A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase III Study of ARN-509 in Men With Non-Metastatic (M0) Castration-Resistant Prostate Cancer
Phase: PHASE3
Conditions: Prostatic Neoplasms
Sponsor: Aragon Pharmaceuticals, Inc.

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Clinical Study Protocol
SPARTAN
(Selective Prostate AR Targeting with ARN-509)
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, 
Phase III Study of ARN-509 in Men with Non-Metastatic (M0) 
Castration-Resistant Prostate Cancer
Protocol Number:
ARN-509-003 
Amendment 8
Investigational Product:
JNJ-56021927 (apalutamide)
IND Number:
104676
EudraCT Number:
2012-004322-24
Development Phase:
3
Sponsor:
Aragon Pharmaceuticals, Inc*
*Aragon Pharmaceuticals, Inc. is a wholly-owned subsidiary of Johnson & Johnson. Janssen 
Research & Development, LLC is part of the Janssen Pharmaceutical Companies of Johnson 
& Johnson and provides various services to its affiliated company, Aragon Pharmaceuticals, 
Inc.
This study will be conducted under US Food & Drug Administration IND regulations 
(21 CFR Part 312).
Status:
Approved
Date:
15 March 2017
Prepared by:
Janssen Research & Development, LLC
Document No.: EDMS-ERI-70784696; 10
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
The confidential information in the following document is provided to you as an investigator, potential 
investigator, or consultant, for review by you, your staff, and appropriate ethical review committee. By 
accepting this document, you agree that the information contained herein will not be disclosed to others 
without written authority from Aragon Pharmaceuticals, Inc., except to the extent necessary to obtain 
approval of this protocol by an ethical review committee.
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PROTOCOL AGREEMENT
I confirm that I have read this protocol. I will comply with the protocol and the principles of 
Good Clinical Practice (GCP), as described in the United States Code of Federal Regulation 
(CFR) 21 Parts 11, 50, 54, 56, and 312 and the appropriate International Conference on 
Harmonisation guidance documents.
Protocol:
ARN-509-003 Amendment 8
Protocol Title:
SPARTAN: A Multicenter, Randomized, Double-Blind, Placebo-
Controlled, Phase III Study of ARN-509 in Men with Non-Metastatic 
(M0) Castration-Resistant Prostate Cancer
Investigator Signature 
Date
Print Name and Title
Site #  ___________
Site Name  _______________________________________
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PROTOCOL SYNOPSIS
Title
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, 
Phase III Study of ARN-509 in Men with Non-Metastatic (M0) 
Castration-Resistant Prostate Cancer
Sponsor
Aragon Pharmaceuticals, Inc
Development Phase
3
Rationale
Prostate cancer is the second most frequently diagnosed cancer and 
the sixth leading cause of cancer death in males, accounting for 
14% (903,500) of the total new cancer cases and 6% (258,400) of 
the total cancer deaths in males worldwide.  The course of prostate 
cancer from diagnosis to death is best categorized as a series of 
clinical stages based on the extent of disease, hormonal status, and 
absence or presence of detectable metastases: localized disease, 
rising levels of prostate-specific antigen (PSA) after radiation 
therapy or surgery with no detectable metastases, and clinical 
metastases in the non-castrate or castrate stage.  Although surgery, 
radiation, or a combination of both can be curative for patients with 
localized disease, a significant proportion of these patients have 
recurrent disease as evidenced by a rising level of PSA, which can 
lead to the development of metastases, especially in the high risk 
group – a transition to the lethal stage of the disease.
Androgen depletion is the standard treatment with a generally 
predictable outcome: decline in PSA, a period of stability in which 
the tumor does not proliferate, followed by rising PSA and 
regrowth as castration-resistant disease.  Molecular profiling studies 
of castration-resistance prostate cancers commonly show increased 
androgen receptor (AR) expression, which can occur through AR 
gene amplification or other mechanisms.
ARN-509 (JNJ-56021927; apalutamide, hereafter referred to as 
apalutamide) is a next-generation anti-androgen that binds directly 
to the ligand-binding domain of AR, impairing nuclear 
translocation and DNA binding.  Apalutamide binds AR with 5-fold 
greater affinity than bicalutamide, and induces partial or complete 
tumor regression in both castration-sensitive and castration-resistant
human prostate cancer xenograft models.
A Phase I/II study (Protocol ARN-509-001) was designed to assess 
the safety, pharmacokinetics, and anti-tumor activity of apalutamide
in men with castration-resistant prostate cancer (CRPC).  The 
Phase I portion of the study has been completed and the Phase II is 
currently ongoing. In the Phase II, 97 patients were enrolled across 
3 different patient population subsets: high risk NM-CRPC, 
treatment-naïve metastatic CRPC (no prior treatment with 
abiraterone acetate or chemotherapy), and metastatic CRPC after 
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failure with abiraterone acetate.
In the NM-CRPC subset (n =51 ), the most frequent 
treatment-related adverse events reported in >10% of subjects as of 
30 November 2013 are fatigue (43%), diarrhea (31%), nausea 
(20%), increased thyroid stimulating hormone (12%), dysgeusia 
(12%), and hot flush 12%.  Eight (16%) patients have discontinued 
the study due to adverse events.  Seven (14%) patients have 
discontinued due to disease progression.  No deaths were reported 
in this subgroup as of the safety cutoff. The 12-week PSA response
(≥50% decline from baseline) is 91%.  
Study Design
This is a randomized (2:1), multicenter, double-blind, 
placebo-controlled, Phase III clinical trial evaluating the efficacy 
and safety of apalutamide versus placebo in men with high risk 
(M0) NM-CRPC, defined as PSA Doubling Time (PSADT) ≤10 
months.
Patients will be stratified based on:

PSADT: > 6 months vs. ≤6 months

Bone-sparing agent use: Yes vs. No

Loco-regional disease: N0 vs. N1
Patients will be followed for safety and efficacy as per the schedule 
of activities and will remain on study treatment until documented 
radiographic progression (development of distant metastases as 
assessed by blinded independent central review) or the development 
of unacceptable toxicity.  
Patients discontinuing treatment due to documented radiographic 
progression will enter the Long-term Follow-up Phase, where they 
will be followed for the development of symptomatic progression 
and initiation of subsequent anti-cancer therapies (in particular, 
cytotoxic chemotherapy) every 4 months until death, loss of follow-
up, or withdrawal of consent, whichever comes first. 
Patients discontinuing treatment prior to documented radiographic 
progression will also enter the Long-term Follow-up Phase where 
they will continue to have scheduled disease assessments every
16 weeks until documented radiographic progression, and will be 
followed for the development of symptomatic progression and 
initiation of subsequent anti-cancer therapies (in particular, 
cytotoxic chemotherapy) every 4 months until death, loss of follow-
up, or withdrawal of consent, whichever comes first.
At the time of study unblinding and in the event of a positive study 
result, all subjects currently receiving placebo will have the 
opportunity to receive active therapy with apalutamide.
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Primary Objective
To demonstrate superiority in the metastasis-free survival (MFS) of 
men with high risk NM-CRPC treated with apalutamide versus 
placebo
Secondary 
Objectives

To compare the overall survival (OS) of men with high risk 
NM-CRPC treated with apalutamide versus placebo

To compare the time to symptomatic progression in men with 
high risk NM-CRPC treated with apalutamide versus placebo

To compare the time to initiation of cytotoxic chemotherapy in 
men with high risk NM-CRPC treated with apalutamide versus 
placebo 

To compare the progression-free survival (PFS) of men with 
high risk NM-CRPC treated with apalutamide versus placebo

To compare the time to metastasis (TTM) in men with high risk 
NM-CRPC treated with apalutamide versus placebo

To evaluate the safety and tolerability of apalutamide
Other Objectives

To compare patient reported outcomes (PROs) of health-related 
quality of life and prostate cancer-specific symptoms in men 
with high risk NM-CRPC treated with apalutamide versus 
placebo

To evaluate the population pharmacokinetics (PK) of 
apalutamide

To evaluate the effect of apalutamide on ventricular 
repolarization in a subset of patients from selected clinical sites

To evaluate exploratory biomarkers predictive of response and 
resistance to apalutamide treatment
Number of Patients
1,200 (apalutamide: 800; placebo: 400)
Enrollment Criteria
The study population includes men 18 years of age or older with 
NM-CRPC at high-risk for metastases defined as a prostate-specific 
antigen doubling time (PSADT) of 10 months or less. Patients are 
excluded if blinded independent central review (BICR) confirms the 
presence of distant metastases including CNS and vertebral or 
meningeal involvement or a history of distant metastases. Patients 
who present at Screening with lymph nodes less than 2 cm in the 
short axis (N1) located below the iliac bifurcation, are eligible. Any 
patient who received first generation anti-androgens must show 
continuing disease (PSA) progression after discontinuation of the 
anti-androgen for at least 4 weeks prior to randomization. Bone 
sparing therapies for the treatment of osteoporosis are allowed if the 
patient were on stable doses for at least 4 weeks before 
randomization. Patients with symptomatic loco-regional disease 
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requiring medical intervention are excluded. An Eastern 
Cooperative Oncology Group (ECOG) Performance Status (PS)
grade of 0 or 1 is required
Dose, and Route of 
Administration
Apalutamide/matched placebo tablets will be administered orally on 
a continuous daily dosing regimen, at a starting dose for 
apalutamide of 240 mg once daily (4 x 60-mg tablets). The only 
difference between apalutamide tablet and its matched placebo
tablet is the absence of the active ingredient in the matched placebo
tablet. 
Safety Assessments
Patients will be assessed for adverse events (AEs) at each monthly 
clinic visit while on the study.  Adverse events will be graded 
according to the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.0.  
Type, incidence, severity, timing, seriousness, and relatedness of 
AEs, and laboratory abnormalities will be reported.
Data Monitoring 
Committee
An Independent Data Monitoring Committee (IDMC) will be 
established to monitor data on an ongoing basis to ensure the safety 
of the subjects enrolled in this study. The committee will meet 
periodically to review interim safety data. After the review, the 
IDMC will make recommendations regarding the conduct of the 
study. The IDMC will serve as the primary reviewers of the 
efficacy analysis. Details are provided in a separate IDMC charter.
Efficacy Assessments
Disease assessments will be performed as scheduled according to 
the calendar, regardless of treatment delays resulting from toxicity.  
Disease assessments (CT scans of the chest, abdomen, and pelvis, 
plus bone scan) will be performed at baseline and at 16-week 
intervals from Cycle 1 Day 1 until documented progression.  All 
scans will be submitted for BICR by a third-party core imaging 
laboratory to confirm patient eligibility (i.e., no presence of distant 
metastases) and disease progression during the study. 
Primary Endpoint

Metastasis-free survival (MFS)
Secondary Endpoints

Time to Metastasis (TTM)

PFS

Time to symptomatic progression

Overall survival (OS)

Time to initiation of cytotoxic chemotherapy
Other Evaluations

Health-related quality of life and prostate cancer-specific 
symptoms
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
Type, incidence, severity, timing, seriousness, and relatedness 
of adverse events and laboratory abnormalities

PSA Response

Time to PSA progression

Population PK

Assessment of ventricular repolarization

Second progression-free survival (PFS2)

Medical resource utilization (MRU)
Statistical Analysis 
Plan and Rationale 
for Number of 
Patients
The primary efficacy analysis will be event-driven.  Based on 
results from a large Phase III study of denosumab versus placebo in 
high risk NM-CRPC patients, the expected median MFS in the 
control arm is 25 months. 
Applying a 2:1 randomization, a planned accrual period of 
24 months and a minimum follow-up period of 9 months, it is 
estimated that approximately 1,200 patients will need to be enrolled 
in order to observe 372 MFS events.  This sample size has 90% 
power to detect a 30% reduction in the risk of developing 
metastases (HR = 0.70) for patients receiving apalutamide, with a 
2-sided α of 0.05.  This treatment effect corresponds to an increase 
in median MFS of approximately 11 months (from 25 to 
36 months), which would be considered clinically relevant.  
The study was also designed to provide 85% power to detect a 25% 
reduction (HR = 0.75) in the risk of death for patients receiving 
apalutamide, based on an assumed median OS of 49 months in the 
placebo arm. This treatment effect represents an increase in median 
OS of approximately 16 months (from 49 to 65 months).  
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Duration of Patient 
Participation and 
Duration of Study
Patients will remain on study treatment until BICR-confirmed
radiographic disease progression (ie, distant metastasis), 
development of unacceptable toxicity, or withdrawal of consent. 
Patients discontinuing study treatment will enter the Long-term 
Follow-up Phase and remain on study until death, loss of follow-up,
or withdrawal of consent, whichever comes first.
With an estimated accrual duration of 24 months, it is assumed that 
patients are expected to be followed for a minimum of 
approximately 9 months beyond Last Patient In (LPI) for the 
primary endpoint of MFS, to approximately 41 months beyond LPI 
for the key secondary endpoint of OS.  This corresponds to a
projected study duration of approximately 65 months.
If the study is not terminated beforehand per the recommendation of 
the IDMC, the end of trial in all participating countries will be 
defined as the time at which the secondary endpoint of OS has been 
met.  
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LIST OF ABBREVIATIONS
ADT
androgen deprivation therapy
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AR
androgen receptor
AST
aspartate aminotransferase
BICR
blinded independent central review
BSE
bovine spongiform encephalopathy
BUN
blood urea nitrogen
CFR
Code of Federal Regulations
CNS
central nervous system
CRF
case report form
CRPC
castration-resistant prostate cancer
CTCAE
Common Terminology Criteria for Adverse Events
DLT
dose-limiting toxicity
ECG
electrocardiogram
FFPE
formalin-fixed paraffin-embedded
EDC
electronic data capture
EWB
emotional well-being
FACT-P
Functional Assessment of Cancer Therapy-Prostate
FDA
Food and Drug Administration
FDHT
16β-[18F] fluoro-α-dihydrotestosterone
FWB
functional well-being
GCP
Good Clinical Practice
GnRHa
gonadotropin releasing hormone analog
HIPAA
Health Insurance Portability and Accountability Act of 1996
HIV
human immunodeficiency virus
ICF
informed consent form
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IRB
Institutional Review Board
MFS
metastasis-free survival
NCI
National Cancer Institute
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NM-CRPC
non metastatic castration-resistant prostate cancer
NOAEL
no observed adverse effect level
OS
overall survival
PCWG2
Prostate Cancer Clinical Trials Working Group 2
PET
positron emission tomography
PFS
progression-free survival
PK
pharmacokinetics
PQC
product quality complaint 
PSA
prostate-specific antigen
PSADT
prostate-specific antigen doubling time
PWB
physical well-being
QTc
corrected QT interval
QTcB
corrected QT interval according to the Bazett correction
QTcF
corrected QT interval according to the Fridericia correction
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
serious adverse event
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamate pyruvate transaminase
SOC
system organ class
SWB
social well-being
TPGS
d-α-tocopheryl polyethylene glycol 1000 succinate
TTM
time to metastasis
ULN
upper limit of normal
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TABLE OF CONTENTS
PROTOCOL AMENDMENTS ........................................................................................ 16
1.
BACKGROUND ....................................................................................................... 38
1.1
APALUTAMIDE .................................................................................................................38
Molecular Formula and Chemical Class..........................................................................39
1.1.1
Pre-Clinical Development Overview ...............................................................................39
1.1.2
Overview of Clinical Studies ...........................................................................................42
1.1.3
2.
STUDY OBJECTIVES............................................................................................. 44
2.1
PRIMARY OBJECTIVE .....................................................................................................44
2.2
SECONDARY OBJECTIVES .............................................................................................44
2.3
OTHER OBJECTIVES ........................................................................................................44
3.
STUDY DESIGN....................................................................................................... 45
3.1
STUDY OVERVIEW AND RATIONALE.........................................................................45
Crossover Option in the Event of Unblinding..................................................................46
3.1.1
Selection of the Primary Endpoint ...................................................................................46
3.1.2
3.2
STUDY OUTCOMES..........................................................................................................47
Primary Endpoint.............................................................................................................47
3.2.1
Secondary Endpoints........................................................................................................47
3.2.2
Other Evaluations.............................................................................................................47
3.2.3
4.
PATIENT SELECTION .......................................................................................... 47
4.1
INCLUSION CRITERIA.....................................................................................................48
4.2
EXCLUSION CRITERIA....................................................................................................50
5.
STUDY TREATMENTS.......................................................................................... 52
5.1
RANDOMIZATION CRITERIA.........................................................................................52
5.2
BLINDING...........................................................................................................................52
5.3
FORMULATION.................................................................................................................53
Apalutamide/Matched Placebo ........................................................................................53
5.3.1
Packaging, Storage, and Labeling....................................................................................53
5.3.2
Drug Administration ........................................................................................................53
5.3.3
Cycle Management ..........................................................................................................53
5.3.4
Dose Modifications..........................................................................................................53
5.3.5
5.4
STUDY DRUG ACCOUNTABILITY ................................................................................54
5.5
MEASURES OF TREATMENT COMPLIANCE ..............................................................55
6.
CONCURRENT MEDICATIONS.......................................................................... 55
6.1
PROHIBITED MEDICATIONS AND TREATMENTS.....................................................55
6.2
RESTRICTED THERAPIES ...............................................................................................55
6.3
LIFE STYLE GUIDELINES ...............................................................................................56
7.
STUDY PROCEDURES AND GUIDELINES....................................................... 58
7.1
CLINICAL ASSESSMENTS...............................................................................................58
Demographics ..................................................................................................................58
7.1.1
Medical History................................................................................................................58
7.1.2
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Physical Examination.......................................................................................................58
7.1.3
Vital Signs........................................................................................................................58
7.1.4
Performance Status ..........................................................................................................59
7.1.5
Adverse Events ................................................................................................................59
7.1.6
Concomitant Medications/Therapies ...............................................................................59
7.1.7
Tumor Assessments .........................................................................................................59
7.1.8
7.1.8.1
Blinded Independent Central Review (BICR)....................................................59
7.2
CLINICAL LABORATORY MEASUREMENTS .............................................................60
PSA ..................................................................................................................................60
7.2.1
Electrocardiogram (ECG) ................................................................................................60
7.2.2
7.3
PHARMACOKINETIC MEASUREMENTS......................................................................60
7.4
PATIENT-REPORTED OUTCOMES ................................................................................61
7.5
EXPLORATORY BIOMARKERS ..................................................................................61
8.
STUDY ASSESSMENTS BY VISIT (APPENDIX 1) ........................................... 62
8.1
PRESCREENING ................................................................................................................62
8.2
SCREENING (WITHIN 35 DAYS OF RANDOMIZATION) ...........................................62
8.3
CYCLE 1 DAY 1 .................................................................................................................62
8.4
DAY 1 OF CYCLES 1-6, THEN DAY 1 OF EVERY 2 CYCLES STARTING FROM 
CYCLE 7 UP TO C13 THEN DAY 1 OF EVERY 4 CYCLES (±2 DAYS) ......................63
8.5
EVERY 16 WEEKS STARTING FROM CYCLE 1 DAY 1 (±2 DAYS)...........................63
8.6
EVERY 16 WEEKS STARTING FROM CYCLE 1 DAY 1 (±7 DAYS)...........................63
8.7
END-OF-TREATMENT VISIT...........................................................................................63
8.8
SAFETY FOLLOW-UP (28 DAYS FOLLOWING THE LAST DOSE OF STUDY DRUG)
..............................................................................................................................................64
8.9
LONG-TERM FOLLOW-UP ..............................................................................................64
8.10
SUBSEQUENT THERAPY WITH ABIRATERONE ACETATE.....................................64
9.
ADVERSE EVENT REPORTING REQUIREMENTS ....................................... 66
9.1
DEFINITIONS .....................................................................................................................66
Adverse Events (AE) .......................................................................................................66
9.1.1
Serious Adverse Events (SAE) ........................................................................................67
9.1.2
Expectedness....................................................................................................................67
9.1.3
Attribution........................................................................................................................68
9.1.4
Severity ............................................................................................................................68
9.1.5
Pregnancy.........................................................................................................................69
9.1.6
9.2
REPORTING REQUIREMENTS........................................................................................69
SAE Reporting.................................................................................................................69
9.2.1
Non-Serious AE Reporting ..............................................................................................70
9.2.2
Sponsor Reporting Requirements to Regulatory Authorities...........................................70
9.2.3
Product Quality Complaint Handling...............................................................................71
9.2.4
9.2.4.1
Procedures ..........................................................................................................71
9.2.4.2
Contacting Sponsor Regarding Product Quality ................................................71
10.
END OF TREATMENT........................................................................................... 71
11.
PROTOCOL VIOLATIONS ................................................................................... 72
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12.
DATA MONITORING COMMITTEE.................................................................. 73
13.
STATISTICAL METHODS AND CONSIDERATIONS ..................................... 73
13.1
ANALYSIS POPULATIONS..............................................................................................73
13.2
EFFICACY ANALYSES.....................................................................................................73
Analysis of Primary Endpoint..........................................................................................74
13.2.1
Analyses of Secondary Endpoints....................................................................................75
13.2.2
13.2.2.1
OS.......................................................................................................................76
13.2.2.2
Time to Symptomatic Progression .....................................................................76
13.2.2.3
Time to Initiation of Cytotoxic Chemotherapy ..................................................76
13.2.2.4
Progression-Free Survival ..................................................................................77
13.2.2.5
Time to Metastasis..............................................................................................78
13.3
SAFETY EVALUATIONS..................................................................................................78
Analysis of Adverse Events .............................................................................................78
13.3.1
Analysis of Clinical Laboratory Results ..........................................................................79
13.3.2
Analysis of Vital Signs ....................................................................................................79
13.3.3
Concomitant Medications/Treatments .............................................................................79
13.3.4
13.4
OTHER EVALUATIONS ...................................................................................................80
Second Progression-free Survival (PFS2)........................................................................80
13.4.1
PSA ..................................................................................................................................80
13.4.2
Health-Related Quality of Life and Prostate Cancer-Specific Symptoms Analysis ........80
13.4.3
Population Pharmacokinetics (Pop PK) Analysis............................................................80
13.4.4
Exploratory Biomarkers Analysis....................................................................................81
13.4.5
Assessment of Ventricular Repolarization.......................................................................81
13.4.6
Medical Resource Utilization Analysis............................................................................81
13.4.7
13.5
INTERIM ANALYSIS.........................................................................................................82
13.6
DETERMINATION OF SAMPLE SIZE.............................................................................82
14.
DATA COLLECTION, RETENTION AND MONITORING............................. 82
14.1
DATA COLLECTION INSTRUMENTS............................................................................82
14.2
DATA MANAGEMENT PROCEDURES ..........................................................................82
14.3
DATA QUALITY CONTROL AND REPORTING ...........................................................83
14.4
ARCHIVAL OF DATA .......................................................................................................83
14.5
AVAILABILITY AND RETENTION OF INVESTIGATIONAL RECORDS..................83
14.6
MONITORING ....................................................................................................................83
14.7
PATIENT CONFIDENTIALITY ........................................................................................84
15.
ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS........ 84
15.1
INVESTIGATOR RESPONSIBILITIES.............................................................................84
15.2
PROTOCOL AMENDMENTS............................................................................................84
15.3
INSTITUTIONAL REVIEW BOARDS AND INDEPENDENT ETHICS COMMITTEES85
15.4
INFORMED CONSENT FORM .........................................................................................85
15.5
REPORTING OF SAFETY ISSUES AND SERIOUS BREACHES OF THE PROTOCOL 
OR ICH GCP........................................................................................................................86
15.6
END OF TRIAL IN ALL PARTICIPATING COUNTRIES ..............................................86
15.7
SPONSOR DISCONTINUATION CRITERIA...................................................................86
15.8
PUBLICATIONS .................................................................................................................87
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16.
REFERENCES.......................................................................................................... 87
17.
APPENDICES........................................................................................................... 89
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PROTOCOL AMENDMENTS
Protocol Version 
Issue Date
Original Protocol
5 November 2012
Amendment INT-1* 
11 January 2013
Amendment INT-2* 
8 May 2013
Amendment INT-3
11 March 2014
Amendment INT-4
16 June 2014
Amendment INT-5
1 July 2014
Amendment INT-6
18 May 2015
Amendment 7
1 June 2016
Amendment 8
15 March 2017
*These amendment changes are provided in a separate document (EDMS-ERI-71567787)
Amendments are listed beginning with the most recent amendment.
Amendment 8 (13 March 2017)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for this amendment is to revise the statistical sections of the protocol. The current statistical 
analysis plan for analysis of secondary endpoints lacks power given the projected low event rates; therefore, the 
Sponsor is revising the multiple testing procedure for the secondary endpoints. In addition, text was added to 
allow, in the event of a positive study result and unblinding, for subjects receiving placebo to begin receiving 
active therapy with apalutamide. The rationale for and description of the changes are listed below, when 
revisions are provided verbatim, bold font denotes new text, and strikethrough denotes deleted text.
Applicable Section(s)
Description of Change(s)
Rationale: The current statistical analysis plan for analysis of secondary endpoints lacks power given the 
projected low event rates; therefore, the Sponsor is revising the multiple testing procedure for the secondary 
endpoints.
Section 13.2.2, 
Analyses of 
Secondary Endpoints
Deleted:
Following the primary analysis of MFS, the analyses of the secondary endpoints will 
be performed at the time of the expected total number of MFS events (372 events  ).  
The secondary endpoints will be subdivided into the following 2 groups:
Group 1:
Time to symptomatic progression
Time to initiation of cytotoxic chemotherapy
PFS
TTM
Group 2: 
OS
The statistical testing of the 2 groups of secondary endpoints will be performed by 
allocating 0.01 to Group 1 and 0.04 for the OS endpoint in Group 2 with an overall 
familywise type I error rate of 0.05. Details of the testing procedure will be provided 
in the statistical analysis plan.  
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Applicable Section(s)
Description of Change(s)
Section 13.2.2, 
Analyses of 
Secondary Endpoints
(cont’s)
Replaced with:
For the secondary endpoints, a hierarchical testing will be performed in the 
following order: 

TTM

PFS

Time to symptomatic progression

OS

Time to initiation of cytotoxic chemotherapy
each at alpha=0.05 (2-sided). Each secondary endpoint will have a final analysis 
but there will be no interim analysis for TTM and PFS. There will be 1 interim 
time to symptomatic progression, and up to 2 interim analyses for OS and time 
to initiation of cytotoxic chemotherapy. The testing of time to symptomatic 
progression, OS and time to initiation of cytotoxic chemotherapy endpoints will 
utilize an adaptive group sequential method, according to the pre-specified 
O’Brien-Fleming-type alpha spending function with possible re-estimation of the 
required number of events necessary for the next analysis to maintain the 
desired conditional power. If time to symptomatic progression is significant at 
the IA, then there will be only 1 interim analysis for OS and time to initiation of 
cytotoxic chemotherapy; otherwise there will be 2 interim analyses for OS and 
time to initiation of cytotoxic chemotherapy. 
The final analysis of TTM and PFS, interim analysis of time to symptomatic 
progression, and the first interim analysis of OS and time to initiation of 
cytotoxic chemotherapy will all be performed at the same time as the primary 
analysis of MFS (approximately 372 events). 
Full details about the adaptive group sequential testing procedure will be 
provided in the statistical analysis plan.
Time-to-event-based secondary endpoint analyses (TTM, PFS, time to symptomatic 
progression, OS, and time to initiation of cytotoxic chemotherapy) will be performed 
using a two-sided log-rank test, stratified by PSADT (> 6 months vs. ≤ 6 months), the 
use of a bone-sparing agent (Yes vs. No), and the presence of loco-regional disease 
(N0 vs. N1).  
Rationale: The next 3 changes were made in the sections identified as a result of changes made to the analysis 
of secondary endpoints (covered in Section 13.2.2).
Section 13.2.2.1, OS
Deleted (text that was following table in this section):
The final analysis of OS will occur after approximately 526 deaths have occurred. 
Two interim analyses are also planned (see Section 13.5). Additional analyses may be 
conducted as appropriate. ). 
Section 13.4.2, PSA
PSA kinetics (e.g., 12-week PSA response and time to PSA progression) will be 
assessed at the time of the primary analysis of MFS according to the Prostate Cancer 
Clinical Trials Working Group (PCWG2) recommendations.
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Applicable Section(s)
Description of Change(s)
Section 13.5, Interim 
Analysis
Deleted:
Two interim analyses and 1 final analysis are planned for the OS endpoint.  The 
testing of the OS endpoint will be performed according to the O’Brien Fleming 
boundary as implemented by the Lan DeMets alpha spending function with a planned 
alpha of 0.04.  For the OS endpoint, the maximum expected total number of death 
events is 526 (final analysis).  At the time of the first interim analysis, approximately 
46% (243/526) of the death events will be observed with an alpha spend of 0.0012.  
The second interim analysis will be performed after observing approximately 70% 
(369/526) of the death events with a cumulative alpha spend of 0.0109.  The actual 
alpha spent for the 2 interim analyses will be based on the number of death events 
observed at the time of the analyses.
Replaced with:
There will be 1 interim analysis for time to symptomatic progression, and up to 2 
interim analyses for OS and time to initiation of cytotoxic chemotherapy; see 
Section 13.2.2 for an outline of analysis methods.  
Rationale: Added details for placebo subjects to begin receiving active treatment with apalutamide, in the event 
of a positive study result and the study is unblinded.
Synopsis, Study 
Design; Section 3.1.1, 
Crossover Option in 
the Event of 
Unblinding; Section 4, 
Patient Selection; and 
Appendix 10, 
Crossover to Open 
Label Apalutamide 
After Study 
Unblinding
Synopsis and Section 3.1.1: At the time of study unblinding and in the event of a 
positive study result, all subjects currently receiving placebo will have the 
opportunity to receive active therapy with apalutamide (refer to Appendix 10).
Section 4: Treatment criteria for placebo subjects who crossover to active 
treatment with apalutamide (in the event of a positive study result and 
unblinding) are described in Appendix 10.
New Appendix 10 added (not included here in summary of changes due to size).
Rationale: Changed ‘is’ to ‘was’ to clarify that the text in this section reflects thinking at the time the original 
protocol was written; deleted text that is no longer applicable.
Section 13.6, 
Determination of 
Sample Size
The study is was also sized to provide 85% power to detect a 25% reduction (HR = 
0.75) in the risk of death for patients receiving apalutamide, based on an assumed 
median OS of 49 months in the placebo arm.  This treatment effect represents an 
increase in the median OS of approximately 16 months (from 49 to 65 months).  The 
final analysis of OS will occur after approximately 526 deaths have occurred.
The total study duration (including the time it takes to reach the secondary endpoint of 
OS) will be approximately 65 months.
Synopsis, Statistical 
Analysis Plan and 
Rationale for Number 
of Patients
The study is was also designed to provide 85% power to detect a 25% reduction (HR 
= 0.75) in the risk of death for patients receiving apalutamide, based on an assumed 
median OS of 49 months in the placebo arm. This treatment effect represents an 
increase in median OS of approximately 16 months (from 49 to 65 months).  
Two interim analyses and 1 final analysis will be performed for the OS endpoint. The 
final analysis for OS will occur after approximately 526 deaths have been observed. 
The first interim analysis of OS (approximately 46% of total death events) will occur 
at the time of the final analysis of the primary endpoint, MFS, and the second interim 
analysis will occur when approximately 70% of total death events are observed.
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Applicable Section(s)
Description of Change(s)
Rationale: Correction of the median OS time in the study population.
Section 3.1.2, 
Selection of the 
Primary Endpoint
In consideration of the relatively long median OS (~4549 months) in this population 
and the opportunity to assess for the development of distant metastasis as a clinically 
important milestone, metastasis-free survival (MFS) was chosen as the primary 
objective of this study.  
Rationale: Correction was made to note that email can be used for reporting of SAEs in addition to fax.
Section 9.2.1, SAE 
Reporting
The initial and follow-up reports of an SAE should be made by facsimile (fax) or 
email.  
Rationale: Clarification for criteria of disease progression for administration of subsequent therapy with 
abiraterone acetate, if the study is unblinded.
Section 8.10, 
Subsequent therapy 
with Abiraterone 
Acetate (second 
bullet)

documented disease progression (ie, meet criteria for the primary endpoint 
[distant metastasis], see Section 13.2.1).  If the study is unblinded, the 
requirement for meeting disease progression by BICR in Section 13.2.1 will 
not be required. 
Rationale: Minor errors were corrected, minor revisions were made.
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made. Minor organizational 
changes were made.
Amendment 7 (1 June 2016)
This amendment is considered to be non-substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union, in that it does not significantly 
impact the safety or physical/mental integrity of subjects, nor the scientific value of the study.
The overall reason for this amendment is to reduce the frequency of visits after Cycle 7 per request of the 
investigators and patients. The revised visit schedule is consistent with other apalutamide Phase 3 protocols.
The tablet formulation with improved shelf-life allows for fewer visits. Collection of medical resource 
utilization (MRU) should continue during the Long-term Follow-up Phase. 
The rationale for and description of the changes are listed below, when revisions are provided verbatim, bold 
font denotes new text, and strikethrough denotes deleted text.
Applicable Section(s)
Description of Change(s)
Rationale: A reduction in the clinic visits will reduce burden to patients and the improved shelf-life of the 
tablets also allows for fewer clinic visits.
Section 8.4 Day 1 of 
Cycles N (±2 Days); 
Appendix 1, Schedule 
of Activities
Visit frequency revised to the following: Every cycle up to Cycle 6, starting at Cycle 7 
reduce to every 2 cycles (eg, C9, C11, etc), starting at Cycle 13 reduce to every 4 
cycles (eg, C17, C21, etc). 
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Applicable Section(s)
Description of Change(s)
Rationale: The PK and biomarker sample collection timings were revised to align with the revised visit 
schedule.
Section 7.3
Pharmacokinetic 
Measurements; 
Section 8.4 Day 1 of 
Cycles N (±2 Days); 
Section 13.4.5 
Exploratory 
Biomarker Analysis; 
Appendix 1, Schedule 
of Activities
To align the PK sample collection with the revised visit schedule, the visits for PK 
collection were changed from Cycle 12 to Cycle 11, Cycle 18 to Cycle 17, and Cycle 
24 to Cycle 25. To align the biomarker sample collection with the revised visit 
schedule, the visits for biomarker sample collection were changed from Cycle 12 to 
Cycle 11, Cycle 18 to Cycle 17, from Cycle 24 to Cycle 25, and from Cycle 36 to 
Cycle 37.
Rationale: The frequency for completion of the FACT-P and EQ-5D questionnaires will coincide with the 
revised clinic visit schedule during the Treatment Phase. 
Appendix 1 Schedule 
of Activities
The collection timing of the questionnaires was aligned with the reduced number of 
clinic visits. 
Rationale: Collection of MRU should continue during the Long-term Follow-up Phase. 
Section 8.9 Long-
term Follow-up; 
Appendix 1, Schedule 
of Activities
Added collection of MRU to the Long-term Follow-up Phase.
Rationale: The Survival Follow-up includes collection of other information and referring to this phase as 
Survival Follow-up was not accurate. 
Synopsis Study 
Design, Duration of 
Patient Participation 
and Duration of 
Study; Section 4.1 
Inclusion Criteria; 
Section 8.9 Long-
term Follow-up; 
Section 10 End of 
Treatment; Section 
15.6 End of Trial in 
all Participating 
Countries; 
Appendix 1, Schedule 
of Activities
Revised the name of this phase of the study to “Long-term Follow-up Phase.”
Inclusion Criterion #13.2 was revised to the following: Willingness and ability to 
comply with scheduled visits, treatment plans, laboratory and radiographic 
assessments, and other study procedures, including ability to swallow study drug 
tablets, the completion of patient reported outcomes questionnaires and survival long-
term follow-up visits
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Applicable Section(s)
Description of Change(s)
Rationale: If thyroid stimulating hormone (TSH) levels are abnormal, additional reflex testing must be 
performed.
Section 8.5 Every 
16 weeks…; 
Appendix 1 Schedule 
of Activities: 
Footnote 11; 
Appendix 2
Added the following statement to Appendix 2: 
If TSH is abnormal; total T3, free T4 (direct), and total T4 are required.
Added reference to Appendix 2 in Footnote 11 of Appendix 1
Rationale: SAE reporting requirements were not aligned with the current Janssen protocol template. 
Section 9.2.1 SAE 
Reporting 
Made the following revision: Information regarding SAEs will be transmitted to the 
Sponsor using the Serious Adverse Event Form, which must be completed and signed 
by a physician from the study site, and transmitted to the Sponsor within 24 hours.The 
initial and follow-up reports of an SAE should be made by facsimile (fax). This 
timeframe also applies to additional new information (follow-up). SAEs should be 
reported by facsimile or email.
Rationale: All patients will have switched from softgel capsules to tablets at the time of implementation of this 
amendment therefore guidance for the switching, is no longer necessary.
Section 5.3.3 Drug 
Administration
Removed guidance for the switch from softgel capsules to tablets. 
Rationale: A generic name for ARN-509 is now available.
Throughout the 
protocol, where 
appropriate
The designation of ARN-509 is changed to the generic name, apalutamide.
Rationale: Updated drug-drug interaction information is available 
Section 6.2 Restricted 
Therapies; 
Attachment 5
Updated drug-drug interaction information. 
Rationale: All Janssen Phase 3 protocols must now include a list of anticipated events.
Section 9.2 Reporting 
Requirements; 
Section 9.2.3 Sponsor 
Reporting 
Requirements to 
Regulatory 
Authorities; 
Appendix 9
Added details for reporting and a list of anticipated events in Appendix 9. A statement 
to reference the Appendix was added to Section 9.2 of the protocol. Additional 
information in cases of serious anticipated events was added to Section 9.2.3 as 
follows: For anticipated events reported as individual serious adverse events the 
Sponsor will make a determination of relatedness in addition to and independent 
of the investigator’s assessment. The Sponsor will periodically evaluate the 
accumulating data and, when there is sufficient evidence and the sponsor has 
determined there is a reasonable possibility that the drug caused a serious 
anticipated event, they will submit a safety report in narrative format to the 
investigators (and the head of the institute).
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Applicable Section(s)
Description of Change(s)
Rationale: Minor errors or clarifications were noted
Synopsis, Duration of 
Patient 
Participation…; 
Section 8.10 
Subsequent Therapy 
with Abiraterone 
Acetate; Section 8.6 
Every 16 Weeks…
Added “distant metastasis” after the term disease progression.
Protocol Synopsis 
Study Design; 
Section 3.1 Study 
Overview and 
Rationale; Section 
8.9 Long-term 
Follow-up  
Appendix 1 Schedule 
of Activities, 
Footnotes 4 and 13
When referring to scan frequency revised from 4 months to 16 weeks for consistency 
with the scan frequency in the Schedule of Activities.
Section 8.9 Long-
term Follow-up; 
Appendix 1 Schedule 
of Activities, 
Footnotes 4 and 21
Added “an alternative contact method per institution policy/practice.” 
Section 4.1 Inclusion 
Criteria; Section 4.2 
Exclusion Criteria
Corrected the formatting per template
Throughout the 
protocol
Removed redundancy and made minor corrections.
Amendment INT-6 (18 May 2015)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union. 
The overall reason for this amendment is to switch softgel capsules to tablets (commercial formulation) for patients 
currently receiving the softgel capsules and to administer tablets to newly enrolled patients. Added the restriction 
that Section 8.10 does not apply in Japan. Additional minor changes were made as outlined below.  
Applicable Section(s)
Description of Change(s)
Rationale: Switch of softgel capsules to tablets is incorporated. 
 is not included in the tablet 
formulation.
(b) (4)
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Applicable Section(s)
Description of Change(s)
Throughout
Changed “softgel capsules” or “capsules” to “tablets.”
Section 5.3.1 
ARN-509/Matched 
Placebo; Section 5.3.2 
Packaging, Storage, 
and Labeling
Removed information on formulation, packaging, and storage of the softgel capsules. 
Replaced with appropriate wording for the tablets. 
Section 5.3.1 
ARN-509/Matched 
Placebo; Section 6.2, 
Restricted Therapies; 
Appendix 5
Removed
 information, no longer applicable with the tablet formulation. 
Section 5.3.3 Study 
Drug Administration
Added a new table showing the conversion from capsule to tablet and clarifying that 
the conversion is 2:1. Provided timing for the switch from the softgel capsules to 
tablets. Revised Table 2. 
Rationale: The twice daily dosing is no longer relevant for the tablet formulation.
Synopsis Dose and 
Route of 
Administration; 
Section 5.3.4 Cycle 
Management; 
Section 5.3.5 Dose 
Modifications
Removed the twice daily dosing option. Removed wording on dose modification due to 
gastrointestinal discomfort. 
Rationale: Revised treatment compliance to account for capsules or tablets
Section 5.5 Measures 
of treatment 
compliance; Schedule 
of Activities 
(Footnote 8)
Changed from “capsules” to “capsules or tablets.” Revised compliance to account for 
the difference in number of capsules versus tablets. 
Rationale: The Statistical Analysis Plan will include additional analyses for safety and for the primary endpoint 
by formulation subgroup. 
Section 13.2.1
Analysis of Primary 
Endpoint
Added the following sentence: Additional analyses by formulation subgroups will be 
performed for the MFS endpoint as described in the Statistical Analysis Plan.
Section 13.3.1 
Analysis of Adverse 
Events
Added the following sentence: An additional analysis by formulation subgroups will be 
performed as outlined in the Statistical Analysis Plan.
Rationale: The population PK analysis will include an additional analysis to explore the effect of the 
formulation switch. 
Section 13.4.4 
Population 
Pharmacokinetics 
(PopPK) Analysis
Added the following wording: “the effect of the formulations will also be explored in 
the covariate analysis.”
(b) (4)
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Applicable Section(s)
Description of Change(s)
Rationale: To clarify that patients who experience loco-regional tumor progression should continue on study 
drug until documentation of distant metastastic disease. Local therapies such as surgery or radiation are allowed 
with study treatment. This was not clearly stated in the protocol.
Section 6 Concurrent 
Medications
Added the following: 
Salvage radiation for locoregional pelvic disease and surgical procedures (eg, 
transurethral resection of the prostate [TURP], urethral and ureteral stent placement) to 
treat localized progression or symptoms are allowed. Patients receiving these therapies 
may continue on study drug.
Rationale: To incorporate a local restriction in Japan into the global protocol in order to avoid the need for a 
separate country-specific protocol. The Sponsor will not provide abiraterone acetate as subsequent therapy. The 
criteria outlined in Section 8.10 are not applicable to sites in Japan.
Section 8.10 
Subsequent Therapy 
with Abiraterone 
Acetate; Schedule of 
Activities
(Footnote 3)
Due to local restrictions in Japan, the Sponsor will not provide abiraterone acetate and 
the criteria outlined in this section do not apply.
Rationale: It is not necessary to administer study drug within 1 hour onsite after the trough PK sampling.
Section 7.3 
Pharmacokinetic 
Measurements; 
Section 8.4 Day 1 of 
Cycles (±2 days); 
Schedule of 
Activities
(Footnote 20)
Removed the requirement that the PK sample be taken up to 1 hour prior to 
administering the study drug in the clinic.  
Rationale: Patients who have a delay of study drug administration for ≥28 days due to toxicity will no longer 
automatically meet the criteria for discontinuation from the study.
Section 5.3.5 Dose 
Modifications; 
Section 10 End of 
Treatment
Revised to indicate that subjects may discontinue study treatment if delayed more than 
28 days due to toxicity and must be discussed with the Sponsor. 
Rationale: Changes were made to improve clarity or correct errors 
Section 4.1 Inclusion 
Criteria; Section 4.2 
Exclusion Criteria;
Section 6 Concurrent 
Medications;
Section 6.2 Restricted 
Therapies; Section 
8.2 Screening (within 
35 Days of 
Randomization); 
Section 8.9 Survival 
Follow-Up; Schedule 
of Activities
Minor changes were made to following eligibility criteria: Inclusion #3, 11, and 13; 
Exclusion  #8 and #9. In Section 6.2, the bullet describing corticosteroid therapy was 
made consistent with other sections. Revised the wording in the last bullet of 
Section 8.2. Clarified in last bullet of Section 8.9 that disease progression refers to 
distant metastasis. Removed 1.7 nM for testosterone concentration. 
Corrected error of footnote for biomarkers in the Schedule of Events and revised 
Footnote 6 to match revision in Section 8.2. 
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Amendment INT-5 (1 July 2014)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union 
The overall reason for the amendment: The overall reason for the amendment is to incorporate a time cutoff for 
the earliest prostate specific antigen (PSA) values used in the calculation of PSA doubling time (PSADT). 
NOTE: Amendment INT-4 was never implemented and has been superseded by Amendment INT-5. The only 
change that affects study conduct between Amendments INT-5 and INT-4 is the addition of a 24 month collection 
time period during which PSA values used to calculate the PSADT can be obtained. This change was made shortly
after finalization of the previous amendment. Please refer below to the table of changes for Amendment INT-4. All 
changes have been incorporated, as appropriate, into the protocol text.
Applicable Section(s)
Description of Change(s)
Rationale: The previous amendment did not include information on a timeframe for PSA values that should be 
used for the calculation of PSADT. A collection period during which PSA values used to calculate the PSADT can 
be obtained, is now specified. Therefore, this amendment will incorporate a cutoff that allows inclusion of PSA 
values collected within 24 months prior to the subject’s randomization.
4.1 Inclusion Criteria, 
Inclusion Criterion #1
Simplified Criterion #1 and referred to Section 5.1 for details on timing and calculation 
of PSADT.
Revised the criterion to read: 
Histologically or cytologically confirmed adenocarcinoma of the prostate without 
neuroendocrine differentiation or small cell features with high risk for development of 
metastases, defined as PSADT ≤10 months. PSADT is calculated using at least 3 PSA 
values obtained during continuous ADT (see Section 5.1). 
5.1 Randomization
Added the requirement for PSA values to be within 24 months prior to randomization 
with the specification that at least 3 values be used. Clarified that the earliest PSA 
value and all subsequent PSA values be entered into the Interactive Voice 
Randomization System (IVRS).
Rationale: Minor revision for consistency with Janssen Research & Development protocol template to 
numbering of eligibility criteria.
4.1 Inclusion Criteria, 
Inclusion Criteria #1; 
#5, and #6
Revised the numbering to incorporate the current template style. 
Rationale: Remove the inclusion of the number of sites as this information is not necessary in the protocol and 
is subject to change..
Synopsis, Number of 
Sites, 3.1 Study 
Overview and 
Rationale
Removed the information on the number of sites from the synopsis and study 
overview.
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Amendment INT-4 (16 June 2014)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union 
The overall reason for the amendment: The overall reason for the amendment is to incorporate investigator 
feedback for Inclusion criteria #1 and 2 in order to clarify the definitions of prostate specific antigen doubling time 
(PSADT) and castration-resistance so that the intended homogenous and high-risk patient population is enrolled.
Section 5.1 is also being revised to reflect the change to Inclusion Criterion #1. The addition of an optional
prescreening period is being incorporated to allow investigators time to obtain the required number of 
prostate-specific antigen (PSA) values for meeting the study eligibility criteria.
Applicable Section(s)
Description of Change(s)
Rationale: The window of requiring prostate specific antigen (PSA) values collected within 6 months prior to 
randomization for calculation of the PSADT has the unintended consequence of excluding patients who are 
otherwise eligible, but who may have had one or more of the required PSAs collected outside the 6 month 
window. Currently, we are asking sites to continue to monitor and collect more recent PSAs from these patients; 
this delay increases the risk of screen fails as these patients are at high risk for metastasis. This requirement 
window has been removed from Inclusion Criterion #1 and a reference to Section 5.1 of the protocol, which details 
the calculation of PSADT for eligibility, has been added.
4.1 Inclusion Criteria, 
Inclusion Criterion #1
Revised the criterion to read: 
Histologically or cytologically confirmed adenocarcinoma of the prostate without 
neuroendocrine differentiation or small cell features with high risk for development of 
metastases, defined as PSADT ≤10 months. PSADT is calculated using at least 3 PSA 
values obtained during continuous ADT. The first and last PSA values used in the 
calculation must be separated by at least 8 weeks (see Section 5.1). 
5.1 Randomization
Removed the requirement for 3 PSA values to be within 6 months prior to 
randomization. For consistency with the eligibility criteria the description of PSADT 
calculation is based on “at least” 3 PSA values. Also added the sentence that the first 
and last PSA values used in the calculation must be separated by at least 8 weeks.
Rationale: Inclusion Criterion # 2 requires that castration resistant prostate cancer is defined as 3 consecutive
rises of PSA. This is not consistent with the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) 
criteria,24 and has the unintended consequence of excluding patients who are otherwise eligible, but who have 
had one or more PSA in a consecutive sequence not rise although there may be 3 rises in total. Currently, we are 
asking sites to continue to monitor and collect more PSAs until the three consecutive rises are met; this delay 
increases the risk of screen fails as these patients are at high-risk for metastasis. The requirement for two 50% 
increases of PSA above the nadir is also considered too stringent and is not consistent with the PCWG2 
criteria.24
4.1 Inclusion Criteria;
Inclusion Criterion #2
Revised the criterion to read:
Castration-resistant prostate cancer demonstrated during continuous ADT, defined as 
3 PSA rises, at least 1 week apart, with the last PSA > 2 ng/mL.
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Applicable Section(s)
Description of Change(s)
Rationale: The washout period following anti-androgen may be longer than 4 weeks depending on the 
anti-androgen. Clarified that the washout period must be at least 4 weeks. 
4.1 Inclusion Criteria;
Inclusion Criterion #5
Revised the criterion to read: 
Patients who received a first generation anti-androgen (e.g., bicalutamide, flutamide, 
nilutamide) must have at least a 4-week washout prior to randomization AND must show 
continuing disease (PSA) progression (an increase in PSA) after washout.
Rationale: Sampling for PSA may not be frequent enough at some sites. In order to ensure eligible patients are 
not “missed,” the patient may be asked to participate in the optional Prescreening Phase and sign a prescreening 
informed consent. The prescreening PSA evaluations will be performed by a local laboratory. As no study 
medication is being introduced at this point, only collection of serious adverse events related to the PSA blood 
draw will be collected.
3.1 Study Overview 
and Rationale; 7.2.1 
PSA; 
8.1 Prescreening;
9.2.1 SAE Reporting; 
9.2.2 Non-Serious AE 
Reporting; 
Appendix 1:Schedule 
of Events; Footnote 1, 
new Footnote 10; new 
Footnote 18.
Added the prescreening details to appropriate sections of the protocol body and
Appendix 1. For clarity, added a separate footnote for PSA evaluations to Appendix 1. 
Added a new section (8.1 Prescreening). Added Footnote 18 to clarify that only SAEs
related to the PSA blood draw will be collected.
All other footnotes were renumbered accordingly.
Section 9.2.1 was modified to add the SAE reporting requirement during the 
Prescreening Period.
Section 9.2.2 was modified to clarify the reporting period and an error was corrected 
(strikethrough text removed): 
Adverse events should be recorded on the AE CRF from the time the patient has signed 
the informed consent at screening (see Section 8.2) taken at least one dose of study drug
until 28 days after the last dose of study drug.
Rationale: The description of androgen deprivation therapy as ADT/post -surgery castration is redundant, wording 
was revised, as applicable. 
Throughout the 
protocol 
ADT/post-surgical castration was revised to ADT
Rationale: The term radiographic progression-free survival or rPFS originated with the ZYTIGA COU-AA-302 
study and has specific criteria for the determination of radiographic progression that is not applicable to the patient 
population in this study. To avoid confusion, the term radiographic PFS or rPFS is being revised to progression-
free survival or PFS.
Throughout the 
protocol
Revised radiographic progression-free survival or radiographic PFS or rPFS terminology 
to progression-free survival or PFS. 
Rationale: Aminoglutethimide was erroneously included under Inclusion Criterion # 6 and should be under 
Exclusion Criterion #4.
4.1 Inclusion Criteria, 
Inclusion Criterion# 6
4.2 Exclusion Criteria,
Exclusion 
Criterion# 4.
Moved aminoglutethimide to the Exclusion Criterion # 4 after ketoconazole.
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Applicable Section(s)
Description of Change(s)
Rationale: Update to pregnancy section for consistency with the Janssen Template wording 
9.1.6 Exposure 
During Pregnancy
Updated with Janssen template wording
Rationale: Clarified timing of submitting the FFPE archival tumor samples or slides.
Footnote 21
Updated the footnote to indicate that FFPE samples can be submitted anytime starting 
from Cycle 1 Day 1. 
Rationale: The number of sites is planned to increase. 
Synopsis, Number of 
Sites; 3.1 Study 
Design Overview and 
Rationale
Increased number of sites from 330 to 400. 
Rationale: Fasting period requirement for the ventricular repolarization study is very long, subjects will be now be 
allowed to have an approved snack. 
Appendix 8, 
Additional Inclusion 
Criteria 
Added that the subject can have an approved snack:
Must agree to fast at least 3 hours prior to dose and continue fasting (except for 
approved snack) until completion of the 4 hour post dose assessments on Cycle 1 Day 
1 and Cycle 3 Day 1.
Rationale: Minor errors or clarifications were noted
Throughout the 
protocol
Minor grammatical, typographical or clarification changes were made.
Amendment 3 (11 March 2014)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union 
The overall reason for the amendment: The overall reasons for the amendment are the following: to incorporate 
modifications to the statistical analysis plan for the secondary endpoints; incorporate provision of abiraterone 
acetate as subsequent therapy for eligible patients; addition of exploratory biomarkers; reduction of population 
pharmacokinetic sample collection and modification of the population PK analysis, and modification of the 
patient-reported outcomes analysis. Additional changes were also implemented based on Health Authority and 
Investigator feedback. Updated nonclinical and clinical data were also incorporated.
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Applicable Section(s)
Description of Change(s)
Rationale: Statistical analysis of the secondary endpoints was modified and will incorporate multiple testing
method in agreement with the FDA proposal.
Synopsis, Secondary 
Objectives and 
Endpoints, Other 
Objectives and 
Evaluations; 2.2 
Secondary Objectives; 
2.3 Other Objectives; 
3.2.2 Secondary 
Endpoints; 3.2.3 Other 
Evaluations; Synopsis, 
Statistical Analysis 
Plan and Rationale for 
Number of Patients; 
13.2.2 Analysis of 
Secondary Endpoints
Overall survival (OS) is no longer a separate key secondary objective or endpoint. 
Removed “key” and “other” secondary endpoints sections and regrouped into 2 groups 
of “Secondary Endpoints.” Group 1 includes: time to symptomatic progression, time to 
initiation of cytotoxic chemotherapy, radiographic progression-free survival (rPFS), and 
time to metastasis (TTM). Group 2 includes OS.
Added “Other “ objectives and evaluations (see additional rationale below).
The statistical testing of the 2 groups of secondary endpoints will be performed by 
allocating 0.01 to Group 1 and 0.04 for the OS endpoint in Group 2 with an overall 
familywise type I error rate of 0.05. Details of the testing procedure will be provided in 
the statistical analysis plan.  
Rationale: Modification of the interim analysis of OS, 2 interim analyses and 1 final analysis are now planned.
Synopsis, Statistical 
Analysis Plan and 
Rationale for Number 
of Patients; 
13.5 Interim Analysis; 
13.6 Determination of 
Sample Size; Synopsis, 
Duration of Patient 
Participation and 
Duration of Study; 
15.6 End of Trial 
Notification in All 
Participating Countries
Two interim analyses and 1 final analysis are planned for the OS endpoint.  With the 
decrease in alpha from 5% to 4%, the number of death events is now 526 (final 
analysis). At the time of the first interim analysis, approximately 46% (243/526) of the 
death events will be observed with an alpha spend of 0.0012.  The second interim 
analysis will be performed after observing approximately 70% (369/526) of the death 
events with a cumulative alpha spend of 0.0109. The actual alpha spent for the 2 interim 
analyses will be based on the number of death events observed at the time of the 
analyses. 
Rationale: Added “Other” Objectives and Evaluations  
Synopsis, Other 
Objectives; Other 
Evaluations; 2.2 Other 
Objectives; 3.2.3 Other 
Evaluations
Also added PSA response and time to PSA progression, analyses are included in 
Section 13.4.1, but they were not listed as evaluations in the previous versions of the 
protocol.
Added medical resource utilization and exploratory biomarkers
Previous endpoints listed as “Other Secondary” Objectives and Evaluations were 
renamed “Other” Objectives and Evaluations.
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Applicable Section(s)
Description of Change(s)
Rationale: Provision of abiraterone acetate as subsequent therapy for those patients who meet the 
protocol-specified eligibility criteria.
8.9 Subsequent 
Therapy with 
abiraterone acetate; 
9.2.1 Serious Adverse 
Event Reporting; 
10 End-of-Treatment
Addition of a new section (8.9) incorporating the provision of abiraterone acetate by the 
Sponsor. 
Rationale: Population pharmacokinetic (PK) sampling and analysis were modified. The number of sparse 
samples for population PK analysis was decreased as steady state of ARN-509 and metabolite ARN000308 can be 
reached within approximately 3 months. Pharmacokinetic samples collected up to 24 months should be sufficient 
to characterize the kinetics of both compounds, and no relevant information would be obtained from later 
timepoints. Analysis of the metabolite ARN000066 is being removed as this is a minor metabolite in humans with 
minimal activity.
7.3 Pharmacokinetic 
Measurements; 
8.2 Cycle 1 Day 1; 8.3 
Day 1 of Cycles n..; 
Appendix 1; 
Footnote 17; 
13.4.3 Population PK 
Analysis; Appendix 8
Removed analysis for the ARN000066 metabolite. Removed sample collection from 
Cycle 36 onwards. Sparse PK samples will not be taken from patients participating in 
the ventricular repolarization substudy (Appendix 8).
Rationale: Exploratory biomarker research was added to study the potential mechanisms of resistance to 
ARN-509. Based on limited published data, approximately 10% of patients with late stage disease may develop 
resistance over the course of treatment. There is not sufficient data to indicate whether resistance develops at a 
different frequency in patients with NM-CRPC. In the original plan proposed 
 FDA, a sample 
size of 300 patients was considered sufficient. Based on follow-up advice from the FDA and assuming lower 
frequencies of mutation emergence in the NM-CRPC, the number of samples was increased from 300 to 400 in 
order to have sufficient power for correlative analysis based on calculation on a sliding scale. To capture the 
F876L mutation status in patients progressing in the later course of treatment, the collection of samples was 
modified to include Day 1 of Cycle 36, the Day 1 of Cycle 6 assessment was removed.
7.5 Exploratory 
Biomarkers; 
13.1 Analysis 
Populations; 
13.4.4 Exploratory 
Biomarkers; 
References; 
14.7 Patient 
Confidentiality
Section 7.5 was added to explain background and rationale for the exploratory 
biomarker research. A new analysis population was added. Long-term storage details for 
biomarker samples was incorporated into Section 14.7.
8.6 End-of-Treatment 
Visit; Appendix 1 and 
added Footnote 19. 
Sample collection details for exploratory biomarkers were incorporated. Archival tumor
formalin-fixed paraffin embedded (FFPE) tumor blocks or tumor slides will be retrieved
from consenting patients on Cycle 1 Day 1, blood samples will be collected before 
dosing on Day 1 of Cycles 1, 12, 18, 24, 36, and end-of-treatment. Footnote 19 indicates 
blood volumes collected during each cycle. 
(b) (4)
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Applicable Section(s)
Description of Change(s)
Rationale: The previous patient-reported outcomes analysis incorporated a 16-point improvement in the 
Functional Assessment of Cancer Therapy-Prostate (FACT-P) total score as the definition for a health-related 
quality of life improvement. Improvement of the total score is not applicable for this study population. The 
magnitude of a clinically meaningful change was redefined.
13.4.2 Health-Related 
Quality of Life and 
Prostate Cancer-
Specific Symptoms 
Analysis
A 10-point change in the FACT-P total score is considered clinically meaningful. 
Therefore, any patient experiencing a 10-point decrement in FACT-P total scores from 
baseline will be considered to have experienced clinically meaningful deterioration in 
functional status.  
Rationale: The completion of the PRO questionnaires was reduced after Cycle 13 to every other cycle to relieve 
the burden to the patient and for consistency with other Sponsor protocols. 
7.4 Patient-Reported 
Outcomes; 8.3 Day 1 
of Cycles n…; 
Appendix 1, 
Footnote 18
Reduced the collection of FACT-P and EQ-5D questionnaires after Cycle 13 to every 
other cycle.  
Rationale: Added second progression-free survival (PFS2) as an evaluation per agreement with health authorities. 
Synopsis, Other 
Evaluations; 
3.2.3 Other 
Evaluations;
8.8 Survival 
Follow-Up;
13.4.1 Second 
progression-free 
survival (PFS2); 
Appendix 1
This endpoint is defined as the time from randomization to second documentation 
(progression on first subsequent therapy) investigator-assessed disease progression 
(PSA, radiographic, symptomatic, or any combination) or death from any cause.
Rationale: Inclusion criterion was modified for consistency with Section 5.1 of the protocol and based on 
Investigator feedback. 
4.1 Inclusion Criteria, 
Criterion #1
Clarified determination of PSADT
Rationale: Inclusion of patients with documented Gilbert’s disease is allowed
4.1 Inclusion Criteria, 
Criterion #11
Added exception to elevated bilirubin in cases of documented Gilbert’s disease. 
Rationale: Bone sparing therapies indicated for the treatment of skeletal events due to bone metastases are not 
allowed as concurrent therapy. 
4.1 Inclusion Criteria, 
Inclusion Criterion #4; 
4.2 Exclusion Criteria, 
Exclusion Criterion 8
Clarified inclusion Criterion #4 to allow bone sparing therapies for the treatment of 
osteoporosis if on stable doses for at least 4 weeks prior to randomization. Modified 
Exclusion Criterion #8 to exclude bone sparing therapy (eg., denosumab [Xgeva®]
indicated for the treatment of skeletal events due to bone metastases. 
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Applicable Section(s)
Description of Change(s)
Rationale: Exclusion criterion #1 was modified to clarify that a history of distant metastases is also exclusionary. 
4.2 Exclusion Criteria, 
Exclusion Criterion #1
Presence of distant metastases confirmed by blinded independent central review 
(BICR), including CNS and vertebral or meningeal involvement, or history of distant 
metastases.  Exception: pelvic lymph nodes < 2 cm in short axis (N1) located below the 
iliac bifurcation are allowed
Rationale: Inclusion Criterion #5 was modified to clarify the criteria for eligibility following previous 
anti-androgen treatment to include the 4 week washout period prior to randomization and documented prostate 
specific antigen (PSA) progression.
4.1 Inclusion Criteria; 
Inclusion Criterion #5 
Patients who received a first generation anti-androgen (e.g., bicalutamide, flutamide, 
nilutamide) must have a 4-week washout prior to randomization AND must show 
continuing disease (PSA) progression (an increase in PSA) once they are off the 
anti-androgen.
Rationale: Inclusion Criteria #6 to clarify that prior estrogen treatment discontinuation is irrespective of dose 
used.
4.1 Inclusion Criteria,
Inclusion Criterion #6
At least 4 weeks must have elapsed from the use of 5-α reductase inhibitors (e.g., 
dutasteride, finasteride, aminoglutethamide), estrogens (irrespective of dose used), and 
any other anti-cancer therapy prior to randomization, including chemotherapy given in 
the adjuvant/neoadjuvant setting (e.g., clinical trial)
Rationale: Clarified that patients with a history of uncontrolled blood pressure are eligible if controlled with 
anti-hypertensive treatment.
4.2 Exclusion Criteria, 
Exclusion Criterion #9
Uncontrolled hypertension (systolic blood pressure ≥160 mmHg or diastolic BP 
≥100 mHg). Patients with a history of uncontrolled hypertension are allowed provided 
blood pressure is controlled by anti-hypertensive treatment
Rationale: Gonadotropin releasing hormone analogs (GnRHa) (or surgical castration) for patients is required as a 
concomitant therapy and should be continuous throughout treatment. 
Inclusion Criterion #3; 
3.1 Study Design 
Overview and 
Rationale;  
6 Concurrent 
Medications
Revised Inclusion Criterion #3 and incorporated text in relevant sections throughout the 
protocol to reiterate the requirement for GnRHa treatment (or surgical castration) for all 
patients (both treatment groups). 
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Applicable Section(s)
Description of Change(s)
Rationale: Per Sponsor policy adverse events (AEs) should be collected from the signing of the informed consent 
form.
8.1 Screening, 8.2 
Cycle 1 Day 1; 8.3 
Day 1 of Cycles n; 
8.6 End-of-Treatment 
Visit; 8.7 Safety 
Follow-up; 9.1.1 
Adverse Events; 
9.2.2 Non-serious AE
Reporting; 
Appendix 1
Modified these sections to include collection of AEs from the signing of the informed 
consent form and not at the time of the first dose of study drug. General addition, where 
needed, for collection of AEs at all times from informed consent up to 28 days after the 
last dose of study drug. 
Rationale: Analysis of vital signs and concomitant medications should be under safety evaluations and not under 
other evaluations 
13.3.3 Vital Signs 
Analysis; 13.3.4 
Concomitant 
Medications 
Moved from the Other Evaluations section to Safety Evaluations Section
Rationale: Clarification that patients are expected to be treated with local standard of care before enrollment. 
Rescreening information for screen failures was added. 
4 Patient Selection
It is expected that all patients will be treated according to local standard of care, 
including radiation therapy if needed for local disease, prior to enrolling.  
Patients considered screen failures may be subsequently rescreened. Rescreening must 
be discussed with and approved by the Sponsor on a case by case basis. Patients who are 
determined to be eligible for the study after rescreening must sign a new ICF and be 
assigned a new patient number.
Rationale: Timing of tumor assessments and collection of blood for thyroid stimulating hormone (TSH), 
testosterone, and fasting lipid panel was modified from every 16 weeks starting from the date of randomization to 
starting from Cycle 1 Day 1. Urinalysis was removed as a required laboratory assessment. 
8.4 and 8.5 Every 
16 weeks from 
Cycle 1 Day 1; 
Appendix 1
Change timing of the start of assessments from date of randomization to Cycle 1 Day 1. 
A separate column for these assessments was added to the Schedule of Events. 
Rationale: Incorporated the Danish Health Authority request for inclusion of detailed methods of contraception 
and required duration of contraceptive methods or donation of sperm after discontinuation of the study drug.
6.3 Life Style 
Guidelines
Added more detailed information for patients and partners of childbearing potential. 
Also added that effective contraception is required during the study and for 3 months 
after the last dose of study drug. Donation of sperm is not allowed during the study and 
for 3 months following the last dose of study drug. 
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Applicable Section(s)
Description of Change(s)
Rationale: Updated nonclinical data
Synopsis; 1.1.2
Preclinical 
Development 
Overview
Revised and updated in vitro metabolism data. Summarized the final 13-week rat and 
dog GLP toxicity results, removed the dog 28-day toxicity summary. Updated the 
genotoxic, clastogenic, and phototoxicity data for ARN-509 and the metabolites 
(ARN000308 and ARN000066).
Rationale: Updated clinical information
1.13 Overview of 
Clinical Studies
Updated with general overview of ongoing clinical studies and data from Study 
ARN-509-001.
Rationale: The protocol had no information regarding product quality complaint handling. Added a Product 
Quality Complaint section to the protocol 
9.2.4 Product Quality 
Complaint Handling
Added new section per Sponsor template.
Rationale: Patient initials will not be used for any documents in this study. 
14.1 Data Collection 
Instruments; 14.7 
Patient Confidentiality; 
15.1 Investigator 
Responsibilities
All reference to patient initials was removed. 
Rationale: Per request of Danish Health Authority, investigator responsibilities section was updated to include a 
Declaration of Helsinki statement. Wording consistent with the current Sponsor template was incorporated. 
15.1 Investigator 
Responsibilities; 
15.4 Informed Consent 
Form
Incorporated Sponsor template language, which meets the requirements of the HA 
request. 
Rationale: Added instruction that subsequent ECG readings should be collected using same position as the 
baseline reading.
7.2.2 
Electrocardiogram 
(ECG)
Subsequent ECG readings should be collected with the patient in the same position 
(e.g., fully supine or semi-recumbent). 
Rationale: Protocol violation forms do not exist.
11 Protocol Violations
Removed paragraph explaining that protocol violation forms would be completed and 
archived. There are no such forms. 
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Applicable Section(s)
Description of Change(s)
Rationale: At the time for the final analysis OS, a decision will be made regarding whether or not an amendment 
of the protocol may be needed. 
Synopsis, Duration of 
Patient Participation 
and Duration of Study; 
15.6 End of Trial in All 
Participating Countries
Removed wording indicating that the protocol may be amended to minimize the number 
of assessments. 
Rationale: Time from screening to randomization was increased from 28 days to 35 days because the required 
28 day washout period for eligibility was not allowing enough time to complete screening assessments in some 
patients. The time from randomization to Cycle 1 Day 1 was also increased by 1 day from 3 days to 4 days to 
accommodate unforeseen delays due to holidays, weather, etc. 
Appendix 1; 
8.1 Screening Within 
35 Days of 
Randomization; 
8.3 Cycle 1 Day 1
Change timing from screening to randomization to 35 days, also revised the timing from 
randomization to Cycle 1 Day 1 from 3 days to 4 days
Rationale: Laboratory assessments deemed nonessential for safety or efficacy were removed
Appendix 2
Removed phosphorus , total protein, chloride, uric acid, and lactate dehydrogenase.
Appendix 1; 
Appendix 2; 
7.2 Clinical Laboratory 
Measurements; 
8.1 Screening within 
35 Days of 
Randomization; 8.4 
Every 16 Weeks 
Starting From Cycle 1 
Day 1 …;8.6 End-of-
Treatment Visit
Removed collection of urine samples and urinalysis. 
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Applicable Section(s)
Description of Change(s)
Rationale: Prostate-specific antigen (PSA) was listed under the wrong column in the Appendix 2 table 
Appendix 2
Moved PSA measurements to the every cycle column for consistency with the Schedule 
of Events. 
Rationale: The approximate number of sites has increased from 250 to 330. 
Synopsis, Number of 
Sites; 3.1 Study 
Overview and 
Rationale
Revised from approximately 250 in the synopsis to 330 and added this information to 
Section 3.1. 
Rationale: Additional eligibility criteria for participation in the QT substudy were incorporated. Holter monitoring 
assessment included at Screening. Informed consent requirement was previously not included in the Appendix 8
Schedule of Activities for Screening. 
Appendix 8
Screening assessment incorporated with the addition of the Holter monitoring and 
requirement for signing of informed consent
Added required fasting conditions for participation in the substudy, exclusion of patients 
if they required a dose reduction at any time from Cycle 1 Day 1 through Cycle 3 Day 1.
Made a minor wording to the sample size determination: A sample size of at least 
100 patients will ensure that at least 60 patients treated with ARN-509 will be enrolled 
on the substudy and 60 patients will provide at least 98.7% power to detect a true effect 
of 10 milliseconds (msec) change from baseline considering only the active group. 
Informed consent was added to Table 1 of Appendix 8. 
Rationale: Inclusion of all criteria in the synopsis was unnecessary. 
Synopsis, Enrollment 
Criteria
Replace the individual criteria with a summary. 
Rationale: Clarified that pomegranate is excluded (not just juice)
Section 4.2 Exclusion
Criteria, Criterion #8; 
Appendix 5
Removed the word “juice.”
Rationale: Added that a patient eligibility form must be completed and submitted to the medical monitor before 
randomization
8.1 Screening Within 
35 Days of 
Randomization 
Added a bullet to Section 8.1. Also added to the subsequent bullet that the medical 
monitor must confirm eligibility before randomization 
Rationale: In order to avoid a protocol amendment in the case where contact information may change, the contact 
information was removed.
9.1.2 Serious Adverse 
Events
Removed contact information, which will be provided separately. 
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Applicable Section(s)
Description of Change(s)
Rationale: The Schedule of Events was confusing to follow and not well organized
Appendix 1 
Revised the entire table and footnotes.
Rationale: Modified wording throughout the document for conciseness or clarity.
Throughout the 
protocol
Included were modifications to the Schedule of Activities to simplify the presentation 
ensure consistency with the body of the protocol, and remove redundant footnotes. The 
Independent Data Monitoring Committee section (Section 12) was condensed. 
Rationale: Minor errors were noted
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.
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1.
BACKGROUND
Prostate cancer is the second most frequently diagnosed cancer and the sixth leading cause of 
cancer death in males, accounting for 14% (903,500) of the total new cancer cases and 6% 
(258,400) of the total cancer deaths in males worldwide.9  Treatment aimed at eradicating the 
primary tumor, typically with surgery or radiation, is unsuccessful in ~30% of men, who 
develop recurrent disease that usually manifests first as a rise in plasma prostate-specific 
antigen (PSA) followed by metastasis to distant sites.29  Given that prostate cancer cells 
depend on androgen receptor (AR) for their proliferation and survival, the standard treatment 
for patients with recurrent disease is androgen deprivation therapy (ADT) with a 
gonadotropin releasing hormone analog (GnRHa) with or without an anti-androgen. 
Treatment results with ADT are generally predictable: a decline in PSA followed by tumor 
regression, a period of stability in which the tumor does not proliferate and PSA remains 
stable, followed by rising PSA and regrowth as a castration-resistant disease.  Nearly all men 
with progressive prostate cancer eventually develop castration-resistant disease. Prostate 
cancer progression despite castrate levels of testosterone represents a transition to a lethal 
disease stage.
Molecular profiling studies of castration-resistant prostate cancer (CRPC) commonly show 
increased AR gene expression.23  The increased AR levels are sufficient to confer resistance 
to anti-androgen therapy in mouse models, shorten tumor latency and confer agonist 
properties to first generation AR antagonists, such as bicalutamide or flutamide.2  The 
potential for agonist activity by these approved anti-androgens in the setting of increased AR 
expression is a potential liability, best illustrated by the observation of tumor regression and 
declines in PSA following discontinuation of either of these AR antagonists, the so-called 
anti-androgen withdrawal syndrome.11  Collectively, these findings implicate increased AR 
levels as one mechanism of drug resistance. They also suggest that drugs retaining 
antagonism and not displaying agonism in cells over-expressing AR levels might be useful 
therapeutically.
ARN-509 (JNJ-56021927; apalutamide, hereafter referred to as apalutamide) is a next
generation AR antagonist that has been developed to overcome the potential therapeutic 
deficiencies of first-generation AR antagonists (e.g., bicalutamide).
1.1
APALUTAMIDE
Apalutamide is an orally available, potent and selective AR antagonist that acts by inhibiting 
the action of androgen, nuclear translocation of the AR and DNA binding to androgen 
response elements and unlike bicalutamide, it exhibits no significant agonist activity in
AR-overexpressing prostate cancer cells.3
Complete information for apalutamide (JNJ-56021927) can be found in the Investigator’s 
Brochure, the safety reference document for this study.
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Figure 1
Tumor Growth Inhibition in Castration-resistant LNCaP/AR-Luc Xenograft 
Model After 28 Days of Treatment with Bicalutamide or apalutamide 
(ARN-509)
Apalutamide is a low clearance molecule with a moderate volume of distribution and high 
bioavailability (when dosed with a lipid-based formulation).  Apalutamide was found to have 
a very low turnover when incubated for up to 120 minutes with rat, dog, and human liver S9 
fraction and liver microsomes.  The primary in vivo metabolites were formed by 
N-demethylation and amide hydrolysis in the rat and dog. In vitro, CYP3A4 may be partially 
involved in the metabolism of apalutamide. 
Apalutamide and its primary metabolite ARN000308 (M3) are inducers of human CYP2B6 
and CYP3A4 in hepatocytes at concentrations up to 30 µM.  Apalutamide is a moderately 
potent inhibitor of human cytochrome P450 isoform CYP2C8 (IC 50=13.9 µM), but a weak 
inhibitor of the other major isoforms (IC50>25 µM); M3 is also a weak inhibitor of CYP 
major isoforms (IC50>25 µM). 
Four metabolites have been identified with different proportions between species.  All four 
were assessed for their on-target effects against the androgen receptor.  Metabolite M1 was 
found to be essentially inactive as an AR antagonist, while metabolites M2 and M4 were 
approximately 30-fold less potent against AR than apalutamide.  Metabolite M3 was the most 
potent AR antagonist, but was still 3-fold less potent than apalutamide. Metabolite M3 is 
considered the predominant metabolite, with a longer elimination half-life than apalutamide.
In vitro and in vivo studies to assess cardiovascular, CNS, and respiratory system effects of 
apalutamide did not reveal any concerns.
Single-dose and repeat-dose toxicology studies up to 13 weeks of dosing have been 
conducted in male Sprague Dawley (SD) rats and male Beagle dogs (repeat-dose studies 
only).  
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Acute administration of apalutamide at 1,000 mg/kg was well tolerated in SD rats, with no 
morbidity, mortality or significant effects on body weight or serum chemistry markers.  
In repeat-dose toxicology studies, apalutamide was well tolerated at doses up to 
100 mg/kg/day in the 13-weeks study in SD rats and 10 mg/kg/day in Beagle dogs.  In male 
SD rats, lethality was observed at doses of 150 mg/kg/day and greater.  The 
morbidity/mortality observed at these doses occurred within the first 5 days of dosing; 
however, animals that did survive at these higher doses, appeared to develop a tolerance for 
the test article with extended exposure.  Clinical signs observed in the moribund animals 
were piloerection, hypothermia, breathing abnormalities, dehydration, and decreased activity.  
The cause of the morbidity/mortality in male rats could not be determined by pathologic 
examination.  Key clinical pathology changes at doses of 150 mg/kg/day or greater included 
significant increases in cholesterol (greater than 200% from controls), decreases in 
erythrocytes, hemoglobin and hematocrit, and increases in reticulocytes, platelets, 
leukocytes, lymphocytes, basophils, and aPTT.  The increase in cholesterol is attributed to 
the anti-androgen activity of apalutamide and is believed to be responsible for the stated 
hematologic changes.  Examination of red blood cell morphology revealed changes that were 
consistent with excess cholesterol being transferred to the outer membrane of the 
erythrocytes, resulting in a mild hemolytic anemia.  Pharmacologic effects were also 
observed in the male accessory sex organs (epididymides, prostate, seminal vesicles and to a 
lesser degree, the testes) at apalutamide doses as low as 50 mg/kg/day.  Other target organs in 
the rat that were observed at apalutamide doses of 150 mg/kg/day or higher included adrenals 
(also at 50 mg/kg/day), liver, pituitary, thyroid, spleen, salivary glands, mammary gland, and 
stomach.  With the exception of the salivary glands and stomach, the effects on those organs 
are also believed to be due to the anti-androgen effect of apalutamide and in many cases are 
specific to the physiology of the rat.
Once daily oral gavage dosing of apalutamide for 13 weeks was well tolerated in male rats up 
to 100 mg/kg/day, i.e. the highest dose tested. Pharmacologic changes characteristic of 
anti-androgen compounds were noted in the adrenal gland, pituitary gland, spleen, mammary 
gland, seminal vesicles, testes, prostate, and epididymides, while changes in the spleen and 
bone marrow correlated with a mild regenerative anemia.The 100 mg/kg/day dose level was 
considered to be the no observed adverse effect level (NOAEL) and was associated with 
steady-state (Day 91) plasma Cmax and AUC0-24h values of 30.1 µg/mL and 521 µg•h/mL, 
respectively, for the parent compound.
In male Beagle dogs, seizures necessitating humane euthanasia occurred at apalutamide
doses of 25 mg/kg/day and greater, 7 to 14 days after dosing was initiated. Daily 
administration of 25 mg/kg/day of apalutamide resulted in tremors and seizures in 3 of 8 
animals after 1 week of dosing. The average apalutamide concentration at the time of first 
observation of central nervous system (CNS) toxicity was determined to be 30.2 μg/mL, 
which was about 4-fold higher than the mean apalutamide steady-state Cmax (7.55 μg/mL) at 
the Phase 3 dose of 240 mg/day measured during repeated dosing in subjects with CRPC.  It
is likely that the convulsive seizures observed in dogs at very high doses are the result of 
apalutamide’s functional antagonism of the GABAA receptor. This is similar to what has been 
observed with other second generation AR antagonists.6,18 The 10 mg/kg/day dose was 
considered to be the NOAEL in the 28-day study, and was associated with an apalutamide
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Cmax of 13.2 μg/mL and an AUC0-24 of 290 μg•h/mL. Other clinical pathology and target 
organ changes were limited to increases in cholesterol (up to 50% compared to controls) and 
effects on the epididymides, prostate and testes at all doses tested and attributed to the anti-
androgen effect of apalutamide.  
Once daily oral capsule administration of apalutamide for 13 weeks was well tolerated in 
male dogs up to 10 mg/kg/day, i.e. the highest dose tested. Gross and microscopic pathology 
changes and organ weight changes characteristic of anti-androgen compounds were noted in 
the pituitary gland, prostate, testes, and epididymides; these changes were reversible and 
were attributable to the expected pharmacologic effect of apalutamide. Based upon the lower 
body weight performance in the group receiving 10 mg/kg/day, the 5 mg/kg/day dose was 
considered to be the NOAEL. Corresponding steady-state (Day 91) plasma Cmax and 
AUC0-24h values were 10.3 µg/mL and 202 µg•h/mL, respectively, for the parent compound. 
Preclinical studies have demonstrated the absence of genotoxic, clastogenic, and phototoxic 
properties for apalutamide and its pharmacologically active metabolite ARN000308 (M3). 
ARN000066 (M4), an inactive metabolite of apalutamide, tested negative in an in vitro 
bacterial reverse mutation (Ames) assay, but was weakly positive in an in vitro chromosome
aberration test in human peripheral blood lymphocytes. However, the totality of nonclinical 
data supports the lack of an in vivo genotoxic potential of ARN000066 (M4).
Overview of Clinical Studies
1.1.3
In addition to Study ARN-509-003, apalutamide is also being evaluated in Phase I studies in 
healthy men and Phase I/II, Phase II, and Phase III studies in patients with prostate cancer. 
Study ARN-509-001 is an ongoing Phase I/II study in patients with progressive advanced 
CRPC. In the Phase I portion of the study, 30 patients with mCRPC received at least 1 dose 
of apalutamide at escalating dose levels: 3 patients each at 30, 60, 90, 120, 180, 240, 390, 
480 mg/day, and 6 patients at 300 mg/day.19,20 Three subgroups are being evaluated in the 
Phase 2 portion (Group 1: NM-CRPC; Group 2: mCRPC without previous ketoconazole, 
abiraterone acetate, enzalutamide or chemotherapy [for mCRPC]; and Group 3: mCRPC post 
abiraterone acetate, no previous chemotherapy [for mCRPC]). All patients received 
apalutamide orally once daily, except those in the 300, 390, and 480 mg cohorts who 
received a twice-daily dosing regimen due to the higher pill burden at those levels. The 
results of the Phase 1 portion of the study from 30 patients with mCRPC demonstrated that 
treatment with apalutamide resulted in PSA declines at all dose levels tested. Eighteen 
subjects (60%) had a ≥50% or higher maximum decrease in PSA from baseline and 6 (20%) 
had ≥90% maximum decrease. Ten patients had measureable soft tissue disease at baseline; 5 
(50%) subjects maintained stable disease response for more than 6 months, 1 (10%) subject 
experienced disease progression, and the remaining 4 subjects had indeterminate responses. 
Apalutamide was well tolerated, with only 1 dose-limiting toxicity (DLT) at the 300 mg dose 
level (Grade 3 treatment-related abdominal pain). The event lasted 6 days and resolved with 
dose interruption and subsequent dose reduction to 240 mg (120 mg twice daily). Three 
additional subjects were treated at the 300 mg dose level with no reported DLTs. No seizures 
were reported at any dose level. The maximum tolerated dose (MTD) was not determined. 
The PK profile is linear and dose-proportional. 
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Sixteen subjects participated in an evaluation of AR binding in vivo using 
16β-[18F] fluor-α-dihydrotestosterone (FDHT) positron emission tomography (PET)/CT 
scan. Apalutamide treatment reduced FDHT uptake across all dose levels (30 to 390 mg dose 
levels). A plateau was reached at approximately 120 mg (with FDHT uptake near 
background) indicating saturation of AR binding. The mean plasma trough levels associated 
with this dose (2.5 µg/mL) were at the lower end of the range that produced tumor regression 
in the LNCaP/AR mouse model. Steady state plasma levels at the 240 mg dose level (3 to 
6 µg/mL) were more in the range sufficient to elicit a tumor response in the mouse xenograft 
model. Therefore, the 240 mg daily regimen was chosen for Phase 2 and Phase 3 dosing. 
Apalutamide was rapidly absorbed, with measurable plasma concentrations within 30 
minutes after ingestion of a single oral dose of 1 to 16 soft gelatin capsules (total apalutamide 
dose, 30 to 480 mg).  On average, peak plasma concentrations occurred 2 to 3 hours after 
administration in each dose group.  The increases in plasma Cmax values and in the area under 
the plasma concentration curve (AUC) were linear and dose proportional.  Plasma 
apalutamide concentrations declined slowly, with a mean half-life value at steady-state of 4 
days.
The percentage of patients with PSA reductions of ≥50% at 12 weeks were 91% for the 
Group 1, 88% for the Group 2, and 24% for Group 3. Similar data were observed after 
24 weeks. The data available to date indicate that apalutamide shows durable PSA responses 
in NM-CRPC and early mCRPC (before treatment with abiraterone acetate or 
chemotherapy). Apalutamide also has activity in a subgroup of patients with mCRPC that 
have progressed on abiraterone actetate. For the NM-CRPC subgroup, the metastasis-free 
survival at 12 months was 87% and with a median follow-up of 15 months the time to PSA 
progression had not been reached.28
In the NM-CRPC subgroup (n =51 ), the most frequent treatment-related adverse events 
reported in >10% as of 30 November 2013 are fatigue (43%), diarrhea (31%), nausea (20%), 
increased thyroid stimulating hormone (12%), dysgeusia (12%), and hot flush 12%.  Eight 
(16%) patients have discontinued the study due to adverse events.  Seven (14%) patients 
have discontinued due to disease progression.  No deaths were reported in this subgroup as of 
the safety cutoff.  
Refer to the Investigator’s Brochure for most up to date information. 
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2.
STUDY OBJECTIVES
2.1
PRIMARY OBJECTIVE

To demonstrate superiority in the metastasis-free survival (MFS) of men with high 
risk NM-CRPC treated with apalutamide versus placebo
2.2
SECONDARY OBJECTIVES

To compare the overall survival (OS) of men with high risk NM-CRPC treated with 
apalutamide versus placebo

To compare the time to symptomatic progression in men with high risk NM-CRPC 
treated with apalutamide versus placebo

To compare the time to initiation of cytotoxic chemotherapy in men with high risk 
NM-CRPC treated with apalutamide versus placebo

To compare the progression-free survival (PFS) of men with high risk NM-CRPC 
treated with apalutamide versus placebo

To compare the time to metastasis (TTM) in men with high risk NM-CRPC treated 
with apalutamide versus placebo

To evaluate the safety and tolerability of apalutamide
2.3
OTHER OBJECTIVES

To compare patient reported outcomes (PROs) of health-related quality of life and 
prostate cancer-specific symptoms in men with high risk NM-CRPC treated with 
apalutamide versus placebo

To evaluate the population pharmacokinetics (PK) of apalutamide

To evaluate the effect of apalutamide on ventricular repolarization in a subset of 
patients from selected clinical sites

To evaluate exploratory biomarkers predictive of response and resistance to 
apalutamide treatment
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3.
STUDY DESIGN
3.1
STUDY OVERVIEW AND RATIONALE
This is a randomized (2:1), multicenter, double-blind, placebo-controlled, Phase III clinical 
trial evaluating the efficacy and safety of apalutamide versus placebo in men with high risk 
(M0) NM-CRPC, defined as PSA Doubling Time (PSADT) ≤10 months. 
Short PSADT has been consistently associated with reduced time to first (bone) metastasis 
and death, thus the selected patient population represents one at high risk for development of 
(distant) metastasis and prostate cancer-specific death.7,25,26
No approved treatments are available for the proposed patient population besides continuous 
administration of ADT (with or without a first generation anti-androgen) as part of the 
current de facto community standard practice, therefore randomization to either apalutamide
or placebo is justified in this setting.14,16 Based on the Phase II preliminary results from 
Study ARN-509-001, apalutamide is associated with a highly favorable safety profile, and 
the encouraging anti-tumor activity observed to date in the subgroup of patients with high 
risk NM-CRPC indicates that apalutamide might have the potential to be efficacious in this 
earlier line of therapy. The placebo arm will allow an objective comparison of safety and 
efficacy between treatment with apalutamide and placebo. 
Additional PSA evaluations may be necessary to determine eligibility. In order to ensure 
investigators can obtain these additional evaluations, there is an optional Prescreening Phase 
with a separate informed consent (see Section 8.1). 
The study will consist of a Screening Phase; a Treatment Phase, and a Posttreatment 
Follow-up Phase. A double-blind study design was chosen to preserve study integrity and 
minimize bias in the assessment of all study endpoints.  A 2:1 randomization scheme will 
increase the probability that eligible patients will be randomized to receive apalutamide, 
thereby improving study feasibility.
Randomization will be stratified by PSADT, the use of a bone-sparing agent and the presence 
of loco-regional disease.  These stratification factors were chosen on the basis that they may 
be sufficiently prognostic such that an imbalance may bias the results.
Apalutamide or matched placebo will be administered orally on a continuous daily dosing 
schedule at a starting dose of 240 mg per day, the recommended Phase II dose selected based 
on preclinical projections of the optimal biological dose combined with safety and the 
PK/pharmacodynamic profiles observed during Phase I.  Apalutamide or matched placebo 
will be given with continuous GnRHa (if patient has not been surgically castrated).
Patients will be followed for safety and efficacy as per the schedule of activities and will 
remain on study treatment until documented radiographic progression (development of 
distant metastases as assessed by blinded independent central review [BICR]) or the 
development of unacceptable toxicity.  Treatment decisions will not be based on PSA as the 
clinical significance of PSA changes during treatment in the setting of NM-CRPC is 
unknown; therefore, PSA will be collected and analyzed by a central laboratory but 
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Investigators, patients, and the Sponsor will be blinded to the results until the time of the 
primary analysis.
Patients discontinuing treatment due to documented radiographic progression will enter the 
Long-term Follow-up Phase (See Section 8.9 and Appendix 1).  Patients discontinuing 
treatment prior to documented radiographic progression will also enter the Long-term 
Follow-up Phase where they will continue to have scheduled disease assessments every
16 weeks until documented radiographic progression. 
Crossover Option in the Event of Unblinding
3.1.1
At the time of study unblinding and in the event of a positive study result, all subjects 
currently receiving placebo will have the opportunity to receive active therapy with 
apalutamide (refer to Appendix 10).
Selection of the Primary Endpoint
3.1.2
Men with high risk NM-CRPC, characterized by rapidly rising PSA in the absence of 
detectable metastases despite castrate levels of testosterone, are at significant risk for 
development of metastases and prostate cancer-specific death. As verified in a recently 
completed Phase III trial of denosumab, men with NM-CRPC who are at high risk for 
development of bone metastasis have a median overall survival of 44.8 months and a median 
bone-metastasis-free survival of 25.2 months (placebo arm).27  To date there are no approved 
treatments or standard of care for men with high risk NM-CRPC and thus this patient 
population represents an area of unmet medical need. 
In consideration of the relatively long median OS (~49 months) in this population and the 
opportunity to assess for the development of distant metastasis as a clinically important 
milestone, metastasis-free survival (MFS) was chosen as the primary objective of this study.
Metastasis from prostate cancer, especially bone metastases, is the source of prostate cancer 
specific morbidity and mortality.15,22  In addition, it triggers the need for a change in therapy 
that can be associated with an increase in morbidity (e.g., toxicity associated with 
chemotherapy), and in some cases leading to a change in quality of life for that patient.  
Delaying the emergence of radiographically detectable distant metastasis, or prolongation of 
MFS as proposed, is a clinically relevant outcome that can be robustly and reliably assessed 
for determination of the true impact of a treatment on the NM-CRPC disease.  In a high risk 
cohort of patients with biochemical recurrence after radical prostatectomy and a PSADT 
< 15 months, metastatic prostate cancer was reported to account for an estimated 90% of all 
deaths7,8 it is therefore conceivable that delaying the development of metastases would likely 
translate to delaying prostate cancer-specific death. The proposed MFS definition 
incorporates not only time to (bone or soft tissue) distant metastasis but also time to death 
and thus MFS can be a reasonable correlate to overall survival.  Of note, based on 
retrospective landmark analyses at 3 and 5 years from the Radiation Therapy and Oncology 
Group 92-02 randomized trial in patients with locally advanced prostate cancer who had been 
treated with ADT and external beam radiation therapy, distant metastasis has been shown to 
be consistent with all four of Prentice’s criteria for being a potential surrogate endpoint for 
prostate cancer-specific survival at 10 years.21
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3.2
STUDY OUTCOMES
Primary Endpoint
3.2.1

Metastasis-Free Survival (MFS)
Secondary Endpoints
3.2.2

OS

Time to symptomatic progression

Time to initiation of cytotoxic chemotherapy

PFS

TTM
Other Evaluations
3.2.3

Health-related quality of life and prostate cancer-specific symptoms

Type, incidence, severity, timing, seriousness, and relatedness of adverse events and 
laboratory abnormalities

PSA response

Time to PSA progression

Population PK

Exploratory biomarkers

Assessment of ventricular repolarization

Second progression-free survival (PFS2)

Medical Resource Utilization (MRU)
4.
PATIENT SELECTION
This study can only fulfill its objectives if appropriate patients are enrolled.  The following 
eligibility criteria are designed to select patients for whom protocol treatment is considered 
appropriate.  All relevant medical and non-medical conditions should be taken into 
consideration when deciding whether this protocol is suitable for a particular patient.  It is 
expected that all patients will be treated according to local standard of care, including 
radiation therapy if needed for local disease, prior to enrolling.  
No waivers will be granted for eligibility criteria deviations.
Patients considered screen failures may be subsequently rescreened. Rescreening must be 
discussed with and approved by the Sponsor on a case-by-case basis. Patients who are 
determined to be eligible for the study after rescreening must sign a new informed consent 
form (ICF) and be assigned a new patient number.
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Treatment criteria for placebo subjects who crossover to active treatment with apalutamide 
(in the event of a positive study result and unblinding) are described in Appendix 10.
4.1
INCLUSION CRITERIA
1.
Criterion modified per Amendment INT-3
1.1
Criterion modified per Amendment INT-5
1.2
Histologically or cytologically confirmed adenocarcinoma of the prostate 
without neuroendocrine differentiation or small cell features, with high risk for development 
of metastases, defined as PSADT ≤10 months. PSADT is calculated using at least 3 PSA 
values obtained during continuous ADT (see Section 5.1). 
2.
Criterion modified per Amendment INT-5
2.1
Castration-resistant prostate cancer demonstrated during continuous ADT, 
defined as 3 PSA rises at least 1 week apart, with the last PSA >2 ng/mL
3.
Criterion modified per Amendment INT-3
3.1
Criterion modified per Amendment INT-6
3.2
Surgically or medically castrated, with testosterone levels of <50 ng/dL. If the 
patient is medically castrated, continuous dosing with GnRHa must have been initiated at 
least 4 weeks prior to randomization and must be continued throughout the study to maintain 
castrate levels of testosterone.
4.
Criterion modified per Amendment INT-3
4.1
Patients receiving bone loss prevention treatment with bone-sparing agents 
indicated for the treatment of osteoporosis at doses and dosing schedule appropriate for the 
treatment of osteoporosis (e.g., denosumab [Prolia®], zoledronic acid [Reclast®]) must be on 
stable doses for at least 4 weeks prior to randomization. 
5.
Criterion modified per Amendment INT-3
5.1 Criterion modified per Amendment INT-5
5.2
Patients who received a first generation anti-androgen (e.g., bicalutamide, 
flutamide, nilutamide) must have at least a 4-week washout prior to randomization AND 
must show continuing disease (PSA) progression (an increase in PSA) after washout. 
6.
Criterion modified per Amendment INT-3
6.1 Criterion modified per Amendment INT-5
6.2
At least 4 weeks must have elapsed from the use of 5-α reductase inhibitors 
(e.g., dutasteride, finasteride), estrogens (irrespective of dose used), and any other anti-cancer 
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therapy prior to randomization, including chemotherapy given in the adjuvant/neoadjuvant 
setting (e.g., clinical trial)
7.
At least 4 weeks must have elapsed from major surgery or radiation therapy prior to 
randomization
8.
Age ≥18 years
9.
Eastern Cooperative Oncology Group (ECOG) Performance Status grade 0 or 1
10.
Resolution of all acute toxic effects of prior therapy or surgical procedure to Grade 1 
or baseline prior to randomization
11.
Criterion modified per Amendment INT-3
11.1
Criterion modified per Amendment INT-6
11.2
Adequate organ function as defined by the following criteria:

Serum aspartate transaminase (AST; serum glutamic oxaloacetic transaminase 
[SGOT]) and serum alanine transaminase (ALT; serum glutamic pyruvic 
transaminase [SGPT]) 2.5 x upper limit of normal (ULN)

Total serum bilirubin ≤1.5 x ULN.  Total serum bilirubin >1.5 x ULN is allowed 
if Gilbert’s disease is documented prior to end of screening procedures.

Serum creatinine 2 x ULN

Absolute neutrophil count (ANC) 1500/L

Platelets 100,000/L

Hemoglobin 9.0 g/dL
o
Administration of growth factors or blood transfusions will not be allowed 
within 4 weeks of the hematology labs required to confirm eligibility
12.
Signed and dated informed consent document indicating that the patient (or legally 
acceptable representative) has been informed of all pertinent aspects of the trial prior to 
randomization
13.
Criterion modified per Amendment INT-6
13.1
Criterion modified per Amendment 7
13.2
Willingness and ability to comply with scheduled visits, treatment plans, 
laboratory and radiographic assessments, and other study procedures, including ability to 
swallow study drug tablets, the completion of patient reported outcomes questionnaires and 
long-term follow-up 
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4.2
EXCLUSION CRITERIA
1.
Criterion modified per Amendment INT-3
1.1
Presence of distant metastases confirmed by blinded independent central 
review (BICR), including CNS and vertebral or meningeal involvement, or history of 
distant metastases.  Exception: Pelvic lymph nodes <2 cm in short axis (N1) located 
below the iliac bifurcation are allowed
2.
Symptomatic loco-regional disease requiring medical intervention, such as moderate 
or severe urinary obstruction or hydronephrosis, due to primary tumor (e.g., tumor 
obstruction of bladder trigone)
3.
Prior treatment with second generation anti-androgens (e.g., enzalutamide)
4.
Criterion modified per Amendment INT-5
4.1
Prior treatment with CYP17 inhibitors (e.g., abiraterone acetate, orteronel, 
galerterone, ketoconazole, aminoglutethimide)
5.
Prior treatment with radiopharmaceutical agents (e.g., Strontium-89), immunotherapy 
(e.g., sipuleucel-T), or any other investigational agent for NM-CRPC
6.
Prior chemotherapy for prostate cancer, except if administered in the 
adjuvant/neoadjuvant setting
7.
History of seizure or condition that may pre-dispose to seizure (e.g., prior stroke 
within 1 year prior to randomization, brain arteriovenous malformation, Schwannoma, 
meningioma, or other benign CNS or meningeal disease which may require treatment with 
surgery or radiation therapy)
8.
Criterion modified per Amendment INT-3
8.1
Criterion modified per Amendment INT-6
8.2
Concurrent therapy with any of the following (all must have been 
discontinued or substituted for at least 4 weeks prior to randomization):

Medications known to lower the seizure threshold (for a complete list please see 
Appendix 5)

Herbal (eg, saw palmetto) and non-herbal (eg, pomegranate) products that may 
decrease PSA levels

Systemic (oral/IV/IM) corticosteroids. Short term use (≤4 weeks) of 
corticosteroids during the study is allowed if clinically indicated, but it should be 
tapered off as soon as possible

Any other experimental treatment on another clinical trial
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
Agents indicated for the prevention of skeletal-related events in patients with 
solid tumors (e.g., denosumab [Xgeva®])
9.
Criterion modified per Amendment INT-3
9.1
Criterion modified per Amendment INT-6
9.2
History or evidence of any of the following conditions:

Any prior malignancy (other than adequately treated basal cell or squamous cell 
skin cancer, superficial bladder cancer, or any other cancer in situ currently in 
complete remission) within 5 years prior to randomization

Any of the following within 6 months prior to randomization: Severe/unstable 
angina, myocardial infarction, symptomatic congestive heart failure, arterial or 
venous thromboembolic events (e.g., pulmonary embolism, cerebrovascular 
accident including transient ischemic attacks), or clinically significant ventricular 
arrhythmias

Uncontrolled hypertension (systolic blood pressure ≥160 mmHg or diastolic BP 
≥100 mmHg). Patients with a history of uncontrolled hypertension are allowed 
provided blood pressure is controlled by anti-hypertensive treatment.

Gastrointestinal disorder affecting absorption

Active infection, such as human immunodeficiency virus (HIV)

Any other condition that, in the opinion of the Investigator, would impair the 
patient’s ability to comply with study procedures.
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5.
STUDY TREATMENTS
5.1
RANDOMIZATION CRITERIA
After patients have provided their written informed consent, completed all Screening
assessments and received confirmation of eligibility, they will be randomized into the study 
using an Interactive Voice Randomization System (IVRS) and stratified based on:

PSADT: > 6 months vs. ≤6 months

Bone-sparing agent use: Yes vs. No

Loco-regional disease: N0 vs. N1 
In order to ensure accurate and consistent determination of PSADT across all sites, the IVRS 
will also provide PSADT calculations (using a linear regression model of the normal 
logarithm of PSA and time) based on at least 3 PSA values obtained during continuous ADT.  
All available consecutive PSA values obtained within 24 months prior to randomization
beginning with the earliest value chosen for the PSADT calculation must be entered in the 
IVRS. The first and last PSA values used in the calculation must be separated by at least 8 
weeks. 
Those same PSA values should be used during Screening to determine whether the patient is 
eligible for the study (inclusion criterion #1.2).  In order to pre-screen patients for possible 
enrollment into the study, PSADT can be calculated using the Memorial Sloan-Kettering 
Cancer Center (MSKCC) PSA Doubling Time prediction tool, available at the following 
website:
http://nomograms.mskcc.org/Prostate/PsaDoublingTime.aspx
5.2
BLINDING
Due to the objectives of the study, the identity of test and control treatments will not be 
known to investigators, research staff, or patients.
Only selected individuals not affiliated with the protocol will be unblinded to individual 
patient treatment assignment during the trial for the purposes of efficacy analyses and safety 
review.  The randomization codes and all data sets will be stored in a secure area accessible 
only to these individuals, and only released on completion of the study and after the study 
database has been locked.
In emergency situations for reasons of patient safety (e.g., a serious unexpected/unlisted 
drug-related event; a medical emergency; a potentially life-threatening drug interaction), the 
blinding code may need to be broken.  In those cases, whenever possible, a request for 
unblinding should be discussed with the Sponsor (or designee) prior to unblinding.  Detailed 
instructions on the method for breaking the blind will be provided during site training and in 
the Investigator Site File.
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5.3
FORMULATION 
Apalutamide/Matched Placebo
5.3.1
The apalutamide tablet supplied for this study contains 60 mg of JNJ-56021927. It will be 
manufactured and provided under the responsibility of the Sponsor. Refer to the 
Investigator's Brochure for a list of excipients. Placebo will be provided as a tablet 
formulation and will be matched in size, color, and shape to active study drug in order to 
maintain the study blind.
Packaging, Storage, and Labeling
5.3.2
The apalutamide 60-mg tablets will packaged in 120-count, 160 cc high-density polyethylene 
(HDPE) bottles with 
. Bottles will include desiccant. 
The study drug will be periodically tested and monitored for its acceptable shelf life for at 
least the duration of the study.  Any study drug that fails to comply with the manufactured 
specifications will be promptly removed from the clinical study site and replaced with new 
supplies by the Sponsor (or designee).  
Each bottle of study drug will be labeled with the required regulatory agency warning 
statement, the protocol number, the Sponsor’s name, and directions for patient use and 
storage.  The Investigator will ensure that the study drug is stored in appropriate conditions in 
a secure location with controlled access. For clinical formulation-specific and batch-specific 
storage instructions, see the packaging label.
Drug Administration
5.3.3
Apalutamide/matched placebo tablets will be administered orally on a continuous daily 
dosing regimen at a dose of 240 mg per day (4 x 60-mg tablets) with or without food.  
Cycle Management
5.3.4
For the purposes of the study, a treatment cycle will consist of 4 weeks (28 days).
It is anticipated that individual patients may occasionally forget to take a dose.  In those 
cases, missed doses should only be replaced if the patient remembers within a 12-hour 
window.  After that, patients should just take the next dose the following day, without 
compensating for the missed dose (including vomited doses).  In the event of dose delays due 
to transient toxicity, tumor assessments should remain on schedule independent of cycle 
length.
Dose Modifications
5.3.5
Intrapatient dose interruptions and/or reductions will be permitted provided that study 
discontinuation criteria have not been met (please see Section 10).

Patients experiencing treatment-related seizure of any grade will have study drug 
permanently discontinued.
(b) (4)
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5.5
MEASURES OF TREATMENT COMPLIANCE
At each clinic visit, patients will be asked to return any remaining study drug from the 
previous dosing cycle as well as all used and unused study drug containers.
The overall treatment compliance will be defined as the total dose in mg taken during the 
study divided by the expected total dose in mg. Patients completing their last cycle on 
capsules should continue with a maximum of 8 capsules per day and patients on tablets 
should have a maximum of 4 tablets per day.
Capsules or tablets that are not returned will be considered to have been taken, unless 
otherwise specified in the case report form (CRF).
6.
CONCURRENT MEDICATIONS
All patients should be maintained on the same medications throughout the entire study 
period, as medically feasible, with minimum introduction of new chronic therapies.  Every 
medication or treatment taken by the patient during the trial and the reason for its 
administration must be recorded on the CRF.  Standard medical treatment as applicable is 
allowed except for treatments noted in the eligibility criteria and/or listed in the prohibited 
medications section below.
Continuous treatment with a GnRHa or surgical castration is mandatory for all patients in 
order to maintain castrate concentrations of testosterone (<50 ng/dL). The choice of GnRHa 
is at the discretion of the investigator. Dose and dose schedule (without interruption) will be 
consistent with the prescribing information and should only be adjusted if clinically indicated 
to maintain castrate concentrations of testosterone.
Salvage radiation for loco-regional pelvic disease and surgical procedures (eg, transurethral 
resection of the prostate [TURP], urethral and ureteral stent placement) to treat localized 
progression or symptoms are allowed. Patients receiving these therapies may continue on 
study drug .
6.1
PROHIBITED MEDICATIONS AND TREATMENTS
As a class effect, androgen receptor antagonists have been associated with seizures due to an 
off-target mechanism of action (GABAA inhibition).6,16 In preclinical studies, at very high 
doses, dogs treated with apalutamide had tremors and generalized seizures.  Patients will be 
closely monitored for seizures, but as a precautionary measure, drugs known to decrease the 
seizure threshold and/or cause seizure will be prohibited while on study. A list of these 
medications can be found in Appendix 5.
6.2
RESTRICTED THERAPIES
Investigators should refer to the apalutamide Investigator’s Brochure (Sections 4.3.3.3 and 
5.10) and associated addenda for complete details on the drug interaction potential of 
apalutamide. Highlights of drug interaction are summarized below.
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
Strong CYP3A4 inducers: the potential for drug-drug interactions with apalutamide has 
not been tested clinically. Strong inducers of CYP3A4 (eg, phenytoin, carbamazepine, 
rifampin, rifabutin, rifapentine, phenobarbital, efavirenz, tipranavir, St. John's wort) 
should be avoided as much as possible. Additional information is provided in Appendix 
5.

Apalutamide may also induce CYP3A4; therefore, caution should be taken when 
administered in conjunction with CYP3A4 substrates that have a narrow therapeutic 
index 

Strong CYP2C8 inhibitors (eg, gemfibrozil) should be used with caution with 
apalutamide

The potential for drug-drug interaction between apalutamide and warfarin (e.g.,
Coumadin) is unknown at present. If a patient is taking warfarin, re-assess (prothrombin) 
PT/(international normalized ratio) INR as clinically indicated and adjust the dose of 
warfarin accordingly.

Corticosteroids (Oral, IV, or IM): due to possible resistance mechanisms, which may be 
contributed by glucocorticoid receptor signaling, concurrent use of corticosteroids during 
the study is not recommended; short term use (≤ 4 weeks) will be allowed if clinically 
indicated, however, its use must be tapered off as soon as possible.
6.3
LIFE STYLE GUIDELINES
To avoid risk of drug exposure through the ejaculate (even men with vasectomies), patients 
must use a condom during sexual activity while on study drug and for 3 months following the 
last dose of study drug. Donation of sperm is not allowed during the study and for 3 months 
following the last dose of study drug.
There are no data on the use of apalutamide in pregnancy. Maternal use of an anti-androgen 
is expected to produce changes in hormone levels that may affect fetal development. It is not 
known if apalutamide or its metabolites are present in semen. 
If the patient is engaged in sexual activity with a woman of childbearing potential, a condom 
is required along with another effective contraceptive method consistent with local 
regulations regarding the use of birth control methods for patients participating in clinical 
studies and their partners. Highly effective forms of contraception include: 

established use of oral, injected or implanted hormonal methods of contraception; 
placement of an intrauterine device (IUD) or intrauterine (IUS) system;

barrier methods: condom with spermicidal foam/gel/film/cream/suppository or 
occlusive cap (diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/suppository;

vasectomy;
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
true abstinence (an option when this is in line with the preferred and usual lifestyle of 
the patient).
Two highly effective forms of contraception are required during the study and for 3 months 
after the last dose of study drug.
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7.
STUDY PROCEDURES AND GUIDELINES
A Schedule of Activities representing the required testing procedures to be performed during
the study is diagrammed in Appendix 1.
Prior to conducting any study-related activities, written informed consent and any other 
authorizations must be signed and dated by the patient or patient’s legal representative.  
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances outside of the control of the Investigator that may make it unfeasible to 
perform the test.  In those cases, the Investigator should take all steps necessary to ensure the 
safety and wellbeing of the patient. When a protocol required test cannot be performed, the 
Investigator will document the reason for this and any corrective and preventive actions 
which he/she has taken to ensure that normal processes are adhered to as soon as possible. 
The study team should be informed of these incidents in a timely fashion.
7.1
CLINICAL ASSESSMENTS
Demographics 
7.1.1
Demographic information (e.g., date of birth, gender, race) will be recorded at Screening, as 
allowed per local country privacy law regulations.
Medical History 
7.1.2
Relevant medical history, including history of current disease, other pertinent clinical 
conditions, and information regarding underlying diseases will be recorded at Screening.
Physical Examination
7.1.3
A complete physical examination will be performed by either the Investigator or a sub-
Investigator at Screening. Qualified staff (e.g., nurses or physician assistants) may complete 
either a full or abbreviated physical exam at all other visits.  New abnormal physical exam 
findings must be documented and followed by a physician or other qualified staff at the next 
scheduled visit.
The complete physical examination should include, but not limited to, general appearance, 
skin, neck, eyes, ears, nose, throat, breast, lungs, heart, abdomen, back, lymph nodes, 
extremities, and nervous system, as well as examination of known and suspected sites of 
disease.  Height will be recorded at Screening only.  Body weight will be recorded at
Screening and every scheduled visit during treatment and at the end of treatment.
Vital Signs
7.1.4
Body temperature, blood pressure, pulse and respiratory rate will be performed after resting 
for 5 minutes at Screening and every scheduled visit during treatment and at the end of 
treatment.
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Performance Status
7.1.5
The Eastern Cooperative Oncology Group (ECOG) performance status scale will be used 
(Appendix 3) and will be assessed at Screening and every subsequent clinic visit.
Adverse Events
7.1.6
Assessment of adverse events will include type, incidence, severity (graded by the National 
Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE], 
Version 4.0), timing, seriousness, and relatedness (Appendix 4).  Adverse events will be 
assessed at every clinic visit.
Concomitant Medications/Therapies
7.1.7
All concomitant medication and concurrent therapies will be documented from the first dose 
of study drug until 28 days after the last dose of study drug.  Name, indication for 
administration, and dates of medication or therapy will be captured.
Tumor Assessments
7.1.8
Disease assessments are to be performed as scheduled according to the calendar, regardless 
of treatment delays resulting from toxicity.  Care must be taken in scheduling disease 
assessments to prevent the introduction of bias based on treatment delays.
Disease assessments will be performed at baseline (Screening), at 16-week intervals from 
Cycle 1 Day 1, whenever disease progression is suspected, and at the end of treatment.  
Imaging studies will include a CT scan of the chest, abdomen, and pelvis, plus a bone scan. 
At Screening, there will be an additional CT of the brain to rule out the presence of CNS
metastases. 
Radiographic confirmation of disease progression (appearance of distant metastasis) will be 
based on RECIST 1.1 and assessed by blinded independent central review (see below). 4 For 
new bone lesions detected on bone scans, a second imaging modality (e.g., CT or MRI) will 
be required to confirm progression. 
The same method of assessment and the same technique should be used at Screening and 
during follow-up.  Intravenous (IV) contrast is required when not medically contraindicated.  
Patients who have a contraindication to IV contrast may have MRI exams of the brain, 
abdomen and pelvis performed in lieu of CTs and a non-contrast CT of the chest.  Tumor 
evaluation by positron emission tomography (PET) scan or by ultrasound may not substitute 
for CT or MRI scans, but the CT portion of a PET/CT may be submitted in lieu of a 
dedicated CT.  Additional requirements are provided in the Imaging Site Manual. 
7.1.8.1
Blinded Independent Central Review (BICR)
All scans will be submitted to a third-party core imaging laboratory for independent review
of patient eligibility (within 3 days of receipt of imaging scans that pass quality assessment)
and disease progression during the study according to an Independent Review Charter to be 
prepared by the core imaging laboratory in consultation with the Sponsor.
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It is important to the integrity of the study that all imaging studies and pertinent clinical 
information (e.g., bone trauma, fracture, or infection) are forwarded to the core imaging 
laboratory throughout the study.  
Further details regarding materials to be forwarded for central review can be found in the 
Imaging Manual and/or Investigator Site File.
7.2
CLINICAL LABORATORY MEASUREMENTS 
Blood will be obtained at the time points described in the Schedule of Activities and sent to a 
central lab for hematology and blood chemistry profile.  Appendix 2 lists all of the specific 
tests that will be performed. Complete details with regards to sample collection and 
shipment processes can be found in the Laboratory Manual and/or Investigator Site File.  
Investigators may have additional blood tests performed for the purpose of planning 
treatment administration, dose modification, or following adverse events.
PSA
7.2.1
Optional prescreening PSA evaluations will be performed by local laboratories.
All other PSA evaluations will be performed at the central laboratory.  Results during 
treatment (until the time of the primary analysis) will be kept blinded to the patients, the 
Investigators, and the Sponsor, in order to preserve the double-blind nature of this study.  
Electrocardiogram (ECG)
7.2.2
A standard 12-lead ECG (with a 10-second rhythm strip) will be collected at Screening and
as clinically indicated.  ECGs should be collected after the patient has rested quietly and is 
awake in a fully supine (or semi-recumbent, if supine is not tolerated) position for 
10 minutes, and prior to any blood draw collection.  Subsequent ECG readings should be 
collected with the patient in the same position (e.g., fully supine or semi-recumbent). For 
patients participating in the ventricular repolarization substudy see Appendix 8 for specific 
instructions. 
7.3
PHARMACOKINETIC MEASUREMENTS
Blood for determination of plasma concentrations of apalutamide and its metabolite,
ARN000308, will be collected as described in the Laboratory Manual on Day 1 of Cycles 1, 
2, 3, 6, 11, 17, and 25.  All samples will be assayed using an analytical method validated for
apalutamide and metabolite. 
On Cycle 1 Day 1, the blood sample must be collected between 0.5 and 4 hours post the first 
dose of study drug. For all other PK blood collections, the blood sample must be collected  
prior to study drug administration.  No sparse PK samples will be collected from patients 
participating in the ventricular repolarization study. All reasonable measures must be taken 
to ensure accurate recording of information on dosing, including the time of the doses of 
study drug administered on the 2 days preceding the PK sampling day and whether the doses 
were taken based on a once daily or twice daily schedule (see also Section 8).
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8.
STUDY ASSESSMENTS BY VISIT (APPENDIX 1)
8.1
PRESCREENING

For this optional Prescreening Phase, review the study with the patient (or patient’s 
legal representative) and obtain written informed consent. The optional prescreening 
PSA evaluations will be performed by the local laboratories. This Prescreening Phase 
will allow additional time to obtain the required number of PSA values for 
determining eligibility. The patient must then sign another informed consent before 
any additional study-related procedures are conducted (see Section 8.2).
8.2
SCREENING (WITHIN 35 DAYS OF RANDOMIZATION)

Review the study with the patient (patient’s legal representative) and obtain written 
informed consent

Calculate PSADT using IVRS to confirm patient eligibility

Obtain CT of the brain, chest, abdomen, and pelvis, plus bone scan and submit for 
BICR to confirm patient eligibility (scans obtained prior to signing informed consent 
will be allowed provided the timing of the scans fall within the Screening window)

Record demographics data

Record medical history, including history of prostate cancer, diagnosis date, and prior 
treatments

Record concomitant medications

Perform a complete physical examination (adverse events must be recorded from the 
time of signed informed consent)

Perform and record vital signs and ECOG performance status grade

Perform and record standard 12-lead ECG 

Collect blood for clinical laboratory assessments

Submit patient eligibility form to medical monitor

If patient is confirmed eligible by the medical monitor, randomize patient and 
proceed to Cycle 1 Day 1 visit (can be same day or within 4 days of randomization)
8.3
CYCLE 1 DAY 1

Administer FACT-P and EQ-5D questionnaires

Record changes to concomitant medications

If available, retrieve archival FFPE tumor blocks or tumor slides from consenting 
patients for exploratory biomarker analysis  

Record any adverse events

Perform abbreviated physical examination 

Perform and record vital signs and ECOG performance status
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
Collect blood for hematology, blood chemistry, TSH, fasting lipid profile, 
testosterone, and PSA (Screening evaluations can be used if done within 4 days of 
Cycle 1 Day 1)

Collect blood for exploratory biomarker analysis from consenting patients prior to 
study drug administration

Administer study drug in clinic

Collect blood for PK sample between 0.5 and 4 hours post-dose and record actual 
time of collection relative to dosing (not required for patients participating in the 
ventricular repolarization substudy; see Appendix 8).
8.4
DAY 1 OF CYCLES 1-6, THEN DAY 1 OF EVERY 2 CYCLES STARTING
FROM CYCLE 7 UP TO C13 THEN DAY 1 OF EVERY 4 CYCLES (±2 DAYS)

Administer FACT-P and EQ-5D questionnaires

Record any adverse events 

Record changes to concomitant medications

Assess study drug compliance

Perform abbreviated physical examination

Perform and record vital signs and ECOG performance status

Collect blood for hematology, blood chemistry, and PSA

For Cycles 2, 3, 6, 11, 17, and 25 collect blood for PK sample prior to study drug 
administration(record time of administration of study drug on the 2 days preceding 
the day of the PK sampling and the dosing regimen [once daily or twice daily]). Not 
required for subjects participating in the ventricular repolarization study (see 
Appendix 8).

Collect blood for exploratory biomarker analysis from consenting patients (Cycles 11, 
17, 25, and 37) prior to study drug administration
8.5
EVERY 16 WEEKS STARTING FROM CYCLE 1 DAY 1 (±2 DAYS)

Collect blood for TSH, fasting lipid panel, and testosterone

If TSH is abnormal; total T3, free T4 (direct), and total T4 are required
8.6
EVERY 16 WEEKS STARTING FROM CYCLE 1 DAY 1 (±7 DAYS)

Obtain CT of the chest, abdomen, and pelvis, plus bone scan and submit for BICR to 
evaluate for disease progression (ie, distant metastasis)
8.7
END-OF-TREATMENT VISIT

Administer FACT-P and EQ-5D questionnaires (optional if performed within 2 weeks
of the last dose of study drug)

Assess study drug compliance
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
Obtain CT of the chest, abdomen, and pelvis, plus bone scan and submit for BICR to 
evaluate for disease progression (optional if performed with 8 weeks of the last dose 
of study drug)

Record any adverse events

Record changes to concomitant medications
The following are optional if the End-of-Treatment Visit is performed within 1 week of 
the last dose of study drug: 

Perform abbreviated physical examination 

Perform and record vital signs and ECOG performance status 

Collect blood for clinical laboratory assessments 

Collect blood for exploratory biomarker analysis from consenting patients 
8.8
SAFETY FOLLOW-UP (28 DAYS FOLLOWING THE LAST DOSE OF STUDY 
DRUG)

Record any adverse events 

Record changes to concomitant medications
8.9
LONG-TERM FOLLOW-UP

Obtain survival status, recording of development of symptomatic progression,
initiation of any new systemic anti-cancer therapies, progression on first subsequent 
therapy (PFS2), and MRU every 4 months via clinic visit, telephone contact, or an 
alternative contact method per institution policy/practice. The FACT-P and EQ-5D
questionnaires will be collected up to 12 months post-progression.

In addition, if patients discontinue study treatment prior to documented disease 
progression (ie, distant metastasis, see Section 7.1.8), obtain CT of the chest, 
abdomen, and pelvis, plus bone scan and submit for BICR to evaluate for disease 
progression (every 16 weeks, until documentation of disease progression)
8.10
SUBSEQUENT THERAPY WITH ABIRATERONE ACETATE
Due to local restrictions in Japan, the Sponsor will not provide abiraterone acetate and the 
criteria outlined in this section do not apply. 
The Sponsor will provide abiraterone acetate to all other patients who meet the following 
criteria:

patient signs informed consent to receive treatment with abiraterone acetate

documented disease progression (ie, meet criteria for the primary endpoint [distant 
metastasis], see Section 13.2.1). If the study is unblinded, the requirement for meeting 
disease progression by BICR in Section 13.2.2 will not be required.  
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
the patient resides in a country in which abiraterone acetate and prednisone (or 
prednisolone) are indicated for the treatment of metastatic CRPC before 
chemotherapy

the investigator caring for the patient decides that abiraterone acetate is the 
appropriate first subsequent treatment after discontinuation of study drug; and 

no other subsequent treatment has been prescribed after the progression event and 
before abiraterone acetate is prescribed.
Abiraterone acetate should be used according to the product label-prescribing information in 
the country of residence.
Prednisone (or prednisolone) should be used according to the product label-prescribing 
information in the country of residence. Prednisone (or prednisolone) will not be provided by 
the Sponsor, but should be prescribed as part of the regimen. 
In countries where abiraterone acetate in combination with prednisone (or prednisolone) is 
not approved for the treatment of asymptomatic or mildly symptomatic mCRPC before 
chemotherapy, patients should be treated according to the local standard of care. Provision of 
abiraterone acetate will continue until the patient or investigator decides not to continue 
further treatment for any reason, unacceptable toxicity or the study is terminated by the 
Sponsor.
Serious adverse events will be collected during subsequent therapy with abiraterone acetate.
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9.
ADVERSE EVENT REPORTING REQUIREMENTS
9.1
DEFINITIONS
Adverse Events (AE)
9.1.1
An AE is any untoward medical occurrence in a clinical study patient administered a 
medicinal (investigational or non investigational) product. An AE does not necessarily have a 
causal relationship with the treatment. An adverse event can therefore be any unfavorable 
and unintended sign (including an abnormal finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational or non investigational) product, 
whether or not related to that medicinal (investigational or non investigational) product. 
(Definition per International Conference on Harmonisation [ICH])
This includes any occurrence that is new in onset or aggravated in severity or frequency from 
the baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Note: The Sponsor collects AEs starting with the signing of the ICF (refer to Section 9.2, for 
time of last AE recording).
Examples of AEs include but are not limited to:

Abnormal test findings

Clinically significant signs and symptoms

Changes in physical examination findings 

Worsening of signs and symptoms of the malignancy under study.  Disease 
progression assessed by measurement of malignant lesions on radiographs or other 
methods should not be reported as an adverse event, unless the outcome is fatal 
during the study or within the safety reporting period – see definition of serious 
adverse event below.

Signs or symptoms resulting from dose overdose, dependency, withdrawal, abuse, 
and/or misuse

Drug interactions

Exposure in utero (pregnancy)
For laboratory abnormalities, the criteria for determining whether an abnormal test finding 
should be reported as an adverse event are as follows:

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 protocol-stipulated dose 
adjustments or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy, and/or
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
Test result is considered to be an adverse event by the Investigator
Serious Adverse Events (SAE)
9.1.2
A serious adverse event (SAE) based on ICH and EU Guidelines on Pharmacovigilance for 
Medicinal Products for Human Use is any untoward medical occurrence that at any dose:

Results in death.  If the malignancy under study has a fatal outcome during the study 
or within the safety reporting period, the event leading to death should be reported as 
a Grade 5 SAE; death is an outcome and not the adverse event in itself.

Is life-threatening (i.e., immediate risk of death from the reaction as it occurred).  It 
does not include a reaction which hypothetically might have caused death had it 
occurred in a more severe form.

Requires or prolongs inpatient hospitalization (i.e., the event required at least a 
24-hour hospitalization or prolonged a hospitalization beyond the expected length of 
stay). Hospitalization admissions and/or surgical operations scheduled to occur during 
the study period, but planned prior to study entry are not considered SAEs if the 
illness or disease existed before the person was enrolled in the trial, provided that it 
did not deteriorate in an unexpected manner during the trial (e.g., surgery performed 
earlier than planned)

Results in persistent or significant disability/incapacity.  Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions

Results in a congenital anomaly or birth defect

Is a suspected transmission of any infectious agent via a medicinal product

Is an important medical event when, based upon appropriate medical judgment, it 
may jeopardize the participant and require medical or surgical intervention to prevent 
one of the outcomes listed above. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home; blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse
Events not considered to be SAEs are hospitalizations for:

Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition

Elective or pre-planned treatment for a pre-existing condition that did not worsen

Emergency outpatient treatment for an event not fulfilling the serious criteria outlined 
above and not resulting in inpatient admission

Respite care or social admissions
Expectedness
9.1.3
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed 
in the Investigator’s Brochure or is not listed at the specificity or severity that has been 
observed. 
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Unexpected, as used in this definition, also refers to adverse events or suspected adverse 
reactions that are mentioned in the Investigator’s Brochure as occurring with a class of drugs 
or as anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation.  Such events would be 
considered unexpected until they have been observed with the drug under investigation. 
Attribution
9.1.4
A suspected adverse reaction means any adverse event for which there is reasonable 
possibility that the study drug caused the adverse event.  For the purposes of IND safety 
reporting, “reasonable possibility” means there is evidence to suggest a causal relationship 
between the drug and the adverse event.  
The Investigator will assign attribution of the possible association of the event with the study 
drug using the following definitions:

Unrelated to study drug: The adverse event is clearly not related or is doubtfully 
related to the study drug

Related to study drug: The adverse event may be related, is likely related, or is 
clearly related to the study drug
Severity
9.1.5
Signs or symptoms should be graded and recorded by the Investigator according to the 
National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) 
Version 4.0 (Appendix 4).  When specific adverse events are not listed in the CTCAE, they 
are to be graded as mild, moderate, severe, or life-threatening according to the following 
grades and definitions:
Table 2
AE Severity Grading
Severity
(Toxicity Grade)
Description
Grade 1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL)
Grade 3
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL
Grade 4
Life-threatening consequences; urgent intervention indicated
Grade 5
Death related to AE
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Pregnancy
9.1.6
Because the effect of the blinded study drug on sperm is unknown, pregnancies in partners of 
male subjects included in the study will be reported by the investigational staff within 
24 hours of their knowledge of the event using the appropriate pregnancy notification form.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in 
the infant will be required.
9.2
REPORTING REQUIREMENTS
All AEs and SAEs whether reported by the patient, discovered during questioning, directly 
observed, or detected by physical examination, laboratory test or other means, will be 
recorded in the patient’s medical record and on the appropriate study-specific CRFs.
Anticipated events will be recorded and reported as described in Appendix 9 (see also 
Section 9.2.3). 
SAE Reporting
9.2.1
During the Prescreening Phase only, the SAE reporting would be limited to SAEs related to 
the PSA blood draw. At screening, the reporting period for SAEs begins from the time the 
patient provides informed consent and prior to the patient’s participation in the study, i.e., 
prior to undergoing any study-related procedure through and including 28 days after the last 
dose of study drug. Serious adverse events will also be collected during subsequent therapy 
with abiraterone acetate (see Section 8.10).
All SAEs occurring during the study must be reported to the appropriate Sponsor contact 
person by study-site personnel within 24 hours of their knowledge of the event. 
Information regarding SAEs will be transmitted to the Sponsor using the Serious Adverse 
Event Form, which must be completed and signed by a physician from the study site, and 
transmitted to the Sponsor within 24 hours. The initial and follow-up reports of an SAE 
should be made by facsimile (fax) or email. The names (and corresponding telephone 
numbers) of the individuals who should be contacted regarding safety issues or questions 
regarding the study will be provided as a separate document.
The Investigator is also responsible for notifying the Institutional Review Board/Independent 
Ethics Committee (IRB/IEC) in accordance with local regulations.
All events should be followed to their resolution, until the Investigator assesses them as 
stable, irreversible, or until the patient is lost to follow-up, whichever comes first.  Any SAEs 
occurring any time after the reporting period must be promptly reported if a causal 
relationship to apalutamide is suspected.
Reporting Deaths: Regardless of relationship to study drug, all deaths on study should be 
reported through and including 28 days after the last dose of study.  Deaths occurring after 
the safety follow-up period do not have to be reported as SAEs unless considered related to 
study drug.
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For all SAEs, the Investigator is obligated to pursue and provide information to the Sponsor 
in accordance with the timeframes for reporting specified above.  In addition, an Investigator
may be requested to obtain specific additional follow-up information in an expedited fashion.  
This information may be more detailed than that captured on the AE CRF.  In general, this 
will include a description of the adverse event in sufficient detail to allow for a complete 
medical assessment of the case and independent determination of possible causality.  
Information on other possible causes of the event, such as concomitant medications and 
illnesses must be provided.  In the case of a patient death, a summary of available autopsy 
findings must be submitted as soon as possible to the Sponsor or its designated 
representative.
Non-Serious AE Reporting
9.2.2
Adverse events should be recorded on the AE CRF from the time the patient has signed the 
informed consent at screening (see Section 8.2) until 28 days after the last dose of study drug.  
All events should be followed to their resolution, until the Investigator assesses them as 
stable, irreversible, or until the patient is lost to follow-up, whichever comes first.  If a patient
begins a new systemic anti-cancer therapy, the AE reporting period for non-SAEs ends at the 
time the new treatment is started.  
Sponsor Reporting Requirements to Regulatory Authorities
9.2.3
Adverse events reporting, including suspected serious unexpected adverse reactions, will be 
carried out in accordance with applicable local regulations. The Sponsor or its designee will 
be responsible for determining whether or not the suspected adverse reaction meets the 
criteria for expedited reporting.

For anticipated events reported as individual serious adverse events the Sponsor will 
make a determination of relatedness in addition to and independent of the 
investigator’s assessment. The Sponsor will periodically evaluate the accumulating 
data and, when there is sufficient evidence and the sponsor has determined there is a 
reasonable possibility that the drug caused a serious anticipated event, they will  
submit a safety report in narrative format to the investigators (and the head of the 
institute).

The Sponsor or its designee will be responsible for reporting relevant SAEs to the 
Competent Authority, other applicable regulatory authorities, and participating 
investigators, in accordance with ICH guidelines, FDA regulations, European Clinical 
Trials Directive (Directive 2001/20/EC), and/or local regulatory requirements.

The Sponsor or its designee will be responsible for reporting unexpected fatal or 
life-threatening events associated with the use of the study drug to the regulatory 
authorities by telephone or fax within 7 calendar days after being notified of the 
event.  

The Sponsor or its designee will report other relevant SAEs associated with the use of 
the study drug to the appropriate regulatory authorities (according to local guidelines) 
and Investigators by a written safety report within 15 calendar days of notification.
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Product Quality Complaint Handling
9.2.4
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may 
have an impact on the safety and efficacy of the product. Timely, accurate, and complete 
reporting and analysis of PQC information from studies are crucial for the protection of 
subjects, investigators, and the sponsor, and are mandated by regulatory agencies worldwide. 
The sponsor has established procedures in conformity with regulatory requirements 
worldwide to ensure appropriate reporting of PQC information; all studies conducted by the 
sponsor or its affiliates will be conducted in accordance with those procedures.
9.2.4.1
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours 
after being made aware of the event.
If the defect is combined with a SAE, the study-site personnel must report the PQC to the 
sponsor according to the SAE reporting timelines (refer to Section 9.2.1). A sample of the 
suspected product should be maintained for further investigation if requested by the sponsor.
9.2.4.2
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be 
contacted regarding product quality issues are listed on the Contact Information page(s), 
which will be provided as a separate document.
10. END OF TREATMENT
A patient may be discontinued from study treatment at any time if the patient, the 
Investigator, or the Sponsor feels that it is not in the patient’s best interest to continue on 
study.  If a patient’s study treatment must be discontinued, this will not result in automatic 
withdrawal of the patient from the study.
The following is a list of possible reasons for early discontinuation of study treatment: 

Disease progression (patients should be highly encouraged to stay on study treatment 
until there is BICR-confirmed radiographic progression; treatment decisions should 
not be based on PSA alone)

Any episode of seizure

Any other adverse event that cannot be adequately managed with dose modifications, 
including dose interruption for ≥28 days may require study drug discontinuation, 
which must be discussed with the Sponsor.

Protocol violation requiring discontinuation of study treatment

Patient is not compliant with study procedures

Lost to follow-up

Patient withdrawal of consent 
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
Sponsor request for early termination of study
All patients discontinuing study treatment will enter the Long-term Follow-up Phase and will 
be followed for the development of symptomatic progression and initiation of subsequent 
anti-cancer therapies every 4 months until death, loss of follow-up, or withdrawal of consent, 
whichever comes first.
If a patient is lost to follow-up, every reasonable effort must be made by the study site 
personnel to contact the patient and determine the reason for discontinuation/withdrawal. The 
measures taken to follow up must be documented.
When a subject withdraws before completing the study, the reason for withdrawal is to be 
documented in the CRF and in the source document. Study drug assigned to the withdrawn 
subject may not be assigned to another subject. Subjects who withdraw will not be replaced. 
Data to be collected for the end of treatment visit are described in Section 8.7.  Patients will 
be followed for at least 28 days after the last dose of study drug. If a patient is withdrawn 
from treatment due to an adverse event, the patient will be followed until the adverse event 
has resolved or stabilized as per Section 9.2.
For information on subsequent therapy with abiraterone acetate see Section 8.10
11. PROTOCOL VIOLATIONS
A protocol violation occurs when the patient or Investigator fails to adhere to significant 
protocol requirements affecting the inclusion, exclusion, patient safety and primary endpoint 
criteria.  Protocol violations for this study include, but are not limited to, the following:

Failure to meet inclusion/exclusion criteria [no waivers will be granted to meet the 
eligibility criteria]

Use of a prohibited concomitant medication

Dose modifications that are not within the protocol specifications

Any other deviation that presents significant risk or safety concerns to the patient
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a protocol 
violation.  The Sponsor, in consultation with the Investigator, will determine if a protocol 
violation should result in withdrawal of a patient.
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12. DATA MONITORING COMMITTEE 
An Independent Data Monitoring Committee (IDMC) will be established to monitor data on 
an ongoing basis to ensure the safety of the subjects enrolled in this study. The committee 
will meet periodically to review interim safety data. After the review, the IDMC will make 
recommendations regarding the conduct of the study. The IDMC will serve as the primary 
reviewers of the efficacy analysis. Further details will be provided in a separate IDMC 
charter.
The IDMC will consist of at least 2 medical experts in the relevant therapeutic area and at 
least 1 statistician. The IDMC responsibilities, authorities, and procedures will be 
documented in the IDMC charter.
13. STATISTICAL METHODS AND CONSIDERATIONS
A detailed methodology for summary and statistical analyses of the data collected in this 
study will be documented in a Statistical Analysis Plan (SAP) that will be dated, version-
controlled and maintained by the Sponsor.  
13.1 ANALYSIS POPULATIONS
Full Analysis (Intent-to-Treat) Population [ITT]: All eligible patients who are randomized 
into the study, with study drug assignments designated according to initial randomization, 
regardless of whether patients receive study drug or receive a different drug from that to 
which they were randomized to will be included in the analyses of all efficacy and clinical 
benefit endpoints and patient characteristics.
Safety Analysis Population [SAFETY]: All patients who receive at least one dose of study 
drug, with treatment assignments designated according to actual study treatment received 
will be the primary population for evaluating safety and treatment compliance and 
administration.

Patient Report Outcomes Population [PRO]: Subset of the safety analysis 
population that has completed at least the baseline assessment (Cycle 1 Day 1) of
either FACT-P or EQ-5D questionnaires.

Population Pharmacokinetics Populations [PK]: Subset of the safety analysis 
population that was randomized to the apalutamide treatment arm and that has at least 
one PK sample collected.

Biomarker Population: Subset of the safety analysis populations that has at least 
1 biomarker sample collected.
13.2 EFFICACY ANALYSES
Efficacy analyses will be performed on the ITT population, incorporating the randomization 
stratification factors as documented on the CRF, unless otherwise specified.
Analyses of efficacy endpoints which are based on radiographic tumor assessments (MFS, 
PFS, and TTM) will be based on the results of the BICR.  Investigator assessments may be 
used for sensitivity analyses, as described in the Statistical Analysis Plan.
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Analysis of Primary Endpoint
13.2.1
The primary endpoint for the study is metastasis-free survival (MFS) which is defined as the 
time from randomization to first evidence of BICR-confirmed radiographically detectable 
bone or soft tissue distant metastasis (simply referred to as “metastasis” from this point 
forward) or death due to any cause (whichever occurs earlier) + 1 day.  
The MFS data for patients without metastasis or death will be censored on the date of the last 
tumor assessment (or, if no tumor assessment was performed after the baseline visit, at the 
date of randomization + 1 day). Additional censoring rules will vary according to whether 
the analysis is performed for US or ex-US regulatory purposes, as shown below; both results 
will be provided in the clinical study report.
Scenario
US regulatory guidance
ex-US regulatory 
guidance1
Data from patients who are 
lost to follow-up or whose 
disease progression 
(development of metastasis) 
or death occurs after 2 or 
more consecutively missing 
or unevaluable tumor 
assessments
Censored on the date of the 
last tumor assessment that 
the patient was known to be 
metastasis-free
Time of progression will be 
determined using the first 
date when there is 
documented evidence of 
progression or death 
(whichever occurs earlier) 
regardless of missed or 
unevaluable tumor 
assessments
Patients that receive new 
systemic anti-cancer therapy 
prior to documented disease 
progression (development of 
metastasis) or death
Censored on the date of the 
last tumor assessment prior 
to the start of the new 
systemic anti-cancer therapy
Time of progression will be 
determined using the first 
date when there is 
documented evidence of 
progression or death 
(whichever occurs earlier) 
regardless of change of 
therapy
The primary efficacy analysis will be completed when approximately 372 MFS events have 
occurred.  The primary analysis will compare the MFS distributions in the two treatment 
arms using a two-sided log-rank test, stratified by PSADT (> 6 months vs. ≤ 6 months), the 
use of a bone-sparing agent (Yes vs. No), and the presence of loco-regional disease (N0 vs. 
N1) at the 0.05 significance level. The unstratified log-rank test will be provided as a 
sensitivity analysis.  A complete list of sensitivity analyses is provided in the Statistical 
Analysis Plan.
Kaplan-Meier methods will be used to estimate median MFS for each treatment arm.  Cox 
proportional-hazard models, including the same factors as above, will be used to estimate the 
hazard ratio and its 95% confidence interval (CI). Additional analyses by formulation 
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subgroups will be performed for the MFS endpoint as described in the Statistical Analysis 
Plan. 
Analyses of Secondary Endpoints
13.2.2
For the secondary endpoints, a hierarchical testing will be performed in the following order: 

TTM

PFS

Time to symptomatic progression

OS

Time to initiation of cytotoxic chemotherapy
each at alpha=0.05 (2-sided). Each secondary endpoint will have a final analysis but there 
will be no interim analysis for TTM and PFS PFS. There will be 1 interim analysis for time 
to symptomatic progression, and up to 2 interim analyses for OS and time to initiation of 
cytotoxic chemotherapy. The testing of time to symptomatic progression, OS and time to 
initiation of cytotoxic chemotherapy endpoints will utilize an adaptive group sequential 
method, according to the pre-specified O’Brien-Fleming-type alpha spending function with 
possible re-estimation of the required number of events necessary for the next analysis to 
maintain the desired conditional power. If time to symptomatic progression is significant at 
the IA, then there will be only 1 interim analysis for OS and time to initiation of cytotoxic 
chemotherapy; otherwise there will be 2 interim analyses for OS and time to initiation of 
cytotoxic chemotherapy. 
The final analysis of TTM and PFS, interim analysis of time to symptomatic progression, and 
the first interim analysis of OS and time to initiation of cytotoxic chemotherapy will all be 
performed at the same time as the primary analysis of MFS (approximately 372 events). 
Full details about the adaptive group sequential testing procedure will be provided in the 
statistical analysis plan.
Time-to-event-based secondary endpoint analyses (TTM, PFS, time to symptomatic 
progression, OS, and time to initiation of cytotoxic chemotherapy) will be performed using a 
two-sided log-rank test, stratified by PSADT (> 6 months vs. ≤ 6 months), the use of a bone-
sparing agent (Yes vs. No), and the presence of loco-regional disease (N0 vs. N1).  
Unstratified log-rank tests will also be provided as sensitivity analyses.  
Kaplan-Meier methods will be used to estimate medians for each treatment arm.  Cox 
proportional-hazard models, including the same factors as above, will be used to estimate the 
hazard ratio and its 95% confidence interval (CI).  One year, 2-year, 3-year, and 5-year 
survival rates will be estimated using the Kaplan-Meier method.
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13.2.2.1 OS
Overall survival will be defined as the time from randomization to the date of death due to 
any cause + 1 day.  Patients who are alive at the time of the analysis will be censored on the 
last known date that they were alive.  In addition, the following censoring rules will apply:
Scenario
Date of Censoring
Patients with no post-baseline 
information
Censored on the date of randomization + 1 day
Patients who are lost to follow-up or 
who withdraw consent for further 
follow-up
Censored on the last known date that they were 
alive
Sensitivity Analysis: Patients that 
receive new systemic anti-cancer 
therapy 
Censored on the day before the start date of the 
new systemic anti-cancer therapy
13.2.2.2 Time to Symptomatic Progression
Time to symptomatic progression will be defined as the time from randomization to 
documentation in the CRF of any of the following (whichever occurs earlier) + 1 day: 

Development of a skeletal-related event (SRE): pathologic fracture, spinal cord 
compression, or need for surgical intervention or radiation therapy to the bone.

Pain progression or worsening of disease-related symptoms requiring initiation of a 
new systemic anti-cancer therapy.

Development of clinically significant symptoms due to loco-regional tumor 
progression requiring surgical intervention or radiation therapy.
Adverse event, concomitant medication, concomitant treatment, or survival follow-up CRFs 
will be the source of these findings.
Time to symptomatic progression for patients who do not experience any of the events 
described above will be censored on the date on which they were last known to be event-free.
13.2.2.3 Time to Initiation of Cytotoxic Chemotherapy
Time to initiation of cytotoxic chemotherapy will be defined as the time from randomization 
to documentation in the CRF of a new cytotoxic chemotherapy being administered to the 
patient (e.g., survival follow-up CRF) + 1 day.
Time to initiation of cytotoxic chemotherapy for patients who do not start cytotoxic 
chemotherapy will be censored on the date of last contact.
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13.2.2.4 Progression-Free Survival
In order to capture loco-regional disease progression, a secondary endpoint of progression-
free survival (PFS) will be assessed and defined as the time from randomization to first 
documentation of BICR-confirmed radiographic progressive disease or death due to any 
cause (whichever occurs first) + 1 day.
Progressive disease will be determined based on RECIST v1.1, and further defined as 
follows:

For patients with at least one measurable lesion, disease progression will be defined 
as at least a 20% increase in the sum of diameters of target lesions taking as reference 
the smallest sum on study (this includes the baseline sum if that is the smallest on 
study).  In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm.  Furthermore, the appearance of one or more new 
lesions is also considered progression.

For patients with only non-measurable disease observed on CT or MRI scans, 
unequivocal progression (representative of overall disease status change) or the 
appearance of one or more new lesions will be considered progression.  For new bone 
lesions detected on bone scans, a second imaging modality (e.g., CT or MRI) will be 
required to confirm progression.
Progression-free survival data for patients without loco-regional disease will be censored on 
the date of the last tumor assessment (or, if no tumor assessment was performed after the 
baseline visit, at the date of randomization + 1 day).  Additional censoring rules will vary 
according to whether the analysis is performed for US or ex-US regulatory purposes, as 
shown below; both results will be provided in the clinical study report.
Scenario
US regulatory guidance
ex-US regulatory guidance
Data from patients who are 
lost to follow-up or whose 
disease progression or death 
occurs after 2 or more 
consecutively missing or 
unevaluable tumor 
assessments
Censored on the date of the 
last tumor assessment that 
the patient was known to be 
progression-free
Time of progression will be 
determined using the first 
date when there is 
documented evidence of 
progression or death 
(whichever occurs earlier) 
regardless of missed or 
unevaluable tumor 
assessments
Patients that receive new 
systemic anti-cancer therapy 
prior to documented disease 
progression or death
Censored on the date of the 
last tumor assessment prior 
to the start of the new 
systemic anti-cancer therapy
Time of progression will be 
determined using the first 
date when there is 
documented evidence of 
progression or death 
(whichever occurs earlier) 
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regardless of change of 
therapy
13.2.2.5 Time to Metastasis
Time to metastasis will be defined as the time from randomization to first evidence of 
BICR-confirmed radiographically detectable bone or soft tissue distant metastasis (simply 
referred to as “metastasis” from this point forward) + 1 day.  
Time to metastasis data for patients without metastasis will be censored on the date of the last 
tumor assessment (or, if no tumor assessment was performed after the baseline visit, at the 
date of randomization + 1 day).  Additional censoring rules will vary according to whether 
the analysis is performed for US or ex-US regulatory purposes, as shown below; both results 
will be provided in the clinical study report.
Scenario
US regulatory guidance
ex-US regulatory guidance
Data from patients who are 
lost to follow-up or whose 
disease progression 
(development of metastasis) 
occurs after 2 or more 
consecutively missing or 
unevaluable tumor 
assessments
Censored on the date of the 
last tumor assessment that 
the patient was known to be 
metastasis-free
Time of progression will be 
determined using the first 
date when there is 
documented evidence of 
progression regardless of 
missed or unevaluable 
tumor assessments
Patients that receive new 
systemic anti-cancer therapy 
prior to documented disease 
progression (development of 
metastasis)
Censored on the date of the 
last tumor assessment prior 
to the start of the new 
systemic anti-cancer therapy
Time of progression will be 
determined using the first 
date when there is 
documented evidence of 
progression regardless of 
change of therapy
13.3 SAFETY EVALUATIONS
The SAFETY population will be the primary population for evaluating safety.
Analysis of Adverse Events
13.3.1
Adverse events (AEs) will be graded according to the NCI Common Terminology Criteria 
for Adverse Events (CTCAE) Version 4.0 and coded to preferred term and system organ 
class (SOC) using the most recent version of MedDRA. 
All AEs reported from the first dose of study drug until 28 days after the last dose of study 
drug will be considered as treatment-emergent AEs and will be summarized by treatment 
arm.
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For each treatment arm, adverse event incidence rates will be summarized with frequency 
and percentage by MedDRA SOC and preferred term, with all patients treated in that 
treatment arm as the denominator, unless otherwise specified.  In addition, AE incidence 
rates will also be summarized by severity and relationship to study drug.  Treatment-related 
AEs are those judged by the Investigator to be at least possibly related to the blinded study 
drug. Adverse events with missing severity or relationship to study drug will be classified as 
severe and treatment-related, respectively. Patients with multiple occurrences of events will 
only be counted once at the maximum severity to study drug for each preferred team, SOC, 
and overall. Deaths that occur within 28 days after the last dose of study drug are defined as 
on-study deaths.
Summary tables and individual patient listings will be prepared as per the Statistical Analysis 
Plan. An additional analysis by formulation subgroups will be performed as outlined in the 
Statistical Analysis Plan. 
Analysis of Clinical Laboratory Results
13.3.2
Only data collected by the central laboratory will be summarized.  Local laboratory data 
collected for the purposes of planning treatment administration, dose modification, or 
monitoring adverse events, will not be summarized.
Normal ranges will be used to identify values that are outside the normal ranges and 
abnormal laboratory results will be graded according to the NCI CTCAE Version 4.0. 
Descriptive statistics will be provided for each test result and for the change from baseline by 
visit.
A shift summary of baseline grade by maximum post-baseline CTCAE grade will be 
presented, as appropriate.  For each laboratory parameter, the baseline laboratory value will 
be defined as the last laboratory value collected on or prior to the first dose of study drug.
Patients who develop toxicities of Grade ≥3 will be summarized. Laboratory test results not 
having CTCAE grade will also be summarized.  Parameters that have criteria available for 
both low and high values (e.g., hypercalcaemia vs. hypocalcaemia) will be summarized for 
both criteria.  Patients will only be counted once for each criterion.
Analysis of Vital Signs
13.3.3
Each vital sign (temperature, blood pressure (systolic and diastolic), respiration rate, and 
heart rate) and respective change from baseline will be summarized and presented by 
treatment arm and study visit.  Patients with clinically significant abnormalities in vital signs 
as compared to baseline will be listed.
Concomitant Medications/Treatments
13.3.4
All medications and/or treatments received during the protocol Treatment Phase will be 
considered as concomitant medications and/or concomitant treatments and will be coded by 
WHO medical dictionary; patients who received concomitant medications and/or treatments 
will be listed.
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13.4 OTHER EVALUATIONS
Second Progression-free Survival (PFS2)
13.4.1
This endpoint is defined as the time from randomization to second documentation of
investigator-assessed disease progression (PSA, radiographic, symptomatic, or any 
combination) or death from any cause.
PSA
13.4.2
PSA kinetics (e.g., 12-week PSA response and time to PSA progression) will be assessed 
according to the Prostate Cancer Clinical Trials Working Group (PCWG2) 
recommendations.24
Summary tables and waterfall plots describing change in PSA relative to baseline will be 
reported at 12 weeks (or earlier for those who discontinue study treatment prior to 12 weeks), 
and separately, the maximum change at any time on study will also be reported for each 
patient using summary tables and waterfall plots.
The time to PSA progression will be calculated as the time from randomization to the time 
when the criteria for PSA progression according to PCWG2 are met + 1 day.  Kaplan-Meier 
methods will be used to estimate the median time to PSA progression and 95% confidence 
intervals for each treatment arm.
Health-Related Quality of Life and Prostate Cancer-Specific Symptoms Analysis
13.4.3
The FACT-P and EQ-5D data will be scored and handled as recommended in their respective 
User’s manuals, including handling of missing data both within the subscales and overall.  
All the analysis for FACT-P and EQ-5D data will be performed in the PRO population.
A 10-point change in the FACT-P total score is considered clinically meaningful. Therefore, 
any patient experiencing a 10-point decrement in FACT-P total scores from baseline will be 
considered to have experienced clinically meaningful deterioration in functional status.  The 
proportion of patients with at least a 10-point decrement in FACT-P total score will be 
summarized by treatment arm.  The decrement in the FACT-P total score between treatment 
arms will be compared using a Mantel-Haenszel test, stratified by PSADT (>6 months vs.≤6 
months), the use of a bone-sparing agent (Yes vs. No), and the presence of loco-regional 
disease (N0 vs. N1) at a two-sided 0.05 significance level.
The EQ-5D data will be summarized descriptively by treatment group and study visit.
Population Pharmacokinetics (Pop PK) Analysis
13.4.4
Population PK analysis will utilize patient covariates to identify sub-populations where 
possible; the effect of the formulations will also be explored in the covariate analysis.  The 
relationship of exposure to apalutamide and active metabolite (ARN000308) to measures of 
efficacy and adverse events will also be modeled to the extent possible.  The PK population 
will be the primary population used for population PK analysis, while placebo data will also 
be included for PK-efficacy or PK-adverse events analyses.
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Population analysis methods will be utilized as applicable. Population PK analysis of plasma 
concentration-time data of apalutamide will be performed using nonlinear mixed-effects 
modeling. The population PK analysis results will be presented in a separate report.
Exploratory Biomarkers Analysis
13.4.5
Blood and plasma samples will be collected at multiple time points and archived FFPE tumor
blocks or tumor slides may be analyzed for development of the F876L mutation (plasma) and 
for high risk features (FFPE tumor blocks or tumor slides) and associations may be made 
with clinical endpoints as follows. 

F876L mutation and other DNA mutations from cfDNA in plasma collected at Day 1 
of Cycles 1, 11, 17, 25, 37, and End-of-Treatment Visit.

AR splice variants or other RNA anomalies in cfRNA in blood collected at Day 1 of 
Cycles 1 and 11, and End-of-Treatment Visit.

Global mRNA expression levels in FFPE tumor blocks or tumor slides to identify 
expression levels of ‘high-risk’ classifier genes.
High-risk genomic classifiers may be evaluated if it can be used to identify a more 
homogeneous population of high-risk patients using appropriate categorical or regression 
methods.
The association of the rest of the biomarkers with clinical response or relevant survival 
endpoints may be assessed using appropriate statistical methods (e.g. analysis of variance 
[ANOVA], categorical or survival models), depending on the endpoints. Analyses may be 
performed within and between each treatment group. Other clinical covariates (such as 
baseline tumor characteristics and patient demographics) may also be included in the model. 
Correlation of baseline biomarker expression levels with clinical response or relevant 
time-to-event endpoints may be performed to identify responsive (or resistant) subgroups. 
Association of biomarkers with clinical response or relevant time-to-event endpoints will 
also be explored in the overall population to identify “high-risk” biomarker profiles that are 
correlated with poor outcome. Appropriate details of these exploratory analyses will be 
included in the statistical analysis plan. Results of these exploratory analyses will be 
presented in separate technical reports.
Assessment of Ventricular Repolarization
13.4.6
The assessment of ventricular repolarization will be a substudy conducted in a subset of 
patients from selected clinical sites and analyzed by an independent cardiac safety laboratory 
(Appendix 8).
Medical Resource Utilization Analysis 
13.4.7
Protocol-mandated procedures, tests, and encounters are excluded. The MRU data may be 
used to conduct economic analyses. 
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13.5 INTERIM ANALYSIS
There will be 1 interim analysis for time to symptomatic progression, and up to 2 interim 
analyses for OS and time to initiation of cytotoxic chemotherapy; see Section 13.2.2 for an 
outline of analysis methods.  
13.6 DETERMINATION OF SAMPLE SIZE
The primary efficacy analysis will be event-driven and will take place when approximately 
372 MFS events have occurred.  The study provides 90% power to detect a 30% reduction in 
the risk of developing metastases (HR = 0.70) for patients receiving apalutamide, with a 
2-sided α of 0.05.  Based on an assumed median MFS of 25 months in the placebo arm, this 
treatment effect represents an increase in the median MFS of approximately 11 months (from 
25 months to 36 months).  Assuming an accrual period of 24 months (with 75% of the 
patients accrued in the second year), approximately 1,200 patients will need to be enrolled.  
The study was also sized to provide 85% power to detect a 25% reduction (HR = 0.75) in the 
risk of death for patients receiving apalutamide, based on an assumed median OS of 49 
months in the placebo arm.  This treatment effect represents an increase in the median OS of 
approximately 16 months (from 49 to 65 months).  
14. DATA COLLECTION, RETENTION AND MONITORING
14.1 DATA COLLECTION INSTRUMENTS
The Investigator will prepare and maintain adequate and accurate source documents designed 
to record all observations and other pertinent data for each patient treated with the study 
drug. 
Study personnel at each site will enter data from source documents corresponding to a 
patient’s visit into the protocol-specific electronic case report form (eCRF) when the 
information corresponding to that visit is available.  Patients will not be identified by name in 
the study database or on any study documents to be collected by the Sponsor (or designee), 
but will be identified by a site number, patient number.
If a correction is required for an eCRF, the time and date stamps track the person entering or 
updating eCRF data and creates an electronic audit trail.  
The Investigator is responsible for reviewing all information collected on patients enrolled in 
this study for completeness and accuracy.  A copy of the eCRF will remain at the 
Investigator’s site at the completion of the study.
14.2 DATA MANAGEMENT PROCEDURES
The data will be entered into a validated database.  The Sponsor-designated data management 
group will be responsible for data processing, in accordance with procedural documentation.  
Database lock will occur once quality assurance procedures have been completed.
All procedures for the handling and analysis of data will be conducted using good computing 
practices meeting FDA guidelines for the handling and analysis of data for clinical trials.
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14.3 DATA QUALITY CONTROL AND REPORTING
After data have been entered into the study database, a system of computerized data 
validation checks will be implemented and applied to the database on a regular basis. Queries 
are entered, tracked, and resolved through the electronic data capture (EDC) system directly.  
The study database will be updated in accordance with the resolved queries.  All changes to 
the study database will be documented.
14.4 ARCHIVAL OF DATA
The database is safeguarded against unauthorized access by established security procedures;
appropriate backup copies of the database and related software files will be 
maintained. Databases are backed up by the database administrator in conjunction with any 
updates or changes to the database.
At critical junctures of the protocol (e.g., production of interim and final reports), data for 
analysis is locked and cleaned per established procedures.
14.5 AVAILABILITY AND RETENTION OF INVESTIGATIONAL RECORDS
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the 
Investigator agrees to keep records, including the identity of all participating subjects 
(sufficient information to link records, e.g., CRFs and hospital records), all original signed 
informed consent forms, copies of all CRFs, safety reporting forms, source documents, and 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (e.g., letters, meeting minutes, telephone calls reports).  The records should 
be retained by the Investigator according to ICH, local regulations, or as specified in the 
Clinical Trial Agreement, whichever is longer, but at a minimum, all study documentation 
must be retained for 2 years after the last marketing application approval in an ICH region or 
after at least 2 years have elapsed since formal discontinuation of clinical development of 
apalutamide.
If the Investigator becomes unable for any reason to continue to retain study records for the 
required period (e.g., retirement, relocation), the Sponsor should be prospectively notified.  
The study records must be transferred to a designee acceptable to the Sponsor, such as 
another investigator, another institution, or to the Sponsor itself.  The Investigator must 
obtain the Sponsor’s written permission before disposing of any records, even if retention 
requirements have been met.
14.6 MONITORING
Monitoring visits will be conducted by representatives of the Sponsor according to the US
CFR Title 21 Parts 50, 56, and 312 and ICH Guidelines for GCP (E6).  By signing this 
protocol, the Investigator grants permission to the Sponsor (or designee), and appropriate 
regulatory authorities to conduct on-site monitoring and/or auditing of all appropriate study 
documentation.
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14.7 PATIENT CONFIDENTIALITY
In order to maintain patient confidentiality, only a site number and patient number will 
identify all study patients on CRFs and other documentation submitted to the Sponsor.  
Additional patient confidentiality issues (if applicable) are covered in the Clinical Trial
Agreement.
Blood samples from approximately 400 patients and archived tumor samples (FFPE tumor 
blocks or tumor slides) from approximately 400 patients may be collected from consenting 
patients for scientific research where local regulations permit.
Long-term Storage of Samples for Future Research
Samples collected for biomarker assessments are planned to be stored until testing and for up 
to 15 years after the end of the study based on local regulations.
15. ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS
15.1 INVESTIGATOR RESPONSIBILITIES
The investigator is responsible for ensuring that the study is performed in accordance with 
current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and 
country-specific requirements.
Good clinical practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human subjects. 
Compliance with this standard provides public assurance that the rights, safety, and 
well-being of the study subjects are protected, consistent with the principles that originated in 
the Declaration of Helsinki, and that the study data are credible. 
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other 
records will be identified by a coded number.  All study records will be kept in a locked file 
cabinet and code sheets linking a patient’s name to a patient identification number will be 
stored separately in another locked file cabinet.  Clinical information will not be released 
without written permission of the patient, except as necessary for monitoring by the FDA.  
The Investigator must also comply with all applicable privacy regulations (e.g., Health 
Insurance Portability and Accountability Act of 1996, EU Data Protection Directive 
95/46/EC).
15.2 PROTOCOL AMENDMENTS
Any amendment to the protocol will be written by the Sponsor.  Protocol amendments cannot
be implemented without prior written IRB/IEC approval except as necessary to eliminate 
immediate safety hazards to patients.  A protocol amendment intended to eliminate an 
apparent immediate hazard to patients may be implemented immediately, provided the 
IRB/IECs are notified within five working days.
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15.3 INSTITUTIONAL REVIEW BOARDS AND INDEPENDENT ETHICS 
COMMITTEES
The protocol, Investigator’s Brochure, the consent forms, any information to be given to the 
patient (including patient recruitment materials) and relevant supporting information must be 
submitted to the IRB/IEC by the Investigator for review and approval before the study is 
initiated.  Any member of the IRB/IEC who is directly affiliated with this study as an 
Investigator or as site personnel must abstain from the IRB/IEC vote on the approval of the 
protocol.  The IRB/IECs unconditional approval statement will be transmitted by the 
Investigator to the Sponsor (or designee) prior to the shipment of study supplies to the site.  
This approval must refer to the study by exact protocol title and number and should identify 
the documents reviewed and the date of review.
Protocol and/or informed consent modifications or changes may not be initiated without prior 
written IRB/IEC approval except when necessary to eliminate immediate hazards to the 
patients or when the change(s) involves only logistical or administrative aspects of the study.  
Such modifications will be submitted to the IRB/IEC and written verification that the 
modification was submitted and subsequently approved should be obtained.  
Investigators are required to promptly report to their respective IRB/IEC all unanticipated 
problems involving risk to human patients.  Some IRBs/IECs may want prompt notification 
of all SAEs, whereas others require notification only about events that are serious, assessed 
to be related to study treatment, and are unexpected.  Investigators may receive written IND 
safety reports or other safety-related communications from the Sponsor.  Investigators are 
responsible for ensuring that such reports are reviewed and processed in accordance with 
regulatory requirements and with the policies and procedures established by their IRB/IEC 
and archived in the site’s study file. 
Finally, the Investigator will keep the IRB/IEC informed as to the progress of the study, 
revisions to documents originally submitted for review, annual updates and/or request for re-
approvals, and when the study has been completed. 
15.4 INFORMED CONSENT FORM
Informed consent will be obtained in accordance with principles that originated in the 
Declaration of Helsinki, current ICH and GCP guidelines, applicable regulatory 
requirements, and Sponsor policy. 
The Sponsor’s master ICF will be provided to each site.  Sponsor or its designee must review 
and approve any proposed deviations from the master ICF or any alternate consent forms 
proposed by the site before IRB/IEC submission.  Patients must be re-consented to the most 
current version of the consent forms during their participation in the study.  The final 
IRB/IEC-approved consent forms must be provided to Sponsor for regulatory purposes.
The ICFs must be signed by the patient or the patient’s legal representative before his 
participation in the study.  The case history for each patient shall document the informed 
consent process and that written informed consent was obtained prior to participation in the 
study. A copy of each signed ICF must be provided to the patient or the patient’s legal 
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representative.  If applicable, it will be provided in a certified translation of the local 
language.
All signed and dated consent forms must remain in each patient’s study file and must be 
available for verification by study monitors at any time.
The ICF should be revised whenever there are changes to procedures outlined in the 
informed consent or when new information becomes available that may affect the willingness 
of the patient to participate.
For any updated or revised consent forms, the case history for each patient shall document 
the informed consent process and that written informed consent was obtained for the 
updated/revised consent form for continued participation in the study.  The final revised 
IRB/IEC-approved Informed Consent Form must be provided to Sponsor for regulatory 
purposes.
15.5 REPORTING OF SAFETY ISSUES AND SERIOUS BREACHES OF THE 
PROTOCOL OR ICH GCP
In the event of any prohibition or restriction imposed (i.e., clinical hold) by an applicable 
Competent Authority in any area of the World, or if the Investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the 
investigational product, the Sponsor should be informed immediately.  
In addition, the Investigator will inform the Sponsor immediately of any urgent safety 
measures taken by the Investigator to protect the study subjects against any immediate 
hazard, and of any serious breaches of this protocol or of ICH GCP that the Investigator
becomes aware of.
15.6 END OF TRIAL IN ALL PARTICIPATING COUNTRIES
Patients will remain on study treatment until BICR-confirmed disease progression, 
development of unacceptable toxicity, or withdrawal of consent.  Patients discontinuing 
study treatment will enter the Long-term Follow-up Phase and remain on study until death, 
loss of follow-up, or withdrawal of consent, whichever comes first.
With an estimated accrual duration of 24 months, it is assumed that patients are expected to 
be followed for a minimum of approximately 9 months beyond Last Patient In (LPI) for the 
primary endpoint of MFS, to approximately 41 months beyond LPI for the key secondary 
endpoint of OS.  This corresponds to total projected study duration of approximately 
65 months.
If the study is not terminated beforehand per the recommendation of the IDMC, the end of 
trial in all participating countries will be defined as the time at which the secondary endpoint 
of OS has been met.   
15.7 SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/IEC, drug safety problems, or at the discretion of the Sponsor.  
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In addition, the Sponsor retains the right to discontinue development of apalutamide at any 
time.
If a study is prematurely terminated or discontinued, the Sponsor will promptly notify the 
Investigator.  After notification, the Investigator must notify the respective IRB/IEC, and 
contact all participating subjects and the hospital pharmacy (if applicable) within a 4-week 
time period.  As directed by the Sponsor, all study materials must be collected and all CRFs 
completed to the greatest extent possible.
15.8 PUBLICATIONS 
Publication of study results is discussed in the Clinical Trial Agreement.  Details regarding 
production of manuscripts and conference presentations will adhere to the International 
Committee of Medical Journal Editors (ICMJE) requirements for authorship and 
contributorship.
http://www.icmje.org/ethical_1author.html
16. REFERENCES
1.
Appendix 1 to the guideline on the evaluation of anticancer medicinal products in man: Methodological 
consideration for using progression-free survival (PFS) or disease-free survival (DFS) in confirmatory 
trials. European Medicines Agency 2011; Doc. Ref. EMA/CHMP/27994/2008.
2.
Chen CD, Welsbie DS, Tran C, et al. Molecular determinants of resistance to antiandrogen therapy. Nat 
Med 2004;10:33-9. 
3.
Clegg N, Wongvipat J, Joseph J, et al. Discovery and development of ARN-509, a novel anti-androgen for 
the treatment of prostate cancer. Cancer Res 2012; 2:1-10. 
4.
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: revised 
RECIST guideline (version 1.1). Eur J Cancer  2009;45:228-47.
5.
Esper P, Mo F, Chodak G, et al. Measuring quality of life in men with prostate cancer using the Functional 
Assessment of Cancer Therapy-Prostate (FACT-P) instrument. Urology 1997;50(6):920-8.
6.
Foster WR, Car BD, Shi H, et al. Drug safety is a barrier to the discovery and development of new 
androgen receptor antagonists. Prostate 2011;71:480-8.  
7.
Freedland SJ, Humphreys EB, Mangold LA, et al. Risk of prostate cancer-specific mortality following 
biochemical recurrence after radical prostatectomy. JAMA 2005;294:433-439. 
8.
Freedland SJ, Humphreys EB, Mangold LA, 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;25:1765-71. 
9.
Jemal A, Bray F, Center MM, et al. Global cancer statistics. Ca Cancer J Clin 2011;61:69-90.
10.
Joseph JD, Lu N, Qian J, et al., A clinically relevant androgen receptor mutation confers resistance to 2nd 
generation anti-androgens enzalutamide and ARN-509. Cancer Disc 2013;3:1020-1029. 
11.
Kelly WK, Slovin S, Scher HI. Steroid hormone withdrawal syndromes: pathophysiology and clinical 
significance.  Urol Clin North Am 1997;24:421-33.
12.
Korpal M, Korn JM, Gao X, et al. An F876L mutation in the androgen receptor confers genetic and 
phenotypic resistance to MDV3100 (enzalutamide). Cancer Disc 2013;3:1030-1043.
13.
Li Y, Chan SC, Brand LJ, et al. Androgen receptor splice variants mediate enzalutamide resistance in 
castration-resistant prostate cancer cell lines. Cancer Res 2013;73:483-489. 
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14.
National Comprehensive Cancer Network (NCCN) Practice Guidelines in Oncology – v.1.2010. 
15.
Norgaard M, Jensen AO, Jacobsen JB et al. Skeletal related events, bone metastasis and survival of 
prostate cancer: a population-based cohort study in Denmark (1999 to 2007). J Urol 2010;184:162-67. 
16.
Pinover WH, Horwitz EM, Hanlon AL et al. Validation of a Treatment Policy for Patients with Prostate 
Specific Antigen Failure after Three-Dimensional Conformal Prostate Radiation Therapy. Cancer 
2003;97:1127-33. 
17.
Pound CR, Partin AW, Eisenberger MA, et al. Natural history of progression after PSA elevation 
following radical prostatectomy. JAMA 1999;281:1591-7.
18.
Rathkopf D, Liu G, Carducci MA, et al. Phase I dose-escalation study of the novel antiandrogen BMD-
641988 in patients with castration-resistant prostate cancer. Clin Cancer Res 2011;17:880-7.
19.
Rathkopf DE, Morris MJ, Fox JJ et al. Phase I study of ARN-509, a novel antiandrogen, in the treatment 
of castration-resistant prostate cancer. J Clin Oncol 2013;31:3525-3530.
20.
Rathkopf DE, Antonarakis ES, Shore ND, et al. ARN-509 in men with metastatic castration-resistant 
prostate cancer. J Clin Oncol 2013;31(suppl 6; abstact 48). 
21.
Ray ME, Bae K, Hussain MH et al. Potential surrogate endpoints for prostate cancer survival: Analysis of 
a Phase III randomized trial. J Natl Cancer Inst 2009;101:228-236. 
22.
Sathiakumar N, Delzell E, Morrisey MA et al. Mortality following bone metastasis and skeletal-related 
events among men with prostate cancer: a population-based analysis of U.S. Medicare beneficiaries, 
1999-2006. Prostate Cancer Prostat Dis 2011;14:177-83.
23.
Scher HI, Sawyers CL.  Biology of progressive, castration-resistant prostate cancer: directed therapies 
targeting the androgen-receptor signaling axis.  J Clin Oncol  2005; 23:8253-61. 
24.
Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical trials for patients with progressive 
prostate cancer and castrate levels of testosterone: recommendations of the prostate cancer clinical trials 
working group. J Clin Oncol  2008;26:1148-59.
25.
Smith MR, Kabbinavar F, Saad F, et al. Natural history of rising serum prostate-specific antigen in men 
with castrate nonmetastatic prostate cancer. J Clin Oncol 2005;23:2918-25.
26.
Smith MR, Cook R, Lee KA, Nelson JB. Disease and host characteristics as predictors of time to first bone 
metastasis and death in men with progressive castration-resistant nonmetastatic prostate cancer. Cancer 
2011;117:2077-85.
27.
Smith MR, Saad F, Coleman R, et al. Denosumab and bone-metastasis-free survival in men with 
castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet  
2012;379:39-46.
28.
Smith M, Antonarakis ES, Ryan CJ, et al. ARN-509 in men with high-risk non-metastatic castration-
resistant prostate cancer (CRPC). J Clin Oncol 2013;31(suppl 6, abstract 7).
29.
Stephenson AJ, Kattan MW, Eastham JA, et al. Defining biochemical recurrence of prostate cancer after 
radical prostatectomy: a proposal for a standardized definition. J Clin Oncol 2005;23:8253-61.
30.
The EuroQol Group. EuroQol-a new facility for the measurement of health-related quality of life. Health 
Policy 1990;16:199-208.
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17. APPENDICES
Appendix 1
Schedule of Activities
Appendix 2
Required Laboratory Tests
Appendix 3
ECOG Performance Status
Appendix 4
National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE)
Appendix 5
Prohibited or Restricted Medications or Supplements While On Study
Appendix 6
FACT-P Questionnaire
Appendix 7
EQ-5D
Appendix 8
Ventricular Repolarization Substudy at Selected Sites
Appendix 9
Anticipated Events
Appendix 10
Crossover to Open Label Apalutamide After Study Unblinding
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Footnotes
1.
Prescreening: Prior to study entry, additional PSA evaluations may be necessary to determine eligibility.  This Prescreening Phase is optional; please also refer to prescreen 
informed consent.
2.
End-of-Treatment: These assessments do not need to be completed if they have been performed within 1 week of the last dose of study drug (Exception: within the last 8 weeks 
for tumor assessments and 2 weeks for PROs, respectively).
3.
Safety Follow-Up: Patients should be evaluated for safety up to 28 days after the last dose of study drug.  All AEs should be followed to their resolution, until the Investigator 
assesses them as stable, irreversible, or until the patient is lost to follow-up, whichever comes first.  If a patient begins a new systemic anti-cancer therapy, the AE reporting 
period for non-SAEs ends at the time the new treatment is started. Serious adverse events will be collected during treatment with abiraterone acetate (as first subsequent 
therapy). Note: See Section 8.10 for additional details. Treatment with abiraterone acetate does not apply in Japan. 
4.
Long-term Follow-up: Obtain survival status, collect information of development of symptomatic progression, initiation of any new systemic anti-cancer therapies, and 
progression on first subsequent therapy (every 4 months via clinic visit, telephone contact or an alternative contact method per institution policy/practice). The FACT-P and EQ-5D 
questionnaires will be collected up to 12 months post-progression (see also Footnote 21). In addition, if patients discontinued study treatment prior to documented disease 
progression, obtain CT of the chest, abdomen, and pelvis, plus bone scan and submit for BICR to evaluate for disease progression (every 16 weeks ±7 days), until documentation 
of disease progression).
5.
Medical/Oncological History: Includes oncologic history, demographics, history of other disease processes (active or resolved) and concomitant illnesses. 
6.
Study Randomization:  The Cycle 1 Day 1 visit can occur on the same day or within 4 days of randomization.  Patient number and treatment assignment will be obtained via 
centralized randomization through the IVRS.  PSADT will be calculated by the IVRS to ensure correct patient stratification.
7.
Apalutamide/Matched Placebo:  Patients will receive oral daily apalutamide or matched placebo continuously, starting on Cycle 1 Day 1. One cycle consists of 28 days.
8.
Study Drug Compliance:  Apalutamide and placebo bottle(s) including any unused tablets/capsules will be returned at the beginning of every cycle starting at Cycle 2 Day 1 and 
at end of treatment for drug accountability.
9.
Samples for Hematology, Blood Chemistry: All laboratory assessments will be performed by a central laboratory. PSA results will be kept blinded until the analysis of the 
primary endpoint.  On Cycle 1 Day 1 only, clinical laboratory tests do not need to be repeated if the Screening tests were done within 4 days of Cycle 1 Day 1.  Sites may perform 
additional local hematology and/or blood chemistry assays for the purposes of planning treatment administration, dose modification, or monitoring adverse events.  
10.
Samples for PSA: Optional prescreening PSA evaluations will be performed by local laboratories. All other PSA valuations will be collected by the central laboratory; patients and 
investigators will be kept blinded until the analysis of the primary endpoint. On Cycle 1 Day 1 only, the PSA evaluation does not need to be repeated if the Screening tests were 
done within 4 days of Cycle 1 Day 1. For all subjects, at the time of unblinding and crossover, PSA data submitted to the central laboratory will no longer be blinded.
11.
Samples for TSH, fasting lipid panel, and testosterone: All laboratory assessments will be performed by a central laboratory every 16 weeks (±2 days) from Cycle 1 Day 1.  
On Cycle 1 Day 1 only, clinical laboratory tests do not need to be repeated if the Screening tests were done within 4 days of Cycle 1 Day 1.  Sites may perform additional local 
assays for the purposes of planning treatment administration, dose modification, or monitoring adverse events. See Appendix 2 for details on additional testing if TSH is 
abnormal.
12.
Brain Imaging: CT (or MRI, if use of contrast agent is contraindicated) scan of the brain will be performed at Screening and submitted for BICR to confirm patient elig bility 
(absence of brain metastasis).
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13.
Tumor Imaging: CT scans of chest, abdomen, and pelvis plus bone scan will be performed at Screening (scans obtained prior to signing informed consent will be allowed 
provided the timing of the scans fall within the Screening window). Scans must be submitted for BICR to confirm patient elig bility. During treatment, CT scans of chest, abdomen 
and pelvis plus bone scan will be performed to assess disease status every 16 weeks (±7 days) from Cycle 1 Day 1, or whenever disease progression is suspected, and at the 
end of treatment.  Note that tumor imaging should continue on this calendar schedule regardless of any delays in dosing.  Patients who have a contraindication to IV contrast may 
have MRI exams of the brain, abdomen, and pelvis performed in lieu of CTs and a non-contrast CT of the chest. All scans will be submitted for blinded independent central review 
to confirm patient eligibility and assess for disease progression on study. Subjects who discontinue treatment before documented disease progression should continue with 
disease assessments during Long-term Follow-up every 16 weeks (±7 days) until disease progression (see also Footnote 4). For all subjects, at the time of unblinding and 
crossover, radiographic scans will no longer be to be submitted for blinded central independent review. Subjects will be followed for progression per Investigator decision 
including symptoms, radiographic scans or PSA.
14.
Progression on First Subsequent Therapy: The date of progression on first subsequent therapy as assessed by the investigator and method of assessment of disease 
progression (radiographic, PSA, or both) will be collected.
15.
Physical Examination:  At Screening, a complete physical examination of major body systems, including known and suspected sites of disease, should be performed.  During 
subsequent visits, either a full or abbreviated physical exam will be performed.  New abnormal physical exam findings must be documented and followed by a physician or other 
qualified staff at the next scheduled visit. Height will be recorded at Screening only.  Body weight will be recorded at Screening and at every scheduled visit during treatment and 
at the end of treatment. 
16.
Vital Signs: Body temperature, blood pressure, pulse and respiratory rate will be performed after resting for 5 minutes at Screening and every scheduled visit during treatment 
and at the end of treatment.
17.
ECG: A standard 12-lead ECG will be collected at Screening and as clinically indicated.  For patients on QTcF substudy, please refer to Appendix 8 for instructions on obtaining 
a screening ECG.
18.
Adverse Events: During this Prescreening Phase, the SAE reporting would be limited to SAEs related to the PSA blood draws. 
19.
Concomitant Medications/Treatments: Concomitant medications and/or treatments will be recorded during the 28-day Screening Phase (prior to the start of study treatment), 
during the study, and up to 28 days post the last dose of study treatment.
20.
PK Samples for Population PK Analyses: The Day 1 Cycle 1 sample will be collected between 0.5 and 4 hours postdose. All samples on Day 1 of the other cycles will be 
collected prior to study drug administration, see Section 8.4).  Record the time for the doses administered on the 2 days preceding the PK sample day and whether the dose was 
administered on a once daily or twice daily schedule. No sparse PK samples will be collected from patients participating in the ventricular repolarization study (see Appendix 8).
For all subjects, at the time of unblinding and crossover, PK samples will no longer need to be collected at the time of unblinding.
21.
FACT-P and EQ-5D questionnaires: Patients will complete the FACT-P and EQ-5D at the clinic during the Treatment Phase PRIOR to any other clinical activity. During 
Long-term Follow-up contact every 4 months via clinic visit or an alternative contact method per institution policy/practice up to 12 months post-progression.
22.
Biomarker samples: Archived FFPE tumor samples or tumor slides will be requested from a subset of approximately 400 patients and can be submitted at any time after Cycle 1 
Day 1. Blood samples, 12.5 mL (on Day 1 of Cycles 1, 11 and end of treatment) and 10 mL (on Day 1 of Cycles 17, 25, and 37) will be collected prior to study drug administration 
from a subset of approximately 400 patients. Samples should be frozen and sent to the central laboratory.
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APPENDIX 3:
ECOG PERFORMANCE STATUS GRADES
0
Fully active, able to carry on all pre-disease activities without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light house work or office work
2
Ambulatory and capable of all selfcare but unable to carry out any work activities.  
Up and about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours
4
Completely disabled.  Cannot carry on any selfcare.  Totally confined to bed or chair
5
Dead
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APPENDIX 4:
NATIONAL CANCER INSTITUTE (NCI) COMMON 
TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (CTCAE)
The NCI CTCAE (Version 4.0) may be reviewed on-line at the following NCI website:
http://ctep.cancer.gov/reporting/ctc.html
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APPENDIX 5:
PROHIBITED OR RESTRICTED MEDICATIONS OR 
SUPPLEMENTS WHILE ON STUDY
Medications that are PROHIBITED while on study:

Aminophylline/theophylline

Atypical antipsychotics (e.g., clozapine, olanzapine, risperidone, ziprasidone)

Buproprion

Lithium

Meperidine and pethidine

Phenothiazine antipsychotics (e.g., chlorpromazine, mesoridazine, thioridazine)

Tricyclic and tetracyclic antidepressants (e.g., amitriptyline, desipramine, doxepin, 
imipramine, maprotiline, mirtazapine)
Supplements that are RESTRICTED while on study:

Pomegranate
Medications that are RESTRICTED while on study: 
Investigators should refer to the apalutamide Investigator’s Brochure (Sections 4.3.3.3 and 
5.10) and associated addenda for complete details on the drug interaction potential of 
apalutamide. Highlights of drug interaction are summarized below.

Strong CYP3A4 inducers: the potential for drug-drug interactions with apalutamide has 
not been tested clinically. Strong inducers of CYP3A4 (eg, phenytoin, carbamazepine, 
rifampin, rifabutin, rifapentine, phenobarbital, efavirenz, tipranavir, St. John's wort) 
should be avoided as much as possible.

Apalutamide may also induce CYP3A4; therefore, caution should be taken when 
administered in conjunction with CYP3A4 substrates that have a narrow therapeutic 
index 

Strong CYP2C8 inhibitors (eg, gemfibrozil) should be used with caution with 
apalutamide

The potential for drug-drug interaction between apalutamide and warfarin (e.g., 
Coumadin) is unknown at present. If a patient is taking warfarin, re-assess (prothrombin) 
PT/(international normalized ratio) INR as clinically indicated and adjust the dose of 
warfarin accordingly.

Corticosteroids (Oral, IV, or IM): due to possible resistance mechanisms, which may be 
contributed by glucocorticoid receptor signaling, concurrent use of corticosteroids during 
the study is not recommended; short term use (≤ 4 weeks) will be allowed if clinically 
indicated, however, its use must be tapered off as soon as possible.
Additional Information on CYP450 Drug Interactions
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractio
nslabeling/ucm093664.htm
http://medicine.iupui.edu/clinpharm/ddis/table.aspx
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APPENDIX 6:
FACT-P QUESTIONNAIRE
Version 4, US English, Copyright 1987, 1997
COPYRIGHT MATERIAL
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COPYRIGHT INFORMATION
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APPENDIX 7:
EQ-5D
COPYRIGHT MATERIAL
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COPYRIGHT MATERIAL
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APPENDIX 8:
VENTRICULAR REPOLARIZATION SUBSTUDY AT SELECTED 
SITES
Study Objectives
To evaluate the effect of apalutamide on ventricular repolarization in a subset of patients 
from selected clinical sites:

The primary objective of this substudy is to evaluate whether apalutamide has a 
threshold pharmacologic effect on cardiac repolarization, as detected by changes in 
electrocardiogram (ECG) QT intervals corrected for heart rate by Fridericia’s 
correction method (QTcF)

The secondary objectives of this study substudy are as follows:
o
To investigate the effect of apalutamide on the following ECG parameters: PR, 
RR, QRS, QT, QTcB (Bazett’s correction method), and T-Wave morphology
o
To determine the relationship between the plasma concentrations of apalutamide
and metabolite ARN000308, and QT/QTc changes
Safety will be assessed as part of the main study. At the time of the analysis of this substudy, 
all safety data from the main study will be provided along with data specific to this subset of 
patients.  In particular, any cardiac-related adverse events will be summarized in both main 
study and substudy populations.
Study Design and Patient Population
The effect of apalutamide on ventricular repolarization will be centrally analyzed by a 
third-party cardiac safety laboratory in a subset of 100 patients enrolled at selected sites that 
will be participating in the main protocol.  Both apalutamide and placebo patients will be 
enrolled in a blinded manner as per the main protocol randomization criteria.  
The subset of 100 patients will undergo the same screening procedures as the main protocol 
in order to be randomized into the study, following the same Inclusion/Exclusion criteria as 
per Section 4 of the protocol, with the following additional enrollment criteria:
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Additional Inclusion Criteria
Additional Exclusion Criteria

Enrollment in the main study

Obtain separate informed 
consent for participation in the 
substudy

Must agree to fast at least 
3 hours prior to dose and 
continue fasting (except for 
approved snack) until 
completion of the 4 hour post 
dose assessments on 
Cycle 1 Day 1 and Cycle 3 
Day 1.

Heart rate outside of 50 to 100 beats/minute

QTcF > 480 msec, determined by central assessment

Diagnosed or suspected congenital long QT 
syndrome, or family history of congenital long QT 
syndrome or sudden death 

History of Mobitz II second degree or third degree 
heart block

Implantable pacemaker or automatic implantable 
cardioverter defibrillator

Complete Bundle Branch Block or ventricular 
conduction delay (QRS > 119 msec)

Chronic or persistent atrial arrhythmia, including 
atrial fibrillation and atrial flutter.

Concurrent therapy with medications known to 
prolong the QT interval and/or associated with TdP 
(Torsade de Pointes) arrhythmia [please refer to 
www.qtdrugs.org for the list of drugs to avoid]

Smokers and planned nicotine replacement therapy 
users
Note:  Sites will receive a notification report for any ECGs received above QTcF > 480msec.  
If patients do not qualify for the ventricular repolarization substudy, they can still participate 
in the main study provided they meet all other inclusion/exclusion criteria as per Section 4 of 
the protocol.
Patient Withdrawal: A patient may withdraw his consent to participate in the substudy at 
any time.  If a patient withdraws such consent, the Investigator should inform the Sponsor (or 
designee) in writing and document in the Investigator Site File.  The patient may continue 
participating in the main protocol.  
Rationale for the Study Design
This substudy has been designed to evaluate the potential of apalutamide to prolong the QTc 
interval in a subset of patients with high-risk, NM-CRPC participating in the main protocol,
Study ARN-509-003.  
In accordance with ICH E14 guideline, QT evaluation is now expected to be routine in 
oncology drug development, and a Thorough QT (TQT) study should be conducted, if 
possible.  In the case of apalutamide, in view of previous FDA advice and the observations to 
date that nonclinical (hERG and CV safety study) and clinical data (ECG collections in the 
Phase I/II Study ARN-509-001) suggest no apparent relationship between apalutamide and 
QT prolongation, an alternative design to the TQT study has been chosen.  In this substudy, 
changes in QT interval following drug administration will be evaluated relative to the 
baseline measurement.  
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Rationale for the ECG Collection Time Points and PK Sampling Schedule
ECG time points have been selected to match the expected PK profile of apalutamide and
metabolite (ARN000308).  The ECG time points have also been selected to explore a 
potential shift between exposure and effect on QT/QTc.
In order to assess the QT interval prior to exposure to apalutamide, baseline triplicate ECG 
assessments will be performed twice prior to first study drug administration on Cycle 1 
Day 1 (at hour -1 and hour 0 pre-dose).  A baseline PK sample will also be collected at the 
hour 0, immediately after the ECGs have been collected and just prior to the first dose of 
apalutamide or placebo.
Subsequently, the purpose of all other ECGs is to assess for potential prolongation of the QT 
interval and other ECG changes as a result of apalutamide administration, with ECG 
collection coinciding with PK measurements to establish correlations between ECG changes 
and drug exposure.  Triplicate ECGs, followed by blood samples for PK assessment, will be 
collected at 2 and 4 hours postdose on Cycle 1 Day 1 and Cycle 3 Day 1 (once steady-state 
can be assured). The 2- and 4-hour time points were selected because the oral plasma Tmax of 
apalutamide is generally between 2 and 4 hours post-dose. Although the primary metabolite 
of apalutamide (ARN000308) typically has a later Cmax than that of apalutamide (i.e., 6 to 12 
hours), the peak to trough fluctuation ratio of this metabolite in patient plasma was shown to 
be minimal (less than 120% for ARN000308).  Therefore, the potential for significant effects 
from this metabolite at later time points not assessed by ECG is deemed very small.
Methods
Digital 12-lead ECG equipment will be provided to each clinical site participating in this 
substudy by the central laboratory for the duration of the substudy.
ECGs should be collected after the patient has rested quietly and is awake in a fully supine 
(or semi-recumbent, if supine is not tolerated) position for 10 minutes, and prior to any blood 
collection.  For each patient the same position (e.g., supine or semi-recumbent) should be 
used for all ECGs collected. Starting on Cycle 1, Day 1, time point matched blood samples 
for PK analyses will be collected immediately following the collection of ECGs and before 
the collection of blood for all other clinical evaluations.  ECGs will be read by independent 
cardiologists from the central laboratory in a blinded manner and via single reader paradigm.
A detailed list of the required assessments is provided below.  All other assessments at the 
other time points will follow the main protocol as per the Schedule of Activities in 
Appendix 1.
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Schedule of Activities Specific to the Ventricular Repolarization Substudy:
Screening

Signed informed consent for participation in this substudy

Collect a set of triplicate 12-lead ECGs, 2 minutes apart (Holter Monitoring using 
a 12-lead ambulatory device)
Cycle 1, Day 1

One hour prior to administering the first dose of study drug, collect a set of 
triplicate 12-lead ECGs, 2 minutes apart

At time 0, just prior to administering the first dose of study drug, collect a second 
set of triplicate 12-lead ECGs, 2 minutes apart, and one blood sample for PK 
analysis

Administer study drug in clinic

At 2 and 4 hours postdose, collect a set of triplicate ECGs, 2 minutes apart, and 
1 blood sample for PK analysis for each time point, respectively.  
Cycle 3, Day 1 (Administer Study Drug in Clinic)

At time 0, just prior to administering the dose of study drug, collect a set of 
triplicate 12-lead ECGs, 2 minutes apart, and one blood sample for trough PK 
analysis 

Administer study drug in clinic

At 2 and 4 hours postdose, collect a set of triplicate ECGs, 2 minutes apart, and 
one blood sample for PK analysis for each time point, respectively
Table 1: Schedule of Events
Screening
Cycle 1, Day 1
Cycle 3, Day 1
Activities and 
Forms to be 
Completed 
Specific to the 
Subtudy Only:
-
Hour 
-1 
pre-
dose
Hour 
0 pre-
dose
2 
Hours 
post-
dose
4 
Hours 
post-
dose
Hour 
0 pre-
dose
2 
Hours 
post-
dose
4 
Hours 
post-
dose
Informed consent
X
Triplicate 12-lead 
ECG
X
X
X
X
X
X
X
X
PK samples*
X
X
X
X
X
X
*PK samples are to be collected immediately after each ECG. Sparse PK samples for the population PK 
analysis will not be collected for patients participating in this substudy. 
Statistical Methods
A detailed Statistical Analysis Plan will be prepared prior to the planned analyses.  
Two analyses will be performed: a primary analysis using the active treatment arm only, and 
a secondary analysis comparing the active and placebo arms, both accompanied by a 
pharmacokinetic/pharmacodynamics analysis.   
Standard ECG parameters will be determined for each ECG recording.  Corrected QTc 
intervals will be determined using Fridericia’s formula (QTcF) and Bazett’s formula (QTcB).  
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Changes in ECG intervals from baseline will be calculated.  Baseline will be defined as the 
mean of the values for the triplicate ECG measurements taken pre-dose on Cycle 1 Day 1 
(Hour -1 and Hour 0).  In addition, QTcFs will be categorized based on ICH E14 guidelines.  
Tables will present the number and percentage of patients meeting or exceeding the 
following categories:

QTc interval prolongation:
o
Absolute values > 450 to ≤480 msec
o
Absolute values > 480 to ≤500 msec
o
Absolute values > 500 msec

QTc interval change from baseline:
o
Increase from baseline > 30 to ≤60 msec
o
Increase from baseline > 60 msec
Pharmacokinetic/Pharmacodynamic analyses will be performed using data from all subjects 
who have ECG data from at least one time point following the first dose.  A linear modeling 
approach will be used to quantify the relationship (if any) between the plasma concentration 
of drug (apalutamide) and its principal metabolite (ARN000308), and the changes from 
baseline in the QTcF interval. 
Sample Size Determination
A sample size of at least 100 patients will ensure that at least 60 patients treated with 
apalutamide will be enrolled on the substudy and 60 patients will provide at least 98.7% 
power to detect a true effect of 10 milliseconds (msec) change from baseline considering 
only the active group. Details for the power calculation and statistical assumptions are 
provided below.
Criteria for a “negative” result
It is assumed that the FDA criterion for regarding the outcome as negative (i.e., no QT 
prolongation concerns) will be that the mean QTcF increase observed in the active group 
should be significantly lower than a threshold of 20 msec at all on-study time points.  
“Significantly lower” means that the upper one-sided 95% confidence limit should be below 
the threshold.  
For the primary analysis, the quantity of interest is the mean change from baseline (ΔQTcF).  
For the secondary analysis, the quantity of interest is the difference between the mean 
changes from baseline in the active and placebo groups (ΔΔQTcF), which should remove any 
fluctuations due to diurnal variation and/or changes due to time-on-study (e.g., disease 
progression).
Statistical Assumptions
The standard deviation of the change from baseline at each time point is assumed to be 
20 msec.  The magnitude of the true QTcF prolongation in the secondary analysis (i.e., the 
expected value of ΔΔQTcF) is taken as 5 msec.  For the primary analysis, an allowance 
should also be made for possible diurnal variation etc., so results are presented assuming the 
true value of ΔQTcF is 8 msec and 10 msec.
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The power calculations have been performed by looking at various possible sample sizes and 
deriving the resulting power for the analysis at a single time point.  However, in order for the 
study to be declared negative, the upper confidence limit has to be below the threshold at all 
on-study time points.  If the results at each on-study time point were uncorrelated, a power of 
about 98% at each individual on-study time point would be required to give an overall power 
(i.e., to achieve the desired result at all on-study time points) of 80%.  Similarly, a 99% 
power at each individual on-study time point would give an overall power of about 90%.  
However, some correlation between the time points is expected to be present, therefore, the 
goal is to aim for a power (for an individual time point) well in excess of 95% in order to 
achieve a reasonable overall power.
Power for the primary analysis: 
Results for sample sizes of 30 to 60 subjects are shown in Table 1.
Table 2: Power (%) for a change from baseline in the active group (at a single time point)
Sample size
Power (%)
True effect 8 msec
True effect 10 msec
30
95.0
86.3
40
98.4
93.5
50
99.5
97.1
60
99.9
98.7
Power for the secondary analysis (assuming a true effect of 5 msec): 
Results for sample sizes (placebo plus active) from 75 to 150 are shown in Table 2.
Table 3: Power (%) for comparing a change from baseline between two groups (at a single 
time point)
Sample size
Power (%)
Active
Placebo
50
25
92.2
60
30
95.6
80
40
98.7
100
50
99.6
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APPENDIX 9:
ANTICIPATED EVENTS
An anticipated event is an adverse event (serious or non-serious) that commonly occurs as a 
consequence of the underlying disease or condition under investigation (disease-related) or 
background regimen. For the purposes of this study, the following events will be considered 
anticipated events: 
Disease-specific Events
Cauda equina syndrome
Erectile dysfunction
Haematospermia
Haematuria
Incontinence
Nocturia
Painful ejaculation
Pathologic fracture
Pollakiuria
Spinal cord compression
Ureteral obstruction
Urethral obstruction
Urinary flow decreased
Urinary retention
Urinary tract obstruction
Urinary hesitation
Lymphoedema
PSA Increased
ADT-Related Events
Depression
Gynaecomastia
Hot flush
Libido decreased
Osteoporosis
Sexual dysfunction
Testicular atrophy
Reporting of Anticipated Events
All adverse events will be recorded in the CRF regardless of whether they are considered to be 
anticipated events and will be reported to the sponsor as described in Section 9.2. Any anticipated 
event that meets serious adverse event criteria will be reported to the sponsor within the appropriate 
timeline as described in Section 9.2.3. These anticipated events are exempt from expedited reporting 
as individual single cases to Health Authorities. (Note: Japan will not identify anticipated events for 
the Health Authorities). However if based on an aggregate review, it is determined that an anticipated 
event is possibly related to study drug, the sponsor will report these events in an expedited manner.
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Anticipated Event Review Committee (ARC)
An Anticipated Event Review Committee (ARC) will be established to perform reviews of pre-
specified anticipated events at an aggregate level. The ARC is a safety committee within the 
sponsor’s organization that is independent of the sponsor’s study team. The ARC will meet to aid in 
the recommendation to the sponsor’s study team as to whether there is a reasonable possibility that an 
anticipated event is related to the study drug.
Statistical Analysis
Details of statistical analysis of anticipated events, including the frequency of review and threshold to 
trigger an aggregate analysis of anticipated events will be provided in a separate Anticipated Events 
Safety Monitoring Plan (ASMP).
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APPENDIX 10: CROSSOVER TO OPEN LABEL APALUTAMIDE AFTER STUDY 
UNBLINDING
At the time the decision is made to unblind the study, investigators will be notified by the 
sponsor. Subjects randomized to placebo who are currently on study treatment will be offered 
treatment with open-label apalutamide at 240 mg/day.  
Subjects previously randomized to apalutamide will continue on protocol and follow the 
current schedule of activities (Appendix 1, with modifications below) and will be given 
open-label apalutamide. 
For subjects who crossover from placebo to apalutamide, radiographic scans will no longer 
be required for the study and submitted for blinded central independent review. Subjects will 
be followed for progression per Investigator decision including symptoms, radiographic 
scans or PSA. PSA data submitted to the central laboratory will no longer be blinded. In
addition, for all subjects, PK samples will no longer need to be collected at the time of 
unblinding.
Eligibility Criteria for Placebo Subjects to Crossover to Open Label Apalutamide
Subjects randomized to placebo must meet the criteria below to be eligible to crossover to 
open label apalutamide. The blood work for organ function criteria can be taken from the last 
study cycle evaluation prior to unblinding as long as not more than 2 months have elapsed 
between the last cycle evaluation and Cycle 1 Day 1 of the crossover phase.  
1a. Subject is willing and able to provide written informed consent to crossover to open-label 
apalutamide
2a. Subject has adequate organ function as defined by the following criteria:

Serum aspartate transaminase (AST; serum glutamic oxaloacetic transaminase 
[SGOT]) and serum alanine transaminase (ALT; serum glutamic pyruvic 
transaminase [SGPT]) 2.5 x upper limit of normal (ULN)

Total serum bilirubin ≤1.5 x ULN.  Total serum bilirubin >1.5 x ULN is allowed 
if Gilbert’s disease has been previously documented

Serum creatinine 2 x ULN

Absolute neutrophil count (ANC) 1500/L

Platelets 100,000/L

Hemoglobin 9.0 g/dL
3a. Subject has not received any other systemic therapy for non-metastastic castrate resistant 
prostate cancer other than blinded study drug and androgen deprivation therapy.
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4a. Subjects who have previously had an end of treatment visit and evidence of distant 
metastasis from the blinded independent central reviewer will not be eligible for open 
label apalutamide. 
5a. Subjects who had study treatment withheld for ≥28 consecutive days at the time of 
unblinding will need approval from the medical monitor to be eligible for crossover.
Study Procedures for Subjects Previously on Placebo Who Crossover
Subjects will start open-label apalutamide with Cycle 1 and will be evaluated every cycle for 
6 cycles, every other cycle for the next 6 cycles and then every 4 cycles thereafter. Refer to 
the Time and Events Schedule for placebo subjects who crossover to open-label apalutamide 
(Table 3).  See Section 7 for the description of study assessments in Table 3. 
Discontinuation Criteria for Subjects Who Crossover 
Subjects who discontinue open label apalutamide will continue in Long-Term Follow-up per 
Section 8.9.
If a subject meets criteria as defined in Section 10 of the protocol, apalutamide must be 
discontinued.
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Footnotes
1.
End-of-Treatment: These assessments do not need to be completed if they have been performed within 4 weeks of the last dose of study drug 
2.
Safety Follow-Up: Patients should be evaluated for safety up to 28 days after the last dose of study drug.  All AEs should be followed to their resolution, until the Investigator 
assesses them as stable, irreversible, or until the patient is lost to follow-up, whichever comes first.  If a patient begins a new systemic anti-cancer therapy, the AE reporting 
period for non-SAEs ends at the time the new treatment is started. 
3.
Long-term Follow-up: Obtain survival status, collect information of development of symptomatic progression, initiation of any new systemic anti-cancer therapies, and 
progression on first subsequent therapy (every 4 months via clinic visit, telephone contact or an alternative contact method per institution policy/practice). 
4.
Apalutamide: Patients will receive open—label oral daily apalutamide continuously; a cycle consists of 28 days.
5.
Study Drug Compliance:  Apalutamide bottle(s) including any unused tablets/capsules will be returned at the beginning of every cycle starting at Cycle 2 Day 1 and at end of 
treatment for drug accountability.
6.
Samples for Hematology, Blood Chemistry: All laboratory assessments will be performed by a central laboratory. On Cycle 1 Day 1 only, clinical laboratory tests do not need 
to be repeated if the Screening tests were done within 28 days of Cycle 1 Day 1.  Sites may perform additional local hematology and/or blood chemistry assays for the purposes 
of planning treatment administration, dose modification, or monitoring adverse events.  
7.
Samples for PSA, TSH, fasting lipid panel, and testosterone: These laboratory assessments will be performed by a central laboratory every 16 weeks.  On Cycle 1 Day 1 
only, clinical laboratory tests do not need to be repeated if the Screening tests were done within 28 days of Cycle 1 Day 1. Sites may perform additional local assays for the 
purposes of planning treatment administration, dose modification, or monitoring adverse events. See Appendix 2 for details on additional testing if TSH is abnormal.
8.
Progression on First Subsequent Therapy: The date of progression on first subsequent therapy as assessed by the investigator and method of assessment of disease 
progression (radiographic, PSA, or both) will be collected.
9.
Physical Examination:  At Screening, a complete physical examination of major body systems. During subsequent visits, either a full or abbreviated physical exam will be 
performed. New abnormal physical exam findings must be documented and followed by a physician or other qualified staff at the next scheduled visit.  Body weight will be 
recorded at Screening and at every scheduled visit during treatment and at the end of treatment. 
10.
Vital Signs: Body temperature, blood pressure, pulse and respiratory rate will be performed after resting for 5 minutes at every scheduled visit during treatment and at the end of 
treatment.
11.
FACT-P and EQ-5D questionnaires: Patients will complete the FACT-P and EQ-5D at the clinic PRIOR to any other clinical activity on Cycle 1 Day 1, then Day 1 of every 
Cycle up to Cycle 13, then Day 1 of every other cycle, and at the End-of-Treatment Visit. During survival follow-up contact every 4 months via clinic visit or telephone up to 12 
months post-progression
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