Clinical trial NCT03641560
Conditions: Metastatic Castration Resistant Prostate Cancer
Keywords: Progressive Metastatic Castration-Resistant Prostate Cancer (mCRPC) Enzalutamide Xtandi MDV3100
Sponsor: Astellas Pharma Inc
Start date: 2018-09-19; Completion date: 2024-02-20
Enrollment: 52 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study was to evaluate the safety and tolerability of enzalutamide in Indian patients with progressive mCRPC previously treated with docetaxel-based chemotherapy. This study also evaluated the effect of enzalutamide on prostate-specific antigen (PSA).

Detailed description:

Arms: arm 1: Participants with progressive mCRPC who had previously been treated with docetaxel-based chemotherapy received 160 milligrams (mg) (4 capsules of 40 mg) enzalutamide orally, once daily until disease progression, unacceptable toxicity or any other discontinuation criteria were met.
Interventions: intervention 1: Enzalutamide intervention 2: Androgen deprivation therapy (ADT)
Intervention descriptions: intervention 1: Enzalutamide was administered orally intervention 2: All participants were required to maintain ADT during study treatment, either using a Gonadotropin Releasing Hormone (GnRH) agonist/antagonist or having a history of bilateral orchiectomy

Protocol documents:
Prot_002.pdf: 
Sponsor: API 
ISN/Protocol 9785-CL-0413 
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A Multicenter Phase 4, Open-label, Single-arm, Safety and 
Efficacy Study of Enzalutamide in Indian Patients with 
Progressive Metastatic Castration-Resistant Prostate Cancer 
(mCRPC) Previously Treated with Docetaxel-Based 
Chemotherapy
ISN/Protocol 9785-CL-0413 
Version <1.0> 
31 May 2018 
Sponsor: 
Astellas Pharma Inc. (API) 
2-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo
-------------------------------------------------------------------------------------------------------------------------------------- 
The information contained in this document is supplied as a background for clinical investigations. This document contains 
confidential information which is the intellectual property of Astellas. By accepting or reviewing this document, you agree 
to hold this information in confidence and not copy or disclose it to others or use it for unauthorized purposes except (1) as 
otherwise agreed to in writing; (2) where required by applicable law; (3) where disclosure is directly related to the care and 
safety of the research participant; and (4) where disclosure of such information is made to a member of the investigator’s 
team who agrees to hold this information in confidence.  


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Table of Contents 
I. 
SIGNATURES ······················································································ 7
 
II. 
CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL ····························· 9
 
III. 
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS ·················· 10
 
IV. 
SYNOPSIS ·························································································· 13
 
V. 
FLOW CHART AND SCHEDULE OF ASSESSMENTS ································· 18
 
1 
INTRODUCTION ················································································· 20
 
1.1 
Background ···················································································· 20
 
1.2 
Nonclinical and Clinical Data ······························································· 21
 
1.2.1 
Nonclinical Data ········································································· 21
 
1.2.2 
Clinical Data ············································································· 23
 
1.3 
Summary of Key Safety Information for Study Drugs ··································· 25
 
1.4 
Risk Benefit Assessment ····································································· 25
 
2 
STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS ·································· 27
 
2.1 
Study Objective(s) ············································································ 27
 
2.1.1 
Primary Objective ······································································· 27
 
2.1.2 
Secondary Objective ···································································· 27
 
2.2 
Study Design and Dose Rationale ··························································· 28
 
2.2.1 
Study Design ············································································· 28
 
2.2.2 
Dose Rationale ··········································································· 28
 
2.3 
Endpoints ······················································································· 28
 
2.3.1 
Primary Endpoints ······································································· 28
 
2.3.2 
Secondary Endpoints ···································································· 28
 
3 
STUDY POPULATION ·········································································· 28
 
3.1 
Selection of Study Population ······························································· 28
 
3.2 
Inclusion Criteria ·············································································· 28
 
3.3 
Exclusion Criteria ············································································· 29
 
4 
TREATMENT(S) ·················································································· 30
 
4.1 
Identification of Investigational Product(s) ················································ 30
 
4.1.1 
Study Drug(s) ············································································ 30
 


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4.2 
Packaging and Labeling ······································································ 30
 
4.3 
Study Drug Handling ········································································· 30
 
4.4 
Blinding ························································································ 31
 
4.5 
Assignment and Allocation ·································································· 31
 
5 
TREATMENTS AND EVALUATION ························································ 31
 
5.1 
Dosing and Administration of Study Drug(s) and Other Medication(s) ················ 31
 
5.1.1 
Dose/Dose Regimen and Administration Period ···································· 31
 
5.1.2 
Increase or Reduction in Dose of the Study Drug(s) ································ 32
 
5.1.3 
Previous and Concomitant Treatment (Medication and NonMedication 
Therapy) ·················································································· 32
 
5.1.3.1 
Required Concomitant Treatment ··············································· 32
 
5.1.3.2 
Prohibited Concomitant Treatment ·············································· 32
 
5.1.3.3 
Enzalutamide Drug Interaction··················································· 33
 
5.1.3.4 
Permitted Concomitant Treatment ··············································· 33
 
5.1.4 
Treatment Compliance ·································································· 34
 
5.1.5 
Criteria for Continuation of Treatment ··············································· 34
 
5.2 
Demographics and Baseline Characteristics ··············································· 34
 
5.2.1 
Demographics ············································································ 34
 
5.2.2 
Medical History ·········································································· 34
 
5.2.3 
Diagnosis of the Target Disease, Severity, and Duration of Disease ·············· 34
 
5.3 
Efficacy and Pharmacokinetics Assessments ·············································· 35
 
5.3.1 
Efficacy Assessments ··································································· 35
 
5.3.2 
Pharmacokinetics Assessments ························································ 35
 
5.4 
Safety Assessment ············································································ 35
 
5.4.1 
Vital Signs ················································································ 35
 
5.4.2 
Adverse Events ·········································································· 35
 
5.4.2.1 
Adverse Events of Possible Hepatic Origin ···································· 35
 
5.4.3 
Laboratory Assessments ································································ 35
 
5.4.4 
Physical Examination ··································································· 36
 
5.5 
Adverse Events and Other Safety Aspects ················································· 36
 
5.5.1 
Definition of Adverse Events ·························································· 36
 
5.5.1.1 
Abnormal Laboratory Findings ·················································· 36
 
5.5.1.2 
Potential Cases of Drug-Induced Liver Injury ································· 37
 
5.5.1.3 
Disease Progression and Study Endpoints ······································ 37
 


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5.5.2 
Definition of Serious Adverse Events (SAEs) ······································· 37
 
5.5.3 
Criteria for Causal Relationship to Study Drug ······································ 38
 
5.5.4 
Criteria for Defining the Severity of an Adverse Event ···························· 39
 
5.5.5 
Reporting of Serious Adverse Events (SAEs) ······································· 39
 
5.5.6 
Follow-up of Adverse Events ·························································· 41
 
5.5.7 
Special Situations ········································································ 41
 
5.5.7.1 
Pregnancy ··········································································· 41
 
5.5.7.2 
Medication Error, Overdose and “Off-Label Use” ···························· 42
 
5.5.7.3 
Misuse/Abuse ······································································ 42
 
5.5.7.4 
Occupational Exposure ··························································· 42
 
5.5.7.5 
Suspected Drug-Drug Interaction ················································ 43
 
5.5.8 
Supply of New Information Affecting the Conduct of the Study ·················· 43
 
5.6 
Test Drug Concentration ····································································· 43
 
5.7 
Other Measurements, Assessments or Methods ··········································· 43
 
5.8 
Total Amount of Blood ······································································· 43
 
6 
DISCONTINUATION ············································································ 43
 
6.1 
Discontinuation of Individual Subject(s) ··················································· 43
 
6.2 
Discontinuation of the Site ··································································· 44
 
6.3 
Discontinuation of the Study ································································ 44
 
7 
STATISTICAL METHODOLOGY ··························································· 45
 
7.1 
Sample Size ···················································································· 45
 
7.2 
Analysis Sets ··················································································· 45
 
7.2.1 
Full Analysis Set (FAS) ································································ 45
 
7.2.2 
Safety Analysis Set (SAF) ······························································ 45
 
7.3 
Demographics and Baseline Characteristics ··············································· 45
 
7.3.1 
Subject Disposition ······································································ 45
 
7.3.2 
Previous and Concomitant Medications ·············································· 45
 
7.3.3 
Medical History ·········································································· 45
 
7.4 
Analysis of Efficacy ·········································································· 46
 
7.5 
Analysis of Safety ············································································· 46
 
7.5.1 
Adverse Events ·········································································· 46
 
7.5.2 
Laboratory Assessments ································································ 46
 
7.5.3 
Physical Examination ··································································· 46
 
7.5.4 
Vital Signs ················································································ 46
 


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7.6 
Analysis of Pharmacokinetics ······························································· 46
 
7.7 
Interim Analysis (and Early Discontinuation of the Clinical Study) ···················· 46
 
7.8 
Handling of Missing Data, Outliers, Visit Windows, and Other Information ········· 46  
8 
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS ···················· 47
 
8.1 
Procedure for Clinical Study Quality Control ············································· 47
 
8.1.1 
Data Collection ·········································································· 47
 
8.1.2 
Specification of Source Documents ··················································· 47
 
8.1.3 
Clinical Study Monitoring ······························································ 48
 
8.1.4 
Direct Access to Source Data/Documents ············································ 48
 
8.1.5 
Data Management ······································································· 48
 
8.1.6 
Major Protocol Deviations ····························································· 48
 
8.1.7 
End of Trial in All Participating Countries ··········································· 49
 
8.2 
Ethics and Protection of Subject Confidentiality ·········································· 49
 
8.2.1 
Institutional Review Board (IRB) / Independent Ethics Committee (IEC) / 
Competent Authorities (CA) ··························································· 49
 
8.2.2 
Ethical Conduct of the Study··························································· 50
 
8.2.3 
Informed Consent of Subjects ························································· 50
 
8.2.3.1 
Subject Information and Consent ················································ 50
 
8.2.3.2 
Supply of New and Important Information Influencing the Subject’s 
Consent and Revision of the Written Information ····························· 50
 
8.2.4 
Subject Confidentiality and Privacy ··················································· 50
 
8.3 
Administrative Matters ······································································· 51
 
8.3.1 
Arrangement for Use of Information and Publication of the Clinical Study ····· 51  
8.3.2 
Documents and Records Related to the Clinical Study ····························· 51
 
8.3.3 
Protocol Amendment and/or Revision ················································ 52
 
8.3.4 
Signatory Investigator for Clinical Study Report ···································· 53
 
9 
QUALITY ASSURANCE ········································································ 53
 
10 
STUDY ORGANIZATION ······································································ 53
 
10.1 
Independent Data-Monitoring Committee (IDMC) | Data and Safety Monitoring 
Board (DSMB) | Monitoring Committee | Other Evaluation Committee(s) ··········· 53
 
10.2 
Other Study Organization ···································································· 53
 
11 
REFERENCES ···················································································· 54
 
12 
APPENDICES ····················································································· 55
 
12.1 
List of Excluded Concomitant Medications ··············································· 55
 


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12.2 
Liver Safety Monitoring and Assessment ·················································· 56
 
12.3 
Common Serious Adverse Events ··························································· 59
 
12.4 
ECOG Performance Status Scale ···························································· 60
 
13 
SPONSOR’S SIGNATURES ···································································· 61
 
 


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I. 
SIGNATURES 
1.  SPONSOR’S SIGNATURES 
Required signatures (e.g. Protocol authors and contributors, etc.) are located in [Section 13 
Sponsor’s Signatures]. 
 
 
 


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2. INVESTIGATOR’S SIGNATURE 
A Multicenter Phase 4, Open-label, Single-arm, Safety and Efficacy Study of 
Enzalutamide in Indian Patients with Progressive Metastatic Castration-Resistant 
Prostate Cancer (mCRPC) Previously Treated with Docetaxel-Based Chemotherapy 
ISN/Protocol 9785-CL-0413, Version 1.0 
31 May 2018 
 
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 International Council for 
Harmonisation (ICH) Good Clinical Practice (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: 
 
 
 
 
 
 
 
 
 
 


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II. 
CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL 
24h-Contact for Serious 
Adverse Events (SAEs) 
 
See [Section 5.5.5 Reporting 
of Serious Adverse Events] for 
SAE Fax Number and Email 
Please fax or email the SAE Worksheet to: 
IQVIA RDS East Asia Pte. Ltd. 
Lifecycle Safety 
Fax number: 000-800001-6750 
Email: QLS_Enzalutamide@iqvia.com 
 
Medical Monitor/Study 
Physician: 
Emergency Phone Numbers: +19736596677 OR 
+15708198565 
Email: MM_Astellas_9785-CL-0413@iqvia.com 
 
Clinical Research Contacts: 
 
Astellas Pharma Inc. 
2-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo,  
103-8411, JAPAN 
 
 
 
 
 
PPD
PPD


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III. 
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS 
Abbreviations 
Description of abbreviations 
ADT 
Androgen deprivation therapy 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
APGD 
Astellas Pharma Global Development, Inc. 
API 
Astellas Pharma Inc. 
AR 
Androgen receptor 
AST 
Aspartate aminotransferase 
BHA 
Butylated hydroxyanisole 
BHT 
Butylated hydroxytoluene 
CIOMS 
Council for International Organizations of Medical Sciences 
CLCR 
Creatinine clearance 
CRF 
Case report form 
CRPC 
Castration-resistant prostate cancer 
CSR 
Clinical Study Report  
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTD 
Common Technical Document 
CYP 
Cytochrome P450 
DCGI 
Drug Controller General of India 
DILI 
Drug Induced Liver Injury  
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EEA 
European Economic Area  
EMA 
European Medicines Agency 
FACT-P 
Functional Assessment of Cancer Therapy-Prostate 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GABA 
γ-aminobutyric acid 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
GnRH 
Gonadotropin Releasing Hormone 
HR 
Hazard ratio 
IB 
Investigator’s Brochure  
ICF 
Informed consent form 
ICH  
International Council for Harmonisation 
IDMC 
Independent Data-Monitoring Committee  
IEC 
Independent Ethics Committee 
IMPD 
Investigational Medicinal Product Dossier 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ISN 
International study number 


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Abbreviations 
Description of abbreviations 
IUD 
Intrauterine Device 
IUS 
Intrauterine System 
J-NDA 
Japan New Drug Application 
LA-CRF 
Liver abnormality case report form 
LFT 
Liver function test 
mCRPC 
Metastatic castration-resistant prostate cancer 
mHSPC 
Metastatic hormone sensitive prostate cancer 
MedDRA 
Medical Dictionary for Regulatory Activities  
MAA 
Marketing Authorization Application 
MRI 
Magnetic resonance imaging 
NA 
Not applicable 
NCI 
National Cancer Institute 
NDA 
New Drug Application 
OS 
Overall survival 
P-gp 
P-glycoprotein 
PRES 
Posterior reversible encephalopathy syndrome 
PSA 
Prostate-specific antigen 
RECIST 
Response Evaluation Criteria in Solid Tumors 
rPFS 
Radiographic progression-free survival 
SAE 
Serious adverse event 
SAF 
Safety Analysis Set  
SAP 
Statistical analysis plan 
SOC 
Standard of care 
SOP 
Standard operating procedure 
TBL 
Total bilirubin 
ULN 
Upper limit of normal 


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Definition of Key Study Terms 
Terms 
Definition of terms 
Baseline  
Assessments of subjects as they enter a trial before they receive any 
treatment.  
Endpoint  
Variable that pertains to the efficacy or safety evaluations of a trial. 
Enroll 
To register or enter a subject into a clinical trial. NOTE: Once a subject has 
received the study drug or placebo, the clinical trial protocol applies to the 
subject.  
Intervention 
The drug, device, therapy or process under investigation in a clinical study 
that is believed to have an effect on outcomes of interest in a study. (e.g., 
health-related quality of life, efficacy, safety, pharmacoeconomics).  
Investigational 
period 
Period of time where major interests of protocol objectives  are observed, 
and where the test drug or comparative drug (sometimes without 
randomization) is usually given to a subject, and continues until the last 
assessment after completing administration of the test drug or comparative 
drug. 
Post investigational 
period 
Period of time after the last assessment of the protocol. Follow-up 
observations for sustained adverse events and/or survival are done in this 
period. 
Screening 
A process of active consideration of potential subjects for enrollment in a 
trial. 
Screen failure 
Potential subject who did not meet 1 or more criteria required for 
participation in a trial. 
Screening period 
Period of time before entering the investigational period, usually from the 
time when a subject signs the consent until just before the test drug or 
comparative drug (sometimes without randomization) is given to a subject.  
Study period 
Period of time from the first site initiation date to the last site completing 
the study. 
Variable 
Any entity that varies; any attribute, phenomenon or event that can have 
different qualitative or quantitative values. 
 
 


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IV. 
SYNOPSIS 
Date and Version No of Protocol Synopsis: 
31 May 2018, Version 1.0 
Sponsor:   
Astellas Pharma Inc. (API) 
Protocol Number:  
9785-CL-0413 
Name of Study Drug: 
Enzalutamide 
Phase of Development:   
Phase 4 
Title of Study:   
A Multicenter Phase 4, Open-label, Single-arm, Safety and Efficacy Study of Enzalutamide in 
Indian Patients with Progressive Metastatic Castration-Resistant Prostate Cancer (mCRPC) 
Previously Treated with Docetaxel-Based Chemotherapy 
Planned Study Period:  
From 2Q2018 
Study Objective(s):  
The objective is to evaluate the safety and efficacy of enzalutamide in Indian patients with 
progressive mCRPC previously treated with docetaxel-based chemotherapy as per locally approved 
prescribing information.  
Primary Objective 
• 
To evaluate the safety and tolerability of enzalutamide in Indian patients with progressive 
mCRPC previously treated with docetaxel-based chemotherapy. 
Secondary Objectives 
• 
To evaluate the effect of enzalutamide on prostate-specific antigen (PSA). 
Planned Total Number of Study Centers and Location(s): 
Approximately 7 centers in India 
Study Population:   
Indian patients with progressive mCRPC previously treated with docetaxel-based chemotherapy 
Number of Subjects to be Enrolled / Randomized:   
Approximately 50 subjects 
Study Design Overview:   
This study is a multicenter Phase 4, open-label, single-arm, safety and efficacy study of 
enzalutamide (160 mg/day) in patients with progressive mCRPC who have previously been treated 
with docetaxel-based chemotherapy. Approximately 50 patients will be enrolled and treated with 
enzalutamide 160 mg once daily until study discontinuation criteria is met. 
Safety and tolerability will be assessed by the collection of adverse events, vital signs, physical 
examinations, and safety laboratory evaluations. 
PSA will be collected for assessment of prostate cancer status on Screening Visit, Days 1, 29, 57, 
85, 169, every subsequent 84 days and Safety Follow-up Visit. 
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 including commercial enzalutamide for 
prostate cancer, whichever occurs first. 
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 


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informed consent and privacy language as per national regulations 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 18 years or more 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. 
4. 
Subject with established diagnosis of metastatic castration-resistant prostate carcinoma. 
5. 
Being newly initiated on Xtandi treatment (Enzalutamide) based on independent clinical 
judgment of treating physicians as per locally approved prescribing information. 
6. 
Subject has an estimated life expectancy of ≥ 6 months as assessed by the Investigator.  
7. 
A sexually active male subject with female partner(s) who are of childbearing potential is 
eligible if: 
• 
Agree to use a male condom starting at screening and continue throughout study treatment 
and for 3 months after the final study drug administration.  
• 
If the male subject has not had a vasectomy or is not sterile as defined below their female 
partner(s) is utilizing 1 form of highly effective birth control starting at screening and 
continue throughout study treatment and for 3 months after the final study drug 
administration. 
• 
Consistent and correct usage of established hormonal contraceptives that inhibit ovulation, 
• 
Established intrauterine device (IUD) or intrauterine system (IUS). 
• 
Bilateral tubal occlusion 
• 
Vasectomy (A vasectomy is a highly effective contraception method provided the absence 
of sperm has been confirmed. If not, an additional highly effective method of contraception 
should be used) 
• 
Male is sterile due to a bilateral orchiectomy 
• 
Sexual Abstinence is considered a highly effective method only if defined as refraining 
from heterosexual activity during the entire period of risk associated with the study drug. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
study and the preferred and usual lifestyle of the participant 
8. 
Male subject with a pregnant or breastfeeding partner(s) must agree to remain abstinent or use a 
condom for the duration of the pregnancy or time partner is breastfeeding throughout the study 
period and for 3 months after the final study drug administration. 
9. 
Male subject must not donate sperm starting at screening and throughout the study period, and 
for 3 months after the final study drug administration. 
10. Subject agrees not to participate in another interventional study while participating in the 
present study. 
 
Exclusion: 
Subject will be excluded from participation if any of the following apply: 
1. 
Subject who is not eligible to receive Xtandi as per the locally approved prescribing 
information. 
2. 
Subject participating or planning to participate in any interventional drug trial during the course 
of this trial. 
3. 
Subject has received investigational study within 28 days or 5 half-lives, whichever is longer, 
prior to screening. 
4. 
Subject has any condition which, in the investigator’s opinion, makes the subject unsuitable for 
study participation. 
Investigational Product(s): 
Enzalutamide 40 mg capsule 
Drug(s): 


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160 mg once daily until study discontinuation criteria is met. 
Mode of Administration: 
Oral, with or without food 
Comparative Drug(s): 
Not applicable 
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 (Androgen deprivation therapy), either bilateral orchiectomy or GnRH agonist or antagonist, 
which must be maintained during study treatment. A GnRH agonist/antagonist will be provided 
from the site’s pharmacy stock and administered in accordance with the prescribing information. 
Concomitant Medication Restrictions or Requirements:    
Required Concomitant Treatment 
All subjects will be required to maintain ADT during study treatment, either using a GnRH 
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; 
• 
Abiraterone 
• 
Biologic or other agents with antitumor activity against prostate cancer (with the exception of 
those therapies identified in inclusion/exclusion criteria); 
• 
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, dehydroepiandrosterone, etc.); 
• 
Investigational agents. 
In addition, bisphosphonates and denosumab are prohibited unless stabilized for 2 weeks prior to 
day 1 and held constant 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 


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moderate CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin, 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. 
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. 
Duration of Treatment:   
Until study discontinuation criteria is met. 
Discontinuation Criteria: 
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. 
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 and/or PSA progression as 
confirmed by the investigator and is no longer deriving clinical benefit. Imaging test can be done 
at the discretion of the investigator and are not part of the study. 
• 
Subject has discontinued ADT (GnRH agonist/antagonist) and has a testosterone value in the 
noncastrate range (> 50 ng/dL). 
• 
Subject who is, in the opinion of the Investigator or the Medical Monitor, noncompliant with 


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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 30 day study 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. 
• 
Study termination by the Sponsor. 
Endpoints for Evaluation:   
Primary: 
Safety 
• 
Nature, frequency and severity of adverse events 
• 
Safety laboratory tests: biochemistry and hematology 
• 
Physical examination 
• 
Vital signs (blood pressure, pulse and temperature) 
Secondary: 
Efficacy 
● 
PSA response rate (≥50% reduction from baseline) 
Statistical Methods: 
Sample size justification:  
The sample size of 50 subjects is not based on a statistical power calculation. 
Safety:   
Adverse events (AEs) will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The number and percentage of subjects with treatment-emergent AEs, serious AEs 
(SAEs), AEs leading to withdrawal of treatment, and AEs possibly related to the study drug will be 
calculated. Changes in laboratory parameters, vital signs, and weight over time will be tabulated. 
Efficacy:   
The PSA response rate will be summarized by time point. 
Pharmacokinetics:   
Not applicable 
Pharmacodynamics:   
Not applicable 
Interim analyses:  
An interim assessment will be conducted at 6 month from first subject enrollment, with respect to 
safety. The report will be submitted to the health authority. 
 
 
 


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V. 
FLOW CHART AND SCHEDULE OF ASSESSMENTS 
  
Flow Chart 
 
 
 
 
 
 
Obtaining informed 
consent 
Screening  
Weeks -4 to -1 
Confirmation of 
inclusion / exclusion 
criteria 
Enzalutamide 
(160 mg once daily) 
Treatment period  
(Until study 
discontinuation 
criteria is met.) 
 


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Table 1: Schedule of Assessments  
Study Day 
Screening 
Visit 
1 
29 
57 
85 
169 & every 
subsequent 84 days 
Safety 
Follow-up 
Unscheduled 
Visit† 
Study Week 
-4 to -1 
(28 Days) 
1 
5 
9 
13 
25 
30 Days after 
Last Dose§ 
Window (Days) 
 
 
± 7 
± 7 
± 7 
± 7 
± 7 
NA 
Informed Consent 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
IRT 
 
X 
 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
including Weight¶ 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
Clinical Labs‡ 
X 
X 
X 
X 
X 
X 
X 
X 
PSA 
X 
X 
X 
X 
X 
X 
X 
 
ECOG Performance Status 
X 
 
 
 
 
 
 
 
Adverse Events§§ 
X 
X 
X 
X 
X 
X 
X 
X 
Previous and Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
Study Drug Dispensing 
 
X 
X 
X 
X 
X 
 
 
Study Drug Treatment 
 
X 
X 
X 
X 
X 
 
 
ECOG: Eastern Cooperative Oncology Group; IRT: Interactive Response Technology; NA: not applicable; PSA: prostate-specific antigen 
† 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. 
§ Or prior to initiation of an investigational agent or new 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. 
§§ 
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 an investigational agent or new 
therapy for prostate cancer. 


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1 
INTRODUCTION 
1.1 
Background 
Worldwide, prostate cancer ranks second in cancer incidence and fifth in cancer mortality in 
men [Globocan, 2012]. Prostate cancer growth is dependent on androgens, and androgen 
deprivation therapy (i.e., treatment with a GnRH analogue or bilateral orchiectomy) is the 
cornerstone of treatment of men with metastatic prostate cancer. Although initial response 
rates are high, the disease can progress despite castrate levels of testosterone at which point it 
is considered castration resistant (i.e., CRPC). CRPC represents a lethal transition in the 
natural history of prostate cancer, with most patients dying of disease progression. 
While the precise mechanism through which tumors progress from being castration sensitive 
to castration resistant is unknown, it is widely believed that a key step includes the 
development of continuous activation of androgen signaling. This activation may arise 
through androgen receptor gene amplification, androgen receptor overexpression, androgen 
receptor mutations, and/or aberrant androgen receptor coregulation [Scher & Sawyers, 2005]. 
In addition, studies have demonstrated that tumor cells display increased sensitivity to 
androgen-mediated cell growth and intratumoral production of androgens. These findings 
suggest that despite androgen deprivation therapy, androgen receptor signaling remains an 
important mediator of tumor cell growth in CRPC and as such, treatment strategies that target 
the androgen receptor may have important therapeutic potential. 
The treatment of patients with metastatic CRPC often includes antiandrogens such as 
bicalutamide, nilutamide, or flutamide; however, these agents have the potential to stimulate 
androgen receptor signaling and can accelerate tumor cell growth [Bohl et al, 2005]. In 2010, 
immunotherapy with sipuleucel-T was shown to be associated with a statistically significant 
improvement in overall survival compared with placebo in men with asymptomatic or 
minimally symptomatic metastatic CRPC [Kantoff et al, 2010]; however, this therapy was 
not associated with improvement in other markers of disease progression such as objective 
radiographic response or prostate-specific antigen (PSA) response. In 2012, abiraterone 
acetate (abiraterone) plus prednisone was shown to significantly improve radiographic 
progression-free survival (rPFS) in asymptomatic or mildly symptomatic chemotherapy-
naïve patients with metastatic CRPC compared with prednisone alone. A strong trend toward 
improvement in overall survival was observed in that study, but results did not meet 
statistical significance [Ryan et al, 2013]. Recently, radium Ra 223 dichloride (radium-223) 
was shown to improve overall survival in the chemotherapy-naïve subgroup in a study 
enrolling patients with metastatic CRPC and symptomatic bone metastases [Parker et al, 
2013]. 
Over time, patients with metastatic CRPC generally experience continued disease 
progression, worsening pain, and become eligible for chemotherapy. Although first-line 
chemotherapy with docetaxel plus prednisone demonstrated a survival benefit in these 
patients [Tannock et al, 2004], its use leads to substantial morbidity from severe neutropenia, 
diarrhea, and other toxicities. Other treatment options that have demonstrated a survival 


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improvement in patients with metastatic CRPC after docetaxel include cabazitaxel plus 
prednisone [de Bono et al, 2010] and abiraterone plus prednisone [de Bono et al, 2011]. 
Because of its potential side effects, many patients are denied chemotherapy. Recently 
published data from the Swedish Prostate Cancer database indicate that a majority of men 
younger than 70 years with CRPC were treated with chemotherapy. In contrast, only half as 
many men between 70 and 79 received chemotherapy. In addition, chemotherapy treatment 
was often administered shortly prior to death [Lissbrant et al, 2013]. Therefore, additional 
treatment options are needed to improve clinical outcomes in patients with metastatic CRPC. 
In India, prostate cancer ranks eight in cancer incidence and 10th in cancer mortality in men 
with Age-Standardized Rate (ASR) of 4.2/100000. Total incidence of prostate cancer is 
around 19000 patients [Globocan, 2012]. Patients with prostate cancer are frequently elderly 
with the median age of death in the 7th to 8th decade of life, which emphasizes the 
importance of treatments with tolerable safety profiles for this patient population. Current 
treatment modalities of early disease predominantly are surgery and radiation. However, for 
the advanced disease, it is predominantly hormonal therapy (Androgen Deprivation Therapy) 
and once the disease becomes refractory to hormonal manipulations, the options are very 
limited. Interventions like Docetaxel, Mitoxantrone and Estramustine with or without 
steroids form the main stay in first line hormone refractory prostate cancer therapy. 
Enzalutamide is a second generation AR (Androgen receptor) 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. Enzalutamide is currently being developed in 
multiple prostate cancer indications. The clinical development program initially focused on 
metastatic disease that progressed on androgen deprivation therapy. For this indication, 
completed phase 3 studies include CRPC2 (AFFIRM) in patients with metastatic CRPC who 
previously received docetaxel and MDV3100-03 (PREVAIL) in chemotherapy-naïve patients 
with metastatic CRPC. CRPC2 was the pivotal study that supported the initial approval of 
enzalutamide in the United States (US) and European Union (EU) and MDV3100-03 was the 
pivotal study that supports the use of enzalutamide in chemotherapy-naïve patients. For 
India, Enzalutamide for post-chemo mCRPC has been approved in April 2016 by the Health 
Authorities. 
The purpose of this study is to evaluate the safety, efficacy and exposure of enzalutamide and 
its major metabolites in Indian patients with progressive mCRPC previously treated with 
docetaxel-based chemotherapy as per locally approved prescribing information.  
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 


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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). 
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. 


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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. 
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). 
1.2.2 
Clinical Data 
As of the data cutoff date of 28 February 2016, over 5500 subjects with prostate cancer, over 
400 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). Enzalutamide was approved by DCGI for 
treatment of adult men with metastatic castration-resistant prostate cancer whose disease has 
progressed on or after docetaxel therapy on 28 April 2016 and commercially available on 
July 2016. As of 26 March 2017, 174 patients have received the treatment.  
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. 
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 


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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 
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 


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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 FDA and EMA and approved in 95 countries including 
India for CRPC. The safety profile of enzalutamide in subjects with CRPC is derived 
primarily from 2 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. 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 (Androgen 
deprivation therapy).  
Findings from the 2 phase 3 CRPC studies showed that adverse events (AEs) occurring in at 
least 5% of the subjects treated with 160 mg/day enzalutamide (n = 1671) and at an incidence 
of at least 2% greater than in placebo subjects were: asthenia, fatigue, back pain, diarrhea, 
constipation, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, 
muscular weakness, insomnia, spinal cord compression, dysgeusia, hematuria, anxiety, 
hypertension, fall, decreased appetite and weight decreased. The proportion of subjects with 
AEs associated with discontinuation of study drug in the combined controlled population was 
17.7% in the enzalutamide group and 23.5% in the placebo group. Seizures occurred in 
7 (0.9%) of the enzalutamide-treated subjects and none (0%) of the placebo-treated subjects 
in the blinded CRPC2 (AFFIRM) study.  A lower seizure rate was observed in MDV3100-03 
(PREVAIL) study (1 enzalutamide-treated subject [0.1%]). 
There have been rare reports of posterior reversible encephalopathy syndrome (PRES) in 
subjects receiving enzalutamide.  PRES is a rare, reversible, neurological disorder that can 
present with rapidly evolving symptoms including seizure, headache, confusion, blindness 
and other visual and neurological disturbances, with or without associated hypertension. 
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. 


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The efficacy of enzalutamide in subjects with metastatic prostate cancer who progressed on 
ADT has been demonstrated in 2 randomized controlled phase 3 studies including 
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.  
Both studies showed a statistically significant advantage of enzalutamide treatment over 
placebo across multiple clinically relevant endpoints such as Overall survival (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).  Notably, 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; Hazard ratio (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). The updated analysis of overall survival was consistent with the interim 
analysis and showed a clinically meaningful and statistically significant decrease in the risk 
of death in patients randomized to enzalutamide compared with placebo (hazard ratio 0.767 
[95% CI: 0.666, 0.882]). The updated median overall survival was 35.3 months (95% CI: 
32.2, NYR) in the enzalutamide group and 31.3 months (95% CI: 28.8, 34.2) in the placebo 
group (cutoff date of 01 Jun 2014 with a total of 784 deaths). 
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 


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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. 
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 
(Metastatic hormone sensitive prostate cancer) patients in this study is expected to be 
consistent with the established safety profile for enzalutamide.  To date, there are 9 important 
identified risks associated with enzalutamide (seizure, PRES, hypertension, fall, neutrophil 
count decreased, nonpathological fracture, cognitive/memory impairment, interactions with 
strong inhibitors or inducers of CYP2C8 and interactions with medicinal products that are 
substrates of CYP3A4, CYP2C9 or CYP2C19). 
While serious adverse events (SAEs) such as seizure and PRES 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. 
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 Indian men with progressive mCRPC 
previously treated with docetaxel-based chemotherapy. 
The totality of the efficacy and safety data demonstrate a favorable benefit-risk balance for 
the use of enzalutamide in Indian men with progressive mCRPC previously treated with 
docetaxel-based chemotherapy. 
2 
STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS 
2.1 
Study Objective(s) 
The objective is to evaluate the safety and efficacy of enzalutamide in Indian patients with 
progressive mCRPC previously treated with docetaxel-based chemotherapy as per locally 
approved prescribing information. 
2.1.1 Primary Objective 
To evaluate the safety and tolerability of enzalutamide in Indian patients with progressive 
mCRPC previously treated with docetaxel-based chemotherapy. 
2.1.2 Secondary Objective 
• To evaluate the effect of enzalutamide on PSA. 


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2.2 
Study Design and Dose Rationale 
2.2.1 
Study Design 
This study is a multicenter Phase 4, open-label, single-arm, safety and efficacy study of 
enzalutamide (160 mg/day) in patients with progressive mCRPC who have previously been 
treated with docetaxel-based chemotherapy. Approximately 50 patients will be enrolled and 
treated with enzalutamide 160 mg once daily until study discontinuation criteria is met. 
Safety and tolerability will be assessed by the collection of adverse events, vital signs, 
physical examinations and safety laboratory evaluations. 
PSA will be collected for assessment of prostate cancer status on Screening Visit, Days 1, 29, 
57, 85, 169, every subsequent 84 days and Safety Follow-up Visit. 
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 including commercial 
enzalutamide for prostate cancer, whichever occurs first. 
2.2.2 
Dose Rationale 
Enzalutamide 160 mg administered orally, once daily, is the daily dose recommended by 
regulatory agencies in India where enzalutamide is approved. 
2.3 
Endpoints  
2.3.1 
Primary Endpoints 
 Safety 
• 
Nature, frequency and severity of adverse events 
• 
Safety laboratory tests: biochemistry and hematology 
• 
Physical examination 
• 
Vital signs (blood pressure, pulse and temperature) 
2.3.2 
Secondary Endpoints  
Efficacy 
• 
PSA response rate (≥ 50% reduction from baseline) 
3 
STUDY POPULATION 
3.1 
Selection of Study Population  
The study population will include approximately 50 men with progressive mCRPC 
previously treated with docetaxel-based chemotherapy. 
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 must be 


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obtained from the subject or legally authorized representative prior to any study-related 
procedures (including withdrawal of prohibited medication, if applicable). 
2. Subject is 18 years or more 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. 
4. Subject with established diagnosis of metastatic castration-resistant prostate carcinoma. 
5. Being newly initiated on Xtandi treatment (Enzalutamide) based on independent clinical 
judgment of treating physicians as per locally approved prescribing information. 
6. Subject has an estimated life expectancy of ≥ 6 months as assessed by the Investigator.  
7. A sexually active male subject with female partner(s) who are of childbearing potential 
is eligible if: 
• 
Agree to use a male condom starting at screening and continue throughout study 
treatment and for 3 months after the final study drug administration.  
• 
If the male subject has not had a vasectomy or is not sterile as defined below their 
female partner(s) is utilizing 1 form of highly effective birth control starting at 
screening and continue throughout study treatment and for 3 months after the final 
study drug administration. 
• 
Consistent and correct usage of established hormonal contraceptives that inhibit 
ovulation, 
• 
Established intrauterine device (IUD) or intrauterine system (IUS). 
• 
Bilateral tubal occlusion 
• 
Vasectomy (A vasectomy is a highly effective contraception method provided the 
absence of sperm has been confirmed. If not, an additional highly effective method 
of contraception should be used) 
• 
Male is sterile due to a bilateral orchiectomy 
• 
Sexual Abstinence is considered a highly effective method only if defined as 
refraining from heterosexual activity during the entire period of risk associated with 
the study drug. The reliability of sexual abstinence needs to be evaluated in relation 
to the duration of the study and the preferred and usual lifestyle of the participant 
8. Male subject with a pregnant or breastfeeding partner(s) must agree to remain abstinent 
or use a condom for the duration of the pregnancy or time partner is breastfeeding 
throughout the study period and for 3 months after the final study drug administration. 
9. Male subject must not donate sperm starting at screening and throughout the study 
period, and for 3 months after the final study drug administration. 
10. Subject agrees not to participate in another interventional study while participating in the 
present study. 
3.3 
Exclusion Criteria 
Subject will be excluded from participation if any of the following apply: 
1. Subject who is not eligible to receive Xtandi as per the locally approved prescribing 
information. 
2. Subject participating or planning to participate in any interventional drug trial during the 
course of this trial. 
3. Subject has received investigational study within 28 days or 5 half-lives, whichever is 
longer, prior to screening. 
4. Subject has any condition which, in the investigator’s opinion, makes the subject 


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unsuitable for study participation. 
4 
TREATMENT(S) 
4.1 
Identification of Investigational Product(s) 
4.1.1 
Study Drug(s) 
Enzalutamide 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).   
 
4.2 
Packaging and Labeling 
The clinical materials are blister packaged according to this study design using the appropriate 
transparent thermo formable film(s) with foil backing and placed in wallets for individual 
subject dispensing. The capsules should be stored in the original package in a secure location 
with limited access at room temperature.  
All study drug(s) used in this study will be prepared, packaged, and labeled under the 
responsibility of qualified staff at Astellas Pharma Inc. (API) or Sponsor’s designee in 
accordance with API or Sponsor’s designee standard operating procedures (SOPs), Good 
Manufacturing Practice (GMP) guidelines, ICH-GCP guidelines, and applicable local 
laws/regulations. 
Each blister sheet will bear a label conforming to regulatory guidelines, GMP and local laws 
and regulations, which identifies the contents as investigational drug. 
The study centers will be provided wallet-type cardboard integrated blister packaging 
containing 28 capsules of enzalutamide 40 mg capsules. 
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; 
● 
Study drug is handled and stored according to labeled storage conditions; 
● 
Study drug with appropriate expiry/retest only is dispensed to study subjects in 
accordance with the protocol, and; 
● 
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. 


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Study drug inventory and accountability records for the study drugs will be kept by the 
Investigator. Study drug accountability throughout the study must be documented and 
reconciled. The following guidelines are therefore pertinent: 
● 
The Investigator 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 or designee will keep the study drugs in a pharmacy 
or other locked and secure storage facility under controlled storage conditions, accessible 
only to those authorized by the investigator to dispense these study drugs. 
● 
A study drug inventory will be maintained by the investigator, head of study site or 
designee. The inventory will include details of material received and a clear record of 
when they were dispensed and to which subject. 
● 
At the conclusion or termination of this study, the Investigator 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. 
● 
The site staff must return study drug to the sponsor or designee at the end of the study or 
upon expiration unless otherwise approved by the sponsor. 
4.4 
Blinding 
This section is not applicable as this is an open label study.  
4.5 
Assignment and Allocation 
Subjects will be entered into the IRT system at screening and assigned a subject number. 
Randomization will be not performed as this is single-arm study. 
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. Study drug is to be taken until disease progression, 
unacceptable toxicity or any other discontinuation criteria are met. 
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.  


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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. 
5.1.3.1 Required Concomitant Treatment 
All subjects are required to receive background therapy with ADT, either bilateral orchiectomy 
or a GnRH agonist or antagonist, which must be maintained during study treatment, as per 
standard of care (SOC). 
A GnRH 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; 
• Abiraterone 
• Biologic or other agents with antitumor activity against prostate cancer (with the 
exception of those therapies identified in inclusion/exclusion criteria); 


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• 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, dehydroepiandrosterone, etc.); 
• Investigational agents. 
In addition, bisphosphonates and denosumab are prohibited unless stabilized for 2 weeks 
prior to day 1 and held constant throughout study treatment or administered for diagnosis of 
osteoporosis. 
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, nafcillin, 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. 
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; 


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• 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.  
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. 
5.1.5 
Criteria for Continuation of Treatment  
This study does not set an expansion cohort, and long-term study in which this study's subject 
can participate is not scheduled either. 
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. 
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. 


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5.3 
Efficacy and Pharmacokinetics Assessments 
5.3.1 
Efficacy Assessments 
PSA response ≥ 50% is defined as ≥ 50% reductions in PSA level from baseline to the lowest 
post-baseline PSA result as determined by the central laboratory, with a consecutive 
assessment conducted at least 3 weeks later to confirm the PSA response. 
5.3.2 
Pharmacokinetics Assessments 
Not applicable 
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. 
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 including commercial enzalutamide, 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. 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 2]. 
Table 2: Laboratory Assessments 
Hematology 
Biochemistry 
Other 
Red blood cell count 
White blood cell count 
White blood cell differential 
Hemoglobin 
Albumin 
Alkaline phosphatase 
Alanine aminotransferase 
Aspartate aminotransferase 
PSA 


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Hematology 
Biochemistry 
Other 
Hematocrit 
Platelet count 
 
Blood urea nitrogen 
Calcium 
Creatinine 
Glucose 
Phosphorus 
Potassium 
Sodium 
Total bilirubin 
Total protein 
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 
Complete physical examination will be performed at the screening visit to assess weight, 
height, general appearance, skin, eyes, ears, nose, throat, neck, cardiovascular, respiratory, 
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]. 
5.5 
Adverse Events and Other Safety Aspects 
5.5.1 
 Definition of Adverse Events  
An AE is any untoward medical occurrence in a subject, temporally associated with the use 
of a medicinal product, whether or not considered related to the medicinal product. An AE 
can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of a 
medicinal product. 
In order to identify any events that may be associated with study procedures and could lead 
to a change in the conduct of the study, Astellas collects AEs even if the subject has not 
received study drug treatment. AE collection begins after the signing of the informed consent 
and will be collected until subject is determined to be ineligible for study entry, or initiation 
of new therapy for prostate cancer including commercial enzalutamide, or 30 days after the 
last dose of study drug, whichever occurs first. 
5.5.1.1 Abnormal Laboratory Findings 
Any abnormal laboratory test result (e.g. hematology, clinical chemistry, or urinalysis) or 
other safety assessment (e.g., ECGs, radiolographic scans, vital signs measurements, physical 
examination), including those that worsen from baseline, that is considered to be clinically 
significant in the medical and scientific judgment of the investigator and not related to 
underlying disease, is to be reported as an (S)AE. 


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Any clinically significant abnormal laboratory finding or other abnormal safety assessment 
which is associated with the underlying disease does not require reporting as an (S)AE, 
unless judged by the investigator to be more severe than expected for the subject’s condition. 
Repeating an abnormal laboratory test or other safety assessment, in the absence of any of the 
above criteria, does not constitute an AE.  Any abnormal test result that is determined to be 
an error does not require reporting as an AE. 
5.5.1.2 Potential Cases of Drug-Induced Liver Injury 
Refer to [Appendix 12.2 Liver Safety Monitoring and Assessment] for detailed 
instructions on Drug Induced Liver Injury (DILI). Abnormal values in aspartate transaminase 
(AST) and/or alanine transaminase (ALT) concurrent or with abnormal elevations in total 
bilirubin that meet the criteria outlined in [Appendix 12.2 Liver Safety Monitoring and 
Assessment], in the absence of other causes of liver injury, are considered potential cases of 
drug-induced liver injury (potential Hy’s Law cases) and are always to be considered 
important medical events and reported per [Section 5.5.5 Reporting of Serious Adverse 
Events]. 
5.5.1.3 Disease Progression and Study Endpoints 
Under this protocol, the following event(s) will not be considered as an(S)AE: 
• 
Disease Progression: events including defined study endpoints that are clearly consistent 
with the expected pattern of progression of the underlying disease are not to be recorded 
as AEs.  These data will be captured as efficacy assessment data as outlined in Section 
5.3.1. If there is any uncertainty as to whether an event is due to anticipated disease 
progression and/or if there is evidence suggesting a causal relationship between the study 
drug and the event, it should be reported as an (S)AE. 
• 
Pre-planned and elective hospitalizations or procedures for diagnostic, therapeutic, or 
surgical procedures for a pre-existing condition that did not worsen during the course of 
the clinical trial. These procedures are collected per the eCRFs Completion Guidelines. 
5.5.2 
Definition of Serious Adverse Events (SAEs) 
An AE is considered “serious” if, in the view of either the investigator or sponsor, it results in 
any of the following outcomes:  
• Results in death 
• Is life-threatening (an AE is considered “life-threatening” if, in the view of either the 
investigator or sponsor, its occurrence places the subject at immediate risk of death. It does 
not 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 inpatient hospitalization (except for planned procedures as allowed per study) or 
leads to prolongation of hospitalization (except if prolongation of planned hospitalization is 


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not caused by an AE). Hospitalization for treatment/observation/examination caused by AE 
is to be considered as serious.)  
• Other medically important events (defined in paragraph below) 
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, usually are 
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.  
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. 
5.5.3 
Criteria for Causal Relationship to Study Drug 
The investigator is obligated to assess the relationship between the study drug and each 
occurrence of each (S)AE. The investigator will use clinical judgment to determine the 
relationship. The investigator should also use the Investigator’s Brochure (IB). The 
investigator is requested to provide an explanation for the causality assessment for each SAE 
(Serious adverse event) and must document this on the SAE worksheet. The causality 
assessment is one of the criteria used when determining regulatory reporting requirements. 
The investigator may revise his/her assessment of causality in light of new information 
regarding the SAE and shall send an SAE follow-up report and update the eCRF (Electronic 
case report form) with the new information and updated causality assessment. Following a 
review of the relevant data, the causal relationship between the study drug and each (S)AE 
will be assessed by answering ‘yes’ or ‘no’ to the question “Do you consider that there is a 
reasonable possibility that the event may have been caused by the study drug”. 
When making an assessment of causality, the following factors are to be considered when 
deciding if there is evidence and/or arguments to suggest there is a ‘reasonable possibility’ 
that an (S)AE may have been caused by the study drug (rather than a relationship cannot be 
ruled out) or if there is evidence to reasonably deny a causal relationship: 
 
• 
Plausible temporal relationship between exposure to the study drug and (S)AE onset 
and/or resolution. Has the subject actually received the study drug? Did the (S)AE occur 
in a reasonable temporal relationship to the administration of the study drug?  
• 
Plausibility; i.e., could the event been caused by the study drug? Consider biologic and/or 
pharmacologic mechanism, half-life, literature evidence, drug class, preclinical and 
clinical study data, etc. 
• 
Dechallenge/Dose reduction/Rechallenge:  


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o Did the (S)AE resolve or improve after stopping or reducing the dose of the 
suspect drug? Also consider the impact of treatment for the event when evaluating 
a dechallenge experience.  
o Did the (S)AE reoccur if the suspected drug was reintroduced after having been 
stopped?   
• 
Laboratory or other test results; a specific lab investigation supports the assessment of the 
relationship between the (S)AE and the study drug (e.g., based on values pre-, during and 
post-treatment) 
• 
Available alternative explanations independent of study drug exposure; such as other 
concomitant drugs, past medical history, concurrent or underlying disease, risk factors 
including medical and family history, season, location, etc. and strength of the alternative 
explanation 
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to delegated CRO. However, it is very important 
that the investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to delegated CRO. With limited or insufficient information 
about the event to make an informed judgment and in absence of any indication or evidence 
to establish a causal relationship, a causality assessment of ‘no’ is to be considered. In such 
instance, the investigator is expected to obtain additional information regarding the event as 
soon as possible and to re-evaluate the causality upon receipt of additional information. 
5.5.4 
Criteria for Defining the Severity of an Adverse Event 
AEs, including abnormal clinical laboratory values, will be graded using the 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 (SAEs) 
The collection of AEs and the expedited reporting of SAEs will start following receipt of the 
informed consent and will continue to safety follow-up visit.  


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In the case of a SAE, the investigator must contact delegated CRO by fax or email 
immediately (within 24 hours of awareness). 
The investigator must complete and submit a SAE worksheet containing all information that 
is required by local and/or regional regulations to delegated CRO by email or fax 
immediately (within 24 hours of awareness).   
For contact details, see [Section II Contact Details of Key Sponsor's Personnel]. Fax or email 
the SAE Worksheet to: 
IQVIA RDS East Asia Pte. Ltd. 
Lifecycle Safety 
Fax number: 000-800001-6750 
Email: QLS_Enzalutamide@iqvia.com 
If there are any questions, or if clarification is needed regarding the SAE, please contact the 
sponsor's Medical Monitor/Study Physician or his/her designee [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, SAE Worksheet and on 
the (e)CRF. 
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 criteria),  
• 
Causal relationship to the study drug (including reason), and 
• 
The drug provided (if any)  
The sponsor or sponsor's designee will submit expedited safety reports (e.g., IND Safety 
Reports, CIOMS-I) to Competent Authorities (CA) and concerned Ethics Committee (cEC) 
per current local regulations, and will inform the investigators of such regulatory reports as 
required. Investigators must submit safety reports as required by their IRB/local IEC within 
timelines set by regional regulations (e.g., EU, FDA) where required. 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 require submission per local requirements. 
The heads of the study sites/investigators should provide written documentation of IRB/IEC 
notification for each report to the sponsor. 


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The investigator may contact the sponsor's Medical Monitor/Study Physician for any other 
problem related to the safety, welfare, or rights of the subject. 
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 by the investigator.  
 If after the protocol defined AE collection period [see Section 5.5.1 Definition of Adverse 
Events], an AE progresses to a SAE, or the investigator learns of any (S)AE including death, 
where he/she considers there is reasonable possibility it is related to the study drug treatment 
or study participation, the investigator must promptly notify the sponsor. 
5.5.7 
Special Situations  
Certain Special Situations observed in association with the study drug(s), such as incorrect 
administration (e.g., wrong dose of study drug, comparator, or background therapy) are 
collected in the eCRF, as Protocol Deviation per [Section 8.1.6 Major Protocol Deviations] 
or may require special reporting, as described below. These Special Situations are not 
considered AEs, but do require to be communicated to Astellas as per the timelines defined 
below. 
If a Special Situation is associated with, or results in, an AE, the AE is to be assessed 
separately from the Special Situation and captured as an AE in eCRF. If the AE meets the 
definition of a SAE, the SAE is to be reported as described in [Section 5.5.5 Reporting of 
Serious Adverse Events] and the details of the associated Special Situation are to be included 
in the clinical description on the SAE worksheet. 
The Special Situations are: 
• Pregnancy 
• Medication Error, Overdose and “Off label use” 
• Misuse/abuse 
• Occupational exposure 
• Suspected Drug-Drug interaction 
5.5.7.1 Pregnancy 
The investigator will attempt to collect pregnancy information on any female partner of a 
male subject who becomes pregnant during the study dosing period or within 90 days from 
the discontinuation of dosing and report the information to delegated CRO according to the 
timelines in [Section 5.5.5 Reporting of Serious Adverse Events] using the Pregnancy 
Reporting Form.  
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. 


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While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
termination (including elective termination) of a pregnancy is to be reported for a female 
study subject as an AE in the eCRF or SAE per [Section 5.5.5 Reporting of Serious Adverse 
Events]. For (S)AEs experienced by a female partner of a male subject, (S)AEs are to be 
reported via the Pregnancy Reporting Form. Additional information regarding the outcome of 
a pregnancy when also categorized as an SAE is mentioned below: 
• "Spontaneous abortion" includes miscarriage, abortion and missed abortion. 
• 
Death of a newborn or infant within 1 month after birth is to be reported as an SAE 
regardless of its relationship with the study drug. 
• 
If an infant who dies more than 1 month after the birth, is to be reported if a relationship 
between the death and intrauterine exposure to the study drug is judged as "possible" by 
the investigator. 
• 
Congenital anomaly (including anomaly in miscarried fetus) 
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. (S)AEs 
experienced by the newborn/infant should be reported via the Pregnancy Reporting Form. 
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery 
date. 
5.5.7.2 Medication Error, Overdose and “Off-Label Use” 
If a Medication Error, Overdose or “Off label Use” (i.e. use outside of what is stated in the 
protocol) is suspected, refer to [Section 8.1.6 Major Protocol Deviations]. Any associated 
(S)AEs are to be reported in the eCRF. If the AE meets the definition of a SAE, the SAE is 
also to be reported as described in [Section 5.5.5 Reporting of Serious Adverse Events] 
together with the details of the medication error, overdose or “Off-Label Use”. 
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. 
5.5.7.3 Misuse/Abuse 
If misuse or abuse of the study drug(s) is suspected, the investigator must forward the Special 
Situation worksheet to delegated CRO by fax or email immediately (within 24 hours of 
awareness). Any associated (S)AEs are to be reported in the eCRF. If the AE meets the 
definition of a SAE, the SAE is also to be reported as described in [Section 5.5.5 Reporting 
of Serious Adverse Events] together with details of the misuse or abuse of the study drug(s). 
5.5.7.4 Occupational Exposure 
If occupational exposure (e.g. inadvertent exposure to the study drug(s) of site staff whilst 
preparing it for administration to the patient) to the study drug(s) occurs, the investigator 


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must forward the Special Situation worksheet to delegated CRO by fax or email immediately 
(within 24 hours of awareness).  Any associated (S)AEs occurring to the individual 
associated with or resulting from the Special Situation are to be reported on the Special 
Situations worksheet. 
5.5.7.5 Suspected Drug-Drug Interaction 
If a suspected drug-drug interaction associated with the study drug(s) is suspected, the 
investigator must forward the Special Situation worksheet to delegated CRO by fax or email 
immediately (within 24 hours of awareness). Any associated (S)AEs are to be reported in the 
eCRF. If the AE meets the definition of a SAE, the SAE is also to be reported as described in 
[Section 5.5.5 Reporting of Serious Adverse Events] together with details of the suspected 
drug-drug interaction.  
5.5.8 
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 investigator will also inform the subjects, who will be required to sign an updated 
informed consent form in order to continue in the clinical study. 
5.6 
Test Drug Concentration 
Not applicable  
5.7 
Other Measurements, Assessments or Methods 
Not applicable 
5.8 
Total Amount of Blood 
The total amount of blood 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 from 
screening visit through day 169/week 25 visit is approximately 50 mL.  
6 
DISCONTINUATION 
6.1 
Discontinuation of Individual Subject(s)  
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. 


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Discontinuation Criteria from Study Drug Treatment for Individual Subjects: 
• 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. 
• 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 and/or PSA progression as 
confirmed by the Investigator and is no longer deriving clinical benefit. Imaging test can 
be done at the discretion of the investigator and are not part of the study. 
• Subject has discontinued ADT (GnRH agonist/antagonist) and has a testosterone value in 
the noncastrate range (> 50 ng/dL). 
• Subject who is, in the opinion of the Investigator or the Medical Monitor, non-compliant 
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 30 day 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. 
• 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. 
6.3 
Discontinuation of the Study 
The sponsor may terminate this study prematurely, either in its entirety or at any study site, 
for reasonable cause provided that written notice is submitted in advance of the intended 
termination. Advance notice is not required if the study is stopped due to safety concerns. If 
the sponsor terminates the study for safety reasons, the sponsor will immediately notify the 
investigator and subsequently provide written instructions for study termination. 


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7 
STATISTICAL METHODOLOGY 
A Statistical Analysis Plan (SAP) will be written to provide details of the analysis, along with 
specifications for tables, listings and figures to be produced. The SAP will be finalized before 
the database hard lock at the latest. Any changes from the analyses planned in SAP will be 
justified in the Clinical Study Report (CSR). 
In general, continuous data will be summarized with descriptive statistics (number of 
subjects, mean, SD, minimum, median and maximum), and frequency and percentage for 
categorical data. 
7.1 
Sample Size 
The sample size of 50 subjects is not based on a statistical power calculation. 
7.2 
Analysis Sets 
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 
Full Analysis Set (FAS) 
The full analysis set will consist of all subjects who received at least one dose of study drug 
and have at least one post baseline measurement. This will be the primary analysis set for 
efficacy analyses. 
7.2.2 
Safety Analysis Set (SAF) 
The SAF consists of all subjects who took at least 1 dose of study drug, and will be used for 
safety analyses. 
For the statistical summary of the safety data, the safety analysis set (SAF) will be used. 
7.3 
Demographics and Baseline Characteristics  
Demographics and baseline characteristics will be summarized for the FAS and SAF. 
7.3.1 
Subject Disposition  
The number and percentage of subjects who completed and discontinued treatment and 
reasons for treatment discontinuation will be presented. Similar tables for screening 
disposition, investigational period disposition and follow-up disposition will also be 
presented. All disposition details and dates of first and last evaluations for each subject will 
be listed. 
7.3.2 
Previous and Concomitant Medications  
All previous and concomitant medications will be presented in a listing. 
7.3.3 
Medical History  
Medical history for each subject will be presented in a listing. 


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7.4 
Analysis of Efficacy  
Efficacy analysis will be conducted on the FAS. 
PSA response ≥ 50% will be calculated for subjects with PSA values at the baseline 
assessment and at least 1 post-baseline assessment. 
7.5 
Analysis of Safety 
Safety analysis will be conducted on the SAF. 
7.5.1 
Adverse Events  
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).   
The number and percentage of subjects with AEs, SAEs, AEs leading to withdrawal of 
treatment, and AEs related to study drug will be summarized by system organ class, preferred 
term. The number and percentage of AEs by severity will also be summarized. All AEs will 
be listed. 
7.5.2 
Laboratory Assessments  
For quantitative laboratory measurements descriptive statistics will be used to summarize 
results and change from baseline for subjects in the SAF.  
Shifts relative to normal ranges from baseline to each time point during treatment period in 
lab tests will also be tabulated.  Laboratory data will be displayed in listings. 
7.5.3 
Physical Examination  
Physical examination will be listed. 
7.5.4 
Vital Signs  
Descriptive statistics will be used to summarize vital sign results and changes from baseline 
for subjects in the SAF. Vital signs data will be displayed in listings. 
7.6 
Analysis of Pharmacokinetics 
Not applicable  
7.7 
Interim Analysis (and Early Discontinuation of the Clinical Study) 
An interim assessment will be conducted at 6 month from first subject enrollment, with 
respect to safety. The report will be submitted to the health authority. 
7.8 
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information 
The final decision on handling of missing data, outliers, and the visit windows for analysis 
will be made before hard lock.  


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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. 
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.  
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. 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, sex, race, ethnicity, height and body weight) 
• 
Inclusion and exclusion criteria details 
• 
Participation in study and original signed and dated informed consent forms  
• 
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 
• 
Details of dispensing and return of study drug  
• 
Reason for premature discontinuation 
• 
Assigned subject number  
• 
Staff notes and telephone conversation documentation; 


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• 
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 delegated CRO is responsible for monitoring the clinical study to ensure that 
subject's human rights, safety, and well-being are protected, that the study is properly 
conducted in adherence to the current protocol and GCP, and study data reported by the 
investigator/sub-investigator are accurate and complete and that they are verifiable with 
study-related records such as source documents. The sponsor is responsible for assigning 
study monitor(s) to this study for proper monitoring. They will monitor the study in 
accordance with planned monitoring procedures.   
8.1.4 
Direct Access to Source Data/Documents 
The investigator and the study site must accept monitoring and auditing by the sponsor or 
delegated CRO as well as inspections from the IRB/IEC and relevant regulatory authorities. 
In these instances, they must provide all study-related records, such as source documents 
[refer to Section 8.1.2 Specification of Source Documents] when they are requested by the 
sponsor monitors and auditors, the IRB/IEC, or regulatory authorities. The confidentiality of 
the subject's identities shall be well protected consistent with local and national regulations 
when the source documents are subject to direct access. 
8.1.5 
Data Management 
Data Management will be coordinated by the Japan-Asia Data Science or designee of the 
sponsor in accordance with the SOPs for data management. All study-specific processes and 
definitions will be documented by Data Management. Coding of medical terms and 
medications will be performed using MedDRA and World Health Organization (WHO) Drug 
Dictionary, respectively. 
8.1.6 
Major Protocol Deviations 
A major 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 study 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. 
The major protocol deviation criteria are 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, 


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PD4 - Received excluded concomitant treatment. 
When a major 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 major deviation impacts the safety of a subject, the investigator must contact the sponsor 
immediately. 
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 (TMF).   
8.1.7 
End of Trial in All Participating Countries 
The end of trial 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 
Institutional Review Board (IRB) / Independent Ethics Committee (IEC) / 
Competent Authorities (CA) 
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol amendments, 
the Investigator’s Brochure, the informed consent 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.  


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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.  
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 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 informed consent form will 
be given to the subject and the original will be placed in the subject’s medical record. An 
entry must also be made in the subject’s dated source documents to confirm that informed 
consent was obtained prior to any study-related procedures and that the subject received a 
signed copy. 
The signed consent forms will be retained by the investigator and made available (for review 
only) to the study monitor and auditor regulatory authorities and other applicable individuals 
upon request. 
8.2.3.2 Supply of New and Important Information Influencing the Subject’s Consent 
and Revision of the Written Information 
1. The investigator or his/her representative will immediately inform the subject orally 
whenever new information becomes available that may be relevant to the subject’s 
consent or may influence the subject’s willingness to continue to participate in the study 
(e.g., report of serious drug adverse drug reaction). The communication must be 
documented in the subject’s medical records and whether the subject is willing to remain 
in the study or not must be confirmed and documented.  
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 informed consent 
form. A copy of the signed informed consent form will be given to the subject and the 
original will be placed in the subject’s medical record. An entry must be made in the 
subject’s records documenting the re-consent process. 
8.2.4 
Subject Confidentiality and Privacy 
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 


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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. 
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 agrees to comply and process personal data in accordance with all applicable 
privacy laws and regulations, including, without limitation, the Personal Information 
Protection Law in Japan and Privacy laws in the US.  If the services will involve the 
collection or processing of personal data (as defined by applicable data protection legislation) 
within the European Economic Area (EEA), then sponsor shall serve as the controller of such 
data, as defined by the European Union (EU) Data Protection Directive, and Investigator 
and/or third party  shall act only under the instructions of the sponsor in regard to personal 
data   If sponsor is not based in the EEA, sponsor must appoint a third party to act as its local 
data protection representative or arrange for a co-controller established in the EU for data 
protection purposes in order to comply with the Directive. 
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) 


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• 
Investigator’s Brochure (and amendments, where applicable) 
• 
eCRFs  
• 
Study drug with all necessary documentation 
• 
Study contract 
In order to start the study, the investigator and/or study site is required to provide the 
following documentation to the sponsor:  
• 
Signed Investigator's Statement in this protocol and eCRF  
• 
Current Curricula Vitae of all investigators 
• 
List of sub-investigators and collaborators  
• 
IRB approval of the protocol, protocol amendments (if applicable) including a 
membership list with names and qualification (COPY) 
• 
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. 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 on the CRFs supplied 
for each subject. 
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 non-substantial 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. 
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. 


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8.3.4 
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 studies are conducted and data are generated, documented, 
recorded, and reported in compliance with the protocol, GCP, and applicable regulatory 
requirement(s). Where applicable, the quality assurance and quality control systems and 
written SOPs of the CRO will be applied. 
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, case report forms, and source documents. Direct access to these documents will 
be required by the auditors. 
10 
STUDY ORGANIZATION 
10.1 
Independent Data-Monitoring Committee (IDMC) | Data and Safety 
Monitoring Board (DSMB) | Monitoring Committee | Other 
Evaluation Committee(s) 
Not applicable 
10.2 
Other Study Organization 
Not applicable 


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11 
REFERENCES  
Bohl CE, Gao W, Miller DD, Bell CE, Dalton JT. Structural basis for antagonism and resistance 
ofbicalutamide in prostate cancer. Proc Natl Acad Sci U S A. 2005 Apr 26;102(17):6201-6. 
Epub 2005 Apr 15. 
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 Jan-
Mar;10(1):93-8. 
de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, et al. Abiraterone and increased 
survival in metastatic prostate cancer. N Engl J Med. 2011 May 26;364(21):1995-2005. 
de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I, et al. Prednisone 
pluscabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing 
after docetaxel treatment: a randomised open-label trial. Lancet. 2010 Oct 2;376(9747):1147-
54. 
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. 
International Agency for Research on Cancer (World Health Organization). Population Factsheets - 
GLOBOCAN 2012: Estimated cancer incidence, mortality and prevalence worldwide in 2012 
[Internet]. cited 27 Feb 2014. Available from: 
http://globocan.iarc.fr/Pages/fact_sheets_population.aspx 
Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, et al. Sipuleucel-T 
immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010 Jul 29;363(5):411-
22. 
Lissbrant IF, Garmo H, Widmark A, Stattin P. Population-based study on use of chemotherapy in 
men with castration resistant prostate cancer. Acta Oncol. 2013;52(8):1593-601. 
Parker C, Nilsson S, Heinrich D, Helle SI, O'Sullivan JM, Fosså SD, et al. Alpha emitter radium-223 
and survival in metastatic prostate cancer. N Engl J Med. 2013 Jul 18;369(3):213-23. 
Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, et al. Abiraterone in 
metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013 Jan 
10;368:138-48. 
Scher HI, Sawyers CL. Biology of progressive, castration-resistant prostate cancer: directed therapies 
targeting the androgen-receptor signaling axis. J Clin Oncol. 2005 Nov 10;23(32):8253-61. 
Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, et al. Docetaxel plus prednisone or 
mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med.2004 Oct 
7;351(15):1502-12. 
Tran C, Ouk S, Clegg NJ et al. Development of a second-generation antiandrogen for treatment of 
advanced prostate cancer. Science 2009;324(5928):787-80. 
 


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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; 
• Abiraterone 
• Biologic or other agents with antitumor activity against prostate cancer (with the 
exception of those therapies identified in inclusion/exclusion criteria); 
• 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, dehydroepiandrosterone, etc.); 
• Investigational agents. 
In addition, bisphosphonates and denosumab are prohibited unless stabilized for 2 weeks 
prior to day 1 and held constant 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 (AT) to > 3 × ULN (to > 5 × ULN in subjects with liver metastases) or 
bilirubin > 2 × ULN should undergo detailed testing for liver enzymes (including at least ALT, 
AST, ALP, and TBL). Testing should be repeated within 72 hours of notification of the test 
results. For studies for which a central laboratory is used, alerts will be generated by the central 
laboratory regarding moderate and severe liver abnormality to inform the investigator, study 
monitor and study team. Subjects should be asked if they have any symptoms suggestive of 
hepatobiliary dysfunction. 
Definition of Liver Abnormalities 
Confirmed abnormalities will be characterized as moderate and severe where ULN: 
  
ALT or AST 
 
Total Bilirubin 
Moderate 
> 3 x ULN (in patients without 
liver metastases), > 5 x ULN (in 
patients 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 International Normalized Ratio (INR) > 1.5 (If INR testing 
is applicable/evaluated). 
● 
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%).  
The investigator may determine that abnormal liver function results, other than as described 
above, may qualify as moderate or severe abnormalities and require additional monitoring and 
follow-up. 
Follow-up Procedures 
Confirmed moderate and severe abnormalities in hepatic functions should be thoroughly 
characterized by obtaining appropriate expert consultations, detailed pertinent history, physical 
examination and laboratory tests. The site should complete the liver abnormality case report 
form (LA-CRF) that has been developed globally and can be activated for any study or 
appropriate document. Subjects with confirmed abnormal liver function testing should be 
followed as described below.  
Confirmed moderately abnormal LFTs should be repeated 2 to 3 times weekly then weekly or 
less if abnormalities stabilize or the study drug has been discontinued and the subject is 
asymptomatic.   


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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 a SAE. The 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 is to be recorded as ”AEs” in the (e)CRF. Illnesses and 
conditions such as hypotensive events, and decompensated cardiac disease that may 
lead to secondary liver abnormalities should be noted. Nonalcoholic steatohepatitis is 
seen in obese hyperlipoproteinemic, and/or diabetic patients and may be associated with 
fluctuating AT 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, is to be entered in the (e)CRF. 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:  
o Acute viral hepatitis (A, B, C, D, E or other infectious agents),  
o Ultrasound or other imaging to assess biliary tract disease, 
o Other laboratory tests including INR, direct bilirubin. 
● 
Consider gastroenterology or hepatology consultations. 
● 
Submit results for any additional testing and possible etiology on the LA-CRF or an 
appropriate document. 
Study Discontinuation 
In the absence of an explanation for increased LFT’s, such as viral hepatitis, 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 patients with liver metastases). 
● 
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%).  


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In addition, if close monitoring for a subject with moderate or severe hepatic laboratory tests 
is not possible, drug should be discontinued. 
*Hy’s Law Definition:  
[Temple, 2006] 
1. Evidence that a drug can cause hepatocellular-type injury, generally shown by a higher rate 
than control of people with 3 X and greater transaminase elevations over the upper limit of 
normal (2 X elevations are too common in treated and untreated patients to be 
discriminating). 
2. Cases of increased bilirubin (to at least 2X ULN) in people with concomitant transaminase 
elevation to at least 3 X ULN (but it is almost invariably higher) and no evidence of intra-or 
extra-hepatic bilirubin obstruction (elevated alkaline phosphatase) or Gilbert’s syndrome.  
 
[Guidance for Industry titled “Drug-Induced Liver Injury: Premarketing Clinical Evaluation” 
issued by FDA on July 2009] 
1. The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold or 
greater elevations above the ULN of ALT or AST than the (nonhepatotoxic) control drug or 
placebo. 
2. Among trial subjects showing such AT elevations, often with ATs much greater than 
3xULN, one or more also show elevation of serum TBL to >2xULN, without initial findings 
of cholestasis (elevated serum ALP). 
3. No other reason can be found to explain the combination of increased AT and TBL, such 
as viral hepatitis A, B, or C; preexisting or acute liver disease; or another drug capable of 
causing the observed injury.  
References 
Temple R. Hy’s law: Predicting Serious Hepatotoxicity. Pharmacoepidemiol Drug Saf. 
2006 April;15(Suppl 4):241-3. 
Guidance for Industry titled “Drug-Induced Liver Injury: Premarketing Clinical Evaluation” 
issued by FDA on July 2009. 
 


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12.3 
Common Serious Adverse Events 
Not applicable 


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12.4 
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. 
 
 
(GPF v.6.0) 
 
 
 
 
 
 
 
 
 
 



SAP_003.pdf: 
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SAP Final Version 
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Page 1 of 21 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
Final Version 3.0, dated 26-Feb 2024 
 
A Multicenter Phase 4, Open-label, Single-arm, Safety and Efficacy Study of Enzalutamide 
in Indian Patients with Progressive Metastatic Castration-Resistant Prostate Cancer (mCRPC) 
Previously Treated with Docetaxel-Based Chemotherapy 
 
 
 
 
 
 
 
 
 
ISN: 9785-CL-0413 
 
 
 
 
Astellas Pharma Inc. (API) 
 
 
 
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 ···················································· 6 
3 
STUDY OBJECTIVE(S) AND DESIGN ······················································· 6 
3.1 
Study Objective(s) ············································································· 6 
3.1.1 
Primary Objective ········································································ 6 
3.1.2 
Secondary Objective ····································································· 6 
3.2 
Study Design ···················································································· 6 
3.3 
Randomization ·················································································· 6 
4 
SAMPLE SIZE······················································································ 7 
5 
ANALYSIS SETS ·················································································· 7 
5.1 
Full Analysis Set (FAS) ······································································· 7 
5.2 
Safety Analysis Set (SAF) ···································································· 7 
6 
ANALYSIS VARIABLES ········································································ 7 
6.1 
Efficacy Endpoints ············································································· 7 
6.2 
Safety Variables ················································································ 7 
6.3 
Other Variables ················································································· 9 
7 
STATISTICAL METHODOLOGY ··························································· 10 
7.1 
General Considerations ······································································· 10 
7.2 
Study Population ·············································································· 10 
7.2.1 
Disposition of Subjects ································································· 10 
7.2.2 
Protocol Deviations ····································································· 11 
7.2.3 
Demographic and Other Baseline Characteristics ··································· 11 
7.2.4 
Previous and Concomitant Medications ·············································· 13 
7.3 
Study Drugs ···················································································· 13 
7.3.1 
Exposure ·················································································· 13 
7.3.2 
Treatment Compliance ·································································· 13 
7.4 
Analysis of Efficacy ·········································································· 13 
7.5 
Analysis of Safety ············································································· 14 
7.5.1 
Adverse Events ·········································································· 14 
7.5.2 
Clinical Laboratory Evaluation ························································ 15 


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7.5.3 
Vital Signs ················································································ 16 
7.6 
Analysis of PK ················································································· 17 
7.7 
Analysis of PD ················································································· 17 
7.8 
Subgroups of Interest ········································································· 17 
7.9 
Other Analyses ················································································ 17 
7.10 
Interim Analysis (and Early Discontinuation of the Clinical Study) ···················· 17 
7.11 
Handling of Missing Data, Outliers, Visit Windows, and Other Information ········· 17 
7.11.1 
Missing Data ············································································· 17 
7.11.2 
Outliers ··················································································· 17 
7.11.3 
Visit Window for Vital Signs, Clinical Labs and PSA ······························ 18 
8 
DOCUMENT REVISION HISTORY ························································· 19 
9 
REFERENCES ···················································································· 20 
10 
APPENDICES ····················································································· 21 
10.1 
Appendix 1: SIGNATURE ·································································· 21 
 


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I. 
LIST OF ABBREVIATIONS AND KEY TERMS 
List of Abbreviations 
Abbreviations 
Description of abbreviations 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
Alb 
Albumin. 
ALP 
Alkaline Phosphatase 
ALT 
Alanine aminotransferase 
API 
Astellas Pharma Inc. 
AST 
Aspartate aminotransferase 
BMI 
Body Mass Index 
BSA 
Body Surface Area 
CSR 
Clinical Study Report  
CTCAE 
Common Terminology Criteria for Adverse Events 
ECOG 
Eastern Cooperative Oncology Group 
FAS 
Full Analysis Set 
Hb 
Hemoglobin 
HLGT 
High Level Group Term 
HLT 
High Level Term 
ICH  
International Council for Harmonisation 
IHD 
Ischemic Heart Disease 
ISN 
International Study Number 
mCRPC 
Metastatic Castration-Resistant Prostate Cancer 
MedDRA 
Medical Dictionary for Regulatory Activities  
NA 
Not Applicable 
NCI 
National Cancer Institute 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PRES 
Posterior Reversible Encephalopathy Syndrome 
PSA 
Prostate-Specific Antigen 
PT 
Preferred Term 
SAF 
Safety Analysis Set  
SAP 
Statistical Analysis Plan 
SCAR 
Severe Cutaneous Adverse Reactions 
SD 
Standard Deviation 
SMQ 
Standardized MedDRA Queries 
SOC 
System Organ Class 
SPM 
Second Primary Malignancies 
TEAE 
Treatment Emergent Adverse Event 
TLFs 
Tables, Listings, and Figures 
ULN 
Upper limit of normal 
WHO 
World Health Organization 
WHODDE(B2) 
WHO Drug Dictionary Enhanced (B-2 Format) 
 


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List of Key Terms 
Terms 
Definition of terms 
Baseline  
Assessments of subjects as they enter a trial before they receive any 
treatment.  
Endpoint  
Variable that pertains to the efficacy or safety evaluations of a trial. 
Enroll 
To register or enter a subject into a clinical trial. NOTE: Once a subject has 
received the study drug or placebo, the clinical trial protocol applies to the 
subject.  
Investigational 
period 
Period of time where major interests of protocol objectives are observed, and 
where the test drug or comparative drug (sometimes without randomization) 
is usually given to a subject, and continues until the last assessment after 
completing administration of the test drug or comparative drug. 
Post investigational 
period 
Period of time after the last assessment of the protocol. Follow-up 
observations for sustained adverse events and/or survival are done in this 
period. 
Screening 
A process of active consideration of potential subjects for enrollment in a 
trial. 
Screen failure 
Potential subject who did not meet 1 or more criteria required for 
participation in a trial. 
Screening period 
Period of time before entering the investigational period, usually from the 
time when a subject signs the consent until just before the test drug or 
comparative drug (sometimes without randomization) is given to a subject.  
Study period 
Period of time from the first site initiation date to the last site completing the 
study. 
Variable 
Any entity that varies; any attribute, phenomenon or event that can have 
different qualitative or quantitative values. 
 


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1 
INTRODUCTION 
This Statistical Analysis Plan (SAP) contains a more technical and detailed elaboration of the 
principal features of the analysis described in the protocol, and includes detailed procedures 
for executing the statistical analysis of the primary and secondary endpoints and other data.  
The SAP is finalized and signed prior to database hard lock. 
This statistical analysis is coordinated by the responsible biostatistician of Data Science, API. 
Any changes from the analyses planned in the SAP will be justified in the Clinical Study 
Report (CSR). 
2 
FLOW CHART AND VISIT SCHEDULE 
Refer to Section V. FLOW CHART AND SCHEDULE OF ASSESSMENTS of the protocol.  
3 
STUDY OBJECTIVE(S) AND DESIGN 
3.1 
Study Objective(s) 
The objective is to evaluate the safety and efficacy of enzalutamide in Indian patients with 
progressive mCRPC previously treated with docetaxel-based chemotherapy as per locally 
approved prescribing information. 
3.1.1 
Primary Objective 
To evaluate the safety and tolerability of enzalutamide in Indian patients with progressive 
mCRPC previously treated with docetaxel-based chemotherapy. 
3.1.2 
Secondary Objective 
To evaluate the effect of enzalutamide on PSA. 
3.2 
Study Design 
This study is a multicenter phase 4, open-label, single-arm, safety and efficacy study of 
enzalutamide (160 mg/day) in patients with progressive mCRPC who have previously been 
treated with docetaxel-based chemotherapy. Approximately 50 patients will be enrolled and 
treated with enzalutamide 160 mg once daily until study discontinuation criteria is met. 
Safety and tolerability will be assessed by the collection of adverse events, vital signs, 
physical examinations and safety laboratory evaluations. 
PSA will be collected for assessment of prostate cancer status on Screening Visit, Days 1, 29, 
57, 85, 169, every subsequent 84 days and Safety Follow-up Visit. 
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 including commercial 
enzalutamide for prostate cancer, whichever occurs first. 
3.3 
Randomization 
Randomization will be not performed as this is single-arm study. 


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4 
SAMPLE SIZE 
The sample size of 50 subjects is not based on a statistical power calculation. 
5 
ANALYSIS SETS 
In accordance with International Conference on Harmonization (ICH) recommendations in 
guidelines E3 and E9, the following analysis sets will be used for the analyses. 
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. 
5.1 
Full Analysis Set (FAS) 
The FAS will consist of all subjects who received at least one dose of study drug and have at 
least one post baseline measurement. This will be the primary analysis set for efficacy 
analyses. 
5.2 
Safety Analysis Set (SAF) 
The SAF consists of all subjects who took at least 1 dose of study drug, and will be used for 
safety analyses. 
For the statistical summary of the safety data, the SAF will be used. 
6 
ANALYSIS VARIABLES 
6.1 
Efficacy Endpoints 
Secondary endpoints 
● 
Confirmed PSA response rate (≥ 50% decline in PSA from baseline to the lowest 
postbaseline PSA result, with a consecutive assessment conducted at least 3 weeks later 
to confirm the PSA response) 
6.2 
Safety Variables 
Primary endpoints 
● 
Nature, frequency and severity of adverse events 
● 
Safety laboratory tests: biochemistry and hematology 
● 
Physical examination 
● 
Vital signs (blood pressure, pulse and temperature) 
Other endpoints 
● 
Weight 
TEAE (Treatment Emergent Adverse Event) is defined as an adverse event observed after 
starting administration of the study drug.  
A drug-related TEAE is defined as any TEAE with a causal relationship of YES by the 
investigator or with missing assessment of the causal relationship. 


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AESI (Adverse Events of Special Interest) are defined as below. 
AESI Category 
Selection based on MedDRA 26.0 
Convulsions (Seizure) 
Narrow SMQ of ‘Convulsions’. 
Hypertension 
Narrow SMQ ‘Hypertension’. 
Neutrophil Count Decreased 
 PTs of ‘Neutrophil Count Decreased’, ‘Neutropenia’, 
‘Agranulocytosis’,’ Granulocyte Count Decreased’, 
‘Granulocytopenia’, ‘Febrile Neutropenia’, ‘Neutrophil 
Percentage Decreased’, ‘Band Neutrophil Count Decreased’, 
‘Band Neutrophil Percentage Decreased’, ‘Neutropenic 
Sepsis’, ‘Neutropenic Infection’ And ‘Neutrophil Count 
Abnormal’. 
Cognitive and Memory Impairment All PTs under the MedDRA HGLT: ‘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’, ‘Ischemic Central Nervous System 
Vascular Conditions’ And ‘Cardiac Failure’. 
Posterior Reversible 
Encephalopathy Syndrome (PRES) 
PT of ‘Posterior Reversible Encephalopathy Syndrome’.
Fatigue 
PTs of ‘Fatigue’, ‘Asthenia’. 
Renal Disorder 
Broad [1] SMQ of ‘Acute Renal Failure’. 
Second Primary Malignancies 
(SPM) [2] 
Narrow SMQs of ‘Malignant Or Unspecified Tumours’ 
Customized To Exclude PTs of ‘Congenital Fibrosarcoma’, 
‘Congenital Malignant Neoplasm’, ‘Congenital 
Retinoblastoma’, ‘Metastases To…’, ‘Metastasis’, 
‘Metastatic Neoplasm’, ‘Prostate Cancer…’, ‘Carcinoid 
Tumour of The Prostate’, And ‘Neoplasm Prostate’ And 
(Inclusive of) Narrow SMQ of ‘Myelodysplastic Syndrome’, 
And (inclusive of)  
All PTs 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’, 'Bowen's disease'). 
Fall 
PT of ‘Fall’. 
Fractures 
 All PTs under the MedDRA HGLT: ‘Fractures’ And ‘Bone 
And Joint Injuries’. 
Loss of Consciousness 
PTs of ‘Loss of Consciousness’, ‘Syncope’, ‘Presyncope’. 
Thrombocytopenia 
PTs of ‘Thrombocytopenia’, ‘Platelet Count Decreased’. 
Musculoskeletal Events 
PTs 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’. 
Footnotes


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AESI Category 
Selection based on MedDRA 26.0 
Angioedema  
Narrow SMQ of ‘Angioedema’. 
Rash  
PTs 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 morbiliform', 'Rash neonatal', Rash papular', 'Rash 
papulosquamus', 'Rash pruritic',  'Rash pustular', 'Rash 
rubelliform', 'Rash scarlataniniform',' Rash vesicular', 'Septic 
rash', 'Systemic lupus erythematosus rash',  'Vasculitic rash',  
'Viral rash', 'Vulvovaginal rash'. 
Hepatic Disorder 
Narrow SMQ of ‘Hepatic Failure, Fibrosis And Cirrhosis 
And Other Liver Damage Related Conditions’, ‘Hepatitis, 
Non-Infectious’ And ‘Liver Related Investigations, Signs 
And Symptoms’. 
SMQ: Standardized MedDRA Query, HLT: High Level Term, HLGT: High Level Group Term. 
[1] Broad includes either broad or narrow. 
[2] AE terms identified as second primary malignancies according to the search criteria undergo review to 
confirm. 
6.3 
Other Variables 
● 
Duration of exposure 
For each subject, the length of time on treatment will be calculated in days, using the 
following formula: 
○ Last dose date of enzalutamide – First dose date of enzalutamide + 1, for 
patients who completed. 
○ Discontinuation dose date of enzalutamide – First dose date of enzalutamide + 
1, for patients who discontinued. 
● 
Percent overall compliance 
○ Percent compliance = Number of taken capsules of enzalutamide / Number of 
planned capsules of enzalutamide x 100 (%) 
○ Number of taken capsules of enzalutamide = Sum of (Number of prescribed 
capsules of enzalutamide – Number of returned capsules of enzalutamide) 
○ Number of planned capsules of enzalutamide = Sum of ((Stop Date – Start 
Date + 1) x Dose / 40). 
● 
Duration of disease at screening (month) 
○ Duration of disease at screening (month) = (Date of screening visit – Date of 
histological or cytological diagnosis of prostate cancer + 1) / 30. 
If the onset day and/or month of diagnosis is unknown, then the day and/or month will 
be imputed by 1st and January respectively. 
● 
Duration of metastatic progression at screening (month) 
○ Duration of metastatic progression at screening (month) = (Date of screening 
visit – First Date of Diagnosis of Metastatic Progression + 1) / 30. 
If the onset day and/or month of diagnosis is unknown, then the day and/or month will 
be imputed by 1st and January respectively. 


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7 
STATISTICAL METHODOLOGY 
7.1 
General Considerations 
● 
All data processing, summarization, and analyses will be performed using SAS® 
Version 9.4 or higher on Red Hat Enterprise Linux.  
● 
For continuous variables, descriptive statistics will include the number of subjects (n), 
mean, standard deviation (SD), median, minimum, and maximum.  
● 
For categorical variables: number and percentages of subjects will be described. 
● 
Specifications for table, figures, and data listing formats can be found in the TLFs 
specifications for this study. 
● 
MedDRA will be used as the coding dictionary for adverse event and medical history.  
● 
WHODDE(B2) will be used as the coding dictionary for previous and concomitant 
medications.  
● 
Baseline is defined as last nonmissing value before the first dose of the study drug. 
● 
Change from baseline to postbaseline will be calculated as: postbaseline value - baseline 
value. If the baseline value is missing, then that subject is not included in the calculation 
at any visit.  
7.2 
Study Population 
7.2.1 
Disposition of Subjects 
The following subject data will be summarized and presented with regard to all subjects with 
Screening Failure Log and Case Report Form: 
● 
Number of subjects with informed consent 
● 
Number of subjects who discontinued before registration 
● 
Number of subjects who registered 
The following subject data will be summarized and presented with regard to subjects with 
informed consent: 
● 
Number and percentage of subjects who prematurely discontinued during the screening 
period 
● 
Number and percentage of subjects who prematurely discontinued during the screening 
period by primary reason for withdrawal 
The following subject data will be summarized and presented with regard to all registered 
subjects: 
● 
Number and percentage of subjects who prematurely discontinued during the study 
period 
● 
Number and percentage of subjects who prematurely discontinued during the study 
period by primary reason for withdrawal 
● 
Number and percentage of subjects who took study drug 
● 
Number and percentage of subjects who were included/excluded in SAF and FAS 


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The following subject data will be summarized and presented with regard to subjects who 
took the study drug: 
● 
Number and percentage of subjects who were excluded from SAF and FAS by reason 
7.2.2 
Protocol Deviations 
Protocol deviations as defined in the study protocol (Section 8.1.6 Protocol Deviations) will 
be assessed for all subjects allocated to treatment. The number and percentage of subjects 
meeting any criteria will be summarized for each criterion and overall, by total as well as by 
study site. Subjects deviating from a criterion more than once will be counted once for the 
corresponding criterion. Any subjects who have more than one protocol deviation will be 
counted once in the overall summary. 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. 
7.2.3 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics will be summarized by descriptive statistics 
or categorical analysis for SAF and FAS. 
The following demographic variables will be summarized and presented. 
Demographic Variables and Analysis Methods 
Item 
Classification 
Analysis Methods 
Age [at the time of informed 
consent] (years) 
Measurement value 
<75, >=75 
<65, 65 to <75, >=75 
Descriptive statistics 
Categorical analysis 
EudraCT Age Category 
>=18 years to <=64 years, 
>=65 years to <=84 years, 
>=85 years 
Categorical analysis 
Sex 
Male, Female 
Categorical analysis 
Self-Reported Race 
White, Black or African American, 
American Indian or Alaska Native, 
Asian Indian, Chinese, Filipino, 
Japanese, Korean, Vietnamese, 
Other Asian, Native Hawaiian, 
Guamanian or Chamorro, Samoan, 
Other Pacific Islander 
Categorical analysis 
Ethnicity 
Not Hispanic or Latino, Hispanic or 
Latino 
Categorical analysis 
Height [Screening] (cm) 
Measurement value 
Descriptive statistics 
Weight [Screening] (kg) 
Measurement value 
Descriptive statistics 
Weight[Day 1] (kg) 
Measurement value 
Descriptive statistics 


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Item 
Classification 
Analysis Methods 
BMI [Screening] (kg/m^2) 
BMI (kg/m^2) = Weight (kg) / 
(Height (cm) / 100)^2 
Descriptive statistics 
BSA [Screening] (m^2) 
BSA (m^2) = Weight (kg) ^ 0.425 
x Height (cm) ^ 0.725 x 0.007184 
Descriptive statistics 
ECOG Performance Status 
Grade 0, Grade 1, Grade 2, Grade 
3, Grade 4, Grade 5 
Categorical analysis 
Previous Disease 
No, Yes 
Categorical analysis 
Concomitant Disease 
No, Yes 
Categorical analysis 
Duration of disease at screening 
(month) 
Measurement value 
<60month, >=60month 
<=Median, >Median 
Descriptive statistics  
Categorical analysis 
Primary Gleason score initial 
histological/cytological diagnosis 
1, 2, 3, 4, 5, Unknown 
Categorical analysis 
Secondary Gleason score initial 
histological/cytological diagnosis 
1, 2, 3, 4, 5, Unknown 
Categorical analysis 
Total Gleason score initial 
histological/cytological diagnosis 
1, 2, 3, 4, 5, 6, 7, 8, 9, 10, Unknown 
Low: 1-4, Medium: 5-7, High: 8-10 
Categorical analysis 
Clinical Tumor Stage (T) initial 
histological/cytological diagnosis 
TX, T0, T1, T2, T3, T4, Unknown 
Categorical analysis 
Pathologic Tumor Stage (pT) 
initial histological/cytological 
diagnosis 
pT2, pT3, pT4, Unknown 
Categorical analysis 
Clinical Lymph Node (N) Stage 
initial histological/cytological 
diagnosis 
NX, N0, N1, Unknown 
Categorical analysis 
Pathological Lymph Node (pN) 
Stage initial 
histological/cytological diagnosis 
pNX, pN0, pN1, Unknown 
Categorical analysis 
Distant Metastasis (M) initial 
histological/cytological diagnosis 
MX, M0, M1, Unknown 
Categorical analysis 
Duration of metastatic progression 
at screening (month) 
Measurement value 
Descriptive statistics 
Location 
Abdominal cavity, Adrenal gland, 
Anus, Bile duct, Bladder, Body, 
Bone, Bone marrow, Brain, Breast, 
Cervix uteri, Chest, Colon, 
Esophagus, Gallbladder, Head, 
Heart, Head and neck, Kidney, 
Liver, Lung, Lymph node, 
Mediastinum, Neck, Omentum, 
Oral cavity, Pancreas, Pelvis, Penis, 
Pericardium, Peritoneum, Pleura, 
Prostate gland, Rectum, 
Retroperitoneum, Skin, Small 
intestine, Spleen, Stomach, Testis, 
Other 
Categorical analysis 
Prostate Cancer Treatment History 
- Radiation 
No, Yes 
Categorical analysis 


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Item 
Classification 
Analysis Methods 
Prostate Cancer Treatment History 
- Procedure 
No, Yes 
Categorical analysis 
Prostate Cancer Treatment History 
- Drug Therapy 
No, Yes 
Categorical analysis 
PSA at Baseline 
Measurement value 
<2 ug/L, >=2 ug/L 
<=Median, >Median 
Descriptive statistics 
 Categorical statistics 
Hb at Baseline 
Measurement value 
<=Median, >Median 
Descriptive statistics  
Categorical analysis 
ALP at Baseline 
Measurement value 
<=Median, >Median 
Descriptive statistics  
Categorical analysis 
Alb at Baseline 
Measurement value 
<=Median, >Median 
Descriptive statistics  
Categorical analysis 
 
7.2.4 
Previous and Concomitant Medications 
Previous Medications/Non-Medication Therapy mean drugs and therapies undergone before 
entering the investigational period and Concomitant Medications/ Non-Medication Therapy 
refer to drugs and therapies used during the investigational period. 
Previous and Concomitant Medications/Non-Medication Therapy will be summarized for 
SAF and FAS.  
Previous and Concomitant Medications/Non-Medication Therapy and Analysis 
Methods 
Item 
Classification 
Analysis Methods 
Previous Medications 
No, Yes 
Categorical analysis 
Previous Non-Medication Therapy 
No, Yes 
Categorical analysis 
Concomitant Medications 
No, Yes 
Categorical analysis 
Concomitant Non-Medication Therapy 
No, Yes 
Categorical analysis 
 
7.3 
Study Drugs 
7.3.1 
Exposure 
Analysis set: FAS, SAF 
Duration of exposure will be summarized using descriptive statistics. 
7.3.2 
Treatment Compliance 
Analysis set: FAS, SAF 
Percent overall compliance will be summarized using descriptive statistics. 
7.4 
Analysis of Efficacy  
Efficacy analysis will be conducted on the FAS. 


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PSA response rate (the proportion of patients with >= 50% decline in PSA from baseline) 
will be summarized at each visit (See Section 7.11.3).  
Confirmed PSA response rate (the proportion of patients with >= 50% decline in PSA from 
baseline to the lowest postbaseline PSA result, with a consecutive assessment conducted at 
least 3 weeks later to confirm the PSA response) will be summarized.  
Summary statistics of measured values and the percent changes from baseline will be 
calculated at each visit and mean ± standard deviation (SD) plots will be constructed. 
7.5 
Analysis of Safety 
All analysis of safety will be presented for SAF, unless specified otherwise.  
7.5.1 
Adverse Events 
Following definitions of AE will be used for analysis. 
The definitions of TEAE and drug-related TEAE are provided in Section 6.2. 
7.5.1.1 An Overview of Adverse Events 
An overview table will include the following details: 
● 
Number and percentage of subjects with TEAEs 
● 
Number and percentage of subjects with drug-related TEAEs 
● 
Number and percentage of subjects with serious TEAEs 
● 
Number and percentage of subjects with drug-related serious TEAEs 
● 
Number and percentage of subjects with TEAEs leading to death 
● 
Number and percentage of subjects with drug-related TEAEs leading to death 
● 
Number and percentage of subjects with TEAEs leading to withdrawal of treatment 
● 
Number and percentage of subjects with drug-related TEAEs leading to withdrawal of 
treatment 
● 
Number and percentage of subjects with grade 3 or higher TEAEs 
● 
Number and percentage of subjects with drug-related grade 3 or higher TEAEs 
● 
Number and percentage of subjects with deaths 
● 
Number of TEAEss 
● 
Number of drug-related TEAEs 
● 
Number of serious TEAEs 
● 
Number of drug-related serious TEAEs 
● 
Number of TEAEs leading to death 
● 
Number of drug-related TEAEs leading to death 
● 
Number of TEAEs leading to withdrawal of treatment 
● 
Number of drug-related TEAEs leading to withdrawal of treatment 
● 
Number of grade 3 or higher TEAEs 
● 
Number of drug-related grade 3 or higher TEAEs 


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7.5.1.2 Adverse Events by SOC and PT 
The number and percentage of subjects with TEAEs and number of TEAEs, as classified by 
SOC and PT will be summarized. Subjects reporting more than one AE for a given MedDRA 
PT will be counted only once for that term. Subjects reporting more than one AE within a 
SOC will be counted only once for the SOC total. Subjects reporting more than one AE will 
be counted only once in the overall AE total. 
For summaries by severity based on National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI-CTCAE) grade (Grade 1 = mild, Grade 2 = moderate, Grade 3 = 
severe or medically significant, Grade 4 = life threatening, Grade 5 = death related to AE), 
subjects reporting more than one AE for a given PT, SOC total and AE total will be counted 
only once for that term in the most severe category reported. If a subject has an AE which has 
a missing severity, then the subject will be counted in the severity category of "Missing" (i.e., 
missing severity will not be imputed). 
Summaries will be provided for: 
● 
TEAEs 
● 
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 death 
● 
Drug-Related TEAEs leading to death 
● 
Grade 3 or higher TEAEs 
● 
Drug-related grade 3 or higher TEAEs 
● 
Common (>=5%) TEAEs 
● 
TEAEs by severity based on NCI-CTCAE grade 
● 
Drug-related TEAEs by severity based on NCI-CTCAE grade 
● 
Common (>=5%) TEAEs excluding serious adverse events 
7.5.1.3 Adverse Events of Special Interest 
An overview table of TEAE of Special Interest will describe the number and percentage of 
patients, as classified by AESI category and PT.  
An overview table of TEAE of Special Interest with Grade 3 or above will describe the 
number and percentage of patients, as classified by AESI category and Severity. 
7.5.2 
Clinical Laboratory Evaluation 
7.5.2.1 All Laboratory Tests 
Descriptive statistics for quantitative clinical laboratory variables, i.e. hematology and 
biochemistry will be presented at each visit (See Section 7.11.3). Additionally, a within-
subject change will be calculated as the postbaseline measurement minus the baseline 
measurement and summarized in the same way. Each laboratory result will be classified as 


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low (L), normal (N), or high (H) at each visit according to the laboratory supplied reference 
ranges. The number and percentage of subjects below and above reference range will be 
summarized using shift table (from baseline to postbaseline). 
The following data will be presented for quantitative clinical laboratory variables graphically: 
● 
Laboratory test results (actual values) using box plot 
● 
Laboratory test results x study days (relative days from administration of the study drug) 
using spaghetti plot 
7.5.2.2 Liver Enzymes and Total Bilirubin  
The following potentially clinically significant criteria for liver tests – defined as Alkaline 
Phosphatase (ALP), Alanine Transaminase (ALT), total bilirubin, Aspartate Transaminase 
(AST) and their combination are defined. The subject’s highest value during the study period 
will be used.  
Parameter 
Criteria 
ALT 
 > 3xULN 
 
 > 5xULN 
 
 > 10xULN 
 
 > 20xULN 
 
 
AST 
 > 3xULN 
 
 > 5xULN 
 
 > 10xULN 
 
 > 20xULN 
 
 
ALT or AST 
 > 3xULN 
 
 > 5xULN 
 
 > 10xULN 
 
 > 20xULN 
 
 
Total Bilirubin 
 > 2xULN 
 
 
Alkaline Phosphatase 
 > 1.5xULN 
 
 
ALT and/or AST AND Total Bilirubin [1] 
ALT and/or AST > 3xULN  
AND Total Bilirubin > 2xULN 
 
 
ALT and/or AST AND Alkaline Phosphatase  
AND Total Bilirubin [1] 
ALT and/or AST > 3xULN  
AND Alkaline Phosphatase < 2xULN  
AND Total Bilirubin > 2xULN 
[1] Combination of values measured within same day or within 1 day apart 
The number and percentage of subjects with potentially clinically significant values in liver 
enzyme and total bilirubin tests during the study period will be presented. 
7.5.3 
Vital Signs 
Descriptive statistics for vital signs (systolic blood pressure, diastolic blood pressure, pulse 
and body temperature) and weight will be presented at each visit (See Section 7.11.3). 


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Additionally, a within-subject change will be calculated per visit as the postbaseline 
measurement minus the baseline measurement and summarized in the same way. 
The following data will be presented graphically: 
● 
Vital sign results (actual values) using box plot 
● 
Vital sign results x study days (relative days from administration of the study drug) using 
spaghetti plot 
7.6 
Analysis of PK 
Not Applicable. 
7.7 
Analysis of PD 
Not Applicable. 
7.8 
Subgroups of Interest  
Not Applicable. 
7.9 
Other Analyses 
Not Applicable. 
7.10 
Interim Analysis (and Early Discontinuation of the Clinical Study) 
An interim assessment will be conducted at 6 months from first subject enrollment, with 
respect to safety. The report will be submitted to the health authority. 
7.11 
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information  
7.11.1 Missing Data 
As a general principle, missing data will not be imputed, except for the following exceptions. 
The partial missing start/end dates of AE (Adverse Events), CM (Prior and Concomitant 
Prostate Cancer Medications, Concomitant Medications, Non-Medication Therapy), MH 
(Medical History, Primary Diagnosis), and PR (Radiation for Prostate Cancer, Procedures for 
Prostate Cancer) will be imputed as below.  
● 
If the start day and/or month is unknown, the day and/or month will be imputed by 1st 
and January, respectively. In case of AE with onset after first dose of study drug, use the 
imputed date or the first dose date of study drug, whichever is later. 
● 
If the end day and/or month is unknown, the day and/or month will be imputed by the 
last day of the month and December, respectively. 
The imputed dates will be used to determine duration of disease at screening (See 
Section 6.3). 
7.11.2 Outliers 
All values will be included in the analyses. 


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7.11.3 Visit Window for Vital Signs, Clinical Labs and PSA 
Analysis visit 
Specified day 
Allowed time window 
Baseline 
Day0001 
Last nonmissing value before the first 
dose. 
Day0029(Week5) 
Day0029 
Specified day ± 7 days 
Day0057(Week9) 
Day0057 
Specified day ± 7 days 
Day0085(Week13) 
Day0085 
Specified day ± 7 days 
Day0169(Week25) 
Day0169 
Specified day ± 7 days 
Day0253(Week37) 
Day0253 
Specified day ± 7 days 
Day0337(Week49) 
Day0337 
Specified day ± 7 days 
Day0421(Week61) 
Day0421 
Specified day ± 7 days 
Day0505(Week73) 
Day0505 
Specified day ± 7 days 
Day0589(Week85) 
Day0589 
Specified day ± 7 days 
Day0673(Week97) 
Day0673 
Specified day ± 7 days 
Day0757(Week109) 
Day0757 
Specified day ± 7 days 
Day0841(Week121) 
Day0841 
Specified day ± 7 days 
Day0925(Week133) 
Day0925 
Specified day ± 7 days 
Day1009(Week145) 
Day1009 
Specified day ± 7 days 
Day1093(Week157) 
Day1093 
Specified day ± 7 days 
Day1177(Week169) 
Day1177 
Specified day ± 7 days 
Day1261(Week181) 
Day1261 
Specified day ± 7 days 
Day1345(Week193) 
Day1345 
Specified day ± 7 days 
Day1429(Week205) 
Day1429 
Specified day ± 7 days 
… 
… 
… 
Safety Follow-up 
30 days after Last Dose 
Specified day ± 7 days 
 
As for the analysis visits of Day XXXX (Week XXX), the values measured on or before 
withdrawal day will be accepted for discontinued subjects. The value which assessment day 
is the closest to the defined specified day within this window is used. If two values are 
equally close, the latter is used in the analysis.  


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8 
DOCUMENT REVISION HISTORY  
Version 
Date 
Changes 
Comment/rationale for change 
1.0 
3-Jun-2019 
NA 
Document finalized 
2.0 
25-Jan-2021 
Protocol Deviations 
Newly added the section. 
To include the analysis of protocol 
deviations according to the change of 
quality documents. 
3.0 
26-Feb-2024 
General 
Considerations 
Removed dictionary 
version of MedDRA and 
WHODDE.  
To comply with the Statistical Analysis 
Plan template. 
Visit Window for Vital 
Signs, Clinical Labs 
and PSA 
Updated time windows 
for visit increase. 
To address visit increase. 
Missing Data 
Updated imputation for 
partial missing start/end 
dates of AE, CM, MH, 
PR. 
To address partial missing dates. 
FLOW CHART AND 
VISIT SCHEDULE 
Removed the flow chart 
and visit schedule and 
changed to refer to the 
protocol. 
 
General 
Considerations 
Updated SAS version. 
 
Appendix 1: 
SIGNATURE 
Removed the list of key 
contributors. 
To follow the contents of latest 
Statistical Analysis Plan format. 
Safety Variables 
Added AESI definition 
. 
Adverse Events of 
Special Interest 
Added AESI analysis. 
To add AESI analysis. 


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Version 
Date 
Changes 
Comment/rationale for change 
An Overview of 
Adverse Events 
Removed AE subgroup 
analysis. 
 
Adverse Events by 
SOC and PT 
Removed AE subgroup 
analysis. 
 
Subgroups of Interest 
Changed to “Not 
Applicable”. 
To remove AE subgroup analysis, 
which is not necessary in CSR 
analysis. 
 
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) 


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10 
APPENDICES 
10.1 
Appendix 1: SIGNATURE 
Author and Approver Signatories  
(E-signatures are attached at end of document)  
This Statistical Analysis Plan was prepared by: 
 
 
 
 Data Science 
 
This Statistical Analysis Plan was approved by: 
 
 
 
 Data Science 
 
This Statistical Analysis Plan was approved by: 
 
 
 
 Data Science 
 
This Statistical Analysis Plan was approved by: 
 
 
 
 Oncology Developmental Sciences 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD