A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase IV Study of Apalutamide in Chinese Participants With Non-Metastatic Castration-Resistant Prostate Cancer (NM-CRPC)
Phase: PHASE4
Conditions: Prostatic Neoplasms
Sponsor: Janssen Research & Development, LLC

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Approved, Date: 20 June 2022
Janssen Research & Development *
Protocol Title
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase IV Study of 
Apalutamide in Chinese Participants with Non-Metastatic Castration-Resistant Prostate 
Cancer (NM-CRPC)
Protocol 56021927PCR4007; Phase IV
AMENDMENT 3
JNJ-56021927 (apalutamide)
*Janssen Research & Development is a global organization that operates through different legal entities in
various countries. 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
Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica NV; Janssen
Sciences Ireland UC; or Janssen Research & Development, LLC. The term “sponsor” is used throughout
the protocol to represent these various legal entities; the sponsor is identified on the Contact Information
page that accompanies the protocol.
Status:
Approved
Date:
20 June 2022
Prepared by:
Janssen Research & Development, LLC
EDMS number:
EDMS-ERI-177074070, 4.0
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.
NCT04108208

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Approved, Date: 20 June 2022
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
COVID-19 Appendix (v 1.0)
20 June 2022
Amendment 3
20 June 2022
Amendment 2
20 February 2020
Amendment 1
7 June 2019
Original Protocol
13 February 2019
Amendment 3 (20 June 2022) 
Overall Rationale for the Amendment: The overall reason for the amendment is to 1) change the 
number of participants to 75 for the final analysis based on CDE consultation, considering that the 
enrollment of study PCR4007 will become more and more challenging at current stage from both ethical 
and operational perspectives and the sample size from 111 to 75 participants is still statistically valid 2) 
remove the interim analysis and revise the role of Independent Data Monitoring Committee (IDMC) from 
reviewing interim analysis results and making recommendations to reviewing the final efficacy and safety 
results.
Section Number
and Name
Description of Change
Brief Rationale
1.1. Synopsis: 
OVERALL
DESIGN;
NUMBER OF 
PARTICIPANTS;
STATISTICAL 
METHODS: 
Interim Analysis
1.2. Schema
4.1. Overall Design
4.4. End of Study 
Definition
9.4. Interim 
Analysis
10.2. Appendix 2—
COMMITTEES 
STRUCTURE

Changed the appropriate number of 
participants to be enrolled from 111 to
75.

Removed the original section for interim 
analysis and clarified that no interim 
analysis is planned for this study.

Changed the role of IDMC from reviewing 
interim analysis result and making 
recommendations to reviewing the final 
efficacy and safety results.

Removed the independent analysis team 
which was planned to be assembled by 
sponsor to prepare and provide study 
data to the IDMC.

Removed the recommendation of IDMC
on the study termination beforehand.
To make change as interim analysis is not 
applicable and 75 participants will be used 
for final analysis.
1.1. Synopsis:
OVERALL 
DESIGN
4.1. Overall Design
6.3. Measures to 
Minimize Bias: 
Randomization and 
Blinding: 
Intervention 
Allocation: 
Blinding

Clarified unblinding will occur “until
completion of the study or the sponsor 
decides to unblind the study at final 
analysis”.

Revised the circumstance of unblinding 
and decoding of randomization to add 
“or the sponsor decides to unblind the 
study at final analysis” and remove the 
IDMC’s intervention. 

To further clarify the conditions of 
unblinding.

To make revision considering IDMC 
recommendation for unblinding and 
IDMC review for interim analysis will 
not be applicable.
1.1. Synopsis:
STATISTICAL 
METHODS: 
Sample Size 
Determination
4.2.1. Study-

Recalculated that approximately 75 
participants will provide approximately 
28 TTPP events at the time of the final 
analysis.

Recalculated only 1-2 participants in this 
study are expected to have metastatic 

The event number was estimated based 
on the number of participants (75), the 
upper limit of 95% CI in the TTPP HR 
results of East Asian from SPARTAN 
(0.11) and accrual period (~ 32 
months).

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Section Number
and Name
Description of Change
Brief Rationale
Specific Ethical 
Design 
Considerations
9.1. Sample Size 
Determination
disease at the first post-baseline scan 
without prior PSA progression given one 
third of 75 Chinese participants (about 25 
participants) are to be randomly assigned 
to placebo arm.

Revised the accrual period from 38 months 
to 32 months and the approximate study 
duration for the TTPP final analysis from 
43 months to 37 months.

32-month accrual period was estimated 
based on the date of FPI (2020.2) and 
LPI (2022.10), and the study duration 
was redefined accordingly.
1.1. Synopsis:
Efficacy Analysis
9.3.1. Efficacy 
Analysis

Changed the time point to estimate the 
PSA progression-free rate from “6 
months, 1-year and 2-year” to “at 
selected timepoint”.

To make revision considering the 
censoring rule for placebo arm.
1.3. Schedule of 
Activities (SoA)-
footnote 1
4.1. Overall Design
Specified the Prescreening Phase will be 
ended with the wording “till the last 
participant screening is successful”.

To define when the prescreening is not 
necessary.
2. 
INTRODUCTION
Updated the approved countries for 
ERLEADA from 40 to 75.
To update approved status for ERLEADA.
2.2. Background

Updated the clinical study status (ongoing 
or completed) regarding 
56021927PCR3003.

Updated the final efficacy analysis data of 
Study ARN-509-003 (SPARTAN), 
including the secondary efficacy analysis 
(time to symptomatic progression, OS, 
and time to initiation of cytotoxic 
chemotherapy), PFS2, and patient-
reported outcome results.

Updated the safety data of Study ARN-
509-003 (SPARTAN), including study 
disposition, treatment exposure, TEAE, 
TEAE leading to death/treatment 
discontinuation/reduction, SAE, and AE 
of special interest.
To align with the study data in current IB 
and Study ARN-509-003 (SPARTAN) 
Clinical Study Report addendum. 
2.2.1. Androgen 
Deprivation 
Therapy

Added specification that GnRHa will be 
provided by the sponsor and should be 
used “during the treatment phase”.
To define the period of GnRHa provided 
and used.
4.2. Scientific 
Rationale for Study 
Design
4.2.1. Study-
Specific Ethical 
Design 
Considerations

Clarified there were no approved therapies
“at the initiation of this study” for the 
treatment of patients with NM-CRPC, 
and added “Since then, 2 other products 
have been conditionally approved or 
approved for the treatment of patients 
with NM-CRPC”.

Removed the description “ADT alone is 
the appropriate control in Chinese NM-
CRPC patients as continuous 
administration of ADT constitutes as part 
of the current de facto community 
standard practice”.
To update and show the unmet need at the 
initiation of this study.
8.3.1. Time Period 
and Frequency for 
Collecting Adverse 
Removed safety report form of the eCRF to be 
used to record SAEs.
To align with the current practice.

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Section Number
and Name
Description of Change
Brief Rationale
Event and Serious 
Adverse Event 
Information
Throughout the 
protocol
Minor grammatical, formatting, or spelling 
changes were made.
Minor errors were noted

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TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 2
TABLE OF CONTENTS ............................................................................................................................... 5
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 7
1.
PROTOCOL SUMMARY ..................................................................................................................... 8
1.1.
Synopsis........................................................................................................................................... 8
1.2.
Schema .......................................................................................................................................... 13
1.3.
Schedule of Activities (SoA)........................................................................................................... 14
2.
INTRODUCTION................................................................................................................................ 17
2.1.
Study Rationale.............................................................................................................................. 18
2.2.
Background .................................................................................................................................... 18
2.2.1.
Androgen Deprivation Therapy................................................................................................... 24
2.3.
Benefit/Risk Assessment ............................................................................................................... 24
3.
OBJECTIVES AND ENDPOINTS ..................................................................................................... 25
4.
STUDY DESIGN ................................................................................................................................ 26
4.1.
Overall Design................................................................................................................................ 26
4.2.
Scientific Rationale for Study Design............................................................................................. 28
4.2.1.
Study-Specific Ethical Design Considerations ........................................................................... 29
4.3.
Justification for Dose...................................................................................................................... 29
4.4.
End of Study Definition................................................................................................................... 29
5.
STUDY POPULATION ...................................................................................................................... 30
5.1.
Inclusion Criteria ............................................................................................................................ 30
5.2.
Exclusion Criteria ........................................................................................................................... 32
5.3.
Screen Failures .............................................................................................................................. 34
6.
STUDY INTERVENTION................................................................................................................... 34
6.1.
Study Interventions Administered .................................................................................................. 34
6.2.
Preparation/Handling/Storage/Accountability ................................................................................ 35
6.3.
Measures to Minimize Bias: Randomization and Blinding............................................................. 36
6.4.
Study Intervention Compliance...................................................................................................... 37
6.5.
Concomitant Therapy..................................................................................................................... 38
6.5.1.
Suggested Therapy .................................................................................................................... 38
6.5.2.
Prohibited Therapy ..................................................................................................................... 39
6.5.3.
Restricted Concomitant Therapy................................................................................................ 40
6.6.
Dose Modification........................................................................................................................... 40
6.6.1.
Dose Modifications for Rash and Rash Management................................................................ 41
6.7.
Long-term Follow-up ...................................................................................................................... 42
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ............................................................................................... 43
7.1.
Discontinuation of Study Intervention ............................................................................................ 43
7.2.
Participant Discontinuation/Withdrawal From the Study................................................................ 44
7.3.
Lost to Follow-up............................................................................................................................ 44
8.
STUDY ASSESSMENTS AND PROCEDURES ............................................................................... 44
8.1.
Efficacy Assessments .................................................................................................................... 45
8.2.
Safety Assessments....................................................................................................................... 46
8.2.1.
Physical Examination.................................................................................................................. 46
8.2.2.
Vital Signs................................................................................................................................... 47
8.2.3.
Electrocardiogram (ECG) ........................................................................................................... 47

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8.2.4.
Clinical Safety Laboratory Assessments .................................................................................... 47
8.2.5.
ECOG Performance Status ........................................................................................................ 48
8.3.
Adverse Events and Serious Adverse Events ............................................................................... 48
8.3.1.
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event 
Information.................................................................................................................................. 49
8.3.2.
Method of Detecting Adverse Events and Serious Adverse Events .......................................... 49
8.3.3.
Follow-up of Adverse Events and Serious Adverse Events ....................................................... 49
8.3.4.
Regulatory Reporting Requirements for Serious Adverse Events ............................................. 49
8.3.5.
Pregnancy................................................................................................................................... 49
8.4.
Treatment of Overdose .................................................................................................................. 50
8.5.
Pharmacokinetics........................................................................................................................... 50
8.5.1.
Evaluations ................................................................................................................................. 50
8.5.2.
Analytical Procedures................................................................................................................. 50
8.5.3.
Pharmacokinetic Parameters and Evaluations........................................................................... 50
8.6.
Medical Resource Utilization and Health Economics .................................................................... 51
9.
STATISTICAL CONSIDERATIONS.................................................................................................. 51
9.1.
Sample Size Determination ........................................................................................................... 51
9.2.
Populations for Analyses................................................................................................................ 51
9.3.
Statistical Analyses ........................................................................................................................ 52
9.3.1.
Efficacy Analyses........................................................................................................................ 52
9.3.2.
Safety Analyses .......................................................................................................................... 53
9.3.3.
Other Analyses ........................................................................................................................... 54
9.4.
Interim Analysis.............................................................................................................................. 54
9.4.1.
Independent Data Monitoring Committee................................................................................... 54
10.
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................ 55
10.1.
Appendix 1: Abbreviations ............................................................................................................. 55
10.2.
Appendix 2: Regulatory, Ethical, and Study Oversight Considerations......................................... 57
REGULATORY AND ETHICAL CONSIDERATIONS .......................................................................... 57
FINANCIAL DISCLOSURE .................................................................................................................. 60
INFORMED CONSENT........................................................................................................................ 60
DATA PROTECTION ........................................................................................................................... 61
COMMITTEES STRUCTURE .............................................................................................................. 62
PUBLICATION POLICY/DISSEMINATION OF CLINICAL STUDY DATA........................................... 62
DATA QUALITY ASSURANCE ............................................................................................................ 63
CASE REPORT FORM COMPLETION ............................................................................................... 64
SOURCE DOCUMENTS ...................................................................................................................... 64
MONITORING ...................................................................................................................................... 65
ON-SITE AUDITS................................................................................................................................. 66
RECORD RETENTION ........................................................................................................................ 66
STUDY AND SITE CLOSURE ............................................................................................................. 67
10.3.
Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting............................................................................................................... 68
ADVERSE EVENT DEFINITIONS AND CLASSIFICATIONS.............................................................. 68
ATTRIBUTION DEFINITIONS.............................................................................................................. 69
SEVERITY CRITERIA .......................................................................................................................... 69
SPECIAL REPORTING SITUATIONS ................................................................................................. 70
PROCEDURES .................................................................................................................................... 70
CONTACTING SPONSOR REGARDING SAFETY............................................................................. 72
PRODUCT QUALITY COMPLAINT HANDLING.................................................................................. 72
10.4.
Appendix 4: Liver Safety: Suggested Actions and Follow-up Assessments.................................. 73
10.5.
Appendix 5: ECOG-PS Score ........................................................................................................ 77
10.6.
Appendix 6: Protocol Amendment History ..................................................................................... 78
11.
REFERENCES................................................................................................................................... 83
INVESTIGATOR AGREEMENT ................................................................................................................. 84

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LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Summary of Secondary Efficacy Analysis (Study ARN-509-003 [SPARTAN])4....................... 20
Table 2:
Description of Interventions ...................................................................................................... 35
Table 3:
Dose Modifications of Apalutamide/Placebo (except for rash, if rash occurs, see Table 
4)............................................................................................................................................... 41
Table 4:
Dose-modification and Management of Drug-related Rash ..................................................... 42
FIGURES
Figure 1:
Kaplan-Meier Plot of Blinded Independent Central Review (BICR) Metastasis-Free 
Survival (MFS); Intent-to-treat Population (Study ARN-509-003 [SPARTAN])4....................... 19
Figure 2:
Kaplan-Meier Plot of Time to PSA Progression; Intent-to-treat Population (Study ARN-
509-003 [SPARTAN])4 .............................................................................................................. 21

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1.
PROTOCOL SUMMARY
1.1.
Synopsis
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase IV Study of Apalutamide in 
Chinese Participants with Non-Metastatic Castration-Resistant Prostate Cancer (NM-CRPC)
Apalutamide (also known as ARN-509 and JNJ-56021927) 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. The current study is designed to validate the 
findings of a global study (ARN-509-003 [SPARTAN]) among Chinese patients.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
To compare the improvement in TTPP (as defined by 
PCWG2) of apalutamide versus (vs) placebo in Chinese 
participants with high-risk NM-CRPC*
TTPP
Secondary
To evaluate the safety and tolerability of apalutamide
AEs and laboratory abnormalities
To compare the PSA response rate in Chinese participants 
with high-risk NM-CRPC treated with apalutamide vs
placebo*
PSA response rate
To evaluate the PK of apalutamide and N-desmethyl 
apalutamide
PK: Predose and 2h postdose plasma 
concentrations after single dose and at 
steady-state.
Abbreviations: AE: adverse event; NM-CRPC: non-metastatic castration-resistant prostate cancer; PK: pharmacokinetic; 
PCWG2: prostate cancer working group 2, PSA: prostate-specific antigen; TTPP: time to PSA progression.
*Participants randomized to placebo arm will be crossed over to receive apalutamide treatment either after completion of a 
maximum 5 cycles of placebo treatment or at the time of having documented PSA progression, whichever comes earlier.
Hypothesis
Participants receiving treatment with apalutamide in conjunction with androgen deprivation therapy 
(ADT), will have a longer time to prostate-specific antigen (PSA) progression (TTPP) compared with 
participants receiving placebo plus ADT.
OVERALL DESIGN
This is a Phase IV, randomized, double-blind, placebo-controlled, multicenter study evaluating the 
efficacy and safety of apalutamide vs placebo in male Chinese participants with high-risk NM-CRPC.
A target of approximately 75 Chinese participants will be randomly assigned in a 2:1 ratio in this study to 
receive apalutamide or matching placebo. Participants will be stratified by PSA doubling time (PSADT)
(>6 months vs ≤6 months)
The study will consist of 4 phases: 

Prescreening Phase (optional)

Screening Phase (≤35 days prior to randomization)

Treatment Phase (starting on Day 1 of Cycle 1 until disease progression/unacceptable toxicity, 
withdrawal of consent, death or termination of the study)

Follow-up Phase (starting after end-of-treatment visit until death, withdrawal of consent for study 
participation, or termination of the study). 

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Apalutamide or matched placebo will be administered orally on a continuous daily dosing schedule at a 
starting dose of 240 mg per day. Androgen deprivation therapy with gonadotrophin-releasing hormone 
agonists (GnRHa) will be continued for all patients who have not been surgically castrated. 
Each treatment cycle will consist of 28 days. Participants randomized to placebo who do not have any
evidence of distant metastasis (according to imaging result at Cycle 5 Day 1, as well as at any other 
relevant unscheduled visit) will be crossed over and start receiving active therapy of apalutamide after 
completion of 5 cycles of placebo plus ADT treatment. Participants who have documented PSA 
progression prior to completion of 5 cycles of study treatment, will cross over to apalutamide at the time 
of PSA progression. Any participants who develop distant metastasis at any time on study will 
discontinue study treatment, and may receive subsequent therapy as per standard of care. Around half of 
the participants in the placebo arm are expected to have documented PSA progression after completion of 
5 cycles treatment, as estimated from the ARN-509-003 (SPARTAN) study data, and would therefore, 
allow sufficient time for the evaluation of TTPP and comparison between apalutamide and placebo.
Prostate-specific antigen will be collected and analyzed by a central laboratory but investigators, 
participants, and the study team will be blinded to the results until completion of the study or the sponsor 
decides to unblind the study at final analysis. The central laboratory will analyze the individual PSA data, 
collected at baseline and post-baseline obtained within the first 5 cycles to flag out documented PSA 
progression per PCWG2 and the data will be entered into the interactive web response system (IWRS) to 
trigger the cross-over by an independent team not affiliated with the study team. The cross-over of control 
arm participants will be handled by IWRS to maintain the blinding of original treatment assignment of 
individual participant.
Participants will be followed for safety and efficacy as per schedule of activities and will remain on study 
treatment until development of distant metastases as assessed by investigators or the development of 
unacceptable toxicity or the end of study defined as metastasis-free survival (MFS) events observed in 
approximately 60% of the study population or 3 years after the final analysis for the primary endpoint 
(TTPP), whichever comes first. 
All participants will be monitored for safety during the Screening and Treatment Phases, and for up to 
30 days after the last dose of study treatment. An End-of-Treatment (EoT) Visit will occur approximately 
30 days of the last dose of study treatment. The Posttreatment Follow-up Phase will begin after the EoT 
visit. For participants entering Posttreatment Follow-up Phase with evidence of distant metastasis, they
will be contacted every 4 months (±7 days) to obtain survival status, recording of development of 
symptomatic progression, initiation of any new systemic anticancer therapies until death, withdrawal of 
consent for study participation, or termination of the study. For participants entering Posttreatment 
Follow-up Phase without evidence of distant metastasis, Posttreatment Follow-up visits including disease 
assessment (computed tomography [CT] or magnetic resonance imaging [MRI] plus bone scans) will 
continue every 16 weeks (±7 days) until the documentation of disease progression, then participants will 
be contacted every 4 months (±7 days) to obtain survival status, recording of development of 
symptomatic progression, initiation of any new systemic anticancer therapies until death, withdrawal of 
consent for study participation, or termination of the study. 
An Independent Data Monitoring Committee (IDMC) will be commissioned for this study to review the 
efficacy and safety results of final analysis. The IDMC will consist of at least 1 medical oncologist or 
urologist or both and at least 1 statistician.
NUMBER OF PARTICIPANTS
A target of 75 Chinese male participants will be randomly assigned in a 2:1 ratio in this study to receive 
apalutamide or matching placebo with ADT.

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INTERVENTION GROUPS AND DURATION
Each treatment cycle will consist of 28 days. Participants will be randomly assigned in a 2:1 ratio:

Investigational group will receive apalutamide 240 mg (4×60 mg tablets) daily.

Control group will receive placebo daily from Cycle 1 Day 1. Participants who do not have distant 
metastasis will switch to treatment with apalutamide after completion of 5 cycles of placebo 
treatment (handling by the IWRS). Participants who have PSA progression prior to completion of 5 
cycles of study treatment, will cross over to apalutamide at the time of PSA progression.
Description of Interventions
Arm Name
Arm A
Arm B
Intervention Name
Apalutamide
Placebo
Type
A drug 
A matching placebo to active drug 
Dose Formulation
Immediate release tablet 
Immediate release tablet
Unit Dose Strength(s)
4×60 mg
4×60 mg
Dosage Level(s)
240 mg daily
240 mg daily
Route of 
Administration
Oral
Oral
Use
Experimental
Placebo-Comparator
Packaging and 
Labeling
120-ct, 160cc HDPE bottles with CRC and 
include desiccant.
120-ct, 160cc HDPE bottles with CRC 
and include desiccant.
Child-resistant 
packaging
Yes
Yes
Delivery instructions
Apalutamide: QD without regard to food
Apalutamide: QD without regard to food
Names/Aliases
JNJ-56021927
NA
ADT: androgen deprivation therapy, being either surgical castration or gonadotrophin-releasing hormone agonists (GnRHa), will 
be continued as background therapy for all participants. ADT with GnRHa will be continued for all patients who have not been 
surgically castrated.; CRC: child-resistant closures; HDPE: high density polyethylene; QD: once daily.
EFFICACY EVALUATIONS
The efficacy evaluations include the following:

Serum PSA evaluation (for TTPP, as defined by PCWG2)

Disease assessment (CT or MRI, bone scans)

Survival status, subsequent anticancer therapy, and skeletal-related events (SREs).
Serum PSA evaluation (for TTPP, as defined by PCWG2): During the treatment phase, PSA will be 
analyzed at the central laboratory. Results will be kept blinded to the participants, the Investigators, and 
the study team, in order to preserve the double-blind nature of this study. On Cycle 1 Day 1 only, the PSA 
evaluation does not need to be repeated if the Screening tests were done within 4 days of Cycle 1 Day 1. 
For all participants, at the time of full unblinding of the study, PSA data submitted to the central 
laboratory will no longer be blinded.
Disease assessment (CT or MRI, bone scans): Disease assessments will be performed at baseline 
(screening: scans obtained prior to signing informed consent as part of the patient’s standard of care may
be allowed, provided the timing of the scans fall within the screening window), and at 16-week intervals 
thereafter. Imaging studies will include a CT scan of the chest, abdomen, and pelvis, plus a bone scan. At 
Screening, there will be an additional CT of the brain to rule out the presence of central nervous system 
(CNS) metastases. For new bone lesions detected on bone scans, a second imaging modality (eg, CT or 
MRI) will be required to confirm progression. The same method of assessment and the same technique 
should be used at Screening and during follow-up. Intravenous (IV) contrast is required when not 

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medically contraindicated. Participants who have a contraindication to IV contrast may have MRI exams 
of the brain, abdomen, and pelvis performed in lieu of CTs and a non-contrast CT of the chest. Tumor 
evaluation by positron emission tomography (PET) scan or by ultrasound or by prostate-specific 
membrane antigen (PSMA)-PET will not replace for standard chest, abdomen, and pelvis CT or MRI 
scans or bone scans as required by the study, but the CT portion of a PET/CT with sufficient quality 
which could meet the study requirement may be submitted in lieu of a dedicated CT. The radiographic 
disease progression (appearance of distant metastasis) will be determined by the investigator. Participants
who discontinue treatment before documented disease progression should continue with disease 
assessments during Posttreatment Follow-up Phase every 16 weeks (±7 days) until disease progression.
Survival status, subsequent anticancer therapy, and SREs: These assessments will be performed during 
the Treatment and Posttreatment Follow-up Phase.
SAFETY EVALUATIONS
Adverse events (AEs) will be reported and followed by the investigator. Any clinically relevant changes 
occurring during the study must be recorded on the electronic case report form (eCRF). Any clinically 
significant abnormalities persisting at the end of the study/early withdrawal will be followed by the 
investigator until resolution or until a clinically stable condition is reached. 
The study will include the following evaluations of safety and tolerability according to the time points as 
scheduled: physical examination, vital signs, electrocardiogram (ECG), clinical safety assessments 
(including laboratory analyses), and Eastern Cooperative Oncology Group (ECOG) performance status 
(PS).
STATISTICAL METHODS
Sample Size Determination
The pivotal ARN-509-003 (SPARTAN) study suggested that East Asian participants (and study 
participants as a whole) treated with ADT only will have a median TTPP of 3.7 months. It is estimated 
that approximately 75 participants will provide approximately 28 TTPP events at the time of the final 
analysis (approximately 5 months after last participant receiving first dose) which yields a power 
exceeding 95% for detecting a hazard ratio (HR) of 0.11 (median TTPP of 3.7 months for the placebo arm 
versus 33.6 months for the apalutamide arm) at a 2-tailed level of significance of 0.05.
Efficacy Analysis
The final analysis of TTPP will be performed at approximately 5 months after last participant receiving 
the first dose. Time to PSA progression will be tested using Stratified log-rank test, stratified by PSADT
(>6 months vs ≤6 months), at a 2-tailed significance level of 0.05. Kaplan-Meier method will be used to 
estimate the median TTPP, as well as the PSA progression-free rate at selected timepoints, and their 95% 
CIs. The estimation of HR and its 95% CI will be based on the stratified Cox proportional-hazard model. 
Non-stratified log-rank tests will also be provided as sensitivity analysis.
Prostate-specific antigen response rate will be evaluated using the Mantel-Haenszel test or the exact test if 
the frequencies are small. Time-to-event-based exploratory analyses (MFS, overall survival [OS], and 
time to symptomatic progression) will be performed descriptively, considering the early cross-over of 
control arm and the expected long medians for apalutamide arm suggested by study ARN-509-003 
(SPARTAN).
Pharmacokinetic Analyses 
Descriptive statistics will be used to summarize plasma apalutamide and its active metabolite 
N-desmethyl apalutamide concentrations at each sampling time point. Population PK analysis of plasma 

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concentration-time data of apalutamide and N-desmethyl apalutamide will be performed using nonlinear 
mixed effects modeling. The population PK analysis results will be presented in a separate report.
Exposure-Response Analyses
Exposure-response analysis between exposure and selective clinical endpoint will be explored if deemed 
necessary and with sufficient data. The exposure-response analysis results will be presented in a separate 
report.
Safety Analyses
Participants 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.
Interim Analysis
No interim analysis is planned for this study.

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2.
INTRODUCTION
Prostate cancer (PC) is the sixth most common cancer in men in China. There has been a marked 
increase in the number of PC cases diagnosed in recent years with an estimated new PC cases 
and deaths of 60,300 and 26,600, respectively in 2015.1 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).11
Given that PC cells depend on the androgen receptor (AR) for their proliferation and survival, 
the standard treatment for patients with recurrent disease is androgen deprivation therapy (ADT) 
with a gonadotropin releasing hormone analog (GnRHa) with or without an anti-androgen. 
The results are predictable, with a decline in PSA followed by tumor regression, a period of 
stability in which tumor burden and PSA remain stable, followed by rising PSA and regrowth as 
a castration-resistant prostate cancer (CRPC). When conventional imaging in CRPC shows no 
evidence of metastatic disease, it is termed non-metastatic castration-resistant prostate cancer 
(NM-CRPC).
Patients with NM-CRPC at high risk for metastases are characterized by rapidly rising PSA 
despite castration levels of testosterone (ie, a PSA doubling time [PSADT] of ≤10 months). Men 
with PC in this setting have a significant risk for the development of distant metastases and 
PC-specific death. Once the disease progresses to mCRPC, patients may develop symptoms of 
their disease and the prognosis is poor. Delaying of metastases for as long as possible is therefore 
the goal of therapy in NM-CRPC.
This is a post approval commitment (PAC) study being conducted to provide safety and efficacy 
data of apalutamide in Chinese participants with high-risk (defined as PSADT ≤10 months) 
NM-CRPC.
ERLEADA™ (apalutamide, also known as JNJ-56021927 and ARN-509) is an orally available, 
potent, new generation and selective AR antagonist that acts by inhibiting the action of androgen, 
nuclear translocation of the AR and DNA binding to androgen response elements. The safety and 
efficacy of apalutamide in the treatment of patients with NM-CRPC is supported by the data 
from 
Study 
ARN-509-003 
(SPARTAN), 
a 
multicenter, 
randomized, 
double-blind,
placebo-controlled study of apalutamide plus ADT or placebo plus ADT in 1207 men with 
NM-CRPC, designed to address this area of unmet medical need. Till now, ERLEADA has been 
approved in more than 75 countries including China since the first approval in the United States 
in February 2018 for the treatment of patients with NM-CRPC.4,2
For the most comprehensive nonclinical and clinical information regarding apalutamide, refer to 
the latest version of the Investigator's Brochure (IB) for apalutamide.7
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.

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2.1.
Study Rationale
This is a PAC study being conducted to provide safety and efficacy data of apalutamide as 
comparing to placebo in Chinese participants with high-risk (defined as PSADT ≤10 months) 
NM-CRPC.
2.2.
Background
Nonclinical Studies
For details on safety pharmacology, toxicology, pharmacokinetics (PK), and metabolism profile 
in a preclinical setting, please refer to the IB.7
Clinical Studies
There are 2 ongoing (56021927PCR3003 [ATLAS] and 56021927PCR3011 [PROTEUS]) and 3 
completed (ARN-509-003 [SPARTAN],2 56021927PCR3001 [ACIS] and 56021927PCR3002 
[TITAN]), double-blind, placebo-controlled Phase 3 clinical studies.,. 
Human Pharmacokinetics
Apalutamide was rapidly absorbed, and the median time to reach the maximum observed plasma 
concentration (tmax) was 2 hours (range: 1 to 5 hours under fasting conditions). The increases in 
plasma Cmax values and in the area under the plasma concentration curve (AUC) were linear and 
dose proportional. Plasma apalutamide concentrations declined slowly, with a mean effective 
half-life value at steady-state of 3 days.
Based on population PK analysis for the ARN-509-003 (SPARTAN) study, there were no 
clinically relevant differences in exposure between White (Caucasian or Hispanic or Latino), 
Black (of African heritage or African American), Asian (non-Japanese), or Japanese 
participants.4 More details please refer to IB.7
Efficacy/Safety Studies
Study ARN-509-003 (SPARTAN):
This multicenter, randomized, double-blind, placebo-controlled study was designed to 
demonstrate superiority in the metastasis-free survival (MFS) of men with high-risk NM-CRPC 
(ie, a PSADT of ≤10 months) treated with apalutamide versus [vs] placebo.2 Upon blinded 
independent central review (BICR) confirmed development of distant metastatic disease, the 
sponsor offered ZYTIGA as an option for the first subsequent treatment after discontinuation of 
study drug, as long as the participant consented and resided in a country in which abiraterone 
acetate plus prednisone (or prednisolone) were indicated for the treatment of mCRPC before 
chemotherapy. Secondary efficacy parameters included time to metastasis, progression-free 
survival (PFS), time to symptomatic progression, overall survival (OS), and time to initiation of 
cytotoxic chemotherapy.
The primary data included 1,207 randomized participants (806 participants in the apalutamide 
arm and 401 participants in the placebo arm). Participants were stratified by PSADT (>6 months 

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vs ≤6 months, loco-regional disease (N0 or N1), and bone-sparing agent use (yes or no). As of 
the final analysis CCO (1 February 2020), the median survival follow-up time for all participants 
was 52 months.7
The clinical cutoff date for the primary analysis occurred on 19 May 2017. The independent data 
monitoring committee (IDMC) concluded that these improvements constituted compelling 
evidence of clinical benefit in the apalutamide group, and unanimously recommended unblinding 
the study and offering participants randomized to placebo group an option to cross over to 
receive apalutamide.
Treatment with apalutamide resulted in a statistically significant improvement in the primary 
endpoint, MFS, compared to placebo (Figure 1). Treatment with apalutamide significantly 
decreased the risk of distant metastasis or death by 72% compared with placebo (hazard ratio 
[HR]=0.280; 95% CI: 0.227, 0.346; p<0.0001). The median MFS was 40.5 months for the 
apalutamide arm and 16.2 months for the placebo arm.4
Figure 1:
Kaplan-Meier Plot of Blinded Independent Central Review (BICR) Metastasis-Free 
Survival (MFS); Intent-to-treat Population (Study ARN-509-003 [SPARTAN])4
All secondary efficacy endpoints in Study ARN-509-003 (SPARTAN) favored treatment with 
apalutamide compared with placebo, based on HR analysis (Table 1). A confirmed PSA response 
was observed in 90% of participants in the apalutamide arm and 2.2% of participants in the 
placebo arm (p<0.0001); total response (confirmed and unconfirmed) was observed in 93% and 
3.5% of apalutamide- and placebo-treated participants, respectively.4

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Table 1:
Summary of Secondary Efficacy Analysis (Study ARN-509-003 [SPARTAN])4
Endpoint [# of events]
Apalutamide
(N=806)
Median (month)
Placebo
(N=401)
Median 
(month)
HR (95% CI)
p-value*
TTM [366]a
40.5
16.6
0.271 (0.219, 0.335)
< 0.0001
PFS [404] a
40.5
14.7
0.291 (0.238, 0.356)
< 0.0001
Time to symptomatic progression 
[264]b
NE
NE
0.567 (0.443, 0.725)
< 0.0001
OS [428] b
73.9
59.9
0.784 (0.643, 0.956)
0.0161
Time to initiation of cytotoxic 
chemotherapy [258] b
NE
NE
0.629 (0.489, 0.808)
0.0002
CI: confidence interval; CCO: clinical cutoff date; PFS: progression-free survival; NE: not estimable; OS: overall 
survival; TTM: time to metastasis.
*p-value from stratified log-rank test.
a
Source: Study ARN-509-003 (SPARTAN) Clinical Study Report (CCO: 19 May 2017): Tables 18 and 20.
b
Source: Study ARN-509-003 (SPARTAN) Clinical Study Report addendum (CCO: 1 February 2020): Table 8, 
10, and Attachment TEFPC 16.
Prostate-specific antigen progression was documented for 192 participants in the apalutamide 
arm (24%) and 334 participants in the placebo arm (83%). Treatment with apalutamide 
significantly decreased the risk of PSA progression by 94% compared with placebo (HR=0.064; 
95% CI: 0.052, 0.080; p<0.0001). The median time to PSA progression was not estimable for the 
apalutamide arm and was 3.7 months in the placebo arm (Figure 2). The lower limit of the 95% 
CI for the median time to PSA progression for the apalutamide arm was 36.8 months.4

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Figure 2:
Kaplan-Meier Plot of Time to PSA Progression; Intent-to-treat Population (Study ARN-509-003 
[SPARTAN])4
[GEFPC13.RTF] [JNJ-56021927\ARN-509-003\DBR_IA\RE_IA\PROD\GEFPC13.SAS] 03AUG2017, 19:57
The second progression-free survival during or after the first subsequent therapy (PFS2) is 
defined as the time from randomization to investigator-assessed disease progression (PSA, 
radiographic, symptomatic, or any combination) or death with the first subsequent therapy. The 
data for the PFS2 analysis were highly censored: 60% censored in the apalutamide arm and 53% 
censored in the placebo arm. The median PFS2 was longer for the apalutamide arm (55.6 
months) compared with the placebo arm (41.2 months). This result represents a 44% reduction in 
the risk of disease progression with the next line of therapy or death in favor of the apalutamide 
arm (HR=0.565; 95% CI: 0.471, 0.677).5
Patient-reported outcome results indicated that there was no detriment to overall health-related 
quality of life with the addition of apalutamide to ADT in this population of generally 
asymptomatic NM-CRPC participants. Differences were observed between arms in FACT-P 
total and most subscale scores, generally showing less decline in HRQoL for participants in the 
apalutamide arm in later cycles, though these differences in group mean were all less than the 
threshold for clinically meaningful change in individual scores. Differences in least square mean 
changes from baseline which are greater than zero indicate less decline in the apalutamide arm 
compared with the placebo arm. Mean changes from baseline in EQ-5D-3L VAS score were 
calculated using mixed models for repeated measures. Differences were seen as scores decline 
for the placebo arm but remained stable for the apalutamide arm, with this difference exceeding a
p<0.05 at Cycles 21 and 25, though the difference between arms remained relatively small with a

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difference in group means well below the minimal important difference (MID) threshold for 
individual differences.5
The Phase 3 Study ARN-509-003 (SPARTAN) included safety data from 1201 participants with 
NM-CPRC who received at least 1 dose of either apalutamide or placebo (803 participants in the 
apalutamide arm and 398 participants in the placebo arm, and 76 participants who crossed over 
from placebo to apalutamide). As of the clinical cutoff date for the final analysis of 1 February 
2020, 30% of participants in the apalutamide arm were continuing study treatment, no 
participants continued placebo treatment after study unblinding and being offered to cross over. 
Forty-six of 76 participants (61%) who crossed over continued to receive apalutamide as of the 
clinical cutoff date for this analysis. The median exposure in the apalutamide arm was nearly 
3-times longer (32.9 months) than in the placebo arm (11.5 months).2,4
TEAEs leading to death were reported for 24 (3.0%) participants in the apalutamide arm and 2 
(0.5%) participants in the placebo arm. Of the 24 participants in the apalutamide arm reported 
with TEAEs with an outcome of death, for 3 participants, progressive disease was their primary 
cause of death. All deaths except one were considered unrelated by the investigator: 1 participant 
in the apalutamide arm died after a TEAE that was considered drug-related by the investigator 
(acute myocardial infarction). The percentage of participants reported with TEAEs leading to 
treatment discontinuation was higher in the apalutamide arm (15%) compared with the placebo 
arm (7.3%), with TEAEs in the system organ class (SOC) of Skin and Subcutaneous Tissue 
Disorders resulting in the highest incidence of treatment discontinuations. Skin rash as the 
grouped term was the most commonly reported TEAE leading to treatment discontinuations and 
was the main reason for the difference in treatment discontinuations between the treatment arms. 
TEAEs leading to dose reduction were reported for 10% of participants in the apalutamide arm 
and 1.8% of participants in the placebo arm, TEAEs in the SOC of Skin and Subcutaneous 
Tissue Disorders and the SOC of General Disorders and Administration Site Conditions are the 
leading cause for dose reductions. Serious adverse reactions occurred in 36% of apalutamide arm 
-treated participants and 25% in participants receiving placebo. Frequently reported SAEs that 
occurred at a higher incidence in the apalutamide arm (>2%) than the placebo arm were fracture 
as a grouped term (5.4% apalutamide versus 1.0% placebo), ischemic heart disease as a grouped 
term (2.9% versus 1.8%), hematuria (2.6% versus 2.0%), urinary tract infection (2.1% versus 
0.8%). Frequently reported SAEs that occurred at a higher incidence in the placebo arm than the 
apalutamide arm were
urinary retention (1.6% apalutamide versus 4.8% placebo), 
hydronephrosis (1.6% versus 2.0%), and urinary tract obstruction (0.7% versus 1.0%); these 
events are frequent in the setting of disease progression.
The most frequently reported treatment-emergent adverse events (TEAEs) (ie, occurring in 
≥15% of participants in either arm) were fatigue (33% apalutamide vs 21% placebo), 
hypertension (28% apalutamide vs 21% placebo), skin rash as the grouped term (26% 
apalutamide vs 6.3% placebo), diarrhea (23% apalutamide vs 15% placebo), nausea (20% 
apalutamide vs 16% placebo), fall (22% apalutamide vs 9.5% placebo), weight decreased (20% 
apalutamide vs 6.5% placebo), arthralgia (20% apalutamide vs 8.3% placebo), back pain (18% 
apalutamide versus 15% placebo), fracture as the grouped term (18% apalutamide versus 7.5% 

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placebo), and hot flush (15% apalutamide versus 8.5% placebo). When adjusted for exposure, 
skin rash, fall, weight decreased, arthralgia, and fracture were more frequent for the apalutamide 
arm.
Falls 
In study ARN-509-003 (SPARTAN),2 falls occurred in 22% of participants in the apalutamide
arm and 9.5% of participants in the placebo arm. Among the 76 participants in the cross-over
placebo-to-apalutamide arm, 11% of participants were reported with a TEAE of fall. Most falls 
were minor without resultant injury or only requiring noninvasive intervention, and very rarely 
were reason for treatment interruption or discontinuation.
Fracture
In study ARN-509-003 (SPARTAN),2 most TEAEs of fracture were of Grade 1 or 2 severity, 
nonserious, and did not result in treatment modification or interruption. The preferred term rib 
fracture accounted for most events of fracture and was reported at a higher incidence in the 
apalutamide arm (7.5% versus 4.3% in the placebo arm). The use of bone-sparing agents at study 
entry did not appear to be protective.4
Seizure
In study ARN-509-003 (SPARTAN),2A total of 5 events of seizure were reported in the
apalutamide arm and none in the placebo arm, nor in the cross-over placebo-to-apalutamide 
arm), all were of Grade 1 or 2 severity. Events of seizure were reported as serious TEAEs, and as 
mandated by the protocol, led to discontinuation of apalutamide therapy.
Skin Rash
In study ARN-509-003 (SPARTAN),2 rash associated with apalutamide was most commonly 
described as macular or maculo-papular, with or without associated symptoms such as pruritus. 
Most TEAEs of skin rash were of Grade 1 or 2 severity. Grade 3 events of skin rash were 
reported for 5.2% of participants in the apalutamide arm. The exposure-adjusted incidence of 
skin rash in the apalutamide arm was lower at the final analysis compared with the first interim 
analysis, suggesting that skin rash is a relatively early event and that the risk for this event 
diminishes over time during apalutamide therapy. There were no reported Stevens-Johnson 
syndrome (SJS) or toxic epidermal necrolysis (TEN) cases. Skin rashes were manageable with 
dose interruption, dose reduction, topical and systemic therapy. No TEAE of skin rash led to 
death. As noted in the first interim analysis, the onset of skin rash typically occurred within the
first 3 months of apalutamide treatment, with a median time of 82 days to the first occurrence of 
rash of any grade. Skin rash was a serious event for 2 participants in the apalutamide arm.
Ischemic Heart Disease
Events of ischemic heart disease were reported for participants in both arms of Study 
ARN-509-003 (5.5% in the apalutamide arm, 2.8% in the placebo arm), they were primarily for 
participants with a history of ischemic heart disease or risk factors. Based on similar risk factors 

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and a higher frequency in the apalutamide arm, ischemic cerebrovascular disorder was also 
considered an ADR for apalutamide. 
Grade 3 or higher events of ischemic heart disease were reported for 2.6% of participants in the 
apalutamide arm, 1.8% of participants in the placebo arm, and 2.6% in the placebo-apalutamide 
arm. Grade 5 events of ischemic heart disease were reported in 2 participants in the apalutamide 
arm and 1 participant in the placebo-apalutamide arm. 
Ischemic Cerebrovascular Disorders
Based on the final analysis of Study ARN-509-003, ischemic cerebrovascular disorders (grouped 
term) was identified as a new AE of special interest and ADR.
Grade 3 events of ischemic cerebrovascular disorders were reported for 1.4% of participants in 
the apalutamide arm, Grade 4 events were reported for 1 participant (0.1%) in the apalutamide 
arm. Ischemic cerebrovascular disorders leading to dose reduction or interruption were reported 
for 0.6% of participants in the apalutamide arm, discontinuation of apalutamide therapy was 
reported for 0.9% of participants in the apalutamide arm.
2.2.1.
Androgen Deprivation Therapy
All participants will be on a stable and continuous regimen of ADT (beginning on Cycle 1 Day 
1). Androgen Deprivation Therapy with continuous GnRHa will be continued for all patients 
who have not been surgically castrated. GnRHa will be provided by the sponsor and should be 
used according to the approved prescribing information in China during the treatment phase.
2.3.
Benefit/Risk Assessment
Based on the results from Study ARN-509-003 (SPARTAN), the addition of apalutamide to an 
ADT regimen resulted in statistically significant and clinically meaningful improvements in 
clinical outcomes compared with ADT alone. A significant improvement was demonstrated in 
favor of the apalutamide arm for the primary endpoint of MFS as well as for the key secondary 
endpoints of time to metastasis (TTM) and PFS. The safety results from this study demonstrated 
an acceptable safety profile for apalutamide plus ADT for the treatment of patients with 
NM-CRPC. Collectively, the results of Study ARN-509-003 (SPARTAN) demonstrate a 
favorable benefit/risk profile for apalutamide plus ADT for treatment of NM-CRPC in the target 
population of this PAC study.2,4
More detailed information about the known and expected benefits and risks of apalutamide may 
be found in the IB.

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3.
OBJECTIVES AND ENDPOINTS
OBJECTIVES
Primary Objective
The primary objective is to compare the improvement in time to PSA progression (TTPP, as 
defined by Prostate Cancer Working Group 2 [PCWG2]) of apalutamide vs placebo in Chinese 
participants with high-risk NM-CRPC.a
Secondary Objectives
The secondary objectives are:

To evaluate the safety and tolerability of apalutamide

To compare the PSA response rate in Chinese participants with high-risk NM-CRPC treated 
with apalutamide vs placebo

To evaluate the PK of apalutamide and N-desmethyl apalutamide
Exploratory Objectives
The exploratory objectives are:

To evaluate the MFS of Chinese participants with high-risk NM-CRPC treated with 
apalutamide 

To evaluate the OS of Chinese participants with high-risk NM-CRPC treated with 
apalutamide

To evaluate the time to symptomatic progression in Chinese participants with high-risk 
NM-CRPC treated with apalutamide
ENDPOINTS
Primary Endpoint

TTPP
Secondary Endpoints

Incidence of AEs and laboratory abnormalities

PSA response rate

PK: Predose and 2 hours postdose plasma concentrations after single dose and at
steady-state.
                                                
a
Participants randomized to placebo arm will be crossed over to receive apalutamide treatment either after completion a maximum 5 cycles placebo 
treatment or at the time of having documented PSA progression, whichever comes earlier.

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Exploratory Variables

MFS

OS

Time to symptomatic progression: 

Development of a skeletal-related event (SRE)

Pain progression or worsening of disease-related symptoms requiring initiation of a new 
systemic anticancer therapy.

Development of clinically significant symptoms due to loco-regional tumor progression 
requiring surgical intervention or radiation therapy.
Refer to Section 8, Study Assessments and Procedures for evaluations related to endpoints.
HYPOTHESIS
Participants receiving treatment with apalutamide in conjunction with ADT will have a longer 
TTPP compared with participants receiving placebo plus ADT.
4.
STUDY DESIGN
4.1.
Overall Design
This is a Phase IV, randomized, double-blind, placebo-controlled, multicenter study in 
evaluating the efficacy and safety of apalutamide vs placebo in male Chinese participants with 
high-risk NM-CRPC.
A target of 75 Chinese participants will be randomly assigned in a 2:1 ratio in this study to 
receive apalutamide or matching placebo. Participants will be stratified by PSADT (>6 months 
vs ≤6 months).
The study will consist of 4 phases: 

Prescreening Phase (optional)

Screening Phase (≤35 days prior to randomization)

Treatment Phase (starting on Day 1 of Cycle 1 until disease progression/ unacceptable 
toxicity, withdrawal of consent, death or termination of the study)

Follow-up Phase (starting after end-of-treatment visit until death, withdrawal of consent for 
study participation, or termination of the study). 
For an optional Prescreening Phase, a separate written informed consent will be obtained from 
the participant (or participant’s legal representative). Optional prescreening PSA evaluations will
be performed by the local laboratories. This Prescreening Phase will allow additional time to 
obtain the required number of PSA values for determining eligibility till the last participant
screening is successful. The participant must then sign another informed consent before any 
additional study-related procedures are conducted.

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Apalutamide or matched placebo will be administered orally on a continuous daily dosing 
schedule at a starting dose of 240 mg per day. Cycle 1 Day 1 must occur within 1 week of 
randomization. Androgen deprivation therapy with continuous GnRHa will be continued for all 
patients who have not been surgically castrated. 
Each treatment cycle will consist of 28 days. Participants randomized to placebo, who do not 
have any evidence of distant metastasis (according to imaging result at Cycle 5 Day 1, as well as 
at any other relevant unscheduled visit) will be crossed over and start receiving active therapy of 
apalutamide after completion of 5 cycles of placebo plus ADT treatment. Participants who have 
PSA progression prior to completion of 5 cycles of study treatment, will cross over to 
apalutamide at the time of PSA progression. Any participant who develops distant metastatic 
disease will discontinue study treatment and may receive subsequent therapy according to 
standard of care. Around half of the participants in the placebo arm are expected to have 
documented PSA progression after completion of 5 cycles treatment, as estimated from the 
ARN-509-003 study data, and would therefore, allow sufficient time for the evaluation of TTPP 
and comparison between apalutamide and placebo.
During the treatment phase, PSA will be collected and analyzed by a central laboratory but 
investigators, participants, and the study team will be blinded to the results until completion of 
the study or the sponsor decides to unblind the study at final analysis. The central laboratory will 
analyze the individual PSA data, collected at baseline and post-baseline obtained within the first 
5 cycles to flag out documented PSA progression per PCWG2 and the data will be entered into 
the interactive web response system (IWRS) to trigger the cross-over by an independent team not 
affiliated with the study team. The cross-over of control arm participants will be handled by 
IWRS to maintain the blinding of original treatment assignment of individual participant.
Participants will be followed for safety and efficacy as per Schedule of Activities (SoA) and will 
remain on study treatment until development of distant metastases as assessed by investigators or 
the development of unacceptable toxicity or the end of study defined as the time at which the 
MFS events are observed in approximately 60% of the study population or 3 years after the final 
analysis for the primary endpoint (TTPP), whichever comes first.
All participants will be monitored for safety during the Screening and Treatment Phases, and for 
up to 30 days after the last dose of study treatment. An End-of-Treatment (EoT) Visit will occur 
approximately 30 days of the last dose of study treatment. The Posttreatment Follow-up Phase 
will begin after the EoT visit. For participants entering Posttreatment Follow-up Phase with 
evidence of distant metastasis, they will be contacted every 4 months (±7 days) to obtain survival 
status, recording of development of symptomatic progression, initiation of any new systemic 
anticancer therapies until death, withdrawal of consent for study participation, or termination of 
the study. For participants entering Posttreatment Follow-up Phase without evidence of distant 
metastasis, Posttreatment Follow-up visits including disease assessment (computed tomography 
[CT] or magnetic resonance imaging [MRI], plus bone scans) will continue every 16 weeks 
(±7 days) until the documentation of disease progression, then participants will be contacted 
every 4 months (±7 days) to obtain survival status, recording of development of symptomatic 

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progression, initiation of any new systemic anticancer therapies until death, withdrawal of 
consent for study participation, or termination of the study.
An IDMC will be commissioned for this study to review the efficacy and safety results of final 
analysis. Refer to Committees Structure in Appendix 2: Regulatory, Ethical, and Study Oversight 
Considerations for details. The IDMC will consist of at least 1 medical oncologist or urologist or 
both and at least 1 statistician. Complete details regarding the IDMC’s responsibilities, 
authorities, and procedures will be documented in the IDMC charter.
A diagram of the study design is provided in Section 1.2, Schema.
4.2.
Scientific Rationale for Study Design
Short PSADT has been consistently associated with reduced time to first metastasis and death. 
Thus, the selected patient population represents 1 at a high risk for development of (distant) 
metastasis and PC-specific death.6,10,9,2
In China, there were no approved therapies at the initiation of this study for the treatment of 
patients with NM-CRPC. In clinical practice, continuous administration of ADT (with or without 
a first-generation anti-androgen) was the most often prescribed treatment thus constituted as part 
of the current de facto community standard practice. Therefore, randomization to either 
apalutamide or placebo was justified in this setting at the time of study initiation as the 
participants randomized to the control arm will be receiving the current standard of care in 
China. Since then, 2 other products have been conditionally approved or approved for the 
treatment of patients with NM-CRPC.
Randomization will be used to minimize bias in the assignment of participants to intervention 
groups, to increase the likelihood that known and unknown participant attributes 
(eg, demographic and baseline characteristics) are evenly balanced across intervention groups, 
and to enhance the validity of statistical comparisons across intervention groups. Blinded 
intervention will be used to reduce potential bias during data collection and evaluation of clinical 
endpoints.
Participants randomized to the placebo arm and without any evidence of distant metastasis will 
be allowed to early switch to receive apalutamide plus ADT at the time they have documented 
PSA progression or after completion of 5 cycles of placebo plus ADT treatment (refer to section 
4.1). will minimize the exposure of participants randomized to the placebo arm to less effective 
treatment, as compelling evidence of efficacy and safety profile of apalutamide has been 
demonstrated in Study ARN-509-003 (SPARTAN).4 Participants who develop distant metastatic 
disease prior to C6 will discontinue study treatment and may receive subsequent therapy as per 
standard of care for mCRPC.
Up to 5 cycles of placebo plus ADT treatment will allow an objective comparison of efficacy, 
measured by primary endpoint of TTPP, between treatment with apalutamide and placebo in 
Chinese high-risk NM-CRPC participants. Around half of the participants in the placebo arm are 
expected to have documented PSA progression by Cycle 5, as estimated from the ARN-509-003

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(SPARTAN) study data, and would therefore, allow sufficient time for the evaluation of TTPP 
and comparison between apalutamide and placebo.4
Time to PSA progression is considered to be an appropriate primary endpoint in this PAC study 
as the clinical benefit observed in the primary and secondary endpoints of study ARN-509-003
(SPARTAN) was associated with significant improvements in TTPP. The proposed design using 
TTPP as primary endpoint will allow early read out and early switch of placebo participants to 
receive apalutamide, thereby improving participant well-being and study feasibility from 
operation perspective.4
4.2.1.
Study-Specific Ethical Design Considerations
Potential participants will be fully informed of the risks and requirements of the study, and during 
the study, participants 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 participants who are fully able to understand the risks, benefits, 
and potential adverse events (AEs) of the study, and provide their consent voluntarily will be 
enrolled.
The primary ethical concern is participants randomized to the placebo arm will be exposed to less 
effective treatment (ADT alone). However, the study design allows for participants to cross over 
to the active arm as soon as PSA progression is determined, thus minimizing the exposure of 
participants to less effective treatment by allowing an early switch to apalutamide plus ADT using 
TTPP as the primary endpoint. Further, on the SPARTAN study about 6.2% of the placebo 
participants were found to have metastatic disease at the first post-baseline scan without prior 
PSA progression and only 1-2 participants in this study are expected to have the same situation 
given one third of 75 Chinese participants (about 25 participants) are to be randomly assigned to
placebo arm. Therefore, the likelihood that a participant would develop metastatic disease before 
having the opportunity to cross over to apalutamide is small.4
4.3.
Justification for Dose
The therapeutic dose was selected to be 240 mg/day given orally. The determination of the dose 
of 240 mg daily was based on an integrated approach, comparing the dose required for maximum 
tumor regression in mouse xenograft models,10 clinical PK and pharmacodynamics (inhibition of 
18-fluorodihydrotestosterone uptake and PSA response), and assessing the safety and tolerability 
at doses up to 480 mg.3,8 For details pertaining to dose-modification, please refer Section 6.6.
4.4.
End of Study Definition
The end of study is considered as the last scheduled study assessment shown in Schedule of 
Activities (SoA) for the last participant in the study. A participant will be considered to have 
completed the study if he has died before the end of the study. Participants lost to follow-up or 
withdrawn consent before the end of the study will not be considered as completing the study.

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The final data from the study site will be sent to the sponsor (or designee) after completion of the 
final participant assessment at that study site, in the time frame specified in the Clinical Trial 
Agreement.
The end of trial will be defined as the time at which the MFS events are observed in 
approximately 60% of the study population or 3 years after the final analysis for the primary 
endpoint TTPP, whichever comes first.
5.
STUDY POPULATION
Screening for eligible participants will be performed within ≤35 days before administration of 
the study intervention. Refer to Section 5.3, Screen Failures for conditions under which the 
repeat of any screening procedures are allowed.
The inclusion and exclusion criteria for enrolling participants in this study are described below. 
If there is a question about these criteria, the investigator must consult with the appropriate 
sponsor representative and resolve any issues before enrolling a participant in the study. Waivers 
are not allowed. 
For a discussion of the statistical considerations of participant selection, refer to Section 9.1, 
Sample Size Determination.
5.1.
Inclusion Criteria
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
1.
Male (according to their reproductive organs and functions assigned by chromosomal 
complement).
2.
≥18 years of age (or the legal age of consent in the jurisdiction in which the study is 
taking place).
3.
Histologically or cytologically confirmed adenocarcinoma of the prostate without 
neuroendocrine differentiation or small cell features, with high risk for development of 
metastases, defined as PSADT ≤10 months. PSADT is calculated using at least 3 PSA 
values obtained during continuous ADT.
4.
Castration-resistant PC demonstrated during continuous ADT, defined as 3 PSA rises at 
least 1 week apart, with the last PSA >2 ng/mL.
5.
Surgically or medically castrated, with testosterone levels of <50 ng/dL. If the 
participant is medically castrated, continuous dosing with GnRHa must have been 
initiated at least 4 weeks prior to randomization and must be continued throughout the 
study to maintain castrate levels of testosterone.
6.
Participants who received a first-generation anti-androgen (eg, bicalutamide, flutamide, 
nilutamide) must have at least a 4-week washout prior to randomization AND must 

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show continuing disease progression (an increase in PSA) after washout.
7.
At least 4 weeks must have elapsed from the use of 5-α reductase inhibitors (eg, 
dutasteride, finasteride), estrogens (irrespective of dose used), and any other anticancer 
therapy 
prior 
to 
randomization, 
including 
chemotherapy 
given 
in 
the 
adjuvant/neoadjuvant setting (eg, clinical trial).
8.
At least 4 weeks must have elapsed from major surgery or radiation therapy prior to 
randomization.
9.
Eastern Cooperative Oncology Group (ECOG) - Performance Status (PS) grade 0 or 1
(Appendix 5: ECOG-PS Score).
10.
Resolution of all acute toxic effects of prior therapy or surgical procedure to Grade 1 or 
baseline prior to randomization.
11.
Adequate organ function as defined by the following criteria:

Serum aspartate aminotransferase (AST; serum glutamic oxaloacetic 
transaminase [SGOT]) and serum alanine aminotransferase (ALT; serum 
glutamic pyruvic transaminase [SGPT]) 2.5x upper limit of normal (ULN).

Total bilirubin ≤1.5 x ULN; participants with Gilbert syndrome can be enrolled 
if conjugated bilirubin is within normal limits (≤1.5 x ULN or direct bilirubin 
≤ULN for participants with total bilirubin levels >1.5 x ULN).

Serum creatinine 2 x ULN.

Absolute neutrophil count (ANC) 1500/L.

Platelets 100,000/L.

Hemoglobin 9.0 g/dL.

Administration of growth factors or blood transfusions will not be allowed 
within 4 weeks of the hematology labs required to confirm eligibility.
12.
Must sign an informed consent form (ICF; or their legally acceptable representative 
must sign) indicating that he understands the purpose of, and procedures required for,
the study and is willing to participate in the study.
13.
Willingness and ability to comply with scheduled visits, treatment plans, laboratory and 
radiographic assessments, and other study procedures, including ability to swallow 
study drug tablets, and long-term survival follow-up visits.
14.
Willing and able to adhere to the lifestyle restrictions specified in this protocol.

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5.2.
Exclusion Criteria
Any potential participant who meets any of the following criteria will be excluded from 
participating in the study:
1.
Presence of distant metastases, including central nervous system (CNS) and vertebral 
or meningeal involvement, or history of distant metastases. Exception: Pelvic lymph 
nodes <2 cm in short axis (N1) located below the iliac bifurcation are allowed.
2.
Symptomatic loco-regional disease requiring medical intervention, such as moderate 
or severe urinary obstruction or hydronephrosis, due to primary tumor (eg, tumor 
obstruction of bladder trigone).
3.
Prior treatment with second generation anti-androgens (eg, enzalutamide).
4.
Prior treatment with CYP17 inhibitors (eg, abiraterone acetate, orteronel, galerterone, 
ketoconazole, aminoglutethimide) for PC.
5.
Prior treatment with radiopharmaceutical agents (eg, Strontium-89), immunotherapy 
(eg, sipuleucel-T), or any other investigational agent for NM-CRPC.
6.
Prior chemotherapy for PC, except if administered in the adjuvant/neoadjuvant 
setting.
7.
History of seizure or condition that may pre-dispose to seizure (eg, prior stroke within 
1 year prior to randomization, brain arteriovenous malformation, Schwannoma, 
meningioma, or other benign CNS or meningeal disease which may require treatment 
with surgery or radiation therapy).
8.
Concurrent therapy with any of the following (all must have been discontinued or 
substituted for at least 4 weeks prior to randomization):

Medications known to lower the seizure threshold.

Herbal and non-herbal products that may decrease PSA levels.

Spironolactone.

Systemic (oral/IV/IM) corticosteroids. Short term use (≤4 weeks) of 
corticosteroids during the study is allowed if clinically indicated, but it will 
be tapered off as soon as possible.

Any other experimental treatment on another clinical trial.

Agents indicated for the prevention of SREs in participants with solid tumors 
(eg, denosumab [XGEVA®]), zoledronic acid [ZOMETA®]). Treatment with 
bone-sparing agents for the treatment of osteoporosis (eg, denosumab 
[PROLIA®], zoledronic acid [ACLASTA®]) is not exclusionary.
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restricted therapy during the study.
9.
History of severe/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.
10.
History of malignancy within 5 years before screening (exceptions are squamous and 
basal cell carcinomas of the skin, superficial bladder cancer.
11.
Uncontrolled hypertension (systolic blood pressure (BP) ≥160 mm Hg or diastolic BP
≥100 mm Hg). Participants with a history of uncontrolled hypertension are allowed 
provided BP is controlled by anti-hypertensive treatment.
12.
Gastrointestinal disorder affecting absorption.
13.
Active infection, such as human immunodeficiency virus, or active hepatitis.
14.
Received an investigational intervention (including investigational vaccines) or used 
an invasive investigational medical device within 4 weeks before the planned first 
dose of study intervention or is currently enrolled in an investigational study.
15.
Men who are sexually active with women of childbearing potential except:

agree to use a condom with spermicidal foam/gel/film/cream/suppository

agree to not donate sperm during the study and for at least 3 months after the last 
dose of study drug

do not plan to father a child during the study or within 3 months after the last 
dose of study drug
16.
Any condition for which, in the opinion of the investigator, participation would not be 
in the best interest of the participant (eg, compromise the well-being) or that could 
prevent, limit, or confound the protocol-specified assessments.
17.
Employee of the investigator or study site, with direct involvement in the proposed 
study or other studies under the direction of that investigator or study site, as well as 
family members of the employees or the investigator.
18.
Known allergies, hypersensitivity, or intolerance to apalutamide or its excipients (refer 
to IB).
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. 
If a participant's clinical status changes (including any available laboratory results or receipt of 
additional medical records) after screening but before the first dose of study intervention is given 
such that he or she no longer meets all eligibility criteria, then the participant should be excluded 
from participation in the study. Section 5.3, Screen Failures, describes options for retesting. The 

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required source documentation to support meeting the enrollment criteria are noted in 
Appendix 2: Regulatory, Ethical, and Study Oversight Considerations.
5.3.
Screen Failures
Participant Identification, Enrollment, and Screening Logs
The investigator agrees to complete a participant identification and enrollment log to permit easy 
identification of each participant during and after the study. This document will be reviewed by 
the sponsor study-site contact for completeness.
The participant identification and enrollment log will be treated as confidential and will be filed 
by the investigator in the study file. To ensure participant confidentiality, no copy will be made. 
All reports and communications relating to the study will identify participants by participant 
identification and age at initial informed consent. In cases where the participant is not 
randomized into the study, the date seen and age at initial informed consent will be used.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once. Rescreening is at the discretion of the investigator. Participants who are to be 
rescreened must sign a new ICF before rescreening. Rescreening and subsequent randomization 
activities must be conducted in accordance with all protocol-defined windows and timelines.
Rescreened participants should be assigned a new participant number.
6.
STUDY INTERVENTION
6.1.
Study Interventions Administered
Treatment will begin on Day 1 of Cycle 1 and each treatment cycle will consist of 28 days. 
Participants will be randomly assigned in a 2:1 ratio to receive either apalutamide or matching 
placebo, as below (refer to Table 2). ADT (surgical castration or GnRHa) will be continued in all
participants.

Investigational group will receive apalutamide 240 mg (4×60 mg tablets) daily.

Control group will receive placebo daily from Cycle 1 Day 1. Participants who do not have 
distant metastasis will switch to treatment with apalutamide after completion of 5 cycles of 
placebo treatment (handling by the IWRS). Participants who have PSA progression prior to 
completion of 5 cycles of study treatment, will cross over to apalutamide at the time of PSA 
progression.
Study drug intake will occur on an outpatient basis on non-PK sampling days. On PK sampling 
days, which include Cycle 1 Day 1, Cycle 2 Day 1, Cycle 3 Day 1, and Cycle 6 Day 1, intake of 
apalutamide must occur at the study site under supervision of site personnel after the predose PK 
samples are collected. On PK sampling days, participants will be fasted at least 2 hours prior to 
dosing, and will continue fasting (except for approved snack) until completion of the 2-hour 
post-dose assessments on Cycle 1 Day 1 and Cycle 3 Day 1. On non-PK sampling days, 
apalutamide may be taken with or without food. A modified dosing schedule may be required on 

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PK sampling days. Study-site personnel will instruct participants on how to store study drug for 
at-home use as indicated for this protocol.
Table 2:
Description of Interventions
Arm Name
Arm A
Arm B
Intervention Name
Apalutamide
Placebo
Type
A drug 
A matching placebo to active drug 
Dose Formulation
Immediate release tablet 
Immediate release tablet
Unit Dose Strength(s)
4×60 mg
4×60 mg
Dosage Level(s)
240 mg daily
240 mg daily
Route of 
Administration
Oral
Oral
Use
Experimental
Placebo-Comparator
Packaging and 
Labeling
120-ct, 160cc HDPE bottles with CRC and 
include desiccant.
120-ct, 160cc HDPE bottles with CRC 
and include desiccant.
Child-resistant 
packaging
Yes
Yes
Delivery instructions
Apalutamide: QD without regard to food
Apalutamide: QD without regard to food
Names/Aliases
JNJ-56021927
NA
ADT: androgen deprivation therapy, being either surgical castration or gonadotrophin-releasing hormone agonists (GnRHa), will 
be continued as background therapy for all participants. ADT with GnRHa will be continued for all patients who have not been 
surgically castrated. CRC: child-resistant closures; HDPE: high density polyethylene; QD: once daily.
Study intervention administration must be captured in the source documents and the electronic 
case report form (eCRF). Study-site personnel will instruct participants on how to store study 
intervention for at-home use as indicated for this protocol.
Apalutamide will be manufactured and provided under the responsibility of the sponsor. Refer to 
the IB for a list of excipients.
For a definition of study intervention overdose, refer to Section 8.4, Treatment of Overdose.
6.2.
Preparation/Handling/Storage/Accountability
All study intervention must be stored at controlled temperatures ranging from 15°C to 30°C.
Refer to the pharmacy manual/study-site investigational product and procedures manual for 
additional guidance on study intervention preparation, handling, and storage.
The dispensing of study intervention to the participant, and the return of study intervention from 
the participant (if applicable), must be documented on the intervention accountability form. 
Participants or their legally acceptable representatives where applicable, must be instructed to 
return all original containers, whether empty or containing study intervention. All study 
intervention will be stored and disposed of according to the sponsor's instructions. Study-site 
personnel must not combine contents of the study intervention containers.
The participants must return unused study intervention to the study site.
Study intervention must be handled in strict accordance with the protocol and the container label, 

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and must be stored at the study site in a limited-access area or in a locked cabinet under 
appropriate environmental conditions. Unused study intervention, and study intervention 
returned by the participant, 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 intervention, or used 
returned study intervention for destruction, will be documented on the intervention return form. 
When the study site is an authorized destruction unit and study intervention supplies are 
destroyed on-site, this must also be documented on the intervention return form.
Potentially hazardous materials such as used ampules, needles, syringes and vials containing 
hazardous liquids, should be disposed of immediately in a safe manner and therefore will not be 
retained for intervention accountability purposes. 
Study intervention 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 intervention will be 
supplied only to participants participating in the study. Returned study intervention must not be 
dispensed again, even to the same participant. Whenever a participant brings his study 
intervention to the study site for pill count, this is not seen as a return of supplies. Study 
intervention may not be relabeled or reassigned for use by other participants. The investigator 
agrees neither to dispense the study intervention from, nor store it at, any site other than the 
study sites agreed upon with the sponsor.
6.3.
Measures to Minimize Bias: Randomization and Blinding
Intervention Allocation
Procedures for Randomization
Central randomization will be implemented in this study. Participants will be randomly assigned 
to 1 of 2 intervention groups no more than 1 week prior to dosing and will be based on a 
computer -generated randomization schedule prepared before the study under the supervision of 
the sponsor. The randomization will be balanced by using randomly permuted blocks and will be 
stratified by PSADT (>6 months vs ≤6 months). The IWRS will assign a unique intervention
code, which will dictate the intervention assignment and matching study intervention kit for the 
participant. The requestor must use his own user identification and personal identification 
number when contacting the IWRS, and will then give the relevant participant details to uniquely 
identify the participant.
To ensure an accurate and consistent determination of PSADT across all sites, the IWRS will 
also provide PSADT calculations (using a linear regression model of the normal logarithm of 
PSA and time) based on at least 3 PSA values obtained during continuous ADT. All available 
consecutive PSA values obtained within 24 months prior to randomization beginning with the 
earliest value chosen for the PSADT calculation must be entered in the IWRS. The first and last
PSA values used in the calculation must be separated by at least 8 weeks.
Those same PSA values will be used during Screening to determine whether the patient is 
eligible for the study (inclusion criterion 3). To pre-screen participants for possible enrollment 

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into the study, PSADT can be calculated using the Memorial Sloan-Kettering Cancer Center 
(MSKCC) PSADT prediction tool, available at the following website:
http://nomograms.mskcc.org/Prostate/PsaDoublingTime.aspx
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 participant.
Prostate-specific antigen will be collected and analyzed by a central laboratory but investigators, 
participants, and the study team will be blinded to the results until the full unblinding of the 
study. Control arm participants without distant metastasis will switch to treatment with 
apalutamide plus ADT at the time PSA progression (per PCWG2) is documented or participants 
have completed 5 cycles treatment of placebo plus ADT. The central laboratory will analyze the 
individual PSA data, collected at baseline and post-baseline obtained within the first 5 cycles to 
flag out documented PSA progression per PCWG2 and the data will be entered into the IWRS to
trigger the cross-over by an independent team not affiliated with the study team. The cross-over 
of control arm participants will be handled by IWRS to maintain the blinding of original 
treatment assignment of individual participant.
Under normal circumstances, the blind should not be broken until completion of the study or the 
sponsor decides to unblind the study at final analysis. Otherwise, the blind should only be broken 
if, in a specific emergency, the treatment or course of action would be dictated by knowing the 
treatment status of the participant. 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 that 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 participant’s source documents in a secure manner.
Randomization codes will be disclosed fully only if the study is completed and the clinical 
database is closed or the sponsor decides to unblind the study at final analysis. 
6.4.
Study Intervention Compliance
At each clinic visit, participants will be asked to return any remaining study drug from the 
previous dosing cycle as well as all used and unused study drug containers.
Treatment compliance will be defined as the number of tablets taken divided by the expected 
number of tablets and reported as percentage. In case of dose reductions, the expected number of 
tablets will reflect the new dose level. Tablets that are not returned will be considered to have 
been taken, unless otherwise specified in the eCRF.

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The investigator or designated study site personnel will be responsible for providing additional 
instruction to any participant who is not compliant with taking the study drug. In the absence of 
toxicity, if the dosing compliance is not 100%, then investigators or designated study site 
personnel should re-instruct participants regarding proper dosing procedures and the participant
may continue study treatment. 
The study site must maintain accurate records demonstrating dates and amount of study drug 
received, to whom dispensed (participant-by-participant 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.
6.5.
Concomitant Therapy
Prestudy therapies administered up to 35 days before first dose of study intervention must be 
recorded at screening.
Concomitant therapies must be recorded throughout the study beginning with start of the first 
dose of study intervention to 30 days after the last dose of study intervention.
All therapies (prescription or over the counter medications, including vaccines, vitamins, herbal 
supplements; non-pharmacologic therapies such as electrical stimulation, acupuncture, special 
diets, exercise regimens) different from the study intervention must be recorded in the eCRF. 
Recorded information will include a description of the type of therapy, duration of use, dosing 
regimen, route of administration, and indication. Modification of an effective preexisting therapy 
should not be made for the explicit purpose of entering a participant into the study.
Continuous treatment with a GnRHa or surgical castration is mandatory. 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 will only be adjusted if clinically indicated to 
maintain castrate concentrations of testosterone.
Salvage radiation for loco-regional pelvic disease and surgical procedures (eg, transurethral 
resection of the prostate [TURP], urethral and ureteral stent placement) to treat localized 
progression or symptoms are allowed. Participants receiving these therapies may continue on 
study drug.
6.5.1.
Suggested Therapy
Fracture, fall and hypothyroidism are known risks associated with apalutamide. Participants will 
be evaluated for fracture and fall risk. Monitor and manage participants at risk for fractures 
according to established treatment guidelines and consider use of bone targeted agents. 
Participants are strongly encouraged to obtain an adequate intake of dietary calcium (at least 
1,000 mg per day, including supplements if necessary) and vitamin D [at least 
800-1,000 international units (or according to the product label-prescribing information in the 
country of residence) per day for adults 50 years of age and older] and to engage in regular 
exercise to maintain muscle strength and bone density.

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Thyroid replacement therapy, when clinically indicated, will be initiated or dose-adjusted.
6.5.2.
Prohibited Therapy
Concurrent enrollment in another investigational drug or device study is prohibited during the 
Treatment Phase.
As a class effect, AR antagonists have been associated with seizures due to an off-target 
mechanism of action (gamma amino butyric acid chloride channel inhibition). Drugs known to 
lower the seizure threshold or cause seizures are prohibited and a representative list is included 
below:

Atypical antipsychotics (eg, clozapine, olanzapine, risperidone, ziprasidone)

Bupropion

Lithium

Meperidine (pethidine)

Phenothiazine antipsychotics (eg, chlorpromazine, mesoridazine, thioridazine)

Tricyclic antidepressants (eg, amitriptyline, desipramine, doxepin, imipramine, maprotiline, 
mirtazapine)

Aminophylline/theophylline.
The following medications are prohibited while on study until the End-of-Treatment Visit or 
30 days after last dose of study drug. The sponsor must be notified in advance (or as soon as 
possible thereafter) of any instances in which prohibited therapies are administered. 
Chemotherapeutic, biologic, or other agents with anti-tumor effect against PC.

Anti-androgens (except as prescribed in the protocol)

5-α reductase inhibitors

Estrogens

Progestational agents (eg, cyproterone acetate)

Androgens

Oral ketoconazole

Spironolactone

Bone targeted agents indicated for the treatment of metastatic PC (bisphosphonates or 
denosumab) are prohibited (NOTE: bone targeted agents indicated for osteoporosis are 
allowed).
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.

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6.5.3.
Restricted Concomitant Therapy
Highlights of drug interaction with apalutamide are summarized below. Refer to Sections 4.3.4 
and 5.10 of the IB and associated addenda for complete details on the drug interaction potential 
of apalutamide, which include examples of medication that 1) may influence the effect of 
apalutamide, and 2) their effects may be influenced by apalutamide.

Medications that inhibit CYP2C8 or CYP3A4: Co-administration of a strong CYP2C8 or 
CYP3A4 inhibitor is predicted to increase the steady-state exposure of the active moieties 
(sum of unbound apalutamide plus
the potency-adjusted unbound N-desmethyl 
apalutamide). No initial dose adjustment is necessary however, consider reducing the 
apalutamide dose based on individual tolerability. Mild or moderate inhibitors of CYP2C8 
or CYP3A4 are not expected to affect the exposure of apalutamide.

Effect of apalutamide on drug metabolizing enzymes: Apalutamide is a strong inducer of 
CYP3A4 and CYP2C19, and a weak inducer of CYP2C9 in humans. Concomitant use of 
apalutamide with medications that are primarily metabolized by CYP3A4, CYP2C19, or 
CYP2C9 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 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-gp, BCRP, and 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.

Corticosteroids (Oral, IV, or IM): due to possible resistance mechanisms, which may be 
contributed by glucocorticoid receptor signaling, concurrent use of corticosteroids during the 
study is not recommended; short term use (≤4 weeks) will be allowed if clinically indicated, 
however, its use must be tapered off as soon as possible.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.
6.6.
Dose Modification
Any dose/dosage adjustment should be overseen by medically-qualified study-site personnel 
(principal or sub-investigator unless an immediate safety risk appears to be present).
General principles on dose modifications (except for rash, see Section 6.6.1 for details):

Grade 1 or Grade 2 toxicities should be managed symptomatically without dose adjustments. 
Appropriate medical treatment should be used.

In the event of a Grade 3 or higher toxicity, study drug should be held as detailed in Table 3
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
For the first occurrence of a Grade 3 or higher toxicity, dose reductions are allowed at 
investigator’s clinical judgment; if the Grade 3 or higher event recurs, dose reduction is 
mandatory.

If Grade 3 or higher toxicity does not resolve to Grade 1 or baseline within 2 cycles, the 
participant should be discontinued from treatment or the investigator ’ s rationale to 
continue treatment must be discussed with the sponsor.

The investigator’s rationale to re-escalate treatment must be discussed with and approved by 
the sponsor’s medical monitor on an individual basis prior to implementation.

Instructions for dose modifications are provided as guidance and should not replace the 
investigator’s own clinical judgment.
Table 3 summarizes apalutamide/placebo dose modifications for drug-related toxicities (except 
rash). Dose modifications for drug-related rash are summarized in Table 4.
Table 3:
Dose Modifications of Apalutamide/Placebo (except for rash, if rash occurs, see Table 4)
Severity
Number of apalutamide/placebo tablets
Grade 1 or 2
No change or hold until return to baseline 
≥Grade 3 
Hold until Grade 1 or baseline, resume at full dose; dose 
reductions are allowed at investigator’s clinical judgment
Recurrence ≥Grade 3
Hold until Grade 1 or baseline; reduce 1 dose level; 2 
dose reductions are allowed for recurrent treatment-
related toxicity (180 mg [3 tablets]) and 120 mg [2 
tablets]). Discontinue if toxicity persists after 2 dose 
reductions.
First occurrence of seizure of any grade 
Discontinue
Note: Adverse events are graded according to NCI-CTCAE Version 4.03
Abbreviation Key: NCI-CTCAE: National Cancer Institute-Common Terminology Criteria for Adverse Events.
6.6.1.
Dose Modifications for Rash and Rash Management 
Dose modifications for rash are allowed and are summarized in Table 4. If the skin rash has any 
component of desquamation, mucosal involvement, or pustules, stop dosing with study 
treatment, refer to a dermatologist for evaluation, and a skin biopsy is recommended (in addition 
to the interventions listed in Table 4) (and complete the skin rash eCRF). If the skin rash is 
Grade 3 or higher, asking the participant to consent to documentation by a photograph and 
further evaluation by a dermatologist will also be considered (and complete the skin rash eCRF). 
Completion of the skin rash eCRF will also be required if the skin rash leads to permanent 
discontinuation of study drug. If the study drug needs to be held for more than 14 days, the 
investigator will discuss with the sponsor’s medical monitor. Apalutamide/placebo can be held 
up to 28 days in the event of rash. If treatment interruption for any AE grade is longer than 28 
days, resumption of treatment may still be feasible. Please reach out to the sponsor to discuss 
further management. Dose re-escalation for rash is allowed for apalutamide/placebo at the 
discretion of the investigator.

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7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1.
Discontinuation of Study Intervention
Discontinuing treatment will not result in an automatic withdrawal from the study. Participants
who discontinue treatment, but do not withdraw consent, should complete the EoT Visit within 
30 days of the last dose of study drug and continue the scheduled assessments according to the 
Posttreatment Follow-up Phase in the Schedule of Activities (SoA).
A participant's study intervention must be discontinued if:

Documented distant metastases

The investigator believes that for safety reasons or tolerability reasons (eg, AE) it is in the 
best interest of the participant to discontinue study intervention

Initiation of any subsequent prostate anticancer therapy or procedure not specified in the 
protocol during treatment phases

Seizure of any grade or Grade 4 neurotoxicity (see Section 6.6);

Other study drug toxicity (see Section 6.6)

Withdrawal of consent for continued treatment.
All participants discontinuing study treatment will enter the Posttreatment Follow-up Phase. For 
participants entering Posttreatment Follow-up Phase with evidence of distant metastasis, they 
will be followed for survival status, the development of symptomatic progression, initiation of 
any new systemic anticancer therapies until death, withdrawal of consent for study participation, 
or termination of the study (every 4 months ±7 days via clinic visit, telephone contact or an 
alternative contact method per institution policy/practice), whichever comes first. In addition, if 
participants discontinued study treatment prior to documented disease progression (distant 
metastases), CT of the chest, abdomen, and pelvis, or MRI, plus bone scan will be obtained and 
evaluated for disease progression in Posttreatment Follow-up visits (every 16 weeks ±7 days), 
until documentation of disease progression, then participants will be contacted every 4 months 
(±7 days) to obtain survival status, recording of development of symptomatic progression, 
initiation of any new systemic anticancer therapies until death, withdrawal of consent for study 
participation, or termination of the study. 
When a participant 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 
participant may not be assigned to another participant. Participants who withdraw will not be 
replaced. 
Participants will be followed for at least 30 days after the last dose of study drug. If a participant
is withdrawn from treatment due to an AE, please refer to Appendix 3: Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-up, and Reporting.

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7.2.
Participant Discontinuation/Withdrawal From the Study
A participant will be withdrawn from the study for any of the following reasons:

Loss of follow-up

Withdrawal of consent for subsequent data collection

Study is terminated by the sponsor
When a participant withdraws from the study, the reason for withdrawal is to be documented in 
the eCRF and in the source document. Study intervention assigned to the withdrawn participant 
may not be assigned to another participant. 
7.3.
Lost to Follow-up
If a participant is lost to follow-up, every reasonable effort must be made by the study-site 
personnel to contact the participant and determine the reason for discontinuation/withdrawal. The 
measures taken to follow-up must be documented. Refer to Section 7.2, Participant 
Discontinuation/Withdrawal From the Study.
8.
STUDY ASSESSMENTS AND PROCEDURES
Overview
Schedule of Activities (SoA) summarizes the frequency and timing of efficacy, PK, and safety 
measurements, and medical resource utilization (MRU) applicable to this study. During the 
Treatment Phase, study visits may occur within -3 ~ +2-day window. Visits for 99mTc bone scans 
or CT/MRI may occur up to 8 days before cycles requiring images. Unscheduled assessments 
can occur at any time as needed if signs of disease progression are observed.
Blood collections for PK should be kept as close to the specified time as possible (see 
Section 6.1). Other measurements may be done earlier than specified timepoints if needed. 
Actual dates and times of assessments will be recorded in the source documentation and eCRF.
For each participant, the maximum amount of blood drawn from each participant in this study 
will not exceed 13 mL per visit.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the eCRF or laboratory 
requisition form.
Refer to the Schedule of Activities (SoA) 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 

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must be under the specified, and where applicable, controlled temperature conditions as indicated 
in the laboratory manual.
Study-Specific Materials
The investigator will be provided with the following supplies:

IB

Pharmacy manual/study-site investigational product and procedures manual

Laboratory manual

National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-
CTCAE) Version 4.03

IWRS Manual

electronic data capture (eDC) Manual

eSource Manual

Sample ICF.
8.1.
Efficacy Assessments
Efficacy evaluations will be conducted as specified in the Schedule of Activities (SoA). The 
efficacy evaluations include the following:

Serum PSA evaluation (for TTPP, as defined by PCWG2): PSA will be analyzed at the 
central laboratory. Results will be kept blinded to the participants, the Investigators, and the 
study team, in order to preserve the double-blind nature of this study. On Cycle 1 Day 1 
only, the PSA evaluation does not need to be repeated if the Screening tests were done 
within 4 days of Cycle 1 Day 1. 
PSA evaluation for Cycle 3 Day 1, Cycle 4 Day 1, and Cycle 5 Day 1 should be collected no 
later than 1 week before each scheduled visit, eg, no later than Cycle 2 Day 21, Cycle 3 Day 
21, and Cycle 4 Day 21 respectively. This will allow availability of laboratory results for 
determination of PSA progression status by each scheduled visit day (eg, Cycle 3 Day 1, 
Cycle 4 Day 1, and Cycle 5 Day 1) so that active treatment can be dispensed without 
delaying to the next scheduled visit if PSA progression has been confirmed for participants 
on Placebo arm.
For all participants, at the time of unblinding, PSA data submitted to the central laboratory 
will no longer be blinded.

Disease assessment (CT or MRI, bone scans): Disease assessments will be performed at 
baseline (screening: scans obtained prior to signing informed consent as part of the patient’s 
standard of care may be allowed, provided the timing of the scans fall within the screening 
window), and at 16-week intervals thereafter.
Imaging studies will include a CT scan of the chest, abdomen, and pelvis, plus a bone scan. 
At Screening, there will be an additional CT of the brain to rule out the presence of CNS 
metastases. For new bone lesions detected on bone scans, a second imaging modality (eg, 
CT or MRI) will be required to confirm progression. 

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The same method of assessment and the same technique should be used at Screening and 
during follow-up. Intravenous (IV) contrast is required when not medically contraindicated. 
Participants who have a contraindication to IV contrast may have MRI exams of brain, 
abdomen, and pelvis performed in lieu of CTs and a non-contrast CT of the chest. Tumor 
evaluation by positron emission tomography (PET) scan or by ultrasound or by prostate-
specific membrane antigen (PSMA)-PET will not replace for standard chest, abdomen, and 
pelvis CT or MRI scans or bone scans as required by the study, but the CT portion of a 
PET/CT with sufficient quality which could meet the study requirement may be submitted in 
lieu of a dedicated CT. 
The radiographic disease progression (appearance of distant metastasis) will be determined 
by the investigator. Participants who discontinue treatment before documented disease 
progression should continue with disease assessments during Posttreatment Follow-up Phase 
every 16 weeks (±7 days) until disease progression.

Survival status, subsequent anticancer therapy, and SREs: These assessments will be 
performed during the Treatment and Posttreatment Follow-up Phase.
8.2.
Safety Assessments
Details regarding the IDMC are provided in Committees Structure in Appendix 2: Regulatory, 
Ethical, and Study Oversight Considerations.
Adverse events will be reported and followed by the investigator as specified in Section 8.3, 
Adverse Events and Serious Adverse Events and Appendix 3: Adverse Events: Definitions and 
Procedures for Recording, Evaluating, Follow-up, and Reporting.
Any clinically relevant changes occurring during the study must be recorded on the AE section 
of the eCRF.
Any clinically significant abnormalities persisting at the end of the study/early withdrawal will 
be followed by the investigator until resolution or until a clinically stable condition is reached. 
The study will include the following evaluations of safety and tolerability according to the time 
points provided in the Schedule of Activities (SoA).
8.2.1.
Physical Examination
The screening physical examination will include, at a minimum, the general appearance of the 
participant, height, weight, and examination of the skin, ears, nose, throat, lungs, heart, abdomen, 
extremities, musculoskeletal system, lymphatic system, and nervous system. The screening 
physical examination will also include a full review of medical/oncological history and a 
complete examination of all organ systems. Screening physical examination abnormalities will 
be recorded in the eCRF under medical history, and post-baseline physical examination 
abnormalities will be recorded in the eCRF as AEs. After screening, limited symptom directed 
physical examinations and weight assessment will be conducted as per the Schedule of Activities 
(SoA).

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8.2.2.
Vital Signs
Temperature, pulse/heart rate, respiratory rate, and Blood pressure (BP) will be assessed during 
screening. At all other visits specified in the Schedule of Activities (SoA), only BP will be 
measured.
Blood pressure and pulse/heart rate measurements should be preceded by at least 5 minutes of 
rest in a quiet setting without distractions (eg, television, cell phones).
8.2.3.
Electrocardiogram (ECG)
During the collection of ECGs, participants should be in a quiet setting without distractions (eg, 
television, cell phones). Participants should rest in a supine position for at least 5 minutes before 
ECG collection and should refrain from talking or moving arms or legs. If blood sampling or 
vital sign measurement is scheduled for the same time point as ECG recording, the procedures 
should be performed in the following order: ECG(s), vital signs, blood draw.
Standard 12-lead ECGs will be recorded at screening and as clinically indicated during study 
treatment. Clinically significant abnormalities noted at screening will be included in the 
medical/oncological history. Participants with ECG findings suspicious for a previously 
undiagnosed myocardial infarction will be evaluated and reassessed for eligibility.
8.2.4.
Clinical Safety Laboratory Assessments
Blood samples for serum chemistry and hematology will be collected. The investigator must 
review the laboratory results, document this review, and record any clinically relevant changes 
occurring during the study in the AE section of the eCRF. The laboratory reports must be filed 
with the source documents.
The following tests will be performed by the central laboratory:

Hematology Panel 
-hemoglobin
-white blood cell (WBC) count 
-platelet count

Serum Chemistry Panel 
-sodium
-potassium
-creatinine
-glucose (fasting)
-aspartate aminotransferase 
-alanine aminotransferase 
-bilirubin*

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- high density lipoprotein-cholesterol (HDL-C) (fasting)
- low density lipoprotein-cholesterol (LDL-C) (fasting)
- triglycerides (fasting)
*: direct and indirect (at screening only if Gilbert’s syndrome is suspected) and total bilirubin

Other Laboratory Tests
-Testosterone
-TSH
- total T3, free T4 (direct) and Total T4 if TSH is not within normal limit
Hepatitis B surface antigen (HBsAg) and anti-hepatitis C virus (HCV) antibody (at Screening 
only). Hepatitis B virus (HBV)-DNA and HCV-ribonucleic acid (RNA) tests may be performed 
to rule out active infection at Screening as needed per the Investigator’s discretion and approval 
from the sponsor.
In the event of additional safety monitoring, unscheduled laboratory assessments may be 
performed as required (and may be done locally when an immediate clinical decision needs to be 
made).
8.2.5.
ECOG Performance Status
The ECOG-PS scale will be used to grade changes in the participant’s daily living activities
(Appendix 5: ECOG-PS Score). The frequency of ECOG-PS assessment is provided in Schedule 
of Activities (SoA).
8.3.
Adverse Events and Serious Adverse Events
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of participants, 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.
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally acceptable representative) for the duration of the study.
For further details on AEs and serious adverse events (SAEs) (Definitions and Classifications; 
Attribution Definitions; Severity Criteria; Special Reporting Situations; Procedures) as well as 
product quality complaints (PQC), refer to Appendix 3: Adverse Events: Definitions and 
Procedures for Recording, Evaluating, Follow-up, and Reporting.

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8.3.1.
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information
All Adverse Events
All AEs and special reporting situations, whether serious or nonserious, will be reported from the 
time a signed and dated ICF is obtained up to 30 days after the last dose of study intervention. 
Serious adverse events, including those spontaneously reported to the investigator within 30 days 
after the last dose of study intervention, 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.
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 SAE Form, which must 
be completed and reviewed 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 transmitted electronically 
or by facsimile (fax).
8.3.2.
Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting AEs or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about AE
occurrence. 
8.3.3.
Follow-up of Adverse Events and Serious Adverse Events
Adverse events, including pregnancy, will be followed by the investigator as specified in 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up, 
and Reporting.
8.3.4.
Regulatory Reporting Requirements for Serious Adverse Events
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). 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. 
8.3.5.
Pregnancy
All initial reports of pregnancy in partners of male participants must be reported to the sponsor 
by the study-site personnel within 24 hours of their knowledge of the event using the appropriate 
pregnancy notification form. Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal 
death, stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs and must be 
reported using the SAE Form.

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Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required.
8.4.
Treatment of Overdose
Not applicable, as overdose for apalutamide has not been defined, and there is no specific 
antidote to apalutamide.
8.5.
Pharmacokinetics
Plasma samples will be used to evaluate the PK of apalutamide and its active metabolite N-
desmethyl apalutamide. Participant confidentiality will be maintained.
8.5.1.
Evaluations
Venous blood samples of approximately 2 mL will be collected for measurement of plasma
concentrations of apalutamide and N-desmethyl apalutamide at approximately the same time for 
each sampling time point specified in the Schedule of Activities (SoA).
The dates and times for the doses administered 1 day preceding and during the PK sample day,
and actual PK sampling dates and times must be recorded. Additional information about the 
collection, handling, and shipment of biological samples can be found in the Laboratory Manual. 
Collected samples must be stored under the specified and controlled conditions for the 
temperatures indicated in the laboratory manual.
8.5.2.
Analytical Procedures
Pharmacokinetics
Plasma will be analyzed to determine concentrations of apalutamide and N-desmethyl 
apalutamide using a validated, specific, and sensitive liquid chromatography-tandem mass 
spectrometry method by or under the supervision of the sponsor.
8.5.3.
Pharmacokinetic Parameters and Evaluations
Parameters
Based on the individual plasma concentration-time data, using the actual dose taken and the 
actual sampling times, PK parameters and exposure information of apalutamide and N-desmethyl 
apalutamide will be derived using population PK modelling. Details will be given in a separate 
population PK analysis plan and the results of the analysis will be presented in a separate report.
Exposure-Response Analysis
Exposure-response analysis between exposure and selective clinical endpoint will be explored if 
deemed necessary and with sufficient data.

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8.6.
Medical Resource Utilization and Health Economics
Medical resource utilization data, associated with medical encounters, will be collected in the 
eCRF by the Investigator and study-site personnel for all participants 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 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.
STATISTICAL CONSIDERATIONS
Statistical analysis will be done by the sponsor or under the authority of 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 (SAP).
9.1.
Sample Size Determination
Participants will be randomized in a 2:1 ratio to receive apalutamide or placebo. Participants
randomized to the placebo arm and without any evidence of distant metastasis (according to 
imaging result at Cycle 5 Day 1, as well as any other relevant unscheduled visit) will start 
receiving active therapy of apalutamide at the time they have documented PSA progression (per 
PCWG2) or after completion of 5 cycles of placebo plus ADT treatment (handling by the 
IWRS).
It is assumed that failure distribution of the primary endpoint TTPP follows an exponential 
distribution with a constant hazard rate. The pivotal ARN-509-003 (SPARTAN) study suggested 
that East Asian participants (and study participants as a whole) treated with ADT only will have 
a median TTPP of 3.7 months.4 It is estimated that approximately 75 participants will provide 
approximately 28 TTPP events at the time of the final analysis (approximately 5 months after 
last participant receiving first dose) which yields a power exceeding 95% for detecting an HR of 
0.11 (median TTPP of 3.7 months for the placebo arm vs 33.6 months for the apalutamide arm) 
at a 2-tailed level of significance of 0.05. With a 32-month accrual period and an additional 
5-months of follow-up, the study duration for the TTPP final analysis will be approximately 37
months.
9.2.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Intent-to-treat 
All eligible participants who are randomized into the study, with study drug assignments 

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(ITT) Population
designated according to initial randomization, regardless of whether participants receive study 
drug or receive a different drug from that to which they were randomized to will be included in 
the analyses of all efficacy and clinical benefit endpoints and participant characteristics
Pharmacokinetic
Population
All participants who receive at least 1 dose of study drug and have at least 1 available plasma 
concentration
Safety
All participants who receive at least 1 dose of study drug, with treatment assignments 
designated according to actual study treatment received will be the primary population for 
evaluating safety and treatment compliance and administration.
9.3.
Statistical Analyses
9.3.1.
Efficacy Analyses
All continuous variables will be summarized using number of participants (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 Population. Kaplan-Meier 
method and Cox model, including stratification factor at baseline, will be used to estimate the 
time-to-event variables and to obtain the HR along with the associated confidence intervals 
(CIs). Stratified log-rank test will be used as the primary analysis method to test the treatment 
effect for time-to-event variables. A participant without an event at the time of the analysis will 
be censored at the last known date the participant did not have a documented record of the 
corresponding event. Detailed censoring rules will be provided in the SAP. Response rate 
variable, ie, PSA response rate, will be evaluated using the Mantel-Haenszel test or the exact test 
if the frequencies are small. The stratification variable will be PSADT (>6 months vs ≤6 months) 
as documented in the IWRS.
The final analysis of TTPP will be performed at approximately 5 months after last participant 
receiving the first dose. TTPP will be tested using Stratified log-rank test, stratified by PSADT 
(>6 months vs ≤6 months), at a 2-tailed significance level of 0.05. The TTPP for control arm will 
be censored at the date of treatment switching for participants who switched treatment and had 
not PSA progressed at that time. For participants who received anticancer subsequent therapy 
before documented PSA progression, the TTPP will be censored at the last date of PSA 
assessment prior to the start of subsequent therapy. Kaplan-Meier method will be used to 
estimate the median TTPP, as well as the PSA progression-free rate at selected timepoints, and 
their 95% CIs. The estimation of HR and its 95% CI will be based on the stratified Cox 
proportional-hazard model. Non-stratified log-rank tests will also be provided as sensitivity 
analysis.
The analyses for exploratory time-to-event variables (MFS, OS, and time to symptomatic 
progression) will be performed descriptively, considering the early cross-over of control arm and 
the expected long medians for apalutamide arm suggested by study ARN-509-003 (SPARTAN), 
for participants who randomized to apalutamide arm.2
The MRU data may be used to conduct exploratory economic analyses separately.

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Criteria 
Not applicable.
9.3.2.
Safety Analyses
Participants 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
The verbatim terms used in the eCRF by investigators to identify AEs will be coded using the 
Medical Dictionary for Regulatory Activities, Version 21.0 or later. and will be graded according 
to the NCI-CTCAE, Version 4.03. Treatment-emergent AEs are AEs that occur or worsen on or 
after first dose of study drug through 30 days after the last dose of study drug. All reported 
intervention-emergent AEs will be included in the analysis. For each AE, the percentage of 
participants who experience at least 1 occurrence of the given event will be summarized by 
intervention group. In addition, comparisons between intervention groups will be provided if 
appropriate.
Treatment-emergent AEs will be summarized by system organ class, preferred term, toxicity 
grade, and relationship to study drug. Serious adverse events and deaths will also be 
summarized. Summaries, listings, datasets, or participant narratives may be provided, as 
appropriate, for those participants who die, who discontinue intervention due to an AE, or who 
experience a severe or a SAE.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Descriptive statistics will be 
calculated for each laboratory analyte at baseline and for observed values and changes from 
baseline at each scheduled time point. A listing of participants with any laboratory results outside 
the reference ranges will be provided. A listing of participants with any markedly abnormal 
laboratory results will also be provided. Normal ranges will be used to identify values that are 
outside the normal ranges and abnormal laboratory results will be graded according to the 
NCI-CTCAE Version 4.03. A shift summary of baseline grade by maximum post-baseline 
CTCAE grade will be presented. For each laboratory parameter, the baseline laboratory value 
will be defined as the last laboratory value collected on or prior to the date of the first dose of 
study drug. Participants who develop toxicities of Grade ≥3 will be listed.
Electrocardiogram
Electrocardiogram data will be summarized by ECG parameter at screening (baseline) only.
Vital Signs
Descriptive statistics of BP (systolic and diastolic) values and changes from baseline will be 
summarized at each scheduled time point. Descriptive statistics of other vital signs (body 

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temperature, heart rate, respiratory rate) at baseline will also be summarized. The percentage of 
participants with values beyond clinically important limits will be summarized.
Physical Examination
Abnormal findings in physical examination will be recorded and summarized as AEs. Weight 
will be summarized.
9.3.3.
Other Analyses
Pharmacokinetic Analyses 
All plasma concentrations below the lowest quantifiable concentration or missing data will be 
labeled as such in the concentration data presentations or SAS dataset. Concentrations below the 
lower quantifiable concentration will be treated as zero in the summary statistics. Participants
will be excluded from the PK analysis if their data do not allow for accurate assessment of the 
PK (eg, incomplete administration of the study drug; missing information of dosing and 
sampling times). All participants and samples excluded from the analysis will be clearly 
documented in the Clinical Study Report.
Descriptive statistics including arithmetic mean, SD, geometric mean, coefficient of variation, 
median, minimum, and maximum will be used to summarize plasma apalutamide and 
N-desmethyl apalutamide concentrations at each sampling time point. 
Mean plasma apalutamide and N-desmethyl apalutamide concentration-time profile will be 
plotted after the first dose of study intervention. And individual plasma concentration-time 
profile may also be plotted.
Population PK analysis of plasma concentration-time data of apalutamide and N-desmethyl
apalutamide will be performed using nonlinear mixed effects modeling. Details will be given in a 
population PK analysis plan and the results of the analysis will be presented in a separate report.
Exposure-Response Analyses
Exposure-response analysis between exposure and selective clinical endpoint (eg, incidence of 
rash) will be explored if deemed necessary and with sufficient data.
9.4.
Interim Analysis
No interim analysis is planned for this study.
9.4.1.
Independent Data Monitoring Committee 
An IDMC will be established as noted in Committees Structure in Appendix 2: Regulatory, 
Ethical, and Study Oversight Considerations. The IDMC will be commissioned to review the 
efficacy and safety data at the final analysis. The IDMC will consist of at least 1 medical 
oncologist or urologist or both and at least 1 statistician. The IDMC’s responsibilities, 
authorities, and procedures will be documented in the IDMC charter.

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10.
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1.
Appendix 1: Abbreviations 
ADT
androgen deprivation therapy
AEs
adverse events
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AR
androgen receptor
AST
aspartate aminotransferase
AUC
area uder the plasma concentration
BICR
blinded independent central review
BP
blood pressure
BSA
body surface area
Cis
confidence intervals
CNS
central nervous system
CRF
case report form(s) (electronic as appropriate for this study)
CRPC
Castration-resistant prostate cancer
CT
computed tomography
ECG
electrocardiogram
ECOG-PS
Eastern Cooperative Oncology Group – performance status
eDC
electronic data capture
EoT
end-of-treatment
FACT-G
Functional Assessment Cancer Therapy-General
FACT-P
Functional Assessment of Cancer Therapy-Prostate
GCP
Good Clinical Practice
GnRHa
gonadotropin releasing hormone analog
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HDL-C
high density lipoprotein-cholesterol
HBV
hepatitis B virus
HR
hazard ratio
IB
investigator’s brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IDMC
independent data monitoring committee
IRB
Institutional Review Board
IWRS
interactive web response system
LDL-C
low density lipoprotein-cholesterol
MedDRA
Medical Dictionary for Regulatory Activities
MFS
metastasis-free survival
MSKCC
Memorial Sloan-Kettering Cancer Center
MRI
magnetic resonance imaging
MRU
medical resource utilization
NCI-CTCAE
National Cancer Institute-Common Terminology Criteria for Adverse Events
NM-CRPC
Non-Metastatic Castration-Resistant Prostate Cancer
OS
overall survival
PAC
post approval commitment
PC
prostate cancer
PCWG2
Prostate Cancer Working Group 2
PFS
progression-free survival
PFS2
progression-free survival with the first subsequent therapy
PK
pharmacokinetic(s)
PQC
Product Quality Complaint
PSA
prostate-specific antigen
PSADT
PSA doubling time

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SAP
statistical analysis plan
SD
standard deviation
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SoA
schedule of activities
SRE
skeletal-related events
SUSAR
TEAE
suspected unexpected serious adverse reaction
Treatment-emergent adverse event
TSH
thyroid stimulating hormone
TTM
time to metastasis
TTPP
time to prostate-specific antigen progression
TURP
transurethral resection of the prostate
ULN
upper limit of normal
VAS
visual analog scale
Versus
vs
Definitions of Terms
Electronic source 
system
Contains data traditionally maintained in a hospital or clinic record to document medical 
care or data recorded in a eCRF as determined by the protocol. Data in this system may be 
considered source documentation.

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10.2.
Appendix 2: Regulatory, Ethical, and Study Oversight Considerations
REGULATORY AND ETHICAL CONSIDERATIONS
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current International Council for Harmonisation (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 participants. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study participants are protected, consistent with the principles that originated in the Declaration 
of Helsinki, and that the study data are credible.
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 participants, 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) involve only logistic or administrative aspects of the study, the 
IEC/IRB (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 in 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.
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.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study intervention
to the study site:

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
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, participant 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 
participant:

Completed investigator financial disclosure forms from all subinvestigators, if applicable

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
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 participants)

Investigator's Brochure (or equivalent information) and amendments/addenda

Sponsor-approved participant recruiting materials

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
Information on compensation for study-related injuries or payment to participants 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 participants

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 participants, data or study conduct, unless required locally), the ICF, applicable 
recruiting materials, and participant 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 participants, data or study conduct)

Revision(s) to ICF and any other written materials to be provided to participants

If applicable, new or revised participant recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to participants 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 AEs that are serious, unlisted/unexpected, and associated with the study 
intervention

New information that may adversely affect the safety of the participants or the conduct of 
the study

Deviations from or changes to the protocol to eliminate immediate hazards to the 
participants

Report of deaths of participants 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 participants, data or study conduct), the amendment and applicable ICF 

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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).
Other Ethical Considerations
For study-specific ethical design considerations, refer to Section 4.2.1.
FINANCIAL DISCLOSURE
If applicable, investigators and subinvestigators will provide the sponsor with sufficient, accurate 
financial information in accordance with local regulations to allow the sponsor to submit 
complete and accurate financial certification or disclosure statements to the appropriate 
regulatory authorities. Investigators are responsible for providing information on financial 
interests during the course of the study and for 1 year after completion of the study.
Refer to Required Prestudy Documentation (above) for details on financial disclosure.
INFORMED CONSENT 
Each participant (or a legally acceptable representative) 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 reviewing IEC/IRB and be in a language that the 
participant 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 participants or their legally acceptable representatives the 
aims, methods, reasonably anticipated benefits, and potential hazards of the study, and any 
discomfort participation in the study may entail. Participants 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 participant will 
receive for the treatment of his disease. Participants 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 participant 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 
participant, to the extent permitted by the applicable law(s) or regulations. By signing the ICF 
the participant or legally acceptable representative is authorizing such access, which includes 

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permission to obtain information about his survival status. It also denotes that the participant 
agrees to allow his study physician to recontact the participant for the purpose of obtaining 
consent for additional safety evaluations, and subsequent disease-related treatments, if needed.
The participant or legally acceptable representative 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 either the participant's or his legally 
acceptable representative's personally dated signature. After having obtained the consent, a copy 
of the ICF must be given to the participant.
If the participant or legally acceptable representative is unable to read or write, an impartial 
witness should be present for the entire informed consent process (which includes reading and 
explaining all written information) and should personally date and sign the ICF after the oral 
consent of the participant or legally acceptable representative is obtained.
When prior consent of the participant is not possible and the participant's legally acceptable 
representative is not available, 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 participant and to ensure compliance with applicable regulatory requirements. The 
participant or legally acceptable representative must be informed about the study as soon as 
possible and give consent to continue.
DATA PROTECTION
Privacy of Personal Data
The collection and processing of personal data from participants 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 participants confidential.
The informed consent obtained from the participant (or his legally acceptable representative) 
includes explicit consent for the processing of personal data and for the investigator/institution to 
allow direct access to his original medical 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 participant 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.

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Exploratory PK research is not conducted under standards appropriate for the return of data to 
participants. 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 
participants 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.
COMMITTEES STRUCTURE
Independent Data Monitoring Committee
An IDMC will be established to review the efficacy and safety data at the final analysis. This 
committee will consist of at least 1 medical expert in the relevant therapeutic area and at least 1
statistician; committee membership responsibilities, authorities, and procedures will be 
documented in its charter.
PUBLICATION POLICY/DISSEMINATION OF CLINICAL STUDY DATA
All information, including but not limited to information regarding 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 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 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 data from all study sites that participated in the study as per protocol. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator for the study. Results of exploratory
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 participant 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 (ICMJE) guidelines, the sponsor shall have the right to publish such primary 

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(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 18 months after the study 
end date, 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 ICMJE Recommendations for the Conduct, Reporting, Editing and 
Publication of Scholarly Work in Medical Journals, which state that the named authors must 
have made a significant contribution to the conception or design of the work; or the acquisition, 
analysis, or interpretation of the data for the work; and drafted the work or revised it critically for 
important intellectual content; and given final approval of the version to be published; and 
agreed to be accountable for all aspects of the work in ensuring that questions related to the 
accuracy or integrity of any part of the work are appropriately investigated and resolved.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as 
required by law.
DATA QUALITY ASSURANCE
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 eCRF 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.

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CASE REPORT FORM COMPLETION
Case report forms are prepared and provided by the sponsor for each participant in electronic 
format. All data relating to the study must be recorded in 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.
The study data will be transcribed by study-site personnel from the source documents onto an 
electronic eCRF, if applicable. Study-specific data will be transmitted in a secure manner to the 
sponsor.
Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any 
such worksheets will become part of the participant's source documents. Data must be entered 
into eCRF in English. The eCRF must be completed as soon as possible after a participant visit 
and the forms should be available for review at the next scheduled monitoring visit.
All participative measurements (eg, pain scale information or other questionnaires) will be 
completed by the same individual who made the initial baseline determinations whenever 
possible.
If necessary, queries will be generated in the eDC tool. If corrections to a eCRF are needed after 
the initial entry into the eCRF, this can be done in either of the following 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 investigator and 
study-site personnel.
SOURCE DOCUMENTS
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: 
participant 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 AEs and follow-up of AEs; concomitant medication; intervention
receipt/dispensing/return records; study intervention administration information; and date of 
study completion and reason for early discontinuation of study intervention 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).
The following data will be recorded directly into the eCRF and will be considered source data: 

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
Race

BP and pulse/heart rate 

Height and weight 

Details of physical examination
The minimum source documentation requirements for Section 5.1, Inclusion Criteria and 
Section 5.2, Exclusion Criteria that specify a need for documented medical history are as 
follows:

Referral letter from treating physician or

Complete history of medical notes at the site

Discharge summaries.
Inclusion and exclusion criteria not requiring documented medical history must be verified at a 
minimum by participant interview or other protocol required assessment (eg, physical 
examination, laboratory assessment) and documented in the source documents.
An eSource 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 eSource is utilized, references made to the eCRF in the protocol include 
the eSource system but information collected through eSource may not be limited to that found 
in the eCRF.
MONITORING
The sponsor will use a combination of monitoring techniques central, remote, or on-site 
monitoring to monitor this study.
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 the data entered into the eCRF with the source documents 
(eg, hospital/clinic/physician’s office medical records). 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 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 

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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.
Central monitoring will take place for data identified by the sponsor as requiring central review.
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. Participant 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 or she has 
been contacted by a regulatory agency concerning an upcoming inspection.
RECORD RETENTION
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRF
and all source documents that support the data collected from each participant, 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 
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.

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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.
STUDY AND SITE CLOSURE
Study Termination
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.
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 participants by the investigator

Discontinuation of further study intervention development

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10.3.
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
ADVERSE EVENT DEFINITIONS AND CLASSIFICATIONS
Adverse Event
An AE is any untoward medical occurrence in a clinical study participant administered a 
medicinal (investigational or non-investigational) product. An AE does not necessarily have a 
causal relationship with the intervention. 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 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 All AEs under 
Section 8.3.1, Time Period and Frequency for Collecting Adverse Events and Serious Adverse 
Events Information, for time of last AE recording).
Serious Adverse Event
A SAE based on ICH and EU Guidelines on Pharmacovigilance for Medicinal Products for 
Human Use is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening
(The participant 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

Results in persistent or significant disability/incapacity

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 
participant or may require intervention to prevent 1 of the other outcomes listed in the definition 
above. These should usually be considered serious.

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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 ADT (GnRHa choice 
based on investigator’s decision), the expectedness of an AE will be determined by whether or 
not it is listed in the specific GnRHa package insert.
Adverse Event Associated With the Use of the Intervention
An AE is considered associated with the use of the intervention if the attribution is possible, 
probable, or very likely by the definitions listed below (see Attribution Definitions).
ATTRIBUTION DEFINITIONS
Not Related
An AE that is not related to the use of the intervention.
Doubtful
An AE for which an alternative explanation is more likely, eg, concomitant treatment(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 intervention. An alternative explanation, 
eg, concomitant treatment(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 intervention. The relationship in time is suggestive 
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant 
treatment(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 treatment(s), concomitant disease(s). The relationship in 
time is very suggestive (eg, it is confirmed by dechallenge and rechallenge).
SEVERITY CRITERIA 
The severity assessment for an AE or SAE should be completed using NCI-CTCAE Version 
4.03. Any AE or SAE not listed in NCI-CTCAE Version 4.03 will be graded according to 
investigator clinical judgment by 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.

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Grade 3 (Severe): Extreme distress, causing significant impairment of functioning or 
incapacitation. Prevents normal everyday activities.
Grade 4: Life-threatening or disabling AE
Grade 5: Death related to the AE.
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the participant (eg, laboratory abnormalities).
SPECIAL REPORTING SITUATIONS
Safety events of interest on a sponsor study intervention in an interventional study that may 
require expedited reporting or safety evaluation include, but are not limited to:

Overdose of a sponsor study intervention

Suspected abuse/misuse of a sponsor study intervention

Accidental or occupational exposure to a sponsor study intervention

Any failure of expected pharmacologic action (ie, lack of effect) of a sponsor study 
intervention

Unexpected therapeutic or clinical benefit from use of a sponsor study intervention

Medication error involving a sponsor product (with or without participant/patient exposure 
to the sponsor study intervention, eg, name confusion)

Exposure to a sponsor study intervention from breastfeeding
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.
PROCEDURES
All Adverse Events
All AEs, regardless of seriousness, severity, or presumed relationship to study intervention, 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.
For all studies with an outpatient phase, including open-label studies, the participant 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: 

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
Study number

Statement, in the local language(s), that the participant 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

Participant number

Any other information that is required to do an emergency breaking of the blind.
Serious Adverse Events
All SAE that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the participant's participation in the study, must be followed until any of the 
following occurs:

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 intervention or to factors unrelated 
to study conduct

It becomes unlikely that any additional information can be obtained (participant 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 a SAE. 
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during the 
course of a participant's participation in a study must be reported as a SAE, except 
hospitalizations for the following:

Hospitalizations not intended to treat an acute illness or AE (eg, social reasons such as 
pending placement in long-term care facility)

Surgery or procedure planned before entry into the study (must be documented in the
eCRF). Note: Hospitalizations that were planned before the signing of the ICF, and where 
the underlying condition for which the hospitalization was planned has not worsened, will 
not be considered SAEs. Any AE that results in a prolongation of the originally planned 
hospitalization is to be reported as a new SAE.

For convenience the investigator may choose to hospitalize the participant for the duration 
of the intervention period.
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 SAE definition (refer to AE Definitions and Classifications in Appendix 3: Adverse 
Events: Definitions and Procedures for Recording, Evaluating, Follow-up, and Reporting).

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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.
PRODUCT QUALITY COMPLAINT HANDLING
A PQC is defined as any suspicion of a product defect related to manufacturing, labeling, or 
packaging, ie, any dissatisfaction relative to the identity, quality, durability, or reliability of a 
product, including its labeling or package integrity. A PQC may have an impact on the safety and 
efficacy of the product. Timely, accurate, and complete reporting and analysis of PQC 
information from studies are crucial for the protection of participants, 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.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after 
being made aware of the event.
If the defect is combined with a SAE, the study-site personnel must report the PQC to the 
sponsor according to the SAE reporting timelines (refer to Section 8.3.1, Time Period and 
Frequency for Collecting Adverse Event and Serious Adverse Event Information). A sample of 
the suspected product should be maintained for further investigation if requested by the sponsor.
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.

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10.4.
Appendix 4: Liver Safety: Suggested Actions and Follow-up Assessments
Guideline Algorithm for Monitoring, Assessment & Evaluation of Abnormal 
Liver Tests in Participants with no Underlying Liver Disease and normal 
baseline ALT, AST, Alkaline Phosphatase and Bilirubin
Although this algorithm is still applicable across all populations, it has been developed assuming normal liver 
function at baseline. For populations with preexisting liver disease and/or AT increases at baseline, product teams 
are strongly encouraged to consult with Hepatic Safety Group for further guidance particularly for discontinuation 
criteria.

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white blood count (WBC) and eosinophil count platelet count, international normalized ratio 
(INR), and total protein and albumin (compute globulin fraction) should also be 
documented. If INR is abnormal, prothrombin time (PT), partial thromboplastin time (PTT) 
should be obtained and these values should be followed until normal, along with 
documentation of whether parenteral vitamin K was given along with the effect of such 
treatment on INR.
4.
If initial LTs and ultrasound do not suggest Gilbert’s syndrome, biliary tract disease or 
obstruction, viral hepatitis serology should be obtained including anti-hepatitis A virus 
immunoglobin M (anti-HAV IgM), anti-HAV total, hepatitis B surface antigen (HBsAg), 
anti-HBs, anti-HB core total, anti-HB core IgM, anti-hepatitis C virus (anti-HCV), anti-
hepatitis E virus IgM (anti-HEV IgM) (even if has not traveled to an endemic area for 
hepatitis E), Epstein-Barr virus (EBV) and Cytomegalovirus (CMV) screen.

If patient is immunosuppressed, test for HCV-RNA and HEV-RNA.

If HBsAg or anti-HB core IgM or anti-HB core IgG positive, also get HBV-DNA to 
detect active HepB, especially in patients who are immunosuppressed.

If all other hepatitis B serologic tests are negative and anti-HBc total is the only positive 
test, HBV-DNA should be obtained to detect reactivation of hepatitis B.
5.
Assuming that the history, physical, and initial imaging and laboratory has not revealed a 
cause of elevated LTs, screen for other causes of liver disease including: Total protein and 
albumin (estimate globulin fraction and obtain quantitative immunoglobulins if elevated), 
antinuclear antibody (ANA), anti-liver kidney microsomal antibody type 1 (anti-LKM1), 
anti-liver-kidney microsomal antibodies (anti-LKM antibodies), anti-smooth muscle 
antibodies (ASMA), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). If 
the pattern of laboratory abnormalities is not hepatocellular, but cholestatic or a mixed 
pattern (see definitions in table above), then gamma-glutamyl transferase (GGT), anti-
mitochondrial antibody (AMA) and anti-neutrophil cytoplasmic antibody (pANCA) should 
also be tested. If there is an indication by history or elevated baseline LTs that there may be 
an underlying chronic liver disease possibly exacerbated by exposure to the study 
intervention in the clinical trial or making the participant more susceptible to DILI, test 
iron/Total iron binding capacity (TIBC) and ferritin (hemochromatosis), and alpha-1-
antitrypsin level. If patient is <50 years of age, ceruloplasmin should also be tested to screen 
for Wilson’s disease. If patient is sick enough to be hospitalized and is under age 50, a slit 
lamp examination to detect Kayser-Fleischer rings and a 24-hour urine collection for copper 
should be measured. Consider serum ethanol and/or acetaminophen level and urine drug 
screen as clinically appropriate.
6.
A liver biopsy should be considered if autoimmune hepatitis remains a competing etiology 
and if immunosuppressive therapy is contemplated.
A liver biopsy may be considered:

if there is unrelenting rise in liver biochemistries or signs of worsening liver function 
despite stopping the suspected offending agent.

if peak ALT level has not fallen by >50% at 30-60 days after onset in cases of 
hepatocellular DILI, or if peak Alk P has not fallen by >50% at 180 days in cases of 
cholestatic DILI despite stopping the suspected offending agent.

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
in cases of DILI where continued use or re-exposure to the implicated agent is expected.

if liver biochemistry abnormalities persist beyond 180 days to evaluate for the presence 
of chronic liver diseases and chronic DILI.
7.
If pertinent, copies of hospital discharge summary, radiology, pathology and autopsy reports 
should be obtained.
Abbreviations
AlkP
alkaline phosphatase
ALT
alanine aminotransferase
AMA
anti-mitochondrial antibody
ANA
antinuclear antibody
Anti-LKM1
anti-liver kidney microsomal antibody type 1
ASMA
anti-smooth muscle antibodies
AST
aspartate aminotransferase
BMI
body mass index
CBC 
complete blood count
CHF
congestive heart failure
CMV
cytomegalovirus 
CRP
C-reactive protein
CT
computerized tomography
DM
diabetes mellitus
DNA
deoxyribonucleic acid
EBV
Epstein-Barr virus
ERCP
endoscopic retrograde cholangiopancreatography
ESR
erythrocyte sedimentation rate
EOI
end of intervention
GGT
gamma-glutamyltransferase
HAV 
hepatitis A virus 
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HepB
hepatitis B virus
HEV
hepatitis E virus
IgM
immunoglobin M
INR
international normalized ratio
LT/LFT
liver tests/liver function tests
MRI
magnetic resonance imaging
MRCP
magnetic resonance cholaniopancreatography
NSAID
non-steroidal anti-inflammatory drugs
OTC
over the counter
PT
prothrombin time
PTT
partial thromboplastin time
RNA
ribonucleic acid
Tbili
total bilirubin
TIBC
total iron binding capacity
ULN
upper limit of normal
WBC
white blood count

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10.5.
Appendix 5: ECOG-PS Score
ECOG Grade Scale (with Karnofsky conversion)
0
Fully active, able to carry on all pre-disease 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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10.6.
Appendix 6: Protocol Amendment History
Amendment 1 (7 June 2019) 
Overall Rationale for the Amendment: The overall reason for the amendment is to extend the time 
cutoff for the earliest prostate-specific antigen (PSA) values used in the calculation of PSA doubling time 
(PSADT) to allow patients who may have had one or more of the required PSAs collected outside the 
previously defined 6 months window who are otherwise eligible. Other changes include clarification of
the way of ADT provided and used, and the window for planned visit and imaging. 
Section Number
and Name
Description of Change
Brief Rationale
1.1 Synopsis: 
OBJECTIVES AND 
ENDPOINTS;
3 OBJECTIVES AND 
ENDPOINTS: footnote 
“a”
Specified that subjects randomized to 
placebo arm will be crossed over to 
receive apalutamide treatment either 
after completion of a maximum 5 cycles 
of placebo treatment or at the time of 
having documented PSA progression, 
whichever comes earlier.
To clarify the expected cross-over time 
for subjects of placebo arm in 
consistency with other sections of the 
protocol.
1.1 Synopsis: OVERALL 
DESIGN;
4.1 Overall design
Specified that subjects will be stratified 
by PSA doubling time (PSADT) (>6 
months vs ≤6 months).
In original protocol, patients will be 
stratified according to PSADT (>6 
months vs ≤6 months) at 
randomization. However, this 
information was missed in a few 
places. Added specification in 
consistency with other sections of the 
protocol.
1.1 Synopsis: 
INTERVENTION 
GROUPS AND 
DURATION; 6.1 Study 
interventions administered 
Table: Changed “30-ct, 100 cc” to “120-
ct, 160 cc” 
To clarify and correct information
1.1 Synopsis: 
INTERVENTION 
GROUPS AND 
DURATION;
2.2.1 Androgen 
Deprivation Therapy;
6.1 Study interventions 
administered
Added specification that ADT will be 
provided by sponsor and clarity ADT 
with GnRHa will be continued for all 
patients who have not been surgically 
castrated in consistency with other 
sections of the protocol.
To specify the way of ADT provided 
and used.
1.1 Synopsis: EFFICACY 
EVALUATIONS;
4.1 Overall design
Added specification that PSA 
evaluations will be performed by a 
central lab “during the treatment phase”.
For patients participating the optional 
prescreening phase, PSA evaluations 
will be performed by the local 
laboratories. Added the specification 
that PSA will be performed by a central 
lab during the treatment phase to avoid 
confusion.
1.1 Synopsis: EFFICACY 
EVALUATIONS;
1.3 Schedule of Activities 
(SoA): footnote 9;
8.1 Efficacy Assessments
Added “intravenous (IV) contrast is 
required when not medically 
contraindicated” for disease assessment.
To clarify and add requirements for 
disease assessment
1.3 Schedule of Activities 
(SoA)
Updated information for 
apalutamide/matched placebo 
administration
In the original protocol, only daily 
dosage was instructed in the SoA. 
Updated the table to reflect the study 
drug dispense.
1.3 Schedule of Activities 
Added specification that during the 
In the original protocol, window 

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Section Number
and Name
Description of Change
Brief Rationale
(SoA)
8 STUDY 
ASSESSMENTS AND 
PROCEDURES: 
Overview
Treatment Phase, study visits may occur 
within ± 3-day window. 
Added specification that imaging may 
occur up to 8 days before cycles 
requiring images and that unscheduled 
assessments can occur at any time as 
needed if signs of disease progression are 
observed.
allowed for planned visit and imaging 
was not specified. This amendment 
added the information that a ±3-day 
window is allowed for planned visit 
during the treatment phase and planned 
imaging may occur up to 8 days before 
cycles requiring imaging.
1.3 Schedule of Activities 
(SoA)
Added time window allowed for PK 
sample collection: predose within 4.8h 
prior to dosing; 2h postdose (± 10 
minutes).
To add the time window allowed in 
consistency with SPARTAN and 
Protocol 56021927PCR1013.
1.3 Schedule of Activities 
(SoA)
Added specification that the SAE 
reporting would be limited to SAEs 
related to the PSA blood draws during 
the prescreening phase.
To clarify the SAE collection during 
the optional prescreening phase
4.4 End of study definition 
Deleted “in all participating countries”.
The study is only in China.
6.2 
Preparation/Handling/Stor
age/Accountability
The temperature range for storage of 
study intervention was changed from 
“20°C to 25°C” to “15°C to 30°C”
Information correction
6.3 Procedures for 
Randomization
Updated the window allowed for PSA 
values for PSADT calculation from 
within 6 months prior to randomization 
to within 24 months prior to 
randomization and specified that the first 
and last PSA values used in the 
calculation must be separated by at least 
8 weeks.
The window of requiring PSA values 
collected within 6 months prior to 
randomization for calculation of the 
PSADT has the unintended 
consequence of excluding patients who 
are otherwise eligible, but who may 
have had one or more of the required 
PSAs collected outside the 6 months 
window. Therefore, this amendment 
will incorporate a cutoff that allows 
inclusion of PSA values collected 
within 24 months prior to the subject’s 
randomization. 
6.6 Dose Modification
Clarified that for toxicities other than 
rash, “The investigator’s rationale to re-
escalate treatment must be discussed 
with and approved by the sponsor’s 
medical monitor on an individual basis 
prior to implementation.”
Dose re-escalation for rash is allowed 
for apalutamide/placebo at the 
discretion of the investigator. This 
revision is to clarify that for toxicities 
other than rash, dose re-escalation is 
generally not allowed unless being 
discussed with and approved by the 
Sponsor.
8.2.1Physical Examination
Added that weight assessment will be 
conducted as part of physical 
examination after screening.
Weight decreased has been reported in 
patients receiving apalutamide 
treatment. Thus, added weight 
assessment to have patients’ weight 
monitored.
8.2.4 Clinical Safety 
Laboratory Assessment
Added specification that unscheduled 
laboratory assessment may be performed 
locally when an immediate clinical 
decision needs to be made.
Per investigator’s feedback, this is to 
add specification that local lab can be 
used due to urgent safety consideration.
Throughout the protocol
Minor grammatical, formatting, or 
spelling changes were made.
Minor errors were noted

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Amendment 2 (20 February 2020) 
Overall Rationale for the Amendment: The overall reason for the amendment is to 1) clarify 
and edit the exclusion criteria and SPARTAN study result in Study-Specific Ethical Design 
Considerations, 2) and clarify specific information including efficacy evaluations, androgen 
deprivation therapy and Clinical Safety Laboratory Assessments.
Section Number
and Name
Description of Change
Brief Rationale
1.1 Synopsis: EFFICACY 
EVALUATIONS
1.3 Schedule of Activities 
(SoA)
8.1 Efficacy Assessments
Added statements for efficacy 
evaluations: “scans obtained prior to 
signing informed consent as part of the 
patient’s standard of care may be 
allowed, provided the timing of the scans 
fall within the screening window”; “The 
same method of assessment and the same 
technique should be used at Screening 
and during follow-up.” And “Tumor 
evaluation by positron emission 
tomography (PET) scan or by ultrasound 
or by prostate-specific membrane antigen 
(PSMA)-PET will not replace for 
standard chest, abdomen, and pelvis CT 
or MRI scans or bone scans as required 
by the study, but the CT portion of a 
PET/CT with sufficient quality which 
could meet the study requirement may be 
submitted in lieu of a dedicated CT.” 
To clarify the scan collection 
requirement. 
1.1 Synopsis: OVERALL 
DESIGN
1.3 Schedule of Activities 
(SoA)-Footnote 3
4.1 Overall Design
7.1 Discontinuation of 
Study Intervention

Specified the study visit window for 
planned Posttreatment Follow-up
visit after documented disease 
progression (distant metastases) to be 
±7 days.

Updated the wordings related to
Posttreatment Follow-up phase.

In the original protocol, window 
allowed for planned Posttreatment 
Follow-up visit after documented 
disease progression (distant 
metastases) was not specified. 

Clarify the Posttreatment 
Follow-up process for participants 
entering Posttreatment Follow-up 
phase with or without evidence of 
distant metastasis.
1.3 Schedule of Activities 
(SoA)
Added comments for physical 
examination “The screening physical 
examination will also include a full 
review of medical or oncological history 
and a complete examination of all organ 
systems. Limited symptom directed 
physical examinations and weight 
assessment will be conducted at other 
visits.” and vital signs “Body 
temperature, pulse/heart rate, respiratory 
rate, and BP are measured at the 
screening. Only BP is recorded at other 
visits.”. 
To clarify the different requirements 
for physical examination and vital 
signs at screening visit and other visits. 
1.3 Schedule of Activities 
(SoA)-Footnote 2
8 STUDY 
ASSESSMENTS AND 
PROCEDURES
Specified the study visit window to be -3 
~ +2-day
Update the study visit window to avoid 
missing dose. 
2.2.1 Androgen 
Specified “Androgen Deprivation 
To further clarify androgen deprivation 

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Approved, Date: 20 June 2022
Section Number
and Name
Description of Change
Brief Rationale
Deprivation Therapy
Therapy with continuous GnRHa will be 
continued for all patients who have not 
been surgically castrated.”
therapy that either continuous GnRHa 
or surgically castration is acceptable. 
4.2.1 Study-Specific 
Ethical Design 
Considerations
Previous statement “Further, on the 
SPARTAN study only 1 placebo subject 
(out of 401 enrolled) was found to have 
metastatic disease at the first post-
baseline scan without prior to PSA 
progression.” was revised to be “Further, 
on the SPARTAN study about 6.2% of 
the placebo participants were found to 
have metastatic disease at the first post-
baseline scan without prior PSA 
progression and only 2-3 participants in 
this study are expected to have the same 
situation given one third of 111 Chinese
participants (about 37 subjects) are to be 
randomly assigned to placebo arm.”
To correct the information.
5.2 Exclusion Criteria No 
15
Corrected exclusion criteria 15 from “For 
men who are sexually active with women 
of child bearing potential” to “Men who 
are sexually active with women of 
childbearing potential except”
To clarify the typo in exclusion criteria 
15
5.2 Exclusion Criteria No 
13
Exclusion criteria 13 was divided into 
two: 13 and 18. 
Error correction
1.1 Synopsis: OVERALL 
DESIGN
4.1 Overall Design
6.3 Measures to Minimize 
Bias: Randomization and 
Blinding: Blinding
Revised “The PSA data collected at 
baseline and post-baseline obtained 
within the first 5 cycles, for individual 
participant will be analyzed by the 
central laboratory to flag out documented 
PSA progression per PCWG2. The data 
will be integrated into the IWRS to 
trigger the cross-over.” to be “The 
central laboratory will analyze the 
individual PSA data, collected at 
baseline and post-baseline obtained 
within the first 5 cycles to flag out 
documented PSA progression per 
PCWG2 and the data will be entered into 
the IWRS to trigger the cross-over by an 
independent team not affiliated with the 
study team. The cross-over of control 
arm participants will be handled by 
IWRS to maintain the blinding of 
original treatment assignment of 
individual participant.”
To clarify the original text and specify 
that an independent team not affiliated 
with the study team will trigger the 
cross-over. 
6.6.1 Dose Modifications 
for Rash and Rash 
Management
Revised and corrected the information to 
be “Apalutamide/placebo can be held up 
to 28 days in the event of rash. If
treatment interruption for any AE grade 
is longer than 28 days, resumption of 
treatment may still be feasible. Please 
reach out to the sponsor to discuss 
Update and align the information at 
different location. 

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Approved, Date: 20 June 2022
Section Number
and Name
Description of Change
Brief Rationale
further management. Dose re-escalation 
for rash is allowed for apalutamide
/placebo at the discretion of the 
investigator.”
8.2.4 Clinical Safety 
Laboratory Assessments
Clarified “total T3, free T4 (direct) and 
Total T4 if TSH is not within normal 
limit” from “T3, T4 (direct) and Total T4 
if TSH is not within normal limit”.
To clarify the information. 
Throughout the protocol
Minor grammatical, formatting, or 
spelling changes were made.
Minor errors were noted

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11.
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