PROSPER: A MULTINATIONAL, PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, EFFICACY AND SAFETY STUDY OF ENZALUTAMIDE IN PATIENTS WITH NONMETASTATIC CASTRATION-RESISTANT PROSTATE CANCER
Phase: PHASE3
Conditions: Nonmetastatic Castration-Resistant Prostate Cancer, Prostate Cancer, Cancer of the Prostate
Sponsor: Pfizer

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Medivation, Inc.
Study Title:
PROSPER: A Multinational, Phase 3, Randomized, 
Double-Blind, Placebo-Controlled, Efficacy and 
Safety Study of Enzalutamide in Patients With 
Nonmetastatic Castration-Resistant Prostate Cancer
Protocol Identifier:
MDV3100-14 (C3431005)
Phase:
3
Investigational Product:
Enzalutamide (formerly MDV3100)
Indication:
Prostate Cancer
Sponsor:
Medivation, Inc., a wholly owned subsidiary of 
Pfizer Inc
525 Market Street, 36th Floor
San Francisco, CA 94105
Telephone:+1 (415) 543-3470
Fax:
+1 (415) 543-3411
Medivation and Astellas Pharma Global 
Development, Inc. are in a partnership to codevelop 
enzalutamide for the treatment of cancer
Reference Numbers:
United States 
EudraCT 2012-005665-12
Sponsor Medical Monitor:
 MD, PhD
Telephone:
Email:
Original Protocol:
v1.0 – 29 Mar 2013
Amendment 1:
v2.0 – 16 May 2013
Amendment 2:
v3.0 – 31 May 2017
Amendment 3:
v4.0 – 11 Aug 2017
Amendment 4:
v5 – 26 Jan 2018
This study will be conducted according to the principles of Good Clinical Practice as described in 
International Council for Harmonisation guidelines, including the archiving of essential documents.
PPD
PPD
PPD
CCI

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SYNOPSIS
Title of Study: PROSPER: A Multinational, Phase 3, Randomized, Double-Blind, Placebo-Controlled, Efficacy 
and Safety Study of Enzalutamide in Patients With Nonmetastatic Castration-Resistant Prostate Cancer
Protocol Identifier: MDV3100-14 (C3431005)
Phase of Development: 3
Number of Patients: Approximately 1440 (960 enzalutamide and 480 placebo)
Study Centers: Approximately 250 (global)
Study Objectives:
Primary:

To determine the efficacy of enzalutamide compared with placebo as assessed by metastasis-free survival 
(MFS). 
Secondary:

To evaluate the benefit of enzalutamide compared with placebo as measured by the following:  

Time to prostate-specific antigen (PSA) progression;

Time to first use of new antineoplastic therapy;

Overall survival;

Time to pain progression;

Time to first use of cytotoxic chemotherapy;

Chemotherapy-free disease-specific survival;

Chemotherapy-free survival;

PSA response rates;

Quality of life as assessed by the Functional Assessment of Cancer Therapy-Prostate (FACT-P) 
questionnaire, European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) health questionnaire, and 
Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) module.

To evaluate safety.
OPEN-LABEL PERIOD
As the study met the primary efficacy endpoint of metastatis-free survival and the
established safety profile of enzalutamide was confirmed, all patients will be 
unblinded.  Eligible patients will be offered enzalutamide at the discretion of the 
investigator.  For patients that have not progressed radiographically, scans (CT
(computed tomography)/MRI (magnetic resonance imaging) and bone scan) will 
be performed per investigator discretion until patient has progressed 
radiographically.  Continuation of treatment on the open-label period after 
radiographic progression will be at the discretion of the investigator.  Patients who 
do not participate in the open-label period or withdraw consent for further 
treatment will continue long-term follow-up assessments per protocol.  Treatment 
with open-labeled Enzalutamide will be stopped upon disease progression when in 
the opinion of the Investigator, there is no added clinical benefit to continue 
treatment with Enzalutamide.
Long-term follow-up data (Includes survival status, new antineoplastic therapies 
for prostate cancer, skeletal-related events, and interventions due to locoregional 
progression) will be collected every 16 weeks.

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Day 1 of the open-label period will occur after consent is signed and eligibility is 
verified.  Patients who choose not to continue in the open-label period will 
discontinue treatment and return for safety follow-up within approximately 
30 days after last dose.
Sites must have all open-label day 1 visits completed within 16 weeks after IRB
(Institutional Review Board)/EC (Ethics Committee) approval of this protocol 
amendment. 
Patients who will receive any other treatment for prostate cancer after unblinding
will not be eligible for an open label enzalutamide extension.
The complete details for the conduct of the open-label period are provided in 
Supplement 1: Open-Label Period.  
DOUBLE-BLIND
The completed double-blind protocol remains unchanged.  The double-blind 
period has concluded and the open-label period is ongoing.
Methods: This multinational, phase 3, randomized, double-blind, placebo-controlled, efficacy and safety study 
will evaluate enzalutamide (formerly MDV3100) versus placebo in approximately 1440 men with nonmetastatic 
castration-resistant prostate cancer (CRPC).  All patients will be required to maintain androgen deprivation 
during the study, either using a gonadotropin-releasing hormone (GnRH) agonist/antagonist or having a history 
of bilateral orchiectomy. 
Central randomization to enzalutamide or placebo treatments (2:1) will be stratified by the following factors:  

PSA doubling time (< 6 months vs ≥6 months);

Baseline use of a bone-targeting agent (yes vs no).
Enzalutamide (160 mg/day) will be administered as four 40-mg soft gelatin capsules by mouth once daily with 
or without food.  Placebo capsules, identical in appearance to enzalutamide capsules, will be administered to 
patients in the control arm in the same manner. 
Study drug administration should continue until radiographic progression as specified in the protocol.  
Investigators are discouraged from obtaining PSA assessments at their local laboratories during the study and 
from discontinuing a patient’s study drug treatment due to PSA rise alone.  Initiation of new therapy for prostate 
cancer (with the exception of cytotoxic chemotherapy, androgen receptor inhibitors, and investigational agents) 
at the time of radiographic progression will not mandate discontinuation of study drug if the investigator 
considers continuing study drug to be beneficial.  Patients will continue with Enzalutamide after radiographic 
progression, if continuation of treatment with Enzalutamide seems clinically beneficial.
Initiation of bisphosphonates or other bone-targeting agents for bone health, such as denosumab, is not allowed 
during the study prior to development of bone metastasis; however, treatment with these agents should continue 
if initiated at least 4 weeks before enrollment.  Standard of care supplementation with calcium and vitamin D is 
encouraged. 
The primary efficacy endpoint is MFS assessed by blinded independent central radiology review, defined as the 
time from randomization to radiographic progression or death on study (death within 112 days of treatment 
discontinuation without evidence of radiographic progression), whichever occurs first.  Assessment of bone 
disease will be done by whole-body radionuclide bone scan.  A bone scan will consist of 5 regions including 
skull, thorax, spine, pelvis, and extremities.  Radiographic progression for bone disease is defined as the 
appearance of 1 or more metastatic lesion on bone scan.  When bone lesions are found in a single region on the 
bone scan, confirmation with a second imaging modality (plain film, CT, or MRI) will be required.  Appearance 
of metastatic lesions in 2 or more of the 5 regions on a bone scan will not require confirmation with a second 
imaging modality.  Assessment of soft tissue disease will be done by CT or MRI.  Radiographic progression for 
soft tissue disease is defined by the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) 
(Eisenhauer et al, 2009).1

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All study films should be read locally at the study site and submitted to the central imaging unit for independent 
central radiology review.  Each study site should designate a radiologist or investigator as the primary imaging 
reviewer to ensure that all images are read consistently as specified by the protocol.  Radiographic assessments 
will be approximately every 16 weeks, but images may be obtained sooner if progression is clinically suspected.  
Radiographic imaging will not be required after radiographic progression is confirmed by independent central 
radiology review according to protocol specifications. 
In addition to imaging, the following assessments of prostate cancer status will be made during the course of the 
study:  survival status, pain intensity and interference using the Brief Pain Inventory Short Form (BPI-SF), PSA 
values, and quality of life as assessed by the FACT-P, EQ-5D-5L and QLQ-PR25 questionnaires.  Assessments 
of safety will include adverse events, clinical laboratory tests, physical examinations, and vital signs.  An 
independent Data Monitoring Committee will periodically monitor the safety data. 
Patients will have safety follow-up approximately 30 days after the last dose of study drug. If a new 
antineoplastic treatment is initiated before 30 days after the last dose of study drug, then safety follow-up will 
occur immediately before starting the new treatment.  Long-term follow-up assessments will include monitoring 
for survival status, new antineoplastic therapies for prostate cancer, opiate medications, skeletal-related events, 
and interventions due to locoregional progression (eg, radiation, transurethral resection of the prostate, 
nephrostomy tube placement).  
Study Schematic:
5
17 and repeating
every 16 weeks
Informed 
Consent
Screening
Day -28 to -1
End of 
Treatment
2:1 
Randomization
Stratification
Safety Follow-Up
Day 1
~30 days 
after 
last dose
Long-Term Follow-Up
Double-Blind Treatment
Week
Enzalutamide
Placebo
Enzalutamide or Placebo Daily
Every 
16 weeks
1
Imaging Every 16 Weeks
Key Eligibility Criteria:
The patients to be included in this study must have nonmetastatic CRPC progressing on androgen deprivation 
therapy with no prior or present evidence of metastatic disease as assessed by whole-body radionuclide bone 
scan for bone disease and CT/MRI for soft tissue disease.  Presence of progressive disease will be based on 
rising PSA ≥2 ng/mL (most recent value in a series of at least 3 measurements at ≥1-week intervals).  The 
PSA doubling time must be ≤10 months and testosterone ≤50 ng/dL.  Patients must agree to use androgen 
deprivation therapy with a GnRH agonist/antagonist for the duration of the study or must have had prior 
bilateral orchiectomy.  No prior cytotoxic chemotherapy for prostate cancer is allowed.  Those who received 
prior androgen receptor inhibitor therapy must have progression by rising PSA criteria after withdrawal 
≥4 weeks.  The Eastern Cooperative Oncology Group score must be 0 or 1 and life expectancy ≥12 months.  
Patients with soft tissue pelvic disease may be eligible if lesions do not qualify as target lesions (eg, lymph 
nodes below aortic bifurcation are permissible if the short axis of the largest lymph node is < 15 mm).  

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Test Product, Dose, and Mode of Administration:
Enzalutamide; chemical name 
4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}-2-fluoro-N-m
ethylbenzamide.  Enzalutamide, 160 mg/day, will be administered as four 40-mg soft gelatin capsules by mouth 
once daily with or without food.  
Reference Therapy, Dose and Mode of Administration:
Placebo capsules, identical in appearance to enzalutamide capsules, will be administered in the same manner as 
enzalutamide.  
Duration of Treatment:
Study drug administration should continue until radiographic progression as specified in the protocol.  
Investigators are discouraged from obtaining PSA assessments at their local laboratories during the study and 
from discontinuing a patient’s study drug treatment due to PSA rise alone.  Initiation of new therapy for prostate 
cancer (with the exception of cytotoxic chemotherapy, androgen receptor inhibitors, and investigational agents) 
at the time of radiographic progression will not mandate discontinuation of study drug if the investigator 
considers continuing study drug to be beneficial. Patients will continue with Enzalutamide after radiographic 
progression, if continuation of treatment with Enzalutamide seems clinically beneficial.
Statistical Methods:
The primary efficacy analysis of MFS will be conducted using an intent-to-treat population defined as all 
patients randomly assigned to study treatment.  Randomization will be central and treatment allocation will be 
2:1.  Stratification will be as described in the Methods section.  All efficacy analyses will use the intent-to-treat 
population and incorporate the stratification used at randomization unless otherwise noted.  Patients who are 
randomized and later found to have metastatic disease at enrollment will be censored for time-to-event analyses, 
and those who receive study drug will be included in all safety analyses. 
The single MFS analysis will be performed after approximately 440 MFS events occur.  All secondary 
endpoints will be evaluated for efficacy at this time.  This will include the single analysis of time to PSA 
progression and time to first use of new antineoplastic therapy as well as the first interim analysis of overall 
survival.  Approximately 135 death events are expected at the time of this analysis.  Two additional interim 
analyses and the final analysis of overall survival are planned after approximately 285, 440, and 596 deaths 
occur, respectively.  A multiplicity adjusted inferential procedure will be used to maintain the family-wise 
2-sided type I error rate at 0.05.  No additional analyses of other efficacy endpoints are planned at the time of 
the additional interim and final analyses of overall survival.  If an interim analysis of overall survival is 
statistically significant, it will be reported as the final analysis and no subsequent analyses will be performed. 
Primary Efficacy Endpoint:
The primary efficacy endpoint of MFS is defined as the time from randomization to radiographic progression or 
death on study (death within 112 days of treatment discontinuation without evidence of radiographic 
progression), whichever occurs first.  Assessment of bone and soft tissue disease will be as described in the 
Methods section.  Assessment of images for determination of progression will be made by an independent, 
central, blinded radiology reviewer. 
A stratified log-rank test will be used to compare the treatment groups using a 2-sided test at the 0.05 level of 
significance. 
Secondary Efficacy Endpoints:
The following key secondary endpoints will be tested utilizing methodology to preserve the family-wise 2-sided 
type I error rate at 5%.  This methodology and the secondary endpoints to which it applies will be described in 
detail in the statistical analysis plan.  A stratified log-rank test will be used to compare the treatment groups 
unless otherwise noted. 

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
Time to PSA Progression: Time to PSA progression is defined as the time from randomization to the 
date of the first PSA value demonstrating progression, which is subsequently confirmed.  For patients 
with PSA decline at week 17, the PSA progression date is defined as the date that a ≥25% increase and 
an absolute increase of ≥2 µg/L (2 ng/mL) above the nadir (or baseline for patients with no PSA 
decline by week 17) is documented, which is confirmed by a second consecutive value obtained at 
least 3 weeks later. 

Time to First Use of New Antineoplastic Therapy: Time to first use of new antineoplastic therapy is 
defined as the time from randomization to the first use of new antineoplastic therapy for prostate 
cancer. 

Overall Survival: Overall survival is defined as the time from randomization to death due to any cause. 
Additional secondary endpoints are as follows:

Time to Pain Progression: Pain will be assessed using the BPI-SF.  Pain progression is defined as a 
2-point or more increase from baseline in the question 3 pain score.  Time to this event is defined as 
the time from randomization to onset of pain progression;

Time to First Use of Cytotoxic Chemotherapy: Time to first use of cytotoxic chemotherapy is defined 
as the time from randomization to the first use of cytotoxic chemotherapy for prostate cancer;

Chemotherapy-Free Disease-Specific Survival: Chemotherapy-free disease-specific survival is defined 
as the time from randomization to the first use of cytotoxic chemotherapy for prostate cancer or death 
due to prostate cancer as assessed by the investigator;

Chemotherapy-Free Survival: Chemotherapy-free survival is defined as the time from randomization 
to the first use of cytotoxic chemotherapy for prostate cancer or death due to any cause;

PSA Response: PSA response will be calculated as a decline from baseline in PSA (ng/mL) to the 
maximal PSA response with thresholds at 50% and 90%.  Additionally, PSA response will be assessed 
as a decline to undetectable levels, where undetectable is defined as below the limit of quantification of 
the centrally assessed PSA results.  A PSA response must be confirmed by a second consecutive value 
at least 3 weeks later.  A stratified Cochran-Mantel-Haenszel mean score test will be used to compare 
response rates between treatment groups;

Quality of Life as Assessed by the FACT-P questionnaire, EQ-5D-5L Health Questionnaire, and 
QLQ-PR25 Module: FACT-P, EQ-5D-5L, and QLQ-PR25 quality-of-life data will be summarized 
descriptively by study visit. 
Safety analyses will include all patients who receive 1 dose or partial dose of study drug (safety population). 
Safety will be evaluated by the frequency of serious adverse events, frequency and severity of adverse events, 
frequency of study drug discontinuation due to adverse events, and frequency of new clinically significant 
changes in clinical laboratory values and vital signs. 
All adverse events will be coded to preferred term and system organ class using the Medical Dictionary for 
Regulatory Activities (MedDRA).  The number and percentage of patients with adverse events will be presented 
by MedDRA system organ class and preferred term, relationship to study treatment, and severity.  Descriptive 
statistics will be used. 

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Central laboratory values will be classified for severity using the National Cancer Institute Common 
Terminology Criteria for Adverse Events (CTCAE), version 4.  Descriptive statistics will be used to analyze the 
laboratory data.  
Sample Size Considerations:
The following assumptions were used in determining the sample size for the MFS endpoint:

2:1 enzalutamide to placebo treatment allocation;

Target hazard ratio of 0.72 at the 5% significance level with 90% power.  The targeted difference in 
Kaplan-Meier estimated medians is 9 months (24 months vs 33 months).  The median MFS of 
24 months for the placebo arm is based on published data from a similar clinical trial (Nelson et al, 
2008).2
A minimum of 440 events provides 90% power to detect a target hazard ratio of 0.72 based on a 2-sided 
log-rank test at an overall significance level of 0.05.  A sample size of approximately 1305 patients will achieve 
440 MFS events within approximately 43 months.  It is assumed that a number of patients will be lost to 
follow-up, will be found to have metastatic disease at enrollment, or will have events censored due to required 
analytical methods.  To account for this anticipated loss in contribution of events to the primary and secondary 
endpoint analyses, an additional 135 patients (approximately 10% of 1305) will be enrolled to achieve a final 
sample size of 1440 patients (960 enzalutamide and 480 placebo).

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TABLE OF CONTENTS
SYNOPSIS.................................................................................................................................3
LIST OF TABLES...................................................................................................................13
LIST OF FIGURES .................................................................................................................13
APPENDICES .........................................................................................................................14
LIST OF ABBREVIATIONS AND TERMS..........................................................................15
1. INTRODUCTION ...............................................................................................................16
1.1. Background .............................................................................................................16
1.2. Summary of Relevant Clinical Experience With Enzalutamide.............................16
1.2.1. Pharmacokinetics and Drug Metabolism....................................................19
1.3. Summary of Relevant Nonclinical Experience With Enzalutamide.......................20
1.4. Enzalutamide Benefits and Risks Assessment........................................................21
2. STUDY OBJECTIVES........................................................................................................22
2.1. Primary Objective ...................................................................................................22
2.2. Secondary Objectives..............................................................................................22
3. INVESTIGATIONAL PLAN..............................................................................................23
3.1. Overall Study Design and Plan:  Description..........................................................23
3.2. Study Schematic......................................................................................................25
3.3. Blinding...................................................................................................................25
3.4. Duration of Study....................................................................................................25
3.5. Discussion of Study Design, Including Choice of Control Group..........................25
4. SELECTION OF STUDY POPULATION .........................................................................26
4.1. Inclusion Criteria.....................................................................................................26
4.2. Exclusion Criteria....................................................................................................27
5. ENROLLMENT AND STUDY PROCEDURES ...............................................................29
5.1. Screening Period .....................................................................................................29
5.1.1. Screening Identification Numbers..............................................................29
5.1.2. Screening Visit Procedures.........................................................................29
5.2. Treatment Period.....................................................................................................31
5.2.1. Visit Windows ............................................................................................31
5.2.2. Day 1 (Randomization)...............................................................................32
5.2.3. Treatment Guidelines..................................................................................33

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5.2.4. Week 5........................................................................................................33
5.2.5. Week 17 and Repeating Every 16 Weeks...................................................34
5.2.6. Unscheduled Visits.....................................................................................36
5.3. Permanent Treatment Discontinuation....................................................................36
5.4. Follow-Up After Permanent Treatment Discontinuation........................................38
5.4.1. Safety Follow-Up........................................................................................38
5.4.2. Long-Term Follow-Up ...............................................................................39
5.5. Loss to Follow-Up...................................................................................................40
6. INVESTIGATIONAL PRODUCT INFORMATION.........................................................40
6.1. General Information ................................................................................................40
6.2. Enzalutamide Product Characteristics.....................................................................40
6.2.1. Packaging....................................................................................................40
6.2.2. Storage........................................................................................................40
6.2.3. Directions for Administration.....................................................................40
6.2.4. Directions for Dose Modification...............................................................41
6.2.5. Treatment Compliance................................................................................41
7. PRIOR AND CONCOMITANT THERAPY......................................................................41
7.1. Prior Therapy...........................................................................................................41
7.2. Concomitant Therapy..............................................................................................41
7.3. Effects of Enzalutamide on Exposure to Other Drugs ............................................42
7.4. Drugs That May Affect Exposure to Enzalutamide................................................42
7.4.1. Drugs That Inhibit or Induce CYP2C8.......................................................42
7.4.2. Drugs That Induce CYP3A4.......................................................................43
7.5. Precautions Regarding Concomitant Medications ..................................................43
8. ADVERSE EVENT REPORTING......................................................................................43
8.1. Requirements...........................................................................................................44
8.1.1. Additional Details On Recording Adverse Events on the CRF..................45
8.1.2. Eliciting Adverse Event Information..........................................................45
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the 
Subject Withdrawal section)............................................................................45
8.1.4. Time Period for Collecting AE/SAE Information......................................45
8.1.4.1. Reporting SAEs to Pfizer Safety...............................................46

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8.1.4.2. Recording Non-serious AEs and SAEs on the CRF .................46
8.1.5. Causality Assessment .................................................................................46
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ..................47
8.2. Special Safety Considerations.................................................................................47
8.2.1. Study Drug Dose Modification Due to Adverse Event ..............................47
8.2.2. Emergency Procedure for Unblinding Treatment Assignment Due to 
Adverse Event..................................................................................................47
8.2.3. Contraception..............................................................................................47
8.3. Definitions...............................................................................................................48
8.3.1. Adverse Events...........................................................................................48
8.3.2. Abnormal Test Findings .............................................................................49
8.3.3. Serious Adverse Events ..............................................................................49
8.3.4. Hospitalization............................................................................................50
8.4. Severity Assessment................................................................................................51
8.5. Special Situations ....................................................................................................52
8.5.1. Protocol- Specified Serious Adverse Events..............................................52
8.5.2. Potential Cases of Drug-Induced Liver Injury............................................52
8.5.3. Exposure to the Investigational Product During Pregnancy of 
Breastfeeding and Occupational Exposure......................................................53
8.5.3.1. Exposure During Pregnancy......................................................54
8.5.3.2. Exposure During Breastfeeding ................................................55
8.5.3.3. Occupational Exposure .............................................................55
8.5.4. Medical Errors and Lack of Efficacy..........................................................56
8.5.4.1. Medication Errors......................................................................56
8.5.4.2. Lack of Efficacy........................................................................57
8.6. Clinical Laboratory Safety Tests.............................................................................57
8.6.1. Estimated Blood Volume............................................................................58
8.7. Physical Examinations, Vital Signs, and Electrocardiograms ................................58
9. ASSESSMENT OF EFFICACY AND SAFETY VARIABLES ........................................58
9.1. Assessment of Efficacy ...........................................................................................58
9.1.1. Assessments for the Primary Efficacy Endpoint ........................................58
9.1.1.1. Determination of Bone Metastasis ............................................59
9.1.1.2. Determination of Soft Tissue Metastasis ..................................59

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9.1.2. Assessments for the Secondary Efficacy Endpoints...................................59
9.1.2.1. Assessment of Survival .............................................................59
9.1.2.2. Assessment of Pain Progression................................................59
9.1.2.3. Assessment of New Cytotoxic Chemotherapy Use...................59
9.1.2.4. Assessment of New Antineoplastic Therapy Use .....................60
9.1.2.5. Assessment of PSA ...................................................................60
9.1.2.6. Assessment of Quality of Life...................................................60
9.2. Assessment of Safety ..............................................................................................61
10. STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION........................61
10.1. Statistical and Analytical Plans.............................................................................61
10.2. Analysis Populations.............................................................................................61
10.3. Efficacy Analyses..................................................................................................61
10.3.1. Primary Efficacy Endpoint Analysis:  Metastasis-Free Survival .............62
10.3.2. Key Secondary Efficacy Endpoint Analyses............................................62
10.3.2.1. Time to PSA Progression ........................................................64
10.3.2.2. Time to First Use of New Antineoplastic Therapy .................64
10.3.2.3. Overall Survival ......................................................................64
10.3.3. Additional Secondary Endpoint Analyses................................................65
10.3.3.1. Time to Pain Progression ........................................................65
10.3.3.2. Time to First Use of Cytotoxic Chemotherapy.......................66
10.3.3.3. Chemotherapy-Free Disease-Specific Survival.......................66
10.3.3.4. Chemotherapy-Free Survival ..................................................66
10.3.3.5. PSA Response .........................................................................66
10.3.3.6. Quality of Life.........................................................................66
10.4. Safety Analyses.....................................................................................................66
10.5. Other Analyses ......................................................................................................67
10.6. Determination of Sample Size...............................................................................67
11. STUDY COMMITTEES AND COMMUNICATIONS ...................................................68
12. LABORATORY REQUIREMENTS ................................................................................68
13. INVESTIGATOR AND ADMINISTRATIVE REQUIREMENTS .................................68
13.1. Ethics.....................................................................................................................69
13.1.1. Ethics Committee......................................................................................69

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13.1.2. Ethical Conduct of the Study....................................................................69
13.1.3. Patient Information and Informed Consent ..............................................69
13.1.4. Maintaining Patient Confidentiality .........................................................70
13.2. Data Quality Assurance.........................................................................................70
13.2.1. Data Management.....................................................................................70
13.2.2. Case Report Forms ...................................................................................70
13.2.3. Study Monitoring......................................................................................70
13.2.4. Study Audits .............................................................................................71
13.3. Investigational Product Accountability.................................................................71
13.4. Compensation, Insurance, and Indemnity.............................................................72
13.5. Retention of Records.............................................................................................72
13.6. Study Termination.................................................................................................73
14. USE OF STUDY INFORMATION AND PUBLICATION .............................................73
15. REFERENCES ..................................................................................................................74
16. INVESTIGATOR SIGNATURE.......................................................................................75
LIST OF TABLES
Table 1.
Screening Procedures............................................................................................30
Table 2.
Day 1 Procedures..................................................................................................33
Table 3.
Week 5 Procedures ...............................................................................................34
Table 4.
Week 17 and Repeating Every 16 Weeks Procedures..........................................35
Table 5.
Primary Reasons for Permanent Treatment Discontinuation ...............................37
Table 6.
Safety Follow Up Procedures ...............................................................................38
Table 7.
Long Term Follow up Procedures ........................................................................39
Table 8.
Criteria for Determining Causal Relationship to Study Drug ..............................46
Table 9.
Criteria for Determining the Severity (Intensity) of an Adverse Event................51
Table 10.
Clinical Laboratory Safety Tests ..........................................................................57
Table 11.
Type I Error Spending for the Overall Survival Analyses ...................................65
LIST OF FIGURES
Figure 1:
Study Schematic ...................................................................................................25
Figure 2:
Testing Strategy for Primary and Key Secondary Endpoints...............................63

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APPENDICES
Appendix 1. Brief Pain Inventory (Short Form)......................................................................76
Appendix 2. Functional Assessment of Cancer Therapy - Prostate.........................................78
Appendix 3. European Quality of Life-5 Dimensions-5 Levels Health Questionnaire...........81
Appendix 4. European Organization for Research and Treatment of Cancer Quality of 
Life Questionnaire Prostate Disease Module: QLQ-PR25...................................83
Appendix 5. Study Schedule of Activities...............................................................................86

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LIST OF ABBREVIATIONS AND TERMS
Abbreviation
Definition
AE
Adverse Event
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC
Area under the curve
AUC0-∞
Area under the curve from time zero to infinity
BPI-SF
Brief Pain Inventory Short Form
CFR
Code of Federal Regulations
CI
Confidence interval
CK
Cmax
Maximum plasma concentration
Ctrough
Predose trough plasma concentration
CRPC
Castration-resistant prostate cancer
CRF
Case Report Form
CT
Computed tomography
CT
Clinical Trial
CTCAE
Common Terminology Criteria for Adverse Events
CYP
Cytochrome P450
DILI
drug induced liver injury
EC
Ethics committee (global term including institutional review boards, independent 
ethics committees, research ethics committees, and the like) 
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDP
Exposure during pregnancy
EORTC
European Organization for Research and Treatment of Cancer
EQ-5D-5L
European Quality of Life-5 Dimensions-5 Levels health questionnaire
FACT-P
Functional Assessment of Cancer Therapy-Prostate
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GGT
Gamma Glutamyl Transferase
GnRH
Gonadotropin-releasing hormone
ICH
International Council for Harmonisation
ID
Identification
INR
International normalized ratio
IRB
Institutional Review Board
IXRS
Interactive voice / web recognition system
MedDRA
Medical Dictionary for Regulatory Activities
MFS
Metastasis-free survival
MRI
Magnetic resonance imaging
PFS
Progression-free survival
PK
Pharmacokinetic
PRES
Posterior reversible encephalopathy syndrome
PSA
Prostate-specific antigen
QLQ-PR25
Quality of Life Questionnaire-Prostate 25 module
RECIST 1.1
Response Evaluation Criteria in Solid Tumors, version 1.1
SAE
Serious Adverse Even
SUSAR
Suspected unexpected serious adverse reaction
TBili
Total bilirubin
ULN
Upper limit of normal
US
United States

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1. INTRODUCTION
1.1. Background
Prostate cancer progresses through a series of characteristic clinical states that reflect both 
the natural history of the disease and response to treatment.3 Following the initial evaluation 
and diagnosis of prostate cancer, approximately 90% of men undergo primary localized 
treatment with curative intent.4 After initiation of androgen deprivation therapy in men with 
rising prostate-specific antigen (PSA) after primary therapy, the next clinical state in the 
current model of prostate cancer progression is that of castration-resistant prostate cancer 
(CRPC), defined as progression despite castrate hormone levels (testosterone ≤50 ng/dL).  
CRPC is present in 10% to 20% of all men with prostate cancer, and is associated with a high 
risk of bone metastases, bone pain, pathologic fractures, spinal cord compression, decreased 
quality of life, and death from prostate cancer. 
PSA doubling time and baseline PSA are useful for identifying the subset of men who are at 
high risk for morbidity and mortality from CRPC.  For example, an analysis of 201 patients 
with nonmetastatic CRPC randomized to the placebo arm in an aborted randomized
controlled trial of zoledronic acid showed that PSA doubling time and baseline PSA 
independently predicted risk of time to first bone metastases, overall survival, and 
metastasis-free survival (MFS).5 The relative risk of a shorter time to first bone metastases 
for patients with a PSA greater than 10 ng/mL was 3.18 (95% confidence interval 
[CI]: 1.74, 5.8) and the relative risk for a 0.01 increase in PSA velocity was 4.34 (95% CI: 
2.30, 8.21). 
Currently, although continued use of androgen deprivation therapy is part of clinical practice, 
no medicine is approved for treatment of patients with nonmetastatic CRPC or for prevention 
of metastasis, and the results of several studies designed to address these needs have been 
disappointing.2,5,6,7 Therefore, no standard of care is defined for nonmetastatic CRPC and 
accordingly, patients are encouraged to participate in clinical trials.8
The androgen receptor remains the main driver of prostate cancer progression in CRPC.  
Enzalutamide is a potent androgen receptor inhibitor that significantly prolonged overall 
survival in men with metastatic CRPC previously treated with docetaxel.9 Patients with 
nonmetastatic CRPC at high risk for metastatic disease may therefore also derive significant 
benefit from treatment with enzalutamide.  The phase 3 study described herein is designed to 
address this unmet medical need. 
1.2. Summary of Relevant Clinical Experience With Enzalutamide
The United States (US) Food and Drug Administration (FDA) first approved Xtandi 
(enzalutamide) capsules in August 2012 based on a benefit in overall survival for men with 
metastatic CRPC who previously received docetaxel therapy.9

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The current enzalutamide investigator brochure provides the most up-to-date information on 
clinical studies evaluating enzalutamide in men with prostate cancer.  The key clinical studies 
evaluating enzalutamide in men with prostate cancer are described briefly as follows:
S-3100-1-01: The pharmacokinetics (PK), tolerability, and antitumor activity of 
enzalutamide (then known as MDV3100) were first studied in a multicenter, open-label, 
first-in-human, dose-escalation study in 140 patients with CRPC.10 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 the safety and efficacy 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. 
CRPC2 (AFFIRM): A 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.9 The primary endpoint was overall 
survival.  The first FDA approval of enzalutamide was based on the results of this study. 
MDV3100-03 (PREVAIL): A multinational, phase 3, randomized, double-blind, 
placebo-controlled, efficacy and safety study of enzalutamide in chemotherapy-naïve 
patients with progressive metastatic after failure of androgen deprivation therapy was 
conducted in 1717 men, 871 of whom received treatment with enzalutamide.  The 
coprimary endpoints were overall survival 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 PFS in 
patients treated with enzalutamide versus placebo.  Enzalutamide treatment resulted in 
prolongation of overall survival (hazard ratio 0.71 [95% CI: 0.60, 0.84]; p < 0.0001) and 
radiographic PFS (hazard ratio 0.19 [95% CI: 0.15, 0.23]; p < 0.0001).  Results of an 
updated survival analysis performed when 784 deaths were observed was consistent 
with the interim analysis (hazard ratio 0.77 [95% CI: 0.67, 0.88]). 
9785-CL-0222 (TERRAIN): A phase 2, randomized, bicalutamide-controlled efficacy 
and safety study in 375 patients with chemotherapy-naïve metastatic CRPC.  Patients 
were randomized to enzalutamide or bicalutamide.  A significant improvement in 
radiographic PFS was demonstrated in patients treated with enzalutamide versus 
bicalutamide with an observed hazard ratio of 0.60 (95% CI:  0.43, 0.83). 
MDV3100-09 (STRIVE): A phase 2, randomized, bicalutamide-controlled efficacy and 
safety study in 396 patients with chemotherapy-naïve metastatic (N = 257) or 
nonmetastatic (N = 139) CRPC.  Patients were randomized to enzalutamide or 
bicalutamide.  A significant improvement in radiographic PFS was demonstrated in the 
overall population with an observed hazard ratio of 0.30 (95% CI: 0.21, 0.44) and in the 
nonmetastatic subgroup with an observed hazard ratio of 0.24 (95% CI:  0.10, 0.56). 

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Across these studies, clinically meaningful and statistically significant improvements were 
demonstrated for the secondary endpoints.  In the CRPC2 and MDV3100-03 studies 
comparing enzalutamide versus placebo, enzalutamide treatment was associated with a delay 
in median time to PSA progression of 5.4 months (8.3 months enzalutamide vs 2.9 months 
placebo; hazard ratio 0.25 [95% CI: 0.20, 0.30]) and 8.4 months (11.2 vs 2.8 months; hazard 
ratio 0.17 [95% CI: 0.15, 0.20]), respectively.  In MDV3100-03, enzalutamide treatment was 
also associated with a delay of 17.2 months in median time to initiation of a subsequent 
cytotoxic chemotherapy (28.0 vs 10.8 months; hazard ratio 0.35 [95% CI: 0.30, 0.40]) and a 
delay of 15.4 months in median time to first postbaseline use of any antineoplastic therapy 
(cytotoxic, hormonal, or investigational) (22.8 vs 7.4 months; hazard ratio 0.27 [95% CI: 
0.24, 0.31]).
Enzalutamide treatment was also associated with a statistically significant reduction in the 
risk of PSA progression compared with bicalutamide treatment.  In 9785-CL-0222, the delay 
in median time to PSA progression was 13.6 months (19.4 months enzalutamide vs 
5.8 months bicalutamide; hazard ratio 0.28 [95% CI: 0.20, 0.39]).  In MDV3100-09, the 
median time to PSA progression was not reached in the enzalutamide group versus a median 
of 8.3 months in the bicalutamide group (hazard ratio 0.19 [95% CI: 0.14, 0.26]) for the 
overall population.  In the metastatic subgroup, the delay in median time to PSA progression 
was 19.2 months (24.9 months enzalutamide vs 5.7 months bicalutamide; hazard ratio 
0.19 [95% CI: 0.13, 0.28]).  In the nonmetastatic subgroup, time to PFS progression was not 
reached in the enzalutamide group versus a median of 11.1 months in the bicalutamide group 
(hazard ratio 0.18 [95% CI: 0.10, 0.34]). 
Medivation and Astellas Pharma Global Development, Inc. are in a partnership to codevelop 
enzalutamide for the treatment of cancer. 
More than 10,000 subjects and patients have been enrolled and treated worldwide in 
completed and ongoing clinical trials evaluating enzalutamide.  The current enzalutamide 
investigator brochure provides the most up to date information on enzalutamide exposure. 
The most common adverse reactions (10%) that occurred more commonly (2% over 
placebo) in enzalutamide-treated patients from the 2 phase 3, randomized, placebo-controlled 
clinical studies (CRPC2, MDV3100-03) were asthenia/fatigue, back pain, decreased appetite, 
constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral 
edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and 
dizziness/vertigo. 
In clinical studies, seizure occurred in 0.5% of patients receiving enzalutamide.  Because of 
the risk of seizure associated with enzalutamide use, patients should be advised of the risk of 
engaging in any activity where sudden loss of consciousness could cause serious harm to 
themselves or others.  Enzalutamide should be permanently discontinued in patients who 
develop a seizure during treatment.  Posterior reversible encephalopathy syndrome (PRES), 
a neurologic disorder that can present with rapidly evolving symptoms including seizure, 
headache, lethargy, confusion, blindness, and other visual and neurologic disturbances, with 
or without associated hypertension, has been reported in patients receiving enzalutamide in 

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the postmarketing setting.  Enzalutamide should be permanently discontinued in patients who 
develop PRES during treatment. 
Additional information on the clinical experience with enzalutamide is provided in the 
enzalutamide investigator brochure. 
1.2.1. Pharmacokinetics and Drug Metabolism
The current enzalutamide investigator brochure provides the most up to date information on 
enzalutamide PK 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 postdose.  No 
major deviations from dose proportionality were observed over the dose range 30 mg to 
600 mg.  Due to the long terminal half-life (approximately 5.8 days), it took approximately 
1 month to reach steady state.  With daily oral administration, enzalutamide accumulation 
was observed at steady state with an 8.3-fold higher exposure (steady-state area under the 
curve, AUC) relative to a single dose.  Based on the mean peak-to-trough ratio, the average 
difference between the peak (maximum plasma concentration, Cmax) and trough (predose 
plasma concentration, Ctrough) concentrations was ≤25%.  As a result of the low daily 
fluctuations, plasma profiles at steady state resembled a constant infusion.  The Ctrough values 
in individual patients remained constant beyond day 28 of chronic therapy, suggesting 
time-linear PK once steady state was achieved.  At steady state, 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 cytochrome P450 (CYP) 2C8, 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 (Section 7.3).  Substrates of CYP3A4, CYP2C9, and CYP2C19 with 
a narrow therapeutic index should be avoided if 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). 
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 if 
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 

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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 (Section 7.4).
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 (Section 7.4). 
Additional information on the PK and drug metabolism of enzalutamide is provided in the 
enzalutamide investigator brochure. 
1.3. Summary of Relevant Nonclinical Experience With Enzalutamide
The current enzalutamide investigator brochure provides the most up to date nonclinical 
information on enzalutamide.  A complete assessment of toxicity has been conducted with 
enzalutamide, including evaluation of impurities.  The toxicity program was designed to 
support treatment of men with CRPC and included acute (single-dose) and repeat-dose (up to 
26 weeks duration in rats, 13 weeks in dogs) oral toxicity studies, genotoxicity studies, safety 
pharmacology studies, specific assessment of the effects on and recovery of the male 
reproductive system in dogs, and studies to determine the phototoxicity potential.  The 
species included in the toxicity program were mice, rats, dogs, and cynomolgus monkeys.  
Toxicokinetic evaluations demonstrated that all of these species produce the 2 major human 
metabolites of enzalutamide, N-desmethyl enzalutamide and an inactive carboxylic acid 
derivative. 
The toxicology studies tested enzalutamide formulated in Labrasol, the same excipient used 
in clinical studies and in the commercial product marketed for CRPC. 
Long-term animal studies are being conducted to evaluate the carcinogenic potential of 
enzalutamide. 
Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and 
was not genotoxic in either the in vitro cytogenetic assay with mouse lymphoma thymidine 
kinase gene mutation or the in vivo mouse micronucleus assay. 
Based on nonclinical findings in repeat-dose toxicology studies, which were consistent with 
the pharmacologic activity of enzalutamide, male fertility may be impaired by treatment with 
enzalutamide.  In a 26-week study in rats, atrophy of the prostate and seminal vesicles was 
observed at ≥30 mg/kg/day (equal to the human exposure based on AUC).  In 4-week and 
13-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides 
were observed at ≥4 mg/kg/day (0.3 times the human exposure based on AUC). 

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Additional toxicology studies are ongoing and planned.  Additional information on the 
nonclinical experience with enzalutamide is provided in the enzalutamide investigator 
brochure. 
1.4. Enzalutamide Benefits and Risks Assessment
The current enzalutamide investigator brochure provides the most up to date information on 
the benefits and risks of enzalutamide treatment.  As stated in Section 1.2, more than 
10,000 subjects and patients have been enrolled and treated worldwide in completed and 
ongoing clinical trials evaluating enzalutamide. 
In the randomized, placebo-controlled phase 3 study CRPC2 (AFFIRM), the prespecified 
interim analysis at the time of 520 events demonstrated a statistically significant 
improvement in overall survival in patients with metastatic CRPC treated with enzalutamide 
versus placebo (hazard ratio = 0.631; 95% CI: 0.529, 0.752, p < 0.0001).9 The median 
survival was 18.4 months in the enzalutamide arm and 13.6 months in the placebo arm 
(Δ = 4.8 months).  The overall survival benefit was consistent across all subgroups, including 
age, baseline pain intensity, geographic region, and type of disease progression at entry.  
Enzalutamide treatment was superior to placebo for all secondary endpoints including the 
proportion of patients with a reduction in PSA level by 50% or more (54% vs 2%, p < 0.001), 
soft tissue response rate (29% vs 4%, p < 0.001), quality-of-life response rate (43% vs 18%, 
p < 0.001), time to PSA progression (8.3 vs 3.0 months; hazard ratio 0.25, p < 0.001), 
radiographic PFS (8.3 vs 2.9 months; hazard ratio 0.40, p < 0.001), and time to first 
skeletal-related event (16.7 vs 13.3 months; hazard ratio 0.69, p < 0.001).  Based on the 
AFFIRM data, the US FDA approved enzalutamide in August 2012 for men with metastatic 
CRPC who previously received docetaxel therapy. 
In the pivotal phase 3 study MDV3100-03 in patients with chemotherapy-naïve metastatic 
CRPC, the prespecified interim analysis at the time of 540 death events demonstrated 
statistically significant improvements in overall survival and radiographic PFS in patients 
treated with enzalutamide versus placebo.  Data from this study resulted in a label extension 
for enzalutamide to include all patients with metastatic CRPC. 
In the phase 2 study 9785-CL-0222, which was also conducted in patients with 
chemotherapy-naïve metastatic CRPC, patients were randomized to enzalutamide or 
bicalutamide.  A significant improvement in radiographic PFS was demonstrated in patients 
treated with enzalutamide versus bicalutamide with an observed hazard ratio of 
0.60 (95% CI:  0.43, 0.83).  In the phase 2 study MDV3100-09, patients with 
chemotherapy-naïve metastatic or nonmetastatic CRPC were randomized to enzalutamide or 
bicalutamide.  A significant improvement in radiographic PFS was demonstrated in the 
overall population with an observed hazard ratio of 0.30 (95% CI: 0.21, 0.44) and in the 
nonmetastatic subgroup with an observed hazard ratio of 0.24 (95% CI: 0.10, 0.56). 
In the 2 phase 3, randomized, placebo-controlled studies (CRPC2, MDV3100-03), the most 
common adverse reactions (≥10%) that occurred more commonly (≥2% over placebo) in 
enzalutamide-treated patients were asthenia/fatigue, back pain, decreased appetite, 
constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral 

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edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and 
dizziness/vertigo.  The important identified risks for enzalutamide, identified as important 
adverse events for which there is adequate evidence of a causal association with 
enzalutamide, include seizure, PRES, hypertension, fall, nonpathological fracture, neutrophil 
count decreased, and cognitive/memory impairment.  Additionally, the important identified 
interactions associated with enzalutamide treatment include interactions with strong 
inhibitors or inducers of CYP2C8 and interactions with medicinal products that are substrates 
of CYP3A4, CYP2C9, or CYP2C19. 
The totality of the efficacy and safety data suggests a positive benefit-risk assessment for the
use of enzalutamide in men with CRPC, and for the continued investigation of enzalutamide 
in men with earlier stage prostate cancer. 
2. STUDY OBJECTIVES
2.1. Primary Objective
The primary objective is to determine the efficacy of enzalutamide compared with placebo as 
assessed by MFS. 
2.2. Secondary Objectives

To evaluate the benefit of enzalutamide compared with placebo as measured by the 
following: 

Time to PSA progression;

Time to first use of new antineoplastic therapy;

Overall survival;

Time to pain progression;

Time to first use of cytotoxic chemotherapy;

Chemotherapy-free disease-specific survival;

Chemotherapy-free survival;

PSA response rates;

Quality of life as assessed by the Functional Assessment of Cancer 
Therapy-Prostate (FACT-P) questionnaire, European Quality of 
Life-5 Dimensions-5 Levels (EQ-5D-5L) health questionnaire, and Quality of 
Life Questionnaire-Prostate 25 (QLQ-PR25) module.

To evaluate safety.

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3. INVESTIGATIONAL PLAN
3.1. Overall Study Design and Plan:Description
This multinational, phase 3, randomized, double-blind, placebo-controlled, efficacy and 
safety study will assess the efficacy and safety of enzalutamide versus placebo in 
approximately 1440 men with nonmetastatic CRPC at approximately 250 study centers.  
All patients will be required to maintain androgen deprivation during the study, either using a 
gonadotropin-releasing hormone (GnRH) agonist/antagonist or having a history of bilateral 
orchiectomy. 
Central randomization to enzalutamide or placebo treatments (2:1) will be stratified by the 
following factors: 

PSA doubling time (< 6 months vs 6 months);

Baseline use of a bone-targeting agent (yes vs no).
Enzalutamide (160 mg/day) will be administered as four 40-mg soft gelatin capsules by 
mouth once daily with or without food.  Placebo capsules, identical in appearance to 
enzalutamide capsules, will be administered to patients in the control arm in the same 
manner. 
Study drug administration should continue until radiographic progression.  Investigators are 
discouraged from obtaining PSA assessments at their local laboratories during the study and 
from discontinuing a patient’s study drug treatment due to PSA rise alone.  Initiation of new 
therapy for prostate cancer (with the exception of cytotoxic chemotherapy, androgen receptor 
inhibitors, and investigational agents) at the time of radiographic progression will not 
mandate discontinuation of study drug if the investigator considers continuing study drug to 
be beneficial.  Patients will continue with Enzalutamide after radiographic progression, if 
continuation of treatment with Enzalutamide seems clinically beneficial.  Prostate cancer is a 
multiclonal disease, and a patient with confirmed disease progression may have other 
clones/foci that may benefit from continued treatment with study drug.  In the ongoing, 
blinded, phase 3 PREVAIL study, approximately 34 of 1715 treated patients (2%) received 
study drug and antiandrogen or abiraterone after radiographic disease progression. 
Initiation of bisphosphonates or other bone-targeting agents for bone health, such as 
denosumab, is not allowed during the study prior to development of bone metastasis; 
however, treatment with these agents should continue if initiated at least 4 weeks before 
enrollment.  Standard of care supplementation with calcium and vitamin D is encouraged. 
The primary efficacy endpoint is MFS assessed by blinded independent central radiology 
review, defined as the time from randomization to radiographic progression or death on study 
(death within 112 days of treatment discontinuation without evidence of radiographic 
progression), whichever occurs first.  Assessment of bone disease will be done by 
whole-body radionuclide bone scan.  A bone scan will consist of 5 regions including skull, 
thorax, spine, pelvis, and extremities.  Radiographic progression for bone disease is defined 
as the appearance of 1 or more metastatic lesion on bone scan.  Confirmation with a second 

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imaging modality (plain film, computed tomography [CT], or magnetic resonance imaging 
[MRI]) will be required when bone lesions are found in a single region on the bone scan.  
Appearance of metastatic lesions in 2 or more of the 5 regions on a bone scan will not require 
confirmation with a second imaging modality.  Assessment of soft tissue disease will be done 
by CT or MRI.  Radiographic progression for soft tissue disease is defined by the Response 
Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1).1
All study films should be read locally at the study site and submitted to the central imaging 
unit for independent central radiology review.  Each study site should designate a radiologist 
or investigator as the primary imaging reviewer to ensure that all images are read consistently 
as specified in Section 9.1.  Radiographic assessments will be approximately every 16 weeks, 
but images may be obtained sooner if progression is clinically suspected.  Radiographic 
imaging will not be required after radiographic progression is confirmed by independent 
central radiology review according to protocol specifications. 
In addition to imaging, the following assessments of prostate cancer status will be made 
during the course of the study: survival status, pain intensity and interference using the Brief 
Pain Inventory Short Form (BPI-SF) (Appendix 1), PSA values, and quality of life as 
assessed by the FACT-P (Appendix 2), EQ-5D-5L (Appendix 3), and 
QLQ-PR25 (Appendix 4) questionnaires.  Assessments of safety will include adverse events, 
clinical laboratory tests, physical examinations, and vital signs.  An independent Data 
Monitoring Committee will periodically monitor the safety data. 
Patients will have safety follow-up approximately 30 days after the last dose of study drug.  
If a new antineoplastic treatment is initiated before 30 days after the last dose of study drug, 
then safety follow-up will occur immediately before starting the new treatment.  Long-term 
follow-up assessments will include monitoring for survival status, new antineoplastic 
therapies for prostate cancer, opiate medications, skeletal-related events, and interventions 
due to locoregional progression (eg, radiation, transurethral resection of the prostate, 
nephrostomy tube placement). 
As the study met the primary efficacy endpoint of metastatis-free survival and the established 
safety profile of enzalutamide was confirmed, all patients will be unblinded.  The complete 
details for the conduct of the open-label period are provided in Supplement 1: Open-Label 
Period. 

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3.2. Study Schematic
Figure 1:
Study Schematic
5
17 and repeating
every 16 weeks
Informed 
Consent
Screening
Day -28 to -1
End of 
Treatment
2:1 
Randomization
Stratification
Safety Follow-Up
Day 1
~30 days 
after 
last dose
Long-Term Follow-Up
Double-Blind Treatment
Week
Enzalutamide
Placebo
Enzalutamide or Placebo Daily
Every 
16 weeks
1
Imaging Every 16 Weeks
3.3. Blinding
All patients, study site personnel (including investigators), and sponsor staff and its 
representatives will be blinded to treatment assignment. 
The blinded control for this study will be placebo capsules (placebo) identical in appearance 
to the enzalutamide capsules. 
The procedure for breaking the blind in an emergency is provided in Section 8.2.2. 
3.4. Duration of Study 
The total duration of this study will be determined at the patient level and will depend on 
individual response to treatment.  Patients are expected to receive study treatment until 
radiographic progression as specified in the protocol, have a safety follow-up visit, and then 
have long-term follow-up until the patient dies. 
The primary analysis of MFS will be performed when approximately 440 MFS events based 
on independent central radiology review are observed. 
3.5. Discussion of Study Design, Including Choice of Control Group
This study is designed to demonstrate the efficacy and safety of enzalutamide in the 
treatment of patients with nonmetastatic CRPC.  The primary efficacy endpoint is MFS. 
Androgen deprivation therapy will be continued for all patients on study as its use is common 
in clinical practice for the treatment of patients with CRPC.  Enzalutamide at a dose of 
160 mg/day will be compared with placebo.  A placebo-controlled trial is considered 
appropriate and ethical because there is no approved or standard treatment for patients with 
nonmetastatic CRPC.

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An independent Data Monitoring Committee will be used for safety oversight in this study. 
4. SELECTION OF STUDY POPULATION
The selected study population will have nonmetastatic CRPC with a rapid PSA doubling 
time.  The specific eligibility criteria for selection of patients are provided in 
Section 4.1 and Section 4.2.  The sponsor will not grant any eligibility waivers.
4.1. Inclusion Criteria
Each patient eligible to participate in this study must meet all of the following criteria:
1. Age 18 years or older and willing and able to provide informed consent. 
2. Histologically or cytologically confirmed adenocarcinoma of the prostate without 
neuroendocrine differentiation, signet cell, or small cell features. 
3. Ongoing androgen deprivation therapy with a GnRH agonist/antagonist or prior 
bilateral orchiectomy (medical or surgical castration). 
4. Testosterone 50 ng/dL (1.73 nmol/L) at screening. 
5. For patients receiving bisphosphonates or denosumab, dose must be stable for at least 
4 weeks before randomization. 
6. Progressive disease on androgen deprivation therapy at enrollment defined as a 
minimum of 3 rising PSA values (PSA1 <PSA2 <PSA3) assessed by a local 
laboratory (local PSA) with an interval of 1 week between each determination. 
7. The most recent local PSA and the screening PSA assessed by the central laboratory 
(central PSA) should be 2 g/L (2 ng/mL).  In the event of prior androgen receptor 
inhibitor use, the most recent local PSA and the central PSA assessed at screening 
must be obtained at least 4 weeks after the last dose of the androgen receptor 
inhibitor. 
8. PSA doubling time 10 months calculated by the sponsor using the method of 
Pound et al, 1999.11
9. No prior or present evidence of metastatic disease as assessed by CT/MRI for soft 
tissue disease and whole-body radionuclide bone scan for bone disease.  If the 
screening bone scan shows a lesion suggestive of metastatic disease, the patient will 
be eligible only if a second imaging modality (plain film, CT, or MRI) does not show 
bone metastasis.  If the imaging results are equivocal or consistent with metastasis, 
the patient is not eligible for enrollment.  Patients with soft tissue pelvic disease may 
be eligible if lesions do not qualify as target lesions (eg, lymph nodes below aortic 
bifurcation are permissible if the short axis of the largest lymph node is <15 mm). 
10. Asymptomatic prostate cancer. 

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11. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
12. Estimated life expectancy 12 months. 
13. Able to swallow the study drug and comply with study requirements. 
14. Male patient and his female partner who is of childbearing potential must use 
2 acceptable methods of birth control (1 of which must include a condom as a barrier 
method of contraception) starting at screening and continuing throughout the study 
period and for 3 months after final study drug administration.  Two acceptable 
methods of birth control thus include the following:

Condom (barrier method of contraception);
AND

One of the following is required:

Established use of oral, or injected or implanted hormonal method of 
contraception by the female partner;

Placement of an intrauterine device (IUD) or intrauterine system (IUS) by the 
female partner;

Additional barrier method: Occlusive cap (diaphragm or cervical/vault caps) 
with spermicidal foam/gel/film/cream/suppository in the female partner;

Tubal ligation in the female partner;

Vasectomy or other procedure resulting in infertility (eg, bilateral 
orchiectomy), for more than 6 months.
15. Male patient must use a condom if having sex with a pregnant woman. 
4.2. Exclusion Criteria
Each patient eligible to participate in this study must NOT meet any of the following 
exclusion criteria:  
1. Prior cytotoxic chemotherapy, aminoglutethimide, ketoconazole, abiraterone acetate, 
or enzalutamide for the treatment of prostate cancer or participation in a clinical trial 
of an investigational agent that inhibits the androgen receptor or androgen synthesis 
(unless treatment was placebo). 
2. Treatment with hormonal therapy (eg, androgen receptor inhibitors, estrogens, 
5-alpha reductase inhibitors) or biologic therapy for prostate cancer (other than 
approved bone-targeting agents and GnRH agonist/antagonist therapy) within 
4 weeks of randomization. 

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3. Use of an investigational agent within 4 weeks of randomization. 
4. Known or suspected brain metastasis or active leptomeningeal disease. 
5. History of another invasive cancer within 3 years of randomization, with the 
exception of fully treated cancers with a remote probability of recurrence in the 
opinion of both the medical monitor and investigator. 
6. Absolute neutrophil count <1000/L, platelet count <100,000/L, or hemoglobin 
<10 g/dL (6.2 mmol/L) at screening.  NOTE: may not have received growth factors or 
blood transfusions within 7 days before obtaining the hematology values at screening. 
7. Total bilirubin 1.5 times the upper limit of normal (ULN) (except patients with 
a diagnosis of Gilbert’s disease); alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) 2.5 times ULN at screening. 
8. Creatinine >2 mg/dL (177 mol/L) at screening. 
9. Albumin <3.0 g/dL (30 g/L) at screening. 
10. History of seizure or any condition that may predispose to seizure (eg, prior cortical 
stroke or significant brain trauma).  History of loss of consciousness or transient 
ischemic attack within 12 months of randomization. 
11. Clinically significant cardiovascular disease including the following:

Myocardial infarction within 6 months before screening;

Uncontrolled angina within 3 months before screening;

Congestive heart failure New York Heart Association class 3 or 4, or a history of 
congestive heart failure New York Heart Association class 3 or 4, unless a 
screening echocardiogram or multigated acquisition scan performed within 
3 months before randomization demonstrates a left ventricular ejection fraction 
≥50%;

History of clinically significant ventricular arrhythmias (eg, sustained ventricular 
tachycardia, ventricular fibrillation, torsades de pointes);

History of Mobitz II second-degree or third-degree heart block without a 
permanent pacemaker in place;

Hypotension as indicated by systolic blood pressure <86 millimeters of mercury 
(mm Hg) at screening;

Bradycardia as indicated by a heart rate of <45 beats per minute on the screening 
electrocardiogram (ECG) and on physical examination;

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
Uncontrolled hypertension as indicated by systolic blood pressure > 170 mm Hg 
or diastolic blood pressure >105 mm Hg at screening.
12. Gastrointestinal disorder affecting absorption (eg, gastrectomy, active peptic ulcer 
disease within 3 months before randomization). 
13. Major surgery within 4 weeks of randomization. 
14. Hypersensitivity reaction to the active pharmaceutical ingredient or any of the capsule 
components, including Labrasol, butylated hydroxyanisole, and butylated 
hydroxytoluene. 
15. Any concurrent disease, infection, or comorbid condition that interferes with the 
ability of the patient to participate in the trial, which places the patient at undue risk, 
or complicates the interpretation of data, in the opinion of the investigator or medical 
monitor. 
5. ENROLLMENT AND STUDY PROCEDURES
Enrollment and study procedures are summarized in the following subsections.  The timing 
of all study procedures is provided in the schedule of activities (Appendix 5). 
5.1. Screening Period
The screening period will be from day -28 through day -1.  Screening procedures are listed in
Table 1.  Certain assessments may be performed as early as day -42.  Assessments not 
completed within the appropriate interval must be repeated. 
For the purposes of this study, there will be no day 0. 
5.1.1. Screening Identification Numbers
Study site personnel will access the interactive voice/web recognition system (IXRS) to 
assign a screening identification (ID) number to a potential study participant. 
For patients who provide informed consent and subsequently do not meet eligibility criteria 
or withdraw consent, study site personnel should ensure that the source record includes 
documentation for the screen failure, such as demographics, medical history, eligibility 
criteria reviewed, procedures performed, etc. 
Patient ID numbers will be assigned to eligible patients at randomization as described in 
Section 5.2.2.
5.1.2. Screening Visit Procedures
At the screening visit, study site personnel must explain to potential study participants all 
aspects of the study, including all scheduled visits and activities.  Study site personnel must 
obtain signed informed consent before any study-specific procedures are conducted unless 

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the procedures are part of routine standard of care, and must document the informed consent 
process in the patient’s clinical record. 
Screening procedures are listed in Table 1.  The investigator will assess and confirm the 
eligibility of each patient.  All screening procedure results and relevant medical history must 
be available before eligibility can be determined.  All inclusion criteria must be met and none 
of the exclusion criteria may apply.  No eligibility waivers will be granted. 
After a patient is screened and the investigator determines the patient is eligible for 
enrollment, study site personnel will complete a randomization authorization form and fax it 
to the medical monitor or designee to approve the enrollment in writing.  Patients approved 
for enrollment will be randomly assigned to treatment on day 1 according to the procedures 
described in Section 5.2.2.
Table 1.
Screening Procedures
Activity / Assessment
Interval (Days)
Comment
-42 to 
-1
-28 to 
-1
General 
Informed consent; obtain 
screening number from IXRS
Must obtain informed consent before performing any study-specific 
procedures.  
Medical history
X
Eligibility criteria
X
All inclusion criteria must be met and none of 
the exclusion criteria may apply.
12-lead electrocardiogram
X
Obtain per local practice and read to confirm 
eligibility.  
Radiographic assessments 
X
Includes whole-body radionuclide bone scan, 
abdominopelvic CT/MRI, and posteroanterior 
and lateral chest x-ray or chest CT scan.
If the screening bone scan shows a lesion 
suggestive of metastatic disease, the patient 
will be eligible only if a second imaging 
modality (plain film, CT, or MRI) excludes 
bone metastasis.  If the imaging results are 
equivocal or consistent with metastasis, the 
patient is not eligible for enrollment. 
Use the same imaging modality for all 
subsequent scans.
Complete physical examination
X
Measure vital signs (temperature, blood 
pressure, and heart rate), weight, and height.
Assess systems such as dermatologic, cardiac, 
respiratory, lymphatic, gastrointestinal, 
musculoskeletal, and neurologic per standard of 
care at the study site.  Assess other systems if 
clinically indicated by symptoms.

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Table 1.
Screening Procedures
Activity / Assessment
Interval (Days)
Comment
-42 to 
-1
-28 to 
-1
Assess ECOG performance 
status
ECOG Status 
Score
Criterion
0
Normal activity
1
Symptoms but 
ambulatory
2
In bed < 50% of time
3
In bed > 50% of time
4
100% bedridden
5
Dead
Source: Based on Oken 1982.12
Concomitant medications
X
Record all ongoing medications and those 
discontinued within 28 days before the visit.
Serious adverse events
X
Collect and report serious adverse event 
information from the time of the signed 
informed consent through screen failure or 
safety follow-up.  Record any serious adverse 
event occurring during the screening period on 
the medical history case report form and in the 
patient’s clinical record for any patient who 
subsequently meets eligibility criteria and 
proceeds to randomization.
Central Laboratory 
Refer to the laboratory manual for sample 
processing.
Hematology, serum chemistry
X
Eligibility will be based on central laboratory 
assessments. 
Refer to analytes listed in Table 8.
Testosterone
X
Eligibility will be based on central laboratory 
assessments.  
Prostate-specific antigen
X
Randomization Authorization 
Form
X
Complete, sign, and fax the form to the medical 
monitor at the number provided on the form at 
least 2 business days before the day 1 visit. 
In addition, fax copies of the items requested 
on the form.  If approved by the medical 
monitor (signed form or email 
correspondence), the patient may proceed to 
the day 1 visit.  
5.2. Treatment Period
Day 1 is the day of randomization.  While on study drug treatment, patients will return to the 
study site at weeks 5, 17, and every 16 weeks thereafter. 
5.2.1. Visit Windows
At each specified study visit, procedures will be performed according to the schedule of 
activities (Appendix 5). 

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A study visit may be scheduled on any day within a specified study week.  For any given day 
within the study week, the visit window is 5 or 7 days, a 10- or 14-day period (ie, the 5- or 
7-day period before or after the given day). 
Drug supplies must be taken into account when scheduling visits during windows.  Visits 
may be split across the window to allow for drug resupply and completion of study 
procedures. 
5.2.2. Day 1 (Randomization)
Day 1 procedures are listed in Table 2.  Study site personnel should ensure that an approved 
randomization authorization form is in the patient’s file before proceeding with 
randomization and day 1 procedures. 
Study site personnel will access the IXRS to randomly assign patients to blinded study 
treatment after receiving approval by the medical monitor (signed randomization 
authorization form or email correspondence). 
The IXRS will assign a patient ID number to each patient who proceeds to randomization.  
This number will identify the patient for the duration of the study.
The IXRS will assign a blinded study drug bottle number according to the randomization 
code.  Patients will be randomly assigned to enzalutamide or placebo treatment.  If study 
drug administration is not logistically feasible on the same day as randomization, the patient 
must come to the clinic within 3 days of randomization for the required procedures and 
initiation of treatment.  Day 1 will be defined as the day of randomization regardless of the 
first dose date.

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Table 2.
Day 1 Procedures
Activity / Assessment 
Comment
General Activities
Brief physical examination
Measure vital signs (temperature, blood pressure, 
and heart rate).
Perform symptom-directed examination.
Assess ECOG performance status
ECOG Status Score
Criterion
0
Normal activity
1
Symptoms but ambulatory
2
In bed < 50% of time
3
In bed > 50% of time
4
100% bedridden
5
Dead
Source: Based on Oken 1982.12
BPI-SF, FACT-P, EQ-5D-5L, and 
QLQ-PR25 questionnaires
Patient to complete these assessments in the clinic.
Adverse events review
Record any new adverse events on the medical 
history case report form and in the patient’s clinical 
record.
Concomitant medications review
Record any new medications or changes in ongoing 
medications.
Randomization (interactive voice/web 
recognition system, IXRS)
Assignment to blinded treatment group (blinded 
study drug bottle number).
Study drug dispensing
Provide the patient with 4 bottles (124-count each) 
for a 16-week supply.  Provide instructions for 
dosing, storage, and return of all bottles (used and 
unused) of study drug at future visits.
Central Laboratory Evaluations
Refer to the laboratory manual for sample 
processing.
Hematology, serum chemistry 
Refer to analytes listed in Table 8.  
Prostate-specific antigen
5.2.3. Treatment Guidelines
Dosing with blinded study drug should continue until radiographic progression.  Investigators 
are discouraged from obtaining PSA assessments at their local laboratories during the study 
and from discontinuing a patient’s study drug treatment due to PSA rise alone.  Initiation of 
new therapy for prostate cancer (with the exception of cytotoxic chemotherapy, androgen 
receptor inhibitors, and investigational agents) at the time of radiographic progression will 
not mandate discontinuation of study drug if the investigator considers continuing study drug 
to be beneficial. 
5.2.4. Week 5
The visit window is ±5 days.  Drug supply must be taken into account if a window is used to 
schedule the next visit. 
Week 5 procedures are listed in Table 3. 

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Table 3.
Week 5 Procedures
Activity / Assessment 
Comment
General Activities
Brief physical examination 
Measure vital signs (temperature, blood pressure, 
and heart rate).
Perform symptom-directed examination.
Assess ECOG performance status
ECOG Status Score
Criterion
0
Normal activity
1
Symptoms but ambulatory
2
In bed < 50% of time
3
In bed > 50% of time
4
100% bedridden
5
Dead
Source: Based on Oken 1982.12
Adverse events review
Record any new or ongoing adverse events.
Concomitant medications review
Record any new medications or changes in ongoing 
medications.  
Drug accountability
Record study drug returned and remind patient to 
return all bottles (used and unused) of study drug at 
each future visit. 
Confirm dosing instructions with patient (4 capsules 
by mouth once daily).  
5.2.5. Week 17 and Repeating Every 16 Weeks
The same procedures are performed at week 17 and repeating every 16 weeks until treatment 
discontinuation (Section 5.3).  Visit windows are ±5 days.  Drug supply must be taken into 
account if a window is used to schedule the next visit.  Week 17 and repeating every 
16 weeks procedures are listed in Table 4.

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Table 4.
Week 17 and Repeating Every 16 Weeks Procedures
Activity / Assessment 
Comment
General Activities
Radiographic assessments
Use the same imaging modality as at screening. 
Perform radiographic assessments approximately 
every 16 weeks, but obtain images sooner if 
progression is clinically suspected.  Radiographic 
imaging should be performed until radiographic 
progression is identified per Section 9.1.1. 
A second imaging modality (plain film, CT, or MRI) 
will be required for confirmation of bone progression 
when bone lesions are found in a single region of the 
bone scan.  Bone lesions in 2 or more of the 5 bone 
scan regions or soft tissue radiographic progression 
on the CT or MRI per RECIST 1.1 will not require 
confirmation.
Determination of radiographic progression should be 
confirmed by independent central radiology review 
before stopping radiographic imaging.  
Brief physical examination 
Measure vital signs (temperature, blood pressure, 
and heart rate).
Perform symptom-directed examination. 
Assess ECOG performance status
ECOG Status Score
Criterion
0
Normal activity
1
Symptoms but ambulatory
2
In bed < 50% of time
3
In bed > 50% of time
4
100% bedridden
5
Dead
Source: Based on Oken 1982.12
BPI-SF, FACT-P, EQ-5D-5L, and 
QLQ-PR25 questionnaires
Patient to complete these assessments in the clinic.
Adverse events review
Record any new or ongoing adverse events.  
Concomitant medications review
Record any new medications or changes in ongoing 
medications.  
Drug accountability
Record study drug returned and remind patient to 
return all bottles (used and unused) of study drug at 
each future visit. 
Confirm dosing instructions with patient (4 capsules 
by mouth once daily).  
Study drug dispensing
Provide the patient with 4 bottles (124-count each) 
for a 16-week supply.  
Central Laboratory Evaluations
Refer to the laboratory manual for sample 
processing.  
Hematology, serum chemistry
Refer to analytes listed in Table 8.  
Prostate-specific antigen

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5.2.6. Unscheduled Visits
Unscheduled visit procedures are listed in Appendix 5.
Unscheduled visits may be performed anytime during the study to assess or follow-up 
adverse events, perform scans, at the patient’s request, or at the request of the investigator.  
The date and reason for the unscheduled visit should be recorded in the source 
documentation.  If an unscheduled visit is necessary to assess toxicity, then a 
symptom-directed physical examination, clinical laboratory evaluation, adverse events 
review, and concomitant medication assessment should be performed.  If disease progression 
is suspected, perform disease assessments including imaging studies as appropriate. 
5.3. Permanent Treatment Discontinuation
Permanent treatment discontinuation is defined as cessation of study drug administration.  
Safety follow-up (Section 5.4.1) and long-term follow-up (Section 5.4.2) will still be 
performed.
Temporary treatment interruption due to an adverse event is not considered permanent 
discontinuation.  Patients whose treatment is interrupted due to an adverse event and restarted 
will continue to have regularly scheduled study visits based on their randomization date. 
The primary reasons for permanent treatment discontinuation are listed in Table 5.  
Cross-references are provided to protocol sections with additional information. 

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Table 5.
Primary Reasons for Permanent Treatment Discontinuation
Reason
Comment
Adverse event or intercurrent illness
Any intolerable adverse event that cannot be ameliorated by 
the use of adequate medical intervention or that in the
opinion of the investigator or medical monitor would lead to 
undue risk if study treatment were continued.  Refer to 
Section 8.  
Gross noncompliance with protocol 
(violation)
The medical monitor or investigator may request permanent 
discontinuation of study drug treatment in the event of a 
major protocol deviation, lack of cooperation, or 
noncompliance.  
Disease progression
Study drug treatment will be discontinued after development 
of radiographic progression if the investigator considers 
continuing study drug not to be beneficial. 
Initiation of new therapy for prostate cancer (with the 
exception of cytotoxic chemotherapy, androgen receptor 
inhibitors, and investigational agents) at the time of 
radiographic progression will not mandate discontinuation of 
study drug if the investigator considers continuing study 
drug to be beneficial.
Laboratory abnormality defined by 
protocol
Creatinine >354 mol/L (4.0 mg/dL)
AST, ALT, or total bilirubin >5 times 
the upper limit of normal (ULN)
AST or ALT > 3 times ULN and total 
bilirubin > 2 times ULN without 
findings of cholestasis
Absolute neutrophil count 750/L
Platelet count <50,000/L
Seizure
Regardless of resolution of any identified etiology.  Refer to
Section 1.4.  
Death
Refer to Section 1.1.
Loss to follow-up
Refer to Section 5.5.
Sponsor discontinuation of study
The sponsor reserves the right to terminate the study anytime 
as described in Section 13.6.  The sponsor will terminate this 
study following completion of the study objectives, or earlier 
if deemed necessary.  
Patient decision
Patients may permanently discontinue study treatment 
anytime for any reason.  Following study drug 
discontinuation, patients should have protocol-required 
safety follow-up and long-term follow-up assessments unless 
the patient specifically declines further follow-up.  
ALT, alanine aminotransferase; AST, aspartate aminotransferase.

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5.4. Follow-Up After Permanent Treatment Discontinuation
5.4.1. Safety Follow-Up
All patients will have safety follow-up after permanent treatment discontinuation.  Safety 
follow-up should occur approximately 30 days after the last dose of study drug.  However, if 
a new antineoplastic treatment is initiated before 30 days after the last dose of study drug,
then the safety follow-up visit will occur immediately before starting the new treatment.
If treatment is discontinued due to an adverse event or serious adverse event, the event(s) 
must be followed up as described in Section 8.  For patients who refuse further clinic study 
visits, telephone contact should be attempted and documented to review for adverse events 
through approximately 30 days after the last dose of study drug. 
Safety follow-up procedures are listed in Table 6. 
Table 6.
Safety Follow Up Procedures
Activity / Assessment
Comment
General Activities
Complete physical examination
Measure vital signs (temperature, blood pressure, 
and heart rate).
Assess systems such as dermatologic, cardiac, 
respiratory, lymphatic, gastrointestinal, 
musculoskeletal, and neurologic systems per 
standard of care at the study site.  Assess other 
systems if clinically indicated by symptoms.
Assess ECOG performance status
ECOG Status Score
Criterion
0
Normal activity
1
Symptoms but ambulatory
2
In bed < 50% of time
3
In bed > 50% of time
4
100% bedridden
5
Dead
Source: Based on Oken 1982.12
BPI-SF, FACT-P, EQ-5D-5L and 
QLQ-PR25 questionnaires
Patient to complete these assessments in the clinic.
Adverse events review
Record any new or ongoing adverse events.  
Concomitant medications review
Record any new medications or changes in ongoing 
medications.  
Drug accountability
If applicable.  Patients must return all study drug 
bottles at this visit.
Central Laboratory Evaluations
Refer to the laboratory manual for sample 
processing.  
Hematology, serum chemistry
Refer to analytes listed in Table 8.  
Prostate-specific antigen

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5.4.2. Long-Term Follow-Up
All patients who permanently discontinue study treatment must have long-term follow-up as 
continuation of their every 16 weeks study visit schedule.  Every reasonable effort must be 
made to obtain the required information.  The long-term follow-up windows are ±7 days. 
Study site personnel may collect follow-up information by any means including telephone, 
during a patient’s clinic visit, chart review, or by communicating with referring healthcare 
providers for patients who do not return to the study site for their subsequent care. 
Long-term follow-up procedures are listed in Table 7. 
Table 7.
Long Term Follow up Procedures
Activity / Assessment 
Comment
General Activities (All Patients)
Collect long-term follow-up information
Survival status.
New antineoplastic therapies for prostate cancer.
Opiate medications.
Skeletal-related events (radiation therapy or surgery 
to bone, clinically apparent pathologic bone 
fractures, and spinal cord compression).
Interventions due to locoregional progression 
(eg, radiation, transurethral resection of the prostate, 
nephrostomy tube placement).
Additional Assessments for Patients Who Do 
Not Have Confirmed Radiographic 
Progression at Time of Study Drug 
Discontinuation
Radiographic assessments
→Obtain approximately every 16 weeks or 
sooner if progression is clinically suspected 
until radiographic progression.
Use the same imaging modality as at screening. 
Radiographic imaging should be performed until 
radiographic progression is identified per 
Section 9.1.1. 
A second imaging modality (plain film, CT, or MRI) 
will be required for confirmation of bone progression 
when bone lesions are found in a single region of the 
bone scan.  Bone lesions in 2 or more of the 5 bone 
scan regions or soft tissue radiographic progression 
on the CT or MRI per RECIST 1.1 will not require 
confirmation.
Determination of radiographic progression should be 
confirmed by independent central radiology review 
before stopping radiographic imaging.  
BPI-SF, FACT-P, EQ-5D-5L and 
QLQ-PR25 questionnaires 
Patient to complete these assessments if at the clinic.  

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5.5. Loss to Follow-Up
Every reasonable effort should be made to contact any patient lost to follow-up during the 
course of the study to complete study-related assessments, record outstanding data, and 
retrieve study drug.  In particular, survival status information is especially critical to the 
analyses of both primary and secondary efficacy endpoints, as described in 
Section 10.3.1 and Section 10.3.2.3. 
Following unsuccessful telephone contact, an effort to contact the patient by mail using a 
method that provides proof of receipt should be attempted.  Alternate contacts are 
permissible if the patient is not reachable (eg, primary care providers, referring physician, 
relatives).  Such efforts should be documented in the source documents. 
6. INVESTIGATIONAL PRODUCT INFORMATION
6.1. General Information
The study drugs include enzalutamide and placebo.  Enzalutamide is approved in the US to 
treat men with metastatic CRPC who previously received docetaxel. 
6.2. Enzalutamide Product Characteristics
Enzalutamide, also known as MDV3100, has the chemical name 
4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1
-yl}-2-fluoro-N-methylbenzamide. The drug substance is formulated in the surfactant 
caprylocaproyl polyoxylglycerides, or Labrasol.  The product will be supplied as white to 
off-white gelatin capsules containing 40 mg of enzalutamide. 
The corresponding placebo consists of Labrasol filled in matching capsules.  Both active and 
placebo formulations contain the same relative concentrations of the 2 preservatives, 
butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT). 
6.2.1. Packaging
Blinded study drug is packaged in bottles with induction-sealed child-resistant caps labeled 
with the study protocol number, contents, directions for use, storage directions, clinical trial 
statement, and sponsor name.  Each bottle contains 124 capsules (31-day supply). 
6.2.2. Storage
Study drug should be handled and stored safely and properly in accordance with the study 
drug label. 
6.2.3. Directions for Administration
The daily dose of enzalutamide/placebo is 160 mg/day given in 4 capsules (40 mg each) by 
mouth. 
Patients should self-administer blinded study drug by mouth once daily, with or without 
food, starting on day 1.  The capsules should be swallowed whole without chewing, 
dissolving, or opening them. 

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Patients should not make up missed or vomited doses; dosing should resume on the next 
calendar day unless otherwise instructed. 
6.2.4. Directions for Dose Modification
Patients who experience a grade 3 or higher toxicity that is attributed to study drug and 
cannot be ameliorated by the use of adequate medical intervention may interrupt treatment 
with blinded study drug for 1 week or until the toxicity grade improves to grade 2 or lower 
severity.  Subsequently, blinded study drug dosing may be restarted at the original dose 
(160 mg/day) or a reduced dose (120 or 80 mg/day) in consultation with the medical monitor. 
If blinded study drug is coadministered with a strong CYP2C8 inhibitor, the dose of blinded 
study drug should be reduced to 80 mg once daily.  If coadministration of the strong 
CYP2C8 inhibitor is discontinued, the blinded study drug dose should return to the dose used 
prior to initiation of the strong CYP2C8 inhibitor. 
6.2.5. Treatment Compliance
Study drug accountability will be performed to document compliance with the blinded dosing 
regimen.  Patients will be asked to bring all used and unused blinded study drug, including 
packaging, to study visits.  Unreturned capsules will be considered to have been taken. 
7. PRIOR AND CONCOMITANT THERAPY
Prior and concomitant medications include all vitamins, herbal remedies, and 
over-the-counter and prescription medications. 
7.1. Prior Therapy
Medications taken within 4 weeks before randomization and any medications prescribed for 
chronic or intermittent use during the study, or dose adjustments of these medications, must 
be recorded on the case report form. 
Treatment with bisphosphonates or denosumab is allowed if initiated at least 4 weeks before 
enrollment and should continue on study. 
In addition to prior therapies that render a patient ineligible per the protocol eligibility 
criteria, the following medication classes are prohibited within 4 weeks before day 1:

Hormonal therapy (eg, androgen receptor inhibitors, 5-alpha reductase inhibitors) or 
biologic therapy for prostate cancer;

Investigational agents.
7.2. Concomitant Therapy
Concomitant medications will be assessed at screening and all clinic visits.  All concomitant 
medications must be recorded on the appropriate case report form.  If the use of any 
medication during the study is due to an adverse event, the adverse event must be recorded 
on the adverse event case report form and in the patient’s clinical record. 

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Initiation of bisphosphonates or other bone-targeting agents for bone health, such as 
denosumab, is not allowed during the study prior to development of bone metastasis; 
however, treatment with these agents should continue if initiated at least 4 weeks before 
enrollment and the dose remains stable.  Standard of care supplementation with calcium and 
vitamin D is encouraged. 
Investigators are strongly discouraged from discontinuing a patient’s study drug and/or 
initiating new treatments for prostate cancer before radiographic progression.  Initiation of 
the following therapies will result in permanent treatment discontinuation (Section 5.3):

Cytotoxic chemotherapy;

Androgen receptor inhibitors;

Investigational agents.
The concomitant use of medications known to lower the seizure threshold is allowed because 
the use of these medications is not restricted in the ongoing phase 3 PREVAIL study.  In 
PREVAIL, 302 of 1715 treated patients received medications known to lower the seizure 
threshold, including selective serotonin reuptake inhibitors, certain antidepressants, 
antipsychotics, and antiasthmatics.  As of May 2013, no seizures were reported for any of 
these patients.  A single patient in PREVAIL was reported to have a seizure, and this patient 
was not receiving a medication known to lower the seizure threshold. 
Deviation from these guidelines should occur only if absolutely necessary for the well-being 
of the patient.  The medical monitor is to be notified to determine the patient’s suitability for 
continued treatment with study drug. 
7.3. 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 (Section 1.2.1).  Concomitant use of enzalutamide with 
narrow therapeutic index drugs 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 coadministration with 
warfarin cannot be avoided, conduct additional INR monitoring. 
7.4. Drugs That May Affect Exposure to Enzalutamide
7.4.1. Drugs That Inhibit or Induce CYP2C8
Coadministration of a strong CYP2C8 inhibitor (eg, gemfibrozil) increased the composite 
AUC0-∞of enzalutamide plus its active metabolite in healthy volunteers (Section 1.2.1); 
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. 

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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. 
7.4.2. Drugs That Induce CYP3A4
The effects of CYP3A4 inducers on the PK of enzalutamide have not been evaluated in vivo.  
Coadministration of enzalutamide with strong CYP3A4 inducers (eg, carbamazepine, 
phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may decrease the plasma exposure 
of enzalutamide and should be avoided if possible.  Selection of a concomitant medication 
with no or minimal CYP3A4 induction potential is recommended.  Moderate 
CYP3A4 inducers (eg, bosentan, efavirenz, etravirine, modafinil, nafcillin) and St. John’s 
Wort may also reduce the plasma exposure of enzalutamide and should be avoided if 
possible. 
7.5. Precautions Regarding Concomitant Medications
Refer to the following websites for updated lists of CYP inhibitors, inducers, and substrates;  

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Dr
ugInteractionsLabeling/ucm093664.htm#potency;

http://medicine.iupui.edu/clinpharm/ddis/table.aspx.
8. ADVERSE EVENT REPORTING
Study assessments of safety include adverse events, clinical laboratory tests, physical 
examinations, and vital signs. 
In the following sections, the sponsor’s safety monitoring procedures are described
(Section 8).  Adverse events are discussed in detail in the context of patient management, 
study drug dose modification, emergency unblinding of treatment assignment, and safety 
reporting requirements, including follow-up procedures (Section 8.2 and Section 8.3).  
Clinical laboratory safety tests are presented including estimates of blood volume to be 
collected during the study (Section 8.6).  The study procedures for physical examinations and 
vital signs are also provided (Section 8.7). 
The sponsor will periodically monitor blinded safety data during the clinical study in addition 
to reviewing individual safety case reports, by examining the incidence and severity of 
adverse events and serious adverse events, changes in laboratory results, and other data (such 
as aggregate analysis of data from other enzalutamide studies) as appropriate and per the 
sponsor’s Safety Management Team Charter.  Any relevant safety concerns will be 
communicated to the Data Monitoring Committee, investigators, and regulatory agencies, as 
appropriate.

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8.1. Requirements
An independent Data Monitoring Committee will meet periodically during the study to 
monitor patient safety (Section 11). 
The table below summarizes the requirements for recording safety events on the Case Report 
Form (CRF) and for reporting safety events on the Clinical Trial (CT) Serious Adverse Event 
(SAE) Report Form to Pfizer Safety.  These requirements are delineated for 3 types of 
events: (1) SAEs; (2) non-serious adverse events (AEs); and (3) exposure to the 
investigational product under study during pregnancy or breastfeeding, and occupational 
exposure.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer Safety 
Within 24 Hours of Awareness
SAE
All
All
Non-serious AE
All
None
Exposure to the investigational 
product under study during 
pregnancy or breastfeeding, and 
occupational exposure
All (regardless of whether 
associated with an AE), except 
occupational exposure
Exposure during pregnancy, 
exposure via breastfeeding, 
occupational exposure (regardless 
of whether associated with an AE)
All observed or volunteered events regardless of suspected causal relationship to the 
investigational product will be reported as described in the following paragraphs.
Events listed in the table above that require reporting to Pfizer Safety on the CT SAE Report 
Form within 24 hours of awareness of the event by the investigator are to be reported 
regardless of whether the event is determined by the investigator to be related to an 
investigational product under study.  In particular, if the SAE is fatal or life-threatening, 
notification to Pfizer Safety must be made immediately, irrespective of the extent of available 
event information.  This time frame also applies to additional new (follow-up) information on 
previously forwarded reports.  In the rare situation that the investigator does not become 
immediately aware of the occurrence of an event, the investigator must report the event 
within 24 hours after learning of it and document the time of his/her first awareness of the 
event.
For each event, the investigator must pursue and obtain adequate information both to 
determine the outcome and to assess whether it meets the criteria for classification as an SAE 
(see the Serious Adverse Events section below).  In addition, the investigator may be 
requested by Pfizer Safety to obtain specific follow-up information in an expedited fashion.  
This information is more detailed than that recorded on the CRF.  In general, this will include 
a description of the event in sufficient detail to allow for a complete medical assessment of 
the case and independent determination of possible causality.  Any information relevant to 
the event, such as concomitant medications and illnesses, must be provided.  In the case of a 
subject death, a summary of available autopsy findings must be submitted as soon as possible 
to Pfizer Safety.  Any pertinent additional information must be reported on the CT SAE 

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Report Form; additional source documents (eg, medical records, CRF, laboratory data) are to 
be sent to Pfizer Safety ONLY upon request.
As part of ongoing safety reviews conducted by the sponsor, any non-serious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.1.1. Additional Details On Recording Adverse Events on the CRF
All events detailed in the table above will be recorded on the AE page(s) of the CRF.  It 
should be noted that the CT SAE Report Form for reporting of SAE information is not the 
same as the AE page of the CRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE Report 
Form for reporting of SAE information.
8.1.2. Eliciting Adverse Event Information
The investigator is to record on the CRF all directly observed AEs and all AEs spontaneously 
reported by the study subject.  In addition, each study subject will be questioned about the 
occurrence of AEs in a non leading manner.
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the Subject 
Withdrawal section)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted below, and recorded on the CRF.  
When a subject withdraws from the study because of an SAE, the SAE must be recorded on 
the CRF and reported, as appropriate, on the CT SAE Report Form, in accordance with the 
Requirements section above.
8.1.4. Time Period for Collecting AE/SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each subject begins from the time the subject provides informed consent, which 
is obtained before the subject’s participation in the study (ie, before undergoing any 
study-related procedure and/or receiving investigational product), through and including a 
minimum of 30 calendar days; except as indicated below after the last administration of the 
investigational product.  
If a patient begins a new anticancer therapy, the recording period for all AEs ends at the time 
the new treatment is started.  However, the reporting of SAEs should continue beyond this 
period if the investigator believes there to be at least a reasonable possibility of the SAE 
being related to investigational product.  Phone patients for follow up if they do not come to 
the clinic within the follow up period.  

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8.1.4.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a subject during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
SAEs occurring in a subject after the active collection period has ended are reported to Pfizer 
Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational 
product must be reported to Pfizer Safety.
Follow up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment.
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF
During the active collection period, both non-serious AEs and SAEs are recorded on the 
CRF.
Follow up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.
8.1.5. Causality Assessment
An investigator’s causality assessment is the determination of whether there exists a 
reasonable possibility that the investigational product caused or contributed to an AE; 
generally the facts (evidence) or arguments to suggest a causal relationship should be 
provided. If the investigator does not know whether or not the investigational product caused 
the event, then the event will be handled as “related to investigational product” for reporting 
purposes, as defined by the sponsor. If the investigator's causality assessment is “unknown 
but not related” to investigational product, this should be clearly documented in the study 
records.  The criteria for determining causal relationship to study drug are presented in 
Table 8.
Table 8.
Criteria for Determining Causal Relationship to Study Drug
Relationship
Critera
Not Related
A clinical event, including laboratory test abnormality, with a temporal 
relationship to drug administration that 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 that 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 that follows a clinically reasonable 
response on re administration (rechallenge) or withdrawal (dechallenge).

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8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
8.2. Special Safety Considerations
8.2.1. Study Drug Dose Modification Due to Adverse Event
The instructions for modifying the dose of study drug due to an adverse event are provided in 
Section 6.2.4.
8.2.2. Emergency Procedure for Unblinding Treatment Assignment Due to Adverse 
Event
An emergency procedure for breaking the blind will be built into the randomization system 
(IXRS).  Unblinding of treatment assignment at the study site should occur only if the 
knowledge will materially change the immediate clinical management of a patient in a 
medical emergency.  When possible, the investigator should attempt to contact the medical 
monitor before unblinding a patient’s treatment assignment. 
To unblind a patient’s treatment assignment, the investigator will access the unblinding 
module within the IXRS.  The reason for breaking the blind must be documented in the 
source documents. 
Patients whose treatment assignment has been unblinded will permanently discontinue study 
treatment, have safety follow-up, and commence long-term follow-up. 
Single patient unblinding may be required for reporting unexpected serious adverse events to 
certain regulatory authorities.  Access to this information will be strictly limited. 
8.2.3. Contraception
Male patients must use condoms if having sex with pregnant women.
Male patients and their female partners of childbearing potential must use 2 acceptable 
methods of birth control (1 of which must include a condom as a barrier method) from the 
screening visit through 3 months after the last dose of study drug. 
The 2 acceptable methods of birth control are as follows:
1. A condom (barrier method is required).
AND
2. One of the following is required:

Established use of oral, injected, or implanted hormonal method;

Placement of an intrauterine device (IUD) or intrauterine system (IUS);

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
Additional barrier method including contraceptive sponge or occlusive cap 
(diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/suppository;

Tubal ligation performed at least 6 months before screening;

Vasectomy or other surgical castration at least 6 months before screening.
Patients must not donate sperm from first dose of study drug through 3 months after the last 
dose of study drug. 
8.3. Definitions
8.3.1. Adverse Events
An AE is any untoward medical occurrence in a study subject administered a product or 
medical device; the event need not necessarily have a causal relationship with the treatment 
or usage.  Examples of AEs include, but are not limited to:

Abnormal test findings;

Clinically significant signs and symptoms;

Changes in physical examination findings;

Hypersensitivity;

Drug abuse;

Drug dependency.
Additionally, AEs may include signs and symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

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
Occupational exposure.
Worsening of signs and symptoms of the malignancy under study should be recorded as AEs 
in the appropriate section of the CRF.  Disease progression assessed by measurement of 
malignant lesions on radiographs or other methods should not be reported as AEs.
8.3.2. Abnormal Test Findings
Abnormal objective test findings should be recorded as AEs when any of the following 
conditions are met: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or

Test result leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy; and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
recording as an AE.
8.3.3. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
Or that is considered to be:

An important medical event.

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Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the subject or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as 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.
Progression of the malignancy under study (including signs and symptoms of progression) 
should not be reported as an SAE unless the outcome is fatal within the active collection 
period.  Hospitalization due to signs and symptoms of disease progression should not be 
reported as an SAE.  If the malignancy has a fatal outcome during the study or within the 
active collection period, then the event leading to death must be recorded as an AE on the 
CRF, and as an SAE with Common Terminology Criteria for Adverse Events (CTCAE) 
Grade 5 (see the Severity Assessment section).
8.3.4. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility, or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit is assessed for medical importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating clinical 
AE is not in itself an SAE.  Examples include:

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of a persistent pretreatment laboratory abnormality);

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
Social admission (eg, subject has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject;

Admission exclusively for the administration of blood products.
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as SAEs.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an SAE.  For example, an acute 
appendicitis that begins during the reporting period should be reported if the SAE 
requirements are met, and the resulting appendectomy should be recorded as treatment of the 
AE.
8.4. Severity Assessment
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed in Table 9.
Table 9.
Criteria for Determining the Severity (Intensity) of an Adverse Event
Grade
Intensity or Severity
Clinical Description
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
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 adverse event.
Source: Common Terminology Criteria for Adverse Events v4.0.

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8.5. Special Situations
8.5.1. Protocol- Specified Serious Adverse Events
There are no protocol-specified SAEs in this study.  All SAEs will be reported to Pfizer 
Safety by the investigator as described in previous sections, and will be handled as SAEs in 
the safety database.
8.5.2. Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some subjects, transaminase elevations are a harbinger of a more 
serious potential outcome.  These subjects fail to adapt and therefore are "susceptible" to 
progressive and serious liver injury, commonly referred to as drug induced liver injury 
(DILI).  Subjects who experience a transaminase elevation above 3 times the upper limit of 
normal (× ULN) should be monitored more frequently to determine if they are an “adaptor” 
or are “susceptible.”
In the majority of DILI cases, elevations in aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) precede total bilirubin (TBili) elevations (>2 × ULN) by several 
days or weeks.  The increase in TBili typically occurs while AST/ALT is/are still elevated 
above 3 × ULN (ie, AST/ALT and TBili values will be elevated within the same lab sample).  
In rare instances, by the time TBili elevations are detected, AST/ALT values might have 
decreased.  This occurrence is still regarded as a potential DILI.  Therefore, abnormal 
elevations in either AST OR ALT in addition to TBili that meet the criteria outlined below 
are considered potential DILI (assessed per Hy’s law criteria) cases and should always be 
considered important medical events, even before all other possible causes of liver injury 
have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the subject’s 
individual baseline values and underlying conditions.  Subjects who present with the 
following laboratory abnormalities should be evaluated further as potential DILI (Hy’s law) 
cases to definitively determine the etiology of the abnormal laboratory values:

Subjects with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available.

For subjects with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT values 
>2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is smaller).

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
Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller).
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor. 
The subject should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment.  
In addition to repeating measurements of AST and ALT and TBili, laboratory tests should 
include albumin, creatine kinase (CK), direct and indirect bilirubin, gamma glutamyl 
transferase (GGT), prothrombin time (PT)/international normalized ratio (INR), total bile 
acids, alkaline phosphatase and acetaminophen drug and/or protein adduct levels.  
Consideration should also be given to drawing a separate tube of clotted blood and an 
anticoagulated tube of blood for further testing, as needed, for further contemporaneous 
analyses at the time of the recognized initial abnormalities to determine etiology.  A detailed 
history, including relevant information, such as review of ethanol, acetaminophen (either by 
itself or as a coformulated product in prescription or over the counter medications), 
recreational drug, supplement (herbal) use and consumption, family history, sexual history, 
travel history, history of contact with a jaundiced person, surgery, blood transfusion, history 
of liver or allergic disease, and potential occupational exposure to chemicals, should be 
collected.  Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging 
(eg, biliary tract) may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found.  Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities. 
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.
8.5.3. Exposure to the Investigational Product During Pregnancy of Breastfeeding and 
Occupational Exposure
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.

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8.5.3.1. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if:

A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;

An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products).

A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy. 
If a subject or subject’s partner becomes or is found to be pregnant during the subject’s 
treatment with the investigational product, the investigator must report this information to 
Pfizer Safety on the CT SAE Report Form and an EDP supplemental form, regardless of 
whether an SAE has occurred.  In addition, the investigator must submit information 
regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a subject 
reports that she is pregnant and has been exposed to a cytotoxic product by inhalation or 
spillage) to Pfizer Safety using the EDP supplemental form.  This must be done irrespective 
of whether an AE has occurred and within 24 hours of awareness of the exposure.  The 
information submitted should include the anticipated date of delivery (see below for 
information related to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP supplemental form.  In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth.  In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
pre-procedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported to Pfizer Safety as SAEs 
follows: 

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
Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product.
Additional information regarding the EDP may be requested by the sponsor.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, the 
investigator will provide the subject with the Pregnant Partner Release of Information Form 
to deliver to his partner.  The investigator must document in the source documents that the 
subject was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.5.3.2. Exposure During Breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the investigator’s awareness, using the 
CT SAE Report Form.  An exposure during breastfeeding report is not created when a Pfizer 
drug specifically approved for use in breastfeeding women (eg, vitamins) is administered in 
accord with authorized use. However, if the infant experiences an SAE associated with such 
a drug’s administration, the SAE is reported together with the exposure during breastfeeding.
8.5.3.3. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to Pfizer Safety within 24 hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE.  Since the information does not pertain to a subject enrolled in the study, the 
information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file.

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8.5.4. Medical Errors and Lack of Efficacy
Other exposures to the investigational product under study may occur in clinical trial settings, 
such as medication errors and lack of efficacy.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
Medication errors and lack of 
efficacy*
All (regardless of whether 
associated with an AE)
Only if associated with an 
SAE
*For lack of efficacy (particularly for studies conducted with vaccines, contraceptives, and products used in the 
treatment of life-threatening diseases or conditions [eg, anti-infectives]), see the Lack of Efficacy section below.
8.5.4.1. Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong subject, or at the wrong time, or at the wrong dosage strength (other 
examples of concern may be added based on the investigational product administration, such 
as inadvertent exposure).  
Medication errors include:

Medication errors involving subject exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified immediately.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and non-serious, are recorded on an AE page of the 
CRF.  
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
8.5.4.1.1. Overdose of Enzalutamide
An overdose is defined as at least 2 daily doses of study drug taken the same calendar day.  
In the event of an overdose, treatment with study drug should be stopped and general 
supportive measures initiated, taking into consideration the half life is 5.8 days for 

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enzalutamide.  Patients may be at increased risk of seizures following an overdose of 
enzalutamide.  The medical monitor must be contacted in the event of a study drug overdose. 
All overdose events are to be reported as special events of interest within 24 hours of 
awareness by the study site according to Section 8.5.4, whether or not the event meets 
adverse event criteria.  Neither the effects of overdose of enzalutamide nor an antidote to 
overdose are known.
8.5.4.2. Lack of Efficacy
Lack of efficacy is reportable to Pfizer Safety only if associated with an SAE.
8.6. Clinical Laboratory Safety Tests
Routine clinical laboratory safety tests (hematology, serum chemistry) will be performed at 
specified study visits according to the schedule of activities (Appendix 5) and at unscheduled 
visits if necessary. 
A list of the required routine clinical laboratory safety tests is provided in Table 10.  All 
samples for laboratory analysis must be collected, prepared, labeled, and shipped according 
to laboratory requirements. 
All clinical laboratory safety tests will be performed by the central laboratory specified in 
Form FDA 1572 Section 4.  The central laboratory reference ranges will be used.  Eligibility 
at screening will be based on central laboratory assessments. 
A different clinical laboratory may be used for unscheduled visits or for the care of a patient 
with an urgent adverse event.  Such laboratory data will not be entered into the study 
database.  The central laboratory should be used whenever possible. 
Table 10.
Clinical Laboratory Safety Tests
Hematology
Chemistry
Hematocrit 
Hemoglobin
Mean corpuscular volume
Platelet count
Red blood cell count
White blood cell count with differential
Albumin 
Alkaline phosphatase 
ALT (alanine aminotransferase)
AST (aspartate transaminase)
Blood urea nitrogen and creatinine
Ca++, total CO2 (bicarbonate) 
Creatine phosphokinase
Glucose 
Lactate dehydrogenase
Magnesium, phosphate
Na+, K+, Cl-
Total bilirubin
Total protein 

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8.6.1. Estimated Blood Volume
Blood samples will be collected for standard safety evaluations (hematology, serum 
chemistry), for monitoring PSA, and for the screening testosterone test according to the 
schedule of activities (Appendix 5).  Samples will be stored until the specified analyses are 
completed and then they will be destroyed in accordance with standard laboratory practice 
and applicable local regulations. 
The total blood volume to be collected at each study visit for safety evaluations and PSA is 
approximately 2.5 to 3 teaspoons (12-15 mL). 
8.7. Physical Examinations, Vital Signs, and Electrocardiograms
The investigator will perform complete or brief physical examinations according to the 
schedule of activities in Appendix 5. 
Complete physical examinations will be per standard care at the study site and may include 
dermatologic, cardiac, respiratory, lymphatic, gastrointestinal, musculoskeletal, and 
neurologic systems and other systems if clinically indicated by symptoms.  Weight will be 
measured as part of the examination.  Height will be measured only at screening. 
Brief physical examinations will be directed toward patient-reported symptoms and include 
investigating any new abnormalities. 
Vital sign measurements will include blood pressure, heart rate, and temperature. 
Standard 12-lead ECGs with rhythm strips will be obtained per local practice.  The 
investigator or designee will be responsible for reading the ECG to assess eligibility. 
9. ASSESSMENT OF EFFICACY AND SAFETY VARIABLES
9.1. Assessment of Efficacy
Study assessments of efficacy are measures of prostate cancer status.  These will include 
MFS; overall survival; pain progression; first use of cytotoxic chemotherapy; first use of new 
antineoplastic therapy; PSA progression; PSA response rates; and quality of life as assessed 
by the FACT-P questionnaire, EQ-5D-5L health questionnaire, and QLQ-PR25 module. 
9.1.1. Assessments for the Primary Efficacy Endpoint
Assessments for the primary efficacy endpoint of MFS will include radiographic assessment 
of bone disease by whole-body radionuclide scan and soft tissue disease by CT scan or MRI.  
The same imaging method should be used throughout the study. 
Radiographic assessments will be done at screening and approximately every 16 weeks, but 
images may be obtained sooner if progression is clinically suspected.  All study films should 
be read locally at the study site and submitted to the central imaging unit for independent 
central radiology review.  Each study site should designate a radiologist or investigator as the 
primary imaging reviewer to ensure that all images are read consistently as specified by the 
protocol.  Radiographic imaging will not be required after radiographic progression is 
confirmed by independent central radiology review according to the specifications in 
Section 9.1.1.1 and Section 9.1.1.2.

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9.1.1.1. Determination of Bone Metastasis
Assessment of bone disease will be done by whole-body radionuclide bone scan.  A bone 
scan will consist of 5 regions including skull, thorax, spine, pelvis, and extremities.  
Radiographic progression for bone disease is defined as the appearance of 1 or more 
metastatic lesion on bone scan.  Confirmation with a second imaging modality (plain film, 
CT, or MRI) will be required when bone lesions are found in a single region on the bone 
scan.  Appearance of metastatic lesions in 2 or more of the 5 regions on a bone scan will not 
require confirmation with a second imaging modality. 
9.1.1.2. Determination of Soft Tissue Metastasis
Assessment of soft tissue disease will be done by CT or MRI.  Radiographic progression for 
soft tissue disease is defined by RECIST 1.1.1
9.1.2. Assessments for the Secondary Efficacy Endpoints
9.1.2.1. Assessment of Survival
The survival status of each patient will be monitored during study treatment and after 
discontinuation of study treatment for any reason.  Survival status will be documented during 
long-term follow-up according to the schedule of activities (Appendix 5).  The cause of death 
will be recorded for patients who die. 
During the course of the study, the medical monitor may request that a survival sweep be 
conducted to obtain an accurate number of deaths across the study.  The medical monitor will 
provide instructions on these survival sweeps immediately before they commence as well as 
a timeline for contacting patients. 
9.1.2.2. Assessment of Pain Progression
The assessment of pain progression will be conducted using the BPI-SF.  The BPI-SF 
questionnaire is a validated instrument that uses a self-reported scale assessing level of pain, 
its effect on activities of daily living, and analgesic medication use. 
This study will use the short form containing 9 main questions related to pain and analgesic 
medication use.  The primary question (paraphrased) is “On a scale of 0 to 10, please rate 
your pain at its worst in the last 24 hours.”  
The questionnaire is provided in Appendix 1.  Study site personnel will collect the 
questionnaire information at the study visits.  It is important that patients are fluent in reading 
the language used in the questionnaire and that they complete it without influence of the 
investigator, study site staff, or anyone else. 
9.1.2.3. Assessment of New Cytotoxic Chemotherapy Use
The assessment of cytotoxic chemotherapy use will use the information collected on the case 
report forms about new cytotoxic chemotherapies initiated for prostate cancer after 
randomization. 

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9.1.2.4. Assessment of New Antineoplastic Therapy Use
The assessment of first use of new antineoplastic therapy will use the information collected 
on the case report forms about new antineoplastic therapies initiated for prostate cancer after 
randomization. 
9.1.2.5. Assessment of PSA
PSA will be assessed at the central laboratory throughout the study according to the schedule 
of activities (Appendix 5).  With the exception of the screening PSA values, PSA values will 
not be provided to study sites or patients. 
PSA values considered undetectable for this study will be those below the limit of 
quantification of centrally assessed PSA results.  Regardless of PSA values, study drug 
administration should continue until radiographic progression and the investigator considers 
continuing study drug not to be beneficial. 
Throughout the study, PSA rise without evidence of radiographic progression is strongly 
discouraged as a criterion to start a new systemic antineoplastic therapy. 
9.1.2.6. Assessment of Quality of Life
The FACT-P questionnaire is a multidimensional, self-reported, quality-of-life instrument 
specifically designed for use in men with prostate cancer.  The questionnaire contains 27 core 
items to assess function in 4 domains during the prior 7 days:  physical, social/family, 
emotional, and functional well-being, as well as 12 site-specific items to assess 
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. 
The questionnaire is provided in Appendix 2.  Study site personnel will collect the 
questionnaire information at the study visits. 
The EQ-5D-5L questionnaire is a standardized instrument that measures health-related 
quality of life for men with prostate cancer.  Patients will self-rate their current state of 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression by choosing 1 of 
5 possible responses that record the level of severity (no problems, slight problems, moderate 
problems, severe problems, or extreme problems) within each dimension.  The questionnaire 
also includes a visual analog scale to self-rate general health state on a scale from “the worst 
health you can imagine” to “the best health you can imagine.” 
The questionnaire is provided in Appendix 3.  Study site personnel will collect the 
questionnaire information at the study visits. 
The European Organization for Research and Treatment of Cancer (EORTC) QLQ-PR25, a 
module of the EORTC QLQ-30 questionnaire, was developed to assess the quality of life of 
patients with prostate cancer.  Patients will self-rate their current state of pain as it relates to 
urination, ease and frequency of urination, and bowel and other problems during the past 

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week.  Patients will also answer 5 questions about weight loss/gain and sexual interest and 
4 questions about sexual activity during the past 4 weeks.  Patients will choose 1 of 
4 possible responses that record level of intensity (not at all, a little, quite a bit, very much) 
within each dimension. 
The questionnaire is provided in Appendix 4.  Study site personnel will collect the 
questionnaire information at the study visits. 
9.2. Assessment of Safety
Assessments of safety will include adverse events, clinical laboratory tests, physical 
examinations, and vital signs.  The reason for discontinuation of study drug will also be 
collected.  The procedures for the investigator assessment of adverse events are presented in 
detail in Section 8.  The procedures for clinical laboratory safety tests including estimates of 
blood volume are presented in Section 8.6, and for physical examinations, vital signs, and 
ECGs in Section 8.7. 
10. STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION
10.1. Statistical and Analytical Plans
A statistical analysis plan will present the detailed statistical methods and analyses for this 
study. 
10.2. Analysis Populations
The intent-to-treat population is defined as all patients randomly assigned to study treatment 
and is based on randomized treatment assignment regardless of whether or not treatment was 
administered.  The intent-to-treat population will be used for all efficacy analyses unless 
otherwise specified in the statistical analysis plan. 
The safety population is defined as all patients who receive 1 dose or partial dose of study 
drug.  The safety population will be used for all safety analyses.  The safety population will 
be analyzed based on the treatment received and not the treatment assigned. 
Patients who are randomly assigned to study treatment and later found to have had metastatic 
disease at enrollment will be censored for time-to-event analyses, and those who receive 
study drug will be included in all safety analyses. 
10.3. Efficacy Analyses
The statistical analysis plan will provide details on additional sensitivity analyses of selected 
endpoints. 
All inferential efficacy analyses will incorporate PSA doubling time (< 6 months vs 
≥6 months) and baseline use of a bone-targeting agent (yes vs no) as the only stratification 
factors, unless otherwise noted. 

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The single MFS analysis will be performed after approximately 440 MFS events occur.  All 
secondary endpoints will be evaluated for efficacy at this time.  This will include the single 
analysis of time to PSA progression and time to first use of new antineoplastic therapy as 
well as the first interim analysis of overall survival.  Approximately 135 death events are 
expected at the time of this analysis.  Two additional interim analyses and the final analysis 
of overall survival are planned after approximately 285, 440, and 596 death events occur, 
respectively.  No additional analyses of other efficacy endpoints are planned at the time of 
the additional interim and final analyses of overall survival.  If an interim analysis of overall 
survival is statistically significant, it will be reported as the final analysis and no subsequent 
analyses will be performed. 
10.3.1. Primary Efficacy Endpoint Analysis: Metastasis-Free Survival
The primary efficacy endpoint is MFS using the assessment of radiographic progression by 
an independent, central, blinded radiology reviewer as described in Section 9.1.1 and defined 
as the time from randomization to radiographic progression or death on study (death within 
112 days of treatment discontinuation without evidence of radiographic progression), 
whichever occurs first.  Patients not known to have had an MFS event at the time of analysis 
will be right censored on the date of the last available scan before the analysis data cutoff 
date for the purposes of analysis.  Both scheduled and unscheduled radiographic imaging will 
be considered in the determination of radiographic events.  The detailed conventions for 
censoring for the primary analysis and sensitivity analyses that incorporate possible sources 
of competing risk for assessment of progression will be described in the statistical analysis 
plan.
The MFS analysis will be performed when approximately 440 MFS events are observed.  
The primary endpoint analysis will be performed using a stratified log-rank test to compare 
the 2 treatment groups using a 2-sided test at the 0.05 level of significance. 
10.3.2. Key Secondary Efficacy Endpoint Analyses
The following key secondary endpoints will be tested:  time to PSA progression, time to first 
use of new antineoplastic therapy, and overall survival.  All secondary endpoint analyses will 
be performed at the time of the single MFS analysis.  To maintain the family-wise 2-sided 
type I error rate at 0.05, the following multiplicity adjusted inferential procedure will be 
performed.
The primary endpoint, MFS, will be tested at a 0.05 significance level.  To maintain the 
family-wise 2-sided type I error rate at 0.05, a parallel testing strategy between overall
survival (with allocated type I error rate 0.03) and remaining key secondary endpoints (time 
to PSA progression and time to first use of new antineoplastic therapy with allocated type I 
error rate 0.02) will be performed.  The testing strategy for primary and key secondary 
endpoints is summarized in Figure 2.

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Figure 2:
Testing Strategy for Primary and Key Secondary Endpoints
MFS, metastasis-free survival; OS, overall survival; TTPSA, time to prostate-specific antigen progression; 
TTFAnti, time to first use of new antineoplastic therapy.
* Overall survival will be tested at 0.05 only if both time to PSA progression and time to first use of new 
antineoplastic therapy endpoints are significant.  If either time to PSA progression or time to first use of new 
antineoplastic therapy endpoints fail to show significance, OS will be tested at 0.03.
Details of primary and key secondary endpoint testing as a step-by-step approach will be 
described in details in the Statistical Analysis Plan.
At the time of the single MFS analysis, an interim analysis of overall survival will be 
performed with a fixed 0.001 significance level.  Approximately 135 death events are 
expected at the time of this analysis.  Two additional interim analyses and the final analysis 
of overall survival are planned after approximately 285, 440, and 596 death events occur, 
respectively. 
No additional analyses of other efficacy endpoints are planned at the time of the additional 
interim and final analyses of overall survival.  If an interim analysis of overall survival is 
statistically significant, it will be reported as the final analysis and no subsequent analyses 
will be performed. 

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10.3.2.1. Time to PSA Progression
PSA progression is defined according to Prostate Cancer Clinical Trials Working 
Group 2 (PCWG2) guidelines.  Time to PSA progression is defined as the time from 
randomization to the date of the first PSA value demonstrating progression, which is 
subsequently confirmed.  Patients without confirmed PSA progression at the time of analysis 
will be right censored on the date of the last PSA assessment before the analysis data cutoff 
date. 
For patients with PSA decline at week 17, the PSA progression date is defined as the date 
that a ≥25% increase and an absolute increase of ≥2 µg/L (2 ng/mL) above the nadir is 
documented, which is confirmed by a second consecutive value obtained at least 3 weeks 
later. 
For patients with no PSA decline at week 17, the PSA progression date is defined as the date 
that a ≥25% increase and an absolute increase of ≥2 µg/L (2 ng/mL) above the baseline is 
documented, which is confirmed by a second consecutive value at least 3 weeks later. 
Time to PSA progression will be compared between the 2 treatment groups using a stratified 
log-rank test. 
10.3.2.2. Time to First Use of New Antineoplastic Therapy
Time to first use of new antineoplastic therapy is defined as the time from randomization to 
the first use of new antineoplastic therapy for prostate cancer.  Patients not starting treatment 
with a new antineoplastic therapy at the time of analysis will be right censored on the date of 
the last assessment before the analysis data cutoff date for the purposes of analysis.  
A stratified log-rank test will be used to compare the 2 treatment groups. 
10.3.2.3. Overall Survival
Overall survival is defined as the time from randomization to death due to any cause.  
Patients not known to have died at the time of analysis will be right censored on the date at 
which they were last known to be alive before the analysis data cutoff date for the purposes 
of analysis. 
Three interim and 1 final efficacy analyses of overall survival are planned.  The first interim 
analysis will be performed at a 0.001 significance level at the time of the single MFS 
analysis.  The number and percentage of death events in each treatment group will be 
summarized, along with Kaplan-Meier curves with the hazard ratio and its 95% CI.  Two 
additional interim analyses and a final analysis of overall survival are planned after 
approximately 285, 440, and 596 deaths occur, respectively.  The overall survival analyses 
will be performed using a stratified log-rank test to compare the 2 treatment groups.  
Depending on the outcome of time to PSA progression and time to first use of new 
antineoplastic therapy endpoints, the total type I error rate across the interim and final 
analyses will be controlled at 0.03 or 0.05 with the O’Brien-Fleming alpha spending 
function.14 The significance level will be fixed at 0.001 for the first interim analysis.  For the 
other overall survival analyses, the significance levels will be recalculated based on the 
actual number of events at each analysis using the O’Brien-Fleming method, using the 

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remaining type I error rate (0.029 or 0.049 depending on the outcome of time to PSA 
progression and time to first use of new antineoplastic therapy endpoints).  If an interim 
analysis of overall survival is statistically significant, it will be reported as the final analysis 
and no subsequent analyses will be performed.  The approximate number of events and 
corresponding significance level at each analysis based on this methodology are provided in 
Table 11.  The interim analysis testing methodology will be described in detail in the 
statistical analysis plan. 
Table 11.
Type I Error Spending for the Overall Survival Analyses
Analysis
Number of Death Events [1]
Significance Level
Error Rate: 0.03 [2]
Error Rate: 0.05 [3]
First interim
135
0.001
0.001
Second 
interim
285
0.001
0.002
Third interim
440
0.009
0.018
Final
596
0.026
0.044
1.
Approximate number of targeted events. 
2.
Will be used if either time to PSA progression or time to first use of new antineoplastic therapy 
endpoint fails to show significance.  The significance level will be fixed at 0.001 for the first interim 
analysis.  For the other analyses, the significance levels will be recalculated based on the actual 
number of events at each analysis using the O’Brien-Fleming method.14
3.
Will be used if both time to PSA progression and time to first use of new antineoplastic therapy 
endpoints show significance.  The significance level will be fixed at 0.001 for the first interim 
analysis.  For the other analyses, the significance levels will be recalculated based on the actual 
number of events at each analysis using the O’Brien-Fleming method.14
10.3.3. Additional Secondary Endpoint Analyses
10.3.3.1. Time to Pain Progression
Pain will be assessed using the score from the BPI-SF question 3: “Please rate your pain by 
marking the box beside the number that best describes your pain at its worst in the last 
24 hours.”  Time to this event is defined as the time from randomization to the onset of pain 
progression, where pain progression is defined as a 2-point or more increase from baseline in 
the question 3 pain score.  Patients without observed pain progression at the time of analysis 
will be right censored on the date of the last pain assessment for the purposes of analysis.  
A stratified log-rank test will be used to compare the 2 treatment groups. 

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10.3.3.2. Time to First Use of Cytotoxic Chemotherapy
Time to first use of cytotoxic chemotherapy is defined as the time from randomization to the 
first use of cytotoxic chemotherapy for prostate cancer.  Patients not starting treatment with a 
cytotoxic chemotherapy for prostate cancer at the time of analysis will be right censored on 
the date of the last assessment before the analysis data cutoff date for the purposes of 
analysis.  A stratified log-rank test will be used to compare the 2 treatment groups. 
10.3.3.3. Chemotherapy-Free Disease-Specific Survival
Chemotherapy-free disease-specific survival is defined as the time from randomization to 
first use of cytotoxic chemotherapy for prostate cancer or death due to prostate cancer as 
assessed by the investigator.  Patients not starting treatment with a cytotoxic chemotherapy or 
not know to have died due to prostate cancer at the time of analysis will be right censored at 
the date of last assessment before the analysis data cutoff date for the purposes of analysis.  
A stratified log-rank test will be used to compare the 2 treatment groups. 
10.3.3.4. Chemotherapy-Free Survival
Chemotherapy-free survival is defined as the time from randomization to first use of 
cytotoxic chemotherapy for prostate cancer or death due to any cause.  Patients not starting 
treatment with a cytotoxic chemotherapy or not known to have died at the time of analysis 
will be right censored at the date of last assessment before the analysis data cutoff date for 
the purposes of analysis.  A stratified log-rank test will be used to compare the 2 treatment 
groups. 
10.3.3.5. PSA Response
PSA response will be calculated as a decline from baseline PSA (ng/mL) to the maximal 
PSA response with thresholds at 50% and 90%.  Additionally, PSA response will be assessed 
as a decline to undetectable levels, where undetectable is defined as below the limit of 
quantification of the centrally assessed PSA results.  A PSA response must be confirmed by a 
second consecutive value at least 3 weeks later.  The percentage of patients with a maximal 
PSA decline of at least 50%, 90%, and undetectable will each be compared between the 
2 treatment groups using a stratified Cochran-Mantel-Haenszel mean score test. 
10.3.3.6. Quality of Life
FACT-P, EQ-5D-5L, and QLQ-PR25 quality-of-life data will be summarized descriptively 
by study visit. 
10.4. Safety Analyses
All safety analyses will use the safety population. 
Safety analyses will be summarized by treatment.  The treatment-emergent period is defined 
as the period of time from the first dose date of study drug to approximately 30 days after the 
last dose of study drug or the date of initiation of a new antineoplastic treatment, whichever 
occurs first.

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Adverse events occurring during the adverse event reporting period will be coded according 
to the Medical Dictionary for Regulatory Activities (MedDRA) and tabulated by system 
organ class and by preferred term within each system organ class.  Tabular summaries will 
include the incidence overall (number and percentage of patients with treatment-emergent 
adverse events classified by system organ class and preferred term); incidence by intensity 
(severity graded according to the CTCAE, version 4), causality, seriousness, and outcome 
(eg, leading to discontinuation of study drug); and other presentations as appropriate. 
Serious adverse events occurring prior to study treatment will be tabulated separately if 
considered related to study procedure. 
Patients with the same adverse event reported more than once will be counted once at the 
maximum severity or strongest relationship to study drug. 
Toxicity for laboratory parameters (hematology, serum chemistry) will be graded using the 
CTCAE, version 4.  Shift tables will be provided as appropriate for each parameter to 
summarize baseline toxicity grade versus postbaseline toxicity grade.  For each laboratory 
parameter that is not gradable by the CTCAE, a shift table based on the normal range (low, 
normal, and high) will be provided to summarize baseline result versus postbaseline result.  
For each laboratory parameter, the baseline laboratory value is defined as the last laboratory 
value collected on or prior to the date of the first dose of study drug. 
10.5. Other Analyses
Exposure: The dose and cumulative dose of enzalutamide (mg) and placebo will be 
summarized with descriptive statistics: n, mean, standard deviation, median, and range. 
Treatment compliance will be measured by the number of capsules taken during the study 
divided by the expected number of capsules, multiplied by 100%. 
10.6. Determination of Sample Size
The following assumptions were used in determining the sample size for the MFS endpoint:

2:1 enzalutamide to placebo treatment allocation;

Target hazard ratio of 0.72 at the 5% significance level with 90% power.  The 
targeted difference in Kaplan-Meier estimated median is 9 months (24 months vs 
33 months).  The median MFS of 24 months for the placebo arm is based on 
published data from a similar clinical trial.2
A minimum of 440 MFS events provides 90% power to detect a target hazard ratio of 
0.72 based on a 2-sided log-rank test at an overall significance level of 0.05.  A sample size 
of approximately 1305 patients will achieve 440 events within approximately 43 months.  It 
is assumed that a number of patients will be lost to follow-up, will be found to have 
metastatic disease at enrollment, or will have events censored due to required analytical 
methods.  To account for this anticipated loss in contribution of events to the primary and 

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secondary endpoint analyses, an additional 135 patients (approximately 10% of 1305) will be 
enrolled to achieve a final sample size of 1440 patients (960 enzalutamide and 480 placebo). 
The study is also powered for overall survival.  Specifically, 590 death events will be 
required to provide 85% power to detect a target hazard ratio of 0.77 with a target difference 
in Kaplan-Meier estimated median of 13.7 months (46 months for placebo vs 59.7 months for 
enzalutamide) at the 5% significance level.  The power analysis for the remaining key 
secondary endpoints will be discussed in the statistical analysis plan. 
11. STUDY COMMITTEES AND COMMUNICATIONS
An independent Data Monitoring Committee consisting of experts in prostate cancer, clinical 
trial safety monitoring, and statistics will periodically evaluate safety data for this study.  
Approximately every 6 months after the first 50 patients are enrolled and have reached their 
week 17 assessment, the Data Monitoring Committee will review all available safety data.  
A separate charter will outline the details for the composition and responsibilities of the Data 
Monitoring Committee. 
12. LABORATORY REQUIREMENTS
A central laboratory will analyze the clinical laboratory safety samples (hematology, serum 
chemistry) as described in Section 8.6, as well as the PSA and testosterone samples for this 
study.  The laboratory manual for this study provides details regarding sample collection 
procedures and laboratory tests. 
13. INVESTIGATOR AND ADMINISTRATIVE REQUIREMENTS
Before initiating the study, the investigator must provide to the sponsor a fully executed and 
signed Form FDA 1572, current curriculum vitae and financial disclosure, signed protocol 
signature page, and signed acknowledgment of receipt of the current enzalutamide 
investigator brochure.  Current curriculum vitae and financial disclosure must also be 
provided for all subinvestigator(s) listed on the Form FDA 1572.  Additional documents may 
also be necessary per local requirements. 
If an investigator changes during the course of the study, the sponsor and any local regulatory 
authorities, as applicable, must first approve the change of investigator and the new 
investigator must provide the sponsor all of the documents listed above. 
Sponsor personnel or representatives may visit the study site, if necessary, before initiation of 
the study to review information with study site personnel about protocol requirements 
pertaining to the study drug, case report forms, monitoring, serious adverse event reporting, 
and other relevant information. 

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13.1. Ethics
13.1.1. Ethics Committee
Before initiating the study, the investigator will obtain written confirmation from the EC that 
the EC is properly constituted and compliant with all requirements and local regulations.  
A copy of the confirmation will be provided to the sponsor. 
The investigator will provide the EC with all appropriate material, such as the protocol, 
current enzalutamide investigator brochure, site-specific informed consent form, and other 
written information provided to the patients.  The trial will not be initiated until appropriate 
EC approval of the protocol, informed consent document, and all recruiting materials are 
obtained in writing by the investigator and copies are received by the sponsor. 
EC approval will be obtained for any substantial protocol amendments and informed consent 
revisions before implementing the changes.  The investigator will provide appropriate reports 
on the progress of the study to the EC and to the sponsor or designee in accordance with 
applicable local regulations. 
13.1.2. Ethical Conduct of the Study
This study will be conducted under the guiding principles of the World Medical Association 
Declaration of Helsinki, and including current Good Clinical Practice (GCP) according to 
ICH guidelines.  Specifically, this study is based on adequately performed laboratory and 
animal experimentation; the study will be conducted under a protocol reviewed and approved 
by an EC; the study will be conducted by scientifically and medically qualified persons; the 
anticipated benefits of the study are in proportion to the risks; the rights and welfare of the 
patients will be respected; the physicians conducting the study do not find the hazards to 
outweigh the potential benefits; and each patient will provide written informed consent 
before any protocol-specific tests or evaluations are performed. 
13.1.3. Patient Information and Informed Consent
A properly executed, written informed consent, in compliance with the Declaration of 
Helsinki, ICH GCP, US Code of Federal Regulations (CFR) for Protection of Human 
Subjects (21 CFR 50.25[a,b], CFR 50.27, and CFR Part 56, Subpart A), and local 
regulations, will be obtained from each patient before entering the patient in the trial.  The 
investigator or designee will prepare the informed consent form and provide the documents 
to the sponsor or designee for approval before submission to the EC.  The sponsor and the 
EC must approve the documents before the investigator implements them. 
The investigator will provide copies of the signed informed consent form to each patient (or 
to the patient’s legal representative) and will maintain the signed original document within 
the patient’s record file per local requirements.  The investigator will also fully document the 
informed consent process in the patient’s source records. 

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13.1.4. Maintaining Patient Confidentiality
All reports and patient samples will be identified only by a screening ID number, a patient ID 
number, and/or actual initials (if permitted) or mock initials and date of birth (month/year 
only if no date is permitted) in order to maintain patient confidentiality.  Additional patient 
confidentiality issues are addressed in the clinical trial agreement and in the informed 
consent form signed by each study participant. 
13.2. Data Quality Assurance
13.2.1. Data Management
Clinical data management will be performed by the sponsor or designee according to 
procedures described in a comprehensive data management plan.  The data management plan 
will include procedures for processing the data from this study, and will describe the 
responsibilities of the sponsor and designee when clinical data management is provided by an 
external vendor.  In particular, the data management plan will include a list of the standard 
operating procedures that apply to this study. 
Adverse events and medications will be coded using MedDRA and the World Health 
Organization Drug Dictionary (WHO-DD), respectively.  The dictionary versions will be 
named in the data management plan. 
Interpretations of the radiographic and clinical data related to tumor assessments will be 
performed centrally by independent blinded review.  Data will be recorded using standard 
source documents and case report forms developed by the blinded independent radiology 
review vendor in accordance with the standard operating procedures of the vendor.  Vendor 
personnel will review the imaging data for completeness and inconsistencies and will 
generate queries as necessary.  All data review will be blinded to treatment assignment. 
13.2.2. Case Report Forms
The study will use an electronic data capture system.  All electronic case report forms will be 
designed and provided electronically to the site by the sponsor or designee and electronic 
data capture system vendor.  All case report form books are to be filled out completely, 
reviewed, and signed by the investigator or subinvestigators listed on the Form FDA 1572 or 
other appropriate local health authority documents. 
13.2.3. Study Monitoring
The sponsor or designee will monitor this study in accordance with current GCP guidelines.  
By signing this protocol, the investigator grants permission to the sponsor or designee and 
appropriate regulatory authorities to conduct onsite monitoring of all appropriate study 
documentation.  To ensure the accuracy of data collected on the case report forms, it is 
mandatory that sponsor representatives (eg, study monitor) have direct access to original 
source documents (eg, paper or electronic patient records, patient charts, and laboratory 
reports) needed to verify the entries on case report forms.  During the review of these 
documents, the anonymity of the patient will be respected with strict adherence to 
professional standards of confidentiality. 

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A study monitor will contact and visit the site regularly and will be allowed, on request at a 
mutually acceptable time, to inspect the various original medical records (paper or electronic) 
related to the study.  The study monitor will be responsible for inspecting the case report 
forms at regular intervals throughout the study, to verify the adherence to the protocol, and 
the completeness and correctness of all case report form entries.  The investigator agrees to 
cooperate with the study monitor to ensure that any problems detected in the course of these 
monitoring visits are resolved. 
13.2.4. Study Audits
During the course of the study and after study completion, it is likely that one or more quality 
assurance audits will be undertaken by authorized sponsor representatives.  The purpose of 
the audit is to ensure that the study is (or was) conducted and monitored in compliance with 
the protocol as well as recognized GCP guidelines and regulations.  These audits will also 
increase the likelihood that the study data and all other study documentation can withstand a 
regulatory authority inspection.  If such audits are to occur, they will be arranged for a 
reasonable and agreed upon time.  By signing this protocol, the investigator grants 
permission to the sponsor or designee to conduct onsite audits of all appropriate facilities and 
study documentation. 
13.3. Investigational Product Accountability
The investigator must maintain accurate records (including dates, quantities, and lot 
numbers) of all study drug supplies received.  All records must be made available to the 
sponsor, authorized representatives, and appropriate regulatory agencies, upon request. 
Current ICH GCP guidelines require the investigator to ensure that study drug deliveries 
from the sponsor are received by a responsible person (eg, pharmacist), and the following:  

That such deliveries are recorded, for example, on the sponsor’s drug accountability 
log or other sponsor-approved pharmacy log;

That study drug is handled and stored safely and properly in accordance with the label 
and the study protocol;

That study drug is only dispensed to study patients in accordance with the protocol;

That any unused study drug is returned to the sponsor-designated facility or standard 
procedures for the alternative disposition of unused study drug are followed and only 
after approval by the sponsor representative.
Drug inventory and accountability records for the study drugs will be kept by the 
investigator/pharmacist.  Study drug accountability throughout the study must be 
documented.  The following guidelines are therefore pertinent:  

The investigator agrees not to supply study drug to any persons except the patients in 
this study;

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
The investigator/pharmacist will keep the study drugs in a pharmacy or other locked 
and secure storage facility under controlled storage conditions, accessible only to 
those authorized by the investigator to dispense these study drugs;

The investigator/pharmacist will maintain a study drug inventory.  The inventory will 
include details of material received and a clear record of when they were dispensed 
and to which patient;

The investigator/pharmacist agrees to conduct a final drug supply inventory and to 
record the results of this inventory on the drug accountability record at the conclusion 
or termination of this study.  It must be possible to reconcile delivery records with 
those of used and returned study drug.  Any discrepancies must be accounted for.  
Appropriate forms of deliveries and returns must be signed by the person responsible;

Used or unused study drug may be destroyed at the study site according to standard 
institutional procedures if the sponsor agrees with the procedure, and after drug 
accountability has been conducted by the sponsor or representative, unless otherwise 
approved.  A copy of the standard institutional procedure for destroying 
investigational drugs will be provided to the sponsor or designee upon request for 
review and approval before the first onsite destruction.  Unused study drug not 
destroyed at the site must be returned to the sponsor-designated facility at the end of 
the study or upon expiration. 
13.4. Compensation, Insurance, and Indemnity
In the event of a side effect or injury, appropriate medical care as determined by the 
investigator or designated alternate will be provided. 
If bodily injury is sustained, resulting directly from the use of the study drug or by required 
study procedures, the sponsor will reimburse for reasonable physician fees and medical 
expenses necessary for treatment of only the bodily injury that is not covered by the patient’s 
medical or hospital insurance, provided that the injury is not due to a negligent or wrongful 
act or omission by the study doctor and study staff.  No other compensation of any type will 
be provided by the sponsor.  Financial compensation for lost wages, disability, or discomfort 
due to the study participation or procedures is not available. 
13.5. Retention of Records
The investigator must make original study data (paper or electronic) accessible to the study 
monitor, other authorized sponsor representatives, and regulatory agency inspectors 
(eg, FDA) upon request.  A file for each patient must be maintained that includes the signed 
informed consent form and copies of all source documentation related to that patient.  The 
investigator must ensure the reliability and availability of source documents from which the 
information on the case report form was derived. 
Patient identity information recorded will be maintained for at least 15 years on the patient 
confidentiality log or longer if required by local regulations. 

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Investigators must maintain all study documentation for at least 2 years following the 
approval of the drug, or until 2 years after the investigational drug program is discontinued, 
or longer if required by local regulations.  Study documentation includes all essential 
documents as defined in ICH E6 Guidelines for Good Clinical Practice.  The sponsor or 
designee will notify the investigator when any records may be discarded, but investigators 
must comply with local regulations. 
13.6. Study Termination
The sponsor will terminate this study following completion of the study objectives, or earlier 
if deemed necessary. 
The sponsor reserves the right to terminate the study anytime.  When the sponsor is aware of 
information on matters concerning the quality, efficacy, and safety of the study drugs, as well 
as other important information that may affect proper conduct of the clinical study, the 
sponsor may terminate the study and send a written notice of the termination along with the 
reasons to the investigator. 
If an investigator or the investigator’s EC intends to terminate participation in the study, the 
investigator must immediately inform the sponsor and provide the reason for it. 
14. USE OF STUDY INFORMATION AND PUBLICATION
The results of this study may be published or presented at scientific meetings.  However, the 
data generated in this clinical trial are the exclusive property of Medivation and are 
confidential.  Written approval from Medivation is required prior to disclosing any 
information related to this clinical trial.  The investigator agrees to submit all manuscripts or 
abstracts to Medivation prior to submission.  This allows the sponsor to protect proprietary 
information and to provide comments based on information from other studies that may not 
yet be available to the investigator.  The details of the processes of producing and reviewing 
reports, manuscripts, and presentations based on the data from this trial will be presented in 
the clinical study agreement. 
In accord with standard editorial and ethical practice, Medivation will generally support 
publication of multicenter trials only in their entirety and not as individual center data.  In 
this case, a coordinating investigator and lead author will be designated by mutual 
agreement. 
Any formal publication of the study in which input of Medivation personnel exceeded that of 
conventional monitoring will be considered as a joint publication by the investigator and the 
appropriate Medivation personnel.  Authorship will be determined by mutual agreement and 
all authors must meet the criteria for authorship established by the International Committee 
of Medical Journal Editors (ICMJE) or stricter local criteria.  Medivation does not 
compensate for authorship of a publication and all authors will be required to disclose, as part 
of the publication submission, any potential conflicts of interest, including pertinent financial 
or personal relationships with Medivation or related entities, including sponsors of competing 
products that might be perceived to be a source of bias. 
Investigators in this study agree to have their name listed as an investigator in any 
publication reporting results from this study, whether or not they are an author on the 
publication. 

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15. REFERENCES
1.
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.
2.
Nelson JB, Love W, Chin JL, et al. Phase 3, randomized, controlled trial of atrasentan in 
patients with nonmetastatic, hormone-refractory prostate cancer. Cancer 2008; 
113(9):2478-87.
3.
Scher HI, Heller G. Clinical states in prostate cancer: toward a dynamic model of 
disease progression. Urology 2000; 55(3):323-7.
4.
Cooperberg MR, Broering JM, Carroll PR. Time trends and local variation in primary 
treatment of localized prostate cancer. J Clin Oncol 2010; 28:1117-23.
5.
Smith MR, Kabbinavar F, Saad F, et al. Natural history of rising serum prostate-specific 
antigen in men with castrate nonmetastatic prostate cancer. J Clin Oncol 2005; 
23(13):2918-25.
6.
Smith MR, Saad F, Coleman R, et al. Denosumab and bone-metastasis-free survival in 
men with castration-resistant prostate cancer: results of a phase 3, randomised, 
placebo-controlled trial. Lancet 2012; 379(9810):39-46.
7.
Yu EY, Miller K, Nelson J, et al. Detection of previously unidentified metastatic disease 
as a leading cause of screening failure in a phase III trial of zibotentan versus placebo in 
patients with nonmetastatic, castration resistant prostate cancer. J Urol 2012; 
188(1):103-9.
8.
Tombal B. Non-metastatic CRPC and asymptomatic metastatic CRPC: which treatment 
for which patient? Ann Oncol 2012 Sep;23 Suppl 10:x251-8.
9.
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.
10.
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.
11.
Pound CR, Partin AW, Eisenberger MA, et al. Natural history of progression after PSA 
elevation following radical prostatectomy. JAMA 1999; 281(17):1591-7.
12.
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.
13.
Food and Drug Administration. Guidance for industry for drug induced liver injury: 
Premarketing clinical evaluation. Federal Register 2009; 74(145):38035-38036.
14.
O’Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics 
1979; 35(3):549-56.

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16. INVESTIGATOR SIGNATURE
Medivation, Inc.
PROSPER: A Multinational, Phase 3, Randomized, Double-Blind, Placebo-Controlled, 
Efficacy and Safety Study of Enzalutamide in Patients With Nonmetastatic 
Castration-Resistant Prostate Cancer
Signature of Agreement for Protocol MDV3100-14 (C3431005) 
Amendment 4, v5.0 – 26 Jan 2018
I have read this protocol and agree to conduct the study as outlined herein, in accordance 
with Good Clinical Practice and the Declaration of Helsinki, and complying with the 
obligations and requirements of clinical investigators and all other requirements listed 
in 21 CFR Part 312.
Print Study Site Name
Study Site Number
Print Investigator Name
Investigator Signature
Date

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Appendix 1. Brief Pain Inventory (Short Form)

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Appendix 2. Functional Assessment of Cancer Therapy - Prostate

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Appendix 3. European Quality of Life-5 Dimensions-5 Levels Health Questionnaire
Adapted from http://www.euroqol.org/ (UK [English] v.2 © 2009).  The original EQ-5D™ is 
a trademark of the EuroQol Group. 
Under each heading, please tick the ONE box that best describes your health TODAY:
Mobility
I have no problems in walking about.

I have slight problems in walking about.

I have moderate problems in walking about.

I have severe problems in walking about.

I am unable to walk about.

Self Care
I have no problems washing or dressing myself.

I have slight problems washing or dressing myself.

I have moderate problems washing or dressing myself.

I have severe problems washing or dressing myself.

I am unable to wash or dress myself.

Usual Activities (eg, work, study, housework, family or leisure activities)
I have no problems doing my usual activities.

I have slight problems doing my usual activities.

I have moderate problems doing my usual activities.

I have severe problems doing my usual activities.

I am unable to do my usual activities.

Pain/Discomfort
I have no pain or discomfort.

I have slight pain or discomfort.

I have moderate pain or discomfort.

I have severe pain or discomfort.

I have extreme pain or discomfort.

Anxiety/Depression
I am not anxious or depressed.

I am slightly anxious or depressed.

I am moderately anxious or depressed.

I am severely anxious or depressed.

I am extremely anxious or depressed.


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We would like to know how good or bad your 
health is TODAY.
This scale is numbered from 0 to 100.
100 means the best health you can imagine.
0 means the worst health you can imagine.
Mark and X on the scale to indicate how your 
health is TODAY.
Now, please write the number you marked on the 
scale in the box below.
YOUR HEALTH TODAY =
100
95
90
85
80
75
70
65
60
55
50
45
40
35
30
25
20
15
10
5
0
The best health 
you can imagine
The worst health 
you can imagine

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Appendix 4. European Organization for Research and Treatment of Cancer Quality of 
Life Questionnaire Prostate Disease Module: QLQ-PR25
Adapted from http://groups.eortc.be/qol/.  EORTC QLQ-PR25 is a copyright of EORTC 
Study Group on Quality of Life (1999). 

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EORTC QLQ-PR25
Patients sometimes report that they have the following symptoms or problems.  Please 
indicate the extent to which you have experienced these symptoms or problems during the 
past week.  Please answer by circling the number that best applies to you.
During the Past Week:
Not at 
All
A 
Little
Quite 
a Bit
Very 
Much
31.
Have you had to urinate frequently during the 
day?
1
2
3
4
32.
Have you had to urinate frequently at night?
1
2
3
4
33.
When you felt the urge to pass urine, did you 
have to hurry to get to the toilet?
1
2
3
4
34.
Was it difficult for you to get enough sleep, 
because you needed to get up frequently at 
night to urinate?
1
2
3
4
35.
Have you had difficulty going out of the house 
because you needed to be close to a toilet?
1
2
3
4
36.
Have you had any unintentional release 
(leakage) of urine?
1
2
3
4
37.
Did you have pain when you urinated?
1
2
3
4
38.
Answer this question only if you wear an 
incontinence aid.  Has wearing an incontinence 
aid been a problem for you?
1
2
3
4
39.
Have your daily activities been limited by your 
urinary problems?
1
2
3
4
40.
Have your daily activities been limited by your 
bowel problems?
1
2
3
4
41.
Have you had any unintentional release 
(leakage) of stools?
1
2
3
4
42.
Have you had blood in your stools?
1
2
3
4
43.
Did you have a bloated feeling in your 
abdomen?
1
2
3
4

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44.
Did you have hot flushes?
1
2
3
4
45.
Have you had sore or enlarged nipples or 
breasts?
1
2
3
4
46.
Have you had swelling in your legs or ankles?
1
2
3
4
Please go to the next page
During the Last 4 Weeks...
Not at 
All
A 
Little
Quite 
a Bit
Very 
Much
47.
Has weight loss been a problem for you?
1
2
3
4
48.
Has weight gain been a problem for you?
1
2
3
4
49.
Have you felt less masculine as a result of your 
illness or treatment?
1
2
3
4
50.
To what extent were you interested in sex?
1
2
3
4
51.
To what extent were you sexually active (with 
or without intercourse)?
1
2
3
4
PLEASE ANSWER THE NEXT FOUR QUESTIONS ONLY IF YOU HAVE BEEN 
SEXUALLY ACTIVE OVER THE LAST 4 WEEKS
52.
To what extent was sex enjoyable for you?
1
2
3
4
53.
Did you have difficulty getting or maintaining 
an erection?
1
2
3
4
54.
Did you have ejaculation problems (eg, dry 
ejaculation)?
1
2
3
4
55.
Have you felt uncomfortable about being 
sexually intimate?
1
2
3
4

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Appendix 5. Study Schedule of Activities
Study Period or Visit
Screening
Treatment
Unschedul
ed
Safety FU
Long-Term 
FU
Study Week
−4 to −1
1
5
17 Then Every 16
Varies [1]
Varies [2]
Every 16
Study Day
-28 to -1
1
29
113
na
na
na
Window (Days) [3]
na
na
±5
±5
na
±7
±7
General Activities
Informed consent and screening number 
(IXRS) [4]
X
Medical history
X
Eligibility criteria
X
12-Lead electrocardiogram (local read)
X
Radiographic assessments 
X [5]
X [6]
X opt [7]
X [6]
Randomization (IXRS) [8]
X
Complete physical examination [9]
X
X
Brief physical examination [10]
X
X
X
X
ECOG performance status
X
X
X
X
X
X
BPI-SF, FACT-P, EQ-5D-5L, 
QLQ-PR25 questionnaires
X
X
X
X [11]

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Study Period or Visit
Screening
Treatment
Unschedul
ed
Safety FU
Long-Term 
FU
Study Week
−4 to −1
1
5
17 Then Every 16
Varies [1]
Varies [2]
Every 16
Study Day
-28 to -1
1
29
113
na
na
na
Window (Days) [3]
na
na
±5
±5
na
±7
±7
Adverse events review [12]
X
X
X
X
X
Concomitant medications review
X
X
X
X
X
X
Study drug dispensing
X
X
Study drug accountability
X
X
X
Long-term follow-up assessments [13]
X
Central Laboratory Evaluations [14]
Hematology, serum chemistry 
X
X
X
X
X
Testosterone
X
Prostate-specific antigen
X
X
X
X

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Study Period or Visit
Screening
Treatment
Unschedul
ed
Safety FU
Long-Term 
FU
Study Week
−4 to −1
1
5
17 Then Every 16
Varies [1]
Varies [2]
Every 16
Study Day
-28 to -1
1
29
113
na
na
na
Window (Days) [3]
na
na
±5
±5
na
±7
±7
1.
Anytime necessary to assess or follow-up adverse events, perform scans, at the patient’s request, or per investigator decision.
2.
Approximately 30 days after the last dose of study drug.  If a new antineoplastic treatment is initiated before 30 days after the last dose of study drug, then 
safety follow-up will occur immediately before starting the new treatment.
3.
Drug supply must be taken into account if a window is used to schedule the next visit.  Visits may be split across the window to allow for drug resupply and 
completion of study procedures.
4.
Must obtain informed consent before performing any study-specific procedures. 
5.
Must be within 42 days before randomization.  Screening includes posteroanterior and lateral chest x-ray or chest CT scan, whole-body radionuclide bone 
scan, and abdominopelvic CT/MRI.  If the screening bone scan shows a lesion suggestive of metastatic disease, the patient will be eligible only if a second 
imaging modality (plain film, CT, or MRI) excludes bone metastasis.  If the imaging results are equivocal or consistent with metastasis, the patient is not 
eligible for enrollment.  Use the same imaging method throughout the study. 
6.
Perform approximately every 16 weeks, but obtain images sooner if progression is clinically suspected.  Radiographic imaging should be performed until 
radiographic progression is identified and confirmed by independent central radiology review per protocol.  A second imaging modality (plain film, CT, or 
MRI) confirmation of bone progression is required when bone lesions are found in a single region on the bone scan. 
7.
If disease progression is suspected, perform imaging studies as appropriate.
8.
Complete, sign, and fax the randomization authorization form to the medical monitor at the number provided on the form at least 2 business days before the 
day 1 visit.
9.
Assess systems per standard of care at the study site and as clinically indicated by symptoms.  Includes assessment of vital signs and weight (height only at 
screening). 
10. Symptom directed and includes investigating any new abnormalities and assessment of vital signs. 
11. Questionnaires will be completed for patients who come to the clinic. 
12. Collect nonserious adverse event information from the time of first dose of study drug through safety follow-up.  If no safety follow-up, collect adverse 
event information through 30 days after the last dose of study drug.  Phone patients for follow-up if they do not come to the clinic. 
13. May obtain at clinic visits, by phone contact, chart review, etc.  Includes survival status, new antineoplastic therapies for prostate cancer, opiate use, 
skeletal-related events, and interventions due to locoregional progression. 
14. Refer to the laboratory instruction manual for sample processing.

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Study Period or Visit
Screening
Treatment
Unschedul
ed
Safety FU
Long-Term 
FU
Study Week
−4 to −1
1
5
17 Then Every 16
Varies [1]
Varies [2]
Every 16
Study Day
-28 to -1
1
29
113
na
na
na
Window (Days) [3]
na
na
±5
±5
na
±7
±7
BPI-SF, Brief Pain Inventory Short Form; CT, computed tomography; ECOG, Eastern Cooperative Oncology Group; EQ-5D-5L, European Quality of 
Life-5 Dimensions-5 Levels health questionnaire; FACT-P, Functional Assessment of Cancer Therapy-Prostate; FU, follow-up; IXRS, interactive voice/web 
recognition system; MRI, magnetic resonance imaging; na, not applicable; opt, optional; QLQ-PR25, Quality of Life Questionnaire-Prostate 25.

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Supplement 1: Open-Label Period
NOTE: This supplement contains cross-references to the main protocol text where study procedures are to be performed in the same 
manner.  
Rationale: As the study met the primary efficacy endpoint of metastatis-free survival and the established safety profile of enzalutamide was confirmed all 
patients will be unblinded.  Eligible patients will receive enzalutamide at the discretion of the investigator.  For patients that have not progressed 
radiographically, scans (CT/MRI and bone scan) will be performed per investigator discretion until patient has progressed radiographically. Continuation of 
treatment on the open-label period after radiographic progression will at the discretion of the investigator.  Patients who do not participate in the open-label 
period or withdraw consent for further treatment will continue long-term follow-up assessments per protocol. Treatment with open-labeled Enzalutamide 
will be stopped upon disease progression when in the opinion of the Investigator, there is no added clinical benefit to continue treatment with Enzalutamide.
Long-term follow-up data (Includes survival status, new antineoplastic therapies for prostate cancer, skeletal-related events, and interventions due to 
locoregional progression) will be collected every 16 weeks.
Day 1 of the open-label period will occur after consent is signed and eligibility for all patients is verified. Patients who choose not to continue in the 
open-label period will discontinue treatment and return for safety follow-up within approximately 30 days after last dose.
Sites must have all open-label day 1 visits completed within 16 weeks after IRB/EC approval of this protocol amendment. 
Patients who will receive any other treatment for prostate cancer after unblinding, will not be eligible for an open label enzalutamide extension.
Schedule and Assessments:
For procedures see Supplement Table 1: Study Schedule of Activities (Open-Label Period).
Patients previously receiving enzalutamide will sign informed consent on open-label day 1 (their next regular scheduled visit following approval and 
activation of this protocol at the study site) and have clinic visits whenever clinically indicated or needed.  Patients previously receiving placebo will sign 
informed consent at screening and have clinic visits on open-label day 1, week 5, week 17, and every 16 weeks thereafter.  All patients must have their 
open-label day 1 visit within 16 weeks after the approval and activation of this protocol at the study site and no later than 6 weeks after screening (for 
placebo patients only).  The enrollment period will end after this time.  
Patients will take enzalutamide as four 40-mg soft gelatin capsules (160 mg/day) by mouth once daily with or without food.  
Study assessments will include survival status, new prostate cancer therapies, and safety evaluations including adverse events, concomitant medications, 
clinical laboratory tests, brief physical examinations, screening electrocardiograms (ECGs), and vital signs.  For patients that have not progressed 
radiographically, scans (CT/MRI and bone scan) will be performed per investigator discretion until patient has progressed radiographically by local 
determination.

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At a minimum, the following laboratory values from those listed in protocol Section 8.6 must be evaluated at screening (for placebo patients) and
throughout the study locally: 

Hematology: hematocrit, hemoglobin, platelet count, red blood cell count, white blood cell count with differential, and absolute neutrophil count 
must be obtained or be able to be calculated.  

Comprehensive chemistry panel: albumin, alkaline phosphatase, ALT (alanine aminotransferase), AST (aspartate aminotransferase), creatinine, 
blood urea nitrogen (BUN) or urea, Ca++, total CO2 (bicarbonate), glucose, Na+, K+, Cl-, total bilirubin.  
Patients are to have a safety follow-up approximately 30 days after the last dose of open-label enzalutamide.  If a new antineoplastic or investigational 
anticancer treatment is initiated before 30 days after the last dose, then safety follow-up should occur immediately before starting the new treatment.  
Long-term follow-up data will be collected every 16 weeks. The information collected will include survival status, new antineoplastic therapies for prostate 
cancer, skeletal-related events, and interventions due to locoregional progression.
Schematic - Open Label Treatment Period: 

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Inclusion Criteria:
The inclusion criteria apply to patients receiving enzalutamide or placebo during double-blind treatment.  Eligible patients must meet all inclusion criteria.  
1.
Received randomized double-blind treatment in PROSPER;
2.
Open-label day 1 visit is within 16 weeks after this amendment is approved and becomes effective at the study site;
3.
Is willing to maintain androgen deprivation therapy with a gonadotropin-releasing hormone (GnRH) agonist/antagonist or has had a bilateral 
orchiectomy;
4.
Is able to swallow enzalutamide capsules whole and to comply with study requirements throughout the study;
5.
Throughout the study, a male patient and his female partner of childbearing potential must use 2 acceptable methods of birth control (1 of which 
must include a condom as a barrier method of contraception) starting at screening and continuing through 3 months after the final study drug 
administration or per local guidelines where these require additional description of contraceptive methods.  Two acceptable methods of birth 
control thus include the following:

Condom (barrier method);
AND

One of the following is required:

Established and ongoing use of oral, injected, or implanted hormonal method by the female partner;

Placement of an intrauterine device or intrauterine system by the female partner;

Additional barrier method: Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository by the 
female partner;

Tubal ligation in the female partner;

Vasectomy or other procedure resulting in infertility (eg, bilateral orchiectomy), for > 6 months.
6.
Male patient agrees to use a condom if having sex with a pregnant woman throughout the study;
7.
Agrees to avoid sperm donation while taking enzalutamide.  

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Exclusion Criteria:
The exclusion criteria apply only to patients starting new treatment with enzalutamide after receiving placebo as randomized treatment.  Each patient must 
NOT meet any of the following criteria: 
1.
Has taken commercially available enzalutamide (Xtandi).
2.
Patients who progressed radiographically on double-blind portion of the trial and stopped treatment with investigational drug due to any reason.  
Note that patients who progressed radiographically on double-blind portion of the trial and continued treatment per protocol are allowed to 
participate in the open-label period. 
3.
Patients who started any other prostate cancer-related treatment after unblinding.
4.
Has any clinically significant cardiovascular, dermatologic, endocrine, gastrointestinal, hematologic, hepatic, infectious, metabolic, neurologic, 
psychological, pulmonary, or renal disorder or any other condition, including excessive alcohol or drug abuse, or secondary malignancy, that may 
interfere with study participation in the opinion of the investigator or medical monitor; 
5.
Has current or previously treated brain metastasis or active leptomeningeal disease;
6.
Has a history of seizure or a condition that may increase the risk of seizure;
7.
Has any of the following: total bilirubin 1.5-times the upper limit of normal (ULN) (except patients with a diagnosis of Gilbert’s disease), ALT 
2.5-times ULN at screening, AST 2.5-times ULN at screening.  For patients with documented liver metastases, ALT and AST exclusion is 
>5-times ULN; Absolute neutrophil count < 1000/μL, platelet count < 100,000/μL, or hemoglobin < 10 g/dL (6.2 mmol/L) at screening.  NOTE: 
may not have received growth factors or blood transfusions within 7 days before obtaining the hematology values at screening. Albumin < 3.0 g/dL 
(30 g/L) at screening.
8.
Has creatinine >2 mg/dL (177 mol/L) at screening.
Enzalutamide Administration, Storage, and Accountability: 
All patients will self-administer four 40-mg soft gelatin enzalutamide capsules (160 mg/day) by mouth once daily with or without food, unless they were 
receiving a reduced dose during double-blind treatment (treatment will continue at the reduced dose).  Patients should return all study drug bottles, including 
unused study drug to the site at each visit.  
Enzalutamide should be handled and stored safely and properly in accordance with the study drug label.  Study site personnel must make all reasonable 
efforts to obtain all bottles and unused study drug from patients who do not routinely return the bottles at study site visits.  Please refer to IP Manual.
Duration of Treatment and Criteria for Discontinuation: 
Open-label enzalutamide administration may continue as long as the investigator considers treatment to be beneficial or until any intolerable adverse event 
develops.  

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Dose modification: Patients who experience a grade 3 or higher toxicity that cannot be ameliorated by the use of adequate medical intervention may 
interrupt treatment for 1 week or until the toxicity grade improves to grade 2 or lower severity.  Subsequently, study drug dosing may be restarted at the 
original dose (160 mg/day) or a reduced dose (120 or 80 mg/day) in consultation with the medical monitor.  
If enzalutamide is coadministered with a strong CYP2C8 inhibitor (ie, gemfibrozil), 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 return to the dose used prior to initiation of the strong 
CYP2C8 inhibitor.  
Patients whose treatment is interrupted due to an adverse event and restarted will continue to have regularly scheduled study visits based on their enrollment 
date in the open-label period.  Patients will permanently discontinue treatment with enzalutamide for the following reasons:

Adverse event: If intolerable and cannot be ameliorated by adequate medical intervention; or that in the opinion of the investigator or medical 
monitor will lead to undue risk if enzalutamide continues;

Seizure or any condition that significantly predisposes the patient to seizure such as brain metastasis or clinically evident stroke;

Initiation of cytotoxic chemotherapy or investigational therapy for prostate cancer;

Persistent laboratory abnormality as follows:

Creatinine >354 mol/L (4.0 mg/dL);

Bilirubin, AST, or ALT >5-times the ULN;

AST or ALT > 3 times ULN and total bilirubin > 2 times ULN without findings of cholestasis;

Absolute neutrophil count 750/L;

Platelet count < 50,000/L.
Patients may also permanently discontinue enzalutamide treatment for the following reasons:

Withdrawal of consent (patient decision anytime for any reason).  Patients may withdraw consent for further treatment, but may still consent to 
participate in the long-term follow-up assessments of survival status and new prostate cancer therapies (via family, physician contacts, and public 
records). Study site personnel should document in the patient’s source records the specific details of the procedures the patient allows (eg, 
long-term follow-up) or declines (eg, further treatment);

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
Gross noncompliance with protocol procedures and/or study drug management;

Sponsor discontinuation of study:  The sponsor has the right to terminate the study anytime.  However, the sponsor will ensure that enzalutamide 
will be available to all patients who participate in the open-label period for as long as they are deriving clinical benefit.  
Patients who discontinue treatment with enzalutamide for any reason will have safety follow-up approximately 30 days after the last dose or before initiating 
treatment with a cytotoxic chemotherapy or investigational agent for prostate cancer.  If a new cytotoxic or investigational anticancer treatment is initiated 
before 30 days after the last dose of enzalutamide, then safety follow-up should occur immediately before starting the new treatment.  Long-term follow-up 
will commence after completion of safety follow-up.  
Loss to follow-up: Every reasonable effort should be made to contact patients apparently lost to follow-up to complete study-related assessments, record 
outstanding data, and retrieve study drug.  Following unsuccessful telephone contact, an effort to contact the patient by mail using a method that provides 
proof of receipt should be attempted.  Alternate contacts are permissible if the patient is not reachable (eg, primary care providers, referring physician, 
relatives).  Such efforts should be documented in the patient’s source documents.  
Prior and Concomitant Medications:
Medications taken within 4 weeks before open-label day 1 and any medications prescribed for chronic or intermittent use, or dose adjustments of these 
medications, must be recorded on the case report forms and source documents.  
Concomitant medications include all vitamins, herbal remedies, and over-the-counter and prescription medications.  Concomitant medications will be 
assessed at screening and all clinic visits.  If the use of any medication during the study is due to an adverse event, the adverse event must be recorded on the 
adverse event case report form and in the patient’s clinical record.  
Ongoing androgen deprivation therapy with a GnRH agonist/antagonist to maintain castrate levels of testosterone is required throughout the study if the 
patient has not had a prior bilateral orchiectomy.  
The use of concurrent cytotoxic chemotherapy or investigational anticancer agents is prohibited.
Initiation of bisphosphonates or denosumab for bone health is allowed.  Standard of care supplementation with calcium and vitamin D is encouraged.

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Statistical Methods: 
Two additional interim analyses and the final analysis of overall survival are planned after approximately 285, 440, and 596 deaths occur, respectively.  
Analyses will be performed using a stratified log-rank test to compare the 2 treatment groups on ITT population.  A multiplicity adjusted inferential 
procedure will be used to maintain the family-wise 2-sided type I error rate at 0.05.  If an interim analysis of overall survival is statistically significant, it 
will be reported as the final analysis and no subsequent analyses will be performed. 
The primary analysis of OS in the aforementioned interim and final analyses will be based on an ITT approach, which does not adjust for the potential 
confounding effects of crossover, and will be performed as planned per protocol. An additional confounding factor for the OS analysis may come from 
patients who choose to access commercial enzalutamide and other commercially available treatments for CRPC.  The sponsors plan to explore the effect of 
crossover and post-study systemic anticancer therapy using Rank-Preserving Structural Failure Time Model (RPSFTM), and the inverse probability of 
treatment weighting (IPTW) method.  Justifications, limitations and assumptions of RPFSTM and IPTW methods will be provided with further details in 
Statistical Analysis Plan.
No other efficacy endpoints will be formally tested. 
•
Time to First Use of New Antineoplastic Therapy: Time to first use of new antineoplastic therapy is defined as the time from randomization to the 
first use of new antineoplastic therapy for prostate cancer;
•
Time to First Use of Cytotoxic Chemotherapy: Time to first use of cytotoxic chemotherapy is defined as the time from randomization to the first 
use of cytotoxic chemotherapy for prostate cancer;
•
Chemotherapy-Free Disease-Specific Survival: Chemotherapy-free disease-specific survival is defined as the time from randomization to the first 
use of cytotoxic chemotherapy for prostate cancer or death due to prostate cancer as assessed by the investigator;
•
Chemotherapy-Free Survival: Chemotherapy-free survival is defined as the time from randomization to the first use of cytotoxic chemotherapy for 
prostate cancer or death due to any cause.
Safety analyses will include all patients who receive 1 dose or partial dose of study drug (safety population).  
Safety will be evaluated by the frequency of serious adverse events, frequency and severity of adverse events, frequency of study drug discontinuation due 
to adverse events, and frequency of new clinically significant changes in clinical laboratory values and vital signs. 
All adverse events will be coded to preferred term and system organ class using the Medical Dictionary for Regulatory Activities (MedDRA).  The number 
and percentage of patients with adverse events will be presented by MedDRA system organ class and preferred term, relationship to study treatment, and 
severity.  Descriptive statistics will be used. 
Central laboratory values (from the double-blind portion study) will be classified for severity using the National Cancer Institute Common Terminology 
Criteria for Adverse Events (CTCAE), version 4.  Descriptive statistics will be used to analyze the laboratory data.
CCI
CCI

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Supplement Table 1:Study Schedule of Activities (Open-Label Period)
Study Period or Visit
OL Screen [1]
Treatment
Unscheduled
Safety FU
Long Term FU
Study Week
na
OL 1 
[2]
OL 5 [3]
OL 17 Then 
Every 16
Varies [4]
Varies [5]
Every 16
Window (Days) [6]
na
na
5
5
na
7
7
General Activities
Informed consent [7]
X
X [8]
Eligibility criteria for OLE
X
Enrollment Authorization Form [9]
X
12 Lead electrocardiogram [10]
X
Brief physical examination [11]
X
X
X
X
X
Radiographic assessments [12]
X
X
X
Serious and non-serious adverse event 
monitoring [13]
X
X [3]
X
X
X
Concomitant medications review
X
X
X [3]
X
X
X
Dispense enzalutamide (via IWRS)
X
X
Study drug accountability
X [3]
X
X
Local  laboratory evaluation [14]
X
X
X
X (optional)
X
Long Tern Follow-up Assessments[15]
X [8]
X

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1.
Only for patients starting new treatment with enzalutamide (previously received placebo).  Qualifying patients continuing treatment with enzalutamide 
may proceed to open label day 1 procedures.  The investigator will assess and confirm patient eligibility for open label extension.  All screening 
procedure results and relevant medical history must be available to determine eligibility.  All inclusion criteria must be met and no exclusion criteria 
may apply.  No eligibility waivers will be granted.
2.
For patients previously receiving placebo, open label day 1, week 1, must be within 16 weeks after the approval and activation of this protocol at the 
study site and no later than 16 weeks after screening.  For patients continuing treatment with enzalutamide, open label day 1 will be their next regular 
scheduled visit following approval and activation of this protocol at the study site.  
3.
Only for patients starting new treatment with enzalutamide (previously received placebo).  
4.
Anytime necessary to assess or follow up adverse events, at the patient’s request, or per investigator decision.
5.
Approximately 30 days after the last dose of study drug.  If a new antineoplastic treatment is initiated before 30 days after the last dose of study drug, 
then safety follow up will occur immediately before starting the new treatment.
6.
Drug supply must be taken into account if a window is used to schedule the next visit.  Visits may be split across the window to allow for drug resupply 
and completion of study procedures.
7.
Must obtain informed consent before performing any study specific procedures at screening for patients starting new treatment with enzalutamide and on
day 1 for all patients continuing treatment with enzalutamide. 
8.
Only for patients continuing enzalutamide treatment.
9.
When the investigator determines a patient is eligible, study site personnel will complete and email this form to the e-mail address provided on the form.  
The sponsor medical monitor will approve the enrollment in writing or contact the study site.  No form is required for patients continuing enzalutamide 
treatment.  
10. Read locally.
11. Symptom directed and includes investigating any new abnormalities and assessment of vital signs.
12. For patients that have not progressed radiographically, scans (CT/MRI and bone scan) will be performed per investigator discretion until patient has 
progressed radiographically.  
13. Collect nonserious adverse event information from the time of signing of informed consent through safety follow up.  Collect and report serious adverse 
event information from the time of signed informed consent through screen failure or safety follow up.  If no safety follow up, collect adverse event 
information through 30 days after the last dose of study drug.  Phone patients for follow up if they do not come to the clinic.
14. Hematology, serum chemistry.  Report any clinically significant abnormalities as adverse events per CTCAE v4 criteria.  For patients previously 
receiving placebo, if the open label day 1 visit occurs within 7 days of performing the screening labs, then the laboratory assessments do not need to be 
repeated on day 1.
15. May obtain at clinic visits, by phone contact, chart review, etc.  Includes survival status, new antineoplastic therapies for prostate cancer, skeletal related 
events, and interventions due to locoregional progression. 
CTCAE v4, Common Terminology Criteria for Adverse Events, version 4; FU, Follow-up; L T, long term; na, not applicable; OL, open label; PC, 
prostate cancer; q16.

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