A Phase 3 Randomized, Placebo-controlled Double-blind Study of JNJ-56021927 in Combination With Abiraterone Acetate and Prednisone Versus Abiraterone Acetate and Prednisone in Subjects With Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer (mCRPC)
Phase: PHASE3
Conditions: Prostatic Neoplasms
Sponsor: Aragon Pharmaceuticals, Inc.

CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved, Date: 14 April 2020
Aragon Pharmaceuticals, Inc. *
Clinical Protocol
COVID-19 Appendix 1
A Phase 3 Randomized, Placebo-controlled Double-blind Study of JNJ-56021927 in 
Combination with Abiraterone Acetate and Prednisone Versus Abiraterone Acetate and 
Prednisone in Subjects with Chemotherapy-naïve Metastatic Castration-resistant Prostate 
Cancer (mCRPC)
Protocol 56021927PCR3001; Phase 3
ACIS
(ARN-509 Chemo-naïve Indicated Subjects)
JNJ-56021927 (apalutamide)
*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. Therefore, the legal entity acting
as the sponsor for Janssen Research & Development studies may vary, such as, but not limited to Janssen
Biotech, Inc.; Janssen Products, LP; Janssen-Cilag International NV; Janssen, Inc.
US sites of this study will be conducted under US Food & Drug Administration IND regulations 
(21 CFR Part 312).
EudraCT NUMBER: 2014-001718-25
Status:
Approved
Date:
14 April 2020
Prepared by:
Janssen Research & Development, LLC
EDMS number:
EDMS-RIM-33929, 1.0
THIS APPENDIX APPLIES TO ALL CURRENT AND APPROVED VERSIONS OF 
PROTOCOL 56021927PCR3001 (EDMS-ERI-81017110)
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential.
NCT02257736

COVID-19 Appendix 1
JNJ-56021927 (apalutamide)
Clinical Protocol 56021927PCR3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
2
Status: Approved,  Date: 14 April 2020
COVID-19 APPENDIX 1
GUIDANCE ON STUDY CONDUCT DURING THE COVID-19 PANDEMIC
This Appendix applies to all current versions of Protocol 56021927PCR3001.
It is recognized that the Coronavirus Disease 2019 (COVID-19) pandemic may have an impact on 
the conduct of this clinical study due to, for example, self-isolation/quarantine by subjects and 
study-site personnel; travel restrictions/limited access to public places, including hospitals; study 
site personnel being reassigned to critical tasks. 
In alignment with recent health authority guidance, the sponsor is providing options for study 
related subject management in the event of disruption to the conduct of the study. This guidance 
does not supersede any local or government requirements or the clinical judgement of the 
investigator to protect the health and well-being of subjects and site staff. If, at any time, a subject’s 
safety is considered to be at risk, study intervention will be discontinued, and study follow-up will 
be conducted.
Scheduled visits that cannot be conducted in person at the study site will be performed to the extent 
possible remotely/virtually or delayed until such time that on-site visits can be resumed. At each 
contact, subjects will be interviewed to collect safety data. Key efficacy endpoint assessments 
should be performed if required and as feasible. Subjects will also be questioned regarding general 
health status to fulfill any physical examination requirement. 
Every effort should be made to adhere to protocol-specified assessments for subjects on study 
intervention, including follow up. Modifications to protocol-required assessments may be 
permitted after consultation between the subject and investigator, and with the agreement of the 
sponsor. Missed assessments/visits will be captured in the clinical trial management system for 
protocol deviations. Discontinuations of study interventions and withdrawal from the study should 
be documented with the prefix “COVID-19-related” in the case report form (CRF). 
The sponsor will continue to monitor the conduct and progress of the clinical study, and any 
changes will be communicated to the sites and to the health authorities according to local guidance. 
If a subject has tested positive for COVID-19, the investigator should contact the sponsor’s 
responsible medical officer to discuss plans for study intervention and follow-up. Modifications 
made to the study conduct as a result of the COVID-19 pandemic should be summarized in the 
clinical study report.

COVID-19 Appendix 1
JNJ-56021927 (apalutamide)
Clinical Protocol 56021927PCR3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
3
Status: Approved,  Date: 14 April 2020
GUIDANCE SPECIFIC TO THIS PROTOCOL:

These emergency provisions are meant to ensure subject safety on study while site capabilities 
are compromised by COVID-19-related restrictions. As restrictions are lifted and the acute 
phase of the COVID-19 pandemic resolves, sites should revert to original protocol conduct as 
soon as feasible.

Study treatment should be continued if, in the assessment of the investigator, it does not result 
in risk to the subject. Remote medical consultation and alternatives to study medication 
dispensing, administration, and clinical safety laboratory assessments (including home health 
nursing) will allow continued study participation for subjects in this trial. If at any time a 
subject’s safety is considered to be at risk due to study treatment, study intervention will be 
temporarily or permanently discontinued, while every effort should be made to maintain 
follow-up on study.  

The benefit of continuing study treatment should be considered by the investigator for each 
individual subject, considering the potential impact of reduced direct clinical supervision on 
subject safety. A temporary interruption of study drugs might be considered based on 
investigator´s discretion and documented. 

Dispensing of study medication:
For subjects unable to visit the clinic/hospital, direct-to-patient (DTP) shipment or handover 
to a caregiver or delegate of oral study drugs may be implemented, where allowed per local 
regulations and if requested by the treating study physician. Where DTP shipments or 
handover to delegates are deemed necessary, the process must be coordinated between the site 
and sponsor staff following standard DTP procedures for arranging shipment and adhering to 
associated approvals and documentation requirements.
For subjects able to visit the clinic/hospital, but who request to reduce visit frequency or for 
who limited access to the site is expected, an additional supply of oral study drugs can be 
provided.

Dispensing and administration of NIMP:
For subjects unable to visit the clinic/hospital, alternatives to NIMP dispensing and 
administration (including specifically GnRH-analogues), home health nursing and application 
by a qualified person at subject´s home may be implemented, where allowed per local 
regulations and if requested by the treating study physician. Where DTP shipments of NIMP 
are deemed necessary, the process must be coordinated between the site and sponsor staff 
following standard DTP procedures for arranging shipment and adhering to associated 
approvals and documentation requirements. 

Delay of study procedures:
If study procedures cannot be performed per study protocol and are delayed, subjects should 
stay on the assigned treatment until these procedures can be performed, which may result in a 
prolongation of study treatment exposure. Investigators should inform the sponsor as soon as 
they become aware of any delays.

Central laboratory testing should be performed according to the current time and events 
schedule as outlined in the protocol under which the site is currently operating. If central 
laboratory tests cannot be performed, the use of a local laboratory is allowed for study 

COVID-19 Appendix 1
JNJ-56021927 (apalutamide)
Clinical Protocol 56021927PCR3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
4
Status: Approved,  Date: 14 April 2020
evaluations. A copy of the local laboratory report should be reviewed by the investigator and 
retained, along with reference ranges, for source documentation and captured in the CRF.

To safely maintain subjects on study treatment while site capabilities are compromised by 
COVID-19-related restrictions, subjects for whom there is no safety concern may have tele-
health visits (conducted via phone or video conversation as per local regulation) until such 
time that on-site visits can be resumed. Normal study procedures should be followed for the 
applicable visit as closely as possible. At each contact, subjects will be interviewed to collect 
safety data. Key efficacy endpoint assessments should be performed if required and as 
feasible. Subjects will also be questioned regarding general health status to fulfill any physical 
examination requirement. If required per protocol, ePRO information should be collected via 
phone or video conversation or by use of the provided electronic device (as applicable for the 
study and per local regulations).

If imaging cannot be performed at the site due to COVID-19 related restrictions, the use of 
local facilities close to the subject’s home is permitted, but provision of scans to the 
investigative site and central readers should be arranged by the investigator and documented 
if required according to the current time and events schedule. If imaging is not possible as 
outlined in time and events tables, missed imaging should be documented as a deviation 
related to COVID-19 and be made up as soon as possible. 

If a subject develops SARS-CoV-2 infection or related disease, the investigator should contact 
the sponsor to discuss plans for study intervention and follow-up. An interruption of study 
treatment should be considered by the investigator, depending on symptoms and concomitant 
medication used for the treatment of COVID-19. Treatment must be interrupted if prohibited 
medication is used. Standard Adverse Event/Serious Adverse Event reporting requirements 
apply. 

When a subject, for whom study treatment has been interrupted, recovers from suspected or 
confirmed SARS-CoV-2 infection or related disease and all toxicities improve to Grade ≤1, 
the investigator should discuss with sponsor about resuming study treatment.

Consenting and re-consenting of subjects will be performed as applicable for the measures 
taken (including also remote consenting by phone or video consultation) and according to 
local guidance for informed consent applicable during the COVID-19 pandemic.

COVID-19 Appendix 1
JNJ-56021927 (apalutamide)
Clinical Protocol 56021927PCR3001
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
5
Status: Approved,  Date: 14 April 2020
INVESTIGATOR AGREEMENT
PPD

1
Status: Approved, Date: 18 February 2020
Aragon Pharmaceuticals, Inc.*
Clinical Protocol
A Phase 3 Randomized, Placebo-controlled Double-blind Study of JNJ-56021927 in 
Combination with Abiraterone Acetate and Prednisone Versus Abiraterone Acetate and 
Prednisone in Subjects with Chemotherapy-naïve Metastatic Castration-resistant Prostate 
Cancer (mCRPC)
Protocol 56021927PCR3001; Phase 3
ACIS
(ARN-509 Chemo-naïve Indicated Subjects)
AMENDMENT 4
JNJ-56021927 (apalutamide)
*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. Therefore, the legal entity acting
as the sponsor for Janssen Research & Development studies may vary, such as, but not limited to Janssen
Biotech, Inc.; Janssen Products, LP; Janssen-Cilag International NV; Janssen, Inc.
This study will be conducted under US Food & Drug Administration IND regulations (21 CFR 
Part 312).
EudraCT NUMBER: 2014-001718-25
Status:
Approved
Date:
18 February 2020
Prepared by:
Janssen Research & Development, LLC
EDMS number:
EDMS-ERI-81017110; 7.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential.
NCT02257736

JNJ-56021927 (apalutamide)
Clinical Protocol 56021927PCR3001 – Amendment 4
2
Status: Approved, Date: 18 February 2020
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 4
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
PROTOCOL AMENDMENTS....................................................................................................................... 6
SYNOPSIS.................................................................................................................................................. 19
TIME AND EVENTS SCHEDULE .............................................................................................................. 25
ABBREVIATIONS ...................................................................................................................................... 30
1.
INTRODUCTION................................................................................................................................ 32
1.1.
Background .................................................................................................................................... 32
1.1.1.
Inhibition of CYP17 and Abiraterone Acetate............................................................................. 32
1.1.2.
Apalutamide................................................................................................................................ 33
1.2.
Control............................................................................................................................................ 35
1.3.
Overall Rationale for the Study...................................................................................................... 36
2.
OBJECTIVES AND HYPOTHESIS ................................................................................................... 37
2.1.
Objectives ...................................................................................................................................... 37
2.2.
Hypothesis ..................................................................................................................................... 38
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 38
3.1.
Overview of Study Design.............................................................................................................. 38
3.2.
Study Design Rationale.................................................................................................................. 40
4.
SUBJECT POPULATION.................................................................................................................. 42
4.1.
Inclusion Criteria ............................................................................................................................ 42
4.2.
Exclusion Criteria ........................................................................................................................... 43
4.3.
Prohibitions and Restrictions ......................................................................................................... 45
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 46
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 47
6.1.
ADT Administration ........................................................................................................................ 47
6.2.
Study Treatment Administration..................................................................................................... 47
6.2.1.
Special Dosing and Meal Instructions for PK Visits.................................................................... 48
6.3.
Dose Modification and Management of Toxicity............................................................................ 48
6.3.1.
Toxicity Attributed to Prednisone................................................................................................ 49
6.3.2.
Toxicity Attributed to Abiraterone Acetate .................................................................................. 49
6.3.2.1.
Abnormal Liver Function Test(s) ............................................................................................. 49
6.3.2.2.
Hypertension, Hypokalemia, and Fluid Retention/Edema Due to Mineralocorticoid 
Excess ..................................................................................................................................... 50
6.3.3.
Toxicity Attributed to Apalutamide/Placebo................................................................................ 51
7.
TREATMENT COMPLIANCE............................................................................................................ 52
8.
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 52
8.1.
Permitted Supportive Care Medications ........................................................................................ 53
8.2.
Prohibited Concomitant Medications ............................................................................................. 53
8.3.
Restricted Concomitant Medications ............................................................................................. 54
9.
STUDY EVALUATIONS .................................................................................................................... 55
9.1.
Study Procedures........................................................................................................................... 55

JNJ-56021927 (apalutamide)
Clinical Protocol 56021927PCR3001 – Amendment 4
3
Status: Approved, Date: 18 February 2020
9.1.1.
Overview..................................................................................................................................... 55
9.1.2.
Screening Phase ........................................................................................................................ 57
9.1.3.
Treatment Phase ........................................................................................................................ 57
9.1.4.
EOT Visit..................................................................................................................................... 58
9.1.5.
Follow-up Phase......................................................................................................................... 58
9.1.6.
After Study Unblinding................................................................................................................ 58
9.1.6.1.
Open-Label Extension Phase.................................................................................................. 59
9.1.6.2.
Long-Term Extension Phase With Limited Data Collection .................................................... 59
9.1.7.
Data Collection Following IDMC Recommendation to Unblind .................................................. 59
9.2.
Efficacy........................................................................................................................................... 59
9.2.1.
Evaluations ................................................................................................................................. 59
9.2.1.1.
Other Efficacy Evaluations ...................................................................................................... 59
9.2.1.2.
Efficacy Criteria ....................................................................................................................... 60
9.2.2.
Endpoints.................................................................................................................................... 60
9.3.
Population Pharmacokinetics......................................................................................................... 62
9.3.1.
Evaluations ................................................................................................................................. 62
9.3.2.
Analytical Procedures................................................................................................................. 62
9.4.
Biomarkers ..................................................................................................................................... 62
9.5.
Patient-reported Outcomes............................................................................................................ 62
9.6.
Medical Resource Utilization.......................................................................................................... 63
9.7.
Safety Evaluations ......................................................................................................................... 63
9.7.1.
Safety Assessments ................................................................................................................... 65
9.8.
Sample Collection and Handling.................................................................................................... 66
10.
SUBJECT COMPLETION/WITHDRAWAL....................................................................................... 66
10.1.
Completion ..................................................................................................................................... 66
10.2.
Discontinuation of Study Treatment............................................................................................... 66
10.3.
Withdrawal from the Study............................................................................................................. 67
11.
STATISTICAL METHODS................................................................................................................. 68
11.1.
Analysis Populations...................................................................................................................... 68
11.2.
Sample Size Determination ........................................................................................................... 68
11.3.
Efficacy Analyses ........................................................................................................................... 69
11.4.
Pharmacokinetic and Pharmacodynamic Analyses....................................................................... 70
11.5.
Biomarker Analyses ....................................................................................................................... 70
11.6.
Patient-reported Outcomes............................................................................................................ 71
11.7.
Medical Resource Utilization.......................................................................................................... 71
11.8.
Safety Analyses ............................................................................................................................. 71
11.9.
Interim Analyses............................................................................................................................. 72
11.10.
Futility Analyses ............................................................................................................................. 72
11.11.
Independent Data Monitoring Committee ...................................................................................... 72
12.
ADVERSE EVENT REPORTING ...................................................................................................... 73
12.1.
Definitions ...................................................................................................................................... 73
12.1.1.
Adverse Event Definitions and Classifications ........................................................................... 73
12.1.2.
Attribution Definitions.................................................................................................................. 74
12.1.3.
Severity Criteria .......................................................................................................................... 75
12.2.
Special Reporting Situations.......................................................................................................... 75
12.3.
Procedures..................................................................................................................................... 75
12.3.1.
All Adverse Events...................................................................................................................... 75
12.3.2.
Serious Adverse Events ............................................................................................................. 76
12.3.3.
Pregnancy................................................................................................................................... 77
12.4.
Contacting Sponsor Regarding Safety........................................................................................... 77
13.
PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 77
13.1.
Procedures..................................................................................................................................... 78
13.2.
Contacting Sponsor Regarding Product Quality ............................................................................ 78

JNJ-56021927 (apalutamide)
Clinical Protocol 56021927PCR3001 – Amendment 4
4
Status: Approved, Date: 18 February 2020
14.
STUDY DRUG INFORMATION......................................................................................................... 78
14.1.
Physical Description of Study Drug(s) ........................................................................................... 78
14.2.
Packaging ...................................................................................................................................... 78
14.3.
Labeling.......................................................................................................................................... 78
14.4.
Preparation, Handling, and Storage............................................................................................... 79
14.5.
Drug Accountability ........................................................................................................................ 79
15.
STUDY-SPECIFIC MATERIALS....................................................................................................... 80
16.
ETHICAL ASPECTS ......................................................................................................................... 80
16.1.
Study-Specific Design Considerations........................................................................................... 80
16.2.
Regulatory Ethics Compliance....................................................................................................... 81
16.2.1.
Investigator Responsibilities ....................................................................................................... 81
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................... 81
16.2.3.
Informed Consent ....................................................................................................................... 82
16.2.4.
Privacy of Personal Data ............................................................................................................ 83
16.2.5.
Country Selection ....................................................................................................................... 84
17.
ADMINISTRATIVE REQUIREMENTS .............................................................................................. 84
17.1.
Protocol Amendments.................................................................................................................... 84
17.2.
Regulatory Documentation ............................................................................................................ 85
17.2.1.
Regulatory Approval/Notification ................................................................................................ 85
17.2.2.
Required Prestudy Documentation............................................................................................. 85
17.3.
Subject Identification, Enrollment, and Screening Logs ................................................................ 86
17.4.
Source Documentation................................................................................................................... 86
17.5.
Case Report Form Completion ...................................................................................................... 86
17.6.
Data Quality Assurance/Quality Control ........................................................................................ 87
17.7.
Record Retention ........................................................................................................................... 87
17.8.
Monitoring ...................................................................................................................................... 88
17.9.
Study Completion/End-of-Study..................................................................................................... 88
17.9.1.
Study Completion ....................................................................................................................... 88
17.9.2.
End-of-Study............................................................................................................................... 88
17.10.
On-Site Audits ................................................................................................................................ 89
17.11.
Use of Information and Publication................................................................................................ 89
REFERENCES............................................................................................................................................ 91
INVESTIGATOR AGREEMENT ............................................................................................................... 120
LIST OF ATTACHMENTS
Attachment 1:
Summary of RECIST Criteria Version 1.1 ..................................................................... 93
Attachment 2:
ECOG Performance Status............................................................................................ 99
Attachment 3:
Prohibited Concomitant Medications Known to Lower the Seizure Threshold or 
Cause Seizures and Additional Information on CYP450 Drug Interactions ........................... 100
Attachment 4:
Sample BPI-SF ............................................................................................................ 101
Attachment 5:
Sample FACT-P........................................................................................................... 103
Attachment 6:
Sample EQ-5D-5L........................................................................................................ 106
Attachment 7:
Guidance Document for PCWG2 Criteria and RECIST 1.1......................................... 109
Attachment 8:
Anticipated Events ....................................................................................................... 111
Attachment 9:
Open-Label Extension in the Event of Subjects Being Offered Cross-over to 
Open-label Apalutamide in Combination With AAP After Study Unblinding........................... 113
Attachment 10:
Long-Term Extension in the Event of Limited Data Collection After Study 
Unblinding ............................................................................................................................... 117

JNJ-56021927 (apalutamide)
Clinical Protocol 56021927PCR3001 – Amendment 4
5
Status: Approved, Date: 18 February 2020
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1: 
Study Treatment Administration ............................................................................................... 47
Table 2: 
Schedule and Dosing Instructions for PK Sample Collection................................................... 48
Table 3: 
Dose Modifications for LFT Abnormalities Attributed to Abiraterone Acetate .......................... 50
Table 4: 
Dose Modifications for Hypokalemia Attributed to Abiraterone Acetate................................... 51
Table 5: 
Dose Modifications for Hypertension and Edema/Fluid Retention Attributed to 
Abiraterone Acetate .................................................................................................................. 51
Table 6: 
Dose Modifications for Toxicity Attributed to Apalutamide/Placebo ......................................... 52
Table 7:
Summary of Blood Volumes (mL) Per Visit .............................................................................. 56
Table 8: 
Study Treatment Administration for the Open-Label Extension Phase.................................. 114
Table 9:
Time and Events Schedule (Open-Label Extension; Subjects Cross-over to Open-
label Apalutamide in Combination With AAP After Study Unblinding) ................................... 116
Table 10:
Study Treatment Administration for the Long-Term Extension Phase ................................... 117
Table 11: Time and Events Schedule (Long-Term Extension With Limited Data Collection After 
Study Unblinding).................................................................................................................... 119
FIGURES
Figure 1:
PSA Response With AR Combination Therapy in mCRPC...................................................... 37
Figure 2:
Schematic Overview of the Study Until the Start of the Extension Phase (Open-Label 
Extension or Long-Term Extension) ......................................................................................... 39

JNJ-56021927 (apalutamide)
Clinical Protocol 56021927PCR3001 – Amendment 4
6
Status: Approved, Date: 18 February 2020
PROTOCOL AMENDMENTS
Protocol Version 
Issue Date
Original Protocol
29 August 2014
Amendment 1
17 November 2014
Amendment 2
04 August 2016
Amendment 3
30 January 2017
Amendment 4
18 February 2020
Amendments are listed beginning with the most recent amendment.
Amendment 4 (18 February 2020)
The overall reason for the amendment: The overall reason for the amendment is to allow for an Open-Label 
Extension Phase or Long-Term Extension Phase after unblinding the study at the planned final analysis.

If cross-over is offered, subjects randomized to placebo and AAP will be offered the option to cross-over to 
open-label apalutamide and AAP, and subjects randomized to apalutamide and AAP will have the option to 
continue on apalutamide and AAP as open-label treatment.

If cross-over is not recommended, subjects will enter the Long-Term Extension Phase with limited data 
collection. Subjects randomized to apalutamide and AAP will be offered the option to receive open-label 
AAP alone or to receive open-label apalutamide and AAP; subjects randomized to placebo and AAP will 
have the option to continue on open-label AAP alone.
In conjunction with the start of the Open-Label Extension Phase or Long-Term Extension Phase, and given the 
well-characterized and over-time consistent safety profiles of apalutamide and AAP, data collection will be 
limited, to lower the burden to subjects.
Applicable Section(s)
Description of Change(s)
Rationale: To provide detailed information for the Open-Label Extension Phase and the Long-Term Extension 
Phase.
Synopsis (Overview of Study 
Design);
3.1 Overview of Study Design;
9.1.1 Overview
Added text to include the Open-Label Extension Phase or Long-Term 
Extension Phase in the study design.
Referred to the new Attachment 9 and Attachment 10 for details of the 
Open-Label Extension Phase and Long-Term Extension Phase, 
respectively.
Revised the heading for Figure 2 to “Schematic Overview of the Study 
Until the Start of the Extension Phase (Open-Label Extension or Long-
Term Extension)”
9.1.6 After Study Unblinding (new 
subheading)
Provided information on options available after the study is unblinded.
9.1.6.1 Open-Label Extension
(new subheading)
Provided information on the Open-Label Extension Phase; details are 
provided in Attachment 9.
9.1.6.2 Long-Term Extension 
With Limited Data Collection 
(new subheading)
Provided information on the Long-Term Extension Phase with limited data 
collection; details are provided in Attachment 10.
Section 9.1.7 Data Collection 
Following IDMC 
Recommendation to Unblind
Deleted the existing details for data to be collected after the study is 
unblinded, and referred to Attachment 9 and Attachment 10 for details.

JNJ-56021927 (apalutamide)
Clinical Protocol 56021927PCR3001 – Amendment 4
7
Status: Approved, Date: 18 February 2020
Applicable Section(s)
Description of Change(s)
Attachment 9: Open-Label 
Extension in the Event of Subjects 
Being Offered Cross-over to 
Open-label Apalutamide in 
Combination With AAP After 
Study Unblinding (new 
attachment)
This attachment includes detailed information, including a Time and Events 
Schedule, for the Open-Label Extension Phase after study unblinding.
Attachment 10: Long-Term 
Extension in the Event of Limited 
Data Collection After Study 
Unblinding (new attachment)
This attachment includes detailed information, including a Time and Events 
Schedule, for the Long-Term Extension Phase with limited data collection 
after study unblinding.
Rationale: Revisions, updates, and clarifications were provided.
Section 8.3 Restricted 
Concomitant Medications
To provide updated information on restricted concomitant medications 
based on current knowledge, revisions were made to the list of restricted 
concomitant medications to reflect the most current information in the 
Investigator’s Brochure.
Section 11.1 Analysis Populations
Specified that for patient-reported outcomes (PROs), all time-to-event 
analyses will be based on the intent-to-treat (ITT) population.
Section 11.5 Biomarker Analyses
Revisions were made to text describing statistical power relating to 
biomarker analyses.
Attachment 8 (Anticipated Events)
Events that are included in efficacy endpoints for the study should not be 
included in the anticipated events list. Therefore, events that pertain to the 
endpoint of “Time to symptomatic skeletal-related event” (cauda equina 
syndrome, pathological fracture, and spinal cord compression) were 
deleted.
The review and reporting requirements for anticipated events were 
clarified. Specified that Japan will not identify anticipated events for the 
Health Authorities.
Revised “Anticipated Event Review Committee” (ARC) to “Safety 
Assessment Committee” (SAC).
Rationale: Minor errors and inconsistencies were noted.
Throughout the protocol
Minor errors and inconsistencies were revised, and grammatical, 
formatting, or spelling changes were made. Abbreviations and references 
were updated as needed.

JNJ-56021927 (apalutamide)
Clinical Protocol 56021927PCR3001 – Amendment 4
8
Status: Approved, Date: 18 February 2020
Amendment 3 (30 January 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 the amendment: Fracture was identified as a new adverse drug reaction for apalutamide, 
limited to the CRPC patient population. As such, the main reason for this amendment is to allow use of bone 
modifying agents (for preserving bone mineral density during cancer treatment as well as skeletal integrity in 
patients with bone metastasis) without restrictions (Investigator Brochure updated as well with this information and 
additional details).
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: Remove requirement for a subject to use a bone modifying agent only if he had been on a stable dose 
for at least 4 weeks prior to randomization. Of note, this change was made only in Section 8.1 (which governs use of 
medications during the treatment phase), but not to the Inclusion/Exclusion criteria, Section 4 (which applies to pre-
treatment/screening phase) because at the time of this amendment, the study is fully enrolled.
Section 8.1, Permitted 
Supportive Care 
Medications
Deleted text:
Bisphosphonates and denosumab for management of bone-related metastasis should be 
used according to their market authorized approved label and only if the subjects are on a 
stable dose for at least 4 weeks prior to randomization
Replaced with:
Bone modifying agents, including bisphosphonates and denosumab, should be used 
in accordance with label indications to help preserve bone mineral density during 
cancer treatment (including ADT) and skeletal integrity in subjects with bone 
metastasis.
Rationale: Included bullet regarding apalutamide’s potential to induce CYP3A4 (for consistency with the 
information provided in the IB).
Section 8.3, Restricted 
Concomitant 
Medications
Added:
Apalutamide may induce CYP3A4; therefore, caution should be taken when 
administered in conjunction with CYP3A4 substrates that have a narrow 
therapeutic index

JNJ-56021927 (apalutamide)
Clinical Protocol 56021927PCR3001 – Amendment 4
9
Status: Approved, Date: 18 February 2020
Applicable Section(s)
Description of Change(s)
Rationale: Correction to the disease evaluation on study as outlined in Attachment 7 from 2 cm in diameter to ≥2 
cm in greatest diameter
Attachment 7, 
Guidance Document 
for PCWG2 Criteria 
and RECIST 1.1
Disease Evaluation on Study

Soft tissue lesions (nodal and non-nodal: Use RECIST 1.1 with caveats)

Only report changes in lymph nodes that were ≥2 cm in greatest diameter at 
baseline
Rationale: Progression-free survival after first subsequent therapy (PFS2) was described in the statistical analysis 
plan but not in the protocol. 
Synopsis, Efficacy 
Evalutations/Endpoints; 
Time & Events 
Schedule; Section 9.1.5 
Follow-up Phase;
Section 9.2.2. 
Endpoints
Added a line to the T&E for collection of progression data on first subsequent therapy, 
added a statement to collect progression data on first subsequent therapy to 
Section 9.1.5, and added PFS2 as another endpoint in the efficacy evaluations section.
Rationale: Update JNJ-56021927 with apalutamide
Throughout synopsis 
and protocol
Replaced ‘JNJ-56021927’ (except in the title and in some aspects of the description of 
the drug) with ‘apalutamide.’
Amendment 2 (4 August 2016)
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 3 main reasons for this amendment are the following: 1) to 
incorporate a non-binding futility analysis based on radiographic progression-free survival (rPFS) per 
recommendation of the Independent Data Monitoring Committee (IDMC); 2) to provide flexibility regarding the 
timing of the primary analysis of rPFS relative to the timing of the analysis for overall survival (OS); and 3) to 
provide greater clarity for disease evaluations based on the Response Evaluation Criteria in Solid Tumors (RECIST) 
v 1.1 and the Prostate Cancer Working Group 2 (PCWG2) criteria.
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: Per recommendation from the IDMC a non-binding futility analysis based on rPFS is being incorporated.
Synopsis, Futility 
Analyses; 11.10 Futility 
Analyses
Added the following statement: In addition, a non-binding futility analysis on rPFS 
will be implemented after observing approximately 
% (
 events) of the total 
number of required 
 events.
Additional statement in Section 11.10: Details for each futility analysis will be 
provided in the statistical analysis plan.
C
CI
CC
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CC
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JNJ-56021927 (apalutamide)
Clinical Protocol 56021927PCR3001 – Amendment 4
10
Status: Approved, Date: 18 February 2020
Applicable Section(s)
Description of Change(s)
Rationale: To provide more flexibility for the timing of the primary rPFS analysis relative to the analysis of OS
11.3 Efficacy Analyses
Revised the current protocol wording:
The primary analysis of rPFS will be performed at the same time as the first interim 
analysis of OS.
Replaced with the following:
The final rPFS analysis will take place after approximately 
 events are observed. 
The timing of the first interim analysis of OS may occur at the same time as the final 
analysis of rPFS. Alternatively, the analyses may be performed at a different time if 
the number of death events needed for a valid interim analysis of OS would require 
a long delay in the analysis of the rPFS endpoint. The alpha-spending for the 
interim analysis of OS will be adjusted accordingly (see Section 11.9).
Rationale: In response to questions from investigators, a guidance document outlining the PCWG2 and RECIST 
v1.1 criteria for evaluation of disease progression, is being provided.
Attachment 1
Added reference to Scher 2008 publication (PCWG2 criteria)
Added Attachment 7
Attachment 7 includes detailed guidance on the PCWG2 criteria
9.2.1.2 Efficacy 
Criteria
Minor revisions were made for improved clarity. 
Rationale: Hepatotoxicity is an important identified risk while using abiraterone acetate; therefore additional 
monitoring (eg, LFT measurements) and drug modifications (eg, discontinuation) were added in the event of clinical 
signs or symptoms suggestive of hepatotoxicity. 
6.3.2 Toxicity 
Attributed to 
Abiraterone Acetate
Added the following: If clinical symptoms or signs suggestive of hepatotoxicity 
develop, serum transaminases, in particular serum ALT, should be measured 
immediately. If subjects develop severe hepatotoxicity (ALT 20 x ULN) anytime 
while on abiraterone acetate, subjects should be discontinued and not be re-treated 
with abiraterone acetate. 
Subjects who develop a concurrent elevation of ALT >3 X ULN and a total bilirubin 
>2 X ULN in the absence of biliary obstruction or other causes responsible for the 
concurrent elevation should be permanently discontinued from treatment with 
abiraterone acetate.
Rationale: Error corrected in Table 3
Table 3
Footnote a: Missing “total” (should be total bilirubin) when describing Grade 3 liver 
function test abnormalities.
Rationale: The measurement of TSH should be performed at the End-of-Treatment (EOT) visit
Time and Events 
Schedule; Table 7
A tickbox for TSH was added under the column EOT. Updated footnote b of Table 7 to 
include the EOT Visit. 
Rationale: The volumes in Table 7 were updated. The chemistry and PSA evaluations are measured from the same 
sample.
Table 7; 9.1.1 
Overview; 16.1 Study-
Specific Design 
Considerations; 
References
Updated the table and revised blood volumes accordingly. Revised the description of 
blood volumes in Section 9.1.1.
Removed the repeat of blood volumes in Section 16.1 and added the American Red Cross 
Reference. 
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I

JNJ-56021927 (apalutamide)
Clinical Protocol 56021927PCR3001 – Amendment 4
11
Status: Approved, Date: 18 February 2020
Applicable Section(s)
Description of Change(s)
Rationale: Subjects who discontinue study drug before radiographic progression will continue with imaging 
assessments during the Follow-up Phase according to the local standard of care. If available, collect information on 
imaging assessments until documentation of radiographic progression.
9.1.5 Follow-up Phase
Added the following: Subjects who discontinue study drug before radiographic 
progression will continue with imaging assessments during the Follow-up Phase 
according to the local standard of care. If available, collect information on imaging 
assessments until documentation of radiographic progression.
Time and Events 
Schedule
Added the following note: If available, collect information on imaging assessments 
until documentation of radiographic progression (see Sections 9.1.5 and 10.2)
Rationale: To provide additional guidance on discontinuation of treatment and collection of the reason for 
discontinuation. 
10.2 Discontinuation of 
Study Treatment
Revised text in this section as follows: Subjects should be encouraged to continue 
treatment until radiographic progression or unequivocal clinical progression. If the 
subject has radiographic progression without evidence of unequivocal clinical 
progression and alternate therapy is not initiated, treatment may continue at the 
discretion of the investigator. Subjects should not discontinue treatment for PSA 
progression in the absence of radiographic progression or unequivocal clinical 
progression. If a subject discontinues study treatment before evidence of 
radiographic progression, data on subsequent imaging assessments performed per 
the local standard of care will be collected if available (see Section 9.1.5). 
Radiographic progression is defined by PCWG2 (see Attachment 7). Bone scan 
worksheets may be used as source documentation for tracking progression or 
response (see Section 17.5).
The primary reason for discontinuation of study treatment is to be recorded in the 
eCRF. A study treatment discontinuation form should be emailed to the sponsor’s 
medical monitor prior to discontinuation in IWRS (see the SIPPM for details). 
Rationale: With the last amendment the duration of the Screening Phase was increased from 35 days to 42 days. 
This change was not captured throughout the protocol. 
Figure 2, Time and 
Events Schedule, 
footnote f, and 9.1.2 
Screening Phase
Corrected 35 days to 42 days. 
Rationale: Clarification that the computed tomography (CT)/magnetic resonance imaging exams must include the 
chest, abdomen, and pelvis.
Time and Events 
Schedule
CT/MRI exams of chest, abdomen and pelvis must be performed
Rationale: Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) grades are part of the safety 
evaluation and was not described in the Safety Evaluations Section
Synopsis Efficacy 
Evaluations/Endpoints; 
Time and Events 
Schedule; 9.2.1 
Evaluations; 9.7 Safety 
Evaluations; 9.7.1 
Safety Assessments
Moved ECOG timing to safety from efficacy. Added a section for ECOG PS to Safety 
Evaluations section. 

JNJ-56021927 (apalutamide)
Clinical Protocol 56021927PCR3001 – Amendment 4
12
Status: Approved, Date: 18 February 2020
Applicable Section(s)
Description of Change(s)
Rationale: A pain assessment was included in the eCRF but was not previously mentioned in the Time and Events 
Schedule of the protocol. 
Time and Events 
Schedule
Added a row for this assessment and the following note: Subjects should also complete 
“How would you rate your pain over the past 7 days?” (0 to 10 scale). Site personnel 
should record response in the eCRF and in the clinic visit record. During non-visit cycles 
the information will be collected by telephone contact.
Rationale: In Japan, an enhanced medical monitoring and IDMC review of the safety was performed for Cycle 1 
data of the first 20 subjects randomized to the study. As this action has been completed, the Japanese protocol can 
align with the global protocol.
Synopsis Safety 
Evaluations, 9.7 Safety 
Evaluations, 
Attachment 7 of the 
country-specific 
amendment.
The wording in these sections of the Japan country-specific amendment pertaining to the 
enhanced monitoring and IDMC review is not applicable to the global protocol. 
Attachment 7 in the country-specific amendment is not applicable to the global protocol. 
Rationale: In Japan, sparse PK samples are being collected from all randomized subjects. 
Synopsis Population 
Pharmacokinetic 
Evaluations; Time and 
Events Schedule; 9.3.1 
Evaluations
Added the following statement to the Time and Events Schedule: In Japan, samples will 
be collected from all randomized subjects.
Added the following statement to the synopsis and Section 9.3.1: In Japan, blood 
samples for PK assessment will be collected from all randomized subjects.
Rationale: Modified compliance wording for consistency with other apalutamide Phase 3 protocols.
7 Treatment 
Compliance
Replaced the current wording: 
If dosing compliance is not 100% in the absence of toxicity, then investigators should re-
instruct subjects regarding proper dosing procedures before continuation with the study. 
Subsequent dosing compliance procedure will be conducted at each study visit. Subjects 
who have study drug dosing compliance of 75% or lower for 2 consecutive cycles 
(independent of an AE) should be discontinued from the study (see Section 10.2).
With current wording: In the absence of toxicity, if the dosing compliance is not 
100%, then investigators or designated study site personnel should re-instruct 
subjects regarding proper dosing procedures and the subject may continue study 
treatment.
10.2 Discontinuation of 
Study Treatment
Removed the following bullet: Dosing noncompliance (75% compliance for 
2 consecutive cycles)
Rationale: Phase 3 protocols are to include an attachment with a listing of anticipated events. The text and 
attachment were taken from the latest protocol template. 
12.3.1 All Adverse 
Events; Attachment 8 
Added the following statements to Section 12.3.1: Anticipated events will be recorded 
and reported as described in Attachment 8. 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 where required).

JNJ-56021927 (apalutamide)
Clinical Protocol 56021927PCR3001 – Amendment 4
13
Status: Approved, Date: 18 February 2020
Applicable Section(s)
Description of Change(s)
Rationale: The generic name for JNJ-56021927, apalutamide, is replacing the compound number as protocols are 
amended.  
Synopsis, 
1 Introduction
The following revised sentence is included in the synopsis and introduction: 
JNJ-56021927 (ARN-509; apalutamide, hereafter referred to as apalutamide) is an orally 
available, small molecule, non-steroidal potent and selective antagonist of the androgen 
receptor (AR) receptor (anti-androgen).
Title page
The generic name apalutamide has replaced ARN-509
Throughout the 
protocol
Replaced “JNJ-56021927” with apalutamide throughout the protocol. 
4.2 Exclusion Criteria
Changed JNJ-56021927 to apalutamide in Exclusion Criterion #12
Rationale: Central laboratories send laboratory data that are not required per protocol but are done per standard 
practice in the central laboratory.
9.7 Safety 
Evaluations
Added the following note: 
Note: Any abnormal WBC evaluations will also be reported by the central 
laboratory.
Rationale: Removed redundant information in Attachment 3. Updated with new drug-drug interaction information 
for apalutamide. 
Attachment 3
Removed redundant or outdated information. Provided website for more information of 
CYP450 drug interactions.
8.3 Restricted 
Concomitant 
Medications
This section was updated with new information. 
Rationale: Additional minor revisions were made to the Time and Events Schedule to reduce redundancy and for 
clarification. 
Time and Events 
Schedule, Footnotes i
and j
The original footnotes i and j were removed and the information was incorporated into the 
notes in the body of the table. Remaining footnotes were revised accordingly. Removed the 
proposed sample sizes for the biomarker samples as this information was included in the 
biomarker section of the protocol. 
Rationale: Dose modification guidance for seizures is incorporated in Table 6 and did not need to be repeated in 
text. .
6.3.3 Toxicity 
Attributed to 
Apalutamide/Placebo
Removed redundant text. 

JNJ-56021927 (apalutamide)
Clinical Protocol 56021927PCR3001 – Amendment 4
14
Status: Approved, Date: 18 February 2020
Applicable Section(s)
Description of Change(s)
Rationale: Updated safety and efficacy information for apalutamide and apalutamide plus abiraterone acetate
1.1.2 Apalutamide; 
References
Revised and updated the information on the ARN-509-001 study and added the clinical 
study report reference. Removed reference to Rathkopf study as data in CSR are more up 
to date. 
Incorporated updated information from Studies ARN-509-004 and 56021927PCR1010.  
Updated with information on new Phase 3 studies. Added references to reference section.
Rationale: The sponsor continually reviews the protocol template for potential improvements. Major revisions to 
the protocol based on the updated template are noted in the following sections. Minor revisions, not noted here, 
have also been made throughout the document.
4.3 Prohibitions and 
Restrictions
Added the following: Refer to Sections 8.2 and 8.3 for details regarding prohibited and 
restricted therapy during the study
12.2 Special 
Reporting Situations 
(bullet #3)
Inadvertent exposure to study drug changed to accidental or occupational exposure.
12.3.1 All Adverse 
Events
Revised wording regarding SUSARs.
16.2.2 Independent 
Ethics Committee or 
institutional Review 
Board
The requirement to document the yearly approval of the protocol by the IEC/IRB was 
changed from a requirement to where required.
16.2.5 Country 
Selection
Clarification that drug will be launched in countries if the need for the product persists. 
17.4 Source 
Documentation
Clarifications to requirements for source documents and the authors of the data entry, and 
the electronic source system utilized for data. 
17.5 Case Report 
Form Completion
Clarifications to case report form completion requirements.
17.6 Data Quality 
Assurance
Added direct transmission of clinical laboratory data from a central laboratory into the 
sponsor’s database
17.8 Monitoring
Clarification of monitoring requirements.
17.10
On-Site Audits
Revised the following sentence: These audits will require access to all study records, 
including source documents, for inspection and comparison with the eCRFs.
Rationale: Program-wide decision to no longer refer to apalutamide as a second-generation anti-androgen, rather it 
should be referred to as a “next” generation anti-androgen. Statements comparing apalutamide with enzalutamide
were removed. 
1.1.2 Apalutamide; 
References
Revised text and references accordingly.
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. 
1.1.2 Apalutamide
For consistency, changed from AR antagonist to anti-androgen.

JNJ-56021927 (apalutamide)
Clinical Protocol 56021927PCR3001 – Amendment 4
15
Status: Approved, Date: 18 February 2020
Applicable Section(s)
Description of Change(s)
Synopsis Biomarker 
Evaluations; 
3.2 Study Design 
Rationale; 
9.4 Biomarkers; 
11.5 Biomarker 
Analyses
For consistency, the wording “up to” 220 or 500 subjects was revised to “approximately” 
220 or 500 subjects.
9.7 Safety 
Evaluations
Removed this statement, details provided in Time and Events Schedule. Required 
laboratory tests must be performed within 48 hours of the scheduled visit.
16.2.4; Privacy of 
Personal Data;
17.10 On-site Audits
Removed “or she” and “or her” wording, only men are enrolled in this study. 
15 Study-Specific 
Materials
Added a link to the NCI-CTCAE version 4.03 criteria. 
Amendment 1 (17 November 2014)
This amendment is considered to be nonsubstantial 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 the amendment: The overall reason for the amendment is to include The Committee for 
Medicinal Products for Human Use/European Medicines Agency (CHMP/EMA) health-technology-assessment 
(HTA) regulatory feedback and some added clarifications to existing text.
Applicable Section(s)
Description of Change(s)
Rationale: To give the most robustness to the study, CHMP/HTA suggested that giving a longer washout period for 
first generation anti-androgens would diminish the effect of prior treatment to the current study.
4.1. Inclusion Criteria, 
Criterion 5.1
For Criterion #5, the washout period for subjects receiving a first generation 
anti-androgen was changed from 4 weeks to 6 weeks.
Rationale: Feedback from Safety Management Team (SMT) for an ongoing JNJ-56021927 study at Janssen 
suggested that the exclusion criterion for subjects with seizures be revised.
4.2. Exclusion Criteria, 
Criterion 10.1
Modified Criterion #10 to specify seizures or known conditions that may pre-dispose a 
subject to a seizure making them ineligible to enroll in the study.
Rationale: The FDA requested scans at 8 week intervals over the first 24 weeks of the study to more accurately 
determine treatment effects based on PFS.
Time and Events 
Schedule, CT or MRI, 
Bone Scan (99mTc)
Added extra scans at Cycle 3 Day 1 and Cycle 5 Day 1; q3 cycle scans will begin at 
Cycle 7
Rationale: The sponsorship statement was revised to delete information that does not apply to this study.
Title Page
The sentence “For this study, Janssen-Cilag International NV (JCI) is the sponsor for 
sites in the European Union.” was deleted.

JNJ-56021927 (apalutamide)
Clinical Protocol 56021927PCR3001 – Amendment 4
16
Status: Approved, Date: 18 February 2020
Applicable Section(s)
Description of Change(s)
Rationale: Clarification to describe that clinical benefit is defined by radiographic progression-free survival (rPFS).
Synopsis, Objectives 
and Hypothesis;
2.1. Objectives
2.2. Hypothesis
In the primary objective and hypothesis statement, replaced "clinical benefit" by 
"radiographic progression-free survival (rPFS)".
Rationale: Clarification to more accurately define the secondary and other objectives.
Synopsis, Objectives 
and Hypothesis;
2.1. Objectives
Pharmacodynamic objective removed from "Secondary Objectives" containing 
pharmacokinetics and made into a separate objective under "Other Objectives".
Rationale: At screening, the need for parenteral or oral opioid analgesics is excluded from the study, so any 
initiation of opioid analgesic lasting for ≥3 weeks for oral, or ≥7 days for non-oral formulation will meet the time to 
pain progression definition.
Synopsis, Efficacy 
Evaluations/Endpoints
9.2.1.1. Other Efficacy 
Evaluations
10.2. Discontinuation 
of Study Treatment
Deleted “or increase in dose or frequency of the existing opioid analgesics” from the 
sentence describing the BPI-SF and chronic opioid use used to measure the secondary 
endpoint of time to pain progression
Rationale: Clarification to explain that 2 separate blood samples will be collected at each sampling time point.
Synopsis, Population 
Pharmacokinetic 
Evaluations;
Time and Events 
Schedule, footnote l;
9.3.1 Evaluations
Modified wording to state that 2 separate blood samples will be collected at 
approximately the same time for each sampling time point (1 for abiraterone and 1for 
JNJ-56021927).
Rationale: Consistency within protocol. Screening period changed to 42 days to account for the increased washout 
period for patients who received a first generation anti-androgen. 
Time and Events 
Schedule, Screening
9.1.2. Screening Phase
Screening period changed from 35 days to 42 days so that the washout period for 
Inclusion Criterion #5 can be achieved.
Rationale: Specified that 72 hours and 3 calendar days are not equivalent.
Time and Events 
Schedule, footnote d;
5. Treatment Allocation 
and Blinding
9.1.3. Treatment Phase
Modified wording by adding "or” to sentence to state that all subjects must commence 
treatment within 72 hours or 3 calendar days of randomization
Added “or 3 calendar days” to describe that sujects must start study drugs within 
72 hours or 3 calendar days after randomization.
Rationale: Clarification. Subjects should complete the BPI-SF ePROs for 7 consecutive days when collecting data.
Time and Events 
Schedule, footnote i
9.5. Patient-Reported 
Outcomes
Added "consecutive" to clarify the number of days information should be entered when 
subjects provide data before Day 1 of each cycle, EOT visit, or druing the Follow-up 
Phase.

JNJ-56021927 (apalutamide)
Clinical Protocol 56021927PCR3001 – Amendment 4
17
Status: Approved, Date: 18 February 2020
Applicable Section(s)
Description of Change(s)
Rationale: Clarification to simplify the instructions on the ePRO device. Subjects should complete the baseline 
ePROs for FACT-P and EQ-5D-5L on Cycle 1 Day 1.
Time and Events 
Schedule, footnote j
9.5. Patient-Reported 
Outcomes
Clarified this footnote to indicate that ePRO timing for FACT-P and EQ-5D-5L 
collection should be completed on Cycle 1 Day 1.
Rationale: Clarification to highlight modified fasting and dosing schedule on days of PK sampling.
Time and Events 
Schedule, footnote l;
6.2.1. Special Dosing 
and Meal Instructions
for PK Visits
Revised wording in footnote to delete special dosing instructions for “2 days prior and on 
the day before” PK sampling.
Deleted text in first paragraph that referred to a modified dosing schedule being required 
on “the 2 days before” PK sampling and included that JNJ-56021927 and AA must be 
administered in the clinic “after initial PK samples are collected”. Revised Table 2 to 
delete colums indicating fasting and dosing times for 2 days prior and on the day before 
PK sampling. Revised other days in Table 2 to show modified fasting and drug 
administration times relative to PK sample collection times.
Rationale: Clarification. Modified criterion to specify 3 ways of documenting prostate cancer progression.
4.1. Inclusion Criteria,
Criterion 6.1
Modified Criterion #6 to include "soft tissue" for radiographic progression evaluations 
according to Response Evaluation Criteria in Solid Tumors (RECIST), clarified that 
RECIST is modified based on Prostate Cancer Clinical Trials Working Group (PCWG2), 
and added radiographic progression of bone evaluationsaccording to PCWG2. Kept 
prostate cancer progression documented by prostate-specific antigen (PSA) according to 
the PCWG2.
Rationale: Clarification. (Initial calculation of testerone level of 1.7 nM was incorrect).
4.1. Inclusion Criteria, 
Criterion 7.1;
6.1. ADT 
Administration
For Criterion #7, deleted 1.7 nM. Testosterone levels is now cited only as <50 ng/dL.
Rationale: Clarification. Modified Inclusion criterion to specify time frame for subjects using a condom during 
sexual activity. Deleted a criterion from Prohibitions and Restrictions that was redundant with an Inclusion criterion.
4.1. Inclusion Criteria,
Criterion 13.1
4.3. Prohibitions and 
Restrictions, Criterion 1
Modified Criterion #13 to include that subjects agree to use a condom during sexual 
activity “while on study drug and for 3 months following the last dose of study drug”.
Deleted Criterion #1 from Prohibitions and Restrictions regarding subjects agreeing to 
use a condom during sexual activity because it is already stated in Inclusion 
Criterion #13.
Rationale: Clarification. More accurately define time frame of “study entry”.
4.2. Exclusion Criteria, 
Criterion 6.1
For Criterion #6, “study entry” was changed to “screening” to more acccurately define 
the time for parenteral or oral opioid analgesics (eg, codeine, dextropropoxyphene) to be 
stopped before a subject can be eligible for entering the study.
Rationale: To give the most robustness to the study, CHMP/HTA suggested that by prohibiting subjects treated 
with 5-α reductase inhibitors within 4 weeks of enrollment would diminish the effect of prior treatment to the 
current study.
4.2. Exclusion Criteria,
Criterion 14
Added Criterion #14 "Treatment with 5-α reductase inhibitors (finasteride, dutasteride), 
estrogens, cyproterone within 4 weeks of enrollment".

JNJ-56021927 (apalutamide)
Clinical Protocol 56021927PCR3001 – Amendment 4
18
Status: Approved, Date: 18 February 2020
Applicable Section(s)
Description of Change(s)
Rationale: Clarification. Add more information for Adverse Event terminology grading.
6.3.2.1. Abnormal 
Liver Function Test(s)
Modified footnote "a" to Table 3 to include reference for NCI-CTCAE, Version 4.03 as 
source for Adverse Event terminology grading.
Added footnote "b" to Table 3 to clarify that the dose modifications for liver function test 
(LFT) abnormalities are from the ZYTIGA label and not and do not follow Version 4 of 
CTCAE.
Rationale: Clarification of timing of at home study drug adminsitration relative to PK sampling for subjects 
participating in PK sampling.
9.1.3. Treatment Phase
Modified wording in paragraph regarding study drugs taken at home for subjects 
participarting in PK sampling.
Rationale: Clarified that PSA measurements, lymph node, and 99mTc bone scan will be evaluated according to an 
adaptation of the PCWG2 criteria.
9.2.1.2 Efficacy 
Criteria
Added "lymph node" will also be evaluated as an efficay criteria.
Rationale: Consistency within the protocol. 
14.4. Preparation, 
Handling, and Storage
Added a sentence that subjects should use a condom while on study drug and for 
3 months following the last dose of study drug so that instructions for use of the study 
drug are consistent with Inclusion Criterion #13.
Rationale: Minor errors were noted
Throughout the 
protocol
Minor grammatical, formatting, or spelling changes were made.

JNJ-56021927 (apalutamide)
Clinical Protocol 56021927PCR3001 – Amendment 4
19
Status: Approved, Date: 18 February 2020
SYNOPSIS
A Phase 3 Randomized, Placebo-controlled Double-blind Study of JNJ-56021927 in Combination 
with Abiraterone Acetate and Prednisone Versus Abiraterone Acetate and Prednisone in Subjects 
with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer (mCRPC)
JNJ-56021927 (ARN-509; apalutamide, hereafter referred to as apalutamide) is an orally available, small 
molecule, non-steroidal potent and selective antagonist of the androgen receptor (AR) (anti-androgen). It 
is currently being developed for the treatment of prostate cancer.
OBJECTIVES AND HYPOTHESIS
Primary Objective
The primary objective is to compare the radiographic progression-free survival (rPFS) of apalutamide in 
combination with abiraterone acetate (AA) plus prednisone or prednisolone (AAP) and AAP in subjects 
with chemotherapy-naïve mCRPC.
Major Secondary Objectives
The major secondary objectives are:

To characterize the safety profile of apalutamide in combination with AAP 

To characterize the pharmacokinetics (PK) of apalutamide and abiraterone
Other Objectives
The other objectives are:

To explore the relationship between PK and pharmacodynamics (PD) of apalutamide and 
abiraterone

To evaluate exploratory biomarkers predictive of response and resistance in subjects when treated 
with apalutamide in combination with AAP compared with AAP

To assess the effect on patient-reported outcomes (PROs) in this study population when treated with 
apalutamide in combination with AAP compared with AAP

To evaluate other endpoints of clinical relevance including additional assessments of pain, objective 
response, time to symptomatic skeletal-related event (SSRE), and PSA response

To evaluate medical resource utilization (MRU) information
Hypothesis
The primary hypothesis of the study is that apalutamide in combination with AAP compared with AAP 
will demonstrate improved rPFS and an acceptable safety profile in subjects with chemotherapy-naïve 
mCRPC.
OVERVIEW OF STUDY DESIGN
This is a randomized, double-blind placebo-controlled, multinational, multicenter Phase 3 study to 
determine if subjects with chemotherapy-naïve mCRPC will benefit from the addition of apalutamide to 
AAP compared with AAP. Subjects will continue receiving gonadotropin releasing hormone analogs 
(GnRHa) if not surgically castrated. Approximately 960 subjects who meet all the inclusion criteria and 
none of the exclusion criteria will be randomized in a 1:1 ratio to receive apalutamide and AAP or 
matching placebo and AAP. Subjects will be stratified by the presence or absence of visceral metastases, 

JNJ-56021927 (apalutamide)
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Status: Approved, Date: 18 February 2020
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) grade of 0 or 1, and region 
(European Union [EU], North America [United States/Canada], and Rest of World [ROW]). The study 
will consist of a Screening Phase; a Treatment Phase, and a Follow-up Phase. The study is anticipated to 
end approximately 84 months after the first subject has been randomized into the study.
A treatment cycle is defined as 28 days. Treatment will continue until disease progression, unacceptable 
toxicity, death or the sponsor terminates the study. Subjects must discontinue study drugs with 
documented unequivocal clinical progression as defined in the protocol. If the subject has radiographic 
progression, but not unequivocal clinical progression, and alternate treatment is not initiated, the subject
may continue on study treatment at the investigator’s discretion.
After discontinuing study drug, subjects will be contacted for survival every 3 months until death, 
withdrawal of consent, lost to follow up or termination of the study. In addition to survival follow up, 
analgesic use, SSREs, ECOG PS, and subsequent therapy for prostate cancer up to and including
chemotherapy will be collected. Patient-reported outcomes (PROs) questionnaires will also be completed
every 3 months up to 12 months after discontinuation of study treatment.
Subjects will be monitored for safety during the Screening and Treatment Phases and up to 30 days after 
the last dose of study drug. Adverse events (AEs) including laboratory AEs, will be graded and 
summarized using National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI-CTCAE), Version 4.03. Dose modification guidelines will be provided.
An Independent Data Monitoring Committee (IDMC) will be commissioned for this study. The 
committee will perform periodic safety review throughout the study and review the safety of the first 
60 subjects randomized to the study after treatment for at least 1 cycle. In addition, the IDMC will review 
the planned efficacy/futility analysis.
Following the decision to unblind the study, the Extension Phase will begin when both the Amendment 4 
is approved at the site and the sponsor has notified the site of the start of the Open-Label Extension Phase 
or Long-Term Extension Phase.
SUBJECT POPULATION
The study population includes men with mCRPC documented by positive bone scan or metastatic lesions 
on CT or MRI, ≥18 years of age, with ECOG PS grade of 0 or 1. A score of 3 or less on item 3 (worst 
pain in the last 24 hours) of the Brief Pain Inventory-Short Form (BPI-SF) is required. Subjects are 
excluded if they received prior chemotherapy for mCRPC (adjuvant/neoadjuvant chemotherapy is 
allowed) and inhibitors of CYP17 or androgen axis signaling. 
DOSAGE AND ADMINISTRATION
All subjects will receive AAP as standard of care (SOC) therapy. Abiraterone acetate 1,000 mg 
(4 × 250 mg tablets) will be taken orally once daily. Abiraterone acetate must be taken on an empty 
stomach. No food should be consumed for at least 2 hours before the dose of AA is taken and for at least 
1 hour after the dose of AA is taken. Tablets should be swallowed whole with water. The daily dose of 
prednisone will be 10 mg (5-mg tablet taken orally twice daily). 
Although not considered study drug, subjects who have not undergone surgical castration will continue to 
receive regularly prescribed GnRHa.
JNJ-56021927 (apalutamide) 240 mg (4 x 60 mg tablets) or Placebo (4 tablets) will be taken orally once 
daily. The tablets can be taken with or without food.

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Status: Approved, Date: 18 February 2020
EFFICACY EVALUATIONS/ENDPOINTS
Efficacy evaluations will be conducted as specified in the Time & Events Schedule. The efficacy 
evaluations include the following:

Tumor measurements (computed tomography [CT] or magnetic resonance imaging [MRI], bone 
scans, other imaging procedures)

Survival status, analgesic use, SSREs, and first cytotoxic chemotherapy for prostate cancer 

Serum PSA evaluation (measurements at a central laboratory)
The same imaging modality used for tumor assessments should be used throughout the evaluation of an 
individual subject. Unscheduled tumor assessment and appropriate imaging should be considered if signs 
or symptoms suggestive of disease progression, including escalating pain not referable to another cause, 
worsening ECOG PS grade, or physical examination findings consistent with disease progression, are 
recorded.
The BPI-SF (item 3) and chronic opioid use (defined as administration of additional opioid analgesics
lasting for ≥3 weeks for oral, or ≥7 days for non-oral formulation) will be used to measure the secondary 
endpoint of time to pain progression. Analgesic usage (for time to analgesic progression endpoint) will be 
scored according to the World Health Organization (WHO) analgesic ladder: 0 for no analgesic, 1 for 
non-opioid
analgesics 
(including 
non-steroidal 
anti-inflammatory 
drugs 
[NSAIDs], 
paracetamol/acetaminophen, antidepressants, and agents intended to treat neuropathic pain), 2 for opioids 
for moderate pain, and 3 for opioids for severe pain.
Efficacy Endpoints
Primary: Radiographic progression-free survival is defined as the time from date of randomization to the 
date of radiographic progression or death, whichever occurs first. Radiographic progression will be 
assessed by the investigator based on soft tissue lesion by CT/MRI per modified Response Evaluation 
Criteria in Solid Tumors (RECIST 1.1) or by bone lesion progression on bone scans per an adaptation of 
the Prostate Clinical Trials Cancer Working Group 2 (PCWG2).
Secondary: Overall survival (OS), time to chronic opioid use, time to initiation of cytotoxic 
chemotherapy, and time to pain progression. 
Other: Time to deterioration of ECOG PS, time to SSRE; objective response rate and duration of 
response in subjects with measurable disease; PROs as assessed by Functional Assessment of Cancer 
Therapy-Prostate (FACT-P), BPI-SF, and EQ-5D-5L; time to PSA progression based on PCWG2 criteria; 
time to analgesic progression, progression-free survival on first subsequent therapy (PFS2), and 
biomarker research to explore AR gene anomalies and other markers responsible for resistance to 
apalutamide.
POPULATION PHARMACOKINETIC EVALUATIONS
Pharmacokinetic assessment will be conducted on as many subjects as feasible (and where regulations 
permit). In Japan, blood samples for PK assessment will be collected from all randomized subjects. Two 
separate blood samples will be collected at approximately the same time for each sampling time point; 
1 for abiraterone and 1 for apalutamide. On Day 1 of Cycle 1, blood samples will be collected at 2 hours
and 4 hours post the first dose for each subject. On Day 1 of Cycle 3, a predose sample (up to 1 hour prior 
to on-site study drugs administration) and postdose samples between 0.5 and 4 hours will be collected. 
For the other PK visits (Cycles 2, 4, 5, and 6), blood samples will be collected predose (up to 1 hour prior 
to on-site study drugs administration).

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Status: Approved, Date: 18 February 2020
BIOMARKER EVALUATIONS
Archived tumor samples (formalin-fixed paraffin-embedded [FFPE] blocks or slides) and serum samples 
will be collected, where country regulations permit, for biomarker evaluations. Plasma samples will be 
collected from approximately 220 subjects during treatment and approximately 500 subjects at the end-of-
treatment or progression; whole blood and serum will be collected from approximately 220 subjects at the 
time points indicated in the Time & Events Schedule. Plasma-based circulating DNA will be used to 
assess the presence of the ARF876L mutation and whole blood or plasma DNA to assess other markers that 
may be associated with resistance to AA alone and in combination with apalutamide. Serum samples will 
be collected to compare the effect of testosterone and steroid metabolites when subjects are treated with 
AAP alone and in combination with apalutamide. Archival FFPE tumor blocks or tumor slides will be 
collected from at least 300 subjects in this study to investigate whether genomic classifiers can be used to 
identify a more homogeneous population of high-risk subjects. This will potentially allow selection of the 
appropriate high-risk patient population for future studies of apalutamide and AAP.
PATIENT-REPORTED OUTCOMES EVALUATIONS
Three PRO instruments, the Functional Assessment of Cancer Therapy-Prostate (FACT-P), BPI-SF, and 
EQ-5D-5L will be administered in this study.
MEDICAL RESOURCE UTILIZATION EVALUATIONS
Medical resource utilization data associated with medical encounters will be collected in this study.
SAFETY EVALUATIONS
Safety evaluations include AEs, vital signs measurements, physical examinations, and clinical laboratory 
tests.
STATISTICAL METHODS
The primary analysis population will use the intent-to-treat (ITT) population, which includes all
randomized subjects. The ITT population will be used for the analysis of subject disposition and efficacy. 
The safety population includes all subjects who received at least 1 dose of study drug. 
This study is sized (approximately 
% power) to detect a hazard ratio (HR) of 
 in the secondary 
endpoint of OS based on an assumed median OS of 
 for the control group (AAP). Under the 
assumption that the failure distribution of OS follows an exponential distribution with a constant hazard 
rate, approximately 
 death events will be required to detect the assumed HR of 
at a maximum two-
sided significance level of 0.05, with enrollment duration of approximately 
 (approximately 
960 subjects) and an additional follow up of approximately
 to reach the total number of death 
events.
It is estimated that approximately 
 rPFS events would be required to provide at least 
% power in 
detecting an HR of 
 (median rPFS of 
 for the control group [AAP alone] versus 
 
for the treatment group of apalutamide plus AAP) at a two-tailed level of significance of 0.05 under the 
assumption of a positive correlation between rPFS and OS; 
Efficacy Analysis 
Kaplan-Meier product limit method and stratified Cox model will be used to estimate the survival 
distribution of the time-to-event variables and to obtain the HR and corresponding confidence interval 
(CI) respectively. The testing of the time-to-event endpoints will be based on the stratified log-rank test. 
Response rate variable will be evaluated using the Chi-square statistic.
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JNJ-56021927 (apalutamide)
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Status: Approved, Date: 18 February 2020
Population PK and Pharmacodynamic Analyses
Population PK analysis of plasma concentration-time data of apalutamide and abiraterone may be 
performed using nonlinear mixed-effects modeling. If sufficient data are available, the relationship of 
exposure to apalutamide and active metabolite JNJ-56142060, and abiraterone to measures of efficacy 
and AEs may also be analyzed. The population PK/PD analysis results will be presented in a separate 
report.
Biomarkers Analyses
The associations of the biomarkers with clinical response or time-to-event endpoints may be assessed 
using appropriate statistical methods (such as analysis of variance [ANOVA], categorical, or survival 
models), depending on the endpoint. A detailed statistical analysis plan will be prepared for these 
exploratory studies.
Patient-Reported Outcomes Analysis
Scales from BPI-SF and FACT-P: Descriptive statistics of each scale score at baseline and follow up 
assessments will be summarized by treatment groups; time to degradation in each scale will be analyzed 
using Kaplan-Meier method and stratified Cox proportional-hazard model. Additional analysis may be 
carried out, if appropriate. Analysis details will be included in the statistical analysis plan. 
The EQ-5D-5L data will be summarized descriptively by treatment group and study visit. Each level of 
every dimension will be summarized using count and percent. EQ-5D-5L Visual Analog Scale (VAS) 
will be described using summary statistics (n, mean, median, etc.).
Medical Resource Utilization Analysis
Medical resource utilization will be descriptively summarized by treatment group. The results will be 
presented in a separate report.
Safety Analyses
The safety parameters to be evaluated are the incidence and intensity of AEs, clinically significant 
changes in the subject’s physical examination findings, vital signs measurements, and clinical laboratory 
results. Exposure to study drug and reasons for discontinuation of study treatment will be tabulated.
Interim Analyses
For the OS endpoint, 2 interim analyses are planned in this study after observing approximately 
% (
events) and 
% (
 of the total number of required (
 events. The final analysis of OS 
will be performed when approximately 
 death events are observed. The testing of the OS endpoint will 
be carried out based on the group sequential design according to the 
 
. Assuming a maximum overall 2-tailed significance level of 
0.05, the estimated cumulative alpha spend are 
 and 
 at the first and second interim analyses, 
respectively. The exact significance levels will be determined according to the observed number of events 
at the time of analysis.
Futility Analyses
A non-binding futility analysis is planned using PSA90 decline rate defined as the proportion of subjects 
with a decline of PSA of 90% or more from baseline. In the case that a PSA90 decline rate of 30% in the 
control group is observed, it is assumed that an absolute increase of 
% over the control group would be
clinically meaningful. This futility analysis will occur when approximately 
subjects have been treated 
for at least  cycles. This sample size should control the type II error rate of approximately % under the 
assumed decline rates. The purpose of this analysis is to provide an early look to ensure the treatment 
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JNJ-56021927 (apalutamide)
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Status: Approved, Date: 18 February 2020
group of apalutamide plus AAP has sufficient antitumor activity compared with AAP alone. This futility 
analysis will not be used to substantiate an efficacy claim. Non-binding futility analyses will be 
implemented at the planned interim analyses for OS.
In addition, a non-binding futility analysis on rPFS will be implemented after observing approximately 
% (
 events) of the total number of required 
 events.
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JNJ-56021927 (apalutamide)
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Status: Approved, Date: 18 February 2020
TIME AND EVENTS SCHEDULE
PHASE
Notes
Screening Phase
Treatment Phasea
Follow-up Phasec
CYCLE (defined as 28 days):
Within 42 days of 
randomization unless 
otherwise specified
Cycle 1
Cycle 2
Cycle 3
Cycle 4 until EOT
EOT Visit
(within 
30 days of 
last dose)b
Every 3 months
CYCLE DAY: Unless otherwise specified, study visits/procedures have a 
±2-day time window 
1
15
1
15
1
15
1
Screening
Informed consent (must be 
performed before any study-specific 
procedures)
X
Inclusion/exclusion criteria
X
Prestudy anti-cancer therapy, 
palliative radiation, or surgical 
therapy for metastatic disease
X
Medical history and demographics
X
Randomizationd
X
Study Drug Administration
Dispense study drug
X
X
X
Every cycle up to 
Cycle 24 then q3
cycles
Dosing compliancee
X
X
Every cycle up to 
Cycle 24 then q3 
cycles
Safety 
Electrocardiogram, 12-leadf
X
Physical examinationg
X
X
X
X
Every cycle up to 
Cycle 24 then q3 
cycles
X
Vital signs
Blood pressure, heart rate, respiratory 
rate, and body temperature at 
screening; afterwards only blood 
pressure
X
X
X
X
Every cycle up to 
Cycle 24 then q3 
cycles
X
ECOG PS
X
X
X
X
Every cycle up to 
Cycle 24 then q3 
cycles
X
X

JNJ-56021927 (apalutamide)
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Status: Approved, Date: 18 February 2020
PHASE
Notes
Screening Phase
Treatment Phasea
Follow-up Phasec
CYCLE (defined as 28 days):
Within 42 days of 
randomization unless 
otherwise specified
Cycle 1
Cycle 2
Cycle 3
Cycle 4 until EOT
EOT Visit
(within 
30 days of 
last dose)b
Every 3 months
CYCLE DAY: Unless otherwise specified, study visits/procedures have a 
±2-day time window 
1
15
1
15
1
15
1
Efficacy
CT or MRI
The same modality (CT or MRI) should 
be used throughout the study. Imaging 
visits may occur up to 8 days before 
cycles requiring images. Unscheduled 
assessments may be performed if 
signs of disease progression are 
observed.
CT/MRI exams of chest, abdomen and 
pelvis must be performed. If available, 
collect information on imaging 
assessments until radiographic 
progression is documented (see 
Sections 9.1.5 and 10.2)
X
X
Cycle 5 then 
q3 cycles 
beginning at 
Cycle 7
Xh
Bone Scan (99mTc)
Scan visits may occur up to 8 days 
before cycles requiring images. 
Unscheduled assessments may be 
performed if signs of disease 
progression are observed.
X
Within 6 weeks of 
randomization
X
Cycle 5 then 
q3 cycles 
beginning at 
Cycle 7
Xh
ePROs
During the Screening Phase, BPI-SF is 
collected from Day-6 prior to 
randomization until C1D1 with the last 
day being completed on C1D1 before 
any other procedures. During the 
Treatment Phase, 7-day assessments 
for each cycle are done with the last 
day being completed D1 before any 
other procedures at on-site visits. 
During the Follow-up Phase, the 7-day 
assessments will be done remotely.
The consecutive 7-day assessments 
will also be completed for the EOT 
Visit.
Start on Day -6 prior 
to randomization
X
X
X
Every cycle
X
q3 months for up to 12 
months after treatment 
discontinuation

JNJ-56021927 (apalutamide)
Clinical Protocol 56021927PCR3001 – Amendment 4
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Status: Approved, Date: 18 February 2020
PHASE
Notes
Screening Phase
Treatment Phasea
Follow-up Phasec
CYCLE (defined as 28 days):
Within 42 days of 
randomization unless 
otherwise specified
Cycle 1
Cycle 2
Cycle 3
Cycle 4 until EOT
EOT Visit
(within 
30 days of 
last dose)b
Every 3 months
CYCLE DAY: Unless otherwise specified, study visits/procedures have a 
±2-day time window 
1
15
1
15
1
15
1
ePROs (continued)
Baseline questionnaires for FACT-P 
and EQ-5D-5L should be completed on 
C1D1. At all clinic visits the 
questionnaires should be completed 
before any other visit procedure. 
During Follow-up Phase, the 
questionnaires will be completed 
remotely. 
Xi
X
X
Cycles 4, 5, 6 then 
q3 cycles
X
q3 months for up to 12 
months after treatment 
discontinuation
Additional pain assessment
Subjects should also complete “How 
would you rate your pain over the past 
7 days?” (0 to 10 scale). Site personnel 
should record response in the eCRF 
and in clinic visit record. On non-visit
cycles, the responses will be collected 
by telephone contact.
X
X
X
Every cycle
X
Medical Resource Utilization
Continuous
X
Survival status and subsequent anti-
cancer therapy (up to and including 
chemotherapy), analgesic use, and 
SSREs (see Section 9.2)
See also Section 9.1.5
X
X
Progression on first subsequent 
therapy
X
Clinical Laboratory
Hematology
Hemoglobin, WBCs including absolute 
neutrophil count, platelet count. 
X
Xi
X
X
Cycles 4,5,6 then 
q2 cycles from 
Cycle 8 to 
Cycle 24 then q3 
cycles
X
Serum chemistry
Potassium, sodium, total protein, 
calcium, creatinine, lactate 
dehydrogenase, 
albumin (Screening only)
X
Xi
X
X
Cycles 4,5,6 then 
q2 cycles from 
Cycle 8 to Cycle 
24 then q3 cycles
X
Liver function tests
ALP, ALT, AST, total bilirubin; direct 
and indirect bilirubin if Gilbert’s is 
suspected at Screening only
X
Xi
X
X
X
X
X
Cycles 4,5,6 then 
q2 cycles from 
Cycle 8 to Cycle 
24 then q3 cycles
X

JNJ-56021927 (apalutamide)
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Status: Approved, Date: 18 February 2020
PHASE
Notes
Screening Phase
Treatment Phasea
Follow-up Phasec
CYCLE (defined as 28 days):
Within 42 days of 
randomization unless 
otherwise specified
Cycle 1
Cycle 2
Cycle 3
Cycle 4 until EOT
EOT Visit
(within 
30 days of 
last dose)b
Every 3 months
CYCLE DAY: Unless otherwise specified, study visits/procedures have a 
±2-day time window 
1
15
1
15
1
15
1
PSA
X
Xi
X
X
Every cycle to 
Cycle 12 then 
q2 cycles up to 
Cycle 24 then 
q3 cycles
X
Fasting glucose and lipids
Lipid panel includes HDL, LDL, 
triglycerides
X
Xi
Cycle 12, then q12 
cycles
Serum testosterone
X
TSH
T3 and T4 only to be done if TSH is 
abnormal
X
Xi
Cycle 4 then 
q2 cycles to 
Cycle 24, then q3 
cycles
X
Ongoing Subject Review
Concomitant therapy
Continuous from time of signing of ICF until 30 days after the last study drug dose
Adverse eventsb
Continuous from time of signing of ICF until 30 days after the last study drug dose
Pharmacokinetics
PK sparse samplingj
Samples will be collected from as 
many subjects as feasible (and where 
regulations permit). In Japan, samples 
will be collected from all randomized 
subjects.
X
X
X
Cycles 4, 5, and 6 
only
Biomarkers (See also Section 9.4).
FFPE tumor blocks or slides for 
biomarker assessments
Samples obtained at time of original 
diagnosis. The tumor blocks or slides 
can be provided anytime on or after 
C1D1.
X
Plasma sample collection
Plasma samples (10 mL at each draw) 
at C1D1 (baseline) and C12D1, and 
EOT or progression.
X
Cycle 12 only
X
Whole blood sample collection
Whole blood samples (2.5 mL at each 
draw) at C1D1 (baseline), C12D1, and 
EOT or progression
X
Cycle 12 only
X
Serum sample collection
Serum samples (8.5 mL at each draw) 
at C1D1 (baseline), C3D1, C12D1, and 
EOT or progression
X
X
Cycle 12 only
X

JNJ-56021927 (apalutamide)
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Status: Approved, Date: 18 February 2020
AE=adverse event; ALP=alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BPI-SF = Brief Pain Inventory - Short Form; C1D1=Cycle 1 Day 1; C12D1=Cycle 12 Day 1; 
CT=computed tomography; ECG=electrocardiogram; eCRF=electronic case report form; ECOG PS=Eastern Cooperative Oncology Group Performance Status; EOT=end-of-treatment; ePRO=electronic device 
for patient-reported outcomes; EQ-5D-5L=Euro-QoL; FACT-P=Functional Assessment of Cancer Therapy-Prostate; FFPE=formalin-fixed paraffin-embedded; ICF=informed consent form; LFT=liver function 
test; MRI=magnetic resonance imaging; MRU=medical resource utilization; PK=pharmacokinetic; PROs=patient-reported outcomes; PSA=prostate-specific antigen; q=every; SOC=standard of care; 
SSRE=symptomatic skeletal-related event; 99mTc=technetium-99m; TSH=thyroid stimulating hormone WBCs=white blood cells
a
Subjects should visit the clinic on Day 1 of each cycle for assessments and on Day 15 of each cycle for LFT assessments for the first 3 cycles. From Cycle 4 to EOT, visits are monthly up to Cycle 24 (q3
cycles); the assessments may differ from cycle to cycle as shown in the table.
b
Subjects who discontinued from treatment due to disease progression, AE or other reasons and enter the Follow-up Phase must have the EOT Visit completed before starting any subsequent anti-cancer 
treatment for prostate cancer. If a subject is unable to return to the site for the EOT Visit, the subject should be contacted to collect AEs that occur within 30 days after the last dose of study drug.
c
Follow up for survival will continue until death, withdrawal of consent, lost to follow up or until study termination. Deaths regardless of causality will be reported in the eCRF. Serious adverse events that 
occur after 30 days following the last drug administration thought to be related to study drug will be collected and reported via the SAE form within 24 hours of discovery or notification of the event and 
documented (see Section 12.3.2). 
d
Subjects must meet all inclusion and none of the exclusion criteria before randomization can occur. Subjects must start study drug on C1D1; C1D1 may occur anytime within 72 hours or 3 calendar days of 
randomization.
e
Includes a tablet count (see Section 7).
f
Serum chemistry results must be available before ECG can be obtained. ECGs obtained within 42 days of randomization should be rechecked if prior ECG was obtained when potassium level was 
<3.5mmol/L or unknown. Serum potassium <3.5 mmol/L should be corrected before ECG recording. Subjects should rest in a supine position for at least 5 minutes before ECG collection and should refrain 
from talking or moving arms or legs. 
g
Weight should be obtained with subjects wearing light clothing and no shoes. The Screening physical examination will include, at a minimum, the general appearance of the subject, height and weight, 
examination of the skin, ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, lymphatic system, and nervous system. Weight and symptom-directed physical examinations should be 
obtained during the Treatment Phase and at the EOT Visit.
h
Bone scans, CT, or MRI scans at EOT Visit are not required if scans were done within the previous 6 weeks.
i
Screening laboratory evaluations can be used for C1D1 assessments if performed within 14 days of C1D1, otherwise the laboratory assessments must be repeated on C1D1.
j
See Section 6.2.1 for special dosing instructions on the day of PK sampling. Two separate blood samples will be collected at approximately the same time for each sampling time point; 1 for abiraterone and 
1 for apalutamide. On Day 1 of Cycle 1, blood samples will be collected at 2 hours and 4 hours post the first dose. On Day 1 of Cycle 3, predose samples (up to 1 hour prior to on-site study drug 
administration) and postdose samples between 0.5 and 4 hours will be collected. For the other PK visits (Cycles 2, 4, 5, and 6), blood samples will be collected predose (up to 1 hour prior to on-site study 
drugs administration). See also Section 9.3.

JNJ-56021927 (apalutamide)
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Status: Approved, Date: 18 February 2020
ABBREVIATIONS
AA
abiraterone acetate
AAP
abiraterone acetate plus prednisone or prednisolone
ACTH
adrenocorticotropic hormone
ADT
androgen deprivation therapy
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AR
androgen receptor
AST
aspartate aminotransferase
BPI-SF
Brief Pain Inventory-Short Form
BCRP
breast cancer resistance protein
CRF
case report form (paper or electronic as appropriate for this study)
CRPC
castration-resistant prostate cancer
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
EBRT
external beam radiation therapy
ECG
electrocardiogram
ECOG PS
Eastern Cooperative Oncology Group Performance Status
eDC
electronic data capture
ePRO
electronic device for patient-reported outcomes
EQ-5D-5L
Euro-QoL
EOT
End-of-Treatment
EU
European Union
FACT-P
Functional Assessment of Cancer Therapy-Prostate
FDHT
16β-[18F] fluoro-α-dihydrotestosterone
FFPE
formalin-fixed paraffin-embedded
GABAA
gamma aminobutyric acid chloride channel
GCP
Good Clinical Practice
GnRHa
gonadotropin releasing hormone analog
HR
hazard ratio
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IWRS
interactive web response system
IUD
intrauterine device
IUS
intrauterine system
LFT
liver function test
LTE
Long-Term Extension
mCRPC
metastatic castration-resistant prostate cancer
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
MRU
medical resource utilization
NCI
National Cancer Institute
NM-CRPC
non-metastatic castration-resistant prostate cancer
OATP1B1
organic anion transporter 1B1
OLE
Open-Label Extension
OS
overall survival
PCWG2
Prostate Cancer Clinical Trials Working Group 2
P-gp
P-glycoprotein
PK
Pharmacokinetics
PQC
product quality complaint
PRO
patient-reported outcome(s)
PSA 
prostate-specific antigen
ROW
rest of world
rPFS
radiographic progression-free survival

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SAC
Safety Assessment Committee
SAE
serious adverse event
SIPPM
study-site investigational product procedures manual
SSRE
symptomatic skeletal-related event
SUSAR
suspected unexpected serious adverse reaction
99mTc
technetium-99m
TSH
thyroid stimulating hormone
WBC
white blood cell
UGT
uridine diphosphate glucuronosyl transferase
ULN
upper limit of normal

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1.
INTRODUCTION
JNJ-56021927 (ARN-509; apalutamide, hereafter referred to apalutamide) is an orally available, 
small molecule, non-steroidal potent and selective antagonist of the androgen receptor (AR) 
(anti-androgen). It is currently being developed for the treatment of prostate cancer.
For the most comprehensive nonclinical and clinical information regarding apalutamide, refer to 
the latest version of the Investigator's Brochure and Addenda for JNJ-56021927 (apalutamide).18
The term "sponsor" used throughout this document refers to the entities listed in the Contact 
Information page(s), which will be provided as a separate document.
1.1.
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.19 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. Prostate cancers are dependent for their growth and 
survival on androgen-mediated signaling.31,34 In patients with locally advanced or metastatic 
disease, the depletion of androgens through either medical9 or surgical15 castration, decreases 
androgen receptor (AR) signaling and leads to tumor regression. Unfortunately, these regressions 
in patients with metastatic prostate cancer are universally transient, with a median duration of 
disease control between 13 and 22 months and median overall survival (OS) of 28 to 
36 months.32
Treatment results with androgen deprivation therapy (ADT; gonadotropin releasing hormone 
analogs [GnRHa] or surgical castration) with or without anti-androgens 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.
1.1.1.
Inhibition of CYP17 and Abiraterone Acetate
Testosterone synthesis occurs in several locations. Peripheral conversion of adrenal androgens to 
testosterone may result in circulating testosterone concentrations approaching 10% of 
pre-castrate concentrations. Prostate cancer tissue can be a source of androgen production that 
stimulates growth in an autocrine or paracrine manner, independent of circulating androgens.24
ZYTIGA® (Abiraterone acetate [JNJ-212082]) is a pro-drug of abiraterone (JNJ-589485) 
17-(3-pyridyl) androsta-5,16-dien-3β-ol], an androgen biosynthesis inhibitor. Specifically, 
abiraterone selectively inhibits the enzyme CYP17. This enzyme is found in testes, adrenals, and 
in prostate tissues and tumors.1,24,25

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The clinical benefits of abiraterone acetate (AA) in combination with prednisone or prednisolone 
(hereafter referred to as AAP) were demonstrated in 2 large randomized, double-blind, 
placebo-controlled Phase 3 studies (COU-AA-301 and COU-AA-302). These studies included 
subjects 
with 
mCRPC 
post-chemotherapy 
(COU-AA-301) 
and 
chemotherapy-naïve 
(COU-AA-302).10,27,29
As of 01 March 2014, AAP is approved in more than 86 countries for patients with mCRPC. The 
combination of AAP has now been adopted as standard front-line therapy for mCRPC and will 
be combined with the experimental compound apalutamide, and will also be the treatment in the 
control arm for this study.
1.1.2.
Apalutamide
Additional clinical benefit beyond suppression of testosterone production might also be obtained 
by the use of next generation anti-androgens in patients with mCRPC. This is supported by 
molecular profiling studies of CRPC, which commonly show increased AR gene expression.4
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 anti-androgens, 
such as bicalutamide or flutamide.5 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 anti-androgens, the so-called anti-androgen withdrawal syndrome.21 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.
Apalutamide has been developed to overcome the potential therapeutic deficiencies of first 
generation anti-androgens. Apalutamide is a potent and selective anti-androgen 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-over-
expressing prostate cancer cells.5
Clinical Studies
Apalutamide is being evaluated in Phase 1, Phase 1/2, and Phase 3 studies in patients with CRPC 
(non-metastatic and metastatic), high-risk localized or locally advanced prostate cancer, and 
biochemically relapsed hormone-sensitive prostate cancer.
Study ARN-509-001 is an ongoing Phase 1/2 study in patients with progressive advanced CRPC. 
A clinical study report was completed based on a clinical cutoff of 31 December 2014. At the 
time of this cutoff, 26 (27%) subjects were continuing to receive treatment.6 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. Ninety-seven subjects divided into 3 subgroups are being evaluated in 
the Phase 2 portion (Cohort 1: NM-CRPC n=51; Cohort 2: mCRPC without previous 
ketoconazole, abiraterone acetate/prednisone, enzalutamide or chemotherapy [for mCRPC] 

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n=25; and Cohort 3: mCRPC post abiraterone acetate/prednisone, no previous chemotherapy [for 
mCRPC] n=21).
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. 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. Eligibility criteria for Phase 1 and 2 
excluded subjects with a history of seizure or a condition that may predispose to seizure and 
concurrent therapy with medications known to have seizure potential were also prohibited. No 
seizures were reported at any dose level. The pharmacokinetic (PK) profile was determined to be 
linear and dose-proportional. The maximum tolerated dose (MTD) was not determined. The 
determination of the recommended Phase 2 dose of 240 mg daily was based on an integrated 
approach: comparing the dose required for maximum tumor regression in mouse xenograft 
models with clinical PK and pharmacodynamics, and assessing the safety and tolerability at 
doses up to 480 mg.
Treatment-related adverse events observed across the 3 cohorts in >10% of patients were fatigue 
(47%), diarrhea (28%), nausea (27%), abdominal pain (13%); and hot flush, hypothyroidism, and 
dysgeusia (each 11%). Treatment -related adverse events of blood TSH increased were reported 
for 8 patients (8%). Decreased appetite and weight decreased were reported as treatment-related 
adverse events for 8 patients (8%) and 5 subjects (5%), respectively. Nineteen (20%) patients 
had reported treatment-related adverse events under the system organ class (SOC) of skin and 
subcutaneous tissue disorders, which included pruritus (7 [7%] patients), rash (7 [7%] patients), 
rash erythematous (3 [3%] patients), dry skin (3 [3%] patients), and rash macular (3 [3%] 
patients).
The efficacy of apalutamide was also evaluated in the Phase 2 portion of Study ARN-509-001. 
The percentage of patients with PSA reductions of 50% at 12 weeks was 89% for Cohort 1, 88% 
for Cohort 2, and 22% for Cohort 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. 
With a median follow up of 28.0 months, the median time to PSA progression for Cohort 1 was 
24.0 months (95% CI: 16.3; NE). With a median follow-up of 22.1 months for Cohort 2, the 
median time to PSA progression was 18.2 months (95% CI: 8.3; NE). The median follow-up for 
Cohort 3 was 5.6 months with a median time to PSA progression of 3.7 months (95% CI: 
2.8; 5.6).
Study ARN-509-004 is an ongoing Phase 1b to assess the safety, PK and preliminary antitumor
activity of ascending doses of apalutamide and AAP in subjects with mCRPC. Six subjects were 
enrolled in this study.8 All 6 subjects received AA (1,000 mg orally once daily) and prednisone 
(5 mg orally once daily) starting on Cycle 1 Day 1. Daily administration of apalutamide as 
softgel capsules was initiated on Cycle 1 Day 8. Three subjects enrolled in Cohort 1 received 

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120-mg apalutamide orally once daily. Three subjects enrolled in Cohort 2 received 240-mg 
apalutamide orally once daily. The pharmacokinetic (PK) samples were collected on Cycle 1 
Day 7 (AAP alone) and Cycle 1 Day 36 (AAP+apalutamide). The PK results suggested that 
apalutamide does not appear to have a major effect on abiraterone exposure. As subjects are 
continuing treatment, safety and preliminary antitumor activity are not yet available.
A Phase 1b study was initiated (Study 56021927PCR1010) to assess the PK of abiraterone and 
its metabolites when dosed alone or in combination with apalutamide in up to 26 subjects with 
mCRPC. Safety data from 29 subjects after a median treatment duration of 12.1 weeks (range: 4 
to 24 weeks) was reported.7 The safety profile of combination treatment with apalutamide plus 
AAP is as expected, based on the known side effects observed to date with apalutamide or AAP, 
individually. No new safety signals were noted with the combination therapy. Most commonly 
reported drug-related AEs (≥10% of subjects) were fatigue (41%), dysgeusia (21%), diarrhea 
(17%), hypokalemia (17%), vomiting (14%), decreased appetite (14%), upper abdominal pain 
(10%), nausea (10%) and dyspepsia (10%). The majority of these drug-related AEs were Grade 1 
and Grade 2 in severity. Drug-related AEs of Grade ≥3 toxicity were reported in 3 (10%) 
subjects and included fatigue, hepatic function abnormal (ALT increase), hypokalemia, and 
hyponatremia. One subject experienced an SAE of Grade 4 hypokalemia. One death was 
reported in this study due to progressive disease. Serious adverse events were reported in 
4 subjects (14%) including influenza, viral infection, hypokalemia and hyponatremia/atrial 
fibrillation. No AEs leading to discontinuation of treatment were reported during the study. 
There were approximately 34%, 25%, and 11% decreases in the geometric mean abiraterone 
Cmax, AUC0-24h, and Cmin, respectively when AAP was co-administered with apalutamide. These 
decreases were not considered to be clinically relevant. Refer to Investigator’s Brochure 
(Section 4.3.3.3) for further details.18
Study ARN-509-003 is a Phase 3 study of apalutamide compared with placebo in patients with 
high-risk (defined as a PSA doubling time ≤10 months) NM-CRPC, which is also ongoing. 
Study 56021927PCR3002 is an ongoing Phase 3 study of apalutamide compared with placebo in 
patients with hormone-sensitive mCRPC, and Study 56021927PCR3003 is an ongoing study of 
apalutamide compared with placebo in subjects with high-risk, localized or locally advanced
prostate cancer receiving treatment with primary radiation therapy.
1.2.
Control
ZYTIGA® (abiraterone acetate; JNJ-212082)
Abiraterone acetate in combination with prednisone or prednisolone is the currently accepted 
standard regimen for front-line treatment of patients with mCRPC, will be used as the active 
control.
In clinical studies in subjects with mCRPC, the most common AEs related to AA have included 
fatigue most likely attributable to the underlying disease, and hypertension, hypokalemia, fluid 
retention/edema, due to mineralocorticoid excess caused by compensatory adrenocorticotropic 
hormone (ACTH) drive. In this study, low-dose prednisone is expected to mitigate these effects 
through abrogation of the ACTH drive.

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Abiraterone acetate should be used with caution in subjects with a history of cardiovascular 
disease. Caution should be exercised when treating subjects whose underlying medical 
conditions might be compromised by increases in blood pressure, hypokalemia, or fluid 
retention. For further information regarding AA, prednisone or prednisolone refer to the local 
prescribing information.
1.3.
Overall Rationale for the Study
Abiraterone acetate and apalutamide are both directed at the androgen axis with very distinct 
mechanisms to inhibit AR activation. AA exerts its effect through inhibition of androgen 
biosynthesis while apalutamide targets the AR. Moreover, they do not appear to have 
overlapping clinical toxicity in patients.
There is also early evidence that the combination of both drugs could theoretically delay the 
emergence of clinical resistance to either drug. Despite the survival benefit associated with AA 
treatment of mCRPC, both primary and secondary resistance to AA has been observed. In 
xenograft models of CRPC, treatment with AA inhibits tumor growth, production of serum PSA, 
and intratumoral androgens, thereby indicating that the anti-tumor activity of AA is primarily 
through effects on tissue androgens. Accompanying the marked suppression of tumor androgen 
levels are increased expression of the AR, ligand-independent AR splice variants, and induction 
of steroidogenic genes including CYP17A1.14 The increased expression of several of these genes 
showed strong correlation with dihydrotestosterone (DHT) levels in recurrent tumors. These data 
suggest that resistance can potentially be targeted by using combinations with potent AR 
antagonists such as apalutamide.
The availability of 2 highly active agents from different classes with complementary mechanisms
raises the important scientific and clinical question of whether the benefit of the combination is 
superior to that of individual agents and can overcome mechanisms of resistance developed to 
either drug alone. Three separate studies conducted at a single institution with AAP, 
enzalutamide, and the combination of AAP and enzalutamide showed improved PSA response 
with AR combination therapy compared with either agent alone (Figure 1).11,12,13,14 In the 
waterfall plot below (far right), the single arm study with the combination of AAP and 
enzalutamide in patients with mCRPC (data from 41 patients) showed a PSA response rate
(12-weeks, ≥ 50% reduction) of 76% (higher than either single agent) and a favorable safety 
profile.12

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Figure 1:
PSA Response With AR Combination Therapy in mCRPC
Source: Efstathiou et al ESMO Oral presentation Sept 2013.12
Taken together, these data suggest that the combination of apalutamide and AAP may have 
activity superior than either drug alone or may help avoid the adaptive responses resulting in 
resistance.11,12,13,14
A randomized, double-blind, placebo-controlled study is needed to obtain definitive data on the 
clinical benefit and safety of combining a potent anti-androgen (apalutamide) and AAP. 
Study 56021927PCR3001 is designed to assess the efficacy and safety of apalutamide in 
combination with AAP compared with AAP in subjects with chemotherapy-naïve mCRPC and 
will explore mechanisms of resistance that may develop with treatment.
2.
OBJECTIVES AND HYPOTHESIS
2.1.
Objectives
Primary Objective
The primary objective is to compare the radiographic progression-free survival (rPFS) of 
apalutamide in combination with AA plus prednisone or prednisolone (AAP) and AAP in 
subjects with chemotherapy-naïve mCRPC.
Major Secondary Objectives
The major secondary objectives are:

To characterize the safety profile of apalutamide in combination with AAP

To characterize the pharmacokinetics (PK) of apalutamide and abiraterone
Other Objectives
The other objectives are:

To explore the relationship between PK and pharmacodynamics (PD) of apalutamide and 
abiraterone

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
To evaluate exploratory biomarkers predictive of response and resistance in subjects when 
treated with apalutamide in combination with AAP compared with AAP

To assess the effect on patient-reported outcomes (PROs) in this study population when 
treated with apalutamide in combination with AAP compared with AAP

To evaluate other endpoints of clinical relevance including additional assessments of pain, 
objective response, time to symptomatic skeletal-related event (SSRE), and PSA response

To evaluate medical resource utilization (MRU) information
2.2.
Hypothesis
The primary hypothesis of the study is that apalutamide in combination with AAP compared 
with AAP will demonstrate improved rPFS and an acceptable safety profile in subjects with 
chemotherapy-naïve mCRPC.
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is a randomized, double-blind placebo-controlled, multinational, multicenter Phase 3 study 
to determine if subjects with chemotherapy-naïve mCRPC will benefit from the addition of 
apalutamide to AAP compared with AAP. Subjects will continue ADT (in this study, GnRHa or 
surgical castration). Approximately 960 subjects who meet all the inclusion criteria and none of 
the exclusion criteria will be randomized in a 1:1 ratio to receive apalutamide and AAP or 
matching placebo and AAP. Subjects will be stratified by the presence or absence of visceral 
metastases, Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) grade of 0 
or 1, and region (European Union [EU], North America [United States/Canada], and Rest of 
World [ROW]). The study will consist of a Screening Phase; a Treatment Phase, and a Follow-
up Phase. The study is anticipated to end approximately 84 months after the first subject is 
randomized. A study design scheme is provided in Figure 2.
A treatment cycle is defined as 28 days. Treatment will continue until disease progression, 
unacceptable toxicity, death or the sponsor terminates the study. Subjects must discontinue study 
drugs with documented unequivocal clinical progression (see Section 10.2). If the subject has 
radiographic progression, but not unequivocal clinical progression, and alternate treatment is not 
initiated, the subject may continue on study treatment at the investigator’s discretion.
After discontinuing study drug, subjects will be contacted every 3 months (see Section 9.1.5)
until death or termination of the study. In addition to survival follow up, analgesic use, SSREs,
ECOG PS, and subsequent therapy for prostate cancer up to and including chemotherapy will be
collected. Patient-reported outcomes (PROs) questionnaires will also be administered every 
3 months for up to 12 months after treatment discontinuation.
Subjects will be monitored for safety during the Screening and Treatment Phases and up to 
30 days after the last dose of study drug. Adverse events, including clinically significant
laboratory abnormalities reported as AEs, will be graded and summarized using National Cancer 

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Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.03. Dose 
modification guidelines will be provided.
An Independent Data Monitoring Committee (IDMC) will be commissioned for the study to 
perform regular safety review and the planned interim analyses. Refer to Section 11.11,
Independent Data Monitoring Committee, for details.
A diagram of the study design is provided below in Figure 2.
Figure 2:
Schematic Overview of the Study Until the Start of the Extension Phase (Open-Label Extension 
or Long-Term Extension)
AAP=abiraterone acetate plus prednisone/prednisolone; ADT=androgen deprivation therapy, BPI-SF=Brief Pain 
Inventory-Short Form; ECOG=Eastern Cooperative Oncology Group; GnRHa=gonadotropin releasing hormone 
analog; mCRPC=metastatic castration-resistant prostate cancer; NA=North America (United States, Canada) 
PRO=patient-reported outcomes; SSRE=symptomatic skeletal-related event; ROW=Rest of World.

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Following the decision to unblind the study, the Extension Phase will begin when both the 
Amendment 4 is approved at the site and the sponsor has notified the site of the start of the 
Open-Label Extension Phase or Long-Term Extension Phase. Details are provided in 
Attachment 9 (Open-Label Extension: to be followed in case of subjects being offered cross-over 
to open-label apalutamide in combination with AAP) and Attachment 10 (Long-Term Extension:
to be followed in case of limited data collection after unblinding when cross-over is not 
recommended).
3.2.
Study Design Rationale
Abiraterone acetate in combination with prednisone has been approved for the treatment of men 
with mCRPC before and after chemotherapy. The efficacy and safety of AAP therapy in patients 
with mCRPC are established by the results of the Phase 3 multinational, randomized, double-
blind, placebo-controlled studies Study COU-AA-301 (post-chemotherapy) and Study 
COU-AA-302 (chemotherapy-naïve).10,27,29
The dose of 1,000 mg AA daily and 5 mg twice daily prednisone is the prescribed dose for 
patients with mCRPC. The rationale for the combination and choice of active comparator is 
discussed in Section 1.3. The dose of 240 mg daily of apalutamide is the dose determined from 
the Study ARN-509-001 PK/pharmacodynamic study and is the therapeutic dose (see 
Section 1.1.2).
Blinding, Control, Study Phase/Periods, Treatment Groups
This is a randomized, double-blind, placebo-controlled study. Randomization will be used to 
minimize bias in the assignment of subjects to treatment groups, to increase the likelihood that 
known and unknown subject attributes (eg, demographic and baseline characteristics) are evenly 
balanced across treatment groups, and to enhance the validity of statistical comparisons across 
treatment groups. Blinding will also enhance the validity of PRO data.
Population Pharmacokinetics
The assessment of PK is important in understanding the exposure levels of apalutamide and 
abiraterone in this patient population when apalutamide and AA are administered concurrently. 
The study includes a sparse pharmacokinetic sampling strategy for population PK purposes, 
which can serve as a means to derive the individual subject’s exposure to apalutamide and 
abiraterone. In addition to determination of covariates that influence the PK of the drug, the data 
may provide supportive evidence for the efficacy and safety analyses and identify at-risk subjects 
who require a dose-adaptation.
Biomarker Collection
The goal of the biomarker study is to obtain additional information on resistance mechanisms. 
Archived tumor samples (formalin-fixed paraffin-embedded [FFPE] blocks or slides) and serum 
samples will be collected, where country regulations permit, for biomarker evaluations. Results 
from Study ARN-509-001 in patients with CRPC provide evidence that an acquired mutation in 
AR (ARF876L) may be associated with resistance to apalutamide.20 Multiple other biomarkers 
have been shown to be associated with resistance to abiraterone, enzalutamide or apalutamide. 

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These include AR gene anomalies (eg,: AR amplification, ARv3/7, and ARv567), and expression 
of AR axis genes such as TMPRSS-ERG, AGR2, HSD3B1, HSD3B2, HSD17B, PGR, 
AKR1C3, SRD5A1, CYB5A, CYP17A1, DUSP5, HNF1A, NR0B1, POR, ANLN, NUSAP, 
etc.2,3,23,33 Circulating tumor DNA and RNA can be detected in blood samples but in limited 
quantities, therefore, corresponding candidate biomarkers representing resistance classes will be 
analyzed in plasma (DNA) or whole blood (PAXgene RNA).26,28 Plasma-based circulating DNA 
will be used to assess the presence of the ARF876L mutation and copy number variations, while 
ribonucleic acid (RNA) extracted from whole blood will be used to assess other markers that 
may be associated with resistance to abiraterone acetate alone and in combination with 
apalutamide. Understanding the frequency of patients developing the ARF876L mutation and the 
timing for development of the ARF876L mutation may inform both how many and when patients 
may need alternative treatments. Understanding the frequency of patients developing other 
resistance mechanisms will inform future combination treatments with apalutamide. Previous 
data show that treatment with AAP decreases testosterone while treatment with enzalutamide can 
increase serum testosterone concentration.11 Serum samples will be collected to test the effect of 
AAP alone and in combination with apalutamide, on testosterone and steroid metabolites.
Plasma samples will be collected from approximately 220 subjects during treatment and 
approximately 500 subjects at EOT and whole blood will be collected from approximately
220 subjects at the time points indicated in the Time & Events Schedule. Samples are being 
collected at baseline, Cycle 12, and at time of progression. The samples collected at Cycle 12 are 
intended to evaluate emergence of acquired resistance such as AR mutation.20 Serum samples 
will be collected from approximately 220 subjects at time points indicated in the Time and 
Events Schedule. Intermediate time points were selected to capture changes in hormone levels.11
Recently, studies have identified molecular classifiers that are superior to existing measures of 
stratifying high-risk disease.17,22 Archival FFPE tumor samples are also being collected to 
determine if genomic classifiers can be used to identify a more homogeneous population of 
high-risk patients. This will potentially allow selection of the appropriate high-risk patient 
population for future studies of apalutamide and AA in early disease settings.
Patient-reported Outcomes
The goal of collecting PRO data is to explore patient benefits in pain, fatigue, and functional 
status. In both Studies COU-AA-301 and COU-AA-302, significant delay in pain progression 
and improvements in functional status were found for AAP compared with prednisone plus 
placebo. Patient-reported outcomes will be measured utilizing the EQ-5D-5L, BPI-SF, and 
FACT-P questionnaires. The FACT-P questionnaire will provide an assessment of the subject’s 
self-reported functional status, well-being, and prostate cancer symptoms over time. It is 
important to establish that addition of apalutamide to AAP does not result in a deterioration of 
functional status compared with AAP. The EQ-5D-5L assessment will provide estimates of 
utility to include in future cost-effectiveness models. Data will be collected throughout the study 
as well as during the Follow-up Period (up to 12 months after study treatment discontinuation) as 
specified in the Time and Events Schedule.

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Medical Resource Utilization Data Collection
Medical resource utilization data, associated with medical encounters, will be collected in the 
electronic case report form (eCRF) by the investigator and staff for all subjects throughout the 
study. For each AE that occurs, MRU information associated with that AE should be recorded 
when possible. Protocol-mandated procedures, tests, and encounters are excluded. Data may be 
used to conduct exploratory economic analyses.
4.
SUBJECT POPULATION
The inclusion and exclusion criteria for enrolling subjects in this study are described in the 
following 2 subsections. If there is a question about the inclusion or exclusion criteria below, the 
investigator should consult with the appropriate sponsor representative before enrolling a subject 
in the study.
4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study.
1.
Subject must be a man age ≥18 years of age inclusive
2.
Adenocarcinoma of the prostate
3.
Metastatic disease as documented by technetium-99m (99mTc) bone scan or metastatic 
lesions by computed tomography (CT) or magnetic resonance imaging (MRI) scans 
(visceral or lymph node disease). If lymph node metastasis is the only evidence of 
metastasis, it must be ≥2 cm in the longest diameter.
4.
Castration-resistant prostate cancer demonstrated during continuous ADT, defined as 
3 rises of PSA, at least 1 week apart with the last PSA ≥2 ng/mL
5.
Criterion modified per Amendment 1
5.1.
Patients who received a first generation anti-androgen (eg, bicalutamide, flutamide,
nilutamide) must have at least a 6-week washout prior to randomization AND must 
show continuing disease (PSA) progression (an increase in PSA) after the washout
period.
6.
Criterion modified per Amendment 1
6.1.
Prostate cancer progression documented by PSA according to the Prostate Cancer
Clinical Trials Working Group (PCWG2); radiographic progression of soft tissues 
according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST) 
(Attachment 1) modified based on PCWG2, or radiographic progression of bone 
according to PCWG2.
7.
Criterion modified per Amendment 1

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7.1.
Surgically or medically castrated, with testosterone levels of <50 ng/dL. If the subject is 
being treated with GnRH analogs (subject who has not undergone bilateral 
orchiectomy), this therapy must have been initiated at least 4 weeks prior to 
randomization and must be continued throughout the study
8.
ECOG PS grade of 0 or 1 (Attachment 2)
9.
A score of ≤3 on the Brief Pain Inventory-Short Form (BPI-SF) Question #3 (worst pain 
in last 24 hours) 
10.
Bisphosphonates or denosumab usage is allowed only if subjects are on a stable dose for 
at least 4 weeks prior to randomization
11.
Clinical laboratory values at Screening: 

Hemoglobin 9.0 g/dL, independent of transfusion and/or growth factors within 
3 months prior to randomization

Platelet count ≥100,000 x 109/µL independent of transfusion and/or growth factors 
within 3 months prior to randomization

Serum albumin ≥3.0 g/dL

Serum creatinine <2.0 × upper limit of normal (ULN)

Serum potassium ≥3.5 mmol/L

Serum total bilirubin 1.5 × ULN (Note: In subjects with Gilbert’s syndrome, if 
total bilirubin is >1.5 × ULN, measure direct and indirect bilirubin and if direct 
bilirubin is ≤1.5 × ULN, subject may be eligible)

Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) <2.5 × ULN
12.
Able to swallow the study drug tablets whole
13.
Criterion modified per Amendment 1
13.1.
Agrees to use a condom (even men with vasectomies) and another effective method of 
birth control if he is having sex with a woman of childbearing potential or agrees to use 
a condom if he is having sex with a woman who is pregnant while on study drug and for 
3 months following the last dose of study drug. Must also agree not to donate sperm 
during the study and for 3 months after receiving the last dose of study drug.
14.
Subject must be willing and able to adhere to the prohibitions and restrictions specified 
in this protocol (refer to Section 4.3)
15.
Each subject must sign an informed consent form (ICF) indicating that he understands
the purpose of and procedures required for the study and are willing to participate in the 
study
4.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study.

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1.
Small cell or neuroendocrine carcinoma of the prostate
2.
Known brain metastases
3.
Prior 
chemotherapy 
for 
prostate 
cancer, 
except 
if 
administered 
in 
the 
adjuvant/neoadjuvant setting
4.
Previously treated with ketoconazole for prostate cancer for greater than 7 days
5.
Therapies that must be discontinued or substituted at least 4 weeks prior to 
randomization include the following:

Medications known to lower the seizure threshold (see Attachment 3)

Herbal and non-herbal products that may decrease PSA levels (eg, saw palmetto, 
pomegranate)

Any investigational agent 
6.
Criterion modified per Amendment 1
6.1.
At screening,
need for parenteral or oral opioid
analgesics (eg, codeine, 
dextropropoxyphene)
7.
Subjects currently treated with spironolactone
8.
Previously treated with abiraterone acetate or other CYP17 inhibitor
9.
Previously treated with enzalutamide or other androgen signaling inhibitors
10.
Criterion modified per Amendment 1
10.1.
History of any of the following:

Seizure or known condition that may pre-dispose to seizure (including but not 
limited to prior stroke, transient ischemic attack, loss of consciousness within 
1 year prior to randomization, brain arteriovenous malformation; or intracranial 
masses such as schwannomas and meningiomas that are causing edema or mass 
effect)

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

Severe or unstable angina, myocardial infarction, symptomatic congestive heart 
failure, arterial or venous thromboembolic events (eg, pulmonary embolism, 
cerebrovascular accident including transient ischemic attacks), or clinically 
significant ventricular arrhythmias within 6 months prior to randomization or New 
York Heart Association (NYHA) Class II to IV heart disease

Any condition that in the opinion of the investigator, would preclude participation 
in this study

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11.
Current evidence of any of the following:

Uncontrolled hypertension (systolic blood pressure ≥160 mmHg or diastolic blood 
pressure ≥90 mmHg)

Gastrointestinal disorder affecting absorption

Active infection (eg, human immunodeficiency virus [HIV] or viral hepatitis) or 
other medical condition that would make prednisone/prednisolone (corticosteroid) 
use contraindicated

Any chronic medical condition requiring a higher dose of corticosteroid than 10 mg 
prednisone/prednisolone once daily

Any condition that in the opinion of the investigator, would preclude participation 
in this study
12.
Subject has known allergies, hypersensitivity, or intolerance to abiraterone acetate or
apalutamide or its excipients (refer to Investigator's Brochure)18
13.
Subject plans to father a child while enrolled in this study or within 3 months after the 
last dose of study drug
14.
Treatment with 5-α reductase inhibitors (finasteride, dutasteride), estrogens, cyproterone 
within 4 weeks of enrollment
4.3.
Prohibitions and Restrictions
Potential subjects must be willing and able to adhere to the following prohibitions and 
restrictions during the course of the study to be eligible for participation:
1.
Refer to Sections 8.2 and 8.3 for details regarding prohibited and restricted therapy 
during the study
2.
If the subject 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 subjects 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 system (IUS);

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
3.
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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5.
TREATMENT ALLOCATION AND BLINDING
Treatment Allocation
Procedures for Randomization and Stratification
Subjects will be randomly assigned to the AAP plus apalutamide group or AAP alone group in a 
1:1 ratio. Randomization will take place across all study-sites using a centralized Interactive Web 
Response System (IWRS). A randomization scheme will be performed using permuted block 
randomization. Subjects will be stratified by presence or absence of visceral metastasis, ECOG
PS grade (0 or 1), and region (NA, EU, ROW).
At randomization, the IWRS will assign a unique subject identification number to each subject. 
The subject’s identification number will be used on all study-related documents including 
eCRFs. A treatment number will also be assigned to each subject. This treatment number is the 
link between a subject’s eCRF and blinded treatment group assignment. Subject identification 
numbers will not be reused. Subjects withdrawn from the study will not be replaced. All subjects 
must commence treatment within 72 hours or 3 calendar days of randomization.
Blinding
The investigator will not be provided with randomization codes. The codes will be maintained 
within the IWRS, which has the functionality to allow the investigator to break the blind for an 
individual subject in the case of an emergency.
Data that may potentially unblind the treatment assignment (ie, study drug serum concentrations,
study drug preparation/accountability data, treatment allocation, biomarker or other specific 
laboratory data) will be handled with special care to ensure that the integrity of the blind is 
maintained and the potential for bias is minimized. This can include making special provisions, 
such as segregating the data in question from view by the investigators, clinical team, or others 
as appropriate until the time of database lock and unblinding.
Under normal circumstances, the blind should not be broken until completion of the study or the 
IDMC recommendation for unblinding is accepted by the sponsor and the database is finalized. 
Otherwise, the blind should be broken only if specific emergency treatment/course of action 
would be dictated by knowing the treatment status of the subject. In such cases, the investigator 
may in an emergency determine the identity of the treatment by contacting the IWRS. It is 
recommended that the investigator contact the sponsor or its designee if possible to discuss the 
particular situation, before breaking the blind. Telephone contact with the sponsor or its designee 
will be available 24 hours per day, 7 days per week. In the event the blind is broken, the sponsor 
must be informed as soon as possible. The date, time, and reason for the unblinding must be 
documented in the IWRS, in the appropriate section of the eCRF and in the source document. 
The documentation received from the IWRS indicating the code break must be retained with the 
subject's source documents in a secure manner.
Subjects who have had their treatment assignment unblinded should be discontinued from the 
Treatment Phase and entered in the Follow-up Phase.

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In general, randomization codes will be disclosed fully only if the study is completed and the 
clinical database is closed. However, if an interim analysis is specified, the randomization codes 
and, if required, the translation of randomization codes into treatment and control groups will be 
disclosed to those authorized and only for those subjects included in the interim analysis.
6.
DOSAGE AND ADMINISTRATION
All subjects will receive AAP as standard of care (SOC) therapy. Investigators should refer to the 
Investigator’s Brochure and package inserts for the storage and handling, and detailed 
instructions on the administration of AA and prednisone/prednisolone. Where prednisone is not 
commercially available, prednisolone will be substituted.
Subjects will be randomized on 1:1 ratio to receive either JNJ-56201927 (apalutamide) or
matching placebo.
6.1.
ADT Administration
Continuous treatment with a GnRHa or surgical castration is mandatory for all subjects 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. For subjects who did not undergo surgical castration, 
concurrent treatment with a GnRHa must be documented in the eCRF.
6.2.
Study Treatment Administration
Study treatment is administered orally on an outpatient basis and a treatment cycle is defined as 
28 days (Table 1). Sufficient study drug for each treatment cycle will be distributed on the first 
day of each cycle up to Cycle 24, then every 3 cycles (see Time and Events Schedule). Subjects 
will begin taking study drug on Day 1 of Cycle 1. Dose modifications for toxicity are provided in
Section 6.3.
Table 1: 
Study Treatment Administration
Study Treatments
Daily Dose
Schedule
apalutamide/placebo
240 mg (4 x 60 mg tablets)
qd with or without food (except during PK 
sampling, see Section 6.2.1)
AA
1,000 (4 x 250 mg tablets)
qd on empty stomach. No food should be 
consumed for at least 2 hours before the 
dose of AA is taken and at least 1 hour 
after the dose of AA is taken. Swallow 
tablets whole with water. 
Prednisone
10 mg (2 x 5 mg tablets)
5 mg twice daily (recommended to be 
taken with food)
AA=abiraterone acetate; qd=once daily

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If a dose of apalutamide (or placebo) alone, AAP alone or both is missed, it should be omitted 
and will not be made up or taken with the next dose the following day. If a subject forgets to take 
a dose of either apalutamide (or placebo) or AAP, the dose should only be replaced if the subject 
remembers and takes the dose within a 12-hour window.
6.2.1.
Special Dosing and Meal Instructions for PK Visits
Table 2 provides a summary of the schedule and dosing instructions for PK sample collection 
(see also Section 9.3.1). A modified dosing schedule will be required on PK sampling days. On 
the days when PK samples are collected (Day 1 of Cycles 1, 2, 3, 4, 5, and 6), apalutamide and 
AA must be administered in the clinic after initial PK samples are collected.
Table 2: 
Schedule and Dosing Instructions for PK Sample Collection
C1D1
C2D1
C3D1
C4D1, C5D1, C6D1
No food for at least 2 hrs 
before dosing and at least 
1 hr after dosing
No predose PK sample
apalutamide and AA 
administered at same time 
in the clinic
PK samples collected at 
2 hrs and 4 hrs postdose
No food for at least 2 hrs 
before dosing and at least 
1 hr after dosing
Predose PK sample taken 
up to 1 hr prior to study 
drug administration
apalutamide and AA 
administered at same time 
in the clinic
No food for at least 2 hrs 
before dosing and at least 
1 hr after dosing
Predose PK sample taken 
up to 1 hr prior to study 
drug administration
apalutamide and AA 
administered at same time 
in the clinic
PK samples collected 
between 0.5 hr and 4 hrs 
postdose
Same as C2D1
AA=abiraterone acetate; PK=pharmacokinetics; C=cycle; D=day
In addition, the following information should be recorded in the eCRF:
1. Actual times of AA and apalutamide/placebo dosing one day before and during the day of all 
PK visits
2. Actual time of last meal time prior to dosing on Day 1 of Cycle 1 and Cycle 3
3. Actual time of first meal time after dosing on Day 1 of Cycle 1 and Cycle 3
6.3.
Dose Modification and Management of Toxicity
General principles on dose modifications:

Grade 1 or Grade 2 toxicities should be managed symptomatically without dose adjustments. 
Appropriate medical treatment should be used.

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
In the event of a Grade 3 or higher toxicity, which cannot definitively be attributed to AA or 
apalutamide/placebo, both AA and apalutamide/placebo should be held until toxicity has 
resolved to Grade 1 or baseline.

If Grade 3 or higher toxicity does not resolve to Grade 1 or baseline within 2 cycles, the 
subject should be discontinued from treatment or the investigator’s rationale to continue 
treatment must be discussed with the sponsor.

Dose reduction guidelines and management of toxicities provided in Sections 6.3.1, 6.3.2, 
and 6.3.3. A subject may have up to 2 dose adjustments for the same toxicity and if the same 
toxicity recurs at Grade 3 or higher after 2 dose adjustments, the subject should discontinue 
study treatment(s); any exceptions are noted in the individual sections.

Dose modifications are provided as guidance and should not replace the investigator’s own 
clinical judgment.

The dose of prednisone can remain unchanged with dose modifications of AA or 
apalutamide/placebo.

The investigator’s rationale to re-escalate treatment must be discussed with the sponsor’s 
medical monitor on an individual basis prior to implementation.
6.3.1.
Toxicity Attributed to Prednisone
Prednisone may be associated with fatigue, increased appetite, insomnia, weakness, 
hyperglycemia, ecchymosis, and symptoms related to gastroesophageal reflux. With long-term 
glucocorticoid therapy, subjects may develop Cushing’s syndrome, characterized by central 
obesity, thin skin, easy bruising, bone loss, avascular necrosis of the hip, cataract and proximal 
myopathy. Withdrawal of the corticosteroid may result in symptoms that include fever, myalgia, 
fatigue, arthralgia, and malaise. This may occur even without evidence of adrenal insufficiency. 
The dose of prednisone may be gradually reduced (to 5 mg) if clinically indicated and must not 
be discontinued while the subject receives AA.
6.3.2.
Toxicity Attributed to Abiraterone Acetate
6.3.2.1.
Abnormal Liver Function Test(s)
Table 3 provides dose modification recommendations for subjects who develop liver function 
test (LFT) abnormalities during treatment. For subjects being re-treated, serum transaminases 
should be monitored at a minimum of every 2 weeks for 3 months and monthly thereafter.

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Table 3: 
Dose Modifications for LFT Abnormalities Attributed to Abiraterone Acetate
Toxicity
Dose of AAb
Dose of 
apalutamide/placebo
Dose of prednisone
Grade 1 or 2a
No change
No change 
No change
Grade 3a
Hold until return to baseline
or to AST or ALT 
≤2.5 x ULN and total bilirubin 
≤1.5 x ULN, resume at 
750 mg (3 tablets) only after 
discussion and agreement 
with medical monitor
Hold until return to baseline 
No change
Recurrence 
Grade 3
Hold until return to baseline
or to AST or ALT 
≤2.5 x ULN and total bilirubin
≤1.5 x ULN, resume at 
500 mg (2 tablets) only after 
discussion and agreement 
with medical monitor
Hold until return to baseline 
No change
Grade 4a
Discontinue AA treatment
Hold until return to baseline 
No change or consider 
tapering if AA discontinued
AA=abiraterone acetate; ALT=alanine aminotransferase; AST=aspartate aminotransferase; LFT=liver function tests;
NCI-CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; ULN=upper limit of 
normal
a  NCI-CTCAE, Version 4.03: Grade 1=AST or ALT from ULN to 3 x ULN, increase in total bilirubin from ULN 
to 1.5 x ULN; Grade 2=AST or ALT from >3 x ULN to 5 x ULN, increase in total bilirubin from >1.5 x ULN to 
3 x ULN; Grade 3=AST or ALT from >5 x ULN to 20 x ULN, increase in total bilirubin to >3 x ULN to 10 x ULN; 
Grade 4=AST or ALT>20 x ULN, increase in total bilirubin >10 x ULN. 
b  Abiraterone acetate dose modifications for LFT abnormalities are from the ZYTIGA label and do not follow
Version 4 of CTCAE.
If clinical symptoms or signs suggestive of hepatotoxicity develop, serum transaminases, in 
particular serum ALT, should be measured immediately. If subjects develop severe 
hepatotoxicity (ALT 20 x ULN) anytime while on abiraterone acetate, subjects should be 
discontinued and not be re-treated with abiraterone acetate.
Subjects who develop a concurrent elevation of ALT >3 X ULN and a total bilirubin >2 X ULN 
in the absence of biliary obstruction or other causes responsible for the concurrent elevation 
should be permanently discontinued from treatment with abiraterone acetate.
6.3.2.2.
Hypertension, Hypokalemia, and Fluid Retention/Edema Due to 
Mineralocorticoid Excess
In subjects who develop hypokalemia on study treatment, consider maintaining the subject’s 
potassium level at 4.0 mM or higher. If hypokalemia persists despite optimal potassium 
supplementation and adequate oral intake, discuss with the sponsor. Table 4 provides dose 
modification recommendations for drug-related hypokalemia.

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Table 4: 
Dose Modifications for Hypokalemia Attributed to Abiraterone Acetate
Toxicity
Dose of AA
Dose of apalutamide/placebo
Dose of prednisone
Grade 1 or 2
Initiate oral potassium 
supplementation, titrate to 
≥3.5 to ≤5.0 mmol/L, 
maintenance at ≥4.0 mmol/L
recommended
No change
No change
≥Grade 3
Hold and initiate IV 
potassium and cardiac 
monitoring, resume only after 
discussion and approval by 
the medical monitor
No change
No change or consider 
tapering if AA is 
discontinued
AA=abiraterone acetate
For subjects who develop drug-related Grade 3 or higher hypertension, AA must be withheld and
adjustment of anti-hypertensive medication should be considered (see also Table 5 below).
Table 5: 
Dose Modifications for Hypertension and Edema/Fluid Retention Attributed to Abiraterone 
Acetate
Toxicity
Dose of AA
Dose of apalutamide/placebo
Dose of prednisone
Grade 1 or 2
No change
No change
No change
≥Grade 3
Hold until Grade 1 or 
baseline, resume at full dose
No change
No change
First 
Recurrence 
≥Grade 3
Hold until Grade 1 or 
baseline, resume at 750 mg 
(3 tablets)
No change
No change
Second
Recurrence 
≥Grade 3
Hold until Grade 1 or 
baseline, resume at 500 mg 
(2 tablets)
No change
No change
Third 
Recurrence 
≥Grade 3
Discontinue
No change
No change or consider 
tapering if AA is 
discontinued
AA=abiraterone acetate
6.3.3.
Toxicity Attributed to Apalutamide/Placebo
Table 6 provides dose modifications for apalutamide/placebo.

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Table 6: 
Dose Modifications for Toxicity Attributed to Apalutamide/Placebo
Toxicity
Dose of AA
Dose of apalutamide/placebo
Dose of prednisone
Grade 1 or 2
No change
No change
No change
≥Grade 3 or 
higher
No change
Hold until Grade 1 or baseline, 
resume at full dose
No change
First 
Recurrence 
≥Grade 3
No change
Hold until Grade 1 or baseline, 
resume at
180 mg (3 tablets)
No change
Second 
Recurrence 
≥Grade 3
No change
Hold until Grade 1 or baseline, 
resume at 120 mg (2 tablets)
No change
Third 
Recurrence 
≥Grade 3
No change
Discontinue
No change
First occurrence 
of seizure of 
any grade or 
Grade 4 
neurotoxicity
No change
Discontinue
No change
AA=abiraterone acetate
7.
TREATMENT COMPLIANCE
Accurate records of all drug shipments as well as tablets dispensed and returned will be 
maintained. This inventory must be available for inspection by designated sponsor or regulatory 
authority representatives at any time. Drug supplies are to be used only in accordance with this 
protocol and under the supervision of the investigator. A count of all study drug provided by the 
sponsor will be conducted during the Treatment Phase of this study. Study drug will be 
dispensed and dosing compliance will be assessed at study visits as described in the Time and 
Events Schedule.
In the absence of toxicity, if the dosing compliance is not 100%, then investigators or designated 
study-site personnel should re-instruct subjects regarding proper dosing procedures and the
subject may continue study treatment.
The study-site must maintain accurate records demonstrating dates and amount of study drug 
received, to whom dispensed (subject by subject accounting), and accounts of any study drug 
accidentally or deliberately destroyed. At the end of the study, reconciliation must be made 
between the amount of study drug supplied, dispensed, and subsequently destroyed or returned to 
sponsor or its representative.
8.
PRESTUDY AND CONCOMITANT THERAPY
Concomitant therapies must be recorded throughout the study beginning with signing of 
informed consent to 30 days after the last dose of study drug. Therapies (prescription or over the 
counter medications for systemic conditions and treatment of AEs) different from the study drug 

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must be recorded in the eCRF. Recorded information will include a description of the type of the 
drug, treatment period, dose and dosing regimen, route of administration, and indication. 
Concurrent enrollment in another investigational drug or device study is prohibited. The sponsor 
must be notified in advance (or as soon as possible thereafter) of any instances in which 
prohibited therapies are administered.
8.1.
Permitted Supportive Care Medications
Supportive care medications are permitted with their use following institutional guidelines. The 
following supportive care medications are considered permissible during the study:

Intermittent short course of opioid analgesics would be allowed for pain control (see also 
Section 10.2 regarding the use of chronic opioid analgesics for pain)

Bone modifying agents, including bisphosphonates and denosumab, should be used in 
accordance with label indications to help preserve bone mineral density during cancer 
treatment (including ADT) and skeletal integrity in subjects with bone metastasis.

Conventional multivitamins, selenium and soy supplements

Eplerenone can be used to manage mineralocorticoid-related toxicities

Additional systemic glucocorticoid administration such as “stress dose” glucocorticoid is 
permitted when clinically indicated for a life-threatening medical condition, and in such 
cases, the use of steroids will be documented as concomitant drug

Transfusions and hematopoietic growth factors per institutional practice guidelines
If the permissibility of a specific drug/treatment is in question, please contact the sponsor.
8.2.
Prohibited Concomitant Medications
As a class effect, AR antagonists (anti-androgens) have been associated with seizures due to an 
off-target mechanism of action (gamma aminobutyric acid chloride channel [GABAA]
inhibition). Therefore, drugs known to lower the seizure threshold or cause seizures are 
prohibited. A list of these prohibited therapies is provided in Attachment 3 of the protocol.
Other prohibited concomitant medications include: 

Investigational agents other than apalutamide

Other anti-cancer therapy

Other agents that target the androgen axis (eg, anti-androgens, CYP17 inhibitors)

Radiotherapy

5-α-reductase inhibitors 

Chemotherapy

Immunotherapy

Systemic ketoconazole (or other azole drugs such as fluconazole or itraconazole) 

Diethylstilbestrol (DES) or similar

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
Other preparations such as pomegranates or pomegranate juice or saw palmetto thought to 
have endocrine effects on prostate cancer

Spironolactone

Radiopharmaceuticals such as strontium (89Sr) or samarium (153Sm) or similar analogs such 
as radium-223 (223Ra)
The concurrent administration of hormonal therapy (except GnRHa as described above), other 
anti-cancer therapy, including cytotoxic, biological, and immunotherapy is prohibited while 
subjects are being treated with study drug.
If the permissibility of a specific drug/treatment is in question, please contact the sponsor.
8.3.
Restricted Concomitant Medications
Highlights of drug interaction with apalutamide and abiraterone are summarized below. Refer to 
the Investigator’s Brochure (Sections 4.3.4 and 5.10) and associated addenda for complete 
details on the drug interaction potential of apalutamide.18

Strong inhibitors of CYP2C8 or CYP3A4: Caution should be used with co-administration of 
a strong CYP2C8 or CYP3A4 inhibitor with apalutamide as it may increase the exposures of 
apalutamide and its active metabolite. No initial dose adjustment is necessary; however, 
consider reducing the apalutamide dose based on individual tolerability (see Section 6.3).

Apalutamide is a moderate to strong inducer of CYP3A4 and CYP2C19, and a weak inducer 
of CYP2C9 in humans. Caution should be used with co-administration of medications that 
are primarily metabolized by CYP3A4, CYP2C19, or CYP2C9 as apalutamide can result in 
lower exposure to these medications. Substitution for these medications is recommended 
when possible or evaluate for loss of efficacy if medication is continued. Concomitant 
administration of apalutamide with medications that are substrates of uridine diphosphate 
glucuronosyl transferase (UGT) can result in decreased exposure. Use caution if substrates 
of UGT must be co-administered with apalutamide and evaluate for loss of efficacy.

Effect of apalutamide on drug transporters: Apalutamide was clinically shown to be a weak 
inducer of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic 
anion transporter 1B1 (OATP1B1). Concomitant use of apalutamide with medications that 
are substrates of P-gp, BCRP, or OATP1B1 can result in lower exposure of these 
medications. Use caution if substrates of P-gp, BCRP or OATP1B1 must be co-administered 
with apalutamide and evaluate for loss of efficacy if medication is continued.

Abiraterone is a strong inhibitor of CYP2D6 in humans. Caution is advised when AA is 
administered with medicinal products activated by or metabolized by CYP2D6, particularly 
with medicinal products that have a narrow therapeutic index. Dose reduction of medicinal 
products with a narrow therapeutic index that are metabolized by CYP2D6 should be 
considered. Examples of medicinal products metabolized by CYP2D6 include metoprolol, 
propranolol, desipramine, venlafaxine, haloperidol, risperidone, propafenone, flecainide, 
codeine, oxycodone and tramadol (the latter 3 products requiring CYP2D6 to form their 
active analgesic metabolites).

Abiraterone is a weak inhibitor of CYP2C8 in humans. When AA is combined with drugs 
that are predominantly eliminated by CYP2C8, subjects should be monitored for signs of 

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toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used 
concomitantly with AA.
For more information see Attachment 3.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.
9.
STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overview
The Time and Events Schedule summarizes the frequency and timing of efficacy, PK, 
pharmacodynamic, biomarker, PROs, MRU, and safety measurements applicable to this study.
For the Open-Label Extension Phase and the Long-Term Extension Phase, this information is 
included in Attachment 9 and Attachment 10, respectively.
All visit-specific PRO assessments should be conducted/completed before any tests, procedures, 
or other consultations for that visit to prevent influencing subject perceptions. The PRO 
assessments will be captured electronically and preprogrammed in the appropriate sequence.
Medical resource utilization data will be collected. Refer to Section 9.6 for details.
Adverse event information will be collected using the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03.
For subjects not participating in the biomarker study, blood volumes drawn during treatment and 
EOT may range from 2.5 mL to 7 mL per visit. Subjects participating in the biomarker study will 
have additional blood volumes drawn that range from 8.5 mL (Cycle 3 Day 1) to 21 mL per visit
(Day 1 of Cycles 1 and 12 and at EOT). For subjects participating in the PK sampling and 
biomarker study, the total blood volume (including laboratory evaluations) on Cycle 1 Day 1 and 
Cycle 3 Day 1 will be 36 mL and 21 mL, respectively. See Table 7 below and the Time and 
Events Schedule for details.

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Table 7:
Summary of Blood Volumes (mL) Per Visit
SCR
C1D1a
C1D15
C2D1
C2D15
C3D1
C3D15
C4D1
C5D1
C6D1
CnD1
EOT
Serum chemistry 
(including LFTs, fasting 
lipids and glucose)/PSAa
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
Hematologya
2
2
--
2
--
2
--
2
2
2
2
2
-TSH
Testosteronea,b
3.5
2.5
--
2.5
--
2.5
--
2.5
2.5
2.5
2.5
2.5
Total laboratory per visit
8
7
2.5
4.5
2.5
4.5
2.5
7
4.5
7
7
7
PK samples (AA)c
--
4
--
2
--
4
--
2
2
2
--
--
PK samples 
(apalutamide)c
--
4
--
2
--
4
--
2
2
2
--
--
Total PK per visit
--
8
--
4
--
8
--
4
4
4
--
--
Total laboratory + PK 
per visit
--
15
--
8.5
--
12.5
--
11
8.5
11
--
--
BM (plasma)d
--
10
--
--
--
--
--
--
--
--
10 (C12)
10
BM (whole blood)d
--
2.5
--
--
--
--
--
--
--
--
2.5 (C12)
2.5
BM (serum)e
--
8.5
--
--
--
8.5
--
--
--
--
8.5 (C12)
8.5
Total BM per visit
--
21
--
--
--
8.5
--
--
--
--
21 (C12)
21
Total laboratory + BM 
per visit
--
28
--
--
--
13
--
--
--
--
28 (C12)
28
Total laboratory + PK + 
BM per visit
--
36
--
--
--
21
--
--
--
--
--
--
AA=abiraterone acetate, BM=biomarker; C1D1=Cycle 1 Day 1, C1D15=Cycle 1 Day 15, etc. EOT=End-of-Treatment Visit; PK=pharmacokinetics; PSA=prostate-
specific antigen; SCR=screening; TSH=thyroid stimulating hormone
Note: unit for blood volume is mL
a Screening laboratory evaluations can be used for C1D1 assessments if performed within 14 days of C1D1, otherwise the laboratory assessments must be repeated 
on C1D1. During the Treatment Phase serum chemistry and hematology samples are collected on D1 of C1 to C6 then on Day 1 of every 2 cycles from C8 to C24, 
then on D1 of every 3 cycles; fasting lipids and glucose samples are collected on C1D1 then every 12 cycles starting on C12D1. PSA is collected on D1 of every 
cycle up to C12 then on D1 of every 2 cycles up to C24, then on D1 of every 3 cycles and at the EOT Visit.
b Testosterone is only collected at screening. Screening laboratory evaluations for TSH and PSA can be used for C1D1 assessments if performed within 14 days of 
C1D1, otherwise the laboratory assessments must be repeated on C1D1. During the Treatment Phase, TSH is collected on C1D1, C4D1 then Day 1 of every 
2 cycles up to C24, then D1 of every 3 cycles and at the EOT Visit.
c PK samples collected on D1 of C1 to C6. 
d BM plasma and whole blood samples collected during the Treatment Phase on D1 of C1, and C12
e BM serum samples collected during the Treatment Phase on D1 of C1, C3, and C12

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9.1.2.
Screening Phase
All subjects must sign an ICF prior to the conduct of any study-related procedures. During this 
phase, eligibility criteria will be reviewed and a complete clinical evaluation will be performed 
as specified in the Time and Event Schedule. Screening procedures will be performed up to 
42 days before randomization unless otherwise specified. Laboratory tests noted in the inclusion 
criteria must be within the limits specified prior to randomization. Testing may be repeated for 
this purpose. The last result obtained prior to start of study treatment will be used to determine 
eligibility. Assessments performed as part of the subject’s routine clinical evaluation and not 
specifically for this study need not be repeated after signed informed consent has been obtained 
provided the assessments fulfill the study requirements and are performed within the specified 
timeframe prior to randomization.
Subjects who do not meet all inclusion criteria or who meet an exclusion criterion may be 
rescreened once. Rescreening is at the discretion of the investigator and requires sponsor 
approval and agreement. The original reason for non-eligibility may be related to duration of an 
event that led to ineligibility or those events that can be managed by appropriate clinical 
measures leading to study eligibility (eg, resolution of a medical condition that required 
treatment with a contraindicated medication, treatment of cause of abnormal laboratory values, 
vital signs).
Subjects who are to be rescreened must sign a new informed consent before rescreening. 
Subjects rescreened within 42 days of planned randomization may use the initial screening 
laboratory results, CT/MRI and bone scans to determine eligibility. Rescreening and subsequent 
randomization activities (with the exception of use of original screening labs and CT/MRI and 
bone scans) must be conducted in accordance with all protocol defined windows and timelines.
9.1.3.
Treatment Phase
The Treatment Phase will begin at Cycle 1 Day 1 of treatment and will continue until study 
drugs are discontinued. Subjects must start study drugs within 72 hours or 3 calendar days after 
randomization. Visits for each cycle will have a ±2 day window. Study visits will be calculated 
from the Cycle 1 Day 1 date. Subjects may have imaging visits up to 8 days before cycles 
requiring images. Please refer to the Time and Events Schedule for treatment visits and 
assessments during the Treatment Phase. The last measurements taken on Day 1 of Cycle 1 
before administration of study drugs or at screening (whichever value was last) will be defined as 
the baseline values.
Investigators will review all clinical, laboratory and imaging data, and will use this information 
to make decisions about the necessity of dose modification or discontinuation during the 
Treatment Phase (see Section 6.3 and Section 10.2).
For subjects participating in the PK sampling, the subject must not take study drugs at home on 
the morning of study visits designated for PK sampling. Study drugs will be taken at the site after 
initial PK sampling.

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Clinical evaluations and laboratory studies may be repeated more frequently, if clinically 
indicated. A subject should ordinarily be maintained on study treatment until confirmed 
radiographic progression is documented. If the subject has radiographic progression without 
clinical progression and alternate therapy is not initiated, treatment may continue at the 
discretion of the investigator. Subjects must discontinue treatment if unequivocal clinical 
progression is documented (see Section 10.2). Discontinuation of study drug (apalutamide) will 
not result in automatic withdrawal from the study. Once the subject discontinues study drug, the 
subject must complete the End-of-Treatment (EOT) Visit within 30 days after the last dose of 
study drug, and enter the Follow-up Phase.
9.1.4.
EOT Visit
An EOT Visit must be scheduled within 30 days after the last dose of study drug for all subjects, 
except those lost to follow up, the subject died, or withdrawal of consent to study participation. 
Subjects who discontinued from treatment due to disease progression, AE or other reasons and 
enter the Follow-up Phase must have the EOT Visit completed before starting any subsequent 
anti-cancer treatment for prostate cancer. If a subject is unable to return to the site for the EOT 
Visit, the subject should be contacted to collect adverse events that occurred within 30 days after 
the last dose of study drug.
9.1.5.
Follow-up Phase
Once a subject has completed the Treatment Phase, survival follow up will be performed every 
3 months until death, withdrawal of consent, lost to follow up or the termination of the study. In 
addition to survival, analgesic use, ECOG PS, time to progression on first subsequent anti-cancer 
therapy, and subsequent anti-cancer therapy (up to and including chemotherapy) will also be 
collected. Visits to the clinic are not required; sites may collect the information by telephone 
interview, chart review, or other convenient methods. If the follow up information is obtained via 
telephone contact, then written documentation of the communication must be available for 
review in the source documents.
The BPI-SF (7-day), FACT-P, and EQ-5D-5L instruments will be completed remotely every 
3 months up to 12 months after treatment discontinuation. Refer to the Time and Events 
Schedule and Section 9.5, for specific details on PRO instruments and timing. 
During the Follow-up Phase, deaths regardless of causality and serious adverse events (SAEs) 
thought to be related to study drugs will be collected and reported within 24 hours of discovery 
or notification of the event. Subjects who discontinue study drug before radiographic progression 
will continue with imaging assessments during the Follow-up Phase according to the local 
standard of care. If available, collect information on imaging assessments until documentation of 
radiographic progression.
9.1.6.
After Study Unblinding
At the final analysis, the study will be unblinded. After the IDMC’s review and the sponsor’s 
subsequent decision and notification to the sites, either the Open-Label Extension Phase or the 
Long-Term Extension Phase will be initiated.

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9.1.6.1.
Open-Label Extension Phase
After unblinding at the final analysis, the IDMC’s review, and the sponsor’s subsequent decision 
and notification to offer cross-over, all subjects still in the double-blind phase of the study will 
be offered the option to enter the Open-Label Extension Phase of the study. All subjects must 
sign the ICF for the Open-Label Extension Phase before entering it. Details for the Open-Label 
Extension Phase are provided in Attachment 9.
If a dedicated Extension study becomes available, then all subjects who comply with the entry 
criteria for that study and consent to that study should be transferred to that study.
9.1.6.2.
Long-Term Extension Phase With Limited Data Collection
After unblinding at the final analysis, the IDMC’s review, and the sponsor’s subsequent decision 
and notification not to offer cross-over, all subjects still in the double-blind phase of the study 
will be offered the option to enter the Long-Term Extension Phase of the study. All subjects 
must sign the ICF for the Long-Term Extension Phase before entering it. Details for the Long-
Term Extension Phase are provided in Attachment 10.
If a dedicated Extension study becomes available, then all subjects who comply with the entry 
criteria for that study and consent to that study should be transferred to that study.
9.1.7.
Data Collection Following IDMC Recommendation to Unblind
After unblinding and notification by the sponsor, sites will collect only the data specified in 
Attachment 9 or Attachment 10.
9.2.
Efficacy
9.2.1.
Evaluations
Efficacy evaluations will be conducted as specified in the Time & Events Schedule. The efficacy 
evaluations include the following:

Tumor measurements (CT or MRI, bone scans, other imaging procedures)

Survival status, analgesic use, SSREs, and first cytotoxic chemotherapy for prostate cancer 

Serum PSA evaluation (measurements at a central laboratory)
The same imaging modality used for tumor assessments should be used throughout the 
evaluation of an individual subject. Unscheduled tumor assessment and appropriate imaging 
should be considered if signs or symptoms suggestive of disease progression, including 
escalating pain not referable to another cause, worsening ECOG PS grade, or physical 
examination findings consistent with disease progression, are recorded.
9.2.1.1.
Other Efficacy Evaluations
The BPI-SF (item 3) and chronic opioid use (defined as administration of additional opioid 
analgesics lasting for ≥3 weeks for oral, or ≥7 days for non-oral formulation) will be used to 
measure time to pain progression. Analgesic usage (for the time to analgesic progression 

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endpoint) will be scored according to the World Health Organization (WHO) analgesic ladder: 
0 for no analgesic, 1 for non-opioid analgesics (including non-steroidal anti-inflammatory drugs 
[NSAIDs], paracetamol/acetaminophen, antidepressants, and agents intended to treat neuropathic 
pain), 2 for opioids for moderate pain, and 3 for opioids for severe pain.
9.2.1.2.
Efficacy Criteria
Tumor response will be assessed utilizing imaging measurements, as defined by Response 
Evaluation Criteria in Solid Tumors (RECIST 1.1 Attachment 1).16 In this study, RECIST 1.1 
has been modified based on PCWG2 criteria, which are specific for this patient population. 
Lymph node and 99mTc bone scan will be evaluated according to an adaptation of the PCWG2 
criteria (see also Attachment 1 and Scher et al.30). Prostate-specific antigen measurements will 
also be evaluated according to PCWG2 criteria. Additional details are provided in Attachment 7.
Evaluation of rPFS will be assessed by the investigator as detailed in the Imaging Manual (see 
Section 9.2.2 for definitions). All subject scans (CT/MRI bone scans), however will be submitted 
to a third-party core imaging laboratory for quality assessment and for audit purposes. It is 
important to the integrity of the study that all imaging studies are forwarded to the core imaging 
laboratory throughout the study. Further details regarding materials to be forwarded for central 
quality assessment can be found in the Imaging Manual and/or Investigator Site File.
9.2.2.
Endpoints
The primary objective of the study is clinical benefit, which is described by the endpoints 
described below.
Primary Endpoint
The primary endpoint is rPFS.
Radiographic progression-free survival, as assessed by the investigator, is defined as the time
from the date of randomization to the date of radiographic progression or death, whichever 
occurs first. Radiographic progression is defined as the time from randomization to the 
occurrence of one of the following:

A subject is considered to have progressed by bone scan if:

The first bone scan with ≥2 new lesions compared with baseline is observed <12 weeks 
from randomization and is confirmed by a second bone scan taken ≥6 weeks later 
showing ≥2 additional new lesions (a total of ≥4 new lesions compared with baseline);

The first bone scan with ≥2 new lesions compared with baseline is observed ≥12 weeks 
from randomization and the ≥2 new lesions are verified on the next bone scan ≥6 weeks 
later (a total of ≥2 new lesions compared with baseline).

Progression of soft tissue lesions measured by CT or MRI as defined in modified RECIST 
1.1 criteria (Attachment 1).

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Secondary Endpoints

Overall survival (OS) is defined as the time from date of randomization to date of death 
from any cause 

Time to chronic opioid use (oral opioid use for ≥3 weeks; parenteral opioid use for ≥7 days) 
is defined as the time from date of randomization to the first date of opioid use 

Time to initiation of cytotoxic chemotherapy is defined as the time from date of
randomization to the date of initiation of cytotoxic chemotherapy

Time to pain progression defined as the time from date of randomization to the first date a 
subject experience an increase by 2 points from baseline in the BPI-SF worst pain intensity 
item 3 observed at 2 consecutive evaluations ≥4 weeks apart or initiation of chronic opioids
(see Section 9.2.1.1), whichever occurs first
Other Endpoints

Time to symptomatic skeletal-related event (SSRE) defined as the time from randomization 
to first occurrence of 1 of the following:

Use of external beam radiation therapy (EBRT) to relieve skeletal symptoms

The occurrence of new symptomatic bone fractures (cancer-related: vertebral or 
non-vertebral)

The occurrence of tumor-related spinal cord compression

Need for tumor-related orthopedic surgical intervention

Time to deterioration of ECOG PS grade is defined as the time from randomization to the 
date of deterioration in ECOG PS grade (increase by at least 1 grade from baseline with 
confirmation)

Objective response rate defined as the proportion of subjects with measurable disease 
achieving a complete or partial response according to (modified RECIST 1.1; Attachment 1)

Duration of response in subjects with measurable disease

PRO as assessed by FACT-P, BPI-SF, and EQ-5D-5L (see Section 9.5)

Time to PSA progression based on PCWG2 criteria30

Time to analgesic progression defined as the time interval from randomization to first date 
of increase in analgesic usage score 30% from baseline observed at 2 consecutive 
evaluation 4 weeks apart (see Section 9.2.1.1)

PFS2 is defined as time from randomization to the date of first progression (radiographic, 
clinical, or PSA progression) on the first subsequent therapy or death from any cause, 
whichever occurs first

Biomarker research to explore AR gene anomalies and other markers previously shown to 
be responsible for resistance to apalutamide

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9.3.
Population Pharmacokinetics
9.3.1.
Evaluations
Pharmacokinetic assessments will be conducted on as many subjects as feasible (and where 
regulations permit). In Japan, blood samples for PK assessment will be collected from all 
randomized subjects. Two separate blood samples will be collected at approximately the same 
time for each sampling time point; 1 for abiraterone and 1 for apalutamide. On Day 1 of Cycle 1, 
blood samples will be collected at 2 hours and 4 hours post the first dose for each subject. On 
Day 1 of Cycle 3, predose samples (up to 1 hour prior to on-site study drugs administration) and 
postdose samples between 0.5 and 4 hours will be collected. For the other PK visits (Cycles 2, 4, 
5, and 6), blood samples will be collected predose (up to 1 hour prior to on-site study drugs 
administration). In total, 16 blood samples will be drawn as described in the Laboratory Manual 
in this study. Four blood samples will be drawn on Day 1 of Cycle 1 and 4 blood samples will be 
drawn on Day 1 of Cycle 3. An additional 8 blood samples will be collected on each Day 1 of 
Cycles 2, 4, 5, and 6 with 2 blood samples drawn on each day.
9.3.2.
Analytical Procedures
Pharmacokinetic samples collected from both treatment arms will be assayed for abiraterone 
using a validated analytical method. PK samples collected from the combination arm will be 
assayed for apalutamide and its active metabolite JNJ-56142060 using a validated analytical 
method.
9.4.
Biomarkers
Results from a Phase 1 study in patients with metastatic CRPC provide evidence that acquired 
mutation in AR (ARF876L) may be associated with resistance to apalutamide treatment.20 Multiple 
other biomarkers have been shown to be associated with resistance to abiraterone acetate, 
enzalutamide or apalutamide. Archived tumor samples (FFPE blocks or slides) and serum 
samples will be collected, where country regulations permit, for biomarker evaluations. Plasma 
samples will be collected from approximately 220 subjects during treatment (as indicated in the 
Time and Events Schedule) and approximately 500 subjects at the end-of-treatment; whole blood 
will be collected from approximately 220 subjects at the time points indicated in the Time & 
Events Schedule. Plasma-based circulating DNA will be used to assess the presence of the 
ARF876L mutation and whole blood or plasma DNA to assess other markers that may be 
associated with resistance to AA alone and in combination with apalutamide. Serum samples will 
be collected to compare the effect of testosterone and steroid metabolites when subjects are
treated with AAP alone and in combination with apalutamide. Archival FFPE tumor blocks or 
tumor slides will be collected from approximately 300 subjects in this study to investigate 
whether genomic classifiers can be used to identify a more homogeneous population of high-risk 
patients. This will potentially allow selection of the appropriate high-risk patient population for 
future studies of apalutamide and AA.
9.5.
Patient-reported Outcomes
All visit-specific PRO assessments should be conducted before any tests, procedures, or other 
consultations for that visit to prevent influencing subject perceptions. All PRO measures will be 

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completed using an electronic device (ePRO). For more details refer to the ePRO user manual.
Sample questionnaires for the BPI-SF, FACT-P, and EQ-5D-5L are provided in Attachment 4, 
Attachment 5, and Attachment 6, respectively. 
For FACT-P and EQ-5D-5L, baseline questionnaires should be completed on Cycle 1 Day 1. 
During the Treatment Phase, the FACT-P and EQ-5D-5L are to be completed at clinic visits as 
outlined in the Time and Events Schedule. During the Follow-up Phase, the questionnaires will 
be completed remotely as outlined in the Time and Events Schedule. 
A consecutive 7-day completion of the BPI-SF is required for determination of eligibility (see 
Section 4.1 (Inclusion Criterion #9) (see also the Time and Events Schedule). The completion of 
questionnaire for Day 7 must occur before or on the day of randomization. During the Treatment 
Phase, the questionnaire should be completed as outlined in the Time and Events Schedule.
During the Follow-up Phase, the BPI-SF (7-day) will be completed remotely as outlined in the 
Time and Events Schedule. 
9.6.
Medical Resource Utilization
Medical resource utilization data, associated with medical encounters, will be collected in the 
eCRF by the investigator and study-site personnel for all subjects throughout the study. Protocol-
mandated procedures, tests, and encounters are excluded. The data collected may be used to 
conduct exploratory economic analyses and will include:

Number and duration of medical care encounters, including surgeries, and other selected 
procedures (inpatient and outpatient)

Duration and cause of hospitalization (total days length of stay, including duration by wards; 
eg, intensive care unit)

Number and character of diagnostic and therapeutic tests and procedures

Outpatient medical encounters and treatments (including physician or emergency room 
visits, tests and procedures, and medications)
9.7.
Safety Evaluations
The study will include the following evaluations of safety and tolerability according to the time 
points provided in the Time and Events Schedule. Any clinically significant abnormalities 
persisting at the End-of-Treatment will be followed by the investigator until resolution or until a 
clinically stable endpoint is reached or until the end of the study.
The study will be overseen by an Independent Data Monitoring Committee (see Section 11.11).
An IDMC charter will be prepared.
Adverse Events
Adverse events will be reported by the subject (or, when appropriate, by a family member, 
caregiver, surrogate, or the subject's legally acceptable representative). Adverse events will be 
followed by the investigator as specified in Section 12, Adverse Event Reporting.

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Any clinically significant abnormalities persisting at the End-of-Treatment will be followed by 
the investigator until resolution or until a clinically stable endpoint is reached or until the end of 
the study.
Clinical Laboratory Tests 
Blood samples for serum chemistry and hematology will be collected. The investigator must 
review the laboratory report, document this review, and record any clinically relevant changes 
occurring during the study in the AE section of the eCRF.
Blood samples to assess the safety of study drug will be collected. Screening laboratory 
evaluations can be used for Cycle 1 Day 1 assessments if performed within 14 days of Cycle 1. 
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. For 
example, laboratory abnormalities leading to an action regarding study drug (dose change, 
temporary stop, delay of the start of a cycle, or permanent stop) or the start of concomitant 
therapy should be reported. For each laboratory abnormality reported as an AE, the following 
laboratory values should be reported in the laboratory section of the eCRF: the value indicative 
of the onset of each toxicity grade; the most abnormal value observed during the AE, and the 
value supporting recovery to Grade 1 or to baseline values.
The following tests will be performed by the central laboratory as outlined in the Time & Events 
Schedule:

Hematology Panel
-hemoglobin
-platelet count
-white blood cell (WBC) count
-absolute neutrophil count (ANC)
NOTE: *Any abnormal WBC evaluations will also be reported by the central laboratory.

Serum Chemistry Panel
-sodium
-lactic acid dehydrogenase (LDH)
-potassium
-calcium
-creatinine
-albumin (screening only)
-fasting glucose
-total protein

Liver Function tests
-aspartate aminotransferase (AST)
-alkaline phosphatase
-alanine aminotransferase (ALT)
-direct and indirect (screening only if 
Gilbert’s disease is suspected) and total 
bilirubin

Fasting Lipid Panel
- high density lipoprotein-cholesterol (HDL-C)
- triglycerides
- low density lipoprotein-cholesterol (LDL-C)

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Testosterone will be evaluated at screening only. Thyroid stimulating hormone (TSH) and PSA 
will be evaluated periodically throughout the study as outlined in the Time and Events Schedule.
In the event of additional safety monitoring, unscheduled laboratory assessments may be 
performed as required.
Electrocardiogram (ECG)
Electrocardiograms (ECGs) (12-lead) will be recorded at screening. Abnormalities noted at 
screening should be included in the medical history. Computer-generated interpretations of 
ECGs should be reviewed for data integrity and reasonableness by the investigator. During the 
collection of ECGs, subjects should be in a quiet setting without distractions (eg, television, cell 
phones). Subjects should rest in a supine position for at least 5 minutes before ECG collection 
and should refrain from talking or moving arms or legs. ECGs should not be obtained when 
serum potassium is <3.5 mmol/L. Hypokalemia should be corrected prior to ECG collection.
Serum chemistry results must be available before an ECG can be obtained
Vital Signs
Body temperature, heart rate, respiratory rate, and blood pressure will be recorded at Screening. 
At all other visits, only blood pressure will be measured.
Physical Examination
The Screening physical examination will include, at a minimum, the general appearance of the 
subject, height and weight, examination of the skin, ears, nose, throat, lungs, heart, abdomen, 
extremities, musculoskeletal system, lymphatic system, and nervous system. During the 
Treatment Phase and at the EOT Visit, limited symptom-directed physical examination and 
weight assessment is required.
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) grade
See Time and Events schedule for the timing of assessment of ECOG PS.
9.7.1.
Safety Assessments

Medical history, vital sign measurements, physical examination, body weight, and ECOG 
PS grade

Concomitant therapy and procedures

Adverse events and SAEs, including laboratory test AEs will be graded and summarized 
according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE), Version 4.03

Hematology, blood chemistry, liver function tests, fasting lipids, and TSH
An IDMC will be convened for this study and will be responsible for review of periodic 
evaluations of safety during the study as outlined in a separate IDMC charter.

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9.8.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the laboratory requisition 
form. Refer to the Time and Events Schedule for the timing and frequency of all sample 
collections.
Instructions for the collection, handling, storage, and shipment of samples are found in the 
Laboratory Manual that will be provided. Collection, handling, storage, and shipment of samples 
must be under the specified, and where applicable, controlled temperature conditions as indicated 
in the Laboratory Manual.
10.
SUBJECT COMPLETION/WITHDRAWAL
10.1.
Completion
A subject will be considered to have completed the study if he died before the end of the study, 
or has not been lost to follow up or withdrawn consent before the end of the study.
10.2.
Discontinuation of Study Treatment
If a subject's study treatment must be discontinued, the subject will not be automatically
withdrawn from the study. 
Subjects should be encouraged to continue treatment until radiographic progression or 
unequivocal clinical progression. If the subject has radiographic progression without evidence of 
unequivocal clinical progression and alternate therapy is not initiated, treatment may continue at 
the discretion of the investigator. Subjects should not discontinue treatment for PSA progression 
in the absence of radiographic progression or unequivocal clinical progression. If a subject 
discontinues study treatment before evidence of radiographic progression, data on subsequent 
imaging assessments performed per the local standard of care will be collected if available (see 
Section 9.1.5). Radiographic progression is defined by PCWG2 (see Attachment 7). Bone scan 
worksheets may be used as source documentation for tracking progression or response (see 
Section 17.5). 
The primary reason for discontinuation of study treatment is to be recorded in the eCRF. A study 
treatment discontinuation form should be emailed to the sponsor’s medical monitor prior to 
discontinuation in IWRS (see the SIPPM for details).
However, a subject's study treatment must be discontinued for:

Unequivocal clinical progression defined as:

Deterioration in ECOG PS to grade 3 or higher

Need to initiate any of the following because of tumor progression (even in the absence 
of radiographic evidence of disease)
o
Alternative anti-cancer therapy for prostate cancer
o
The use of EBRT to relieve skeletal symptoms

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o
The need for tumor-related orthopedic surgical intervention
o
Need for chronic opioid analgesics (defined as administration of additional opioid 
analgesics lasting for ≥3 weeks for oral, or ≥7 days for non-oral formulation). 
NOTE: Administration of as needed (eg, not fixed or scheduled dosage) use of 
opioid analgesics or extended opioid use for treatment other than the subject’s 
prostate cancer does not require discontinuation from study treatment
(eg, codeine/acetaminophen 
combinations, 
hydrocodone/acetaminophen 
combinations hydrocodone/ibuprofen combinations,
oxycodone/acetaminophen 
combinations oxycodone/aspirin combinations, tramadol)

Withdrawal of consent for continued treatment

Subjects who have had their treatment assignment unblinded (exception IDMC 
recommendation to unblind the study) should discontinue treatment and enter the Follow-up 
Phase

The investigator believes that for safety reasons (eg, AE) it is in the best interest of the 
subject to discontinue study treatment
All attempts to obtain imaging studies at the time of treatment discontinuation or 
End-of-Treatment Visit should be made to assess for radiographic progression.
Study data will continue to be collected after discontinuation of study treatment, unless the 
subject withdraws consent for further study participation.
10.3.
Withdrawal from the Study
A subject will be considered withdrawn from the study for any of the following reasons:

Lost to follow up

Withdrawal of consent for subsequent data collection
If a subject is lost to follow up, every reasonable effort must be made by the study-site personnel 
to contact the subject and to determine endpoint status and the reason for the 
discontinuation/withdrawal. The measures taken for follow up must be documented. The 
informed consent will stipulate that even if a subject decides to discontinue double-blind study 
drug, he will agree to be contacted periodically by the investigator to assess endpoint status. 
Furthermore, the subject will be asked to agree to grant permission for the investigator to consult 
family members or public records to determine the subject’s endpoint status, in the event the 
subject is not reachable by conventional means (eg, office visit, telephone, e-mail, or certified 
mail).
When a subject withdraws before completing the study, the reason for withdrawal is to be 
documented in the eCRF 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.
If a subject discontinues study treatment before the end of the Treatment Phase, 
End-of-Treatment and follow-up assessments should be obtained.

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11.
STATISTICAL METHODS
Statistical analysis will be done by the sponsor. A general description of the statistical methods 
to be used to analyze the efficacy and safety data is outlined below. Specific details will be 
provided in the statistical analysis plan.
11.1.
Analysis Populations
Intent-to-Treat Population (ITT): All eligible subjects who are randomized into the study and 
who will be classified according to their assigned treatment group, regardless of the actual 
treatment received. This population will be used for subject disposition and efficacy analyses.
Safety Population: All subjects who received at least one dose of study drug, with treatment 
assignments designated according to actual study treatment received. This population will be 
used for evaluating safety and treatment compliance.
Patient-reported Outcomes Population [PRO]: All randomized subjects who have completed at 
least the baseline assessment of BPI-SF, FACT-P or EQ-5D-5L questionnaires; all time-to-event 
analysis will be based on the ITT population.
Pharmacokinetics Populations [PK]: All randomized subjects who have at least 1 PK sample 
collected.
Biomarker Population: All randomized subjects who have at least 1 biomarker sample collected.
11.2.
Sample Size Determination
Subjects will be randomized in a 1:1 ratio to receive apalutamide plus AAP or placebo plus 
AAP. The study is sized to detect the hypothesized HR for OS as well as rPFS endpoints.
This study is designed to provide sufficient power (approximately 
%) to detect a HR of 
 in 
the secondary endpoint of OS based on an assumed median OS of 
 for the control 
group (AAP).27 The assumption for OS is a HR of 
which represents an improvement of 
 
 versus 
) in the median time to death in the treatment group 
of apalutamide plus AAP compared with the control group of AAP alone. Under the assumption 
that the failure distribution of OS follows an exponential distribution with a constant hazard rate, 
approximately 
 death events will be required to detect the assumed HR at a maximum two-
sided significance level of 0.05 (see Section 11.9 for details on significance level), with 
enrollment duration of approximately 
 (approximately 960 subjects) and an additional 
follow up of 
 to reach the total number of death events. The median time of OS in the 
control group of AAP alone and the enrollment projection are assumed based on the observation 
in the COU-AA-302 study.27
It is assumed that the failure distribution of the primary endpoint, rPFS follows an exponential 
distribution with a constant hazard rate. Based on simulations accounting for the correlation of 
 between rPFS and OS, it is estimated that approximately 
 rPFS events would be required 
to provide at least 
% power in detecting a hazard ratio (HR) of 
 (median rPFS of 
 for the control group [AAP] versus 
 for the treatment group of apalutamide
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plus AAP) at a 2-tailed level of significance of 0.05. The median time of rPFS in the control 
group of AAP and the correlation between rPFS and OS are based on the observation in the 
COU-AA-302 study.27 The same enrollment assumptions as described for OS are assumed.
11.3.
Efficacy Analyses
All continuous variables will be summarized using number of subjects (n), mean, standard 
deviation (SD), median, minimum, and maximum. Discrete variables will be summarized with n 
and percent. All efficacy endpoints will be analyzed using the ITT set of population. 
Kaplan-Meier product limit method and Cox model will be used to estimate the distribution of 
the time-to-event variables and to obtain the HR along with the associated confidence intervals, 
respectively. Unless otherwise specified, stratified log-rank test will be used as the primary 
analysis method to test the treatment effect for time-to-event variables; response rate variables 
will be evaluated using the Chi-square statistic or the exact test if the cell counts are small. The 
stratification variables are presence or absence of visceral metastases, ECOG PS grade of 0 or 1, 
and region (EU, North America [United States/Canada], and Rest of World [ROW]).
Primary Endpoint (Analysis of the rPFS Primary Endpoint)
The progression events of the rPFS endpoint will be based on investigator radiographic 
assessment of progression. The final rPFS analysis will take place after approximately 
events are observed. The timing of the first interim analysis of OS may occur at the same 
time as the final analysis of rPFS. Alternatively, the analyses may be performed at a different 
time if the number of death events needed for a valid interim analysis of OS would require a long 
delay in the analysis of the rPFS endpoint. The alpha-spending for the interim analysis of OS 
will be adjusted accordingly (see Section 11.9). A subject without an event at the time of analysis 
will be censored at the last known date the subject did not have a documented radiographic 
progression. Detailed censoring rules will be provided in the statistical analysis plan. Stratified 
log-rank test will be used in the analysis. Non-stratified log-rank test will also be provided as 
sensitivity analysis. Stratified Cox proportional-hazard model will be used to obtain the HR and 
its 95% CI.
Secondary Endpoints (Analysis of Secondary Endpoints)
The analyses of the secondary endpoints will be performed at the time of the first interim 
analysis of OS (approximately 
events). 
 
 
 
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 Details of the testing procedure will be provided in the statistical analysis plan.
The analyses of the secondary endpoints will be performed using stratified log-rank test. 
Non-stratified log-rank tests will also be provided as sensitivity analyses.
Kaplan-Meier methods will be used to estimate the medians for each treatment arm. Stratified 
Cox proportional-hazard models, including the same stratification factors as above, will be used 
to estimate the HR and its 95% confidence interval (CI). One year, 2-year, 3-year, survival rates 
will be estimated using the Kaplan-Meier method.
For the OS analysis, subjects without an event will be censored on the last date known to be 
alive. The final analysis will occur when approximately 
events are observed.
11.4.
Pharmacokinetic and Pharmacodynamic Analyses
Population PK analysis of plasma concentration-time data of apalutamide and abiraterone may
be performed using nonlinear mixed-effects modeling. The population PK modeling will include 
all subjects with sufficient and interpretable PK assessments. The data from the population PK 
samples may be combined together with the data from other studies for the population PK 
analysis. If sufficient data are available, the relationship of exposure to apalutamide and 
JNJ-56142060, and abiraterone to measures of efficacy and AEs may also be analyzed. The 
population PK/PD analysis results will be presented in a separate report.
11.5.
Biomarker Analyses
Initial biomarker analyses will be conducted on approximately 220 plasma and whole blood 
samples to assess the frequency of ARF876L mutation and other resistance markers respectively 
from both treatment groups. Sample size is estimated to provide meaningful biomarker analysis
based on frequency of this mutation as previously reported.20
Further associations may be made with clinical endpoints with:

F876L mutation in plasma DNA collected at progression from approximately 500 subjects

AR splice variants or other RNA anomalies in whole blood collected from approximately
220 subjects

Testosterone and steroid metabolites in serum samples collected from approximately
220 subjects
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.
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The association of the rest of the biomarkers with clinical response or time-to-event endpoints 
may be assessed using appropriate statistical methods, (such as 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 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.
11.6.
Patient-reported Outcomes 
Scales from BPI-SF and FACT-P: Descriptive statistics of each scale score at baseline and 
follow-up assessments will be summarized by treatment groups; time to degradation in each 
scale will be analyzed using Kaplan-Meier method and stratified Cox proportional-hazard model.
Additional analysis may be carried out, if appropriate. Analysis details will be included in the 
statistical analysis plan.
The EQ-5D-5L data will be summarized descriptively by treatment group and study visit. Each 
level of every dimension will be summarized using count and percent. EQ-5D-5L Visual Analog 
Scale (VAS) will be described using summary statistics (n, mean, median, etc.).
11.7.
Medical Resource Utilization
Medical resource utilization will be descriptively summarized by treatment group. This report 
will be prepared separately and will not be a part of the clinical study report.
11.8.
Safety Analyses
Subjects who receive at least 1 dose of study drug will be analyzed for safety. The safety 
parameters to be evaluated are the incidence, intensity, and type of AEs, vital signs 
measurements, and clinical laboratory results. Exposure to study drug and reasons for 
discontinuation of study treatment will be tabulated.
Adverse Events
Treatment-emergent AEs will be coded using the most current Medical Dictionary for 
Regulatory Activities (MedDRA) and will be graded according to the NCI-CTCAE, 
Version 4.03. Treatment-emergent AEs are those events that occur or worsen on or after first 
dose of study drug through 30 days after the last dose of study drug and will be included in the 
analysis. Adverse events will be summarized by system organ class and preferred term, and will 
be presented overall and by treatment group. Serious adverse events and deaths will be provided 
in a listing. All AEs resulting in discontinuation, dose modification, dosing interruption, or 
treatment delay of study drug will also be listed and tabulated by preferred term.

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Clinical Laboratory Tests
Clinical laboratory test results will be collected from Screening and through 30 days after last 
dose of study drug. Laboratory data will be summarized by type of laboratory test. Parameters 
with predefined National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI-CTCAE) toxicity grades will be summarized. Change from baseline to the worst AE grade 
experienced by the subject during the study will be provided as shift tables.
Vital Signs
Descriptive statistics of blood pressure (systolic and diastolic) values and changes from baseline 
will be summarized at each scheduled time point. The percentage of subjects with values beyond 
clinically important limits will be summarized.
11.9.
Interim Analyses
There will be no planned interim analysis of the primary endpoint, rPFS.
Two interim analyses and one final analysis are planned for the OS endpoint. The testing of the 
OS endpoint will be carried out according to the 
 
 
Assuming the OS endpoint will be tested at a maximum two-sided
overall alpha of 0.05, the expected total number of death events is 
 at final analysis. At the 
time of the first interim analysis, approximately 
% (
) of the total death events will be 
observed. The second interim analysis will be performed after observing approximately 
% 
(
) of the total death events. Assuming a maximum overall 2-tailed significance level of 
0.05, the estimated cumulative alpha spend are 
 and 
 at the first and second interim 
analyses, respectively. The actual alpha to be spent and the exact significance level at each of the 
analysis will be based on the number of death events observed at the time of analysis.
11.10. Futility Analyses
A non-binding futility analysis is planned using PSA90 decline rate defined as the proportion of 
subjects with a decline of PSA of 90% or more from baseline. In the case that a PSA90 decline 
rate of 30% in the control group is observed, it is assumed that an absolute increase of 
% over 
the control group would be clinically meaningful. This analysis will occur when approximately 
subjects have been treated for at least  cycles. The purpose of this analysis is to provide an 
early look to ensure that sufficient antitumor activity is observed in the treatment group of 
apalutamide plus AAP compared with AAP. This futility analysis will not be used to substantiate 
an efficacy claim. Non-binding futility analyses will be implemented at the planned interim 
analyses for OS.
In addition, a non-binding futility analysis on rPFS will be implemented after observing 
approximately 
% (
 events) of the total number of required 
 events. Details for each 
futility analysis will be provided in the statistical analysis plan. 
11.11. Independent Data Monitoring Committee
An IDMC will be established to monitor data on an ongoing basis to ensure the continuing safety 
of the subjects enrolled in this study and to review efficacy information. The committee will 
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perform periodic safety review throughout the study and review the safety of the first 60 subjects 
randomized to the study and after treatment for at least 1 cycle. In addition, the IDMC will 
review the planned efficacy/futility analyses.
The IDMC responsibilities, authorities, and procedures will be documented in a separate charter.
12.
ADVERSE EVENT REPORTING
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures.
12.1.
Definitions
12.1.1.
Adverse Event Definitions and Classifications
Adverse Event
An AE is any untoward medical occurrence in a clinical study subject administered a medicinal 
(investigational or non-investigational) product. An AE does not necessarily have a causal 
relationship with the treatment. An AE 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 12.3.1, All 
Adverse Events, for time of last AE recording).
Serious Adverse Event
A serious AE 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

Is life-threatening
(The subject was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.)

Requires inpatient hospitalization or prolongation of existing hospitalization

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
Is a congenital anomaly/birth defect

Is a suspected transmission of any infectious agent via a medicinal product

Is medically important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the subject 
or may require intervention to prevent one of the other outcomes listed in the definition above. 
These should usually be considered serious.
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An AE is considered unlisted if the nature or severity is not consistent with the applicable 
product reference safety information. For apalutamide the expectedness of an AE will be 
determined by whether or not it is listed in the Investigator's Brochure. For ZYTIGA®
(abiraterone acetate) with a marketing authorization, the expectedness of an AE will be 
determined by whether or not it is listed in the local product information.
Adverse Event Associated With the Use of the Drug
An AE is considered associated with the use of the drug if the attribution is possible, probable, or 
very likely by the definitions listed in Section 12.1.2.
12.1.2.
Attribution Definitions
Not Related
An AE that is not related to the use of the drug.
Doubtful
An AE for which an alternative explanation is more likely, eg, concomitant drug(s), concomitant 
disease(s), or the relationship in time suggests that a causal relationship is unlikely.
Possible
An AE that might be due to the use of the drug. An alternative explanation, eg, concomitant 
drug(s), concomitant disease(s), is inconclusive. The relationship in time is reasonable; therefore, 
the causal relationship cannot be excluded.
Probable
An AE that might be due to the use of the drug. The relationship in time is suggestive 
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant 
drug(s), concomitant disease(s).
Very Likely
An AE that is listed as a possible adverse reaction and cannot be reasonably explained by an 
alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship in time 
is very suggestive (eg, it is confirmed by dechallenge and rechallenge).

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12.1.3.
Severity Criteria
The NCI-CTCAE Version 4.03 will be used to grade the severity of AEs. Any AE not listed in 
the NCI-CTCAE will be graded according to the investigator’s clinical judgment using the 
standard grades as follows:
Grade 1 (Mild): Awareness of symptoms that are easily tolerated, causing minimal discomfort 
and not interfering with everyday activities.
Grade 2 (Moderate): Sufficient discomfort is present to cause interference with normal activity.
Grade 3 (Severe): Extreme distress, causing significant impairment of functioning or 
incapacitation. Prevents normal everyday activities.
Grade 4 (Life-threatening): Urgent intervention indicated.
Grade 5 (Death): Death.
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities).
12.2.
Special Reporting Situations
Safety events of interest on a sponsor study drug that may require expedited reporting and/or 
safety evaluation include, but are not limited to:

Overdose of a sponsor study drug

Suspected abuse/misuse of a sponsor study drug

Accidental or occupational exposure to a sponsor study drug

Medication error involving a sponsor product (with or without subject exposure to the 
sponsor study drug, eg, name confusion)
Special reporting situations should be recorded in the eCRF. Any special reporting situation that 
meets the criteria of an SAE should be recorded on the SAE page of the eCRF.
12.3.
Procedures
12.3.1.
All Adverse Events
All AEs and special reporting situations, whether serious or non-serious, will be reported from 
the time a signed and dated ICF is obtained until 30 days after the last dose of study drug. 
Serious adverse events, including those spontaneously reported to the investigator within 30 days 
after the last dose of study drug, must be reported using the Serious Adverse Event Form. The 
sponsor will evaluate any safety information that is spontaneously reported by an investigator 
beyond the time frame specified in the protocol. Anticipated events will be recorded and reported 
as described in Attachment 8. 

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All AEs, regardless of seriousness, severity, or presumed relationship to study drug, must be 
recorded using medical terminology in the source document and the eCRF. Whenever possible, 
diagnoses should be given when signs and symptoms are due to a common etiology (eg, cough, 
runny nose, sneezing, sore throat, and head congestion should be reported as "upper respiratory 
infection"). Investigators must record in the eCRF their opinion concerning the relationship of 
the AE to study therapy. All measures required for AE management must be recorded in the 
source document and reported according to sponsor instructions.
The sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities. 
The sponsor will also report to the investigator (and the head of the investigational institute 
where required) all suspected unexpected serious adverse reactions (SUSARs). For anticipated 
events, if the sponsor has determined there is a reasonable possibility that the drug caused a 
serious anticipated event the sponsor will provide a safety report in narrative format to the 
investigators (and the head of the institute where required). The investigator (or sponsor where 
required) must report SUSARs to the appropriate Independent Ethics Committee/Institutional 
Review Board (IEC/IRB) that approved the protocol unless otherwise required and documented 
by the IEC/IRB. A SUSAR will be reported to regulatory authorities unblinded. Participating 
investigators and IEC/IRB will receive a blinded SUSAR summary, unless otherwise specified. 
For all studies with an outpatient phase, the subject must be provided with a "wallet (study) card" 
and instructed to carry this card with them for the duration of the study indicating the following:

Study number

Statement, in the local language(s), that the subject is participating in a clinical study

Investigator's name and 24-hour contact telephone number

Local sponsor's name and 24-hour contact telephone number (for medical staff only)

Site number

Subject number

Any other information that is required to do an emergency breaking of the blind
12.3.2.
Serious Adverse Events
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).
All SAEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the subject's participation in the study, must be followed until any of the 
following occurs:

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
The event resolves

The event stabilizes

The event returns to baseline, if a baseline value/status is available

The event can be attributed to agents other than the study drug or to factors unrelated to 
study conduct

It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow up after demonstration 
of due diligence with follow-up efforts)
Suspected transmission of an infectious agent by a medicinal product will be reported as an SAE. 
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during the 
course of a subject's participation in a study must be reported as an SAE, except hospitalizations 
for the following:

Surgery or procedure planned before entry into the study (must be documented in the 
eCRF).
Disease progression should not be recorded as an AE or SAE term; instead, signs and symptoms 
of clinical sequelae resulting from disease progression/lack of efficacy will be reported if they 
fulfill the serious adverse event definition (refer to Section 12.1.1, Adverse Event Definitions 
and Classifications).
During the Follow-up Phase of the study, deaths regardless of causality will be reported in the 
eCRF. Serious adverse events including those spontaneously reported to the investigator within 
30 days after the last dose of study drug, must be reported using the Serious Adverse Event 
Form. Serious adverse events that occur after 30 days following the last drug administration 
thought to be related to study drug will be collected and reported via the SAE form within 
24 hours of discovery or notification of the event and documented.
12.3.3.
Pregnancy
Because the effect of the study drug on sperm is unknown, pregnancies in partners of male subjects 
included in the study will be reported by the study-site personnel 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.
12.4.
Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed in the Contact Information 
page(s), which will be provided as a separate document.
13.
PRODUCT QUALITY COMPLAINT HANDLING
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, 

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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.
13.1.
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 serious adverse event, the study-site personnel must report the 
PQC to the sponsor according to the serious adverse event reporting timelines (refer to 
Section 12.3.2, Serious Adverse Events). A sample of the suspected product should be 
maintained for further investigation if requested by the sponsor.
13.2.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed in the Contact Information page(s), which will be 
provided as a separate document.
14.
STUDY DRUG INFORMATION
14.1.
Physical Description of Study Drug(s)
The JNJ-56021927 (apalutamide) tablet supplied for this study contains 60 mg of JNJ-56021927 
(apalutamide). It will be manufactured and provided under the responsibility of the sponsor.
Refer to the Investigator's Brochure for a list of excipients.18
Abiraterone acetate 250 mg tablets supplied for this study are oval, white to off-white in color. It 
will be manufactured and provided under the responsibility of the sponsor.
Placebo will be provided as a tablet formulation and will be matched in size, color, and shape in 
order to maintain the study blind.
14.2.
Packaging
JNJ-56021927 (apalutamide) 60 mg tablets will be packaged in 120-count, in high-density 
polyethylene bottles with child-resistant closures.
Abiraterone acetate will be supplied by the sponsor as 250-mg tablets packaged in high-density 
polyethylene bottles with child-resistant closures. There are 120 tablets per bottle.
14.3.
Labeling
Study drug labels will contain information to meet the applicable regulatory requirements.

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14.4.
Preparation, Handling, and Storage
The study drugs must be stored in a secure area and administered only to subjects entered into 
the clinical study in accordance with the conditions specified in this protocol. Additional
information for AA is provided in the local product information. Subjects should be advised to 
keep all medications out of reach and sight of children.
Abiraterone Acetate Handling Requirements: AA is contraindicated in women who are or may 
potentially be pregnant. There are no human data on the use of AA in pregnancy. Maternal use of 
CYP17 inhibitor is expected to produce changes in hormonal levels that may affect the 
development of the fetus. Women who are pregnant or may be pregnant should not handle AA
without protection, eg gloves.
In an oral developmental toxicity study in the rat, AA affected pregnancy.
It is not known whether abiraterone or its metabolites are present in semen. A condom is 
required if the subject is engaged in sexual activity with a pregnant woman. If the subject is 
engaged in sex with a woman of childbearing potential, a condom is required along with another 
effective contraceptive method. In either case, the subject should use a condom while on study 
drug and for 3 months following the last dose of study drug.
Refer to the pharmacy manual/study-site investigational product manual for additional guidance on 
study drug preparation, handling, and storage.
14.5.
Drug Accountability
The investigator is responsible for ensuring that all study drug received at the site is inventoried 
and accounted for throughout the study. The dispensing of study drug to the subject, and the 
return of study drug from the subject, must be documented on the drug accountability form. 
Subjects, or their legally acceptable representatives where applicable, must be instructed to 
return all original containers, whether empty or containing study drug. All study drug will be 
stored and disposed of according to the sponsor's instructions. Study-site personnel must not 
combine contents of the study drug containers.
Study drug must be handled in strict accordance with the protocol and the container label, and 
must be stored at the study-site in a limited-access area or in a locked cabinet under appropriate 
environmental conditions. Unused study drug, and study drug returned by the subject must be 
available for verification by the sponsor's study-site monitor during on-site monitoring visits.
The return to the sponsor of unused study drug, or used returned study drug for destruction, will 
be documented on the drug return form. When the study-site is an authorized destruction unit and 
study drug supplies are destroyed on-site, this must also be documented on the drug return form.
Study drug should be dispensed under the supervision of the investigator or a qualified member 
of the study-site personnel, or by a hospital/clinic pharmacist. Study drug will be supplied only 
to subjects participating in the study. Returned study drug must not be dispensed again, even to 
the same subject. Study drug may not be relabeled or reassigned for use by other subjects. The 

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investigator agrees neither to dispense the study drug from, nor store it at, any site other than the 
study-sites agreed upon with the sponsor.
15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:

Investigator Brochure(s) and package insert(s) as applicable

Pharmacy manual/SIPPM

Laboratory Manual

Link to NCI-CTCAE Version 4.03: 
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf

ePRO device and user manual

IWRS Manual 

eDC Manual

Imaging manual
16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
This is a randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety 
of combining apalutamide with AAP in subjects with chemotherapy-naïve mCRPC. All subjects 
will receive active treatment with AAP as standard of care. The study is blinded to adequately 
test the hypothesis that the addition of apalutamide will prolong rPFS in this subject population 
and provide additional clinical benefit and an acceptable safety profile. 
Potential subjects will be fully informed of the risks and requirements of the study including the 
fact that limited data exists for the use of apalutamide with AAP in combination and, during the 
study, subjects will be given any new information that may affect their decision to continue 
participation. They will be told that their consent to participate in the study is voluntary and may be 
withdrawn at any time with no reason given and without penalty or loss of benefits to which they 
would otherwise be entitled. Only subjects who are fully able to understand the risks, benefits, and 
potential adverse events of the study, and provide their consent voluntarily will be enrolled.
All participating subjects will receive full supportive care and will be followed closely for safety 
and efficacy throughout the study. As rPFS is the primary endpoint, scheduled imaging is 
incorporated into the protocol. The timing of imaging is designed to capture progression events 
and allow the clinical investigator to make timely treatment decisions, yet balancing this with 
preventing subject overexposure to radiation. Efficacy assessments will occur as recommended 
by the internationally accepted RECIST 1.1 criteria and PCWG2 criteria.16,30
An IDMC will be established to review the safety and efficacy of the treatment combination and 
make recommendations as to the future conduct of the study. The sponsor will monitor blinded 

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data on an ongoing basis to ensure the safety of the subjects enrolled in this study. A futility 
analysis will provide an early look to ensure that sufficient antitumor activity is observed in the 
treatment group of apalutamide plus AAP compared with AAP. An ongoing Phase 1 study will 
also inform for the Phase 3 study.
See Section 9.1.1 for details on blood volumes. The volume of blood to be drawn is considered 
to be customary and acceptable for subjects participating in a cancer clinical study and is deemed 
reasonable over the time frame of the study, based upon the standard of the American Red Cross 
(2014).1
16.2.
Regulatory Ethics Compliance
16.2.1.
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, 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 
study subjects are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible.
16.2.2.
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the 
IEC/IRB with current and complete copies of the following documents (as required by local 
regulations):

Final protocol and, if applicable, amendments

Sponsor-approved ICF (and any other written materials to be provided to the subjects)

Investigator's Brochure (or equivalent information) and amendments/addenda

Sponsor-approved subject recruiting materials

Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable

Investigator's curriculum vitae or equivalent information (unless not required, as 
documented by the IEC/IRB)

Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for subjects

Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final 
protocol, amendments (if any, excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct, unless required locally), the ICF, applicable 

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recruiting materials, and subject compensation programs, and the sponsor has received a copy of 
this approval. This approval letter must be dated and must clearly identify the IEC/IRB and the 
documents being approved.
During the study the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate:

Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct)

Revision(s) to ICF and any other written materials to be provided to subjects

If applicable, new or revised subject recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable

New edition(s) of the Investigator's Brochure and amendments/addenda

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually)

Reports of adverse events that are serious, unlisted/unexpected, and associated with the 
study drug

New information that may adversely affect the safety of the subjects or the conduct of the 
study

Deviations from or changes to the protocol to eliminate immediate hazards to the subjects

Report of deaths of subjects under the investigator's care

Notification if a new investigator is responsible for the study at the site

Development Safety Update Report and Line Listings, where applicable

Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of 
the change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this study, where 
required. 
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB 
about the study completion (if applicable, the notification will be submitted through the head of 
investigational institution).
16.2.3.
Informed Consent
Each subject must give written consent according to local requirements after the nature of the 
study has been fully explained. The ICF(s) must be signed before performance of any study-
related activity. The ICF(s) that is/are used must be approved by both the sponsor and by the 

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reviewing IEC/IRB and be in a language that the subject can read and understand. The informed 
consent should be in accordance with principles that originated in the Declaration of Helsinki, 
current ICH and GCP guidelines, applicable regulatory requirements, and sponsor policy.
Before enrollment in the study, the investigator or an authorized member of the study-site 
personnel must explain to potential subjects the aims, methods, reasonably anticipated benefits, 
and potential hazards of the study, and any discomfort participation in the study may entail. 
Subjects will be informed that their participation is voluntary and that they may withdraw 
consent to participate at any time. They will be informed that choosing not to participate will not 
affect the care the subject will receive for the treatment of their disease. Subjects will be told that 
alternative treatments are available if they refuse to take part and that such refusal will not 
prejudice future treatment. Finally, they will be told that the investigator will maintain a subject 
identification register for the purposes of long-term follow up if needed and that their records 
may be accessed by health authorities and authorized sponsor personnel without violating the 
confidentiality of the subject, to the extent permitted by the applicable law(s) or regulations. By 
signing the ICF the subject is authorizing such access, which includes permission to obtain 
information about his survival status. It also denotes that the subject agrees to allow his study 
physician to re-contact the subject for the purpose of obtaining consent for additional safety 
evaluations, if needed, and subsequent disease-related treatments, or to obtain information about 
his survival status.
The subject will be given sufficient time to read the ICF and the opportunity to ask questions. 
After this explanation and before entry into the study, consent should be appropriately recorded 
by means of the subject's personally dated signature. After having obtained the consent, a copy of 
the ICF must be given to the subject.
When prior consent of the subject is not possible, enrollment procedures should be described in 
the protocol with documented approval/favorable opinion by the IEC/IRB to protect the rights, 
safety, and well-being of the subject and to ensure compliance with applicable regulatory 
requirements. The subject must be informed about the study as soon as possible and give consent 
to continue.
16.2.4.
Privacy of Personal Data
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized 
disclosures or access, accidental or unlawful destruction, or accidental loss or alteration must be 
put in place. Sponsor personnel whose responsibilities require access to personal data agree to 
keep the identity of subjects confidential.
The informed consent obtained from the subject includes explicit consent for the processing of 
personal data and for the investigator/institution to allow direct access to his original medical 

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records (source data/documents) for study-related monitoring, audit, IEC/IRB review, and 
regulatory inspection. This consent also addresses the transfer of the data to other entities and to 
other countries.
The subject has the right to request through the investigator access to his personal data and the 
right to request rectification of any data that are not correct or complete. Reasonable steps will be 
taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations.
Exploratory pharmacodynamics, biomarker, and PK research is not conducted under standards 
appropriate for the return of data to subjects. In addition, the sponsor cannot make decisions as to 
the significance of any findings resulting from exploratory research. Therefore, exploratory 
research data will not be returned to subjects or investigators, unless required by law or local 
regulations. Privacy and confidentiality of data generated in the future on stored samples will be 
protected by the same standards applicable to all other clinical data.
16.2.5.
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise 
help ensure access to the developed product if the need for the product persists, unless explicitly 
addressed as a specific ethical consideration in Section 16.1, Study-Specific Design
Considerations.
17.
ADMINISTRATIVE REQUIREMENTS
17.1.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment 
by the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by 
the investigator. Protocol amendments must not be implemented without prior IEC/IRB 
approval, or when the relevant competent authority has raised any grounds for non-acceptance, 
except when necessary to eliminate immediate hazards to the subjects, in which case the 
amendment must be promptly submitted to the IEC/IRB and relevant competent authority. 
Documentation of amendment approval by the investigator and IEC/IRB must be provided to the 
sponsor. When the change(s) involves only logistic or administrative aspects of the study, the 
IRB (and IEC where required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor 
representative (listed on the Contact Information page(s), which will be provided as a separate 
document). Except in emergency situations, this contact should be made before implementing 
any departure from the protocol. In all cases, contact with the sponsor must be made as soon as 
possible to discuss the situation and agree on an appropriate course of action. The data recorded 
in the eCRF and source documents will reflect any departure from the protocol, and the source 
documents will describe this departure and the circumstances requiring it.

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17.2.
Regulatory Documentation
17.2.1.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.
17.2.2.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study drug to the 
study-site:

Protocol and amendment(s), if any, signed and dated by the principal investigator

A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, subject compensation programs. This approval must clearly identify the specific 
protocol by title and number and must be signed (or sealed, where appropriate per local 
regulations) by the chairman or authorized designee.

Name and address of the IEC/IRB, including a current list of the IEC/IRB members and 
their function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, 
from the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the study-site personnel is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the 
vote/opinion of the study.

Regulatory authority approval or notification, if applicable

Signed and dated statement of investigator (eg, Form FDA 1572), if applicable

Documentation of investigator qualifications (eg, curriculum vitae)

Completed investigator financial disclosure form from the principal investigator, where 
required

Signed and dated Clinical Trial Agreement, which includes the financial agreement

Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first subject:

Completed investigator financial disclosure forms from all subinvestigators

Documentation of subinvestigator qualifications (eg, curriculum vitae)

Name and address of any local laboratory conducting tests for the study, and a dated copy of 
current laboratory normal ranges for these tests, if applicable

Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(eg, accreditation/license), if applicable

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17.3.
Subject Identification, Enrollment, and Screening Logs
The investigator agrees to complete a subject identification and enrollment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by the 
sponsor study-site contact for completeness.
The subject identification and enrollment log will be treated as confidential and will be filed by 
the investigator in the study file. To ensure subject confidentiality, no copy will be made. All 
reports and communications relating to the study will identify subjects by subject identification
and date of birth. In cases where the subject is not randomized into the study, the date seen and 
date of birth will be used. The investigator must also complete a subject screening log, which 
reports on all subjects who were seen to determine eligibility for inclusion in the study.
17.4.
Source Documentation
At a minimum, source documents consistent in the type and level of detail with that commonly 
recorded at the study-site as a basis for standard medical care, must be available for the 
following subject identification, eligibility, and study identification; study discussion and date of 
signed informed consent; dates of visits; results of safety and efficacy parameters as required by 
the protocol; record of all adverse events and follow-up of adverse events; concomitant 
medication; drug receipt/dispensing/return records; study drug administration information; and 
date of study completion and reason for early discontinuation of study drug or withdrawal from 
the study, if applicable. The author of an entry in the source documents should be identifiable.
Specific details required as source data for the study and source data collection methods will be 
reviewed with the investigator before the study and will be described in the monitoring
guidelines (or other equivalent document). Subject- and investigator-completed scales and 
assessments designated by the sponsor (PROs) will be recorded directly into an electronic device 
and will be considered source data.
An electronic source system may be utilized, which contains data traditionally maintained in a 
hospital or clinic record to document medical care (eg, electronic source documents) as well as 
the clinical study-specific data fields as determined by the protocol. This data is electronically 
extracted for use by the sponsor. If an electronic source is utilized, references made to the CRF 
in the protocol include the electronic source system but information collected through electronic 
source may not be limited to that found in the CRF.
17.5.
Case Report Form Completion
Case report forms are provided by the sponsor for each subject in electronic format. All data 
relating to the study must be recorded in the eCRF. All eCRF entries, corrections, and alterations 
must be made by the investigator or authorized study-site personnel. The investigator must verify 
that all data entries in the eCRF are accurate and correct. 
Electronic Data Capture (eDC) will be used for this study. The study data will be transcribed by 
study-site personnel from the source documents onto an eCRF, if applicable. Study-specific data 
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Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any 
such worksheets will become part of the subject's source documents Data must be entered into 
eCRFs in English. The eCRF must be completed as soon as possible after a subject visit, and the 
forms should be available for review at the next scheduled monitoring visit.
All eCRF entries, corrections, and alterations must be made by the investigator or other 
authorized study-site personnel. If necessary, queries will be generated in the eDC tool. If 
corrections to an eCRF are needed after the initial entry into the eCRF, this can be done in 
2 different ways:

Investigator and study-site personnel can make corrections in the eDC tool at their own 
initiative or as a response to an auto query (generated by the eDC tool).

Sponsor or sponsor delegate can generate a query for resolution by the study-site personnel.
17.6.
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study-sites, review of protocol procedures with the investigator and 
study-site personnel before the study, and periodic monitoring visits by the sponsor and direct 
transmission of clinical laboratory data from a central laboratory into the sponsor’s database. 
Written instructions will be provided for collection, handling, storage, and shipment of samples.
Guidelines for eCRF completion will be provided and reviewed with study-site personnel before 
the start of the study. The sponsor will review eCRFs for accuracy and completeness during on-
site monitoring visits and after transmission to the sponsor; any discrepancies will be resolved 
with the investigator or designee, as appropriate. After upload of the data into the study database 
they will be verified for accuracy and consistency with the data sources.
17.7.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRFs 
and all source documents that support the data collected from each subject, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a 
Clinical Trial, and all study documents as specified by the applicable regulatory requirement(s). 
The investigator/institution will take measures to prevent accidental or premature destruction of 
these documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents will be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the sponsor. It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 

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accept the responsibility. The sponsor must be notified in writing of the name and address of the 
new custodian. Under no circumstance shall the investigator relocate or dispose of any study 
documents before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator/institution must permit access to such 
reports.
17.8.
Monitoring
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a study-site visit log that will be kept at the study-site. The first 
post-initiation visit will be made as soon as possible after enrollment has begun. At these visits, 
the monitor will compare data entered into the eCRFs with the source documents
(eg hospital/clinic/physician’s office medical records); a sample may be reviewed. The nature 
and location of all source documents will be identified to ensure that all sources of original data 
required to complete the eCRF are known to the sponsor and study-site personnel and are 
accessible for verification by the sponsor study-site contact. If electronic records are maintained 
at the study-site, the method of verification must be discussed with the study-site personnel. 
Direct access to source documents (medical records) must be allowed for the purpose of 
verifying that the recorded eCRF data are consistent with the original source data. Findings from 
this review will be discussed with the study-site personnel. The sponsor expects that, during 
monitoring visits, the relevant study-site personnel will be available, the source documents will 
be accessible, and a suitable environment will be provided for review of study-related 
documents. The monitor will meet with the investigator on a regular basis during the study to 
provide feedback on the study conduct.
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during 
these remote contacts, study-site personnel will be available to provide an update on the progress 
of the study at the site.
17.9.
Study Completion/End-of-Study
17.9.1.
Study Completion
The study is considered completed with the last study assessment for the last subject 
participating in the study. The final data from the study site will be sent to the sponsor (or 
designee) after completion of the final subject assessment at that study site, in the time frame 
specified in the Clinical Trial Agreement.
17.9.2.
End-of-Study
The sponsor reserves the right to close the study-site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A
study-site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed.

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The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study-site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of subjects by the investigator

Discontinuation of further study drug development
17.10. On-Site Audits
Representatives of the sponsor's clinical quality assurance department may visit the study-site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection. Subject privacy must, however, be 
respected. The investigator and study-site personnel are responsible for being present and 
available for consultation during routinely scheduled study-site audit visits conducted by the 
sponsor or its designees. 
Similar auditing procedures may also be conducted by agents of any regulatory body, either as 
part of a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The investigator should immediately notify the sponsor if he has been 
contacted by a regulatory agency concerning an upcoming inspection.
17.11. Use of Information and Publication
All information, including but not limited to information regarding JNJ-56021927 (apalutamide)
or the sponsor's operations (eg, patent application, formulas, manufacturing processes, basic 
scientific data, prior clinical data, formulation information) supplied by the sponsor to the 
investigator and not previously published, and any data, including exploratory biomarker
research data, generated as a result of this study, are considered confidential and remain the sole 
property of the sponsor. The investigator agrees to maintain this information in confidence and 
use this information only to accomplish this study, and will not use it for other purposes without 
the sponsor's prior written consent.
The investigator understands that the information developed in the study will be used by the 
sponsor in connection with the continued development of JNJ-56021927 (apalutamide), and thus 
may be disclosed as required to other clinical investigators or regulatory agencies. To permit the 
information derived from the clinical studies to be used, the investigator is obligated to provide 
the sponsor with all data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain eCRF data from all study-sites that participated in the study, and direct transmission 
of clinical laboratory data from a central laboratory into the sponsor's database. Recruitment 

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performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator. Results of exploratory biomarker 
analyses performed after the Clinical Study Report has been issued will be reported in a separate 
report and will not require a revision of the Clinical Study Report. Study subject identifiers will 
not be used in publication of results. Any work created in connection with performance of the 
study and contained in the data that can benefit from copyright protection (except any 
publication by the investigator as provided for below) shall be the property of the sponsor as 
author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors guidelines, the sponsor shall have the right to publish such primary (multicenter) data 
and information without approval from the investigator. The investigator has the right to publish 
study-site-specific data after the primary data are published. If an investigator wishes to publish 
information from the study, a copy of the manuscript must be provided to the sponsor for review 
at least 60 days before submission for publication or presentation. Expedited reviews will be 
arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in 
writing, the investigator will withhold such publication for up to an additional 60 days to allow 
for filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor 
will not mandate modifications to scientific content and does not have the right to suppress 
information. For multicenter study designs and substudy approaches, secondary results generally 
should not be published before the primary endpoints of a study have been published. Similarly, 
investigators will recognize the integrity of a multicenter study by not submitting for publication 
data derived from the individual study-site until the combined results from the completed study
have been submitted for publication, within 12 months of the availability of the final data (tables, 
listings, graphs), or the sponsor confirms there will be no multicenter study publication. 
Authorship of publications resulting from this study will be based on the guidelines on 
authorship, such as those described in the Uniform Requirements for Manuscripts Submitted to 
Biomedical Journals, which state that the named authors must have made a significant 
contribution to the design of the study or analysis and interpretation of the data, provided critical 
review of the paper, and given final approval of the final version.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and/or disclose the existence of and the results of clinical studies as 
required by law.

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Arora VK, Schenkeine E, Murali R, et al. Glucocorticoid receptor confers resistance to antiandrogens by 
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Chang K-H, Li R, Kuri B, et al. A gain-of-function mutation in DHT synthesis in castration-resistant 
prostate cancer. Cell. 2013;154:1074-1084.
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the treatment of prostate cancer. Cancer Res. 2012; 2:1494-1503.
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Clinical Study Report ARN-509-001. An Open-label, Phase I/II Safety, PK, and Proof-of-Concept Study of 
ARN-509 in Patients with Progressive Advanced Castration-resistant Prostate Cancer. Janssen R&D 
(14 December 2015).
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Clinical Study Report 56021927PCR1010. A drug-drug interaction, safety and efficacy study with JNJ-
56021927 (ARN-509) and abiraterone acetate in subjects with metastatic castration-resistant prostate 
cancer. Janssen R&D (13 June 2017).
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Synoptic Pharmacokinetics Report ARN-509-004. Phase 1b, Open-Label Study to Assess the Safety, 
Tolerability, Pharmacokinetics, and Preliminary Anti-tumor Activity of Ascending Doses of ARN-509 in 
Combination with Abiraterone Acetate in Patients With Metastatic Castrate Resistant Prostate 
Cancer(CRPC). Janssen R&D (11 January 2016).
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Crawford ED, Eisenberger MA, McLeod DG, et al. A controlled trial of leuprolide with and without 
flutamide in prostatic carcinoma. N Engl J Med. 1989;321:419-424.
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de Bono J, Logothetis C, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. 
N Engl J Med. 2011;364(21):1995-2005.
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Efstathiou E, Titus M, Tsavachidou D et al. Effects of abiraterone acetate on androgen signaling in 
castrate-resistant prostate cancer in bone. J Clin Oncol. 2012;30:637-643. 
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Efstathiou E, Titus M, Wen AS, et al. The effects of enzalutamide (ENZA) in combination with abiraterone 
acetate (AA) in patients with bone metastatic castration resistant prostate cancer (mCRPC). Presented at: 
European Cancer Congress 2013; September 27-October 1, 2013; Amsterdam, The Netherlands. 
Abstract 2854.
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Efstathiou E, Titus M, Wen S, et al. Enzalutamide (ENZA) in combination with abiraterone acetate (AA) in 
bone metastatic castration resistant prostate cancer (mCRPC).J Clin Oncol. 32:5s, 2014 (suppl; abstr 5000).
14.
Efstathiou E, Titus M, Wen S, et al. Molecular Characterization of Enzalutamide-treated Bone Metastatic 
Castration-resistant Prostate Cancer. European Urol http://dx.doi.org/10.1016/j.eururo.2014.05.005.
15.
Eisenberger MA, Blumenstein BA, Crawford ED, et al. Bilateral orchiectomy with or without flutamide for 
metastatic prostate cancer. N Engl J Med. 1998;339:1036-1042.
16.
Eisenhauer EA, Therasse P, Bogaerts, et al. New response evaluation criteria in solid tumours: Revised 
RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-247.
17.
Erho N, Crisan A, Vergana IA et al. Discovery and validation of a prostate cancer genomic classifier that 
predicts early metastasis following radical prostatectomy. PLOS ONE 2013;8:e66855 www.plosone.com 
Accessed 20 May 2014.
18.
Investigator’s Brochure: JNJ-56021927 (apalutamide), Edition 12. Janssen Research & Development
(02 April 2019).
19.
Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA: Cancer J Clin. 2011;61:69-90.
20.
Joseph JD, Lu N, Qian J, et al. A clinically relevant androgen reception mutation confers resistance to 2nd
generation anti-androgens enzaluatamide and ARN-509. Cancer Disc. 2012;3:1020-1029.

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21.
Kelly WK, Slovin S, Scher HI. Steroid hormone withdrawal syndromes: pathophysiology and clinical 
significance. Urol Clin North Am. 1997;24:421-431.
22.
Knezevic D, Goddard AD, Natraj N, et al. Analytical validation of the Oncotype DX prostate cancer 
assay-a clinical RT-PCR assay optimized for prostate needle biopsies. BMC Genomics. 2013;14: 691 
doi:10.1186/1471 2164-14-690.
23.
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.
24.
Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic 
prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68:4447-4454.
25.
O'Donnell A, Judson I, Dowsett M, et al. Hormonal impact of the 17hydroxylase/C17,20-lyase inhibitor 
abiraterone acetate (CB7630) in patients with prostate cancer. Br J Cancer. 2004;90:2317-2325.
26.
Olmos, D, Brewer D, Clarke J, et al. Prognostic value of blood mRNA expression signatures in 
castration-resistant prostate cancer: a prospective, two-stage study. Lancet Oncology. 2012;13:1114-1124.
27.
Rathkopf DE, Smith MR, DeBono JS, et al. Updated Interim Efficacy Analysis and Long-term Safety of 
Abiraterone Acetate in Metastatic Castration-resistant Prostate 5 Cancer Patients Without Prior 
Chemotherapy (COU-AA-302).European Urol 2014; http://dx.doi.org/10.1016/j.eururo.2014.02.056.
28.
Ross RW, Galsky MD, Scher HI, et al. A whole-blood RNA transcript-based prognostic model in men with 
castration-resistant prostate cancer: a prospective study. Lancet Oncology. 2012;13:1105-1113.
29.
Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous 
chemotherapy. N Engl J Med. 2013;368:138-148. Published online December 10, 2012.
30.
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;26:1148-1159.
31.
Scher HI, Sawyers CL. Biology of progressive, castration-resistant prostate cancer: directed therapies 
targeting the androgen-receptor signaling axis. J Clin Oncol. 2005; 23:8253-8261.
32.
Schmitt B, Wilt TJ, Schellhammer PF, et al. Combined androgen blockade with nonsteroidal antiandrogens 
for advanced prostate cancer: a systematic review. Urology. 2001;57:727-732.
33.
Sharifi N. Steroid receptors aplenty in prostate cancer. N Eng J Med. 2014;370:970-971.
34.
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;23:8253-8261.
35.
Wang SK, Tsiatis AA. Approximately optimal one parameter boundaries for group sequential trials. 
Biometrics. 1987:43;193-199.

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Attachment 1: Summary of RECIST Criteria Version 1.1
The following information was extracted from Section 3, Section 4, and Appendix I of the New Response 
Evaluation Criteria in Solid Tumors:  revised RECIST guideline (version 1.1) authored by Eisenhauer et 
al (2009). Refer to the European Journal of Cancer article (2009;45(2):228-247) for the complete 
publication.16 For modifications based on the Prostate Cancer Working Group 2 (PCWG2) criteria refer to 
Scher et al. J Clin Oncol (2008;26:1148-1159).30
3.
Measurability of tumor at baseline
3.1
Definitions
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as follows:
3.1.1
Measurable 
Tumor lesions:  Must be accurately measured in at least one dimension (longest diameter in the plane of 
measurement is to be recorded) with a minimum size of:

10 mm by CT scan (CT scan slice thickness no greater than 5 mm)
The following two methods of measure are not allowed in this protocol:

10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured with 
calipers should be recorded as non-measurable)

20 mm by chest X-ray 

Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a lymph node 
must be 15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to 
be no greater than 5 mm).  At baseline and in follow up, only the short axis will be measured and 
followed.  See also ‘Baseline documentation of target and non-target lesions’ in section 4.2 of the 
RECIST guideline for information on lymph node measurement.
3.1.2
Non-measurable 
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes with 
10 to <15 mm short axis) as well as truly non-measurable lesions.  Lesions considered truly non-
measurable include: leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, and abdominal masses/abdominal organomegaly 
identified by physical exam that is not measurable by reproducible imaging techniques.
3.2
Specifications by methods of measurements
3.2.1
Measurement of lesions
All measurements should be recorded in metric notation, using calipers if clinically assessed.  All baseline 
evaluations should be performed as close as possible to the treatment start and never more than 4 weeks 
before the beginning of the treatment.
3.2.2
Method of assessment
The same method of assessment and the same technique should be used to characterize each identified 
and reported lesion at baseline and during follow up.  Imaging based evaluation should always be done 
rather than clinical examination.

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4.
Tumor response evaluation
4.1
Assessment of overall tumor burden and measurable disease 
To assess objective response or future progression, it is necessary to estimate the overall tumor burden at 
baseline and use this as a comparator for subsequent measurements.
4.2
Baseline documentation of ‘target’ and ‘non-target’ lesions
When more than one measurable lesion is present at baseline all lesions up to a maximum of five lesions 
total (and a maximum of two lesions per organ) representative of all involved organs should be identified 
as target lesions and will be recorded and measured at baseline (this means in instances where patients 
have only one or two organ sites involved a maximum of two and four lesions respectively will be 
recorded).  For evidence to support the selection of only five target lesions, see analyses on a large 
prospective database in the article by Bogaerts et al. (Reference #10 in Eisenhauer publication).
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to reproducible 
repeated measurements.  It may be the case that, on occasion, the largest lesion does not lend itself to 
reproducible measurement in which circumstance the next largest lesion, which can be measured 
reproducibly, should be selected.  
Lymph nodes merit special mention since they are normal anatomical structures, which may be visible by 
imaging even if not involved by tumor.  As noted in Section 3, pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 15 mm by 
CT scan.  Only the short axis of these nodes will contribute to the baseline sum.  The short axis of the 
node is the diameter normally used by radiologists to judge if a node is involved by solid tumor.  Nodal 
size is normally reported as two dimensions in the plane in which the image is obtained (for CT scan this 
is almost always the axial plane; for MRI the plane of acquisition may be axial, sagittal or coronal).  The 
smaller of these measures is the short axis.  For example, an abdominal node which is reported as being 
20 mm•30 mm has a short axis of 20 mm and qualifies as a malignant, measurable node.  In this example, 
20 mm should be recorded as the node measurement (See also the example in Fig. 4 in Appendix II of the 
Eisenhauer reference).  All other pathological nodes (those with short axis 10 mm but <15 mm) should 
be considered non-target lesions.  Nodes that have a short axis <10 mm are considered non-pathological 
and should not be recorded or followed.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions 
will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be included in the 
sum, then as noted above, only the short axis is added into the sum.  The baseline sum diameters will be 
used as reference to further characterize any objective tumor regression in the measurable dimension of 
the disease.  
All other lesions (or sites of disease) including pathological lymph nodes should be identified as non-
target lesions and should also be recorded at baseline.  Measurements are not required and these lesions 
should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ (more details to 
follow).  In addition, it is possible to record multiple nontarget lesions involving the same organ as a 
single item on the case record form (e.g. ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver 
metastases’). 
4.3
Response criteria
This section provides the definitions of the criteria used to determine objective tumor response for target 
lesions.

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4.3.1
Evaluation of target lesions
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph nodes (whether 
target or non-target) must have reduction in short axis to <10 mm.
Partial Response (PR):  At least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum diameters.
Progressive Disease:  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.  (Note:  the appearance of one or more new lesions is also considered progression). 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
progressive disease, taking as reference the smallest sum diameters while on study.
4.3.2
Special notes on the assessment of target lesions 
Lymph nodes.  Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), even if the 
nodes regress to below 10 mm on study.  This means that when lymph nodes are included as target 
lesions, the ‘sum’ of lesions may not be zero even if complete response criteria are met, since a normal 
lymph node is defined as having a short axis of <10 mm.  Case report forms or other data collection
methods may therefore be designed to have target nodal lesions recorded in a separate section where, in 
order to qualify for CR, each node must achieve a short axis <10 mm.  For PR, SD and progressive 
disease, the actual short axis measurement of the nodes is to be included in the sum of target lesions.
Target lesions that become ‘too small to measure’.  While on study, all lesions (nodal and non-nodal) 
recorded at baseline should have their actual measurements recorded at each subsequent evaluation, even 
when very small (eg 2 mm).  However, sometimes lesions or lymph nodes which are recorded as target 
lesions at baseline become so faint on CT scan that the radiologist may not feel comfortable assigning an 
exact measure and may report them as being ‘too small to measure’.  When this occurs it is important that 
a value be recorded on the CRF.  If it is the opinion of the radiologist that the lesion has likely 
disappeared, the measurement should be recorded as 0 mm.  If the lesion is believed to be present and is 
faintly seen but too small to measure, a default value of 5 mm should be assigned (Note:  It is less likely 
that this rule will be used for lymph nodes since they usually have a definable size when normal and are 
frequently surrounded by fat such as in the retroperitoneum; however, if a lymph node is believed to be 
present and is faintly seen but too small to measure, a default value of 5 mm should be assigned in this 
circumstance as well).  This default value is derived from the 5 mm CT slice thickness (but should not be 
changed with varying CT slice thickness).  The measurement of these lesions is potentially non-
reproducible; therefore providing this default value will prevent false responses or progressions based 
upon measurement error.  To reiterate, however, if the radiologist is able to provide an actual measure, 
that should be recorded, even if it is below 5 mm.
Lesions that split or coalesce on treatment. When non-nodal lesions ‘fragment’, the longest diameters of 
the fragmented portions should be added together to calculate the target lesion sum.  Similarly, as lesions 
coalesce, a plane between them may be maintained that would aid in obtaining maximal diameter 
measurements of each individual lesion.  If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal longest diameter for 
the ‘coalesced lesion’. 
4.3.3
Evaluation of non-target lesions
This section provides the definitions of the criteria used to determine the tumor response for the group of 
non-target lesions.  While some non-target lesions may actually be measurable, they need not be 
measured and instead should be assessed only qualitatively at the timepoints specified in the protocol.  

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Complete Response (CR):  Disappearance of all non-target lesions and normalization of tumor marker 
level.  All lymph nodes must be non-pathological in size (<10 mm short axis).  
Non-CR/Non-progressive disease:  Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker level above the normal limits.  
Progressive Disease:  Unequivocal progression (see comments below) of existing non-target lesions. 
(Note:  the appearance of one or more new lesions is also considered progression).
4.3.4
Special notes on assessment of progression of non-target disease
The concept of progression of non-target disease requires additional explanation as follows:
When the patient also has measurable disease.  In this setting, to achieve ‘unequivocal progression’ on 
the basis of the non-target disease, there must be an overall level of substantial worsening in non-target 
disease such that, even in presence of SD or PR in target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy.  A modest ‘increase’ in the size of one or more non-target 
lesions is usually not sufficient to quality for unequivocal progression status.  The designation of overall 
progression solely on the basis of change in non-target disease in the face of SD or PR of target disease 
will therefore be extremely rare.  
When the patient has only non-measurable disease.  This circumstance arises in some Phase studies when 
it is not a criterion of study entry to have measurable disease.  The same general concepts apply here as 
noted above, however, in this instance there is no measurable disease assessment to factor into the 
interpretation of an increase in non-measurable disease burden.  Because worsening in non-target disease 
cannot be easily quantified (by definition: if all lesions are truly non-measurable) a useful test that can be 
applied when assessing patients for unequivocal progression is to consider if the increase in overall 
disease burden based on the change in non-measurable disease is comparable in magnitude to the increase 
that would be required to declare progressive disease for measurable disease:  i.e. an increase in tumor 
burden representing an additional 73% increase in ‘volume’ (which is equivalent to a 20% increase 
diameter in a measurable lesion).  Examples include an increase in a pleural effusion from ‘trace’ to 
‘large’, an increase in lymphangitic disease from localized to widespread, or may be described in 
protocols as ‘sufficient to require a change in therapy.’  If ‘unequivocal progression’ is seen, the patient 
should be considered to have had overall progressive disease at that point.  While it would be ideal to 
have objective criteria to apply to non-measurable disease, the very nature of that disease makes it 
impossible to do so, therefore the increase must be substantial.  
4.3.5
New lesions
The appearance of new malignant lesions denotes disease progression; therefore, some comments on 
detection of new lesions are important.  There are no specific criteria for the identification of new 
radiographic lesions; however, the finding of a new lesion should be unequivocal:  i.e. not attributable to 
differences in scanning technique, change in imaging modality or findings thought to represent something 
other than tumor (for example, some ‘new’ bone lesions may be simply healing or flare of pre-existing 
lesions). This is particularly important when the patient’s baseline lesions show partial or complete 
response.  For example, necrosis of a liver lesion may be reported on a CT scan report as a ‘new’ cystic 
lesion, which it is not. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at baseline is 
considered a new lesion and will indicate disease progression.  An example of this is the patient who has 
visceral disease at baseline and while on study has a CT or MRI brain ordered which reveals metastases. 
The patient’s brain metastases are considered to be evidence of progressive disease even if he/she did not 
have brain imaging at baseline. 

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If a new lesion is equivocal, for example because of its small size, continued therapy and follow-up 
evaluation will clarify if it represents truly new disease.  If repeat scans confirm there is definitely a new 
lesion, then progression should be declared using the date of the initial scan. 
4.4.1
Timepoint response
It is assumed that at each protocol specified timepoint, a response assessment occurs.  Table 1 in this 
attachment provides a summary of the overall response status calculation at each timepoint for patients 
who have measurable disease at baseline.  
When patients have non-measurable (therefore non-target) disease only, Table 2 in this attachment is to 
be used. 
4.4.2
Missing assessments and inevaluable designation 
When no imaging/measurement is done at all at a particular timepoint, the patient is not evaluable (NE) at 
that timepoint.  If only a subset of lesion measurements are made at an assessment, usually the case is also
considered NE at that timepoint, unless a convincing argument can be made that the contribution of the 
individual missing lesion(s) would not change the assigned timepoint response.  This would be most 
likely to happen in the case of progressive disease. For example, if a patient had a baseline sum of 50 mm 
with three measured lesions and at follow up only two lesions were assessed, but those gave a sum of 
80 mm, the patient will have achieved progressive disease status, regardless of the contribution of the 
missing lesion. 
4.4.3
Best overall response:  all timepoints 
The best overall response is determined once all the data for the patient is known. 
Best response determination in studies where confirmation of complete or partial response IS NOT 
required:  Best response in these studies is defined as the best response across all timepoints (for 
example, a patient who has SD at first assessment, PR at second assessment, and progressive disease on 
last assessment has a best overall response of PR).  When SD is believed to be best response, it must also 
meet the protocol specified minimum time from baseline.  If the minimum time is not met when SD is 
otherwise the best timepoint response, the patient’s best response depends on the subsequent assessments.  
For example, a patient who has SD at first assessment, progressive disease at second and does not meet 
minimum duration for SD, will have a best response of progressive disease.  The same patient lost to 
follow up after the first SD assessment would be considered inevaluable.
Table 1 - Timepoint response:  patients with Target (+/- non-target) disease
Target lesions
Non-target lesions
New lesions
Overall response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease; NE = not evaluable.

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Table 2 - Timepoint response:  patients with non-target disease only
Non-target lesions
New lesions
Overall response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR = complete response; PD = progressive disease; NE = not evaluable.
a
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as endpoint 
for assessment of efficacy in some studies so to assign this category when no lesions can be measured is not advised.

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Attachment 2: ECOG Performance Status
ECOG Grade
Scale (with Karnofsky conversion)
0
Fully active, able to carry on all predisease performance without restriction. 
(Karnofsky 90-100)
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work on a light or sedentary nature, eg, light housework, office work. (Karnofsky 
70-80)
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours. (Karnofsky 50-60)
3
Capable of only limited self-care; confined to bed or chair more than 50% of 
waking hours. (Karnofsky 30-40)
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair. (Karnofsky 10-20)
5
Dead. (Karnofsky 0)

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Attachment 3: Prohibited Concomitant Medications Known to Lower the Seizure Threshold or 
Cause Seizures and Additional Information on CYP450 Drug Interactions
Prohibited medications known to lower the seizure threshold or cause seizures include the 
following: 

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)
Additional information on CYP450 drug interactions can found on the following websites: 
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionsla
beling/ucm093664.htm
http://medicine.iupui.edu/clinpharm/ddis/table.aspx

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Attachment 4: Sample BPI-SF

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Attachment 5: Sample FACT-P

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Attachment 6: Sample EQ-5D-5L

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Attachment 7: Guidance Document for PCWG2 Criteria and RECIST 1.1 
Criteria of Progression for Study Eligibility by Disease Manifestation

Target (nodal and visceral) lesions or measurable disease:
o
Use RECIST 1.1 to record soft tissue (nodal and visceral) lesions as target or 
non-target

Baseline Assessment of Lymph node:
o
PCWG2: the greatest diameter of a lymph node must measure ≥2 cm by spiral CT 
to be considered a target lesion.

Bone Lesions: 
o
PCWG2: When the bone scan is the sole indicator of progression, PCWG2 
defines progression in bone when ≥2 new lesions are seen on bone scan compared 
with a prior scan for study entry.

PSA Progression :
o
PCWG2 requires a sequence of rising PSA values on at least 1 week apart and a 
minimum starting value of 2.0 ng/mL .
Disease Evaluation on Study

Soft tissue lesions (nodal and non-nodal: Use RECIST 1.1 with caveats)
o
Only report changes in lymph nodes that were ≥2 cm in greatest diameter at 
baseline 
o
Record changes in nodal and visceral soft tissue sites separately
o
Record complete elimination of disease at any site separately
o
Confirm favorable change with second scan

Bone lesions 
o
The appearance of 2 new lesions, and, for the first reassessment only, a 
confirmatory scan performed 6 or more weeks later that shows a minimum of 2 or 
more additional new lesions
o
The date of progression is the date of the first scan that shows the change

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ACIS study:
Eligibility
Disease Evaluation
Bone 
Inclusion criterion 6.1:
radiographic progression of bone 
according to PCWG2. 
A subject is considered to have progressed by 
bone scan if:
a. The first bone scan with ≥2 new lesions 
compared with baseline is observed 
<12 weeks from randomization and is 
confirmed by a second bone scan taken 
≥6 weeks later showing ≥2 additional new 
lesions (a total of ≥4 new lesions compared 
with baseline);
b. The first bone scan with ≥ 2 new lesions 
compared with baseline is observed 
≥12 weeks from randomization and the 
≥2 new lesions are verified on the next bone 
scan ≥6 weeks later (a total of ≥ 2 new 
lesions compared with baseline).
Lymph 
Nodes 
The greatest diameter of a lymph 
node must measure ≥2 cm by 
spiral CT to be considered a 
target lesion
Follow RECIST 1.1 
Complete Response (CR): Disappearance of 
all target lesions. Any pathological lymph 
nodes (whether target or non-target) must 
have reduction in short axis to <10 mm
(Section 4.3.1 of Attachment 1).
Soft tissues 
Inclusion criterion 6.1:
radiographic progression of soft 
tissues according to Response 
Evaluation Criteria in Solid 
Tumors, version 1.1 (RECIST 
1.1)
Follow RECIST 1.1 
PSA
Inclusion criterion 4: 
Castration-resistant prostate 
cancer demonstrated during 
continuous ADT, defined as 
3 rises of PSA, at least 1 week 
apart with the last PSA 
≥2 ng/mL
Inclusion criterion 6.1: Prostate 
cancer progression documented 
by PSA according to the Prostate 
Cancer Clinical Trials Working
Group (PCWG2)

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Attachment 8: Anticipated Events
An anticipated event is an adverse event (serious or nonserious) 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
Erectile dysfunction
Haematospermia
Haematuria
Incontinence
Lymphoedema
Nocturia
Painful ejaculation
Pollakiuria
PSA Increased
Urinary hesitation
Ureteral obstruction
Urethral obstruction
Urinary flow decreased
Urinary retention
Urinary tract obstruction
ADT-Related Events
Depression
Gynaecomastia
Hot flush
Libido decreased
Osteoporosis
Sexual dysfunction
Testicular atrophy
Reporting of Anticipated Events
All AEs will be recorded in the eCRF regardless of whether considered to be anticipated events and will 
be reported to the sponsor as described in Section 12.3.1. Any anticipated event that meets serious criteria 
will be reported to the sponsor as described in Section 12.3.2. Each anticipated event will be assessed by 
the investigator at the individual case level and if considered to be drug-related will undergo expedited 
reporting (if appropriate) per applicable clinical trial legislation to Health Authorities and IRB/ECs (Note: 
Japan will not identify anticipated events for the Health Authorities). If an anticipated event is considered 
disease-related or not related to study drug the event will be exempt from expedited reporting.
To meet US regulatory clinical trial legislation, the sponsor will perform aggregate review of anticipated 
events as outlined below, and if determined to be drug-related will implement expedited reporting of these 
events to Health Authorities and IRBs/ECs. If an interim analysis of trial results leads to an unblinded, 
aggregate review of safety data by the study team, the sponsor may terminate the review of pre-specified 
anticipated events outlined above.
Safety Assessment Committee (SAC)
A Safety Assessment Committee (SAC) will be established to perform reviews of pre-specified 
anticipated events at an aggregate level. The SAC is a safety committee within the sponsor’s organization 
that is independent of the sponsor’s study team. The SAC 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 intervention based on a review of the aggregate data by arm.

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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.

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Attachment 9: Open-Label Extension in the Event of Subjects Being Offered Cross-over to Open-
label Apalutamide in Combination With AAP After Study Unblinding
After unblinding at the final analysis, the IDMC and sponsor’s decision to offer cross-over, and 
subsequent notification, subjects assigned to AAP alone are offered the option to receive open-
label apalutamide in combination with AAP. The decision to cross-over should be made by the 
subject and his investigator, and should also take into consideration that there is no information 
about the effectiveness of adding apalutamide to AAP following treatment with AAP alone.
The Open-Label Extension Phase will begin when both the Amendment 4 is approved at the site 
and the sponsor has notified the site of the start of the Open-Label Extension Phase:

Subjects who are still receiving apalutamide in combination with AAP in the double-blind 
phase of the study will be offered the option to continue to receive open-label apalutamide in 
combination with AAP until they reach a reason for discontinuation of treatment (see 
protocol Section 10.2) or until further notification by the sponsor on a different means for 
continued supply of study treatment, whichever occurs first.

Subjects who are still receiving AAP alone in the double-blind phase of the study will be 
offered the option to either receive AAP alone or cross-over to receive open-label 
apalutamide in combination with AAP until they reach a reason for discontinuation of 
treatment (see protocol Section 10.2) or until further notification by the sponsor on a 
different means for continued supply of study treatment, whichever occurs first.
If a subject still receiving AAP alone chooses to cross-over and start receiving open-label 
apalutamide in combination with AAP, the investigator will evaluate eligibility based on the 
criteria below.

Subjects who have already ended treatment and are in the Follow-up Phase in the main study 
will be discontinued from the study and all data collection will cease.
Eligibility Criteria for Subjects who Cross-over from AAP Alone to Open-label 
Apalutamide in Combination With AAP after Unblinding
Subjects planned for cross-over to open-label apalutamide in combination with AAP must meet 
the eligibility criteria below. The laboratory evaluations listed below must be completed within 
28 days before the start of receiving open-label apalutamide in combination with AAP. If a 
subject does not meet these criteria, he can continue on AAP alone.
1.
Was still participating in the double-blind phase of the study and receiving AAP alone
2.
Willing and able to provide written informed consent to receive open-label apalutamide in 
combination with AAP
3.
ECOG PS grade of 0 or 1 or 2 (see Attachment 2)
4.
Adequate organ function as defined by the following:
a.
Serum AST or serum ALT ≤2.5-times the ULN;
b. Serum total bilirubin ≤1.5×ULN (Note: In subjects with Gilbert’s syndrome, if total 
bilirubin is >1.5×ULN, measure direct and indirect bilirubin, and if direct bilirubin is 
≤1.5×ULN, subject may be eligible)

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c.
Serum creatinine <2.0×ULN
d. Platelet count ≥100,000×109/µL independent of transfusion/growth factors within 
3 months before the evaluation
e.
Hemoglobin ≥9.0 g/dL (independent of transfusion/growth factors within 3 months before 
the evaluation)
f.
Serum potassium ≥3.5 mmol/L
Study Treatment Administration
ADT administration
Refer to Section 6.1 of the protocol.
Open-label study treatment
Study treatment is administered orally on an outpatient basis and a treatment cycle is defined as 
28 days (Table 8). Sufficient study drug for each treatment cycle will be distributed as specified
in Table 9. Dose modifications for toxicity are provided in Section 6.3 of the protocol. Guidance 
for apalutamide/placebo applies to open-label apalutamide.
If a subject was on a lower dose of apalutamide or AAP in the double-blind phase of the study, 
he should continue on that lower dose in the Open-Label Extension Phase.
Table 8: 
Study Treatment Administration for the Open-Label Extension Phase
Study Treatments
Daily Dose
Schedule
apalutamide
240 mg (4×60 mg tablets)
Once daily with or without food
abiraterone acetate
(AA)
1,000 mg (4×250 mg 
tablets)
Once daily on empty stomach. No food should be 
consumed for at least 2 hours before the dose of AA is 
taken and at least 1 hour after the dose of AA is taken. 
Swallow tablets whole with water.
Prednisone
10 mg (2×5 mg tablets)
5 mg twice daily (recommended to be taken with food)
If a dose of apalutamide alone, AAP alone, or both is missed, it should be omitted and will not be 
made up or taken with the next dose the following day. If a subject forgets to take a dose of 
either apalutamide or AAP, the dose should only be replaced if the subject remembers and takes 
the dose within a 12-hour window.
Prohibitions and Restrictions
Refer to protocol Sections 4.3, 8.1, 8.2, and 8.3.
Study Procedures for the Open-Label Extension
Subjects who meet the eligibility criteria and cross-over from AAP alone to open-label 
apalutamide in combination with AAP will begin open-label apalutamide and AAP treatment 
with Cycle 1 Day 1 of the Open-Label Extension Phase. All subjects continuing in the Open-

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Label Extension Phase will follow the schedule of procedures provided in Table 9. After a 
subject discontinues from study treatment in the Open-Label Extension Phase, there will only be 
an End-of-Treatment Visit, after which no additional data are collected.
Subjects will be followed up for disease evaluation per the local practice; no efficacy data other 
than date and type of progression and survival (as specified in Table 9) will be collected.
Blood samples for serum chemistry and hematology will be collected as prespecified in Table 9. 
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during Period 1 (or until notification by the sponsor) of the 
Open-Label Extension Phase of the study in the AE section of the eCRF. For example, 
laboratory abnormalities leading to an action regarding study drug (dose change, temporary stop, 
delay of the start of a cycle, or permanent stop) or the start of concomitant therapy should be 
reported.
The following tests will be performed (by the local laboratory) as specified in Table 9:
Hematology Panel: hemoglobin, WBC count, platelet count, and ANC
Serum chemistry panel: sodium, potassium, calcium, creatinine, fasting glucose
Liver function tests: AST, ALT, alkaline phosphatase, and total bilirubin
Fasting Lipid panel: HDL-C, LDL-C, and triglycerides
TSH, with T3 and T4 to be done only if TSH is abnormal; only for subjects on apalutamide
In the event of additional safety monitoring, unscheduled laboratory assessments may be 
performed as required.
For Period 2, sites can follow the subjects for disease assessment and safety per the local 
practice. No efficacy data will be collected; no safety data other than SAEs as specified in 
Table 9 will be collected. However, based on local regulations, additional safety data may be 
collected.
Discontinuation Criteria for the Open-Label Extension
If a subject meets the discontinuation criteria as defined in Section 10.2 of the protocol, study 
treatment must be discontinued.
The assessments and timing are specified in the Time and Events Schedule (Table 11) and in this 
attachment.

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Table 9:
Time and Events Schedule (Open-Label Extension; Subjects Cross-over to Open-label
Apalutamide in Combination With AAP After Study Unblinding)
AAP=abiraterone acetate plus prednisone or prednisolone; AE=adverse event; C=cycle; CCO-FA=clinical cutoff for final 
analysis; D=day; EOT=End-of-Treatment; ICF=informed consent form; IWRS=interactive web response system; OLE=Open-
Label Extension; PD=progressive disease; PSA=prostate-specific antigen; SAE=serious adverse event.
Procedures
Comments
Open-Label Extension Phase, Period 1
(first 6 months after CCO-FA date or until 
notification by the sponsor)
Open-Label 
Extension Phase, 
Period 2
(after previous 
period until
reaching criteria in 
Section 10.2, or 
notification by 
sponsor)
Subjects who Cross-over 
to Open-label 
Apalutamide and AAP 
(ie, receiving 
apalutamide for first 
time)
Subjects Remaining 
on Previously 
Received Study 
Treatment
Screening
Informed consent
All subjects must sign the 
ICF for the OLE Phase
X
X
Eligibility criteria for 
starting open-label 
apalutamide and AAP
Criteria for cross-over in 
Attachment 9.
Lab tests for eligibility 
must be completed within 
28 days before the start of 
receiving open-label 
apalutamide.
X
Study Drug Dispensing
Open-label 
Apalutamide+AAP (or 
AAP alone)
Continuous; sufficient study drug until next visit 
will be dispensed
Continuous; 
sufficient study drug 
until next visit will 
be dispensed
Study drug compliance
Bottle(s) including any unused medication will be 
returned at every visit in Period 1
X (via IWRS)
Visit Frequency
Subject should visit the 
site
Visits with window of 
± 3 days
Visits on D1 of OLE C1-5 
and on D28 of C6. EOT 
Visit (if applicable).
Visits on D1 of OLE 
C1, C4, and on D28 
of C6. EOT Visit (if 
applicable).
Per local practice
Clinical Laboratory (Local Laboratory)
No data will be 
collected
Hematology and blood 
chemistry
See Attachment 9 for 
required laboratory tests.
On D1 of C1-6
On D1 of C1 and C4
Per local practice
Safety
No data other than 
SAEs will be 
collected
Physical examination 
and vital signs
At each visit. Clinically relevant abnormalities 
should be reported as AEs.
Per local practice
Adverse events
Continuous during this period and until 30 days 
after the last dose if discontinued during this period
Per local practice
SAEs
Continuous during this period and until 30 days 
after the last dose if discontinued during this period
Collection of SAEs; 
see Section 12.3.2 of 
protocol
Efficacy
No data will be 
collected
Tumor assessments, 
PSA
Efficacy assessment per 
local practice
Date and type of PD (radiographic, clinical, or PSA
progression) will be collected; no other data are 
collected
Per local practice
Survival
X

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Attachment 10: Long-Term Extension in the Event of Limited Data Collection After Study 
Unblinding
After unblinding at the final analysis, the IDMC and the sponsor’s decision, and subsequent 
notification not to offer cross-over, the study will enter the Long-Term Extension Phase. The 
sponsor will continue to provide study drug until subjects reach a reason for discontinuation of 
treatment (see protocol Section 10.2) or until further notification by the sponsor on a different 
means for continued supply of study treatment, whichever occurs first.
The Long-Term Extension Phase will begin when both the Amendment 4 is approved at the site 
and the sponsor has notified the site of the start of the Long-Term Extension:

Subjects who are still receiving AAP alone in the double-blind phase of the study will be 
offered the option to continue to receive AAP.

Subjects who are still receiving apalutamide in combination with AAP in the double-blind 
phase of the study: depending on investigator discretion, subjects will be offered the option 
to either receive open-label AAP alone (ie, discontinue apalutamide) or receive open-label 
apalutamide in combination with AAP.

Subjects who have already ended treatment and who are in the Follow-up Phase in the main 
study will be discontinued from the study and all data collection will cease.
Study Treatment Administration
ADT administration
Refer to Section 6.1 of the protocol.
Open-label study treatment
Study treatment is administered orally on an outpatient basis and a treatment cycle is defined as 
28 days (Table 10). Sufficient study drug for each treatment cycle will be distributed as specified 
in Table 11. Dose modifications for toxicity are provided in Section 6.3 of the protocol. 
Guidance for apalutamide/placebo applies to open-label apalutamide.
If a subject was on a lower dose of apalutamide or AAP in the double-blind phase of the study, 
he should continue on that lower dose in the Open-Label Extension Phase.
Table 10:
Study Treatment Administration for the Long-Term Extension Phase
Study Treatments
Daily Dose
Schedule
apalutamide
240 mg (4×60 mg tablets)
Once daily with or without food
abiraterone acetate 
(AA)
1,000 mg (4×250 mg 
tablets)
Once daily on empty stomach. No food should be 
consumed for at least 2 hours before the dose of AA is 
taken and at least 1 hour after the dose of AA is taken. 
Swallow tablets whole with water.
Prednisone
10 mg (2×5 mg tablets)
5 mg twice daily (recommended to be taken with food)

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If a dose of apalutamide alone, AAP alone, or both is missed, it should be omitted and will not be 
made up or taken with the next dose the following day. If a subject forgets to take a dose of 
either apalutamide or AAP, the dose should only be replaced if the subject remembers and takes 
the dose within a 12-hour window.
Prohibitions and Restrictions
Refer to protocol Sections 4.3, 8.1, 8.2, and 8.3.
Study Procedures for the Long-Term Extension
All subjects continuing in the Long-Term Extension Phase will follow the schedule of 
procedures provided in Table 11.
Sites can follow the subjects for disease assessment and safety per the local practice. No efficacy 
data will be collected; only SAEs will be collected for safety as specified in Table 11. Based on 
local regulations, additional safety data may be collected.
Discontinuation Criteria for the Long-Term Extension
If a subject meets the discontinuation criteria as defined in Section 10.2 of the protocol, study 
treatment must be discontinued.
The assessments and timing are specified in the Time and Events Schedule (Table 11) and in this 
attachment.

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Table 11: 
Time and Events Schedule (Long-Term Extension With Limited Data Collection After Study 
Unblinding)
AAP=abiraterone acetate plus prednisone or prednisolone; EU=European Union; ICF=informed consent form; IWRS=interactive 
web response system; LTE=Long-Term Extension; SAE=serious adverse event; SmPC=Summary of Product Characteristics; 
TSH=thyroid-stimulating hormone; USPI=United States Package Insert.
Procedures
Comments
Long-Term Extension Phase (until reaching criteria 
in Section 10.2, or termination of the study)
Continuing to Receive 
Apalutamide +AAP
Receiving AAP only
Screening
Informed consent
All subjects must sign the ICF for 
the LTE Phase
X
X
Study Drug Dispensing
Open-label Apalutamide+AAP 
(or AAP alone)
Continuous; sufficient study drug until next visit will 
be dispensed
Study drug compliance
X (via IWRS)
Clinical Laboratory (Local Laboratory)
Hematology and blood 
chemistry
Per local practice and local label for apalutamide and 
abiraterone acetate/prednisone or the USPI/ EU SmPC
TSH
T3 and T4 only to be done if TSH 
is abnormal
Per local label for 
apalutamide or the 
USPI/EU SmPC
Safety
SAEs
Collection of SAEs; see Section 12.3.2 of protocol

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INVESTIGATOR AGREEMENT
PPD