Clinical trial NCT02677896
Conditions: Metastatic Hormone Sensitive Prostate Cancer
Keywords: Androgen Deprivation Therapy (ADT) Metastatic hormone sensitive prostate cancer Xtandi Enzalutamide
Sponsor: Astellas Pharma Global Development, Inc.
Start date: 2016-03-09; Completion date: 2024-07-31
Enrollment: 1150 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to evaluate the efficacy of enzalutamide plus androgen deprivation therapy (ADT) as measured by radiographic progression-free survival (rPFS) based on central review. The study also evaluated the safety of enzalutamide plus ADT in mHSPC.

Detailed description:
Following unblinding at the end of the double-blind period and demonstration of a statistically significant advantage of enzalutamide over placebo when added to ADT as assessed by the primary endpoint of rPFS, subjects were eligible to transition to an open-label portion of the study.

Arms: arm 1: Participants received 160 mg enzalutamide orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide during double-blind treatment period and provided informed consent to take part in open-label period continued to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or Luteinizing hormone-releasing hormone (LHRH) agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock. arm 2: Participants received matching placebo orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock. arm 3: Eligible participants who received enzalutamide matching placebo during double-blind treatment period and provided informed consent to take part in open-label period switched to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.
Interventions: intervention 1: Enzalutamide intervention 2: Placebo
Intervention descriptions: intervention 1: Oral intervention 2: Oral

Protocol documents:
Prot_002.pdf: 
Sponsor: APGD 
ISN/Protocol 9785-CL-0335 
EudraCT number 2015-003869-28 
 
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Astellas 
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Version 5.1 Incorporating Nonsubstantial Amendment 6 
ARCHES: A Multinational, Phase 3, Randomized, Double-blind, 
Placebo-controlled Efficacy and Safety Study of Enzalutamide Plus 
Androgen Deprivation Therapy (ADT) Versus Placebo Plus ADT in 
Patients with Metastatic Hormone Sensitive Prostate Cancer 
(mHSPC) 
ISN/Protocol 9785-CL-0335 
Version 5.1 
Incorporating Nonsubstantial Amendment 6 [See Section 13] 
18 Apr 2022 
IND 74563 
EudraCT 2015-003869-28 
Sponsor: 
Astellas Pharma Global Development, Inc (APGD) 
1 Astellas Way 
Northbrook, IL 60062 
Co-Sponsor: 
Medivation, a wholly owned subsidiary of Pfizer 
525 Market Street, 36th Floor 
San Francisco, CA 94105 
Telephone:  +1 (415) 543-3470 
Fax:  +1 (415) 543-3411 
Protocol History: 
Version 1.0 [10Nov2015] 
Version 1.1 [FR] Nonsubstantial Amendment 1 [21Apr2016] 
Version 1.2 [SE] Nonsubstantial Amendment 2 [21Apr2016] 
Version 2.0 Substantial Amendment 1 [02Jun2016] 
Version 2.1 [CA, US] Nonsubstantial Amendment 3 [04Oct2017] 
Version 3.0 Substantial Amendment 2 [14Dec2017] 
Version 4.0 Substantial Amendment 3 [10Dec2018] 
Version 4.1 [JP] Nonsubstantial Amendment 4 [18Feb2020] 
Version 4.2 Nonsubstantial Amendment 5 [22Apr2020] 
Version 5.0 Substantial Amendment 4 [31Mar2021] 
 
Investigator:  Investigator information is on file at Astellas 
 
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: APGD 
ISN/Protocol 9785-CL-0335 
EudraCT number 2015-003869-28 
 
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Table of Contents  
I. 
SIGNATURES ······················································································ 8 
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 ································· 26 
1 
INTRODUCTION ················································································· 29 
1.1 
Background ···················································································· 29 
1.2 
Nonclinical and Clinical Data ······························································· 31 
1.2.1 
Nonclinical Data ········································································· 31 
1.2.2 
Clinical Data ············································································· 33 
1.3 
Summary of Key Safety Information for Study Drugs ··································· 35 
1.4 
Risk-Benefit Assessment ····································································· 36 
2 
STUDY OBJECTIVE(S), DESIGN AND ENDPOINTS ··································· 38 
2.1 
Study Objectives ·············································································· 38 
2.1.1 
Primary Objective ······································································· 39 
2.1.2 
Secondary Objectives ··································································· 39 
2.1.3 
Safety Objective ········································································· 39 
2.1.4 
Exploratory Objective (North America sites only) ·································· 39 
2.2 
Study Design and Dose Rationale ··························································· 40 
2.2.1 
Study Design ············································································· 40 
2.2.2 
Dose Rationale ··········································································· 41 
2.3 
Endpoints ······················································································· 41 
2.3.1 
Primary Endpoints ······································································· 41 
2.3.2 
Secondary Endpoints ···································································· 41 
2.3.3 
Safety Endpoints ········································································· 42 
2.3.4 
Exploratory Endpoint (North America sites only) ··································· 42 
3 
STUDY POPULATION ·········································································· 42 
3.1 
Selection of Study Population ······························································· 42 
3.2 
Inclusion Criteria ·············································································· 42 
3.3 
Exclusion Criteria ············································································· 43 
4 
TREATMENT(S) ·················································································· 45 


Sponsor: APGD 
ISN/Protocol 9785-CL-0335 
EudraCT number 2015-003869-28 
 
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4.1 
Identification of Investigational Product(s) ················································ 45 
4.1.1 
Test Drug(s) ·············································································· 45 
4.1.2 
Comparative Drug(s) ···································································· 46 
4.2 
Packaging and Labeling ······································································ 46 
4.3 
Study Drug Handling ········································································· 46 
4.4 
Blinding ························································································ 47 
4.4.1 
Blinding Method ········································································· 47 
4.4.2 
Retention of the Assignment Schedule and Procedures for Treatment Code 
Breaking ·················································································· 48 
4.4.3 
Breaking the Treatment Code ·························································· 48 
4.4.4 
Breaking the Treatment Code by the Sponsor ······································· 48 
4.5 
Assignment and Allocation ·································································· 48 
5 
TREATMENTS AND EVALUATION ························································ 49 
5.1 
Dosing and Administration of Study Drug(s) and Other Medication(s) ················ 49 
5.1.1 
Dose/Dose Regimen and Administration Period ···································· 49 
5.1.2 
Increase or Reduction in Dose of the Study Drug(s) ································ 49 
5.1.3 
Previous and Concomitant Treatment (Medication and Nonmedication 
Therapy) ·················································································· 49 
5.1.3.1 
Required Concomitant Treatment ··············································· 50 
5.1.3.2 
Prohibited Concomitant Treatment ·············································· 50 
5.1.3.3 
Enzalutamide Drug Interaction ··················································· 51 
5.1.3.4 
Permitted Concomitant Treatment ··············································· 51 
5.1.4 
Treatment Compliance ·································································· 52 
5.2 
Demographics and Baseline Characteristics ··············································· 52 
5.2.1 
Demographics ············································································ 52 
5.2.2 
Medical History ·········································································· 52 
5.2.3 
Diagnosis of the Target Disease, Severity, and Duration of Disease ·············· 52 
5.3 
Efficacy Assessment ·········································································· 52 
5.3.1 
Efficacy Assessment ···································································· 52 
5.3.1.1 
CT/MRI and Bone Scan ·························································· 52 
5.3.1.2 
Subject Reported Outcomes ······················································ 54 
5.4 
Safety Assessment ············································································ 54 
5.4.1 
Vital Signs ················································································ 54 
5.4.2 
Adverse Events ·········································································· 55 


Sponsor: APGD 
ISN/Protocol 9785-CL-0335 
EudraCT number 2015-003869-28 
 
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5.4.2.1 
Adverse Events of Possible Hepatic Origin ···································· 55 
5.4.3 
Laboratory Assessments ································································ 55 
5.4.4 
Physical Examination including Weight and Height ································ 55 
5.4.5 
Electrocardiogram ······································································· 56 
5.5 
Adverse Events and Other Safety Aspects ················································· 56 
5.5.1 
Definition of Adverse Events ·························································· 56 
5.5.2 
Definition of Serious Adverse Events················································· 57 
5.5.3 
Criteria for Causal Relationship to the Study Drug ································· 58 
5.5.4 
Criteria for Defining the Severity of an Adverse Event ···························· 58 
5.5.5 
Reporting of Serious Adverse Events ················································· 58 
5.5.6 
Follow-up of Adverse Events ·························································· 60 
5.5.7 
Monitoring of Common Serious Adverse Events ··································· 60 
5.5.8 
Procedure in Case of Pregnancy ······················································· 60 
5.5.9 
Emergency Procedures and Management of Overdose ····························· 61 
5.5.10 
Supply of New Information Affecting the Conduct of the Study ·················· 61 
5.5.11 
Deviations from the Protocol and Other Actions Taken to Avoid 
Life-threatening Risks to Subjects (Specific to Sites in Japan) ···················· 62 
5.6 
Test Drug Concentration ····································································· 62 
5.7 
Other Measurements, Assessments or Methods ··········································· 62 
5.7.1 
Optional Blood Sample for Mutation Analysis (North America Sites Only) ···· 62 
5.7.2 
Optional Blood Sample for Future Pharmacogenomic Analysis 
(Retrospective Pharmacogenomic Analysis) ········································· 63 
5.8 
Total Amount of Blood ······································································· 63 
6 
DISCONTINUATION ············································································ 63 
6.1 
Discontinuation of Individual Subject(s) ··················································· 63 
6.2 
Discontinuation of the Site ··································································· 64 
6.3 
Discontinuation of the Study································································· 64 
7 
STATISTICAL METHODOLOGY ··························································· 64 
7.1 
Sample Size ···················································································· 65 
7.2 
Analysis Set ···················································································· 65 
7.2.1 
Intent-to-Treat Population ······························································ 65 
7.2.2 
Safety Population ········································································ 66 
7.3 
Demographics and Other Baseline Characteristics ········································ 66 
7.4 
Analysis of Efficacy ·········································································· 66 


Sponsor: APGD 
ISN/Protocol 9785-CL-0335 
EudraCT number 2015-003869-28 
 
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7.4.1 
Analysis of Primary Endpoint ························································· 66 
7.4.1.1 
Subgroup Analysis ································································· 66 
7.4.2 
Analysis of Secondary Endpoints ····················································· 66 
7.5 
Analysis of Safety ············································································· 69 
7.5.1 
Adverse Events ·········································································· 70 
7.5.2 
Laboratory Assessments ································································ 70 
7.5.3 
Vital Signs ················································································ 70 
7.5.4 
Physical Examination ··································································· 70 
7.5.5 
Electrocardiogram ······································································· 70 
7.6 
Analysis of Exploratory Endpoint ··························································· 70 
7.7 
Analysis of Pharmacokinetics ······························································· 70 
7.8 
Protocol Deviations and Other Analyses (Unique to JP: Other Analyses) ············· 71 
7.9 
Interim Analysis ··············································································· 71 
7.10 
Handling of Missing Data, Outliers, Visit Windows, and Other Information ········· 71 
8 
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS ···················· 71 
8.1 
Procedure for Clinical Study Quality Control ············································· 71 
8.1.1 
Data Collection ·········································································· 71 
8.1.2 
Specification of Source Documents ··················································· 72 
8.1.3 
Clinical Study Monitoring ······························································ 72 
8.1.4 
Direct Access to Source Data/Documents ············································ 73 
8.1.5 
Data Management ······································································· 73 
8.1.6 
Protocol Deviations ····································································· 73 
8.1.7 
End of Trial in All Participating Countries ··········································· 74 
8.2 
Ethics and Protection of Subject Confidentiality ·········································· 74 
8.2.1 
IRB/IEC/Competent Authorities······················································· 74 
8.2.2 
Ethical Conduct of the Study ··························································· 74 
8.2.3 
Informed Consent of Subjects ························································· 75 
8.2.3.1 
Subject Information and Consent ················································ 75 
8.2.3.2 
Supply of New and Important Information Influencing the Subject’s 
Consent and Revision of the Written Information ····························· 75 
8.2.4 
Subject Confidentiality ································································· 75 
8.3 
Administrative Matters ······································································· 76 
8.3.1 
Arrangement for Use of Information and Publication of the Clinical Study ····· 76 
8.3.2 
Documents and Records Related to the Clinical Study ····························· 76 


Sponsor: APGD 
ISN/Protocol 9785-CL-0335 
EudraCT number 2015-003869-28 
 
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8.3.3 
Protocol Amendment and/or Revision ················································ 78 
8.3.4 
Insurance of Subjects and Others ······················································ 79 
8.3.5 
Signatory Investigator for Clinical Study Report ···································· 79 
9 
QUALITY ASSURANCE ········································································ 79 
10 
STUDY ORGANIZATION ······································································ 80 
10.1 
Data Safety Monitoring Board ······························································· 80 
10.2 
Other Study Organization ···································································· 80 
11 
REFERENCES ···················································································· 81 
12 
APPENDICES ····················································································· 83 
12.1 
List of Excluded Concomitant Medications················································ 83 
12.2 
Liver Safety Monitoring and Assessment ·················································· 84 
12.3 
Common Serious Adverse Events ··························································· 87 
12.4 
Retrospective Pharmacogenomic Substudy ················································ 88 
12.5 
ECOG Performance Status Scale ···························································· 90 
12.6 
Open-Label Extension ········································································ 91 
12.6.1 
Rationale ·················································································· 91 
12.6.2 
Schedule and Assessments ····························································· 91 
12.6.3 
Inclusion Criteria ········································································ 96 
12.6.4 
Exclusion Criteria ······································································· 96 
12.6.5 
Enzalutamide Administration, Storage and Accountability ························ 96 
12.6.6 
Duration of Treatment and Criteria for Discontinuation ···························· 97 
12.6.7 
Statistical Methods ······································································ 97 
12.6.8 
Phase 4 Post-marketing Study after Marketing Authorization in Japan 
(Sites in Japan Only) ···································································· 98 
12.7 
Clinical Study Continuity ···································································· 99 
13 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ···························· 105 
14 
SPONSOR’S SIGNATURES ·································································· 106 
 


Sponsor: APGD 
ISN/Protocol 9785-CL-0335 
EudraCT number 2015-003869-28 
 
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List of Tables 
Table 1 
Schedule of Assessments ····································································· 27 
Table 2 
Protocol-specified Documentation for Radiographic Evidence of Disease 
Progression ····················································································· 53 
Table 3 
Laboratory Assessments ······································································ 55 
Table 4 
Open-Label Extension Schedule of Assessments ········································· 94 
Table 5 
Alternative Schedule of Assessments in Response to a Crisis ························· 101 
Table 6 
Nonsubstantial Changes ···································································· 105 
 
List of Figures 
Figure 1 
Clinical States Model of Prostate Cancer Progression ···································· 29 
Figure 2 
Testing Strategy for the Primary and 6 Selected Secondary Endpoints ················ 67 
Figure 3 
Schematic – Open-Label Extension ························································· 93 
 
 


Sponsor: APGD 
ISN/Protocol 9785-CL-0335 
EudraCT number 2015-003869-28 
 
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I. 
SIGNATURES 
1.  SPONSOR’S SIGNATURE 
Required signatures (e.g., Protocol authors, sponsor’s reviewers and contributors, etc.) are 
located in [Section 14, Signatures]; e-signatures (when applicable) are located at the end of 
this document. 
 


Sponsor: APGD 
ISN/Protocol 9785-CL-0335 
EudraCT number 2015-003869-28 
 
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2.  INVESTIGATOR’S SIGNATURE 
ARCHES:  A Multinational, Phase 3, Randomized, Double-blind, Placebo-
controlled Efficacy and Safety Study of Enzalutamide Plus Androgen 
Deprivation Therapy (ADT) Versus Placebo Plus ADT in Patients with 
Metastatic Hormone Sensitive Prostate Cancer (mHSPC)  
ISN/Protocol 9785-CL-0335 
Version 5.1 Incorporating Nonsubstantial Amendment 6 
18 Apr 2022 
I have read all pages of this clinical study protocol for which Astellas is the sponsor. I agree 
to conduct the study as outlined in the protocol and to comply with all the terms and 
conditions set out therein. I confirm that I will conduct the study in accordance with ICH 
GCP guidelines and applicable local regulations. I will also ensure that subinvestigator(s) and 
other relevant members of my staff have access to copies of this protocol and the ICH GCP 
guidelines to enable them to work in accordance with the provisions of these documents. 
Principal Investigator: 
 
 
Signature: 
 
 
Printed Name: 
Date (DD Mmm YYYY) 
 
Address: 
 
 
 
 
 
 
 
 
 
 
  




Sponsor: APGD 
ISN/Protocol 9785-CL-0335 
EudraCT number 2015-003869-28 
 
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III. 
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS 
List of Abbreviations 
Abbreviations 
Description of abbreviations 
ADT 
Androgen deprivation therapy 
AE 
Adverse event 
AESI 
Adverse events of special interest 
ALT 
Alanine aminotransferase 
APEBV 
Astellas Pharma Europe B.V. 
APGD 
Astellas Pharma Global Development, Inc 
AR 
Androgen receptor 
AST 
Aspartate aminotransferase 
AUST 
Astellas United States Technologies, Inc 
BHA 
Butylated hydroxyanisole 
BHT 
Butylated hydroxytoluene 
BPI-SF 
Brief Pain Inventory-Short Form 
CIOMS 
Council for International Organizations of Medical Sciences 
CLCR 
Creatinine clearance 
CRF 
Case report form 
CRPC 
Castration-resistant prostate cancer 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EGFR 
Epidermal growth factor receptor 
EQ-5D-5L 
EuroQol Group-5 Dimension-5 Level Instrument 
FACT-P 
Functional Assessment of Cancer Therapy-Prostate 
GABA 
γ-aminobutyric acid 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HDPE 
High-density polyethylene 
HR 
Hazard ratio 
ICF 
Informed consent form 
ICH  
International Council on Harmonisation 


Sponsor: APGD 
ISN/Protocol 9785-CL-0335 
EudraCT number 2015-003869-28 
 
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Abbreviations 
Description of abbreviations 
IEC 
Independent Ethics Committee 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ISN 
International study number 
ITT 
Intent-to-treat 
KRAS 
Kirsten rat sarcoma viral oncogene homolog 
LA-CRF 
Liver abnormality case report form 
LFT 
Liver function test 
LHRH 
Luteinizing hormone-releasing hormone 
LHRHA 
Luteinizing hormone-releasing hormone analogue 
mCRPC 
Metastatic castration-resistant prostate cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
mHSPC 
Metastatic hormone sensitive prostate cancer 
MRI 
Magnetic resonance imaging 
NASH 
Nonalcoholic steatohepatitis 
NCI 
National Cancer Institute 
NRAS 
Neuroblastoma RAS viral oncogene homolog 
NSAA 
Nonsteroidal antiandrogen 
ORR 
Objective response rate 
OS 
Overall survival 
P-gp 
P-glycoprotein 
PIK3CA 
Phosphatidylinositol-4, 5-bisphosphate 3-kinase, catalytic subunit alpha 
PGx 
Pharmacogenomics 
PRES 
Posterior reversible encephalopathy syndrome 
PSA 
Prostate-specific antigen 
PSADecR 
Rate of PSA decline to < 0.2ng/mL 
QLQ-PR25 
Quality of Life Prostate-specific Questionnaire 
QoL 
Quality of Life 
RECIST 
Response Evaluation Criteria in Solid Tumors 
rPFS 
Radiographic progression-free survival 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SOC 
Standard of care 
SOP 
Standard operating procedure 
SSE 
Symptomatic Skeletal Event 
SUSAR 
Suspected unexpected serious adverse reaction 


Sponsor: APGD 
ISN/Protocol 9785-CL-0335 
EudraCT number 2015-003869-28 
 
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Abbreviations 
Description of abbreviations 
TBL 
Total bilirubin 
TTNAnti 
Time to initiation of a new antineoplastic therapy 
TTPSA 
Time to PSA progression 
TTUri 
Time to deterioration in urinary symptoms 
ULN 
Upper limit of normal 
 


Sponsor: APGD 
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Definition of Key Study Terms 
Terms 
Definition of terms 
Baseline  
Observed values/findings that are regarded observed starting point for 
comparison.   
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 and 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. 
Postinvestigational 
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. 
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. 
Screen failure 
Potential subject who did not meet 1 or more criteria required for participation 
in a trial. 
Screening 
A process of active consideration of potential subjects for enrollment in a trial. 
Study period 
Period of time from the first site initiation date to the last site completing the 
study. 


Sponsor: APGD 
ISN/Protocol 9785-CL-0335 
EudraCT number 2015-003869-28 
 
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Version 5.1 Incorporating Nonsubstantial Amendment 6 
IV. 
SYNOPSIS 
Date and Version # of Protocol Synopsis: 
18 Apr 2022, Version 5.1 
Sponsor:  
Astellas Pharma Global Development, Inc (APGD) 
Protocol Number:  
9785-CL-0335 
Name of Study Drug:  
Enzalutamide 
Phase of Development:  
Phase 3 
Title of Study:  
ARCHES: A Multinational, Phase 3, Randomized, Double-blind, Placebo-controlled Efficacy and 
Safety Study of Enzalutamide Plus Androgen Deprivation Therapy (ADT) Versus Placebo Plus ADT 
in Patients with Metastatic Hormone Sensitive Prostate Cancer (mHSPC) 
Planned Study Period: 
1Q2016 to 1Q2024 
Study Objective(s): 
The objective of this phase 3 study is to evaluate the efficacy and safety of enzalutamide plus 
androgen deprivation therapy (ADT) versus placebo plus ADT in subjects with metastatic hormone 
sensitive prostate cancer (mHSPC). 
Primary Objective 
• To determine the benefit of enzalutamide plus ADT as compared to placebo plus ADT as assessed 
by radiographic progression-free survival (rPFS) based on central review 
Secondary Objectives 
• To determine the benefit of enzalutamide plus ADT as compared to placebo plus ADT as assessed 
by overall survival (OS) 
• To determine the benefit of enzalutamide plus ADT as compared to placebo plus ADT as assessed 
by time to first Symptomatic Skeletal Event (SSE) 
• To determine the benefit of enzalutamide plus ADT as compared to placebo plus ADT as assessed 
by time to castration resistance 
• To determine the benefit of enzalutamide plus ADT as compared to placebo plus ADT as assessed 
by Quality of Life (QoL) (as measured by Quality of Life Prostate-specific Questionnaire [QLQ-
PR25] / Functional Assessment of Cancer Therapy-Prostate [FACT-P] and EuroQol Group-
5 Dimension-5 Level Instrument [EQ-5D-5L]), in particular by: 
o time to deterioration in urinary symptoms using a modified urinary symptoms scale from 
QLQ-PR25 
o time to deterioration in QoL using the FACT-P global score 
• To determine the benefit of enzalutamide plus ADT as compared to placebo plus ADT as assessed 
by time to start of new antineoplastic therapy 
• To determine the benefit of enzalutamide plus ADT as compared to placebo plus ADT as assessed 
by time to prostate-specific antigen (PSA) progression 
• To determine the benefit of enzalutamide plus ADT as compared to placebo plus ADT as assessed 
by PSA undetectable rate (< 0.2 ng/mL)  
• To determine the benefit of enzalutamide plus ADT as compared to placebo plus ADT as assessed 
by objective response rate (ORR) 
• To determine the benefit of enzalutamide plus ADT as compared to placebo plus ADT as assessed 
by worsening of pain (as measured by Brief Pain Inventory-Short Form [BPI-SF]) 
Safety Objective 
• To determine the safety of enzalutamide plus ADT as compared to placebo plus ADT 


Sponsor: APGD 
ISN/Protocol 9785-CL-0335 
EudraCT number 2015-003869-28 
 
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Exploratory Objective (North America sites only) 
• 
To determine gene mutations potentially related to resistance of enzalutamide plus ADT as 
assessed by DNA mutation testing in plasma 
Planned Total Number of Study Centers and Location(s): 
Approximately 250 centers globally  
Study Population: 
The study population will consist of subjects with mHSPC.   
Number of Subjects to be Randomized: 
Approximately 1100 subjects 
Study Design Overview: 
This is a multinational phase 3, randomized, double-blind, placebo-controlled efficacy and safety 
study of enzalutamide plus ADT versus placebo plus ADT in subjects with mHSPC. 
Approximately 1100 subjects will be randomized centrally 1:1, and the randomization will be 
stratified by volume of disease (low versus high) and prior docetaxel therapy for prostate cancer (no 
prior docetaxel, 1-5 cycles, 6 cycles).  High volume of disease is defined as metastases involving the 
viscera or, in the absence of visceral lesions, there must be 4 or more bone lesions, at least 1 of which 
must be in a bony structure beyond the vertebral column and pelvic bone.  Prior docetaxel therapy is 
defined as 1 or more cycles of docetaxel but no more than 6 cycles. 
Study drug therapy should be continued as long as the subject is tolerating the study drug and 
continues ADT until radiographic disease progression is documented as outlined in the table below or 
starting an investigational agent or new therapy for treatment of prostate cancer. It is recommended 
that subjects remain on study treatment until radiographic progression is confirmed by independent 
central imaging review.  Subjects who discontinue study treatment without radiographic progression 
will continue to follow the radiographic assessment schedule until radiographic progression event is 
confirmed by the central imaging independent reviewer or until the target number of progression 
events is reached as assessed by the central review. All subjects will be followed until death to assess 
for OS. Once the final number of events has been reached to trigger the final OS analysis, survival 
follow-up will be considered complete and subjects will be discontinued from long term follow-up. 
Study films (computed tomography [CT]/magnetic resonance imaging [MRI] and bone scan) should 
be read on site and also be submitted in digital format to the Sponsor-designated facility for 
independent central review.  Each site should ideally designate the same reader who will evaluate the 
images for any one subject for the duration of the trial. 
Radiographic disease progression is defined by Response Evaluation Criteria in Solid Tumors 
(RECIST) version 1.1 for soft tissue disease or the appearance of 2 or more new lesions on bone scan.  
The documentation and confirmation required for the determination of radiographic progression is 
listed in the following table. 
Protocol-specified Documentation for Radiographic Evidence of Disease Progression 
Date 
Progression 
Detected (Visit)† 
Criteria for Progression 
Criteria for Confirmation 
of Progression 
(Requirement and Timing) 
Criteria for Documentation of 
Disease Progression on 
Confirmatory Scan 
Week 13 
Bone lesions: ≥ 2 new 
lesions compared to baseline 
bone scan 
Timing: ≥ 6 weeks after 
progression identified or at 
week 25 visit 
≥ 2 new bone lesions on bone scan 
compared to week 13 scan (≥ 4 
new lesions compared to baseline 
bone scan) 
Soft tissue lesions: 
progressive disease on CT or 
MRI by RECIST v1.1 
No confirmatory scan 
required for soft tissue 
disease progression 
Not applicable 
Table continued on next page 


Sponsor: APGD 
ISN/Protocol 9785-CL-0335 
EudraCT number 2015-003869-28 
 
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Date Progression 
Detected (Visit)† 
Criteria for Progression 
Criteria for Confirmation of 
Progression (Requirement 
and Timing) 
Criteria for 
Documentation of 
Disease Progression on 
Confirmatory Scan 
Week 25 or Later 
Bone lesions: ≥ 2 new lesions on bone 
scan compared to best response on 
treatment 
No confirmatory scan required 
Not applicable 
Soft tissue lesions: progressive 
disease on CT or MRI by RECIST 
v1.1 
No confirmatory scan required 
for soft tissue disease 
progression 
Not applicable 
CT: computed tomography; MRI: magnetic resonance imaging; RECIST v1.1: Response Evaluation Criteria in Solid 
Tumors version 1.1 
† Progression detected by bone scan at an unscheduled visit prior to week 25 will require the same criteria for documentation 
of disease progression as week 13 with a confirmatory scan at least 6 weeks later or at the next scheduled scan. 
The following assessments of prostate cancer status will be collected during the course of the study: 
PSA, soft tissue disease on CT scan or on MRI, bone disease on radionuclide bone scans, survival 
status, EQ-5D-5L, QLQ-PR25, FACT-P for QoL and BPI-SF for pain symptom assessment. Once the 
final number of events has been reached to trigger the final OS analysis, sites will no longer be 
required to collect EQ-5D-5L, QLQ-PR25, FACT-P for QoL and BPI-SF. 
Throughout the study, safety and tolerability will be assessed by the recording of adverse events, vital 
signs, physical examinations, 12-lead electrocardiograms (ECGs), and safety laboratory evaluations. 
An independent Data Safety Monitoring Board (DSMB) will monitor the safety data on an ongoing 
basis. 
Subjects will have a safety follow-up visit 30 days after their last dose of study drug or prior to 
initiation of another investigational agent or new therapy for prostate cancer, whichever occurs first.  
All subjects are to be followed for survival until death, loss to follow-up, withdrawal of consent, final 
OS analysis or study termination by the Sponsor.  Once a sufficient number of death events has been 
reached for the OS analysis, survival follow-up will be considered complete and the long term 
follow-up process and QoL assessments collection will discontinue for all study participants. 
Subjects who are continuing to receive clinical benefit from treatment with enzalutamide after the OS 
analysis data cutoff or at study termination and have not met any discontinuation criteria may 
continue their open-label treatment in another Astellas-sponsored study.  
The sponsor will monitor study enrollment for proportion of subjects enrolled with a history of prior 
docetaxel treatment, and may either change the sample size, or cap the number of subjects who 
received prior docetaxel to ensure that the primary endpoint is not driven either by the subjects who 
received prior docetaxel, or by the subjects who did not receive prior docetaxel. 
The data gathered from the ARCHES study may be used to support future research studies. 
Inclusion/Exclusion Criteria: 
Inclusion: 
Subject is eligible for the study if all of the following apply: 
1. 
Institutional Review Board (IRB)-/Independent Ethics Committee (IEC)-approved written 
informed consent and privacy language as per national regulations (e.g., Health Insurance 
Portability Accountability Act authorization for United States sites) must be obtained from the 
subject or legally authorized representative prior to any study-related procedures (including 
withdrawal of prohibited medication, if applicable). 
2. 
Subject is considered an adult according to local regulation at the time of signing informed 
consent. 


Sponsor: APGD 
ISN/Protocol 9785-CL-0335 
EudraCT number 2015-003869-28 
 
- CONFIDENTIAL - 
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3. 
Subject is diagnosed with histologically or cytologically confirmed adenocarcinoma of the 
prostate without neuroendocrine differentiation, signet cell or small cell histology.  Specific to 
subjects enrolled in France, histological diagnosis is required. 
4. 
Subject has metastatic prostate cancer documented by positive bone scan (for bone disease) or 
metastatic lesions on CT or MRI scan (for soft tissue).  Subjects whose disease spread is limited 
to regional pelvic lymph nodes are not eligible. 
5. 
Once randomized at day 1, subject must maintain ADT with a luteinizing hormone-releasing 
hormone (LHRH) agonist or antagonist during study treatment or have a history of bilateral 
orchiectomy (i.e., medical or surgical castration). 
6. 
Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at 
screening. 
7. 
Subject has an estimated life expectancy of ≥ 12 months as assessed by the investigator. 
8. 
Subject is able to swallow the study drug and comply with study requirements. 
9. 
A sexually active male subject and his female partner who is of childbearing potential must use 
2 acceptable methods of birth control (1 of which must include a condom as a barrier method of 
contraception) from screening through 3 months after the last dose of study drug.  Two 
acceptable methods of birth control include condom (barrier method is required) AND 1 of the 
following: 
• Consistent and correct usage of established, proper use of hormonal contraceptives that 
inhibit ovulation by the female partner;  
• 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 applicable to 
subjects enrolled in Japan only). 
10. Subject must use a condom throughout the study if engaging in sexual intercourse with a 
pregnant woman. 
11. Subject must agree not to donate sperm from first dose of study drug through 3 months after the 
last dose of study drug. 
12. 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 participation if any of the following apply: 
1. 
Subject has received any prior pharmacotherapy, radiation therapy or surgery for metastatic 
prostate cancer (the following exceptions are permitted): 
• 
Up to 3 months of ADT with LHRH agonists or antagonists or orchiectomy with or without 
concurrent antiandrogens prior to day 1, with no radiographic evidence of disease 
progression or rising PSA levels prior to day 1; 
• 
Subject may have 1 course of palliative radiation or surgical therapy to treat symptoms 
resulting from metastatic disease if it was administered at least 4 weeks prior to day 1; 
• 
Up to 6 cycles of docetaxel therapy with final treatment administration completed within 
2 months of day 1 and no evidence of disease progression during or after the completion of 
docetaxel therapy; 


Sponsor: APGD 
ISN/Protocol 9785-CL-0335 
EudraCT number 2015-003869-28 
 
- CONFIDENTIAL - 
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• 
Up to 6 months of ADT with LHRH agonists or antagonists or orchiectomy with or without 
concurrent antiandrogens prior to day 1 if subject was treated with docetaxel, with no 
radiographic evidence of disease progression or rising PSA levels prior to day 1; 
• 
Prior ADT given for < 39 months in duration and > 9 months before randomization as 
neoadjuvant/adjuvant therapy. 
2. 
Subject had a major surgery within 4 weeks prior to day 1. 
3. 
Subject received treatment with 5-α reductase inhibitors (finasteride, dutasteride) within 4 weeks 
prior to day 1. 
4. 
Subject received treatment with estrogens, cyprotoerone acetate or androgens within 4 weeks 
prior to day 1. 
5. 
Subject received treatment with systemic glucocorticoids greater than the equivalent of 10 mg 
per day of prednisone within 4 weeks prior to day 1, intended for the treatment of prostate 
cancer. 
6. 
Subject received treatment with herbal medications that have known hormonal antiprostate 
cancer activity and/or are known to decrease PSA levels within 4 weeks prior to day 1. 
7. 
Subject received prior aminoglutethimide, ketoconazole, abiraterone acetate or enzalutamide for 
the treatment of prostate cancer or participation in a clinical study of an investigational agent that 
inhibits the androgen receptor or androgen synthesis (e.g., TAK-700, ARN-509, ODM-201). 
8. 
Subject received investigational agent within 4 weeks prior to day 1. 
9. 
Subject has known or suspected brain metastasis or active leptomeningeal disease. 
10. Subject has a history of another invasive cancer within 3 years of screening, with the exception 
of fully treated cancers with a remote probability of recurrence based on investigator assessment. 
11. Subject has absolute neutrophil count < 1500/μL, platelet count < 100000/μL or hemoglobin 
< 10 g/dL (6.2 mmol/L) at screening.  NOTE: May not have received any growth factors within 
7 days or blood transfusions within 28 days prior to the hematology values obtained at screening. 
12. Subject has total bilirubin ≥ 1.5 x the upper limit of normal (except subjects with documented 
Gilbert’s disease), or alanine aminotransferase or aspartate aminotransferase ≥ 2.5 x the upper 
limit of normal at screening. 
13. Subject has creatinine > 2 mg/dL (177 μmol/L) at screening. 
14. Subject has albumin < 3.0 g/dL (30 g/L) at screening. 
15. Subject has a history of seizure or any condition that may predispose to seizure (e.g., prior 
cortical stroke or significant brain trauma, brain arteriovenous malformation).  
16. Subject has history of loss of consciousness or transient ischemic attack within 12 months prior 
to day 1. 
17. Subject has clinically significant cardiovascular disease, including the following: 
• 
Myocardial infarction within 6 months prior to screening; 
• 
Unstable angina within 3 months prior to screening; 
• 
New York Heart Association class III or IV congestive heart failure or a history of New 
York Heart Association class III or IV congestive heart failure unless a screening 
echocardiogram or multigated acquisition scan performed within 3 months before the 
randomization date demonstrates a left ventricular ejection fraction ≥ 45%; 
• 
History of clinically significant ventricular arrhythmias (e.g., sustained ventricular 
tachycardia, ventricular fibrillation, torsades de pointes);  


Sponsor: APGD 
ISN/Protocol 9785-CL-0335 
EudraCT number 2015-003869-28 
 
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• 
History of Mobitz II second-degree or third-degree heart block without a permanent 
pacemaker in place; 
• 
Hypotension as indicated by systolic blood pressure < 86 mm Hg at screening; 
• 
Bradycardia as indicated by a heart rate of ≤ 45 beats per minute on the screening ECG; 
• 
Uncontrolled hypertension as indicated by a minimum of 2 consecutive blood pressure 
measurements showing systolic blood pressure > 170 mm Hg or diastolic blood pressure 
> 105 mm Hg at screening. 
18. Subject has gastrointestinal disorder affecting absorption. 
19. Subject has any concurrent disease, infection or comorbid condition that interferes with the 
ability of the subject to participate in the study, which places the subject at undue risk or 
complicates the interpretation of data in the opinion of the investigator. 
20. Subject received bisphosphonates or denosumab within 2 weeks prior to day 1 unless 
administered at stable dose or to treat diagnosed osteoporosis. 
21. Subject has shown a hypersensitivity reaction to the active pharmaceutical ingredient or any of 
the study capsule components, including Labrasol®, butylated hydroxyanisole (BHA), and 
butylated hydroxytoluene (BHT). 
Waivers to the exclusion criteria will NOT be allowed.  
Investigational Product(s): 
Enzalutamide 40 mg capsule 
Dose(s): 
160 mg once daily 
Mode of Administration: 
Oral, with or without food 
Comparative Drug(s): 
Placebo capsules that are identical in appearance to enzalutamide will be administered in the same 
manner and frequency as enzalutamide. 
Enzalutamide Dose Reduction / Dose Adjustment 
Subjects who experience a grade 3 or higher toxicity that is attributed to the study drug and cannot be 
ameliorated by the use of adequate medical intervention and/or dose reduction may interrupt study 
drug treatment for 1 week or until the toxicity grade improves to grade 2 or lower in severity.  Study 
drug may be restarted at the original dose (160 mg/day) or a reduced dose (120 mg or 80 mg/day). If 
restarted at a lower dose or if interrupted for > 2 weeks, the Medical Monitor must be consulted. 
Other Treatment for Prostate Cancer during the Study:  
ADT (either bilateral orchiectomy or LHRH agonist/antagonist) will be maintained during study 
treatment.  LHRH agonist/antagonist will be provided from the site’s pharmacy stock and 
administered in accordance with the prescribing information. 


Sponsor: APGD 
ISN/Protocol 9785-CL-0335 
EudraCT number 2015-003869-28 
 
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Concomitant Medication Restrictions or Requirements: 
Required Concomitant Treatment 
All subjects will be required to maintain ADT during study treatment, either using an LHRH 
agonist/antagonist or having a history of bilateral orchiectomy. 
Prohibited Concomitant Treatments 
The following medications are prohibited within 4 weeks of day 1 and during the study treatment 
period: 
• 5 α-reductase inhibitors (finasteride, dutasteride); 
• Estrogens; 
• Cyproterone acetate; 
• Biologic or other agents with potential antitumor activity against prostate cancer (with the 
exception of those therapies identified in exclusion criterion No. 1); 
• Systemic glucocorticoids greater than the equivalent of 10 mg per day of prednisone intended for 
the treatment of prostate cancer; 
• Herbal medications that have known hormonal antiprostate cancer activity and/or are known to 
decrease PSA levels (i.e., saw palmetto); 
• Androgens (testosterone, dihydroepiandrosterone, etc.); 
• Investigational agents. 
In addition, bisphosphonates and denosumab are prohibited unless stabilized for 2 weeks prior to 
randomization and held constant, as tolerated, throughout study treatment or administered for 
diagnosis of osteoporosis. 
Enzalutamide Drug Interaction 
There is a potential for enzalutamide to affect exposures to other medicinal products, or for other 
medicinal products to affect exposure to enzalutamide: 
• Strong cytochrome P450 (CYP) 2C8 inhibitors (e.g., gemfibrozil) are to be avoided.  If subject 
must be coadministered a strong CYP2C8 inhibitor, the dose of enzalutamide should be reduced to 
80 mg once daily.  If coadministration of the strong inhibitor is discontinued, the enzalutamide 
dose should be returned to the dose used prior to initiation of the strong CYP2C8 inhibitor. 
• Strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifampin) or moderate 
CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcilin, St. John’s Wort) 
should be avoided if possible as they may reduce enzalutamide plasma concentration if 
coadministered.  Selection of a concomitant medication with no or minimal CYP3A4 induction 
potential is recommended. 
• Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C9 and CYP2C19.  
Medicinal products with a narrow therapeutic range that are substrates of CYP3A4 (e.g., alfentanil, 
cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, 
tacrolimus), CYP2C9 (e.g., phenytoin, warfarin), or CYP2C19, or UGT1A1 (e.g., S-mephenytoin) 
should be avoided if possible, as enzalutamide may decrease their exposure. 
• If enzalutamide coadministration with warfarin cannot be avoided, additional international 
normalized ratio (INR) monitoring should be conducted. 
• Enzalutamide is an inhibitor of human P-glycoprotein (P-gp) and may increase exposure to 
medicines that are P-gp substrates.  Medicinal products with a narrow therapeutic range that are 
substrates for P-gp (e.g., digoxin, colchicine, dabigatran etexilate) should be used with caution 
when administered concomitantly with enzalutamide. 


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Permitted Concomitant Treatment 
The following treatments are allowed during the study (and do not require study drug discontinuation) 
including, but not limited to: 
• Blood transfusions and growth factor support per standard of care and institutional guidelines; 
• Steroid use (for indication other than prostate cancer) per standard of care; 
• Pain therapy per standard of care and institutional guidelines; 
• Palliative radiation therapy including external beam radiotherapy or systemic radionuclides (e.g., 
Samarium or Strontium); 
• Vaccine therapy that has prior market authorization and is not intended to treat prostate cancer; 
• Palliative surgical procedures to treat skeletal-related events. 
Hormonal treatment for treating complications of LHRH analogue treatment (e.g., hot flashes) will be 
allowed with Medical Monitor approval. In addition, flutamide, bicalutamide or nilutamide are 
permitted only if given concurrently with LHRH agonist or antagonist to prevent flare.  
Duration of Treatment: 
Study drug should be continued as long as the subject is tolerating the study drug and until 
radiographic progression or starting an investigational agent or new therapy for treatment of prostate 
cancer.  
Subjects may be asked to continue their open-label treatment in another Astellas-sponsored study. 
Discontinuation Criteria: 
Subject will be discontinued from the study drug treatment if any of the following occur: 
• Any adverse event that is intolerable to the subject which cannot be ameliorated by the use of 
adequate medical intervention and/or dose reduction or that in the opinion of the investigator 
would lead to undue risk to the subject if dosing is continued. 
• Subject who experiences a seizure or any condition that significantly predisposes the subject to 
seizure such as brain metastasis or clinically evident stroke. 
• Subject who experiences a confirmed event of posterior reversible encephalopathy syndrome 
(PRES) by brain imaging, preferably by MRI. 
• Subject initiates an investigational agent or new therapy for prostate cancer. 
• Subject who has evidence of radiological disease progression as confirmed by the independent 
reader and in the judgment of the investigator is no longer deriving clinical benefit. 
• Subject has discontinued ADT (LHRH agonist/antagonist) and has a testosterone value in the 
noncastrate range (> 50 ng/dL) as confirmed by the central laboratory. 
• Subject who is, in the opinion of the investigator or the Medical Monitor, noncompliant with the 
protocol requirements. 
• Subject is lost to follow-up despite reasonable efforts by the investigator to locate the subject. 
• Subject withdraws consent for the study. 
Subject will be discontinued from the study follow-up (Safety or Long-term Follow-up) if any of the 
following occur: 
• Subject is lost to follow-up despite reasonable efforts by the investigator to locate the subject. 
• Subject withdraws consent for further follow-up. 
• Death. 
• Final analysis for OS completed. 
• Study termination by the Sponsor. 
Formal Stopping Rules: 
Not applicable 


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Endpoints for Evaluation:  
Primary Endpoints 
• rPFS (based on central review) 
Secondary Endpoints 
• OS 
• Time to first SSE 
• Time to castration resistance 
• Time to deterioration of QoL 
• Time to deterioration in urinary symptoms  
• Time to initiation of new antineoplastic therapy 
• Time to PSA progression (≥ 2 ng/mL) (Prostate Cancer Clinical Trials Working Group 2 criteria) 
• PSA undetectable rate (< 0.2 ng/mL) 
• ORR 
• Time to pain progression 
Safety Endpoints 
• Nature, frequency and severity of adverse events 
• Safety laboratory tests: biochemistry and hematology 
• Physical examination 
• ECG 
• Vital signs (blood pressure, pulse and temperature) 
Exploratory Endpoint (North America sites only) 
• Mutation status in plasma of genes potentially related to resistance of enzalutamide plus ADT 
Statistical Methods: 
Sample Size Justification: 
Approximately 1100 subjects (550 subjects per treatment arm) will be randomized in the study.   
The final analysis of rPFS will be conducted with a minimum of 262 progression events based on the 
following considerations: 
A target hazard ratio (HR) is 0.67.  The expected median rPFS for the ADT arm is 20 months as 
measured from the date of randomization.  A target HR of 0.67 corresponds to approximately 50% 
increase in median rPFS for the enzalutamide plus ADT arm relative to the placebo plus ADT arm 
(approximately 30 versus 20 months). 
The required minimum of 262 rPFS events (radiographic progression or death on study, defined as 
death from any cause within 24 weeks after treatment discontinuation, whichever occurs first) provides 
90% power to detect a target HR of 0.67 based on a 2-sided log-rank test and significance level of 
0.05.  


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Subject Populations: 
Intent-to-Treat Population: 
The Intent-to-Treat (ITT) population is defined as all subjects who were randomized in this study.   
The ITT population will be analyzed by treatment arm as randomized (i.e., treatment arm based on 
randomization assignment). The ITT population will be used to conduct efficacy analyses.  For the 
ORR, only subjects with measurable disease at baseline will be included in the analysis. 
Safety Population: 
The safety population is defined as all randomized subjects who received at least 1 dose of study drug. 
The safety population will be analyzed by treatment arm as treated (i.e., based on the treatment the 
subject actually received rather than the treatment to which the subject was randomized). The safety 
population will be used to conduct safety analyses. 
Efficacy: 
Primary Endpoint 
• rPFS: Defined as the time from randomization to the first objective evidence of radiographic 
disease progression as assessed by central review or death (defined as death from any cause within 
24 weeks from study drug discontinuation), whichever occurs first.  
Secondary Endpoints 
• OS: Defined as the time from randomization to death from any cause. 
• Time to first SSE: Defined as the time from randomization to the occurrence of the first SSE.  SSE 
is defined as radiation or surgery to bone, clinically apparent pathological bone fracture or spinal 
cord compression. 
• Time to castration resistance: Defined as the time from randomization to the first 
castration-resistant event (radiographic disease progression, PSA progression or SSE), whichever 
occurs first. 
• Time to deterioration of QoL: Defined as time from randomization to a 10-point reduction of the 
FACT-P total score. 
• Time to deterioration in urinary symptoms: Defined as time from randomization to an increase of 
≥ 50% of the standard deviation at baseline in the modified urinary symptoms score of QoL PR25. 
• Time to initiation of a new antineoplastic therapy: Defined as the time from randomization to the 
initiation of antineoplastic subsequent to the study treatments. 
• Time to PSA progression: Defined as the time from randomization to PSA progression, which is a 
≥ 25% increase and an absolute increase of ≥ 2 µg/L (2 ng/mL) above the nadir (i.e., lowest PSA 
value observed post baseline or at baseline), which is confirmed by a second consecutive value at 
least 3 weeks later.  
• PSA undetectable rate: Defined as percentage of subjects with detectable (≥ 0.2 ng/mL) PSA at 
baseline which become undetectable (< 0.2 ng/mL) during study treatment. 
• ORR: Defined as the percentage of subjects with measureable disease at baseline who achieved a 
complete or partial response in their soft tissue disease using the RECIST version 1.1 criteria. 
• Time to pain progression: Defined as time from randomization to an increase of ≥ 30% in pain 
severity score from baseline using the BPI-SF. 
All secondary endpoint analyses will be performed at the time of the rPFS primary analysis. 
Six secondary endpoints (OS, time to PSA progression, time to initiation of a new antineoplastic 
therapy, the rate of PSA decline to < 0.2 ng/mL, ORR and time to deterioration in urinary symptoms) 
will be tested utilizing a parallel testing strategy. The methodology used will be described in detail in 
the statistical analysis plan. 


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Time to event endpoints such as rPFS, time to PSA progression, OS, time to first SSE, time to 
castration resistance, time to deterioration of QoL, time to deterioration in urinary symptoms, time to 
pain progression and time to initiation of new antineoplastic therapy will be analyzed using the 
stratified log-rank test. The stratified Cox Regression analysis will be used to estimate the HR and the 
associated 95% CI. The median will be estimated using the Kaplan-Meier method. 
One interim analysis and the final analysis are planned for OS.  The interim analysis of OS will be 
performed at the time of the rPFS final analysis.  The significance level will be determined by the 
O’Brien-Fleming alpha spending function based on the number of events observed at the interim look. 
The final analysis of OS will be conducted when approximately 342 deaths are observed to ensure an 
adequate number of events for the evaluation of OS. 
The proportion endpoints such as PSA undetectable rate and ORR will be analyzed using the stratified 
Cochran-Mantel-Haenszel score test. 
Safety: 
Frequency and severity of adverse events, safety laboratory tests, physical examinations, ECG and 
vital signs will be summarized descriptively. 
Exploratory: 
Mutations status will be summarized by descriptive statistics, including number of subjects, variant 
frequency, mean, standard deviation, minimum, median and maximum, and individual mutation status 
over time will be evaluated for samples collected in North America. 
Interim Analysis: 
No formal interim analysis is planned for rPFS. One interim analysis of OS will be performed at the 
time of the rPFS final analysis.  If this interim analysis of OS is statistically significant, it will be 
reported as the final analysis and no subsequent analysis will be performed. 
 


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V. 
FLOW CHART AND SCHEDULE OF ASSESSMENTS 
Flow Chart 
 
LHRH: luteinizing hormone-releasing hormone; rPFS: radiographic progression-free survival 
 
Screening 
Weeks -4 to -1 
Double-blind Treatment Period 
Safety Follow-up 
Long-term Follow-up 
Documented 
radiographic 
progression or 
initiation of new 
therapy for 
prostate cancer or 
other 
discontinuation 
criteria met 
30 days after last dose 
of study drug or prior 
to initiation of new 
therapy for prostate 
cancer, whichever 
occurs first 
Every 12 weeks 
 
For those subjects who 
discontinue study 
treatment without 
radiographic disease 
progression confirmed 
by central review, 
radiographic 
assessments will 
continue every 12 weeks 
until confirmed 
radiographic 
progression by central 
review or the target 
number of rPFS events 
is reached. 
Obtain 
informed 
consent prior 
to performing 
any study- 
related 
procedures 
Enzalutamide 
With LHRH 
agonist/antagonist or 
bilateral orchiectomy 
Placebo 
With LHRH 
agonist/antagonist or 
bilateral orchiectomy 
Randomized 1:1 


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Table 1 
Schedule of Assessments 
Study Day 
Screening Visit 
1 
29 
85 and Every 
Subsequent 84 Days 
Safety Follow-up 
Unscheduled 
Visit† 
Long Term 
Follow-up‡ 
Study Week 
-4 to -1 
(28 Days) 
1 
5 
13 and Every 
Subsequent 12 Weeks 
30 Days after 
Last Dose§ 
Every 
12 Weeks 
Window (Days) 
 
 
± 5 
± 5 
± 7 
NA 
± 7 
Informed Consent 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
Randomization (IRT) 
 
X 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
 
Physical Examination including Weight¶ 
X 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
12-lead ECG  
X 
X 
 
 
X 
 
 
Clinical Labs†† 
X 
X 
X 
X 
X 
X 
 
PSA 
X 
X 
X 
X 
X 
 
 
Sample for Genotyping Analysis‡‡ 
 
X 
 
 
 
 
 
Sample for Mutation Analysis∫∫ 
 
X 
 
X 
 
 
 
Testosterone 
 
 
 
X 
 
 
 
CT/MRI and Bone Scan§§, ¶¶ 
X§§ 
 
 
X¶¶ 
 
 
X 
Chest X-ray or Chest CT/MRI††† 
X 
 
 
X 
 
 
X 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
 
QoL Assessment (QLQ-PR25, EQ-5D-5L, FACT-P, 
Brief Pain Inventory-Short Form) 
 
X 
 
X 
X 
 
X‡ 
Adverse Events§§§ 
X 
X 
X 
X 
X 
X 
 
Previous and Concomitant Medications 
X 
X 
X 
X 
X 
X 
 
Study Drug Dispensing 
 
X 
X 
X 
 
 
 
Study Drug Treatment 
 
X 
X 
X 
 
 
 
CT: computed tomography; ECG: electrocardiogram; ECOG: Eastern Cooperative Oncology Group; EQ-5D-5L: EuroQol Group-5 Dimension-5 Level Instrument; FACT-P: 
Functional Assessment of Cancer Therapy-Prostate; IRT: Interactive Response Technology; MRI: magnetic resonance imaging; NA: not applicable; PSA: prostate-specific antigen;  
QLQ-PR25: Quality of Life Prostate-specific Questionnaire; QoL: quality of life; rPFS: radiographic progression-free survival 
Footnotes continued on next page 


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† 
Unscheduled visits may be performed at any time during the study whenever necessary to assess for or follow-up on adverse events at the subject’s request or if deemed necessary 
by the investigator.  Procedures and assessments are to be performed as clinically indicated.  Testosterone testing through central laboratory at unscheduled visit requires prior 
sponsor approval. 
‡ 
After treatment discontinuation, all subjects MUST undergo long term follow-up.  Long term follow-up assessments will include monitoring for survival status, new 
antineoplastic therapies for prostate cancer and symptomatic skeletal events.  Follow-up may be conducted by telephone interview.  Subjects will continue to be scanned every 
12 weeks until radiographic progression is confirmed by independent review or the number of rPFS events is reached.  For subjects continuing with radiological assessments,  
if seen in clinic, QoL assessment will also be completed until the initiation of new antineoplastic therapy for prostate cancer or the number of progression events is reached.  
Additional follow-up contacts may be requested.  Subjects will be followed for OS until death, lost to follow up, final OS analysis or termination of the study by the sponsor. 
When the final number of events has been reached to trigger the final OS analysis, QoL assessments will no longer be collected. 
§ 
Or prior to initiation of new antineoplastic therapy for prostate cancer, whichever occurs first. 
¶ 
A brief physical examination is required at each visit, with the exception of the screening visit during which a complete physical examination will be completed. 
†† 
Laboratory assessments include serum chemistries and hematology. 
‡‡ 
Genotyping samples will only be collected from subjects who agree to provide genotyping samples as documented by signing a separate genotyping informed consent form. 
∫∫ 
For sites in North America only: Blood samples for mutation analysis will be collected from subjects who agree to provide samples as documented by signing a separate 
genotyping informed consent form.  Samples will be collected at randomization, at week 49 and at study treatment discontinuation. 
§§ 
The abdominal-pelvic CT scan or MRI, bone scan, chest x-ray or chest CT must occur within 6 weeks of day 1; otherwise the screening visit assessment must be repeated.  
Radiographic assessments performed prior to informed consent, as part of the routine care, may be used as the baseline assessment if performed within 6 weeks of day 1 and  
if digital format images are available for submission to the sponsor-designated independent central review facility. 
¶¶ 
The window for all radiological (CT/MRI) assessments is ± 7 days.  For subjects who discontinue study treatment without radiographic progression confirmed by central review, 
subjects will continue to be scanned every 12 weeks until radiographic progression is confirmed by independent review or the number of rPFS events is reached.  
††† Chest CT/MRI is required at all imaging time points if screening chest x-ray demonstrates metastatic chest disease. 
§§§ Adverse events will be collected from the time the subject signs the consent form until the end of the safety reporting period (or until screen failure). The safety reporting period 
ends at the time of the safety follow-up visit, 30 days after last dose of study drug or initiation of new antineoplastic therapy for prostate cancer. 
 


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1 
INTRODUCTION 
Worldwide, prostate cancer ranks second in cancer incidence and sixth in cancer mortality in 
males [Jemal et al, 2011].  Prostate cancer progresses through a series of characteristic clinical 
states that represent both the natural history of the disease and response to treatment, as 
indicated in the figure below [Scher & Heller, 2000] [Figure 1].  
Figure 1 
Clinical States Model of Prostate Cancer Progression 
 
CRPC: castration-resistant prostate cancer; PSA: prostate-specific antigen; M0: nonmetastatic  
Source: modified from [Scher & Heller, 2000] 
Early in the disease, prostate cancers need relatively high levels of androgens to grow.  Such 
prostate cancers are referred to as androgen dependent or hormone sensitive; therefore, 
treatments that decrease androgen levels or block androgen activity can inhibit their growth. 
Combined androgen deprivation therapy (ADT) with a luteinizing hormone-releasing hormone 
analogue (LHRHA) or surgical castration, plus a conventional nonsteroidal antiandrogen 
(NSAA) such as bicalutamide, nilutamide or flutamide, is widely used as initial treatment for 
hormone sensitive prostate cancer.  Meta-analysis of randomized controlled trials showed a 3% 
absolute improvement in 5-year survival rates with the addition of a conventional NSAA to an 
LHRHA or surgical castration [Lancet, 2000].  Residual, low-level androgen receptor (AR) 
signaling, or agonist activity from conventional NSAA, may provide a stimulatory signal to 
hormone sensitive prostate cancer cells. 
1.1 
Background 
ADT has been the preferred initial treatment for locally advanced and metastatic prostate 
cancer [Singer et al, 2008].  Presently available androgen deprivation therapies include 
luteinizing hormone-releasing hormone (LHRH) agonists, LHRH antagonists and 
antiandrogens.  Treatment with LHRH analogues results in prostate-specific antigen (PSA) 
decline (the secreted protein product of the AR regulated gene), tumor regression and 
improved survival, in concert with an increased morbidity and poor quality of life (QoL).  
LHRH analogue-induced side effects include, but are not limited to, hot flushes, sexual 
dysfunction, fatigue, reduced cognition, emotional instability/depression, bone loss, insulin 
resistance, hyperlipidemia, and cardiovascular disease [Keating et al, 2012; Isbarn et al, 
2009; Taylor et al, 2009; Tombal & Berges, 2008].  


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In addition, antiandrogens such as bicalutamide, nilutamide and flutamide are used as standard 
treatment for hormone sensitive prostate cancer because they block the effect of androgen 
directly at the AR, although the blockade of the AR is incomplete and partial agonist properties 
are observed with these agents.  According to guidelines, antiandrogen monotherapy should be 
considered as an alternative to castration in subjects with locally advanced disease.  In fact, 
subjects with an indication for castration therapy may benefit from AR antagonist monotherapy 
that offers a similar efficacy profile to castration without the reduction in QoL [Makarov & 
Partin, 2008; Iversen et al, 1998; Kaisary et al, 1995].  It is possible that a more effective and 
profound AR blockade with a more potent AR blocker like enzalutamide might improve 
progression-free survival in patients with hormone sensitive prostate cancer. 
Also, in a large study (CHAARTED), the use of docetaxel with ADT versus ADT alone was 
evaluated in subjects with newly diagnosed metastatic hormone sensitive prostate cancer 
(mHSPC) [Sweeney et al, 2015].  This study enrolled 790 subjects (397 subjects in the ADT 
plus docetaxel group and 393 subjects in the ADT alone group).  ADT plus docetaxel 
significantly improved median overall survival (OS) (57.6 months) versus ADT alone 
(44.0 months) (hazard ratio [HR] = 0.61 [95% CI: 0.47, 0.80]; P < 0.001).  Median time to 
clinical progression (symptoms or radiographic) was significantly longer in subjects treated 
with ADT plus docetaxel (33.0 months) versus subjects treated with ADT alone 
(19.8 months) (HR = 0.61 [95% CI: 0.50, 0.75]; P < 0.001). 
Consistent with the docetaxel data from CHAARTED, emerging data from another study 
(STAMPEDE) also noted that the addition of docetaxel to standard hormonal therapy 
significantly improved survival among men with newly diagnosed, hormone-naïve, high-risk, 
locally advanced or metastatic prostate cancer [James et al, 2015; Scher et al, 2015].  In 
addition, a recent meta-analysis of 3 randomized controlled trials (GETUG-AFU, 
CHAARTED and STAMPEDE) that evaluated the combination of docetaxel and ADT in 
hormone sensitive metastatic prostate cancer, demonstrated that in subjects with metastatic 
prostate cancer the addition of docetaxel was associated with improved OS (HR = 0.74 
[95% CI: 0.61, 0.91]; P = 0.003) and improvement in progression-free survival (metastatic 
patients: HR = 0.63 [95% CI: 0.57, 0.70]; P < 0.001) [Tucci et al, 2015]. 
These studies concluded that the combination of standard ADT and 6 cycles of docetaxel 
resulted in significantly longer OS than that with standard ADT alone in men with hormone 
sensitive metastatic prostate cancer.  The clinical benefit was more pronounced among 
subjects with a higher burden of disease.  Docetaxel treatment was associated with toxicities, 
but the risk–benefit ratio for its early use in combination with ADT is clearly favorable for 
use in subjects with high-volume metastatic prostate cancer. 
More effective therapies for subjects with mHSPC are needed because a proportion of 
mHSPC subjects treated with current therapies still develop castration-resistant prostate 
cancer (CRPC) relatively quickly and suffer from disease-related morbidity and mortality.  
This study is designed to determine the benefit of enzalutamide plus ADT as compared to 
placebo plus ADT in subjects with mHSPC. 


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Enzalutamide is a second generation AR inhibitor that competitively binds the AR with great 
potency.  Additionally, enzalutamide inhibits nuclear translocation of AR, inhibits the 
association of AR with DNA [Tran et al, 2009], and has no known agonist activity when the 
AR is overexpressed. 
This protocol is based on the hypothesis that earlier use of a therapy shown to be effective in 
the more advanced state of CRPC will delay progression, emergence of castration-resistant 
disease and prolong OS.  As such, this study aims to determine whether enzalutamide with its 
superior ability of androgen suppression will improve radiographic progression-free survival 
(rPFS) of men starting androgen suppression for newly diagnosed metastatic prostate cancer.  
1.2 
Nonclinical and Clinical Data 
1.2.1 
Nonclinical Data 
The primary pharmacodynamic effect of enzalutamide is inhibition of the AR signaling 
pathway.  Primary pharmacodynamics have been defined in experiments that demonstrated 
inhibition of AR binding, inhibition of AR nuclear translocation, inhibition of AR chromatin 
association, inhibition of AR-dependent transcription and cancer cell proliferation, induction 
of cell death and tumor regression.  The nonclinical data on the primary pharmacodynamics 
of enzalutamide show that it is an AR inhibitor and further, that it is distinct from other 
antiandrogens in affecting multiple steps in the AR signaling pathway in the setting of AR 
overexpression.  A major human metabolite of enzalutamide, N-desmethyl enzalutamide, 
demonstrated key primary pharmacodynamics with similar potency to the parent molecule. 
Enzalutamide and N-desmethyl enzalutamide bind to and antagonize the γ-aminobutyric 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 nonclinical 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 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 is not expected to induce CYP1A2 at 
therapeutically relevant concentrations. 
In vitro data show that enzalutamide and its active metabolite N-desmethyl enzalutamide are 
potential inhibitors, but not substrates, of the efflux transporter P-glycoprotein (P-gp). 


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Overall, enzalutamide was generally well tolerated in nonclinical species with the most 
prominent effects occurring in reproductive and hormone sensitive tissues.  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 organ weight with atrophy of the prostate and epididymis. 
Additional changes related to reproductive and hormone sensitive tissues 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.  Gender 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. 
Hepatocellular toxicity is commonly associated with other antiandrogen compounds such as 
flutamide and nilutamide and both compounds are associated with liver injury in humans 
[Brahm et al, 2011; Gomez et al, 1992].  In contrast to other antiandrogens, enzalutamide 
showed no evidence of hepatotoxicity in animals or in the clinical program. 
Electrocardiogram (ECG) and cardiovascular assessments in a toxicity study in dogs showed 
no treatment-related effects.  In vivo and in vitro safety pharmacology studies also 
demonstrated the absence of cardiovascular enzalutamide-related effects. 
In a 6-month study in transgenic rasH2 mice, enzalutamide did not show carcinogenic 
potential (absence of neoplastic findings) at doses up to 20 mg/kg per day 
(AUC24h ≈317 μg∙h/mL), which resulted in plasma exposure levels similar to the clinical 
exposure (AUC24h 322 μg∙h/mL) in metastatic CRPC patients receiving 160 mg, daily.  Daily 
oral dosing of rats with enzalutamide at 10 to 100 mg/kg for 2 years increased the incidence 
of neoplastic findings (compared to control) that were considered related to the primary 
pharmacology of enzalutamide.  These included benign thymoma, fibroadenoma in the 
mammary glands and benign Leydig cell tumors in the testes in males; benign granulosa cell 
tumor in the ovaries in females; and adenoma in the pars distalis of the pituitary in both sexes.  
In addition, urothelial papilloma and carcinoma of urinary bladder in male rats were observed 
at the 100 mg/kg per day dose and were considered secondary to the irritation caused by the 
increased urinary crystal/calculi, which is known to occur in rodent species.  Leydig cell 
tumors in rats are generally not considered relevant to humans based on experience with 
other anti-androgens.  The human relevance of thymoma, pituitary adenoma and 
fibroadenoma in rats is unclear, but a potential relevance cannot be ruled out.  The exposure 
levels (based on AUC) achieved in this study for enzalutamide and its metabolites (M1 and 
M2) in rats were less than or similar to those in prostate cancer patients at the recommended 
dose of enzalutamide (Section 5.3, Company Core Data Sheet version 6.0). 
Enzalutamide was nonmutagenic in bacteria, nonclastogenic in mammalian cells and 
nongenotoxic 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 (refer to the current Investigator’s Brochure).  


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Enzalutamide could cause fetal harm when administered to a pregnant woman based on its 
mechanism of action and embryo-fetal toxicity observed in mice.  Based on nonclinical 
findings in repeat-dose toxicology studies, which were consistent with the pharmacological 
activity of enzalutamide, male fertility may be impaired by treatment with enzalutamide.  In 
studies in mice (4 weeks), rats (4 and 26 weeks) and dogs (4, 13 and 39 weeks), changes in 
the reproductive organs associated with enzalutamide were decreases in organ weight with 
atrophy of the prostate and epididymis (studies PRO3100NC39, PRO3100NC18 and 
PRO3100NC38 referenced in Company Core Data Sheet version 6.0).  In a pharmacokinetic 
study in pregnant rats with a single oral 30 mg/kg enzalutamide administration on gestation 
day 14, enzalutamide and/or its metabolites were present in the fetus at a Cmax that was 
approximately 0.3 times the concentration found in maternal plasma and occurred 4 hours 
after administration (study 9785-ME-0046 referenced in Company Core Data Sheet version 
6.0).  Following a single oral administration in lactating rats on postnatal day 14, 
enzalutamide and/or its metabolites were present in milk at a Cmax that was 4 times higher 
than concentrations in the plasma and occurred 4 hours after administration. 
1.2.2 
Clinical Data 
As of the data cutoff date of 30 Aug 2019, over 9000 subjects with prostate cancer, over 
300 women with breast cancer, and over 300 subjects with no known cancer including 
healthy male subjects and subjects with hepatic impairment have received at least 1 dose of 
enzalutamide in completed and ongoing clinical studies (not including the expanded access 
program or 2 compassionate use programs). 
The pharmacokinetics and metabolism of enzalutamide have been evaluated in more than 
2500 subjects with prostate cancer and in more than 200 healthy male subjects and subjects 
with mild, moderate, or severe hepatic impairment.  Individual daily doses have ranged from 
30 to 600 mg. 
The pharmacokinetics of a single oral 160 mg dose of enzalutamide were examined in 
subjects with baseline mild, moderate or severe hepatic impairment (Child-Pugh Class A, B, 
and C, respectively) and in matched control subjects with normal hepatic function 
(Study 9785-CL-0009 and Study 9785-CL-0404).  Mild, moderate or severe hepatic 
impairment did not have a clinically relevant effect on the composite AUC of enzalutamide 
plus N-desmethyl enzalutamide.  Therefore, the results indicate that no starting dose 
adjustment is necessary for subjects with baseline mild, moderate or severe hepatic 
impairment. 
After oral administration to subjects with CRPC, the median time to reach maximum 
enzalutamide plasma concentrations was 1 hour, and the mean terminal half-life was 
5.8 days.  Enzalutamide steady state was achieved by day 28, and the accumulation ratio was 
8.3-fold.  At steady state, enzalutamide showed approximately dose-proportional 
pharmacokinetics over the range of 30 to 360 mg/day.  Steady-state plasma levels of the 
active metabolite are similar to those of enzalutamide. 


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A mass balance and biotransformation study in healthy male volunteers showed that 
enzalutamide is primarily eliminated by hepatic metabolism.  A food-effect study showed 
that food does not have a clinically relevant effect on the AUC of enzalutamide or 
N-desmethyl enzalutamide; therefore, enzalutamide can be taken with or without food. 
Based on population pharmacokinetics modeling, age, weight and renal function (creatinine 
clearance [CLCR ≥ 30 mL/minute] do not have clinically meaningful effects on enzalutamide 
exposures; therefore, no dose adjustments are indicated for these covariates.  Based on 
pharmacokinetic data from a study in Japanese subjects with prostate cancer, there were no 
clinically relevant differences in exposure between Japanese and Caucasian subjects.  
Clinical data are insufficient to assess the potential effect of severe renal impairment 
(CLCR < 30 mL/minute) and end-stage renal disease on enzalutamide pharmacokinetics. 
A clinical drug-drug interaction study in prostate cancer subjects showed that enzalutamide 
can affect exposures to certain comedications.  At steady state, enzalutamide reduced the 
AUC of oral midazolam (CYP3A4 substrate), S-warfarin (CYP2C9 substrate) and 
omeprazole (CYP2C19 substrate) by 86%, 56% and 70%, respectively.  Therefore, 
enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer.  
Substrates of CYP3A4, CYP2C9 and CYP2C19 with a narrow therapeutic index are to be 
avoided, as enzalutamide may decrease plasma exposure of these drugs.  If enzalutamide is 
coadministered with warfarin (CYP2C9 substrate), additional international normalized ratio 
(INR) monitoring needs to be conducted.  Enzalutamide (160 mg/day) did not have a 
clinically relevant effect on exposure to intravenous docetaxel (CYP3A4 substrate) or to oral 
caffeine (CYP1A2 substrate), dextromethorphan (CYP2D6 substrate) or pioglitazone 
(CYP2C8 substrate). 
Another clinical drug-drug interaction study in healthy subjects showed that concomitant 
medications can affect exposure to enzalutamide.  Coadministration of gemfibrozil (a strong 
CYP2C8 inhibitor) increased the composite AUC of enzalutamide plus N-desmethyl 
enzalutamide by 2.2-fold; therefore, strong CYP2C8 inhibitors are to be avoided.  If 
coadministration with a strong CYP2C8 inhibitor is necessary, the dose of enzalutamide 
needs to be reduced to 80 mg once daily.  Coadministration of itraconazole (strong CYP3A4 
inhibitor) increased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 
1.3-fold; as this small change is not clinically meaningful, no starting dose adjustment is 
needed when coadministering enzalutamide with CYP3A4 inhibitors.  Coadministration of 
rifampin (strong CYP3A4 and moderate CYP2C8 inducer) decreased the composite AUC of 
enzalutamide plus N-desmethyl enzalutamide by 37%, while Cmax remained unchanged 
(Study 9785-CL-0405); as these changes are not considered clinically relevant, no starting 
dose adjustment is needed when coadministering enzalutamide with moderate CYP2C8 
inducers or CYP3A4 inducers. 
The potential for enzalutamide to affect the pharmacokinetics of other drugs via effects on 
drug transporters was assessed through a series of in vitro experiments.  Based on in vitro 
data, enzalutamide, N-desmethyl enzalutamide and/or the carboxylic acid metabolite may be 
inhibitors of BCRP, MRP2 and OAT3 at clinically relevant systemic concentrations or in the 


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gastrointestinal wall during absorption.  Thus, enzalutamide may increase the plasma 
concentrations of coadministered medicinal products that are BCRP, MRP2 or OAT3 
substrates.  In vitro experiments also suggest enzalutamide, N-desmethyl enzalutamide and 
the carboxylic acid metabolite do not inhibit OATP1B1, OAT1B3, OCT1, OCT2, OAT1 and 
OAT3-mediated transport at clinically relevant concentrations.  Enzalutamide is not a 
substrate for OATP1B1, OATP1B3 or OCT1, and N-desmethyl enzalutamide is not a 
substrate for P-gp or BCRP.  Based on in vitro data, enzalutamide is an inhibitor but not a 
substrate for P-gp; however, under conditions of clinical use, enzalutamide may be an inducer 
of P-gp via activation of pregnane X receptor.  Thus, enzalutamide may alter the plasma 
concentrations of coadministered medicinal products that are P-gp substrates (refer to current 
Investigator’s Brochure). 
1.3 
Summary of Key Safety Information for Study Drugs 
Enzalutamide has been approved by the FDA, the EMA and Japan MHLW for metastatic 
CRPC.  Worldwide, enzalutamide has been approved for the treatment of metastatic CRPC in 
more than 100 countries.  Enzalutamide has also been approved for nonmetastatic CRPC in 
the US, EU and Japan as well as in more than 60 countries.  In Dec 2019, enzalutamide was 
approved for the treatment of metastatic CSPC in the US (also referred to as mHSPC) and a 
marketing application for this indication is currently in review in the EU.   
The safety profile of enzalutamide in subjects with CRPC is derived primarily from 5 phase 3 
studies.  Study CRPC2 (AFFIRM) was a randomized, double-blind, placebo-controlled, 
efficacy and safety clinical study of enzalutamide (160 mg daily) in 1199 subjects with 
progressive metastatic CRPC (mCRPC) previously treated with docetaxel-based 
chemotherapy.  Study MDV3100-03 (PREVAIL) was a multinational, randomized, 
double-blind, placebo-controlled, efficacy and safety clinical study of enzalutamide in 
1717 chemotherapy naïve subjects with mCRPC who have failed ADT.  Study 
9785-CL-0232 (Asian PREVAIL) was similar to PREVAIL except in an Asian population of 
388 subjects.  Study MDV3100-14 (PROSPER) was a randomized, double-blind, placebo-
controlled, efficacy and safety clinical study of enzalutamide (160 mg daily) in 1401 subjects 
with nonmetastatic CRPC at high risk of disease progression based on baseline 
prostate-specific antigen (PSA) level and short PSA doubling time. 
An analysis of 5 pooled phase 3 studies (AFFIRM, PREVAIL, Asian PREVAIL, PROSPER 
and ARCHES) indicated that the most frequently reported treatment-emergent adverse events 
(TEAEs) reported in ≥ 10% of patients in the enzalutamide group (n = 3371; enzalutamide 
dose; 160 mg/day) were:fatigue, back pain, nausea, hot flush, constipation, arthralgia, 
decreased appetite, diarrhea, hypertension, asthenia, fall, pain in extremity, musculoskeletal 
pain and headache.  With the exception of nausea and pain in extremity, each of these events 
occurred in the pooled phase 3 enzalutamide group with a ≥ 2% higher incidence than in the 
placebo group (n = 2472).  Only 2 TEAEs showed a higher rate in the enzalutamide vs the 
placebo group (event rate per 100 patient-years of treatment): fall (8.9% enzalutamide vs 
4.6% placebo) and hypertension (8.2% vs 5.5%).   


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When adjusted for treatment duration, the event rates for grade ≥ 3 TEAEs showed small 
differences (≤ 1.2 events per 100 patient years) between the enzalutamide group and the 
placebo group.   
Study drug-related TEAEs reported in ≥ 5% of patients in the enzalutamide group were 
fatigue (24.1% enzalutamide vs 14.1% placebo), hot flush (14.0% vs 8.7%), nausea (11.7% 
vs 10.4%), decreased appetite (8.2% vs 5.5%), asthenia (7.4% vs 4.4%), diarrhea (5.6% vs 
4.4%) and hypertension (5.6% vs 2.0%). 
The incidence of TEAEs leading to death was low in the pooled enzalutamide groups (4.8%) 
and in the placebo group (2.8%) and the adjusted event rates for serious TEAEs were also 
comparable in both groups.   
The incidence of TEAEs leading to permanent discontinuation of study drug was similar in 
both groups; 17.2% in the pooled enzalutamide groups and 16.1% in the placebo group.  The 
incidence of TEAEs leading to a dose reduction was 5.6% in the phase 3 enzalutamide group 
and 2.0% in the phase 3 placebo group. The incidence of TEAEs leading to a dosing 
interruption was 15.0% in the phase 3 enzalutamide group and 9.9% in the phase 3 placebo 
group 
The pooled phase 3 safety data confirms that convulsion/seizure, cognitive and memory 
impairment, fatigue-related events, neutropenia/neutrophil count decreased, fall, fracture and 
hypertension are adverse events of special interest (AESI) for enzalutamide.  Posterior 
reversible encephalopathy syndrome (PRES) is also considered an AESI for enzalutamide; 
however, this is based on cases reported during postapproval use of enzalutamide and not on 
events occurring in clinical studies.   
Severe cutaneous adverse reactions, including acute generalized exanthematous pustulosis, 
dermatitis bullous, dermatitis exfoliative generalized, drug reaction with eosinophilia and 
systemic symptoms, erythema multiforme, exfoliative rash, Stevens-Johnson syndrome, toxic 
epidermal necrolysis and toxic skin eruption have been reported in post-marketing cases. 
For more information on the investigational product enzalutamide and on the clinical study 
experience, refer to the current Investigator’s Brochure of enzalutamide. 
1.4 
Risk-Benefit Assessment 
Enzalutamide is a novel small molecule designed to have an increased affinity for the AR and 
more effective suppression of the androgen pathway in the setting of androgen overexpression 
[Tran et al, 2009].  Enzalutamide has a higher binding affinity to the AR (8 times greater), has 
no agonist activity and has demonstrated superior AR downstream effects in the setting of 
androgen overexpression compared to bicalutamide in preclinical studies. 
The efficacy of enzalutamide in subjects with metastatic prostate cancer who progressed on 
ADT has been demonstrated in 5 randomized controlled phase 3 studies including study 
MDV3100-03 (PREVAIL) in asymptomatic or mildly symptomatic subjects and CRPC2 
(AFFIRM) in subjects with more advanced disease who previously received docetaxel.  
Regardless of study arm, subjects remained on ADT in both PREVAIL and AFFIRM studies.  
These studies demonstrate a statistically significant advantage of enzalutamide treatment over 


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placebo across multiple clinically relevant endpoints such as OS, rPFS, time to first 
skeletal-related event, time to PSA progression, PSA response rate, best overall soft tissue 
response, and QoL as measured by the Functional Assessment of Cancer Therapy-Prostate 
(FACT-P).  Study MDV3100-03 (PREVAIL) showed a significant benefit of enzalutamide in 
time to initiation of cytotoxic chemotherapy.   
Study MDV3100-03 (PREVAIL; chemotherapy naïve mCRPC subjects) was stopped after a 
planned interim analysis (conducted when 540 deaths had been reported) and showed a 
benefit of the active treatment.  The rate of rPFS at 12 months was 65% among subjects 
treated with enzalutamide, as compared with 14% among subjects receiving placebo (81% 
risk reduction; HR in the enzalutamide group, 0.19; 95% CI, 0.15 to 0.23; P < 0.001). A total 
of 626 subjects (72%) in the enzalutamide group, as compared with 532 subjects (63%) in the 
placebo group, were alive at the data cutoff date (29% reduction in the risk of death; HR, 
0.71; 95% CI, 0.60 to 0.84; P < 0.0001).  The benefit of enzalutamide was shown with 
respect to all secondary endpoints, including the time until the initiation of cytotoxic 
chemotherapy (HR, 0.35), the time until the first skeletal-related event (HR, 0.72), a complete 
or partial soft tissue response (59% versus 5%), the time until PSA progression (HR, 0.17), 
and a rate of decline of at least 50% in PSA (78% versus 3%) (P < 0.001 for all 
comparisons). 
Study CRPC2 (AFFIRM; postchemotherapy mCRPC subjects) demonstrated that 
enzalutamide treatment decreased the risk of death by 37% (HR, 0.631; P < 0.0001) 
compared with placebo treatment.  The median survival was 18.4 months in the enzalutamide 
arm and 13.6 months in the placebo arm (difference = 4.8 months).  The statistically 
significant and clinically meaningful benefit of enzalutamide treatment as measured by OS 
was seen in all prespecified subject subgroups and observed despite 42.0% of 
enzalutamide-treated and 61.4% of placebo-treated subjects receiving subsequent therapies to 
treat prostate cancer, including abiraterone (20.9% versus 24.3%) and cabazitaxel (9.8% 
versus 13.8%), both shown to improve OS following docetaxel treatment.  Enzalutamide 
treatment also resulted in significant improvements over placebo treatment in all key 
secondary efficacy endpoints. 
In addition, in a phase 2, open-label, single-arm study (9785-CL-0321) in patients with 
hormone-naïve prostate cancer, 92.5% (62 of 67) of patients had a ≥ 80% decline in PSA 
from baseline at week 25.  Of the 54 patients who were on treatment for 1 year (week 49), 
100% had a ≥ 80% decline in PSA from baseline.  Eleven (42.3%) of 26 evaluable patients 
with metastatic disease at study entry had a derived objective response (confirmed complete 
response + confirmed partial response), 8 (30.8%) patients with confirmed complete 
response, and 3 (11.5%) patients with confirmed partial response. 
The primary efficacy analysis in PROSPER demonstrated a statistically significant, robust 
and substantial improvement in metastasis-free survival together with clinically meaningful 
improvements in the key secondary endpoints of time to PSA progression and time to first 
use of new antineoplastic therapy and a trend in OS in favor of enzalutamide treatment.  The 


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final OS analysis demonstrated a statistically significant and clinically meaningful 
improvement favoring enzalutamide and a 26.6% reduction in the risk of death.   
Lastly, the primary efficacy analysis in ARCHES demonstrated a statistically significant, 
robust and substantial improvement in radiographic progression-free survival together with 
clinically meaningful improvements in the key secondary endpoints of time to PSA 
progression, time to start of a new antineoplastic therapy, PSA undetectable rate and objective 
response rate and a trend in OS (observed at the time of interim analysis) in favor of 
enzalutamide plus ADT versus placebo plus ADT treatment.  For the secondary endpoints, 
the ARCHES study demonstrated that enzalutamide prolonged the time to the first 
symptomatic skeletal event and time to castration-resistance.  Assessments of patient-
reported outcomes data showed that patients receiving enzalutamide plus ADT in ARCHES 
had a high baseline level of quality of life, which was maintained over time. 
Based on the safety information collected to date in clinical trials and in commercial use, the 
safety profile experienced by patients remains consistent with the approved product label as 
well as events that can be seen in patients with prostate cancer.  The safety profile in mHSPC 
patients in this study is expected to be consistent with the established safety profile for 
enzalutamide.  To date, there are 4 important identified risks associated with enzalutamide 
(seizure, fall, nonpathological fracture and ischemic heart disease). While serious adverse 
events (SAEs) such as seizure have occurred in patients receiving treatment with 
enzalutamide, these events have been rare.  To mitigate the risk of seizure, subjects with a 
history of seizure or any condition that may predispose to seizure (e.g., prior cortical stroke 
or significant brain trauma, brain arteriovenous malformation) are excluded from the trial.  
Study drug discontinuation is required for subjects experiencing either seizure or PRES.  In 
addition to these patient exclusion and discontinuation requirements, the study design 
includes safety labs, scans and guidance related to concomitant medications to minimize the 
risks associated with enzalutamide and ensure timely intervention if needed. 
Based on the information known about the drug and the efficacy results that have been 
consistently demonstrated in both PREVAIL and AFFIRM, the risk-benefit assessment 
supports the investigation of enzalutamide plus ADT in men with mCRPC who are hormone 
sensitive.  As described in Section 10.1, a Data Safety Monitoring Board (DSMB) will be 
responsible for reviewing the unblinded data from the trial to ensure the safety of the 
subjects. 
The totality of the efficacy and safety data demonstrate a favorable benefit-risk balance for 
the use of enzalutamide in men with mCRPC and for the continued investigation of 
enzalutamide in men with advanced stage prostate cancer. 
2 
STUDY OBJECTIVE(S), DESIGN AND ENDPOINTS 
2.1 
Study Objectives 
The objective of this phase 3 study is to evaluate the efficacy and safety of enzalutamide plus 
ADT versus placebo plus ADT in subjects with mHSPC. 


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2.1.1 
Primary Objective 
● 
To determine the benefit of enzalutamide plus ADT as compared to placebo plus ADT as 
assessed by rPFS based on central review 
2.1.2 
Secondary Objectives 
● 
To determine the benefit of enzalutamide plus ADT as compared to placebo plus ADT as 
assessed by OS 
● 
To determine the benefit of enzalutamide plus ADT as compared to placebo plus ADT as 
assessed by time to first Symptomatic Skeletal Event (SSE) 
● 
To determine the benefit of enzalutamide plus ADT as compared to placebo plus ADT as 
assessed by time to castration resistance 
● 
To determine the benefit of enzalutamide plus ADT as compared to placebo plus ADT as 
assessed by QoL (as measured by Quality of Life Prostate-specific Questionnaire 
[QLQ-PR25] / FACT-P and EuroQol Group-5 Dimension-5 Level Instrument 
[EQ-5D-5L]), in particular by: 
o time to deterioration in urinary symptoms using a modified urinary symptoms scale 
from QLQ-PR25 [Section 7.4.2 Analysis of Secondary Endpoints] 
o time to deterioration in QoL using the FACT-P global score 
● 
To determine the benefit of enzalutamide plus ADT as compared to placebo plus ADT as 
assessed by time to start of new antineoplastic therapy 
● 
To determine the benefit of enzalutamide plus ADT as compared to placebo plus ADT as 
assessed by time to PSA progression 
● 
To determine the benefit of enzalutamide plus ADT as compared to placebo plus ADT as 
assessed by PSA undetectable rate (< 0.2 ng/mL)  
● 
To determine the benefit of enzalutamide plus ADT as compared to placebo plus ADT as 
assessed by objective response rate (ORR) 
● 
To determine the benefit of enzalutamide plus ADT as compared to placebo plus ADT as 
assessed by worsening of pain (as measured by Brief Pain Inventory-Short Form [BPI-SF]) 
2.1.3 
Safety Objective 
● 
To determine the safety of enzalutamide plus ADT as compared to placebo plus ADT 
2.1.4 
Exploratory Objective (North America sites only) 
● 
To determine gene mutations potentially related to resistance of enzalutamide plus ADT as 
assessed by DNA mutation testing in plasma 


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2.2 
Study Design and Dose Rationale 
2.2.1 
Study Design 
This is a multinational phase 3, randomized, double-blind, placebo-controlled efficacy and 
safety study of enzalutamide plus ADT versus placebo plus ADT in subjects with mHSPC. 
Approximately 1100 subjects will be randomized centrally 1:1, and the randomization will be 
stratified by volume of disease (low versus high) and prior docetaxel therapy for prostate 
cancer (no prior docetaxel, 1-5 cycles, 6 cycles).  High volume of disease is defined as 
metastases involving the viscera or, in the absence of visceral lesions, there must be 4 or 
more bone lesions, at least 1 of which must be in a bony structure beyond the vertebral 
column and pelvic bone.  Prior docetaxel therapy is defined as 1 or more cycles of docetaxel 
but no more than 6 cycles.  
Study drug therapy should be continued as long as the subject is tolerating the study drug and 
continues ADT until radiographic disease progression is documented as outlined in 
[Section 5.3.1.1 Computed Tomography (CT)/Magnetic Resonance Imaging (MRI) and Bone 
Scan] or starting an investigational agent or new therapy for treatment of prostate cancer.  It 
is recommended that subjects remain on study treatment until radiographic progression is 
confirmed by independent central imaging review.  Subjects who discontinue study treatment 
without radiographic progression will continue to follow the radiographic assessment 
schedule until radiographic progression event is confirmed by the central imaging 
independent reviewer or until the target number of progression events is reached as assessed 
by the central review.  All subjects will be followed for OS until the final OS analysis.  Once 
the final number of events has been reached to trigger the final OS analysis, survival follow-
up will be considered complete and subjects will be discontinued from long term follow-up.  
At the time of primary endpoint analysis and recommendation of the DSMB on study 
continuation, subjects may be asked to continue their open-label treatment in another 
Astellas-sponsored study. 
Study films (CT/MRI and bone scan) should be read on site and also be submitted in digital 
format to the sponsor-designated facility for independent central review.  Each site should 
ideally designate the same reader who will evaluate the images for any one subject for the 
duration of the trial. 
Radiographic disease progression is defined by Response Evaluation Criteria in Solid 
Tumors (RECIST) version 1.1 for soft tissue disease or the appearance of 2 or more new 
lesions on bone scan.  The documentation and confirmation required for the determination of 
radiographic progression is listed in [Section 5.3.1.1 CT/MRI and Bone Scan]. 
The following assessments of prostate cancer status will be collected during the course of the 
study: PSA, soft tissue disease on CT scan or on MRI, bone disease on radionuclide bone 
scans, survival status, EQ-5D-5L, QLQ-PR25, FACT-P for QoL and BPI-SF for pain 
symptom assessment. Once the final number of events has been reached to trigger the final 
OS analysis, sites will no longer be required to collect EQ-5D-5L, QLQ-PR25, FACT-P for 
QoL and BPI-SF. 


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Throughout the study, safety and tolerability will be assessed by the recording of adverse 
events (AEs), vital signs, physical examinations, 12-lead ECGs, and safety laboratory 
evaluations. 
An independent DSMB will monitor the safety data on an ongoing basis. 
Subjects will have a safety follow-up visit 30 days after their last dose of study drug or prior 
to initiation of new antineoplastic therapy for prostate cancer, whichever occurs first.  All 
subjects are to be followed for survival until death, loss to follow-up, withdrawal of consent, 
or study termination by the sponsor.  At the time of consent, staff will collect contact 
information for secondary contacts and other country-specific subject identifying information 
for purposes of assisting the site with determination of subject survival status. Once a 
sufficient number of death events has been reached for the OS analysis, survival follow-up 
will be considered complete and the long term follow-up process and QoL assessments 
collection will discontinue for all study participants.  
Subjects who are continuing to receive clinical benefit from treatment with enzalutamide 
after the OS analysis data cutoff or at study termination and have not met any discontinuation 
criteria may continue their open-label treatment in another Astellas-sponsored study. 
Subjects who choose not to continue open-label treatment in another Astellas-sponsored 
study after the OS analysis data cutoff will discontinue from treatment and complete a 
30-day follow-up visit from the last dose of enzalutamide or prior to the initiation of another 
anticancer therapy, whichever occurs first. 
The sponsor will monitor study enrollment for proportion of subjects enrolled with a history 
of prior docetaxel treatment, and may either change the sample size, or cap the number of 
subjects who received prior docetaxel to ensure that the primary endpoint is not driven either 
by the subjects who received prior docetaxel, or by the subjects who did not receive prior 
docetaxel. 
The data gathered from the ARCHES study may be used to support future research studies. 
2.2.2 
Dose Rationale 
Enzalutamide 160 mg administered orally, once daily, is the daily dose recommended by 
regulatory agencies in countries where enzalutamide is approved. 
2.3 
Endpoints  
2.3.1 
Primary Endpoints 
● 
rPFS (based on central review) 
2.3.2 
Secondary Endpoints  
● 
OS 
● 
Time to first SSE 
● 
Time to castration resistance 
● 
Time to deterioration of QoL 
● 
Time to deterioration in urinary symptoms  


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● 
Time to initiation of new antineoplastic therapy 
● 
Time to PSA progression (≥ 2 ng/mL) (Prostate Cancer Clinical Trials Working Group 2 
criteria) 
● 
PSA undetectable rate (< 0.2 ng/mL) 
● 
ORR 
● 
Time to pain progression 
2.3.3 
Safety Endpoints 
● 
Nature, frequency and severity of AEs 
● 
Safety laboratory tests: biochemistry and hematology 
● 
Physical examination 
● 
ECG 
● 
Vital signs (blood pressure, pulse and temperature) 
2.3.4 
Exploratory Endpoint (North America sites only) 
● 
Mutation status in plasma of genes potentially related to resistance of enzalutamide plus 
ADT 
3 
STUDY POPULATION 
3.1 
Selection of Study Population  
The study population will include approximately 1100 men with metastatic hormone sensitive 
prostate cancer. 
3.2 
Inclusion Criteria 
Subject is eligible for the study if all of the following apply: 
1. Institutional Review Board (IRB)-/Independent Ethics Committee (IEC)-approved 
written informed consent and privacy language as per national regulations (e.g., Health 
Insurance Portability Accountability Act authorization for United States sites) must be 
obtained from the subject or legally authorized representative prior to any study-related 
procedures (including withdrawal of prohibited medication, if applicable). 
2. Subject is considered an adult according to local regulation at the time of signing 
informed consent. 
3. Subject is diagnosed with histologically or cytologically confirmed adenocarcinoma of 
the prostate without neuroendocrine differentiation, signet cell or small cell histology.  
Specific to subjects enrolled in France, histological diagnosis is required. 
4. Subject has metastatic prostate cancer documented by positive bone scan (for bone 
disease) or metastatic lesions on CT or MRI scan (for soft tissue). Subjects whose 
disease spread is limited to regional pelvic lymph nodes are not eligible. 
5. Once randomized at day 1, subject must maintain ADT with an LHRH agonist or 
antagonist during study treatment or have a history of bilateral orchiectomy (i.e., medical 
or surgical castration). 


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6. Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 
1 at screening. 
7. Subject has an estimated life expectancy of ≥ 12 months as assessed by the investigator. 
8. Subject is able to swallow the study drug and comply with study requirements. 
9. A sexually active male subject and his female partner who is of childbearing potential 
must use 2 acceptable methods of birth control (1 of which must include a condom as a 
barrier method of contraception) from screening through 3 months after the last dose of 
study drug.  Two acceptable methods of birth control include condom (barrier method is 
required) AND 1 of the following: 
● Consistent and correct usage of established, proper use of hormonal contraceptives 
that inhibit ovulation by the female partner; 
● 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 applicable 
to subjects enrolled in Japan only). 
10. Subject must use a condom throughout the study if engaging in sexual intercourse with a 
pregnant woman. 
11. Subject must agree not to donate sperm from first dose of study drug through 3 months 
after the last dose of study drug. 
12. 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 participation if any of the following apply: 
1. Subject has received any prior pharmacotherapy, radiation therapy or surgery for 
metastatic prostate cancer (the following exceptions are permitted): 
● Up to 3 months of ADT with LHRH agonists or antagonists or orchiectomy with or 
without concurrent antiandrogens prior to day 1, with no radiographic evidence of 
disease progression or rising PSA levels prior to day 1; 
● Subject may have 1 course of palliative radiation or surgical therapy to treat 
symptoms resulting from metastatic disease if it was administered at least 4 weeks 
prior to day 1; 
● Up to 6 cycles of docetaxel therapy with final treatment administration completed 
within 2 months of day 1 and no evidence of disease progression during or after the 
completion of docetaxel therapy; 


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● Up to 6 months of ADT with LHRH agonists or antagonists or orchiectomy with or 
without concurrent antiandrogens prior to day 1 if subject was treated with 
docetaxel, with no radiographic evidence of disease progression or rising PSA levels 
prior to day 1; 
● Prior ADT given for < 39 months in duration and > 9 months before randomization 
as neoadjuvant/adjuvant therapy. 
2. Subject had a major surgery within 4 weeks prior to day 1. 
3. Subject received treatment with 5-α reductase inhibitors (finasteride, dutasteride) within 
4 weeks prior to day 1. 
4. Subject received treatment with estrogens, cyprotoerone acetate or androgens within 
4 weeks prior to day 1. 
5. Subject received treatment with systemic glucocorticoids greater than the equivalent of 
10 mg per day of prednisone within 4 weeks prior to day 1, intended for the treatment of 
prostate cancer. 
6. Subject received treatment with herbal medications that have known hormonal 
antiprostate cancer activity and/or are known to decrease PSA levels within 4 weeks 
prior to day 1. 
7. Subject received prior aminoglutethimide, ketoconazole, abiraterone acetate or 
enzalutamide for the treatment of prostate cancer or participation in a clinical study of an 
investigational agent that inhibits the AR or androgen synthesis (e.g., TAK-700, 
ARN-509, ODM-201). 
8. Subject received investigational agent within 4 weeks prior to day 1. 
9. Subject has known or suspected brain metastasis or active leptomeningeal disease. 
10. Subject has a history of another invasive cancer within 3 years of screening, with the 
exception of fully treated cancers with a remote probability of recurrence based on 
investigator assessment. 
11. Subject has absolute neutrophil count < 1500/μL, platelet count < 100000/μL or 
hemoglobin < 10 g/dL (6.2 mmol/L) at screening.  NOTE: May not have received any 
growth factors within 7 days or blood transfusions within 28 days prior to the 
hematology values obtained at screening. 
12. Subject has total bilirubin (TBL) ≥ 1.5 x the upper limit of normal (ULN) (except 
subjects with documented Gilbert’s disease), or alanine aminotransferase (ALT) or 
aspartate aminotransferase (AST) ≥ 2.5 x the ULN at screening. 
13. Subject has creatinine > 2 mg/dL (177 μmol/L) at screening. 
14. Subject has albumin < 3.0 g/dL (30 g/L) at screening. 
15. Subject has a history of seizure or any condition that may predispose to seizure (e.g., 
prior cortical stroke or significant brain trauma, brain arteriovenous malformation).  


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16. Subject has history of loss of consciousness or transient ischemic attack within 
12 months prior to day 1. 
17. Subject has clinically significant cardiovascular disease, including the following: 
● Myocardial infarction within 6 months prior to screening; 
● Unstable angina within 3 months prior to screening; 
● New York Heart Association class III or IV congestive heart failure or a history of 
New York Heart Association class III or IV congestive heart failure unless a 
screening echocardiogram or multigated acquisition scan performed within 3 months 
before the randomization date demonstrates a left ventricular ejection fraction ≥ 
45%; 
● History of clinically significant ventricular arrhythmias (e.g., sustained ventricular 
tachycardia, ventricular fibrillation, torsades de pointes);  
● History of Mobitz II second-degree or third-degree heart block without a permanent 
pacemaker in place; 
● Hypotension as indicated by systolic blood pressure < 86 mm Hg at screening; 
● Bradycardia as indicated by a heart rate of ≤ 45 beats per minute on the screening 
ECG; 
● Uncontrolled hypertension as indicated by a minimum of 2 consecutive blood 
pressure measurements showing systolic blood pressure > 170 mm Hg or diastolic 
blood pressure > 105 mm Hg at screening. 
18. Subject has gastrointestinal disorder affecting absorption. 
19. Subject has any concurrent disease, infection or comorbid condition that interferes with 
the ability of the subject to participate in the study, which places the subject at undue risk 
or complicates the interpretation of data in the opinion of the investigator. 
20. Subject received bisphosphonates or denosumab within 2 weeks prior to day 1 unless 
administered at stable dose or to treat diagnosed osteoporosis. 
21. Subject has shown a hypersensitivity reaction to the active pharmaceutical ingredient or 
any of the study capsule components, including Labrasol®, butylated hydroxyanisole 
(BHA), and butylated hydroxytoluene (BHT). 
Waivers to the exclusion criteria will NOT be allowed.  
4 
TREATMENT(S) 
4.1 
Identification of Investigational Product(s) 
4.1.1 
Test Drug(s) 
Enzalutamide (formerly MDV3100) will be supplied to sites as 40 mg white to off-white 
oblong capsules.  The oral soft gelatin capsules are filled with a clear, yellowish solution that 
contains the 2 antioxidants, BHA and BHT, and enzalutamide active ingredient (40 mg), all 
dissolved in the nonionic surfactant, Labrasol (caprylocaproyl polyoxylglycerides).   


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Enzalutamide capsules should be swallowed whole and should not be chewed, dissolved or 
opened.  Enzalutamide capsules can be taken with or without food.  Enzalutamide capsules 
should not be handled by persons other than the patient or his caregivers.  Based on its 
mechanism of action and embryo-fetal toxicity observed in mice, enzalutamide may harm a 
developing fetus.  Women who are or may become pregnant should not handle damaged or 
opened enzalutamide capsules without protection, e.g., gloves.  See nonclinical safety data in 
Section 1.2.1.  Enzalutamide capsules should be kept out of the reach of children. 
The clinical material is packaged in high-density polyethylene (HDPE) bottles with 
child-resistant closures.  The capsules should be stored in the original bottle in a secure 
location with limited access at 20°C to 25°C (68°F to 77°F); excursions from 15°C to 30°C 
(59°F to 86°F) are permitted.  Subjects will be instructed to store study drug in the original 
bottle at room temperature out of the reach of children. 
4.1.2 
Comparative Drug(s)  
The placebo for enzalutamide will be supplied as oral soft gelatin capsules that consist of 
Labrasol and the same relative concentration of the 2 preservatives, BHA and BHT, that are 
also present in the active drug. 
The clinical material is packaged in HDPE bottles with child-resistant closures.  The capsules 
should be stored in the original bottle in a secure location with limited access at 20°C to 25°C 
(68°F to 77°F); excursions from 15°C to 30°C (59°F to 86°F) are permitted.  Subjects will be 
instructed to store study drug in the original bottle at room temperature out of the reach of 
children. 
4.2 
Packaging and Labeling 
All medication used in this study will be prepared, packaged, and labeled under the 
responsibility of qualified staff at Astellas Pharma Global Development, Inc (APGD)- Astellas 
United States Technologies, Inc (AUST) or sponsor’s designee in accordance with 
APGD-AUST or sponsor’s designee standard operating procedures (SOPs), Good 
Manufacturing Practice (GMP) guidelines, International Conference on Harmonisation (ICH) 
Good Clinical Practice (GCP) guidelines, and applicable local laws/regulations. 
Each bottle will bear a label conforming to regulatory guidelines, GMP and local laws and 
regulations, which identifies the contents as investigational drug. 
A qualified person of Astellas Pharma Europe B.V. (APEBV) or sponsor’s designee will 
perform the final release of the medication according to Directive 2003/94/EC annex 13. 
The study centers will be provided bottles containing 124 capsules of enzalutamide 40 mg 
capsules and bottles containing 124 capsules of matching placebo. 
4.3 
Study Drug Handling  
Current ICH GCP Guidelines require the investigator to ensure that study drug deliveries 
from the sponsor are received by the investigator/or designee and 
● 
that such deliveries are recorded; 


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● 
that study drug is handled and stored according to labeled storage conditions; 
● 
that study drug with appropriate expiry/retest only is dispensed to study subjects in 
accordance with the protocol, and; 
● 
that any unused study drug is returned to the sponsor, unless prior approval is received 
from the sponsor allowing local standard procedures for the alternative disposition of 
unused study drug. 
Drug inventory and accountability records for the study drugs will be kept by the 
investigator, head of study site (specific to sites in Japan) or designee. Study drug 
accountability throughout the study must be documented and reconciled. The following 
guidelines are therefore pertinent: 
● 
The investigator, head of study site (specific to sites in Japan) or designee agrees not to 
supply study drugs to any persons except the eligible subjects in this study in accordance 
with the protocol. 
● 
The investigator, head of study site (specific to sites in Japan) or designee will store and 
take accountability of the study drugs in conforming to the procedures for handling the 
study drugs as written by the sponsor. 
● 
The investigator, head of study site (specific to sites in Japan) or designee will 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 
if approved by the sponsor. These records should include dates, quantities, batch/serial 
numbers, expiration dates, and the unique code numbers assigned to the study drugs and 
subjects. 
● 
At the conclusion or termination of this study, the investigator, head of study site 
(specific to sites in Japan) or designee agrees to conduct a final drug supply inventory 
and to record the results of this inventory on the Drug Accountability Record. It must be 
possible to reconcile delivery records with those of used and/or returned medication.   
Any discrepancies must be accounted for and documented. Appropriate forms of deliveries 
and returns must be signed by the site staff delegated for this responsibility. 
4.4 
Blinding 
This is a double-blind study.  Subjects will be randomized to receive enzalutamide or placebo 
in a double-blind fashion such that neither the investigator, sponsor’s study management 
team, clinical staff, nor the subject will know which agent is being administered.  The 
randomization number will be assigned based on information obtained from the Interactive 
Response Technology (IRT). 
4.4.1 
Blinding Method 
For the purpose of this study, the efficacy and safety of enzalutamide and placebo will be 
compared in a double-blind manner.  Enzalutamide 40 mg capsule and placebo will be 
indistinguishable from one another in appearance, and packaging for each treatment group 
will also be indistinguishable from one another in appearance. 


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4.4.2 
Retention of the Assignment Schedule and Procedures for Treatment Code 
Breaking 
The randomization list and study medication blind will be maintained by the IRT system. 
The DSMB will be provided access to the dosing assignment for periodic review of the 
unblinded data as documented in the DSMB Charter. 
4.4.3 
Breaking the Treatment Code  
The treatment code for each randomized subject will be provided by the IRT in the event of a 
medical emergency requiring knowledge of the treatment assigned to the subject.  If possible, 
the Astellas Medical Monitor should be contacted prior to unblinding.  The time, date, subject 
number and reason for obtaining any of these codes, and therefore breaking the blind, must 
be documented in the study file.  They must only be requested by the investigator or other 
persons designated as subinvestigators.  No subjects or other study personnel will be made 
aware of the treatment given to any subject unless a medical emergency necessitates such 
disclosure. 
Unblinding of the study treatment assignment may be performed if the subject discontinues 
from the study treatment due to disease progression (must be confirmed by central review) 
and in the judgment of the investigator this information is necessary to determine the next 
course of therapy.  Prior to unblinding in this scenario, the investigator must contact the 
Astellas Medical Monitor. 
Any unblinding by the investigational staff must be reported immediately to the sponsor and 
must include an explanation of why the study medication was unblinded.  
4.4.4 
Breaking the Treatment Code by the Sponsor 
The sponsor may break the treatment code for subjects who experience a suspected 
unexpected serious adverse reaction (SUSAR), in order to determine if the individual case or 
a group of cases requires expedited regulatory reporting.  Individual Emergency Codes will 
be provided to the limited staff that is responsible to break the codes for all SUSAR cases for 
reporting purposes. 
4.5 
Assignment and Allocation 
Subjects will be entered into the IRT system at screening and assigned a subject number.  
Randomization will be performed via the IRT system and treatment assigned in a 1:1 ratio to 
enzalutamide 160 mg/day or placebo.  Prior to the initiation of the study treatment, on day 1, 
the site staff will contact the IRT system in order to determine the randomly assigned 
treatment.  Subjects will be stratified by prior docetaxel (None, 1-5 cycles, 6 cycles) and 
disease volume (low versus high).  High-volume disease is defined as metastases involving 
the viscera or, in the absence of visceral lesions, there must be 4 or more bone lesions, at least 
1 of which must be in a bony structure beyond the vertebral column and pelvic bone.  
Specific procedures for randomization through the IRT system are contained in the study 
procedures manual. 


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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 
Study drug consists of enzalutamide provided as 40 mg capsules to be taken as 160 mg 
(4 capsules) orally once daily or matching placebo.  Study drug is to be taken until disease 
progression, unacceptable toxicity or any other discontinuation criteria are met. 
Subjects who are continuing to receive clinical benefit from treatment with enzalutamide 
after the OS analysis data cutoff or at study termination and have not met any discontinuation 
criteria may continue their open-label treatment in another Astellas-sponsored study. 
Study drug will be self-administered at home by the subject and taken as close to the same 
time each day as possible.  Study drug can be taken with or without food.  Subjects should 
not make up missed or vomited doses; dosing should resume the following day unless 
otherwise instructed.  
5.1.2 
Increase or Reduction in Dose of the Study Drug(s) 
During the study, subjects who experience a National Cancer Institute (NCI)-Common 
Terminology Criteria for Adverse Events (CTCAE) guidelines (version 4.03) grade 3 or 
higher AE (except liver function test [LFT] AE) toxicity that is attributed to the study drug 
and cannot be ameliorated by the use of adequate medical intervention and/or dose reduction 
may interrupt study drug treatment for 1 week or until the toxicity grade improves to grade 2 
or lower in severity.  Study drug may be restarted at the original dose (160 mg/day) or a 
reduced dose (120 mg or 80 mg/day).  If restarted at a lower dose or if interrupted for 
> 2 weeks, the Medical Monitor must be consulted.  After dose reduction, based on subject 
tolerance, study drug may be increased to a maximum dose of 160 mg/day per investigator 
discretion.  
Enzalutamide must be interrupted during the evaluation of symptoms suspicious of PRES 
(headache, lethargy, confusion, blindness and other visual and neurological disturbances, 
with or without associated hypertension). 
5.1.3 
Previous and Concomitant Treatment (Medication and Nonmedication 
Therapy) 
Medications taken within 28 days prior to the screening visit and up to the first dose of study 
medication will be documented on the appropriate case report form (CRF) as a prior 
medication. 
Medications taken after the first dose of study medication up until the final follow-up visit 
will be documented on the appropriate CRF as concomitant medication. 
Prior and concomitant medications include all vitamins, herbal remedies, over the counter, 
and prescription medications. 


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5.1.3.1 Required Concomitant Treatment 
All subjects are required to receive background therapy with ADT, either bilateral 
orchiectomy or an LHRH agonist or antagonist, which must be maintained during study 
treatment, as per standard of care (SOC). 
An LHRH agonist or antagonist will be provided from the site’s stock and administered in 
accordance with prescribing information. 
5.1.3.2 Prohibited Concomitant Treatment 
A list of excluded concomitant medications is provided in [Appendix 12.1 List of Excluded 
Concomitant Medications]. The following medications are prohibited within 4 weeks of 
day 1 and during the study treatment period:  
● 
5 α-reductase inhibitors (finasteride, dutasteride); 
● 
Estrogens; 
● 
Cyproterone acetate; 
● 
Biologic or other agents with potential antitumor activity against prostate cancer (with 
the exception of those therapies identified in exclusion criterion No. 1); 
● 
Systemic glucocorticoids greater than the equivalent of 10 mg per day of prednisone 
intended for the treatment of prostate cancer; 
● 
Herbal medications that have known hormonal antiprostate cancer activity and/or are 
known to decrease PSA levels (i.e., saw palmetto); 
● 
Androgens (testosterone, dihydroepiandrosterone, etc.); 
● 
Investigational agents. 
In addition, bisphosphonates and denosumab are prohibited unless stabilized for 2 weeks 
prior to randomization and held constant, as tolerated, throughout study treatment or 
administered for diagnosis of osteoporosis. 


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5.1.3.3 Enzalutamide Drug Interaction 
There is a potential for enzalutamide to affect exposures to other medicinal products, or for 
other medicinal products to affect exposure to enzalutamide: 
● 
Strong CYP2C8 inhibitors (e.g., gemfibrozil) are to be avoided. If subject must be 
coadministered a strong CYP2C8 inhibitor, the dose of enzalutamide should be reduced 
to 80 mg once daily. If coadministration of the strong inhibitor is discontinued, the 
enzalutamide dose should be returned to the dose used prior to initiation of the strong 
CYP2C8 inhibitor. 
● 
Strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifampin) or 
moderate CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcilin, St. 
John’s Wort) should be avoided if possible as they may reduce enzalutamide plasma 
concentration if coadministered. Selection of a concomitant medication with no or 
minimal CYP3A4 induction potential is recommended. 
● 
Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C9 and 
CYP2C19. Medicinal products with a narrow therapeutic range that are substrates of 
CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, 
pimozide, quinidine, sirolimus, tacrolimus), CYP2C9 (e.g., phenytoin, warfarin), or 
CYP2C19, or UGT1A1 (e.g., S-mephenytoin) should be avoided if possible, as 
enzalutamide may decrease their exposure. 
● 
If enzalutamide coadministration with warfarin cannot be avoided, additional INR 
monitoring should be conducted. 
● 
Enzalutamide is an inhibitor of human P-glycoprotein (P-gp) and may increase exposure 
to medicines that are P-gp substrates. Medicinal products with a narrow therapeutic 
range that are substrates for P-gp (e.g., digoxin, colchicine, dabigatran etexilate) should 
be used with caution when administered concomitantly with enzalutamide. 
5.1.3.4 Permitted Concomitant Treatment 
The following treatments are allowed during the study (and do not require study drug 
discontinuation) including, but not limited to: 
● 
Blood transfusions and growth factor support per SOC and institutional guidelines; 
● 
Steroid use (for indication other than prostate cancer) per SOC; 
● 
Pain therapy per SOC and institutional guidelines; 
● 
Palliative radiation therapy including external beam radiotherapy or systemic 
radionuclides (e.g., Samarium or Strontium); 
● 
Vaccine therapy that has prior market authorization and is not intended to treat prostate 
cancer; 
● 
Palliative surgical procedures to treat skeletal-related events.  
Hormonal treatment for treating complications of LHRH analogue treatment (e.g., hot flashes) 
will be allowed with Medical Monitor approval. In addition, flutamide, bicalutamide or 
nilutamide are permitted if given concurrently with LHRH agonist or antagonist to prevent 
flare.  


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5.1.4 
Treatment Compliance 
Study subjects should be counseled on the need to meet 100% compliance with study drug 
unless study drug is withheld for a toxicity.  Investigator or designee should ensure that study 
subjects meet this goal throughout the study period.  Compliance will be verified by the 
accounting of study drug.  When study drug is administered at the research facility, it will be 
administered under the supervision of study personnel.  If compliance is less than 80% and 
study drug was not withheld and there were no study drug reductions, the investigator or 
designee is to counsel the subject on the importance of taking the study drug. 
Compliance of the study drug will be monitored by the accounting of unused medication 
returned by the subject at visits. Compliance will be documented. 
5.2 
Demographics and Baseline Characteristics 
5.2.1 
Demographics 
Demographic information will be collected at the screening visit for all subjects and will 
include age or date of birth, gender, race and ethnicity (as local regulations allow). 
5.2.2 
Medical History 
Medical history will be collected at the screening visit for all subjects and includes all 
significant medical conditions that have occurred or are currently ongoing at time of consent.  
The condition, onset date and recovery date will be collected.  NCI-CTCAE (version 4.03) 
grade will be collected for conditions that are ongoing at time of consent.  Cancer risk factor 
information will also be collected. 
5.2.3 
Diagnosis of the Target Disease, Severity, and Duration of Disease 
Prostate cancer history will be collected at the screening visit and will include histological or 
cytological diagnosis, date of diagnosis, Gleason score and associated treatment.  Date of 
diagnosis of metastatic disease, location of metastatic disease lesions, and all previous and/or 
ongoing treatment will also be documented during screening visit. 
5.3 
Efficacy Assessment 
5.3.1 
Efficacy Assessment 
5.3.1.1 CT/MRI and Bone Scan 
Radiographic imaging will be performed using CT or MRI and bone scan. 
Radiographic assessments performed prior to informed consent, as part of routine care, may 
be used as the baseline assessment if performed within 6 weeks of day 1 and should also be 
submitted if digital format images are available for submission to the sponsor designated 
facility for independent central review. 
Following baseline imaging, subsequent scans including abdominal-pelvic CT, chest CT (if 
screening visit chest X-ray demonstrated metastatic chest disease) and bone scan will be 
repeated at day 85/week 13 visit and every 12 weeks thereafter.  Imaging may be performed 
at any time to confirm suspected disease progression.  Assessment will include tumor 


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measurements for target lesions and nontarget lesions and assessment for any new lesions.  
An overall assessment will be documented for each time point evaluation.  At the end of the 
study for each subject, an overall best response will be documented. 
Study films should be read on site and also submitted in digital format to the sponsor 
designated facility for independent central review.  The initial imaging/scanning technique 
should be applied for the duration of the study for the subject and assessed by the same site 
designated reader, whenever possible. 
Radiographic disease progression is defined as progressive disease by RECIST version 1.1 
for soft tissue disease or by appearance of 2 or more new lesions on bone scan.  The 
documentation and confirmation required for the determination of radiographic progression is 
listed in [Table 2].  
Table 2 
Protocol-specified Documentation for Radiographic Evidence of Disease 
Progression 
Date 
Progression 
Detected (Visit)† 
Criteria for Progression 
Criteria for Confirmation 
of Progression 
(Requirement and 
Timing) 
Criteria for Documentation 
of Disease Progression on 
Confirmatory Scan 
Week 13 
Bone lesions: ≥ 2 new 
lesions compared to 
baseline bone scan 
Timing: ≥ 6 weeks after 
progression identified or at 
week 25 visit 
≥ 2 new bone lesions on bone 
scan compared to week 13 
scan (≥ 4 new lesions 
compared to baseline bone 
scan) 
Soft tissue lesions: 
progressive disease on CT 
or MRI by RECIST v1.1 
No confirmatory scan 
required for soft tissue 
disease progression 
Not applicable 
Week 25 or Later 
Bone lesions: ≥ 2 new 
lesions on bone scan 
compared to best response 
on treatment 
No confirmatory scan 
required 
Not applicable 
Soft tissue lesions: 
progressive disease on CT 
or MRI by RECIST v1.1 
No confirmatory scan 
required for soft tissue 
disease progression 
Not applicable 
CT: computed tomography; MRI: magnetic resonance imaging; RECIST v1.1: Response Evaluation Criteria in 
Solid Tumors version 1.1 
† Progression detected by bone scan at an unscheduled visit prior to week 25 will require the same criteria for 
documentation of disease progression as week 13 with a confirmatory scan at least 6 weeks later or at the next 
scheduled scan. 
Study drug treatment should be continued as long as the subject is tolerating the study drug 
and continues ADT until radiographic disease progression is documented as outlined in 
[Table 2] or the initiation of new antineoplastic therapy for treatment of prostate cancer.  It is 
recommended that subjects remain on study treatment until radiographic disease progression 
is confirmed by independent central imaging review.  Subjects will continue to be scanned 
every 12 weeks until radiographic progression is confirmed by independent review or the 
number of progression events is reached.  


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PSA 
Blood samples for PSA will be collected at each scheduled visit during study treatment and at 
the safety follow-up visit. All samples will be analyzed by sponsor designated central 
laboratory. 
5.3.1.2 Subject Reported Outcomes 
Subject reported outcomes will be collected according to the schedule of assessments 
[Table 1, Table 4 (Open Label) and Table 5 (Study Continuation)]. 
BPI-SF 
The BPI-SF pain questionnaire is a validated instrument that is a subject self-rating scale 
assessing level of pain, effect of the pain on activities of daily living and analgesic use. The 
BPI used in this study is the short form and contains 9 questions. The BPI uses simple 
numeric rating scales from 0 to 10. 
QLQ-PR25 
The QLQ-PR25 is a 25-item module designed to assess QoL in prostate cancer subjects. The 
extent of occurrence of 25 defined symptoms related to bowel, bladder and hormones as well 
as interest in and occurrence of sexual activity are rated by selecting 1 of 4 categories ranging 
from not at all to very much. 
EQ-5D-5L 
The EQ-5D-5L is a QoL instrument for self-reported assessment of 5 domains of health: 
mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each domain is 
rated by selecting 1 of 5 standardized categorizations ranging from no problem to extreme 
problem. The final question is a visual analogue scale to rank health status from best health 
imaginable to worst health imaginable. 
FACT-P 
The FACT-P questionnaire is a multi-dimensional, self-reported QoL instrument specifically 
designed for use with prostate cancer subjects. It consists of 27 core items that assess subject 
function in 4 domains: physical, social/family, emotional, and functional wellbeing, which is 
further supplemented by 12 site-specific items to assess for prostate-related symptoms. Each 
item is rated on a 0 to 4 Likert-type scale. 
5.4 
Safety Assessment 
5.4.1 
Vital Signs 
Routine vital signs, including blood pressure, pulse and temperature will be assessed at the 
screening visit, at every clinic visit while on study drug and at the safety follow-up visit. 


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5.4.2 
Adverse Events 
AE collection will begin at the time the informed consent form (ICF) is signed and continue 
until subject is determined to be ineligible for study entry, or initiation of new therapy for 
prostate cancer, or 30 days after the last dose of study drug, whichever occurs first. 
See [Section 5.5 Adverse Events and Other Safety Aspects] for information regarding AE 
collection and data handling.  
5.4.2.1 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 LFTs (e.g., AST, ALT, bilirubin, etc.) or 
is suspected to be due to hepatic dysfunction.  Subjects with AEs of hepatic origin 
accompanied by LFT abnormalities should be carefully monitored. 
5.4.3 
Laboratory Assessments 
Routine laboratory samples for hematology, chemistry and PSA will be collected at the 
screening visit, at every clinic visit while on study drug and at the safety follow-up visit. 
Testosterone will be collected at week 13 and every subsequent 12 weeks while on study 
drug.  Other laboratory assessments will be collected according to the schedule of 
assessments [Table 1].  Samples will be analyzed at sponsor designated central laboratory. 
Analytes included are identified in [Table 3]. 
Table 3 
Laboratory Assessments 
Hematology 
Biochemistry 
Other 
Red blood cell count 
White blood cell count 
White blood cell differential 
Hemoglobin 
Hematocrit 
Platelet count 
 
Albumin 
Alkaline phosphatase 
Alanine aminotransferase 
Aspartate aminotransferase 
Blood urea nitrogen 
Calcium 
Creatinine 
Glucose 
Phosphorus 
Potassium 
Sodium 
Total bilirubin 
Total protein 
Testosterone 
PSA 
Clinical significance of out-of-range laboratory findings is to be determined and documented 
by the investigator/subinvestigator who is a qualified physician. 
5.4.4 
Physical Examination including Weight and Height 
Complete physical examination will be performed at the screening visit to assess weight, 
height, general appearance, skin, eyes, ears, nose, throat, neck, cardiovascular, respiratory, 


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gastrointestinal, musculoskeletal, neurologic status, mental status, lymphatic and 
genitourinary systems. 
A brief physical examination with weight will be performed at day 1, all subsequent clinic 
visits while on study drug and at the safety follow-up visit. New or worsening clinically 
significant findings on physical examination will be recorded as AEs if they meet the criteria 
in [Section 5.5.1 Definition of Adverse Events]. 
5.4.5 
Electrocardiogram 
Standard 12-lead ECGs will be performed at the local institution and interpreted by the local 
institution’s medically trained staff.  ECGs will be performed at screening, day 1 and the 
safety follow-up visit. Parameters that include heart rate, PR interval, RR interval, QRS 
interval, QT interval, and interpretation and clinical significance as judged by the investigator 
will be collected. 
ECGs should be obtained after the subject has rested quietly and is awake in a fully supine 
position (or semirecumbent if supine is not tolerated) for 10 minutes. It is recommended that 
ECG reports are printed in duplicate and photocopied to prevent fading.  
5.5 
Adverse Events and Other Safety Aspects 
5.5.1 
Definition of Adverse Events 
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. 
Some countries may have additional local requirements for events that are required to be 
reported as AEs or in an expedited manner similar to a SAE. In these cases, it is the 
investigator’s responsibility to ensure these AEs or other reporting requirements are followed 
and the information is appropriately recorded in the electronic case report form (eCRF) 
accordingly. 
An abnormality identified during a medical test (e.g., laboratory parameter, vital sign, ECG 
data, physical examination) should be defined as an AE only if the abnormality meets 1 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 symptoms of disease progression will be recorded as AEs. However, disease 
progression itself should not be recorded as an AE unless the disease progression results in 
death; this event is recorded as an AE with ‘disease progression’ as the reported term. 


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5.5.2 
Definition of Serious Adverse Events 
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 include an AE that, had it occurred in a more severe form, 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 in-subject hospitalization (except for planned procedures as allowed per study) 
or leads to prolongation of hospitalization (except if prolongation of planned 
hospitalization is not caused by an AE).  Hospitalization for 
treatment/observation/examination caused by AE is to be considered as serious;  
● 
Other medically important events. 
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 1 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 on the medicinal products administered to the subject as part of the 
study (e.g., study drug, comparator and background therapy) that may require expedited 
reporting and/or safety evaluation include, but are not limited to: 
● 
Overdose of the medicinal product(s); 
● 
Suspected abuse/misuse of the medicinal product(s); 
● 
Inadvertent or accidental exposure to the medicinal product(s); 
● 
Medication error involving the medicinal product(s) (with or without subject/subject 
exposure to the sponsor medicinal product, e.g., name confusion). 
All of the special situations noted above should be recorded on the eCRF. Any situation 
involving these events that also meets the criteria for an SAE should be recorded on the AE 
page of the eCRF and marked ‘serious’ on the SAE worksheet/report. 
The sponsor has a list of events that they classify as “always serious” events. If an AE is 
reported that is considered to be an event per this classification as “always serious,” 
additional information on the event may be requested.   


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5.5.3 
Criteria for Causal Relationship to the Study Drug 
AEs that fall under either "Possible" or "Probable" 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 readministration (rechallenge) or 
withdrawal (dechallenge). 
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 4.03).  
The items that are not stipulated in the NCI-CTCAE (version 4.03) 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 
In the case of a SAE, the investigator must contact the sponsor by fax or email immediately 
(within 24 hours of awareness). 
The investigator should complete and submit an SAE Worksheet containing all information 
that is required by the Regulatory Authorities to the sponsor immediately (within 24 hours of 
awareness). If the submission of an SAE Worksheet is not possible or is not possible within 
24 hours, the local drug safety contact should be informed by phone. 


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Specific to sites in Japan, in the case of a SAE, the investigator or subinvestigator must report 
to the head of the study site and must contact the sponsor by telephone or fax 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 
the sponsor by fax immediately (within 24 hours of awareness) and to the head of the 
hospital.  If the faxing of JUTOKUNA YUUGAIJISHOU HOUKOKUSHO is not possible or 
is not possible within 24 hours, the sponsor should be informed by phone. 
For contact details, see [Section II Contact Details of Key Sponsor's Personnel]. Fax or email 
the SAE Worksheet to: 
Astellas Pharma Global Development, Inc – United States 
Pharmacovigilance 
North America fax number: 1-888-396-3750 
North America alternate fax number: 1-847-317-1241 
International fax number: +44 800 471 5263 
Email: safety-us@astellas.com 
Specific to sites in Japan, fax the SAE worksheet (JUTOKUNA YUUGAIJISHOU 
HOUKOKUSHO) to: 
Astellas Pharma Inc – Japan 
Japan/Asia Clinical Development 
Fax: 03-3243-5737 
If there are any questions, or if clarification is needed regarding the SAE, contact the 
sponsor's Medical Monitor or his/her designee (see [Section II Contact Details of Key 
Sponsor’s Personnel]).   
Follow-up information for the event should be sent promptly (within 7 days of the initial 
notification. 
Full details of the SAE should be recorded on the medical records and on the eCRF. 
The following minimum information is required: 
● 
International study number (ISN)/Study number 
● 
Subject number, sex and age 
● 
The date of report 
● 
A description of the SAE (event, seriousness of the event) 
● 
Causal relationship to the study drug 
The sponsor or sponsor's designee will submit expedited safety reports (i.e., IND Safety 
Reports) to the regulatory agencies (i.e., FDA) as necessary, and will inform the investigators 
of such regulatory reports.  Investigators must submit safety reports as required by their 
IRB/local IEC within timelines set by regional regulations (i.e., EU, eCTD, FDA).  


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Documentation of the submission to and receipt by the IRB/local IEC of expedited safety 
reports should be retained by the site. 
The sponsor or designee will notify all investigators responsible for ongoing clinical studies 
with the study drug of all SAEs which may require submission to the IRB/local IEC/head of 
the study site per local requirements. 
The investigator may contact the sponsor's Medical Monitor for any other problem related to 
the safety, welfare or rights of the subject. 
Specific to sites in Europe, for SUSAR from a blinded trial, unblinded Council for 
International Organizations of Medical Sciences (CIOMS)-I report will be submitted to the 
authorities and IRB/Central IEC where required.  
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. 
Refer to [Appendix 12.2 Liver Safety Monitoring and Assessment] for detailed instructions 
on Drug Induced Liver Injury. 
5.5.7 
Monitoring of Common Serious Adverse Events 
Common SAEs are SAEs commonly anticipated to occur in the study population independent 
of drug exposure.  SAEs classified as “common” are provided in [Appendix 12.3 Common 
Serious Adverse Events] for reference. The list does NOT change the investigator’s reporting 
obligations or prevent the need to report an AE meeting the definition of an SAE as detailed 
above.  The purpose of this list is to note that some events reported as SAEs may not require 
expedited reporting to the regulatory authorities based on the classification of “common 
SAEs” as specified in [Appendix 12.3 Common Serious Adverse Events].  The sponsor will 
monitor these events throughout the course of the study for any change in frequency. Any 
changes to this list will be communicated to the participating investigational sites.  
Investigators must report individual occurrences of these events as stated in [Section 5.5.5 
Reporting of Serious Adverse Events]. 
5.5.8 
Procedure in Case of Pregnancy 
If a female partner of a male subject becomes pregnant during the study dosing period or 
within 90 days from the discontinuation of dosing, the investigator should report the 
information to the sponsor 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. 


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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 is identified prior to spontaneous abortion or miscarriage, 
the embryo or fetus should be assessed for congenital defects by visual examination. 
5.5.9 
Emergency Procedures and Management of Overdose 
An overdose is defined as any dose greater than the protocol specified dose of enzalutamide 
160 mg once daily. In the event of an enzalutamide overdose, the study drug should be 
stopped and subject should receive supportive care and monitoring. The Medical Monitor 
should be contacted. 
Neither the effects of overdose of enzalutamide or an antidote to overdose are known.  
Subjects may be at increased risk of seizures following an overdose of enzalutamide. 
All overdose events are to be reported within 24 hours of awareness as per [Section 5.5.2 
Definition of Serious Adverse Events].  
5.5.10 Supply of New Information Affecting the Conduct of the Study 
When new information becomes available necessary for conducting the clinical study 
properly, the sponsor will inform all investigators involved in the clinical study as well as the 
regulatory authorities. Investigators should inform the IRB/IEC of such information when 
needed.  
The following 2 paragraphs are specific to sites in Japan: 
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 Act on 
Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, 
Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics, in 
compliance with Article 80-2 Paragraph 6 of the Act on Securing Quality, Efficacy and 
Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy 
Products, Gene Therapy Products, and Cosmetics, 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 


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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 Investigator’s Brochure, 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. 
5.5.11 Deviations from the Protocol and Other Actions Taken to Avoid 
Life-threatening Risks to Subjects (Specific to Sites in Japan) 
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 
5.7.1 
Optional Blood Sample for Mutation Analysis (North America Sites Only) 
At randomization, at week 49, and at study treatment discontinuation, a 10 mL whole blood 
sample will be collected for subjects who are randomized in North America and provide 
consent.   
Whole blood will be processed to plasma using standard centrifugation methods.  Analysis 
methods [Romanel et al, 2015; Azad et al, 2015] will be adapted and used to perform a 
targeted mutation evaluation of specific target genes including, AR, epidermal growth factor 
receptor (EGFR), neuroblastoma RAS viral oncogene homolog (NRAS), Kirsten rat sarcoma 
viral oncogene homolog (KRAS), phosphatidylinositol-4, 5-bisphosphate 3-kinase and 
catalytic subunit alpha (PIK3CA).  Other genes potentially related to resistance to 
enzalutamide may be analyzed. 
Samples will be shipped to a sponsor designated laboratory for analysis.  Details on sample 
collection, labeling, storage and shipment procedures will be provided in a separate 
laboratory manual.  


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5.7.2 
Optional Blood Sample for Future Pharmacogenomic Analysis (Retrospective 
Pharmacogenomic Analysis) 
Pharmacogenomic (PGx) research may be conducted in the future to analyze or determine 
genes of relevance to clinical response and toxicity/safety issues. After randomization 
[Table 1], a 5 mL sample of whole blood for possible retrospective PGx analysis will be 
collected using a vacutainer tube containing EDTA for subjects who provide consent.  
Samples will be shipped to a sponsor designated laboratory for sample banking. 
Details on sample collection, labeling, storage and shipment procedures will be provided in a 
separate laboratory manual. 
See [Appendix 12.4, Retrospective PGx Substudy] for further details on the banking 
procedures. 
5.8 
Total Amount of Blood 
The total amount of blood to be drawn for a subject will vary depending on the course of 
their disease and their duration on study treatment.  At any time during the study, if 
laboratory values are determined to be abnormal, additional blood samples may be required 
for monitoring subject safety.  The maximum amount of blood estimated to be collected over 
the protocol outlined visits from screening visit through day 85/week 13 visit is 
approximately 30 mL.  Approximately 10 mL will be drawn at each subsequent study visit 
while on study drug.  For those subjects randomized in North America who agree to provide 
samples for mutation analysis, an additional 10 mL sample will be collected at each time 
point of day 1, week 49 and at study treatment discontinuation. 
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 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.  
Subject will be discontinued from the study drug treatment if any of the following occur: 
● Any AE that is intolerable to the subject which cannot be ameliorated by the use of 
adequate medical intervention and/or dose reduction or that in the opinion of the 
investigator would lead to undue risk to the subject if dosing is continued. 


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● Subject who experiences a seizure or any condition that significantly predisposes the 
subject to seizure such as brain metastasis or clinically evident stroke. 
● Subject who experiences a confirmed event of PRES by brain imaging, preferably by 
MRI. 
● Subject initiates an investigational agent or new therapy for prostate cancer. 
● Subject who has evidence of radiological disease progression as confirmed by the 
independent reader and in the judgment of the investigator is no longer deriving clinical 
benefit. 
● Subject has discontinued ADT (LHRH agonist/antagonist) and has a testosterone value in 
the noncastrate range (> 50 ng/dL) as confirmed by the central laboratory. 
● Subject who is, in the opinion of the investigator or the Medical Monitor, noncompliant 
with the protocol requirements. 
● Subject is lost to follow-up despite reasonable efforts by the investigator to locate the 
subject. 
● Subject withdraws consent for the study. 
Subject will be discontinued from the study follow-up (Safety or Long-term Follow-up) if 
any of the following occur: 
● Subject is lost to follow-up despite reasonable efforts by the investigator to locate the 
subject. 
● Subject withdraws consent for further follow-up. 
● Death. 
● Final analysis for OS completed. 
● Study termination by the sponsor. 
6.2 
Discontinuation of the Site 
If an investigator intends to discontinue participation in the study, the investigator must 
immediately inform the sponsor and, specific to sites in Japan, the head of the study site must 
also be informed immediately. 
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. 
7 
STATISTICAL METHODOLOGY 
The statistical analysis will be coordinated by the responsible biostatistician from Astellas.  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 


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before the database lock at the latest.  Any changes from the analyses planned in SAP will be 
justified in the clinical study report. 
Prior to database lock, a Final Review of Data and Tables, Listings and Figures Meeting will 
be held to allow a review of the clinical trial data and to verify the data that will be used for 
analysis set classification.  If required, consequences for the statistical analysis will be 
discussed and documented.  A meeting to determine analysis set classifications may also be 
held prior to database lock. 
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 
As originally planned, approximately 1100 subjects (550 subjects per treatment arm) will be 
randomized in the study.  
The final analysis of rPFS will be conducted with a minimum of 262 progression events 
based on the following considerations:  
● 
A target HR is 0.67.  The expected median rPFS for the ADT arm is 20 months as 
measured from the date of randomization. A target HR of 0.67 corresponds to 
approximately 50% increase in median rPFS for the enzalutamide plus ADT arm relative 
to the placebo plus ADT arm (approximately 30 versus 20 months). 
● 
The required minimum of 262 rPFS events (radiographic progression or death on study, 
defined as death from any cause within 24 weeks after treatment discontinuation, 
whichever occurs first) provides 90% power to detect a target HR of 0.67 based on a 
2-sided log-rank test and significance level of 0.05.  
Additionally the study is powered for OS.  Specifically, 342 death events will be required to 
provide 80% power to detect a target hazard ration of 0.73 with a target difference in 
Kaplan-Meier estimated median of approximately 15 months (40 months for placebo versus 
55 months for enzalutamide) at the 4% significance level. This significance level was chosen 
to apply a parallel testing strategy between OS and some other secondary endpoints (with 
allocated type I error rate of 1%) as described in Section 7.4.2. 
7.2 
Analysis Set 
Detailed criteria for analysis sets will be laid out in Classification Specifications and the 
allocation of subjects to analysis sets will be determined prior to database hard lock.  
7.2.1 
Intent-to-Treat Population 
The Intent-to-Treat (ITT) population is defined as all subjects who were randomized in this 
study.  The ITT population will be analyzed by treatment arm as randomized (i.e., treatment 
arm based on randomization assignment). The ITT population will be used to conduct 
efficacy analyses. For the ORR, only subjects with measurable disease at baseline will be 
included in the analysis.  


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7.2.2 
Safety Population 
The safety population is defined as all randomized subjects who received at least 1 dose of 
study drug.  The safety population will be analyzed by treatment arm as treated (i.e., based on 
the treatment the subject actually received rather than the treatment to which the subject was 
randomized). The safety population will be used to conduct safety analyses. 
7.3 
Demographics and Other Baseline Characteristics  
Demographics and other baseline characteristics will be summarized by treatment group for 
the ITT population. 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  
7.4.1 
Analysis of Primary Endpoint  
rPFS is defined as the time from randomization to the first objective evidence of radiographic 
disease progression as assessed by central review or death (defined as death from any cause 
within 24 weeks from study drug discontinuation), whichever occurs first. 
Radiographic disease progression is defined as progressive disease by RECIST version 1.1 
for soft tissue disease or by appearance of 2 or more new lesions on bone scan. 
The effect of enzalutamide plus ADT compared to ADT will be tested using a stratified 
log-rank test at the level of significance of 0.05 (2-sided).  The benefit of enzalutamide plus 
ADT compared to ADT will be summarized by a single HR with its 95% CI based on the 
Cox regression model. Kaplan-Meier curves will be used to estimate the distribution of the 
duration of rPFS.  Median duration of rPFS will be estimated using the corresponding 50% 
percentile of the Kaplan-Meier estimates. A 2-sided 95% CI will be provided for these 
estimates. 
The analysis will be conducted when at least 262 rPFS events have occurred. 
7.4.1.1 Subgroup Analysis 
Subgroup analyses of rPFS will be conducted to assess the consistency of the treatment effect 
across the subgroups. 
7.4.2 
Analysis of Secondary Endpoints  
All secondary endpoint analyses will be performed at the time of the rPFS final analysis. 
The following 6 secondary endpoints will be tested:  OS, time to PSA progression (TTPSA), 
time to initiation of a new antineoplastic therapy (TTNAnti), the rate of PSA decline to 
< 0.2ng/mL (PSADecR), the objective response rate (ORR) and time to deterioration in 
urinary symptoms (TTUri).  A parallel testing strategy between OS (with allocated type I 
error rate 0.04) and the other 5 endpoints (with allocated type I error rate 0.01) will be 
performed, as summarized in Figure 2.   


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Figure 2 
Testing Strategy for the Primary and 6 Selected Secondary Endpoints 
 
OS: overall survival; ORR: objective response rate; PSADecR: rate of PSA decline to < 0.2 ng/mL;  
rPFS: radiographic progression-free survival; TTNAnti: time to initiation of a new antineoplastic therapy; 
TTPSA: time to PSA progression; TTUri: time to deterioration in urinary symptoms from the QLQ-PR25. 
*OS will be tested at 0.05 only if the other 5 secondary endpoints analyses are statistically significant at 0.01. 
Details of the primary and the selected secondary endpoints testing as a step-by-step 
approach will be described in the Statistical Analysis Plan (SAP). 
One interim analysis and a final analysis are planned for OS.  The interim analysis of OS will 
be performed at the time of the rPFS final analysis.  If this interim analysis of OS is 
statistically significant, it will be reported as the final analysis and no subsequent analysis 
will be performed.  At the time of the planned final analysis of OS, no additional analyses of 
other efficacy endpoints will be conducted.  
OS: 
The duration of OS is defined as the time from randomization to death from any cause.  OS 
will be analyzed as for rPFS. 
The O’Brien-Fleming alpha spending function will be used to determine the stopping 
boundaries based on the number of events observed at the interim look to control the overall 
2-sided alpha at 0.05 or at 0.04 (as described in Figure 2). 


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The interim analysis of OS expected at the time of the final analysis of rPFS will be 
performed at an expected significance level of 0.006 based on approximately 170 death 
events.  If this interim analysis of OS is not statistically significant, the final analysis of OS is 
planned when approximately 342 deaths are observed to ensure an adequate number of events 
for the evaluation of OS. 
Time to first SSE: 
Time to first SSE is defined as the time from randomization to the occurrence of the first 
SSE.  SSE is defined as radiation or surgery to bone, clinically apparent pathological bone 
fracture or spinal cord compression.  The analysis method will be the same as for rPFS. 
Time to castration resistance: 
Castration resistance is defined as occurrence of radiographic disease progression, PSA 
progression or SSE with castrate levels of testosterone (< 50 ng/dL).  Time to castration 
resistance is defined as the time from randomization to the first castration-resistant event 
(radiographic disease progression, PSA progression or SSE), whichever occurs first.  The 
analysis method will be the same as for rPFS. 
Time to deterioration of QoL: 
A deterioration of QoL is defined as a 10-point decrease in the total FACT-P score from 
baseline.  Time to deterioration of QoL is defined as time from randomization to a 10-point 
reduction of the FACT-P total score.  The analysis method will be the same as for rPFS. 
Time to deterioration in urinary symptoms:  
A deterioration in urinary symptoms is defined as an increase in urinary symptoms scores, 
using a modified urinary symptoms scale derived from a selected subset of symptoms from 
the QLQ-PR25 questionnaire module (including 3 items: Q31 – Q33), by ≥ 50% of the 
standard deviation observed in the modified urinary symptoms scale score at baseline 
[Tombal et al, 2018].  Time to deterioration in urinary symptoms is defined as time from 
randomization to the first deterioration in urinary symptoms.  The analysis method will be the 
same as for rPFS. 
Time to initiation of a new antineoplastic therapy: 
All antineoplastic therapies, including cytotoxic and hormone therapies, will be considered 
for this endpoint.  Time to initiation of a new antineoplastic therapy is defined as the time 
from randomization to the initiation of antineoplastic subsequent to the study treatments.  The 
analysis method will be the same as for rPFS. 
Time to PSA progression: 
Time to PSA progression is defined as a ≥ 25% increase and an absolute increase of 
≥ 2 ng/mL above the nadir (i.e., lowest PSA value observed postbaseline or at baseline), 
which is confirmed by a second consecutive value at least 3 weeks later.  The method of 
analysis for time to PSA progression will be the same as for rPFS.  


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PSA undetectable rate: 
The undetectable level of PSA is defined as < 0.2 ng/mL.  The PSA undetectable rate is 
defined as the percentage of subjects with detectable (≥ 0.2 ng/mL) PSA at baseline, which 
becomes undetectable (< 0.2 ng/mL) during study treatment.  Only subjects with detectable 
PSA at baseline will be included in this analysis. 
ORR: 
The ORR is defined as the percentage of subjects with measureable disease at baseline who 
achieved a complete or partial response in their soft tissue disease using the RECIST 
version 1.1 criteria.  Only subjects with measureable soft tissue disease at baseline will be 
included in this analysis. 
Time to pain progression: 
Pain progression is defined an increase of ≥ 30% from baseline in the average BPI-SF item 
scores.  Time to pain progression is defined as time from randomization to an increase of 
30% in pain severity score from baseline using the BPI-SF.  The analysis method will be the 
same as for rPFS. 
Time to event endpoints such as rPFS, time to PSA progression, OS, time to first SSE, time 
to castration resistance, time to deterioration of QoL, time to deterioration in urinary 
symptoms, time to pain progression and time to initiation of new antineoplastic therapy will 
be analyzed using the stratified log-rank test.  The stratified Cox Regression analysis will be 
used to estimate the HR and the associated 95% CI.  The median will be estimated using the 
Kaplan-Meier method. 
The proportion endpoints such as PSA undetectable rate and ORR will be analyzed using the 
stratified Cochran-Mantel-Haenszel score test. 
7.5 
Analysis of Safety 
Safety analyses will be conducted using the safety population and summarized by treatment 
arms as treated. 
Baseline laboratory results will be summarized using descriptive statistics by treatment arms.  
Worst toxicity grades per subject will be tabulated for selected AEs and laboratory analytes.  
Clinical safety data (including AEs, grade 3 and 4 hematologic and nonhematologic events, 
clinical laboratory evaluations, vital signs, ECGs and physical examinations) will be 
summarized by treatment groups using descriptive statistics or frequency distribution as 
appropriate. 
Treatment-emergent period is defined as the duration of the study treatment plus 30 days.  
AEs occurring in this period are termed TEAEs. 
Duration of treatment and total dose administered will be summarized by treatment groups.  
In addition, the number and percentage of subjects with dose reduction will be tabulated. 


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7.5.1 
Adverse Events 
Treatment-emergent AEs will be coded to system organ class and preferred terms using 
MedDRA and graded using NCI-CTCAE (version 4.03). 
Treatment-emergent AEs will be tabulated alphabetically by system organ class and by 
preferred terms within system organ class. 
Treatment-emergent AEs will be presented within each system organ class by preferred term, 
by relationship to study drug and by severity (NCI-CTCAE grade).  Treatment-emergent AEs 
leading to permanent discontinuation of study drug, SAEs and SAEs by NCI-CTCAE grade 
will be summarized. 
7.5.2 
Laboratory Assessments 
Clinical laboratory evaluations (including hematology and serum chemistry) will be 
presented for each visit using descriptive statistics (n, mean, SD, median, minimum and 
maximum values). Change from baseline will also be presented. Shift analysis tables will 
present the shift from baseline for using NCI-CTCAE grade and lab reference range 
indicator.  All clinically significant abnormal laboratory values will be recorded as AEs and 
graded using NCI-CTCAE guidelines. A listing of subject laboratory values will be provided. 
7.5.3 
Vital Signs  
Descriptive statistics (n, mean, SD, median, minimum and maximum) will be presented for 
each vital sign at each time point and the change from baseline. 
7.5.4 
Physical Examination 
All clinically significant abnormal findings will be recorded as medical history or AEs.  AEs 
will be graded using NCI-CTCAE guidelines. 
7.5.5 
Electrocardiogram 
Overall ECG interpretation will be summarized for each time point.  A shift analysis table 
showing change from baseline in overall ECG (normal, abnormal not clinically significant, 
and abnormal clinically significant) will be provided. 
7.6 
Analysis of Exploratory Endpoint 
An exploratory mutation analysis of specific gene targets including AR, EGFR, NRAS, 
KRAS, and PIK3CA will be conducted for samples collected in North America.  Other genes 
potentially related to resistance to enzalutamide may be analyzed.  Mutations status will be 
summarized by descriptive statistics, including number of subjects, variant frequency, mean, 
standard deviation, minimum, median and maximum, and individual mutation status over 
time will be evaluated. 
7.7 
Analysis of Pharmacokinetics 
Not applicable.  


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7.8 
Protocol Deviations and Other Analyses (Unique to JP: Other 
Analyses) 
Protocol deviations as defined in [Section 8.1.6 Protocol Deviations] will be summarized for 
all randomized subjects by treatment group and total as well as by site. A data listing will be 
provided by site and subject.  
The protocol deviation criteria will be uniquely identified in the summary table and listing.  
The unique identifiers will be as follows: 
PD1 - Entered into the study even though they did not satisfy entry criteria,  
PD2 - Developed withdrawal criteria during the study and was not withdrawn, 
PD3 - Received wrong treatment or incorrect dose, 
PD4 - Received excluded concomitant treatment, 
7.9 
Interim Analysis 
No formal interim analysis is planned for rPFS.  One interim analysis of OS will be 
performed at the time of the rPFS final analysis.  If this interim analysis of OS is statistically 
significant, it will be reported as the final analysis and no subsequent analysis will be 
performed. 
7.10 
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information 
Imputation for missing data, if applicable, will be addressed in the SAP. 
8 
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS 
8.1 
Procedure for Clinical Study Quality Control 
8.1.1 
Data Collection 
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 record data (including laboratory values, if applicable) in the eCRF 
within 5 days after the subject visit. 
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. 
Subject reported outcomes questionnaires will be completed by the subject on an electronic 
device.  Information completed by the subject on the electronic device will be automatically 
uploaded to a central website.  The investigator or site designee should review the data status 
for completion while the subject is at the site. The questionnaire data will be transferred 


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electronically to the sponsor or designee at predefined intervals during the study.  The vendor 
will provide the sponsor or designee with a complete and clean copy of the data. 
Laboratory tests are performed at the sponsor designated central laboratory. Laboratory data 
will be transferred electronically to the sponsor or designee at predefined intervals during the 
study.  The laboratory will provide the sponsor or designee with a complete and clean copy of 
the data.  
Independent central imaging review results are performed at a sponsor designated central 
imaging review facility. Central imaging review data will be transferred electronically to the 
sponsor or designee at predefined intervals during the study. The central imaging review 
facility will provide the sponsor or designee with a complete and clean copy of the data. 
For screen failures, the minimum demographic data (gender, birth date or age, race and 
informed consent date) and reason for screen failure will be collected in the eCRF and the 
screen failure log, if applicable. This information will be entered into the study database. 
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.  Unless otherwise specified, source data 
must include the original documents relating to the study, as well as the medical treatment 
and medical history of the subject.   
The following information should be included in the source medical records: 
● 
Demographic data (age, gender, race, ethnicity, height and body weight); 
● 
Inclusion and exclusion criteria details; 
● 
Participation in study and original signed and dated ICFs;  
● 
Visit dates; 
● 
Medical history and physical examination details; 
● 
Key efficacy and safety data as specified in the protocol; 
● 
AEs and concomitant medication;  
● 
Results of relevant examinations (e.g., ECG charts, X-ray films etc.); 
● 
Laboratory printouts; 
● 
Dispensing and return of study drug details; 
● 
Reason for premature discontinuation (if applicable); 
● 
Randomization number (if applicable); 
● 
Staff notes and telephone conversation documentation; 
● 
Medical records from other departments or hospitals (photocopy or faxed document of 
original record is acceptable if obtained from an outside institution).  
8.1.3 
Clinical Study Monitoring 
The sponsor or designee 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/subinvestigator are accurate and complete and that they are verifiable with study-


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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.   
8.1.4 
Direct Access to Source Data/Documents 
The investigator and the study site must accept monitoring and auditing by the sponsor or 
designee 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 the Data Science department of the sponsor in 
accordance with the SOPs for data management. All study specific processes and definitions 
will be documented by data management. eCRF completion will be described in the eCRF 
instructions. Coding of medical terms and medications will be performed using MedDRA 
and World Health Organization Drug Dictionary, respectively. 
8.1.6 
Protocol Deviations 
A protocol deviation is generally an unplanned excursion from the protocol that is not 
implemented or intended as a systematic change. The investigator is responsible for ensuring 
the study is conducted in accordance with the procedures and evaluations described in this 
protocol and must protect the rights, safety and welfare of subjects. The investigator should 
not implement any deviation from, or changes of, the protocol, unless it is necessary to 
eliminate an immediate hazard to trial subjects. 
A protocol waiver is a documented prospective approval of a request from an investigator to 
deviate from the protocol.  Protocol waivers are strictly prohibited. 
For the purposes of this protocol, deviations requiring notification to sponsor are defined as 
any subject who: 
● 
Entered into the study even though they did not satisfy entry criteria;  
● 
Developed withdrawal criteria during the study and not withdrawn; 
● 
Received wrong treatment or incorrect dose; 
● 
Received excluded concomitant treatment. 
When a deviation from the protocol is identified for an individual subject, the investigator or 
designee must ensure the sponsor is notified.  The sponsor will follow-up with the 
investigator, as applicable, to assess the deviation and the possible impact to the safety and / 
or efficacy of the subject to determine subject continuation in the study. 
If a deviation impacts the safety of a subject, the investigator must contact the sponsor 
immediately.  


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The investigator will also assure that deviations meeting IRB/IEC and applicable regulatory 
authorities’ criteria are documented and communicated appropriately. All documentation and 
communications to the IRB/IEC and applicable regulatory authorities will be provided to the 
sponsor and maintained within the Trial Master File. 
NOTE:  Other deviations outside of the categories defined above that are required to be 
reported by the IRB/IEC in accordance with local requirements will be reported, as 
applicable.  
8.1.7 
End of Trial in All Participating Countries 
The end of trial in all participating countries is defined as the last subject’s last visit or last 
subject’s last contact, whichever is longer. 
8.2 
Ethics and Protection of Subject Confidentiality  
8.2.1 
IRB/IEC/Competent Authorities 
GCP requires that the clinical protocol, any protocol amendments, the Investigator’s 
Brochure, the ICF and all other forms of subject information related to the study (e.g., 
advertisements used to recruit subjects) and any other necessary documents be reviewed by 
an IEC/IRB.  The IEC/IRB will review the ethical, scientific and medical appropriateness of 
the study before it is conducted.  IEC/IRB approval of the protocol, informed consent and 
subject information and/or advertising, as relevant, will be obtained prior to the authorization 
of drug shipment to a study site. 
Any substantial amendments to the protocol will require IEC/IRB approval prior to 
implementation of the changes made to the study design at the site. The investigator will be 
required to submit, maintain and archive study essential documents according to ICH GCP. 
Any SAEs that meet reporting criteria, as dictated by local regulations, will be reported to 
both responsible Ethics Committees and Regulatory Agencies, as required.  During the 
conduct of the study, the investigator should promptly provide written reports (e.g., ICH 
Expedited Reports, and any additional reports required by local regulations) to the IEC/IRB 
of any changes that affect the conduct of the study and/or increase the risk to subjects.  
Written documentation of the submission to the IEC/IRB should also be provided to sponsor. 
If required by local regulations, the investigator shall make accurate and adequate written 
progress reports to the IEC/IRB at appropriate intervals, not exceeding 1 year. The 
investigator shall make an accurate and adequate final report to the IRB/IEC within 90 days 
after the close-out visit for APGD-sponsored studies. 
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 or 
his/her guardian or legal representative, 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 (specific to sites in Japan, place a personal 
seal) 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 (specific to sites in Japan, or sealed) ICF 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/IEC.  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 reconsent 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 and date the ICF (specific to 
sites in Japan, place a personal seal). A copy of the signed (specific to sites in Japan, or 
sealed) ICF 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 
reconsent 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. 
The sponsor shall not disclose any confidential information on subjects obtained during the 
performance of their duties in the clinical study without justifiable reasons. 


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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. 
The sponsor affirms the subject's right to protection against invasion of privacy.  Only a 
subject identification number and/or initials will identify subject data retrieved by the 
sponsor.  However, the sponsor requires the investigator to permit the sponsor, sponsor's 
representative(s), the IRB/IEC and when necessary, representatives of the regulatory health 
authorities to review and/or to copy any medical records relevant to the study. 
The sponsor will ensure that the use and disclosure of protected health information obtained 
during a research study complies with the federal and/or regional legislation related to the 
privacy and protection of personal information (i.e., Health Insurance Portability 
Accountability Act). 
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, the Investigator's Brochure 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 in connection with the development of the 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. 
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); 
● 
Investigator’s Brochure (and amendments, where applicable); 
● 
eCRFs; 
● 
JUTOKUNA YUUGAIJISHOU HOUKOKUSHO (specific to sites in Japan); 
● 
Study drug with all necessary documentation; 
● 
Study contract. 


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In order to start the study, the investigator and/or study site is required to provide the 
following documentation to the sponsor:  
● 
Financial disclosure in compliance with federal regulation 21CFR Part 54; 
● 
Signed and dated FDA form 1572, if conducted under a U.S. IND; 
● 
Signed Investigator's Statement in this protocol and eCRF; 
● 
Current Curricula Vitae of all investigators; 
● 
List of subinvestigators and collaborators;  
● 
IRB approval of the protocol, protocol amendments (if applicable) including a 
membership list with names and qualification; 
● 
Instruction and decision of the head of the study site (specific to sites in Japan); 
● 
Study contract; 
● 
Laboratory normal reference ranges (if applicable, signed and dated by the responsible 
laboratory employee). 
The investigator will archive all study data (e.g., Subject Identification Code List, source 
data, CRFs and Investigator's File) and relevant correspondence.  These documents are to be 
kept on file for the appropriate term determined by local regulation (for US sites, 2 years after 
approval of the NDA or discontinuation of the IND).  The sponsor will notify the 
site/investigator if the NDA/MAA/J-NDA is approved or if the IND/IMPD/CHIKEN 
TODOKE is discontinued.  The investigator agrees to obtain the sponsor's agreement prior to 
disposal, moving, or transferring of any study-related records.  The sponsor will archive and 
retain all documents pertaining to the study according to local regulations. 
Data generated by the methods described in the protocol will be recorded in the subjects' 
medical records and/or study progress notes.  All data will be entered into the eCRFs. 
Specific to sites in Japan, 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. 
Specific to sites in Japan, 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 defined in 1 or 2 below, whichever comes later. 
1. Approval date of marketing of the test drug (if development of the drug is stopped, until 
3 years after the decision to discontinue development is notified); 
2. Until 3 years after discontinuation or termination of the study. 
The following are the major documents to be retained at the study site. 
1. Source documents (e.g., clinical data, documents, and records for preparing the CRF, 
hospital records, medical records, test records, memoranda, subject diary or check lists 
for evaluation, administration 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 


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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 ICFs, 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 (including revisions), CVs of investigators, list of 
subinvestigators, list of signatures and print of seals (copy), and CRFs (copy), 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 1 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), Investigator's 
Brochure (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 inventory and accountability record, 
vouchers for the receipt and return of the study drugs, and the prescriptions for 
concomitant medications 
The documents of the Efficacy and Safety Evaluation Committee (minutes and SOPs and 
others) and the judgment committee outside the study sites (minutes and SOPs and others) 
shall be retained by the sponsor. 
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: substantial amendments and/or nonsubstantial amendments.  
Depending on the nature of the amendment, either IRB/IEC, Competent Authority approval 
or notification may be required.  The changes will become effective only after the approval of 
the sponsor, the investigator, the regulatory authority and the IRB/IEC (if applicable). 
Amendments to this protocol must be signed by the sponsor and the investigator. Written 
verification of IRB/IEC approval will be obtained before any amendment is implemented 
which affects subject safety or the evaluation of safety, and/or efficacy.  Modifications to the 
protocol that are administrative in nature do not require IRB/IEC approval, but will be 
submitted to the IRB/IEC for their information, if required by local regulations. 


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If there are changes to the informed consent, written verification of IRB/IEC approval must 
be forwarded to the Sponsor.  An approved copy of the new informed consent must also be 
forwarded to the Sponsor. 
8.3.4 
Insurance of Subjects and Others 
The sponsor has covered this study by means of an insurance of the study according to 
national requirements.  The name and address of the relevant insurance company, the 
certificate of insurance, the policy number and the sum insured are provided in the 
Investigator's File.  
Specific to sites in Japan, 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.   
Specific to sites in Japan, 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.  
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 
ICH E3 guidelines recommend and EU Directive 2001/83/EC requires that a final study 
report which forms part of a marketing authorization application be signed by the 
representative for the Coordinating Investigator(s) or the Principal Investigator(s).  The 
representative for the Coordinating Investigator (s) or the Principal Investigator(s) will have 
the responsibility to review the final study results to confirm to the best of his/her knowledge 
it accurately describes the conduct and results of the study.  The representative for 
Coordinating Investigator(s) or the Principal Investigator(s) will be selected from the 
participating investigators by the sponsor prior to database lock. 
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). 


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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, CRFs, and source documents.  Direct access to these documents will be required 
by the auditors. 
10 
STUDY ORGANIZATION 
10.1 
Data Safety Monitoring Board 
A DSMB will evaluate the unblinded safety data of subjects enrolled on a periodic basis 
during this study.  DSMB members will be clinicians with expertise in prostate cancer trials 
and are not investigators participating in this trial or Astellas employees.  A separate charter 
will outline the activities of this committee. 
10.2 
Other Study Organization 
Specific to sites in Japan: the Japan site contact list is kept as a separate attachment to the 
protocol. 


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11 
REFERENCES  
Azad AA, Volik SV, Wyatt AW, Haegert A, Le Bihan S, Bell RH, Anderson SA, McConeghy B, 
Shukin R, Bazov J, Youngren J, Paris P, Thomas G, Small EJ, Wang Y, Gleave ME, Collins 
CC, Chi KN. Androgen receptor gene aberrations in circulating cell-free DNA: biomarkers of 
therapeutic resistance in castration-resistant prostate cancer. Clin Cancer Res. 
2015;21(10):2315-24. 
Brahm J, Brahm M, Segovia R, Latorre R, Zapata R, Poniachik J, et al. Acute and fulminant hepatitis 
induced by flutamide: case series report and review of the literature. Ann Hepatol. 
2011;10(1):93-8. 
Enzalutamide (MDV3100) for the treatment of cancer. Investigator’s Brochure. Current edition. 
Gomez JL, Dupont A, Cusan L, Tremblay M, Suburu R, Lemay M, et al. Incidence of liver toxicity 
associated with the use of flutamide in prostate cancer patients. Am J Med. 1992;92(5):465-70. 
Isbarn H, Boccon-Gibod L, Carroll PR, Montorsi F, Schulman C, Smith MR, et al. Androgen 
deprivation therapy for the treatment of prostate cancer: consider both benefits and risks. Eur 
Urol. 2009;55(1):62-75. Epub 2008 Oct 14. 
Iversen P, Tyrrell CJ, Kaisary AV, Anderson JB, Baert L, Tammela T, et al. Casodex (bicalutamide) 
150-mg monotherapy compared with castration in patients with previously untreated 
nonmetastatic prostate cancer: results from two multicenter randomized trials at a median 
follow-up of 4 years. Urology. 1998;51(3):389-96. 
James ND, Spears MR, Clarke NW, Dearnaley DP, De Bono JS, Gale J, et al. Survival with newly 
diagnosed metastatic prostate cancer in the "docetaxel era": data from 917 patients in the 
control arm of the STAMPEDE trial (MRC PR08, CRUK/06/019). Eur Urol. 
2015;67(6):1028-38. 
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J 
Clin. 2011;61(2):69-90. Epub 2011 Feb 4. 
Kaisary AV, Tyrrell CJ, Beacock C, Lunglmayr G, Debruyne F. A randomised comparison of 
monotherapy with Casodex 50 mg daily and castration in the treatment of metastatic prostate 
carcinoma. Casodex Study Group. Eur Urol. 1995;28(3):215-22. 
Keating NL, O’Malley A, Freedland SJ, Smith MR. Diabetes and cardiovascular disease during 
androgen deprivation therapy: observational study of veterans with prostate cancer. J Natl 
Cancer Inst. 2012;104(19):1518-23. 
Makarov DV, Partin AW. Weighing the risks: prostate cancer versus cardiovascular disease. Rev 
Urol. 2008;10(2):171-3. 
Maximum androgen blockade in advanced prostate cancer: an overview of the randomized trials. 
Prostate Cancer Trialists’ Collaborative Group. Lancet. 2000;355(9214):1491-8. 
Romanel A, Gasi Tandefelt D, Conteduca V, Jayaram A, Casiraghi N, Wetterskog D, Salvi S, 
Amadori D, Zafeiriou Z, Rescigno P, Bianchini D, Gurioli G, Casadio V, Carreira S, Goodall J, 
Wingate A, Ferraldeschi R, Tunariu N, Flohr P, De Giorgi U, de Bono JS, Demichelis F, Attard 
G. Plasma AR and abiraterone-resistant prostate cancer. Sci Transl Med. 2015;7(312):312re10. 


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Scher HI. Observed advantages of the STAMPEDE study design. Eur Urol. 2015;67(6):1039-41. 
Scher HI, Heller G. Clinical states in prostate cancer: toward a dynamic model of disease progression. 
Urology. 2000;55(3):323-7. 
Singer EA, Golijanin DJ, Messing EM. Androgen deprivation therapy for advanced prostate cancer: 
why does it fail and can its effects be prolonged? Can J Urol. 2008;15(6):4381-7. 
Sweeney CJ, Chen YH, Carducci M, Liu G, Jarrard DF, Eisenberger M, et al. Chemohormonal 
therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med. 2015;373(8):737-46. 
Taylor LG, Canfield SE, Du XL. Review of major adverse effects of androgen-deprivation therapy in 
men with prostate cancer. Cancer. 2009;115(11):2388-99. 
Tombal B, Berges R. Optimal control of testosterone: a clinical case-based approach of modern 
androgen-deprivation therapy. Eur Urol Suppl. 2008;7(1):15-21. 
Tombal B, Hussain M, Penson D, Attard G, Sternberg CN, Phung D, et al. Prolonged urinary and 
bowel symptom control in men with nonmetastatic castration-resistant prostate cancer 
(nmCRPC) treated with enzalutamide: Results from the PROSPER study. Ann Oncol. 
2018;29(8):viii278 
Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, et al. Development of a second-generation 
antiandrogen for treatment of advanced prostate cancer. Science. 2009;324(5928):787-90. Epub 
2009 Apr 9. 
Tucci M, Bertaglia V, Vignani F, Buttigliero C, Fiori C, Porpiglia F, et al. Addition of docetaxel to 
androgen deprivation therapy for patients with hormone-sensitive metastatic prostate cancer: a 
systematic review and meta-analysis. Eur Urol. 2015 Sep 25; pii: S0302-2838(15)00907-0. doi: 
10.1016/j.eururo.2015.09.013. [Epub ahead of print].  


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12 
APPENDICES 
12.1 
List of Excluded Concomitant Medications 
The following medications are prohibited within 4 weeks of day 1 and during the study 
treatment period:  
● 
5 α-reductase inhibitors (finasteride, dutasteride); 
● 
Estrogens; 
● 
Cyproterone acetate; 
● 
Biologic or other agents with potential antitumor activity against prostate cancer (with 
the exception of those therapies identified in exclusion criterion No. 1); 
● 
Systemic glucocorticoids greater than the equivalent of 10 mg/day of prednisone 
intended for the treatment of prostate cancer; 
● 
Herbal medications with known hormonal antiprostate cancer activity and/or known to 
decrease PSA levels (i.e., saw palmetto); 
● 
Androgens (testosterone, dehydroepiandrosterone, etc.); 
● 
Investigational agents. 
In addition, bisphosphonates and denosumab are prohibited unless stabilized for 2 weeks 
prior to randomization and held constant, as tolerated, throughout study treatment or 
administered for diagnosis of osteoporosis. 


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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 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, alkaline phosphatase, 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 or 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 or severe where ULN: 
  
ALT or AST 
 
TBL 
Moderate 
> 3 x ULN (in subjects without liver metastases), 
> 5 x ULN (in subjects with liver metastases) 
or 
> 2 x ULN 
 
 
 
 
Severe* 
> 3 x ULN 
and 
> 2 x 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 or 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) that has been developed globally and can be activated for any 
study, or appropriate document. Subjects with confirmed abnormal LFTs should be followed 
as described below.  
Confirmed moderately abnormal LFTs should be repeated 2-3 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 eCRF. Illnesses 
and conditions such as hypotensive events, and decompensated cardiac disease that may 
lead to secondary liver abnormalities should be noted. Nonalcoholic steatohepatitis 
(NASH) is seen in obese hyperlipoproteinemic, and/or diabetic subjects and may be 
associated with fluctuating aminotransferase levels. The investigator should ensure that 
the medical history form captures any illness that predates study enrollment that may be 
relevant in assessing hepatic function.     
● 
Obtain a history of concomitant drug use (including nonprescription 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 LFTs, such as viral hepatitis, preexisting 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 and (TBL > 2 × ULN in subjects 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 10–50% mortality 
(or transplant).  The 2 “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 
than 3 times the ULN (“2 x ULN elevations are too common in treated and untreated subjects 
to be discriminating”).  2. Cases of increased bilirubin (at least 2 x ULN) with concurrent 
transaminase elevations at least 3 x ULN and no evidence of intra- or extra-hepatic bilirubin 
obstruction (elevated alkaline phosphatase) or Gilbert’s syndrome [Temple, 2006]. 
Reference 
Guidance for Industry titled “Drug-Induced Liver Injury: Premarketing Clinical Evaluation” issued by 
FDA on July 2009. 
Temple R. Hy's law: predicting serious hepatotoxicity.  Pharmacoepidemiol Drug Saf. 2006 
Apr;15(4):241-3. 


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12.3 
Common Serious Adverse Events 
The following is a list of SAEs that the sponsor considers to be associated with the disease 
state being studied.  The list does NOT change the investigator’s reporting obligations or 
prevent the need to report an AE meeting the definition of an SAE as detailed in 
[Section 5.5.2 Definition of Serious Adverse Events].  The purpose of this list is to note that 
some events reported as SAEs may not require expedited reporting to the regulatory 
authorities based on the classification of “common SAEs.”  The investigator is required to 
follow the requirements detailed in [Section 5.5.5 Reporting of Serious Adverse Events].  
For IND safety reporting, single occurrences of the following events may be excluded from 
expedited reporting to the FDA. If aggregate analysis of these events indicates they occur 
more frequently with study drug, an expedited IND safety report may be submitted to the 
FDA.  
● 
Anemia 
● 
Anorexia 
● 
Asthenia/Fatigue 
● 
Bone pain 
● 
Back pain 
● 
Catheter-related infection 
● 
Dyspnea 
● 
Hematuria 
● 
Hydronephrosis 
● 
Metastases to bone 
● 
Metastases to central nervous system 
● 
Nausea 
● 
Obstructive uropathy 
● 
Pain 
● 
Prostate cancer metastatic 
● 
Renal failure 
● 
Renal failure acute 
● 
Spinal compression fracture 
● 
Spinal cord compression 
● 
Urinary retention 
● 
Urinary tract infection 
● 
Urinary tract obstruction 
● 
Vomiting 


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12.4 
Retrospective Pharmacogenomic Substudy 
INTRODUCTION 
PGx research aims to provide information regarding how naturally occurring changes in a 
subject’s gene and/or expression based on genetic variation may impact what treatment 
options are best suited for the subject. Through investigation of PGx by technologies such as 
genotyping, gene sequencing, statistical genetics and Genome-Wide Association Studies, the 
relationship between gene profiles and a drug’s kinetics, efficacy or toxicity may be better 
understood.  As many diseases may be influenced by 1 or more genetic variations, PGx 
research may identify which genes are involved in determining the way a subject may or may 
not respond to a drug. 
OBJECTIVES 
The PGx research that may be conducted in the future with acquired blood samples is 
exploratory. The objective of this research will be to analyze or determine genes of relevance 
to clinical response, pharmacokinetics and toxicity/safety issues. 
By analyzing genetic variations, it may be possible to predict an individual subject’s response 
to treatment in terms of efficacy and/or toxicity.  
SUBJECT PARTICIPATION 
Subjects who have consented to participate in this study may participate in this PGx substudy.  
As part of this substudy, subjects must provide separate written consent prior to providing 
any blood samples that may be used at a later time for genetic analysis. 
SAMPLE COLLECTION AND STORAGE 
Subjects who consent to participate in this substudy will provide one 5 mL tube of whole 
blood per Astellas’ instructions. Each sample will be identified by the unique subject number.  
Samples will be shipped frozen to a designated banking contract research organization either 
directly from site or via a central laboratory as directed by Astellas.  
PGx ANALYSIS 
Details on the potential PGx analysis cannot be established yet. Astellas may initiate the PGx 
analysis in case evidence suggests that genetic variants may be influencing the drug’s kinetics, 
efficacy and/or safety.  
DISPOSAL OF PGx SAMPLES/DATA 
All PGx samples collected will be stored for a period of up to 15 years following study 
database hardlock. If there is no requirement for analysis, the whole blood sample will be 
destroyed after the planned storage period. The subject has the right to withdraw consent at 
any time. When a subject’s withdraw notification is received, the PGx sample will be 
destroyed. The results of any PGx analysis conducted on a sample prior to its withdrawal will 
be retained at Astellas indefinitely.  


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INFORMATION DISCLOSURE TO THE SUBJECTS 
Exploratory PGx analysis may be conducted following the conclusion of the clinical study, if 
applicable. The results of the genetic analysis will not be provided to any investigators or 
subjects, nor can the results be requested at a later date. Any information that is obtained 
from the PGx analysis will be the property of Astellas.  


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12.5 
ECOG Performance Status Scale 
 
*Reference 
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response 
criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-55. 
 
 


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12.6 
Open-Label Extension 
NOTE:  The extension study described below and outlined in Figure 3 Open-Label Extension 
schematic will be conducted if the ARCHES study results in a positive outcome. With the 
exception of those procedures and processes indicated below, this extension study will be 
performed using the same general approach as described in the protocol.  Refer to the main 
protocol for any study details not contained in this supplemental open-label extension section.  
12.6.1 Rationale 
Following unblinding at the end of the double-blind period and demonstration of a 
statistically significant advantage of enzalutamide over placebo when added to ADT, as 
assessed by the primary endpoint, all eligible subjects may be treated on study with 
open-label enzalutamide at the discretion of the subject and investigator. 
Day 1 of the open-label extension will occur after consent is signed and eligibility is 
confirmed.  Treatment with open-label enzalutamide will be stopped upon disease 
progression when, in the opinion of the investigator, there is no added clinical benefit to 
continue treatment with enzalutamide, and/or when discontinuation criteria are met 
[Section 12.6.6 Duration of Treatment and Criteria for Discontinuation]. 
Subjects who do not participate in the open-label extension or who withdraw consent for 
further treatment will discontinue study treatment and return for a 30-day safety follow-up 
visit as per protocol.  Long-term follow-up assessments will be completed as per protocol. 
12.6.2 Schedule and Assessments 
For procedures see Table 4 (Open-Label Extension Schedule of Assessments). 
Subjects treated with enzalutamide during the double-blind period will sign informed consent 
on Open-Label Day 1 and are required to return for study visits every 12 weeks (see Figure 3 
Open-Label Extension schematic).  Subjects treated with placebo during the double-blind 
period will sign informed consent at the Open-Label Day 1 visit after which they will be 
switched to enzalutamide (dosing below); these subjects will be required to return for study 
visits at Open-Label Week 5 (Day 29), Week 13 and every subsequent 12 weeks.  All 
Open-Label Day 1 visits should occur within approximately 16 weeks after the approval and 
activation of this protocol amendment at the study site. 
Subjects will take enzalutamide as four 40-mg soft gelatin capsules (160 mg/day) by mouth 
once daily with or without food.  Subjects treated with enzalutamide during the double-blind 
period and dosed at a lower daily dose may continue at the lower dose as appropriate. 
Study assessments will include safety evaluations including AEs, concomitant medications, 
clinical laboratory tests, brief physical examinations, ECGs and vital signs.  Radiographic 
assessments (CT/MRI and bone scan) will be performed as per the Open-Label Extension 
Schedule of Assessments [Table 4] until the subject progresses radiographically based on 
local assessment and/or meets other treatment discontinuation criteria [Section 12.6.6 
Duration of Treatment and Criteria for Discontinuation]. 


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Subjects are to have a safety follow-up 30 days after the last dose of open-label enzalutamide.  
If a new antineoplastic or investigational anticancer treatment is started before 30 days after 
the last dose of open-label enzalutamide, then safety follow-up should occur immediately 
before starting the new treatment. 
Long-term follow-up data will be collected every 12 weeks until the completion of OS 
analysis.  The information collected will include survival status, new antineoplastic therapies 
for prostate cancer, skeletal-related events and associated interventions. 
 


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Figure 3 
Schematic – Open-Label Extension 
 
Randomized 
Double-Blind            
Treatment 
 
                                   Informed Consent    Informed Consent 
Open-Label 
Treatment                
 
End of Open-Label    
Treatment 
 
 
 * Week 5 visit required only for subjects previously receiving placebo. 
 
 
Day 1/Week 1 Enzalutamide 
Placebo 
Enzalutamide 
Week 5* 
Week 13 and 
every 12 weeks 
until 
discontinuation 
criteria are met 
Safety Follow-up 
30 days after last dose 
or before new 
anticancer treatment 
Long-Term Follow-up every 
12 weeks until the final 
number of OS events are 
achieved


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Table 4 
Open-Label Extension Schedule of Assessments 
Study Period or Visit 
OL Treatment1 
Unscheduled 
Visit 
OL Safety 
Follow-up 
OL Long Term 
Follow-up2 
Study Week 
OL 13 
(Day 1) 
OL 54 
(Day 29) 
OL 13 and Every 
Subsequent 12 Weeks 
(Day 85 and Every 
Subsequent 84 Days) 
Varies5 
30 Days after Last 
Dose6 
Every 12 Weeks 
Window (Days) 
NA 
± 3 
± 5 
NA 
± 7 
± 7 
Informed Consent7 
X 
 
 
 
 
 
Inclusion/Exclusion for OLE 
X 
 
 
 
 
 
Open-Label Enrollment (via IRT) 
X 
 
 
 
 
 
Brief Physical Examination 
X 
 
X 
X 
X 
 
Vital Signs including Weight 
X 
X 
X 
X 
X 
 
ECOG Performance Status 
X 
X 
X 
X 
X 
 
12-lead Electrocardiogram 
X 
 
 
 
X 
 
Clinical Labs 
X 
X 
X 
X 
X 
 
Sample for Mutation Analysis8 
X 
 
X8 
 
 
 
Radiographic Assessments9 
X9 
 
X 
 
 
 
QoL Assessment (QLQ-PR25, EQ-5D-5L, FACT-P, Brief 
Pain Inventory-Short Form) 
X 
 
X 
 
X 
X10 
Adverse Events11 
X 
X 
X 
X 
X 
 
Concomitant Medication Review 
X 
X 
X 
X 
X 
 
Study Drug Dispensing (via IRT) 
X 
X 
X 
 
 
 
Study Drug Accountability 
X 
X 
X 
 
X 
 
Long-Term Follow-up Assessments2 
 
 
 
 
 
X 
ECOG: Eastern Cooperative Oncology Group; EQ-5D-5L: EuroQol Group-5 Dimension-5 Level Instrument; FACT-P: Functional Assessment of Cancer Therapy-Prostate; IRT: 
Interactive Response Technology; NA: not applicable; OL: Open-Label; OLE: Open-Label Extension; QLQ-PR25: Quality of Life Prostate-specific Questionnaire; QoL: Quality of 
Life. 
Footnotes continued on next page 


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1  Subjects continuing into the Open-Label (OL) extension period may be asked to complete their extension period participation in another Astellas-sponsored study upon activation 
of the roll-over extension study. An OL 30-day follow-up visit is not required for subjects who choose to participate in the other Astellas-sponsored study. 
2  Long-term follow-up assessments include survival status, symptomatic skeletal events and new antineoplastic therapies for prostate cancer.  May be obtained by telephone contact, 
chart review or clinic visit. This assessment will be collected until death, withdrawal of consent, final OS analysis or study termination. 
3  For subjects previously receiving placebo, OL Day 1/Week 1 should occur within approximately 16 weeks after the approval and activation of this protocol at the study site and no 
later than 6 weeks after screening.  For subjects continuing treatment with enzalutamide, OL Day 1/Week 1 will be their next regular scheduled visit following approval and 
activation of this protocol at the study site. 
4  Only for subjects starting new treatment with enzalutamide (previously received placebo). 
5  As necessary to assess or follow up adverse events. 
6  Prior to initiation of new antineoplastic therapy for prostate cancer, or 30 days after last dose of enzalutamide, whichever occurs first.  
7  Informed consent must be obtained before performing any study-specific procedures on Day 1/Week 1 for all subjects participating in OL Period  
8  Blood samples for mutation analysis will be collected at sites in North America only in subjects who have previously signed a genotyping informed consent.  For subjects starting 
new treatment with enzalutamide, samples will be collected on OL Day 1/Week 1 at OL Week 49 and at time of discontinuation of enzalutamide.  Subjects previously treated with 
enzalutamide will have a final sample collected at the time of discontinuation of enzalutamide. 
9  For subjects who have not progressed radiographically, scans (CT/MRI and bone scan) will be performed every 12 weeks for the first year on enzalutamide and then every 
24 weeks until the subject has progressed radiographically, as assessed by local read. 
10 QoL assessments will no longer be collected once the overall survival assessment is complete. 
11  Adverse events will be collected from the time the subject signs the consent form until screen failure or through safety follow-up visit (prior to initiation of new antineoplastic 
therapy for prostate cancer, or 30 days after last dose of enzalutamide, whichever occurs first). 
 
 


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12.6.3 Inclusion Criteria 
The inclusion criteria apply to subjects receiving enzalutamide or placebo during 
double-blind treatment.  Eligible subjects must meet all inclusion criteria below. 
1. Subject received randomized double-blind treatment in ARCHES. 
2. Subject has not met any of the discontinuation criteria in the main ARCHES protocol 
[Section 6 Discontinuation]. 
3. Subject is willing to maintain ADT with LHRH agonist or antagonist or has had a 
bilateral orchiectomy. 
4. Subject is able to swallow enzalutamide capsules whole and to comply with study 
requirements throughout the study. 
5. Subject and subject’s female partner agree to follow contraception and sperm donation 
requirements in main protocol. 
12.6.4 Exclusion Criteria 
The exclusion criteria apply only to subjects starting new treatment with enzalutamide after 
receiving placebo during double-blind period.  Subjects will be excluded from participation if 
any of the following apply: 
1. Subject has taken commercially available enzalutamide (Xtandi). 
2. Subject’s disease has progressed radiographically during the double-blind period of the 
study and treatment with study drug was stopped prior to study-wide unblinding. (Note: 
Subjects who progressed radiographically while in the double-blind portion of the study 
and continued treatment per protocol are allowed to participate in the open label 
extension.) 
3. After study-wide unblinding, subject has started any new investigational agent or 
anti-neoplastic therapy intended to treat prostate cancer. 
4. Subject has any clinically significant disorder or condition including excessive alcohol or 
drug abuse, or secondary malignancy, which may interfere with study participation in the 
opinion of the investigator or medical monitor. 
5. Subject has current or previously treated brain metastasis or active leptomeningeal 
disease. 
6. Subject has a history of seizure or any condition that may increase the risk of seizure. 
12.6.5 Enzalutamide Administration, Storage and Accountability 
All subjects will self-administer four 40-mg soft gelatin enzalutamide capsules (160 mg/day) 
by mouth once daily with or without food, unless they were receiving a reduced dose during 
double-blind treatment.  Subjects previously receiving a reduced dose may continue at the 
reduced dose.  Subjects should return all enzalutamide bottles, including unused 
enzalutamide to the site at each visit.  


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Enzalutamide should be handled and stored safely and properly in accordance with the bottle 
label.  Study site personnel must make all reasonable efforts to obtain all bottles and unused 
enzalutamide from subjects who do not routinely return the bottles at study site visits. 
12.6.6 Duration of Treatment and Criteria for Discontinuation 
Open-label enzalutamide administration may continue as long as the investigator considers 
treatment to be beneficial or until any of the following discontinuation criteria are met: 
● Any AE that is intolerable to the subject and which cannot be ameliorated by adequate 
medical intervention and/or dose reduction or that in the opinion of the investigator or 
medical monitor would lead to undue risk if enzalutamide continues. 
● Seizure or any condition that significantly predisposes the subject to seizure such as brain 
metastasis or clinically evident stroke. 
● Confirmed event of PRES by brain imaging, preferably MRI. 
● Initiation of investigational agent or new therapy for prostate cancer. 
● Gross noncompliance with protocol procedures and/or enzalutamide study drug 
management. 
● Withdrawal of consent by subject for any reason. Subject may withdraw consent for 
further treatment with enzalutamide study drug, but may still participate in the long-term 
follow-up assessments.  Specific details of procedures declined or allowed should be 
documented by study staff. 
● Subject is lost to follow-up despite reasonable efforts by the investigator to contact 
subject to complete study related assessments, record outstanding data and retrieve 
enzalutamide study drug. Following unsuccessful telephone contact, an effort should be 
made to contact the subject by mail using a method that provides proof of receipt.  
Alternate contacts are permissible if subject is not reachable and allowed by local 
guidelines. 
• Study termination by sponsor.  
● Completion of final OS analysis. 
● Death. 
12.6.7 Statistical Methods 
Subject disposition data (patients who continued to the open-label extension and primary 
reasons for treatment discontinuation and study discontinuation) will be summarized 
descriptively by study periods, in the ITT population for the blind study period and on 
patients who started open-label enzalutamide for the open-label extension. 
Data collected in the open-label extension will only be summarized by descriptive statistics 
unless otherwise specified.  Descriptive statistics will include number of subjects, mean, 
standard deviation, minimum, median and maximum for continuous endpoints, and 
frequency and percentage for categorical endpoints.  
An open-label extension data summary will be presented for subjects who switched treatment 
from placebo+ADT to enzalutamide+ADT (i.e., subjects who received placebo+ADT during 
the blinded period).  A combined double-blind and open-label data summary on 


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enzalutamide+ADT will be presented for all subjects who received enzalutamide+ADT either 
during the blind period or the open-label extension (i.e., overall).  
Enzalutamide exposure will be summarized and listed in the open-label extension and in the 
combined double-blind and open-label, as appropriate.  
Adverse events will be coded using 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 and preferred term.  The number and percentage of AEs by severity (reported 
according to NCI-CTCAE version 4.03) will also be summarized.  All AEs will be listed. 
For quantitative laboratory measurements and vital signs, descriptive statistics will be used to 
summarize results and change from baseline by visit.  Baseline will be defined as the latest 
value recorded prior to the first enzalutamide administration.  Using the NCI-CTCAE version 
4.03, laboratory values will be classified as Grade 1 through 4, where possible.  Laboratory 
and vital sign data will be displayed in listings. 
A final OS analysis will be conducted after approximately 342 deaths are observed.  
12.6.8 Phase 4 Post-marketing Study after Marketing Authorization in Japan (Sites in 
Japan Only) 
In case that Enzalutamide is approved for marketing with the indication of mHSPC, the study 
will continue as “Phase 4 post-marketing study” in accordance with Good Post-marketing 
Study Practice (GPSP) after marketing authorization based on Notification No. 1061, dated 
01 Dec 1998 by the Evaluation and Licensing Division, Pharmaceutical and Medical Safety 
Bureau, Ministry of Health. In this case, “Study” in the protocol is read as “Post-marketing 
study”. The formulation of 40-mg soft gelatin enzalutamide capsule will be switched to the 
40 mg round film-coated oral tablet. The enzalutamide film-coated tablets contain 
hypromellose acetate succinate along with standard tabletting excipients; microcrystalline 
cellulose, light anhydrous silicic acid, croscarmellose sodium, magnesium stearate. The 
tablets are film-coated using Opadry® yellow, which contains hypromellose, talc, 
polyethylene glycol 8000, titanium dioxide and yellow ferric oxide. 
The clinical material is a solid drug product and is packaged in HDPE bottles with 
child-resistant closures. The tablets should be stored in original bottle at 20°C to 25°C  
(68°F to 77°F); excursions from 15°C to 30°C (59°F to 86°F) are permitted.  


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12.7 
Clinical Study Continuity  
INTRODUCTION 
The purpose of this appendix is to provide acceptable alternate methods to assess safety and 
efficacy parameters, as appropriate, in the event the clinical study is interrupted at the 
country, state, site or participant level during any crisis (e.g., natural disaster, pandemic).  
BENEFIT-RISK RATIONALE 
Maintaining the safety of clinical study participants and delivering continuity of care in the 
clinical study setting is paramount during any crisis. The site is expected to follow the 
protocol and associated Schedule of Assessments/Table 1 unless the site principal 
investigator discusses the need with the Astellas Medical Monitor to implement the alternate 
measures.  
The approach outlined within this appendix defines which assessments are required to 
maintain a favorable benefit/risk to the participant, to maintain overall study integrity and to 
provide acceptable alternate methods to complete the study required assessments and 
procedures if study activities are unable to be performed as described in Section 5 due to a 
crisis. 
INFORMED CONSENT 
Participants who need to follow any or all of the alternate measures outlined in this Appendix 
will be required to provide informed consent which explicitly informs them of the nature of, 
and rationale for these changes, and gain their agreement to continue participation in the 
study prior to the implementation of any of these changes. In the event the urgency of 
implementing the alternate measures does not allow for the participant to provide written 
consent prior to implementation, the principal investigator or designee will obtain oral 
agreement from the subject followed by written documentation as soon as is feasible. A 
separate addendum to the study informed consent will be provided to document the 
participant’s consent of the changes. 
PARTICIPANT PROCEDURES ASSESSMENT 
Sites with participants who are currently enrolled into this clinical study may consider 
implementing the alternate methods outlined below if one or more of the following 
conditions are met due to the crisis:  
● 
Regional or local travel has been restricted, inclusive of mandatory shelter in place 
measures, which makes participant travel to/from the study site nearly impossible 
● 
Site facilities have been closed for clinical study conduct  
● 
Site has been restricted to treating patients with conditions outside of the scope of the 
study 
● 
Site personnel have temporarily relocated the conduct of the study to a location that 
place a burden on the participant with respect to time and travel 
● 
Participant(s) have temporarily relocated from the current study site to an alternate study 
site avoid placing a burden on the participant with respect to travel 


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● 
Participant(s) have temporarily relocated from their home location and the new distances 
from the site would cause undue burden with respect to time and travel 
● 
Participant has risk factors for which traveling to the site poses an additional risk to the 
participant’s health and safety 
Adherence to the original protocol as reflected in the Schedule of Assessment Table 1 is 
expected, where plausible, in the case of a crisis. The alternate measures as noted in Table 5 
below are only permissible in the event of a crisis, and after discussing the need with the 
Astellas Medical Monitor to implement the alternate measures.  This is to allow for 
continuity of receiving investigational medicinal product and maintaining critical safety and 
efficacy assessments for patients participating in the study at a time of crisis. 
If one or more of the alternate measures noted below is implemented for a participant, the site 
should document in the participant’s source document the justification for implementing the 
alternate measure and the actual alternate measures that were implemented, along with the 
corresponding time point(s). 
 


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Table 5 
Alternative Schedule of Assessments in Response to a Crisis  
Study Period or Visit 
Alternative Measures 
OL Treatment1 
Unscheduled Visit 
OL Safety 
Follow-up 
OL Long 
Term Follow-
up2 
Study Week 
 
OL 13 (Day 1) 
OL 54 (Day 29) 
OL 13 and Every  
Subsequent 12 
Weeks 
(Day 85 and 
Every  
Subsequent 84 
Days) 
Varies5 
30 Days after 
Last  
Dose6 
Every 12 
Weeks 
Window (Days) 
NA 
NA 
± 3 
± 5 
NA 
± 7 
± 7 
Informed Consent7 
 
X 
 
 
 
 
 
Inclusion/Exclusion for OLE 
 
X 
 
 
 
 
 
Open-Label Enrollment (via 
IRT) 
 
X 
 
 
 
 
 
Brief Physical Examination 
 
X 
 
X 
X 
X 
 
Vital Signs including Weight 
 
X 
X 
X 
X 
X 
 
ECOG Performance Status 
 
X 
X 
X 
X 
X 
 
12-lead Electrocardiogram 
 
X 
 
 
 
X 
 
Clinical Labs 
Visit collection of samples at 
local facility acceptable if 
results can be made available 
to investigative site 
X 
X 
X 
X 
X 
 
Sample for Mutation Analysis8 
 
X 
 
X8 
 
 
 
Radiographic Assessments9 
 
X9 
 
X 
 
 
 
QoL Assessment (QLQ-PR25, 
EQ-5D-5L, FACT-P, Brief  
Pain Inventory-Short Form) 
 
X 
 
X 
 
X 
X10 
Adverse Events11 
Remote/Virtual/Telemedicine 
Visits allowed for non-dosing 
visits. Please refer to protocol 
schedule of assessments. 
X 
X 
X 
X 
X 
 
Table continued on next page 


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Study Period or Visit 
Alternative Measures 
OL Treatment1 
Unscheduled Visit 
OL Safety 
Follow-up 
OL Long 
Term Follow-
up2 
Study Week 
 
OL 13 (Day 1) 
OL 54 (Day 29) 
OL 13 and Every  
Subsequent 12 
Weeks 
(Day 85 and 
Every  
Subsequent 84 
Days) 
Varies5 
30 Days after 
Last  
Dose6 
Every 12 
Weeks 
Concomitant Medication 
Review 
Remote/Virtual/Telemedicine 
Visits allowed for non-dosing 
visits. Please refer to protocol 
schedule of assessments. 
X 
X 
X 
X 
X 
 
Study Drug Dispensing (via 
IRT) 
Courier service directly to 
patient allowed 
X 
X 
X 
 
 
 
Study Drug Accountability 
 
X 
X 
X 
 
X 
 
Long-Term Follow-up 
Assessments2 
Remote/Virtual/Telemedicine 
Visits allowed. Please refer to 
protocol schedule of 
assessments. 
 
 
 
 
 
X 
AE: adverse event; CBC: complete blood count; ECG: electrocardiogram; ECOG: eastern cooperative oncology group; EOT: end of treatment; EQ-5D-5L: EuroQol Group-5 
Dimension-5 Level Instrument; FACT-P: Functional Assessment of Cancer Therapy-Prostate; iCPD: “immune” confirmed progressive disease; IP: investigational product; IRT: 
Interactive Response Technology; NA: not applicable; OL: Open-Label; OLE: Open-Label Extension; QLQ-PR25: Quality of Life Prostate-specific Questionnaire; QoL: Quality of 
Life.  
1. Subjects continuing into the Open-Label (OL) extension period may be asked to complete their extension period participation in another Astellas-sponsored study upon activation 
of the other Astellas-sponsored study. An OL 30 day follow-up visit is not required for subjects who chose to participate in the other study. 
2. Long-term follow-up assessments include survival status, symptomatic skeletal events and new antineoplastic therapies for prostate cancer.  May be obtained by telephone contact, 
char review or clinic visit. This assessment will be collected until death, withdrawal of consent, final overall survival analysis, or study termination. 
3. For subjects previously receiving placebo, OL Day 1/Week 1 should occur within approximately 16 weeks after the approval and activation of this protocol at the study site and no 
later than 6 weeks after screening.  For subjects continuing treatment with enzalutamide, OL Day 1/Week 1 will be their next regular scheduled visit following approval and 
activation of this protocol at the study site. 
4. Only for subjects starting new treatment with enzalutamide (previously received placebo). 
5. As necessary to assess or follow up adverse events. 
Footnotes continued on next page 


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6. Prior to initiation of new antineoplastic therapy for prostate cancer, or 30 days after last dose of enzalutamide, whichever occurs first. 
7. Informed consent must be obtained before performing any study-specific procedures on Day 1/Week 1 for all subjects participating in OL Period. 
8. Blood samples for mutation analysis will be collected at sites in North America only in subjects who have previously signed a genotyping informed consent.  For subjects starting 
new treatment with enzalutamide, samples will be collected on OL Day 1/Week 1 at OL Week 49 and at time of discontinuation of enzalutamide.  Subjects previously treated 
with enzalutamide will have a final sample collected at the time of discontinuation of enzalutamide. 
9. For subjects who have not progressed radiographically, scans (CT/MRI and bone scan) will be performed every 12 weeks for the first year on enzalutamide and then every 24 
weeks until the subject has progressed radiographically, as assessed by local read. 
10. QoL assessments will no longer be collected once the overall survival assessment is complete. 
11. Adverse events will be collected from the time the subject signs the consent form until screen failure or through safety follow-up visit (prior to initiation of new antineoplastic 
therapy for prostate cancer, or 30 days after last dose of enzalutamide, whichever occurs first). 
 
 


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INVESTIGATIONAL MEDICINAL PRODUCT SUPPLY 
If any of the conditions outlined above in the Participants Procedures Assessment are met, 
one or all of the following mitigating strategies will be employed, as needed, to ensure 
continuity of investigational medicinal product supply to the participants:   
● 
Increase stock of investigational medicinal product on site to reduce number of 
shipments required, if site space will allow.  
● 
Direct-to-Participant shipments of investigational medicinal product from the site to the 
participant’s home.  
DATA COLLECTION REQUIREMENTS 
Additional data may be collected in order to indicate how participation in the study may have 
been affected by a crisis and to accommodate data collection resulting from alternate 
measures implemented to manage the conduct of the study and participant safety.  
● 
Critical assessments for safety and efficacy based on study endpoints to be identified as 
missing or altered (performed virtually, at alternative locations, out of window, or other 
modifications) due to the crisis.  


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13 
PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Version 5.1 Nonsubstantial Amendment 6 [18 APR 2022] 
This amendment is considered to be nonsubstantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the European 
Union and EU Clinical Trial Regulation because it neither significantly impacts the safety or 
physical/mental integrity of participants nor the scientific value of the study. 
Overall Rationale for the Amendment: 
To extend the planned study period to the first quarter of 2024. 
Summary of Changes 
Table 6 
Nonsubstantial Changes 
Section Number 
Description of Change 
Brief Rationale 
Cover Page 
The date listed for Version 4.0 
Substantial Amendment 3 is 
revised to 10 Dec 2018. 
The date has been corrected. 
IV 
The planned study period is 
extended to the first quarter of 
2024. 
The study timeline has been 
extended to allow continued 
treatment until study subjects can 
enroll in Astellas Study 9785-CL-
0123 at the respective study sites 
should the study site choose to 
participate in Study 9785-CL-0123. 
12.6.2 
Table 4 is moved to Section 12.6.2 
Schedule of Assessments. 
The location of Table 4 has been 
corrected.  
 


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SPONSOR’S SIGNATURES 
 

SAP_003.pdf: 
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STATISTICAL ANALYSIS PLAN FOR OPEN LABEL 
EXTENSION 
 
Version 1.0, dated 18 July 2021 
 
ARCHES: A Multinational, Phase 3, Randomized, Double-blind, Placebo-controlled Efficacy and 
Safety Study of Enzalutamide Plus Androgen Deprivation Therapy (ADT) Versus Placebo Plus ADT 
in Patients with Metastatic Hormone Sensitive Prostate Cancer 
 
 
 
 
 
ISN: 9785-CL-0335 
 
EudraCT number: 2015-003869-28  
IND number: 74,563 
 
 
 
Astellas Pharma Global Development, Inc  
1 Astellas Way 
Northbrook, IL 60062 
 
Co-Sponsor: 
Medivation, Inc., a wholly owned subsidiary of Pfizer Inc 
525 Market Street, 36th Floor 
San Francisco, CA 94105 
 
 
 
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. 


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Table of Contents 
I. 
LIST OF ABBREVIATIONS AND KEY TERMS ··········································· 4 
1 
INTRODUCTION ·················································································· 6 
2 
FLOW CHART AND VISIT SCHEDULE ···················································· 7 
2.1 
Double blind Period ············································································ 7 
2.2 
Open Label Extension ········································································· 8 
3 
STUDY OBJECTIVE(S) AND DESIGN ······················································ 12 
3.1 
Study Objective(s) ············································································ 12 
3.2 
Study Design ··················································································· 12 
3.3 
Randomization ················································································· 13 
4 
SAMPLE SIZE····················································································· 13 
5 
ANALYSIS SETS ················································································· 13 
5.1 
Intent-to-Treat Population ···································································· 13 
5.2 
Safety Population·············································································· 13 
6 
ANALYSIS VARIABLES ······································································· 13 
6.1 
Overall Survival ··············································································· 13 
6.2 
Time to Initiation of a New Antineoplastic Therapy ······································ 14 
6.3 
Treatment Emergent Adverse Event (TEAE) ·············································· 14 
7 
STATISTICAL METHODOLOGY ··························································· 15 
7.1 
General Considerations ······································································· 15 
7.2 
Study Population ·············································································· 16 
7.2.1 
Disposition of Subjects ································································· 16 
7.2.2 
Protocol Deviations ····································································· 16 
7.2.3 
Demographic and Other Baseline Characteristics ··································· 17 
7.2.4 
Concomitant Medications and New Antineoplastic Therapy ······················ 17 
7.3 
Study Drugs ···················································································· 18 
7.3.1 
Exposure ·················································································· 18 
7.3.2 
Compliance ··············································································· 19 
7.4 
Analysis of Efficacy ·········································································· 19 
7.4.1 
Overall Survival ········································································· 19 
7.4.2 
Time to Initiation of a New Antineoplastic Therapy ································ 23 
7.5 
Analysis of Safety ············································································· 23 


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7.5.1
Adverse Events ·········································································· 23
7.5.2
Clinical Laboratory Evaluation ························································ 26
7.5.3
Vital Signs ················································································ 27
7.5.4
Electrocardiograms ······································································ 28
7.5.5
Pregnancy ················································································ 28
7.5.6
Other Safety-Related Observations ··················································· 28
7.6
Analysis of Exploratory Endpoint ··························································· 28
7.7
Analysis of Pharmaco-kinetic ······························································· 28
7.8
Analysis of Pharmaco-dynamic ····························································· 28
7.9
Subgroups of Interest ········································································· 28
7.10
Other Analyses ················································································ 29
7.11
Interim Analysis (and Early Discontinuation of the Clinical Study) ···················· 29
7.12
Handling of Missing Data, Outliers, Visit Windows, and Other Information ········· 29
7.12.1
Missing Data ············································································· 30
7.12.2
Outliers ··················································································· 31
7.12.3
Visit Windows ··········································································· 31
8
DOCUMENT REVISION HISTORY ························································· 32
9
REFERENCES ···················································································· 32
10
APPENDICES ····················································································· 34
10.1
Appendix 1 - Key Contributors and Approvers ··········································· 35
List of In-text Tables 
Table 1
Double-Blind Period Schedule of Assessments ············································ 9
Table 2 
Open-Label Extension Schedule of Assessments ········································· 11
Table 3
Selection Criteria for AEs of Special Interest ·············································· 25
Table 4
Analysis Visit Windows ······································································ 31
List of In-text Figures 
Figure 1
Testing Strategy for the Primary and Six Selected Secondary Endpoints ·············· 20


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I. 
LIST OF ABBREVIATIONS AND KEY TERMS 
List of Abbreviations 
Abbreviations 
Description of abbreviations 
ADT 
Androgen deprivation therapy 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BPI-SF 
Brief pain inventory - Short form 
COVID-19 
Coronavirus Disease 2019 
CRF 
Case report form 
CRPC 
Castration-resistant prostate cancer 
CT 
Computed tomography 
CTCAE 
Common terminology criteria for adverse events 
ECG 
Electrocardiogram 
ECOG 
Eastern cooperative oncology group 
eCRF 
Electronic case report form 
EQ-5D-5L 
EuroQol group-5 dimension-5 level instrument 
FACT-P 
Functional assessment of cancer therapy - prostate 
HR 
Hazard ratio 
ICF 
Informed consent form 
ICH  
International conference on harmonization 
ICR 
Independent central review 
IRT 
Interactive response technology 
ITT 
Intent-to-treat 
LHRH 
Luteinizing hormone-releasing hormone 
mHSPC 
Metastatic hormone sensitive prostate cancer 
M1  
metastatic disease 
MRI 
Magnetic resonance imaging 
NCI 
National cancer institute 
ORR 
Objective response rate 
OS 
Overall survival 
PSADecR 
Rate of PSA decline to <2ng/mL 
PSA 
Prostate-specific antigen 
QLQ-PR25 
Quality of life prostate-specific questionnaire 
QoL 
Quality of life 
RECIST 
Response evaluation criteria in solid tumors 
rPD 
Radiographic disease progression (i.e. radiographic progression; radiographic 
progression of disease) 
rPFS 
Radiographic progression-free survival 
SAP 
Statistical analysis plan 
SOC 
System organ class 
SMQ 
Standardised MedDRA Queries 
SSE 
Symptomatic skeletal event 
TTPP 
Time to PSA progression 
ULN 
Upper limit of normal  
WHO 
World Health Organization 
 


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List of Key Terms 
Terms 
Definition of terms 
Adverse Event  
An adverse event is any untoward medical occurrence in a patient 
administered a study drug or has undergone study procedure and which 
does not necessarily have a causal relationship with this treatment. 
Data analysis cut-off 
date 
A cut-off date will be set so that a minimum of 262 events for the primary 
variable, radiographic progression-free survival, occurred by that date. All 
data available for all visits occurring prior to or on the cut-off date will be 
reported. 
Baseline  
Observed values/findings that are considered as the value at the starting 
point. 
Enroll 
To register or enter into a clinical trial. 
Note: once a patient has been enrolled, the clinical trial protocol applies to 
the patient. 
Endpoint 
A variable that pertains to the trial objectives 
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 is usually given to a patient 
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. 
Randomization 
The process of assigning trial patients to treatment or control groups using 
an element of chance to determine assignments in order to reduce bias. 
Screen failure 
Potential patient who did not meet 1 or more criteria required for 
participation in a trial. 
Screening 
A process of active consideration of potential patients for enrollment in a 
trial. 
Screening period 
Period of time before entering the investigational period, usually from the 
time of starting a patient signing consent until just before the test drug or 
comparative drug is allocated to a patient (i.e. randomization). 
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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1 
INTRODUCTION 
A 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. 
This SAP contains details related to analyses specific to the Open Label Extension Period 
(OLE), in addition to the SAP (version 3.0) used for the primary analysis. 
The SAP is finalized and signed prior to database hard lock to ensure lack of bias. If needed, 
revisions to the approved SAP may be made prior to database hard lock. Revisions will be 
version controlled. 
This statistical analysis is coordinated by the responsible biostatistician of Astellas Pharma. 
Any changes from the analyses planned in the SAP will be justified in the Clinical Study 
Report. 
Prior to database hard lock, a final blinded review of data and TLFs meeting will be held to 
allow a review of the clinical trial data and to verify the data that will be used for any new 
analysis set classification. If required, consequences for the statistical analysis will be 
discussed and documented. A meeting to determine analysis set classifications may also be 
held prior to database hard lock. 
This SAP for the open-label extension is a supplement to the main study SAP which was 
completed prior to unblinding the study. The methods for the analysis of overall survival 
were established in the main study SAP. This SAP includes those methods and adds 
sensitivity and subgroup analyses for overall survival and an updated analysis for time to new 
antineoplastic. This SAP also describes the planned summaries for safety, disposition, and 
other data to incorporate the placebo patients who crossed over to open-label enzalutamide.   
 


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2 
FLOW CHART AND VISIT SCHEDULE 
2.1 
Double blind Period 
 
 
Screening 
Weeks -4 to -1 
Double-blind Treatment Period 
Safety Follow-up 
Long-term Follow-up 
Documented 
radiographic 
progression or 
initiation of new 
therapy for 
prostate cancer or 
other 
discontinuation 
criteria met 
30 days after last dose 
of study drug or prior 
to initiation of new 
therapy for prostate 
cancer, whichever 
occurs first 
Every 12 weeks 
 
For those patients who 
discontinue study 
treatment without 
radiographic disease 
progression confirmed 
by central review, 
radiographic 
assessments will 
continue every 12 weeks 
until confirmed 
radiographic 
progression by central 
review or the target 
number of radiographic 
progression-free 
survival events is 
reached. 
Obtain 
informed 
consent prior 
to performing 
any study- 
related 
procedures 
Enzalutamide 
With LHRH 
agonist/antagonist or 
bilateral orchiectomy 
Placebo 
With LHRH 
agonist/antagonist or 
bilateral orchiectomy 
Randomized 1:1 


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2.2 
Open Label Extension 
 
 
Randomized 
Double-Blind 
Treatment 
 
 
 
 
 
 
 
Informed Consent Obtained 
 
 
Open-Label 
Treatment 
 
 
 
End of Open-Label 
Treatment 
 
 
 
*Week 5 visit required only for subjects who received placebo + ADT during the double-blind period 
Placebo + ADT 
Enzalutamide+ ADT 
Day 1/ Week 1 Enzalutamide+ ADT 
Week 5* 
Week 13 and every 
12 weeks until 
discontinuation 
criteria are met 
Safety Follow-up 30 days 
after last study dose or 
before start of new 
anticancer treatment 
Long-Term 
Follow-up 
every 12 weeks 


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Table 1 
Double-Blind Period Schedule of Assessments 
Study Day 
Screening 
Visit 
1 
29 
85 and Every 
Subsequent 84 Days 
Safety 
Follow-up 
Unscheduled 
Visit† 
Long Term 
Follow-up‡ 
Study Week 
-4 to -1 
(28 Days) 
1 
5 
13 and Every 
Subsequent 12 Weeks 
30 Days after 
Last Dose§ 
Every 
12 Weeks 
Window (Days) 
 
 
± 5 
± 5 
± 7 
NA 
± 7 
Informed Consent 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
Randomization (IRT) 
 
X 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
 
Physical Examination including Weight¶ 
X 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
12-lead Electrocardiogram  
X 
X 
 
 
X 
 
 
Clinical Labs†† 
X 
X 
X 
X 
X 
X 
 
Prostate-specific antigen  
X 
X 
X 
X 
X 
 
 
Sample for Genotyping Analysis‡‡ 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
Testosterone 
 
 
 
X 
 
 
 
CT/MRI and Bone Scan§§, ¶¶ 
X§§ 
 
 
X¶¶ 
 
 
X 
Chest X-ray or Chest CT/MRI††† 
X 
 
 
X 
 
 
X 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
 
QoL Assessment (QLQ-PR25, EQ-5D-5L, FACT-P, 
BPI-SF) 
 
X 
 
X 
X 
 
X‡ 
Adverse Events§§§ 
X 
X 
X 
X 
X 
X 
 
Previous and Concomitant Medications 
X 
X 
X 
X 
X 
X 
 
Study Drug Dispensing 
 
X 
X 
X 
 
 
 
Study Drug Treatment 
 
X 
X 
X 
 
 
 
CT: computed tomography; ECOG: Eastern Cooperative Oncology Group; EQ-5D-5L: EuroQol Group-5 Dimension-5 Level Instrument; IRT: Interactive Response Technology; MRI: 
magnetic resonance imaging; NA: not applicable; FACT-P: Functional Assessment of Cancer Therapy-Prostate; QLQ-PR25: Quality of Life Prostate-specific Questionnaire; QoL: 
quality of life; BPI-SF: Brief Pain Inventory-Short Form 
† Unscheduled visits may be performed at any time during the study whenever necessary to assess for or follow-up on adverse events at the patient’s request or if deemed necessary 
by the Investigator.  Procedures and assessments are to be performed as clinically indicated. Testosterone testing through central laboratory at unscheduled visit requires prior 
approval by sponsor. 
Footnotes continued on next page 
CCI






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3 
STUDY OBJECTIVE(S) AND DESIGN 
3.1 
Study Objective(s) 
Refer to the study protocol for a full list of study objectives.  
Efficacy objective in the open label extension period is to determine the benefit of 
enzalutamide plus ADT as compared to placebo plus ADT as assessed by overall survival 
(OS). Additionally, time to new antineoplastic therapy will be summarized descriptively as 
supportive information in the evaluation of the overall survival endpoint. 
Safety objective is to determine the safety of enzalutamide plus ADT as compared to placebo 
plus ADT.  
3.2 
Study Design 
This is a multinational phase 3, randomized, double-blind, placebo-controlled efficacy and 
safety study of enzalutamide plus ADT versus placebo plus ADT in patients with mHSPC. 
After the double-blind period has completed, eligible patients were allowed to received open 
label enzalutamide in an open label extension period. 
Approximately 1100 subjects were randomized centrally 1:1, and the randomization was 
stratified by volume of disease (low versus high) and prior docetaxel therapy for prostate 
cancer (no prior docetaxel, 1-5 cycles, 6 cycles). High volume of disease is defined as 
metastases involving the viscera or, in the absence of visceral lesions, there must be 4 or 
more bone lesions, at least 1 of which must be in a bony structure beyond the vertebral 
column and pelvic bone. Prior docetaxel therapy is defined as 1 or more cycles of docetaxel 
but no more than 6 cycles.  
In this study, patients received 4 capsules of enzalutamide (40 mg each) or placebo per day 
orally in the double-blind period. After the double-blind period has completed, eligible 
patients received 4 capsules of enzalutamide (40 mg each) in the open label extension period. 
As long as the patient is tolerating the study drug, the treatment should be continued until 
radiographic disease progression (rPD) or starting an investigational agent or new therapy for 
treatment of prostate cancer. Patients who discontinue study drug without radiographic 
progression will continue to follow the radiographic assessment schedule until radiographic 
progression event or until the target number of deaths is reached for the final analysis of OS.  
The following assessments of prostate cancer status will be collected during OLE: soft tissue 
disease on CT scan or on MRI, bone disease on radionuclide bone scans, survival status, EQ-
5D-5L, QLQ-PR25, FACT-P for QoL and BPI-SF for pain symptom assessment. Throughout 
the study, safety and tolerability were assessed by the recording of adverse events (AE), vital 
signs, physical examinations, 12-lead electrocardiograms (ECG), and safety laboratory 
evaluations (including PSA). 
Patients will have a safety follow-up visit 30 days after their last dose of study drug or prior 
to initiation of new antineoplastic therapy for prostate cancer, whichever occurs first. All 


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patients are to be followed for survival until death, loss to follow-up, withdrawal of consent, 
or study termination by the sponsor. All patients will be followed until the final OS analysis. 
3.3 
Randomization 
Subjects were entered into the Interactive Response Technology system (IRT) at screening 
and assigned a subject number. 
After the double-blind period, which included random assignment to enzalutamide or placebo 
(stratified by prior docetaxel use and disease volume), eligible patients were allowed to 
received open label enzalutamide, as recorded in the IRT system. 
4 
SAMPLE SIZE 
For OS, 342 death events will be required to provide 80% power to detect a target HR of 
0.73 with a target difference in Kaplan-Meier estimated median of approximately 15 months 
(40 months for placebo versus 55 months for enzalutamide) at the 4% significance level 
under the assumption of an exponential distribution. This significance level was chosen to 
apply a parallel testing strategy between OS and other key secondary endpoints (with 
allocated type I error rate of 1%) as described in section 7.4.1. 
5 
ANALYSIS SETS 
5.1 
Intent-to-Treat Population 
The Intent-to-Treat (ITT) population is defined as all subjects who were randomized in this 
study. The ITT population will be analyzed by treatment arm as randomized, (i.e., treatment 
arm by randomization assignment) regardless of whether or not study drug was administered. 
The ITT population will be used to conduct efficacy analyses, unless otherwise specified. 
5.2 
Safety Population 
The safety (SAF) population is defined as all randomized subjects who received at least 
1 dose of study drug. The safety population will be used to conduct safety analyses by 
treatment arm as treated (i.e., based on the actual study drug the subject mostly received, 
rather than the study drug to which the subject was randomized to). 
Detailed criteria for analysis sets will be laid out in Classification Specifications (CS) and the 
allocation of subjects to analysis sets will be determined prior to database hard lock. This was 
done prior to unblinding. 
6 
ANALYSIS VARIABLES 
Analysis variables are defined in the SAP for the primary analysis. This section further 
details those for which data derivation require to be modified.  
6.1 
Overall Survival 
OS is defined as the time from randomization to death from any cause.  All deaths on or 
before the data cut-off will be included. 


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For patients who are alive at the time of the cut-off date, OS time will be censored on the last 
date the patient is known to be alive or the cut-off date, whichever occurs first.  The date the 
patient is last known alive by the cut-off date will be derived as follows: 
● 
for patients on treatment by the cut-off date (i.e., patients who did not discontinue 
from treatment), the date last known alive will be the cut-off date. 
● 
for patients who withdraw consent by the cut-off date, the date last known alive is the 
date of consent withdrawal. 
● 
for patients lost to follow up, the date last known alive depends on the period the 
patient was lost to follow-up. It will be as follows: 
Period lost to follow-up 
The date last known alive 
Since randomization (i.e. without 
further post-randomization visit) 
The date of randomization 
During treatment period 
The last assessment/visit date or the date of the last 
dose of study drug, whichever occurs later  
Safety follow-up period 
The date of the last dose of study drug or the last 
treatment visit date collected on the End of Treatment 
Case Report Form (CRF) page, whichever occurs last. 
Long-term follow-up period 
The last visit/contact date (collected either on the 
30 Day Follow-Up Status CRF page, or the Patient 
Status - Survival CRF page or the Long-Term Follow-
Up Status CRF page). 
● 
for other patients (i.e., not on treatment, not withdrawn and not lost to follow-up) who 
are alive by the cut-off date, the date last known alive is the date of last visit 
(collected either on the Patient Status - Survival CRF page or the Long-Term Follow-
Up Status CRF page) or the date of randomization, whichever occurs last. 
6.2 
Time to Initiation of a New Antineoplastic Therapy 
The initiation of a new antineoplastic therapy is based on the information collected in the 
(new) prostate cancer therapy CRF pages about all antineoplastic therapies, including 
cytotoxic and hormone therapies, initiated for prostate cancer subsequent to the study drug. 
In patients with a new antineoplastic therapy initiated for prostate cancer, time to initiation of 
a new antineoplastic therapy (i.e., time to new antineoplastic therapy) is defined as the time 
interval from randomization to the date of first dose administration of the first antineoplastic 
therapy. 
In patients with no new antineoplastic therapy initiated for prostate cancer, time to start of 
new antineoplastic therapy will be censored on the last visit date or the date of 
randomization, whichever occurs last. 
6.3 
Treatment Emergent Adverse Event (TEAE) 
A TEAE is defined as an AE that occurs or worsen at any time during the treatment emergent 
period. The treatment emergent period is time interval encompassing the double-blind 
treatment emergent period and the OLE treatment emergent period. 


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The double-blind treatment emergent period is defined as the time interval from the first 
double-blind study drug intake up to 30 days after the date of the last dose of double-blind 
study drug, study discontinuation, the start of new antineoplastic therapy, or the first dose of 
OLE treatment, whichever occurs first.   
If AE start date is the same date as the study start, then it will be considered as a TEAE if the 
box ‘Onset after first dose of study’ is ticked in the Electronic case report form(eCRF). If a 
patient experiences an event both during the pre-investigational period and during the 
investigational period, the event will be considered as TEAE only if it has worsened in 
severity (i.e. it is reported with a new start date).  
The OLE treatment emergent period is defined as the time interval from the OLE study drug 
intake up to 30 days after the date of the last dose of OLE study drug, study discontinuation, 
or the start of new antineoplastic therapy, whichever occurs first.   
AE with both a missing start and stop dates, and AEs with a missing start date but has a 
known stop date which is on or after the first dose of study drug will be considered treatment-
emergent. 
For each treatment group, the treatment emergent period is as follows; 
● 
Enzalutamide group: from the first DBT study drug intake up to 30 days after the date 
of the last dose of study drug, study discontinuation, or the start of new antineoplastic 
therapy, whichever occurs first.   
● 
Placebo group: from the first DBT study drug intake up to 30 days after the date of 
the last dose of placebo, start of open-label enzalutamide, study discontinuation, or 
the start of new antineoplastic therapy, whichever occurs first. 
● 
Placebo crossover group: from the first OLE study drug intake up to 30 days after the 
date of the last dose of OLE study drug, study discontinuation, or the start of new 
antineoplastic therapy, whichever occurs first.   
AEs will be coded to System Organ Class (SOC) and preferred term using MedDRA v23.0 
and severity graded using National Cancer Institute’s Common Terminology Criteria version 
4.03 (NCI-CTCAE v4.03) for AEs. 
7 
STATISTICAL METHODOLOGY 
7.1 
General Considerations 
For continuous variables, descriptive statistics will include the number of patients (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. Unless otherwise 
specified, percentages by categories will be based on the number of patients with no missing 
data, i.e. will add up to 100%.   
All listings will be produced by site and patient id numbers in ascending order.  


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Disposition, demographics, other baseline characteristics and efficacy data will be 
summarized based on the ITT population, unless stated otherwise. Safety analysis summary 
and other summaries based on SAF are presented by actual treatment received, unless stated 
otherwise. 
All statistical comparisons will be made using two sided tests. All null hypotheses will be of 
no treatment difference. 
All data processing, summarization, and analyses will be performed using SAS® Version 9.4 
or higher on Unix. Specifications for table, figures, and data listing formats can be found in 
the TLF specifications for this study. 
For the definition of subgroups of interest, please refer to section 7.9. 
A data analysis cut-off date for the database will be used. All data from visits or assessments 
done on or prior to the cut-off date will be reported.  
7.2 
Study Population 
7.2.1 
Disposition of Subjects 
The following subject data will be presented for Enzalutamide, Placebo and Placebo 
crossover group: 
• 
Number of patients randomized in DBP, received treatment in DBP, with ICF for 
OLE and received treatment in OLE (All Randomized Subjects). 
• 
Treatment disposition in DBP (All Randomized Subjects) and OLE (All subjects on 
Enzalutamide) 
• 
Number of patients who took study drug, patients who did not take study drug in DBP 
and OLE 
• 
Number and percentage of patients by study visits completed in DBP and OLE, based 
on the SAF 
• 
Number and percentage of patients who discontinued from the treatment in DBP and 
OLE by primary reason for discontinuation 
• 
Number and percentage of patients who discontinued from the 30 day safety follow-
up in DBP and OLE by primary reason for discontinuation 
• 
Number and percentage of patients who discontinued from the long term follow-up in 
DBP, OLE and overall by primary reason for discontinuation 
• 
Number of patients with protocol deviations in DBP and OLE 
• 
Number of OLE patients by site and country 
Treatment disposition, 30 day follow-up disposition, and long term follow-up disposition, 
randomization information will be listed. The protocol deviations, as well as the description 
of protocol deviation criteria will also be listed.  
7.2.2 
Protocol Deviations 
Protocol deviations as defined in the study protocol (Section 8.1.6 Protocol Deviations) will 
be assessed for all randomized patients.  


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The protocol deviation criteria will be uniquely identified in the summary table by study 
period (DBP and OLE) and in listing. The unique identifiers will be as follows: 
PD1 - Entered into the study even though they did not satisfy entry criteria,  
PD2 - Developed withdrawal criteria during the study and was not withdrawn, 
PD3 - Received wrong treatment or incorrect dose, 
PD4 - Received excluded concomitant treatment. 
Patients deviating from a criterion more than once will be counted once for the corresponding 
criterion. Any patients who have more than one protocol deviation will be counted once in 
the overall summary. 
The number and percentage of patients meeting any criteria will be summarized for each 
criterion and in total, for Enzalutamide, Placebo and Placebo crossover group, as well as by 
country, study site and by study period. Inclusion and exclusion criteria will be summarized 
for each criterion for Placebo crossover group.  
A data listing will be provided by site and patient, where each protocol deviation will be 
indicated according to the period in which it had occurred.    
7.2.3 
Demographic and Other Baseline Characteristics 
Demographic and baseline characteristics (at the time of randomization) will be summarized 
for Placebo crossover group on the ITT. 
Descriptive statistics for age and height at study entry will be presented along with frequency 
tabulations for age group (< 65, 65- <75 and >= 75; and EudraCT age groups), ethnicity, 
race, Geographic region, at study entry. The weight, body mass index (BMI), ECOG status, 
PSA, and ALP at baseline will also be presented by descriptive statistics. The 10%, 25%, 
75% and 90% percentiles will be provided for PSA, and ALP at baseline. 
Disease History, Results of Metastasis at screening, Prostate Cancer Treatment History 
(Radiation and Procedures) and Non-Prostate Cancer Related Medical History will be 
summarized for Placebo cross-over group on the ITT. 
Number and percentage of patients randomized in each country and site will also be 
summarized.  
7.2.4 
Concomitant Medications and New Antineoplastic Therapy 
Concomitant medications will be summarized Enzalutamide, Placebo and Placebo crossover 
group and by study period on the SAF. 
Those medications, including prostate cancer drug therapies, will be coded with World 
Health Organization Drug Reference List (WHO-DD), and will be summarized by presenting 
the number and percentage of patients by therapeutic subgroup (ATC 2nd level) and 
chemical subgroup (ATC 4th level) and preferred WHO name. It will be ordered 
alphabetically by ATC subgroup and decreasing order of frequency of preferred WHO name 


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within each ATC class. Patients taking the same medication multiple times will be counted 
once per medication and period. 
Concomitant medications are those medications or therapies with at least one dose taken 
between the date of first dose (inclusive) of enzalutamide and the date of last dose (inclusive) 
of enzalutamide and up to 30 day safety follow-up visit. All concomitant medications will be 
summarized. 
New antineoplastic prostate cancer therapy will be summarized for patients from the ITT 
population. 
New antineoplastic prostate cancer therapy are therapies with at least one dose taken after the 
last dose of study drug (enzalutamide or placebo), including cytotoxic and hormone 
therapies. They are recorded as ‘antineoplastic medication’ in the eCRF (either prostate 
cancer concomitant eCRF page, with ‘antineoplastic medication’ ticked; or on the new 
prostate cancer drug therapy eCRF page with ‘antineoplastic medication’ ticked).  
All concomitant prostate cancer related medications or therapies reported in the 
corresponding eCRF will be summarized separately. All (new) antineoplastic prostate cancer 
therapies (started on or after first dose of study drug date) will also be summarized 
separately, along with a summary table on the first new antineoplastic prostate cancer after 
study drug (after placebo or enza [in double blind or OLE]) ended. 
All concomitant non prostate cancer related medication which can be classified into several 
chemical and/or therapeutic subgroups is presented in all chemical and therapeutic 
subgroups. 
All concomitant medications recorded in the eCRF will be listed, as well as all new prostate 
cancer therapies. 
7.3 
Study Drugs 
7.3.1 
Exposure 
The following information on drug exposure will be presented for Enzalutamide, Placebo and 
Placebo crossover group on the SAF. 
• 
The duration of exposure (number of months) to study medication will be 
summarized using descriptive statistics, including 10%, 25%, 75% and 90% 
percentiles. 
• 
Number and percentage of patients on study drug at 6 months and at year 1, 2, 3, and 
4 (that is with duration of exposure superior or equal to day 182, 365, 730, 1095, and 
1461). 
• 
Number and percent of patient with dose reductions or interruptions, the reasons for 
these, as well as the number of these per patient  
• 
Descriptive statistics for the average daily dose of the drug patient was exposed to 
• 
Time to study drug discontinuation will be analyzed using the same analysis methods 
as OS, but formal statistical test will not be conducted. 


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7.3.2 
Compliance 
Compliance data will be presented for the SAF, on subjects whose total study drug count and 
first and last days of treatment are known. 
Overall compliance will be summarized in two ways for the SAF: 
• Descriptive statistics will be presented by treatment group. 
• Percent compliance will be categorized according to the following categories for each 
age group and overall by treatment group: 
o less than 70% 
o at least 70%, less than 90% 
o at least 90%, less than 110% 
o greater than 110% 
o Unknown. 
Treatment compliance details, including all data relevant to the calculation, will be listed for 
each subject by study visit and overall for all randomized subjects. 
7.4 
Analysis of Efficacy  
Efficacy analyses will be conducted on the ITT population unless otherwise specified. 
The categories ‘1-5 cycles’ and ‘6 cycles’ used at randomization for the stratification factor 
‘prior docetaxel use’ are regrouped in the stratified analyses because of the small number of 
randomized patients with 1 to 5 cycles of docetaxel as prior medication. This stratification 
factor therefore becomes prior docetaxel use (yes versus no) in the stratified analyses. 
The statistical analyses in this SAP follow the methods already outlined in the main study 
SAP and include additional sensitivity and subgroup analyses. 
7.4.1 
Overall Survival 
At the time of the primary analysis of rPFS, the interim analysis of OS was not significant 
(84 deaths from any cause, 39 in Enzalutamide + ADT group and 45 in Placebo + ADT 
group, p=0.3361 from stratified log-rank test). The final analysis of OS will be conducted 
when approximately 342 events (death from any cause) have occurred. 
At the time of the primary analysis of rPFS, the following six key secondary endpoints were 
tested:  OS, Time to PSA progression, time to initiation of a new antineoplastic therapy, the 
rate of PSA decline to <0.2ng/mL (PSADecR), objective response rate and the time to 
deterioration in urinary symptoms from the QLQ-PR25.  To maintain the family-wise 2-sided 
type I error rate at 0.05, a parallel testing strategy between OS (with allocated type I error 
rate 0.04) and the other five endpoints (with allocated type I error rate 0.01) was performed, 
as summarized in Figure 1. 


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Figure 1 
Testing Strategy for the Primary and Six Selected Secondary Endpoints 
 
rPFS: radiographic progression-free survival; OS: overall survival; TTPP: time to PSA progression; 
TTNAnti: time to initiation of a new antineoplastic therapy; PSADecR: rate of PSA decline to <0.2 ng/mL;  
ORR: objective response rate; TTUri: the time to deterioration in urinary symptoms from the QLQ-PR25  
*OS will be tested at 0.05 only, if all other 5 secondary endpoints analyses are statistically significant at 0.01. 
As the analysis for time to deterioration in urinary symptoms from the QLQ-PR25 was not 
significant, the final analysis of OS will be conducted at the level of significance of 0.04 
(2-sided). The effect of Enzalutamide+ADT compared to placebo+ADT will be tested using a 
log-rank test stratified by prior docetaxel use (yes versus no) and disease volume (low versus 
high). 
The null and alternative hypotheses to be tested are as follows: 
The null hypothesis: OS for Placebo+ADT and Enzalutamide+ADT are not different 
The alternative hypothesis: OS for Placebo+ADT and Enzalutamide+ADT are different 
The following SAS code will be used to compute the Kaplan-Meier estimates and curves, and 
the stratified log-rank test: 
PROC LIFETEST DATA=INPUT   
                              ATRISK  


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                              PLOTS=SURVIVAL(CB)  
                              OUTSURV=SURVPL   
                              ALPHA=0.04  
                              ALPHAQT=0.04 METHOD=KM; 
      TIME AVAL*CNSR(1); 
      STRATA STRATUM/ GROUP=TREATMENT; 
RUN; 
where INPUT is the input dataset 
          AVAL is the time to the event variable,  
          CNSR is 0 (patients with events) or 1 (patients without no event, i.e. patient censored) 
          STRATUM is the stratification variable (volume of disease and prior docetaxel use) 
          TREATMENT is the treatment variable  
Kaplan-Meier methods will be used to estimate the distribution of OS events by treatment 
group. The median OS will be estimated using the corresponding 50th percentile of Kaplan-
Meier estimates. A two-sided 95% confidence interval will be provided for this estimate by 
use of the Brookmeyer and Crowley method. The 25th percentile and the 75th percentile of OS 
will also be provided. A Kaplan-Meier plot by treatment group will be presented. The 
estimates of the event free rate on a 3-monthly basis up to 1 year and every 6 months 
thereafter will be summarized by treatment group, as long as at least 10 patients are at risk. 
The benefit of Enzalutamide+ADT compared to placebo+ADT will be summarized by a 
single HR with its 95% CI based on a Cox regression model stratified for the prior docetaxel 
use and disease volume. The null and alternative hypotheses regarding OS can be rephrased 
in terms of the HR, λArmA / λArmB, where λArmA represents the hazard of OS for 
Enzalutamide+ADT and λArmB represents the hazard of OS for placebo+ADT. A HR of  1 
indicates that the OS is prolonged for patients randomized to Enzalutamide+ADT compared 
with patients randomized to placebo+ADT.  The null and alternative hypotheses, 
respectively, can be written as follows:  
H0: 
1
ArmA
ArmB


=        H1: 
1
ArmA
ArmB



 
The estimated HR of Enzalutamide+ADT to placebo+ADT, λArmA / λArmB , and its 95% 
confidence interval will be provided.  
SAS PROC PHREG will be used for the analysis with the “DISCRETE” option for tie 
breaker as follows:  
PROC PHREG DATA=ADTTE; 
     WHERE PARAMCD=&ENDPOINT; 
     CLASS TRTP(REF='PLACEBO + ADT') STRATUM1 STRATUM2; 
     MODEL AVAL*CNSR(1)= TREATMENT / RL TIES=DISCRETE; 
     STRATA STRATUM1 STRATUM2; 
RUN; 
 where INPUT is the input dataset 
          AVAL is the time to the event variable,  


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          CNRS is 1 (patients with no events) or 0 ( patients with events) 
          STRATUM are the stratification variables (volume of disease and prior docetaxel use) 
          TREATMENT is the treatment variable  
If the estimate of the HR λArmA / λArmB < 1 and the results from the log-rank test lead to the 
rejection of H0 in favor of HA, then it will be concluded that Enzalutamide+ADT prolongs 
OS compared to placebo+ADT. 
The primary cause of death will be summarized and listed.  
The median follow-up time on study will be calculated as the 50th percentile of Kaplan-
Meier estimates from the OS time analysis when reverting the censoring (flag). 
Subgroup analyses 
Subgroup analyses of OS will similarly be performed to determine whether the treatment 
effect is concordant among subgroups. To avoid possible issue related to small number of 
events, subgroup analyses will not be adjusted for the stratification factors used at 
randomization. Subgroups are defined in Section 7.9. 
A forest plot displaying the HR for treatment comparison and 95% confidence interval will 
be presented by subgroup. The HR will be estimated by use of Cox proportional hazards 
models with treatment as covariate. 
SAS PROC PHREG will be used for these subgroup analyses:  
PROC PHREG DATA=ADTTE; 
     WHERE PARAMCD=&ENDPOINT; 
     CLASS TRTP(REF='PLACEBO + ADT') STRATUM1 STRATUM2; 
     MODEL AVAL*CNSR(1)= TREATMENT / RL TIES=DISCRETE; 
   BY SUBGROUP; 
RUN; 
Sensitivity analyses 
• To adjust the treatment crossover effect on OS, the following methods may be used. 
o Rank-Preserving Structural Failure Time Model (RPSFTM) [Robins and 
Tsiatis, 1991]). This method is to assess the impact of patients who switched 
placebo to enzalutamide by reconstructing the survival duration of placebo 
patients, as if they had never received enzalutamide. 
• To assess potential impact of COVID-19, the following analyses may be conducted. 
o Same as OS primary analysis, except that patients died due to COVID-19 
infection will be censored at the date of death. 
o Same as OS primary analysis, but exclude the subjects died due to COVID-19 
infection from the analysis. 
• 
To estimate the size of the treatment effect separately for 2 time periods, before and 
after the first 6 months from randomization, piecewise exponential model may be 
used to estimate the HR. 


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7.4.2 
Time to Initiation of a New Antineoplastic Therapy 
This will be analyzed using the same analysis methods as OS, but formal statistical test will 
not be conducted. 
7.5 
Analysis of Safety 
All analysis of safety will be presented for Enzalutamide, Placebo and Placebo crossover 
group on the SAF, unless specified otherwise. All AEs will be listed. 
7.5.1 
Adverse Events 
The coding dictionary for this study will be MedDRA v23.0. Treatment-emergent AEs will 
be coded to SOC and preferred terms using MedDRA and graded using NCI-CTCAE v4.03. 
Treatment-emergent AEs will be tabulated alphabetically by SOC and by preferred terms 
within SOC. 
An overview table will include the following details for Enzalutamide, Placebo and Placebo 
crossover group: 
• 
Number of TEAEs, 
• 
Number and percentage of patients with TEAEs, 
• 
Number of NCI-CTC grades 3 and 4 TEAEs, 
• 
Number and percentage of patients with NCI-CTC grades 3 and 4 TEAEs, 
• 
Number of drug related TEAEs, 
• 
Number and percentage of patients with causally drug related TEAEs, 
• 
Number of serious TEAEs, 
• 
Number and percentage of patients with serious TEAEs, 
• 
Number of serious drug related TEAEs, 
• 
Number and percentage of patients with serious drug related TEAEs, 
• 
Number of TEAEs leading to death, 
• 
Number and percentage of patients with TEAEs leading to death, 
• 
Number of drug related TEAEs leading to death, 
• 
Number and percentage of patients with drug related TEAEs leading to death, 
• 
Number of TEAEs leading to withdrawal of treatment, 
• 
Number and percentage of patients with TEAEs leading to withdrawal of treatment, 
• 
Number of drug related TEAEs leading to withdrawal of treatment, 
• 
Number and percentage of patients with drug related TEAEs leading to withdrawal of 
treatment. 
• 
Number of TEAEs leading to dose reduction, 
• 
Number and percentage of patients with TEAEs leading to dose reduction, 
• 
Number and percentage of death 
The number and percentage of patients with TEAEs, as classified by SOC and preferred 
terms will be summarized for each treatment group. Summaries will be provided for: 
• 
TEAEs 
• 
NCI-CTC grade 3 or higher TEAEs 


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• 
drug related TEAEs, 
• 
serious TEAEs,  
• 
drug related serious TEAEs, 
• 
TEAEs leading to withdrawal of treatment,  
• 
drug related TEAEs leading to withdrawal of treatment, 
• 
TEAEs leading to dose reduction, 
• 
TEAEs leading to dose interruption, 
• 
TEAEs, excluding serious AEs, that equal to or exceed a threshold of 5.0% in any 
treatment group,  
• 
TEAEs leading to death,  
• 
drug related TEAEs leading to death,  
The number and percentage of patients with TEAEs, classified by preferred terms by 
decreasing frequency within the enzalutamide group will also be summarized. 
The number and percentage of patients with TEAEs, as classified by SOC and preferred 
terms will also be summarized by maximum severity (reported according to NCI-CTCAE 
version 4.03).  
In the patient count, if a patient has multiple TEAEs with the same SOC or PT, but with 
different severity, then the patient will be counted only once with the worst severity. 
However, if any of the severity values are missing then the patient will be counted only once 
with missing severity. In the AE count, the AEs will be presented in each category they were 
classified to.  Summaries will be provided for: 
• 
TEAEs by NCI- CTCAE 
• 
drug related TEAEs by NCI- CTCAE, 
• 
serious TEAEs by NCI- CTCAE  
The number and percentage of patients with TEAEs that equal to or exceed a threshold of 
5.0% in any treatment group, classified by preferred terms (by decreasing frequency within 
the enzalutamide group) will be summarized by treatment group and time interval.  The 
percentage of patients are calculated based on the number of patients still on treatment at the 
time-point corresponding to the lower limit of the time intervals.  Time intervals will be 
categorized according to the following categories: 
• ≤3 months; 
• >3 months to ≤6 months; 
• >6 months to ≤12 months; 
• >12 months to ≤24 months; 
• >24 months to ≤36 months; 
• >36 months. 
To adjust for the treatment duration, the number of TEAEs per 100 patients-years will be 
summarized, as classified by SOC and PT, per treatment group and CTI-CTC grade (3-5 and 
total).  The number of TEAEs per 100 patients-years is calculated as the number of events 


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*100 / (sum of the treatment emergent period duration of all patients treated in the 
corresponding treatment group, in years). 
AEs of Special Interest 
AEs of special interest are defined in Table 3. 
Table 3 
Selection Criteria for AEs of Special Interest 
Event of special interest 
Convulsions (seizure) 
Narrow SMQ of ‘Convulsions’ 
Hypertension 
Narrow SMQ of ‘Hypertension’ 
Neutrophil count decreased  
 Preferred terms of ‘Neutrophil count decreased’, ‘Neutropenia’, 
‘Agranulocytosis’,’ Granulocyte count decreased’, ‘Granulocytopenia’, 
‘Febrile neutropenia’, ‘Neutrophil percentage decreased’, ‘Band 
neutrophil count decreased’, and ‘Band neutrophil percentage decreased’ 
‘Neutropenic sepsis’, ‘Neutropenic infection’, ‘Neutrophil count 
abnormal’ 
Cognitive and memory 
impairment 
All preferred terms in MedDRA HLGT ‘Mental impairment disorders’ 
Ischemic Heart Disease (IHD) 
Narrow SMQs of ‘Myocardial Infarction’ and ‘Other ischemic heart 
disease’ 
Other selected cardiovascular 
events 
Narrow SMQs of ‘Haemorrhagic central nervous system vascular 
conditions,’ ‘Ischaemic central nervous system vascular conditions’ and 
‘Cardiac failure’ 
Posterior reversible 
encephalopathy syndrome 
(PRES) 
Preferred term ‘Posterior reversible encephalopathy syndrome’  
Fatigue 
Preferred terms of ‘Fatigue’, ‘Asthenia’ 
Renal disorder 
Broad SMQ of ‘Acute Renal Failure’ 
Second primary malignancies 
Narrow SMQs of ‘Malignant or unspecified tumours’ customized to 
exclude preferred terms of ‘Congenital fibrosarcoma’, ‘Congenital 
malignant neoplasm’, ‘Congenital retinoblastoma’, ‘, “Metastases to…”, 
‘Metastasis’, ‘Metastatic neoplasm’, ‘Prostate cancer…’, ‘Carcinoid 
tumour of the prostate’,‘neoplasm prostate’ 
AND (inclusive of) Narrow SMQ of ‘Myelodysplastic syndrome’ 
AND (inclusive of) All preferred terms under HLT of ‘Myeloproliferative 
disorders (excl. leukaemias)’ 
 
Note: Non-melanoma skin cancers are excluded (preferred terms of ‘Basal 
cell carcinoma’, ‘Basosquamous carcinoma’, ‘Basosquamous carcinoma of 
skin’, ‘Keratoacanthoma’, ‘Skin cancer’, ‘Skin cancer metastatic’, 
‘Squamous cell carcinoma’, ‘Squamous cell carcinoma of skin’, ‘Lip 
squamous cell carcinoma’) 
Table continued on next page 


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Event of special interest 
 
Fall  
Preferred term of ‘Fall’ 
Fracture 
All preferred terms under the MedDRA HLGT of ‘Fractures’, ‘Bone and 
joint injuries’ 
Loss of consciousness  
Preferred terms of ‘Loss of consciousness’, ‘Syncope’,’ Presyncope’ 
Thrombocytopenia 
Preferred terms of ‘Thrombocytopenia’, ‘Platelet count decreased’ 
Musculoskeletal events 
Preferred terms of ‘Back pain’, ‘Arthralgia’, ‘Myalgia’, ‘Musculoskeletal 
pain’, ‘Pain in extremity’, ‘Musculoskeletal stiffness’, ‘Muscular 
weakness’, ‘Muscle spasms’ 
Severe cutaneous adverse 
reactions (SCAR) 
Narrow SMQ of ‘Severe cutaneous adverse reactions’ 
Angioedema 
Narrow SMQ of ‘Angioedema’ 
Rash 
Preferred terms of ‘Butterfly rash’, ‘Exfoliative rash’, ‘Eyelid rash’, 
‘Genital rash’, ‘Heliotrope rash’, ‘Mucocutaneous rash’, ‘Nodular rash’, 
‘Paraneoplastic rash’, ‘Penile rash’, ‘Perineal rash’, ‘Rash’, ‘Rash 
erythematous’, ‘Rash follicular’, ‘Rash macular’, ‘Rash maculo-papular’, 
‘Rash maculovesicular’, ‘Rash morbilliform’, ‘Rash neonatal’, ‘Rash 
papular’, ‘Rash papulosquamous’, ‘Rash pruritic’, ‘Rash pustular’, ‘Rash 
rubelliform’, ‘Rash scarlatiniform’, ‘Rash vesicular’, ‘Septic rash’, 
‘Systemic lupus erythematosus rash’, ‘Vasculitic rash’, ‘Viral rash’, 
‘Vulvovaginal rash’ 
Hepatic disorder 
Narrow SMQs of ‘hepatic failure, fibrosis and cirrhosis and other liver 
damage related conditions’, ‘hepatitis, non-infectious’ and ‘liver related 
investigations, signs and symptoms’ 
 
An overview table of the TEAEs of special interest will be described by the number and 
percentage of patients with TEAEs of special interest per treatment group and overall. 
7.5.2 
Clinical Laboratory Evaluation 
Laboratory assessment will be done for the following parameters: 
Hematology 
Biochemistry 
Other 
Red blood cell count 
White blood cell count 
White blood cell differential 
Hemoglobin 
Hematocrit 
Platelet count 
Albumin 
Alkaline phosphatase (ALP) 
Alanine aminotransferase (ALT) 
Aspartate aminotransferase (AST) 
Blood urea nitrogen 
Calcium 
Creatinine 
Glucose 
Phosphorus 
Potassium 
Sodium 
Total bilirubin 
Total protein 
Testosterone 
PSA 
 
Quantitative clinical laboratory variables (hematology, serum chemistry and testosterone), 
will be summarized using mean, standard deviation, minimum, maximum and median for 
Enzalutamide, Placebo and Placebo crossover group at each visit. Additionally, a within-
patient change will be calculated as the post-baseline measurement minus the baseline 


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measurement and summarized in the same way. Baseline is defined as the last available 
measurement prior to the first dose (double-blind or open-label extension). 
Based on the NCI-CTCAE grade of laboratory data, clinical laboratory evaluations will be 
summarized by grade and by visit, for their comparison to the upper limit. Shift analysis tables 
on the enzalutamide group will present the shift from baseline to each visit and to the highest 
grade among the post-baseline visits, by grade. The number and percentage of patients with an 
increase in grade will be summarized by visit. 
Each laboratory result will also be classified as low (L), normal (N), or high (H) at each visit 
according to the laboratory supplied reference ranges. 
Laboratory data will be displayed in listings, along with their NCI-CTCAE grade. 
7.5.2.1 Liver Enzymes and Total Bilirubin  
The following potentially clinically significant criteria for liver tests - ALP, ALT, total 
bilirubin, AST, and their combination - are defined. The patient’s highest value during the 
investigational period will be used.  
Parameter 
Criteria (Upper limit of normal[ULN]) 
ALT or AST 
> 3xULN 
 
> 5xULN  
 
> 8xULN 
 
 
Total Bilirubin 
> 2xULN 
ALT and/or AST AND Total Bilirubin(*) 
(ALT and/or AST > 3xULN) and 
total bilirubin > 2xULN 
ALT and/or AST AND Total Bilirubin (*) 
(ALT and/or AST > 3xULN) and 
AND Alkaline phosphatase   
 
total bilirubin > 2xULN and Alk phos <2x ULN 
 (*) Combination of values measured within same sample 
The number and percentage of patients with potentially clinically significant values in liver 
enzyme and total bilirubin tests during the investigational period will be presented by 
treatment group and overall. 
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 for 
Enzalutamide, Placebo and Placebo crossover group at each visit. Additionally, a within-
patient change will be calculated per visit as the post-baseline measurement minus the 
baseline measurement and summarized in the same way. Baseline is defined as the last 
available measurement prior to the first dose (double-blind or open-label extension).  
Finally based on the patient’s highest value during the treatment period, a summary will 
present the number and percentage of patients with blood pressure elevation (systolic: 
≥ 140 mmHg, ≥ 180 mmHg; diastolic: ≥ 90 mmHg, ≥ 105 mmHg), with increase from 


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baseline (systolic: ≥ 10 mmHg, ≥ 20 mmHg; diastolic: ≥ 5 mmHg, ≥ 15 mmHg) or 
combination criteria (systolic: ≥ 140 mmHg & ≥ 20 mmHg increase from baseline, 
≥ 180 mmHg & ≥ 20 mmHg increase from baseline; diastolic: ≥ 90 mmHg & ≥ 15 mmHg 
increase from baseline, ≥ 105 mmHg & ≥ 15 mmHg increase from baseline) or any of these 
criteria. 
All vital signs results will be provided in a listing. 
7.5.4 
Electrocardiograms  
12 Lead ECG results and change from baseline will be summarized using mean, standard 
deviation, minimum, maximum and median for Enzalutamide, Placebo and Placebo 
crossover group at each visit. Baseline is defined as the last available measurement prior to 
the first dose (double-blind or open-label extension).  
Number and percent of patients with normal, not clinically significant abnormal and 
clinically significant abnormal results for the 12 lead ECG will be tabulated by treatment arm 
and visit.  
QTc will be calculated using Fridericia Formula, QTcF= QT interval / RR1/3. 
Note: unit for RR is seconds. 
All ECG results will be provided in a listing. 
Any abnormal findings/conditions identified during the physical examination are reported in 
the medical history form or AE form. As a consequence, no separate physical examination 
listing can be produced. 
7.5.5 
Pregnancy 
Not applicable. 
7.5.6 
Other Safety-Related Observations 
The number and percentage of patients falling in each category of the performance status 
ECOG score will be summarized per visit and will be listed. 
7.6 
Analysis of Exploratory Endpoint 
Not applicable.  
7.7 
Analysis of Pharmaco-kinetic 
Not applicable 
7.8 
Analysis of Pharmaco-dynamic 
Not applicable. 
7.9 
Subgroups of Interest  
Subgroup analyses of OS will be conducted to assess the consistency of the treatment effect 
across the following subgroups of interest:  
• 
Age category (less than 65 years old versus 65 years old or more); 


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• 
Geographic region (Europe, North America, Rest of the World); 
• 
ECOG Performance Status (0 versus 1) at baseline; 
• 
Gleason score (less than 8 versus 8 or more) at initial diagnosis; 
• 
Disease location (bone only, versus soft tissue only, versus both bone and soft tissue) 
at baseline; 
• 
Baseline PSA value (at or below overall median versus above overall median); 
• 
Volume of disease at baseline (low versus high) 
• 
Prior docetaxel use (yes versus no)  
• 
Previous use of ADT or orchiectomy (yes versus no) 
7.10 
Other Analyses 
Not applicable. 
7.11 
Interim Analysis (and Early Discontinuation of the Clinical Study) 
Not applicable 
7.12 
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information 
The baseline measurement is the last measurement taken prior to initial study drug 
administration (double-blind or open-label extension). Both date and time of drug 
administration and measurement should be considered to identify the baseline value. If the 
time is not available, then date only will be used, and it will be considered that assessments 
on day 1 are done pre-dose. 
Change from baseline is defined as (post baseline value - baseline value). 
To calculate time interval duration, a month is 30.4375 days and a year 365.25 days. 
Duration expressed in years or months are rounded up to 1 significant digit. The duration 
between 2 dates d1 and d2 is (d2-d1+1) in days (with d1 before d2). 
Treatment day and study day will be calculated in reference to the date of the first dose of 
study drug. Treatment Day 1 corresponds to the date the patient 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. 
Unless otherwise specified, the date of study drug discontinuation refers to the study drug last 
dose date.  
Time to event endpoints will be based on the actual date of event rather than visit date. The 
date of randomization will always be considered as the start date for the time interval. 
For laboratory results collected as < or > a numeric value, 0.0000000001 will be subtracted 
or added, respectively, to the value unless otherwise specified. 
Percentages will be calculated based on the number of patients with non-missing data as the 
denominator unless otherwise specified. 


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7.12.1 Missing Data 
As a general principle, no imputation of missing data will be done. Exceptions are the start 
and stop dates of AEs, previous and concomitant medications, the date of initial diagnosis (to 
estimate the relative study day to calculate cancer duration), dates of cancer treatment (e.g. 
previous procedure, previous radiotherapy, etc.…), the last dose date and the date of death.  
The imputed dates will be used to allocate the relative study day, and in addition to determine 
whether an AE is/is not treatment emergent.  
Cases where the onset date of an AE is (partially) missing, will be addressed during the data 
review meeting in order to determine whether the AE must be considered treatment emergent 
or not. 
Imputation on missing non-prostate cancer related medication dates (to categorize them as 
previous medications or concomitant medications, or post treatment) and AE dates (to 
categorize them as TEAE or not) will be done as follows: 
• 
Incomplete Start Day from start date and the corresponding end date is complete: use 
the later of (first day of the month, first dosing day if first dosing month); but if later 
than the end date, then impute the start day as the day of the end date. 
• 
Incomplete Start Day from start date and incomplete End Day from end date: use the 
later of (first day of the month, first dosing day if first dosing month). 
• 
Incomplete End Day from end date: use the earliest of (last day of the month, day of 
the 30-day follow-up visit if it is the month of the 30-day follow-up visit); 
• 
Incomplete Month or Year: no imputation. 
Imputation on missing date of initial diagnosis (cancer duration) and prior cancer treatment, 
including prostate cancer drug medication/therapies, (e.g. start date, stop date, or date of 
procedure) will be done as follows: 
• 
Incomplete Day: use the 15th day of the month, if month/year is before first dosing or 
after last dosing (-for start date imputation- but if later than the end date, then impute 
the start day as the day of the end date; -for end date imputation- but if earlier than the 
start date, then impute the end day as the day of the start date). 
• 
Incomplete Month: use 1st of July if the Year is before Year of first dosing, otherwise 
missing.  
• 
Incomplete Year: no imputation, the derived variable is considered to be missing. 
If missing for subjects who started treatment, the last dose date of treatment will be imputed 
as follows: 
• 
Incomplete Day only: use the earliest of (last day of the month, end of treatment 
[form] day -if on the same month and year-, day of the 30-day follow-up visit-if on 
the same month and year-); 
• 
If fully missing or Incomplete Month or/and Year: the date will be imputed by the 
earliest of (end of treatment [form] date, date of the 30-day follow-up visit) 


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If partially missing, the date of death will be imputed as follows: 
• 
Incomplete Day: use the earliest of (last day of the month, end of study [form] day) 
• 
Incomplete Month or Year: no imputation 
Imputation methods will not be used to determine other endpoints. 
Listings will always show the original date information without imputation, and derived 
parameters requiring imputation (e.g., TEAE indicator, start day, end day, study day) will be 
flagged.  
7.12.2 Outliers 
All values will be included in the analyses. 
7.12.3 Visit Windows 
Visit windows are allowed for certain visits per the schedule of assessments. Patient data will 
not be excluded from analyses due to the patient’s failure to comply with the visit schedule.  
For summary tables reporting results by visit, analyses of efficacy and safety variables will 
be performed according to the analysis visit windows described in the following Table 4. 
In the case of multiple observations in the same analysis visit window, the observation which 
is closest to the target date will be used. If the observations have the same distance to the 
target visit day, the latest one will be used (using date, and time if available). Should there be 
two assessments documented at the same time due to the repetition of analysis of the same 
sample, the one reported as scheduled will be used. 
Table 4 
Analysis Visit Windows 
Visit Day Interval 
Scheduled Visit 
Analysis Visit* 
Up to Day 1 
Week 1 (Day 1) 
Baseline** 
Day 2 - Day 57  
Week 5 (Day 29) 
Week 5 
Day 58 - Day 127 
Week 13 (Day 85) 
Week 13 
For the next visits during the treatment period: 
Week X = Week (i*12+13), (i=1,2,3, …) 
Week X target day = i*12*7 + 85, (i=1,2,3, …) 
Week X (Wk X target day - 41 days; Wk X target day + 42 days)   
However, for the (last) visit during the treatment period, i.e. the last dose day of study drug is 
recorded,  
the upper boundary of the analysis visit window is 5 days after the last dose day, e.g.: 
Week X = Week (i*12+13), (i=0,1,2,3, …) 
Week X target day = i*12*7 + 85, (i=0,1,2,3, …) 
Week X (Wk X target day - 41 days; last dose day + 5 days) 
(last dose day + 6; last dose day + 
42) 
last dose day + 30 
days 
30 Day Safety F-up  
(after last dose or prior to new 
therapy) 
Table continued on next page 


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Visit Day Interval 
Scheduled Visit 
Analysis Visit* 
Patients who end treatment before the data analysis cut-off date and have long-term (LT) follow-up 
visits,  
have visits every 12 weeks after last dose day: 
LT F-up j = j*12 weeks visit after last dose day, (j=1,2,3, …) 
LT F-up j target day = j*12*7 + last dose day, (j=1,2,3, …) 
LT F-up j (j*12*7 + last dose day - 41; j*12*7 + last dose day + 42) 
F-up: follow-up 
*Post-baseline analysis visits in the OLE are defined similarly to the analysis visits in the double-blind period 
and are labeled “OLE Week XXX”.  
**OLE baseline is defined as the last visit prior to the administration of enzalutamide + ADT in OLE period. 
8 
DOCUMENT REVISION HISTORY  
Version 
Date 
Changes 
Comment/rationale 
for change 
1.0 
18-JUL-2021 
NA 
Document finalized 
9 
REFERENCES 
ICH Harmonized Tripartite Guideline E 3. Structure and Content of Clinical Study Reports, 
November 1995. (www.ich.org; Guidelines; "Efficacy" Topics) 
ICH Harmonized Tripartite Guideline E 9. Statistical Principles for Clinical Trials, February 1998. 
(www.ich.org; Guidelines; "Efficacy" Topics) 
Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, May 
2007, US Department of Health and Human Services, FDA 
European Journal of Cancer. New Response Evaluation Criteria in Solid Tumours: Revised RECIST 
guideline, 2009 (www.ejconline.com; version 1.1;228-247) 
Journal of Clinical Oncology. Design and End Points of Clinical Trials for Patients with Progressive 
Prostate Cancer and Castrate Levels of Testosterone: Recommendations of the Prostate Cancer 
Trials Working Group, March 2008. (www.jco.org; vol 26:1148 1159) 
O’Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics 35:549-56, 1979.  
Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika 70:659-663, 
1983. 
Applied Survival Analysis, Regression Modeling of Time to Event Data, David W. Hosmer, Jr. and 
Stanley Lemeshow, 1999, John Wiley & Sons, Inc. 
Ryan CJ, Morris M, Molina A, Piulats JR, De Souza P, Li J, et al. Association of radiographic 
progression-free survival (rPFS) adapted from prostate cancer working group 2 (PCWG2) 
consensus criteria (APCWG2) with overall survival (OS) in patients (PTS) with metastatic 
castration-resistant prostate cancer (mCRPC): results from COU AA-302. Annals of Oncol. 
2012;23;suppl 9:ix294-ix318. 


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Fizazi K et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. N 
England Journal of Medicine. 2017; 377:352-36 
Robins JM, Tsiatis AA. Correcting for non-compliance in randomized trials using rank preserving 
structural failure time models. Commun Stat Theory Methods. 1991;20(8):2609–31. 
Robins JM, Finkelstein DM. Correcting for noncompliance and dependent censoring in an AIDS 
Clinical Trial with inverse probability of censoring weighted (IPCW) log-rank tests. 
Biometrics. 2000;56(3):779–88. 
 


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10 
APPENDICES 
 


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10.1 
Appendix 1 - Key Contributors and Approvers 
List of Key Contributors and Approvers 
 
Key Contributors 
The following contributed to or reviewed this SAP as relevant to their indicated discipline or 
role. 
 
Primary author (s) 
 
 
 
 
Astellas Data Science 
 
Main Contributors and Reviewers 
 
 
 
 
Astellas Data Science 
 
 
 
Astellas Development Medical 
Science 
 
 
 
Astellas Data Science 
PPD
PPD
PPD
PPD