A Phase 3, Randomized, Efficacy and Safety Study of Enzalutamide Plus Leuprolide, Enzalutamide Monotherapy, and Placebo Plus Leuprolide in Men With High-Risk Nonmetastatic Prostate Cancer Progressing After Definitive Therapy
Phase: PHASE3
Conditions: Hormone Sensitive Prostate Cancer, Prostate Cancer, Cancer of the Prostate
Sponsor: Pfizer

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Medivation, Inc.
Study Title:
A Phase 3, Randomized, Efficacy and Safety Study of 
Enzalutamide Plus Leuprolide, Enzalutamide Monotherapy, 
and Placebo Plus Leuprolide in Men With High-Risk 
Nonmetastatic Prostate Cancer Progressing After Definitive 
Therapy 
Protocol Identifier:
MDV3100-13 (C3431004)
Phase:
3
Investigational Product:
Enzalutamide (formerly MDV3100)
Indication:
Prostate Cancer
Sponsor:
Medivation, Inc., a wholly owned subsidiary of Pfizer Inc.
66 Hudson Boulevard East
New York, NY 10001
Telephone: +1 (212) 573-2323
Medivation and Astellas Pharma Global Development, Inc. 
are in a partnership to codevelop enzalutamide for the 
treatment of cancer
Reference Numbers:
United States IND 
EudraCT 2014-001634-28
Original Protocol:
v1.0 – 03 Sep 2014
Amendment 1:
v2.0 – 09 Mar 2017
Amendment 2: 
v3.0 – 20 Aug 2018
Amendment 3:
v4.0 – 31 Mar 2020
Amendment 4:
v5.0 – 29 Oct 2021
Amendment 5:
v6.0 – 18 May 2023
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.
CCI

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Confidentiality Statement
The information contained in this document and all information provided to you related to 
enzalutamide are the confidential and proprietary information of Medivation, Inc. 
(“Medivation”) and except as may be required by federal, state, or local laws or 
regulations, may not be disclosed to others without prior written permission of Medivation.  
However, the investigator may disclose such information to supervised individuals 
working on enzalutamide, provided such individuals agree to be bound to maintain the 
confidentiality of such information.

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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
Amendment 5 (18 May 2023)
Overall Rationale for the Amendment: Primary endpoint analyses demonstrated that the 
primary efficacy endpoint of metastasis free survival (MFS) was established and the safety 
profile of enzalutamide was confirmed, therefore, the treatment codes for all patients will be 
unblinded and an open-label treatment period is being implemented.  The final analysis of the 
key secondary endpoint overall survival (OS) will be performed as planned.  Patients will 
continue to receive their originally assigned study treatment in this open-label study period.  
Patients assigned to the placebo plus leuprolide arm will no longer take the placebo capsules.  
No crossover treatment will be implemented. 
For patients whose cancer has not progressed radiographically, locally (change was effective 
as of 31 March 2023) performed scans (CT/MRI and bone scan) will be conducted until the 
patient’s cancer progresses radiographically.  Scans read centrally by blinded independent 
central reviewer (BICR) ceased as of 31 March 2023.  Prostate-specific antigen (PSA) levels 
will also be done at a local lab and monitored by the investigator per standard of care (SOC).  
Additionally, patients who are in treatment suspension (due to prior undetectable PSA at 
study Week 36) will have their PSA values done at the local lab and will be evaluated by the 
investigator every 3 months for possible treatment reinitiation per protocol criteria.
Patients who do not participate in the open-label treatment period (eg, patients who decide to 
discontinue treatment, withdraw consent from treatment, or patients who the investigator 
does not believe are continuing to benefit from study drugs) will continue long-term 
follow-up assessments per protocol.  Long-term follow-up data including survival status, new 
antineoplastic therapies for prostate cancer, skeletal-related events, and progression on first 
subsequent therapy (PFS2) will be collected every 12 weeks until the final OS analysis.  The 
associated endpoints will be summarized descriptively at the time of the final OS analysis.
Description of Change
Brief Rationale
Section # and Name
Substantial Modification(s)
Updates regarding the 
open-label and double-
blind periods were added.
The double-blind period has concluded 
and the open-label period is ongoing. 
The complete details for the conduct of 
the open-label period are provided in 
Supplement 1: Open-Label Study 
Period.  The completed double-blind 
protocol has not changed.
Synopsis
New section was added for 
description of activities 
during open-label period.
Complete details for the conduct of the 
open-label period are provided
Section 18. Supplement 1: 
Open-Label Study Period
Non-substantial Modification(s)
Abbreviations section was 
moved to Appendix 7 and 
new abbreviations were 
added.
Protocol template structure updated
Appendix 7

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Description of Change
Brief Rationale
Section # and Name
Updates regarding the 
double-blind and 
open-label periods were 
added.
Clarification regarding treatment 
periods.
Section 5.2
Regulatory and Ethical 
Considerations section was 
updated.
To comply with current regulations.
Section 13.1
Case Report Forms section
was updated.
A clarification was added regarding 
deletion of participant data.
Section 13.2.2
Retention of Records 
section was updated.
To comply with current regulations.
Section 13.5
Dissemination of Clinical 
Study Data information
was moved from Section 
14 to Section 13.7 and 
updated.
To comply with current regulations.
Sections 13.7 and 14
Publication Policy 
information was moved 
from Section 14 to Section 
13.8 and updated.
To comply with current regulations.
Sections 13.8 and 14
Investigator Signature page 
was removed from 
Protocol and provided 
separately.
To comply with current regulations.
Section 16 
Minor administrative, 
editorial, typographical, or 
formatting changes
Updated for grammatical correctness, 
consistency, and/or clarity as 
applicable, including update to Protocol 
Table of Contents
Global

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SYNOPSIS
Title of Study: A Phase 3, Randomized, Efficacy and Safety Study of Enzalutamide Plus Leuprolide, 
Enzalutamide Monotherapy, and Placebo Plus Leuprolide in Men With High-Risk Nonmetastatic Prostate 
Cancer Progressing After Definitive Therapy
Protocol Identifier: MDV3100-13 (C3431004)
Phase of Development: 3
Number of Patients: Approximately 1050 (350 per group)
Study Centers: Approximately 200 (international)
Study Objectives:
All efficacy and safety objectives will compare enzalutamide plus leuprolide and enzalutamide monotherapy 
versus placebo plus leuprolide.
Primary Endpoint: Metastasis-free survival (MFS) between enzalutamide plus leuprolide and placebo plus 
leuprolide.
Key Secondary Endpoints:
To evaluate efficacy, as measured by the following: 

MFS between enzalutamide monotherapy versus placebo plus leuprolide; 

Time to prostate-specific antigen (PSA) progression;

Time to first use of new antineoplastic therapy;

Overall survival.
Other Secondary Endpoints:

Time to distant metastasis;

Proportion of patients per group who remain treatment-free 2 years after suspension of study drug 
treatment at week 37 due to undetectable PSA;

Proportion of patients per group with undetectable PSA 2 years after suspension of study drug 
treatment at week 37 due to undetectable PSA;

Proportion of patients per group with undetectable PSA at 36 weeks on study drug;

Time to resumption of any hormonal therapy following suspension at week 37 due to undetectable 
PSA;

Time to castration resistance;

Time to symptomatic progression;

Time to first symptomatic skeletal event;

Time to clinically relevant pain;

Quality of life;

Safety.
Exploratory Endpoint :

Progression-free survival on first subsequent therapy (PFS2).
OPEN-LABEL PERIOD
As the study met the primary efficacy endpoint of MFS and the established 
safety profile of enzalutamide was confirmed, the treatment codes for all 
patients will be unblinded. 
Patients remaining on study treatment will continue to receive their originally 
assigned study treatment in an open-label study treatment period.  Patients 
assigned to the placebo plus leuprolide arm will no longer take the placebo 
capsules.  No crossover treatment will be implemented. For patients whose 
cancer has not progressed radiographically, locally performed scans (computed 
tomography [CT]/magnetic resonance imaging [MRI] and bone scan) will be 
performed per each institution’s standard of care until the patient’s cancer 
progresses radiographically.  PSA levels will be done at a local lab and 

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monitored by the investigator per standard of care. Patients who are in 
treatment suspension will have their assigned treatment reinitiated if 
subsequent local laboratory PSA values increase to ≥2.0 ng/mL for patients 
with prior prostatectomy or ≥5.0 ng/mL for patients who had prior radiation 
therapy.  Patients will not continue in the open-label period if they have had 
radiographic cancer progression.  
Patients who do not participate in the open-label period or withdraw consent 
for further treatment will continue safety follow-up (within approximately 30 
days after last dose) and long-term follow-up assessments per protocol.  
Long-term follow-up data (including survival status, new antineoplastic 
therapies for prostate cancer, skeletal-related events, and PFS2) will be 
collected every 12 weeks.
Day 1 of the open-label period will occur after consent is signed and eligibility 
is verified.  No crossover treatment will be implemented.  Sites must have all 
open-label Day 1 visits completed within 16 weeks after Institutional Review 
Board (IRB)/Ethics Committee (EC)  approval of this protocol amendment.  
Patients who will receive any other treatment for prostate cancer after 
unblinding will not be eligible for the open-label enzalutamide period (these 
patients will remain in the study, complete safety follow-up, and subsequently 
commence long-term follow-up).  
The complete details for the conduct of the open-label period are provided in
Supplement 1: Open-Label Study Period.
DOUBLE-BLIND PERIOD
The double-blind period has concluded and the open-label period is ongoing.  
The completed double-blind protocol has not changed.
Methods: This is an international, phase 3, randomized study of enzalutamide plus leuprolide, enzalutamide 
monotherapy, and placebo plus leuprolide in approximately 1050 men with high-risk nonmetastatic prostate 
cancer progressing after radical prostatectomy or radiotherapy or both.  No prior cytotoxic chemotherapy or 
androgen deprivation therapy (with exceptions) is allowed.  The primary efficacy endpoint is MFS.
Central randomization (1:1:1) will be used to assign patients to one of the following study drug treatments:

Enzalutamide plus leuprolide;

Enzalutamide monotherapy;

Placebo plus leuprolide.
Randomization will be stratified by screening PSA ≤10 ng/mL versus >10 ng/mL, PSA doubling time 
≤3 months versus >3 to ≤9 months, and prior hormonal therapy versus no prior hormonal therapy.  Treatment 
with enzalutamide monotherapy will be open label.  Treatment with enzalutamide and placebo will be 
double-blinded in combination with open-label leuprolide.

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Study drug treatments will be administered as follows, depending on treatment assignment:

Enzalutamide will be administered as four 40 mg soft gelatin capsules by mouth once daily 
(160 mg/day) with or without food.

Placebo capsules, identical in appearance to enzalutamide capsules, will be administered in the same 
manner as enzalutamide.

Leuprolide acetate (leuprorelin acetate), 22.5 mg will be given as a single intramuscular or 
subcutaneous injection once every 12 weeks (for a minimum of 3 doses, providing 36 weeks of 
treatment).
PSA will be monitored throughout the study, and at week 37, study drug treatment will be suspended for 
patients whose PSA values are undetectable (<0.2 ng/mL) at week 36 as determined by the central laboratory; 
PSA and testosterone will be measured every 3 months thereafter by the central laboratory.  As the PSA values 
will not be provided to study sites or patients, study sites will be notified whether a patient’s PSA value meets 
the specified threshold to determine whether or not to continue or suspend study drug treatment at week 37.  
Study drug treatment may be suspended only once (at week 37) due to undetectable PSA and will be reinitiated 
if subsequent central laboratory PSA values increase to ≥2.0 ng/mL for patients with prior prostatectomy or 
≥5.0 ng/mL for patients without prostatectomy.  Study sites will be notified if the PSA value meets the 
threshold specified for reinitiation of study drug treatment.  Patients with detectable PSA values at week 36 will 
continue treatment without suspension until permanent treatment discontinuation criteria are met.
All patients will have safety follow-up- after permanent discontinuation of randomized study drug treatment.  
Safety follow-up should occur approximately 30 days after the last dose of randomized study drug.  Long-term 
follow-up will occur after safety follow-up (every 12 weeks based on the 12-week visit schedule determined at 
randomization).
Throughout the study, investigators are encouraged not to obtain PSA assessments at their local laboratory.  
Beginning 22 Feb 2019, investigators started to be notified when any of their patients develop protocol defined 
PSA progression with a PSA doubling time (PSADT) ≤10 months while on study treatment based on central 
laboratory assessments.  Randomized study drug treatment must be permanently discontinued upon initiation of 
cytotoxic chemotherapy or antiandrogen therapy (eg, bicalutamide, nilutamide, or flutamide).  All patients who 
permanently discontinue study drug treatment will remain in the study, complete safety follow-up, and 
subsequently commence long-term follow-up, which may include imaging for patients who have not yet had 
confirmed radiographic progression.
Patients are strongly encouraged to obtain an adequate intake of dietary calcium (at least 1000 mg per day, 
including supplements if necessary) and vitamin D (at least 800-1000 international units per day for adults 
50 years of age and older) and to engage in regular exercise to maintain muscle strength and bone density.  
Study Assessments:
The following assessments of prostate cancer status will be made during the course of the study: soft tissue 
disease on computed tomography (CT) scan or on magnetic resonance imaging (MRI), bone disease on whole-
body radionuclide bone scans, survival status, PSA values, testosterone, resumption of any hormonal therapy, 
new antineoplastic therapy and surgery/interventions for prostate cancer, symptomatic skeletal events, pain 
using the Brief Pain Inventory (Short Form), and quality of life using the Functional Assessment of Cancer 
Therapy Prostate (FACT-P) questionnaire, European Quality of Life 5-Dimensions 5-Levels Health 
Questionnaire (EQ-5D-5L), and the Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) module.
Imaging with CT or MRI for soft tissue disease and whole-body radionuclide bone scans for bone disease will 
be conducted every 6 months to assess for radiographic progression.  A bone scan will assess 5 regions of the 
skeleton 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.  Assessment of soft tissue disease will be 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).

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Reference Therapy, Dose, and Mode of Administration:
Placebo capsules, identical in appearance to enzalutamide capsules, administered in the same manner as 
enzalutamide.  The sponsor will provide blinded placebo capsules for the blinded treatment group.  Leuprolide 
injections will not be blinded with a placebo injection.
Duration of Treatment:
Study drug treatment will continue uninterrupted in the absence of disease progression until the central 
laboratory PSA evaluation at week 36.  Based on PSA values at week 36, study drug treatment will either 
continue or be suspended at week 37.  Following week 37, PSA and testosterone will be measured every 
3 months by the central laboratory.  Study drug treatment will be reinitiated if subsequent central laboratory 
PSA values increase to ≥2.0 ng/mL for patients with prior prostatectomy or ≥5.0 ng/mL for patients without 
prostatectomy.  Study drug treatment may be suspended only once during this study (at week 37) due to 
undetectable PSA.  Patients with detectable PSA values at week 36 will continue treatment without suspension 
until permanent treatment discontinuation criteria are met.
Statistical Methods:
The primary efficacy analysis of MFS will be conducted using the intent to treat (ITT) population, defined as all 
patients randomly assigned to study treatment.  Central randomization will be used, and treatment allocation 
will be 1:1:1.  Randomization will be stratified as described in the Methods section.  All efficacy analyses will 
incorporate the stratification factors used at randomization unless otherwise noted.  The analytical approach will 
be described in detail in the statistical analysis plan.  Treatment group comparisons will be between the 
combination arm of enzalutamide plus leuprolide versus placebo plus leuprolide and between enzalutamide 
monotherapy therapy versus placebo plus leuprolide.
Primary Efficacy Endpoint: 
For the primary endpoint, MFS, the stratified log-rank test will be used to compare enzalutamide plus leuprolide 
versus placebo plus leuprolide.  The primary efficacy endpoint is MFS using independent, blinded central 
radiology reviewer assessment of radiographic progression.  MFS is defined as the duration of time in months 
between randomization and the earliest objective evidence of radiographic progression by central imaging or 
death.
The primary endpoint analysis will be performed when at least 197 MFS events occur in the 3 treatment groups 
combined, at which time approximately 142 MFS events are expected to occur in the 2 blinded treatment groups 
combined for the primary hypothesis.
Secondary Efficacy Endpoints:
A hierarchical approach will be utilized to preserve the family wise type I error rate.  The family-wise 
type I error adjustment for key secondary endpoint analyses will be described in detail in the statistical analysis 
plan.  Kaplan–Meier methods will be used to describe the distributions of all time-to-event endpoints with 
inferential testing conducted using the stratified log-rank test.  If the combination demonstrates statistical 
significance compared to placebo plus leuprolide for MFS, alpha will be split to allow for the testing of key 
secondary endpoints between these arms and key secondary endpoints between enzalutamide monotherapy 
versus the placebo plus leuprolide.  All secondary endpoints will be reported at the time of the primary MFS 
analysis except for symptomatic skeletal related events, which will be reported at the time of the final overall 
survival analysis.  
Key Secondary Endpoints 
Metastasis-free survival between enzalutamide monotherapy versus placebo plus leuprolide will be defined as 
above for the combination comparison.
Time to PSA progression is defined as the time from randomization to the date of the first PSA value 
demonstrating progression, while patients are on study treatment, which is subsequently confirmed at least 
3 weeks later.
In patients who DO NOT have treatment suspended due to undetectable PSA at week 36: Those with PSA 
decline at week 25, 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 25).

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For patients who have treatment suspended due to undetectable PSA at week 36: Following treatment 
suspension and reinitiation of study drug, 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 at week 36 is documented, which is confirmed 
by a second consecutive value obtained at a subsequent study visit.
Time to first use of new antineoplastic therapy is defined as the time from randomization to first use of new 
antineoplastic for prostate cancer.  Patients not starting treatment with a new antineoplastic therapy at the time 
of analysis will be censored at the date of last assessment before the analysis data cutoff date.  It will be 
compared between treatment groups using a 2-sided stratified log rank test.  This will include medications used 
specifically for prostate cancer treatment including hormonal treatments, immunotherapy, chemotherapy and 
investigative agents.
Overall survival is defined as the time between randomization and death of any cause.  Overall survival will be 
compared between treatment groups using a 2-sided stratified log-rank test.  Long-term follow-up data (survival 
status and skeletal related events and new prostate cancer therapies) will be collected every 12 weeks up until 
the final analysis of OS.
Other Secondary Endpoints
The time to distant metastasis is defined as the time in months from randomization to the earliest objective 
evidence of distant soft tissue metastases or metastatic bone disease by central imaging.  Soft tissue disease 
including lymph nodes above the aortic bifurcation and outside the pelvis and any bone metastases will be 
counted as distant metastases.
The proportion of patients who remain treatment-free 2 years after suspension of study drug treatment at 
week 37 due to undetectable PSA will be compared between treatment groups using the stratified 
Cochran-Mantel-Haenszel test.
The proportion of patients per group with undetectable PSA at 36 weeks will be compared between treatment 
groups using the stratified Cochran-Mantel-Haenszel test.
The time to resumption of any hormonal therapy is defined as the time between the date of treatment suspension 
at week 37 due to undetectable PSA and the date that hormonal therapy is restarted.
The time to first symptomatic skeletal event is defined as the time from randomization to use of radiation 
therapy (external beam radiation therapy or radionuclides) or surgery to bone for prostate cancer, findings of 
clinically apparent pathologic bone fracture or of spinal cord compression, or new use of opiate and/or systemic 
antineoplastic therapy due to bone pain, whichever occurs first.  Because skeletal events are expected to occur 
after radiographic progression, the analysis of time to first symptomatic skeletal event will be performed with 
the final overall survival analysis.
Time to castration resistance applies only to patients receiving leuprolide treatment and is defined as the first 
occurrence of radiographic disease progression, PSA progression (as defined above) or symptomatic skeletal 
event with castrate levels of testosterone (<50 ng/dL).
Time to symptomatic progression is defined as the time from randomization to development of a skeletal-related 
event, worsening of disease-related symptoms requiring initiation of a new systemic anti-cancer therapy, or 
development of adverse events and clinically significant signs and/or symptoms due to loco-regional tumor 
progression requiring opiate use, surgical intervention or radiation therapy, whichever occurs first.
Time to clinically relevant pain (defined as a 2-point increase from baseline on the Brief Pain Inventory [Short 
Form] question 3) and quality of life (measured by the time to a 10-point decline in global FACT-P quality of 
life score) will be compared between treatment groups using a 2-sided log-rank test.  FACT-P, EQ-5D-5L, and 
QLQ-PR25 data will be summarized descriptively by study visit.

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Exploratory Endpoints
PFS2 is defined as the time from the date of randomization to the first occurrence of investigator-determined 
disease progression (PSA progression, progression on imaging, or clinical progression) or death due to any 
cause, whichever occurred first, while the patient was receiving first subsequent therapy for prostate cancer.  
PFS2 will be compared between treatment groups using a 2-sided log rank test.  The HR and 95% CI will be 
provided.  The median PFS2 and 95% CI for the median will be provided for each treatment arm.
Safety will be evaluated by the incidence of serious adverse events, incidence and severity of adverse events, 
incidence of permanent treatment discontinuation due to adverse events, and incidence of new clinically 
significant changes in clinical laboratory values and vital signs.  Safety data will be collected from the first dose 
of any randomized study drug treatment through 30 days after the last dose (ie, permanent discontinuation) of 
randomized study drug treatment, and includes the period following potential protocol-specified suspension and 
potential resumption of study drug treatment through subsequent permanent treatment discontinuation.  All 
safety analyses will be performed using the safety population, defined as all patients who receive any amount of 
study drug.  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.
Laboratory values will be classified for severity using the National Cancer Institute Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.  Laboratory shift tables of baseline results to each subsequent 
visit will be produced as appropriate.  

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Sample Size Considerations: 
The following assumptions are used in determining the sample size for this study:

Overall type I error rate: 0.05;

Patient accrual rate: An adaptive enrollment rate has been modified into two arms to fit into 
EAST v6.4 software from Cytel;

Randomization: 1:1:1;

Median MFS for the control group: 55 months.
An observed 142 MFS events in the 2 blinded treatment groups will provide approximately 90% power to detect 
a target hazard ratio of 0.58 using a 2-sided log-rank test with a 0.05 level of significance.  This target hazard 
ratio corresponds to a difference of approximately 40 months in median MFS assuming an exponential 
distribution in the duration of MFS and a constant hazard rate for each group.  For the key secondary hypothesis 
of MFS for the monotherapy arm, the target effect size, and expected number of MFS events will be the same as 
the primary hypothesis in the combination arm.  As a 2-sided alpha of 0.03 will be utilized for the monotherapy 
comparison, the power for this analysis will be 86% with 142 MFS events observed.  At the time of the final 
analysis, at least 197 MFS events total are required for the 3 treatment groups. An enrollment of approximately 
1050 patients (350 in each group) is required to achieve the targeted total of 197 MFS events allowing for a 5% 
loss to follow-up as outlined in the Statistical Analysis Plan.
The actual enrollment of 1068 patients will also allow for an assessment for the key secondary endpoint of OS, 
assuming a 5-year OS rate of 80% for the control arm and hazard ratio of 0.67.
The significance level associated with the test of OS, in blinded treatment arm and monotherapy arm 
comparisons, will depend on the outcome of the key secondary endpoints. If the key secondary endpoints of 
time to PSA progression and time to first use of antineoplastic therapy, for the blinded treatment arms, are 
statistically significant then an alpha of 0.02 will be contributed to the comparison of OS according to the 
gatekeeping procedure.  Similarly, if the key secondary endpoints of MFS, time to PSA progression, and time to 
first use of antineoplastic therapy, for the monotherapy treatment arm, are statistically significant then an alpha 
of 0.03 will be contributed to the comparison of OS.  With 191 deaths the power to detect a hazard ratio of 0.67 
is 79.0% (if all key secondary endpoints are significant for both the blinded arm and monotherapy arm 
comparisons), 72.3% (if the key secondary endpoints are significant for the monotherapy arm only) or 67.0% (if 
the key secondary endpoints are significant for the blinded arms only) using a 2-sided log-rank test at a 
significance level of 0.05, 0.03 or 0.02, respectively, and a 2-look group sequential design with a Haybittle-Peto 
efficacy boundary.

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TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE......................................3
SYNOPSIS.................................................................................................................................5
LIST OF TABLES...................................................................................................................20
LIST OF FIGURES .................................................................................................................20
APPENDICES .........................................................................................................................21
1. INTRODUCTION ...............................................................................................................22
1.1. Background .............................................................................................................22
1.2. Summary of Relevant Clinical Experience with Enzalutamide..............................23
1.2.1. Pharmacokinetics and Drug Metabolism....................................................25
1.3. Summary of Relevant Nonclinical Experience With Enzalutamide.......................26
1.4. Enzalutamide Benefits and Risks Assessment........................................................27
2. STUDY OBJECTIVES........................................................................................................27
2.1. Primary Objective ...................................................................................................27
2.1.1. Primary Endpoint........................................................................................27
2.2. Secondary Objectives..............................................................................................28
2.3. Key Secondary Endpoints .......................................................................................28
2.4. Other Secondary Endpoints.....................................................................................28
2.5. Exploratory Endpoint ..............................................................................................28
3. INVESTIGATIONAL PLAN..............................................................................................28
3.1. Overall Study Design and Plan: Description...........................................................28
3.2. Study Schematic......................................................................................................30
3.3. Blinding...................................................................................................................31
3.4. Duration of Study....................................................................................................31
3.5. Discussion of Study Design, Including Choice of Control Group..........................32
4. SELECTION OF STUDY POPULATION .........................................................................32
4.1. Inclusion Criteria.....................................................................................................32
4.2. Exclusion Criteria....................................................................................................34
5. ENROLLMENT AND STUDY PROCEDURES ...............................................................36
5.1. Screening Period .....................................................................................................36
5.1.1. Screening Identification Numbers..............................................................36
5.1.2. Screening Visit Procedures.........................................................................37

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5.2. Treatment Period.....................................................................................................38
5.2.1. Visit Windows ............................................................................................38
5.2.2. Week 1, Day 1 ............................................................................................39
5.2.3. Week 13......................................................................................................40
5.2.4. Week 25......................................................................................................41
5.2.5. Week 36......................................................................................................42
5.2.6. Week 37......................................................................................................42
5.2.7. Week 41......................................................................................................43
5.2.8. Week 49 and Repeating Every 12 Weeks...................................................43
5.2.9. Unscheduled Visits.....................................................................................44
5.3. Permanent Treatment Discontinuation....................................................................45
5.4. Safety Follow-Up ....................................................................................................47
5.5. Long-Term Follow-Up............................................................................................48
5.6. Loss to Follow-Up...................................................................................................49
6. INVESTIGATIONAL PRODUCT INFORMATION.........................................................49
6.1. General Information ................................................................................................49
6.2. Enzalutamide Product Characteristics.....................................................................50
6.2.1. Packaging of Enzalutamide or Placebo ......................................................50
6.2.2. Storage of Enzalutamide or Placebo...........................................................50
6.2.3. Directions for Administration of Enzalutamide or Placebo .......................50
6.2.4. Directions for Dose Modification of Enzalutamide or Placebo..................50
6.3. Leuprolide Product Characteristics .........................................................................51
6.3.1. Packaging of Leuprolide.............................................................................51
6.3.2. Storage of Leuprolide .................................................................................51
6.3.3. Directions for Administration of Leuprolide..............................................51
6.3.4. Directions for Dose Modification of Leuprolide........................................51
6.4. Treatment Compliance ............................................................................................52
7. PRIOR AND CONCOMITANT THERAPY......................................................................52
7.1. Prior Therapy...........................................................................................................52
7.2. Concomitant Therapy..............................................................................................52
7.3. Potential Interactions Between the Test Products and Concomitant 
Medications ...............................................................................................................53

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7.3.1. Enzalutamide ..............................................................................................53
7.3.2. Effects of Enzalutamide on Exposure to Other Drugs................................53
7.3.2.1. Drugs That May Affect Exposure to Enzalutamide..................53
7.3.3. Leuprolide...................................................................................................54
7.4. Precautions Regarding Concomitant Medications ..................................................54
8. ADVERSE EVENT REPORTING......................................................................................54
8.1. Requirements...........................................................................................................55
8.1.1. Additional Details On Recording Adverse Events on the Case Report 
Form.................................................................................................................56
8.1.2. Eliciting Adverse Event Information..........................................................56
8.1.3. Withdrawal From the Study Due to Adverse .............................................56
8.1.4. Time Period for Collecting AE/SAE Information......................................57
8.1.5. Reporting SAEs to Pfizer Safety ................................................................57
8.1.6. Recording Non-serious AEs and SAEs on the Case Report Form .............57
8.1.7. Causality Assessment .................................................................................57
8.1.8. Sponsor’s Reporting Requirements to Regulatory Authorities ..................58
8.2. Special Safety Considerations.................................................................................58
8.2.1. Study Drug Dose Modification Due to Adverse Event ..............................58
8.2.2. Emergency Procedure for Unblinding Treatment Assignment Due to 
Adverse Event..................................................................................................58
8.2.3. Contraception..............................................................................................59
8.3. Definitions...............................................................................................................59
8.3.1. Adverse Events...........................................................................................59
8.3.2. Abnormal Test Findings .............................................................................60
8.3.3. Serious Adverse Events ..............................................................................61
8.3.4. Hospitalization............................................................................................61
8.4. Severity Assessment................................................................................................63
8.5. Special Situations ....................................................................................................63
8.5.1. Protocol –Specified Serious Adverse Events .............................................63
8.5.2. Potential Cases of Drug-Induced Liver Injury............................................63
8.5.3. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................65
8.5.3.1. Exposure During Pregnancy......................................................65

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8.5.3.2. Exposure During Breastfeeding ................................................66
8.5.3.3. Occupational Exposure .............................................................66
8.5.4. Medication Errors .......................................................................................67
8.5.4.1. Medication Errors......................................................................67
8.5.5. Serious Adverse Event and Event of Special Interest Reporting ...............68
8.5.5.1. Clarification in Reporting of Seizures.......................................69
8.5.5.2. Clarification in Reporting of Deaths .........................................69
8.5.6. Follow-Up of Serious and Nonserious Adverse Events .............................69
8.6. Clinical Laboratory Safety Tests.............................................................................69
8.7. Physical Examinations, Vital Signs, and Electrocardiograms ................................70
9. ASSESSMENT OF EFFICACY AND SAFETY ENDPOINTS ........................................71
9.1. Assessment of Efficacy ...........................................................................................71
9.1.1. Assessments for the Primary Efficacy Endpoint ........................................71
9.1.2. Assessment of Radiographic Progression...................................................71
9.1.3. Assessments for the Secondary and Exploratory Efficacy Endpoints........72
9.1.3.1. Assessment of PSA ...................................................................72
9.1.3.2. Assessment of Time to First Use of New Antineoplastic 
Therapy..............................................................................................73
9.1.3.3. Assessment of Time to Distant Metastasis................................73
9.1.3.4. Assessment of Survival .............................................................73
9.1.3.5. Assessment of Resumption of any Hormonal Therapy.............73
9.1.3.6. Assessment of Symptomatic Skeletal Events............................73
9.1.3.7. Assessment of Castration Resistance ........................................73
9.1.3.8. Assessment of Time to Symptomatic Progression....................74
9.1.3.9. Assessment of Pain....................................................................74
9.1.3.10. Assessment of Quality of Life.................................................74
9.1.3.11. Assessment of PFS2................................................................75
9.2. Assessment of Safety ..............................................................................................75
9.3. ECOG Performance Status Assessments ................................................................76
10. STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION........................76
10.1. Statistical and Analytical Plans.............................................................................76
10.2. Randomization Methods .......................................................................................76

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10.3. Analysis Populations.............................................................................................76
10.4. Efficacy Analyses..................................................................................................77
10.4.1. Primary Efficacy Endpoint Analysis: Metastasis-Free Survival ..............77
10.4.2. Key Secondary Efficacy Endpoint Analyses............................................77
10.4.2.1. Time to PSA Progression ........................................................79
10.4.2.2. Time to First Use of New Antineoplastic Therapy .................79
10.4.2.3. Overall Survival ......................................................................79
10.4.3. Other Secondary Efficacy Endpoint Analyses .........................................79
10.4.3.1. Time to Distant Metastasis......................................................79
10.4.3.2. Proportion of Patients who Remain Treatment-Free at 
2 Years After Suspension of Study Drug Treatment.........................80
10.4.3.3. Proportion of Patients With Undetectable PSA at 2 Years .....80
10.4.3.4. Proportion of Patients With Undetectable PSA at 
36 Weeks ...........................................................................................80
10.4.3.5. Time to Resumption of any Hormonal Therapy .....................80
10.4.3.6. Time to First Symptomatic Skeletal Event .............................80
10.4.3.7. Time to Castration Resistance.................................................80
10.4.3.8. Time to Symptomatic Progression ..........................................81
10.4.3.9. Time to Clinically Relevant Pain ............................................81
10.4.3.10. Quality of Life.......................................................................81
10.4.4. Exploratory Analyses................................................................................81
10.4.5. PFS2..........................................................................................................81
10.5. Safety Analyses.....................................................................................................81
10.6. Other Analyses ......................................................................................................82
10.7. Determination of Sample Size...............................................................................82
10.8. Interim Analysis ....................................................................................................84
11. STUDY COMMITTEES AND COMMUNICATIONS ...................................................85
12. LABORATORY REQUIREMENTS ................................................................................85
13. INVESTIGATOR AND ADMINISTRATIVE REQUIREMENTS .................................85
13.1. Regulatory and Ethical Considerations.................................................................86
13.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or 
ICH GCP..........................................................................................................87
13.1.2. Informed Consent Process ........................................................................87

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13.1.3. Data Protection .........................................................................................88
13.2. Data Quality Assurance.........................................................................................89
13.2.1. Data Management.....................................................................................89
13.2.2. Case Report Forms ...................................................................................89
13.2.3. Study Monitoring......................................................................................89
13.2.4. Study Audits .............................................................................................90
13.3. Investigational Product Accountability.................................................................90
13.4. Compensation, Insurance, and Indemnity.............................................................91
13.5. Retention of Records.............................................................................................91
13.6. Study Termination.................................................................................................91
13.7. Dissemination of Clinical Study Data...................................................................92
13.8. Publication Policy .................................................................................................93
14. USE OF STUDY INFORMATION AND PUBLICATION .............................................96
15. REFERENCES ..................................................................................................................97
16. INVESTIGATOR SIGNATURE.......................................................................................99
17. APPENDICES .................................................................................................................100
18. SUPPLEMENT 1: OPEN-LABEL STUDY PERIOD ....................................................114
18.1. Rationale and Treatment Plan .............................................................................114
18.1.1. Blinding ..................................................................................................116
18.2. Open-Label Study Period....................................................................................116
18.3. Study Procedures and Assessments.....................................................................117
18.3.1. Telehealth Visits.....................................................................................118
18.3.2. Safety Assessments.................................................................................118
18.3.3. Radiographic Assessments .....................................................................119
18.3.4. Monitoring PSA Progression..................................................................119
18.4. Investigational Product........................................................................................119
18.4.1. Enzalutamide Administration, Storage, and Accountability ..................119
18.4.2. Leuprolide Administration, Storage, and Accountability.......................120
18.4.3. Shipment of Enzalutamide to Study Participants ...................................120
18.5. Duration of Treatment and Dose Modification...................................................120
18.6. Concomitant Medications – Follow-up Anticancer Medications .......................121
18.7. Treatment Interruption and Discontinuation.......................................................121

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18.7.1. Loss to Follow-Up..................................................................................121
18.8. Safety Follow-up and Long-Term Follow-Up ....................................................122
18.9. Statistical Methods ..............................................................................................123

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LIST OF TABLES
Table 1.
Screening Procedures................................................................................37
Table 2.
Week 1, Day 1 Procedures........................................................................39
Table 3.
Week 13 Procedures .................................................................................40
Table 4.
Week 25 Procedures .................................................................................41
Table 5.
Week 37 Procedures .................................................................................42
Table 6.
Week 49 and Repeating Every 12 Weeks Procedures..............................44
Table 7.
Unscheduled Visit Procedures..................................................................45
Table 8.
Safety Follow-Up Procedures...................................................................48
Table 9.
Long-Term Follow-Up Procedures...........................................................49
Table 10.
Criteria for Determining Causal Relationship to Study Drug ..................58
Table 11.
Criteria for Determining the Severity (Intensity) of an Adverse 
Event.........................................................................................................63
Table 12.
Clinical Laboratory Safety Tests ..............................................................70
Table 13.
ECOG Performance Status Assessments..................................................76
Table 14.
MFS Based on Independent Review (2 blinded treatment arms) -
Efficacy Boundary....................................................................................84
Table 15.
OS (2 blinded treatment arms) - Efficacy Boundaries..............................85
Table 16.
Supplement Table 1: Study Schedule of Activities (Open-Label 
Period).....................................................................................................115
Table 17.
Safety Follow-Up Procedures (Open-Label Period)...............................122
Table 18.
Long-Term Follow-Up Procedures (Open-Label Period) ......................122
LIST OF FIGURES
Figure 1.
Study Schematic .......................................................................................31
Figure 2.
Testing Flowchart for Primary Endpoint and Key Secondary 
Endpoints of Combination Therapy and Monotherapy ............................78
Figure 3.
Schematic – Open-Label Treatment Period............................................117

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APPENDICES
Appendix 5. Study Schedule of Activities.............................................................................104
Appendix 6. Alternative Measures During Public Emergencies ...........................................107
Appendix 7. Abbreviations....................................................................................................111
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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.[1] Following the initial evaluation 
and diagnosis of prostate cancer, approximately 90% of men in the United States undergo 
primary localized treatment with curative intent.[2] Of those, approximately one-third 
experience rising prostate-specific antigen (PSA) or biochemical recurrence after primary 
therapy.[3] This rise in PSA uniformly represents recurrence of prostate cancer, the likely 
presence of micrometastatic disease, and an increased risk of morbidity and mortality from 
prostate cancer.[4],[5]
Despite the recurrence of prostate cancer, most men with biochemical recurrence after 
primary therapy do not develop metastases or die from prostate cancer.[5],[6],[7] However, 
a subset of men with rising PSA following primary therapy will develop clinically apparent 
metastases and will die as a result of the disease.[6],[8] Despite available prognostic factors, 
no therapies are approved for hormone-sensitive high-risk nonmetastatic prostate cancer with 
evidence of disease recurrence by PSA but without overt metastases. 
To benefit men with early-stage disease and features indicating a high risk of morbidity and 
mortality from prostate cancer progression, a desirable therapy must demonstrate a favorable 
safety profile and good efficacy in terms of delaying metastasis and death from prostate 
cancer, that is, in prolonging metastasis-free survival (MFS).  Ideally, short-term treatment 
with such a therapy may eradicate or suppress the disease manifestations for a prolonged 
period, thereby decreasing the need for exposure to the harmful effects of Long-term surgical 
or medical castration.
This phase 3 randomized study is designed to address this unmet medical need in a defined 
patient population of men with hormone-sensitive high-risk nonmetastatic prostate cancer 
progressing after definitive therapy, and will determine whether enzalutamide plus leuprolide 
or enzalutamide monotherapy is more effective than placebo plus leuprolide.  High-risk 
prostate cancer is defined in this study as biochemical recurrence with a PSA doubling time 
≤9 months and screening PSA by the central laboratory of ≥1 ng/mL for patients who had 
prior radical prostatectomy (with or without radiotherapy) and at least 2 ng/mL above the 
nadir for patients who had prior primary radiotherapy only.
The rationale for repowering the study’s primary endpoint and reassessing relevant 
secondary endpoints is based on recent clinical trial results of enzalutamide and other 
androgen targeting agents in similar comparator populations wherefrom it became apparent 
that the original statistical analysis plan for EMBARK was too conservative with a target 
hazard ratio of 0.75 for MFS.  The PROSPER[9] (hazard ratio = 0.29; refer to Section 1.2)
and SPARTAN[10] (hazard ratio = 0.28) studies demonstrated statistically significant and 
clinically meaningful improvement in MFS in patients with nonmetastatic castration-resistant 
prostate cancer.  Additionally, data from a subpopulation of STAMPEDE showed[11] robust 
clinical and radiological activity in patients similar to EMBARK with nonmetastatic 
hormone-sensitive prostate cancer.  The nonmetastatic population from STAMPEDE 

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represents the best analog for clinical data in this setting.  While not identical, the primary 
endpoint of MFS (hazard ratio = 0.21) (which includes PSA, clinical and radiographic 
progression) had a hazard ratio of 0.21, suggesting a robust effect of abiraterone in the 
nonmetastatic-hormone-sensitive setting.  Historically, treatment with enzalutamide has 
shown robust activity in relevant endpoints in all prostate cancer studies thus far ranging 
from earlier nonmetastatic castration-resistant prostate cancer (CRPC) stage to metastatic 
CRPC post-multiple lines of chemo as in the PREVAIL and AFFIRM studies (refer to 
Section 1.2) thus further supporting the expectation of a significant treatment effect.
1.2. Summary of Relevant Clinical Experience with Enzalutamide
The 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.[12] Xtandi was later approved in Canada, the 
European Union, and other countries for use in this patient population.  Xtandi has 
subsequently been approved in multiple countries for the treatment of all patients with 
metastatic or nonmetastatic castration-resistant prostate cancer and metastatic 
castration-sensitive cancer (in the US).[13],[14]
Medivation, a wholly owned subsidiary of Pfizer, and Astellas Pharma Global Development, 
Inc. are in a partnership to codevelop enzalutamide for the treatment of cancer.
The key clinical studies evaluating enzalutamide in men with CRPC are described briefly as 
follows:
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.[12] The primary endpoint was 
overall survival.  The prespecified interim analysis at the time of 520 events
demonstrated a statistically significant improvement in overall survival in patients 
treated with enzalutamide versus placebo (hazard ratio 0.63 [95% confidence interval 
(CI): 0.53, 0.75]; p <0.0001).  Current marketing application approvals are based on the 
results of this pivotal study.
MDV3100-03 (PREVAIL): A phase 3, randomized, double-blind, placebo-controlled, 
efficacy and safety study of enzalutamide (160 mg daily) in chemotherapy-naïve 
patients with progressive metastatic prostate cancer who have failed 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.  The prespecified interim analysis at the time of 540 death 
events demonstrated statistically significant improvements in overall survival and 
radiographic progression-free survival in patients treated with enzalutamide versus 
placebo.  Enzalutamide treatment resulted in prolongation of overall survival (hazard 
ratio 0.71 [95% CI: 0.60, 0.84]; p <0.0001) and radiographic progression-free survival 
(hazard ratio 0.19 [95% CI: 0.15, 0.23]; p <0.0001).

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MDV3100-14 (PROSPER): A phase 3, randomized (2:1), double-blind, placebo-
controlled efficacy and safety study of enzalutamide (160 mg daily) was conducted in 
1401 men with nonmetastatic, castration-resistant prostate cancer and a PSA doubling 
time of 10 months or less, continuing on androgen-deprivation therapy received 
enzalutamide or placebo once daily.  The primary end point was MFS.  The median 
MFS was 36.6 months in the enzalutamide group versus 14.7 months in the placebo 
group (hazard ratio for metastasis or death, 0.29; 95% confidence interval, 
0.24 to 0.35; P<0.001).  The time to the first use of a subsequent antineoplastic therapy 
was longer with enzalutamide treatment than with placebo (39.6 vs. 17.7 months; hazard 
ratio, 0.21; P<0.001; such therapy was used in 15% vs. 48% of patients) as was the time 
to PSA progression (37.2 vs. 3.9 months; hazard ratio, 0.07; P<0.001; progression 
occurred in 22% vs. 69% of patients).  At the third interim and final analysis of OS, 
conducted when 466 deaths were observed, a statistically significant improvement in 
overall survival was demonstrated in patients randomized to receive enzalutamide 
compared with patients randomized to receive placebo with a 26.6% reduction in risk of 
death (hazard ratio = 0.734; 95% CI: 0.608, 0.885; p = 0.0011).
In addition to the clinical studies in men with metastatic CRPC, a key clinical study
evaluated enzalutamide monotherapy in men with hormone-sensitive prostate cancer as 
follows:
9785-CL-0321: A phase 2, open-label, single-arm, multicenter, efficacy and safety study 
of enzalutamide monotherapy (160 mg daily) was conducted in 67 patients with 
hormone-naïve prostate cancer for whom androgen deprivation therapy was indicated.  
The primary objective was to determine the incidence of patients with a ≥80% PSA 
response at week 25.  Secondary objectives included evaluation of safety and 
tolerability; exploratory objectives included evaluation of lipids, body mass, bone 
density, markers of bone turnover, and quality of life.  At week 25, the PSA response 
was 93% (62 of 67 patients; 95% CI, 86%-99%) and the median PSA decrease was 
99.6%. 
Including these studies, approximately 8000 subjects and patients have been enrolled 
worldwide in completed and ongoing clinical trials evaluating enzalutamide, including more 
than 7000 men with prostate cancer.
In the phase 3 study CRPC2 (AFFIRM; N = 1199), the most common adverse drug reactions 
(≥5%) in patients treated with enzalutamide (N = 800) were asthenia/fatigue, back pain, 
diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, upper 
respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, 
spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and 
hypertension.  Discontinuations due to adverse events were reported for 16% of 
enzalutamide-treated patients and 18% of placebo-treated patients.  The most common 
adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of 
the enzalutamide-treated patients and none (0%) of the placebo-treated patients. 

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In the phase 3 study MDV3100-03 (PREVAIL; N = 1717 enrolled), enzalutamide was 
generally well tolerated with an overall safety profile consistent with that observed in 
study CRPC2, with a lower seizure rate observed in study MDV3100-03 (1 patient [0.1%] 
each in the enzalutamide and placebo treatment groups).  The new adverse drug reactions 
observed in study MDV3100-03, gynecomastia and restless legs syndrome, were uniformly 
nonserious events occurring at low frequency (3.3% and 2.1%, respectively, in 
enzalutamide-treated patients vs 1.3% and 0.4%, respectively, in placebo-treated patients).
In the phase 2 study 9785-CL-0321, enzalutamide monotherapy was well tolerated.  Most 
common treatment-emergent adverse events were grade 1, and included gynecomastia (36%), 
fatigue (34%), nipple pain (19%), and hot flush (18%).  Five patients had serious adverse 
events; none of the events were assessed as related to enzalutamide treatment.  Mean changes 
from baseline for fasting metabolic variables were +5.0% total cholesterol, 
+8.9% triglycerides, -3.5% hemoglobin A1C, and +19.7% insulin resistance (homeostasis 
model assessment-estimated insulin resistance).  Total body bone mineral density was 
maintained (-0.3% from baseline).  Quality of life scores at 1 year demonstrated maintenance 
of global health status, and decreased sexual activity and sexual functioning.
Additional information on the clinical experience with enzalutamide is provided in the 
Enzalutamide Investigator Brochure.
1.2.1. Pharmacokinetics and Drug Metabolism
In pharmacokinetics (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.  At steady state, enzalutamide showed 
approximately dose proportional PK over the daily dose range of 30 to 360 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) 
administered orally 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 7.3.2).  Orally administered 
substrates of CYP3A4, CYP2C9, and CYP2C19 with a narrow therapeutic index should be 

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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 
CYP2C8 inhibitor is discontinued, the enzalutamide dose should be returned to the dose used 
before initiation of the strong CYP2C8 inhibitor.  The effects of CYP2C8 inducers on the PK 
of enzalutamide have not been evaluated in vivo (Section 7.3.2.1.1).
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 7.3.2.1.2). 
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
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 and 49 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 toxicologic profile of N-desmethyl enzalutamide appears to be very similar 
to enzalutamide.
The toxicity studies tested enzalutamide formulated in Labrasol, the same excipient used in 
clinical studies and in the commercial product marketed for CRPC.

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Based on nonclinical findings in repeat-dose toxicity 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). 
Long term carcinogenicity studies for enzalutamide include a completed 26-week study in 
Tg.rasH2 mice and a 2-year study in Wistar Han rats.  There were no enzalutamide-related 
neoplastic findings in Tg.rasH2 mice.  In the 2-year rat study, there were increased 
incidences of secondary urothelial carcinomas and tumors in hormone sensitive organs that 
included Leydig cell tumors, benign thymomas, pituitary gland adenomas and fibroadenomas 
of the mammary gland.  The tumors in the hormone sensitive organs are considered related to 
the primary pharmacology of enzalutamide and the Leydig cell tumors are not considered 
relevant to humans. The human relevance of thymoma, pituitary adenoma and fibroadenoma 
of the mammary gland in rats is not well known but the potential cannot be ruled out.
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.
Additional information on the nonclinical experience with enzalutamide is provided in the 
Enzalutamide Investigator Brochure (IB), which is the single reference safety document 
(SRSD) for this study 
1.4. Enzalutamide Benefits and Risks Assessment
Approximately 8000 subjects and patients have been enrolled worldwide in completed and 
ongoing clinical trials evaluating enzalutamide, including more than 7000 men with prostate 
cancer.  Available data for enzalutamide in men with metastatic prostate cancer that has 
progressed despite therapy with a luteinizing hormone-releasing hormone (LHRH) analogue 
or bilateral orchiectomy support a positive benefit-risk profile for the use of enzalutamide as 
an investigational agent for treatment in earlier-stage prostate cancer, including patients with 
high-risk nonmetastatic prostate cancer progressing after definitive therapy.  The clinical 
experience with enzalutamide is discussed briefly in Section 1.2. 
2. STUDY OBJECTIVES
All efficacy and safety objectives will compare enzalutamide plus leuprolide and 
enzalutamide monotherapy versus placebo plus leuprolide. 
2.1. Primary Objective
To evaluate efficacy as measured by the following:
2.1.1. Primary Endpoint
To evaluate efficacy of the combination of enzalutamide plus leuprolide versus placebo plus 
leuprolide, as measured by MFS.

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2.2. Secondary Objectives
To evaluate efficacy as measured by the following:
2.3. Key Secondary Endpoints

To evaluate efficacy, as measured by MFS between enzalutamide monotherapy 
versus placebo plus leuprolide.

Time to PSA progression:
Time to first use of new antineoplastic therapy;
Overall survival.
2.4. Other Secondary Endpoints

Time to distant metastasis;

Proportion of patients per group who remain treatment-free 2 years after suspension 
of study drug treatment at week 37 due to undetectable PSA;

Proportion of patients per group with undetectable PSA 2 years after suspension of 
study drug treatment at week 37 due to undetectable PSA;

Proportion of patients per group with undetectable PSA at 36 weeks on study drug;

Time to resumption of any hormonal therapy following suspension at week 37 due to 
undetectable PSA;

Time to first symptomatic skeletal event;

Time to castration resistance;

Time to symptomatic progression;

Time to clinically relevant pain;

Quality of life;

Safety. 
2.5. Exploratory Endpoint

Progression-free survival on first subsequent therapy (PFS2).
3. INVESTIGATIONAL PLAN
3.1. Overall Study Design and Plan: Description
This is an international, phase 3, randomized study of enzalutamide plus leuprolide, 
enzalutamide monotherapy, and placebo plus leuprolide in approximately 1050 men with 
high-risk nonmetastatic prostate cancer progressing after radical prostatectomy or 
radiotherapy or both.  No prior cytotoxic chemotherapy or androgen deprivation therapy 

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(with exceptions) is allowed.  The primary efficacy endpoint is MFS in the combination arm 
of enzalutamide plus leuprolide versus placebo plus leuprolide. 
Central randomization (1:1:1) will be used to assign patients to one of the following study 
drug treatments:

Enzalutamide plus leuprolide;

Enzalutamide monotherapy;

Placebo plus leuprolide.
Randomization will be stratified by screening PSA ≤10 ng/mL versus >10 ng/mL, PSA 
doubling time ≤3 months versus >3 to ≤9 months, and prior hormonal therapy versus no prior 
hormonal therapy.
Treatment with enzalutamide monotherapy will be open label.  Treatment with enzalutamide 
and placebo will be double-blind in combination with open-label leuprolide.
Study drug treatments will be administered as follows, depending on treatment assignment:

Enzalutamide will be administered as four 40 mg soft gelatin capsules by mouth once 
daily (160 mg/day) with or without food.

Placebo capsules, identical in appearance to enzalutamide capsules, will be 
administered in the same manner as enzalutamide.

Leuprolide acetate (leuprorelin acetate), 22.5 mg will be given as a single 
intramuscular or subcutaneous injection once every 12 weeks (for a minimum of 
3 doses, providing 36 weeks of treatment).
PSA will be monitored throughout the study, and at week 37, study drug treatment will be 
suspended for patients whose PSA values are undetectable (<0.2 ng/mL) at week 36 as 
determined by the central laboratory; PSA and testosterone will be measured every 3 months 
thereafter by the central laboratory.  As the PSA values will not be provided to study sites or 
patients, study sites will be notified whether a patient’s PSA value meets the specified 
threshold to determine whether or not to continue or suspend study drug treatment at 
week 37.  Study drug treatment may be suspended only once (at week 37) due to 
undetectable PSA and will be reinitiated if subsequent central laboratory PSA values increase 
to ≥2.0 ng/mL for patients with prior prostatectomy or ≥5.0 ng/mL for patients without 
prostatectomy.  Study sites will be notified if the PSA value meets the threshold specified for 
reinitiation of study drug treatment.  Patients with detectable PSA values at week 36 will 
continue treatment without suspension until permanent treatment discontinuation criteria are 
met. 
All patients will have safety follow-up after permanent discontinuation of randomized study 
drug treatment.  Safety follow-up should occur approximately 30 days after the last dose of 

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randomized study drug. Long-term follow - up will occur after safety follow-up (every 
12 weeks based on the 12-week visit schedule determined at randomization). 
Throughout the study, investigators are encouraged not to obtain PSA assessments at their 
local laboratory.  Beginning 22 Feb 2019, investigators started to be notified when any of 
their patients develop protocol defined PSA progression with a PSADT ≤10 months while on 
study treatment based on central laboratory assessments.  Randomized study drug treatment 
must be permanently discontinued upon initiation of cytotoxic chemotherapy or antiandrogen 
therapy (eg, bicalutamide, nilutamide, or flutamide).  All patients who permanently 
discontinue study drug treatment will remain in the study, complete safety follow-up, and 
subsequently commence long-term follow-up, which may include imaging for patients who 
have not yet had confirmed radiographic progression.
Pain will be assessed using the Brief Pain Inventory (Short Form).  Quality of life will be 
evaluated using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) 
questionnaire, the European Quality of Life 5-Dimensions 5-Levels Health Questionnaire 
(EQ-5D-5L), and the Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) module.  
Patients who are illiterate, blind, or dyslexic; have motor deficit of their hands or difficulty 
working with electronic devices; or are otherwise unable to independently complete the 
questionnaires are not required to complete the electronic questionnaires.
Patients are strongly encouraged to obtain an adequate intake of dietary calcium (at least 
1000 mg per day, including supplements if necessary) and vitamin D (at least 
800-1000 international units per day for adults 50 years of age and older) and to engage in 
regular exercise to maintain muscle strength and bone density.
Primary efficacy endpoint analyses have been completed and the safety profile is consistent 
with the product prescribing information.  The open-label period of the study has been 
established and the study has been unblinded for all study patients.  The final analysis of the 
key secondary endpoint OS will be performed as planned.
3.2. Study Schematic
The study schematic is provided in Figure 1.

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3.5. Discussion of Study Design, Including Choice of Control Group
This study is designed to test whether enzalutamide plus leuprolide treatment or 
enzalutamide monotherapy can prolong MFS compared with placebo plus leuprolide 
treatment in men with biochemical recurrence of prostate cancer after primary therapy who 
are at high risk of morbidity and mortality.  Prolongation of MFS is likely to delay or prevent 
prostate cancer symptoms and delay the need for subsequent therapies to treat prostate cancer 
(including cytotoxic chemotherapy).
The study population will be a subset of men with rising PSA following primary therapy that 
is at high risk for developing metastases, castration-resistant disease, and who will ultimately 
die as result of prostate cancer.  High-risk prostate cancer is defined in this study as 
biochemical recurrence with a PSA doubling time ≤9 months and screening PSA by the 
central laboratory of ≥1 ng/mL for patients who had prior radical prostatectomy (with or 
without radiotherapy) and at least 2 ng/mL above the nadir for patients who had prior 
primary radiotherapy only.  In theory, men who have rising PSA following definitive therapy 
have either occult metastatic disease or local progression, and it is likely that the great 
majority of these men have occult metastatic disease.[4],[15] Enzalutamide is hypothesized to 
be effective in this setting of minimal tumor burden and disease that is not yet castration 
resistant based on an understanding of the mechanism of action of enzalutamide and data 
obtained in patients with hormone-naïve prostate cancer treated with enzalutamide 
monotherapy.[16]
A key feature of the study design is to treat patients for a prespecified interval (36 weeks) 
and then to suspend treatment based on response as indicated by undetectable PSA 
(<0.2 ng/mL), thus potentially averting the adverse effects associated with long-term 
continuous androgen deprivation therapy.  Study drug treatment may be reinitiated if PSA 
rises to ≥2.0 ng/mL for patients who had prior radical prostatectomy or ≥5.0 ng/mL for 
patients who had prior radiation therapy.  For patients whose PSA values are detectable at 
36 weeks, assigned study drug treatment will continue.  Only 1 such study drug treatment 
suspension is permitted during this study. 
The control group is placebo with androgen deprivation therapy using leuprolide.  Androgen 
deprivation therapy is appropriate in this disease setting as it is commonly used when 
a decision is made to treat patients with high-risk nonmetastatic disease with biochemical 
recurrence following definitive therapy.
4. SELECTION OF STUDY POPULATION
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.

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2. Histologically or cytologically confirmed adenocarcinoma of the prostate at initial 
biopsy, without neuroendocrine differentiation, signet cell, or small cell features.
3. Prostate cancer initially treated by radical prostatectomy or radiotherapy (including 
brachytherapy) or both, with curative intent.  Prostate cryoablation is not considered 
definitive therapy for this study, but its prior use is not exclusionary.
4. PSA doubling time ≤9 months as calculated by the sponsor.[17]
5. Screening PSA by the central laboratory ≥1 ng/mL for patients who had radical 
prostatectomy (with or without radiotherapy) as primary treatment for prostate cancer 
and at least 2 ng/mL above the nadir for patients who had radiotherapy only as 
primary treatment for prostate cancer.
6. Serum testosterone ≥150 ng/dL (5.2 nmol/L) at screening.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at 
screening.
8. Estimated life expectancy of ≥12 months.
9. Able to swallow the study drug and comply with study requirements.
10. Throughout the study, the 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) from screening through 3 months 
after the last dose of study drug 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 is required);

AND
One of the following is required:

Established and ongoing use of oral, injected, or implanted hormonal method 
of contraception by the female partner;

Placement of an intrauterine device or intrauterine system by the female 
partner;

Additional barrier method including contraceptive sponge and occlusive cap 
(diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/suppository by the female partner;

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
Tubal ligation in the female partner performed at least 6 months before 
screening;

Vasectomy or other procedure resulting in infertility (eg, bilateral 
orchiectomy), performed at least 6 months before screening.
11. Throughout the study, the patient must use a condom if having sex with a pregnant 
woman. 
12. Must agree not to donate sperm from first dose of study drug through 3 months after 
the last dose of study drug.
4.2. Exclusion Criteria
Each patient eligible to participate in this study must NOT meet any of the following 
exclusion criteria:
1. Prior or present evidence of distant metastatic disease as assessed by computed 
tomography (CT) or magnetic resonance imaging (MRI) or chest x-ray for soft tissue 
disease and whole-body radionuclide bone scan for bone disease.  Patients with soft 
tissue pelvic disease may be eligible if the short axis of the largest lymph node is 
< 20 mm for lymph nodes below aortic bifurcation.  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 by central radiology 
review, the patient is not eligible for enrollment.  Positron-emission tomography 
(PET) is not an evaluable imaging modality for this study.
2. Prior hormonal therapy.  Neoadjuvant/adjuvant therapy to treat prostate cancer 
≤36 months in duration and ≥9 months before randomization, or a single dose or a 
short course (≤6 months) of hormonal therapy given for rising PSA ≥9 months before 
randomization is allowed.
3. Prior cytotoxic chemotherapy, aminoglutethimide, ketoconazole, abiraterone acetate, 
or enzalutamide for prostate cancer.
4. Prior systemic biologic therapy, including immunotherapy, for prostate cancer.
5. Major surgery within 4 weeks before randomization date.
6. Treatment with 5-reductase inhibitors (finasteride, dutasteride) within 4 weeks of 
randomization.
7. For patients who had a prior prostatectomy, a suitable candidate for salvage 
radiotherapy as determined by the investigator in consideration of appropriate 
guidelines (eg, American Society for Radiation Oncology/American Urological 
Association [ASTRO/AUA]; European Association of Urology [EAU]).

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8. Participation in a clinical study of an investigational agent that inhibits the androgen 
receptor or androgen synthesis (eg, TAK-700, ARN-509, ODM-201); patients who 
received placebo are allowed.
9. Use of any other investigational agent within 4 weeks before randomization date.
10. Known or suspected brain metastasis or active leptomeningeal disease.
11. History of another invasive cancer within 3 years before screening, with the exception 
of fully treated cancers with a remote probability of recurrence.  The medical monitor 
and investigator must agree that the possibility of recurrence is remote.
12. Absolute neutrophil count <1500/µL, platelet count <100,000/µL, or hemoglobin 
<10 g/dL (6.2 mmol/L) at screening.  NOTE: May not have received any growth 
factors or blood transfusions within 7 days before the hematology values obtained at 
screening.
13. Total bilirubin (TBili) ≥1.5-times the upper limit of normal (except patients with 
documented Gilbert’s disease), or alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) ≥2.5-times the upper limit of normal at screening.
14. Creatinine >2 mg/dL (177 µmol/L) at screening.
15. Albumin <3.0 g/dL (30 g/L) at screening.
16. History of seizure or any condition that may predispose to seizure (eg, prior cortical 
stroke or significant brain trauma).  History of loss of consciousness (unless of 
cardiac origin) or transient ischemic attack within 12 months before randomization. 
17. Clinically significant cardiovascular disease including the following:

Myocardial infarction within 6 months before screening;

Unstable angina within 3 months before screening;

New York Heart Association class III or IV congestive heart failure or 
a history of New York Heart Association class III or IV congestive heart 
failure unless a screening echocardiogram or multigated acquisition scan 
performed within 3 months before the randomization date demonstrates a left 
ventricular ejection fraction ≥45%;

History of clinically significant ventricular arrhythmias (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;

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
Hypotension as indicated by systolic blood pressure <86 mm Hg at screening;

Bradycardia as indicated by a heart rate of ≤45 beats per minute on the 
screening electrocardiogram (ECG);

Uncontrolled hypertension as indicated by a minimum of 2 consecutive blood 
pressure measurements showing systolic blood pressure >170 mm Hg or 
diastolic blood pressure >105 mm Hg at screening.
18. Gastrointestinal disorder affecting absorption.
19. Hypersensitivity reaction to enzalutamide or any of the capsule components, 
including Labrasol, butylated hydroxyanisole, and butylated hydroxytoluene.
20. Contraindication to the use of leuprolide, such as a previous hypersensitivity reaction 
to an LHRH analogue or any of the excipients in the leuprolide injection.
21. Ongoing drug or alcohol abuse as per investigator judgment.
22. Any concurrent disease, infection, or comorbid condition that interferes with the 
ability of the patient to participate in the study, 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
Study enrollment and procedures are summarized in the following subsections.  The timing 
of all study procedures is also provided in the schedule of activities (Appendix 5).  The 
interactive web response system (IWRS) user manual contains the information needed for 
registering patient status (eg, assigning screening and randomization numbers, indicating 
screen failure, temporary suspension of treatment, reinitiation of treatment, end of treatment).
5.1. Screening Period
The screening period will be from day -28 through day -1.  Screening procedures are listed in 
Table 1.  Radiographic assessments may be performed as early as day -42.  Assessments not 
completed within the applicable screening window may be repeated and/or patients may 
rescreen if clinically appropriate. 
For the purposes of this study, there will be no day 0.
5.1.1. Screening Identification Numbers
After obtaining informed consent, study site personnel will access the IWRS 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 before randomization, study site personnel should document the screen 
failure in the patient’s source documents.  The documentation should include demographics 

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and medical history, the reason for screen failure, the eligibility criteria reviewed, procedures 
performed, etc.
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 
the procedures are part of routine standard of care, and must document the informed consent 
process in the patient’s source documents.  Informed consent may be obtained before the 
screening period.  Standard of care procedures must be clearly documented as such in the 
source in order to use for screening eligibility.
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 
randomization, study site personnel will complete a Randomization Authorization Form and 
fax or email it to the medical monitor or designee to approve the randomization in writing.
Table 1.
Screening Procedures
Activity/Assessment/Timing
Comment
General 
All screening procedures must be performed within the 28-day 
screening period, unless noted otherwise.
Informed consent
Must obtain informed consent before performing any study-specific 
procedures.  May obtain before the screening period.
Ensure consent is on the current version of the form approved by the 
ethics committee.
Screening number 
Obtain from IWRS
Medical history
Review any time after obtaining informed consent.
Eligibility criteria
All inclusion criteria must be met and none of the exclusion criteria 
may apply per Section 4.
12-Lead ECG
Obtain per local practice and read locally to confirm eligibility.
Vital signs and complete physical 
examination
Measure blood pressure, heart rate, temperature, weight, and height. 
Assess systems per standard of care at the study site.
ECOG performance status
Refer to Table 13.
Serious adverse event review
Collect serious adverse event information from the time of signed 
informed consent Section 8.1.4.
Record any serious adverse event for any patient who subsequently 
meets eligibility criteria and proceeds to randomization.
Concomitant medications review
Record all ongoing medications and those discontinued within 28 days 
before the visit.  Record all prior hormonal therapy for prostate cancer 
treatment regardless of time period.  

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Table 1.
Screening Procedures
Activity/Assessment/Timing
Comment
Central Laboratory Evaluations
Refer to the central laboratory manual for sample processing. 
Eligibility will be based on central laboratory assessment.
Serum chemistry, hematology
Refer to analytes listed in Table 12.
PSA, testosterone
Central Radiology Evaluations
Submit all imaging results (bone scan, CT, MRI, or X-ray) for central 
radiology review to confirm absence of metastases before enrollment.  
Submit the clinical information form (CIF) if there is clinically 
relevant information available (such as biopsy results, trauma history, 
other medical diagnosis to inform the central readers that suspicious 
findings are not metastatic disease).
Radiographic assessments 
→ Perform within 42 days 
(6 weeks) before randomization
Includes posteroanterior and lateral chest x-ray or chest CT scan, 
abdominopelvic CT/MRI, and whole-body radionuclide bone scan to 
verify the absence of metastatic disease.  PET is not an evaluable 
imaging modality for this study.
Randomization Authorization Form
Complete, sign, and fax or email the form with requested items to the 
medical monitor or designee at least 3 business days before the 
anticipated day 1 visit. 
The patient may proceed to the day 1 visit and randomize when the 
medical monitor or designee approves by signed form or email 
correspondence.
5.2. Treatment Period
Day 1 is the day of randomization, which is usually the day of the first dose of randomized 
study drug treatment.  Patients will return to the study site at week 13 and every 12 weeks 
thereafter.  Patients will also have a PSA assessment at week 36 to determine the course of 
study treatment at week 37 and be contacted by telephone at week 41 for assessment of 
adverse events.
The double-blind period has concluded and the open-label period is ongoing.  The complete 
details for the conduct of the open-label period are provided in SUPPLEMENT 1: OPEN-
LABEL STUDY PERIOD.  The completed double-blind protocol has not changed.
5.2.1. Visit Windows
At each specified study visit, procedures will be performed according to the schedule of 
activities (Appendix 5).
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 days (ie, 5 days before or after the given day) 
unless otherwise stated.

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Study drug supplies must be taken into account when scheduling visits during windows.  
Procedures for a given visit may be split across the window to allow for drug resupply and 
completion of study procedures.
5.2.2. Week 1, Day 1
Study site personnel will access the IWRS to assign a randomization ID number to a study 
participant.  This number will be used to identify the patient for the remainder of the study.
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 
day 1 procedures.
The blood samples for central laboratory evaluations should be collected and the patient 
questionnaires should be completed before the first dose of study drug to establish baseline.
If study drug cannot be administered on the same day as randomization, the patient must 
come to the clinic within 3 business days after randomization for the required procedures and 
initiation of study treatment.  Day 1 is the day of randomization regardless of the date of the 
first dose of study drug.  Note that time of first dose will be recorded in the electronic data 
capture (EDC) system.
Table 2.
Week 1, Day 1 Procedures
Activity/Assessment 
Comment
Randomization
Access the IWRS to assign randomization ID number and study drug 
treatment.  May occur up to 3 business days before the day of first 
dose.
General Activities
Vital signs and brief physical 
examination
May skip these assessments if performed within prior 7 days. 
Measure blood pressure, heart rate, temperature, and weight. 
Perform symptom-directed examination and investigate any new 
abnormalities.
ECOG performance status
Refer to Table 13.
BPI-SF, FACT-P, EQ-5D-5L, and 
QLQ-PR25 questionnaires
Complete BEFORE the first dose of study drug.
Refer to Appendix 1, Appendix 2, Appendix 3, and Appendix 4.
Adverse events review
Record adverse events that occurred in enrolled patients in the 
patient’s source documents.
Concomitant medications review
Record any new medications or changes in ongoing medications.
Central Laboratory Evaluations
Collect blood samples BEFORE the first dose of study drug. 
Refer to the central laboratory manual for sample processing
Serum chemistry, hematology 
Refer to analytes listed in Table 12.
PSA, testosterone
Study Drugs Dosing/Dispensing
As appropriate for treatment assignment.
Leuprolide injection 
(if applicable)
Single intramuscular or subcutaneous injection (22.5 mg).

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Table 2.
Week 1, Day 1 Procedures
Activity/Assessment 
Comment
Open-label enzalutamide 
dispensing
(if applicable)
Provide the patient with a 12-week supply.  Provide instructions for 
dosing, storage, and return of all study drug at future visits.
Blinded study drug dispensing 
(if applicable)
Provide the patient with a 12-week supply.  Provide instructions for 
dosing, storage, and return of all study drug at future visits.
5.2.3. Week 13
The visit window is ± 5 days.  Drug supply must be taken into account if a window is used to 
schedule the next visit.
Week 13 procedures are listed in Table 3.
Table 3.
Week 13 Procedures
Activity/Assessment 
Comment
General Activities
Vital signs and brief physical 
examination
Measure blood pressure, heart rate, temperature, and weight. 
Perform symptom-directed examination and investigate any new 
abnormalities.
ECOG performance status 
Refer to Table 13.
BPI-SF, FACT-P, EQ-5D-5L, 
and QLQ-PR25 questionnaires
Refer to Appendix 1, Appendix 2, Appendix 3, and Appendix 4. 
Symptomatic skeletal events
Record use of radiation therapy (external beam radiation therapy or 
radionuclides) or surgery to bone for prostate cancer, findings of 
clinically apparent pathologic bone fracture or of spinal cord 
compression, and use of opiate and/or systemic antineoplastic therapy 
due to bone pain.
Adverse events review
Record any new or ongoing adverse events.
Concomitant medications review
Record any new medications or changes in ongoing medications.
Study Drugs Dosing/Dispensing
As appropriate for treatment assignment.
Leuprolide injection 
(if applicable)
Single intramuscular or subcutaneous injection (22.5 mg).
Open-label enzalutamide 
dispensing (if applicable)
Provide the patient with a 12-week supply.  Confirm dosing 
instructions with patient.
Blinded study drug dispensing 
(if applicable)
Provide the patient with a 12-week supply.  Confirm dosing 
instructions with patient.
Study drug accountability 
Record study drug returned and remind patient to return all study drug 
at each future visit.

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5.2.4. Week 25
The visit window is ± 5 days.  Drug supply must be taken into account if a window is used to 
schedule the next visit.
Week 25 procedures are listed in Table 4.
Table 4.
Week 25 Procedures
Activity/Assessment 
Comment
General Activities
Radiographic assessments 
Includes abdominopelvic CT/MRI scan and whole-body radionuclide 
bone scan.
Chest imaging is not required.
PET is not an evaluable imaging modality for this study.
Vital signs and brief physical 
examination
Measure blood pressure, heart rate, temperature, and weight.
Perform symptom-directed examination and investigate any new 
abnormalities.
ECOG performance status
Refer to Table 13.
BPI-SF, FACT-P, EQ-5D-5L, and 
QLQ-PR25 questionnaires
Refer to Appendix 117, Appendix 2, Appendix 3, and Appendix 4.
Symptomatic skeletal events
Record use of radiation therapy (external beam radiation therapy or 
radionuclides) or surgery to bone for prostate cancer, findings of 
clinically apparent pathologic bone fracture or of spinal cord 
compression, and use of opiate and/or systemic antineoplastic therapy 
due to bone pain.
Adverse events review
Record any new or ongoing adverse events.
Concomitant medications review
Record any new medications or changes in ongoing medications.
Study Drugs Dosing/Dispensing
As appropriate for treatment assignment.
Leuprolide injection 
(if applicable)
Single intramuscular or subcutaneous injection (22.5 mg).
Open-label enzalutamide 
dispensing (if applicable)
Provide the patient with a 12-week supply.  Confirm dosing 
instructions with patient.
Blinded study drug dispensing 
(if applicable)
Provide the patient with a 12-week supply.  Confirm dosing 
instructions with patient.
Study drug accountability 
Record study drug returned and remind patient to return all study drug 
at each future visit.
Central Laboratory Evaluations
Refer to the central laboratory manual for sample processing.
Serum chemistry, hematology
Refer to analytes listed in Table 12.
PSA, testosterone

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5.2.5. Week 36
The visit window is ± 5 days.  The purpose of this visit is to collect a blood sample for PSA 
determination by the central laboratory.  The course of study treatment at week 37 will be 
based on this test result.
5.2.6. Week 37
The visit window is ± 5 days.  Drug supply must be taken into account if a window is used to 
schedule the next visit.
The PSA value at week 36 (central laboratory result) will determine the course of each 
patient’s study drug treatment as follows:

For patients with detectable PSA (≥0.2 ng/mL), assigned study drug treatment will 
continue.

For patients with undetectable PSA (<0.2 ng/mL), assigned study drug treatment will 
be suspended at week 37.  Study visits will continue every 12 weeks.  If subsequent 
PSA values increase to prespecified levels (Section 3.1), assigned study drug 
treatment should resume.
As PSA values will not be provided to study sites or patients, study sites will be notified 
whether or not PSA is undetectable to determine whether or not to suspend study drug 
treatment.
Week 37 procedures are listed in Table 5.
Table 5.
Week 37 Procedures
Activity/Assessment 
Comment
General Activities
Vitals signs and brief physical 
examination
Measure blood pressure, heart rate, temperature, and weight.
Perform symptom-directed examination and investigate any new 
abnormalities.
ECOG performance status
Refer to Table 13.
BPI-SF, FACT-P, EQ-5D-5L, and 
QLQ-PR25 questionnaires
Refer to Appendix 117, Appendix 2, Appendix 3, and Appendix 4.
Symptomatic skeletal events
Record use of radiation therapy (external beam radiation therapy or 
radionuclides) or surgery to bone for prostate cancer, findings of 
clinically apparent pathologic bone fracture or of spinal cord 
compression, and use of opiate and/or systemic antineoplastic therapy 
due to bone pain.  
Adverse events review
Record any new or ongoing adverse events.
Concomitant medications review
Record any new medications or changes in ongoing medications.

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Table 5.
Week 37 Procedures
Activity/Assessment 
Comment
Study Drugs Dosing/Dispensing
As appropriate for treatment assignment and PSA value.
The study sites will be notified whether or not PSA is undetectable 
to determine whether or not to continue or suspend study drug 
treatment.  Register the week 37 visit in the IWRS (as either a 
suspension visit or IP dispensing visit, accordingly).  Refer to the IWRS 
Site Manual.
Leuprolide injection 
(if applicable)
Single intramuscular or subcutaneous injection (22.5 mg).
Continued dosing depends on PSA value; see above.
Blinded study drug dispensing 
(if applicable)
Provide the patient with a 12-week supply.  Confirm dosing 
instructions with patient. 
Continued dosing depends on PSA value; see above.
Open-label enzalutamide 
dispensing (if applicable)
Provide the patient with a 12-week supply.  Confirm dosing 
instructions with patient.
Continued dosing depends on PSA value; see above.
Study drug accountability
Record study drug returned and remind patient to return all study drug 
at each future visit (if applicable).
Central Laboratory Evaluations
Refer to the central laboratory manual for sample processing.
Serum chemistry, hematology
Refer to analytes listed in Table 12.  
PSA, testosterone
5.2.7. Week 41
The week 41 (± 5 days) telephone contact will be a telephone call to all patients to collect 
adverse event information only. 
5.2.8. Week 49 and Repeating Every 12 Weeks
Visits repeat every 12 weeks (± 5 days) until criteria are met for permanent treatment 
discontinuation (Section 5.3).  Drug supply must be taken into account if a window is used to 
schedule the next visit.
Week 49 and repeating every 12 weeks procedures are listed in Table 6.

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Table 6.
Week 49 and Repeating Every 12 Weeks Procedures
Activity/Assessment/Timing
Comment
General Activities
Radiographic assessments 
→ Perform at week 49 and at 
24-week intervals thereafter
Includes abdominopelvic CT/MRI and whole-body radionuclide bone 
scan. 
Chest imaging is not required.
PET is not an evaluable imaging modality for this study.
Vital signs and brief physical 
examination
Measure blood pressure, heart rate, temperature, and weight. 
Perform symptom-directed examination and investigate any new 
abnormalities.
ECOG performance status
Refer to Table 13.
BPI-SF, FACT-P, EQ-5D-5L, and 
QLQ-PR25 questionnaires
Refer to Appendix 117, Appendix 2, Appendix 3, and Appendix 4.
Symptomatic skeletal events
Record use of radiation therapy (external beam radiation therapy or 
radionuclides) or surgery to bone for prostate cancer, findings of 
clinically apparent pathologic bone fracture or of spinal cord 
compression, and use of opiate and/or systemic antineoplastic therapy 
due to bone pain.
Adverse events review
Record any new or ongoing adverse events.
Concomitant medications review
Record any new medications or changes in ongoing medications.
Study Drugs Dosing/Dispensing
As appropriate for treatment assignment and PSA value.
The study sites will be notified if the PSA value meets the 
threshold specified for reinitiation of study drug treatment.
If a PSA value requires treatment reinitiation, ask the patient to 
return to the study site as soon as possible for study drug 
dispensing.  
Leuprolide injection 
(if applicable)
Single intramuscular or subcutaneous injection (22.5 mg).
Open-label enzalutamide 
dispensing (if applicable)
Provide the patient with a 12-week supply.  Confirm dosing 
instructions with patient.  
Blinded study drug dispensing 
(if applicable)
Provide the patient with a 12-week supply.  Confirm dosing 
instructions with patient.
Study drug accountability 
(if applicable)
Record study drug returned and remind patient to return all study drug 
at each future visit.
Central Laboratory Evaluations
Refer to the central laboratory manual for sample processing.
Serum chemistry, hematology 
Refer to analytes listed in Table 12.
PSA, testosterone
5.2.9. Unscheduled Visits
Unscheduled visits may be performed anytime to assess or follow-up adverse events, to 
perform scans, to dispense study drug, at the patient’s request, or at the investigator’s request.  
The date and reason for the unscheduled visit must be recorded in the source documentation.

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If an unscheduled visit is necessary to assess toxicity or for suspected disease progression, 
then diagnostic tests may be performed based on investigator assessment as appropriate.
Unscheduled visit procedures are listed in Table 7.
Table 7.
Unscheduled Visit Procedures
Activity/Assessment 
Comment
General Activities 
Radiographic assessments 
If disease progression is suspected, protocol specified imaging should 
be obtained and sent to the central reader with a request for an 
expedited read.
Vital signs and brief physical 
examination 
Measure blood pressure, heart rate, temperature, and weight. 
Perform symptom-directed examination and investigate any new 
abnormalities.
ECOG performance status
Refer to Table 13.
Symptomatic skeletal events
Record use of radiation therapy (external beam radiation therapy or 
radionuclides) or surgery to bone for prostate cancer, findings of 
clinically apparent pathologic bone fracture or of spinal cord 
compression, and use of opiate and/or systemic antineoplastic therapy 
due to bone pain.
Adverse events review
Record any new or ongoing adverse events.
Concomitant medications review
Record any new medications or changes in ongoing medications.  
Study Drugs Dosing/Dispensing
(eg, for patients resuming 
treatment following suspension at 
week 37)
As appropriate for treatment assignment and PSA value.
Leuprolide injection 
(if applicable)
Single intramuscular or subcutaneous injection (22.5 mg).
Open-label enzalutamide 
dispensing (if applicable)
Provide the patient with a 12-week supply.  Confirm dosing 
instructions with patient.
Blinded study drug dispensing 
(if applicable)
Provide the patient with a 12-week supply.  Confirm dosing 
instructions with patient.
Central Laboratory Evaluations
Refer to the central laboratory manual for sample processing.  
Serum chemistry, hematology 
Refer to analytes listed in Table 12.
PSA, testosterone
If missed during a regularly scheduled visit.
5.3. Permanent Treatment Discontinuation
Permanent treatment discontinuation is defined as cessation of randomized study drug 
treatment administration.  Safety follow-up will be performed per Section 5.4. Information 
on study discontinuation related to COVID-19 is provided in Appendix 6. 
Temporary treatment interruption (eg, due to an adverse event) is not considered permanent 
discontinuation. 

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Suspension of study drug treatment due to undetectable PSA is discussed in Section 5.2.6.
The primary reasons that require patients to permanently discontinue randomized study drug 
treatment are as follows:

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: The medical monitor or investigator and/or study 
management may request permanent treatment discontinuation in the event of a major 
protocol deviation, lack of cooperation, or noncompliance.

Development of radiographic progression confirmed by central review after initial 
local read.

Administration of prohibited concomitant therapy: Refer to Section 7.2.  
NOTE: Patients who discontinue due to administration of a prohibited concomitant 
therapy will remain in the study and complete safety follow-up assessments per 
Section 5.4, then begin long-term follow-up per Section 5.5.

Laboratory abnormality defined by protocol as follows:
Creatinine >354 µmol/L (>4.0 mg/dL);
AST, ALT, or TBili >5 times the upper limit of normal;
Absolute neutrophil count ≤750/µL.

Platelet count <50,000/µL.

Seizure: Regardless of resolution of any identified etiology.  Refer to Section 8.5.5.1.

Death: Refer to Section 8.5.5.2.

Loss to follow-up: Refer to Section 5.6.

Investigator conclusion that it is in the patient’s best interest to discontinue therapy 
(eg, poor compliance with either protocol monitoring or with taking the study 
medications, etc.).

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.

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
Patient decision : Patients may permanently discontinue randomized study drug 
treatment anytime for any reason.  Following permanent treatment discontinuation, 
patients should have protocol-required safety follow-up assessments approximately 
30 days after the last dose of randomized study drug treatment (enzalutamide plus 
leuprolide, enzalutamide monotherapy, or placebo plus leuprolide), unless the patient 
specifically declines further follow-up.  Study site personnel must document the 
patient’s decision in the source documents.  Patients are strongly encouraged to 
continue in long-term follow-up as described in Section 5.5, even if they choose to 
permanently discontinue study drug treatment.
5.4. Safety Follow-Up
All patients will have safety follow-up after permanent discontinuation of randomized study 
drug treatment (enzalutamide plus leuprolide, enzalutamide monotherapy, or placebo plus 
leuprolide).  Safety follow-up should occur approximately 30 days after the last dose of 
randomized study drug treatment. 
In the event that antineoplastic treatment is initiated before safety follow-up occurs 
(eg, a physician not associated with protocol MDV3100-13(C3431004) initiates the 
treatment, and study site personnel are not aware of the treatment until afterward), safety 
follow-up should be scheduled as soon as possible.
If treatment is discontinued due to an adverse event or serious adverse event, the event(s) 
must be followed up as described in Section 8.5.6.  Patients who discontinue study drugs due 
to adverse events are encouraged to continue long-term follow-up in the clinic (Section 5.5).
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 
randomized study drug treatment.  If the patient does not respond to or refuses telephone 
contact, the patient’s medical records from the treating physician may be reviewed.  If all 
methods fail, the procedures for loss to follow-up in Section 5.6 should be followed.
Safety follow-up procedures are listed in Table 8.  The visit window is -3 to +10 days from 
the last dose of randomized study drug treatment.  For patients who permanently discontinue 
study treatment during the suspension period, the safety follow-up visit may be scheduled 
any time after 28 days post the last dose of randomized study drug treatment.

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Table 8.
Safety Follow-Up Procedures
Activity/Assessment
Comment
General Activities
Vital signs and complete physical 
examination
Measure blood pressure, heart rate, temperature, and weight. 
Assess systems per standard of care at the study site and as clinically 
indicated by symptoms.
ECOG performance status
Refer to Table 13.
BPI-SF, FACT-P, EQ-5D-5L, and 
QLQ-PR25 questionnaires
Refer to Appendix 117, Appendix 2, Appendix 3, and Appendix 4.
Symptomatic skeletal events
Record use of radiation therapy (external beam radiation therapy or 
radionuclides) or surgery to bone for prostate cancer, findings of 
clinically apparent pathologic bone fracture or of spinal cord 
compression, and use of opiate and/or systemic antineoplastic therapy 
due to bone pain.
Adverse events review
Record any new or ongoing adverse events.
Concomitant medications review
Record any new medications or changes in ongoing medications.
Study drug accountability 
(if applicable)
Record study drug returned and remind patient to return all study 
drug.
Central Laboratory Evaluations
Refer to the central laboratory manual for sample processing.  
Serum chemistry, hematology
Refer to analytes listed in Table 12.
PSA, testosterone
5.5. Long-Term Follow-Up
Long-term follow up begins after safety follow-up.  Visits repeat every 12 weeks (± 7 days) 
based on the 12-week visit schedule determined at randomization.  For patients who 
permanently discontinue randomized study drug treatment before radiographic progression is 
documented and confirmed by central review, radiographic assessments will continue until 
radiographic progression is identified and confirmed by independent central radiology review 
per protocol.
For all patients in long-term follow-up, the site should make every effort to collect 
information on  prostate cancer related treatments and  investigator assessed disease 
progression.
For patients who refuse to return to the clinic for long-term follow-up, long-term follow-up 
may be conducted by telephone call.  If the patient does not respond to or refuses telephone 
contact, alternate contacts are permissible (eg, primary care providers, treating physicians, 
relatives).  The patient’s medical records may be retrieved from the treating physician for 
review of medical, treatment, and survival information.
Long-term follow-up procedures are listed in Table 9.

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Table 9.
Long-Term Follow-Up Procedures
Activity/Assessment/Timing
Comment
General Activities
BPI-SF, FACT-P, EQ-5D-5L, 
and QLQ-PR25 questionnaires
Refer to Appendix 1, Appendix 2, Appendix 3, and Appendix 4.
Not applicable if patient does not return to the study clinic.
Symptomatic skeletal events
Record use of radiation therapy (external beam radiation therapy 
or radionuclides) or surgery to bone for prostate cancer, findings 
of clinically apparent pathologic bone fracture or of spinal cord 
compression, and use of opiate and/or systemic antineoplastic 
therapy due to bone pain.
Other information
Survival status. 
Subsequent therapies for prostate cancer, including opiate 
medication to treat bone pain.
Dates of investigator assessed progression on first subsequent 
therapy, including clinical, radiographic or PSA progression.
Radiographic assessments 
→ Perform at 24-week 
intervals (± 14 days)
Includes abdominopelvic CT/MRI and whole-body radionuclide 
bone scan for patients who have not yet had radiographic 
progression. 
PET is not an evaluable imaging modality for this study.
Standard of care scans will be accepted to meet the MFS endpoint 
for patients in long-term follow-up (LTFU).
5.6. Loss to Follow-Up
Every reasonable effort should be made to contact any patient apparently lost to follow-up 
during the course of the study 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).  The patient’s medical records may be retrieved from the treating physician for 
review of medical, treatment, and survival information.  Such efforts should be documented 
in the patient’s source documents.
If all efforts fail to establish contact, the patient will be considered lost to follow-up.
6. INVESTIGATIONAL PRODUCT INFORMATION
6.1. General Information
The study drugs include enzalutamide, placebo, and leuprolide (leuprorelin acetate).  Xtandi 
(enzalutamide) is approved in the US and other regions to treat men with metastatic CRPC 
who have previously received docetaxel.  Leuprolide is an LHRH agonist indicated for 
palliative treatment of advanced prostate cancer.[18],[19]

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The sponsor will provide enzalutamide and placebo capsules.  The sponsor will provide 
leuprolide.
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.[20] The chemical properties and list of excipients are presented in the 
investigator brochure.
The corresponding placebo consists of Labrasol and other excipients filled in matching 
capsules.
6.2.1. Packaging of Enzalutamide or Placebo
Enzalutamide or placebo 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.
6.2.2. Storage of Enzalutamide or Placebo
Enzalutamide or placebo study drug should be handled and stored safely and properly in 
accordance with the study drug label.
6.2.3. Directions for Administration of Enzalutamide or Placebo
The daily dose of enzalutamide or placebo is 160 mg/day given in 4 capsules (40 mg each) 
by mouth.
Patients should self-administer enzalutamide or placebo by mouth once daily, with or without 
food.  The capsules should be swallowed whole without chewing, dissolving, or opening 
them.
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 of Enzalutamide or Placebo
Patients who experience a grade 3 or higher toxicity that is attributed to enzalutamide or 
placebo and cannot be ameliorated by the use of adequate medical intervention may interrupt 
treatment with enzalutamide or placebo 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 (4 capsules/day) or a reduced dose (3 or 2 capsules/day) in recommended consultation 
with the medical monitor.
If enzalutamide or placebo is coadministered with a strong CYP2C8 inhibitor, the dose of 
enzalutamide or placebo should be reduced to 80 mg once daily.  If coadministration of the 

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strong CYP2C8 inhibitor is discontinued, the enzalutamide or placebo dose should return to 
the dose used before initiation of the strong CYP2C8 inhibitor.
6.3. Leuprolide Product Characteristics
Leuprolide acetate (leuprorelin acetate) is a synthetic nonapeptide analog of naturally 
occurring LHRH.  The chemical name is 
5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl-N-eth
yl-L-prolinamide acetate (salt).[18],[19] The chemical properties and a list of excipients are 
presented in the prescribing information.
6.3.1. Packaging of Leuprolide
Leuprolide acetate for depot suspension, 22.5 mg for 3-month administration, is packaged 
as a kit with a prefilled dual-chamber syringe for reconstitution before administration as an 
intramuscular injection.[18]
Leuprolide acetate suspension for subcutaneous injection, 22.5 mg for 3-month 
administration, is packaged as a single-use kit with a 2-syringe mixing system for 
constitution before administration.[19]
If leuprolide acetate, 22.5 mg for 3-month administration is not available, a suitable 
substitute may be allowed upon approval by the medical monitor.
6.3.2. Storage of Leuprolide
Leuprolide should be handled and stored safely and properly in accordance with the 
prescribing information.
6.3.3. Directions for Administration of Leuprolide
Leuprolide acetate for administration as a 22.5 mg injection once every 12 weeks formulated 
for either intramuscular or subcutaneous injection is allowed.  Three injections will provide 
36 weeks of treatment.
The leuprolide acetate formulation for intramuscular injection is supplied as sterile 
lyophilized microspheres along with an accompanying diluent.  The microspheres are to be 
reconstituted as described in the prescribing information and administered as a single 
intramuscular injection of 22.5 mg once every 12 weeks.
The leuprolide acetate formulation for subcutaneous injection is supplied as sterile powder 
along with an accompanying liquid gel solution. The powder is to be mixed with the liquid 
as described in the prescribing information and administered in clinic by study site personnel 
as a single subcutaneous injection of 22.5 mg once every 12 weeks.
6.3.4. Directions for Dose Modification of Leuprolide
There are no provisions for dose modification of leuprolide on this study.

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6.4. Treatment Compliance
Accountability for the study drug capsules (enzalutamide, placebo) will be performed to 
document compliance with the dosing regimens.  Patients will be asked to bring all study 
drug including empty bottles to study visits.  Study site personnel must make reasonable 
efforts to obtain study drug from patients who do not routinely return them at study site 
visits.  Unreturned capsules will be considered to have been taken.
Compliance with leuprolide treatment will be determined by testosterone suppression.
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, all prior hormonal therapies, 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 and in the 
patient’s source documents.
Per the study eligibility criteria, patients who received certain prior medications and therapies 
for prostate cancer are excluded from study participation.
7.2. Concomitant Therapy
Concomitant medications will be assessed at all clinic visits.  All concomitant medications, 
including analgesic medications and opiates (including opioid-containing 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 source documents.
Initiation of bisphosphonates or denosumab for the prevention of bone metastases is 
prohibited following randomization; however, treatment with these agents should continue at 
a stable dose if initiated at least 4 weeks before randomization.  Initiation of bisphosphonates 
or denosumab at doses to treat osteoporosis is allowed if a diagnosis of osteoporosis is made 
during the study.
Patients are strongly encouraged to obtain an adequate intake of dietary calcium (at least 
1000 mg per day, including supplements if necessary) and vitamin D (at least 
800-1000 international units per day for adults 50 years of age and older) and to engage 
in regular exercise to maintain muscle strength and bone density.
Initiation of abiraterone or antiandrogen therapy is prohibited before radiographic disease 
progression.
Randomized study drug treatment must be permanently discontinued upon initiation of 
anti-cancer chemotherapy or antiandrogen therapy (eg, bicalutamide, nilutamide, or 

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flutamide).  Note: Localized anticancer therapy (eg, topical treatment of non-melanoma skin 
malignancy, intravesical Bacillus Calmette-Guerin [BCG] treatment) may be acceptable upon 
prior Sponsor and Investigator agreement and written Sponsor approval.
Patients who discontinue study drug treatment due to initiation of any such therapy will 
remain in the study, complete safety follow-up per Section 5.4, and then begin long-term 
follow-up assessments every 12 weeks thereafter based on the 12-week visit schedule 
determined at randomization per Section 5.5.
The following treatments are allowed:

Blood transfusions and growth factor support per standard of care and institutional 
guidelines;

Corticosteroids for nonprostate cancer indication;

Pain therapy per standard of care and institutional guidelines;

Palliative procedures to treat skeletal-related events.
In addition, the administration of COVID-19 vaccine is permitted. Administration of 
COVID-19 vaccine should be recorded on the eCRF as a concomitant medication with 
applicable standard adverse event collection and reporting processes.
Deviation from these guidelines should occur only if absolutely necessary for the well-being 
of the patient, and the medical monitor is to be notified to determine the patient’s suitability 
for continued treatment with study drug.
7.3. Potential Interactions Between the Test Products and Concomitant Medications
7.3.1. Enzalutamide
7.3.2. 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 
drugs with a narrow therapeutic index that are metabolized by CYP3A4 (eg, alfentanil, 
cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, 
tacrolimus), CYP2C9 (eg, phenytoin, warfarin), and CYP2C19 (eg, S-mephenytoin) should 
be avoided if possible as enzalutamide may decrease their exposure.  If coadministration with 
warfarin cannot be avoided, additional INR monitoring should be conducted at local 
laboratories. 
7.3.2.1. Drugs That May Affect Exposure to Enzalutamide
7.3.2.1.1. 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 by 2.2-fold 
(Section 1.2.1); therefore, coadministration of enzalutamide with strong CYP2C8 inhibitors 

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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 before initiation of the strong 
CYP2C8 inhibitor. 
The effects of CYP2C8 inducers on the PK of enzalutamide have not been evaluated in vivo.  
Coadministration of enzalutamide with strong or moderate CYP2C8 inducers (eg, rifampin) 
may alter the plasma exposure of enzalutamide and should be avoided if possible.  Selection 
of a concomitant medication with no or minimal CYP2C8 induction potential is 
recommended.
7.3.2.1.2. 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.
7.3.3. Leuprolide
Leuprolide is a nonapeptide that is metabolized by hydrolysis.  No known CYP interactions 
have been elucidated and no interaction studies have been performed.[18],[19]
7.4. 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.  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, Section 8.3, and Section 8.5).  
Clinical laboratory safety tests are presented (Section 8.6).  The study procedures for 
physical examinations, vital signs, and ECGs are also provided (Section 8.7).

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The sponsor will periodically monitor 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).  Any relevant safety concerns 
will be communicated to the investigators and regulatory agencies, as appropriate.
A Data Monitoring Committee will meet periodically during the study to monitor patient 
safety, identify potential safety signals and patterns, and perform benefit-risk assessments 
(Section 11).
8.1. Requirements
The table below summarizes the requirements for recording safety events on the Case Report 
Form and in the database for reporting safety events on the Clinical Trial Serious Adverse 
Event (CT SAE) Report Form to Pfizer Safety.  These requirements are delineated for 3 types 
of events: (1) Serious Adverse Events (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 Case 
Report Form
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 treatment group or suspected causal 
relationship to the investigational product(s) 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 

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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 case report form.  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 Report Form; additional source documents (eg, medical records, case report 
form, 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 Case Report Form
All events detailed in the table above will be recorded on the AE page(s) of the case report 
form.  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 case report form.  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 case report form 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 case report form 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
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 case report form. 
When a subject withdraws from the study because of an SAE, the SAE must be recorded on 
the case report form and reported, as appropriate, on the CT SAE Report Form, in accordance 
with the Requirements section above and Section 5.3.

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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 days after the last administration of the investigational product.
8.1.5. 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.
If a patient begins a new anticancer therapy, SAEs occurring during the above-indicated 
active collection period must still be reported to Pfizer Safety irrespective of any intervening 
treatment.
8.1.6. Recording Non-serious AEs and SAEs on the Case Report Form
During the active collection period, both non-serious AEs and SAEs are recorded on the case 
report form.
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.
If a patient begins a new anticancer therapy, the recording period for non-serious AEs ends at 
the time the new treatment is started; however, SAEs must continue to be recorded on the 
case report form during the above-indicated active collection period.
8.1.7. 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 on study 
records. 

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The investigator will assess the relationship of an adverse event to study drug according to 
the criteria in Table 10 and document the relationship in the patient’s source documents.
Adverse events considered in the relationship categories of “Possible” or “Probable” should 
be considered “adverse events whose relationship to the study drugs could not be ruled out.”
Table 10.
Criteria for Determining Causal Relationship to Study Drug
Relationship
Criteria 
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).
8.1.8. 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 for enzalutamide or placebo.  This study has no provisions for dose 
modification of leuprolide.
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 
(IWRS).  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 IWRS.  The reason for breaking the blind must be documented in the 
source documents.
Patients whose treatment assignment has been unblinded will permanently discontinue 
randomized study drug treatment, have safety follow-up, and commence long-term 
follow-up.

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8.2.3. Contraception
A patient must use a condom if having sex with a pregnant woman.  Patients must not donate 
sperm from first dose of study drug through 3 months after the last dose of study drug.
The 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) from screening through 
3 months after the last dose of study drug or per local guidelines where these require 
additional description of contraceptive methods.  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 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 including contraceptive sponge or occlusive cap 
(diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/suppository by the female partner;
Tubal ligation in the female partner performed at least 6 months before screening;
Vasectomy or other procedure resulting in infertility (eg, bilateral orchiectomy) 
performed at least 6 months before screening.
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;

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
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;

Occupational exposure.
Worsening of signs and symptoms of the malignancy under study should be recorded as AEs 
in the appropriate section of the case report form.  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.

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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.
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 
case report form, and as an SAE with Common Terminology Criteria for Adverse Events 
(CTCAE version 4) 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.

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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);

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.

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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 11.
Table 11.
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.
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 AST and/or ALT precede 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 

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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).
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)/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 co-formulated 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. 

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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 liver function test (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 or 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.
8.5.3.1. Exposure During Pregnancy
The investigator will follow the medical status of the mother, as well as the fetus, and will 
report the outcome to the sponsor.
For both unapproved/unlicensed products and for marketed products, an 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).

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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: 

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.

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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 case report form; however, a copy of the completed CT SAE 
Report Form is maintained in the investigator site file.
8.5.4. Medication Errors
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 Case 
Report Form
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
Medication errors
All (regardless of whether 
associated with an AE)
Only if associated with an 
SAE
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.
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 case report form, 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 case report 
form and, if applicable, any associated AE(s), serious and non-serious, are recorded on an AE 
page of the case report form.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.

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8.5.4.1.1. Overdose of Enzalutamide
The medical monitor must be contacted in the event of a study drug overdose.
An overdose is defined as any dose greater than the protocol-specified dose of enzalutamide 
160 mg once daily.  In the event of an overdose, treatment with study drug should be stopped 
and general supportive measures initiated, taking into consideration the half-life is 5.8 days 
for enzalutamide.  Patients may be at increased risk of seizures following an overdose of 
enzalutamide.  There is no known antidote to 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 8.5.5, whether or not the event meets 
adverse event criteria.
8.5.4.1.2. Overdose of Leuprolide
There is no experience with overdose of leuprolide in clinical trials.  In rats, a single 
subcutaneous dose of 100 mg/kg (approximately 4000 times the estimated daily human dose 
based on body surface area) resulted in dyspnea, decreased activity, and excessive scratching.  
In early clinical studies with daily subcutaneous leuprolide acetate, doses as high as 
20 mg/day for up to 2 years caused no adverse effects differing from those observed with the 
1 mg/day dose.
8.5.5. Serious Adverse Event and Event of Special Interest Reporting
Study site personnel will collect serious adverse event information from the time the patient 
signs the informed consent form through screen failure and 30 days after the last dose of 
randomized study drug (permanent discontinuation). 
Using a Pfizer CT SAE Report Form, all serious adverse events and events of special interest 
must be reported within 24 hours of the study site personnel’s knowledge of the event to 
Pfizer Safety.  All second malignancies (with the exception of uncomplicated nonmelanoma 
skin cancers) must be reported as a serious adverse event.
The initial report should include, at minimum, the following:

Study number (MDV3100-13, C3431004);

Country and site number;

Investigator name;

Patient number, sex, and age;

Details of study drug administration;

The date of the report;

A description of the serious adverse event (event term, seriousness of the event);

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
Causal relationship to the study drug.
If the patient died, the report should include the cause of death as the event term (with fatal 
outcome) and whether or not the death was related to study drug.
Single patient unblinding may be required for reporting suspected unexpected serious 
adverse reactions (SUSARs) to certain regulatory authorities.  Access to this information 
will be strictly limited and will not require unblinding at the study site.
8.5.5.1. Clarification in Reporting of Seizures
Any event of seizure is to be reported as serious adverse event.
8.5.5.2. Clarification in Reporting of Deaths
As overall survival is one of the study endpoints, all patients must be followed for survival 
status until death, and information relating to the death (eg, date and primary cause) should 
be obtained and recorded.  Deaths due to prostate cancer should be recorded as such by the 
investigator to allow for determination of prostate cancer-specific survival.
Fatal events (regardless of relationship to study drug) should be reported as serious adverse 
events during the treatment-emergent safety reporting period (through 30 days after 
permanent treatment discontinuation).
Death is not an adverse event but is an outcome of an adverse event.  For this protocol, 
reports of death without an adverse event will be managed as expedited reports (SUSARs) 
until the sponsor receives additional information.
8.5.6. Follow-Up of Serious and Nonserious Adverse Events
All adverse events reported during the study should be followed at appropriate intervals until 
resolution, or until the event has stabilized or reached a new baseline (all follow-up results 
are to be reported to the sponsor or designee).
Adverse events that remain unresolved at the conclusion of the study may continue to be 
monitored if warranted based on clinical assessment by the investigator and medical monitor.
Patients should be contacted by phone and written requests as appropriate for adverse event 
follow-up if they do not come to the clinic for safety follow-up as specified in Section 5.4.
8.6. Clinical Laboratory Safety Tests
Routine clinical laboratory safety tests (hematology, serum chemistry) will be performed 
according to the schedule of activities (Appendix 5), as will PSA and testosterone tests.  
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.

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A list of the required routine clinical laboratory safety tests is provided in Table 12.  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 
FDA 1572 or Investigator ICH GCP Attestation form Section 4.  The central laboratory 
reference ranges will be used.  Eligibility at screening will be based on central laboratory 
assessments.
For unscheduled visits or for urgent care, central laboratory kits should be used when 
possible; however, a different clinical laboratory may be used.  Such laboratory data will not 
be entered into the study database and local laboratories will not be included on the 
FDA 1572 or Investigator ICH GCP Attestation form.
For protocol-specified safety laboratory evaluations that can be performed at a local 
laboratory because of the COVID-19 pandemic, refer to Appendix 6 Section A6-2.1. 
Table 12.
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 aminotransferase)
Blood urea nitrogen and creatinine
Ca++
Creatine phosphokinase
Glucose 
Lactate dehydrogenase
Magnesium, phosphate
Na+, K+, total CO2 (bicarbonate), Cl-
Total bilirubin (TBili)
Total protein
8.7. Physical Examinations, Vital Signs, and Electrocardiograms
The investigator will perform complete or brief physical examinations according to the 
schedule of activities (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.  Weight will be measured as part of the examination.
Vital sign measurements will include blood pressure, heart rate, and temperature.

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Standard 12-lead ECGs will be obtained and read locally for study eligibility purposes.
9. ASSESSMENT OF EFFICACY AND SAFETY ENDPOINTS
9.1. Assessment of Efficacy
Study assessments of efficacy are measures of prostate cancer status to evaluate the primary 
and secondary study endpoints.  These assessments will include disease status, survival 
status, PSA, testosterone, symptomatic skeletal events, pain scores, quality of life and PFS2. 
9.1.1. Assessments for the Primary Efficacy Endpoint
On study assessments for the primary efficacy endpoint of MFS will include radiographic 
assessment of disease and monitoring of survival status.
9.1.2. Assessment of Radiographic Progression
Assessment for the primary efficacy endpoint of MFS will include radiographic assessment 
of soft tissue disease on CT or MRI, and bone disease on whole-body radionuclide bone 
scans.  The determination of radiographic progression for the primary efficacy endpoint will 
be made by the independent, blinded central radiology reviewer.
Radiographic assessments will be obtained approximately every 6 months from the date of 
randomization until metastatic disease is observed.  Scans may be obtained sooner if disease 
progression is clinically suspected.  The study films (CT/MRI and bone scan) will be read at 
the local study site.  Each study site should designate a radiologist or investigator to ensure 
that all images are read as specified by the protocol and to ensure consistency in the readings.  
Study sites will be instructed to send the scans to a designated central facility.
9.1.2.1.1. Determination of Radiographic Progression in Soft Tissue
Soft tissue disease will be assessed using 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) and in accordance with the central radiology reviewer 
agreement.[21] PET is not an evaluable imaging modality for this study.  No confirmatory 
scans are required for soft tissue disease.
9.1.2.1.2. Determination of Radiographic Progression in Bone
Assessment of metastatic bone disease will be done by whole-body radionuclide bone scan.  
A bone scan will assess 5 regions of the skeleton, including skull, thorax, spine, pelvis, and 
extremities.  Radiographic progression for bone disease is defined as the appearance of 1 or 
more metastatic lesions 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.  PET is not an evaluable 
imaging modality for this study.

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9.1.3. Assessments for the Secondary and Exploratory Efficacy Endpoints
On study assessments for the secondary and exploratory efficacy endpoints will include 
radiographic assessment of disease (Section 9.1.2), monitoring of survival status 
(Section 9.1.3.4), PSA, castration resistance (testosterone and PSA), resumption of any 
hormonal therapy, new antineoplastic therapy, and surgery/interventions for prostate cancer, 
symptomatic skeletal events, pain scores, quality of life, PFS2 therapy, and safety.
9.1.3.1. Assessment of PSA
PSA will be measured at the central laboratory throughout the study according to the 
schedule of activities (Appendix 5).  With the exception of screening PSA values, PSA 
values will not be provided to study sites or patients.  When PSA values are needed to make 
treatment decisions (such as the week 36 PSA value or subsequent PSA values for patients 
who are on study drug treatment suspension for undetectable PSA at week 36), study sites 
will be notified whether a patient’s PSA value meets the specified threshold to determine 
whether or not to continue or suspend treatment at week 37, or whether to reinitiate study 
drug treatment.
Study sites will be notified when a suspended patient’s central PSA meets the criteria for 
treatment reinitiation; suspended patients are to remain on treatment suspension until notified 
by the Sponsor to reinitiate study treatment.
If a central laboratory PSA value requires treatment reinitiation, the patient must return to the 
study site as soon as possible for study drug dispensing.  The reinitiation must be registered 
in the IWRS to obtain study treatment assignment and provide a 12-week supply of study 
drug. (Refer to the IWRS Site Manual).  Note after reinitiation dispensation, the patient will 
return to the clinic for their next expected study visit based on the 12-week visit schedule 
determined at randomization.  Sites should attempt to bring in the patient after reinitiation 
notification as soon as possible, so that the treatment arm can be reinitiated immediately.  If a 
patient is on the leuprolide arm, they will restart leuprolide and continue with their 
subsequent IP administration (including leuprolide as applicable) at their next study visit.
PSA values < 0.2 ng/mL will be considered undetectable for this study.  Except for the 
week 36 PSA value (as described in the week 37 assessment in Section 5.2.6), study drug 
administration should continue regardless of PSA values until radiographic progression is 
confirmed by central imaging and the investigator considers continuing study drug not to be 
beneficial.

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9.1.3.2. Assessment of Time to First Use of New Antineoplastic Therapy
The assessment of first use of new antineoplastic therapy will use the information collected 
on the case report forms for new and subsequent antineoplastic therapies used for prostate 
cancer after discontinuation of study drug treatment.  This will include, medications used 
specifically for prostate cancer treatment including hormonal treatments, immunotherapy, 
chemotherapy and investigative agents.
9.1.3.3. Assessment of Time to Distant Metastasis
The assessment of distant metastasis in soft tissue and/or bone will be provided by the 
independent central radiology vendor.  Soft tissue disease including lymph nodes above the 
aortic bifurcation and outside the pelvis and any bone metastases will be counted as distant 
metastases.
9.1.3.4. Assessment of Survival
The survival status of each patient will be monitored during study treatment, after suspension 
of study treatment at week 37 (if applicable), and after permanent treatment discontinuation 
for any reason.  Survival status will be documented during long-term follow-up according to 
the schedule of activities (Appendix 5).  The date and cause of death will be recorded for 
patients who die. 
During the course of the study, the sponsor may request that a survival sweep be conducted 
to obtain an accurate number of deaths across the study.  Blinded treatment assignments will 
remain blinded.  The sponsor will provide instructions on these survival sweeps immediately 
before they commence as well as a timeline for contacting patients.
9.1.3.5. Assessment of Resumption of any Hormonal Therapy
The assessment of resumption of any hormonal therapy will use the information collected 
on the case report forms about hormonal therapies used for prostate cancer after treatment 
suspension at week 37 due to undetectable PSA.
9.1.3.6. Assessment of Symptomatic Skeletal Events
The assessment of symptomatic skeletal events will include monitoring use of radiation 
therapy (external beam radiation therapy or radionuclides) or surgery to bone for prostate 
cancer, findings of clinically apparent pathologic bone fracture or of spinal cord 
compression, and use of opiate and/or systemic antineoplastic therapy due to bone pain 
throughout the study.  The assessment of opiate use will be based on questioning patients 
regarding their analgesic medication use.  Opiate use for bone pain will be derived from the 
indication associated with the new use of an opiate.
9.1.3.7. Assessment of Castration Resistance
The assessment of castration resistance will include PSA and testosterone tests by the central 
laboratory, and assessments obtained in evaluation of radiographic progression and 
symptomatic skeletal events throughout the study according to the schedule of activities 
(Appendix 5).  With the exception of screening PSA and testosterone values, 
castration-resistance status will not be provided to study sites or patients.

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9.1.3.8. Assessment of Time to Symptomatic Progression
The assessment of time to symptomatic progression will be conducted using a composite of 
the assessments used in collecting time to development of symptomatic skeletal events, 
prostate cancer related pain, or worsening of disease-related symptoms requiring initiation of 
new systemic anti-cancer therapy, or development of adverse events or clinically significant 
signs and/or symptoms due to loco-regional tumor progression requiring opiate use, 
surgery/procedural intervention or radiation therapy, whichever occurs first.
9.1.3.9. Assessment of Pain
The assessment of pain progression will be conducted using the Brief Pain Inventory 
(Short Form).  This 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.  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 4.  It is important that patients are fluent in 
reading the language used in the questionnaire and that they complete it at the beginning of 
their clinic visits and without influence of the investigator, study site staff, or anyone else.  
Patients who are illiterate, blind, or dyslexic; have motor deficit of their hands or difficulty 
working with electronic devices; or are otherwise unable to independently complete the 
questionnaires are not required to complete the electronic questionnaires.
9.1.3.10. Assessment of Quality of Life
The assessment of quality of life will include the Functional Assessment of Cancer 
Therapy-Prostate (FACT-P) questionnaire, the European Quality of Life 5-Dimensions 
5-Levels Health Questionnaire (EQ-5D-5L), and the Quality of Life 
Questionnaire-Prostate 25 (QLQ-PR25) module.  Patients should complete the questionnaire 
information at the beginning of study visits, while alone.  Patients who are illiterate, blind, or 
dyslexic; have motor deficit of their hands or difficulty working with electronic devices; or 
are otherwise unable to independently complete the questionnaires are not required to 
complete the electronic questionnaires.
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 during the prior 7 days in the 4 domains of physical, social/family, 
emotional, and functional well-being; it also contains 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 FACT-P questionnaire is 
provided in Appendix 1.

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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 EQ-5D-5L questionnaire 
is provided in Appendix 2.
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 
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 QLQ-PR25 module is provided in Appendix 3.
9.1.3.11. Assessment of PFS2
The assessment of PFS2 will use the information collected on the case report forms during 
long-term follow-up related to subsequent prostate cancer treatments and investigator 
assessed disease progression on the subsequent treatment.  The date and cause of progression 
including, radiographic, clinical or PSA progression will be recorded.
PFS2 is defined as the time from the date of randomization to the first occurrence of 
investigator-determined disease progression (PSA progression, progression on imaging, or 
clinical progression)  or death due to any cause, whichever occurred first, while the patient 
was receiving first subsequent therapy for prostate cancer.  PFS2, an exploratory analysis, 
will be compared between treatment groups using a 2-sided log rank test.  The HR and 95% 
CI will be provided.  The median PFS2 and 95% CI for the median will be provided for each 
treatment arm.
9.2. Assessment of Safety
Assessments of safety will include adverse events, clinical laboratory tests, physical 
examinations, and vital signs.  The reason for permanent treatment discontinuation 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 are presented in
Section 8.6, and for physical examinations, vital signs, and ECGs in Section 8.7.
If the safety of a study participant is at risk, because the participant cannot complete required 
evaluations or adhere to critical mitigation steps, the Sponsor should be consulted before the 
participant is discontinued from study treatment/intervention. If patient discontinuation is 
associated with the COVID-19 pandemic, and not related to any Adverse event, enter 
“COVID-19” in the “Other, specify” field of the eCRF.

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9.3. ECOG Performance Status Assessments
ECOG performance status assessments are required to assess patient functional status for 
study eligibility purposes and will be performed throughout the study according to the 
schedule of activities (Appendix 5).  Details of the assessment are shown in Table 13. 
Table 13.
ECOG Performance Status Assessments
Score
Description of Functional Status
0
Fully active, able to carry on all predisease performance without restriction.
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, eg, light house work, office work.
2
Ambulatory and capable of all self-care but unable to carry out any work activities.  Up and about 
more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours.
4
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair.
5
Dead.
Source: Oken et al (1982).[22]
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. Randomization Methods
Central randomization will be used and treatment allocation to the 3 treatment groups will 
be 1:1:1.  Randomization will be stratified by screening PSA ≤10 ng/mL versus >10 ng/mL, 
PSA doubling time ≤3 months versus >3 to ≤9 months, and prior hormonal therapy versus no 
prior hormonal therapy.
10.3. Analysis Populations
The intent-to-treat population (ITT) is defined as all patients randomly assigned to study 
treatment.  The intent-to-treat population will be used for all efficacy analyses unless 
otherwise specified, and will be analyzed based on randomized treatment assignment.
The evaluable ITT population is defined as all patients in the ITT population who have 
confirmed nonmetastatic disease at baseline by independent central radiology review.  This 
analysis population will be used for certain efficacy analyses as specified in the statistical 
analysis plan.
The safety population is defined as all patients who receive any amount 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.

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10.4. Efficacy Analyses
All efficacy analyses will incorporate the randomization stratification by screening PSA 
≤10 ng/mL versus >10 ng/mL, PSA doubling time ≤3 months versus >3 to ≤9 months, and by 
prior hormonal therapy versus no prior hormonal therapy, unless otherwise noted.
The analytical approach will be described in detail in the statistical analysis plan. 
Patients who are randomized and later found to have metastatic disease at enrollment will 
be censored at randomization for time-to-event analyses.  The statistical analysis plan will 
provide details for additional sensitivity analyses of selected endpoints.
10.4.1. Primary Efficacy Endpoint Analysis: Metastasis-Free Survival
For the primary endpoint, MFS, the stratified log-rank test will be used to compare 
enzalutamide plus leuprolide versus placebo plus leuprolide.
The primary efficacy endpoint is MFS using independent, central, blinded radiology reviewer 
assessment of radiographic progression as described in Section 9.1.  MFS is defined as the 
duration of time in months between randomization and the earliest objective evidence of 
radiographic progression by central imaging or death.  Emergent metastatic disease and 
deaths that occur while study drug treatment is suspended at week 37 due to undetectable 
PSA per protocol will be counted as MFS events regardless of their timing.
The primary endpoint analysis will be performed when at least 197 MFS events occur in the 
3 treatment groups combined, at which time at least approximately 142 MFS events are 
expected to occur in the 2 blinded treatment groups combined for the primary hypothesis.  
A 2-sided stratified log-rank test will be used to compare enzalutamide plus leuprolide versus 
placebo plus leuprolide at 0.05 level of significance.
10.4.2. Key Secondary Efficacy Endpoint Analyses
Secondary endpoints will be evaluated using the ITT population.  Kaplan-Meier methods will 
be used to describe the distributions of all time to event endpoints with inferential testing 
conducted using the stratified log rank test.  Stratification factors at randomization will be 
included in the analyses as specified.  Treatment group comparisons will be between the 
combination arm of enzalutamide plus leuprolide versus placebo plus leuprolide and between 
enzalutamide monotherapy therapy versus placebo plus leuprolide.
If the MFS test at the combination level is significant at the full alpha level of 0.05, the key 
secondary endpoints will be tested at alpha 0.02 utilizing a hierarchical approach to preserve 
the family-wise type I error rate for the combination arm.  The remaining 0.03 alpha will be 
allocated to compare MFS as well as other key secondary endpoints for enzalutamide 
monotherapy versus placebo plus leuprolide.
For the combination arm comparisons, if time to PSA progression is significant at the alpha 
level of 0.02, the alpha level is carried forward to test for the time to first use of 
antineoplastic therapy endpoint.  If this is also significant at alpha level of 0.02, then the 
alpha level is carried forward to test the third endpoint of overall survival.

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10.4.2.1. 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, while patients are on study treatment which is 
subsequently confirmed at least 3 weeks later.
In patients who DO NOT have treatment suspended due to undetectable PSA at 
week 36: Those with PSA decline at week 25, 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 25).
For patients who have treatment suspended due to undetectable PSA at week 36: Following 
treatment suspension and reinitiation of study drug, 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 
at week 36 is documented, which is confirmed by a second consecutive value obtained at a 
subsequent study visit.  It will be compared between treatment groups using a 2-sided 
stratified log rank test.
10.4.2.2. Time to First Use of New Antineoplastic Therapy 
Time to first use of new antineoplastic therapy is defined as the time from randomization to 
first use of new antineoplastic for prostate cancer.  This will include medications used 
specifically for prostate cancer treatment including hormonal treatments, immunotherapy, 
chemotherapy and investigative agents.  Patients not starting treatment with a new 
antineoplastic therapy at the time of analysis will be censored at the date of last assessment 
before the analysis data cutoff date.  It will be compared between treatment groups using a 
2-sided stratified log rank test.
10.4.2.3. Overall Survival
Overall survival is defined as the time between randomization and death of any cause.  
Overall survival will be compared between treatment groups using a 2-sided stratified log 
rank test.  Long-term follow-up data (survival status, skeletal related events and new prostate 
cancer therapies) will be collected every 12 weeks up until the final analysis of OS.
10.4.3. Other Secondary Efficacy Endpoint Analyses
The following efficacy analyses will be performed for the ITT population.  The resulting 
p-values will be considered descriptive and no adjustment will be made for multiplicity. 
Treatment group comparisons will be between the combination arms of enzalutamide plus 
leuprolide versus placebo plus leuprolide and between enzalutamide monotherapy therapy 
versus placebo plus leuprolide.
10.4.3.1. Time to Distant Metastasis
The time to distant metastasis is defined as the time in months from randomization to the 
earliest objective evidence of distant soft tissue metastases or metastatic bone disease by 
central imaging.  Soft tissue disease including lymph nodes above the aortic bifurcation and 

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outside the pelvis and any bone metastases will be counted as distant metastases.  It will be 
compared between treatment groups using a 2-sided stratified log rank test.
10.4.3.2. Proportion of Patients who Remain Treatment-Free at 2 Years After 
Suspension of Study Drug Treatment
The proportion of patients per group who remain treatment-free 2 years after suspension 
of study drug treatment at week 37 due to undetectable PSA will be compared between 
treatment groups using the stratified Cochran-Mantel-Haenszel test.  Two-sided 95% CIs 
per group will be reported using the Clopper-Pearson method.
10.4.3.3. Proportion of Patients With Undetectable PSA at 2 Years
The proportion of patients per group with undetectable PSA 2 years after suspension of study 
drug treatment at week 37 due to undetectable PSA will be compared between treatment 
groups using the stratified Cochran-Mantel-Haenszel test.  Two-sided 95% CIs per group 
will be reported using the Clopper-Pearson method. 
10.4.3.4. Proportion of Patients With Undetectable PSA at 36 Weeks
The proportion of patients per group with undetectable PSA at 36 weeks will be compared 
between treatment groups using the stratified Cochran-Mantel-Haenszel test.
10.4.3.5.   Time to Resumption of any Hormonal Therapy
The time to resumption of any hormonal therapy is defined as the time between the date of 
treatment suspension at week 37 due to undetectable PSA and the date that hormonal therapy 
is restarted.  The time to resumption of any hormonal therapy will be compared between 
treatment groups using a 2-sided log-rank test. 
10.4.3.6. Time to First Symptomatic Skeletal Event
The time to first symptomatic skeletal event is defined as the time from randomization to use 
of radiation therapy (external beam radiation therapy or radionuclides) or surgery to bone for 
prostate cancer, findings of clinically apparent pathologic bone fracture or of spinal cord 
compression, or new use of opiate and/or systemic antineoplastic therapy due to bone pain, 
whichever occurs first.  Because skeletal events are expected to occur after radiographic 
progression, the analysis of time to first symptomatic skeletal event will be performed with 
the final overall survival analysis.  The time to first symptomatic skeletal event will be 
compared between treatment groups using a 2-sided stratified log - rank test.
10.4.3.7. Time to Castration Resistance
Castration resistance applies only to patients receiving leuprolide treatment and is defined as 
the first occurrence of radiographic disease progression, PSA (as defined above) progression 
or symptomatic skeletal event with castrate levels of testosterone (<50 ng/dL).  Time to 
castration resistance is defined as the time from randomization to the first castration-resistant 
event (radiographic disease progression, PSA progression or symptomatic skeletal event), 
whichever occurs first.

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10.4.3.8. Time to Symptomatic Progression
Time to symptomatic progression is defined as the time from randomization to development 
of a skeletal-related event,  worsening of disease-related symptoms requiring initiation of a 
new systemic anti-cancer therapy, or development of adverse events and clinically significant 
signs and/or symptoms due to loco-regional tumor progression requiring opiate use, surgical 
intervention or radiation therapy, whichever occurs first. 
10.4.3.9. Time to Clinically Relevant Pain
Clinically relevant pain is defined as a 2-point increase from baseline on the Brief Pain 
Inventory (Short Form) question 3.  The time to clinically relevant pain will be compared 
between treatment groups using a 2-sided log-rank test.
10.4.3.10. Quality of Life
Quality of life will be measured by time to a 10-point decline in global FACT-P score and 
assessed using the EQ-5D-5L and QLQ-PR25 questionnaires.  The time to decline in global 
FACT-P score will be compared between treatment groups using a 2-sided log-rank test.  
FACT-P, EQ-5D-5L, and QLQ-PR25 data will be summarized descriptively by study visit.
10.4.4. Exploratory Analyses
10.4.5. PFS2
PFS2 is defined as the time from the date of randomization to the first occurrence of 
investigator-determined disease progression (PSA progression, progression on imaging, or 
clinical progression)  or death due to any cause, whichever occurred first, while the patient 
was receiving first subsequent therapy for prostate cancer.  PFS2 will be compared between 
treatment groups using a 2-sided log-rank test.  The HR and 95% CI will be provided.  The 
median PFS2 and 95% CI for the median will be provided for each treatment arm.
10.5. Safety Analyses
All safety analyses will be performed using the safety population.
Safety analyses will be summarized by treatment.  Safety will be evaluated by the incidence 
of serious adverse events, incidence and severity of adverse events, incidence of permanent 
treatment discontinuation due to adverse events, and incidence of new clinically significant 
changes in clinical laboratory values and vital signs.
The treatment-emergent period is defined as the duration of time from the date and time of 
the first dose of any randomized study drug treatment (enzalutamide plus leuprolide, 
enzalutamide monotherapy, or placebo plus leuprolide) through 30 days after the last dose of 
randomized study drug treatment (permanent treatment discontinuation).  The 
treatment-emergent period will include the period from first dose through potential 
protocol-specified suspension and potential resumption of study drug treatment before 
permanent treatment discontinuation.  Safety data collected following 30 days after study 
drug suspension and during the time off study drug treatment will be analyzed and described. 

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Adverse events 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 before 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 when applicable.  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 before the date of the first dose of study drug.
10.6. Other Analyses
Exposure: The dose and cumulative dose of enzalutamide (mg), placebo, and leuprolide (mg) 
will be summarized with descriptive statistics: n, mean, standard deviation, median, and 
range.
1. Summary of exposure during the time that patients actually receive protocol therapies 
(excludes days that study drug treatment is suspended due to undetectable PSA at 
week 36).
2. Summary of exposure during the entire study period (includes days that study drug 
treatment is suspended due to undetectable PSA at week 36).
Treatment compliance: For enzalutamide, will be measured by the number of capsules taken 
during the entire study divided by the expected number of capsules, multiplied by 100%.
10.7. Determination of Sample Size
The following assumptions were used in determining the sample size for this study:

Overall type I error rate: 0.05;

Patient accrual rate: Utilizing an adaptive enrollment rate, the following rate has been 
modified into two arms to fit into EAST v6.4 software from Cytel.

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Period #
Starting at Time
Accrual Rate
1
0
6
2
12
17.3
3
24
16.6
4
27
19.3
5
30
28.3
6
34
22
7
38
30
8
42
33.3
9
44
28.7
10
48
33.3

Randomization: 1:1:1;

Median MFS for the control group: 55 months.
An observed 142 MFS events in the 2 blinded treatment groups will provide approximately 
90% power to detect a target hazard ratio of 0.58 using a 2-sided log-rank test with 
a 0.05 level of significance.  This target hazard ratio corresponds to a difference of 
approximately 40 months in median MFS assuming an exponential distribution in the 
duration of MFS and a constant hazard rate for each group.  For the key secondary 
hypothesis of MFS between the monotherapy arm, the target effect size, and expected 
number of MFS events will be the same as the primary hypothesis in the combination arm.  
As the 2-sided alpha level will be 0.03 for the monotherapy arm comparison, the power for 
this analysis will be 86% with 142 MFS events observed.  At the time of the final analysis, at 
least 197 MFS events total are required for the 3 treatment groups. An enrollment of 
approximately 1050 patients (350 in each group) is required to achieve the targeted total of 
197 MFS events allowing for a 5% loss to follow-up, as outlined in the Statistical Analysis 
Plan.
An actual enrollment of 1068 patients will also allow for an assessment for the key secondary 
endpoint of OS, assuming a 5-year OS rate of 80% for the control arm and hazard ratio of 
0.67.
The significance level associated with the test of OS, in blinded treatment arm and 
monotherapy arm comparisons, will depend on the outcome of the key secondary endpoints 
(see Figure 2). If both time to PSA progression and time to first use of antineoplastic therapy 
are statistically significant for the blinded treatment arms, then an alpha of 0.02 will be 
contributed to the comparison of OS according to the gatekeeping procedure.  Similarly, if 
MFS, time to PSA progression, and time to first use of antineoplastic therapy are all 
statistically significant for the monotherapy treatment arm then an alpha of 0.03 will be 
contributed to the comparison of OS.  With 191 deaths, the power to detect a hazard ratio of 
0.67 is 79.0% (if all key secondary endpoints are significant for both the blinded arm and 
monotherapy arm comparisons), 72.3% (if the key secondary endpoints are significant for the 
monotherapy arm only) or 67.0% (if the key secondary endpoints are significant for the 
blinded arms only) using a 2-sided log-rank test at a significance level of 0.05, 0.03 or 0.02, 
respectively, and a 2-look group sequential design with a Haybittle-Peto efficacy boundary.

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The data cut-off for the final MFS analysis will occur when at least 197 MFS events, based 
on independent central review, have occurred in the 3 treatment arms.
The data cut-off for the final OS analysis will occur after 271 OS events have occurred in the 
3 treatment arms.
10.8. Interim Analysis
There will be no interim analysis for the primary endpoint (MFS).  The interim and final 
analyses for the key secondary endpoint OS will be performed after the target number of 
events have occurred in the 3 treatment arms.  A maximum of 2 distinct analysis cut-offs are 
planned according to the approximate number of events as described below:

Final MFS and OS Interim: when at least 197 MFS events have occurred as assessed 
by the independent central radiology review have occurred in the 3 treatment groups;

Final OS: when 271 deaths have occurred in the 3 treatment groups.
Table 14 shows the efficacy boundary associated with the final analysis of the primary 
endpoint of MFS between enzalutamide plus leuprolide and placebo plus leuprolide, 
according to independent central radiology review.  
Table 14.
MFS Based on Independent Review (2 blinded treatment arms) - Efficacy 
Boundary
Analysis
Analysis 
Cut-off 
Trigger
Number of MFS 
Events
(2 blinded arms)a
Fraction of 
Required MFS 
Events
p-value
(z-value) for 
Efficacy
Final MFS
197 MFS events 
in 3 arms
142
100%
≤0.05
(-1.9600)
a. 
Number of events expected for MFS in blinded treatment arms assuming a hazard ratio of 0.58.
Table 15 shows the analysis triggers for OS as well the associated Haybittle-Peto efficacy 
boundaries.  The significance level for the analyses of this key secondary endpoint is 
determined by the gatekeeping procedure.

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Table 15.
OS (2 blinded treatment arms) - Efficacy Boundaries
Analysis
Analysis Cut-off 
Trigger
Number of OS 
Events
(2 blinded 
arms)a
Fraction of 
Required 
OS Events
p-value (z-value) for 
Efficacyb
IA OS
197 MFS events in 
3 arms
82
43%
≤0.0001 (-3.89059)
Final OS
271 OS events
in 3 arms
191
100%
≤0.04999 (-1.96001)
a.
Number of events expected for OS in blinded treatment arms assuming a hazard ratio of 0.67. 
b.
The p-values and z-values noted for OS are those associated with the scenario where all the key secondary 
endpoints for the blinded treatment arms and the monotherapy arm are statistically significant (α=0.05).
Safety data will be summarized as described in Section 10.5.  The timing and details of the 
E-DMC review are described in Section 11.  The Statistical Analysis Plan (SAP) will 
describe the planned interim analysis in greater detail.
11. STUDY COMMITTEES AND COMMUNICATIONS
The independent E-DMC consisting of experts in prostate cancer, clinical trial safety 
monitoring, and statistics will evaluate safety data on a periodic basis for this study.  
Approximately every 6 months after the first 50 patients are enrolled and have reached their 
week 13 assessment, the E-DMC will review all available safety data and survival data.  A 
separate charter will outline the details for the composition and responsibility of the E-DMC.
12. LABORATORY REQUIREMENTS
A central laboratory will analyze the clinical laboratory safety samples (hematology, serum 
chemistry) as well as the samples for PSA and testosterone for this study, as described in
Section 8.6.  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 the following documents to the 
sponsor or designee:

Fully executed and signed Form FDA 1572, or Investigator ICH GCP Attestation 
Form (as appropriate) ;

Fully executed clinical trial agreement;

Current curriculum vitae (also applies to all subinvestigators listed on the 
Form FDA 1572 or Investigator ICH GCP Attestation Form);

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
Financial disclosure (also applies to all subinvestigators listed on the Form FDA 1572 
or Investigator ICH GCP Attestation Form);

Signed protocol signature page;

Signed acknowledgment of receipt of the current Enzalutamide Investigator 
Brochure;

Signed acknowledgment of receipt of the prescribing information for leuprolide;

Ethics committee (EC) approval letter;

EC-approved informed consent form;

Additional documents as 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.
The 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.
13.1. Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines;

Applicable ICH GCP guidelines;

Applicable laws and regulations, including applicable privacy laws.
The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents 
(eg, advertisements) must be reviewed and approved by the sponsor, submitted to an IRB/EC 
by the investigator, and reviewed and approved by the IRB/EC before the study is initiated.
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard to 
study participants.

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The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC.

Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures.

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH GCP guidelines, the IRB/EC, European regulation 
536/2014 for clinical studies, European Medical Device Regulation 2017/745 for 
clinical device research, and all other applicable local regulations.
13.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the study 
intervention, Pfizer should be informed immediately.  In addition, the investigator will 
inform Pfizer immediately of any urgent safety measures taken by the investigator to protect 
the study participants against any immediate hazard, and of any serious breaches of this 
protocol or of the ICH GCP that the investigator becomes aware of.
13.1.2. Informed Consent Process
The investigator or the investigator’s representative will explain the nature of the study, 
including the risks and benefits, to the participant or their legally authorized representative 
and answer all questions regarding the study. The participant or their legally authorized 
representative should be given sufficient time and opportunity to ask questions and to decide 
whether or not to participate in the trial.
Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative (if allowed by local regulations) will be required to sign a 
statement of informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH GCP guidelines, privacy and data protection requirements, where applicable, and the 
IRB/EC or study center.
The investigator must ensure that each study participant or their legally authorized 
representative is fully informed about the nature and objectives of the study, the sharing of
data related to the study, and possible risks associated with participation, including the risks 
associated with the processing of the participant’s personal data. 
The participant or their legally authorized representative must be informed that their personal 
study-related data will be used by the sponsor in accordance with local data protection law. 
The level of disclosure must also be explained to the participant or their legally authorized 
representative.

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The participant or their legally authorized representative must be informed that their medical 
records may be examined by Clinical Quality Assurance auditors or other authorized 
personnel appointed by the sponsor, by appropriate IRB/EC members, and by inspectors 
from regulatory authorities.
The investigator further must ensure that each study participant or their legally authorized 
representative is fully informed about his or her right to access and correct their personal data 
and to withdraw consent for the processing of his or her personal data.
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date on which the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICD.
Participants or their legally authorized representative must be reconsented to the most current 
IRB/EC version of the IRB/EC-approved ICD(s) during their participation in the study as 
required per local regulations.
A copy of the ICD(s) must be provided to the participant or their legally authorized 
representative (if allowed by local regulations).
13.1.3. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data.
Participants’ personal data will be stored at the study site in encrypted electronic and/or paper 
form and will be password-protected or secured in a locked room to ensure that only 
authorized study staff have access. The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster. In the event of a potential personal data breach, the study site will be responsible for 
determining whether a personal data breach has in fact occurred and, if so, providing breach 
notifications as required by law.
To protect the rights and freedoms of participants with regard to the processing of personal 
data, participants will be assigned a single, participant-specific numerical code. Any 
participant records or data sets that are transferred to the sponsor will contain the numerical 
code; participant names will not be transferred. All other identifiable data transferred to the 
sponsor will be identified by this single, participant-specific code. The study site will 
maintain a confidential list of participants who participated in the study, linking each 
participant’s numerical code to their actual identity and medical record ID. In case of data 
transfer, the sponsor will protect the confidentiality of participants’ personal data consistent 
with the clinical study agreement and applicable privacy laws.
Information technology systems used to collect, process, and store study-related data are 
secured by technical and organizational security measures designed to protect such data 
against accidental or unlawful loss, alteration, or unauthorized disclosure or access. 

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The sponsor maintains SOPs on how to respond in the event of unauthorized access, use, or 
disclosure of sponsor information or systems.
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.
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. When participant data are to be deleted, 
the investigator will ensure that all copies of such data are promptly and irrevocably deleted 
from all systems.
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.
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.

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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 
identification 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 used or unused drug is returned by the patient at each required visit;

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.

The investigator/pharmacist will keep the study drugs in a pharmacy or other locked 
and secure storage facility under controlled storage conditions as required by the 
study drug label, accessible only to those authorized by the investigator to dispense 
these study drugs.

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
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
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. The 
investigator must ensure that the records continue to be stored securely for as long as they are 
maintained.
13.6. Study Termination
The sponsor will terminate this study following completion of the study objectives, or earlier 
if deemed necessary.

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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.
13.7. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT/CTIS, and/or 
www.pfizer.com, and other public registries and websites in accordance with applicable local 
laws/regulations. In addition, Pfizer reports study results outside of the requirements of local 
laws/regulations pursuant to its SOPs.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional 
studies (conducted in patients) that evaluate the safety and/or efficacy of a product, 
regardless of the geographical location in which the study is conducted. These results are 
submitted for posting in accordance with the format and timelines set forth by US law.
EudraCT/CTIS
Pfizer posts clinical trial results on EudraCT/CTIS for Pfizer-sponsored interventional studies 
in accordance with the format and timelines set forth by EU requirements.  
www.pfizer.com
Pfizer posts CSR synopses and plain-language study results summaries on www.pfizer.com 
for Pfizer-sponsored interventional studies at the same time the corresponding study results 
are posted to www.clinicaltrials.gov. CSR synopses will have personally identifiable 
information anonymized.
Documents within marketing applications 
Pfizer complies with applicable local laws/regulations to publish clinical documents included 
in marketing applications. Clinical documents include summary documents and CSRs 
including the protocol and protocol amendments, sample CRFs, and SAPs. Clinical 
documents will have personally identifiable information anonymized.

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Data sharing
Pfizer provides researchers secure access to participant-level data or full CSRs for the 
purposes of “bona-fide scientific research” that contributes to the scientific understanding of 
the disease, target, or compound class. Pfizer will make data from these trials available 
18 months after study completion. Participant-level data will be anonymized in accordance 
with applicable privacy laws and regulations. CSRs will have personally identifiable 
information anonymized.
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
13.8. Publication Policy
The results of this study will be published or presented at scientific meetings in a timely, 
objective, and clinically meaningful manner that is consistent with good science, industry and 
regulator guidance, and the need to protect the intellectual property of Medivation and 
Astellas (sponsors), regardless of the outcome of the trial.  The data generated in this clinical 
trial are the exclusive property of the sponsors and are confidential.  Written approval from 
the sponsors is required before disclosing any information related to this clinical trial, and no 
publications initiated by investigators may be published until all protocol-defined primary 
and secondary endpoints are published in a manuscript.  Every attempt will be made to 
minimize the interval between the completion of data analysis and publication of the study 
results.  Recommendations for the timing of presentation of trial endpoint data and the 
publication venues (congresses/journals) will be given by the sponsor’s Publications Steering 
Committee.
The primary publication will be a joint publication developed by the investigator and 
sponsors reporting the primary endpoint(s) of the study covering all study sites. The 
investigator agrees to refer to the primary publication in any subsequent publications. 
Each investigator agrees to submit all manuscripts or congress abstracts and 
posters/presentations to the sponsors prior to submission.  This allows the sponsors to protect 
proprietary information, provide comments based on information from other studies that may 
not yet be available to the investigator, and ensure scientific and clinical accuracy.  
The investigator will provide the sponsors an opportunity to review any proposed publication 
or any other type of disclosure of the study results (collectively, “publication”) before it is 
submitted or otherwise disclosed and will submit all publications to the sponsors 30 days 
before submission. If any patent action is required to protect intellectual property rights, the 
investigator agrees to delay the disclosure for a period not to exceed an additional 60 days 
upon request from the sponsors. This allows the sponsors to protect proprietary information 
and to provide comments, and the investigator will, on request, remove any previously 
undisclosed confidential information before disclosure, except for any study-intervention or  
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understanding of the study results. For joint publications, should there be disagreement 
regarding interpretation and/or presentation of specific analysis results, resolution of, and 
responsibility for, such disagreements will be the collective responsibility of all authors of 
the publication. 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 
investigator’s clinical study agreement.
In accord with standard editorial and ethical practice, the sponsors 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. Investigators are free to publish individual center results that they deem to be 
clinically meaningful after publication of the overall results of the study or 12 months after 
primary completion date or study completion at all sites, whichever occurs first, subject to 
the other requirements described in this section.
For all publications relating to the study, the investigator and the sponsors will comply with 
recognized ethical standards concerning publications and authorship, including those 
established by the International Committee of Medical Journal Editors. The investigator will 
disclose any relationship with the sponsors and any relevant potential conflicts of interest, 
including any financial or personal relationship with the sponsors, in any publications. All 
authors will have access to the relevant statistical tables, figures, and reports (in their original 
format) required to develop the publication. The results of this study may be published or 
presented at scientific meetings by the investigator after publication of the overall study 
results or 1 year after the end of the study (or study termination), whichever comes first.  
Any formal publication of the study in which input of sponsor personnel exceeded that of 
conventional monitoring will be considered as a joint publication by the investigator and the 
appropriate sponsor 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) Uniform Requirements for Manuscripts or stricter local 
criteria.[23] The sponsors do not compensate for authorship of a publication. The sponsors 
will not provide any financial compensation for the investigator’s participation in the 
preparation of the primary congress abstract, poster, presentation, or primary manuscript for 
the study. 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 the 
sponsors or related entities, including sponsors of competing products that might be 
perceived to be a source of bias.  Authorship is decided on an individual basis and the 
sponsor’s Publications Steering Committee and sponsor representatives will mutually 
determine authors and their sequence on individual publications based on the relative 
contribution of each author to the study and/or publication.
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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Professional medical writing support is permissible, and any writing support will be 
acknowledged in each applicable publication, explaining the role the professional writer had 
in the drafting of the publication.  Medical writing and publications support funded by the 
sponsors on behalf of investigator authors will be considered as a transfer of value under the 
reporting requirements of the Patient Protection Affordable Care Act: Physician Payment 
Sunshine Provision.[24] Transfer of value will be allocated to authors following sponsor 
guidelines.

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14. USE OF STUDY INFORMATION AND PUBLICATION
See Sections 13.7 and 13.8.

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15. REFERENCES
1.
Scher, H.I. and G. Heller, Clinical states in prostate cancer: toward a dynamic model 
of disease progression. Urology, 2000. 55(3): p. 323-7.
2.
Cooperberg, M.R., J.M. Broering, and P.R. Carroll, Time trends and local variation 
in primary treatment of localized prostate cancer. J Clin Oncol, 2010. 28(7): p. 1117-
23.
3.
Han, M., et al., Long-term biochemical disease-free and cancer-specific survival 
following anatomic radical retropubic prostatectomy. The 15-year Johns Hopkins 
experience. Urol Clin North Am, 2001. 28(3): p. 555-65.
4.
Deguchi, T., et al., Detection of micrometastatic prostate cancer cells in the bone 
marrow of patients with prostate cancer. Br J Cancer, 1997. 75(5): p. 634-8.
5.
Pound, C.R., et al., Natural history of progression after PSA elevation following 
radical prostatectomy. JAMA, 1999. 281(17): p. 1591-7.
6.
Freedland, S.J., et al., Risk of prostate cancer-specific mortality following 
biochemical recurrence after radical prostatectomy. JAMA, 2005. 294(4): p. 433-9.
7.
Antonarakis, E.S., et al., The natural history of metastatic progression in men with 
prostate-specific antigen recurrence after radical prostatectomy: long-term follow-
up. BJU Int, 2012. 109(1): p. 32-9.
8.
Freedland, S.J., et al., Death in patients with recurrent prostate cancer after radical 
prostatectomy: prostate-specific antigen doubling time subgroups and their 
associated contributions to all-cause mortality. J Clin Oncol, 2007. 25(13): p. 1765-
71.
9.
Hussain, M., et al., Enzalutamide in Men with Nonmetastatic, Castration-Resistant 
Prostate Cancer. N Engl J Med, 2018. 378(26): p. 2465-2474.
10.
Smith, M.R., et al., Apalutamide Treatment and Metastasis-free Survival in Prostate 
Cancer. N Engl J Med, 2018. 378(15): p. 1408-1418.
11.
James, N.D., et al., Abiraterone for Prostate Cancer Not Previously Treated with 
Hormone Therapy. N Engl J Med, 2017. 377(4): p. 338-351.
12.
Scher, H.I., et al., Increased survival with enzalutamide in prostate cancer after 
chemotherapy. N Engl J Med, 2012. 367(13): p. 1187-97.
13.
XTANDI® [United States Package Insert], Northbrook (IL): Astellas Pharma US, 
Inc.; 2012 Aug. Package insert.
14.
XTANDI [Summary of Product Characteristics], The Netherlands: Astellas Pharma 
Europe BV; 2018.
15.
Pantel, K., et al., Immunocytochemical monitoring of micrometastatic disease: 
reduction of prostate cancer cells in bone marrow by androgen deprivation. Int J 
Cancer, 1997. 71(4): p. 521-5.
16.
Smith MR, B.M., Rathenborg P, Werbrouck P, Van Poppel H, Heidenreiche A, et al, 
Efficacy and safety of enzalutamide (ENZA) monotherapy in hormone naive prostate 
cancer (HNPC) [abstract]. J Clin Oncol 2013;31(Suppl):5001.
17.
Arlen, P.M., et al., Prostate Specific Antigen Working Group guidelines on prostate 
specific antigen doubling time. J Urol, 2008. 179(6): p. 2181-5; discussion 2185-6.
18.
Lupron Depot (leuprolide acetate) for depot suspension, North Chicago (IL): AbbVie 
Inc.; 2013 Jul. Package insert.

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19.
Eligard (leuprolide acetate) suspension for subcutaneous injection, Bridgewater (NJ): 
sanofi aventis U.S. LLC; 2013 Feb. Package insert.
20.
XTANDI (enzalutamide) capsules, Northbrook (IL): Astellas Pharma US, Inc.; 2012 
Aug. Package insert.
21.
Eisenhauer, E.A., et al., New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). Eur J Cancer, 2009. 45(2): p. 228-47.
22.
Oken, M.M., et al., Toxicity and response criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol, 1982. 5(6): p. 649-55.
23.
International Committee of Medical Journal Editors (ICMJE). Recommendations for 
the conduct, reporting, editing, and publication of scholarly work in medical journals 
[Internet]. 2013 Aug [cited 2014 Jul 15].
24.
111th Congress. HR 3590-Patient Protection and Affordable Care Act. Section 6002: 
Physician payment sunshine provision. In: gpo.gov [Internet]. 2010 [cited 2014 Jul 
21].
25.
Memorial Sloan Kettering Cancer Center (MSKCC), Prostate Cancer Nomograms: 
PSA Doubling Time.

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16. INVESTIGATOR SIGNATURE
The Investigator Signature page will be provided separately.

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17. APPENDICES
CCI

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CCI

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CCI

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CCI

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Study Period or Visit
Screening
Treatment
Unsched 
[1]
Safety 
FU [2]
LTFU 
[3]
Study Week
-4 to -1
1
1
3
2
5
3
6
37
41
49 [3]
Varies
Varies
Every 
12
Study Day
-28 to -1
1
8
5
1
6
9
2
4
6
253
281
337
na
na
Every 
84
Window (Days) [4]
na
na
±
5
±
5
±
5
±5
±5
±5
na
-3 to 
+10
±7
General Activities
[16]
Record use of radiation therapy (external beam radiation therapy or radionuclides) or surgery to bone for 
prostate cancer, findings of clinically apparent pathologic bone fracture or of spinal cord compression, and 
use of opiate and/or systemic antineoplastic therapy due to bone pain.
[17]
Collect serious and nonserious adverse event information from the time of signed informed consent 
through and including a minimum of 30 days after the last administration of investigational product.  
Phone patients for follow-up if they do not come to the clinic.
[18]
Telephone call to collect adverse event information.
[19]
Specific study drug treatment (ie, leuprolide, open-label enzalutamide monotherapy, or blinded 
enzalutamide/placebo) is based on randomized treatment assignment.
[20]
PSA values will not be provided to study sites or patients.  The study sites will be notified at treatment 
decision points whether the PSA value meets the specified threshold to determine whether or not to 
continue or suspend treatment at week 37, or whether to reinitiate study drug treatment.  
[21]
For patients resuming study drug after treatment suspension.  
[22]
May obtain at clinic visits, by phone contact, chart review, etc.  Includes survival status, subsequent 
therapies for prostate cancer, including opiate medication to treat bone pain, and dates of investigator 
assessed progression on first subsequent therapy, including clinical, radiographic or PSA progression.
[23]
Refer to the central laboratory instruction manual for sample processing and for estimated turnaround time 
for PSA results.
[24]
If missed during a regularly scheduled visit. 
[25]
If a PSA value requires treatment reinitiation, ask the patient to return for an unscheduled visit as soon as 
possible for study drug dispensing.  If PSA values meet the criteria of PSA progression with PSADT 
≤10m, the investigator for the patient will be notified.
√PSA, check prostate specific-antigen; BP, blood pressure; CT/MRI, computed tomography/magnetic resonance 
imaging; ECG, electrocardiogram; 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; lab, laboratory; LTFU, long-term follow-up; na, not applicable; PSA, prostate-specific antigen; 
QLQ-PR25, Quality of Life Questionnaire-Prostate 25; unsched, unscheduled.

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Appendix 6. Alternative Measures During Public Emergencies
The alternative study measures described in this section are to be followed during public 
emergencies, including the COVID-19 pandemic. This appendix applies for the duration of 
the COVID-19 pandemic (as dictated by applicable governing laws of study site locations) 
and will become effective for other public emergencies only upon written notification from 
Pfizer.  For patients who have missing data as local or site guidance during the public 
emergency (eg, COVID-19) has resulted in a change in study visit schedules, missed study 
visits, or missed study evaluations, the reason for the missing data and the relationship to the 
public emergency should be reported in the source documents and relevant CRFs.
Use of these alternative study measures are expected to cease upon the return of 
business-as-usual circumstances (including the lifting of any quarantines and travel 
bans/advisories). 
A6-1. Telehealth/Remote Visits
In the event that in-clinic study visits cannot be conducted, every effort should be made to 
follow-up on the safety of study participants at scheduled visits per the Schedule of 
Activities or unscheduled visits. Telehealth (ie, remote) visits may be used to continue to 
assess participant safety and collect data points. Telehealth includes the exchange of 
healthcare information and services via telecommunication technologies (eg, audio, video, 
video-conferencing software) remotely, allowing the participant and the investigator to 
communicate on aspects of clinical care, including medical advice, reminders, education, and 
safety monitoring. 
Telehealth/remote visits should be recorded as COVID-19-related protocol deviations.
The following assessments must be performed during a telehealth visit:

Review and record study intervention(s), including compliance and missed doses.

Review and record any AEs and SAEs since the last contact. Refer to Section 8.3.

Review and record any new concomitant medications (including COVID-19 vaccine) 
or changes in concomitant medications since the last contact.

Review and record contraceptive method. Confirm that the participant is adhering to 
the contraception method(s) required in the protocol. Refer to Section 8.2.3 for 
acceptable methods of contraception.
In addition, every effort should be made to administer the ERT Clinical ePRO questionnaires 
(FACT-P, EQ-5D-5L, QLQ-PR25, BPI-SF) at all scheduled study visits per protocol.  The 
ERT Clinical ePRO questionnaires may be administered remotely via telephone by delegated 
site staff using the study provisioned device in the event that an in-clinic study visit cannot be 
conducted due to the COVID-19 pandemic. ERT Clinical ePRO questionnaires should be 
administered prior to gathering any other study information. Study staff will read the 

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questionnaire questions to the participant and record participant answers on the study site 
tablet.  Any questionnaires administered via telephone should be indicated as such in the 
EDC system.
Study participants must be reminded to promptly notify site staff about any change in their 
health status.
A6-2. Alternative Facilities for Safety Assessments
A6-2.1.  Laboratory Testing
If a study participant is unable to visit the site for protocol-specified safety laboratory 
evaluations, testing (except PSA tests) may be conducted at a local laboratory if permitted by 
local regulations. The local laboratory may be a standalone institution or within a hospital.
If a local laboratory is used, qualified study site personnel must order, receive, and review 
results. Site staff must collect the local laboratory reference ranges and 
certifications/accreditations for filing at the site. Laboratory test results are to be provided to 
the site staff as soon as possible. The local laboratory reports should be filed in the 
participant’s source documents/medical records. Any abnormal laboratory results from the 
local laboratory report should be recorded on the CRF as an AE.
Protocol-specified laboratory safety testing (hematology, serum chemistry, testosterone) that 
is performed at a local laboratory because the study participant was unable to visit the study 
site because of COVID-19, should be recorded as a COVID-19-related protocol deviation.
For participants with missed or delayed central PSA tests, as PSA results are blinded, all PSA 
study testing should be handled by the central laboratory.  Investigators and study 
participants should make every effort to follow the protocol required schedule for PSA 
testing.
A6-2.2.   Imaging
If the participant is unable to visit the study site for protocol-required CT/MRI, the 
participant may visit an alternative facility to have the CT/MRI performed. CT/MRI scans, 
regardless of where they are obtained, must be sent to the central reader as outlined in the 
Site Operations Manual. 
Patient protocol-specified laboratory that was performed at a at a location other than the 
study site should be recorded as a COVID-19-related protocol deviation.

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A6-2.3. Electrocardiograms
If the participant is unable to visit the study site for ECGs, the participant may visit an 
alternative facility to have the ECGs performed. Qualified study site personnel must order, 
receive, and review results. 
A6-3. Study Intervention
If the safety of a trial participant is at risk because they cannot complete required evaluations 
or adhere to critical mitigation steps, then discontinuing that participant from study 
intervention must be considered.  
Study drugs (enzalutamide open label or enzalutamide/placebo) assigned to the participant 
via IWRS may be shipped by courier to study participants if permitted by local regulations 
and in accordance with applicable storage and transportation requirements. Participants must 
provide verbal consent (and written informed consent if required by local regulatory 
authorities) for providing their contact details for shipping purposes.  The verbal consent 
should be documented in the source document.  If required by local regulatory authorities, 
verbal consent will be followed up by consent via a short form informed consent document 
(ICD) amendment.  The amount of study drug shipped via courier should correspond to the 
amount of study drug that is dispensed at the specific study visit. The tracking record of 
shipments and the chain of custody of study drug must be kept in the participant’s source 
documents/medical records.  If the total transport time of study drug shipped to the 
participant is less than 36 hours than temperature monitoring is not mandated; however, for 
total transport time is 36 hours or more, temperature monitoring should be used.
Delivery of study drugs to the participant at a location other than the study site should be 
recorded as a COVID-19-related protocol deviation.
The following is recommended for the continued administration of study drug for 
participants who have active [confirmed (positive by regulatory authority-approved test) or 
presumed (test pending/clinical suspicion)] SARS-CoV-2 infection:

For symptomatic participants with active SARS-CoV-2 infection, study drug should 
be delayed for at least 14 days from the start of symptoms. This delay is intended to 
allow the resolution of symptoms of SARS-CoV-2 infection.

Prior to restarting treatment, the participant should be afebrile for 72 hours, and 
SARS-CoV-2-related symptoms should have recovered to Grade ≤1 for a minimum 
of 72 hours. Notify the study team when treatment is restarted.

Continue to consider potential drug-drug interactions as described in Section 7.3 for 
any concomitant medication administered for treatment of SARS-CoV-2 infection.

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A6-4. Adverse Events and Serious Adverse Events
If a participant has reported symptoms of COVID-19 or has tested positive for SARS-CoV-2 
during the study, this should be reported as an adverse event (AE) or serious adverse event 
(SAE) and appropriate medical intervention provided. 
For confirmed COVID-19 cases, defined as laboratory confirmation of COVID-19 infection 
irrespective of clinical signs and symptoms, the result of the SARS-CoV-2 test should be 
recorded in the AE CRF.  “Positive SARS-CoV-2 infection” should be entered in the AE 
description field and, if known, the type of assay (eg, PCR or Antibody).  The remainder of 
the AE form should be completed in the usual manner.
For participants who currently report or who have reported signs and symptoms indicative of 
COVID-19 infection, but who have not received a SARS-CoV-2 test, “Unconfirmed 
COVID-19 infection” should be entered in the AE description field. The remainder of the AE 
form should be completed in the usual manner.
It is recommended that the investigator discuss temporary or permanent discontinuation of 
study intervention with the study medical monitor. Study treatment should continue unless 
the investigator/treating physician is concerned about the safety of the participant, in which 
case temporary or permanent discontinuation may be required.
For participants who are discontinuing the study due to COVID-19-related reasons, the most 
appropriate status for discontinuation should be promptly reported in the CRF. 

For End of Treatment, if treatment discontinuation is associated with the current 
COVID-19 pandemic, and not related to any AE, record “COVID-19” in the “Other, 
specify” field on the discontinuation electronic CRF (eCRF). If treatment 
discontinuation was due to COVID-19 infection, record the primary reason for study 
drug discontinuation of COVID-19 infection as an AE. 

For End of Survival Follow-up, if discontinuation of follow-up is associated with the 
current COVID-19 pandemic, record “COVID-19” in the “Other, specify” field on 
the EOS form under the primary reason patient is no longer followed for survival.

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Appendix 7. Abbreviations
Abbreviation
Definition
ADT
Androgen deprivation therapy
AE
Adverse Event
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC
Area under the curve
AUC0-∞
Area under the curve from time zero to infinity
BCG
Bacillus Calmette-Guerin
BICR
Blinded independent central reviewer
BPI-SF
Brief Pain Inventory (Short Form)
BUN
Blood urea nitrogen
Ca
Calcium
CFR
Code of Federal Regulations
CI
Confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CIF
Clinical information form
CK
Creatine kinase
Cl
Chlorine
Cmax
Maximum plasma concentration
CO2
Carbon dioxide
COVID-19
Coronavirus disease 2019
CRF
Case report form
CRPC
Castration-resistant prostate cancer 
CSR
Clinical Study Report
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTIS
Clinical Trials Information System
CT SAE
Clinical trial serious adverse event
Ctrough
Predose trough plasma concentration
CYP
Cytochrome P450
DIL
Dear Investigator Letter
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
eCRF
Electronic case report form
EDC
Electronic data capture
E-DMC
External data monitoring committee
EDP
Exposure during pregnancy
EMBARK
Safety and Efficacy Study of Enzalutamide Plus Leuprolide in Patients With 
Nonmetastatic Prostate Cancer
EORTC
European Organization for Research and Treatment of Cancer
ePRO
Electronic patient-reported outcome
EQ-5D-5L
European Quality of Life 5-Dimensions 5-Levels Health Questionnaire
EU
European Union
FACT-P
Functional Assessment of Cancer Therapy-Prostate
FDA
Food and Drug Administration
FU
Follow-up
GCP
Good Clinical Practice

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Abbreviation
Definition
GGT
Gamma-glutamyl transferase
HR
Hazard ratio
IA
Interim analysis
IB
Investigator’s Brochure
ICD
Informed consent document
ICH
International Council for Harmonisation
ID
Identification
INR
International normalized ratio
IP
Investigational Product
IPCW
Inverse probability of censoring weighting
IRB
Institutional Review Board
ITT
Intent-to-treat
IWRS
Interactive web response system
K
Potassium
LFT
Liver function test
LHRH
Luteinizing hormone-releasing hormone
LT
Long term
LTFU
Long-term follow-up
MedDRA
Medical Dictionary for Regulatory Activities
MFS
Metastasis-free survival
Mo
Months
MRI
Magnetic resonance imaging
na
not applicable
Na
Sodium
OL
Open-label
OS
Overall Survival
PACL
Protocol Administrative Change Letter
PCD
Protocol completion date
PCR
Polymerase chain reaction
PET
Positron-emission tomography
PFS2
Progression-free survival on first subsequent therapy
PK
Pharmacokinetic
PROSPER
Prospective Study of Pravastatin in the Elderly at Risk
PSA
Prostate-specific antigen
PSADT
Prostate-specific antigen doubling time
PT
Prothrombin time
q
Every
QLQ-PR25
Quality of Life Questionnaire-Prostate 25 module
RPSFTM
Rank-preserving structural failure time model
RECIST 1.1
Response Evaluation Criteria in Solid Tumors, version 1.1
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SOA
Schedule of activities
SOC
Standard of care
SOP
Standard operating procedure
SPARTAN
A Study of Apalutamide (ARN-509) in Men With Non-Metastatic Castration-Resistant 
Prostate Cancer
SRSD
Single reference safety document
STAMPEDE
Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug 
Efficacy
SUSAR
Suspected unexpected serious adverse reaction

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Abbreviation
Definition
TBili
Total bilirubin
ULN
Upper limit of normal
US
United States
Wk
Week

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18. SUPPLEMENT 1: OPEN-LABEL STUDY PERIOD 
NOTE: This supplement contains cross-references to the main protocol text where study 
procedures are to be performed in the same manner.
18.1. Rationale and Treatment Plan 
Primary endpoint analyses demonstrated that the primary efficacy endpoint of metastasis free 
survival (MFS) was established and the safety profile of enzalutamide was confirmed, 
therefore, the treatment codes for all patients will be unblinded and an open-label treatment 
period is being implemented.  The final analysis of the key secondary endpoint for overall 
survival (OS) will be performed as planned.  Patients will continue to receive their originally 
assigned study treatment in this open-label (OL) study period.  Patients assigned to the 
placebo plus leuprolide arm will no longer take the placebo capsules.  No crossover treatment 
will be implemented.  
For patients whose cancer has not progressed radiographically, locally (change was effective 
as of 31-Mar-2023) performed scans (CT/MRI and bone scan) will be conducted until the 
patient’s cancer progresses radiographically. Scans read centrally by blinded independent 
central reviewer (BICR) ceased as of 31-Mar-2023.  Prostate-specific antigen (PSA) levels
will also be done at a local lab and monitored by the investigator per standard of care (SOC)
effective date of 31-May-2023.  Patients who are in treatment suspension (due to prior 
undetectable PSA at study Week 36) will continue to have their PSA values, done at the local 
lab, evaluated by the investigator every 3 months for possible treatment reinitiation per 
protocol criteria.  For details, refer to Table 16.
Patients who discontinue study treatment or withdraw consent for further treatment will 
continue safety follow-up and long-term follow-up assessments per protocol (see Section 
18.8). Long-term follow-up data including survival status, documentation of new 
antineoplastic therapies for prostate cancer, skeletal-related events, and progression on first 
subsequent therapy (PFS2) will be collected every 12 weeks until the final OS analysis.  The 
associated endpoints will be summarized descriptively at the time of the final OS analysis. 
Patients who receive any treatment other than their assigned study treatment for prostate
cancer after unblinding will not be eligible for this OL period.  All patients who permanently 
discontinue study drug treatment will remain in the study, complete safety follow-up, and 
subsequently commence long-term follow-up.
Randomized study drug treatment must be permanently discontinued upon initiation of 
systemic anti-prostate cancer therapy (eg, bicalutamide, nilutamide, or flutamide).
The Brief Pain Inventory (Short Form) (BPI-SF) and quality of life measurements including 
the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire, European 
Quality of Life 5-Dimensions 5-Levels Health Questionnaire (EQ-5D-5L), and the Quality of 
Life Questionnaire-Prostate 25 (QLQ-PR25) module are no longer required as of 31-Mar-
2023.

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Table 16.
Supplement Table 1: Study Schedule of Activities (Open-Label Period)
Study Period or Visit
Abbreviations used in this table may be found in 
Appendix 7
Treatment
Un-
scheduled
Safety 
FU
Long-
Term
FU
Study Week
1
Wk 13 &
Every 12 
wks
Wk 25 & 
Every 6 
months
Varies
[2]
Varies
[3]
Every 
12 wks
Study Day 
1 [1]
85
169
na
na
Every 84 
days 
Windows [4]
na
±5
±7
na
±7
±7
should be reported per Section 18.6.
12. Contraceptive review per Section 8.2.3 applicable through 3 months after the last dose of study drug or 
per local guidelines. 
13. Specific study drug treatment (ie, enzalutamide, enzalutamide plus leuprolide, or leuprolide) is based on 
randomized treatment assignment.
14. For patients resuming study drug after treatment suspension, if applicable.  
15. Leuprolide acetate (leuprorelin acetate), 22.5 mg will be given as a single intramuscular or subcutaneous 
injection once every 12 weeks.
16. Performed, collected and assessed locally per Institution’s SOC. Hematology and serum chemistry. 
Report any clinically significant abnormalities as adverse events per CTCAE v4 criteria. PSA levels for 
patients in treatment suspension should be entered into the study database.
17. If missed during regularly scheduled visit.
18. Perform and assess PSA locally.  Evaluate if PSA value meets threshold for treatment reinitiation in 
patients on treatment suspension, if so study drug dispensing should be arranged.  The investigator to 
monitor PSA values for PSA progression. Refer to Section 18.3.4.
19. May obtain at clinic visits, by telephone contact, chart review, etc.  Includes survival status, new 
antineoplastic therapies for prostate cancer, skeletal-related events, and PFS2 up to final OS analysis.
18.1.1. Blinding
Participants will be unblinded to their assigned study intervention at the start of this OL study 
period. Investigators and other site staff will be unblinded to participants’ assigned study 
intervention. Sponsor staff will be unblinded to participants’ assigned study intervention.
18.2. Open-Label Study Period 
Day 1 of the OL period will occur after consent is signed and eligibility is verified. Patients 
will continue their assigned treatment, return for safety follow-up within approximately 30 
days after last dose, and will enter long-term follow-up.
Sites must have all OL Day 1 visits completed within 16 weeks after IRB/EC approval of this 
protocol amendment (see Figure 3).

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Figure 3.
Schematic – Open-Label Treatment Period
18.3. Study Procedures and Assessments
Patients will sign informed consent on OL Day 1 (their next regular scheduled visit following 
approval and activation of this amendment at the study site). All patients must have their OL 
Day 1 visit within 16 weeks after the approval and activation of this protocol at the study site.  
The enrollment period will end after this time. For detailed procedures see the Schedule of 
Activities (Table 16).
Study participants must be reminded to promptly notify site staff about any change in their 
health status.  In addition to the protocol-specified visits, participants should attend clinic 
visits whenever clinically indicated or needed.
During the OL Period, study assessments will include monitoring as clinically indicated for 
adverse events, clinical laboratory tests, brief physical examinations including vital signs and 
drug accountability. For patients whose cancer has not progressed radiographically, scans 
(CT/MRI and bone scan) will be performed every 6 months until the patient’s cancer 
progresses radiographically by local determination.
The following laboratory values are recommended to be evaluated throughout the study in 
accordance with the schedule of activities (SOA).  These evaluations are to take place 
locally, per each Institution’s SOC:

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.
PFS2
→
 Enzalutamide
→
Daily enzalutamide
|
Enzalutamide
Daily enzalutamide
→
+
→
+
→
→
→
Leuprolide
Leuprolide q 3 mo
→
Leuprolide
→
Leuprolide q 3 mo
30 days
Day 1
after last
dose
Study Visits at Wk 
13 and q 12 wks 
following. CT/MRI, 
Bone Scans q 6 mo. 
INFORMED 
CONSENT
END OF 
TREAT-
MENT
Survival Status (OS)
Collect antineoplastics 
Skeletal related events
SAFETY 
FOLLOW-
UP
LTFU 

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
Comprehensive chemistry panel: albumin, alkaline phosphatase, ALT, AST, 
creatinine, blood urea nitrogen (BUN), Ca++, total CO2 (bicarbonate), glucose, Na+, 
K+, Cl-, total bilirubin, and testosterone.

PSA. 
Patients in survival follow-up will be followed for their survival status, new anti-prostate 
cancer therapies and scans every 6 months until they progress on the first anti-prostate cancer 
follow-up therapy.
18.3.1. Telehealth Visits
Telehealth visits may be used to assess participant safety and collect data points. Telehealth 
includes the exchange of healthcare information and services via telecommunication 
technologies (eg, audio, video, videoconferencing software) remotely, allowing the 
participant and the investigator to communicate on aspects of clinical care, including medical 
advice, reminders, education, and safety monitoring.  The following assessments must be 
performed during a telehealth visit:

Review and record study intervention(s), including compliance and missed doses.

Review and record any AEs and SAEs since the last contact (see Section 8).

Review and record any new concomitant medications or changes in concomitant
medications since the last contact per Section 18.6.

Review for presence of symptomatic skeletal events.

Review and record contraceptive method. Confirm that the participant is adhering to 
the contraception method(s) required in the protocol (see Section 8.2.3).
18.3.2. Safety Assessments  
Safety data will continue to be collected in the OL period through 30 days after the last dose 
(ie, permanent discontinuation) of study drug including the period following 
protocol-specified treatment suspension (due to prior undetectable PSA at study Week 36) 
and resumption of study drug treatment through permanent treatment discontinuation per 
Protocol Section 8. Assessments of safety will include all adverse events, clinical laboratory 
tests (hematology, serum chemistry), physical examinations and vital signs according to the 
Schedule of Activities for the OL treatment period (Table 16).  Local clinical laboratory test 
results will no longer be required to be entered into the clinical database with the exception 
of the PSA levels collected for patients who are in treatment suspension. All second primary 
malignancies (with the exception of uncomplicated nonmelanoma skin cancers) must be 
reported as a serious adverse event (see Section 8).

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18.3.3. Radiographic Assessments
For patients entering the OL treatment period whose cancer has not progressed 
radiographically, scans (CT/MRI and bone scan) will be performed locally every 6 months 
according to the Schedule of Activities (Table 16) until progression is identified 
radiographically.  The study Investigator will review and assess the radiographic scans for 
disease progression.  Study treatment will be stopped upon disease progression as assessed 
by the investigator.  Patients who do not participate in the OL treatment period or withdraw 
consent for further treatment will continue long-term follow-up assessments per protocol 
(Table 18).
18.3.4. Monitoring PSA Progression 
PSA levels will be measured and monitored by the investigator locally to make decisions 
during the OL study period.  For details, refer to Schedule of Activities (Table 16). 
Time to PSA progression is defined in Section 10.4.2.1.
For patients who have been in treatment suspension since Week 37 for undetectable 
(<0.2 ng/ml) PSA values at Week 36, the study investigator will directly monitor and assess 
the patient’s locally obtained PSA levels.  Open-labeled treatment will be reinitiated if 
subsequent local laboratory PSA values increase to ≥2.0 ng/mL for patients with prior 
prostatectomy, or ≥5.0 ng/mL for patients who had prior radiation therapy.  If laboratory 
PSA values meet the requirement for treatment reinitiation, the patient should return to the 
study site as soon as possible for drug dispensing and reinitiation of study treatment.  
Treatment reinitiation must be registered in the IWRS to obtain the enzalutamide treatment 
for patients on the enzalutamide treatment arms and provision of a 12 week supply of study 
drug for resumption of treatment.  (Refer to the IWRS Site Manual).  If a patient is on the 
leuprolide arm, they will restart leuprolide and continue with their subsequent IP 
administration (including leuprolide as applicable) at their next study visit.  Study drug 
administration should continue regardless of PSA values until radiographic progression is 
confirmed by local imaging (CT/MRI) per investigator’s assessment and the investigator 
considers continuing study drug not to be beneficial.
A prostate cancer nomogram will be provided to investigational sites for uniform calculation 
of the PSA doubling time.[25]
18.4. Investigational Product
18.4.1. 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 (open-labeled treatment will continue at the reduced dose). Patients 
should return all study drug bottles, including unused study drug to the site as indicated in the
study drug accountability visits (Table 16).

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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. 
18.4.2. Leuprolide Administration, Storage, and Accountability
For patients receiving leuprolide acetate (leuprorelin acetate), 22.5 mg will be given as a 
single intramuscular or subcutaneous injection once every 12 weeks.
The leuprolide acetate formulation for intramuscular injection is supplied as sterile 
lyophilized microspheres along with an accompanying diluent.  The microspheres are to be 
reconstituted as described in the prescribing information and administered as a single
intramuscular injection of 22.5 mg once every 12 weeks.
The leuprolide acetate formulation for subcutaneous injection is supplied as sterile powder 
along with an accompanying liquid gel solution. The powder is to be mixed with the liquid 
as described in the prescribing information and administered in clinic by study site personnel 
as a single subcutaneous injection of 22.5 mg once every 12 weeks.
Leuprolide should be handled and stored safely and properly in accordance with the 
prescribing information. Pfizer does not permit the shipment of leuprolide by mail.
18.4.3. Shipment of Enzalutamide to Study Participants
Enzalutamide may be shipped by courier to study participants if permitted by local 
regulations and in accordance with storage and transportation requirements for  
enzalutamide. The tracking record of shipments, including temperature monitoring data, and 
the chain of custody of enzalutamide must be kept in the participant’s source 
documents/medical records.
18.5. Duration of Treatment and Dose Modification 
Open-label study treatment administration may continue for patients whose prostate cancer 
has not progressed radiographically.
Enzalutamide 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 (4 capsules/day [160 mg/day]) or a 
reduced dose (3 or 2 capsules/day [120 or 80 mg/day]) in consultation with the medical 
monitor.
There are no provisions for dose modification of leuprolide on this study.  If enzalutamide is 
coadministered with a strong CYP2C8 inhibitor (eg, 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.

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18.6. Concomitant Medications – Follow-up Anticancer Medications 
Concomitant medications will be assessed at all clinic visits.  Record only concomitant
medications given for prostate cancer, hormonal therapies, antineoplastic therapies, and 
opioids on the concomitant medication CRF.  All other concomitant medications do not need 
to be added to the concomitant medication CRF in this OL study period.  Additionally, the
use of any medication given during the study that is due to an adverse event is no longer
required to be entered in the concomitant medication CRF but, the adverse event for which 
the drug was prescribed should be recorded on the adverse event CRF and in the patient’s 
clinical record.  
The use of concurrent cytotoxic chemotherapy or investigational anticancer agents while on 
study treatment is prohibited.  Initiation of bisphosphonates or denosumab for bone health is 
now allowed and SOC supplementation with calcium and vitamin D is encouraged.
18.7. Treatment Interruption and Discontinuation
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 OL period. 
Permanent treatment discontinuation is defined as cessation of randomized study drug 
treatment administration.  Temporary treatment interruption (eg, due to an adverse event) is 
not considered permanent discontinuation.  For more details, refer to Section 5.3.  Safety 
follow-up will be performed per Table 17.  Information on study discontinuation related to 
COVID-19 is provided in Appendix 6. 
Sponsor discontinuation of study: The sponsor has the right to terminate the study anytime.
However, the sponsor will ensure that study treatment will be available to all patients who 
participate in the OL period for as long as they are deriving clinical benefit.
Patients who discontinue study treatment (with exception of patients who withdraw consent) 
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 anti-cancer treatment is initiated before 30 days after the last 
dose of enzalutamide/leuprolide, then safety follow-up should occur immediately before 
starting the new treatment.  Long-term follow-up will commence after completion of safety 
follow-up. For more details, refer to Section 18.8.
18.7.1. 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.  If all 
efforts fail to establish contact, the patient will be considered lost to follow‑up.

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18.8. Safety Follow-up and Long-Term Follow-Up
Patients are to have a safety follow-up approximately 30 days after the last dose of OL study 
treatment.  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 
any new treatment (Table 17).
Table 17.
Safety Follow-Up Procedures (Open-Label Period)
Activity/Assessment
Comment
General Activities
Vital signs and physical examination
As clinically indicated, measure blood pressure, heart rate, 
temperature and weight. 
Assess body systems per institution’s SOC at the study site 
and as clinically indicated by symptoms.
ECOG performance status
Refer to Table 13.
Symptomatic skeletal events
Record use of radiation therapy (external beam radiation 
therapy or radionuclides) or surgery to bone for prostate 
cancer, findings of clinically apparent pathologic bone 
fracture or of spinal cord compression, and use of opiate 
and/or systemic antineoplastic therapy due to bone pain.
Adverse events review
Record any new or ongoing adverse events.
Concomitant medications 
review/contraceptive check
Record any new medications for prostate cancer, hormonal, 
antineoplastic therapies, and opiates.  
Study drug accountability (if applicable)
Record study drug returned and remind patient to return all 
study drug.
Local Laboratory Evaluations
Serum chemistry, hematology
Performed per SOC, refer to analytes listed in Section 18.3
Long-term follow-up data will be collected every 12 weeks. The information collected will 
include survival status, new antineoplastic therapies for prostate cancer, skeletal-related 
events, and PFS2 (Table 18). 
Table 18.
Long-Term Follow-Up Procedures (Open-Label Period)
Activity/Assessment/Timing
Comment
General Activities
Symptomatic skeletal events
Record use of radiation therapy (external beam radiation 
therapy or radionuclides) or surgery to bone for prostate 
cancer, findings of clinically apparent pathologic bone 
fracture or of spinal cord compression, and use of opiate 
and/or systemic antineoplastic therapy due to bone pain.

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Table 18.
Long-Term Follow-Up Procedures (Open-Label Period)
Activity/Assessment/Timing
Comment
Other information
Survival status. 
Subsequent therapies for prostate cancer, including opiate 
medication to treat bone pain.
Dates of investigator assessed progression on first 
subsequent therapy, including clinical, radiographic or PSA 
progression.
Radiographic assessments 
→ Perform at 24-week intervals (± 14 days)
Includes abdominopelvic CT/MRI and whole-body 
radionuclide bone scan for patients who have not yet had 
radiographic progression.
18.9. Statistical Methods
The final analysis of overall survival is planned after approximately 271 deaths occur across 
the 3 arms.  Analyses will be performed using a stratified log-rank test to compare OS for 
enzalutamide plus leuprolide versus placebo plus leuprolide and for enzalutamide 
monotherapy versus placebo plus leuprolide on ITT population respectively. 
The final analysis of the key secondary endpoint OS will be performed as planned 
(Section 10.4.2).  Based on the planned testing procedure in Section 10.4.2 and the actual 
results from tests for the primary endpoint and key secondary endpoint at the time of final 
analysis for primary endpoint, the analysis of OS for the combination arm will be tested at 
the alpha level of 0.05.  The analysis of OS for the monotherapy comparison will be tested 
hierarchically as planned at the same alpha level as the combination arm comparison if 
significant (Figure 2 and Table 15). 
In the final OS analysis, the significance level will be adjusted for the interim OS analysis 
following the specified Haybittle-Peto efficacy boundaries (Section 10.8 and Table 15). 
The analysis of OS in the aforementioned final analyses will be based on an ITT approach, 
and will be performed as the SAP.  An additional confounding factor for the OS analysis may 
come from patients who choose to access commercial enzalutamide, combination of 
enzalutamide and leuprolide and other commercially available treatments for the patients.  
The sponsors may explore the effect of crossover and post-study systemic anticancer therapy 
using rank-preserving structural failure time model (RPSFTM), and the inverse probability of 
censoring weighting (IPCW) method if appropriate.  Justifications, limitations and 
assumptions of RPFSTM and IPCW methods will be provided with further details in SAP.
At the time of final analysis of OS, updated results from following secondary endpoints 
including time to first use of new antineoplastic therapy, time to first symptomatic skeletal 
event and progression free survival on first subsequent therapy will be summarized 
descriptively and provided as exploratory analysis.  No other efficacy endpoints will be 
formally tested.  

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All exploratory efficacy analyses will be performed in ITT population.
Safety analyses will include all patients who receive 1 dose or partial dose of study drug 
(safety population).  Safety data for the patients treated in OL stage will be summarized by 
double blinded stage and OL stage separately.  
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.  For more 
details, refer to Section 10.5.
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.