the study, which is 
considered by the investigator or sub-investigator to cause excessive risk to the subject 
or make the interpretation of safety data difficult.  
 
Waivers to the exclusion criteria will NOT be allowed. 
 
3.4 
Criteria to Shift from 1st Line AAT to 2nd Line AAT 
If any of the following is satisfied, the study drug will be shifted to the 2nd line AAT after 
the discontinuation of the 1st line AAT: 
1. PSA progression 
2. In case where the 1st line AAT is to be discontinued due to AEs, but the investigator or 
sub-investigator considers that there is no problem in the subject tolerance to transition 
to the 2nd line AAT 
3. In case where the 1st line AAT is to be discontinued due to progression of disease other 
than PSA progression, but the investigator or sub-investigator considers that there is no 
problem in the subject tolerance to transition to the 2nd line AAT. 
 
In any of the following cases, study treatment will be discontinued without shifting to the 2nd 
line AAT:  
1. In case of enzalutamide as 2nd line AAT, subjects with seizure as an AE 


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2. In case of flutamide as 2nd line AAT, subjects with the latest AST or ALT exceeding the 
upper limit of normal 
3. Other cases that the investigator or sub-investigator considers unsuitable for study 
continuation 
 
4 
TREATMENT(S) 
4.1 
Identification of Investigational Product(s) 
4.1.1 
Test Drug(s) 
The investigational product (enzalutamide capsule 40 mg) is shown as follows.  
Generic name 
Enzalutamide 
Chemical name 
4-{3-[4 - Cyano - 3- (trifluoromethyl)phenyl]- 5,5 -dimethyl- 4- oxo- 2- 
sulfanylideneimidazolidin- 1- yl}-2-fluoro -N -methylbenzamide 
Molecular formula 
and molecular weight  
C21H16F4N4O2S (molecular weight : 464.44) 
Content and dosage 
form 
Enzalutamide capsule 40 mg:  
One capsule contains 40 mg of enzalutamide. This drug is a white to pale 
yellowish white, oval capsule.  
Size 
Longer diameter: Approx. 21 mm; shorter diameter: Approx. 10 mm 
Lot No. 
Specified by the Procedure for handling study drugs 
Storage 
At room temperature 
Manufacturer 
Astellas Pharma Inc. 
 
4.1.2 
Comparative Drug(s) 
The comparative drug (flutamide tablets 125 mg) is as follows.  
Generic name 
Flutamide 
Chemical name 
2-Methyl-N-[4-nitro-3- (trifluoromethyl)phenyl] propanamide 
Molecular formula 
and molecular weight  
C11H11F3N2O3 (molecular weight : 276.21) 
Content and dosage 
form 
Flutamide tablets 125 mg:  
One tablet contains 125 mg of flutamide. This drug is a round, pale yellow 
tablet.  
Size 
Diameter: Approx. 8.5 mm; thickness: Approx. 4.0 mm 
Lot No. 
Specified by the Procedure for handling study drugs 
Storage 
Shielded from light at room temperature 
Manufacturer 
Nippon Kayaku Co., Ltd. 
 
 
4.2 
Packaging and Labeling 
All medication used in this study will be prepared, packaged, and labeled under the 
responsibility of qualified staff at API or Sponsor’s designee in accordance with API or 


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Sponsor’s designee Standard Operating Procedures (SOPs), Good Manufacturing Practice 
(GMP) guidelines, ICH GCP guidelines, and applicable local laws/regulations. 
 
(1) Packaging 
1) Enzalutamide capsule 40 mg 
A PTP sheet contains 14 capsules of enzalutamide capsule 40 mg. An aluminum 
pillow contains 2 PTP sheets, and 4 aluminum pillows are packed in a small box.  
 
2) Flutamide tablets 125 mg 
A PTP sheet contains 21 tablets of flutamide tablets 125 mg. An aluminum pillow 
contains  PTP sheets, and is packed in a small box.  
 
(2) Labeling 
1) Enzalutamide capsule 40 mg 
 
Lot No. ○○○○○○ 
112 capsules (14 capsules × 8 sheets) 
Enzalutamide post-marketing clinical study 
Enzalutamide capsule 40 mg 
 
Caution: 1. Use the drug for the same intended patient. Do not use for other patients.  
2. Do not dispose the remaining drugs and package. Store them until the Sponsor collects them.  
Storage: At room temperature 
Expiration date: Specified by the Procedure for handling study drugs 
 
Subject ID Code: 
 
Astellas Pharma Inc. 
2-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo 
 
 
 
Lot No. ○○○○○○ 
Enzalutamide post-marketing clinical study 
Enzalutamide capsule 40 mg 
 
 
For post-marketing clinical study 
For post-marketing clinical study 


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2) Flutamide tablets 125 mg 
 
Lot No. ○○○○○○ 
84 tablets (21 tablets × 4 sheets) 
Enzalutamide post-marketing clinical study 
Flutamide tablets 125 mg 
 
Caution: 1. Use the drug for the same intended patient. Do not use for other patients.  
2. Do not dispose the remaining drugs and package. Store them until the Sponsor collects them.  
Storage: Shielded from light at room temperature 
Expiration date: Specified by the Procedure for handling study drugs 
 
 
Subject ID Code: 
 
Astellas Pharma Inc. 
2-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo 
 
3)  
 
Lot No. ○○○○○○ 
Enzalutamide post-marketing clinical study 
Flutamide tablets 125 mg 
 
 
4.3 
Study Drug Handling 
The head of the study site or the study drug storage manager should take accountability of the 
study drugs as following issues. 
● 
The study drug storage manager should store and take accountability of the study drugs 
in conforming to the procedures for handling the study drugs written by the Sponsor. 
● 
The study drug storage manager should prepare and retain records of the study drug’s 
receipt, the inventory at the study site, the use by each subject, and the return to the 
Sponsor or alternative disposal of unused study drugs. These records should include 
dates, quantities, batch/serial numbers, expiration dates (if applicable), and the unique 
code numbers assigned to the study drugs and subjects. 
● 
The study drug storage manager should prepare and retain records that document 
adequately that the subjects were provided the doses specified by the protocol, and 
reconcile all the study drugs supplied from the Sponsor. 
 
4.4 
Blinding 
This section is not applicable as this is an open-label study.  
 
4.5 
Assignment and Allocation 
The subject registration center will perform dynamic allocation with minimization with 
biased coin technique according to the subject registration procedure in the ratio of 1:1 to the 
For post-marketing clinical study 
For post-marketing clinical study 


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initial enzalutamide 160 mg/day group or the initial flutamide 125 mg/day group. The 
facilities and the following stages (M0/N0, M0/N1, or M1) will be used as allocation factors.  
● 
M0/N0: No distant metastasis, and no lymph node metastasis 
● 
M0/N1: Without distant metastasis, but with metastasis in lymph nodes distal to the 
aortic bifurcation 
● 
M1: With distant metastasis (including metastasis in lymph nodes proximal to the 
aortic bifurcation)  
After the investigator or sub-investigator confirmed the eligibility of the subject on Day 1, 
the staff in charge at the study site will register the subject via the Subject Registration 
System, and confirm the study drugs that are randomly allocated.  
 
5 
TREATMENTS AND EVALUATION 
5.1 
Dosing and Administration of Study Drug(s) and Other 
Medication(s) 
5.1.1 
Dose/Dose Regimen and Administration Period 
Enzalutamide capsule 40 mg:  
Orally administer 160 mg (4 capsules) of enzalutamide once daily at the same time every day 
wherever possible. 
 
Flutamide tablets 125 mg:  
Orally administer 125 mg (1 tablet) of flutamide after each meal thrice a day.  
If the subject fails to take the drug, or vomit it immediately after taking it, do not take another 
dose. Restart a dose the following day.  
 
5.1.2 
Increase or Reduction in Dose of the Study Drug(s) 
If an adverse reaction that falls under Grade 3 or higher according to the National Cancer 
Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 
occurred in association with the study drug during the study period, and is not improved by a 
proper medical intervention, stop the treatment for a week or until the severity of the adverse 
reaction improves to Grade 2 or lower. After the improvement, the study drug may be 
restarted at the original or reduced dose at the discretion of the investigator or sub-
investigator.  
If a strong CYP2C8 inhibitor (e.g., gemfibrozil) should be used concurrently with the study 
drug enzalutamide, reduce the dose of enzalutamide to 80 mg once daily. When the CYP2C8 
inhibitor is discontinued, return the dose of enzalutamide to the original dose.  
The study drug cannot be increased.  


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5.1.3 
Previous and Concomitant Treatment (Medication and Non-Medication 
Therapy) 
5.1.3.1 Previous Treatment 
Enter in the electronic Case Report Form (eCRF) medication (previous medication) and non-
medication therapy (prior therapy) that were used until the day before initiating the study 
drug as follows.  
Previous treatment 
Survey period 
Information to be entered in eCRF 
Previous medication 
4 weeks (28 days) before Day 
1 to the day before initial 
study treatment 
Medication name, treatment period, reason 
for use 
Prior therapy 
Therapy name, treatment period, reason for 
treatment 
Radiation therapy for 
prostate cancer 
From diagnosis of prostate 
cancer to the day before initial 
study treatment 
Irradiation site, irradiation dose, treatment 
period, reason for treatment 
Other prior therapies 
that include surgical 
treatment for prostate 
cancer 
Therapy name, treatment period 
Bicalutamide 
Treatment period 
GnRH 
agonists/antagonists 
Medication name, treatment period 
Other previous 
medication for 
prostate cancer 
Medication name, treatment period 
 
5.1.3.2 Concomitant Treatment 
Enter in the eCRF medication (concomitant medication) and non-medication therapy 
(combination therapy) that were used since initiation of the study drug until safety follow-up 
visit as follows.  
Previous treatment 
Survey period 
Information to be entered in eCRF 
Concomitant 
medication 
From initial study treatment to 
safety follow-up visit 
Medication name, treatment period, reason 
for use 
Combination therapy 
Therapy name, treatment period, reason for 
treatment 
 
5.1.3.3 Required Concomitant Medications 
All subjects must undergo continuous ADT with GnRH agonist/antagonist or bilateral 
orchiectomy during the study period. GnRH agonist/antagonist will be prepared and 
administered by the study site. Do not change the medications in principle.  
 


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5.1.3.4 Prohibited Concomitant Treatment (Medication and Non-Medication Therapy) 
The use of the following drugs and therapies are prohibited during the study treatment and in 
the period from the end of the 1st line AAT to the start of the 2nd line AAT:  
● 
Anti-androgenic agents (steroid or non-steroid) other than study drugs such as 
chlormadinone and bicalutamide 
● 
CYP17 inhibitor (abiraterone) 
● 
Cytocidal chemotherapy that includes estramustine 
● 
Systemic corticosteroids for prostate cancer or systemic corticosteroids greater than 
the equivalent of 10 mg per day of prednisone (Decadron 1 mg/day) for other 
diseases 
● 
5-α reductase inhibitors (finasteride, dutasteride) 
● 
Estrogen or progesterone agents such as medroxyprogesterone and diethylstilbestrol 
(DES) 
● 
Biological agents or other drugs with anticancer activity to prostate cancer  
● 
Herbal medicines that may exhibit hormonal anti-prostate cancer activity or herbal 
medicines that decrease serum PSA (saw palmetto) 
● 
Androgen (e.g., testosterone, dehydroepiandrosterone [DHEA]) 
● 
Study drugs for prostate cancer 
● 
Surgery or radiation therapy for primary lesion 
● 
Warfarin 
 
5.1.3.5 Precautions for Concomitant Medication with Enzalutamide (Drug 
Interactions) 
Enzalutamide may affect the exposure to other medications. Other medications also may 
affect the exposure to enzalutamide.  
● 
Concomitant use with strong CYP2C8 inhibitors (e.g., gemfibrozil) may elevate the 
plasma concentration of enzalutamide. Therefore, it is desirable to avoid the concomitant 
use. If the subject needs a strong CYP2C8 inhibitor, reduce the dose of enzalutamide to 
80 mg once daily. Return the dose of enzalutamide to the level that is the same as before 
the initiation of strong CYP2C8 inhibitors when the concomitant use is discontinued.  
● 
Concomitant use with strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, 
phenytoin, and rifampicin) or moderate CYP3A4 inducers (e.g., bosentan, efavirenz, 
etravirine, modafinil, nafcillin, and hypericum erectum) may decrease the plasma 
concentration of enzalutamide. Therefore, it is desirable to avoid the concomitant use 
where possible. It is recommended to select a drug that is less likely to induce CYP3A4, 
or minimize the induction.  
● 
Enzalutamide is a strong inducer of CYP3A4, and moderate inducer of CYP2C9 and 
CYP2C19. Enzalutamide decreases the exposure to drugs of CYP3A4 substrate with a 
small therapeutic range (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, 
fentanyl, pimozide, quinidine, sirolimus, and tacrolimus), drugs of CYP2C9 substrate 


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with a small therapeutic range (e.g., phenytoin and warfarin), drugs of CYP2C19 
substrate with a small therapeutic range, and drugs of UGT1A1 substrate with a small 
therapeutic range (e.g., S-mephenytoin). Therefore, it is desirable to avoid the 
concomitant use where possible.  
● 
Enzalutamide is an inhibitor of human P-gp and may increase the exposure to drugs of P-
gp substrate. Precaution is required for the combination use of drugs of P-gp substrate 
with a small therapeutic range (e.g., digoxin, colchicine, and dabigatran etexilate) with 
enzalutamide.  
 
5.1.4 
Treatment Compliance 
Study subjects should be counseled on the need to meet 100% compliance with the study 
drug with an exception of drug discontinuation due to adverse reactions. Investigator or 
designee should ensure that study subjects meet this goal throughout the study period. At 
each visit, compliance will be verified based on the information from subjects, the amount of 
study drug prescribed, the amount unused and lost, etc. and recorded in the medical record or 
other source materials. The amount of study drug prescribed, the amount returned and lost 
will be entered in the eCRF. The consistency with the study drug control table will be 
confirmed where necessary.  
The investigator or designee will, if there is a problem in the drug compliance, investigate the 
reason, and instruct the subject to improve the compliance. The investigator or designee will 
also carefully monitor the treatment compliance, and report deviation, if any, to the Sponsor. 
 
5.1.5 
Restrictions During the Study 
The investigator or site designee will take heed of the following, in particular, before 
prescribing the study drug, and explain the subjects how to take the study drug.  
● 
Take the study drug with water.  
● 
Take the study drug from the day after the initial prescription of each study drug. Take 
the study drug from the day of prescription thereafter. 
● 
Bring the unused study drug at the subsequent visit. Report the compliance to the 
investigator or site designee.  
● 
If treatment is stopped at the discretion of the subject, visit the hospital as soon as 
possible for medical consultation with the investigator or sub-investigator.  
 
5.2 
Demographics and Baseline Characteristics 
5.2.1 
Demographics 
When obtaining written informed consent and at screening visit, the date of birth, sex, height, 
and body weight will be checked, and entered in the medical record or other source materials, 
and in the eCRF.  


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5.2.2 
Medical History 
(1) Medical history 
Medical history includes diseases that were cured before the start of the study drug. 
Medical history within 1 year before the start of the study drug will be surveyed. 
Diagnosis, time of onset, and time of cure will be entered in the medical record or other 
source materials, and in the eCRF. Transient diseases (e.g., cold), otorhinolaryngologic 
diseases, dental diseases, skin diseases, and ophthalmologic diseases will not be entered 
in principle.  
(2) Complications 
Diseases that have not been cured at the start of the study drug will be handled as 
complications, surveyed, and confirmed. Diagnosis and time of onset will be entered in 
the medical record or other source materials, and in the eCRF.  
 
5.2.3 
Diagnosis of the Target Disease, Severity, and Duration of Disease 
At screening visit, the date of prostate cancer diagnosed, and PSA, TNM classification, and 
Gleason score on the day of diagnosis will be confirmed. The date of metastasis diagnosed 
and metastatic site will also be checked and entered in the eCRF.  
 
5.3 
Efficacy Assessment 
5.3.1 
PSA 
In the screening period, at study visit at Week 1 (Day 1), Week 13, Week 17, and every 
subsequent 4 weeks of 1st line AAT and 2nd line AAT, at completion or discontinuation, and 
at safety follow-up visit, blood sample for PSA will be collected, and PSA will be measured 
by the central laboratory designated by the Sponsor. The PSA measured on Week 1 (Day 1) 
of 1st line AAT and 2nd line AAT will be handled as baseline. The following items will be 
calculated based on the measured PSA for evaluation.  
 
5.3.1.1 Time to PSA Progression with 1st Line AAT (TTPP1) 
PSA progression will be defined according to the consensus guidelines of PCWG2. For 
patients with PSA declines at Week 13, the PSA progression date is defined as the date that a 
≥ 25% increase and an absolute increase of ≥ 2 ng/mL above the nadir is documented, which 
is confirmed by a second consecutive value obtained 3 or more weeks later. For patients with 
no PSA decline at Week 13, the PSA progression date is defined as the date that a ≥ 25% 
increase and an absolute increase of ≥ 2 ng/mL above the baseline is documented.  


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TTPP1 is defined as the period from the date of randomization to the date of PSA 
progression in the 1st line AAT period.  
 
5.3.1.2 Time to PSA Progression with 1st Line AAT + 2nd Line AAT (TTPP2) 
Time to PSA progression with 2nd line AAT is defined as the period from Day 1 of 2nd line 
AAT to the date of PSA progression with 2nd line AAT. TTPP2 will be the total of time to 
PSA progression with 1st line AAT and time to PSA progression with 2nd line AAT.  
 
5.3.1.3 PSA Response Rate to 1st Line AAT (Decrease by at Least 50% or 90% from 
Baseline) 
PSA response will be defined as PSA decreased by at least 50% or 90% from baseline when 
at least 3 weeks passed after the lowest PSA decreased by at least 50% or 90% from baseline 
in the 1st line AAT period after baseline. The proportion of the subjects who achieved PSA 
response will be evaluated.  
 
5.3.1.4 PSA Response Rate to 1st Line AAT at Week 13 (Decrease by at Least 50% or 
90% from Baseline) 
PSA response will be defined as the lowest PSA at Week 13 decreased by at least 50% or 
90% from baseline in the 1st line AAT period. The proportion of the subjects who achieved 
PSA response will be evaluated.  
 
5.3.1.5 Time to PSA Decrease by 50% from Baseline with 1st Line AAT 
Time to PSA decrease by 50% with 1st line AAT is defined as the period from the date of 
randomization to the day when the decrease of PSA from baseline by 50% is first identified. 
 
5.3.1.6 Time to PSA Progression with 2nd Line AAT (2nd TTPP) 
2nd TTPP is defined as the period from the start date of 2nd line AAT (Day 1) to the date of 
PSA progression.  
 
5.3.1.7 PSA Response Rate to 2nd Line AAT (Decrease by at Least 50% or 90% from 
Baseline) 
PSA response will be defined as PSA decreased by at least 50% or 90% from baseline when 
at least 3 weeks passed after the lowest PSA decreased by at least 50% or 90% from baseline 
in the 2nd line AAT period after baseline. The proportion of the subjects who achieved PSA 
response will be evaluated.  


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5.3.2 
CT/MRI and Bone Scintigraphy 
Imaging examination will be performed with chest CT, abdominopelvic CT or MRI, and 
bone scintigraphy in the screening period, at study visit every 12 weeks after Week 1 (Day 1) 
of 1st line AAT irrespective of switching the drugs, and at completion or discontinuation 
(chest CT will not be necessary at study visits after the screening period if chest metastasis is 
not observed in the image taken during the screening period). During the study period, 
imaging examination will be performed under the same condition for the same subject, and 
the image should be interpreted by the same reader at each study site wherever possible. 
Images taken within 42 days before randomization as part of daily consultation before 
informed consent may be used as data in the screening period. In case of disease progression 
suspected, imaging examination may be performed for confirmation at any time other than 
the scheduled examination.  
The following will be evaluated with the images in the screening period as baseline.  
 
5.3.2.1 Radiographic Progression-Free Survival (rPFS) 
rPFS is defined as the period from randomization to the time when radiographic disease 
progression is observed or death of any cause during the study period, whichever occurs 
earlier. With regard to radiographic disease progression, soft tissue lesion will be defined by 
RECIST guidelines version 1.1 (RECIST 1.1), bone lesion will be defined as the occurrence 
of at least 2 new bone lesions confirmed by bone scintigraphy in line with PCWG2 
recommendation. Evaluation will be made in subjects with distant metastasis at baseline.  
The following are procedures necessary for confirmation of radiographic disease progression.  
 


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Study visit 
where disease 
progression is 
observed 
Criteria for disease progression 
Criteria for 
confirmation of disease 
progression (necessity 
for imaging for 
confirmation and time 
of confirmation) 
Criteria for imaging for 
confirmation of disease 
progression 
Visits up to 
Week 13 of 
1st line AAT 
Bone lesion: ≥2 new bone 
lesions in comparison with 
baseline bone scintigraphy by 
PCWG2 
Timing: ≥6 weeks after 
disease progression 
confirmed or at Week 
25 Visit 
≥2 new bone lesions in 
comparison with bone 
scintigraphy at Week 
13 of 1st line AAT 
Soft tissue lesion: Disease 
progression detected by CT or 
MRI, and defined by RECIST 
1.1 
No need of imaging for 
confirmation 
N/A 
Visits after 
Week 13 of 
1st line AAT 
Bone lesion: ≥2 new bone 
lesions in comparison with bone 
scintigraphy at Week 13* of 1st 
line AAT 
No need of imaging for 
confirmation 
N/A 
Soft tissue lesion: Disease 
progression detected by CT or 
MRI, and defined by RECIST 
1.1 
No need of imaging for 
confirmation 
N/A 
*: Compare with baseline bone scintigraphy if data from Week 13 are missing. 
 
5.3.2.2 Metastasis-Free Survival (MFS) 
MFS is defined as the period from randomization to new radiographic metastatic lesion or 
death of any cause during the study period, whichever occurs earlier. Evaluation will be 
made in subjects in whom distant metastasis is not confirmed at baseline.  
 
5.3.2.3 Objective Response Rate (ORR) in Best Overall Soft Tissue Response of 
RECIST Guidelines with 1st Line AAT 
According to RECIST 1.1, the investigator or sub-investigator will evaluate the overall 
response in target, non-target, and new lesions in soft tissue at each time point. At the end of 
the 1st line AAT period, the best overall response will be assessed. Of subjects with 
measurable soft tissue lesion (at least 1 target lesion according to RECIST 1.1) in baseline 
imaging, the proportion of subjects with objective response (complete or partial response) 
will be evaluated.  
 
5.3.3 
Time to Treatment Failure 
Time to treatment failure is defined as the period to study drug discontinuation for any reason 
that includes disease progression, onset of AEs, subjects’ request, or death. The following 
will be evaluated.  


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5.3.3.1 Time to Treatment Failure of 1st Line AAT (TTF1) 
The period from randomization to discontinuation of 1st line AAT will be evaluated.  
 
5.3.3.2 Time to Treatment Failure of 2nd Line AAT (TTF2) 
The period from randomization to discontinuation of 2nd line AAT will be evaluated.  
 
5.3.4 
Subject Reported Outcome 
The investigator or sub-investigator will instruct the subjects to record the following subject 
reported outcome, and evaluate the efficacy with Week 1 (Day 1) of 1st line AAT and 2nd 
line AAT as baseline based on the information recorded in subject reported outcome.  
 
5.3.4.1 Functional Assessment of Cancer Therapy–Prostate (FACT–P) 
The assessment will be conducted at study visit at Week 1 (Day 1), Week 13, and every 
subsequent 12 weeks of 1st line AAT and 2nd line AAT, and at completion or 
discontinuation.  
FACT–P is a multi-faceted QOL scale of self-assessment for patients with prostate cancer. 
FACT–P includes 27 major items to evaluate subjects’ functions in 4 areas; that is, physical 
health, social/family, emotional, and functional well-being. Site-specific 12 items are added 
for assessment of prostate-related symptoms. Each item will be assessed with a 5-grade 
Likert scale. The subtotal in each area is a low rank score. The total of all items is the overall 
QOL score. The higher the QOL score, the higher is the QOL.  
 
5.3.4.2 European Quality of Life 5-Dimension-5 Level Instruments (EQ-5D-5L) 
EQ-5D-5L will be performed at study visit at Week 1 (Day 1), Week 13, and every 
subsequent 12 weeks of 1st line AAT and 2nd line AAT, and at completion or 
discontinuation.  
EQ-5D-5L is a QOL scale for self-assessment that consists of 5 items related to health, such 
as mobility, self care, usual activities, pain/discomfort, and anxiety/depression. Each item 
will be evaluated in 5 levels from “no problem” to “extreme problem.” The last question is a 
visual analog scale to evaluate the present health status in the range from “best imaginable 
health status” to “worst imaginable health status.”  
 


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5.3.4.3 Brief Pain Inventory-Short Form (BPI-SF) 
BPI-SF will be performed in the screening period, at study visit at Week 1 (Day 1), Week 13, 
and every subsequent 12 weeks of 1st line AAT and 2nd line AAT, and at completion or 
discontinuation.  
BPI is a questionnaire slip verified as a self-assessment scale for subjects about the level of 
pain, effect of the pain on activities of daily living, and analgesic use. BPI used in this study 
is an abbreviated version (short form) that consists of questions in 9 items for which simple 
numerical evaluation scales from 0 to 10 are used. In order to evaluate prostate cancer-related 
pain in this study, the investigator or sub-investigator will instruct the subjects to describe 
prostate cancer-related pains. 
 
5.3.4.4 Brief Fatigue Inventory (BFI) 
BFI will be performed in the screening period, at study visit at Week 1 (Day 1), Week 13, 
and every subsequent 12 weeks of 1st line AAT and 2nd line AAT, and at completion or 
discontinuation.  
BFI is a simple questionnaire slip that consists of questions in 10 items to evaluate the 
malaise (subjective symptoms characterized as debility that includes physical and mental 
wasting) of cancer patients.  
 
5.4 
Safety Assessment 
5.4.1 
Vital Signs (Blood Pressure and Pulse Rate) 
Resting blood pressure in sitting position and pulse rate will be measured in the screening 
period, at each visit in 1st line AAT and 2nd line AAT, at completion or discontinuation, and 
at safety follow-up visit. The date and result of measurement will be entered in the medical 
record or other source materials, and in the eCRF.  
 
5.4.2 
ECOG Performance Status 
In the screening period, at each visit in 1st line AAT and 2nd line AAT, at completion or 
discontinuation, and at safety follow-up visit, the investigator or sub-investigator will 
evaluate the general condition of subjects in line with the ECOG Performance Status, and 
enter it in the medical record or other source materials, and in the eCRF.  
 
5.4.3 
Adverse Events  
See Section 5.5 Adverse Events and Other Safety Aspects for information regarding AE 
collection and data handling. 
 


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5.4.3.1 Adverse Events of Possible Hepatic Origin 
See Appendix 12.2 Liver Safety Monitoring and Assessment for detailed information on liver 
abnormalities, monitoring and assessment, if the AE for a subject enrolled in a study and 
receiving study drug is accompanied by increases in liver function testing (LFT, e.g.: AST, 
ALT, bilirubin, etc.) or is suspected to be due to hepatic dysfunction. Subjects with AE’s of 
hepatic origin accompanied by LFT abnormalities should be carefully monitored.  
 
5.4.4 
Laboratory Assessments 
Below is a table of the laboratory tests that will be performed during the conduct of the study. 
Specimen will be collected at scheduled and unscheduled visits where necessary (see V. 
FLOW CHART AND SCHEDULE OF ASSESSMENTS). All specimen will be collected 
and measured by the central laboratory designated by the Sponsor.  


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Visits 
 
Item 
Collection Tube 
Screening, 
Each visit in 1st 
line AAT, 
Each visit in 
2nd line AAT, 
At completion 
or 
discontinuation, 
Safety follow-
up 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
RBC count 
WBC count 
Differential WBC 
count 
Hemoglobin 
Hematocrit 
Platelet count 
2 mL 
Biochemistry 
Albumin  
AST 
ALT 
γ-GTP 
LDH 
ALP 
Total bilirubin 
Total protein 
BUN 
Calcium 
Phosphatase 
Potassium  
Sodium 
Creatinine 
Testosterone 
9 mL 
Blood glucose test 
Glucose 
2 mL 
Urinalysis  
 
 
 
 
 
 
 
 
 
Specific gravity 
pH 
Protein 
Glucose 
Ketone 
Bilirubin 
Blood 
Nitrite 
Leucocyte 
Urobilinogen 
10 mL 
Screening,  
Week 1 (Day 
1), Week 13, 
Week 17, every 
subsequent 4 
weeks of 1st 
line AAT and 
2nd line AAT, 
At completion 
or 
discontinuation,  
Safety follow-
up 
Biochemistry 
 
 
PSA 
 
 
 
 
Use the same 
specimen 
collected for 
other 
biochemistry 
tests 
 


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Clinical significance of out-of-range laboratory findings is to be determined and documented 
by the investigator/sub-investigator who is a qualified physician. 
 
5.5 
Adverse Events and Other Safety Aspects 
5.5.1 
Definition of Adverse Events (AEs) 
An AE is defined as any untoward medical occurrence in a subject administered a study drug 
or has undergone study procedures and which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product. 
An abnormality identified during a medical test (e.g., laboratory parameter, vital sign, 
physical exam) should be defined as an AE only if the abnormality meets one of the 
following criteria:  
● 
Induces clinical signs or symptoms 
● 
Requires active intervention 
● 
Requires interruption or discontinuation of study medication 
● 
The abnormality or investigational value is clinically significant in the opinion of the 
investigator. 
Clinical signs or clinical symptoms associated with disease progression should be reported as 
AEs, but should not be reported in the event name, “disease progression.” Disease 
progression leading to death will be reported in the event name, “disease progression.”  
 
5.5.2 
Definition of Serious Adverse Events (SAEs) 
An AE is considered “serious” if, in the view of either the investigator or Sponsor, it results 
in any of the following outcomes:  
● 
Results in death 
● 
Is life threatening (an AE is considered “life-threatening” if, in the view of either the 
investigator or Sponsor, its occurrence places the subject at immediate risk of death. It 
does not assume that if the event had occurred in a more severe form, it might have 
caused death) 
● 
Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions  
● 
Results in congenital anomaly, or birth defect 
● 
Requires inpatient hospitalization or leads to prolongation of hospitalization 
(hospitalization for treatment/observation/examination caused by AE is to be considered 
as serious) 
● 
Other medically important events 


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Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require intervention to prevent one of the other outcomes listed in the 
definition above. These events, including those that may result in disability/incapacity, 
should also usually be considered serious. Examples of such events are intensive treatment in 
an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
that do not result in hospitalization; or development of drug dependency or drug abuse. 
Safety events of interest in case the study drug administered to the subject that may require 
expedited reporting and/or safety evaluation include, but are not limited to cases as follows:  
● 
Overdose 
● 
Suspected abuse/misuse 
● 
Inadvertent or accidental exposure to the study drug 
● 
Medication error involving the study drug 
All of the events of interest noted above should be recorded on the eCRF. Any situation 
involving these events of interest that also meets the criteria for an SAE should be recorded 
on the AE page of the eCRF and marked ‘serious’ and on the SAE worksheet/report.  
In addition, if an AE indicated in “Appendix 12.3 Always Serious Events” occurs, it must be 
reported as SAE whether or not it meets the conditions above. 
 
5.5.3 
Criteria for Causal Relationship to the Study Drug 
AEs that fall under either “Possible,” “Probable,” or “Not assessable” should be defined as 
“AEs whose relationship to the study drugs could not be ruled out.” 
Causal relationship to 
the study drug 
Criteria for causal relationship 
Not related 
A clinical event, including laboratory test abnormality, with a temporal 
relationship to drug administration which makes a causal relationship 
improbable, and/or in which other drugs, chemicals or underlying disease 
provide plausible explanations. 
Possible 
A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to administration of the drug, but which could also be 
explained by concurrent disease or other drugs or chemicals. Information 
on drug withdrawal may be lacking or unclear. 
Probable 
A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to administration of the drug, unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and which follows a 
clinically reasonable response on re-administration (rechallenge) or 
withdrawal (dechallenge). 
Not assessable 
A report suggesting an adverse reaction which cannot be judged because 
Information is insufficient or contradictory, and which cannot be 
supplemented or verified. 
 


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5.5.4 
Criteria for Defining the Severity of an Adverse Event 
AEs, including abnormal clinical laboratory values, will be graded using the NCI-CTCAE 
guidelines (version 4.0). The items that are not stipulated in the NCI-CTCAE version 4.0 will 
be assessed according to the criteria below and entered into the eCRF:  
Grade 
Assessment Standard 
1-Mild 
Asymptomatic, or mild symptoms, clinical or diagnostic observations noted; 
intervention not indicated. 
2-Moderate 
Local or noninvasive intervention indicated. 
3-Severe 
Medically significant but not immediately life threatening, hospitalization or 
prolonged hospitalization. 
4-Life Threatening 
Life threatening consequences, urgent intervention indicated 
5-Death 
Death related to AE 
 
5.5.5 
Reporting of Serious Adverse Events (SAEs) 
In the case of an SAE, the investigator or sub-investigator must report to the head of the 
study site and must contact delegated CRO by telephone/fax or email immediately (within 24 
hours of awareness).  
The investigator should complete and submit JUTOKUNA YUUGAIJISHOU 
HOUKOKUSHO containing all information that is required by the Regulatory Authorities to 
delegated CRO by fax or email immediately (within 24 hours of awareness) and to the head 
of the hospital. If the faxing or emailing of  JUTOKUNA YUUGAIJISHOU 
HOUKOKUSHO  is not possible or is not possible within 24 hours, delegated CRO should 
be informed by phone.   
For contact details, see Section II.CONTACT DETAILS OF KEY SPONSOR’S 
PERSONNEL. Please fax JUTOKUNA YUUGAIJISHOU HOUKOKUSHO to the following 
address, or report by email to an address arranged in advance.  
Contract Research Organization (CRO) 
 
Fax: 
 
 
5.5.6 
Follow-up of Adverse Events 
All AEs occurring during or after the subject has discontinued the study are to be followed up 
until resolved or judged to be no longer clinically significant, or until they become chronic to 
the extent that they can be fully characterized.  
If during AE follow-up, the AE progresses to an “SAE,” or if a subject experiences a new 
SAE, the investigator must immediately report the information to the Sponsor. 


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Even if the subject does not return to normal or baseline level, and the investigator or sub-
investigator judged follow-up survey is not necessary or will be completed, the reason for the 
judgment should be recorded in the source materials.  
Please refer to Appendix 12.2 Liver Safety Monitoring and Assessment for detailed 
instructions on drug-induced liver injury (DILI).  
 
5.5.7 
Procedure in Case of Pregnancy 
If a female subject or partner of a male subject becomes pregnant during the study dosing 
period or within 3 months from the discontinuation of dosing, the investigator should report 
the information to the Sponsor or delegated CRO as if it is an SAE. The expected date of 
delivery or expected date of the end of the pregnancy, last menstruation, estimated 
conception date, pregnancy result and neonatal data etc., should be included in this 
information. 
The investigator will follow the medical status of the mother, as well as the fetus, as if the 
pregnancy is an SAE and will report the outcome to the Sponsor. 
When the outcome of the pregnancy falls under the criteria for SAEs [spontaneous abortion, 
induced abortion, stillbirth, death of newborn, congenital anomaly (including anomaly in a 
miscarried fetus)], the investigator should respond in accordance with the report procedure 
for SAEs. Additional information regarding the outcome of a pregnancy (which is 
categorized as an SAE) is mentioned below. 
● 
“Spontaneous abortion” includes miscarriage, abortion and missed abortion 
● 
Death of an infant within 1 month after birth should be reported as an SAE regardless of 
its relationship with the study drug 
● 
If an infant dies more than 1 month after the birth, it should be reported if a relationship 
between the death and intrauterine exposure to the study drug is judged as “possible” by 
the investigator 
● 
In the case of a delivery of a living newborn, the “normality” of the infant is evaluated at 
the birth 
● 
Unless a congenital anomaly are identified prior to spontaneous abortion or miscarriage, 
the embryo or fetus should be assessed for congenital defects by visual examination 
 
5.5.8 
Emergency Procedures and Management of Overdose 
1. Enzalutamide 
Seizure, rash, confusional state, severe fatigue, etc. may be caused by overdose. In the 
overseas phase 1 study, with doses that exceed the maximum tolerable dose of enzalutamide 
240 mg/day, seizure (1 event each with 360 mg/day, 480 mg/day, and 600 mg/day), rash (1 
event with 600 mg/day), and confusional state (1 event with 600 mg/day) were reported. In 
the study, enzalutamide was reduced due to fatigue in some subjects, indicating dose-
dependently increasing incidence with doses that exceed 240 mg. In the overseas phase 3 


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study, some subjects mistakenly took 640 mg/day for 8 days, and reported fatigue and 
asthenia as AEs whose causal relationship with enzalutamide cannot be ruled out.  
There is no detoxicant specific to overdosed enzalutamide. Enzalutamide has a large 
distribution volume, and high protein bonding rate. Thus, intermittent hemodialysis and 
continuous ambulatory peritoneal dialysis are not an effective means to eliminate 
enzalutamide from body. For suspected overdose, stop the administration, and take 
appropriate measures according to the symptoms.  
 
2. Flutamide 
In the clinical study, flutamide up to 1500 mg per day was administered to a maximum of 36 
weeks. No significant adverse reactions were reported. It has not been clear whether a single 
administration of flutamide will usually cause symptoms of overdose or life-threatening 
symptoms.  
Most of flutamide is bonded with protein, and dialysis is not useful to treat an overdose. 
Similar to means taken against an overdose of any drug, we should note that multiple drugs 
may have been taken. If voluntary vomiting does not occur, vomiting should be induced for 
conscious patients. Vital signs should be frequently checked, and general supportive care that 
includes thorough observation will be conducted.  
 
5.5.9 
Supply of New Information Affecting the Conduct of the Study 
1. When information is obtained regarding serious and unexpected adverse drug reactions 
(or other) that are specified in Article 273 of the Enforcement Regulations of the 
Pharmaceutical Affairs Law, in compliance with Article 80-2 Paragraph 6 of the 
Pharmaceutical Affairs Law, the Sponsor should inform all the investigators involved in 
the clinical study, the head of the study site, and the regulatory authorities of such 
information. The head of the study site who receives such information will decide 
whether the clinical study should be continued after hearing the opinions of the IRB. The 
investigator will supply the new information to the subjects, in compliance with Section 
8.2.3.2 Supply of New and Important Information Influencing the Subject’s Consent and 
Revision of the Written Information. 
2. In addition to the above item (1), when the head of the study site receives the revisions of 
the protocol or written information, information on the matters covering the quality of 
the study drug, efficacy and safety, information necessary for conducting the clinical 
study properly, or documents to be examined by the IRB should be sent to the IRB. 
 
 


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5.5.10 Deviations from the Protocol and Other Actions Taken to Avoid Life-
Threatening Risks to Subjects  
The investigator must not deviate from or amend the protocol, excluding an emergency case 
for avoiding risks to the subjects. When the investigator does not follow the protocol in order 
to avoid urgent risks for subjects, the investigator should take the following actions.  
1. Describe the contents of the deviation or amendment and the reasons for it in a written 
notice, and immediately send the document stating the deviation or amendment and the 
reasons to the Sponsor and the head of the study site. Keep a copy of the notice. 
2. Consult with the Sponsor at the earliest possibility for cases in which it is necessary to 
amend the protocol. Obtain approval for a draft of the amended protocol from the IRB 
and the head of the study site as well as written approval from the Sponsor. 
 
5.6 
Test Drug Concentration 
Not applicable. 
 
5.7 
Other Measurements, Assessments or Methods 
Not applicable. 
 
5.8 
Total Amount of Blood 
The total amount of blood collected from a subject differs according to the course of the 
disease and study drug treatment period. The total amount of blood collected at each visit 
will be 13 mL (hematology: 2 mL, biochemistry: 9 mL, blood glucose test: 2 mL).  
 
6 
DISCONTINUATION 
6.1 
Discontinuation of Individual Subject(s) 
A discontinuation is a subject who enrolled in the study and for whom study treatment is 
permanently discontinued prematurely for any reason.   
The subject is free to withdraw from the study treatment and/or study for any reason and at 
any time without giving reason for doing so and without penalty or prejudice. The 
investigator is also free to terminate a subject’s involvement in the study at any time if the 
subject’s clinical condition warrants it. 
If a subject is discontinued from the study with an ongoing AE or an unresolved laboratory 
result that is significantly outside of the reference range, the investigator will attempt to 
provide follow-up until the condition stabilizes or no longer is clinically significant. 
 


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Discontinuation Criteria from Treatment:  
1. AEs (excluding events in the discontinuation criteria 2 and 3) that are intolerable for the 
subject, and are not improved by proper medical intervention or reduction of the study 
drug; or AEs, which the investigator or sub-investigator considers that continuation of 
the study drug may cause an excessive risk to subjects. 
2. Seizure during the treatment period of enzalutamide (subjects who had seizure on the1st 
line AAT may be shifted to the 2nd line AAT.) 
3. Liver disorder (abnormal AST or ALT that exceed 3 fold of the upper limit of normal) or 
interstitial pneumonia (subjects who had a case on the 1st line AAT may be shifted to the 
2nd line AAT.) during the treatment period with flutamide 
4. With or without PSA progression, the investigator or sub-investigator considers that the 
study should be discontinued due to the progression of the disease 
5. Subject withdraws the informed consent. 
 
6. Observation cannot be continued (e.g., subject stops study visit; subjects lose contact) 
7. The Sponsor, investigator, or sub-investigator considers that the study should be 
discontinued due to deviation from the protocol (excluding the discontinuation criterion 
8). 
8. It turns out after the enrollment that the subject did not satisfy the inclusion criteria or 
met the exclusion criteria at the time of registration, and the continuation of the study is 
judged inappropriate. 
9. Other 
For reasons other than those mentioned above, the investigator or sub-investigator 
considers that the study should be discontinued.  
 
For discontinuation after the start of the study drug, a discontinuation 
examination/observation will be conducted wherever possible after the decision of 
discontinuation.  
 
6.2 
Discontinuation of the Site 
If an investigator intends to discontinue participation in the study, the investigator must 
immediately inform the Sponsor and the head of the study site. 
 
6.3 
Discontinuation of the Study 
The Sponsor may terminate this study prematurely, either in its entirety or at any study site, 
for reasonable cause provided that written notice is submitted in advance of the intended 
termination. Advance notice is not required if the study is stopped due to safety concerns. If 
the Sponsor terminates the study for safety reasons, the Sponsor will immediately notify the 
investigator and subsequently provide written instructions for study termination. 
 


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7 
STATISTICAL METHODOLOGY 
The statistical analysis will be coordinated by the responsible biostatistician of CRO to whom 
the Sponsor delegates the operation. A Statistical Analysis Plan (SAP) will be written to 
provide details of the analysis, along with specifications for tables, listings and figures to be 
produced. The SAP will be finalized before the database hard-lock at the latest. Any changes 
from the analyses planned in SAP will be justified in the Clinical Study Report (CSR). 
In general, all data will be summarized with descriptive statistics (number of subjects, mean, 
standard deviation, minimum, median and maximum) for continuous endpoints, and 
frequency and percentage for categorical endpoints. 
 
7.1 
Sample Size 
The number of evaluable subjects will be approximately 200 subjects (1st line AAT 
enzalutamide group: 100, 1st line AAT flutamide group: 100).  
The sample size to evaluate the time to PSA progression with 1st line AAT (TTPP1), which 
is the primary endpoint of the study, was calculated in consideration of the following points:  
● 
Median TTPP1 with enzalutamide: 10.5 months.  
 
 
  
● 
Median TTPP1 with flutamide: 6 months.  
Values reported in the literature: 5 months according to [Okihara et al., 2007], 6.25 
months according to [Narimoto et al., 2010].  
● 
The ratio of randomization of 1st line AAT enzalutamide and flutamide groups is 1:1.  
● 
Subject enrollment period is 12 months, and the observation period is 24 months from 
the enrollment of the last subject.  
● 
Type I error of the two-sided test is 0.05, and power is 90%.  
● 
A log-rank test with the TTPP1 parameters shown above requires 135 events. The 
necessary number of subjects calculated based on the required number of events is 74 
subjects per group.  
Required number of events and necessary number of subjects above are calculated with 
the formulas below based on [Schoenfeld, 1983]. The codes in the formulas are defined 
as follows.  
𝑀𝑀𝑡𝑡: Median TTPP1 in enzalutamide group 
𝑀𝑀𝑐𝑐: Median TTPP1 in flutamide group 
𝑡𝑡𝑎𝑎: Enrollment period 
𝑡𝑡𝑓𝑓: Observation period from the last subject enrollment 
𝑍𝑍1−𝛼𝛼: 1-α% point of standard normal distribution 
𝑍𝑍1−𝛽𝛽: 1-β% point of standard normal distribution 
 


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Hazard in enzalutamide group (𝐻𝐻𝑡𝑡) =
log𝑒𝑒2
𝑀𝑀𝑡𝑡 
Hazard in flutamide group (𝐻𝐻𝑐𝑐) =
log𝑒𝑒2
𝑀𝑀𝑐𝑐 
Hazard ratio for enzalutamide group/flutamide group (𝐻𝐻𝐻𝐻) =
𝐻𝐻𝑡𝑡
𝐻𝐻𝑐𝑐 
Required number of events (𝑁𝑁𝑑𝑑) =
4× (𝑍𝑍1−𝛼𝛼+𝑍𝑍1−𝛽𝛽)2
 (log𝑒𝑒𝐻𝐻𝐻𝐻)2
  *The number after the decimal 
point will be rounded up to the nearest integer. 
Incidence of events of enzalutamide group 
(𝑃𝑃𝑡𝑡) = 1 −1
6 ൬exp൫−𝐻𝐻𝑡𝑡× 𝑡𝑡𝑓𝑓൯+ 4 × exp൬−𝐻𝐻𝑡𝑡× (𝑡𝑡𝑓𝑓+ 1
2 × 𝑡𝑡𝑎𝑎)൰+ exp (−𝐻𝐻𝑡𝑡× (𝑡𝑡𝑓𝑓+ 𝑡𝑡𝑎𝑎))൰ 
Incidence of events of flutamide group 
(𝑃𝑃𝑐𝑐) = 1 −1
6 ൬exp൫−𝐻𝐻𝑐𝑐× 𝑡𝑡𝑓𝑓൯+ 4 × exp൬−𝐻𝐻𝑐𝑐× (𝑡𝑡𝑓𝑓+ 1
2 × 𝑡𝑡𝑎𝑎)൰+ exp (−𝐻𝐻𝑐𝑐× (𝑡𝑡𝑓𝑓+ 𝑡𝑡𝑎𝑎))൰ 
Incidence of events of both groups (𝑃𝑃) =
1
2 × (𝑃𝑃𝑡𝑡+ 𝑃𝑃𝑐𝑐) 
Necessary number of subjects per group (𝑁𝑁) =
1
2 ×
𝑁𝑁𝑑𝑑
𝑃𝑃    * The number after the 
decimal point will be rounded up to the nearest integer. 
● 
Considering the dropout rate of approximately 25%, 100 subjects are to be enrolled in 
each group.  
 
 
Number of 
subjects 
 
 
With PSA 
progression 
 
 
Censored 
 
 
25% 
 
 
50% 
 
 
75% 
 
 
 
7.2 
Analysis Set 
7.2.1 
Intent-to-Treat (ITT) 
Intent-to-Treat (ITT) population is defined as all subjects randomized in this study. The ITT 
population will be analyzed by randomized treatment group (treatment group based on 
randomization). Efficacy analyses will be done in the ITT population.  
 
7.2.2 
Safety Analysis Set (SAF) 
For the statistical summary of the safety data, the safety analysis set (SAF) will be used. The 
SAF consists of all subjects who took at least one dose of study medication, and will be used 
for safety analyses. 
 


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7.2.3 
Pharmacokinetic Analysis Set (PKAS) 
The pharmacokinetic analysis set (PKAS) will not be established for this study. 
 
7.2.4 
Pharmacodynamic Analysis Set (PDAS) 
The pharmacodynamic analysis set (PDAS) will not be established for this study. 
 
7.3 
Demographics and Other Baseline Characteristics 
Demographics and other baseline characteristics will be summarized by treatment group for 
the SAF and ITT. Descriptive statistics will include number of subjects, mean, standard 
deviation, minimum, median and maximum for continuous endpoints, and frequency and 
percentage for categorical endpoints. 
 
7.4 
Analysis of Efficacy 
Efficacy analysis will be conducted on the ITT. The interpretation of results from statistical 
tests will be based on the ITT.  
7.4.1 
Analysis of Primary Endpoint 
7.4.1.1 Primary Analysis 
TTPP1 is the period from randomization to the first day when PSA progression is objectively 
identified. Convention of censoring is specified in Section 7.10.  
The benefit of enzalutamide as compared to flutamide will be assessed with the stratified log-
rank test as the primary efficacy analysis. The stratification factor will be the disease stages 
(M0/N0, M0/N1, or M1) used as stratification factor for allocation.  
The hypothesis for comparisons is as follows:  
H0: The survival time distribution of enzalutamide group is the same as that with flutamide 
group. 
H1: The survival time distribution of enzalutamide group is not the same as that with 
flutamide group. 
The significance level is 0.05 (two-sided). ITT is used for the primary analysis.  
 
7.4.1.2 Secondary Analysis 
As the secondary analysis of the primary endpoint, TTPP1, the benefit of enzalutamide as 
compared to flutamide will be also assessed with the hazard ratio and its 95% CI based on the 
Cox proportional hazards model. Disease stages (M0/N0, M0/N1, or M1) will be used as a 
covariate for adjustment. Furthermore, the distribution of time to PSA progression will be 


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estimated using the Kaplan–Meier method. The median time to PSA progression will be 
estimated using the 50 percentile value of the Kaplan–Meier curve. The two-sided 95% CI 
will be calculated based on the estimation. The significance level is 0.05 (two-sided). ITT is 
used for the primary analysis.  
 
7.4.1.3 Subgroup Analysis 
For the primary and secondary analyses on the primary endpoint, TTPP1, subgroup analyses 
will be performed. Subgroup setting is specified by the SAP.  
 
7.4.2 
Analysis of Secondary Endpoints 
7.4.2.1 Time to PSA Progression with 1st Line AAT + 2nd Line AAT (TTPP2) 
TTPP2 is defined as the period from Day 1 of 2nd line AAT to the date of PSA progression 
with 2nd line AAT. The total of time to PSA progression with 1st line AAT and time to PSA 
progression with 2nd line AAT will be evaluated. Convention of censoring is specified in 
Section 7.10.  
The distribution of the TTPP2 will be estimated using the Kaplan–Meier method. The 
median TTPP2 will be estimated using the 50 percentile value of the Kaplan–Meier curve. 
The two-sided 95% CI will be calculated based on the estimation. The benefit of 
enzalutamide as compared to flutamide will be descriptively assessed.  
 
7.4.2.2 PSA Response Rate to 1st Line AAT (Decrease by at Least 50% or 90% from 
Baseline) 
The PSA response rate decreasing by at least 50% will be calculated by treatment groups of 
subjects with baseline PSA value and PSA measured at least once after baseline. For the 
comparison of the response rate between the enzalutamide and flutamide groups, the 
stratified Cochran–Mantel–Haenszel test will be used. The stratification factor will be the 
disease stages (M0/N0, M0/N1, or M1) used as stratification factor for allocation.  
PSA decrease by at least 90% will also be compared at the 0.05 significance level (two-
sided) between the enzalutamide and flutamide groups using the stratified Cochran–Mantel–
Haenszel test.  
 
7.4.2.3 PSA Response Rate to 1st Line AAT at Week 13 (Decrease by at Least 50% or 
90% from Baseline) 
The PSA response rate decreasing by at least 50% (or by at least 90%) will be calculated by 
treatment groups of subjects with baseline PSA value with 1st line AAT and PSA measured 
at Week 13.  


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The response rate between the enzalutamide and flutamide groups will be compared using the 
stratified Cochran–Mantel–Haenszel test. The stratification factor will be the disease stages 
(M0/N0, M0/N1, or M1) used as stratification factor for allocation.  
 
7.4.2.4 Time to PSA Decrease by 50% from Baseline with 1st Line AAT 
The time to PSA decrease by 50% with 1st line AAT is defined as the period from 
randomization to the day when the decrease of PSA from baseline by 50% is first identified. 
Convention of censoring is specified in Section 7.10.  
The benefit of enzalutamide as compared to flutamide will be assessed by the stratified log-
rank test. The significance level is 0.05 (two-sided). The stratification factor will be the 
disease stages (M0/N0, M0/N1, or M1) used as stratification factor for allocation.  
The distribution of the period when PSA decreases by 50% will be estimated using the 
Kaplan–Meier method. The median period when PSA decreases by 50% will be estimated 
using the 50 percentile value of the Kaplan–Meier curve. The two-sided 95% CI will be 
calculated based on the estimation.  
 
7.4.2.5 Time to Treatment Failure of 1st Line AAT (TTF1) 
TTF1 is defined as the period from randomization to the date of discontinuation of 1st line 
AAT. Convention of censoring is specified in Section 7.10.  
The benefit of enzalutamide as compared to flutamide will be assessed with the stratified log-
rank test. The significance level is 0.05 (two-sided). The stratification factor will be the 
disease stages (M0/N0, M0/N1, or M1) used as stratification factor for allocation.  
The distribution of the TTF1 will be estimated using the Kaplan–Meier method. The median 
TTF1 will be estimated using the 50 percentile value of the Kaplan–Meier curve. The two-
sided 95% CI will be calculated based on the estimation.  
 
7.4.2.6 Time to Treatment Failure of 2nd Line AAT (TTF2) 
TTF2 is defined as the period from randomization to the date of discontinuation of 2nd line 
AAT. Convention of censoring is specified in Section 7.10.  
The distribution of the TTF2 will be estimated using the Kaplan–Meier method. The median 
TTF2 will be estimated using the 50 percentile value of the Kaplan–Meier curve. The two-
sided 95% CI will be calculated based on the estimation. The benefit of enzalutamide as 
compared to flutamide will be descriptively assessed.  
 


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7.4.2.7 Radiographic Progression-Free Survival (rPFS) 
rPFS will be assessed using the same method as that with TTPP1 in subjects with distant 
metastasis confirmed at baseline.  
 
7.4.3 
Analysis of Exploratory Endpoints 
7.4.3.1 Time to PSA Progression with 2nd Line AAT (2nd TTPP) 
2nd TTPP is defined as the period from the start of 2nd line AAT to the first day when PSA 
progression is objectively identified. Convention of censoring is specified in Section 7.10.  
The distribution of the 2nd TTPP will be estimated using the Kaplan–Meier method. The 
median 2nd TTPP will be estimated using the 50 percentile of the Kaplan–Meier curve. The 
two-sided 95% CI will be calculated based on the estimation. The benefit of enzalutamide as 
compared to flutamide will be descriptively evaluated.  
 
7.4.3.2 PSA Response Rate to 2nd line AAT 
The PSA response rate to 2nd line AAT will be assessed by the same method as that with the 
PSA response rate to 1st line AAT.  
 
7.4.3.3 Metastasis-Free Survival (MFS) 
MFS will be assessed using the same method as that with 2nd TTPP in subjects without 
distant metastasis at baseline.  
 
7.4.3.4 FACT–P and EQ-5D-5L with 1st Line AAT and 2nd Line AAT 
For FACT–P and EQ-5D-5L, summary statistics will be calculated at each assessment.  
 
7.4.3.5 Brief Fatigue Inventory (BFI) with 1st Line AAT and 2nd Line AAT 
For BFI, summary statistics will be calculated at each assessment.  
 
7.4.3.6 Objective Response Rate (ORR) in best Overall Soft Tissue Response of 
RECIST Guidelines with 1st Line AAT 
ORR will be assessed using the same method as that with the PSA response rate.  
 


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7.5 
Analysis of Safety 
The safety analysis will be performed in the safety analysis set, and summarized by the time 
of assessment and by the treatment group that actually received the study drugs. The period 
of onset in the treatment period with the study drug is defined up to 28 days after the final 
treatment with the study drug, start date of cytocidal chemotherapy, or start date of new 
treatment for prostate cancer, whichever occurs first. Safety will be assessed by AEs, 
frequency of treatment discontinuation associated with AEs, and laboratory test value 
summary statistics. Descriptive statistics, and not inferential statistics, will be used.  
 
7.5.1 
Adverse Events 
The severity of all AEs will be evaluated by the investigator or sub-investigator based on 
NCI-CTCAE version 4.0. AEs will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). The number and percentage of AEs, SAEs, AEs leading to 
discontinuation, and AEs related to study drug will be summarized by system organ class, 
preferred term and treatment group. The number and percentage of AEs by severity will also 
be summarized. All AEs will be listed. 
 
7.5.2 
Laboratory Assessments 
For quantitative laboratory measurements descriptive statistics will be used to summarize 
results and change from baseline by treatment group and time point. Shifts relative to normal 
ranges from baseline to each time point during treatment period in lab tests will also be 
tabulated. Laboratory data will be displayed in listings. 
 
7.5.3 
Vital Signs 
Descriptive statistics will be used to summarize vital sign results and changes from baseline 
by treatment group and time point. Vital signs data will be displayed in listings. 
 
7.5.4 
ECOG Performance Status 
For actual measurement of ECOG Performance Status, frequency distribution will be 
calculated by time point. ECOG Performance Status data will be displayed in listings. 
 
7.5.5 
Physical Examination 
Physical examination will not be performed in this study. 
 


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7.5.6 
ECGs 
ECGs will not be performed in this study. 
 
7.5.7 
Imaging 
A list of data on disease progression collected from imaging examinations, which includes 
abdominopelvic CT/MRI, bone scintigraphy, and chest CT (by treatment group and time 
point), will be prepared.  
 
7.6 
Analysis of Pharmacokinetics 
Pharmacokinetics will not be analyzed in this study. 
 
7.6.1 
Estimation of Pharmacokinetic Parameters 
Pharmacokinetic parameters will not be estimated in this study. 
 
7.6.2 
Statistical Analysis 
A statistical analysis will not be performed in this study. 
 
7.6.3 
Concentration-Response Relationship Analysis 
A concentration-response relationship analysis will not be performed in this study. 
 
7.7 
Analysis of Pharmacodynamics 
An analysis of pharmacodynamics will not be performed in this study. 
 
7.8 
Protocol Deviations and Other Analyses 
Protocol deviations and other analyses that are not included in the preceding sections, if 
performed, will be specified by the statistical analysis plan.  
 
7.9 
Interim Analysis (and Early Discontinuation of the Clinical Study) 
No formal interim analysis is planned. 
 


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7.10 
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information 
As a general principle, no imputation of missing data will be done. Exceptions are the start 
and stop dates of AEs and concomitant medication. The imputed dates will be used to 
allocate the concomitant medication and AEs to a treatment group, in addition to determining 
whether an AE is/is not treatment emergent. Listings of the AEs and concomitant 
medications will present the actual partial dates; imputed dates will not be shown. Subjects 
who do not receive the study drug to which they have been randomized will be analyzed as 
treated. 
See the SAP for details of the definitions for windows to be used for analyses by time point. 
Sites that do not enroll at least 10 subjects will be pooled for analyses by site. The pooling 
decisions will be made and documented prior to study database hard-lock. The handling of 
outlier is specified by the SAP. The acceptable time range for study visit is specified by “VI. 
ACCEPTABLE RANGE OF SCHEDULE OF ASSESSMENTS.” Values that fall out of the 
range will be excluded. Convention of censoring for each endpoint are defined in the table 
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TTPP1 
TTPP2 
2nd TTPP 
Time to PSA 
50%/90% 
decline 
TTF1 
TTF2 
rPFS 
MFS 
Subjects without PSA value at 
baseline or in observation 
period 
Considered as 
censoring at 
randomization 
Considered as 
censoring at 
randomization 
Excluded from 
analysis 
Considered as 
censoring at 
randomization 
Not considered 
as censoring 
*To be judged 
based on 
continuation of 
study treatment 
 
Not considered 
as censoring 
*To be judged 
based on 
continuation of 
study treatment 
 
Not considered 
as censoring 
*To be judged 
based on result 
of radiographic 
assessment 
Not considered 
as censoring 
*To be judged 
based on result 
of radiographic 
assessment 
Subjects without the result of 
radiographic assessment at 
baseline or in observation 
period 
Not considered 
as censoring 
*To be judged 
based on result 
of PSA 
measurement 
 
Not considered 
as censoring 
*To be judged 
based on result 
of PSA 
measurement 
Not considered 
as censoring 
*To be judged 
based on result 
of PSA 
measurement 
Not considered 
as censoring 
*To be judged 
based on result 
of PSA 
measurement 
Not considered 
as censoring 
*To be judged 
based on 
continuation of 
study treatment 
Not considered 
as censoring 
*To be judged 
based on 
continuation of 
study treatment 
Considered as 
censoring at 
randomization 
Considered as 
censoring at 
randomization 
Subjects without PSA 
progression at final data cut-off 
 (Including cases inconsistent 
with PSA progression defined 
by the protocol) 
Subjects who 
continue the 
first study drug 
are considered 
as censoring at 
final PSA 
measurement 
Considered as 
censoring at 
final PSA 
measurement 
Subjects who 
continue the 
first study drug 
are excluded 
from analysis 
Subjects who 
have shifted to 
the second 
study drug are 
considered as 
censoring at 
final PSA 
measurement 
 
Considered as 
censoring at 
final PSA 
measurement 
Not considered 
as censoring 
*To be judged 
based on 
continuation of 
study treatment 
Not considered 
as censoring 
*To be judged 
based on 
continuation of 
study treatment 
Not considered 
as censoring 
*To be judged 
based on result 
of radiographic 
assessment 
Not considered 
as censoring 
*To be judged 
based on result 
of radiographic 
assessment 
Subjects without radiographic 
progression at final data cut-off 
(Including cases inconsistent 
with progression defined by the 
protocol) 
Not considered 
as censoring 
*To be judged 
based on result 
of PSA 
measurement 
Not considered 
as censoring 
*To be judged 
based on result 
of PSA 
measurement 
Not considered 
as censoring 
*To be judged 
based on result 
of PSA 
measurement 
Not considered 
as censoring 
*To be judged 
based on result 
of PSA 
measurement 
Not considered 
as censoring 
*To be judged 
based on 
continuation of 
study treatment 
Not considered 
as censoring 
*To be judged 
based on 
continuation of 
study treatment 
Considered as 
censoring at 
final 
radiographic 
assessment 
Considered as 
censoring at 
final 
radiographic 
assessment 


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TTPP1 
TTPP2 
2nd TTPP 
Time to PSA 
50%/90% 
decline 
TTF1 
TTF2 
rPFS 
MFS 
Death during the study 
Subjects who 
died during 
treatment with 
the first study 
drug are 
considered as 
censoring at 
final PSA 
measurement 
before death 
Considered as 
censoring at 
final PSA 
measurement 
before death 
Subjects who 
died during 
treatment with 
the first study 
drug are 
excluded from 
analysis 
Subjects who 
died during 
treatment with 
the second 
study drug are 
considered as 
censoring at 
final PSA 
measurement 
before death 
Considered as 
censoring at 
final PSA 
measurement 
before death 
The event is 
considered to 
occur at the 
time of death  
The event is 
considered to 
occur at the 
time of death  
The event is 
considered to 
occur at the 
time of death  
The event is 
considered to 
occur at the 
time of death  
Subjects who discontinued 
treatment during the study 
Subjects who 
discontinue the 
first study drug 
are considered 
as censoring at 
final PSA 
measurement 
before 
discontinuation 
Considered as 
censoring at 
final PSA 
measurement 
before 
discontinuation 
Subjects who 
discontinue the 
first study drug 
are excluded 
from analysis 
Subjects who 
discontinue the 
second study 
drug are 
considered as 
censoring at 
final PSA 
measurement 
before 
discontinuation 
Considered as 
censoring at 
final PSA 
measurement 
before 
discontinuation 
The event is 
considered to 
occur at the 
time of 
discontinuation 
The event is 
considered to 
occur at the 
time of 
discontinuation 
Considered as 
censoring at 
final 
radiographic 
assessment 
before 
discontinuation 
Considered as 
censoring at 
final 
radiographic 
assessment 
before 
discontinuation 


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TTPP1 
TTPP2 
2nd TTPP 
Time to PSA 
50%/90% 
decline 
TTF1 
TTF2 
rPFS 
MFS 
Subjects who used prohibited 
concomitant medication or 
therapy during the study  
Subjects who 
use one with 
the first study 
drug are 
considered as 
censoring at 
final PSA 
measurement 
before use 
Considered as 
censoring at 
final PSA 
measurement 
before use 
Subjects who 
use one with 
the first study 
drug are 
excluded from 
analysis 
Subjects who 
use one with 
the second 
study drug are 
considered as 
censoring at 
final PSA 
measurement 
before use 
Considered as 
censoring at 
final PSA 
measurement 
before use 
Not considered 
as censoring 
*To be judged 
based on 
continuation of 
study treatment 
Not considered 
as censoring 
*To be judged 
based on 
continuation of 
study treatment 
Considered as 
censoring at 
final 
radiographic 
assessment 
before use 
Considered as 
censoring at 
final 
radiographic 
assessment 
before use 
Subjects who miss PSA data at 
least twice consecutively at 
scheduled PSA measurement 
points 
Considered as 
censoring at 
final PSA 
measurement 
before missing 
data occur 
Considered as 
censoring at 
final PSA 
measurement 
before missing 
data occur 
Subjects who 
continue the 
first study drug 
are excluded 
from analysis 
Subjects who 
have shifted to 
the second 
study drug are 
considered as 
censoring at 
final PSA 
measurement 
before missing 
data occur 
Considered as 
censoring at 
final PSA 
measurement 
before missing 
data occur 
Not considered 
as censoring 
*To be judged 
based on 
continuation of 
study treatment 
Not considered 
as censoring 
*To be judged 
based on 
continuation of 
study treatment 
Not considered 
as censoring 
*To be judged 
based on result 
of radiographic 
assessment 
Not considered 
as censoring 
*To be judged 
based on result 
of radiographic 
assessment 
Subjects who miss 
radiographic assessment at 
least twice consecutively at 
scheduled radiographic 
assessment points 
Not considered 
as censoring 
*To be judged 
based on result 
of PSA 
measurement 
Not considered 
as censoring 
*To be judged 
based on result 
of PSA 
measurement 
Not considered 
as censoring 
*To be judged 
based on result 
of PSA 
measurement 
Not considered 
as censoring 
*To be judged 
based on result 
of PSA 
measurement 
Not considered 
as censoring 
*To be judged 
based on 
continuation of 
study treatment 
Not considered 
as censoring 
*To be judged 
based on 
continuation of 
study treatment 
Considered as 
censoring at 
final 
radiographic 
assessment 
before missing 
data occur 
Considered as 
censoring at 
final 
radiographic 
assessment 
before missing 
data occur 


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8 
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS 
8.1 
Procedure for Clinical Study Quality Control 
8.1.1 
Data Collection 
8.1.1.1 Case Report Forms 
The investigator or site designee will enter data collected using an Electronic Data Capture 
(EDC) system. In the interest of collecting data in the most efficient manner, the investigator 
or site designee should enter data (including laboratory values, if applicable) in the eCRF 
within 5 days after the subject visit wherever possible. For subjects who dropped out before 
randomization and after obtaining written informed consent, the minimum demographic data 
(subject No., sex, date of birth, date of informed consent) and the reason for dropout will be 
collected in screen failure log (SFL).  
The investigator or site designee is responsible to ensure that all data in the eCRFs and 
queries are accurate and complete and that all entries are verifiable with source documents. 
These documents should be appropriately maintained by the site. 
The monitor should verify the data in the eCRFs with source documents and confirm that 
there are no inconsistencies between them. In case of correction to data, confirm that an 
appropriate record is retained.  
 
8.1.1.2 Subject Reported Outcome 
The investigator or site designee will confirm the subject reported outcome questionnaire slip 
(FACT–P, EQ-5D-5L, BPI-SF, BFI) entered by subjects, and enter in the eCRF. Subjects 
will confirm the content with the investigator or site designee at study visit, make addition 
and modification where necessary in case of unclear description, enter the date of correction 
to the place of addition/modification, and sign or affix the seal.  
 
8.1.1.3 Examination Data 
Laboratory tests are performed at central laboratory. Laboratory data will be electronically 
transferred at predefined intervals during the study to the Sponsor or CRO to whom the 
Sponsor delegates the operation. The laboratory will provide a complete and clean copy of 
the data for the Sponsor or CRO to whom the Sponsor delegates the operation.  
 
 
8.1.2 
Specification of Source Documents 
Source data must be available at the site to document the existence of the study subjects and 
to substantiate the integrity of study data collected. Source data must include the original 


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documents relating to the study, as well as the medical treatment and medical history of the 
subject. 
In this study, the following source materials and content entered in the eCRF (including the 
content of follow-up report if follow-up of AEs is conducted) will be verified.  
The following information should be included in the source medical records:  
● 
Demographic data (e.g., date of birth, sex, height, body weight, etc.) 
● 
Inclusion and exclusion criteria 
● 
Participation in study and original signed and dated informed consent forms  
● 
Medical record and document attached to it 
● 
Medical history and physical examination details 
● 
Key efficacy and safety data (as specified in the protocol) 
● 
Results of relevant examinations (e.g., image films, image photos, etc.) 
● 
Laboratory printouts (including central measurement result slip) 
● 
Subject reported outcome questionnaire slip 
● 
Dispensing and return of study drug details (e.g., study drug control table) and the 
prescriptions etc. for concomitant medications. 
 
If the following data are not entered in the medical record, the content of the eCRF (or 
follow-up report) will be handled as source materials. However, if the following data are 
entered in the medical record or records attached to or stored with the medical record, or the 
following data can be obtained from source materials, data entered in source materials will be 
handled as source data.  
● 
Route of administration, reason for use, and treatment period of previous medication 
and concomitant medication 
● 
Reason for treatment, and treatment period of prior therapy and combination therapy 
● 
Detail of AEs (severity, seriousness, outcome, intervention, relationship with the 
study drug, and rationale for the judgment of relationship) 
● 
Date of final observation, date of discontinuation, reason for discontinuation, 
background of discontinuation 
● 
Comment in the eCRF (or follow-up report) 
 
 
8.1.3 
Clinical Study Monitoring 
The Sponsor or delegated CRO is responsible for monitoring the clinical study to ensure that 
subject’s human rights, safety, and well-being are protected, that the study is properly 
conducted in adherence to the current protocol and GCP, and study data reported by the 
investigator/sub-investigator are accurate and complete and that they are verifiable with 
study-related records such as source documents. The Sponsor is responsible for assigning 
study monitor(s) to this study for proper monitoring. They will monitor the study in 
accordance with planned monitoring procedures. 


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8.1.4 
Direct Access to Source Data/Documents 
The investigator and the study site must accept monitoring and auditing by the Sponsor or 
delegated CRO as well as inspections from the IRB/IEC and relevant regulatory authorities. 
In these instances, they must provide all study-related records, such as source documents 
(refer to Section 8.1.2 “Specification of Source Documents”) when they are requested by the 
Sponsor monitors and auditors, the IRB/IEC, or regulatory authorities. The confidentiality of 
the subject’s identities shall be well protected consistent with local and national regulations 
when the source documents are subject to direct access. 
 
8.1.5 
Data Management 
Data management will be coordinated by CRO to whom the Sponsor delegates the operation 
in accordance with the standard operating procedures (SOPs) for data management. All study 
specific processes and definitions will be documented by Data Management. eCRF retrieval 
and correction process will be referenced in the CRF instructions. Coding of medical terms 
and medications will be performed using MedDRA and World Health Organization Drug 
Dictionary Enhanced (WHODDE) respectively. 
 
8.1.6 
End of Trial 
The end of trial is defined as the last subject’s last visit, decision on discontinuation of the 
study, or the last contact to the last subject, whichever occurs last. 
 
8.2 
Ethics and Protection of Subject Confidentiality 
8.2.1 
Institutional Review Board (IRB) 
Prior to signing the contract agreement of this study, the IRB at each study site will review 
and approve the protocol, and other materials used to obtain informed consent from patients 
in order to ensure the protection of human right, safety, and welfare of the patients. Any 
agreement should not be signed without the approval of the IRB. 
 
8.2.2 
Ethical Conduct of the Study 
The study will be conducted in accordance with the protocol, ICH guidelines, applicable 
regulations and guidelines governing clinical study conduct and the ethical principles that 
have their origin in the Declaration of Helsinki. 
 


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8.2.3 
Informed Consent of Subjects 
8.2.3.1 Subject Information and Consent 
The investigator or his/her representative will explain the nature of the study to the subject, 
and answer all questions regarding this study. Prior to any study-related screening procedures 
being performed on the subject, the informed consent statement will be reviewed and signed 
or placed a personal seal on and dated by the subject or his/her guardian or legal 
representative, the person who administered the informed consent and any other signatories 
according to local requirements. A copy of the signed or sealed informed consent form will 
be given to the subject and the original will be placed in the subject’s medical record. An 
entry must also be made in the subject’s dated source documents to confirm that informed 
consent was obtained prior to any study-related procedures and that the subject received a 
signed copy. 
The signed consent forms will be retained by the investigator and made available (for review 
only) to the study monitor and auditor regulatory authorities and other applicable individuals 
upon request. 
 
8.2.3.2 Supply of New and Important Information Influencing the Subject’s Consent 
and Revision of the Written Information 
1. The investigator or his/her representative will immediately inform the subject orally 
whenever new information becomes available that may be relevant to the subject’s 
consent or may influence the subject’s willingness to continue to participate in the study 
(e.g., report of serious drug adverse drug reaction). The communication must be 
documented in the subject’s medical records and must document whether the subject is 
willing to remain in the study or not. 
2. The investigator must update their ICF and submit it for approval to the IRB. The 
investigator or his/her representative must obtain written informed consent from the 
subject on all updated ICFs throughout their participation in the study. The investigator 
or his/her designee must re-consent subjects with the updated ICF even if relevant 
information was provided orally. The investigator or his/her representative who obtained 
the written informed consent and the subject should sign or place a personal seal, and 
date the informed consent form. A copy of the signed or sealed informed consent form 
will be given to the subject and the original will be placed in the subject’s medical record. 
An entry must be made in the subject’s records documenting the re-consent process. 
 
8.2.4 
Subject Confidentiality 
Individual subject medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited. Such medical information may be 
given only after approval of the subject to the subject’s physician or to other appropriate 
medical personnel responsible for the subject’s well-being. 


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The Sponsor shall not disclose any confidential information on subjects obtained during the 
performance of their duties in the clinical study without justifiable reasons. 
All individuals and organizations involved in the study must pay very careful attention to 
protect subjects’ privacy with appropriate measures, for example, by prohibiting the use of 
any private information that may identify a subject (e.g., name or address). These details 
shall be processed in accordance with the applicable local and regional laws. 
Even though any individuals involved in the study, including the study monitors and auditors, 
may get to know matters related to subject’s privacy due to direct access to source documents, 
or from other sources, they may not leak the content to third parties. 
 
8.3 
Administrative Matters 
8.3.1 
Arrangement for Use of Information and Publication of the Clinical Study 
Information concerning the study drug, patent applications, processes, unpublished scientific 
data, and other pertinent information is confidential and remains the property of the Sponsor. 
Details should be disclosed only to the persons involved in the approval or conduct of the 
study. The investigator may use this information for the purpose of the study only. It is 
understood by the investigator that the Sponsor will use the information obtained during the 
clinical study for the collection of information on proper use of the study drug and therefore 
may disclose it as required to other clinical investigators or to regulatory agencies. In order to 
allow for the use of the information derived from this clinical study, the investigator 
understands that he/she has an obligation to provide the Sponsor with all data obtained during 
the study. 
Publication of the study results is discussed in the Clinical Study Agreement. 
After agreement between investigator(s) and sponsor, the manuscript can be submitted for 
publication. 
 
8.3.2 
Documents and Records Related to the Clinical Study 
The Sponsor will provide the investigator and/or institution with the following:  
● 
Study protocol (and amendments, where applicable) 
● 
eCRFs and their relevant documents, JUTOKUNA YUUGAIJISHOU 
HOUKOKUSHO, and follow-up report 
● 
Study drug with all necessary documentation 
● 
Study contract 
In order to start the study, the investigator and study site is required to provide the following 
documentation to the Sponsor: 
● 
Agreement with the investigator on this protocol 
● 
Current Curricula Vitae of all investigators 


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● 
List of sub-investigators and collaborators  
● 
IRB approval of the protocol, protocol amendments (if applicable) including a 
membership list with names and qualification (COPY) 
● 
Instruction and decision of the head of the study site 
● 
Study contract 
● 
Laboratory normal reference ranges (including modified or revised versions) 
 
At the end of the study, the sponsor is responsible for the collection of:  
● 
Unused study documentation,  
● 
Unused study drug 
 
The investigator will archive all study data (e.g., Subject Identification Code List, source data, 
eCRFs, and Investigator’s File) and relevant correspondence. These documents are to be kept 
on file for the appropriate term determined by local regulation. 
The records to be retained at the study sites are the ones listed as essential documents in GCP. 
These records shall be retained by the head of the study site or the record keeper designated 
by the head until notice issued by the Sponsor on completion of the retention period is 
received. These documents are also subject to direct access and should be provided upon 
request from the Sponsor or regulatory authorities. 
The head of the study site will retain the essential documents that should be stored at the 
study site in an appropriate manner according to the rules of the study site concerned until the 
date of the end of re-examination/re-evaluation of the test drug. 
The following are the major documents to be retained at the study site. 
1. Source documents (clinical data, documents, and records for preparing the CRF)  
Hospital records, medical records and record attached to the medical records, test records, 
memoranda, subject reported outcome questionnaire slip, prescription records, data 
recorded by automatic measuring instruments, reproductions or transcripts verified as 
precise copies, microfiche, negative films, microfilms/magnetic media, X-ray films, 
subject files and study-related records kept at either a pharmacy, a laboratory, or medical 
technical office, as well as subject registration forms, laboratory test slips including 
central measurement, worksheets specified by the Sponsor, records of clinical 
coordinators, and records related to the clinical study selected from those verified in 
other departments or hospitals.  
2. Contracts, written informed consent forms, written information, and other documents or 
their copies prepared by the study personnel.  
A letter of request for clinical study (including a request for continuation/amendment), 
letter of request for review, notice of clinical study contract, clinical study contract, 
notification of discontinuation or completion of clinical study, written information for 
informed consent (including revisions), signed and dated written informed consent 


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(including revisions), CVs of investigators, list of sub-investigators, list of signatures and 
print of seals (copy), and electronic media that contain data of eCRFs, etc.  
3. The protocol, documents obtained from the IRB related to the adequacy of conducting 
the clinical study by the head of the study sites (Article 32-1, MHW Ordinance No. 28), 
documents obtained from the IRB related to the adequacy of conducting a clinical study 
whose period exceeds one year or the adequacy of continuously conducting the clinical 
study from which information on adverse drug reactions is obtained, and other 
documents obtained.  
An agreed-upon protocol (including revisions), operational procedures for the 
investigator, materials and information supplied by the Sponsor (e.g., AE report), matters 
reported by the investigator (revisions of the protocol, AE reports, etc.), operational 
procedures for the IRB, the list of names of the IRB members, materials for IRB review 
(including continuous deliberation), IRB review records (including continuous 
deliberation), and the review result report of the IRB (including continuous deliberation), 
etc.  
4. Records of control for study drugs and other duties related to the clinical study.  
Procedure for controlling the study drugs, drug accountability record, vouchers for the 
receipt and return of the study drugs, and the prescriptions for concomitant medications. 
 
8.3.3 
Protocol Amendment and/or Revision 
Any changes to the study that arise after approval of the protocol must be documented as 
protocol amendments and/or revisions. Depending on the nature of the amendment, either 
IRB, Competent Authority approval or notification may be required. The changes will 
become effective only after the approval of the Sponsor, the investigator, and the IRB 
followed by the approval of the head of the study site. 
 
8.3.4 
Insurance of Subjects and Others 
If a subject suffers any study-related injury, the Sponsor will compensate appropriately 
according to the severity and duration of the damage. However, if it was caused intentionally 
or was due to gross negligence by the study site, the Sponsor will consult with the study site 
about handling the injury, based on the agreed study contract. Compensation for the study-
related injury is provided by the following procedures:  
1. If a subject incurs an injury as a result of participation in the clinical study, the study site 
should provide medical treatment and other necessary measures. The Sponsor should be 
notified of the injury.  
2. When the subject claims compensation from the study site for the above study-related 
injury, or such compensation may be claimed, the study site should immediately 
communicate the fact to the Sponsor. Both parties should work together towards 
compensation settlement.  


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3. The Sponsor shall pay compensation or indemnification and bear expenses necessary for 
the settlement as provided in the clinical contract.  
4. The Sponsor shall make an arranging for insurance and take measures necessary to 
ensure the compensation or indemnification mentioned above. 
 
8.3.5 
Signatory Investigator for Clinical Study Report 
Not applicable. 
 
9 
QUALITY ASSURANCE 
The Sponsor is implementing and maintaining quality assurance and quality control systems 
with written SOPs to ensure that trials are conducted and data are generated, documented, 
recorded, and reported in compliance with the protocol, GCP, and applicable regulatory 
requirement(s). 
The Sponsor or Sponsor’s designee may arrange to audit the clinical study at any or all 
investigational sites and facilities. The audit may include on-site review of regulatory 
documents, eCRFs, and source documents. Direct access to these documents will be required 
by the auditors. 
 
10 
STUDY ORGANIZATION 
10.1 
Independent Data-Monitoring Committee (IDMC) | Data and Safety 
Monitoring Board (DSMB) | Monitoring Committee | Other 
Evaluation Committee(s) 
Not applicable. 
 
10.2 
Other Study Organization 
See Attachments 1 and 2. 
 
10.3 
Registration of Subjects 
The investigator or sub-investigator will survey the background of prospective subjects, 
obtain written informed consent, and confirm inclusion/exclusion criteria during the 
screening period. The investigator or site designee will enter necessary information in a 
subject registration form on the web registration system at study visit at Week 1 (Day 1) of 
1st line AAT, and transmit it to the registration center. The registration center will receive the 
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drug to qualified subjects. The registration center will notify the judgment of subject 
registration and allocated drug name to the study site via the web registration system.  
The investigator or sub-investigator will confirm that the registration is appropriate, and 
prescribe the study drug instructed by the registration center as 1st line AAT. For patients 
who are judged unqualified for the registration, the study for those subjects will be 
discontinued at that time.  
The investigator or sub-investigator will confirm the criteria for shifting from 1st line AAT to 
2nd line AAT at study visit at Week 1 (Day 1) of 2nd line AAT. The investigator or site 
designee will enter necessary information in a subject registration form on the web 
registration system, and transmit it to the registration center. Thereafter, the investigator or 
sub-investigator will confirm that the registration is appropriate, and prescribe the drug of 
2nd line AAT, which is different from the drug of 1st line AAT.  
The investigator or site designee will, at completion or discontinuation of the study, enter 
necessary information in a subject registration form on the web registration system, and 
transmit it to the registration center.  
 


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Flow of subject enrollment:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
Screening 
Confirm inclusion/exclusion criteria 
Registration 
Register subject information 
Confirm subject enrollment 
(applicable) 
Prescribe the instructed study drug 
Registration 
Register subject information 
1st line AAT 
2nd line AAT 
web 
web 
Drug allocation 
web 
web 
Confirm subject enrollment 
(applicable) 


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11 
REFERENCES 
Matsuda A, Matsuda T, Shibata A, Katanoda K, Sobue T, Nishimoto H and The Japan Cancer 
Surveillance Research Group. Cancer Incidence and Incidence Rates in Japan in 2008: A Study 
of 25 Population-based Cancer Registries for the Monitoring of Cancer Incidence in Japan 
(MCIJ) Project. Japanese Journal of Clinical Oncology, 44(4):388-396, 2013. 
Narimoto K, Mizokami A, Izumi K, Mihara S, Sawada K, Sugata T, Shimamura M, Miyazaki K, 
Nishino A, Namiki M. Adrenal androgen levels as predictors of outcome in castration-resistant 
prostate cancer patients treated with combined androgen blockade using flutamide as a second-
line anti-androgen. Int J Urol. 2010 Apr;17(4):337-45. 
The Japanese Urological Association, (ed.). Prostate Cancer Treatment Guideline 2012. KANEHARA 
& Co., LTD.; 2012. 
Okihara K, Ukimura O, Kanemitsu N, Mizutani Y, Kawauchi A, Miki T. Kyoto Prefectural 
University of Medicine Prostate Cancer Research Group. Clinical efficacy of alternative 
antiandrogen therapy in Japanese men with relapsed prostate cancer after first-line hormonal 
therapy. Int J Urol. 2007 Feb;14(2):128-32. 
Schoenfeld DA. Sample-Size Formula for the Proportional-Hazards Regression Model. Biometrics. 
1983 June;39(2):499-503. 
Sobue T, Katanoda K, Ajiki W, Tsukuma H, Ioka A, Center for Cancer Control and Information 
Services, National Cancer Center. Cancer/Statistics White Paper 2012−for data-based measures 
against cancer. Shinoharashinsha Publishers Inc.; 2012. 
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A, Global cancer statistics, 2012. CA 
Cancer J Clin. 2015 Mar;65(2):87-1082. 
 


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12 
APPENDICES 
12.1 
List of Excluded Concomitant Medications 
● 
Anti-androgenic agents (steroid or non-steroid) other than study drugs such as 
chlormadinone and bicalutamide 
● 
CYP17 inhibitor (abiraterone) 
● 
Cytocidal chemotherapy that includes estramustine 
● 
Systemic corticosteroids for prostate cancer or systemic corticosteroids greater than the 
equivalent of 10 mg per day of prednisone (Decadron 1 mg/day) for other diseases  
● 
5-α reductase inhibitors (finasteride, dutasteride) 
● 
Estrogen or progesterone agents such as medroxyprogesterone and diethylstilbestrol 
(DES) 
● 
Biological agents or other drugs with anticancer activity to prostate cancer 
● 
Herbal medications that may have hormonal anti-prostate cancer activity or herbal 
medications (saw palmetto) that may decrease serum PSA levels 
● 
Androgen (e.g., testosterone, dehydroepiandrosterone [DHEA]) 
● 
Study drug for prostate cancer 
● 
Warfarin 


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12.2 
Liver Safety Monitoring and Assessment 
Any subject enrolled in a clinical study with active drug therapy and reveals an increase of 
serum aminotransferases (AT) to > 3 × ULN (to > 5 × ULN in subjects with liver metastases), 
or bilirubin > 2 × ULN, should undergo detailed testing for liver enzymes (including at least 
ALT, AST, ALP, and TBL). Testing should be repeated within 48 to 72 hours of notification 
of the test results. For studies for which a central laboratory is used, alerts will be generated 
by the central lab regarding moderate and severe liver abnormality to inform the investigator, 
study monitor, and study team. Subjects should be asked if they have any symptoms 
suggestive of hepatobiliary dysfunction. 
Definition of Liver Abnormalities 
Confirmed abnormalities will be characterized as moderate and severe where ULN:  
 
 
ALT or AST 
 
Total Bilirubin 
Moderate 
 
> 3 × ULN (in patients 
without liver metastases),  
>5 × ULN (in patients 
with liver metastases) 
or 
> 2 × ULN 
Severe* 
 
> 3 × ULN 
and 
> 2 × ULN 
 
In addition, the subject should be considered to have severe hepatic abnormalities for any of 
the following:  
● 
ALT or AST > 8 × ULN 
● 
ALT or AST > 5 × ULN for more than 2 weeks (in the absence of liver metastases) 
● 
ALT or AST > 3 × ULN and INR > 1.5 (If INR testing is applicable/evaluated). 
● 
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%).  
The investigator may determine that abnormal liver function results, other than as described 
above, may qualify as moderate or severe abnormalities and require additional monitoring 
and follow-up. 
Follow-up Procedures 
Confirmed moderate and severe abnormalities in hepatic functions should be thoroughly 
characterized by obtaining appropriate expert consultations, detailed pertinent history, 
physical examination and laboratory tests. The site should complete the Liver Abnormality 
Case Report Form (LA-CRF) or an appropriate document. Subjects with confirmed abnormal 
liver function testing should be followed as described below. 
Confirmed moderately abnormal LFTs should be repeated 2 to 3 times weekly then weekly 
or less if abnormalities stabilize or the study drug has been discontinued and the subject is 
asymptomatic.  
Severe hepatic liver function abnormalities as defined above, in the absence of another 
etiology may be considered an important medical event and may be reported as an SAE. The 


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Sponsor should be contacted and informed of all subjects for whom severe hepatic liver 
function abnormalities possibly attributable to study drug are observed. 
To further assess abnormal hepatic laboratory findings, the investigator is expected to:  
● 
Obtain a more detailed history of symptoms and prior or concurrent diseases. Symptoms 
and new onset-diseases should be recorded as ‘AEs’ on the AE page of the eCRF. 
Illnesses and conditions such as hypotensive events, and decompensated cardiac disease 
that may lead to secondary liver abnormalities should be noted. Non-alcoholic 
steatohepatitis (NASH) is seen in obese hyperlipoproteinemic, and/or diabetic patients 
and may be associated with fluctuating aminotransferase levels. The investigator should 
ensure that the medical history form captures any illness that pre-dates study enrollment 
that may be relevant in assessing hepatic function.  
● 
Obtain a history of concomitant drug use (including non-prescription medication, 
complementary and alternative medications), alcohol use, recreational drug use, and 
special diets. Medications, including dose, should be entered on the concomitant 
medication page of the eCRF. Information on alcohol, other substance use, and diet 
should be entered on the LA-CRF or an appropriate document. 
● 
Obtain a history of exposure to environmental chemical agents. 
● 
Based on the subject’s history, other testing may be appropriate including:  
○ acute viral hepatitis (A, B, C, D, E or other infectious agents) 
○ ultrasound or other imaging to assess biliary tract disease 
○ other laboratory tests including INR, direct bilirubin 
● 
Consider gastroenterology or hepatology consultations. 
● 
Submit results for any additional testing and possible etiology on the LA-CRF or an 
appropriate document. 
Study Discontinuation 
In the absence of an explanation for increased LFT’s, such as viral hepatitis, pre-existing or 
acute liver disease, presence of liver metastases, or exposure to other agents associated with 
liver injury, the subject may be discontinued from the study. The investigator may determine 
that it is not in the subject’s best interest to continue study enrollment. Discontinuation of 
treatment should be considered if:  
● 
ALT or AST > 8 × ULN 
● 
ALT or AST > 5 × ULN for more than 2 weeks (in subjects without liver metastases) 
● 
ALT or AST > 3 × ULN and TBL > 2 × ULN or INR > 1.5 (If INR testing is 
applicable/evaluated) 
● 
ALT or AST > 5 × ULN (TBL > 2 × ULN in patients with liver metastases) 
● 
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%).  
In addition, if close monitoring for a subject with moderate or severe hepatic laboratory tests 
is not possible, drug should be discontinued. 


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*Hy’s Law Definition-Drug-induced jaundice caused by hepatocellular injury, without a 
significant obstructive component, has a high rate of bad outcomes, from 10% to 50% 
mortality (or transplant). The two “requirements” for Hy’s Law are: 1. Evidence that a drug 
can cause hepatocellular-type injury, generally shown by an increase in transaminase 
elevations higher 3 times the ULN (“2 × ULN elevations are too common in treated and 
untreated patients to be discriminating”). 2. Cases of increased bilirubin (at least 2 × ULN) 
with concurrent transaminase elevations at least 3 × ULN and no evidence of intra- or extra-
hepatic bilirubin obstruction (elevated alkaline phosphatase) or Gilbert’s syndrome. [Temple 
R. Hy’s law: predicting serious hepatotoxicity. Pharmacoepidemiol Drug Saf 2006 
Apr;15(4):241-3.] 
Reference 
Guidance for Industry titled “Drug-Induced Liver Injury: Premarketing Clinical Evaluation” issued by 
FDA on July 2009.  
 
 


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12.3 
Always Serious Events 
The following events must be reported as SAEs in accordance with Section 5.5.5 Reporting 
of Serious Adverse Events (SAEs). 
● 
Acute liver failure 
● 
Acute renal failure 
● 
Acute respiratory failure 
● 
Agranulocytosis 
● 
Anaphylaxis 
● 
Any malignancy 
● 
Aplastic anaemia 
● 
Confirmed or suspected transmission of infectious agents by marketed product 
● 
Congenital anomalies 
● 
Hepatic necrosis 
● 
Malignant hypertension 
● 
Pulmonary hypertension 
● 
Convulsion 
● 
Torsades de pointe 
● 
Toxic epidermal necrolysis 
● 
Ventricular fibrillation 
● 
Haemolytic anaemia 
● 
Bone marrow failure 
● 
Myocardial infarction 
● 
Cardiac arrest 
● 
Deafness 
● 
Blindess 
● 
Pancreatitis acute 
● 
Acute graft versus host disease 
● 
Septic shock 
● 
Sepsis 
● 
Rhabdomyolysis 
● 
Respiratory failure 
● 
Stevens-Johnson syndrome 
 


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12.4 
ECOG Performance Status 


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12.5 
FACT–P 
 


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12.6 
EQ-5D-5L 


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12.7 
BPI-SF 
 
 
 


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12.8 
BFI 


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(GPF 4.1J) 

SAP_001.pdf: 
Sponsor: Astellas Pharma Inc.
SAP Final Version 1.00
ISN/Protocol 9785-MA-3051
8 July 2020
Astellas
Page 1 of 51
STATISTICAL ANALYSIS PLAN
Final Version 1.00, dated 8-July 2020
A Randomized Phase IV Study Comparing Enzalutamide versus Flutamide in CRPC Patients 
Who Have Failed Combined Androgen Blockade Therapy with Bicalutamide plus ADT
This confidential document is the property of the sponsor. No unpublished information 
contained in this document may be disclosed without prior written approval of the sponsor.
ISN: 9785-MA-3051
Sponsor name
Astellas Pharma Inc. (API)/
2-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo


Sponsor: Astellas Pharma Inc.
SAP Final Version 1.00
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8 July 2020
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Page 2 of 51
Table of Contents
I.
LIST OF ABBREVIATIONS AND KEY TERMS········································ 5
List of Abbreviations······················································································ 5
List of Key Terms ························································································· 6
1
INTRODUCTION ············································································· 7
2
FLOW CHART AND VISIT SCHEDULE················································· 8
3
STUDY OBJECTIVE(S) AND DESIGN··················································13
3.1
Study Objective(s) ············································································13
3.1.1
Primary Objective·············································································13
3.1.2
Secondary Objectives·········································································13
3.1.3
Safety Objective···············································································13
3.1.4
Exploratory Objectives ·······································································13
3.2
Study Design···················································································14
3.3
Randomization·················································································15
4
SAMPLE SIZE················································································15
5
ANALYSIS SETS ············································································17
5.1
Intent-to-Treat (ITT)··········································································17
5.2
Safety Analysis Set (SAF) ···································································17
5.3
Pharmacokinetic Analysis Set (PKAS)·····················································17
5.4
Pharmacodynamic Analysis Set (PDAS)···················································17
6
ANALYSIS VARIABLES···································································17
6.1
Efficacy Endpoints············································································17
6.1.1
Primary Efficacy Endpoint(s)································································17
6.1.2
Secondary Efficacy Endpoints·······························································18
6.1.3
Safety Endpoints ··············································································20
6.1.4
Exploratory Efficacy Endpoints·····························································20
6.1.5
Other Efficacy Variables ·····································································22
6.2
Safety Variables···············································································22
6.3
Pharmacokinetic Variables···································································23
6.4
Pharmacodynamic Variables ································································23
6.5
Other Variables················································································23


Sponsor: Astellas Pharma Inc.
SAP Final Version 1.00
ISN/Protocol 9785-MA-3051
8 July 2020
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7
STATISTICAL METHODOLOGY ························································25
7.1
General Considerations·······································································25
7.1.1
General Principles·············································································25
7.1.2
Definitions and Computations·······························································26
7.2
Study Population ··············································································28
7.2.1
Disposition of Subjects·······································································28
7.2.2
Demographic and Other Baseline Characteristics·········································28
7.2.3
Medical History ···············································································29
7.2.4
Previous and Concomitant Medications····················································29
7.2.5
Previous Therapies for Prostate Cancer ····················································30
7.2.6
Prior Surgical Procedures for Prostate Cancer·············································30
7.3
Study Drugs····················································································30
7.3.1
Exposure ·······················································································30
7.3.2
Dose Modification ············································································31
7.3.3
Treatment Compliance ·······································································31
7.4
Analysis of Efficacy ··········································································31
7.4.1
Analysis of Primary Endpoint ·······························································31
7.4.2
Analysis of Secondary Endpoints ···························································32
7.4.3
Analysis of Exploratory Endpoints ·························································34
7.4.4
Analysis of Other Variables ·································································40
7.5
Analysis of Safety·············································································40
7.5.1
Adverse Events················································································40
7.5.2
Clinical Laboratory Evaluation······························································42
7.5.3
Vital Signs ·····················································································43
7.5.4
ECOG performance status ···································································43
7.5.5
Electrocardiograms (ECGs)··································································43
7.5.6
Pregnancies ····················································································43
7.5.7
Other Safety-Related Observations ·························································43
7.6
Analysis of PK·················································································44
7.7
Analysis of PD·················································································44
7.8
Subgroups of Interest ·········································································44


Sponsor: Astellas Pharma Inc.
SAP Final Version 1.00
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8 July 2020
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7.9
Other Analyses ················································································45
7.10
Interim Analysis (and Early Discontinuation of the Clinical Study)····················45
7.11
Handling of Missing Data, Outliers, Visit Windows, and Other Information ·········45
7.11.1
Missing Data···················································································45
7.11.2
Outliers ·························································································45
7.11.3
Visit Windows·················································································45
8
DOCUMENT REVISION HISTORY······················································48
9
REFERENCES ················································································48
10
APPENDICES·················································································50
10.1
Appendix 1: Key Contributors and Approvers ············································50


Sponsor: Astellas Pharma Inc.
SAP Final Version 1.00
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8 July 2020
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I.
LIST OF ABBREVIATIONS AND KEY TERMS
List of Abbreviations
Abbreviations
Description of abbreviations
AAT
Alternative Antiandrogen Therapy
CI
Confidence Interval
ADT
Androgen Deprivation Therapy
AE
Adverse Event
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
BFI
Brief Fatigue Inventory
BPI-SF
Brief Pain Inventory-Short Form
BMI
Body Mass Index
CAB
Combined Androgen Blockade
CR
Complete Response
CSR
Clinical Study Report
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EQ-5D-5L
European Quality of Life-5 Dimension-5 Level Instruments
FACT-P
Functional Assessment of Cancer Therapy–Prostate
GnRH
Gonadotropin Releasing Hormone
ICH
International Conference on Harmonization
ITT
Intent-to-Treat
LDH
Lactate Dehydrogenase
HIFU
High Intensity Focused Ultrasound
MedDRA
Medical Dictionary for Regulatory Activities
MFS
Metastasis-Free Survival
MRI
Magnetic Resonance Imaging
NE
Non-evaluable
ORR
Objective Response Rate
PCWG2
Prostate Cancer Clinical Trials Working Group 2
PD
Progressive Disease
PDAS
Pharmacodynamic Analysis Set
PK
Pharmacokinetics
PKAS
Pharmacokinetic Analysis Set
PR
Partial Response
PT
Preferred Term
PSA
Prostate-Specific Antigen
QOL
Quality of Life
RECIST
Response Evaluation Criteria in Solid Tumors
rPFS
Radiographic Progression-Free Survival
SAE
Serious Adverse Event
SAF
Safety Analysis Set
SAP
Statistical Analysis Plan
SOC
System Organ Class
SMQ
Standard MedDRA Query
TURP
Transurethral Resection of the Prostate


Sponsor: Astellas Pharma Inc.
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List of Key Terms
TTF1
Time to Treatment Failure 1
TTF2
Time to Treatment Failure 2
TTPP1
Time to PSA Progression 1
TTPP2
Time to PSA Progression 2
2nd TTPP
2nd Time to PSA Progression
ULN
Upper Limit of Normal
WHO-DD
World Health Organization Drug Dictionary
Terms
Definition of terms
Endpoint
A variable that pertains to the trial objectives
Variable
Any quantity that varies; any attribute, phenomenon or event that can have 
different qualitative or quantitative values.


Sponsor: Astellas Pharma Inc.
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1
INTRODUCTION
This Statistical Analysis Plan (SAP) contains a more technical and detailed elaboration of the 
principal features of the analysis described in the protocol, and includes detailed procedures 
for executing the statistical analysis of the primary and secondary endpoints and other data. 
The SAP is finalized and signed prior to database hard lock.
This statistical analysis is prepared by 
 and approved by the responsible 
biostatistician of Astellas Pharma Inc.. Any changes from the analyses planned in the SAP 
will be justified in the Clinical Study Report (CSR).


Sponsor: Astellas Pharma Inc.
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2
FLOW CHART AND VISIT SCHEDULE
Flow Chart
*1: 28 days after final study treatment, or before starting other study drugs, or before starting other treatment for prostate cancer, whichever comes first
*2:
Subjects who discontinued the 1st line AAT due to PSA progression will start the 2nd line AAT within 6 weeks after the date of examination that identified 
PSA progression. Subjects who discontinued the 1st line AAT due to other reasons will start the 2nd line AAT within 6 weeks from the day when the 
investigator or subinvestigator decided the discontinuation.
Group A
Group B
PSA progression
PSA progression
*2
*2
Flutamide 375 mg/day
+
Androgen Deprivation Therapy
Enzalutamide 160 mg/day
+
Androgen Deprivation Therapy
Flutamide 375 mg/day
+
Androgen Deprivation Therapy
Randomization
Obtaining 
informed 
consent
Enzalutamide 160 mg/day
+
Androgen Deprivation Therapy
Screening period
Weeks −4 to −1 (Days −28 to −7)
Confirmation 
of in/exclusion 
criteria
1st line AAT
(Every 4-week visit)
2nd line AAT
(Every 4-week visit)
Safety follow-up
(28 days after final study 
treatment*1)
Safety follow-up


Sponsor: Astellas Pharma Inc.
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Table 1: Schedule of Assessments
1st line AAT
Screening period
1st line AAT
Unscheduled*a
Visit Days
Days −28 to −7
1
29
57
85 and every 
subsequent 84 days
113 and every 
subsequent 28 days 
–
Visit Weeks
−4 to −1
1
5
9
13 and every 
subsequent 12 weeks 
17 and every 
subsequent 4 weeks 
–
Allowed visit window (days)
–
–
± 7
± 7
± 7
± 7
–
Informed consent*b
X *b
Subject background survey
X
Confirmation of in/exclusion criteria
X
X
Randomization/enrollment
X *c
Vital signs*d
X
X
X
X
X
X
X
Height/body weight
X
Laboratory tests*e
X
X
X
X
X
X
X
PSA
X
X
X
X
X
Abdominopelvic CT/MRI and bone 
scintigraphy (every 3 months) 
X *f
X
X
Chest CT
X *f
X *g
X
ECOG Performance Status
X
X
X
X
X
X
X
FACT-P
X
X
EQ-5D-5L
X
X
Brief Pain Inventory-Short Form 
(BPI-SF)*h
X
X
X
Brief Fatigue Inventory (BFI) 
X
X
X
Adverse event survey*i
X
X
X
X
X
X
Survey on previous/concomitant 
medication 
X
X
X
X
X
X
X
Study drug prescription (every month) 
X
X
X
X
X
CT: Computed Tomography, ECOG: Eastern Cooperative Oncology Group, FACT-P: Functional Assessment of Cancer Therapy–Prostate
*a:
Unscheduled visit may be made whenever adverse events should be assessed, or PSA progression and disease progression should be confirmed. Laboratory 
tests, PSA measurement, and diagnostic imaging will be performed when assessment is required. 
*b:
Informed consent will be obtained within 42 days before enrollment (Day 1) and before initiating the scheduled study procedures. 
*c:
Randomization should be performed on Day 1 after the confirmation of eligibility. 


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*d:
Measure vital signs (blood pressure and pulse rate) at each visit. 
*e:
Laboratory tests include hematology, biochemistry, blood glucose test, and urinalysis. 
*f:
Imaging diagnosis performed before informed consent and within 42 days before randomization can be used as baseline data. 
*g:
Not required if no chest metastasis is identified in the screening chest CT. 
*h:
Instruct subjects to assess prostate cancer-related pains. 
*i:
Collect all adverse events in the period from the start of study treatment to the date of safety follow-up visit. 


Sponsor: Astellas Pharma Inc.
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2nd line AAT
2nd line AAT
Unscheduled*1
At the end or 
discontinuation*2
Safety 
follow-up
Visit Days 
1
29
57
85 and every 
subsequent 84 days 
113 and every 
subsequent 28 
days 
–
–
–
Visit Weeks 
1
5
9
13 and every 
subsequent 12 
weeks
17 and every 
subsequent 4
weeks 
–
Final treatment
28 days 
after final 
treatment*3
Allowed visit window (days)
–
± 7
± 7
± 7
± 7
–
Within 7 days 
after final 
treatment*11
± 7
Enrollment
X
X
Vital signs*4
X
X
X
X
X
X
X
X
Laboratory tests *5
X
X
X
X
X
X
X
X
PSA
X
X
X
X
X
X
Abdominopelvic CT/MRI and bone 
scintigraphy (every 3 months) 
X *6
X
X *12
Chest CT
X *6,7
X
X *12
ECOG Performance Status
X
X
X
X
X
X
X
X
FACT-P
X *8
X *8
X *12
EQ-5D-5L
X *8
X *8
X *12
Brief Pain Inventory-Short Form 
(BPI-SF) *9
X *8
X *8
X *12
Brief Fatigue Inventory (BFI) 
X *8
X *8
X *12
Adverse event survey*10
X
X
X
X
X
X
X
X
Previous/concomitant medication 
X
X
X
X
X
X
X
X
Study drug prescription (every 
month) 
X
X
X
X
X
CT: Computed Tomography, ECOG: Eastern Cooperative Oncology Group, FACT-P: Functional Assessment of Cancer Therapy–Prostate
*1:
Unscheduled visit may be made during the study period whenever adverse events should be assessed, or PSA progression and disease progression should be 
confirmed. Laboratory tests, PSA measurement, and diagnostic imaging will be performed when assessment is required. If the study is discontinued at an 
unscheduled visit, perform laboratory tests, PSA measurement, and diagnostic imaging wherever possible. 


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*2:
For subjects who finished or discontinued the study with the 1st line AAT or 2nd line AAT, immediately perform examination/observation wherever 
possible. 
*3:
Conduct a visit for safety follow-up 28 days after the final study treatment, or before start of cytocidal chemotherapy, or before start of other new treatment 
for prostate cancer, whichever comes first. 
*4:
Measure vital signs (blood pressure and pulse rate) at each visit. 
*5:
Laboratory tests include hematology, biochemistry, blood glucose test, and urinalysis. 
*6:
Perform diagnostic imaging every 12 weeks after Day 1 of 1st line AAT, independently from switching medications. 
*7:
Not required if no chest metastasis is identified in screening chest CT. 
*8:
Start the evaluation after switching the drugs on Day 1 of 2nd line AAT, and implement every subsequent 12 weeks. 
*9:
Instruct subjects to assess prostate cancer-related pains. 
*10: Collect all adverse events until the date of safety follow-up visit. If there is no safety follow-up visit, collect adverse events until 28 days after the final study 
treatment. If subjects do not show up on the safety follow-up visit, confirm adverse events by the telephone wherever possible. 
*11: For subjects who discontinued the study treatment after the treatment interruption due to adverse events, adopt data within 7 days after the final study 
treatment as discontinuation data. If no data is available in the period within 7 days after the final study treatment, perform a discontinuation 
examination/observation immediately after the decision of discontinuation. 
*12: Not required if it occurs within 28 days from the latest measurement.


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3
STUDY OBJECTIVE(S) AND DESIGN
3.1
Study Objective(s)
3.1.1
Primary Objective
●
To determine the benefit of enzalutamide + Androgen Deprivation Therapy (ADT)
therapy as compared to flutamide + ADT therapy as assessed by time to prostate-specific 
antigen (PSA) progression with 1st line alternative antiandrogen therapy (AAT) (time to 
PSA progression 1 [TTPP1]).
3.1.2
Secondary Objectives
●
To determine the order of AAT treatment as assessed by time to PSA progression with 
1st line AAT + 2nd line AAT (time to PSA progression 2 [TTPP2]). 
●
To determine the benefit of enzalutamide + ADT therapy as compared to flutamide + 
ADT therapy as assessed by PSA response rate to 1st line AAT (proportion of subjects 
with a decrease by at least 50% or 90% from baseline irrespective of the timing). 
●
To determine the benefit of enzalutamide + ADT therapy as compared to flutamide + 
ADT therapy as assessed by PSA response rate to 1st line AAT at Week 13 (proportion 
of subjects with a decrease by at least 50% or 90% from baseline). 
●
To determine the benefit of enzalutamide + ADT therapy as compared to flutamide + 
ADT therapy as assessed by time to PSA decrease by 50% from baseline with 1st line 
AAT. 
●
To determine the benefit of enzalutamide + ADT therapy as compared to flutamide + 
ADT therapy as assessed by time to treatment failure of 1st line AAT (time to treatment 
failure 1 [TTF1]). 
●
To determine the order of AAT treatment as assessed by time to treatment failure of 2nd 
line AAT (time to treatment failure 2 [TTF2]). 
●
To determine the benefit of enzalutamide + ADT therapy as compared to flutamide + 
ADT therapy as assessed by radiographic progression-free survival (rPFS). 
3.1.3
Safety Objective
●
To determine the safety of enzalutamide + ADT therapy as compared to flutamide + ADT 
therapy. 
3.1.4
Exploratory Objectives
●
To evaluate time to PSA progression with 2nd line AAT (2nd time to PSA progression
[2nd TTPP]). 
●
To evaluate PSA response rate to 2nd line AAT. 
●
To determine the benefit of enzalutamide + ADT therapy as compared to flutamide + 
ADT therapy as assessed by metastasis-free survival (MFS). 


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●
To evaluate Quality of Life (QOL) on 1st line AAT and 2nd line AAT using Functional 
Assessment of Cancer Therapy–Prostate (FACT-P) and European Quality of Life 5-
Dimension-5 Level instruments (EQ-5D-5L).
●
To evaluate Brief Pain Inventory-Short Form (BPI-SF) with 1st line AAT and 2nd line 
AAT. 
●
To evaluate Brief Fatigue Inventory (BFI) with 1st line AAT and 2nd line AAT. 
●
To determine the benefit of enzalutamide + ADT therapy as compared to flutamide + 
ADT therapy as assessed by objective response rate (ORR) in soft tissue with 1st line 
AAT based on the best overall response in Response Evaluation Criteria in Solid Tumors
(RECIST) guidelines. 
●
To evaluate the efficacy in subgroups according to disease-related patient demographics. 
3.2
Study Design
This is a randomized, open-label, comparative study on enzalutamide and flutamide. 
Patients with M0 or M1 castration-resistant prostatic neoplasm that relapsed during combined 
androgen blockade (CAB) therapy with bicalutamide will be randomized to Group A or B. 
Dynamic allocation will be performed with minimization with biased coin technique. The 
following stages (M0/N0, M0/N1, or M1) will be used as allocation factors. 
●
M0/N0: No distant metastasis, and no lymph node metastasis
●
M0/N1: Without distant metastasis, but with metastasis in lymph nodes distal to the 
aortic bifurcation
●
M1: With distant metastasis (including metastasis in lymph nodes proximal to the 
aortic bifurcation)
For subjects in Group A, enzalutamide is administered as the 1st line AAT. After the 
confirmation of PSA progression, medication is changed from enzalutamide to flutamide as 
the 2nd line AAT. For subjects in Group B, flutamide is administered as the 1st line AAT. 
After the confirmation of PSA progression, medication is changed from flutamide to 
enzalutamide as the 2nd line AAT. The treatment period with each drug should not be more 
than 2 years from the enrollment of the last subjects. 
PSA progression will be defined according to the consensus guidelines of prostate cancer 
clinical trials working group 2 (PCWG2). For patients with PSA declines at Week 13, the 
PSA progression date is defined as the date that a ≥ 25% increase and an absolute increase of 
≥ 2 ng/mL above the nadir is documented, which is confirmed by a second consecutive value 
obtained 3 or more weeks later. For patients with no PSA decline at Week 13, the PSA 
progression date is defined as the date that a ≥ 25% increase and an absolute increase of ≥ 2 
ng/mL above the baseline is documented.
Data for the analysis of primary endpoint TTPP1 will be cut-off if not less than 135 events of
PSA progression occurred in association with the 1st line AAT. 
After the discontinuation of the 1st line AAT due to PSA progression or other reasons, the 
2nd line AAT will be started. Subjects who discontinued the 1st line AAT due to PSA 


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progression will start the 2nd line AAT within 6 weeks after the date of examination that 
identified PSA progression. Subjects who discontinued the 1st line AAT due to other reasons
will start the 2nd line AAT within 6 weeks from the day when the investigator or sub-
investigator decided the discontinuation. 
A safety follow-up visit should be performed wherever possible in 28 days from the final 
study treatment, or before starting other study drugs, or before starting other treatment for 
prostate cancer, whichever comes first. If subjects do not show up on the safety follow-up
visit, confirm Adverse Events (AEs) by the telephone wherever possible.
3.3
Randomization
The subject registration center will perform dynamic allocation with minimization with 
biased coin technique according to the subject registration procedure in the ratio of 1:1 to the 
initial enzalutamide 160 mg/day group or the initial flutamide 125 mg × 3 times daily (375 
mg/day) group. The facilities and the following stages (M0/N0, M0/N1, or M1) will be used 
as allocation factors. 
●
M0/N0: No distant metastasis, and no lymph node metastasis
●
M0/N1: Without distant metastasis, but with metastasis in lymph nodes distal to the 
aortic bifurcation
●
M1: With distant metastasis (including metastasis in lymph nodes proximal to the 
aortic bifurcation)
After the investigator or sub-investigator confirmed the eligibility of the subject on Day 1, 
the staff in charge at the study site will register the subject via the Subject Registration 
System, and confirm the study drugs that are randomly allocated. 
4
SAMPLE SIZE
The number of evaluable subjects will be approximately 200 subjects (1st line AAT 
enzalutamide group: 100, 1st line AAT flutamide group: 100). 
The sample size to evaluate the time to PSA progression with 1st line AAT (TTPP1), which 
is the primary endpoint of the study, was calculated in consideration of the following points:
●
Median TTPP1 with enzalutamide: 10.5 months. 
 
 
 
●
Median TTPP1 with flutamide: 6 months. 
Values reported in the literature: 5 months according to [Okihara et al., 2007], 6.25 
months according to [Narimoto et al., 2010]. 
●
The ratio of randomization of 1st line AAT enzalutamide and flutamide groups is 1:1. 


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●
Subject enrollment period is 12 months, and the observation period is 24 months from 
the enrollment of the last subject. 
●
Type I error of the two-sided test is 0.05, and power is 90%. 
●
A log-rank test with the TTPP1 parameters shown above requires 135 events. The 
necessary number of subjects calculated based on the required number of events is 74 
subjects per group. 
Required number of events and necessary number of subjects above are calculated with 
the formulas below based on [Schoenfeld, 1983]. The codes in the formulas are defined 
as follows. 
: Median TTPP1 in enzalutamide group
: Median TTPP1 in flutamide group
	: Enrollment period

: Observation period from the last subject enrollment
: 1-α% point of standard normal distribution
: 1-β% point of standard normal distribution
Hazard in enzalutamide group () =
 

Hazard in flutamide group () =
 

Hazard ratio for enzalutamide group/flutamide group () =


Required number of events () =
 × ("#$%&"#$')(
( ))(
  *The number after the decimal 
point will be rounded up to the nearest integer.
Incidence of events of enzalutamide group
(*) = 1 −1
6 .exp2− × 
3 + 4 × exp.− × (
 + 1
2 × 	)7 + exp (− × (
 + 	))7
Incidence of events of flutamide group
(*) = 1 −1
6 .exp2− × 
3 + 4 × exp.− × (
 + 1
2 × 	)7 + exp (− × (
 + 	))7
Incidence of events of both groups (*) =

 × (* + *)
Necessary number of subjects per group () =

 ×
89
:     * The number after the 
decimal point will be rounded up to the nearest integer.
●
Considering the dropout rate of approximately 25%, 100 subjects are to be enrolled in 
each group. 


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Number of 
subjects
With PSA 
progression
Censored
25%
50%
75%
5
ANALYSIS SETS
In accordance with International Conference on Harmonization (ICH) recommendations in 
guidelines E3 and E9, the following analysis sets will be used for the analyses.
5.1
Intent-to-Treat (ITT)
Intent-to-Treat (ITT) population is defined as all subjects randomized in this study. The ITT 
population will be analyzed by randomized treatment group (treatment group based on 
randomization). Efficacy analyses will be done in the ITT population. 
5.2
Safety Analysis Set (SAF)
For the statistical summary of the safety data, the safety analysis set (SAF) will be used. The 
SAF consists of all subjects who took at least one dose of study medication, and will be used 
for safety analyses.
5.3
Pharmacokinetic Analysis Set (PKAS)
The pharmacokinetic analysis set (PKAS) will not be established for this study.
5.4
Pharmacodynamic Analysis Set (PDAS)
The pharmacodynamic analysis set (PDAS) will not be established for this study.
6
ANALYSIS VARIABLES
6.1
Efficacy Endpoints
6.1.1
Primary Efficacy Endpoint(s)
Time to PSA Progression with 1st Line AAT (TTPP1)
PSA progression will be defined according to the consensus guidelines of PCWG2. For 
patients with PSA declines at Week 13, the PSA progression date is defined as the date that a 


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≥ 25% increase and an absolute increase of ≥ 2 ng/mL above the nadir is documented, which 
is confirmed by a second consecutive value obtained 3 or more weeks later. For patients with 
no PSA decline at Week 13, the PSA progression date is defined as the date that a ≥ 25% 
increase and an absolute increase of ≥ 2 ng/mL above the baseline is documented. 
TTPP1 is defined as the period from the date of randomization to the date of PSA 
progression in the 1st line AAT period.
6.1.2
Secondary Efficacy Endpoints
Time to PSA progression with 1st line AAT + 2nd line AAT (TTPP2)
Time to PSA progression with 2nd line AAT is defined as the period from Day 1 of 2nd line 
AAT to the date of PSA progression with 2nd line AAT. TTPP2 will be the total of time to 
PSA progression with 1st line AAT and time to PSA progression with 2nd line AAT.
PSA response rate to 1st line AAT (decrease by at least 50% or 90% from baseline)
PSA response will be defined as PSA decreased by at least 50% or 90% from baseline when 
at least 3 weeks passed after the lowest PSA decreased by at least 50% or 90% from baseline 
in the 1st line AAT period after baseline. The proportion of the subjects who achieved PSA 
response will be evaluated. 
PSA response rate to 1st line AAT at Week 13 (decrease by at least 50% or 90% from 
baseline)
PSA response will be defined as the lowest PSA at Week 13 decreased by at least 50% or 
90% from baseline in the 1st line AAT period. The proportion of the subjects who achieved 
PSA response will be evaluated.
Time to PSA decrease by 50% from baseline with 1st line AAT
Time to PSA decrease by 50% with 1st line AAT is defined as the period from the date of 
randomization to the day when the decrease of PSA from baseline by 50% is first identified.
Time to treatment failure of 1st line AAT (TTF1)
Time to treatment failure is defined as the period to study drug discontinuation for any reason 
that includes disease progression, onset of AEs, subjects’ request, or death. The following 
will be evaluated.
The period from randomization to discontinuation of 1st line AAT will be evaluated.
Time to treatment failure of 2nd line AAT (TTF2)
The period from randomization to discontinuation of 2nd line AAT will be evaluated.
rPFS
Imaging examination will be performed with chest CT, abdominopelvic CT or magnetic 
resonance imaging (MRI), and bone scintigraphy in the screening period, at study visit every 
12 weeks after Week 1 (Day 1) of 1st line AAT irrespective of switching the drugs, and at 


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completion or discontinuation (chest CT will not be necessary at study visits after the 
screening period if chest metastasis is not observed in the image taken during the screening 
period). During the study period, imaging examination will be performed under the same 
condition for the same subject, and the image should be interpreted by the same reader at 
each study site wherever possible. Images taken within 42 days before randomization as part 
of daily consultation before informed consent may be used as data in the screening period. In 
case of disease progression suspected, imaging examination may be performed for 
confirmation at any time other than the scheduled examination. 
The following will be evaluated with the images in the screening period as baseline.
rPFS is defined as the period from randomization to the time when radiographic disease 
progression is observed or death of any cause during the study period, whichever occurs 
earlier. With regard to radiographic disease progression, soft tissue lesion will be defined by 
RECIST guidelines version 1.1 (RECIST 1.1), bone lesion will be defined as the occurrence 
of at least 2 new bone lesions confirmed by bone scintigraphy in line with PCWG2 
recommendation. Evaluation will be made in subjects with distant metastasis at baseline. 
The following are procedures necessary for confirmation of radiographic disease progression. 
Study visit 
where disease 
progression is 
observed
Criteria for disease progression
Criteria for 
confirmation of 
disease progression 
(necessity for imaging 
for confirmation and 
time of confirmation)
Criteria for imaging 
for confirmation of 
disease progression
Visits up to 
Week 13 of 
1st line AAT
Bone lesion: ≥2 new bone 
lesions in comparison with 
baseline bone scintigraphy by 
PCWG2
Timing: ≥6 weeks 
after disease 
progression confirmed 
or at Week 25 Visit
≥2 new bone lesions in 
comparison with bone 
scintigraphy at Week 
13 of 1st line AAT
Soft tissue lesion: Disease 
progression detected by CT or 
MRI, and defined by RECIST 
1.1
No need of imaging 
for confirmation
N/A
Visits after 
Week 13 of 
1st line AAT
Bone lesion: ≥2 new bone
lesions in comparison with 
bone scintigraphy at Week 13*
of 1st line AAT
No need of imaging 
for confirmation
N/A
Soft tissue lesion: Disease 
progression detected by CT or 
MRI, and defined by RECIST 
1.1
No need of imaging 
for confirmation
N/A
*: Compare with baseline bone scintigraphy if data from Week 13 are missing.


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6.1.3
Safety Endpoints
●
Characteristics, frequency, and severity of AEs
●
Safety-related laboratory tests (biochemistry and hematology)
●
Vital signs (blood pressure and pulse rate)
●
ECOG Performance Status
6.1.4
Exploratory Efficacy Endpoints
Time to PSA progression with 2nd line AAT (2nd TTPP) 
2nd TTPP is defined as the period from the start date of 2nd line AAT (Day 1) to the date of 
PSA progression.
PSA response rate to 2nd line AAT (decrease by at least 50% or 90% from baseline) 
PSA response will be defined as PSA decreased by at least 50% or 90% from baseline when 
at least 3 weeks passed after the lowest PSA decreased by at least 50% or 90% from baseline 
in the 2nd line AAT period after baseline. The proportion of the subjects who achieved PSA 
response will be evaluated.
MFS 
MFS is defined as the period from randomization to new radiographic metastatic lesion or 
death of any cause during the study period, whichever occurs earlier. Evaluation will be 
made in subjects in whom distant metastasis is not confirmed at baseline. 
QOL assessment with 1st line AAT and 2nd line AAT by FACT-P) and EQ-5D-5L
FACT-P
The assessment will be conducted at study visit at Week 1 (Day 1), Week 13, and every 
subsequent 12 weeks of 1st line AAT and 2nd line AAT, and at completion or 
discontinuation. 
FACT-P is a multi-faceted QOL scale of self-assessment for patients with prostate cancer. 
FACT-P includes 27 major items to evaluate subjects’ functions in 4 areas; that is, physical 
health, social/family, emotional, and functional well-being. Site-specific 12 items are added 
for assessment of prostate-related symptoms. Each item will be assessed with a 5-grade 
Likert scale. The subtotal in each area is a low rank score. The total of all items is the overall 
QOL score. The higher the QOL score, the higher is the QOL.
If there are missing items, subscale scores can be prorated. This is done by multiplying the 
sum of subscale by the number of items in the subscale, then dividing by the number of items 
actually answered. This can be done on the scoring guide or by using the formula below: 
Prorated subscale score = [Sum of item scores] x [N of items in subscale]÷ [N of items 
answered]
When there are missing data, prorating by subscale in this way is acceptable as long as more 
than 50% of the items were answered (e.g., a minimum of 4 of 7 items, 4 of 6 items, etc). The 
total score is then calculated as the sum of the unweighted subscale scores. The FACT scale 


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is considered to be an acceptable indicator of patient quality of life as long as overall item 
response rate is greater than 80% (e.g., at least 22 of 27 FACT-G items completed). This is 
not to be confused with individual subscale item response rate, which allows a subscale score 
to be prorated for missing items if greater than 50% of items are answered.
For the Prostate Cancer-specific subscale, the procedure for scoring is the same as described 
above for the FACT-G. Again, over 50% of the items (e.g., 5 of 9 items, 7 of 12 items) must 
be completed in order to consider each subscale score valid. The total score consists of the 
sum of the FACT-G (the first 4 subscales common to almost all scales) plus the prostate-
specific subscale.
EQ-5D-5L
EQ-5D-5L will be performed at study visit at Week 1 (Day 1), Week 13, and every 
subsequent 12 weeks of 1st line AAT and 2nd line AAT, and at completion or 
discontinuation. 
EQ-5D-5L is a QOL scale for self-assessment that consists of 5 items related to health, such 
as mobility, self care, usual activities, pain/discomfort, and anxiety/depression. Each item 
will be evaluated in 5 levels from “no problem” to “extreme problem.” The last question is a 
visual analog scale to evaluate the present health status in the range from “best imaginable
health status” to “worst imaginable health status.”
QOL utility index will be derived in accordance with the scoring method of the EQ-5D-5L
Japanese version.
BPI-SF with 1st line AAT and 2nd line AAT
BPI-SF will be performed in the screening period, at study visit at Week 1 (Day 1), Week 13,
and every subsequent 12 weeks of 1st line AAT and 2nd line AAT, and at completion or 
discontinuation.
BPI is a questionnaire slip verified as a self-assessment scale for subjects about the level of 
pain, effect of the pain on activities of daily living, and analgesic use. BPI used in this study 
is an abbreviated version (short form) that consists of questions in 9 items for which simple 
numerical evaluation scales from 0 to 10 are used. In order to evaluate prostate cancer-related 
pain in this study, the investigator or sub-investigator will instruct the subjects to describe 
prostate cancer-related pains.
The 4 individual items used to evaluate pain intensity are ‘worst’, ‘least’, ‘average’, and ‘now’ 
(current pain). Pain ratings range from 0 to 10 for each item. The mean pain severity score will be 
calculated using the 4 individual items. This mean can be used if all 4 items are completed at a 
given assessment. If any individual item is not completed, the mean cannot be used. Descriptive 
statistics will be provided to summarize each individual item and the mean score at baseline, and 
each visit for the ITT population. 


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The 7 individual items used to evaluate pain interference include general activity, mood, walking 
ability, normal work, relations with other people, sleep, and enjoyment of life. Interference rating 
ranges from 0 to 10 for each item. BPI-SF pain interference will be scored as the mean of the 7 
individual interference items. This mean can be used if more than 50%, or 4 of 7, of the total 
items have been completed at a given assessment.
BFI with 1st line AAT and 2nd line AAT
BFI will be performed in the screening period, at study visit at Week 1 (Day 1), Week 13,
and every subsequent 12 weeks of 1st line AAT and 2nd line AAT, and at completion or 
discontinuation. 
BFI is a simple questionnaire slip that consists of questions in 10 items to evaluate the 
malaise (subjective symptoms characterized as debility that includes physical and mental 
wasting) of cancer patients.
The mean of the 9items (except for the first Yes/No question) are used as a global BFI score.
When there are missing data, global BFI score can be acceptable as long as more than 50% of 
the 9 items (except for the first Yes/No question) were answered (e.g., a minimum of 5 of 9
items). The global BFI score is then calculated as the mean of answered questions.
ORR in best overall soft tissue response of RECIST guidelines with 1st line AAT
According to RECIST 1.1, the investigator or sub-investigator will evaluate the overall 
response in target, non-target, and new lesions in soft tissue at each time point. At the end of 
the 1st line AAT period, the best overall response will be assessed. Of subjects with 
measurable soft tissue lesion (at least 1 target lesion according to RECIST 1.1) in baseline 
imaging, the proportion of subjects with objective response (complete or partial response) 
will be evaluated.
6.1.5
Other Efficacy Variables
PSA measurement
In the screening period, at study visit at Week 1 (Day 1), Week 13, Week 17, and every 
subsequent 4 weeks of 1st line AAT and 2nd line AAT, at completion or discontinuation, and 
at safety follow-up visit, blood sample for PSA will be collected, and PSA will be measured 
by the central laboratory designated by the Sponsor. The PSA measured on Week 1 (Day 1) 
of 1st line AAT and 2nd line AAT will be handled as baseline.
6.2
Safety Variables
Safety will be assessed by evaluation of the following variables:


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●
AEs (frequency, severity, seriousness, and relationship to study drug).
●
Clinical laboratory variables (hematology, biochemistry including liver enzymes and 
total bilirubin, and urinalysis)
●
Vital signs (systolic and diastolic blood pressure, pulse rate)
●
ECOG Performance Status
AEs will be recorded from time of actually received the study drugs until the Safety Follow-
up visit (28 days after the final treatment with the study drug, start date of cytocidal
chemotherapy, or start date of new treatment for prostate cancer, whichever occurs first.).
AEs will be assigned on treatment period (treatment arm) according to definition of 
treatment-emergent period in section 7.1.2. When assigning treatment arm cannot be judged 
due to starting date and/or end date of AE is missing, such AEs will be assigned on treatment 
depending on recorded CRF page. However, the AE that recorded as continues from 1st line 
AAT will be excluded from assignment of 2nd line AAT. TEAE is defined as an AEs 
observed within above treatment-emergent period or AEs that assigned the treatment arms.  
The severity of all AEs is to be evaluated by the investigator based on the National Cancer 
Institute’s Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. 
A drug-related AE is defined as any AE with at least possible relationship to study treatment 
as assessed by the investigator or with missing assessment of the causal relationship.
6.3
Pharmacokinetic Variables
Not applicable.
6.4
Pharmacodynamic Variables
Not applicable.
6.5
Other Variables
●
The duration of exposure
For each subject and period, the length of time on treatment will be calculated in months, 
using the following formula.
Treatment duration for 1st line (Months) = (Date of last dose study drug in 1st line-Date 
of first dose of study drug in 1st line+1)/30.4375
Treatment duration for 2nd line (Months) = (Date of last dose study drug in 2nd line-
Date of first dose of study drug in 2nd line+1)/30.4375
Total treatment duration for 1st and 2nd line (Months) = Treatment duration for 1st line
+ Treatment duration for 2nd line
●
Total number of study drugs taken


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Total number of study drugs taken during the study is calculated as (number of study 
drugs dispensed at all study visits - number of study drugs indicated as having been 
returned and lost). Study drugs not returned will be assumed to have been taken.
Treatment compliance
Study drug accountability will be performed to document compliance with the dosing 
regimen. Subjects will be asked to bring back all remaining study drug at each study 
visit. Treatment compliance will be defined as the number of study drugs taken during 
the study divided by the expected number of study drugs, multiplied by 100%.
Treatment compliance for 1st or 2nd line (%)=
            [Total number of study drugs taken during 1st or 2nd line]
           --------------------------------------------------------------------------- x 100
            [Expected number of study drugs during corresponding line]
Expected number of study drugs is calculated as sum for i (Xi x Yi x (assessment date of 
arbitrary visit i excluding first treatment of each line – date of visit (i-1) +1 )) within
each line, where i is visit sequence (=2nd ,3rd,...) which include unscheduled visit,  X=1
and Y=4 for Enzalutamide plus ADT arm and X=3 and Y=1 for Flutamide plus ADT 
arm which are number of study drugs to be taken par day according to protocol. When 
prescribed dose amount is reduced, Y will be changed as reduced number of study drugs. 
Example: Expected number of study drugs during corresponding line is calculated as 
=(1 x 4) x (2016/1/29-2016/1/1+1) + (1 x 2) x (2016/2/10-2016/1/29+1) for following 
records are reported; 
For patient of enzalutamide plus ADT arm
Date of visit 1st: 2016/1/1 and 4 study drugs per day are prescribed
Date of visit 2nd: 2016/1/29 and 2 study drugs per day are prescribed (e.g. due to AE)
Date of visit 3rd (un schedule): 2016/2/10 and 2 study drugs per day are prescribed (e.g. 
due to AE)
●
Previous and concomitant medication
Treatment duration of bicalutamide (Months)=(End date of bicalutamide - Start date of 
bicalutamide + 1) / 30.4375
●
Previous and concomitant medication
Previous medication is defined as medication with at least one dose taken 4 weeks (28 
days) before Day 1 to the day before initial study treatment. 


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Concomitant medication for 1st line is defined as medication with at least one dose 
taken between the date of first dose (inclusive) of study drug for 1st line AAT and the 
date of first dose (not inclusive) of study drug for 2st line AAT.
Concomitant medication for 2nd line is defined as medication with at least one dose 
taken between the date of first dose (inclusive) of study drug for 2nd line AAT and the 
date of safety visit (inclusive).
Concomitant medication through study medication is defined as medication with at 
least one dose taken between of first dose (inclusive) and the date of safety visit 
(inclusive).
●
PSA doubling time (PSADT)
PSA doubling time is defined from two consecutive PSA measurements (*;<, *;<) 
and measured dates (=>?, =>?) before study Day 1 as follow;
PSA doubling time (month) =
ln(2) ∗12
365.25 ∗ln(*;<) −ln(*;<)
=>? −=>?
7
STATISTICAL METHODOLOGY
7.1
General Considerations
7.1.1
General Principles
For continuous variables, descriptive statistics will include the number of subjects (n), mean, 
standard deviation, median, minimum and maximum. When needed, the use of other 
percentiles (e.g.10%, 25%, 75% and 90%) will be mentioned in the relevant section.
Frequencies and percentages will be displayed for categorical data. A missing category will 
be added to categorical variables where data is missing. 
Summaries based on ITT (e.g. disposition, baseline and efficacy data) will be presented by 
planned treatment group, unless specifically stated otherwise. Safety analysis and other 
summaries based on SAF will be presented by actual treatment received. 
All statistical comparisons will be made using two sided tests at the α=0.05 significance level 
unless specifically stated otherwise. All null hypotheses will be of no treatment difference, all 
alternative hypotheses will be two-sided, unless specifically stated otherwise.
All data processing, summarization, and analyses will be performed using SAS® Version 9.4
or higher on Windows. Specifications for table, figures, and data listing formats can be found 
in the TLF specifications for this study.
The Age (Derived) variable from EDC will be used for analysis. If date of birth is 
incomplete, the variable Age from EDC will be used for analysis. 


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Year will be calculated as (days/365.25) rounded up to 1 significant digit.
Month will be calculated as (days/30.4375) rounded up to 1 significant digit. 
Time to event or duration of event endpoints will be based on the actual date rather than Visit 
Day.
For the definition of subgroups of interest please refer to section 7.8.
7.1.2
Definitions and Computations
●
Study Day 
Study day will be calculated in reference to the date of randomization (study day 1). For 
assessments conducted on or after the randomization date, study day is calculated as 
(assessment date – randomization date + 1). For assessments conducted prior to the 
randomization date, study day is calculated as (assessment date – randomization date). There 
will be no study day 0. 
●
Study Day for each line
Study day for each line will be calculated by same definition of "Study Day" replacing the 
reference date with date of randomization for 1st line AAT, and replacing with date of 
enrollment for 2nd line AAT respectively.
i.e. when assessment date be included between date of informed consent and date of 
enrollment for 2nd line AAT - 1 day: (assessment date – randomization date + 1). when 
assessment date is same or after date of enrollment for 2nd line AAT: (assessment date – date 
of enrollment for 2nd line AAT + 1)
●
Date of First Dose and Date of Last Dose of Study Drug 
The date of the first dose of study drug is defined as the date the subject received the first 
dose of any study drug (enzalutamide or flutamide, whichever comes first). The date of the 
last dose of study drug is defined as the date the subject received the last dose of study drug 
(enzalutamide or flutamide). 
●
Date of First Dose in each line and Date of Last Dose of Study Drug in each line
The date of the first dose of study drug in each line (1st or 2nd line) is defined as the date the 
subject received the first dose of study drug in each line (enzalutamide or flutamide). The 
date of the last dose of study drug in each line is defined as the date the subject received the 
last dose of study drug in each line (enzalutamide or flutamide). 
●
Treatment Day 
Treatment day will be calculated in reference to the date of the first dose of study drug. 
Treatment day 1 corresponds to the date the subject received the first dose of study drug. For 
assessments conducted on or after the date of the first dose of study drug, treatment day will 
be calculated as (assessment date – date of first dose of study drug + 1). There will be no 
treatment day 0. Study day 1 is not planed date of first dose of study drug, administration will 


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be started study day 2.
●
Treatment-Emergent Period 
The treatment-emergent period will be defined as the period of time from the date of the first 
dose of study drug to 28 days after the date of the last dose of study drug, or 1 day prior to 
the date of initiation of cytotoxic chemotherapy for prostate cancer or an investigational 
agent treating prostate cancer, whichever occurs first. And 1st line treatment-emergent period 
is defined as the period of time from the date of the first dose of study drug in 1st line to 28 
days after the date of the last dose of study drug in 1st line, or 1 day prior to the date of 
initiation of cytotoxic chemotherapy for prostate cancer or an investigational agent treating 
prostate cancer, whichever occurs first. Regarding 2nd line treatment-emergent period is 
applied same rule for 2nd line date.
●
Baseline Value and Post-Baseline Value 
Unless otherwise specified, the baseline value is defined as the last non-missing measurement 
prior to the randomization of study drug. When analysis be provided separately by treatment 
lines, baseline value for 2nd line AAT is defined as the last non-missing value measurement 
prior to the enrollment for 2nd line AAT of study drug.
Post-baseline value is defined as a measurement taken after the randomization of study drug.
For Post-baseline value for 2nd line is defined as a measurement taken after enrollment
during of study for 2nd line AAT.
Baseline value is defined as the last non-missing measurement prior to randomization (or 
register of 2nd line AAT) and post-baseline value is defined as a measurement taken after 
randomization for subjects who did not receive study drug. Change from baseline is defined 
as (post-baseline value - baseline value). Both date and time of drug administration and 
measurement should be considered when calculating baseline value. If time is not available, 
then date only should be used.
●
Treatment Group
Treatment group is defined as planned randomized treatment sequence which divide to initial 
enzalutamide 160 mg/day group or the initial flutamide 125 mg × 3 times daily (375 mg/day)
group. 
●
Treatment Arm
Treatment arm is defined as administration drug group regardless 1st line or 2nd line 
treatment. That is enzalutamide plus ADT arm include subject who receive enzalutamide plus 
ADT at 1st line and 2nd line. Flutamide plus ADT include who receive flutamide plus ADT 
at 1st line and 2nd line.
●
Treatment Line 
Treatment line is defined as 1st line AAT and 2nd line AAT. When analysis by treatment line 
is provided, divided to data of 1st line AAT and 2nd line AAT, and calculate descriptive
summarization or frequency etc.


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7.2
Study Population
7.2.1
Disposition of Subjects
●
Number of subjects with informed consent (overall only) 
●
Number of subjects randomized with discontinued before randomization (overall only) 
●
Number of subjects randomized, by treatment group and overall 
●
Number and percentage of subjects in each analysis set, by treatment group and overall 
●
Number and percentage of subjects in with transition to 2nd line AAT, by treatment 
group and overall
●
Number and percentage of subjects who had discontinued study drug during 1st line 
AAT to end of 2nd line AAT, by treatment group and overall
●
Number and percentage of subjects who had discontinued study drug by primary reason 
for treatment discontinuation during 1st line AAT to end of 2nd line AAT, by treatment 
group and overall 
●
Number and percentage of subjects who had discontinued study drug during 1st line
AAT and not transition to 2nd line AAT, by treatment group and overall
●
Number and percentage of subjects who had discontinued study drug by primary reason 
for treatment discontinuation during 1st line AAT, by treatment group and overall 
●
Number and percentage of subjects who had discontinued study drug by primary reason 
for treatment discontinuation during 2nd line AAT, by treatment group and overall 
●
Number and percentage of screening failure subjects for overall 
●
Number and percentage of subjects who participated in each study visit, by treatment 
group and overall for the ITT population 
A listing of all randomized subjects discontinued from study treatment, by center and by 
treatment group, the specific reason for discontinuation, and the last dose day and date will 
be presented.
7.2.2
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics will be summarized by treatment group as 
randomized for all subjects in the ITT population. Additionally same summaries will be 
provided for subject in the SAF population. 
Descriptive summary statistics will be presented for continuous variables of:
●
Age
●
Height
●
Weight
●
Body Mass Index (BMI)
●
Baseline serum PSA value 
●
Baseline lactate dehydrogenase (LDH) value 
●
Baseline hemoglobin value 
●
Baseline alkaline phosphatase (ALP) value 


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●
Baseline serum albumin 
●
Baseline creatinine value 
Frequency tabulations will be presented for categorical variables of: 
●
Age category (grouped as <65, 65 to 74, 75 to 84, ≥85 years) 
●
Baseline ECOG performance status (0, 1, 2, 3/4) 
●
Baseline brief pain inventory question # 3 (0-1, 2-3, >3) 
●
History of prior cardiovascular disease (Yes, No) 
●
Disease stages at randomization (M0/N0, M0/N1, M1)
●
Regional Lymph Nodes at randomization (Nx, N0, N1, Unknown)
●
Distant Metastasis at randomization (Mx, M0, M1, Unknown)
7.2.3
Medical History
Summary statistics will be presented for the ITT population and SAF population for numeric 
variables of: 
●
Time (months) from initial diagnosis.
●
Total Gleason score at initial diagnosis 
Frequency tabulations will be presented for categorical variables of: 
●
Gleason score: primary score + secondary score (< 3 + 3, 3 + 3, 3 + 4, 4 + 3, 4 + 4, 4 + 5, 
5 + 4, 5 + 5, other, and missing) 
●
Total Gleason score category at initial diagnosis (low [2-4], medium [5-7], high [8-10], 
Unknown or missing) 
●
Clinical Tumor Stage at initial diagnosis (Tx, T0, T1, T2, T3, T4, Unknown)
●
Regional Lymph Nodes at initial diagnosis (Nx, N0, N1, Unknown)
●
Distant Metastasis at initial diagnosis (Mx, M0, M1, Unknown)
●
PSA progression at study entry (Yes, No) 
●
PSA doubling time (PSADT)
●
Type of disease progression (PSA progression only, radiographic progression 
with/without PSA progression) at study entry 
●
Disease localization (bone only, soft tissue only, both bone and soft tissue, and none) at 
screening 
●
Target or nontarget soft tissue disease (i.e., at least one target or nontarget lesion per 
RECIST 1.1) at screening (Yes, No) 
●
Extent of disease at (bone, lymph node, visceral lung, visceral liver, visceral lung and/or 
liver, and other soft tissue) screening 
In addition, ongoing medical history at randomization which not related to prostate cancer 
will be summarized by System Organ Class (SOC) and Preferred Term (PT). Medical history 
ongoing at randomization will be summarized.
7.2.4
Previous and Concomitant Medications
Medications will be coded with World Health Organization Drug Dictionary (WHO-DD)


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(September 2016, HD Format B2). 
Previous medication is defined as medication with at least one dose taken before initial study 
treatment. Number and percentage of subjects taking the previous medication by treatment 
arm for the ITT/SAF population. 
Concomitant medication for 1st line is defined as medication with at least one dose taken 
between the date of first dose (inclusive) and the date of last dose of study drug for 1st line 
AAT and the date of first dose (not inclusive) of study drug for 2nd line AAT. Concomitant 
medication for 2nd line is defined as medication with at least one dose taken between the 
date of first dose (inclusive) and the date of last dose of study drug for 2nd line AAT and the 
date of safety visit (inclusive). As with previous medications, number and percentage of 
subjects taking the concomitant medication by treatment arm for the ITT/SAF population. 
Number of subjects with at least one previous and concomitant medications will be 
summarized.
Data listings will be presented for previous and concomitant medications and therapies.
7.2.5
Previous Therapies for Prostate Cancer
Previous therapies for prostate cancer will be summarized by treatment group as randomized 
for the ITT population and SAF population as follows: 
●
Summary statistics for treatment duration of bicalutamide
●
Number of subjects with gonadotropin releasing hormone (GnRH) agonist / antagonist 
and each drug
●
Number of subjects with other drug therapies
●
Number of subjects with radiation therapy
7.2.6
Prior Surgical Procedures for Prostate Cancer
Number and percentage of subjects with any prior surgical procedures for prostate cancer 
(prostatectomy, orchiectomy, transurethral resection of the prostate (TURP), cryoablation, 
pelvic lymph node dissection, high intensity focused ultrasound (HIFU), and other) will be 
tabulated by treatment group as randomized for the ITT population and SAF population.
7.3
Study Drugs
7.3.1
Exposure
Duration of exposure will be summarized in two ways for the ITT population and SAF. 
●
Descriptive statistics will be presented by treatment group and treatment line. 
●
Exposure time will be categorized according to the following categories by treatment 
group and treatment line: 
○
less than 3 months 
○
at least 3 months, less than 6 months 
○
at least 6 months, less than 12 months 
○
at least 12 months, less than 24 months 
○
24 months or more 
Counts and percentages of subjects in each of these categories will be summarized for each 
treatment group.


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Total treatment duration will be summarized by treatment group applying same rule as 
above.
7.3.2
Dose Modification
Subjects with at least one dose modification, including dose reduction and interruption, and 
the reason for the dose modification (adverse event or other) will be summarized by 
treatment group and treatment line for the ITT population and SAF. Also, subjects with at 
least one dose reduction and those reason will be summarized by treatment group and 
treatment line for the ITT population and SAF.
7.3.3
Treatment Compliance
Treatment compliance will be examined for subjects in the ITT population and SAF. For the 
details of treatment compliance calculation please refer to section 6.5.
Descriptive statistics will be presented for total number of study drugs taken per subject by 
treatment group and treatment line. 
Percent compliance will be summarized in two ways: 
●
Descriptive statistics will be presented by treatment group and treatment line.
●
Percent compliance will be categorized according to the following categories by 
treatment group and treatment line: 
○
less than 20% 
○
at least 20%, less than 40% 
○
at least 40%, less than 60% 
○
at least 60%, less than 80% 
○
at least 80%, less or equal to 100% 
○
greater than 100%, less than 120% 
○
greater or equal to 120% 
7.4
Analysis of Efficacy 
All analysis of efficacy will be presented by planned treatment group for ITT population, 
unless specified otherwise. The data obtained at Day 1 visit will be used as the baseline for 
efficacy assessment except for rPFS for which the data at the Screening visit will be used as 
the baseline.
7.4.1
Analysis of Primary Endpoint
The primary efficacy analysis will be performed on the TTPP1 for the subjects in the ITT 
population. TTPP1 is the period from randomization to the first day when PSA progression is 
objectively identified. Convention of censoring is specified in table 7-1. 
If a subject meets the criteria for more than one censoring rule, they will be censored with the 
earliest censoring date. The PSA progression date is the first date where progression 
definition is met, not confirmed.
Methodology


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The benefit of enzalutamide as compared to flutamide will be assessed with the stratified log-
rank test as the primary efficacy analysis. The stratification factor will be the disease stages 
(M0/N0, M0/N1, or M1) used as stratification factor for allocation. 
The hypothesis for comparisons is as follows: 
H0: The survival time distribution of enzalutamide group is the same as that with flutamide 
group.
H1: The survival time distribution of enzalutamide group is not the same as that with 
flutamide group.
The significance level is 0.05 (two-sided). ITT is used for the primary analysis.
Unstratified Cox’s Proportional Hazards Model with treatment and disease stage as the
covariate will be used to support the log rank test. 
The benefit of enzalutamide compared to flutamide will be evaluated by hazard ratio
(enzalutamide/flutamide) with its 95% confidence interval (CI) based on Cox Proportional 
Hazard Model.
Kaplan-Meier curves will be used to estimate the distribution of duration of TTPP1 and 
Stratified curve will be estimated by disease stage. The 50th percentile of Kaplan-Meier 
estimates will be used to estimate the median duration of TTPP1. A two-sided 95% CI will 
be provided for this estimate. The 25th and 75th percentiles, and the range (minimum, 
maximum) will be presented as well. The range will be determined including censored 
observations. Estimated Kaplan-Meier curve will be plotted.
7.4.2
Analysis of Secondary Endpoints 
7.4.2.1 Time to PSA Progression with 1st Line AAT + 2nd Line AAT (TTPP2)
TTPP2 is defined as the period from randomization to the date of PSA progression with 2nd 
line AAT. The total of time to PSA progression with 1st line AAT and time to PSA 
progression with 2nd line AAT will be evaluated. Convention of censoring is specified in 
Table 7-1.
The distribution of the TTPP2 will be estimated using the Kaplan–Meier method. The 
median TTPP2 will be estimated using the 50 percentile value of the Kaplan–Meier curve. 
The two-sided 95% CI will be calculated based on the estimation. 
7.4.2.2 PSA Response Rate to 1st Line AAT (Decrease by at Least 50% or 90% from 
Baseline)
The PSA response rate decreasing by at least 50% will be calculated by treatment groups of 
subjects with baseline PSA value and PSA measured at least once at least 3 weeks passed 
after the lowest PSA. For the comparison of the response rate between the enzalutamide and 
flutamide groups, the stratified Cochran–Mantel–Haenszel test will be used. The 
stratification factor will be the disease stages (M0/N0, M0/N1, or M1) used as stratification 
factor for allocation. 


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PSA decrease by at least 90% will also be compared at the 0.05 significance level (two-
sided) between the enzalutamide and flutamide groups using the stratified Cochran–Mantel–
Haenszel test. 
Response rate, its Clopper-Pearson exact confidence interval and its count within 
stratification will be summarized for each treatment. Mantel-Haenszel common risk
difference for response (enzalutamide - flutamide) and its 95% confidence interval based on 
the variance claimed by Sato (1989) will be estimated. 
Water fall plot will be made to present the percent change of PSA from baseline at the lowest 
PSA value (except within 3 weeks from baseline) for patient who have at least one time point 
PSA reduction in the 1st line AAT period, and the highest PSA value (except within 3 weeks 
from baseline) for patient who have never had PSA reduction, respectively.
7.4.2.3 PSA Response Rate to 1st Line AAT at Week 13 (Decrease by at Least 50% or 
90% from Baseline)
The PSA response rate decreasing by at least 50% (or by at least 90%) will be calculated by 
treatment groups of subjects with baseline PSA value with 1st line AAT and PSA measured 
at week 13. The PSA response rate at week 13 will be assessed by the same method as that 
with the PSA response rate to 1st line AAT. Water fall plot will be made to present the 
percent change of PSA from baseline at Week 13 PSA value for each patient.
7.4.2.4 Time to PSA Decrease by 50% from Baseline with 1st Line AAT
The time to PSA decrease by 50% with 1st line AAT is defined as the period from 
randomization to the day when the decrease of PSA from baseline by 50% is first identified. 
Convention of censoring is specified in Table 7-1.
The benefit of enzalutamide as compared to flutamide will be assessed with the stratified log-
rank test as the primary efficacy analysis. The stratification factor will be the disease stages 
(M0/N0, M0/N1, or M1) used as stratification factor for allocation. 
The distribution of the time to PSA decrease by 50% with 1st line AAT will be estimated 
using the Kaplan–Meier method. The median time to PSA decrease by 50% will be estimated 
using the 50 percentile value of the Kaplan–Meier curve. The two-sided 95% CI will be 
calculated based on the estimation.
7.4.2.5 Time to Treatment Failure of 1st Line AAT (TTF1)
TTF1 is defined as the period from randomization to the date of discontinuation of 1st line 
AAT. Convention of censoring is specified in Table7-1.
TTF1 will be assessed using the same method as that with time to PSA decrease by 50% 
from baseline with 1st Line AAT.
7.4.2.6 Time to Treatment Failure of 2nd Line AAT (TTF2)
TTF2 is defined as the period from randomization to the date of discontinuation of 2nd line 
AAT. Convention of censoring is specified in Table 7-1. 


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The distribution of the time to treatment failure of 2nd line AAT will be estimated using the 
Kaplan–Meier method. The median time to treatment failure of 2nd line AAT will be 
estimated using the 50 percentile value of the Kaplan–Meier curve. The two-sided 95% CI 
will be calculated based on the estimation.
7.4.2.7 Radiographic Progression-Free Survival (rPFS)
The rPFS is defined as the time from randomization to the first objective evidence of 
radiographic disease progression assessed by the blinded independent central review facility 
or on-study death, defined as death within 28 days after treatment discontinuation, whichever 
occurs first. rPFS will be assessed in the ITT population. Radiographic disease progression 
will include soft tissue disease progression and confirmed bone disease progression. The 
censoring rules are shown in Table 7-1. The analysis of rPFS will be presented by planned 
treatment group for subjects that having least one distant metastasis at baseline in ITT 
population.
rPFS will be assessed using the same method as that with TTPP1. i.e. Stratified log-rank test
and unstratified cox regression will be applied to rPFS and estimate the distribution using
Kaplan-Meier method.
7.4.3
Analysis of Exploratory Endpoints 
7.4.3.1 Time to PSA Progression with 2nd Line AAT (2nd TTPP)
2nd TTPP is defined as the period from the start of 2nd line AAT to the first day when PSA 
progression is objectively identified. Convention of censoring is specified in Table 7-1.
The 2nd TTPP will be assessed by the same method as that with the Time to Treatment 
Failure of 2nd Line AAT (TTF2). 
7.4.3.2 PSA Response Rate to 2nd line AAT (Decrease by at Least 50% or 90% from 
Baseline)
The PSA response rate to 2nd line AAT decreasing by at least 50% (or by at least 90%) will 
be calculated by treatment groups of subjects with baseline PSA value and PSA measured at 
least once at least 3 weeks passed after the lowest PSA. The PSA response rate to 2nd line 
AAT will be assessed by the same method as that with the PSA response rate to 1st line 
AAT.
Water fall plot will be made to present the percent change of PSA from baseline at the lowest 
PSA value (except within 3 weeks from baseline) for patient who have at least one time point 
PSA reduction in the 2nd line AAT period, and the highest PSA value (except within 3 weeks 
from baseline) for patient who have never had PSA reduction, respectively.
7.4.3.3 Metastasis-Free Survival (MFS)
MFS is defined as the period from randomization to new radiographic metastatic lesion or 
death of any cause during the study period, whichever occurs earlier. Evaluation will be 
made in subjects in whom distant metastasis is not confirmed at baseline. MFS will be 


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assessed by the same method as that with the Time to Treatment Failure of 2nd Line AAT 
(TTF2). 
7.4.3.4 Functional Assessment of Cancer Therapy–Prostate (FACT-P) with 1st Line 
AAT and 2nd Line AAT
The FACT-P domain scores and total score and their change from baseline will be 
summarized by treatment group as randomized for the ITT population. These measurement 
values and changes from baseline will be plotted as mean +/- SD plot. The FACT-P domain 
score and total score will be calculated using the Manual of Functional Assessment of 
Chronic Illness Therapy (FACIT) Measurement System.
7.4.3.5 European Quality of Life-5 Dimension-5 Level Instruments (EQ-5D-5L) with 
1st Line AAT and 2nd Line AAT
Following analysis will be applied for the ITT population. The subjects’ current health state 
is assessed using a visual analogue scale form 0 (worst imaginable health state) to 100 (best 
imaginable health state). The current health state score will be summarized by visit and 
treatment group. QOL utility index will be derived according to section 6.1.4 will also be
summarized by visit and treatment group. These measurement values will be plotted as mean 
+/- SD plot. Additionally, a within-subject change will be calculated per visit as the post-
baseline measurement minus the baseline measurement and summarized by visit and 
treatment group in the same way.
7.4.3.6 Brief Pain Inventory-Short Form (BPI-SF) with 1st Line AAT and 2nd Line 
AAT
Descriptive statistics for Pain severity and Pain Interference and their change from baseline
will be summarize by visit and treatment group for the ITT population. These measurement 
values and changes from baseline will be plotted as mean +/- SD plot.
7.4.3.7 Brief Fatigue Inventory (BFI) with 1st Line AAT and 2nd Line AAT
Descriptive statistics for global fatigue score and its change from baseline will be summarize 
by visit and treatment group for the ITT population. These measurement values and changes 
from baseline will be plotted as mean +/- SD plot.
Global fatigue score will be categorized according to the following categories by treatment 
group: 
○
Mild : global fatigue score be in range from 1 to 3.
○
Moderate : global fatigue score be in range from 4 to 6.
○
Severe : global fatigue score be in range from 7 to 10.
Counts and percentages of subjects in each of these categories will be summarized for each 
treatment group.


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7.4.3.8 Objective Response Rate (ORR) in best Overall Soft Tissue Response of 
RECIST Guidelines with 1st Line AAT
For the comparison of ORR between the enzalutamide and flutamide groups, the stratified 
Cochran–Mantel–Haenszel test will be used. The stratification factor will be the disease 
stages (M0/N0, M0/N1, or M1) used as stratification factor for allocation. 
ORR, its Clopper-Pearson exact confidence interval and its count within stratification will be 
summarized for each treatment. Mantel-Haenszel common risk difference for response 
(enzalutamide - /flutamide) and its 95% confidence interval based on the variance claimed by 
Sato (1989) will be estimated. And count and percentage of overall soft tissue response 
which is assessment using RECIST 1.1 will be tabulated. The summarized category is shown 
as follows: 
●
Complete response (CR) 
●
Partial response (PR) 
●
Progressive disease (PD) 
●
Stable disease (SD) 
●
Non-evaluable (NE) 


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Table 7-1 : Definition of time to event and censor
TTPP1
TTPP2
2nd TTPP
Time to PSA
50%/90% 
decline
TTF1
TTF2
rPFS
MFS
Subjects without PSA 
value at baseline or in 
observation period
Considered as 
censoring at 
randomization
Considered as 
censoring at 
randomization
Excluded from 
analysis
Considered as 
censoring at 
randomization
Not considered 
as censoring
*To be judged 
based on 
continuation of 
study treatment
Not considered 
as censoring
*To be judged 
based on 
continuation of 
study treatment
Not considered 
as censoring
*To be judged 
based on result 
of radiographic 
assessment
Not considered 
as censoring
*To be judged 
based on result 
of radiographic 
assessment
Subjects without the 
result of radiographic 
assessment at baseline 
or in observation 
period
Not considered 
as censoring
*To be judged 
based on result 
of PSA 
measurement
Not considered 
as censoring
*To be judged 
based on result 
of PSA 
measurement
Not considered 
as censoring
*To be judged 
based on result 
of PSA 
measurement
Not considered 
as censoring
*To be judged 
based on result 
of PSA 
measurement
Not considered 
as censoring
*To be judged 
based on 
continuation of 
study treatment
Not considered 
as censoring
*To be judged 
based on 
continuation of 
study treatment
Considered as 
censoring at 
randomization
Considered as 
censoring at 
randomization
Subjects without PSA 
progression at final 
data cut-off
(Including cases 
inconsistent with PSA 
progression defined by 
the protocol)
Subjects who 
continue the 
first study drug 
are considered 
as censoring at 
final PSA 
measurement
Considered as 
censoring at 
final PSA 
measurement
Subjects who 
continue the 
first study drug 
are excluded 
from analysis
Subjects who 
have shifted to 
the second 
study drug are 
considered as 
censoring at 
final PSA 
measurement
Considered as 
censoring at 
final PSA 
measurement
Not considered 
as censoring
*To be judged 
based on 
continuation of 
study treatment
Not considered 
as censoring
*To be judged 
based on 
continuation of 
study treatment
Not considered 
as censoring
*To be judged 
based on result 
of radiographic 
assessment
Not considered 
as censoring
*To be judged 
based on result 
of radiographic 
assessment


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Subjects without 
radiographic 
progression at final 
data cut-off
(Including cases 
inconsistent with 
progression defined by 
the protocol)
Not considered 
as censoring
*To be judged 
based on result 
of PSA 
measurement
Not considered 
as censoring
*To be judged 
based on result 
of PSA 
measurement
Not considered 
as censoring
*To be judged 
based on result 
of PSA 
measurement
Not considered 
as censoring
*To be judged 
based on result 
of PSA 
measurement
Not considered 
as censoring
*To be judged 
based on 
continuation of 
study treatment
Not considered 
as censoring
*To be judged 
based on 
continuation of 
study treatment
Considered as 
censoring at 
final 
radiographic 
assessment
Considered as 
censoring at 
final 
radiographic 
assessment
Death during the study
Subjects who 
died during 
treatment with 
the first study 
drug are 
considered as 
censoring at 
final PSA 
measurement 
before death
Considered as 
censoring at 
final PSA 
measurement 
before death
Subjects who 
died during 
treatment with 
the first study 
drug are 
excluded from 
analysis
Subjects who 
died during 
treatment with 
the second 
study drug are 
considered as 
censoring at 
final PSA 
measurement 
before death
Considered as 
censoring at 
final PSA 
measurement 
before death
The event is 
considered to 
occur at the 
time of death 
The event is 
considered to 
occur at the 
time of death 
The event is 
considered to 
occur at the 
time of death 
The event is 
considered to 
occur at the 
time of death 
Subjects who 
discontinued treatment 
during the study
Subjects who 
discontinue the 
first study drug 
are considered 
as censoring at 
final PSA 
measurement 
before 
discontinuation
Considered as 
censoring at 
final PSA 
measurement 
before 
discontinuation
Subjects who 
discontinue the 
first study drug 
are excluded 
from analysis
Subjects who 
discontinue the 
second study 
drug are 
considered as 
censoring at 
final PSA 
measurement 
before 
discontinuation
Considered as 
censoring at 
final PSA 
measurement 
before 
discontinuation
The event is 
considered to 
occur at the 
time of 
discontinuation
The event is 
considered to 
occur at the 
time of 
discontinuation
Considered as 
censoring at 
final 
radiographic 
assessment 
before 
discontinuation
Considered as 
censoring at 
final 
radiographic 
assessment 
before 
discontinuation


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Subjects who used 
prohibited concomitant 
medication or therapy 
during the study 
Subjects who 
use one with the 
first study drug 
are considered 
as censoring at 
final PSA 
measurement 
before use
Considered as 
censoring at 
final PSA 
measurement 
before use
Subjects who 
use one with the 
first study drug 
are excluded 
from analysis
Subjects who 
use one with the 
second study 
drug are 
considered as 
censoring at 
final PSA 
measurement 
before use
Considered as 
censoring at 
final PSA 
measurement 
before use
Not considered
as censoring
*To be judged 
based on 
continuation of 
study treatment
Not considered 
as censoring
*To be judged 
based on 
continuation of 
study treatment
Considered as 
censoring at 
final 
radiographic 
assessment 
before use
Considered as 
censoring at 
final 
radiographic 
assessment 
before use
Subjects who miss 
PSA data at least twice 
consecutively at 
scheduled PSA 
measurement points
Considered as 
censoring at 
final PSA 
measurement 
before missing 
data occur
Considered as 
censoring at 
final PSA 
measurement 
before missing 
data occur
Subjects who 
continue the 
first study drug 
are excluded 
from analysis
Subjects who 
have shifted to 
the second 
study drug are 
considered as 
censoring at 
final PSA 
measurement 
before missing 
data occur
Considered as 
censoring at 
final PSA 
measurement 
before missing 
data occur
Not considered 
as censoring
*To be judged 
based on 
continuation of 
study treatment
Not considered 
as censoring
*To be judged 
based on 
continuation of 
study treatment
Not considered 
as censoring
*To be judged 
based on result 
of radiographic 
assessment
Not considered 
as censoring
*To be judged 
based on result 
of radiographic 
assessment
Subjects who miss 
radiographic 
assessment at least 
twice consecutively at 
scheduled radiographic 
assessment points
Not considered 
as censoring
*To be judged 
based on result 
of PSA 
measurement
Not considered 
as censoring
*To be judged 
based on result 
of PSA 
measurement
Not considered 
as censoring
*To be judged 
based on result 
of PSA 
measurement
Not considered 
as censoring
*To be judged 
based on result 
of PSA 
measurement
Not considered 
as censoring
*To be judged 
based on 
continuation of 
study treatment
Not considered 
as censoring
*To be judged 
based on 
continuation of 
study treatment
Considered as 
censoring at 
final 
radiographic 
assessment 
before missing 
data occur
Considered as 
censoring at 
final 
radiographic 
assessment 
before missing 
data occur


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7.4.4
Analysis of Other Variables 
PSA measurement
Descriptive statistics for PSA measurement and its change from baseline will be summarized 
at by visit and treatment group. These measurement value and change from baseline will be
plotted as mean +/- SD plot.
Swimmer’s plot
Swimmer’s plot will be made to present treatment flow and event occurrence for each 
patient. This plot will include time on and off of the 1st/2nd line AAT continuations as a bar 
chart, and the points at which drug related AEs (by CTCAE grades), PSA progression, 
radiographic progression, PSA response, and death.
7.5
Analysis of Safety
All analysis of safety will be presented by actual treatment group for SAF, unless specified 
otherwise. The last non-missing measurement prior to the first dose of study drug will be used as 
the baseline.
7.5.1
Adverse Events
The severity of all AEs is to be evaluated by the investigator based on the National Cancer 
Institute’s CTCAE version 4.0. The coding dictionary for this study will be Medical 
Dictionary for Regulatory Activities (MedDRA) version 19.1. It will be used to summarize 
AEs by SOC and PT. 
The safety analysis will be performed in the safety analysis set, and summarized by the time 
of assessment and by the treatment group that actually received the study drugs. The period 
of onset in the treatment period with the study drug is defined up to 28 days after the final 
treatment with the study drug, start date of cytocidal chemotherapy, or start date of new 
treatment for prostate cancer, whichever occurs first. Safety will be assessed by AEs, 
frequency of treatment discontinuation associated with AEs, and laboratory test value 
summary statistics. Descriptive statistics, and not inferential statistics, will be used.
The total number of AEs reported will be presented by treatment arm (i.e. enzalutamide v.s. 
flutamide) and overall total for the SAF. The same analysis will be provided dividing 
treatment lines. AEs which have occurred during 1st line AAT and 2nd line AAT will be 
included to analysis. In this ‘event level’ analyses, all AEs will be counted separately. The 
following categories will be presented: 
●
Number of AEs, 
●
Number of AEs leading to study drug discontinuation, 
●
Number of drug-related AEs, 
●
Number of drug-related AEs leading to study drug discontinuation, 
●
Number of grade 3 or higher AEs, 
●
Number of grade 3 or higher drug-related AEs,
●
Number of serious adverse events (SAEs), 


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●
Number of drug-related SAEs, 
●
Number of SAEs leading to study drug discontinuation, 
●
Number of drug-related SAEs leading to study drug discontinuation,
●
Number of SAEs leading to death, 
●
Number of drug-related SAEs leading to death. 
The number and percentage of subjects experiencing AEs will be presented by treatment arm
and overall total for the SAF. The same analysis will be provided dividing treatment lines.
AEs which have occurred during 1st line AAT and 2nd line AAT will be included to 
analysis. In this ‘subject level’ analyses, multiple AEs within the same category for a 
particular subject will only be counted once and the denominator for the percentage 
calculation will be the number of subjects in the SAF. The following categories will be 
presented:
●
Number and percentage of subjects with AEs, 
●
Number and percentage of subjects with AEs leading to study drug discontinuation, 
●
Number and percentage of subjects with drug-related AEs, 
●
Number and percentage of subjects with drug-related AEs leading to study drug 
discontinuation, 
●
Number and percentage of subjects with grade 3 or higher AEs, 
●
Number of grade 3 or higher drug-related AEs,
●
Number and percentage of subjects with SAEs, 
●
Number and percentage of subjects with drug-related SAEs, 
●
Number and percentage of subjects with SAEs leading to study drug discontinuation, 
●
Number and percentage of subjects with drug-related SAEs leading to study drug 
discontinuation, 
●
Number and percentage of subjects with SAEs leading to death, 
●
Number and percentage of subjects with drug-related SAEs leading to death. 
The number and percentage of subjects experiencing AEs will be tabulated by SOC, PT, 
treatment arm and overall total for the SAF. The same analysis will be provided dividing 
treatment lines. AEs which have occurred during 1st line AAT and 2nd line AAT will be 
included to analysis. For this and similar analyses, an AE will only be counted once for each 
subject if the same AE is experienced on more than one occasion. Tables will be sorted by 
descending overall total of SOC and PT frequency. The following summaries will be 
produced:
●
AEs, 
●
AEs leading to study drug discontinuation, 
●
drug-related AEs, 
●
drug-related AEs leading to study drug discontinuation, 
●
grade 3 or higher AEs, 
●
SAEs, 


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●
drug-related SAEs, 
●
SAEs leading to study drug discontinuation, 
●
drug-related SAEs leading to study drug discontinuation,
●
SAEs leading to death,
●
drug-related SAEs leading to death,
●
TEAEs excluding serious adverse events that equal to or exceed a threshold of 2.0% in 
any treatment group, and 
●
Common TEAEs that equal to or exceed a threshold of 2.0% in any treatment group.
The number and percentage of subjects experiencing AEs will be tabulated by SOC, PT, 
maximum severity, treatment arm and overall total for the SAF. The same analysis will be 
provided dividing treatment lines. AEs which have occurred during 1st line AAT and 2nd 
line AAT will be included to analysis. For this and similar analyses, a subject reporting the 
same adverse event more than once is counted once at the maximum severity when 
calculating incidence. Tables will be sorted by descending overall total of SOC and PT 
frequency. The following summaries will be produced:
●
AEs, 
●
drug-related AEs, 
●
SAEs, 
The listing for subjects those who meet the special situations such as overdose, drug abuse, 
inadvertent or accidental exposure, or medication error will be prepared.
7.5.2
Clinical Laboratory Evaluation
Laboratory data consist of hematology, chemistry, and urinalysis laboratory tests. The National 
Cancer Institute’s CTCAE version 4.0, will be used to categorize toxicity grade for the laboratory 
parameters. Normal ranges will be implemented to identify values that are outside the normal 
range. 
Quantitative clinical laboratory variables from the hematology, chemistry, and urinalysis panels 
will be summarized using mean, standard deviation, minimum, maximum and median for each 
treatment group at each visit. These measurement values will be plotted as mean +/- SD plot. 
Additionally, a within-subject change will be calculated per visit as the post-baseline 
measurement minus the baseline measurement and summarized in the same way. 
For laboratory parameters that are gradable by the CTCAE, a shift table will be provided for each 
parameter to summarize baseline toxicity grade versus worst post-baseline toxicity grade during 
the treatment-emergent period by treatment line, separately. The number and percentage of 
subjects with at least one occurrence of grade 3 or grade 4 laboratory values in the treatment-
emergent period will be summarized for each parameter and treatment group. The number and 
percentage of subjects with toxicity grade increase of two or more above baseline will also be 
summarized for each parameter and treatment group. 
Each laboratory result will be classified as low (L), normal (N), or high (H) at each visit 
according to the laboratory supplied reference ranges. A high level overview shift table will be 
presented per parameter for each treatment group. Subjects who are normal at baseline and 
become low/high/low or high at any post-baseline time point will be summarized in the tables. 


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7.5.2.1 Liver function tests 
The following potentially clinically significant criteria for liver tests – defined as ALP, 
Alanine Transaminase (ALT), total bilirubin, Aspartate Transaminase (AST) and their 
combination are defined. The subject’s highest value during the investigational period will be 
used. 
Parameter
Criteria
ALT
> 3xULN
> 5xULN
AST
> 3xULN
> 5xULN
Total Bilirubin
> 2xULN
ALP
> 1.5xULN
ALT and/or AST AND Total Bilirubin(*)
(ALT and/or AST > 3xULN) and 
total bilirubin > 2xULN
(*) Combination of values measured within same sample
The number and percentage of subjects with potentially clinically significant values in liver 
enzyme and total bilirubin tests during the investigational period will be presented by 
treatment arm. The same analysis will be provided dividing treatment lines.
7.5.3
Vital Signs
Vital signs (systolic blood pressure, diastolic blood pressure, and pulse rate) will be 
summarized using mean, standard deviation, minimum, maximum and median by treatment 
group and visit. These measurement values will be plotted as mean +/- SD plot. Additionally, 
a within-subject change will be calculated per visit as the post-baseline measurement minus 
the baseline measurement and summarized by treatment group and visit in the same way. 
7.5.4
ECOG performance status
The number and percentage ECOG performance status will be presented by treatment arm. 
The same analysis will be provided dividing treatment lines.
7.5.5
Electrocardiograms (ECGs)
Not applicable.
7.5.6
Pregnancies
Not applicable.
7.5.7
Other Safety-Related Observations
Not applicable.
.


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7.6
Analysis of PK
Not applicable.
7.7
Analysis of PD
Not applicable.
7.8
Subgroups of Interest 
Primary efficacy endpoint, TTPP2, PSA Response Rate to 1st Line AAT, PSA Response 
Rate to 1st Line AAT at Week 13 and rPFS, analyses will be repeated by the subgroups 
defined on the basis of the categorized variables listed below:
●
Baseline ECOG performance status (0 vs ≥1) 
●
Age category (<75 and ≥75 years), (at or below median vs above median)
●
Total Gleason score (≤7 and ≥8) at diagnosis 
●
Type of progression (PSA progression only vs radiographic progression with or without 
PSA progression) at study entry 
●
Baseline PSA value (at or below median vs above median) 
●
PSA value at initial diagnosis (at or below median vs above median)
●
Baseline LDH value (at or below median vs above median) 
●
Baseline hemoglobin value (at or below median vs above median) 
●
Baseline ALP value (at or below median vs above median)
●
Treatment duration of bicalutamide (at or below 12 months vs above 12 months), (at or 
below median vs above median) 
●
PSA nadir value on CAB therapy (≤4ng/mL vs >4ng/mL), (≤0.2ng/mL vs >0.2ng/mL)
●
PSA response rate to 1st line AAT at Week 13 (below 50% vs at or above 50% reduction 
from baseline), (below 90% vs at or above 90% reduction from baseline) *except for the 
analysis of PSA Response Rate to 1st Line AAT at Week 13.
●
Baseline NLR value (at or below median vs above median)
●
Baseline testosterone value (at or below median vs above median)
●
Treatment duration of first line hormonal therapy (at or below 12 months vs above 12 
months), (at or below median vs above median)
●
Disease stages (M0/N0 vs M0/N1 vs M1)
●
PSA doubling time (at or below median vs above median)
Also, selected safety variables (treatment emergent adverse events) will be summarized by 
the treatment group for the subgroups defined on the basis of the categorized variables listed 
below:
●
Baseline ECOG performance status (0 vs ≥1) 
●
Age category (<75 and ≥75 years), (at or below median vs above median)


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7.9
Other Analyses
A list of Flutamide-related and non-serious adverse event will be derived. 
7.10
Interim Analysis (and Early Discontinuation of the Clinical Study)
Not applicable.
7.11
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information
Refer to the data specification document in which more details are provided. 
7.11.1
Missing Data
As a general principle, no imputation of missing data will be done. Exceptions are the start 
and stop dates of concomitant medication and radiotherapy for prostate cancer. The imputed 
dates will be used to determining whether a medication or radiotherapy is prior to/on or after 
the first dose of study drug. The following rules will be applied to impute partial dates for 
medications and radiotherapy for prostate cancer: 
If start date of a medication/radiotherapy is partially missing, impute as follows: 
● If both Month and Day are missing, then set to January 1 
● If only Day is missing, then set to the first day of the month 
If end date of a medication/radiotherapy is partially missing, impute as follows: 
● If both Month and Day are missing, then set to December 31 
● If only Day is missing, then set to last day of the month 
If start date and/or end date of a medication/radiotherapy is completely missing, do not 
impute. 
Listings will present the actual partial dates; imputed dates will not be shown.
7.11.2
Outliers
All values will be included in the analyses.
7.11.3
Visit Windows
[Acceptable Time Ranges of Efficacy Tests]
(1) PSA
1st line AAT


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Study Visit
Reference Date
Acceptable Range
Screening visit
−28 days to −7 days
28 days to 7 days before 
randomization
Week 1 (Day 1)
1
-
Week 13 (Day 85)
85
Reference date ± 7 days
Week 17 (Day 113)
113
Reference date ± 7 days
Every subsequent 4 weeks
Every subsequent 28 
days
Reference date ± 7 days
2nd line AAT
Study Visit
Reference Date
Acceptable Range
Week 1 (Day 1)
1
-
Week 13 (Day 85)
85
Reference date ± 7 days
Week 17 (Day 113)
113
Reference date ± 7 days
Every subsequent 4 weeks
Every subsequent 28 
days
Reference date ± 7 days
At completion or 
discontinuation
Day of completion or 
discontinuation visit
Reference date + 7 days
Safety follow-up
Final study treatment 
+ 28 days
Reference date ± 7 days
(2) Abdominopelvic CT/MRI, Bone scintigraphy, Chest CT
Study Visit
Reference Date
Acceptable Range
Screening visit*1
−28 days to −7 days
28 days to 7 days before 
randomization
Week 13 (Day 85)
85
Reference date ± 14 days
Every subsequent 12 
weeks*2
Every subsequent 84 
days
Reference date ± 14 days
At completion or 
discontinuation*3
Day of completion or 
discontinuation visit
Reference date + 14 days
*1: Images taken within 42 days before randomization as part of daily consultation before informed consent 
may be used as data in the screening period. 
*2: Perform every 12 weeks, irrespective of switching medications. 
*3: Not required if it occurs within 28 days from the latest measurement.
(3) FACT-P*1, EQ-5D-5L*1, BPI-SF, BFI
1st line AAT


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Study Visit
Reference Date
Acceptable Range
Screening visit
−28 days to −7 days
28 days to 7 days before 
randomization
Week 1 (Day 1)
1
-
Week 13 (Day 85)
85
78 days to 92 days
Every subsequent 12 
weeks
Every subsequent 84 
days
Reference date ± 7 days
2nd line AAT
Study Visit
Reference Date
Acceptable Range
Week 1 (Day 1)
1
-
Week 13 (Day 85)
85
78 days to 92 days
Every subsequent 12 
weeks
Every subsequent 84 
days
Reference date ± 7 days
At completion or 
discontinuation*2
Day of completion or 
discontinuation visit
Reference date + 7 days
*1: Do not perform on screening visit.
*2: Not required if it occurs within 28 days from the latest measurement.
[Acceptable Time Ranges of Safety Tests]
Laboratory test (biochemistry, hematology, and urinalysis), Vital signs (blood pressure and 
pulse rate), ECOG Performance Status


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1st line AAT
Study Visit
Reference Date
Acceptable Range
Screening visit
−28 days to −7 days
28 days to 7 days before 
randomization
Week 1 (Day 1)
1
-
Week 5 (Day 29)
29
Reference date ± 7 days
Week 9 (Day 57)
57
Reference date ± 7 days
Week 13 (Day 85)
85
Reference date ± 7 days
Every subsequent 4 weeks
Every subsequent 28 
days
Reference date ± 7 days
2nd line AAT
Study Visit
Reference Date
Acceptable Range
Week 1 (Day 1)
1
-
Week 5 (Day 29)
29
Reference date ± 7 days
Week 9 (Day 57)
57
Reference date ± 7 days
Week 13 (Day 85)
85
Reference date ± 7 days
Every subsequent 4 weeks
Every subsequent 28 
days
Reference date ± 7 days
At completion or 
discontinuation
Day of completion or 
discontinuation visit
Reference date + 7 days
Safety follow-up
Final study treatment 
+ 28 days
Reference date ± 7 days
The value which assessment day is the closest to the defined target day within these windows 
is used. If two values are equally close, the earlier is used in the analysis. Note that a value 
which is assessed prior to Day 1 of the 1st line AAT or 2nd line AAT will be available as 
baseline assessment once it is investigated and approved by the review board. Also, a value 
which is assessed as Day 1 of the 2nd line AAT will be utilized as end/discontinuation of 1st 
line AAT when a subject start 2nd line AAT without confirmation of PSA progression or 
because of other than PSA progression.
8
DOCUMENT REVISION HISTORY
9
REFERENCES
●
Ikeda S, Shiroiwa T, Igarashi A, Noto S, Fukuda T, Saito S, Shimozuma K. Developing 
a Japanese version of the EQ-5D-5L value set. J. Natl. Inst. Public Health, 64(1):47-55, 
2015. 
Version
Date
Changes
Comment/rationale for change
1.00
8-July-2020
NA
Document finalized


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●
Sato, T. On the Variance Estimator of the Mantel-Haenszel Risk Difference. Biometrics, 
45, 1323–4, letter to the editor, 1989.


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10
APPENDICES
10.1
Appendix 1: Key Contributors and Approvers
List of Key Contributors and Approvers
Key Contributors
The following contributed to or reviewed this Statistical Analysis Plan as relevant to their 
indicated discipline or role.
Primary author (s)
 
Contributors and Reviewers