Conditions: Metastatic Castration Resistant Prostate Cancer
Keywords: Metastatic Castration-resistant Docetaxel Chemotherapy- Naïve Enzalutamide Prostate Cancer Chemotherapy Naïve Metastatic Castration Resistant Prostate Cancer Prednisolone Xtandi Metastatic Castration Resistant Prostate Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 688
Healthy volunteers: no

Brief summary:
The purpose of the study was to understand if there was benefit in continued treatment with a medicine called enzalutamide, when starting treatment with docetaxel and prednisolone (a standard chemotherapy for prostate cancer), after the prostate cancer had gotten worse when treated with enzalutamide alone.

Detailed description:
The study was conducted in consecutive periods of open label treatment with enzalutamide followed by randomized double-blind treatment with continued enzalutamide or placebo, in combination with docetaxel and prednisolone.

Open Label (Period 1)

Participants received open label treatment (OL) with enzalutamide. At week 13, all participants were assessed by prostate-specific antigen (PSA) and imaging. Participants with no confirmed PSA response or evidence of radiographic progression were ineligible for participation in Period 2 and typically had safety follow up; however, Period 1 treatment continued for some participants as long as the investigator considered it to be of clinical benefit (stopping on initiation of any new antineoplastic therapy). Participants with confirmed PSA response continued Period 1 until disease progression.

Enrollment to Period 2 ceased after approximately 274 participants had been enrolled or 182 primary endpoint events had been reached, whichever occurred first. Participants who were not randomized into period 2 at this time continued to receive open label treatment in an extension period.

Randomization (Double Blind \[DB\]) (Period 2)

Participants with confirmed disease progression on enzalutamide alone who continued to meet all eligibility criteria proceeded to randomization. Treatment allocation was in a 1:1 ratio, stratified by disease progression in Period 1 to the following treatments:

* Enzalutamide with docetaxel and prednisolone
* Placebo with docetaxel and prednisolone

Any ongoing participants in Period 2 at the point of unblinding in the enzalutamide+docetaxel arm that were still receiving and benefitting from enzalutamide treatment, had the option to continue treatment via an extension period.

Arms:
arm 1: Participants (Pts) received OL enzalutamide 160 mg QD from Day 1 in Period 1 (P1) until they were either randomized to Period 2 (P2), were ineligible, experienced intolerable toxicity, withdrew, or died. Pts with confirmed disease progression in P1, meeting eligibility, were randomized to receive placebo/enzalutamide 160 mg QD with docetaxel 75 mg/m\^2 in 1hour infusion every 3 weeks \& prednisolone 5mg twice daily in P2. Docetaxel \& prednisolone were administered for upto 10 cycles (1 cycle=3 weeks) or more per investigator discretion, while placebo/enzalutamide continued until progression, toxicity, withdrawal, or death. Extension(EXT) phase was available for Pts in P1\& P2 who were not meeting primary endpoint. Enzalutamide continued until disease progression, intolerable toxicity, withdrawal, or death. Pts not entering EXT discontinued and received local care. Those benefiting from enzalutamide in EXT at study closure continued in study 9785-CL-0123 or via commercial enzalutamide. arm 2: Participants received an OL treatment with enzalutamide 160 mg capsules, orally once daily from day 1 in period 1 until randomization to period 2 treatment, confirmation of ineligibility for period 2 treatment, intolerable toxicity, withdrawal, or death, whichever occurred first. Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received placebo matched to enzalutamide, orally once daily in combination with docetaxel 75 mg/m\^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, DB in period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle = 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants discontinued the study and received local standard of care.

Interventions: intervention 1: Enzalutamide intervention 2: Docetaxel intervention 3: Prednisolone intervention 4: Placebo
Intervention descriptions: intervention 1: Oral intervention 2: intravenous infusion intervention 3: Oral intervention 4: Oral

Protocol document:
Prot_002.pdf: 
Sponsor: APEL 
ISN/Protocol 9785-MA-1001 
EudraCT number 2013-004711-50 
- CONFIDENTIAL - 
1 Mar 2022 
Astellas 
Page 1 of 85 
V4.3, Incorporating Non Substantial Amendment 6, 1 Mar 2022 
 
A Randomized, Double-Blind, Placebo-Controlled, Phase IIIb 
Study of the Efficacy and Safety of Continuing Enzalutamide in 
Chemotherapy Naïve Metastatic Castration Resistant Prostate 
Cancer Patients Treated with Docetaxel plus Prednisolone Who 
Have Progressed on Enzalutamide Alone 
Protocol for Phase IIIb Study of Enzalutamide (ASP9785) 
A study to assess the benefit of treatment beyond progression with enzalutamide in men 
who are starting treatment with docetaxel after worsening of their prostate cancer 
when taking enzalutamide alone 
ISN/Protocol: 9785-MA-1001 
Version: Final v4.3 (1 Mar 2022) 
Incorporating Non-Substantial Amendment 6, 1 Mar 2022 
  
  
EudraCT 2013-004711-50 
 
Sponsor: 
Astellas Pharma Europe Ltd. (APEL) 
300 Dashwood Lang Road, Bourne Business Park 
Addlestone KT15 2NX 
United Kingdom 
 
Investigator information is on file at Astellas 
 
This confidential document is the property of the Sponsor. No unpublished information contained in this 
document may be disclosed without prior written approval of the Sponsor. 


Sponsor: APEL 
ISN/Protocol 9785-MA-1001 
EudraCT number 2013-004711-50 
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Page 2 of 85 
V4.3, Incorporating Non Substantial Amendment 6, 1 Mar 2022 
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 ································· 27 
1 
INTRODUCTION ················································································· 33 
1.1 
Background ···················································································· 33 
1.2 
Non-clinical and Clinical Data ······························································ 34 
1.2.1 
Non-clinical data ········································································ 34 
1.2.2 
Clinical Data ············································································· 35 
1.3 
Summary of Key Safety Information for Study Drugs ··································· 37 
1.3.1 
Enzalutamide ············································································· 37 
1.3.2 
Docetaxel with Prednisolone ··························································· 38 
1.3.3 
Enzalutamide in combination with Docetaxel and Prednisolone ·················· 38 
1.4 
Risk-Benefit Assessment ····································································· 38 
2 
STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS ·································· 39 
2.1 
Study Objectives ·············································································· 39 
2.2 
Study Design and Dose Rationale ··························································· 39 
2.2.1 
Study Design ············································································· 39 
2.2.2 
Dose Rationale ··········································································· 41 
2.3 
Endpoints ······················································································· 42 
2.3.1 
Primary Endpoints ······································································· 42 
2.3.2 
Secondary Endpoints ···································································· 42 
2.3.3 
Other Endpoints ········································································· 43 
2.3.5 
Safety Endpoints ········································································· 43 
3 
STUDY POPULATION ·········································································· 43 
3.1 
Selection of Study Population ······························································· 43 
3.1.1 
Subject re-screening ····································································· 43 
3.2 
Inclusion Criteria ·············································································· 43 
3.2.1 
Inclusion Criteria - Period 1 (assessed at the Screening Visit) ····················· 43 
3.2.2 
Inclusion Criteria – Period 2 (assessed at the Period 2 Eligibility 
Assessment) ·············································································· 44 
3.3 
Exclusion Criteria ············································································· 45 
3.3.1 
Exclusion Criteria - Period 1 (assessed at the Screening Visit) ···················· 45 


Sponsor: APEL 
ISN/Protocol 9785-MA-1001 
EudraCT number 2013-004711-50 
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3.3.2 
Exclusion Criteria - Period 2 (assessed at the Period 2 Eligibility 
Assessment) ·············································································· 47 
4 
TREATMENT(S) ·················································································· 47 
4.1 
Identification of Study Drugs ································································ 47 
4.1.1 
Investigational Medicinal Product - Enzalutamide ·································· 47 
4.1.2 
Comparative Drug - Placebo ··························································· 47 
4.1.3 
Non-Investigational Medicinal Products ············································· 48 
4.2 
Packaging and Labeling ······································································ 48 
4.2.1 
Docetaxel ················································································· 48 
4.3 
Study Drug Handling ········································································· 48 
4.4 
Blinding ························································································ 49 
4.4.1 
Blinding Method ········································································· 49 
4.4.2 
Confirmation of the Indistinguishability of the IMP ································ 49 
4.4.3 
Breaking the Treatment Code for Emergency ······································· 49 
4.4.4 
Breaking the Treatment Code by the Sponsor ······································· 49 
4.5 
Assignment and Allocation ·································································· 50 
4.5.1 
Period 1 – Open Label IMP ···························································· 50 
4.5.2 
Period 2 – Randomized IMP ··························································· 50 
4.5.3 
Continuation of Treatment after Completion of Randomization,and  before 
and after Unblinding.···································································· 50 
5 
TREATMENTS AND EVALUATION ························································ 51 
5.1 
Dosing and Administration of Study Drug(s) and Other Medication(s) ················ 51 
5.1.1 
Dose/Dose Regimen and Administration Period ···································· 51 
5.1.2 
Interruption and Reduction in Dose of the Study Drugs ···························· 51 
5.1.3 
Previous and Concomitant Medication (Drugs and Therapies) ···················· 52 
5.1.4 
Potential Interactions Between the Test Products and Concomitant 
Medications ·············································································· 53 
5.1.5 
Treatment Compliance ·································································· 54 
5.2 
Demographics and Baseline Characteristics ··············································· 54 
5.2.1 
Demographics ············································································ 54 
5.2.2 
Diagnosis, Severity, and Duration of Prostate Cancer ······························ 54 
5.2.3 
Chest X-Ray or Chest CT ······························································ 54 
5.2.4 
Medical History ·········································································· 55 
5.2.5 
Performance Status ······································································ 55 
5.3 
Efficacy Assessment ·········································································· 55 
5.3.1 
CT/MRI and Bone Scans ······························································· 55 
5.3.2 
Prostate Specific Antigen ······························································· 56 
5.3.3 
Brief Pain Inventory (BPI) ····························································· 56 


Sponsor: APEL 
ISN/Protocol 9785-MA-1001 
EudraCT number 2013-004711-50 
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5.4 
Safety Assessment ············································································ 56 
5.4.1 
Vital Signs ················································································ 56 
5.4.2 
Adverse Events ·········································································· 56 
5.4.3 
Laboratory Assessments ································································ 56 
5.4.4 
Physical Examination, Height and Weight ··········································· 57 
5.4.5 
Electrocardiogram ······································································· 57 
5.5 
Adverse Events and Other Safety Aspects ················································· 57 
5.5.1 
Definition of Adverse Events ·························································· 57 
5.5.2 
Definition of Serious Adverse Events (SAEs) ······································· 58 
5.5.3 
Criteria for Causal Relationship to the Study Drug ································· 58 
5.5.4 
Criteria for Defining the Severity of an Adverse Event····························· 59 
5.5.5 
Reporting of Serious Adverse Events (SAEs) ······································· 59 
5.5.6 
Follow-up of Adverse Events ·························································· 60 
5.5.7 
Monitoring of Common Serious Adverse Events ··································· 60 
5.5.8 
Procedure in Case of Pregnancy ······················································· 61 
5.5.9 
Emergency Procedures and Management of Overdose ····························· 61 
5.5.10 
Supply of New Information Affecting the Conduct of the Study ·················· 62 
5.6 
Other Measurements, Assessments or Methods ··········································· 62 
5.6.1 
FACT-P ··················································································· 62 
5.6.2 
EQ-5D-5L ················································································ 62 
5.6.3 
Health Resource Use ···································································· 62 
5.7 
Total Amount of Blood ······································································· 63 
6 
DISCONTINUATION ············································································ 63 
6.1 
Discontinuation of Individual Subject(s) ··················································· 63 
6.2 
Discontinuation of the Site ··································································· 64 
6.3 
Discontinuation of the Study ································································ 65 
7 
STATISTICAL METHODOLOGY ··························································· 65 
7.1 
Sample Size ···················································································· 65 
7.2 
Analysis Set ···················································································· 65 
7.2.1 
Full Analysis Set (FAS) ································································ 66 
7.2.2 
Safety Analysis Set (SAF) ······························································ 66 
7.3 
Demographics and Other Baseline Characteristics ········································ 66 
7.3.1 
Demographics ············································································ 66 
7.3.2 
Medical History ·········································································· 66 
7.3.3 
Diagnosis of the Target Disease, Severity and Duration of Disease ·············· 66 
7.4 
Analysis of Efficacy ·········································································· 66 
7.4.1 
Analysis of Primary Endpoint ························································· 66 


Sponsor: APEL 
ISN/Protocol 9785-MA-1001 
EudraCT number 2013-004711-50 
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7.4.2 
Analysis of Secondary Endpoints (Period 2) ········································· 67 
7.4.3 
Analysis of Biomarkers ································································· 68 
7.5 
Analysis of Safety ············································································· 69 
7.5.1 
Adverse Events ·········································································· 69 
7.5.2 
Laboratory Assessments ································································ 69 
7.5.3 
Vital Signs ················································································ 70 
7.5.4 
Physical Examination ··································································· 70 
7.5.5 
ECGs ······················································································ 70 
7.5.6 
Deaths ····················································································· 70 
7.6 
Protocol Deviations ··········································································· 70 
7.7 
Interim Analysis (and Early Discontinuation of the Clinical Study) ···················· 70 
7.8 
Handling of Missing Data, Outliers, Visit Windows, and Other Information ········· 70 
8 
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS ···················· 71 
8.1 
Procedure for Clinical Study Quality Control ············································· 71 
8.1.1 
Data Collection ·········································································· 71 
8.1.2 
Specification of Source Documents ··················································· 71 
8.1.3 
Clinical Study Monitoring ······························································ 72 
8.1.4 
Direct Access to Source Data/Documents ············································ 72 
8.1.5 
Data Management ······································································· 72 
8.1.6 
Protocol Deviations ····································································· 72 
8.1.7 
End of Trial in All Participating Countries ··········································· 73 
8.2 
Ethics and Protection of Subject Confidentiality ·········································· 73 
8.2.1 
Independent Ethics Committee/Competent Authorities ···························· 73 
8.2.2 
Ethical Conduct of the Study ··························································· 73 
8.2.3 
Informed Consent of Subjects ························································· 74 
8.2.4 
Subject Confidentiality ································································· 74 
8.3 
Administrative Matters ······································································· 75 
8.3.1 
Arrangement for Use of Information and Publication of the Clinical Study ····· 75 
8.3.2 
Documents and Records Related to the Clinical Study ····························· 75 
8.3.3 
Protocol Amendment and/or Revision ················································ 75 
8.3.4 
Insurance of Subjects and Others ······················································ 76 
8.3.5 
Signatory Investigator for Clinical Study Report ···································· 76 
9 
QUALITY ASSURANCE ········································································ 76 
10 
STUDY ORGANIZATION ······································································ 76 
10.1 
Independent Data-Monitoring Committee ················································· 76 
10.2 
Study Steering Committee ··································································· 76 
11 
REFERENCES ···················································································· 77 


Sponsor: APEL 
ISN/Protocol 9785-MA-1001 
EudraCT number 2013-004711-50 
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12 
APPENDICES ····················································································· 79 
12.1 
List of Excluded Concomitant Medications ··············································· 79 
12.2 
Central Laboratory Tests ····································································· 80 
12.3 
Liver Safety Monitoring and Assessment ·················································· 81 
12.4 
Common Serious Adverse Events ··························································· 84 
SIGNATURES ······························································································· 85 
 
 


Sponsor: APEL 
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I. 
SIGNATURES 
 
1. SPONSOR’S SIGNATURE 
A Randomized, Double-Blind, Placebo-Controlled, Phase IIIb Study of the Efficacy and Safety 
of Continuing Enzalutamide in Chemotherapy Naïve Metastatic Castration Resistant Prostate 
Cancer Patients Treated with Docetaxel plus Prednisolone Who Have Progressed on 
Enzalutamide Alone 
ISN/Protocol: 9785-MA-1001 Version: 4.3 
Required signatures (e.g. Protocol authors, Sponsor’s reviewers and contributors, etc.) are 
located in Section 13, Signatures; e-signatures (when applicable) are located at the end of this 
document. 
2. COORDINATING INVESTIGATORS’ SIGNATURES 
A Randomized, Double-Blind, Placebo-Controlled, Phase IIIb Study of the Efficacy and Safety 
of Continuing Enzalutamide in Chemotherapy Naïve Metastatic Castration Resistant Prostate 
Cancer Patients Treated with Docetaxel plus Prednisolone Who Have Progressed on 
Enzalutamide Alone 
ISN/Protocol: 9785-MA-1001 Version: 4.3 
I have read all pages of this clinical study protocol for which Astellas is the Sponsor. I agree 
that it contains all the information required to conduct this study. 
Coordinating Investigators: 
 
 
 
PPD


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3. INVESTIGATOR’S SIGNATURE 
A Randomized, Double-Blind, Placebo-Controlled, Phase IIIb Study of the Efficacy and 
Safety of Continuing Enzalutamide in Chemotherapy Naïve Metastatic Castration Resistant 
Prostate Cancer Patients Treated with Docetaxel plus Prednisolone Who Have Progressed on 
Enzalutamide Alone 
ISN/Protocol: 9785-MA-1001 Version: 4.3 
 
I have read all pages of this clinical study protocol for which Astellas is the Sponsor. I 
agree to conduct the study as outlined in the protocol and to comply with all the terms and 
conditions set out therein. I confirm that I will conduct the study in accordance with ICH 
GCP guidelines and applicable local regulations. I will also ensure that Sub-investigator(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: 
 
<Insert name and qualifications of the Investigator> 
 
Printed Name: 
Date (DD Mmm YYYY) 
 
Address: 
 
 
 
 
 
 
 
 
 
 
  


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II. 
CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL 
 
Contact for Serious Adverse 
Events (SAEs) 
 
See Section 5.5.5 
Astellas Pharma Global Development, Inc. 
Global Pharmacovigilance 
Fax number: +44 800 471 5263 
Email: safety-us@astellas.com 
Medical Expert 
  
 
Medical Affairs EMEA 
Astellas Pharma Europe Ltd,  
Telephone 
 
Email: 
 
Medical Monitor 
  
 
Parexel FSP 
Tel: 
 
Email: 
 
Clinical Research Contact: 
 
 
Medical Affairs EMEA 
Astellas Pharma Europe Ltd.,  
Telephone 
  
Email: 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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III. 
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS 
List of Abbreviations 
Abbreviations 
Description of abbreviations 
ADT 
Androgen Deprivation Therapy 
AE 
Adverse event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase (GPT) 
AST 
Aspartate Aminotransferase (GOT) 
ANC 
Absolute Neutrophil Count 
APEB 
Astellas Pharma Europe BV 
APEL 
Astellas Pharma Europe Ltd. 
AR 
Androgen Receptor 
AUC 
Area under the curve 
BPI-SF 
Brief Pain Inventory – Short Form 
CA 
Competent Authority 
Cmax 
Maximum concentration 
CR 
Complete Response 
CRPC 
Castration-resistant Prostate Cancer 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CT 
Computed Tomography 
CYP 
Cytochrome P450 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EQ-5D-5L 
EuroQol 5 dimension, 5 level health state utility index 
EU 
European Union 
FACT-P 
Functional Assessment of Cancer Therapy - Prostate 
FAS 
Full Analysis Set 
FDA 
Food and Drugs Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practices 
HR 
Hazard Ratio 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH  
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
ISN 
International Study Number 
IRT 
Interactive Response Technology 
LA-CRF 
Liver Abnormality Case Report Form 
LFT 
Liver Function Tests 


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Abbreviations 
Description of abbreviations 
LHRH 
Luteinizing hormone-releasing hormone 
LSLV 
Last Subject Last Visit 
MedDRA 
Medical Dictionary for Regulatory Activities 
mCRPC 
Metastatic Castration-Resistant Prostate Cancer  
MRI 
Magnetic Resonance Imaging 
N/A 
Not Applicable 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NYHA 
New York Heart Association 
OS 
Overall Survival 
PCWG2 
Prostate Cancer Working Group 2 
PK 
Pharmacokinetics 
PFS 
Progression-Free Survival 
PPS 
Per Protocol Set 
PR 
Partial Response 
PSA 
Prostate-specific Antigen 
PSA-DT 
Prostate-specific Antigen Doubling Time 
RECIST 
Response Evaluation Criteria In Solid Tumors 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure 
SRE 
Skeletal-related Event 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TBL 
Total Bilirubin 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cell 
Definition of Key Study Terms 
Terms 
Definition of terms 
Baseline  
Observed values/findings which are regarded observed starting point for 
comparison.  
Chronic opiate 
analgesia 
Parenteral opiate use for ≥7 days or use of WHO Analgesic Ladder Level 3 
oral opiates for ≥3 weeks. 
Enroll 
To register or enter into a clinical trial. NOTE: Once a subject has been 
enrolled, the clinical trial protocol applies to the subject.  
Intervention 
The drug, therapy or process under investigation in a clinical study that is 
believed to have an effect on outcomes of interest in a study. (e.g., 
health-related quality of life, efficacy, safety, pharmacoeconomics).  
Investigational 
period 
Period of time where major interests of protocol objectives are observed, and 
where the test drug or comparative drug (sometimes without randomization) 
is usually given to a subject, and continues until the last assessment after 
completing administration of the test drug or comparative drug. 


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Post 
investigational 
period 
Period of time after the last assessment of the protocol. Follow-up 
observations for sustained adverse events and/or survival are done in this 
period. 
Screening period 
Period of time before entering the investigational period, usually from the 
time of starting a subject signing consent until just before the test drug or 
comparative drug (sometimes without randomization) is given to a subject.  
Randomization 
The process of assigning trial subjects to treatment or control groups using an 
element of chance to determine assignments in order to reduce bias. 
Screening 
A process of active consideration of potential subjects for enrollment in a 
trial. 
Screen failure 
Potential subject who did not meet one or more criteria required for 
participation in a trial. 
Study period 
Period of time from the first site initiation date to the last site completing the 
study. 
Variable 
Any quantity that varies; any attribute, phenomenon or event that can have 
different qualitative or quantitative values. 


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IV. 
SYNOPSIS 
Date and Version # of Protocol Synopsis: 
1 Mar 2022  v4.3 (Final) 
Sponsor: Astellas Pharma Europe Ltd. (APEL) 
Protocol Number: 9785-MA-1001 
Name of Investigational Product: Enzalutamide 
Phase of Development: IIIb 
Title of Study: 
A Randomized, Double-Blind, Placebo-Controlled, Phase IIIb Study of the Efficacy and 
Safety of Continuing Enzalutamide in Chemotherapy Naïve Metastatic Castration Resistant 
Prostate Cancer Patients Treated with Docetaxel Plus Prednisolone Who Have Progressed on 
Enzalutamide Alone 
Planned Study Period:  
Q3 2014 – Q4 2022 
Study Objective(s):  
Primary: 
To compare the efficacy of continuing treatment with enzalutamide after adding docetaxel and 
prednisolone versus placebo plus docetaxel and prednisolone, as measured by progression-free 
survival (PFS) in subjects with chemotherapy-naïve metastatic castration-resistant prostate cancer 
(mCRPC) with progression during treatment with enzalutamide alone. 
Secondary: 
To evaluate the effect of continuing treatment with enzalutamide after adding docetaxel and 
prednisolone versus placebo plus docetaxel and prednisolone, as measured by the following endpoints 
in subjects with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) with 
progression during treatment with enzalutamide alone: 
• 
Time to prostate-specific antigen (PSA) progression; 
• 
PSA response; 
• 
Objective response rate; 
• 
Time to pain progression; 
• 
Time to opiate use for cancer-related pain; 
• 
Time to first skeletal-related event; 
• 
Quality of life. 
Safety profile including cumulative dose of docetaxel and Health Resource Use will be described for 
these subjects. 
Planned Total Number of Study Centers and Location(s): Approximately 80-90 centers in 
Europe 


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Study Population: Patients with progressive metastatic prostate cancer who have failed 
androgen-deprivation therapy (ADT) but who are naïve to chemotherapy will be recruited to 
Period 1 of the study. 
Subjects from Period 1 who subsequently progress on enzalutamide alone and continue to 
meet entry criteria will be randomized to treatment in Period 2. 
Number of Subjects to be Enrolled / Randomized: Approx 650 enrolled (Period 1) / 
274 randomized (Period 2) 
Study Design Overview: This double-blind, randomized, placebo-controlled trial of patients 
with chemotherapy- naïve mCRPC will evaluate the efficacy and safety of continuing 
treatment with enzalutamide plus docetaxel and prednisolone compared with treatment with 
placebo in combination with docetaxel and prednisolone. 
The study will be conducted in consecutive periods; period 1 of open label treatment with 
enzalutamide followed by period 2, randomized double-blind treatment with continued enzalutamide 
or placebo in combination with docetaxel and prednisolone. 
Open Label (Period 1): 
Subjects will attend a Screening Visit to determine eligibility for open label treatment in 
Period 1. 
Following Screening, enrolled subjects will receive open label treatment with enzalutamide 
(160 mg/day). At Week 13, all subjects will be assessed by PSA and imaging. The initial 
PSA response (stable or declining) must be confirmed by a second consecutive value at least 
3 weeks later. As PSA may not remain stable or decline in all subjects who subsequently 
benefit from enzalutamide, this study design is based on the hypothesis that subsequent 
addition of docetaxel will be of greater benefit in those subjects who have a confirmed initial 
PSA response. Therefore, subjects with no confirmed PSA response or evidence of 
radiographic progression (assessed at Week 13) will be ineligible for participation in Period 2 
and will typically have safety follow-up; however, Period 1treatment may continue for some 
subjects as long as the investigator considers it to be of clinical benefit (stopping on initiation 
of any new antineoplastic therapy). Subjects with confirmed PSA response will continue 
Period 1 until disease progression as supported by evidence of at least one of the following 
criteria (see Assessments): 
• PSA progression with rapid PSA doubling time (PSA-DT); 
• Radiographic progression defined as: 
• Bone disease progression, or; 
• Soft tissue disease progression. 
Administration of open label enzalutamide will continue until randomization to Period 2 
treatment, confirmation of ineligibility for Period 2 treatment (subjects will be discontinued 
from the study), intolerable toxicity, subject withdrawal, or death, whichever occurs first. 
Enrolment to Period 2 will cease after approximately 274 subjects have been enrolled or 182 


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primary endpoint events have been reached, whichever occurs first. Subjects who are not 
randomized into period 2 at this time may continue receiving open label treatment in an 
extension period in another Astellas-sponsored study. Subjects who decides not to enter the 
extension period, will discontinue from the study and be treated as per standard of care. 
Subjects will have a 30 day safety follow-up visit as per protocol following discontinuation. 
After enrolment to Period 2 has ceased, subjects will be followed per the site’s standard of 
care in relation to efficacy assessments (e.g., PSA testing, radiographic scans), which will 
enable the investigator to confirm if the subject is still deriving clinical benefit. There are no 
protocol-specific efficacy assessments that are to be completed for this study after end of 
enrolment. Subjects will be required to return to the site to review AEs, record concomitant 
medications, confirm that no discontinuation criteria are met, the return of unused 
enzalutamide and to receive more study drug if applicable. 
Randomization (Period 2): 
Subjects with confirmed disease progression on enzalutamide alone who continue to meet all 
eligibility criteria may proceed to randomization. Randomization must occur within 4 weeks of 
progression observed in Period 1. 
Treatment allocation will be in a 1:1 ratio, stratified by disease progression (evidence of radiographic 
progression or not) in Period 1 to the following treatments: 
• 
Enzalutamide (160 mg daily) in combination with docetaxel (75 mg/m2 every 3 weeks) and 
prednisolone (10 mg daily); 
• 
Enzalutamide placebo (daily) in combination with docetaxel (75 mg/m2 every 3 weeks) and 
prednisolone (10 mg daily). 
Administration of docetaxel will continue for up to 10 cycles, however, subjects assessed by the 
Investigator to be benefiting from treatment may continue on docetaxel for additional cycles. 
Administration of blinded enzalutamide/placebo will continue until disease progression, intolerable 
toxicity, subject withdrawal or death, whichever occurs first. 
When the required number of evaluable endpoint-events for primary analysis have been reached, 
subjects ongoing in period 2 will be able to continue receiving double blind treatment until the 
database is unblinded after database lock for the primary analysis. 
Any ongoing subjects in Period 2 at the point of unblinding in the enzalutamide+docetaxel arm that 
are still receiving and benefitting from enzalutamide treatment, will have the option to continue 
treatment via an extension period in another Astellas-sponsored study.  Subjects in the docetaxel plus 
placebo arm will leave the study and be treated as per local standard of care. Those subjects that 
decide not to enroll into the extension study will then leave the study and be treated as per local 
standard of care. Subjects will have a 30 day safety follow-up visit as per protocol. 
Follow-up:  
All subjects will have a safety follow-up visit 30 days after the last dose of Investigational Medicinal 
Product (IMP) or prior to the initiation of a subsequent antineoplastic therapy for prostate cancer, 
whichever occurs first. 


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In Period 2, subjects who discontinue IMP for a reason other than disease progression will continue to 
attend study visits (at 12 weekly intervals) for assessments until withdrawal of consent, disease 
progression or death. 
Follow-up will be performed for a maximum of 112 days or until radiographic progression, or 
initiation of a new anti-neoplastic therapy is documented.  Follow-up will cease after database lock 
for the primary analysis. 
Assessments: 
PSA testing will be performed at every scheduled visit excepting Period 1, Week 5 visit and Period 2, 
Weeks 4, 7 and 10 visits. 
PSA progression with rapid PSA-DT will be defined as: 
• 
PSA rise of ≥ 25% and an absolute increase of ≥ 2 ng/mL above nadir (in the event of a 
decline from baseline, the increase must be confirmed by a second PSA value 3 or more 
weeks later), and 
• 
PSA-DT of ≤ 12 weeks determined in at least 3 PSA measurements collected at intervals of 4 
or more weeks apart during a period of 3 or more months. 
Radiographic assessment of disease will be determined in bone by whole-body radionuclide 
bone scan and in soft tissue by computed tomography (CT) or magnetic resonance imaging 
(MRI). Each study site should have a designated radiologist or Investigator as the primary 
imaging reviewer and designate the same reader to evaluate the images for any one subject 
for the duration of the trial. 
• 
Radiographic images will be assessed every 12 weeks, but images may be obtained sooner if 
progression is clinically suspected. Scans may be performed up to 7 days prior to the 
scheduled visit. 
Radiographic disease progression will be defined as one (or both) of the following: 
• Bone disease progression defined by the appearance of 2 or more new bone lesions on 
whole body radionuclide bone scan per the Prostate Cancer Clinical Trials Working 
Group 2 (PCWG2) criteria. 
Progression at Week 13 in either Period requires a confirmatory scan performed six or 
more weeks later (or the next scheduled scan). Confirmation scans, if taken, must 
show 2 additional lesions compared with the first (Week 13) scan; 
• Soft tissue disease progression per the Response Evaluation Criteria in Solid Tumors 
(RECIST) Version 1.1 with a consistent methodology applied to assess any given 
subject. 
Functional status will be assessed by the Eastern Cooperative Oncology Group (ECOG) score, 
cancer-related pain will be assessed by the Brief Pain Inventory Short Form (BPI-SF), Quality of Life 
will be assessed by the Functional Assessment of Cancer Therapy-Prostate (FACT-P), and EuroQol 5 
dimension, 5 level health state utility index (EQ-5D-5L). Health Resource Use information will be 
collected. 


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Assessments of safety will include adverse events (AEs), clinical laboratory tests, physical 
examinations, vital signs, and 12-lead electrocardiograms (ECGs). An Independent Data Monitoring 
Committee (IDMC) will monitor safety data on an ongoing basis. 
Biomarker Sub-study: 
Subjects in a subset of countries and sites will be invited to participate in a voluntary, exploratory, 
biomarker sub-study. For subjects who have consented to provide samples for this sub-study,   blood 
samples for circulating biomarker analysis will be taken at the following timepoints:  
Period 1:  
Week 1/Day1 (pre dosing with enzalutamide), Week 5, Week 13, and when subjects progress 
clinically (4 samples).  
Period 2: Week 1/Day 1 (pre study drug in Period 2), Cycle 2 (Week 4), Cycle 5 (Week 13), Cycle 9 
(Week 25), when subjects progress clinically or reach another endpoint in the study and at Follow-Up 
(30 days after last dose of IMP) (6 samples) 
Any subject who consents to participate in the biomarker sub-study but fails to provide a valid 
baseline sample for Period 1, may still participate in Period 2 of the biomarker sub-study. In this case, 
the last sample of Period 1 (the sample taken when they progress clinically) should be taken as part of 
the baseline for Period 2. Informed Consent for the biomarker samples must be taken before any 
samples are collected.  Samples are to be handled according to the laboratory manual and shipped to a 
central laboratory for processing. The analysis of the exploratory biomarkers will be described in a 
separate biomarker plan. 
Extension Period: 
When sufficient numbers of subjects have been randomized into Period 2 (around 274) or when 182 
evaluable events for the primary endpoint are reached, whichever occurs first, enrollment to Period 2 
will close. Subjects who are still on enzalutamidein Period 1 at this timepoint and who are still 
benefitting from treatment will have the opportunity to continue with open label enzalutamide via an 
Extension Period in another Astellas-sponsored study, until the investigator or subject  decides it is no 
longer in the subject’s best interests to continue; a decision to initiate alternative antineoplastic 
therapy is made; or there is disease progression, intolerable toxicity, subject withdrawal or death, 
whichever occurs first. Assessments will be limited to collection of efficacy and laboratory 
assessments that are performed as part of standard of care for the subject, Serious Adverse Events 
(SAEs) and Adverse Events (AEs). Protocol-specified efficacy and laboratory assessments will cease.  
Similarly, when at least 182 endpoint-events have occurred in Period 2 of the study, the data will be 
cleaned and analyzed. Allowing for attrition, there may be some subjects still active in Period 2 when 
this data analysis cut-off is reached. These subjects will be able to continue to receive blinded study 
drug until the study is unblinded after database lock, at which time, subjects in the 
enzalutamide+docetaxel arm, who are still on enzalutamide will be  able to continue receiving 
enzalutamide ) until the investigator or subject decides it is no longer in the subject’s best interests to 
continue study drug; a decision to initiate alternative antineoplastic therapy is made; or there is 


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disease progression, intolerable toxicity, subject withdrawal or death, whichever occurs first. 
Assessments will be limited as described above.  
Subjects in the docetaxel plus placebo arm will leave the study and be treated as per standard of care. 
Subjects who decide not to continue treatment via the extension periods, will leave the study and be 
treated as per standard of care. 
Inclusion/Exclusion Criteria: 
Inclusion: 
Inclusion Criteria - Period 1 (assessed at the Screening Visit) 
Subjects must meet the following criteria prior to initiation of IMP: 
1. Age 18 or older; 
2. Independent Ethics Committee (IEC)-approved written 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); 
3. Histologically confirmed adenocarcinoma of the prostate without neuroendocrine 
differentiation or small cell features; 
4. Ongoing ADT with a luteinizing hormone-releasing hormone (LHRH) agonist or antagonist 
at a stable dose and schedule within 4 weeks of initiation of IMP, or bilateral orchiectomy 
(i.e., surgical or medical castration); 
5. Serum testosterone level ≤ 1.73 nmol/L (≤ 50 ng/dL); 
6. Metastatic (M1) disease documented by at least 2 bone lesions on bone scan, or soft tissue 
disease documented by CT/MRI; 
7. Progressive disease at study entry defined as the following occurring in the setting of castrate 
levels of testosterone: 
• 
PSA progression defined by a minimum of three rising PSA levels with an interval of 
≥ 1 week between each determination. 
• 
The PSA value at Screening should be ≥ 2 μg/L (≥ 2 ng/mL). In the event of prior 
androgen receptor inhibitor use, the most recent local PSA and the Screening PSA 
assessed by the central laboratory (central PSA) must be obtained at least 4 weeks after 
the last dose of androgen receptor inhibitor; 
8. Asymptomatic or minimally symptomatic prostate cancer (BPI-SF question 3 score of < 4) at 
Screening; 
9. ECOG performance score of 0-1 at Screening; 
10. Estimated life expectancy of ≥ 12 months from Screening; 
11. Be suitable and willing to receive chemotherapy as part of the trial; 


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12. Able to swallow the IMP and comply with study requirements; 
13. Subjects and their female spouse/partners who are of childbearing potential must be using 
highly effective contraception consisting of 2 forms of birth control* (one of which must be a 
condom) starting at Screening and continue throughout the study period and for 3 months 
after the final IMP administration; 
14. Subjects must not donate sperm starting at Screening and throughout the study period and for 
3 months after the final IMP administration. A condom is required throughout the study 
period and for 3 months after the final IMP administration if the subject is engaged in sexual 
activity with a pregnant woman; 
15. Subject agrees not to participate in another interventional study while on treatment. Subjects 
who are participating in a control arm of an interventional study which includes only standard 
of care, or in an observational phase following an interventional study, may be eligible for 
this study, providing they meet all the other entry criteria.  
Inclusion Criteria – Period 2 (assessed at the Period 2 Eligibility Assessment) 
Subjects must meet the following criteria prior to randomization: 
1. Have confirmed progressive disease on open label enzalutamide treatment, defined as one or 
more of:  
• 
PSA progression with rapid PSA-DT defined as a PSA rise of ≥ 25% and an absolute 
increase of ≥ 2 ng/mL above nadir, confirmed by a second PSA value at least 3 weeks 
later and a PSA-DT of ≤ 12 weeks determined in at least 3 PSA measurements collected 
at intervals of 4 or more weeks apart during a period of 3 or more months; 
• 
Bone disease progression defined by the appearance of 2 or more new bone lesions on 
whole-body radionuclide bone scan per the PCWG2 criteria; 
• 
Soft tissue disease progression per the RECIST 1.1, with a consistent methodology 
applied to assess any given subject; 
2. Ongoing ADT with a LHRH agonist or antagonist at a stable dose and schedule for at least 
4 weeks, or bilateral orchiectomy (i.e., surgical or medical castration); 
3. Serum testosterone level ≤ 1.73 nmol/L (≤ 50 ng/dL); 
4. ECOG performance score of 0-2; 
5. Subjects receiving bisphosphonates or denosumab for bone health must have been on a stable 
dose for at least 4 weeks; 
6. Able to swallow the IMP and comply with study requirements; 
7. Subjects and their female spouse/partners who are of childbearing potential must be using 
highly effective contraception consisting of 2 forms of birth control* (one of which must be a 
condom) starting at Screening and continue throughout the study period and for the later of 3 
months after the final IMP administration or 6 months after the final docetaxel 
administration; 


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8. Subjects must not donate sperm starting at Screening and throughout the study period and for 
the later of 3 months after the final IMP administration or 6 months after the final docetaxel 
administration. A condom is required throughout the study period and for 3 months after the 
final IMP administration if the subject is engaged in sexual activity with a pregnant woman; 
9. Be suitable and willing to receive chemotherapy as part of the trial. 
*Acceptable forms of birth control include: 
• 
Established use of oral, injected or implanted hormonal methods of contraception. 
• 
Placement of an intrauterine device (IUD) or intrauterine system (IUS). 
• 
Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault 
caps) with spermicidal foam/gel/film/cream/suppository. 
Exclusion Criteria 
Exclusion Criteria - Period 1 (assessed at the Screening Visit) 
Subject will be excluded from participation if any of the following apply: 
1. Absolute neutrophil count (ANC) < 1,500/μL, platelet count < 100,000/μL, or hemoglobin 
< 6.2 mmol/L (< 10 g/dL) 
(NOTE: subjects must not have received any growth factors or blood transfusions within 
seven days prior to the hematologic laboratory values obtained at Screening); 
2. Total bilirubin > upper limit of normal (ULN); alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) ≥ 2.5 times ULN; Child-Pugh B and C hepatic impairment; 
3. Creatinine > 177 μmol/L (> 2 mg/dL); 
4. Albumin ≤ 30 g/L (≤ 3.0 g/dL; 
5. Prior treatment with the following agents for the treatment of prostate cancer: 
• 
Aminoglutethimide; 
• 
Ketoconazole; 
• 
Abiraterone; 
• 
Enzalutamide or participation in a clinical trial of enzalutamide; 
• 
223Ra, 89Sr, 153Sm, 186Re/188Re; 
• 
Immunomodulatory therapies (e.g. Sipuleucel-T, DCVAC); 
• 
Cytotoxic chemotherapy (e.g. docetaxel, cabazitaxel, mitoxantrone, estramustine); 
• 
Participation in a clinical trial of an investigational agent that inhibits the androgen 
receptor or androgen synthesis (e.g. ARN-509, ODM-201, VT-464; unless the treatment 
was placebo); 
6. Current or prior treatment within 4 weeks prior to initiation of IMP with the following agents 
for the treatment of prostate cancer: 


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• 
Antiandrogens (e.g., bicalutamide, nilutamide, flutamide); 
• 
5-α reductase inhibitors (e.g., finasteride, dutasteride); 
• 
Estrogens; 
• 
Anabolic steroids; 
• 
Drugs with antiandrogenic properties such as spironolactone > 50 mg/kg; 
• 
Progestational agents; 
7. Subject has received investigational therapy within 28 days or 5 half-lives, whichever is 
longer, prior to initiation of IMP; 
8. Use of opiate analgesia for pain from prostate cancer within 4 weeks prior to initiation of 
IMP; 
9. Radiation therapy to bone lesions or prostatic bed within 4 weeks prior to initiation of IMP; 
10. Major surgery within 4 weeks prior to initiation of IMP; 
11. History of seizure or any condition that may predispose to seizures at any time in the past 
(e.g., prior cortical stroke, brain arteriovenous malformation, head trauma with loss of 
consciousness requiring hospitalization). History of loss of consciousness or transient 
ischemic attack within 12 months prior to Screening; 
12. Known or suspected brain metastasis or active leptomeningeal disease; 
13. History of another malignancy within the previous 5 years other than non-melanoma skin 
cancer; 
14. Clinically significant cardiovascular disease including: 
• 
Myocardial infarction within six months prior to Screening; 
• 
Uncontrolled angina within three months prior to Screening; 
• 
Congestive heart failure New York Heart Association (NYHA) class 3 or 4, or subjects 
with history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening 
echocardiogram or multi-gated acquisition scan (MUGA) performed within 3 months 
results in a left ventricular ejection fraction that is ≥ 45%; 
• 
History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, 
ventricular fibrillation, torsades de pointes); 
• 
History of Mobitz II second degree or third degree heart block without a permanent 
pacemaker in place; 
• 
Bradycardia as indicated by a heart rate < 45 beats per minute on the screening ECG or 
physical examination; 
• 
Uncontrolled hypertension as indicated by a resting systolic blood pressure > 170 mmHg 
or diastolic blood pressure > 105 mmHg at Screening; 


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15. Gastrointestinal disorders affecting absorption (e.g., extensive small bowel resection, active 
inflammatory bowel disease); 
16. Medical contraindications to the use of prednisolone or docetaxel; 
17. Allergies to any of the active ingredients or excipients in the study drugs; 
18. Any condition which, in the Investigator’s opinion, makes the subject unsuitable for study 
participation. 
Exclusion Criteria - Period 2 (assessed at the Period 2 Eligibility Assessment) 
Subject will be excluded from participation if any of the following apply: 
1. Cancer pain requiring chronic administration of opiate analgesia (parenteral opiate use for ≥7 
days or use of WHO Analgesic Ladder Level 3 oral opiates for ≥3 weeks; 
2. ANC < 1,500/μL, platelet count < 100,000/μL, or hemoglobin < 6.2 mmol/L (< 10 g/dL) 
(NOTE: subjects must not have received any growth factors or blood transfusions within 
seven days prior to the hematologic laboratory values obtained at the Period 2 Eligibility 
Assessment); 
3. Total bilirubin >  ULN; ALT or AST ≥ 2.5 times ULN; Child-Pugh B and C hepatic 
impairment; 
4. Creatinine > 177 μmol/L (> 2 mg/dL); 
5. Albumin ≤ 30 g/L (≤ 3.0 g/dL). 
Investigational Products: 
Period 1 and 2: Enzalutamide soft gelatin capsules 
Dose: 160mg once daily (4 x 40 mg capsules) 
Mode of Administration: Oral, with or without food 
Period 2 only: Placebo capsules, identical in appearance to enzalutamide capsules 
Dose: 4 capsules once daily 
Mode of Administration: Oral, with or without food 
Comparative Drug(s): 
n/a 
Background Therapy (Non-Investigational Medicinal Products): 
Period 2 only: Docetaxel and prednisolone (or prednisone as a substitute) 
Dose(s): Docetaxel: 75 mg/m2/3 weeks; Prednisolone/Prednisone: 10 mg/day 
Mode of Administration: Docetaxel: intravenous infusion, administered every 3 weeks over 
1 hour; Prednisolone/Prednisone: 5 mg, will be administered as 1 tablet by mouth twice daily 
with food. 


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Concomitant Medication Restrictions or Requirements: 
Required: All subjects who have not had a bilateral orchiectomy are required to maintain castration 
therapy with an LHRH agonist/antagonist for the duration of the study. 
Prohibited: The following medications are prohibited while the subject is on IMP: 
• 
Aminoglutethimide; 
• 
Ketoconazole (for the treatment of prostate cancer); 
• 
Abiraterone; 
• 
223Ra, 89Sr, 153Sm 186Re/188Re; 
• 
Immunomodulatory therapies (e.g. Sipuleucel-T, DCVAC); 
• 
Cytotoxic chemotherapy not required by protocol (e.g. cabazitaxel, mitoxantrone, 
estramustine); 
• 
Investigational agents; 
• 
Antiandrogens (e.g. bicalutamide, nilutamide, flutamide); 
• 
5-α reductase inhibitors (e.g. finasteride, dutasteride); 
• 
Estrogens; 
• 
Anabolic steroids; 
• 
Drugs with antiandrogenic properties such as spironolactone > 50 mg/kg; 
• 
Progestational agents. 
Restricted: The dosage and regimen of bisphosphonates or denosumab for bone health and any 
chronic permitted concomitant medications should be stabilized during Period 1 (> 4 weeks prior to 
randomization) and held constant throughout Period 2. 
Duration of Treatment: Subjects will continue IMP until disease progression, intolerable 
toxicity or withdrawal. 
Endpoints for Evaluation: 
Primary:  
The primary efficacy endpoint is PFS with progression defined as radiographic progression, 
unequivocal clinical progression, or death on study. 
PFS is defined as the time from randomization to the earliest objective evidence of 
radiographic progression, unequivocal clinical progression, or death on study, whichever 
occurs first. 
• Radiographic disease progression is defined for bone disease by the appearance of 2 
or more new lesions on whole-body radionuclide bone scan per PCWG2 criteria or 
for soft tissue disease by RECIST 1.1; 


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• Unequivocal clinical progression is defined as any of the following: 
o new onset cancer pain requiring chronic administration of opiate analgesia; 
o deterioration from prostate cancer of ECOG performance status score to 3 or 
higher; 
o initiation of subsequent lines of cytotoxic chemotherapy or radiation therapy 
or surgical intervention due to complications of tumor progression. 
Radiotherapy for palliative management of symptoms due to prostate cancer 
will not be considered unequivocal clinical progression; 
• Death on study is defined as death within 112 days of treatment discontinuation 
without objective evidence of radiographic progression. 
Secondary: 
Secondary endpoints include: 
• 
Time to PSA progression, defined as the time from randomization to the date of the first PSA 
value in Period 2 demonstrating progression (Period 2). The PSA progression date is defined 
as the date that a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL above the nadir 
recorded in Period 2 is documented, which must be confirmed by a second consecutive value 
obtained at least 3 weeks later; 
• 
PSA response, defined as the percentage change in PSA from randomization to Week 13 (or 
earlier for those that discontinue therapy), as well as the maximum decline in PSA that occurs 
at any point after treatment; 
• 
Objective response rate, defined as the best overall radiographic response after randomization 
as per Investigator assessments of response for soft tissue disease per RECIST 1.1, in subjects 
who have a measurable tumor; 
• 
Time to pain progression, defined as the time to an increase of ≥ 30% from randomization in 
the mean of BPI-SF pain intensity item scores (items 3, 4, 5, and 6); 
• 
Time to opiate use for cancer-related pain, defined as the time to initiation of chronic 
administration of opiate analgesia; 
• 
Time to first SRE, defined as the time from randomization to radiation therapy or surgery to 
bone, pathologic bone fracture, spinal cord compression, or change of antineoplastic therapy 
to treat bone pain; 
• 
Quality of life, as assessed using FACT-P and EQ-5D-5L. 
Other Endpoints: 
• 
Cumulative dose of docetaxel. 
• 
Health resource use (hospitalization and duration thereof; number and types of visits to a 
health professional) in Period 1 and Period 2 
Exploratory Endpoints: 


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• 
To analyze candidate biomarkers in circulation for association with response or progression 
and for identifying mechanisms of resistance. 
Safety Endpoints: 
• 
Safety in both Periods will be assessed by AEs, clinically significant changes in physical 
examination, vital signs, laboratory values, and ECGs. 
• 
Deaths, defined as deaths due to any cause, will be summarized descriptively. 
Statistical Methods: All efficacy analyses will be based on the full analysis set (FAS) 
population, defined as all subjects who are randomized and receive at least one dose of IMP. 
Randomization will be central and treatment allocation will be 1:1 stratified by disease 
progression in Period 1 (evidence of radiographic progression or not). 
Sample Size Justification: The following assumptions were used to determine the sample 
size calculation for the primary endpoint of PFS: 
• 
The estimated median PFS is 6 months for the control group (placebo plus docetaxel and 
prednisolone); 
• 
Assuming the true treatment effect has a Hazard Ratio (HR) of 0.66, with 2-sided type 1 error 
rate of 0.05 and 80% power, at least 182 progression events are needed. This will allow 
statistical significance be claimed at the conclusion of the study if the observed HR is <=0.75, 
approximately; 
• 
If the recruitment period is up to 18 months, the follow-up of subjects in Period 2 is 
approximately 6 months, and the recruitment rate is non-uniform, at least 274 subjects will 
need to be randomized. 
Allowing for attrition prior to randomization, approximately 650 subjects will be enrolled. 
Efficacy: 
Primary Efficacy Endpoint: 
The treatment effect of enzalutamide compared to placebo based on PFS disease progression will be 
tested using a stratified log-rank test, stratified by the randomization stratification factor, at the 0.05 
2-sided significance level (based on 182 events). 
Secondary Endpoints: 
• 
Time to PSA Progression: The median time to PSA progression and the corresponding 
confidence intervals will be calculated. A stratified log-rank test will be used to compare the 
time to PSA progression between the 2 treatment groups. Kaplan-Meier curves will be used 
to estimate the distribution of time to PSA progression; 
• 
PSA response will be reported using a waterfall plot for each treatment group; 
• 
Objective Response Rate: Rates of complete response (CR), partial response (PR), stable 
disease (SD), CR+PR, and CR+PR+SD will be tabulated along with exact binomial 
confidence intervals (Clopper-Pearson); 


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• 
Time to pain progression: The statistical analyses for evaluating treatment effect of 
enzalutamide compared to placebo on time to pain progression will be the same as that 
described for time to PSA progression; 
• 
Time to opiate use for cancer-related pain: The statistical analyses for evaluating treatment 
effect of enzalutamide compared to placebo on time to opiate use for cancer-related pain will 
be the same as that described for time to PSA progression; 
• 
Time to first SRE: The statistical analyses for evaluating treatment effect of enzalutamide 
compared to placebo on time to first SRE will be the same as that described for time to PSA 
progression; 
• 
Quality of Life: The FACT-P and EQ-5D-5L data will be summarized descriptively by 
treatment group and study visit. 
Analysis of Other Endpoints: 
• 
Health Resource Use: Will be summarized descriptively for both Periods (by treatment group 
in Period 2); 
• 
Cumulative dose of docetaxel: Will be summarized descriptively by treatment group. 
Exploratory Endpoints: 
• 
Whole blood will be collected for the purpose of obtaining and analyzing Circulating Tumor 
Cells (CTCs) as well as evaluation of biomarkers in serum or plasma that may be temporally 
associated with disease progression and the development of resistance to enzalutamide 
treatment. These biomarkers include circulating tumor DNA and RNA, to identify mutations, 
genomic aberrations and expression levels of the androgen receptor and other candidate genes 
and inflammatory cytokines, growth factors and metabolites. Changes of CTC genetic, 
transcriptome or protein levels and/or cancer-specific circulating plasma nucleic acids as well 
as other plasma factors following androgen receptor targeting may be associated with clinical 
outcomes in CRPC. Standard descriptive statistics (mean, median, standard deviation, range, 
minimum, maximum, etc) will be used to summarize these correlative endpoints by treatment 
group and study visit as appropriate. The analysis of the exploratory biomarkers will be 
described in a separate biomarker plan. 
Pharmacokinetics: Not applicable 
Safety: All safety analyses will include the safety population, defined as all subjects who 
receive 1 dose or partial dose of IMP in each Period. A safety population will be defined for 
each Period (1 or 2). 
Safety will be summarized in Period 1 and Period 2 by the frequency of serious AEs, frequency and 
severity of AEs, frequency of IMP discontinuation due to adverse events, and frequency of new 
clinically significant changes in clinical laboratory values, vital signs, and ECGs. 
Laboratory values will be classified and summarized for severity using the National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03. All 
data will be listed by period in the study. 


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V. 
FLOW CHART AND SCHEDULE OF ASSESSMENTS 
Flow Chart 
 


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Schedule of Assessments - Period 1 
Visit 
Screening 
Open label Enzalutamide 
Unschedi 
Extension 
Period 1n 
FU 
After last 
drugj or q 
Week 
-4 to -1 
1 
5 
13 
25 then 
q12wk 
n/a 
q12wk 
30d after last 
drug 
Day 
-28 to -1 
1 
29 
85 
169 + q84d 
n/a 
n/a 
n/a 
Window (days) 
n/a 
n/a 
±7 
±7 
±7 
n/a 
±7 
±3 
Informed Consent 
X 
 
 
 
 
 
 
 
Demographics/Medical Historya 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
Xp 
X 
Physical Examinationb 
X 
X 
X 
X 
X 
X 
Xp 
X 
12-lead ECG 
X 
 
 
 
 
 
 
 
Hematology/Clinical Chemistryc 
X 
X 
X 
X 
X 
X 
Xo 
X 
PSA 
X 
X 
 
Xg 
X 
X 
Xo 
 
Informed Consent for Biomarker 
samplesk 
X 
 
 
 
 
Xk 
 
 
Biomarker sample  
 
Xl 
X 
X 
 
Xm 
 
 
Testosterone 
X 
 
 
 
 
 
 
 
ECOG 
X 
X 
X 
X 
X 
X 
Xp 
X 
BPI-SF 
X 
 
 
 
 
 
 
 
FACT-P, EQ-5D-5L 
X 
 
 
 
 
 
 
 
Health Resource Use 
X 
 
 
X 
X 
 
 
 
Radiographic assessmentsd 
Xf 
 
 
Xh 
X 
X 
Xp 
 
Enzalutamide dispensing 
 
X 
 
X 
X 
 
X 
 
Enzalutamide accountability 
 
 
X 
X 
X 
 
X 
X 
Adverse Eventse 
X 
X 
X 
X 
X 
X 
X 
X 
Prior/Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
 
 


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a. 
Includes age, initial diagnosis of prostate cancer, Gleason score at time of diagnosis along with details and dates of all treatments for prostate cancer; 
b. All physical examinations will include weight. 
Screening physical examination will be a full examination including height, subsequent examinations will be brief only and symptom-focused; 
c. 
Clinical labs (also PSA and testosterone) will be collected for central laboratory assessment; 
d. Whole body radionuclide bone scan and abdominopelvic computed tomography (CT) or magnetic resonance imaging (MRI) for soft tissue may be performed up to 7 days prior to 
the scheduled visit to permit review of results at the visit; 
e. 
All Adverse Events (AEs) and Serious adverse events (SAEs) including death will be collected from the time the subject signs the consent form until 30 days after last dose of 
IMP. 
f. 
Screening imaging assessments should include a Chest X-ray (CXR) or chest CT as well as whole body radionuclide bone scan and abdominopelvic CT/MRI. 
Radiographic assessments collected within 42 days prior to Day 1 may be used to establish the presence of metastatic disease; 
g. Subjects will be assessed for PSA response at Week 13 which should be confirmed by a subsequent test at least 3 weeks later. Subjects without a confirmed PSA response at 
Week 13 will be ineligible for participation in Period 2; 
h. Radiographic progression by bone scan at the first assessment at Week 13 requires a confirmatory scan 6 or more weeks later. Subjects with confirmed radiographic progression 
at Week 13 will be ineligible for participation in Period 2 and will typically have safety follow up; however, Period 1treatment may continue for some subjects as long as the 
investigator considers it to be of clinical benefit (stopping on initiation of any new antineoplastic therapy); 
i. 
Unscheduled visit assessments are optional and should be dictated by the clinical reason for visit attendance (e.g. if progression is suspected, radiographic assessments may be 
performed); 
j. 
Safety follow-up in subjects not progressing to Period 2 before the data cut off will be 30 days after the last dose of IMP or prior to initiation of new antineoplastic therapy, 
whichever is earliest. 
k. Participation in the Biomarker sub-study is optional, and a separate Informed Consent is to be signed prior to collecting any samples for it. If a subject is already enrolled in Period 
1 of the study, but agrees to provide biomarker samples, consent for the biomarker collection for Period 2 can be taken at any time prior to the biomarker sample collection;  
l. 
To be taken pre-enzalutamide administration; 
m. Sample to be taken when subject progresses clinically, as part of the baseline samples for Period 2 of the study. If a subject misses week 1/day 1 samples in Period 1, and consents  
to the sub-study, this should be the first sample taken.  
n. Open-label enzalutamide treatment may be continued for subjects still in treatment in Period 1 when enrollment to Period 2 closes or when the 182 primary endpoints events are 
reached, whichever occurs first (approximately 274 subjects randomized into Period 2) 
o. Laboratory tests to be performed locally as required for the subject’s standard of care. Relevant results will only be collected in the event of SAEs and AEs. 
p. Results to be collected in the eCRF if the assessments are performed as part of the standard of care of the subject. 
q. Safety follow up in subjects after the data cut off will be 30 days after the last dose of IMP or prior to initiation of new antineoplastic therapy, whichever is earliest. Laboratory 
tests to be performed locally as required for the subject’s standard of care. Relevant results will only be collected in the event of SAEs and AEs. 
 
 


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ECG – Electrocardiogram; PSA - Prostate-specific Antigen; ECOG - Eastern Cooperative Oncology Group; BPI-SF - Brief Pain Inventory – Short Form; FACT-P - Functional 
Assessment of Cancer Therapy - Prostate, EQ-5D-5L - EuroQol 5 dimension, 5 level health state utility index; FU – Follow up 


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Schedule of Assessments - Period 2 
Visit 
Eligibility 
Assessment 
for Period 2e 
Randomized (Double-Blind) Treatment 
on background of Docetaxel + Prednisoloneg 
Ongoing 
(Double-
Blind) 
Treatmentp 
Unschedk 
Extension Period 2 
FU 
After 
last 
IMPl 
or s 
Cycle 
n/a 
1 
2-4 
5 
6-8 
9 
10 
Additional  
n/a 
n/a 
Additional 
n/a 
n/a 
Week 
-4 to -1 
1 
4/7/10 
13 
16/19/22 
25 
28 
Varies 
q3wk 
cyclesj 
37 then 
q12wk 
n/a 
Varies 
q3wk 
cycles 
37 
then  q12wk 
 
30d 
after 
last 
drug 
Day 
-28 to -1 
1 
22/43/64 
85 
106/127/148 
169 
190 
n/a 
253 then 
q84d 
n/a 
n/a 
q84d 
n/a 
Window (days) 
 
n/a 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
n/a 
±7 
±7 
±7 
Inclusion/Exclusiona 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xr 
X 
Physical Examinationb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xr 
X 
12-lead ECG 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
X 
Hematology/Clinical Chemistryc 
X 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
X 
X 
Xq 
Xq 
X 
PSA 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Xq 
Xq 
X 
Biomarker sample  
 
Xm 
Xn 
X 
 
X 
 
 
 
Xo 
 
 
X 
Testosterone 
X 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xr 
X 
BPI-SF 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
FACT-P, EQ-5D-5L 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
Health Resource Use 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
Radiographic Assessmentsd 
Xf 
 
 
Xi 
 
X 
 
 
X 
X 
Xr 
Xr 
 
IMP dispensing 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
Docetaxel administration 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
IMP accountability 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a. 
Eligibility will be checked against criteria for Period 2; 
b. All physical examinations will include weight; 


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c. 
Clinical labs (also PSA and testosterone) will be collected for central laboratory assessment during scheduled clinic visits; 
d. Whole body radionuclide bone scan and abdominopelvic computed tomography (CT) or magnetic resonance imaging (MRI) for soft tissue may be performed up to 7 days prior to 
the scheduled visit to permit review of results at the visit; 
e. 
The window for assessment of suitability to continue into Period 2 will commence from the point that progression is determined in Period 1 (i.e. confirmation of PSA or 
radiographic progression).  Assessments collected at the last visit in Period 1 may be used to determine eligibility for Period 2 if collected within 4 weeks prior to randomization; 
f. 
Period 2 baseline scans may utilize the most recent scans collected in Period 1 if collected within 4 weeks prior to randomization. 
Scans should include a Chest X-ray (CXR) or chest CT; 
g. Subjects who discontinue docetaxel before completion of 10 cycles (e.g. for toxicity) may continue with double-blind treatment and continue to attend study visits (at 12 weekly 
intervals) for assessments until IMP discontinuation criteria or endpoint criteria are met. 
h. Local laboratory hematology samples for nadir count assessment will be collected approximately 1 week after docetaxel administration in all cycles; during the first 3 cycles 
additional hematology samples will be collected approximately 2 weeks after docetaxel administration. 
Local laboratory hematology should also be collected to support dosing decisions prior to administration of docetaxel. 
Patients with elevated liver function tests (LFTs) should have LFTs assessed prior to administration of docetaxel; 
i. 
Radiographic progression by bone scan at the first assessment at Week 13 requires a confirmatory scan 6 or more weeks later; 
j. 
If docetaxel treatment continues such that there is overlap with the subsequent 12-weekly visit cycle (e.g. Week 37, Week 49) then all assessments of those visits should be 
performed in addition to those required for docetaxel treatment; 
k. Unscheduled visit assessments are optional and should be dictated by the clinical reason for visit attendance (e.g., if progression is suspected radiographic assessments may be 
performed); 
l. 
Safety follow-up will be 30 days after the last dose of IMP or prior to initiation of new antineoplastic therapy, whichever is earliest 
Subjects who discontinue IMP for a reason other than disease progression will continue to attend study visits (at 12 weekly intervals) for assessments until withdrawal of consent, 
disease progression or death. 
m. Biomarker sample to be taken prior to first dose of double-blind study medication in Period 2;   
n. Biomarker sample to be taken at Cycle 2 (Week 4); 
o. Biomarker sample to be taken when the subject progresses clinically or reaches one of the endpoints of the study.  
p. Double blind treatment may be continued for any subjects still in treatment in Period 2 between data cut-off and unblinding 
q. Laboratory tests to be performed locally as required for the subject’s standard of care. The results will only be collected in the event of SAEs and AEs. 
r. 
Results to be collected in the eCRF if the assessments are performed as part of the standard of care of the subject.  
s. 
 Safety follow up in subjects after unblinding will be 30 days after the last dose of IMP or prior to initiation of new antineoplastic therapy, whichever is earliest. Laboratory tests to 
be performed locally as required for the subject’s standard of care. Biomarker sampling will cease. Relevant results will only be collected in the event of SAEs and AEs.  
 
ECG – Electrocardiogram; PSA - Prostate-specific Antigen; ECOG - Eastern Cooperative Oncology Group; BPI-SF - Brief Pain Inventory – Short Form; FACT-P - Functional 
Assessment of Cancer Therapy - Prostate, EQ-5D-5L - EuroQol 5 dimension, 5 level health state utility index; FU – Follow up 


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1 
INTRODUCTION 
1.1 
Background 
Prostate cancer represents the most common non-skin cancer neoplasm amongst men in 
Europe and is ranked the third most common cause of cancer death in men, after lung and 
colorectal cancer based on 2008 estimates (Ferlay et al 2010). 
A variety of strategies (surgery, radiotherapy, androgen-deprivation therapy [ADT]) are 
employed in the management of early disease (Horwich et al 2013, Heidenreich et al 2014). 
As the disease advances, treatment strategies focus on continuing deprivation of androgens, 
which are well established as drivers of tumor growth in prostate cancer (Huggins and 
Hodges 1941; Ryan and Tindall 2011). Inevitably, tumors acquire characteristics enabling 
survival and growth despite androgen deprivation, resulting in a clinical state of castration-
resistant prostate cancer (CRPC), defined as progression despite castrate hormone levels 
(testosterone <50ng/dL). Second-line hormonal therapies aim to delay time to progression, 
metastasis and limit symptoms. Metastatic castration-resistant prostate cancer (mCRPC), 
where tumors have spread beyond the primary site, is associated with symptoms related to 
bony or soft-tissue metastases, such as bone pain, pathologic fractures, or spinal cord 
compression, which worsen quality of life and ultimately accelerate progression to death 
within 24-48 months after onset of castration resistance. 
Standard first-line therapy in mCRPC after failure of classic hormonal therapies is with 
docetaxel. Docetaxel is a β-actin binding taxane that triggers apoptosis through effects on the 
microtubule and cell mitosis (Fitzpatrick and de Wit 2014). Recent studies have reported that 
docetaxel also has antitumor activity associated with disruption of androgen receptor (AR) 
signaling (Thadani-Mulero et al 2012). The duration of response to docetaxel remains 
limited, however, and novel therapies for second-line treatment have recently been approved 
for use in Europe, including enzalutamide, abiraterone, cabazitaxel and Radium-223 chloride 
(Merseburger et al 2013). 
Enzalutamide is an AR inhibitor that targets several steps in the AR-signaling pathway. It 
competitively inhibits binding of androgens to the AR, impedes movement of the AR to the 
nucleus of prostate cancer cells (nuclear translocation), and inhibits the association of the AR 
with DNA, even in the setting of AR overexpression and in prostate cancer cells resistant to 
antiandrogens (Tran et al 2009). Enzalutamide demonstrated a survival benefit in men with 
mCRPC who had received prior docetaxel (Scher et al 2012). In addition to treatment in the 
post-chemotherapy setting, enzalutamide and abiraterone have been investigated for 
treatment of patients who have not yet received chemotherapy and appear to show additional 
benefit (Ryan et al 2013, Beer et al 2014). 
An important area of investigation is to determine the appropriate therapeutic strategies for 
patients who have progressed on these treatments. Continuing an agent beyond disease 
progression is one such strategy which has been demonstrated to improve outcomes in a 
range of cancers (Kuczynski et al 2013) and indeed current treatment guidelines for mCRPC 
recommend continuation of ADT despite progression on treatment (Heidenrich et al 2014). 
In the PREVAIL study of enzalutamide vs placebo in chemotherapy naïve mCRPC (Beer et 
al 2014) the majority of patients treated with enzalutamide derived a clinical response (78.0% 
PSA response [>50% decline from baseline], 58.8% Objective Response). Acquired 


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resistance, the emergence of progressive disease following a period of response to 
enzalutamide as a single agent, thus represents the most common clinical resistance scenario. 
Resistance may emerge over time under the pressure of enzalutamide therapy therefore 
upfront drug combinations may not represent an optimal strategy to circumvent resistance. 
As castration-resistance is known to be mediated through both AR-dependent and 
AR-independent pathways, there is potential for metastatic lesions to be composed of 
different clones possessing these different characteristics (Ahmed and Li 2013). The 
hypothesis for the proposed study is that sub-populations of the CRPC lesions will continue 
to be controlled under ongoing enzalutamide treatment (AR signaling is a driver of prostate 
cancer growth and survival throughout the disease course; Ryan and Tindall, 2011), while 
addition of docetaxel to the therapeutic regimen will target those clones that have adopted 
accessory pathways to enhance survival and proliferation.  
A series of ongoing studies are targeting mechanisms of resistance using a two-step trial 
design to follow treatment beyond progression. PLATO (NCT01995513) treats patients with 
enzalutamide in the chemotherapy-naïve setting with standard follow up; at the time of 
emergence of PSA progression, patients will be randomized to receive continued 
enzalutamide plus abiraterone or abiraterone alone. ABIDO (NCT02036060) treats patients 
with abiraterone before randomization to continued abiraterone plus docetaxel or docetaxel 
alone upon emergence of progression (radiographic or clinical). This study will evaluate 
continued treatment with enzalutamide after progression in chemotherapy-naïve patients with 
mCRPC. The purpose of the study is to evaluate whether continued treatment with 
enzalutamide in combination with docetaxel chemotherapy offers clinical benefit over 
switching to treatment with docetaxel chemotherapy alone. 
1.2 
Non-clinical and Clinical Data 
1.2.1 
Non-clinical data 
Nonclinical pharmacology data demonstrate that enzalutamide is an AR signaling inhibitor 
that blocks multiple steps in the AR signaling pathway. Enzalutamide competitively inhibits 
androgen-induced receptor activation, inhibits nuclear translocation of activated AR and 
inhibits the association of the activated AR with chromatin. These inhibitory effects occur 
even in the setting of AR overexpression and in prostate cancer cells that are resistant to 
anti-androgens. By inhibiting AR signaling, enzalutamide elicits several downstream effects, 
which include reduced expression of AR dependent genes, decreased growth of prostate 
cancer cells, induction of cancer cell death and tumor regression. Enzalutamide lacks agonist 
activities such as those that may limit the sustained efficacy of current anti-androgens (Tran 
et al 2009). 
Embryo-fetal development studies showed that enzalutamide treatment of dams in mice, but 
not in rabbits, resulted in an increased incidence of embryo-fetal deaths and external and 
skeletal changes. Studies on male and female fertility were not conducted with enzalutamide, 
but in studies in rats (4 and 26 weeks) and dogs (4, 13 and 39 weeks), atrophy, 
aspermia/hypospermia, and hypertrophy/hyperplasia in the reproductive system were noted, 
consistent with the pharmacological activity of enzalutamide. In studies in mice (4 weeks), 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. Leydig cell hypertrophy and/or hyperplasia were observed in mice (4 weeks), 


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rats (2 weeks) and dogs (39 weeks). Additional changes to reproductive tissues included 
hypertrophy/hyperplasia of the pituitary gland and atrophy in seminal vesicles in rats and 
testicular hypospermia and seminiferous tubule degeneration in dogs. Gender differences 
were noted in rat mammary glands (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. 
Enzalutamide did not induce mutations in the microbial mutagenesis (Ames) assay and was 
not clastogenic in either the in vitro cytogenetic assay with mouse lymphoma cells or the in 
vivo mouse micronucleus assay. N-desmethyl enzalutamide and the major inactive 
carboxylic acid metabolite did not induce mutations in the bacterial reverse mutation (Ames) 
assay. Long-term animal studies to evaluate the carcinogenic potential of enzalutamide have 
not been conducted. Enzalutamide was not phototoxic in vitro. 
Additional information on the nonclinical experience with enzalutamide is provided in the 
Enzalutamide Investigator’s Brochure (IB). 
1.2.2 
Clinical Data 
As of 01 January 2014, the cumulative exposure to enzalutamide is estimated to be over 2500 
male prostate cancer patients and over 200 subjects with no known cancer including healthy 
male subjects and subjects with hepatic impairment who received at least 1 dose in any 
clinical study (i.e., not including the expanded access or compassionate use programs). 
The key clinical studies evaluating enzalutamide in men with prostate cancer are described 
briefly as follows: 
1.2.2.1 S-3100-1-01 
The pharmacokinetics (PK), tolerability, and antitumor activity of enzalutamide were first 
studied in a multicenter, open label, first-in-human, dose-escalation study in 140 patients 
with CRPC (Scher et al 2010). Patients who were chemotherapy-naïve or who had previous 
docetaxel-based chemotherapy failure were treated with enzalutamide at doses of 30 to 
600 mg/day until disease progression or intolerable side effects developed. The maximum 
tolerated dose was determined to be 240 mg daily. After review of all data available from 
S-3100-1-01, the optimal dose of enzalutamide for evaluation in Phase 3 clinical trials was 
determined to be 160 mg/day. 
1.2.2.2 CRPC2 (AFFIRM) 
A multinational Phase 3, randomized, double-blind, placebo-controlled, efficacy and safety 
study of enzalutamide (160 mg daily) in patients with progressive CRPC previously treated 
with docetaxel-based chemotherapy was conducted in 1199 men, 800 of whom received 
treatment with enzalutamide (Scher et al 2012). The primary endpoint was overall survival 
(OS). European Medicines Agency (EMA) and Food and Drug Administration (FDA) 
approval of enzalutamide was based on the results of this study. 
1.2.2.3 MDV3100-03 (PREVAIL) 
A multinational, Phase 3, randomized, double-blind, placebo-controlled, efficacy and safety 
study of enzalutamide (160 mg daily) in chemotherapy-naïve patients with progressive 


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metastatic prostate cancer who have failed ADT was conducted in 1717 men, 871 of whom 
received treatment with enzalutamide and 845 received treatment with placebo. The 
co-primary endpoints were OS and radiographic progression-free survival (PFS). The 
prespecified interim analysis at the time of 540 death events demonstrated statistically 
significant improvements in overall survival and radiographic progression free survival in 
patients treated with enzalutamide versus placebo. Enzalutamide treatment resulted in 
prolongation of overall survival (HR 0.71, p < 0.0001) and radiographic progression free 
survival (HR 0.19, p < 0.0001; Beer et al 2014). 
1.2.2.4 MDV3100-06 
A phase I study was conducted to explore the safety profile of the combination of docetaxel 
(75 mg/m2 by 1h infusion every 3 weeks) and enzalutamide given at 160 mg daily in men 
with mCRPC on ADT. Twenty-two patients were enrolled of whom 21 received the 
docetaxel-enzalutamide combination and 18 were evaluable for the PK analysis. Exploratory 
analyses of PSA response rates showed treatment with enzalutamide and docetaxel resulted 
in rapid, substantial, and sustained PSA responses in almost all patients in the study; 95% of 
patients had a ≥ 50% reduction in PSA with a median duration of approximately 7.4 months. 
The combination was generally well tolerated, with no clinically meaningful PK drug-drug 
interaction. 
1.2.2.5 Pharmacokinetics and Drug Metabolism 
In PK investigations in men with CRPC, enzalutamide was absorbed rapidly after oral 
administration, with the time to maximum plasma concentration (tmax) after a single dose 
typically occurring at 1 hour post dose. No major deviations from dose proportionality were 
observed over the dose range 30 mg to 600 mg. 
Terminal half-life was approximately 5.8 days. The average difference between peak 
(Cmax)and trough (predose plasma concentration, Ctrough) concentrations was ≤ 25%. 
Therefore, plasma profiles at steady state resembled a constant infusion. Time-liner PK was 
observed beyond steady state at Day 28. Plasma concentrations of enzalutamide and the 
active metabolite, N-desmethyl enzalutamide, were approximately the same. 
In a drug-drug interaction study in male patients with CRPC (9785-CL-0007), a single oral 
dose of a substrate for CYP2C8, CYP2C9, CYP2C19, or CYP3A4 was administered before 
and concomitantly with enzalutamide (after at least 55 days of dosing at 160 mg daily). 
Enzalutamide at steady state reduced the plasma exposure to midazolam (CYP3A4 
substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate) by 86%, 
56%, and 70%, respectively. Based on the magnitude of the decreases in exposure, 
enzalutamide is considered a strong inducer of CYP3A4 and a moderate inducer of CYP2C9 
and CYP2C19. Substrates of CYP3A4, CYP2C9, and CYP2C19 with a narrow therapeutic 
index should be avoided when possible, as enzalutamide may decrease plasma exposure of 
these drugs. If enzalutamide is coadministered with warfarin (CYP2C9 substrate), additional 
international normalized ratio (INR) monitoring should be conducted. Enzalutamide did not 
cause clinically meaningful changes in exposure to pioglitazone (CYP2C8 substrate). 
Docetaxel is cleared by CYP3A4/5-dependent pathways therefore the potential for a drug-
drug interaction with enzalutamide was studied (see Section 1.2.2.4 MDV3100-06). 
Docetaxel AUC decreased by 11.8% and peak concentration (Cmax) decreased by 3.7% when 


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docetaxel was administered concomitantly with enzalutamide relative to when docetaxel was 
administered without enzalutamide. These small changes in exposure to docetaxel were not 
clinically relevant. 
In a drug-drug interaction study in healthy male volunteers (9785-CL-0006), a single 160 mg 
oral dose of enzalutamide was administered alone or after multiple oral doses of gemfibrozil 
(strong CYP2C8 inhibitor). Gemfibrozil increased the composite area under the curve from 
time zero to infinity (AUC0-∞) of enzalutamide plus N-desmethyl enzalutamide by 2.2-fold 
with minimal effect on Cmax; therefore, strong CYP2C8 inhibitors should be avoided when 
possible as they can increase plasma exposure to enzalutamide plus N-desmethyl 
enzalutamide. If coadministration with a strong CYP2C8 inhibitor is necessary, the dose of 
enzalutamide should be reduced to 80 mg once daily. If coadministration of the strong 
CYP2C8 inhibitor is discontinued, the enzalutamide dose should be returned to the dose used 
prior to initiation of the strong CYP2C8 inhibitor. The effects of CYP2C8 inducers on the PK 
of enzalutamide have not been evaluated in vivo. 
In the drug-drug interaction study in healthy male volunteers (9785-CL-0006), a single 
160 mg oral dose of enzalutamide was administered alone or after multiple oral doses of 
itraconazole (strong CYP3A4 inhibitor). Itraconazole increased the composite AUC0-∞ of 
enzalutamide plus N-desmethyl enzalutamide by 1.3-fold with no effect on Cmax. As this 
small change is not clinically meaningful, no starting dose adjustment is needed when 
coadministering enzalutamide with CYP3A4 inhibitors. The effects of CYP3A4 inducers on 
the PK of enzalutamide have not been evaluated in vivo. 
Additional information on the clinical experience with enzalutamide is provided in the 
Enzalutamide IB. 
1.3 
Summary of Key Safety Information for Study Drugs 
1.3.1 
Enzalutamide 
The most common adverse reactions (≥ 5%) in patients treated with enzalutamide (N = 1671) 
in the phase 3 studies CRPC2 (AFFIRM) and MDV3100-03 (PREVAIL) were anemia, 
nausea, constipation, diarrhea, vomiting, abdominal pain, fatigue, asthenia, peripheral edema, 
urinary tract infection, nasopharyngitis, fall, weight decreased, decreased appetite, back pain, 
arthralgia, pain in extremity, musculoskeletal pain, bone pain, musculoskeletal chest pain, 
muscular weakness, myalgia, headache, dizziness, dysgeusia, spinal cord compression, 
paraesthesia, insomnia, anxiety, haematuria, pollakiuria, dyspnoea, cough, hot flush, and 
hypertension. Events leading to discontinuation of study drug with a higher incidence in the 
enzalutamide group were nausea, back pain, cerebrovascular accident, convulsion, and 
syncope; however, the differences between treatment groups were small. 
The safety and tolerability of enzalutamide were evaluated in an integrated safety analysis 
and continues to be evaluated on an ongoing basis for all enzalutamide program studies. No 
study has been terminated early for safety reasons. 
The reference safety information for enzalutamide is contained in section 5.2.3 of the 
enzalutamide investigator brochure 


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1.3.2 
Docetaxel with Prednisolone 
Safety information for docetaxel is available in the current SPC (Docetaxel SPC). The most 
frequent adverse reactions observed with docetaxel include neutropenia, anaemia, anorexia, 
nausea, vomiting, diarrhea, hypersensitivity reactions (flushing, rash with or without pruritus, 
chest tightness, back pain, dyspnoea and fever or chills, hypotension and/or bronchospasm or 
generalized rash/erythema); peripheral neurotoxicity (paresthesia, dysesthesia or pain 
including burning, weakness); reversible cutaneous reactions (rash including localised 
eruptions, stomatitis, pruritus); nail disorders (hypo- or hyperpigmentation and sometimes 
pain and onycholysis); infusion site reactions and fluid retention (peripheral oedema and less 
frequently pleural effusion, pericardial effusion, ascites and weight gain). 
1.3.3 
Enzalutamide in combination with Docetaxel and Prednisolone 
During the combination therapy window, the most common adverse events reported in 5 or 
more patients (≥ 22.7%) were neutropenia, fatigue, peripheral neuropathy, nausea, 
constipation, diarrhea, peripheral sensory neuropathy, alopecia, arthralgia, back pain, 
decreased appetite, dyspnea, dysgeusia, and increased lacrimation. The most common 
grade 3 or higher adverse events reported in 2 or more patients (≥ 9.1%) were neutropenia 
(86.4%), febrile neutropenia (18.2%), white blood cell (WBC) count decreased (18.2%), and 
blood phosphorus decreased (9.1%). 
1.4 
Risk-Benefit Assessment 
The results from Phase III studies (see Sections 1.2.2.2 CRPC2 (AFFIRM), 1.2.2.3 
MDV3100-03 (PREVAIL)) indicate the benefit of enzalutamide in men with mCRPC 
following and prior to initiation of chemotherapy. Docetaxel with prednisolone is well-
established for the treatment of mCRPC. The results from a Phase I study examining the 
combination of enzalutamide with docetaxel (see Section 1.2.2.4 MDV3100-06) indicated 
that enzalutamide does not have a clinically meaningful impact on docetaxel PK and the PSA 
response rate observed in combination was more favorable than the PSA response rate 
reported in previous studies of enzalutamide or docetaxel alone. These insights justify a 
larger, randomized study to characterize the potential efficacy benefit and confirm whether 
the safety profile of enzalutamide plus docetaxel differs from that of docetaxel alone. 
Available data then suggest a positive benefit-risk assessment for the investigation of 
enzalutamide in combination with docetaxel plus prednisolone in men with mCRPC 
following progression on enzalutamide treatment. As an increase in the occurrence of 
docetaxel-induced neutropenia during co-administration of enzalutamide cannot be excluded, 
the Independent Data Monitoring Committee (IDMC; see Section 10.1 Independent Data-
Monitoring Committee) will be requested to give specific attention to any emerging 
differences in prevalence of known adverse events, especially hematological toxicities, 
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2 
STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS 
2.1 
Study Objectives 
The primary objective of the study is to compare the efficacy of continuing treatment with 
enzalutamide after adding docetaxel and prednisolone versus placebo plus docetaxel and 
prednisolone, as measured by PFS in subjects with chemotherapy-naïve mCRPC with 
progression during treatment with enzalutamide alone. 
The secondary objectives of the study are to evaluate the effect of continuing treatment with 
enzalutamide and adding docetaxel and prednisolone versus placebo plus docetaxel and 
prednisolone, as measured by the following in subjects with chemotherapy-naïve mCRPC 
with progression during treatment with enzalutamide alone: 
● 
Time to Prostate-specific antigen (PSA progression 
● 
PSA response 
● 
Objective response rate 
● 
Time to pain progression 
● 
Time to opiate use for cancer-related pain 
● 
Time to first SRE 
● 
Quality of life 
Safety profile, including cumulative dose of docetaxel, and Health Resource Use will be 
described for these subjects. The safety profile as well as Health Resource Use of 
enzalutamide alone when administered to chemotherapy naïve subjects will also be 
described. 
2.2 
Study Design and Dose Rationale 
2.2.1 
Study Design 
This double-blind, randomized, placebo controlled trial of subjects with chemotherapy naïve 
mCRPC will evaluate the efficacy and safety of continued treatment with enzalutamide after 
adding docetaxel and prednisolone compared with treatment with placebo in combination 
with docetaxel and prednisolone. 
The study will be conducted in consecutive periods; period 1 of open label treatment with 
enzalutamide followed by period 2, randomized double-blind treatment with continued 
enzalutamide or placebo, adding with docetaxel and prednisolone. 
2.2.1.1 Open Label (Period 1): 
Subjects will attend a screening visit to determine eligibility for open label treatment in 
Period 1. 
Following screening, enrolled subjects will receive open label treatment with enzalutamide 
(160 mg/day). At Week 13, all subjects will be assessed by PSA and imaging. The initial 
PSA response (stable or declining) must be confirmed by a second consecutive value at least 
3 weeks later. As PSA may not remain stable or decline in all subjects who subsequently 
benefit from enzalutamide, this study design is based on the hypothesis that subsequent 
addition of docetaxel will be of greater benefit in those subjects who have a confirmed initial 
PSA response. Therefore, subjects with no confirmed PSA response or evidence of 
radiographic progression (assessed at Week 13) will be ineligible for participation in Period 2 


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and will typically have safety follow up; however, Period 1treatment may continue for some 
subjects as long as the investigator considers it to be of clinical benefit (stopping on initiation 
of any new antineoplastic therapy). Subjects with confirmed PSA response will continue 
Period 1 until disease progression as supported by evidence of at least one of the following 
criteria (see Sections 5.2 Demographics and Baseline Characteristics; 5.3 Efficacy 
Assessment; 5.4 Safety Assessment): 
● 
PSA progression with rapid PSA doubling time (PSA-DT) defined as: 
o 
PSA rise of ≥ 25% and an absolute increase of ≥ 2 ng/mL above nadir, confirmed 
by a second PSA value at least 3 weeks later, and 
o 
PSA-DT of ≤ 12 weeks determined in at least 3 PSA measurements collected at 
intervals of 4 or more weeks apart during a period of 3 or more months (Arlen et al 
2008); 
● 
Radiographic progression defined as: 
o 
Bone disease progression, or; 
o 
Soft tissue disease progression. 
Administration of open label enzalutamide will continue until randomization to Period 2 
treatment, confirmation of ineligibility for Period 2 treatment (subjects will be discontinued 
from the study), intolerable toxicity, subject withdrawal, or death, whichever occurs first. 
When sufficient numbers of subjects have been randomized into Period 2 (around 274) or the 
number of evaluable events for the primary endpoint have been reached (182), enrollment to 
Period 2 will close. Investigators will be notified, and subjects who are still in Period 1 and 
are benefiting from treatment will have the opportunity to continue with open label 
enzalutamide via an Extension Period in another Astellas-sponsored study. 
 
2.2.1.2 Randomization (Period 2): 
Subjects with confirmed disease progression on enzalutamide alone who continue to meet all 
eligibility criteria may proceed to randomization. Randomization must occur within 4 weeks 
of progression observed in Period 1. 
Treatment allocation will be in a 1:1 ratio, stratified by disease progression (evidence of 
radiographic progression or not) in Period 1 to the following treatments: 
● 
Enzalutamide (160 mg daily) in combination with docetaxel (75 mg/m2 every 3 weeks) 
and prednisolone (10 mg daily); 
● 
Enzalutamide placebo (daily) in combination with docetaxel (75 mg/m2 every 3 weeks) 
and prednisolone (10 mg daily). 
Administration of docetaxel will continue for up to 10 cycles, however subjects assessed by 
the Investigator to be benefiting from treatment may continue on docetaxel for additional 
cycles. Subjects who discontinue docetaxel before completion of 10 cycles (e.g. for toxicity) 
may continue treatment with IMP and will continue to attend study visits (at 12 weekly 
intervals) for assessments until IMP discontinuation criteria or endpoint criteria are met. 
Administration of blinded enzalutamide/placebo will continue until disease progression, 
intolerable toxicity, subject withdrawal or death, whichever occurs first. When the required 
number of evaluable events for primary endpoint  have been reached, subjects ongoing in 


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period 2 will be able to continue receiving double blind treatment until the database is 
unblinded after database lock for the primary analysis. 
 
2.2.1.3 Biomarker Sub-study  
Subjects in a subset of countries and sites will be invited to participate in a voluntary, 
exploratory, biomarker sub-study. For subjects who have consented to provide samples for 
this sub-study, blood samples for circulating biomarker analysis will be taken at the 
following timepoints:  
Period 1:  
Week 1/Day1 (pre dosing with enzalutamide), Week 5, Week 13, and when subjects progress 
clinically (4 samples).  
Period 2: Week 1/Day 1 (pre study drug in Period 2), Cycle 2 (Week 4), Cycle 5 (Week 13), 
Cycle 9 (Week 25), when subjects progress clinically or reach another endpoint in the study 
and at Follow-Up (30 days after last dose of IMP) (6 samples). Any subject who consents to 
participate in the biomarker sub-study but fails to provide a valid baseline sample for Period 
1, may still participate in Period 2 of the biomarker sub-study. In this case, the last sample of 
Period 1 (the sample taken when they progress clinically) should be taken as part of the 
baseline for Period 2. Informed Consent for the biomarker samples must be taken before any 
samples are collected.  Samples are to be handled according to the laboratory manual and 
shipped to a central laboratory for processing. The analysis of the exploratory biomarkers 
will be described in a separate biomarker plan. 
2.2.1.4 Follow-up: 
All subjects will have a safety follow-up visit 30 days after the last dose of Investigational 
Medicinal Product (IMP) or prior to the initiation of a subsequent antineoplastic therapy for 
prostate cancer, whichever occurs first. 
In Period 2, subjects who discontinue IMP for a reason other than disease progression will 
continue to attend study visits (at 12 weekly intervals) for assessments until withdrawal of 
consent, disease progression or death. 
Follow-up will be performed for a maximum of 112 days or until radiographic progression, 
or initiation of a new anti-neoplastic therapy is documented.   Follow-up will cease after 
database lock for the primary analysis. 
 
2.2.1.5 Extension Period: 
For those subjects who are still receiving study drug in Period 1  when enrollment to Period 2 
closes (approximately 274 subjects randomized, or when the data cut-off for analysis is 
reached in Period 2, whichever occurs first), there will be the opportunity to continue 
receiving enzalutamide treatment via  an Extension Period in another Astellas-sponsored 
study. (see section 4.5.3). 
2.2.2 
Dose Rationale 
Enzalutamide 160 mg/day will be evaluated in this study. This is the approved dose in 
mCRPC patients who have progressed after treatment with docetaxel (Enzalutamide SPC), 


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and is the dose studied in the chemotherapy-naïve mCRPC patient MDV3100-03 study 
(PREVAIL). 
In Period 2, docetaxel will be administered at 75mg/m2 as a 1h infusion every 3 weeks in 
accordance with the approved dose for mCRPC patients. The combination of enzalutamide 
and docetaxel has been evaluated previously (see Section 1.2.2.4 MDV3100-06). 
2.3 
Endpoints 
2.3.1 
Primary Endpoints 
The primary efficacy endpoint is PFS with progression defined as radiographic progression, 
unequivocal clinical progression, or death on study. 
PFS is defined as the time from randomization to the earliest objective evidence of 
radiographic progression, unequivocal clinical progression, or death on study, whichever 
occurs first: 
● 
Radiographic disease progression is defined for bone disease by the appearance of 2 or 
more new lesions on whole-body radionuclide bone scan per Prostate Cancer Clinical 
Trials Working Group 2 (PCWG2) criteria or for soft tissue disease by Response 
Evaluation Criteria in Solid Tumors (RECIST) 1.1. 
● 
Unequivocal clinical progression is defined as any of the following: 
o 
new onset cancer pain requiring chronic administration of opiate analgesia, 
o 
deterioration from prostate cancer of Eastern Cooperative Oncology Group 
(ECOG) performance status score to 3 or higher, 
o 
initiation of subsequent lines of cytotoxic chemotherapy or radiation therapy or 
surgical intervention due to complications of tumor progression. 
● 
Death on study is defined as death within 112 days of treatment discontinuation without 
objective evidence of radiographic progression. 
2.3.2 
Secondary Endpoints 
Secondary efficacy endpoints include: 
● 
Time to PSA progression, defined as the time from randomization to the date of the first 
PSA value in Period 2 demonstrating progression (Period 2). The PSA progression date 
is defined as the date that a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL above 
the nadir recorded in Period 2 is documented, which must be confirmed by a second 
consecutive value obtained at least 3 weeks later. 
● 
PSA response, defined as the percentage change in PSA from randomization to Week 13 
(or earlier for those that discontinue therapy), as well as the maximum decline in PSA 
that occurs at any point after treatment. 
● 
Objective response rate, defined as the best overall radiographic response after 
randomization as per Investigator assessments of response for soft tissue disease per 
RECIST 1.1, in subjects who have a measurable tumor. 
● 
Time to pain progression, defined as the time to an increase of ≥ 30% from 
randomization in the mean of Brief Pain Inventory Short Form (BPI-SF) pain intensity 
item scores (items 3, 4, 5, and 6). 


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● 
Time to opiate use for cancer-related pain, defined as the time to initiation of chronic 
administration of opiate analgesia (parenteral opiate use for ≥7 days or use of WHO 
Analgesic Ladder Level 3 oral opiates for ≥3 weeks). 
● 
Time to first SRE, defined as the time from randomization to radiation therapy or 
surgery to bone, pathologic bone fracture, spinal cord compression, or change of 
antineoplastic therapy to treat bone pain. 
● 
Quality of life, as assessed using Functional Assessment of Cancer Therapy - Prostate 
(FACT-P) and EuroQol 5 dimension, 5 level health state utility index (EQ-5D-5L). 
2.3.3 
Other Endpoints 
● 
Cumulative dose of docetaxel. 
● 
Health resource use (hospitalization and duration thereof; number and types of visits to a 
health professional) in Period 1 and Period 2. 
 
2.3.4       Exploratory Endpoints  
To analyze candidate biomarkers in circulation for association with response or progression 
and for identifying mechanisms of resistance. 
2.3.5 
Safety Endpoints 
Safety in both Periods will be assessed by AEs, clinically significant changes in physical 
examination, vital signs, laboratory values, and electrocardiograms (ECGs) as described in 
Section 5.4 Safety Assessment. 
Deaths, defined as deaths due to any cause, will be summarized descriptively. 
3 
STUDY POPULATION 
3.1 
Selection of Study Population  
The study population for Period 1 will include approximately 650 men with mCRPC who 
have progressed while on luteinizing hormone-releasing hormone (LHRH) agonist/antagonist 
or after receiving a bilateral orchiectomy and have not yet received chemotherapy. 
Approximately 274 subjects from Period 1 who subsequently progress on enzalutamide alone 
and continue to meet entry criteria will be randomized to treatment in Period 2. 
Waivers to the inclusion or exclusion criteria will NOT be allowed. 
3.1.1 
Subject re-screening 
Re-screening is allowed only in situations in which a subject underwent the screening 
procedures (i.e., scans and laboratory work) and due to logistical circumstances, the allocated 
time window for these tests has expired. Re-screening is not permitted in cases in which the 
initial test results do not support eligibility. No more than one re-screening attempt will be 
allowed for each subject in the study. 
3.2 
Inclusion Criteria 
3.2.1 
Inclusion Criteria - Period 1 (assessed at the Screening Visit) 
Subjects must meet the following criteria prior to initiation of IMP: 
1. Age 18 or older; 


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2. Independent Ethics Committee (IEC)-approved written 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); 
3. Histologically confirmed adenocarcinoma of the prostate without neuroendocrine 
differentiation or small cell features; 
4. Ongoing ADT with a LHRH agonist or antagonist at a stable dose and schedule within 
4 weeks of initiation of IMP, or bilateral orchiectomy (i.e., surgical or medical 
castration); 
5. Serum testosterone level ≤ 1.73 nmol/L (≤ 50 ng/dL); 
6. Metastatic (M1) disease documented by at least 2 bone lesions on bone scan, or soft 
tissue disease documented by computed tomography (CT)/magnetic resonance imaging 
(MRI); 
7. Progressive disease at study entry defined as the following occurring in the setting of 
castrate levels of testosterone: 
• 
PSA progression defined by a minimum of three rising PSA levels with an interval 
of ≥ 1 week between each determination. 
• 
The PSA value at Screening should be ≥ 2 μg/L (≥ 2 ng/mL). 
In the event of prior AR inhibitor use, the most recent local PSA and the Screening 
PSA assessed by the central laboratory (central PSA) must be obtained at least 
4 weeks after the last dose of AR inhibitor; 
8. Asymptomatic or minimally symptomatic prostate cancer (BPI-SF question 3 score 
of < 4) at Screening; 
9. ECOG performance score of 0-1 at Screening; 
10. Estimated life expectancy of ≥ 12 months from Screening; 
11. Be suitable and willing to receive chemotherapy as part of the trial; 
12. Able to swallow the IMP and comply with study requirements; 
13. Subjects and their female spouse/partners who are of childbearing potential must be 
using highly effective contraception consisting of 2 forms of birth control* (one of which 
must be a condom) starting at Screening and continue throughout the study period and 
for 3 months after the final IMP administration; 
14. Subjects must not donate sperm starting at Screening and throughout the study period 
and for 3 months after the final IMP administration. A condom is required throughout 
the study period and for 3 months after the final IMP administration if the subject is 
engaged in sexual activity with a pregnant woman; Subject agrees not to participate in 
another interventional study while on treatment.  
15. Subject agrees not to participate in another interventional study while on treatment. Subjects 
who are participating in a control arm of an interventional study which includes only 
standard of care, or in an observational phase following an interventional study, may be 
eligible for this study, providing they meet all the other entry criteria. 
 
3.2.2 
Inclusion Criteria – Period 2 (assessed at the Period 2 Eligibility Assessment) 
Subjects must meet the following criteria prior to randomization: 
1. Have confirmed progressive disease on open label enzalutamide treatment, defined as 
one or more of:  


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• 
PSA progression with rapid PSA-DT defined as: 
PSA rise of ≥ 25% and an absolute increase of ≥ 2 ng/mL above nadir, confirmed by 
a second PSA value at least 3 weeks later, and 
PSA-DT of ≤ 12 weeks determined in at least 3 PSA measurements collected at 
intervals of 4 or more weeks apart during a period of 3 or more months; 
• 
Bone disease progression defined by the appearance of 2 or more new bone lesions 
on whole-body radionuclide bone scan per the PCWG2 criteria; 
• 
Soft tissue disease progression per RECIST 1.1 with a consistent methodology 
applied to assess any given subject; 
2. Ongoing ADT with a LHRH agonist or antagonist at a stable dose and schedule for at 
least 4 weeks, or bilateral orchiectomy (i.e., surgical or medical castration); 
3. Serum testosterone level ≤ 1.73 nmol/L (≤ 50 ng/dL); 
4. ECOG performance score of 0-2; 
5. Subjects receiving bisphosphonates or denosumab for bone health must have been on a 
stable dose for at least 4 weeks; 
6. Able to swallow the IMP and comply with study requirements; 
7. Subjects and their female spouse/partners who are of childbearing potential must be 
using highly effective contraception consisting of 2 forms of birth control* (one of which 
must be a condom) starting at Screening and continue throughout the study period and 
for the later of 3 months after the final IMP administration or 6 months after the final 
docetaxel administration; 
8. Subjects must not donate sperm starting at Screening and throughout the study period 
and for the later of 3 months after the final IMP administration or 6 months after the final 
docetaxel administration. A condom is required throughout the study period and for 3 
months after the final IMP administration if the subject is engaged in sexual activity with 
a pregnant woman; 
9. Be suitable and willing to receive chemotherapy as part of the trial. 
*Acceptable forms of birth control include: 
● 
Established use of oral, injected or implanted hormonal methods of contraception. 
● 
Placement of an intrauterine device (IUD) or intrauterine system (IUS). 
● 
Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault 
caps) with spermicidal foam/gel/film/cream/suppository. 
3.3 
Exclusion Criteria 
3.3.1 
Exclusion Criteria - Period 1 (assessed at the Screening Visit) 
Subjects will be excluded from participation if any of the following apply: 
1. Absolute neutrophil count (ANC) < 1,500/μL, platelet count < 100,000/μL, or 
hemoglobin < 6.2 mmol/L (< 10 g/dL) 
(NOTE: subjects must not have received any growth factors or blood transfusions within 
seven days of the hematologic laboratory values obtained at Screening); 
1. Total bilirubin > upper limit of normal (ULN); alanine aminotransferase (ALT) or 
aspartate aminotransferase (AST) ≥ 2.5 times ULN; Child-Pugh B and C hepatic 
impairment. 
2. Creatinine > 177 μmol/L (> 2 mg/dL); 


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3. Albumin ≤ 30 g/L (≤ 3.0 g/dL); 
4. Prior treatment with the following agents for the treatment of prostate cancer: 
• 
Aminoglutethimide; 
• 
Ketoconazole; 
• 
Abiraterone; 
• 
Enzalutamide or participation in a clinical trial of enzalutamide; 
• 
223Ra, 89Sr, 153Sm, 186Re/188Re; 
• 
Immunomodulatory therapies (e.g. Sipuleucel-T, DCVAC); 
• 
Cytotoxic chemotherapy (e.g. docetaxel, cabazitaxel, mitoxantrone, estramustine); 
• 
Participation in a clinical trial of an investigational agent that inhibits the AR or 
androgen synthesis (e.g. ARN-509, ODM-201, VT-464; unless the treatment was 
placebo); 
5. Current or prior treatment within 4 weeks prior to initiation of IMP with the following 
agents for the treatment of prostate cancer: 
• 
Antiandrogens (e.g. bicalutamide, nilutamide, flutamide); 
• 
5-α reductase inhibitors (e.g. finasteride, dutasteride); 
• 
Estrogens; 
• 
Anabolic steroids; 
• 
Drugs with antiandrogenic properties such as spironolactone > 50 mg/kg; 
• 
Progestational agents; 
6. Subject has received investigational therapy within 28 days or 5 half-lives whichever is 
longer, prior to initiation of IMP; 
7. Use of opiate analgesia for pain from prostate cancer within 4 weeks prior to initiation of 
IMP; 
8. Radiation therapy to bone lesions or prostatic bed within 4 weeks prior to initiation of 
IMP; 
9. Major surgery within 4 weeks prior to initiation of IMP; 
10. History of seizure or any condition that may predispose to seizures at any time in the 
past (e.g., prior cortical stroke, brain arteriovenous malformation, head trauma with loss 
of consciousness requiring hospitalization). History of loss of consciousness or transient 
ischemic attack within 12 months prior to Screening; 
11. Known or suspected brain metastasis or active leptomeningeal disease; 
12. History of another malignancy within the previous 5 years other than non-melanoma 
skin cancer; 
13. Clinically significant cardiovascular disease including: 
• 
Myocardial infarction within six months prior to Screening; 
• 
Uncontrolled angina within three months prior to Screening; 
• 
Congestive heart failure New York Heart Association (NYHA) class 3 or 4, or 
subjects with history of congestive heart failure NYHA class 3 or 4 in the past, 
unless a screening echocardiogram or multi-gated acquisition scan (MUGA) 
performed within 3 months results in a left ventricular ejection fraction that is 
≥ 45%; 
• 
History of clinically significant ventricular arrhythmias (e.g., ventricular 
tachycardia, ventricular fibrillation, torsades de pointes); 


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• 
History of Mobitz II second degree or third degree heart block without a permanent 
pacemaker in place; 
• 
Bradycardia as indicated by a heart rate < 45 beats per minute on the screening ECG 
or physical examination; 
• 
Uncontrolled hypertension as indicated by a resting systolic blood pressure > 
170 mmHg or diastolic blood pressure > 105 mmHg at Screening; 
14. Gastrointestinal disorders affecting absorption (e.g. extensive small bowel resection, 
active inflammatory bowel disease); 
15. Medical contraindications to the use of prednisolone or docetaxel; 
16. Allergies to any of the active ingredients or excipients in the study drugs; 
17. Any condition which, in the Investigator’s opinion, makes the subject unsuitable for 
study participation. 
3.3.2 
Exclusion Criteria - Period 2 (assessed at the Period 2 Eligibility Assessment) 
Subjects will be excluded from participation if any of the following apply: 
1. Cancer pain requiring chronic administration of opiate analgesia (parenteral opiate use 
for ≥7 days or use of WHO Analgesic Ladder Level 3 oral opiates for ≥3 weeks; 
2. Absolute neutrophil count (ANC) < 1,500/μL, platelet count < 100,000/μL, or 
hemoglobin < 6.2 mmol/L (10 g/dL) 
(NOTE: subjects must not have received any growth factors or blood transfusions within 
seven days prior to the hematologic laboratory values obtained at the Period 2 Eligibility 
Assessment); 
3. Total bilirubin > ULN; ALT or AST ≥ 2.5 times ULN; Child-Pugh B and C hepatic 
impairment; 
4. Creatinine > 177 μmol/L (2 mg/dL); 
5. Albumin ≤ 30 g/L (3.0 g/dL). 
4 
TREATMENT(S) 
4.1 
Identification of Study Drugs 
4.1.1 
Investigational Medicinal Product - Enzalutamide 
The IMP, enzalutamide, has the chemical name 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-
dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}-2-fluoro-N-methylbenzamide. It is a white 
to off-white solid that is insoluble in water and no salt forms are available at approximately pH 
2 to 10. 
The drug substance is formulated in the surfactant Labrasol® to create a solution. Enzalutamide 
will be provided as 40 mg liquid-filled soft gelatin capsules. The capsules are white to off-white 
oblong capsules. 
4.1.2 
Comparative Drug - Placebo 
The corresponding placebo for enzalutamide consists of identical capsules filled with the 
same excipients but no active product. 


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4.1.3 
Non-Investigational Medicinal Products 
Docetaxel will be provided by the Sponsor or may be provided locally. Handling and 
administration of docetaxel should be in accordance with the SPC (Docetaxel SPC) and local 
practice for administration of cytotoxic agents. Infusion materials (diluents, pumps, catheters) 
will be provided locally. 
Prednisolone 5 mg will be provided by the Site, along with any other pre-treatments given as 
standard of care. 
4.2 
Packaging and Labeling 
The IMP used in this study will be prepared, packaged, and labeled under the responsibility 
of a qualified person at Astellas Pharma Europe B.V. (APEB) or Sponsor’s designee in 
accordance with APEB or Sponsor’s designee Standard Operating Procedures (SOPs), Good 
Manufacturing Practice (GMP) guidelines, International Conference on Harmonization of 
Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH GCP) 
guidelines, and applicable local laws/regulations. 
The IMP will be labeled according to the requirements as published in Annex 13 of the GMP 
guidelines and local laws and regulations. 
A qualified person of APEB or Sponsor’s designee will perform the final release of the IMP 
according to Directive 2003/94/EC annex 13. 
4.2.1 
Docetaxel 
Docetaxel should be stored and handled in accordance with the SPC (Docetaxel SPC) and 
local practice for storage of cytotoxic agents. Docetaxel provided for the study is not 
intended for use outside of the study site. 
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, 
● 
that study drug is handled and stored according to labeled storage conditions, 
● 
that study drug with appropriate expiry/retest and is only dispensed to study subjects in 
accordance with the protocol, and 
● 
that any unused study drug is returned to the Sponsor. 
Drug inventory and accountability records for the study drugs will be kept by the 
Investigator/or designee. Study drug accountability throughout the study must be documented 
and reconciled. The following guidelines are therefore pertinent: 
● 
The Investigator agrees not to supply study drugs to any persons except the eligible 
subjects in this study in accordance with the protocol. 
● 
The Investigator 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 test drugs. 


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● 
A study drug inventory will be maintained by the Investigator 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 this responsibility. 
● 
The site must return study drug to the Sponsor or designee at the end of the study or 
upon expiration. 
4.4 
Blinding 
Period 2 of the study will be conducted in a double-blind manner. Subjects will be 
randomized to receive enzalutamide or placebo in a double-blind fashion such that the 
Investigator, Sponsor’s study management team, clinical staff, nor the subject will know 
which agent is being administered. Docetaxel will be administered open label. 
4.4.1 
Blinding Method 
The study medication blind will be maintained by the Interactive Response Technology 
(IRT), which will be accessed by the study sites for subject number and study medication 
assignments.  
4.4.2 
Confirmation of the Indistinguishability of the IMP 
The control for this blinded study will be placebo capsules that appear identical to the 
enzalutamide capsules. IMP will be dispensed in the same manner regardless of assigned 
treatment arm. Subjects will ingest the same number of capsules throughout the study. 
4.4.3 
Breaking the Treatment Code for Emergency 
Treatment unblinding may only occur if the knowledge of the treatment assignment will 
materially change the planned management of a medical emergency.  
For unblinding a subject, the assigned study medication information is accessible through the 
IRT. The sponsor must be notified immediately if the blind is broken. The date, time, and 
reason the blind was broken must be recorded in the source documents and on the appropriate 
Electronic Case Report Form (eCRF) if applicable. 
If the Investigator is unblinded, study medication must be stopped immediately and the 
subject must be discontinued from the study. No subjects or other study personnel will be 
made aware of the treatment given to any subject unless a medical emergency necessitates 
such disclosure. 
4.4.4 
Breaking the Treatment Code by the Sponsor 
The Sponsor may break the treatment code for subjects who experience a Suspected 
Unexpected Serious Adverse Reaction (SUSAR) in order to determine if the individual case 
or a group of cases requires expedited regulatory reporting. Individual Emergency Codes will 
be provided to the limited staff who are responsible to break the codes for all SUSAR cases 
for reporting purposes. 


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The IDMC will be provided access to the dosing assignment for periodic review of the 
unblinded data as documented in the IDMC Charter. 
4.5 
Assignment and Allocation 
4.5.1 
Period 1 – Open Label IMP 
The Investigator or designee will contact the IRT to register the subject into the study prior to 
the commencement of screening activities in Period 1. Subjects who meet the 
inclusion/exclusion criteria will be assigned to receive active treatment with enzalutamide. 
The identification number of the medication to be dispensed will be provided by the IRT. At 
subsequent drug dispensing visits, the Investigator or designee will again contact the IRT to 
request additional study medication for a subject. The medication number provided by the 
IRT should be included in the source documentation. 
4.5.2 
Period 2 – Randomized IMP 
Subjects who meet the inclusion/exclusion criteria will be randomly assigned to receive 
enzalutamide or placebo using a 1:1 randomization schedule. Subjects will be stratified by 
disease progression (evidence of radiographic progression or not). The sponsor or designee 
will generate the randomization schedule. 
The Investigator or designee will contact the IRT to randomize the subject into the study 
prior to the initiation of IMP in Period 2. IMP dispensing will be performed as described in 
Section 4.5.1 Period 1 – Open Label IMP. 
4.5.3 
Continuation of Treatment after Completion of Randomization and before and 
after Unblinding. 
When sufficient numbers of subjects have been randomized into Period 2 (around 274), or 
the number of evaluable events for the primary endpoint have been reached (182), whichever 
occurs first, enrollment to Period 2 will close. Subjects who are still in Period 1 will have the 
opportunity to continue with open label enzalutamide via an Extension Period in another 
Astellas-sponsored study, until the investigator or subject decides it is no longer in the 
subject’s best interests to continue; a decision to initiate alternative antineoplastic therapy is 
made; or there is disease progression, intolerable toxicity, subject withdrawal or death, 
whichever occurs first.  Assessments will be limited to collection of efficacy and laboratory 
assessments that are performed as part of standard of care for the subject, Serious Adverse 
Events (SAEs) and Adverse Events (AEs). Protocol-specified efficacy and laboratory 
assessments will cease.  
Similarly, when at least 182 endpoint-events have occurred in Period 2 of the study, the data 
will be cleaned and analyzed. Allowing for attrition, there may be some subjects still active 
in Period 2 when this data analysis cut-off is reached. These subjects will be able to continue 
to receive blinded study drug  until the study is unblinded after database lock, at which time, 
subjects in the enzalutamide+docetaxel arm, who are still on enzalutamide will be able to continue 
receiving enzalutamide until the investigator or subject decides it is no longer in the subject’s 
best interests to continue study drug; a decision to initiate alternative antineoplastic therapy is 
made; or there is disease progression, intolerable toxicity, subject withdrawal or death, 
whichever occurs first. Assessments will be limited as described above. 


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Subjects that are in the docetaxel plus placebo arm will leave the study and be treated as per 
standard of care. Subjects who decide not to continue receiving treatment via the extension 
periods will leave the study and be treated as per local standard of care. 
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 
5.1.1.1 Period 1 Open label IMP 
All subjects will receive open label enzalutamide 160 mg (4 x 40 mg capsules), orally once 
daily. 
IMP should be taken as close to the same time each day as possible. IMP can be taken with 
or without food. 
5.1.1.2 Period 2 Randomized IMP 
Subjects will be randomized to receive blinded oral doses of IMP: 
• Enzalutamide treatment arm - 160 mg (4 x 40 mg capsules) of active enzalutamide orally 
once daily. 
• Placebo treatment arm - matching placebo (4 capsules) orally once daily. 
IMP should be taken as close to the same time each day as possible. IMP can be taken with 
or without food. 
5.1.1.3 Period 2 Non-IMP 
Docetaxel in combination with prednisone or prednisolone is indicated for the treatment of 
patients with hormone refractory metastatic prostate cancer (Docetaxel SPC). In accordance 
with the SPC, docetaxel 75 mg/m2 will be administered as a one-hour infusion every 3 
weeks. 
Prednisolone 5 mg orally twice daily will be administered continuously during docetaxel 
dosing cycles. 
5.1.2 
Interruption and Reduction in Dose of the Study Drugs 
5.1.2.1 Enzalutamide/Placebo 
If a subject misses taking a dose at the usual time, the prescribed dose should be taken as 
close as possible to the usual time. If a subject misses a dose for a whole day, treatment 
should be resumed the following day with the usual daily dose. 
If a subject experiences a ≥ Grade 3 toxicity or an intolerable adverse reaction, dosing should 
be withheld for 1 week or until symptoms improve to ≤ Grade 2, then resumed at the same or 
a reduced dose (3 capsules or 2 capsules) if warranted. 
If a subject must be dosed with a strong CYP2C8 inhibitor (e.g. gemfibrozil) then treatment 
should be administered at a reduced dose (2 capsules) during concomitant treatment (see 
Section 5.1.4.2 Drugs That May Affect Exposure to Enzalutamide). 


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5.1.2.2 Docetaxel 
In accordance with the SPC (Docetaxel SPC), docetaxel should be administered when the 
neutrophil count is ≥1,500 cells/mm3. Dosing may be delayed until the neutrophil count has 
recovered. 
In subjects who experience either febrile neutropenia, neutrophil count <500 cells/mm3 for 
more than one week, severe or cumulative cutaneous reactions or severe peripheral 
neuropathy during docetaxel therapy, the dose of docetaxel should be reduced from 
75 mg/m2 to 60 mg/m2. If the subject continues to experience these reactions at 60 mg/m2, 
the treatment should be discontinued. 
A 50% docetaxel dose reduction should be considered if subjects require co-administration of 
a strong CYP3A4 inhibitor such as azole antifungals, ritonavir and some macrolides 
(clarithromycin, telithromycin; see Section 5.1.4.4 Drugs That May Affect Exposure to 
Docetaxel). 
For subjects with total bilirubin > ULN and/or ALT and AST > 3.5 times the ULN 
concurrent with ALP > 6 times the ULN, docetaxel should not be used. Subjects with 
elevated LFTs should have LFTs assessed prior to each cycle of docetaxel; see Schedule of 
Assessments - Period 2. 
5.1.3 
Previous and Concomitant Medication (Drugs and Therapies) 
5.1.3.1 Previous Medication (Drugs and Therapies) 
Medication taken within four weeks prior to the Period 1 Screening Visit must be captured in 
the eCRF. 
5.1.3.2 Concomitant Medication (Drugs and Therapies) 
Concomitant medications will be assessed at Screening (Period 1) and all subsequent clinic 
visits. All concomitant medications must be recorded in the eCRF. If the use of any 
medication during the study is due to an AE, the AE must be recorded on the AE case report 
form (CRF) and in the subject’s clinical record. 
Throughout the study, ongoing ADT with a LHRH agonist/antagonist is required if the 
subject has not undergone prior bilateral orchiectomy.  
Initiation of bisphosphonates or denosumab for bone health is prohibited following 
randomization. The dosage and regimen of bisphosphonates or denosumab for bone health 
and any chronic permitted concomitant medication should be stabilized during Period 1 
(> 4 weeks prior to randomization) and held constant throughout Period 2. Standard of care 
supplementation with calcium and vitamin D is encouraged. 
Radiotherapy for palliative management of symptoms due to prostate cancer will not be 
considered unequivocal clinical progression and will not mandate study drug discontinuation 
during Period 2. Palliative radiotherapy is discouraged during period 1. 
Initiation of excluded concomitant medications (see Appendix 12.1 List of Excluded 
Concomitant Medications) during Periods 1 or 2 will result in permanent treatment 
discontinuation. 


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For the purpose of this study, chronic opiate analgesia is defined as parenteral opiate use for 
≥7 days or use of WHO Analgesic Ladder Level 3 oral opiates for ≥3 weeks. 
Level 
WHO Analgesic Ladder 
0 
No analgesia 
1 
Non-opioids (e.g. paracetamol, NSAIDs) 
2 
Weak opioids (e.g. codeine, dihydrocodeine, meptazinol) 
3 
Strong opioids (e.g. buprenorphine, diamorphine, fentanyl, hydromorphone, 
methadone, morphine, oxycodone,pethidine, tramadol) 
5.1.4 
Potential Interactions Between the Test Products and Concomitant 
Medications 
5.1.4.1 Effects of Enzalutamide on Exposure to Other Drugs 
Clinical data indicate that enzalutamide is a strong inducer of CYP3A4 and a moderate 
inducer of CYP2C9 and CYP2C19. Concomitant use of enzalutamide with drugs with a 
narrow therapeutic index that are metabolized by CYP3A4 (eg, alfentanil, cyclosporine, 
dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus), 
CYP2C9 (eg, phenytoin, warfarin), and CYP2C19 (eg, S-mephenytoin) should be avoided if 
possible as enzalutamide may decrease their exposure. If co-administration with warfarin 
cannot be avoided, additional INR monitoring should be conducted utilizing local 
laboratories. 
5.1.4.2 Drugs That May Affect Exposure to Enzalutamide 
Coadministration of a strong CYP2C8 inhibitor (eg, gemfibrozil) increases the exposure of 
enzalutamide plus its active metabolite; therefore, coadministration of enzalutamide with 
strong CYP2C8 inhibitors should be avoided if possible. If coadministration of enzalutamide 
with strong CYP2C8 inhibitors cannot be avoided, the enzalutamide dose 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. 
The effects of CYP2C8 inducers on the PK of enzalutamide have not been evaluated in vivo. 
Coadministration of enzalutamide with strong or moderate CYP2C8 inducers (eg, rifampin) 
may alter the plasma exposure of enzalutamide and should be avoided if possible. Selection 
of a concomitant medication with no or minimal CYP2C8 induction potential is 
recommended. 
5.1.4.3 Effects of Docetaxel on Exposure to Other Drugs 
In vitro studies have shown that the metabolism of docetaxel may be modified by the 
concomitant administration of compounds which induce, inhibit or are metabolized by (and 
thus may inhibit the enzyme competitively) CYP3A4 such as ciclosporine, terfenadine, 
ketoconazole, erythromycin and troleandomycin. As a result, caution should be exercised 
when treating subjects with these medicinal products as concomitant therapy since there is a 
potential for a significant interaction. 


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5.1.4.4 Drugs That May Affect Exposure to Docetaxel 
Clinical data indicate that docetaxel exposure and hence toxicity is increased when 
co-administered with a strong CYP3A4 inhibitor. A 50% docetaxel dose reduction should be 
considered if subjects require co-administration of a strong CYP3A4 inhibitor such as azole 
antifungals, ritonavir and some macrolides (clarithromycin, telithromycin). 
Docetaxel PK in the presence of prednisone was studied in patients with metastatic prostate 
cancer. Docetaxel is metabolized by CYP3A4 and prednisone is known to induce CYP3A4. 
No statistically significant effect of prednisone on the PK of docetaxel was observed 
(Docetaxel SPC). 
5.1.4.5 Potential Pharmacokinetic Interactions Between Enzalutamide and Docetaxel 
As a strong CYP3A4 inducer, enzalutamide has theoretical potential to decrease plasma 
exposure to docetaxel which is cleared by pathways including CYP3A4. 
Results from a phase I study indicated that enzalutamide did not have a clinically meaningful 
impact on docetaxel PK in patients with mCRPC. 
5.1.5 
Treatment Compliance 
Study subjects should be counseled on the need to meet 100% compliance with IMP. 
Study drug accountability will be performed to document compliance with the dosing 
regimen. Subjects will be asked to bring back all remaining IMP and all IMP packaging at 
each study visit for drug accountability. 
Treatment compliance should be monitored closely and deviation in compliance should be 
reported to the Sponsor. 
5.2 
Demographics and Baseline Characteristics 
5.2.1 
Demographics 
Demographic information will be obtained at the Period 1 Screening visit and will include 
date of birth (or age, if local regulations do not allow recording of subject’s date of birth), 
race as described by the subject (unless local regulations do not allow recording of subject’s 
race), height and weight. 
5.2.2 
Diagnosis, Severity, and Duration of Prostate Cancer 
A complete medical history of the target disease will be recorded at the Period 1 Screening 
Visit. This includes documenting the subject’s initial diagnosis of prostate cancer, Gleason 
score at time of diagnosis, dates and types of therapy and other disease specific information 
as designated in the eCRF. 
5.2.3 
Chest X-Ray or Chest CT 
At the Period 1 Screening visit and Period 2 Eligibility Assessment 2 visit, a Chest x-ray or 
Chest CT will be performed. A Chest CT is required if the screening Chest x-ray 
demonstrates metastatic chest disease. Other required scans at Screening are described in 
Section 5.3.1 CT/MRI and Bone Scans. 


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5.2.4 
Medical History 
Medical history will include any significant conditions or diseases other than prostate cancer 
that occurred prior to informed consent. 
5.2.5 
Performance Status 
The ECOG scale (Oken et al, 1982) will be used to assess performance status. 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair 
5 
Dead 
ECOG score will be collected at all visits. 
5.3 
Efficacy Assessment 
5.3.1 
CT/MRI and Bone Scans 
Radiographic evaluation of metastatic disease is determined separately for soft -tissue and 
bone disease. Positron emission tomography (PET) scans should not be used to determine 
disease progression. 
Radiographic disease assessment for soft tissue disease is based on an abdominopelvic CT or 
MRI scan and is defined by RECIST 1.1 (Eisenhauer et al 2009). Chest CT or MRI scans are 
also required if the Period 1 Screening visit/Period 2 Eligibility Assessment 2 visit Chest 
x-ray/CT demonstrates lung metastasis, or if clinically indicated. Assessment will include 
tumor measurements for target lesions, non-target lesions, and assessment for any new 
lesions. An overall assessment will be characterized for that time point evaluation. At the end 
of study for that subject, the overall best response to the study regimen will be characterized. 
Radiographic disease assessment for bone lesions is based on whole body radionuclide bone 
scan and is considered progression when a minimum of 2 new metastatic lesions are 
observed following randomization in accordance with PCWG2 criteria (Scher et al 2008). 
Progression on bone scan within 12 weeks of baseline scans in either Period requires a 
confirmation scan (showing 2 additional lesions compared with the first scan) performed 6 or 
more weeks later. 
Study imaging should be read on site. Each site should ideally designate the same reader who 
will evaluate the images for any one subject for the duration of the study. The imaging 
method utilized for baseline scans must be utilized throughout the entire study. 
Period 1 imaging will be performed during the Period 1 Screening Visit window then 
assessed at 12 week intervals after Day 1. Period 2 imaging will be performed during the 
Period 2 Eligibility Assessment window (or use the most recent Period 1 imaging if within 


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4 weeks prior to randomization) then assessed at 12 week intervals after Day 1. Additionally, 
imaging may be performed at any time to confirm suspected progression of disease. Scans 
may be performed up to 7 days prior to the scheduled visit to facilitate availability of results. 
5.3.2 
Prostate Specific Antigen 
Samples for PSA will be collected and analyzed at a central laboratory, see Appendix 12.2 
Central Laboratory Tests. 
PSA testing will be performed at every scheduled visit excepting Period 1, Week 5 visit and 
Period 2, Weeks 4, 7 and 10 visits. 
5.3.3 
Brief Pain Inventory (BPI) 
The BPI pain questionnaire is a validated instrument that is a subject self rating scale 
assessing level of pain, effect of the pain on activities of daily living, and analgesic use 
(http://www.mdanderson.org/education-and-research/departments-programs-and-
labs/departments-and-divisions/symptom-research/symptom-assessment-tools/brief-pain-
inventory.html). The BPI used in this study is modified from the short form (BPI-SF) and 
contains 7 questions (questions 2 and 7 from the standard BPI-SF will not be collected). The 
BPI uses simple numeric rating scales from 0 to 10. 
Subjects will be asked to complete a BPI-SF questionnaire to record their cancer-related pain 
at Screening in Period 1 and then at every scheduled visit during Period 2. 
5.4 
Safety Assessment 
5.4.1 
Vital Signs 
Vital signs including blood pressure, pulse rate and temperature will be assessed at screening, 
at every clinic visit while on IMP and at the safety follow-up visit. 
5.4.2 
Adverse Events 
All Adverse Events (AEs) will be collected from the time the subject signs the consent form 
until 30 days after last dose of IMP. See Section 5.5 Adverse Events and Other Safety 
Aspects for information regarding adverse event collection and data handling. 
5.4.2.1 Adverse Events of Possible Hepatic Origin 
See Appendix 12.3 Liver Safety Monitoring and Assessment for detailed information on 
liver abnormalities, monitoring and assessment, if the AE for a subject enrolled in a study 
and receiving study drug is accompanied by increases in liver function testing (LFT, e.g.: 
AST, ALT, bilirubin, etc.) or is suspected to be due to hepatic dysfunction. 
Subjects with AEs of hepatic origin accompanied by LFT abnormalities should be carefully 
monitored.  
5.4.3 
Laboratory Assessments 
Central laboratory tests that will be performed during the conduct of the study are defined in 
Appendix 12.2 Central Laboratory Tests. Central safety laboratory tests will be collected 
at all scheduled visits. Additional local safety laboratory tests will be collected in accordance 
with the Docetaxel SPC prior to each treatment cycle; see Schedule of Assessments - Period 
2. 


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Clinical significance of out-of-range laboratory findings is to be determined and documented 
by the Investigator/Sub-investigator who is a qualified physician. 
5.4.4 
Physical Examination, Height and Weight 
A standard, full physical examination will be performed at the Period 1 Screening Visit to 
assess weight, general appearance, skin, eyes, ears, nose, throat, neck, cardiovascular, chest 
and lungs, abdomen, musculoskeletal, neurologic status, mental status, lymphatic, 
genitourinary, and rectal systems. Any abnormalities will be collected as medical history or 
AEs. Subsequent physical examinations will be brief (i.e. symptom-directed only). 
Physical examinations will be performed at all scheduled visits. Weight will be recorded at 
each visit. Height will be recorded at the Period 1 screening visit only. 
5.4.5 
Electrocardiogram 
A standard 12-lead ECG will be performed on all subjects. Parameters that include heart rate, 
PR interval, RR interval, QRS interval, QT interval will be collected on the eCRF. 
Abnormalities and clinical significance as judged by the Investigator will be reported as well. 
It is recommended that ECG reports are printed in duplicate and photocopied to prevent 
fading. 
An ECG will be performed at Screening in Period 1, at the Eligibility Assessment for 
Period 2 and then every 12 weeks during Period 2 after Day 1. 
5.5 
Adverse Events and Other Safety Aspects 
5.5.1 
Definition of Adverse Events 
An AE is defined as any untoward medical occurrence in a subject administered a study drug 
or has undergone study procedures and which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product.  
An abnormality identified during a medical test (e.g., laboratory parameter, vital sign, ECG 
data, physical exam) should be defined as an AE only if the abnormality meets one of the 
following criteria: 
● 
Induces clinical signs or symptoms 
● 
Requires active intervention 
● 
Requires interruption or discontinuation of study medication 
● 
The abnormality or investigational value is clinically significant in the opinion of the 
Investigator. 
5.5.1.1 Disease Progression 
It is anticipated that a proportion of subjects will experience disease progression. Disease 
progression should not be reported as an AE. Clinical signs and symptoms due to disease 
progression will be collected as AEs. Individual signs and symptoms will be listed rather than 
the term “disease progression” with the following exception: if disease progression is the 
cause of death, this event may be recorded as an AE with “disease progression” as the 
reported term. 


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5.5.2 
Definition of Serious Adverse Events (SAEs) 
An adverse event 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 or leads to prolongation of hospitalization 
(hospitalization for treatment/observation/examination caused by AE is to be considered 
as serious) 
● 
Other medically important events 
Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require intervention to prevent one of the other outcomes listed in the 
definition above. These events, including those that may result in disability/incapacity, 
should also usually be considered serious. Examples of such events are intensive treatment in 
an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
that do not result in hospitalization; or development of drug dependency or drug abuse.  
Safety events of interest on the medicinal products administered to the subject as part of the 
study (e.g., study drug, comparator, background therapy) that may require expedited 
reporting and/or safety evaluation include, but are not limited to: 
● 
Overdose of the medicinal product(s) 
● 
Suspected abuse/misuse of the medicinal product(s) 
● 
Inadvertent or accidental exposure to the medicinal product(s) 
● 
Medication error involving the medicinal product(s) (with or without subject/patient 
exposure to the Sponsor medicinal product, e.g., name confusion) 
● 
Suspect drug-drug interaction 
All of the events of interest noted above should be recorded on the eCRF. Any situation 
involving these events of interest that also meets the criteria for an SAE should be recorded 
on the AE page of the eCRF and marked ‘serious’ and the SAE worksheet.  
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 the Study Drug 
Adverse events that fall under either "Possible" or "Probable" should be defined as "AEs 
whose relationship to the study drugs could not be ruled out". 


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Causal 
relationship to 
the study drug 
Criteria for causal relationship 
Not Related 
A clinical event, including laboratory test abnormality, with a temporal 
relationship to drug administration which makes a causal relationship 
improbable, and/or in which other drugs, chemicals or underlying 
disease provide plausible explanations. 
Possible 
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the drug, but which 
could also be explained by concurrent disease or other drugs or 
chemicals. Information on drug withdrawal may be lacking or unclear. 
Probable 
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the drug, unlikely to be 
attributed to concurrent disease or other drugs or chemicals, and which 
follows a clinically reasonable response on re- administration 
(rechallenge) or withdrawal (dechallenge). 
5.5.4 
Criteria for Defining the Severity of an Adverse Event 
Severity of AEs, including abnormal clinical laboratory values, will be graded using the 
National Cancer Institute Common Terminology Criteria for Adverse Event (NCI-CTCAE) 
guidelines (Version 4.03). The items that are not stipulated in the NCI-CTCAE Version 4.03 
will be assessed according to the criteria below and entered into the eCRF: 
Grade 
Assessment Standard 
1-Mild 
Asymptomatic or mild symptoms; clinical or 
diagnostic observations only; intervention not 
indicated. 
2-Moderate 
Minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of 
daily living. 
3-Severe or medically significant 
but not immediately life-
threatening 
Hospitalization or prolongation of hospitalization 
indicated; disabling; limiting self care activities of 
daily living. 
4-Life Threatening 
Life threatening consequences, urgent intervention 
indicated 
5-Death 
Death related to AE 
5.5.5 
Reporting of Serious Adverse Events (SAEs) 
In the case of an SAE, the Investigator must contact the Sponsor by telephone or fax 
immediately (within 24 hours of awareness). 
The Investigator should complete and submit an SAE Worksheet containing all information 
that is required by the Regulatory Authorities to the Sponsor by fax immediately (within 
24-hours of awareness). If the faxing of an SAE Worksheet is not possible or is not possible 
within 24 hours, the local drug safety contact should be informed by phone. 
For contact details, see Section II Contact Details of Key Sponsor's Personnel.  


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If there are any questions, or if clarification is needed regarding the SAE, please contact the 
Sponsor's Medical Monitor/Expert or his/her designee (see Section II Contact Details of Key 
Sponsor’s Personnel).  
Follow-up information for the event should be sent promptly (within 7-days of the initial 
notification. 
Full details of the SAE should be recorded on the medical records and on the (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 of the event), and 
● 
Causal relationship to the study drug. 
The Sponsor or Sponsor's designee will submit expedited safety reports to the regulatory 
agencies (e.g. EMA, national authorities) as necessary, and will inform the Investigators of 
such regulatory reports. Investigators must submit safety reports as required by their IEC 
within timelines set by regional regulations (i.e. European Union [EU], Electronic Common 
Technical Document [eCTD], FDA). Documentation of the submission to and receipt by the 
IEC of expedited safety reports should be retained by the site. 
The Sponsor will notify all Investigators responsible for ongoing clinical studies with the 
study drug of all SAEs which require submission per local requirements to the IEC. 
The Investigators should provide written documentation of IEC notification for each report to 
the Sponsor. 
You may contact the Sponsor's Medical Monitor/Expert for any other problem related to the 
safety, welfare, or rights of the subject. 
For SUSARs from a blinded trial, unblinded Council for International Organizations of 
Medical Sciences [CIOMS]-I report will be submitted to the authorities and IEC where 
required. 
New SAEs occurring until 30 days after the last study drug treatment must be reported. 
5.5.6 
Follow-up of Adverse Events 
All AEs occurring during or after the subject has discontinued the study are to be followed up 
until resolved or judged to be no longer clinically significant, or until they become chronic to 
the extent that they can be fully characterized.  
If during AE follow-up, the AE progresses to an "SAE", or if a subject experiences a new 
SAE, the Investigator must immediately report the information to the Sponsor.  
Please refer to Appendix 12.3 Liver Safety Monitoring and Assessment for detailed 
instructions on Drug Induced Liver Injury (DILI). 
5.5.7 
Monitoring of Common Serious Adverse Events 
Common serious AEs are SAEs commonly anticipated to occur in the study population 
independent of drug exposure. SAEs classified as “common” are provided in Appendix 12.4 


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Common Serious Adverse Events for your reference. The list does NOT change your 
reporting obligations or prevent the need to report an AE meeting the definition of an SAE as 
detailed above. The purpose of this list is to alert you that some events reported as SAEs may 
not require expedited reporting to the regulatory authorities based on the classification of 
“common serious adverse events” as specified in Appendix 12.4 Common Serious Adverse 
Events. The Sponsor will monitor these events throughout the course of the study for any 
change in frequency. Any changes to this list will be communicated to the participating 
investigational sites. Investigators must report individual occurrences of these events as 
stated in Section 5.5.5 Reporting of Serious Adverse Events (SAEs). 
5.5.8 
Procedure in Case of Pregnancy 
If during the conduct of the clinical trial, a male subject impregnates his partner the subject 
should report the pregnancy to the Investigator. The Investigator will report the pregnancy to 
the Sponsor as an SAE within 30 days from discontinuation of dosing. The expected date of 
delivery or expected date of the end of the pregnancy, last menstruation, estimated 
conception date, pregnancy result and neonatal data etc., should be included in this 
information. 
The Investigator will follow the medical status of the mother, as well as the fetus, as if the 
pregnancy is an SAE and will report the outcome to the Sponsor. 
When the outcome of the pregnancy falls under the criteria for SAEs (spontaneous abortion, 
induced abortion, stillbirth, death of newborn, congenital anomaly [including anomaly in a 
miscarried fetus]), the Investigator should respond in accordance with the report procedure 
for SAEs. Additional information regarding the outcome of a pregnancy (which is 
categorized as an SAE) is mentioned below. 
● 
"Spontaneous abortion" includes miscarriage, abortion and missed abortion 
● 
Death of an infant within 1 month after birth should be reported as an SAE regardless of 
its relationship with the study drug 
● 
If an infant dies more than 1 month after the birth, it should be reported if a relationship 
between the death and intrauterine exposure to the study drug is judged as "possible" by 
the Investigator 
● 
In the case of a delivery of a living newborn, the "normality" of the infant is evaluated at 
the birth 
● 
Unless a congenital anomaly are identified prior to spontaneous abortion or miscarriage, 
the embryo or fetus should be assessed for congenital defects by visual examination 
5.5.9 
Emergency Procedures and Management of Overdose 
Enzalutamide 
An overdose is defined as 2 days of IMP taken over the course of a 24 hour period. Neither 
the effects of overdose of enzalutamide nor an antidote to overdose are known. In the event 
of an overdose of enzalutamide, general supportive measures should be initiated, taking into 
consideration the half-life is 5.8 days for enzalutamide. Subjects may be at increased risk of 
seizures following an overdose of enzalutamide.  
Docetaxel 
There is no known antidote for docetaxel overdose. In case of overdose, the subject should be 
kept in a specialized unit and vital functions closely monitored. In cases of overdose, 


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exacerbation of AEs may be expected. The primary anticipated complications of overdose 
would consist of bone marrow suppression, peripheral neurotoxicity and mucositis. Subjects 
should receive therapeutic granulocyte-colony stimulation factor (G-CSF) as soon as possible 
after discovery of overdose. Other appropriate symptomatic measures should be taken, as 
needed. 
5.5.10 Supply of New Information Affecting the Conduct of the Study 
When new information becomes available necessary for conducting the clinical study 
properly, the Sponsor will inform all Investigators involved in the clinical study as well as 
the regulatory authorities. Investigators should inform the IEC of such information when 
needed.  
5.6 
Other Measurements, Assessments or Methods 
5.6.1 
FACT-P 
The FACT-P quality of life questionnaire is a multi-dimensional, self-reported quality of life 
instrument specifically designed for use with prostate cancer patients 
(http://www.facit.org/FACITOrg). It consists of 27 core items which assess patient function 
in four domains: physical, social/family, emotional, and functional well-being, which is 
further supplemented by 12 site-specific items to assess for prostate-related symptoms. Each 
item is rated on a 0 to 4 Likert-type scale, and then combined to produce subscale scores for 
each domain, as well as a global quality of life score with higher scores representing better 
quality of life. 
Subjects will be asked to complete a FACT-P survey at Screening in Period 1 and then every 
12 weeks during Period 2 from Day 1. 
5.6.2 
EQ-5D-5L 
EQ-5D-5L is a standardized instrument for use as a measure of health outcome 
(http://www.euroqol.org/home.html). It provides a simple descriptive profile and a single 
index value for health status. EQ-5D-5L is designed for self-completion by respondents. It 
consists of 2 pages comprising the following five dimensions: mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels and the 
subject is asked to indicate his health state by ticking the box with the most appropriate 
statement. 
Subjects will be asked to complete a EQ-5D-5L instrument at Screening in Period 1 and then 
every 12 weeks during Period 2 from Day 1. 
5.6.3 
Health Resource Use 
Health Resource Use will be assessed by a member of the study team by subject interview 
and review of the medical record to ascertain responses to the following questions, which 
will be recorded and transcribed into the eCRF. 
Subjects will be questioned for health resource use information at the Period 1 Screening 
Visit and then every 12 weeks, and every 12 weeks during Period 2 from Day 1. 


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How many time have you seen the following healthcare professionals in the last 12 
weeks? (If more than one health care professional was seen please count them separately) 
• General Practitioner/family doctor 
• Hospital Doctor 
• Practice/district nurse 
• Hospital nurse 
Have you been you been hospitalized in the last 12 weeks? If yes: 
• Provide length of stay (days) 
• Was this a: 
o Routine admission, or 
o Unscheduled/Emergency room admission? 
If this was an Unscheduled/Emergency room admission, what was the reason? 
o Treatment side effect, or 
o Other (reason to be recorded) 
5.7 
Total Amount of Blood 
The total amount of blood for each subject will vary depending on how long they stay on 
treatment. 
The expected blood draw for hematology assessment is approximately 3 mL and 
biochemistry (including any testosterone or PSA assessment) approximately 10.5 mL. The 
maximum amount of blood collected for a subject within 24 hours during the treatment 
Period is approximately 15 mL (including >10% overage). 
For a subject in Period 1, the total expected maximum blood draw over 1 year would be 
approximately 105 mL (assuming 7 study visits). For a subject in Period 2, the total expected 
blood draw over 1 year would be approximately 266 mL (assuming 14 study visits and 
allowing for local hematology collection nadir counts [4 mL assumed] during docetaxel 
treatment). 
The maximum amount of blood during the follow-up period is approximately 15 mL.  
Furthermore, if any laboratory abnormalities are found for a subject, additional blood may be 
drawn for monitoring.  
For subjects who consent to provide samples for biomarker analysis, a maximum of 30ml of 
whole blood will be collected according to the laboratory manual to be provided, at specified 
time points (described in Section V, Schedule of Assessments). Subjects will have a 
maximum of 4 samples in Period 1, and 6 samples in Period 2  (an addition of no more than 
approximately 300ml of blood during the study for subjects enrolled in the biomarker sub-
study,  in addition to the amounts specified above for the main study).   
6 
DISCONTINUATION 
6.1 
Discontinuation of Individual Subject(s) 
A discontinuation is a subject who enrolled in the study and for whom IMP is permanently 
discontinued prematurely for any reason. 


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The subject is free to withdraw from the IMP and/or study for any reason and at any time 
without giving reason for doing so and without penalty or prejudice. The Investigator is also 
free to terminate a subject's involvement in the study at any time if the subject's clinical 
condition warrants it. 
If a subject is discontinued from the study with an ongoing adverse event or an unresolved 
laboratory result that is significantly outside of the reference range, the Investigator will 
attempt to provide follow-up until the condition stabilizes or no longer is clinically 
significant.  
Subjects will be discontinued from IMP if any of the following occur:  
● 
Initiation of excluded concomitant medications defined in Appendix 12.1 List of 
Excluded Concomitant Medications. 
● 
Period 1 subjects who do not meet the disease response criteria at Week 13 and 
continuation of treatment is not warranted. 
● 
Period 1 subjects meeting the criteria for disease progression but who do not meet the 
criteria for randomization into Period 2. 
● 
Subject develops an AE or toxicity, where continued administration of study drug is 
deemed not in the subject’s best interest by the Investigator and/or the Sponsor. Refer to 
Appendix 12.3 Liver Safety Monitoring and Assessment. 
● 
Subject withdraws consent for further treatment. 
Unless the subject withdraws consent, all subjects discontinuing IMP for any reason will 
have a safety follow-up visit 30 days after their last dose of IMP or prior to initiation of 
subsequent antineoplastic therapy for prostate cancer, whichever occurs first. 
Subject in Period 1 who do not meet the disease response criteria at Week 13 but who 
continue treatment will continue to attend study visits until initiation of any new 
antineoplastic therapy. 
Subjects that discontinue IMP in Period 2 for a reason other than disease progression will 
continue to attend study visits (at 12 weekly intervals) until withdrawal of consent, disease 
progression or death. Reasonable effort should be made to contact any subject lost to follow-
up during the course of the study in order to complete study related assessments and retrieve 
any outstanding data and IMP. Following unsuccessful telephone contact, an effort to contact 
the subject by mail using a method that provides proof of receipt should be attempted. Such 
efforts should be documented in the source documents. 
After discontinuation from IMP further treatment is at the discretion of the subject and the 
treating physician. 
Subjects who discontinue docetaxel before completion of 10 cycles (e.g. for toxicity) may 
continue treatment with IMP and will continue to attend study visits (at 12 weekly intervals) 
for assessments until IMP discontinuation criteria or endpoint criteria are met. 
6.2 
Discontinuation of the Site 
If an Investigator intends to discontinue participation in the study, the Investigator must 
immediately inform the Sponsor. 


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6.3 
Discontinuation of the Study 
The Sponsor may terminate this study prematurely, either in its entirety or at any study site, 
for reasonable cause provided that written notice is submitted in advance of the intended 
termination. Advance notice is not required if the study is stopped due to safety concerns. If 
the Sponsor terminates the study for safety reasons, the Sponsor will immediately notify the 
Investigator and subsequently provide written instructions for study termination. 
7 
STATISTICAL METHODOLOGY 
The statistical analysis will be coordinated by the Sponsor’s responsible biostatistician. 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 soft lock at the latest. Any changes from the analyses planned in SAP will be 
justified in the Clinical Study Report (CSR). 
Prior to Database Lock, a Final Review of Data and Tables, Listings and Figures Meeting 
will be held to allow a review of the clinical trial data and to verify the data that will be used 
for analysis set classification. If required, consequences for the statistical analysis will be 
discussed and documented. A meeting to determine analysis set classifications may also be 
held prior to database lock. 
In general, all data will be summarized with descriptive statistics (number of subjects, mean, 
standard deviation, minimum, median and maximum) for continuous endpoints, and 
frequency and percentage for categorical endpoints. 
7.1 
Sample Size 
The following assumptions were used to determine the sample size calculation for the 
primary endpoint of PFS: 
• The estimated median PFS is 6 months for the control group (placebo plus docetaxel and 
prednisolone). 
• Assuming the true treatment effect has a hazard ratio (HR) of 0.66, with 2-sided type 1 
error rate of 0.05 and 80% power, at least 182 progression events are needed. This will 
allow statistical significance be claimed at the conclusion of the study if the observed HR 
is <=0.75, approximately. 
• If the recruitment period is up to 18 months, the follow-up of subjects in Period 2 is 
approximately 6 months, and the recruitment rate is non-uniform, at least 274 subjects 
will need to be randomized. 
Allowing for attrition prior to randomization, it is estimated that approximately 650 subjects 
will be enrolled. During the study, discontinuation rate, PSA response and disease 
progression rates will be monitored and if necessary, the total number of subjects enrolled 
may be adjusted to reach the required number of events at the end of Period 2 (at least 182 
events). 
7.2 
Analysis Set 
Detailed criteria for analysis sets will be laid out in Classification Specifications and the 
allocation of subjects to analysis sets will be determined prior to database hard-lock.  


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7.2.1 
Full Analysis Set (FAS) 
The full analysis set will consist of all subjects who are randomized and receive at least one 
dose of IMP. This will be the primary analysis set for efficacy analyses. All subjects will be 
analyzed as randomized when FAS population is used. 
 
7.2.2 
Safety Analysis Set (SAF) 
For the statistical summary of the safety data, the SAF will be used. The SAF consists of all 
subjects who took at least one dose of IMP, and will be used for safety analyses, separated 
for Period 1 and Period 2. All subjects will be analyzed as treated when SAF population is 
used. 
If the subject, at any moment during Period 2, accidently received the wrong treatment, then 
the subject will be analyzed as if they received enzalutamide as at least one of the actual 
treatments given was enzalutamide. 
 
7.3 
Demographics and Other Baseline Characteristics  
7.3.1 
Demographics 
Demographic information will be summarized using descriptive statistics by treatment arm 
and stratum. 
7.3.2 
Medical History 
A detailed medical history for each subject will be obtained during Screening and will be 
summarized by treatment arm and stratum. 
7.3.3 
Diagnosis of the Target Disease, Severity and Duration of Disease 
Each subject’s complete cancer history will be collected during the Screening Visit prior to 
Period 1 treatment. The number and percentage of subjects will be used to summarize the 
type of cancer, disease status, incidence of metastases and previous therapies. Descriptive 
statistics will be used to summarize the duration of disease. 
7.4 
Analysis of Efficacy 
Efficacy will be assessed, for the primary and the secondary endpoints, in period 2 only. In 
addition, exploratory analyses for biomarkers will be conducted, which will be described in a 
separate Statistical Analysis Plan (SAP)   
7.4.1 
Analysis of Primary Endpoint  
7.4.1.1 Primary Analysis 
The primary efficacy endpoint of PFS is defined as the time from randomization to the 
earliest objective evidence of radiographic progression, unequivocal clinical progression or 
death on study, whichever occurs first. 
The treatment effect of enzalutamide compared to placebo based on PFS disease progression 
will be tested using a stratified log-rank test, stratified by the randomization stratification 
factor, at the 0.05 2-sided significance level (based on 182 events).  


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Additionally, the benefit of enzalutamide compared to placebo will be evaluated by a single 
hazard ratio (enzalutamide /placebo) with its 95% confidence interval based on a Cox 
regression model stratified by the randomization stratification factor. Kaplan-Meier curves 
will be used to estimate the distribution of duration of PFS time to disease progression. The 
50th percentile of Kaplan-Meier estimates will be used to estimate the median duration of 
PFS until disease progression. A 2-sided 95% confidence interval will be provided for this 
estimate. The 25th percentile and its 2-sided 95% confidence interval will also be provided.  
A sensitivity analysis for PFS will be conducted using an unstratified log-rank test. A single 
hazard ratio (enzalutamide /placebo) with its 95% confidence interval based on an 
unstratified Cox regression model will also be provided. 
The duration of PFS will be calculated for all randomized subjects as the duration of time 
from the date of randomization to the earliest date of disease progression. 
The duration of PFS until earliest disease progression date will be right-censored based on 
one of the following conditions: 
● 
Lost to follow-up since randomization; 
● 
Not known to have disease progression at the data analysis cutoff. 
7.4.1.2 Subgroup Analysis 
There is one stratification at the start of Period 2 by disease progression. For the primary 
variable, a Kaplan Meier curve will be created and will be descriptively tabulated by strata. 
No formal analysis will be performed by strata. 
Additionally for randomized patients, the analysis of the primary endpoint will be repeated 
using Period 1 data analysed by subgroup (type of progression (PSA or radiographic) 
observed in that period. 
 
7.4.2 
Analysis of Secondary Endpoints (Period 2) 
7.4.2.1.1 
Time to PSA Progression: 
PSA progression is defined according to PCWG2 criteria. Time to PSA progression is 
defined as the time from randomization to the date of the first PSA value demonstrating 
progression, which must be subsequently confirmed. The median time to PSA progression 
and the corresponding confidence intervals will be calculated. 
The treatment effect of enzalutamide compared to placebo based on time to PSA progression 
will be tested with a stratified log-rank test at the 2-sided 0.05 significance level.  
Additionally, the benefit of enzalutamide compared to placebo will be evaluated by a single 
hazard ratio (enzalutamide/placebo) with its 95% confidence interval based on a Cox 
regression model stratified by the 1 randomization stratification factor. Kaplan-Meier curves 
will be used to estimate the distribution of time to PSA progression. The 50th percentile of 
Kaplan-Meier estimates will be used to estimate the median time to PSA progression. 
A 2-sided 95% confidence interval will be provided for this estimate. The 25th percentile and 
its 2-sided 95% confidence interval will also be provided. 


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7.4.2.2 Objective Response Rate: 
The best overall radiographic response after randomization will use Investigator assessments 
of response for soft tissue disease per RECIST 1.1. 
Rates of complete response (CR), partial response (PR), stable disease (SD), CR+PR, and 
CR+PR+SD will be tabulated along with exact binomial confidence intervals (Clopper 
Pearson). 
7.4.2.3 Time to Pain Progression: 
Time to pain progression is defined as the interval from randomization to the first date a 
subject experiences a BPI-SF increase by ≥30% from baseline in the average of BPI-SF pain 
intensity item scores (items 3, 4, 5, and 6) observed at 2 consecutive evaluations ≥3 weeks 
apart without decrease in analgesic usage. Only subjects experiencing average pain intensity 
item scores (items 3, 4, 5 and 6) of ≥4 at the time of progression will be included in the 
calculation.  
The statistical analyses for evaluating treatment effect of enzalutamide compared to placebo 
on time to pain progression will be the same as that described for time to PSA progression.  
7.4.2.4 Time to opiate use for cancer-related pain: 
Time to opiate use for cancer-related pain is defined as the interval from randomization to 
initiation of chronic administration of opiate analgesia (parenteral opiate use for ≥7 days or 
use of WHO Analgesic Ladder Level 3 oral opiates for ≥3 weeks). 
The statistical analyses for evaluating treatment effect of enzalutamide compared to placebo 
on time to pain progression will be the same as that described for time to PSA progression. 
7.4.2.5 Time to First Skeletal Related Event: 
Time to first SRE is defined as the interval from randomization to the first date of radiation 
therapy or surgery to bone, pathologic bone fracture, spinal cord compression, or change of 
antineoplastic therapy to treat bone pain. 
The statistical analyses for evaluating treatment effect of enzalutamide compared to placebo 
on time to first SRE will be the same as that described for time to PSA progression.  
7.4.2.6 Quality of Life 
Quality of life will be assessed using FACT-P and EQ-5D-5L data and will be summarized 
descriptively by treatment group and study visit. 
7.4.2.7 Cumulative Dose of Docetaxel 
Cumulative dose of docetaxel will be summarized descriptively by treatment group. 
7.4.2.8 Health Resource Use 
Health resource use will be summarized descriptively for both Periods (by treatment group in 
Period 2). 
7.4.3 
Analysis of Biomarkers  
These will include exploratory studies of blood samples to identify biomarkers that are 
prognostic and/or predictive of disease progression, response to treatment, and resistance to 


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study treatment (associations of biomarkers with clinical outcomes). Due to the ongoing 
rapid advances in the scientific understanding of prostate cancer and enzalutamide resistance, 
it is currently not possible to pre-define all the biomarkers that are linked to disease 
progression and treatment response. Therefore, blood samples will be collected, processed 
and stored frozen at -80 oC at an accredited central laboratory until further analysis, for a 
maximum of 10 years after collection (or as specified by local regulatory authorities). Definitive 
biomarker studies will be performed at a future timepoint and may include, but are not 
limited to: 
• Investigating changes in tumor-derived RNA (single mRNA, whole transciptome, 
miRNA) and DNA (single genes or whole genome/exome, germ line vs tumour), such as 
mutations, variants and expression level of the androgen receptor and other prostate 
cancer related genes in plasma in understanding mechanisms of resistance to 
enzalutamide. 
• Isolation and investigation of Circulating Tumor Cells (CTCs) to identify changes in 
protein and/or nucleic acid biomarkers that may be related to disease progression or 
treatment response. 
• Investigating other serum biomarkers such as cytokines (eg. IL6, IL8) that may be 
predictive/prognostic for treatment response.  
• Investigations of how enzalutamide works in people with prostate cancer. 
• Studies that may help to understand the course of prostate cancer and related diseases. 
 
Subjects may withdraw consent to have their samples analysed at any time prior to the 
analysis taking place. The treating doctor of the participant will be notified of any 
analytically or clinically valid findings that may emerge significant to the participant or their 
family regarding cancer.  
The analysis of the exploratory biomarkers will be described in a separate biomarker plan. 
7.5 
Analysis of Safety 
Safety will be assessed separately for Period 1 and Period 2. 
7.5.1 
Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The number and percentage of AEs, SAEs, AEs leading to discontinuation, and 
AEs related to IMP will be summarized by system organ class, preferred term and treatment 
group. The number and percentage of AEs by severity will also be summarized. All AEs will 
be listed. 
7.5.2 
Laboratory Assessments 
For quantitative laboratory measurements descriptive statistics will be used to summarize 
results and change from baseline by treatment group and time point. Using the definitions 
provided in the NCI CTCAE Version 4.03, lab values will be classified as Grade 1 through 5, 
where possible. Shifts relative to normal ranges from baseline to each time point during 
treatment period in lab tests will also be tabulated regarding either normal ranges or CTC 
CTCAE grade. Laboratory data will be displayed in listings and summary tables. 


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7.5.3 
Vital Signs 
Descriptive statistics will be used to summarize vital sign results and changes from baseline 
by treatment group and time. Vital signs data will be displayed in listings. 
7.5.4 
Physical Examination 
Physical examination results will be listed by treatment group. 
7.5.5 
ECGs 
The 12-lead ECG results will be summarized by treatment group and time point. 
7.5.6 
Deaths 
Deaths will be summarized by treatment group and time point. 
7.6 
Protocol Deviations  
Protocol deviations as defined in Section 8.1.6 Protocol Deviations will be summarized for 
all randomized subjects by treatment group and total as well as by site. A data listing will be 
provided by site and subject.  
The protocol deviation criteria will be uniquely identified in the summary table and listing. 
The unique identifiers will be as follows: 
• PD1 - Entered into the study even though they did not satisfy entry criteria; 
• PD2 - Developed withdrawal criteria during the study and was not withdrawn; 
• PD3 - Received wrong treatment or incorrect dose; 
• PD 4- Received excluded concomitant treatment 
7.7 
Interim Analysis (and Early Discontinuation of the Clinical Study) 
No formal interim analysis is planned. 
7.8 
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information 
As a general principle, no imputation of missing data will be done. Exceptions are the start 
and stop dates of AEs and concomitant medication. The imputed dates will be used to 
determine whether an AE is/is not treatment emergent. Listings of the AEs and concomitant 
medications will present the actual partial dates; imputed dates will not be shown. 
Imputation of partial dates for AEs for treatment emergent determination will follow a worst 
case scenario where AEs that are possible Treatment Emergent are flagged as such. 
See the SAP for details of the definitions for windows to be used for analyses by visit and the 
clear descriptions of imputation of AE dates. 
All “time to” analysis will be right-censored based on one of the following conditions: 
• Lost to follow-up since randomization; 
• Not known to have the event at the data analysis cut-off; 
• Death will also be a censoring condition for all events that do not include death. 


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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 eCRF. 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 working 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 local and central laboratories. Central 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 demographic data, reason for failing, informed consent, inclusion and 
exclusion criteria and AEs will be collected in the eCRF. 
Subject questionnaires will be completed by the subject on paper. The Investigator or site 
designee should review the questionnaire data while the subject is at the site. The Investigator 
or site designee will enter the subject questionnaire data directly into the eCRF. 
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 (ICFs) 
● 
Visit dates 
● 
Medical history and physical examination details 
● 
Key efficacy and safety data, if applicable (as specified in the protocol) 
● 
Adverse events and concomitant medication  
● 
Results of relevant examinations (e.g., ECG charts, X-ray films etc.) 
● 
Laboratory printouts 
● 
Dispensing and return of study drug details 
● 
Reason for premature discontinuation (if applicable) 


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


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If a deviation impacts the safety of a subject, the Investigator must contact the Sponsor 
immediately. 
 
The Investigator will also assure that deviations meeting IEC and applicable regulatory 
authorities’ criteria are documented and communicated appropriately. All documentation and 
communications to the IEC and applicable regulatory authorities will be provided to the 
Sponsor and maintained within the Trial Master File (TMF).  
NOTE: Other deviations outside of the categories defined above that are required to be 
reported by the IEC in accordance with local requirements will be reported, as applicable.  
8.1.7 
End of Trial in All Participating Countries 
The end of trial in all participating countries is defined as the Last Subject’s Last Visit 
(LSLV). 
8.2 
Ethics and Protection of Subject Confidentiality  
8.2.1 
Independent Ethics Committee/Competent Authorities 
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol amendments, 
the IB, 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. The IEC will review the ethical, scientific and medical appropriateness 
of the study before it is conducted. IEC 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 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 IECs and Competent Authorities (CAs), 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 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 should also be provided to Sponsor. 
If required by local regulations, the Investigator shall make accurate and adequate written 
progress reports to the IEC at appropriate intervals, not exceeding one year. The Investigator 
shall make an accurate and adequate final report to the IEC within one year after LSLV or 
termination of the study. 
8.2.2 
Ethical Conduct of the Study 
The study will be conducted in accordance with the protocol, ICH guidelines, applicable 
regulations and guidelines governing clinical study conduct and the ethical principles that 
have their origin in the Declaration of Helsinki.  


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8.2.3 
Informed Consent of Subjects 
8.2.3.1 Subject Information and Consent 
The Investigator or his/her representative will explain the nature of the study to the subject or 
his/her guardian or legal representative, and answer all questions regarding this study. Prior 
to any study-related screening procedures being performed on the subject, the informed 
consent statement will be reviewed and signed 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 ICF will be given to the 
subject and the original will be placed in the subject’s medical record. An entry must also be 
made in the subject’s dated source documents to confirm that informed consent was obtained 
prior to any study-related procedures and that the subject received a signed copy. 
The signed consent forms will be retained by the Investigator and made available (for review 
only) to the study monitor and auditor regulatory authorities and other applicable individuals 
upon request. 
8.2.3.2 Supply of New and Important Information Influencing the Subject’s Consent 
and Revision of the Written Information 
1. The Investigator or his/her representative will immediately inform the subject orally 
whenever new information becomes available that may be relevant to the subject’s 
consent or may influence the subject’s willingness to continue to participate in the study 
(e.g., report of serious drug adverse drug reaction). The communication must be 
documented in the subject’s medical records and must document whether the subject is 
willing to remain in the study or not. 
2. The Investigator must update their ICF and submit it for approval to the 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 re-consent subjects with the updated ICF even if relevant 
information was provided orally. The Investigator or his/her representative who obtained 
the written informed consent and the subject should sign and date the ICF. A copy of the 
signed ICF will be given to the subject and the original will be placed in the subject’s 
medical record. An entry must be made in the subject’s records documenting the re-
consent process. 
8.2.4 
Subject Confidentiality 
Individual subject medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited. Such medical information may be 
given only after approval of the subject to the subject's physician or to other appropriate 
medical personnel responsible for the subject's well-being. 
The Sponsor shall not disclose any confidential information on subjects obtained during the 
performance of their duties in the clinical study without justifiable reasons. 
The Sponsor affirms the subject's right to protection against invasion of privacy. Only a 
subject identification number will identify subject data retrieved by the Sponsor. However, 
the Sponsor requires the Investigator to permit the Sponsor, Sponsor's representative(s), the 
IEC and when necessary, representatives of the regulatory health authorities to review and/or 
to copy any medical records relevant to the study. 


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The Sponsor will ensure that the use and disclosure of protected health information (PHI) 
obtained during a research study complies with the federal and/or regional legislation related 
to the privacy and protection of personal information (i.e. Health Insurance Portability and 
Accountability Act [HIPAA]).  
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 IB 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 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 IEC, CA 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 IEC (if applicable). 
Amendments to this protocol must be signed by the Sponsor and the Investigator. Written 
verification of 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 IEC approval, but will be submitted 
to the IEC for their information, if required by local regulations. 
If there are changes to the Informed Consent, written verification of IEC approval must be 
forwarded to the Sponsor. An approved copy of the new Informed Consent must also be 
forwarded to the Sponsor. 


Sponsor: APEL 
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8.3.4 
Insurance of Subjects and Others  
The Sponsor has covered this study by means of an insurance of the study according to 
national requirements. The name and address of the relevant insurance company, the 
certificate of insurance, the policy number and the sum insured are provided in the 
Investigator's File.  
8.3.5 
Signatory Investigator for Clinical Study Report 
ICH E3 guidelines recommend and EU Directive 2001/83/EC requires that a final study 
report which forms part of a marketing authorization application be signed by the 
representative for the Coordinating Investigator(s) or the Principal Investigator(s). The 
representative for the Coordinating Investigator (s) or the Principal Investigator(s) will have 
the responsibility to review the final study results to confirm to the best of his/her knowledge 
it accurately describes the conduct and results of the study. The representative for 
Coordinating Investigator(s) or the Principal Investigator(s) will be selected from the 
participating Investigators by the Sponsor prior to database lock. 
9 
QUALITY ASSURANCE 
The Sponsor is implementing and maintaining quality assurance and quality control systems 
with written SOPs to ensure that trials are conducted and data are generated, documented, 
recorded, and reported in compliance with the protocol, GCP, and applicable regulatory 
requirement(s). 
The Sponsor or Sponsor's designee may arrange to audit the clinical study at any or all 
investigational sites and facilities. The audit may include on-site review of regulatory 
documents, CRFs, and source documents. Direct access to these documents will be required 
by the auditors. 
10 
STUDY ORGANIZATION 
10.1 
Independent Data-Monitoring Committee 
An IDMC will be charged with reviewing safety data. 
A separate charter will describe the activities of this committee. 
10.2 
Study Steering Committee 
A Steering Committee will be implemented to provide oversight of the conduct of the trial. 
This includes input into design of the study, oversight of the practical aspects of the study, as 
well as ensuring that the study continues to be run in a way which is both safe for the subjects 
and will provide appropriate safety and efficacy data to the Investigators and Sponsor. In 
fulfilling the safety role, the Committee will work in conjunction with an IDMC being 
established for this trial. 
A separate charter will describe the activities of this committee. 
 
 


Sponsor: APEL 
ISN/Protocol 9785-MA-1001 
EudraCT number 2013-004711-50 
- CONFIDENTIAL - 
1 Mar 2022 
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V4.3. (Final) Incorporating Non Substantial Amendment 6, 1 Mar 2022 
11 
REFERENCES  
Ahmed M, Li LC. Adaptation and clonal selection models of castration-resistant prostate cancer: 
current perspective. Int J Urol. 2013;20(4):362-71. 
Arlen PM, Bianco F, William L et al. Prostate Specific Antigen Working Group Guidelines on 
Prostate Specific Antigen Doubling Time. J Urol 2008; 179:2181-2186 
Astellas Pharma Ltd. Xtandi (enzalutamide) 40mg soft capsules. Summary of Product Characteristics. 
26 June 2013. 
Beer TM, Armstrong AJ, Rathkopf DE et al. Enzalutamide in Metastatic Prostate Cancer before 
Chemotherapy. N Engl J Med 2014 Jun 1. [Epub ahead of print] 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). Eur J Cancer. 2009; 45(2):228-47. 
Ferlay J, Parkin DM, Steliarova-Foucher E. Estimates of cancer incidence and mortality in Europe in 
2008. Eur J Cancer 2010;46:765–81 
Fitzpatrick JM, de Wit R. Taxane Mechanisms of Action: Potential Implications for Treatment 
Sequencing in Metastatic Castration-resistant Prostate Cancer. Eur Urol. 2014;65(6):1198–
1204 
Heidenreich A, Bastian PJ, Bellmunt J, et al. EAU Guidelines on Prostate Cancer. Part II: Treatment 
of Advanced, Relapsing, and Castration-Resistant Prostate Cancer. Eur Urol. 2014;65(2):467–
479 
Horwich A, Parker C, de Reijke T, et al. Prostate cancer: ESMO Clinical Practice Guidelines for 
diagnosis, treatment and follow-up. Ann Oncol. 2013;24 Suppl 6:106-14 
Hospira UK Ltd. Docetaxel Hospira 10 mg/ml Concentrate for Solution for Infusion. Summary of 
Product Characteristics 07 March 2011. 
Huggins C, Hodges CV. Studies on prostatic cancer: I. The effect of castration, of estrogen and of 
androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res 
1941;1(4): 293-7 
Kuczynski EA, Sargent DJ, Grothey A, et al. Drug rechallenge and treatment beyond progression - 
implications for drug resistance. Nat. Rev. Clin. Oncol. 2013;10, 571–587 
Merseburger AS, Bellmunt J, Jenkins C, et al. Perspectives on treatment of metastatic castration-
resistant prostate cancer. Oncologist 2013;18(5):558-67. 
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol 1982;5(6):649-55. 
Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous 
chemotherapy. N Engl J Med. 2013; 368(2):138-48 
Ryan CJ, Tindall DJ. Androgen Receptor Rediscovered: The New Biology and Targeting the 
Androgen Receptor Therapeutically. J Clin Oncol 2011; 29:3651-3658 
Scher HI, Beer TM, Higano CS, et al. Antitumour activity of MDV3100 in castration-resistant 
prostate cancer: a phase 1-2 study. Lancet 2010; 375(9724):1437-46 
Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after 
chemotherapy. N Engl J Med 2012; 367(13):1187-97 


Sponsor: APEL 
ISN/Protocol 9785-MA-1001 
EudraCT number 2013-004711-50 
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Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical trials for patients with 
progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate 
Cancer Clinical Trials Working Group. J Clin Oncol. 2008; 26(7):1148-59 
Thadani-Mulero M, Nanus DM, Giannakakou P. Androgen receptor on the move: boarding the 
microtubule expressway to the nucleus. Cancer Res 2012; 72(18):4611–5. 
Tran C, Ouk S, Clegg NJ et al. Development of a second-generation antiandrogen for treatment of 
advanced prostate cancer. Science 2009; 324(5928): 787-790. 
 
 


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V4.3. (Final) Incorporating Non Substantial Amendment 6, 1 Mar 2022 
12 
APPENDICES 
12.1 
List of Excluded Concomitant Medications 
● 
Aminoglutethimide; 
● 
Ketoconazole (for the treatment of prostate cancer; treatment for fungal infections is 
permitted, but refer to Section 5.1.4 Potential Interactions Between the Test Products 
and Concomitant Medications); 
● 
Abiraterone; 
● 
223Ra, 89Sr, 153Sm, 186Re/188Re; 
● 
Immunomodulatory therapies (e.g. Sipuleucel-T, DCVAC); 
● 
Cytotoxic chemotherapy not required by protocol (e.g. cabazitaxel, mitoxantrone, 
estramustine); 
● 
Investigational agents; 
● 
Antiandrogens (e.g. bicalutamide, nilutamide, flutamide); 
● 
5-α reductase inhibitors (e.g. finasteride, dutasteride); 
● 
Estrogens; 
● 
Anabolic steroids; 
● 
Drugs with antiandrogenic properties such as spironolactone > 50 mg/kg; 
● 
Progestational agents. 


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12.2 
Central Laboratory Tests 
Samples will be analyzed by Bioanalytical Research Corporation (BARC nv, Gent, 
Belgium). 
 
Hematology 
Red Blood Cell count (RBC) 
Hemoglobin (Hb) 
Hematocrit (HCT) 
White Blood Cell count (WBC) 
WBC differential 
Mean Corpuscular Volume (MCV) 
Platelet Count 
Biochemistry 
Alanine Aminotransferase (ALT) 
Albumin 
Alkaline Phosphatase (ALP) 
Aspartate Aminotransferase (AST) 
Bicarbonate 
Blood Urea Nitrogen (BUN) 
Calcium 
Chloride 
Creatinine 
Gamma-glutamyl Transferase (GGT) 
Glucose (non-fasting) 
Lactate Dehydrogenase (LDH) 
Phosphate 
Potassium 
Sodium 
Total Bilirubin 
Total Protein 
Other Tests 
Testosterone (for eligibility only) 
Prostate Specific Antigen (see Section 5.3.2 Prostate Specific Antigen) 
Liver Function Tests (see Appendix 12.3 Liver Safety Monitoring and 
Assessment) 
 


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12.3 
Liver Safety Monitoring and Assessment 
Any subject enrolled in a clinical study with active drug therapy and reveals an increase of 
serum aminotransferases (AT) to > 3 × ULN (to > 5 × ULN in subjects with liver 
metastases), or bilirubin > 2 × ULN, should undergo detailed testing for liver enzymes 
(including at least ALT, AST, ALP, and TBL). Testing should be repeated within 
48-72 hours of notification of the test results. For studies for which a central laboratory is 
used, alerts will be generated by the central lab regarding moderate and severe liver 
abnormality to inform the Investigator, study monitor and study team. Subjects should be 
asked if they have any symptoms suggestive of hepatobiliary dysfunction. 
Definition of Liver Abnormalities 
Confirmed abnormalities will be characterized as moderate and severe where ULN: 
  
ALT or AST 
 
Total Bilirubin 
Moderate 
> 3 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 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 2-3 times weekly then weekly or 
less if abnormalities stabilize or the study drug has been discontinued and the subject is 
asymptomatic.  
Severe hepatic liver function abnormalities as defined above , in the absence of another 
etiology may be considered an important medical event and may be reported as a Serious 
Adverse Event (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. 


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To further assess abnormal hepatic laboratory findings, the Investigator is expected to: 
● 
Obtain a more detailed history of symptoms and prior or concurrent diseases. Symptoms 
and new onset-diseases should be recorded as ‘adverse events’ on the AE page of 
(e)CRF. Illnesses and conditions such as hypotensive events, and decompensated cardiac 
disease that may lead to secondary liver abnormalities should be noted. Non-alcoholic 
steatohepatitis (NASH) is seen in obese hyperlipoproteinemic, and/or diabetic patients 
and may be associated with fluctuating aminotransferase levels. The Investigator should 
ensure that the medical history form captures any illness that pre-dates study enrollment 
that may be relevant in assessing hepatic function. 
● 
Obtain a history of concomitant drug use (including non-prescription medication, 
complementary and alternative medications), alcohol use, recreational drug use, and 
special diets. Medications, including dose, should be entered on the concomitant 
medication page of the (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, pre-existing or 
acute liver disease, presence of liver metastases, or exposure to other agents associated with 
liver injury, the subject may be discontinued from the study. The Investigator may determine 
that it is not in the subject’s best interest to continue study enrollment. Discontinuation of 
treatment should be considered if: 
● 
ALT or AST > 8 × ULN 
● 
ALT or AST > 5 × ULN for more than 2 weeks (in subjects without liver metastases) 
● 
ALT or AST > 3 × ULN and TBL > 2 × ULN or INR > 1.5 (If INR testing is 
applicable/evaluated) 
● 
ALT or AST > 5 × ULN 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%).  
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-Drug-induced jaundice caused by hepatocellular injury, without a 
significant obstructive component, has a high rate of bad outcomes, from 10–50% mortality 
(or transplant).” The 2 “requirements” for Hy’s Law are:1. Evidence that a drug can cause 
hepatocellular-type injury, generally shown by an increase in transaminase elevations higher 
3 times the upper limit of normal (“2 x ULN elevations are too common in treated and 
untreated patients to be discriminating”). 2. Cases of increased bilirubin (at least 2 x ULN) 
with concurrent transaminase elevations at least 3 x ULN and no evidence of intra- or extra-


Sponsor: APEL 
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hepatic bilirubin obstruction (elevated alkaline phosphatase) or Gilbert’s syndrome. [Temple 
R. Hy's law: predicting serious hepatotoxicity. Pharmacoepidemiol Drug Saf. 2006 
Apr;15(4):241-3.] 
Reference 
Guidance for Industry titled “Drug-Induced Liver Injury: Premarketing Clinical Evaluation” 
issued by FDA on July 2009. 


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12.4 
Common Serious Adverse Events 
The following is a list of serious adverse events that the Sponsor considers to be associated 
with the disease state being studied. The list does NOT change your reporting obligations 
or prevent the need to report an adverse event meeting the definition of an SAE as 
detailed in Section 5.5.2 Definition of Serious Adverse Events (SAEs). The purpose of this 
list is to alert you that some events reported as SAEs may not require expedited reporting to 
the regulatory authorities based on the classification of “common serious adverse events”. 
You are required to follow the requirements detailed in Section 5.5.5 Reporting of Serious 
Adverse Events (SAEs). 
For IND safety reporting, single occurrences of the following events may be excluded from 
expedited reporting to the FDA. If aggregate analysis of these events indicate they occur 
more frequently with study drug, an expedited IND safety report may be submitted to the 
FDA. 
● 
Anemia 
● 
Anorexia 
● 
Asthenia / Fatigue 
● 
Back pain 
● 
Bone pain 
● 
Catheter related infection 
● 
Dyspnea 
● 
Haematuria 
● 
Hydronephrosis 
● 
Metastases to bone 
● 
Metastases to central nervous system 
● 
Nausea 
● 
Obstructive uropathy 
● 
Pain 
● 
Prostate cancer metastatic 
● 
Renal failure 
● 
Renal failure acute 
● 
Spinal compression fracture 
● 
Spinal cord compression 
● 
Urinary retention 
● 
Urinary tract infection 
● 
Urinary tract obstruction 
● 
Vomiting 



SAP_003.pdf: 
Sponsor: Astellas Pharma Europe Ltd. (APEL)
SAP Final 2.1
ISN/Protocol 9785-MA-1001
23-JAN-2024
Astellas
Page 1 of 56
STATISTICAL ANALYSIS PLAN
SAP Final 2.1, dated 23 JAN-2024
A Randomized, Double-Blind, Placebo-Controlled, Phase IIIb Study of the Efficacy and 
Safety of Continuing Enzalutamide in Chemotherapy Naïve Metastatic Castration Resistant 
Prostate Cancer Patients Treated with Docetaxel plus Prednisolone Who Have Progressed on 
Enzalutamide Alone
ISN: 9785-MA-1001
EudraCT number: 2013-004711-50
Astellas Pharma Europe Ltd. (APEL)
Bourne Business Park, 
200 & 300 Dashwood Lang Rd, 
Addlestone, KT15 2NX
United Kingdom
This confidential document is the property of the sponsor. No unpublished information 
contained in this document may be disclosed without prior written approval of the sponsor.


Sponsor: Astellas Pharma Europe Ltd. (APEL) 
SAP Final 2.1 
ISN/Protocol 9785-MA-1001 
23-JAN-2024 
Astellas 
Page 2 of 56 
Table of Contents 
I. 
LIST OF ABBREVIATIONS AND KEY TERMS .......................................................... 6 
1. 
INTRODUCTION ............................................................................................................ 9 
2. 
FLOW CHART AND VISIT SCHEDULE .................................................................... 10 
3. 
STUDY OBJECTIVES AND DESIGN ......................................................................... 15 
3.1 
Study Objectives ...................................................................................................... 15 
3.1.1 
Primary Objective ............................................................................................. 15 
3.1.2 
Secondary Objectives ........................................................................................ 15 
3.1.3 
Exploratory Objective ....................................................................................... 15 
3.2 
Study Design ............................................................................................................ 15 
3.3 
Randomization ......................................................................................................... 17 
4. 
SAMPLE SIZE ............................................................................................................... 17 
5. 
ANALYSIS SETS .......................................................................................................... 18 
5.1 
Full Analysis Set (FAS) ........................................................................................... 18 
5.2 
Safety Analysis Set (SAF) ........................................................................................ 18 
5.2.1 
Safety Analysis Set 1 (SAF1) ........................................................................... 18 
5.2.2 
Safety Analysis Set 2 (SAF2) ........................................................................... 18 
6. 
ANALYSIS VARIABLES ............................................................................................. 19 
6.1 
Efficacy Endpoints ................................................................................................... 19 
6.1.1 
Primary Efficacy Endpoint ............................................................................... 19 
6.1.2 
Secondary Efficacy Endpoints .......................................................................... 19 
6.1.2.1 
Time to PSA Progression .......................................................................... 20 
6.1.2.2 
PSA Response ............................................................................................ 20 
6.1.2.3 
Objective Response Rate ........................................................................... 21 
6.1.2.4 
Time to Pain Progression ........................................................................... 21 
6.1.3 
Time to opiate use for cancer-related pain ........................................................ 22 
6.1.4 
Time to First Skeletal Related Event ................................................................ 22 
6.1.5 
Exploratory Endpoints ...................................................................................... 22 
6.2 
Safety Variables ....................................................................................................... 22 
6.2.1 
Adverse Events ................................................................................................. 23 
6.2.2 
Safety Laboratory Tests .................................................................................... 23 
6.2.2.1 
Liver Enzymes and Total Bilirubin ........................................................... 24 
6.2.3 
Vital Signs ......................................................................................................... 25 
6.2.4 
Weight ............................................................................................................... 25 


Sponsor: Astellas Pharma Europe Ltd. (APEL) 
SAP Final 2.1 
ISN/Protocol 9785-MA-1001 
23-JAN-2024 
Astellas 
Page 3 of 56 
6.2.5 
Electrocardiogram ............................................................................................. 25 
6.3 
Other Variables ........................................................................................................ 26 
6.3.1 
Demographics and Baseline Characteristics ..................................................... 26 
6.3.2 
Duration of exposure ......................................................................................... 27 
6.3.3 
Cumulative dose of Docetaxel .......................................................................... 27 
6.3.4 
Previous and Concomitant Medications ........................................................... 27 
6.3.5 
Treatment Compliance ...................................................................................... 27 
6.3.6 
Performance Status ........................................................................................... 28 
6.3.7 
Functional Assessment of Cancer Therapy - Prostate ...................................... 29 
6.3.8 
EuroQol 5-Dimensions 5-Levels ...................................................................... 30 
6.3.9 
Health Resource Use ......................................................................................... 30 
7. 
STATISTICAL METHODOLOGY ............................................................................... 31 
7.1 
General Considerations ............................................................................................ 31 
7.2 
Study Population ...................................................................................................... 31 
7.2.1 
Disposition of Subjects ..................................................................................... 31 
7.2.2 
Protocol Deviations ........................................................................................... 32 
7.2.3 
Demographic and Other Baseline Characteristics ............................................ 32 
7.2.4 
Previous and Concomitant Medications ........................................................... 33 
7.3 
Study Drugs .............................................................................................................. 34 
7.3.1 
Exposure ........................................................................................................... 34 
7.3.2 
Treatment Compliance ...................................................................................... 34 
7.4 
Analysis of Efficacy ................................................................................................. 35 
7.4.1 
Analysis of Primary Endpoint ........................................................................... 35 
7.4.1.1 
Primary Analysis of Primary Endpoint...................................................... 35 
7.4.1.2 
Secondary Analysis of Primary Endpoint.................................................. 36 
7.4.1.3 
Subgroup Analysis of Primary Endpoint ................................................... 36 
7.4.2 
Analysis of Secondary Endpoints ..................................................................... 37 
7.4.2.1 
Time to PSA Progression .......................................................................... 37 
7.4.2.2 
PSA Response ............................................................................................ 37 
7.4.2.3 
Objective Response Rate ........................................................................... 37 
7.4.2.4 
Time to Pain Progression ........................................................................... 38 
7.4.3 
Time to Opiate Use for Cancer-Related Pain.................................................... 38 
7.4.4 
Time to First Skeletal Related Event ................................................................ 38 
7.5 
Analysis of Safety .................................................................................................... 38 


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7.5.1 
Adverse Events ................................................................................................. 38 
7.5.2 
Clinical Laboratory Evaluation ......................................................................... 40 
7.5.2.1 
Liver Enzymes and Total Bilirubin ........................................................... 41 
7.5.3 
Vital Signs ......................................................................................................... 41 
7.5.4 
Weight ............................................................................................................... 41 
7.5.5 
Electrocardiograms (ECGs) .............................................................................. 41 
7.6 
Analysis of PK ......................................................................................................... 41 
7.7 
Analysis of PD ......................................................................................................... 41 
7.8 
Subgroups of Interest ............................................................................................... 41 
7.9 
Other Analyses ......................................................................................................... 43 
7.9.1 
Performance Status ........................................................................................... 43 
7.9.2 
Functional Assessment of Cancer Therapy - Prostate ...................................... 43 
7.9.3 
EuroQol 5-Dimensions 5-Levels ...................................................................... 43 
7.9.4 
Health Resource Use ......................................................................................... 43 
7.9.5 
Impact of Covid 19 Pandemic ........................................................................... 43 
7.10 Interim Analysis (and Early Discontinuation of the Clinical Study) ....................... 44 
7.11 Handling of Missing Data, Outliers, Visit Windows, and Other Information ......... 44 
7.11.1 Missing Data ..................................................................................................... 44 
7.11.1.1 
Missing Adverse Event Dates .................................................................... 44 
7.11.1.2 
Other Missing Dates .................................................................................. 44 
7.11.2 Outliers .............................................................................................................. 44 
7.11.3 Visit Windows .................................................................................................. 44 
8. 
DOCUMENT REVISION HISTORY ............................................................................ 45 
9. 
REFERENCES ............................................................................................................... 45 
10. 
APPENDICES ............................................................................................................ 46 
10.1 Appendix 1: List of Hormonal Therapies ................................................................ 46 
10.2 Appendix 2: List of Anti-Androgens ....................................................................... 47 
10.3 Appendix 3: List of Bisphosphonates ...................................................................... 48 
10.4 Appendix 4: List of Corticosteroids ......................................................................... 49 
10.5 Appendix 5: List of Anticoagulants ......................................................................... 50 
10.6 Appendix 6: Identification of Start Date of AE/TEAE ............................................ 51 
10.7 Appendix 7: PFS Derivation .................................................................................... 54 
10.8 Appendix 8: Key Contributors and Approvers ........................................................ 56 
 


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I. 
LIST OF ABBREVIATIONS AND KEY TERMS 
List of Abbreviations 
Abbreviations 
Description of abbreviations 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Transaminase 
APEL 
Astellas Pharma Europe Ltd 
ASCM 
Analysis Set Classification Meeting  
AST 
Aspartate Transaminase 
ATC 
Anatomical Therapeutic Chemical 
BDRM 
Blinded Data Review Meeting 
BMI 
Body Mass Index 
BPI-SF 
Brief Pain Inventory – Short Form 
CI 
Confidence Intervals 
CM 
Concomitant Medication 
CR 
Complete Response 
CRF 
Case Report Form 
CS 
Classification Specifications 
CSR 
Clinical Study Report 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EQ-5D-5L 
EuroQoL-5 Dimensions-5 Levels 
FACT-P 
Functional Assessment of Cancer Therapy - Prostate 
FAS 
Full Analysis Set 
FU 
Follow-Up 
H 
High 
HR 
Hazard Ratio 
ICH 
International Conference on Harmonization 
IMP 
Investigational Medicinal Product 
INR 
International Normalized Ratio 
IRT 
Interactive Response Technology 
L 
Low 
LDH 
Lactate Dehydrogenase 
LHRH 
Luteinizing Hormone-Releasing Hormone 
mCRPC 
metastatic Castration-Resistant Prostate Cancer  
MedDRA 
Medical Dictionary for Regulatory Activities 
N 
Normal 
NCI-CTCAE 
National Cancer Institute-Common Toxicity Criteria Adverse Events 
PCWG2 
Prostate Cancer Working Group 2 
PD1-x 
Protocol Deviation 1-x 
PFS 
Progression Free Survival 
PR 
Partial Response 
PSA 
Prostate-specific Antigen 
PT 
Preferred Term 
QTc 
Corrected Q-T Interval 
 


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Abbreviations 
Description of abbreviations 
RECIST 
Response Evaluation Criteria In Solid Tumors 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SAS  
Statistical Analysis Software 
SD 
Stable Disease 
SOC 
System Organ Class 
SRE 
Skeletal-related Event 
TBL 
Total Bilirubin 
TEAE 
Treatment Emergent Adverse Event 
TLF 
Tables, Listings and Figures 
ULN 
Upper Limit of Normal 
VAS 
Visual Analogue Scale 
WHO-DD 
World Health Organization Drug Dictionary 
 


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List of Key Terms 
Terms 
Definition of terms 
Baseline  
Observed values/findings which are regarded observed starting point for 
comparison.  
Chronic opiate 
analgesia 
Parenteral opiate use for ≥7 days or use of WHO Analgesic Ladder Level 
3 oral opiates for ≥3 weeks. 
Enroll 
To register or enter into a clinical trial. NOTE: Once a subject has been 
enrolled, the clinical trial protocol applies to the subject.  
Intervention 
The drug, therapy or process under investigation in a clinical study that is 
believed to have an effect on outcomes of interest in a study. (e.g., 
health-related quality of life, efficacy, safety, pharmacoeconomics).  
Investigational period 
Period of time where major interests of protocol objectives are observed, 
and where the test drug or comparative drug (sometimes without 
randomization) is usually given to a subject, and continues until the last 
assessment after completing administration of the test drug or comparative 
drug. 
Post investigational 
period 
Period of time after the last assessment of the protocol. Follow-up 
observations for sustained adverse events and/or survival are done in this 
period. 
Screening period 
Period of time before entering the investigational period, usually from the 
time of starting a subject signing consent until just before the test drug or 
comparative drug (sometimes without randomization) is given to a 
subject.  
Randomization 
The process of assigning trial subjects to treatment or control groups using 
an element of chance to determine assignments in order to reduce bias. 
Screening 
A process of active consideration of potential subjects for enrollment in a 
trial. 
Screen failure 
Potential subject who did not meet one or more criteria required for 
participation in a trial. 
Study period 
Period of time from the first site initiation date to the last site completing 
the study. 
Variable 
Any quantity that varies; any attribute, phenomenon or event that can have 
different qualitative or quantitative values. 
 


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1. INTRODUCTION 
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 soft lock. For operational efficiency an 
earlier time is usually targeted (before first subject in target date). If needed, revisions to the 
approved SAP may be made prior to database hard lock. Revisions will be version controlled. 
This statistical analysis is coordinated by the responsible biostatistician of APEL. Any 
changes from the analyses planned in the SAP will be justified in the Clinical Study Report 
(CSR). 
Prior to database hard lock, a final review of data and tables, listings and figures (TLFs) 
meeting will be held to allow a review of the clinical trial data and to verify the data that will 
be used for analysis set classification. If required, consequences for the statistical analysis 
will be discussed and documented. A meeting to determine analysis set classifications may 
also be held prior to database hard lock. 


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2. FLOW CHART AND VISIT SCHEDULE 
Figure 1 
Flow Chart  
 
 


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Table 1 
Schedule of Assessments – Period 1 
Visit 
Screening 
Open label Enzalutamide 
Unschedi 
Extension 
Period 1n 
FU 
After last 
drugj or q 
Week 
-4 to -1 
1 
5 
13 
25 then 
q12wk 
n/a 
q12wk 
30d after last 
drug 
Day 
-28 to -1 
1 
29 
85 
169 + q84d 
n/a 
n/a 
n/a 
Window (days) 
n/a 
n/a 
±7 
±7 
±7 
n/a 
±7 
±3 
Informed Consent 
X 
 
 
 
 
 
 
 
Demographics/Medical Historya 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
Xp 
X 
Physical Examinationb 
X 
X 
X 
X 
X 
X 
Xp 
X 
12-lead ECG 
X 
 
 
 
 
 
 
 
Hematology/Clinical Chemistryc 
X 
X 
X 
X 
X 
X 
Xo 
X 
PSA 
X 
X 
 
Xg 
X 
X 
Xo 
 
Informed Consent for Biomarker 
samplesk 
X 
 
 
 
 
Xk 
 
 
Biomarker sample  
 
Xl 
X 
X 
 
Xm 
 
 
Testosterone 
X 
 
 
 
 
 
 
 
ECOG 
X 
X 
X 
X 
X 
X 
Xp 
X 
BPI-SF 
X 
 
 
 
 
 
 
 
FACT-P, EQ-5D-5L 
X 
 
 
 
 
 
 
 
Health Resource Use 
X 
 
 
X 
X 
 
 
 
Radiographic assessmentsd 
Xf 
 
 
Xh 
X 
X 
Xp 
 
Enzalutamide dispensing 
 
X 
 
X 
X 
 
X 
 
Enzalutamide accountability 
 
 
X 
X 
X 
 
X 
X 
Adverse Eventse 
X 
X 
X 
X 
X 
X 
X 
X 
Prior/Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
 
a. 
Includes age, initial diagnosis of prostate cancer, Gleason score at time of diagnosis along with details and dates of all treatments for prostate cancer; 
b. All physical examinations will include weight. 
Screening physical examination will be a full examination including height, subsequent examinations will be brief only and symptom-focused; 


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c. 
Clinical labs (also PSA and testosterone) will be collected for central laboratory assessment; 
d. Whole body radionuclide bone scan and abdominopelvic computed tomography (CT) or magnetic resonance imaging (MRI) for soft tissue may be performed up to 7 days prior to 
the scheduled visit to permit review of results at the visit; 
e. 
All Adverse Events (AEs) and Serious adverse events (SAEs) including death will be collected from the time the subject signs the consent form until 30 days after last dose of 
IMP. 
f. 
Screening imaging assessments should include a Chest X-ray (CXR) or chest CT as well as whole body radionuclide bone scan and abdominopelvic CT/MRI. 
Radiographic assessments collected within 42 days prior to Day 1 may be used to establish the presence of metastatic disease; 
g. Subjects will be assessed for PSA response at Week 13 which should be confirmed by a subsequent test at least 3 weeks later. Subjects without a confirmed PSA response at 
Week 13 will be ineligible for participation in Period 2; 
h. Radiographic progression by bone scan at the first assessment at Week 13 requires a confirmatory scan 6 or more weeks later. Subjects with confirmed radiographic progression 
at Week 13 will be ineligible for participation in Period 2 and will typically have safety follow up; however, Period 1treatment may continue for some subjects as long as the 
investigator considers it to be of clinical benefit (stopping on initiation of any new antineoplastic therapy); 
i. 
Unscheduled visit assessments are optional and should be dictated by the clinical reason for visit attendance (e.g. if progression is suspected, radiographic assessments may be 
performed); 
j. 
Safety follow-up in subjects not progressing to Period 2 before the data cut off will be 30 days after the last dose of IMP or prior to initiation of new antineoplastic therapy, 
whichever is earliest. 
k. Participation in the Biomarker sub-study is optional, and a separate Informed Consent is to be signed prior to collecting any samples for it. If a subject is already enrolled in Period 
1 of the study, but agrees to provide biomarker samples, consent for the biomarker collection for Period 2 can be taken at any time prior to the biomarker sample collection;  
l. 
To be taken pre-enzalutamide administration; 
m. Sample to be taken when subject progresses clinically, as part of the baseline samples for Period 2 of the study. If a subject misses week 1/day 1 samples in Period 1, and consents  
to the sub-study, this should be the first sample taken.  
n. Open-label enzalutamide treatment may be continued for subjects still in treatment in Period 1 when enrollment to Period 2 closes or when the 182 primary endpoints events are 
reached, whichever occurs first (approximately 274 subjects randomized into Period 2) 
o. Laboratory tests to be performed locally as required for the subject’s standard of care. Relevant results will only be collected in the event of SAEs and AEs. 
p. Results to be collected in the eCRF if the assessments are performed as part of the standard of care of the subject. 
q. Safety follow up in subjects after the data cut off will be 30 days after the last dose of IMP or prior to initiation of new antineoplastic therapy, whichever is earliest. Laboratory 
tests to be performed locally as required for the subject’s standard of care. Relevant results will only be collected in the event of SAEs and AEs. 
 
ECG – Electrocardiogram; PSA - Prostate-specific Antigen; ECOG - Eastern Cooperative Oncology Group; BPI-SF - Brief Pain Inventory – Short Form; FACT-P - Functional 
Assessment of Cancer Therapy - Prostate, EQ-5D-5L - EuroQol 5 dimension, 5 level health state utility index; FU – Follow up 


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Table 2 
 Schedule of Assessments – Period 2 
Visit 
Eligibility 
Assessment 
for Period 2e 
Randomized (Double-Blind) Treatment 
on background of Docetaxel + Prednisoloneg 
Ongoing 
(Double-
Blind) 
Treatmentp 
Unschedk 
Extension Period 2 
FU 
After 
last 
IMPl 
or s 
Cycle 
n/a 
1 
2-4 
5 
6-8 
9 
10 
Additional  
n/a 
n/a 
Additional 
n/a 
n/a 
Week 
-4 to -1 
1 
4/7/10 
13 
16/19/22 
25 
28 
Varies 
q3wk 
cyclesj 
37 then 
q12wk 
n/a 
Varies 
q3wk 
cycles 
37 
then  q12wk 
 
30d 
after 
last 
drug 
Day 
-28 to -1 
1 
22/43/64 
85 
106/127/148 
169 
190 
n/a 
253 then 
q84d 
n/a 
n/a 
q84d 
n/a 
Window (days) 
 
n/a 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
n/a 
±7 
±7 
±7 
Inclusion/Exclusiona 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examinationb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
X 
Hematology/Clinical Chemistryc 
X 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
X 
X 
Xq 
Xq 
X 
PSA 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Xq 
Xq 
X 
Biomarker sample  
 
Xm 
Xn 
X 
 
X 
 
 
 
Xo 
 
 
X 
Testosterone 
X 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BPI-SF 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
FACT-P, EQ-5D-5L 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
Health Resource Use 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
Radiographic Assessmentsd 
Xf 
 
 
Xi 
 
X 
 
 
X 
X 
Xr 
Xr 
 
IMP dispensing 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
Docetaxel administration 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
IMP accountability 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a. 
Eligibility will be checked against criteria for Period 2; 
b. All physical examinations will include weight; 
c. 
Clinical labs (also PSA and testosterone) will be collected for central laboratory assessment during scheduled clinic visits; 


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d. Whole body radionuclide bone scan and abdominopelvic computed tomography (CT) or magnetic resonance imaging (MRI) for soft tissue may be performed up to 7 days prior to 
the scheduled visit to permit review of results at the visit; 
e. 
The window for assessment of suitability to continue into Period 2 will commence from the point that progression is determined in Period 1 (i.e. confirmation of PSA or 
radiographic progression).  Assessments collected at the last visit in Period 1 may be used to determine eligibility for Period 2 if collected within 4 weeks prior to randomization; 
f. 
Period 2 baseline scans may utilize the most recent scans collected in Period 1 if collected within 4 weeks prior to randomization. 
Scans should include a Chest X-ray (CXR) or chest CT; 
g. Subjects who discontinue docetaxel before completion of 10 cycles (e.g. for toxicity) may continue with double-blind treatment and continue to attend study visits (at 12 weekly 
intervals) for assessments until IMP discontinuation criteria or endpoint criteria are met. 
h. Local laboratory hematology samples for nadir count assessment will be collected approximately 1 week after docetaxel administration in all cycles; during the first 3 cycles 
additional hematology samples will be collected approximately 2 weeks after docetaxel administration. 
Local laboratory hematology should also be collected to support dosing decisions prior to administration of docetaxel. 
Patients with elevated liver function tests (LFTs) should have LFTs assessed prior to administration of docetaxel; 
i. 
Radiographic progression by bone scan at the first assessment at Week 13 requires a confirmatory scan 6 or more weeks later; 
j. 
If docetaxel treatment continues such that there is overlap with the subsequent 12-weekly visit cycle (e.g. Week 37, Week 49) then all assessments of those visits should be 
performed in addition to those required for docetaxel treatment; 
k. Unscheduled visit assessments are optional and should be dictated by the clinical reason for visit attendance (e.g., if progression is suspected radiographic assessments may be 
performed); 
l. 
Safety follow-up will be 30 days after the last dose of IMP or prior to initiation of new antineoplastic therapy, whichever is earliest 
Subjects who discontinue IMP for a reason other than disease progression will continue to attend study visits (at 12 weekly intervals) for assessments until withdrawal of consent, 
disease progression or death. 
m. Biomarker sample to be taken prior to first dose of double-blind study medication in Period 2;   
n. Biomarker sample to be taken at Cycle 2 (Week 4); 
o. Biomarker sample to be taken when the subject progresses clinically or reaches one of the endpoints of the study.  
p. Double blind treatment may be continued for any subjects still in treatment in Period 2 between data cut-off and unblinding 
q. Laboratory tests to be performed locally as required for the subject’s standard of care. The results will only be collected in the event of SAEs and AEs. 
r. 
Results to be collected in the eCRF if the assessments are performed as part of the standard of care of the subject.  
s. 
 Safety follow up in subjects after unblinding will be 30 days after the last dose of IMP or prior to initiation of new antineoplastic therapy, whichever is earliest. Laboratory tests to 
be performed locally as required for the subject’s standard of care. Biomarker sampling will cease. Relevant results will only be collected in the event of SAEs and AEs.  
 
ECG – Electrocardiogram; PSA - Prostate-specific Antigen; ECOG - Eastern Cooperative Oncology Group; BPI-SF - Brief Pain Inventory – Short Form; FACT-P - Functional 
Assessment of Cancer Therapy - Prostate, EQ-5D-5L - EuroQol 5 dimension, 5 level health state utility index; FU – Follow up. 


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3. STUDY OBJECTIVES AND DESIGN  
3.1 
Study Objectives 
3.1.1 
Primary Objective 
The primary objective of the study is to compare the efficacy of continuing treatment with 
enzalutamide after adding docetaxel and prednisolone versus placebo plus docetaxel and 
prednisolone, as measured by Progression Free Survival (PFS) in subjects with 
chemotherapy-naïve metastatic Castration-Resistant Prostate Cancer (mCRPC) with 
progression during treatment with enzalutamide alone. 
3.1.2 
Secondary Objectives 
The secondary objectives of the study are to evaluate the effect of continuing treatment with 
enzalutamide and adding docetaxel and prednisolone versus placebo plus docetaxel and 
prednisolone, as measured by the following in subjects with chemotherapy-naïve mCRPC 
with progression during treatment with enzalutamide alone: 
● 
Time to Prostate-Specific Antigen (PSA) progression 
● 
PSA response 
● 
Objective response rate 
● 
Time to pain progression 
● 
Time to opiate use for cancer-related pain 
● 
Time to first Skeletal-related Event (SRE) 
● 
Quality of life 
Safety profile, including cumulative dose of docetaxel, and Health Resource Use will be 
described for these subjects. The safety profile as well as Health Resource Use of 
enzalutamide alone when administered to chemotherapy naïve subjects will also be 
described. 
3.1.3 
Exploratory Objective  
To analyze candidate biomarkers in circulation for association with response or progression 
and for identifying mechanisms of resistance. 
 
3.2 
Study Design 
This is a double-blind, randomized, placebo controlled trial of subjects with chemotherapy 
naïve mCRPC to evaluate the efficacy and safety of continued treatment with enzalutamide 
after adding docetaxel and prednisolone compared with treatment with placebo in 
combination with docetaxel and prednisolone. 
The study will be conducted in consecutive periods of open label treatment with 
enzalutamide followed by randomized double-blind treatment with continued enzalutamide 
or placebo, adding with docetaxel and prednisolone. 


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In period 1 subjects will attend a Screening visit to determine eligibility for open label 
treatment with enzalutamide (160 mg/day). At Week 13, all subjects will be assessed by PSA 
and imaging. The initial PSA response (stable or declining) must be confirmed by a second 
consecutive value at least 3 weeks later. Subjects with no confirmed PSA response or 
evidence of radiographic progression (assessed at Week 13) will be ineligible for 
participation in Period 2 and will typically have safety follow up. Those subjects with 
confirmed PSA response will continue Period 1 until disease progression as supported by 
evidence of at least one of the following criteria: 
● 
PSA progression with rapid PSA doubling time (PSA-DT) defined as: 
o 
PSA rise of ≥ 25% and an absolute increase of ≥ 2 ng/mL above nadir, confirmed 
by a second PSA value at least 3 weeks later, and 
o 
PSA-DT of ≤ 12 weeks determined in at least 3 PSA measurements collected at 
intervals of 4 or more weeks apart during a period of 3 or more months; 
● 
Radiographic progression, defined as: 
o 
Bone disease progression, or; 
o 
Soft tissue disease progression. 
Administration of open label enzalutamide will continue until randomization to Period 2 
treatment, confirmation of ineligibility for Period 2 treatment (subjects will be discontinued 
from the study), intolerable toxicity, subject withdrawal, or death, whichever occurs first. 
Subjects with confirmed disease progression on enzalutamide alone who continue to meet all 
eligibility criteria may proceed to randomization. Randomization must occur within 4 weeks 
of progression observed in Period 1. 
Treatment allocation will be in a 1:1 ratio, stratified by disease progression (evidence of 
radiographic progression or not) in Period 1 to the following treatments: 
● 
Enzalutamide (160 mg daily) in combination with docetaxel (75 mg/m2 every 3 weeks) 
and prednisolone (10 mg daily); 
● 
Enzalutamide placebo (daily) in combination with docetaxel (75 mg/m2 every 3 weeks) 
and prednisolone (10 mg daily). 
Administration of docetaxel will continue for up to 10 cycles, however subjects assessed by 
the Investigator to be benefiting from treatment may continue on docetaxel for additional 
cycles. Subjects who discontinue docetaxel before completion of 10 cycles (e.g., for toxicity) 
may continue treatment with Investigational Medicinal Product (IMP) and will continue to 
attend study visits (at 12 weekly intervals) for assessments until IMP discontinuation criteria 
or endpoint criteria are met. 
Administration of blinded enzalutamide/placebo will continue until disease progression, 
intolerable toxicity, subject withdrawal or death, whichever occurs first. 
All subjects will have a safety follow-up visit 30 days after the last dose of IMP or prior to 
the initiation of a subsequent antineoplastic therapy for prostate cancer, whichever occurs 
first. 


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In Period 2, subjects who discontinue IMP for a reason other than disease progression will 
continue to attend study visits (at 12 weekly intervals) for assessments until withdrawal of 
consent, disease progression or death. 
Two extension periods may be available in the study: 
x Extension period 1: For those subjects who are still receiving study drug in Period 1 
when enrollment to Period 2 closes (approximately 274 subjects randomized in Period 
2). 
x Extension period 2: When the data cut-off for analysis is reached in Period 2 (when at 
least 182 endpoint events have been reached),  for patients still in the study who did 
not not reach primary endpoint, there will be the opportunity to continue their 
treatment in an extension period in another Astellas-sponsored study (see CTP section 
4.5.3).  
 
3.3 
Randomization 
Subjects who meet the inclusion/exclusion criteria will be randomly assigned to receive 
enzalutamide or placebo using a 1:1 randomization schedule. Subjects will be stratified by 
disease progression (evidence of radiographic progression or not). The sponsor or designee 
will generate the randomization schedule. 
The Investigator or designee will contact the Interactive Response Technology (IRT) to 
randomize the subject into the study prior to the initiation of IMP in Period 2. 
4. SAMPLE SIZE 
The following assumptions were used to determine the sample size calculation for the 
primary endpoint of PFS at the timepoint of the primary analysis: 
● 
The estimated median PFS is 6 months for the control group (placebo plus docetaxel and 
prednisolone). 
● 
Assuming the true treatment effect has a hazard ratio (HR) of 0.66, with 2-sided type 1 
error rate of 0.05 and 80% power, 182 progression events are needed. This will allow 
statistical significance be claimed at the conclusion of the study if the observed HR is 
<=0.75, approximately. 
● 
If the recruitment period is up to 18 months, the follow-up of subjects in Period 2 is 
approximately 6 months, and the recruitment rate is non-uniform, at least 274 subjects 
will need to be randomized. 
Allowing for attrition prior to randomization, it is estimated that approximately 650 subjects 
will be enrolled. During the study, discontinuation rate, PSA response and disease 
progression rates will be monitored and if necessary, the total number of subjects enrolled 
may be adjusted to reach the required number of events at the end of Period 2 (182 events). 


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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 (CS) and the 
allocation of subjects to analysis sets will be determined prior to database hard lock.  
5.1 
Full Analysis Set (FAS) 
The Full Analysis Set (FAS) will consist of all subjects who are randomized and receive at 
least one dose of IMP. 
The selection of subjects for the FAS will be confirmed in the Analysis Set Classification 
Meeting (ASCM), held prior to unblinding. 
This will be the primary analysis set for efficacy analyses. Demographics and all baseline 
characteristics except non-prostate cancer medical history will also be presented in the FAS. 
Subjects in the FAS will be presented by the treatment they were randomized, even if the 
actual treatment received was different from the treatment to which they were randomized. 
Note that FAS will be equal to SAF2 if all subjects take in fact the same medication they 
were randomized to. 
 
5.2 
Safety Analysis Set (SAF) 
Two sets of Safety Analysis Set (SAF) will be defined for this study. 
5.2.1 
Safety Analysis Set 1 (SAF1) 
SAF1 consists of all subjects who took at least one dose of IMP during Period 1. 
SAF1 will be used for previous medications, ECOG performance status and health resources 
use in Period 1 and all safety data in Period 1. 
5.2.2 
Safety Analysis Set 2 (SAF2) 
SAF2 consists of all subjects who took at least one dose of IMP during Period 2. 
SAF2 will be used for demographic and baseline characteristics, CMs, ECOG performance 
status and health resources use in Period 2 and all safety data in Period 2. 
Subjects in the SAF2 will be presented by the treatment they actually received, even if the 
actual treatment received was different from the treatment to which they were randomized. 
If the subject, at any moment during Period 2, accidently received the wrong treatment, then 
the subject will be analyzed as if they received enzalutamide as at least one of the actual 
treatments given was enzalutamide. 
Note that SAF2 will be equal to FAS if all subjects take in fact the same medication they 
were randomized to. 
 


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6. ANALYSIS VARIABLES 
6.1 
Efficacy Endpoints 
6.1.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is PFS with progression defined as radiographic progression, 
unequivocal clinical progression, or death on study. 
● 
Radiographic disease progression is defined for bone disease by the appearance of 2 or 
more new lesions on whole-body radionuclide bone scan per Prostate Cancer Clinical 
Trials Working Group 2 (PCWG2) criteria (i.e., unconfirmed progressive disease) that 
needs to be confirmed in the next assessment (i.e., progressive disease in the next 
assessment) or for soft tissue disease by Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1. 
 
Note: For disease progression in bone disease, when a subject has unconfirmed 
progression with confirmed progression disease in the next assessment, the date of 
unconfirmed progression will be used for the analysis. 
● 
Unequivocal clinical progression is defined as any of the following: 
o 
new onset cancer pain requiring chronic administration of opiate analgesia, 
o 
deterioration from prostate cancer of Eastern Cooperative Oncology Group 
(ECOG) performance status score to 3 or higher, within the investigational period 
o 
initiation of subsequent lines of cytotoxic chemotherapy or radiation therapy or 
surgical intervention due to complications of tumor progression. 
● 
Death on study is defined as death within 112 days of treatment discontinuation without 
objective evidence of radiographic progression. 
 
PFS is defined as the time (in months) from randomization (Period 2 Week 1) to the earliest 
progression event. Subjects who do not show progression as defined above at the data 
analysis cutoff date will be censored on the date of the last assessment of disease progression 
before data analysis cutoff date , and subjects discontinuing for any reason before data 
analysis cutoff date and without progression will be censored at the last assessment of disease 
progression before discontinuation. The data analysis cutoff date will take place after the 
disease progression date that corresponds to the 182nd disease progression event. 
PFS = ((‘Date progression event or censored date’ - ‘Date randomization’) + 1) / 
30.4375. 
More detailed information on derivation of the primary endpoint can be found in Appendix 7 
of this SAP. 
 
6.1.2 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints include: 
● 
Time to PSA progression. 


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● 
PSA response. 
● 
Objective response rate. 
● 
Time to pain progression. 
● 
Time to opiate use for cancer-related pain. 
● 
Time to first SRE. 
6.1.2.1 Time to PSA Progression 
Time to PSA progression is defined as the time (in months) from randomization (Period 2 
Week 1) to the date of the first PSA value in Period 2 demonstrating progression. 
The PSA progression date is defined as the date that a ≥ 25% increase and an absolute 
increase of ≥ 2 ng/mL above the nadir recorded in Period 2 is documented, which must be 
confirmed by a second consecutive value obtained at least 3 weeks later. The date of PSA 
progression is the date the first evidence of PSA progression is documented. 
Subjects who do not show PSA progression at the data analysis cutoff date (see Section 6.1.1 
for details) will be censored on the date of the last assessment of PSA before data analysis 
cutoff date . Subjects without PSA progression prior to 2 or more consecutive missed PSA 
assessments will be censored on the date of last PSA assessment prior to missed assessments 
without PSA progression. Subjects who have no PSA at baseline (last available non-missing 
value, usually Period 2 Week 1) or have the PSA at baseline only will be censored on the 
date of randomization. And subjects discontinuing for any reason before data analysis cutoff 
date and without PSA progression will be censored at the last assessment of PSA before 
discontinuation. 
Time to PSA Progression = ((‘Date PSA progression or censored date’ - ‘Date 
randomization’) + 1) / 30.4375. 
6.1.2.2 PSA Response 
Percentage change in PSA levels from randomization (Period 2 Week 1) to Week 13 (or 
earlier for those that discontinue therapy), as well as the maximum decrease in percentage 
change from randomization in PSA levels that occur at any point after randomization in 
Period 2 will be derived. 
Percentage change from Period 2 Week 1 to Week 13 of PSA levels will be calculated as: 
Percentage change from Period 2 Week 1 = [(Week 13 PSA value – Randomization 
PSA value) / Randomization PSA value] x 100. 
PSA response is defined as a decrease in percentage change from randomization of 50% or 
more. PSA response will be derived at Week 13 and at any time after randomization in 
Period 2. 
 


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6.1.2.3 Objective Response Rate 
Objective response rate is defined as the best overall radiographic response after 
randomization as per Investigator assessments of response for soft tissue disease per 
RECIST 1.1, in subjects who have a measurable tumor. 
6.1.2.4 Time to Pain Progression 
Time to pain progression is defined as the time (in months) to an increase of ≥ 30% from 
randomization (Period 2 Week 1) in the average of Brief Pain Inventory Short Form (BPI-SF) 
pain intensity item scores (items 3, 4, 5 and 6) observed at 2 consecutive evaluations 
≥3 weeks apart without decrease in analgesic usage score according to the World Health 
Organization (WHO) scale (0 for no medication, 1 for non-opioid pain medication, 2 for 
opioids for moderate pain, and 3 for opioids for severe pain). Only subjects experiencing 
average pain intensity item scores (items 3, 4, 5 and 6) of ≥4 at the time of progression will 
be included in the calculation. 
Subjects who do not show pain progression at the data analysis cutoff date (see Section 6.1.1 
for details) will be censored on the date of the last assessment of BPI-SF before data analysis 
cutoff date , and subjects discontinuing for any reason before data analysis cutoff date and 
without pain progression will be censored at the last assessment of BPI-SF before 
discontinuation. 
Time to Pain Progression = ((‘Date pain progression or censored date’ - ‘Date 
randomization’) + 1) / 30.4375. 
The BPI-SF is an instrument to document pain-related functional impairment. It will be 
completed by the subjects at Screening in Period 1 and then at every scheduled visit during 
Period 2. The BPI used in this study is modified from the short form (BPI-SF) and contains 
7 questions (questions 2 and 7 from the standard BPI-SF will not be collected). It is a 
questionnaire that includes: 
● 
Pain intensity (items 3, 4, 5 and 6): worst pain, least pain, average pain and current pain, 
with scales from 0 (no pain) to 10 (pain as bad as you can imagine)  
● 
Pain interference (items 9A to 9G): general activity, mood, walking ability, normal 
work, relations with other people, sleep and enjoyment of life, with scales from 0 (does 
not interfere) to 10 (completely interferes). 
The BPI-SF total score for pain intensity will be calculated as the mean of the 4 scores for the 
4 items of pain intensity, if any individual item is not completed the mean cannot be 
calculated. 
The BPI-SF total score for pain interference will be calculated as the mean of the 7 scores of 
pain interference questions, if less than 50% of the items (i.e., 3 or less items out of 7) are not 
completed the mean cannot be calculated. 
Change from baseline, defined as the post-baseline value minus the baseline value (last non 
missing value prior to first dosing in the analysis period) will be calculated for each 
assessment. 


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6.1.3 
Time to opiate use for cancer-related pain 
Time to opiate use for cancer-related pain is defined as the time (in months) from 
randomization (Period 2 Week 1) to initiation of chronic administration of opiate analgesia, 
defined as parenteral opiate use for ≥7 days or use of WHO Analgesic Ladder Level 3 oral 
opiates (strong opioids [e.g., buprenorphine, diamorphine, fentanyl, hydromorphone, 
methadone, morphine, oxycodone, pethidine, tramadol]) for ≥3 weeks. 
Subjects who do not initiate chronic administration of opiate analgesia at the data analysis 
cutoff date (see Section 6.1.1 for details) will be censored on the date of the last assessment 
done before data analysis cutoff date , and subjects discontinuing for any reason before data 
analysis cutoff date and without initiating chronic administration of opiate analgesia will be 
censored at their last assessment in study before discontinuation. 
Time to Opiate Use for Cancer-Related Pain = ((‘Date event or censored date’ - ‘Date 
randomization’) + 1) / 30.4375. 
6.1.4 
Time to First Skeletal Related Event 
Time to first SRE is defined as the time from randomization (Period 2 Week 1) to radiation 
therapy or surgery to bone, pathologic bone fracture, spinal cord compression, or change of 
antineoplastic therapy to treat bone pain. 
Subjects who do not have any skeletal related event at the data analysis cutoff date (see 
Section 6.1.1 for details) will be censored on the date of the last assessment done before data 
analysis cutoff date , and subjects discontinuing for any reason before data analysis cutoff 
date and without having any skeletal related event will be censored at the last assessment in 
study before discontinuation. 
Time to First SRE = ((‘Date event or censored date’ - ‘Date randomization’) + 1) / 
30.4375. 
6.1.5 
Exploratory Endpoints  
Biomarker from EPIC laboratory will be summarized using descriptive statistics. 
 
6.2 
Safety Variables 
Safety will be assessed by evaluation of the following variables: 
● 
Treatment-emergent adverse events (TEAEs)/serious adverse events (SAEs). 
● 
Clinical laboratory variables (hematology and biochemistry including liver enzymes and 
total bilirubin). 
● 
Vital signs (systolic and diastolic blood pressure, pulse rate and temperature). 
● 
Weight. 
● 
12-lead electrocardiogram (ECG) 


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6.2.1 
Adverse Events 
The coding dictionary for adverse events (AEs) will be the Medical Dictionary for 
Regulatory Activities (MedDRA). Version number of MedDRA will be provided in the TLFs 
specifications document. 
Pre-treatment AEs 
AEs which started or worsened during the pre-investigational period (i.e., during the period 
from obtaining informed consent to the start of Period 1). 
Period 1 TEAEs  
TEAEs which started or worsened during Period 1 (i.e., during the period from first 
enzalutamide intake during the Period 1 and before first intake of randomized study 
medication in Period 2). If a subject experiences an event both during the pre-investigational 
period and during Period 1, the event will be considered as TEAE only if it has changed in 
NCI CTCAE Grade or seriousness after the first dose of enzalutamide (i.e. it is reported with 
a new start date). 
Period 2 TEAEs 
TEAEs which started or worsened during Period 2 (i.e., from first dose of randomized study 
medication in Period 2), and until the Follow-up Visit. If a subject experiences an event both 
during Period 1 and during Period 2, the event will be considered as Period 2 TEAE only if it 
has changed in NCI CTCAE Grade or seriousness after the first dose of IMP in Period 2 
(i.e., it is reported with a new start date). 
 
The following counting rules for AEs are used: 
● 
A subject having experienced the same event more than once will be counted only once 
in the number of subjects with AEs within a system organ class or preferred term.  
● 
When the table counts AEs only by NCI CTCAE Grade, then only the highest NCI 
CTCAE Grade will be counted for each event within a system organ class or preferred 
term.  
A treatment related AE is defined as any AE whose relationship to IMP is assessed as 
“possible” or “probable” by the investigator, or where the relationship to IMP is missing. 
See Section 7.11.1.1 of this document for imputation rules regarding missing/incomplete AE 
start and end dates. 
6.2.2 
Safety Laboratory Tests 
Blood samples for hematology and biochemistry will be collected at each visit of the study as 
depicted in the schedule of assessments (Table 1 and Table 2). All evaluations will be done 
by a central laboratory. 
The following variables will be derived for laboratory tests: 
● 
Change from baseline, defined as the post-baseline value minus the baseline value (last 
non-missing value prior to first dose in the analysis period). 


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● 
Classification of results according to the National Cancer Institute-Common Toxicity 
Criteria Adverse Events (NCI-CTCAE) v4.03, and worst post-baseline toxicity grade by 
Period. 
6.2.2.1 Liver Enzymes and Total Bilirubin 
Liver tests (Alanine Aminotransferase [ALT], Aspartate Aminotransferase [AST], total 
bilirubin [TBL] and Alkaline Phosphatase [ALP]) will be assessed at each visit of the study. 
The following  levels will be defined, as flags on a subject level, during the treatment period, 
based on the maximum on-treatment (for Period 1 and for Period 2 separately) value, 
according to the Upper Limit of Normal (ULN): 
● 
ALT > 3X ULN, > 5X ULN, > 8X ULN  
● 
AST > 3X ULN, > 5X ULN, > 8X ULN 
● 
AST or ALT > 3X ULN > 5X ULN 
● 
TBL > 2X ULN 
● 
ALP > 1.5X ULN 
● 
ALT or AST > 3X ULN or TBL > 2X ULN 
● 
ALT or AST > 5X ULN or TBL > 2X ULN 
● 
ALT or AST > 3X ULN and TBL > 2X ULN 
● 
ALT or AST > 3 × ULN and INR > 1.5 
For the ALT and/or AST > 3X ULN and TBL > 2X ULN criteria, the subject’s ALT and/or 
AST and the TBL values must be measured within the same sample to be counted. 
The maximum on-treatment value is defined as the maximum value of all post-baseline 
assessments for each period. 
Note that the above levels are meant to facilitate the review and reporting and do not fully 
correspond to the protocol defined criteria for liver abnormalities that would define subjects 
who require further liver investigation: 
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 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%).  


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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. 
 
6.2.3 
Vital Signs 
Vital signs including blood pressure (systolic and diastolic), pulse rate and temperature will 
be measured at all visits of the study. 
Change from baseline, defined as the post-baseline value minus the baseline value (last non-
missing value prior to first dose in the analysis period) will be calculated for each 
assessment. 
Systolic and diastolic blood pressure values will be classified according to NCI-CTCAE 
v4.03 hypertension grading scores at each visit. 
6.2.4 
Weight 
Weight will be measured at all visits in the study as indicated on the schedule of assessment 
(Table 1 and Table 2). 
Change from baseline, defined as the post-baseline value minus the baseline value (last non-
missing value prior to first dose in the analysis period) will be calculated for each 
assessment. 
6.2.5 
Electrocardiogram 
A 12-lead ECG will be performed at Screening in Period 1, at the Eligibility Assessment for 
Period 2 and then every 12 weeks during Period 2 from Week 13 as indicated on the schedule 
of assessments (Table 1 and Table 2). 
The interpretation of the ECGs will be recorded as normal, abnormal not clinically 
significant, or abnormal clinically significant. Any abnormal clinically significant results will 
be reported in electronic Case Report Form (eCRF) as AE. 
Parameters that include heart rate, PR interval, RR interval, QRS interval, QT interval will 
also be collected on the eCRF. 
Parameters QTcB, using Bazett’s correction formula: 
QTcB=QT/(RR in seconds)1/2 
And QTcF, using Fridericia correction formula: 
QTcF=QT/(RR in seconds)1/3  
Will be calculated for each subject and assessment. 
Change from baseline for ECG parameters, defined as the post-baseline value minus the 
baseline value last non-missing value prior to first dose in the analysis period) will be 
calculated for each assessment. 


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6.3 
Other Variables 
6.3.1 
Demographics and Baseline Characteristics 
The subject’s age, gender, race, height, body weight and Body Mass Index (BMI), calculated 
as: 
BMI (kg/m²) = weight (kg) / (height (m) x height (m))  
will be recorded at Screening. 
At the Screening visit a detailed non-prostate cancer medical history for each subject will be 
obtained. All relevant past and present conditions, as well as any relevant prior surgical 
procedures, will be recorded for the main body systems documenting diagnoses and durations 
of the diseases. 
With regards to disease history and previous prostate cancer therapies the following variables 
will be recorded or derived: 
● 
Time since initial diagnosis, defined as time (in years) since initial diagnosis of prostate 
cancer until date of informed consent 
● 
Gleason score at diagnosis, which will be categorized as low (2-4), medium (5-7) and 
high (8-10), and also as low/medium (<8) and high (≥8). 
● 
Localization of disease (bone, soft tissue, both) 
● 
Target/non-target soft tissue disease 
● 
Distribution of metastatic disease (bone, lymph, visceral [split to lung, liver, both], other) 
● 
Time since diagnosis of metastases, defined as time (in months) since diagnosis of 
metastases until date of informed consent 
● 
Diagnostic test confirming metastases 
● 
For subjects with nodal disease, time since confirmed nodal disease, defined as time (in 
days) since confirmed nodal disease until date of informed consent 
● 
Luteinizing Hormone-Releasing Hormone (LHRH) agonist/antagonist initiation or 
bilateral orchiectomy relative to diagnosis of metastasis (before or after diagnosis of 
metastasis) 
● 
Localization of metastases 
● 
Number of bone metastases categorized as 0, 1, 2-4, 5-9, 10-20  
● 
Previous radiation therapy (yes, no) and area irradiated 
● 
Previous surgeries or procedures (yes, no) and type of procedure 
● 
Number of previous prostate cancer therapies categorized as 0, 1, 2, 3 and ≥4 
● 
Number of unique previous hormonal therapies (see appendix 1) categorized as 0, 1, 2, 3 
and ≥4 
● 
Previous anti-androgen (see appendix 2) use (yes, no) and number of previous 
anti-androgen therapies categorized as 0, 1, 2, 3 and ≥4 
● 
Previous bisphosphonate (see appendix 3) use (yes, no) 
● 
Results of chest x-ray and chest CT scan 
See Section 7.11.1 of this document for imputation rules regarding missing/incomplete 
diagnosis dates. 


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6.3.2 
Duration of exposure 
The length of time on treatment for both Period 1 and Period 2 will be calculated in weeks, 
using the following formula: 
Duration of exposure= ((‘Date last dose of IMP during the period’ - ‘Date first dose 
during the period’) + 1) / 30.4375 
Dose reductions and dose interruptions of enzalutamide/placebo will be counted and 
categorized as 0, 1, 2 and >2 in each Period (for Period 1 only enzalutamide). 
The number of cycles received of docetaxel will also be counted. 
6.3.3 
Cumulative dose of Docetaxel 
Cumulative dose of docetaxel (mg/m²) per subject will be calculated as the sum of the total 
doses that the subject received during the study. 
6.3.4 
Previous and Concomitant Medications  
Previous medications and CMs will be coded with World Health Organization Drug 
Dictionary (WHO-DD). 
Previous Medications 
Previous medications are defined as medications for which a subject took at least one dose 
during the pre-investigational period (i.e., during the period from obtaining informed consent 
to the start of Period 1). 
Period 1 CMs 
Period 1 CMs are defined as medications for which a subject took at least one dose during 
Period 1 (i.e., during the period from first enzalutamide intake during the Period 1 and before 
first intake of randomized study medication in Period 2). 
Period 2 CMs 
Period 2 CMs are defined as medications for which a subject took at least one dose during 
Period 2 (i.e., from first dose of randomized study medication in Period 2), and until the 
Follow-up Visit. 
 
See Section 7.11.1 of this document for imputation rules regarding missing/incomplete 
previous and concomitant medication dates. 
6.3.5 
Treatment Compliance 
Treatment compliance of enzalutamide for Period 1 and enzalutamide/placebo for Period 2 
will be calculated separately for subjects for whom total number of capsules taken and the 
complete date of the first dose and last dose are known. Subjects are to take 4 capsules once 
daily in both periods. Percentage compliance is defined as the total number of capsules taken 
divided by the total number of capsules that should have been taken: 
 
[Total number of capsules consumed in Period x] 


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----------------------------------------------------------------------------------------------- x 100 
       [(‘Date last dose of IMP in Period x’ - ‘Date first dose in Period x’) + 1] x 4 
where, total number of capsules consumed will be calculated as: 
(total number of capsules dispensed) – (total number of capsules returned). 
Missing data will not be imputed so missing dispensed/returned information will lead to 
missing compliance calculations to avoid incorrect results. 
Compliance will only be calculated for the main study part, treatment extension will be 
excluded from the compliance calculations. 
 
6.3.6 
Performance Status 
The ECOG scale will be used to assess performance status at all visits in the study. 
Table 3 
ECOG Grades 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair 
5 
Dead 
Baseline score for each period is defined as last non-missing value prior to first dose in the 
analysis period 
Post-baseline ECOG scores will be classified as follows according to baseline score in each 
Period: 
● 
Better or same score as baseline, defined as a post-baseline score lower or equal than 
baseline score. 
● 
Worse than baseline, defined as a post-baseline score higher than baseline score. 
● 
Another classification of post-baseline ECOG scores will be: 
● 
Better than baseline, defined as a post-baseline score lower than baseline score. 
● 
Same as baseline, defined as a post-baseline score equal to baseline score. 
● 
Worse than baseline, defined as a post-baseline score higher than baseline score. 


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6.3.7 
Functional Assessment of Cancer Therapy - Prostate 
The FACT-P quality of life questionnaire is a multi-dimensional, self-reported quality of life 
instrument specifically designed for use with prostate cancer patients. It consists of 27 core 
items which assess patient function in four domains: physical, social/family, emotional, and 
functional well-being, which is further supplemented by 12 site-specific items to assess for 
prostate-related symptoms. Each item is rated on a 0 to 4 Likert-type scale (0=Not at all, 1=A 
little bit, 2=Some-what, 3=Quite a bit, 4=Very much), and then combined to produce 
subscale scores for each domain, as well as a global quality of life score with higher scores 
representing better quality of life. 
Table 4 
Functional Assessment of Cancer Therapy – Prostate Scoring 
Domain 
Item Codes 
Score Calculation 
Score 
Range 
Physical Well-
Being (PWB) 
GP1, GP2, GP3, 
GP4, GP5, GP6, 
GP7 
[((4-GP1) + (4-GP2) + (4-GP3) + (4-GP4) + (4-
GP5) + (4-GP6) + (4-GP7)) * 7] / [No. items 
answered] 
0-28 
Social/Family 
Well-Being 
(SWB) 
GS1, GS2, GS3, 
GS4, GS5, GS6, 
GS7 
[(GS1 + GS2 + GS3) + GS4 + GS5 + GS6 + GS7) 
* 7] / [No. items answered] 
0-28 
Emotional 
Well-Being 
(EWB) 
GE1, GE2, GE3, 
GE4, GE5, GE6 
[((4-GE1) + GE2 + (4-GE3) + (4-GE4) + (4-GE5) 
+ (4-GE6)) * 6] / [No. items answered] 
0-24 
Functional 
Well-Being 
(FWB) 
GF1, GF2, GF3, 
GF4, GF5, GF6, 
GF7 
[(GF1 + GF2 + GF3 + GF4 + GF5 + GF6 + GF7) * 
7] / [No. items answered] 
0-28 
Prostate 
Cancer 
Subscale 
(PCS) 
C2, C6, P1, P2, 
P3, P4, P5, P6, 
P7, BL2, P8, BL5 
[((4-C2) + C6 + (4-P1) + (4-P2) + (4-P3) + P4 + P5 
+ (4-P6) + (4-P7) + (4-BL2) + (4-P8) + BL5) * 12] 
/ [No. items answered] 
0-48 
Global Score 
PWB, SWB, 
EWB, FWB, PCS 
PWB + SWB + EWB + FWB + PCS 
0-156 
 
Subjects will be asked to complete a FACT-P survey at Screening in Period 1 and then every 
12 weeks during Period 2 from Week 1. 
Change from baseline, defined as the post-baseline value minus the baseline value (last non-
missing value prior to first dose in the analysis period) will be calculated for each 
assessment. 
Post-baseline domain scores and global score will be classified as follows according to 
baseline scores in each Period: 
● 
Better or same score as baseline, defined as a post-baseline score higher or equal than 
baseline score. 
● 
Worse than baseline, defined as a post-baseline score lower than baseline score. 
● 
Another classification of post-baseline domain scores and global score will be: 


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● 
Better than baseline, defined as a post-baseline score higher than baseline score. 
● 
Same as baseline, defined as a post-baseline score equal to baseline score. 
● 
Worse than baseline, defined as a post-baseline score lower than baseline score. 
 
Time to degradation of FACT-P will also be calculated as time (in months) from 
randomization (Period 2 Week 1) to the date of post-randomization degradation. 
Degradation of FACT-P for the global score is defined as at least a 10-point decrease from 
randomization for the global score. Degradation of FACT-P for the subscales is defined as at 
least a 3-point decrease from randomization for each subscale. 
Subjects who do not show degradation of FACT-P at the data analysis cutoff date (see 
Section 6.1.1 for details) will be censored on the date of the last assessment of FACT-P 
before data analysis cutoff date, and subjects discontinuing for any reason before data 
analysis cutoff date and without degradation of FACT-P will be censored at the last 
assessment of FACT-P before discontinuation. 
6.3.8 
EuroQol 5-Dimensions 5-Levels 
Quality of life is also to be assessed using the EQ-5D-5L questionnaire at Screening in 
Period 1 and then every 12 weeks during Period 2 from Week 1. This is an international and 
standardized non-disease specific (i.e., generic) instrument for describing and valuing health 
status. 
This questionnaire consists of two parts: 
● 
5-dimensions (EQ-5D-5L): mobility, self-care, usual activities, pain/discomfort and 
anxiety/depression. 
● 
Visual Analog Scale (VAS) where 0 represents the worst imaginable health state and 
100 the best imaginable health state. 
Change from baseline for the VAS score, defined as the post-baseline value minus the 
baseline value (last non-missing value prior to first dose in the analysis period) will be 
calculated for each assessment. 
6.3.9 
Health Resource Use 
Health resource use, including: 
● 
Visits to general practitioner/family doctor, hospital doctor, practice/district nurse and 
hospital nurse, 
● 
Length of hospital stay (in days) for routine admission or for unscheduled/emergency 
room, if applicable, 
● 
Reason for admission to hospital, if applicable. 
will be assessed at the Period 1 Screening Visit and then every 12 weeks, and every 12 weeks 
during Period 2 from Week 1. 


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7. STATISTICAL METHODOLOGY 
7.1 
General Considerations 
For continuous variables, descriptive statistics will include the number of subjects (n), mean, 
standard deviation, median, minimum and maximum. When needed, the use of other 
percentiles (e.g., 10%, 25%, 75% and 90%) will be mentioned in the relevant section. 
Frequencies and percentages will be displayed for categorical data. Percentages by categories 
will be based on the number of subjects with no missing data, i.e., will add up to 100%. 
Summaries based on FAS will be presented by planned treatment group, unless specifically 
stated otherwise. Safety analysis and other summaries based on SAF will be presented by 
actual treatment received. 
All tables based on SAF2 and FAS will be presented by treatment group, strata (evidence of 
radiographic progression or not [PSA progression]) and overall unless specifically stated 
otherwise. 
All statistical comparisons will be made using two sided tests at the α=0.05 significance level 
unless specifically stated otherwise.  All null hypotheses will be of no treatment difference, 
all alternative hypotheses will be two-sided, unless specifically stated otherwise. 
The primary analysis (with data cut-off after at least 182 events) should be considered as the 
main analysis for this trial and will contain all the outputs as defined in the TLF Specs 
document.   
At the time of database lock, both safety and primary efficacy TLFs will be rerun on the 
complete data up to the extension period. This analysis is to be viewed as descriptive in 
nature. 
Separate listings will be provided to report key safety information on the extension period 
using the safety population (all subjects treated) 
No separate baseline will be calculated for the extension period so the baseline for extension 
period 1 and extension period 2 will be period 1 and period 2 baseline respectively 
All data listings will be sorted by centre, treatment group and visit time point (where 
applicable). 
All data processing, summarization, and analyses will be performed using SAS® Version 9.3 
or higher on Unix. Specifications for table, figures, and data listing formats can be found in 
the TLF specifications document for this study. 
7.2 
Study Population 
7.2.1 
Disposition of Subjects 
The following subject data will be presented: 
● 
For all subjects with  informed consent, subjects who discontinued before Period 1 
(screen failures), subjects who received Enzalutamide in Period 1, subjects who 
discontinued before Period 2 and subjects randomized; 


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● 
Number and percentage of subjects that completed, discontinued, and the reason for 
discontinuation of treatment for all subjects who entered Period 1, overall, during 
Period1 and for all randomized subjects, by treatment group and overall, during Period 2; 
● 
Number and percentage of subjects in each analysis set for all subjects who entered 
Period 1, overall, for Period 1 and for all randomized subjects, by treatment group and 
overall for Period 2; 
Data collected or derived for informed consent, inclusion/exclusion criteria not met, 
completion and discontinuation dates, and reasons for discontinuation and/or exclusion from 
analysis sets will be listed. 
7.2.2 
Protocol Deviations 
Protocol deviations will be assessed for all randomized subjects. The number and percentage 
of subjects meeting any criteria will be summarized for each criterion and overall, by 
treatment group, strata and 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. 
Number and percentage of subjects randomized in each country and site will be presented by 
treatment group, strata and overall for all randomized subjects. 
Descriptive statistics for age, weight, BMI and height at study entry and frequency 
tabulations for gender and race will be presented by treatment group and strata, and overall 
for SAF2 and FAS. 
Disease history variables described in Section 6.3.1 of this document, will also be presented 
by treatment group and stratum, and overall for SAF2 and FAS. 
Additionally the following variables will also be presented in the same way: 
● 
Baseline ECOG performance status 
● 
Baseline pain intensity total score from the BPI-SF 
● 
Baseline (Period 1 Week 1, or Screening if missing) haemoglobin value 
● 
Baseline (Period 1 Week 1, or Screening if missing) alkaline phosphatase value 
● 
Baseline (Period 1 Week 1, or Screening if missing) lactate dehydrogenase (LDH) value 


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● 
Baseline (Period 1 Week 1, or Screening if missing) serum albumin 
● 
Baseline (Period 1 Week 1, or Screening if missing) serum PSA 
● 
Baseline (Period 1 Week 1, or Screening if missing) creatinine value 
● 
Baseline (Period 1 Week 1, or Screening if missing) neutrophil:lymphocyte ratio value 
● 
Baseline (Screening) testosterone value 
● 
History of prior cardiovascular disease(*) (yes, no) 
● 
Baseline (at Period 1 Week 1) use of corticosteroids (see Appendix 4) (yes, no) 
● 
Baseline (at Period 1 Week 1) use of anticoagulants (see Appendix 5) (yes, no) 
(*)  History of cardiovascular diseases can be identified by selecting the SOC terms 
“vascular disorders” and “cardiac disorders”. 
All demographics and baseline characteristics data will be listed. 
Non-prostate cancer medical history is coded using MedDRA. The number and percent of 
subjects by System Organ Class (SOC) and PT will be summarized by treatment group and 
stratum, and overall for the SAF2. 
Subjects will only be counted once per MedDRA level. Medical History will be sorted by 
decreasing incidence of the overall treatment group by SOC and within that by PT. Medical 
history will also be listed by SOC and PT. 
7.2.4 
Previous and Concomitant Medications 
For both prostate cancer drug therapies and non-prostate cancer drug therapies, the number 
and percentage of subjects within therapeutic subgroup (Anatomical Therapeutic Chemical 
(ATC) level 2) and chemical subgroup (ATC level 4) will be presented for all the 
medications summaries overall for Period 1 and by treatment group, stratum and overall for 
Period 2. 
Subjects will only be counted once per ATC level. Previous prostate cancer and non-prostate 
cancer medications and CMs will be sorted by decreasing incidence of the overall treatment 
group by ATC level 2 and within that by ATC level 4. 
A summary will be produced for the following: 
● 
Previous medications (SAF1) 
● 
Previous prostate cancer drug therapies (SAF1) 
● 
CMs in Period 1 (SAF1) 
● 
CMs in Period 2 (SAF2) 
● 
Concomitant prostate cancer drug therapies in Period 1 (SAF1) 
● 
Concomitant prostate cancer drug therapies in Period 2 (SAF2) 
Subjects taking the same medication multiple times will be counted once per medication and 
period. 
All medications data will be provided in a listing. Listings will only contain data for subjects 
who reported taking medication. 
Non-medication treatment will also be listed. 


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7.3 
Study Drugs 
7.3.1 
Exposure 
Duration of exposure will be summarized by Period in two ways. 
● 
Descriptive statistics will be presented overall in Period 1 and by treatment group, strata 
and overall in Period 2. 
● 
For Period 1 exposure time will be categorized according to the following categories: 
○ ≤6 weeks (42 days) 
○ >6 weeks (42days), and ≤12 weeks (84 days) 
○ >12 weeks (84 days), and ≤24 weeks (168 days) 
○ >24 weeks (168 days), and ≤48 weeks (336 days)  
○ >48 weeks (336 days), and ≤96 weeks (672 days) 
○ >96 weeks (672 days), and ≤192 weeks (1344 days) 
○ >192 weeks (1344 days) 
● 
For Period 2 exposure time will be categorized according to the following categories by 
treatment group, strata and overall: 
○ ≤6 weeks (42 days) 
○ >6 weeks (42 days), and ≤12 weeks (84 days) 
○ >12 weeks (84 days), and ≤18 weeks (126 days) 
○ >18 weeks (126 days), and ≤24 weeks (168 days) 
○ >24 weeks (168 days), and ≤30 weeks (210 days) 
○ >30 weeks (210 days), and ≤36 weeks (252 days) 
○ >36 weeks (252 days), and ≤42 weeks (294 days) 
○ >42 weeks (294 days), and ≤48 weeks (336 days) 
○ >48 weeks (336 days), and ≤54 weeks (378 days) 
○ >54 weeks (378 days), and ≤60 weeks (420 days) 
○ >60 weeks (420 days) 
Counts and percentages of subjects in each of these categories will be summarized for each 
treatment group for the SAF1 in Period 1 and for the SAF2 in Period 2. 
Descriptive statistics will be presented for cumulative dose of docetaxel by treatment group, 
strata and overall for the SAF2. 
All exposure data will be provided in a listing. 
7.3.2 
Treatment Compliance 
Compliance with IMP will be summarized overall in Period 1 for SAF1 and by treatment 
group, strata and overall in Period 2 for SAF2. Refer to Section 6.3.5 for definition of 
treatment compliance. 
Percentage compliance by treatment period will be summarized in two ways: 
● 
Descriptive statistics. 
● 
Number and percentage of subjects within the following categories: 
○ <80% 


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○ ≥80% to 100% 
○ ≥100% 
○ Unknown (not enough data to calculate compliance) 
All compliance data will be listed. 
7.4 
Analysis of Efficacy 
All efficacy data will be presented using descriptive statistics and will be summarized in 
tabular and/or graphical form. 
All efficacy data will be included in listings. 
7.4.1 
Analysis of Primary Endpoint 
The primary efficacy endpoint is PFS, with progression defined as radiographic progression, 
unequivocal clinical progression, or death on study. 
7.4.1.1 Primary Analysis of Primary Endpoint 
The survival functions in both treatment groups will be estimated using the Kaplan-Meier 
method and displayed graphically. Median (50th percentile) with its corresponding 95% CI, 
together with the number of subjects with and without progression, will be summarized by 
treatment group and strata for FAS. The comparison of the survival curves of the two 
treatment groups will be done using a stratified log-rank test, stratified by disease progression 
in Period 1 (evidence of radiographic progression or not), at the 0.05 2-sided significance 
level (based on 182 events). 
The following SAS code may be used: 
PROC LIFETEST data=dataset; 
STRATA progression_P1 / GROUP=treatment; 
TIME time*censor(1); 
RUN; 
where, progression_P1 is disease progression in Period 1 (evidence of radiographic 
progression or not). 
 
A Cox proportional hazards model will be performed with covariates for treatment and 
evidence of radiographic progression in Period 1. HR for treatment group, 95% profile 
likelihood confidence interval (CI) and the correspondent p-value will be shown. 
The following SAS code may be used: 
PROC PHREG data=dataset; 
CLASS treatment progression_P1; 
MODEL time*censor(1) = treatment progression_P1 / TIES=DISCRETE RL=PL; 
RUN; 
where, progression_P1 is disease progression in Period 1 (evidence of radiographic 
progression or not). 
 


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Proportional hazards assumption will be tested by examining plots of complementary 
log(-log(survival)) versus log(time). 
For doing this, the first line in the first PROC LIFETEST statement above may be changed 
by: 
PROC LIFETEST data=dataset PLOT=(S,LLS); 
If the proportional hazards assumption is not met the Cox model will not be applied and 
treatment effect will only be estimated using the median time to event in each treatment 
group. 
7.4.1.2 Secondary Analysis of Primary Endpoint 
A sensitivity analysis for PFS will be conducted using an unstratified log-rank test for the 
FAS. 
The following SAS code may be used: 
PROC LIFETEST data=dataset; 
STRATA treatment; 
TIME time*censor(1); 
RUN; 
 
As part of the sensitivity analysis a Cox proportional hazards model will be performed for the 
FAS with covariate for treatment only. HR for treatment group, 95% profile likelihood CI 
and the correspondent p-value will be shown. Proportional hazards assumption will also be 
tested firstly in the same way as explained in Section 7.4.1.1 but excluding variable disease 
progression in Period 1 from the model. 
7.4.1.3 Subgroup Analysis of Primary Endpoint 
Subgroup analyses for the primary endpoint will be performed using the FAS for the 
following factors:  
● 
Disease progression in Period 1 (evidence of radiographic progression or not). 
● 
ECOG performance status (0 or 1 or 2) at baseline 
● 
Age category (<75 or ≥75 years) at eligibility assessment for Period 2 visit 
● 
Total Gleason score (<8 and ≥8) at diagnosis 
● 
Disease location (bone only versus soft tissue only versus both bone and soft tissue) at 
Screening 
● 
Visceral disease (yes or no) at screening 
● 
Baseline (Period 1 Week 1, or Screening if missing) serum PSA value (≤median, 
>median) 
● 
Baseline (Period 1 Week 1, or Screening if missing) LDH value (≤median, >median) 
● 
Baseline (Period 1 Week 1, or Screening if missing) hemoglobin value (≤median, 
>median) 
● 
Baseline (Period 1 Week 1, or Screening if missing) ALP value (≤median, >median) 
● 
Previous anti-androgen therapy (see ) use (yes, no) 
● 
Previous bisphosphonate (see ) use (yes, no) 


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The same analysis as described in Section 7.4.1.1, excluding the stratification factor for the 
first subgroup defined above, will be performed in each subgroup category. 
P-values resulting from inferential tests conducted in context of the subgroup analysis are of 
descriptive nature only and should be interpreted cautiously. 
7.4.2 
Analysis of Secondary Endpoints  
7.4.2.1 Time to PSA Progression 
Time to PSA progression will be described and analyzed in the same way as the primary 
endpoint (see Section 7.4.1.1) for FAS. 
7.4.2.2 PSA Response 
Percentage change from baseline (see Section 6.1.2.2 for definition) of PSA levels will be 
summarized at Week 13 by treatment group and strata for FAS. Maximum decrease in 
percentage change from baseline will also by summarized by treatment group and strata for 
FAS. 
PSA response (see Section 6.1.2.2 for definition)  at Week 13 and at any time after 
randomization will also be summarized by treatment group and strata for FAS. 
Percentage change from baseline to Week 13 and maximum decrease in percentage change 
from baseline will also be reported using waterfall plots for each treatment group. 
7.4.2.3 Objective Response Rate 
Rates of complete response (CR), partial response (PR), stable disease (SD), objective 
response (CR+PR), and CR+PR+SD will be tabulated along with exact binomial 95% 
confidence intervals (Clopper Pearson) by treatment group stratified by disease progression 
in Period 1 (evidence of radiographic progression or not) for FAS. 
The following SAS code may be used: 
PROC FREQ data=dataset; 
BY progression_P1 treatment; 
TABLE response / BINOMIAL;  
RUN; 
where, progression_P1 is disease progression in Period 1 (evidence of radiographic 
progression or not). 
The proportion of subjects with objective response will be compared between treatment 
groups using a Cochran-Mantel-Haenszel test stratified by disease progression in Period 1 
(evidence of radiographic progression or not) for FAS. 
The following SAS code may be used: 
PROC FREQ data=dataset; 
TABLES progression_P1 * treatment * obj_response / CMH; 
RUN; 


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where, progression_P1 is disease progression in Period 1 (evidence of radiographic 
progression or not) and obj_response is objective response. 
 
7.4.2.4 Time to Pain Progression 
Time to pain progression will be described and analyzed in the same way as the primary 
endpoint (see Section 7.4.1.1) for FAS. 
Total scores for pain intensity and pain interference will be summarized by treatment group, 
strata and visit, including change from baseline to each post baseline assessment for FAS. 
7.4.3 
Time to Opiate Use for Cancer-Related Pain 
Time to opiate use for cancer-related pain will be described and analyzed in the same way as 
the primary endpoint (see Section 7.4.1.1) for FAS. 
7.4.4 
Time to First Skeletal Related Event 
Time to first SRE will be described and analyzed in the same way as the primary endpoint 
(see Section 7.4.1.1) for FAS. 
7.5 
Analysis of Safety 
All safety and tolerability data will be presented using descriptive statistics and will be listed 
and summarized in tabular and/or graphical form for SAF1 when referring to Period 1 and for 
SAF2 when referring to Period 2. No formal statistical testing will be performed on these 
data except otherwise specified.  
7.5.1 
Adverse Events 
TEAEs will be summarized for Period 1 and Period 2 separately, overall and by treatment 
group, strata and overall respectively, by SOC and PT. 
Overview summary tables will be provided for each Period with the following information: 
● 
Number and percentage of subjects with AEs/TEAEs 
● 
Number of TEAEs 
● 
Number and percentage of subjects with drug-related TEAEs 
● 
Number of drug-related TEAEs 
● 
Number and percentage of subjects with docetaxel-related TEAEs (only for Period 2) 
● 
Number of docetaxel-related TEAEs (only for Period 2) 
● 
Number and percentage of deaths 
● 
Number and percentage of subjects with serious TEAEs 
● 
Number of serious TEAEs 
● 
Number and percentage of subjects with drug-related serious TEAEs 
● 
Number of drug-related serious TEAEs 
● 
Number and percentage of subjects with docetaxel-related serious TEAEs (only for 
Period 2) 
● 
Number of docetaxel-related serious TEAEs (only for Period 2) 


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● 
Number and percentage of subjects with TEAEs leading to permanent discontinuation of 
study drug 
● 
Number of TEAEs leading to permanent discontinuation of study drug 
● 
Number and percentage of subjects with drug-related TEAEs leading to permanent 
discontinuation of study drug 
● 
Number of drug-related TEAEs leading to permanent discontinuation of study drug 
● 
Number and percentage of subjects with docetaxel-related TEAEs leading to permanent 
discontinuation of study drug (only for Period 2) 
● 
Number of docetaxel-related TEAEs leading to permanent discontinuation of study drug 
(only for Period 2) 
The following summaries of subjects with TEAE will be produced and presented overall for 
Period 1 by treatment group, strata and overall for Period 2: 
● 
The number (percentage) of subjects with at least one TEAE, classified by SOC and PT, 
will be summarized; subjects will be counted only once within a PT or a SOC; 
● 
The number (percentage) of subjects with at least one TEAE, classified by SOC and PT, 
will be summarized by NCI CTCAE Grade (V4.03); subjects will be counted only once 
with the worst (maximum) NCI CTCAE Grade within a PT or a SOC; 
● 
The number (percentage) of subjects with at least one TEAE, excluding serious AEs, that 
equal to or exceed a threshold of 2% in either treatment group, classified by SOC and 
PT, will be summarized; subjects will be counted only once within a PT or a SOC; 
● 
The number (percentage) of subjects with at least one TEAE considered to be treatment 
related (relationship type identified as possibly, probably or missing on the eCRF), 
classified by SOC and PT, will be summarized; subjects will be counted only once 
within a PT or a SOC; 
● 
The number (percentage) of subjects with at least one TEAE considered to be docetaxel 
related (relationship type identified as possibly, probably or missing on the eCRF), 
classified by SOC and PT, will be summarized; subjects will be counted only once 
within a PT or a SOC; 
● 
The number (percentage) of subjects with at least one TEAE considered to be treatment 
related (relationship type identified as possibly, probably or missing on the eCRF), 
classified by SOC and PT, will be summarized by NCI CTCAE Grade (V4.03); subjects 
will be counted only once for the worst (maximum) NCI CTCAE Grade within a PT or a 
SOC; 
● 
The number (percentage) of subjects with at least one TEAE considered to be docetaxel 
related (relationship type identified as possibly, probably or missing on the eCRF), 
classified by SOC and PT, will be summarized by NCI CTCAE Grade (V4.03); subjects 
will be counted only once for the worst (maximum) NCI CTCAE Grade within a PT or a 
SOC; 
● 
The number (percentage) of subjects with at least one serious TEAE, classified by SOC 
and PT, will be summarized; subjects will be counted only once within a PT or a SOC; 
● 
The number (percentage) of subjects with at least one serious TEAE considered to be 
treatment related (relationship type identified as possibly, probably or missing on the 


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eCRF), classified by SOC and PT, will be summarized; subjects will be counted only 
once within a PT or a SOC; 
● 
The number (percentage) of subjects with at least one serious TEAE considered to be 
docetaxel related (relationship type identified as possibly, probably or missing on the 
eCRF), classified by SOC and PT, will be summarized; subjects will be counted only 
once within a PT or a SOC; 
● 
The number (percentage) of subjects with a TEAE leading to permanent discontinuation 
of study drug, classified by SOC and PT, will be summarized; subjects will be counted 
only once within a PT or a SOC; 
● 
The number (percentage) of subjects with a TEAE leading to permanent discontinuation 
of study drug considered to be treatment related (relationship type identified as possibly, 
probably or missing on the eCRF), classified by SOC and PT, will be summarized; subjects 
will be counted only once within a PT or a SOC. 
● 
The number (percentage) of subjects with a TEAE leading to permanent discontinuation 
of study drug considered to be docetaxel related (relationship type identified as possibly, 
probably or missing on the eCRF), classified by SOC and PT, will be summarized; subjects 
will be counted only once within a PT or a SOC. 
Listings by treatment period will be provided for the following: 
● 
All subjects experiencing an AE; 
● 
All subjects experiencing a drug-related AE; 
● 
All deaths; 
● 
All subjects experiencing a serious AE; 
● 
All subjects experiencing AEs leading to permanent discontinuation of study drug. 
 
7.5.2 
Clinical Laboratory Evaluation 
Clinical laboratory test results (hematology and biochemistry) will be summarized for 
Period 1 and Period 2 separately, overall and by treatment group, strata and overall 
respectively, and will be presented in SI units. 
Additionally, within-subject changes from baseline (see Section 6.2.2 for definition) will be 
calculated. 
Each hematology and biochemistry result will be classified as grades 1 to 4 according to 
NCI-CTCAE at each visit. Number and percentage of subjects in each grade by laboratory 
test and visit, overall in Period 1 and treatment group, strata and overall in Period 2 will be 
shown. Shift tables of NCI CTC grade changes from baseline to each post-baseline 
assessment will be calculated for each Period by laboratory test, overall in Period 1 and 
treatment group, strata and overall in Period 2. Listings of all laboratory measurements, 
including flagging of abnormal value with high and low, will be made.  
Clinically significant abnormal values will be reported as AEs. 


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7.5.2.1 Liver Enzymes and Total Bilirubin 
For the groups defined in Section 6.2.2.1, the number and percent of subjects who meet the 
criteria at any time during Period 1 and during Period 2 will be summarized overall and by 
treatment group, strata and overall respectively. 
The following listings will be included for subjects who require further liver investigation: 
● 
Results of ALT, AST, TBL, ALP and International Normalized Ratio (INR) 
● 
Study drug interruptions due to liver abnormalities 
● 
Alcohol history and drug abuse 
● 
Liver imaging 
● 
Serology 
● 
Investigator Comments on the liver abnormalities 
7.5.3 
Vital Signs 
Vital signs (systolic blood pressure, diastolic blood pressure, temperature and pulse rate) will 
be summarized by visit for Period 1 and Period 2, overall and by treatment group, strata and 
overall respectively. Additionally, within-subject change from baseline (see Section 6.2.3 for 
definition) will also be summarized by visit in both periods. 
Number and percentage of subjects in each hypertension grade according to NCI-CTCAE by 
visit, overall in Period 1 and treatment group, strata and overall in Period 2 will be shown. 
7.5.4 
Weight 
Weight will be summarized by visit for Period 1 and Period 2, overall and by treatment 
group, strata and overall respectively. Additionally, within-subject change from baseline (see 
Section 6.2.4 for definition) will also be summarized by visit in both periods. 
7.5.5 
Electrocardiograms (ECGs) 
ECG interpretation will be summarized by treatment group, strata and overall, and visit. 
ECG variables (PR interval, RR interval, heart rate, QRS interval, QT interval, QTcF interval 
and QTcB interval) will be summarized for each treatment group, strata and overall at each 
visit and including changes from baseline to each visit. 
All of the QTc analyses will be presented for both the Fridericia and Bazett correction 
methods. 
7.6 
Analysis of PK 
Not applicable. 
7.7 
Analysis of PD 
Not applicable. 
7.8 
Subgroups of Interest  
Primary efficacy endpoint will be summarized by treatment group for the subgroup defined 
on the basis of the categorized variables listed below: 


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Grouping variable 
 
 
Subgroups 
Disease Progression in Period 1 
Evidence of radiographic progression 
No evidence of radiographic progression (PSA 
progression) 
ECOG performance status 
 
0 
 
 
 
 
 
1 
 
 
 
 
 
2 
Visceral disease 
 
 
Yes 
 
 
 
 
 
No 
Age category  
 
 
<75 years 
 
 
 
 
 
≥75 years 
Total Gleason score at diagnosis 
≤7 
 
 
 
 
 
≥8 
Disease location at Screening  
Bone only 
 
 
 
 
 
Soft tissue only 
 
 
 
 
 
Bone and soft tissue 
Baseline serum PSA value 
 
≤median 
 
 
 
 
 
>median 
Baseline LDH value  
 
≤median 
 
 
 
 
 
>median 
Baseline hemoglobin value 
 
≤median 
 
 
 
 
 
>median 
Baseline ALP value  
 
≤median 
 
 
 
 
 
>median 
Previous anti-androgen therapy use Yes 
 
 
 
 
 
No 
Previous bisphosphonate use  
Yes 
 
 
 
 
 
No 
For more details refer to Section 7.4.1.3. 


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7.9 
Other Analyses 
7.9.1 
Performance Status 
Number and percentage of subjects in each category of ECOG will be presented by visit, 
overall in Period 1 for the SAF1 and by treatment group, strata and visit in Period 2 for the 
FAS. 
Number and percentage of subjects with better or equal score and worse score at each 
post-baseline assessment vs. baseline and number and percentage of subjects with better, 
equal and worse score at each post-baseline assessment vs. baseline in each Period will be 
presented, overall in Period 1 for the SAF1 and by treatment group and strata in Period 2 for 
the FAS. 
7.9.2 
Functional Assessment of Cancer Therapy - Prostate 
Each of the 4 domain scores, the prostate cancer subscale and the global quality of life score 
will be summarized by treatment group, strata and overall, and visit for FAS, including 
change from baseline to each post baseline assessment. 
For each domain score and global score, number and percentage of subjects with better or 
equal score and worse score at each post-baseline assessment vs. baseline and number and 
percentage of subjects with better, equal and worse score at each post-baseline assessment vs. 
baseline will be presented by treatment group, strata and overall for FAS. 
Time to degradation of FACT-P for each domain and global score will be described and 
analyzed in the same way as the primary endpoint (see Section 7.4.1.1) for FAS. 
7.9.3 
EuroQol 5-Dimensions 5-Levels 
Each of the 5 dimensions for EQ-5D-5L will be summarized by treatment group, strata and 
overall, and visit as categorical variables for FAS. 
EQ-5D-5L VAS score will be summarized by treatment group, strata and overall, and visit, 
including change from baseline to each post baseline assessment for FAS. 
7.9.4 
Health Resource Use 
Number of visits to general practitioner/family doctor, hospital doctor, practice/district nurse 
and hospital nurse for all subjects and length of hospital stay for a routine admission and for 
unscheduled/emergency room in subjects admitted to hospital will be summarized overall in 
Period 1 and by treatment group, strata and overall in Period 2. 
Reason for admission to hospital in subjects admitted to hospital will be listed. 
7.9.5 
Impact of Covid 19 Pandemic 
Following the Covid 19 pandemic, impact of Covid 19 on the trial conduct and results is 
reported according to Astellas guidelines with the inclusion of appropriate categories in 
existing outputs and addition of dedicated outputs to report the impact on both visit based and 
non-visit based assessments in the trial. 
 


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7.10 
Interim Analysis (and Early Discontinuation of the Clinical Study) 
Not applicable. 
7.11 
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information 
All “time to” analysis will be right-censored based on one of the following conditions: 
● 
Lost to follow-up since randomization; 
● 
Not known to have the event at the data analysis cut-off; 
● 
Death will also be a censoring condition for all events that do not include death. 
7.11.1 Missing Data 
7.11.1.1 Missing Adverse Event Dates 
For AEs with incomplete or missing start or end date, a worst-case scenario will be used to 
determine treatment emergence of this adverse event and imputation of dates (see 
Appendix 6 for incomplete or missing start dates rules). 
For incomplete or missing end dates the following rule will be adopted: 
● 
If day and month are missing, month and day should be imputed by 31st December 
● 
If day is missing, day will be imputed with the last day of the month 
7.11.1.2 Other Missing Dates 
For other incomplete or missing dates a worst-case scenario will be used. 
For start dates the following rule will be adopted: 
● 
If day and month are missing, month and day should be imputed by 1st January 
● 
If day is missing, day will be imputed with the first day of the month 
For end dates the following rule will be adopted: 
● 
If day and month are missing, month and day should be imputed by 31st December 
● 
If day is missing, day will be imputed with the last day of the month 
7.11.2 Outliers 
All values will be included in the analyses. 
7.11.3 Visit Windows 
The study protocol gives the overall study schedule and the permissible intervals for these 
visits expressed as the number of days relative to Screening for Period 1 and to eligibility 
assessment for Period 2. 
Analyses will not exclude subject data due to the subject’s failure to comply with the visit 
schedule. 
The value which assessment day is the closest to the defined target day within these windows 
is used. If two values are equally close, the later is used in the analysis.  


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8. UPDATES IN CSR 
Primary CSR was signed on 28 Apr 2021. Data cut performed 30 Apr 2020. 
Updated (FINAL) CSR will be done when last patient has left the study, anticipated to occure 
Q1 2024.  
 
This CSR will include ALL data available in the database that are linked to the described 
endpoints.  
9. DOCUMENT REVISION HISTORY 
Version 
Date 
Changes 
Comment/rationale for change 
1.00 
12-Nov-2014 
NA 
Document finalized 
1.1 
27-Oct-2016 
CTA included 
Update to include CTP changes 
1.2 
12-Apr-2019 
CTP v 5.0 
Include changes from CTP v5 and refine 
treatment extension 
2.0 
23-Apr-2021 
Categorizations 
 
 
 
Covid 19 
 
Clarifications 
Implement decissions w.r.t. changes of 
categorization categories  made during 
DRM meetings. 
 
Inclusion of impact assessment 
 
General clarifications to existing 
defenitions 
2.1 
23-Jan-2024 
Updated to refine 
final analysis 
wording  
Include full rerun of safety and primary 
efficacy, handling of extension period 
10. 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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11. APPENDICES 
10.1 
Appendix 1: List of Hormonal Therapies 
ATC Code 
Name 
Defined Daily Dose 
Units 
Route of Administration 
Note 
L02AE01 
Buserelin 
0.11 
mg 
Implant 
 
1.2 
mg 
N 
 
1.5 
mg 
P 
 
L02AE02 
Leuprorelin 
60 
mcg 
Implant 
 
0.134 
mg 
P 
Depot inj 
1 
mg 
P 
 
L02AE03 
Goserelin 
0.129 
mg 
Implant 
 
L02AE04  
Triptorelin 
0.134 
mg 
P 
Depot inj 
0.1 
mg 
P 
 
L02AE05 
Histrelin 
0.137 
mg 
Implant 
 
L02BX01 
Abarelix 
 
 
 
 
L02BX02 
Degarelix 
2.7 
mg 
P 
 
 


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10.2 
Appendix 2: List of Anti-Androgens 
ATC Code 
Name 
Defined Daily Dose 
Units 
Route of Administration 
Note 
L02BB01 
Flutamide 
0.75 
g 
O 
 
L02BB02 
Nilutamide 
0.3 
g 
O 
 
L02BB03 
Bicalutamide 
50 
mg 
O 
 
 


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10.3 
Appendix 3: List of Bisphosphonates 
ATC Code 
Name 
Defined Daily 
Dose 
Units 
Route of 
Administration 
Note 
M05BA01 
etidronic acid 
0.4 
g 
O 
 
 
 
1.5 
g 
P 
Course dose 
M05BA02 
clodronic acid 
1.6 
g 
O 
 
 
 
1.5 
g 
P 
Course dose 
M05BA03 
pamidronic acid 
60 
mg 
P 
Course dose 
M05BA04 
alendronic acid 
10 
mg 
O 
 
M05BA05 
tiludronic acid 
0.4 
g 
O 
 
M05BA06 
ibandronic acid 
6 
mg 
P 
Course dose 
 
 
5 
mg 
O 
 
M05BA07 
risedronic acid 
5 
mg 
O 
 
M05BA08 
zoledronic acid 
4 
mg 
P 
 
M05BB01 
etidronic acid and calcium, sequential 
0.4 
g 
O 
Refers to etidronic acid 
M05BB02 
risedronic acid and calcium, sequential 
 
 
 
 
M05BB03 
alendronic acid and colecalciferol 
10 
mg 
O 
Refers to etidronic acid 
M05BB04 
risedronic acid, calcium and colecalciferol, 
sequential 
5 
mg 
O 
Refers to etidronic acid 
M05BB05 
alendronic acid, calcium and colecalciferol, 
sequential 
10 
mg 
O 
Refers to etidronic acid 
M05BB06 
alendronic acid and alfacalcidol, sequential 
10 
mg 
O 
Refers to etidronic acid 
 


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10.4 
Appendix 4: List of Corticosteroids 
ATC Code 
Name 
H02AB 
Glucocorticoids 
H02BX 
Corticosteroids for systemic use, combinations 
 


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10.5 
Appendix 5: List of Anticoagulants 
ATC Code 
Name 
B01AA 
Vitamin K antagonists 
B01AB 
Heparin group 
 








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10.7 
Appendix 7: PFS Derivation 
The objective of this document is to provide a detailed description of the derivation of the 
Progression Free Survival (PFS), as defined in Section 6.1.1 of the SAP. 
 
The analysis requires the derivation of the progression events and their corresponding dates. 
 
The primary efficacy endpoint is PFS with progression defined as radiographic progression, 
unequivocal clinical progression, or death on study. 
 
At first, the collection of all dates is required for the derivation: 
- 
Date of randomization: 
 
Table 
Variable 
Randomization 
date 
SDTM.ADSL 
RANDDT 
 
- 
Date of progression events: 
 
Table, and selection if necessary 
Variable 
Date of 
radiographic 
disease 
progression 
- Bone:  
SDTM.RS.RSTESTCD= "BONERESP" 
and SDTM.RS.RSORRES = 
"PROGRESSIVE DISEASE" 
(choose unconfirmed PD data, if available) 
 
- Soft tissue: 
SDTM.RS.RSTESTCD=" OVSTRESP" 
and SDTM.RS.RSORRES = 
"PROGRESSIVE DISEASE" 
SDTM.RS.RSDTC 
where RSDTC>= RANDDT 
(in order to select only the 
progression appear after the 
randomization) 
 
For bone disease progression:  
- If a subject has an unconfirmed 
progression with confirmed 
progression, the date of unconfirmed 
progression will be used. 
- If a subject has only an unconfirmed 
progression, it won’t be used for the 
analysis. 
Date of 
unequivocal 
clinical 
progression 
- New onset cancer pain requiring chronic 
administration of opiate analgesia: 
SDTM.RS rstestcd=CAPAINOP 
 
- Deterioration from prostate cancer of 
ECOG PS score to 3 or Higher: 
SDTM.QS.QSTESTCD="ECOG" and 
SDTM.QS.QSSTRESN>=3 
 
- Initiation of subsequent lines of cytotoxic 
chemotherapy or radiation therapy or surgical 
CMSTDTC1=SDTM.CM.CMSTDTC 
where CMSTDTC ≥ RANDDT 
 
 
 
 
SDTM.QS.QSDTC 
where QSDTC >= RANDDT 
 
 
 


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intervention due to complications of tumor 
progression: 
SDTM.RS rstestcd=COMPTUPR 
 
 
CMSTDTC2=SDTM.CM.CMSTDTC 
where CMSTDTC ≥ RANDDT 
 
Date of death  SDTM.DS.DSTERM="DEATH" and  
SDTM.DS.EPOCH="30 DAY FOLLOW-
UP" 
 
 
SDTM.DSDTC 
where DSDTC ≥ RANDDT 
 
- 
Date of the last assessment of disease progression: 
 
Table, and selection if necessary 
Variable 
Date of the 
last 
assessment of 
disease 
progression 
Last disease assessment available (time point 
response and FU) 
SDTM.RS.RSDTC 
where RSDTC> RANDDT 
 
Then, the derivation of the main variables of the ADTTE ADaM dataset: 
Variable 
Subjects with a progression event 
Subjects with no progression 
event 
PARCAT1N 
1 
PARCAT1 
PRIMARY ENDPOINT 
PARAMCD 
PFS 
PARAM 
PROGRESSION FREE SURVIVAL 
AVISITN 
AVISITN 
AVISIT 
AVISIT 
ADT 
min(RSDTC,CMSTDTC1,QSDTC,CMSTDT
C2,DSDTC) 
RSDTC 
AVAL1 
[min(RSDTC,CMSTDTC1,QSDTC,CMSTDT
C2,DSDTC) - Date of randomization) + 1] / 
30.4375 
 
[(date of last assessment - Date of 
randomization) + 1] / 30.4375 
STARTDT 
RANDDT 
CSNR 
0 
1 
EVNTDESC 
- RADIOGRAPHIC DISEASE 
PROGRESSION if ADT = RSDTC 
- UNEQUIVOCAL CLINICAL 
PROGRESSION if ADT in 
(CMSTDTC1,QSDTC,CMSTDTC2) 
- DEATH if ADT = DSDTC 
NO PROGRESSION 
NOTE:  
1 The PFS is defined as the time (in months) from randomization (period 2 week 1) to the 
earliest progression event. 


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10.8
Appendix 8: Key Contributors and Approvers
List of Key Contributors and Approvers
Key Contributors
The following contributed to or reviewed this Statistical Analysis Plan as relevant to their 
indicated discipline or role.
Primary author (s)
 
Contributors and Reviewers
 
Global Data Sciences
Medical Affairs
Author and Approver Signatories 
(E-signatures are attached at end of document) 
Approved by:
PPD
PPD
PPD
PP
D
PPD
PPD
PPD
PPD