Conditions: Prostatic Neoplasms
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 108
Healthy volunteers: no

Brief summary:
Main Study: The purpose of main study is to assess if the combination of apalutamide and androgen deprivation therapy (ADT) in participants with high-risk localized prostate cancer improves the biochemical recurrence (BCR) free rate.

Sub-study: The purpose of the sub-study is to assess if the co administration of apalutamide and relugolix is able to maintain castrate levels of testosterone.

Detailed description:

Arms:
arm 1: In the main study, participants will receive apalutamide 240 milligram (mg) once daily orally along with ADT for 12 cycles (Each cycle is of 28 days). Participants who enrolled in the sub-study will receive apalutamide 240 mg once daily along with relugolix (a type of ADT) 120 mg once daily following a loading dose of 360 mg relugolix orally. Sub-study participants will be receiving relugolix up to Day 28 after which they will be transitioned into the main study from Cycle 2 Day 1 and will continue to receive conventional or oral ADT.

Interventions: intervention 1: Apalutamide intervention 2: ADT intervention 3: Relugolix
Intervention descriptions: intervention 1: Participants will receive apalutamide 240 mg (4 tablets of 60 mg each) oral tablets during the main study and sub-study. intervention 2: Participants will receive ADT intramuscular or subcutaneously during the main study. intervention 3: Participants will receive 120 mg of relugolix following a loading dose of 360 mg of (3 tablets of 120 mg each) relugolix during the sub-study.

Protocol document:
Prot_000.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved,  Date: 20 April 2021
Janssen Research & Development *
Clinical Protocol
A Multi-center, Open-label, Single-arm Phase 2 Study of the Adjuvant Treatment of 
Apalutamide and Androgen Deprivation Therapy (ADT) in Treatment-naïve Participants Who 
Have Undergone Radical Prostatectomy (RP) for Non-metastatic Prostate Cancer and Who Are 
at High Risk for Metastases
Protocol 56021927PCR2041; Phase 2
AMENDMENT 2
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; Janssen Biopharma Inc.; 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.
IND: 104676
Status:
Approved
Date:
20 April 2021
Prepared by:
Janssen Research & Development, LLC; Janssen Research & Development, a division 
of Janssen Pharmaceutica NV
EDMS number:
EDMS-ERI-203744111, 3.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company 
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient 
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or 
otherwise.
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CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved,  Date: 20 April 2021
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 2
20-Apr-2021
Amendment 1
12-Aug-2020
Original Protocol
14-May-2020
Amendment 2 (20-April-2021)
Overall Rationale for the Amendment: The main reason for the amendment is to add a sub-study to assess 
testosterone dynamics when relugolix is administered concurrently with apalutamide. Other clarifications 
to the main study have also been made.
Section number
and Name
Description of Change
Brief Rationale
1.1 Synopsis
The rationale for sub-study is added.
To add the details of sub-study.
1.1 Synopsis 
Overall Design;
1.2 Schema;
4.1 Overall Design 
of Main Study
5.1 Inclusion 
Criteria 3;
5 Study Population
6.1 Study 
Intervention 
Administered
The maximum duration from post radical 
prostatectomy (RP) to start of study intervention or 
enrollment in the study is updated from 60 days to 
between Day 29 and Day 90 post-RP.
Screening duration is changed from 60 to 90 days 
before administration of the study intervention.
The window for initiation of study intervention 
was updated as between Day 29 and Day 90 
post-RP.
To reflect the practices where 
patients may be seen later after 
surgery and to provide additional 
clarification in other sections due to 
updated eligibility criteria.
1.1 Synopsis 
Number of 
Participants
Following sentence was added: The sub-study 
consisting of 12 participants will be in addition to 
the 94 main ApaRP protocol participants and 
statistical analyses will be performed separately.
Upon completion of the sub-study, participants will 
be transitioned into the main study beginning at 
Cycle 2 Day 1.
To add the details of sub-study.
1.1 Synopsis 
Biomarker 
Evaluations;
1.3 Schedule of 
Events and footnote 
j;
4.1 Overall Design 
of Main Study
8.6 Biomarkers
RP tissue analysis results may be utilized in 
addition to the primary biopsy and sent to 
sponsor’s laboratory partner.
To clarify the wordings related to 
biomarker collection as in some 
cases RP tissue may be used.
1.2 Schema;
5.1 Inclusion 
Criteria 5
Definition of high-risk population is updated.
To clarify that high risk can be 
determined from RP pathology 
report in addition to biopsy 
as in some cases only RP tissue 
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may be available or may more 
accurately reflect the disease state.
1.3 Schedule of 
Events
Post-operative PSA evaluation at screening was 
separated from PSA evaluation for efficacy.
To separate screening evaluation 
from efficacy evaluation.
1.1 Synopsis 
Overall Design;
4.1 Overall Design 
of the Main Study
The evaluation standards for patients under 
androgen deprivation were added.
To meet current standards for 
patients under androgen 
deprivation.
5.1 Inclusion 
Criteria 4
Following words in bold were added: have 
recovered from RP procedure and have had no 
worsening in cardiac risk in the peri-operative 
period per the clinical judgment of the 
investigator.
To ensure reassessment of 
cardiovascular risk prior to 
reinitiating study intervention after 
surgery.
1.3 Schedule of 
Events footnote g
8.2.1 Physical 
examinations
Following sentence was added for focused physical 
examination: Any new complaints, symptoms 
reported by participants or adverse events noted by 
providers should guide the need and extent of 
physical examination.
To provide clarity on focused 
physical examination.
1.2 Schema;
4.1 Overall Design 
of Main Study
8 Study 
Assessments and 
Procedures
“Main study” was added to the sub-section 
heading.
It was clarified that blood volume mentioned is for 
main study.
To differentiate the main study 
from sub-study.
5.2 Exclusion 
Criteria 8
It was specified that malignancies considered cured 
for more than 24 months are allowed. 
To allow participants cured for 
more than 24 months to enroll in 
the study.
5.2 Exclusion 
Criteria 9
Duration of cardiac abnormalities prior to baseline 
changed from 6 months to 12 months.
To comply with the new guidance 
from other registrational studies for 
peri-operative use of apalutamide in 
clinical trials
8.6 Biomarkers
Following sentence was added: Biopsy tissue is 
required for risk scores (Prolaris) and is preferred 
for HRD testing
To clarify type of tissue required 
for biomarker collection.
10.13 Appendix 13
Description of sub-study protocol, including 
rationale, schema, endpoints, and schedule of 
activities was added.
Study testosterone dynamics of 
novel oral hormonal agent relugolix 
when administered concurrently 
with apalutamide.
10.14 Appendix 14
New Appendix with detailed information of 
sub-study pill diary was added.
To provide the details of the pill 
dairy required for the sub-study.
10.15 Appendix 15
Amendment summary table for Amendment 1 was 
moved to Appendix 15.
The older amendment is moved to 
the appendix.
References
New references were added.
To provide references for new text. 
Throughout protocol
Minor grammatical, spelling, and formatting
changes are made.
Minor errors were noted.
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TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 2
TABLE OF CONTENTS ............................................................................................................................... 4
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 7
1.
PROTOCOL SUMMARY ..................................................................................................................... 8
1.1.
Synopsis........................................................................................................................................... 8
1.2.
Schema .......................................................................................................................................... 11
1.3.
Schedule of Activities (SoA)........................................................................................................... 12
2.
INTRODUCTION................................................................................................................................ 15
2.1.
Study Rationale.............................................................................................................................. 15
2.2.
Background .................................................................................................................................... 16
2.3.
Benefit-Risk Assessment ............................................................................................................... 16
3.
OBJECTIVES AND ENDPOINTS ..................................................................................................... 16
4.
STUDY DESIGN ................................................................................................................................ 17
4.1.
Overall Design of the Main Study .................................................................................................. 17
4.2.
Scientific Rationale for Study Design............................................................................................. 18
4.2.1.
Participant Input Into Design ...................................................................................................... 19
4.2.2.
Study-Specific Ethical Design Considerations ........................................................................... 19
4.3.
Justification for Dose...................................................................................................................... 19
4.4.
End of Study Definition................................................................................................................... 19
5.
STUDY POPULATION ...................................................................................................................... 20
5.1.
Inclusion Criteria ............................................................................................................................ 20
5.2.
Exclusion Criteria ........................................................................................................................... 22
5.3.
Lifestyle Considerations................................................................................................................. 23
5.4.
Screening Failures ......................................................................................................................... 24
5.5.
Criteria for Temporary Delaying (Enrolment/Randomization/Administration of Study 
Intervention) (Not Applicable) ........................................................................................................ 24
6.
STUDY INTERVENTION................................................................................................................... 24
6.1.
Study Intervention Administered .................................................................................................... 24
6.2.
Preparation/Handling/Storage/Accountability ................................................................................ 25
6.3.
Measures to Minimize Bias: Randomization and Blinding (Not Applicable) .................................. 26
6.4.
Study Intervention Compliance...................................................................................................... 26
6.5.
Dose Modification........................................................................................................................... 26
6.6.
Continued Access to Study Intervention After the End of the Study (Not Applicable)................... 26
6.7.
Treatment of Overdose .................................................................................................................. 26
6.8.
Concomitant Therapy..................................................................................................................... 26
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ............................................................................................... 27
7.1.
Discontinuation of Study Intervention ............................................................................................ 27
7.1.1.
Rechallenge................................................................................................................................ 27
7.2.
Participant Discontinuation/Withdrawal From the Study................................................................ 27
7.2.1.
Withdrawal From the Use of Research Samples ....................................................................... 28
7.3.
Lost to Follow-up............................................................................................................................ 29
7.4.
National Disaster/Extra Ordinary Circumstances .......................................................................... 29
8.
STUDY ASSESSMENTS AND PROCEDURES ............................................................................... 29
8.1.
Efficacy Assessments .................................................................................................................... 30
8.2.
Safety Assessments....................................................................................................................... 30
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8.2.1.
Physical Examinations................................................................................................................ 31
8.2.2.
Vital Signs................................................................................................................................... 31
8.2.3.
Electrocardiograms..................................................................................................................... 31
8.2.4.
Clinical Safety Laboratory Assessments .................................................................................... 31
8.3.
Adverse Events and Serious Adverse Events ............................................................................... 31
8.3.1.
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event 
Information.................................................................................................................................. 32
8.3.2.
Method of Detecting Adverse Events and Serious Adverse Events .......................................... 32
8.3.3.
Follow-up of Adverse Events and Serious Adverse Events ....................................................... 32
8.3.4.
Regulatory Reporting Requirements for Serious Adverse Events ............................................. 33
8.3.5.
Pregnancy................................................................................................................................... 33
8.3.6.
Cardiovascular and Death Events .............................................................................................. 33
8.3.7.
Disease-Related Events and Disease-Related Outcomes not Qualifying as Adverse 
Events or Serious Adverse Events ............................................................................................. 33
8.3.8.
Adverse Events of Special Interest............................................................................................. 34
8.4.
Pharmacokinetics (Not Applicable) ................................................................................................ 34
8.5.
Genetics ......................................................................................................................................... 34
8.6.
Biomarkers ..................................................................................................................................... 34
8.7.
Immunogenicity Assessments (Not Applicable)............................................................................. 35
8.8.
Health Economics (Not Applicable) ............................................................................................... 35
9.
STATISTICAL CONSIDERATIONS.................................................................................................. 35
9.1.
Statistical Hypotheses.................................................................................................................... 35
9.2.
Sample Size Determination ........................................................................................................... 35
9.3.
Populations for Analysis Sets ........................................................................................................ 35
9.4.
Statistical Analyses ........................................................................................................................ 35
9.4.1.
General Considerations.............................................................................................................. 36
9.4.2.
Primary Endpoint ........................................................................................................................ 36
9.4.3.
Secondary Endpoint ................................................................................................................... 36
9.4.4.
Exploratory Endpoint .................................................................................................................. 36
9.4.5.
Safety Analyses .......................................................................................................................... 36
9.4.6.
Other Analyses ........................................................................................................................... 37
9.5.
Interim Analysis (Not Applicable) ................................................................................................... 37
10.
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................ 38
10.1.
Appendix 1: Abbreviations ............................................................................................................. 38
10.2.
Appendix 2: Clinical Laboratory Tests ........................................................................................... 40
10.3.
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations......................................... 41
10.3.1.
Regulatory and Ethical Considerations ...................................................................................... 41
10.3.2.
Financial Disclosure.................................................................................................................... 44
10.3.3.
Informed Consent Process ......................................................................................................... 44
10.3.4.
Data Protection ........................................................................................................................... 45
10.3.5.
Long-Term Retention of Samples for Additional Future Research ............................................ 46
10.3.6.
Committee Structure................................................................................................................... 46
10.3.7.
Publication Policy/Dissemination of Clinical Study Data ............................................................ 46
10.3.8.
Data Quality Assurance.............................................................................................................. 47
10.3.9.
Case Report Form Completion................................................................................................... 48
10.3.10.
Source Documents ..................................................................................................................... 48
10.3.11.
Monitoring ................................................................................................................................... 49
10.3.12.
On-site Audits ............................................................................................................................. 50
10.3.13.
Record Retention........................................................................................................................ 50
10.3.14.
Study and Site Start and Closure ............................................................................................... 51
10.4.
Appendix 4: Adverse Events, Serious Adverse Events, Product Quality Complaints, and 
Other Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up, 
and Reporting................................................................................................................................. 52
10.4.1.
Adverse Event Definitions and Classifications ........................................................................... 52
10.4.2.
Attribution Definitions.................................................................................................................. 53
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10.4.3.
Severity Criteria .......................................................................................................................... 53
10.4.4.
Special Reporting Situations ...................................................................................................... 54
10.4.5.
Procedures ................................................................................................................................. 54
10.4.6.
Product Quality Complaint Handling........................................................................................... 55
10.4.7.
Contacting Sponsor Regarding Safety, Including Product Quality............................................. 56
10.5.
Appendix 5: Contraceptive Guidance ............................................................................................ 57
10.6.
Appendix 6: Prohibited Concomitant Medications ......................................................................... 60
10.7.
Appendix 7: Restricted Concomitant Medications ......................................................................... 61
10.8.
Appendix 8: Medications with the Potential for Drug-drug Interactions ......................................... 62
10.9.
Appendix 9: Recommendations for Management of Drug-related Rash....................................... 65
10.10.
Appendix 10: Phone calls with Participants ................................................................................... 67
10.11.
Appendix 11: Instructions for Gentle Skin Care............................................................................. 68
10.12.
Appendix 12: Guidance on Study Conduct during the COVID-19 Pandemic................................ 69
10.13.
Appendix 13: Sub-Study Protocol .................................................................................................. 72
10.13.1.
Protocol Summary ...................................................................................................................... 72
10.13.2.
Schema....................................................................................................................................... 73
10.13.3.
Schedule of Activities (SoA) ....................................................................................................... 74
10.13.4.
Introduction ................................................................................................................................. 76
10.13.4.1.
Study Rationale ....................................................................................................................... 76
10.13.4.2.
Benefit-Risk Assessment......................................................................................................... 77
10.13.5.
Objectives and Endpoints........................................................................................................... 77
10.13.6.
SUB-Study Design...................................................................................................................... 77
10.13.6.1.
Overall Design ......................................................................................................................... 77
10.13.6.2.
Scientific Rationale for Study Design ...................................................................................... 79
10.13.6.3.
Justification for Dose ............................................................................................................... 79
10.13.6.4.
End of Study Definition............................................................................................................ 79
10.13.7.
Study Population......................................................................................................................... 79
10.13.8.
Study Intervention....................................................................................................................... 80
10.13.8.1.
Study Intervention Administered.............................................................................................. 80
10.13.8.2.
Preparation/Handling/Storage/Accountability.......................................................................... 81
10.13.8.3.
Study Intervention Compliance................................................................................................ 81
10.13.8.4.
Dose Modification .................................................................................................................... 81
10.13.8.5.
Treatment of Overdose............................................................................................................ 82
10.13.8.6.
Concomitant Therapy .............................................................................................................. 82
10.13.9.
Discontinuations of study intervention and Participant discontinuations/withdrawal.................. 82
10.13.9.1.
Discontinuation of Study Intervention...................................................................................... 82
10.13.9.2.
Rechallenge............................................................................................................................. 83
10.13.9.3.
Participant Discontinuation/Withdrawal From the Study ......................................................... 83
10.13.9.4.
Lost to Follow-up ..................................................................................................................... 83
10.13.9.5.
National Disaster/Extra Ordinary Circumstances.................................................................... 83
10.13.10. Study Assessments and Procedures.......................................................................................... 83
10.13.10.1. Efficacy Assessments.............................................................................................................. 84
10.13.10.2. Safety Assessments ................................................................................................................ 84
10.13.10.2.1. Electrocardiograms .............................................................................................................. 84
10.13.10.2.2. Adverse Events and Serious Adverse Events ..................................................................... 85
10.13.11. Statistical Considerations ........................................................................................................... 85
10.14.
Appendix 14: Sub-Study Pill Diary................................................................................................. 86
10.15.
Appendix 15: Protocol Amendment History ................................................................................... 88
REFERENCES............................................................................................................................................ 91
INVESTIGATOR AGREEMENT ................................................................................................................. 93
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LIST OF IN-TEXT TABLES AND FIGURES
TABLES
No entries found.
FIGURES
Figure 1:
Schematic Overview of the Main Study.................................................................................... 11
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1.
PROTOCOL SUMMARY
1.1.
Synopsis
A Multi-center, Open-label, Single-arm Phase 2 Study of the Adjuvant Treatment of Apalutamide and 
Androgen Deprivation Therapy (ADT) in Treatment-naïve Participants Who Have Undergone Radical 
Prostatectomy (RP) for Non-metastatic Prostate Cancer and Who Are at High Risk for Metastases
Apalutamide (ERLEADA®), is an orally available, non-steroidal small molecule, which acts as a potent and 
selective antagonist of androgen receptors (ARs). Apalutamide is indicated for the treatment of patients 
with non-metastatic castration-resistant prostate cancer (nmCRPC) and with metastatic castration sensitive 
prostate cancer (mCSPC). Apalutamide is currently being studied for the treatment of prostate cancer at all 
stages.
Given that prostate cancer cells depend on AR for proliferation and survival, a standard treatment for 
patients with recurrent disease is to lower the level of testosterone by surgical castration or with a 
gonadotropin releasing hormone (GnRH) agonist or antagonist, commonly referred to as androgen 
deprivation therapy (ADT).
As a new oral GnRH antagonist (relugolix) has been recently FDA approved, this agent will be part of a 
sub-study detailed in Section 10.13, Appendix 13.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To assess if the combination of apalutamide and ADT 
in participants with high-risk localized prostate cancer 
improves the BCR-free rate.

BCR-free rate at 24 months. BCR is 
defined 
as 
a 
confirmed 
PSA 
>0.2 ng/mL.
Secondary

To determine the BCR-free rate at 12 months.

BCR-free rate at 12 months.

To determine the time to serum testosterone recovery.

Testosterone recovery rate at 18 and 
24 months.
Exploratory

To evaluate the incidence of rash.

Incidence of rash.
Key: ADT=androgen-deprivation therapy; BCR=biochemical recurrence; PSA=prostate-specific antigen
Hypothesis
The primary hypothesis of this study is that adjuvant treatment with apalutamide and ADT will improve 
the biochemical recurrence (BCR)-free rate at 24 months post radical prostatectomy (RP) in this 
treatment-naïve, non-metastatic prostate cancer population who are at high risk for the development of 
metastases compared to historical data from patients without adjuvant treatment.
OVERALL DESIGN
This is a single-arm, open-label, multi-center study of apalutamide and ADT in approximately 
94 participants with high risk localized prostate cancer who are treatment naïve, documented to have no 
evidence of metastatic disease prior to study entry, who are between Day 29 and Day 90 post-RP, whose 
prostate-specific antigen (PSA) is ≤0.2 ng/mL at study entry and who have recovered from surgery, per the 
clinical judgment of the investigator. There will be one study intervention group receiving apalutamide for 
12 cycles (a cycle is defined as 28 days); the participants will also receive an ADT of investigator’s choice
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(3-month depot preferred) for 12 months. Treatment with apalutamide and ADT will start following 
screening and completion of RP and no later than postoperative Day 90. Participants will receive 12 cycles 
of therapy. During treatment, participants should continuously be re-evaluated for emerging and worsening 
cardiovascular risk factors per current standards for patients under androgen deprivation. Approximately 
30 days post-treatment, a safety follow-up examination will be completed (end of treatment visit). There 
will be a follow-up period during which serum PSA and testosterone levels will be measured and clinical 
status monitored every 6 months after the completion of treatment until the end of the study (EOS). The 
EOS is defined as the date of last participant’s enrollment +24 months or discontinuation of all study 
participants from the study, whichever occurs first. Study enrollment is defined as the day when the 
participant receives the first dose of apalutamide after having met all prescreening criteria.
A Steering Committee will be commissioned for this study.
NUMBER OF PARTICIPANTS
This study will be conducted in approximately 30 urology practices in the United States and enroll 
approximately 94 participants. The sub-study consisting of 12 participants will be in addition to the 94 main 
ApaRP protocol and statistical analyses will be performed separately. Upon completion of the sub-study, 
participants will be transitioned into the main study beginning at Cycle 2 Day 1.
INTERVENTION GROUPS AND DURATION
Participants will be instructed to take their assigned dose of the study intervention (apalutamide) orally
once daily for 12 cycles per apalutamide United States Package Insert (ERLEADA® USPI). A treatment 
cycle is defined as 28 days. There will be one study intervention group receiving apalutamide along with 
ADT of investigator’s choice (3-month depot preferred). Androgen deprivation therapy will be given for 
12 months.
EFFICACY EVALUATIONS
Efficacy assessments include serum PSA and testosterone and will be assessed prior to first dose of study 
intervention and throughout the study per the Schedule of Activities (SoA). A PSA level >0.2 ng/mL, 
(confirmed within 3-4 weeks), will be considered an indicator of BCR.
BIOMARKER EVALUATIONS
Biomarker samples may be collected as outlined in the SoA. Biomarker analysis is planned to 
retrospectively evaluate risk scores and other genomic markers and correlate with participants’ response to 
treatment and explore homologous recombinant deficiency (HRD) and efficacy of apalutamide in this 
subpopulation. To address these objectives, tumor tissue will be collected and sent to sponsor’s laboratory 
partner along with a copy of the full histopathology report of the specimen. Also, whole blood and plasma
samples may be collected at baseline, 12 months or end of treatment, and at 24 months or progression 
(whichever comes first).
SAFETY EVALUATIONS
Participants will be monitored for safety from the beginning of the treatment and at each study visit. Events 
related to and associated with the recovery from the pre-planned RP will not be collected.
Focused physical examinations including skin assessment will be completed prior to treatment, and at 2, 3, 
4, 7, 10, 13, and 14 months. A 12-lead electrocardiogram (ECG) will be conducted prior to treatment to 
assess for QT prolongation, if not available from pre-operative evaluation. Blood samples specific to the 
study will be collected only for PSA, testosterone levels, and biomarkers.
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STATISTICAL METHODS
The primary hypothesis of this study is that adjuvant treatment with apalutamide and ADT will improve 
the BCR-free rate at 24 months in the treatment-naïve, non-metastatic prostate cancer population who are 
at high risk for the development of metastases compared to historical data from patients without adjuvant 
treatment (76%).
It is estimated that approximately 94 participants treated for 12 months and followed for an additional 
12 months would be required to provide at least 80% power in detecting a 10% absolute increase in 
BCR-free rate at 24 months from 76% to 86% at a 1-tailed significance level of 0.05. Sample size was 
calculated using PASS 15 (Power Analysis and Sample Size Software [2017]). Time to BCR 
(ie, PSA >0.2 ng/mL) will be analyzed using Kaplan-Meier method. The secondary endpoint of 
testosterone recovery will be analyzed similarly to the primary endpoint. Incidence of rash will be 
summarized descriptively.
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1.2.
Schema
Figure 1:
Schematic Overview of the Main Study
*
See Section 9.4.5, Safety Analyses for details.
Key: ADT=androgen deprivation therapy; EOS=end of study; N=number of participants; post-op=postoperative; 
PSA=prostate-specific antigen; RP=radical prostatectomy.
Definition of High-Risk population:
• PSA ≥20 ng/mL or 
• Gleason Score ≥9 in any core on biopsy or 
• Gleason Score ≥8 (4+4 or 5+3) in >80% of 2 cores on biopsy or 
• Gleason Score = 8 (4+4 or 5+3) in 1 core as long 5 or more other cores with minimum Gleason Score of 4+3 on biopsy
The determination of high risk may be based on pathology report of biopsy or equivalent criteria from radical 
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Status: Approved,  Date: 20 April 2021
f
A PSA level >0.2 ng/mL will be an indicator of BCR and will be confirmed within 3 to 4 weeks regardless of study visit and timing. Depending on timing, this may 
be captured as an unscheduled visit.
g
Focused examinations are generally limited to the body systems or regions based on participant’s self-assessment and AE reporting. Any new complaints, symptoms
reported by participants or adverse events noted by providers should guide the need and extent of physical examination.
h
ECG assessment at screening if not available from preoperative information.
i
Collected at baseline, 12 months or end of treatment, and at 24 months or progression (whichever comes first).
j
Tissue sample to be collected and sent to sponsor’s laboratory partner along with a copy of the full histopathology report of the specimen. Biopsy tissue is preferred.
See Section 8.6 for further details.
k
Collection of concomitant therapies does not begin until time of first dose of apalutamide.
L
Collection of AEs does not begin until time of first dose of apalutamide.
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Status: Approved,  Date: 20 April 2021
2.
INTRODUCTION
Prostate cancer is the second most frequently diagnosed cancer and the sixth leading cause of 
cancer death in males worldwide.12 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 prostate-specific antigen (PSA) followed by spread to distant 
sites.27 Given that prostate cancer cells depend on androgens for proliferation and survival, a
standard treatment for patients with recurrent disease is to lower the level of testosterone by 
surgical castration or with a gonadotropin releasing hormone (GnRH) agonist or antagonist, 
commonly referred to as androgen deprivation therapy (ADT).
Apalutamide (ERLEADA®) is an orally available, non-steroidal small molecule, which acts as a 
potent and selective antagonist of androgen receptors (ARs). To date, apalutamide has been 
approved for the treatment of patients with non-metastatic castration-resistant prostate cancer 
(nmCRPC) and with metastatic castration-sensitive prostate cancer (mCSPC). Apalutamide is 
currently being studied for the treatment of prostate cancer at all stages.
For the most comprehensive nonclinical and clinical information regarding apalutamide, refer to 
the latest version of the Investigator's Brochure (IB)11 and US Package Insert (ERLEADA® USPI) 
for apalutamide.
Common terms used throughout the protocol are noted. The term “study intervention” throughout 
the protocol, refers to apalutamide + ADT. The term "sponsor" refers to the entities listed in the 
Contact Information page(s), which will be provided as a separate document. The term 
"participant" throughout the protocol refers to the common term "subject".
2.1.
Study Rationale
Men with high risk localized prostate cancer frequently undergo radical prostatectomy (RP)17 with 
curative intent. While a significant proportion of patients with clinically localized prostate cancer
are
cured
by
definitive
local
therapy,22
patients
with
high-risk
features,
including
Gleason score 8 to 10, positive lymph node involvement, high initial prostate-specific antigen, 
seminal vesicle invasion and extra prostatic extension have a 40% to 75% chance of disease
recurrence in 10 years.5,16,26 In the National Comprehensive Cancer Network (NCCN)
guidelines,17 there is a Category 1 adjuvant radiation therapy option but no standard adjuvant 
systemic therapy option for men with most of these clinical features. There is evidence supporting 
ADT in the adjuvant setting but only for men with node positive prostate cancer.15 There is also 
evidence supporting postoperative adjuvant radiation therapy28 in patients with high and very high
risk disease but it is infrequently and inconsistently applied in these situations. Apalutamide and 
ADT have demonstrated the ability to significantly prolong metastasis-free survival (MFS), 
radiographic progression free survival (rPFS), and overall survival in 2 large randomized, double 
blind, placebo controlled registrational trials.4,25 This study will investigate whether treatment with 
apalutamide and ADT for 12 months can improve the chance of maintaining participants free of 
biochemical recurrence (BCR) with a serum PSA ≤0.2 ng/mL 24 months after RP. In other solid 
tumors, robust adjuvant strategies are available that guide treatment decision-making after surgery. 
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This guidance is lacking in prostate cancer and this study can help to inform the development of 
such a strategy for this unmet need.
2.2.
Background
High-risk prostate cancer accounts for approximately 15% of newly diagnosed prostate cancers.3
For patients with high-risk, locally advanced prostate cancer, prostatectomy alone may be 
inadequate. Cure rates from prostatectomy are less than 25%.2,15,23 High-risk patients experience 
the highest recurrence after prostatectomy, with a disease progression rate of approximately 50%.13
Patients with recurring disease after local therapy require salvage radiotherapy, which is associated 
with morbidity that has detrimental impact on quality of life. In a retrospective analysis of 379 
men who developed a BCR after RP, it was found that patients with a Gleason score of 8 to 10 
were more likely to die from prostate cancer than patients with a Gleason score of 7 or less.7
Several deﬁnitions of high-risk prostate cancer are used in the urological literature. Patients with 
high-risk localized or locally advanced prostate cancer include those with Gleason scores ≥8, 
clinical stage ≥cT2c (disease in both or extension outside of the lobes), high baseline 
PSA ≥20 ng/mL, or involvement of regional nodes. For the current study, high risk is defined by 
Gleason score or PSA.
For adjuvant use of ADT, prospective randomized studies have shown that early use of long-term
ADT extends survival, compared with treatment that is delayed until disease progression.2,5,6,9,21
In a randomized study in 100 patients to determine whether immediate ADT extends survival in 
patients with node-positive prostate cancer who have undergone RP and pelvic lymphadenectomy 
compared with those who received ADT only at disease progression, it was shown that early ADT 
benefits patients as compared to deferred treatment.15
2.3.
Benefit-Risk Assessment
More detailed information about the known and expected benefits and risks of apalutamide may 
be found in the IB and ERLEADA USPI.
As noted in Section 2.1, there is evidence that adjuvant therapy may provide benefit.
3.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To assess if the combination of apalutamide and ADT 
in participants with high-risk localized prostate cancer 
improves the BCR-free rate.

BCR-free rate at 24 months. BCR is 
defined 
as 
a 
confirmed 
PSA 
>0.2 ng/mL.
Secondary

To determine the BCR-free rate at 12 months.

BCR-free rate at 12 months.

To determine time to serum testosterone recovery.

Testosterone recovery rate at 18 and 
24 months.
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Objectives
Endpoints
Exploratory

To evaluate the incidence of rash.

Incidence of rash.
Key: ADT=androgen-deprivation therapy; BCR=biochemical recurrence; PSA=prostate-specific antigen
Refer to Section 8, Study Assessments and Procedures for evaluations related to endpoints.
HYPOTHESIS
The primary hypothesis of this study is that adjuvant treatment with apalutamide and ADT will 
improve the BCR-free rate at 24 months post-RP in this treatment-naïve, non-metastatic prostate 
cancer population who are at high risk for the development of metastases compared to historical 
data from patients without adjuvant treatment.14
4.
STUDY DESIGN
4.1.
Overall Design of the Main Study
This is a single-arm, open-label, multi-center study of apalutamide and ADT in approximately
94 participants with high risk localized prostate cancer who are treatment naïve, documented to 
have no evidence of metastatic disease prior to study entry, who are between Day 29 and Day 90
post-RP, whose PSA is ≤0.2 ng/mL at study entry and who have recovered from surgery, per the 
clinical judgment of the investigator.
This study will be conducted in approximately 30 urology practices in the US and enroll 
approximately 94 participants. There will be one study intervention group receiving apalutamide 
for 12 cycles; the participants will also receive an ADT of investigator’s choice (3-month depot 
preferred) for 12 months. Treatment with apalutamide and ADT will start following screening and 
completion of RP and no later than postoperative Day 90. Approximately 30 days post-treatment, 
a safety follow-up examination will be completed (end of treatment visit). There will be a 
follow-up period during which serum PSA and testosterone levels will be measured and clinical 
status monitored every 6 months after the completion of treatment until the end of study (EOS). 
The EOS is defined as the date of last participant’s enrollment +24 months or discontinuation of 
all study participants from the study, whichever occurs first. Study enrollment is defined as the 
day when the participant receives the first dose of apalutamide after having met all prescreening 
criteria.
During treatment, participants should continuously be re-evaluated for emerging and worsening 
cardiovascular risk factors per current standards for patients under androgen deprivation. 
Management of risk factors, including but not limited to hypertension (inclusive of blood pressure 
fluctuations and interim hypotension), overweight/obesity, and hyperlipidemia is required for all 
participants based on recent guidelines.
The timing and frequencies of study assessments are presented in the SoA (Section 1.3). Efficacy 
assessments include serum PSA and testosterone and will be assessed after the start of apalutamide 
treatment. A PSA level >0.2 ng/mL (confirmed within 3-4 weeks) is considered an indicator of 
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BCR. Safety assessments from the time of enrollment and during treatment and end of treatment 
visit will include focused physical examinations, monitoring of adverse events (AEs). A 12-lead 
electrocardiogram (ECG) will be conducted at screening to examine QT prolongation, if not 
available from preoperative evaluation. Safety evaluations will be conducted based on AE 
reporting. Blood and plasma samples for biomarker analysis as well as tumor tissue will be 
collected per the Schedule of Activities (SoA).
A Steering Committee will be commissioned for this study. Refer to Committees Structure in 
Section 10.3, Appendix 3, Regulatory, Ethical, and Study Oversight Considerations for details.
A diagram of the study design is provided in Section 1.2, Schema.
4.2.
Scientific Rationale for Study Design
The single-arm, open-label design is appropriate for a Phase 2 study to evaluate the clinical benefit 
of adjuvant apalutamide with ADT for patients with high-risk localized prostate cancer following 
RP. The occurrence of rash with apalutamide and subsequent specific management could make 
blinding impractical. The participants have previously selected to undergo RP as opposed to any 
other option and their participation in this study with adjuvant treatment could provide added 
benefit to them.
Following the work conducted by the ICECaP investigators29 whose results were obtained mostly 
in patients who had undergone radiation therapy with curative intent, Martini et al14 described the 
biochemical and clinical recurrence patterns in a cohort of 3,507 patients with high risk localized 
prostate cancer who had undergone RP and extended pelvic lymph node dissections. These 
investigators noted negligible serum PSA (≤0.2 ng/mL) rates of 84% and 76% at 12 and 
24 months, respectively after surgery, in the absence of any adjuvant treatment. These findings on 
biochemical recurrence form the basis for the statistical assumptions and rationale for clinical 
endpoints in this adjuvant study (see Section 9.2).
Biomarker Collection
It is recognized that genetic variation can be an important contributory factor to interindividual 
differences in intervention and response and can also serve as a marker for disease susceptibility 
and prognosis.
Biomarker samples may be collected to evaluate progression or help to explain interindividual 
variability in clinical outcomes and may help to identify population subgroups that respond 
differently to this intervention. The goal of the biomarker analyses is to evaluate localized high-risk
prostate cancer population and aid in evaluating the intervention-clinical response relationship of 
apalutamide with ADT.
Biomarker samples may be used to help address emerging issues and to enable the development 
of safer, more effective, and ultimately individualized therapies.
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4.2.1.
Participant Input Into Design
As part of the Patient Voice Project, members of the Prostate Cancer Patient Engagement Research 
Council who are all patients/survivors of prostate cancer favorably reviewed the study design and 
visit schedule.
The consensus was that the open-label design, without placebo, of this study is preferable to 
randomized double-blind studies for patients. Additionally, the visit schedule and duration of time 
on study was not considered “burdensome”. Longer follow-up was suggested and follow-up every 
6 months until the end of the study was added with subsequent follow-up to be covered by
treatment per standard of care.
4.2.2.
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 AEs of the study, and provide their consent voluntarily will be enrolled.
While participants have selected RP independent from this study, the primary ethical concern is 
that adjuvant therapy with apalutamide following RP is not currently standard of care. The cure 
rate for patients with high-risk localized prostate cancer is approximately 25%. Apalutamide has 
been proved to significantly delay metastases and improve overall survival, and has a manageable 
safety profile.25 Participants may discontinue from the study if there are signs of disease 
progression and then be eligible for other forms of treatment including radiation.
An additional ethical concern is germline and other genetic testing which may warrant counselling. 
This information and potential interventions may affect not only the participant, but his family. 
Genetic counselling will be made available through the genetic testing facility.
The total blood volume to be collected is considered to be an acceptable amount of blood to be 
collected over this time period from the population in this study based upon the standard of the
American Red Cross.1
4.3.
Justification for Dose
The dose of 240 mg (4 × 60 mg tablets) is the approved dose per ERLEADA USPI.
4.4.
End of Study Definition
End of Study Definition
The EOS is defined as the date of last participant’s enrollment +24 months or discontinuation of 
all study participants from the study, whichever occurs first. The final data from the study site will 
be sent to the sponsor (or designee) after completion of the final participant visit at that study site, 
in the time frame specified in the Clinical Trial Agreement.
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Study Completion Definition
Participants will be considered to have completed the study if they have completed EOS 
assessments.
Participants who prematurely discontinue study intervention for any reason before study 
completion will not be considered to have completed the study. If a participant misses a dose for 
>28 days, consult the sponsor regarding continuation in the study.
5.
STUDY POPULATION
The study population will consist of participants that are treatment-naïve, who have undergone RP 
for non-metastatic prostate cancer, and who are at high risk for metastases, as defined by Gleason 
score or PSA.
Screening for eligible participants will be performed within 90 days before administration of the 
study intervention. Refer to Section 5.4, 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 9.2, 
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 >18 years of age
2.
must be willing and able to sign an informed consent form and be able to fully comply 
with all of the required procedures, restrictions, and prohibitions specified in this protocol
3.
Criterion modified per Amendment 2
3.1
The participant should be
a.
a candidate for RP or status post-RP
b. eligible to receive study intervention between Day 29 and Day 90 post-RP
c.
post-RP PSA of <0.2 ng/mL 
d. has not received other treatment for prostate cancer
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4.
Criterion modified per Amendment 2
4.1
have recovered from RP procedure and have had no worsening in cardiac risk in 
the peri-operative period per the clinical judgment of the investigator
5.
Criterion modified per Amendment 1
5.1.
Criterion modified per Amendment 2
5.2
histologically confirmed adenocarcinoma of the prostate and categorized as high 
risk for recurrent prostate cancer. High risk can be defined based on PSA alone or biopsy 
or RP specimen as follows:

PSA ≥20 ng/mL
or

Gleason Score ≥9 in any core on biopsy
or

Gleason Score ≥8 (4+4 or 5+3) in >80% of 2 cores on biopsy
or

Gleason Score = 8 (4+4 or 5+3) in 1 core as long 5 or more other cores with 
minimum Gleason Score of 4+3 on biopsy
The determination of high risk may be based on pathology report of biopsy or equivalent 
criteria from radical prostatectomy.
6.
adequate organ function (hepatic, renal, hematologic and cerebral) determined at the 
discretion of the treating physician
7.
Eastern Cooperative oncology Group (ECOG) Performance Status Score of 0 or 1
8.
able to take apalutamide per the ERLEADA USPI and able to receive ADT for up to 1 
year
9.
must be willing to wear a condom when engaging in any activity that allows for passage 
of ejaculate to another person. Male participants should also be advised of the benefit for 
a female partner to use a highly effective method of contraception as condom may break 
or leak
10.
must be willing to agree not to donate sperm for the purpose of reproduction during the 
study and for a minimum 90 days after receiving the last dose of study intervention
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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.
Criterion modified per Amendment 1
1.1. history or presence of soft tissue/bone metastasis or metastasis in distant lymph 
nodes (pelvic lymph nodes below the iliac bifurcation that are <2 cm in diameter [short 
axis] either radiographically or pathologically are allowed.)
2.
history of bilateral orchiectomy
3.
taking any disallowed therapies or chronic need for prohibited medications (per 
ERLEADA USPI) as noted in Section 6.8, Concomitant Therapy before the planned 
first dose of study intervention
4.
received an investigational intervention ≤4 weeks before the planned first dose of study 
intervention
5.
history of seizure or any condition that in the opinion of the investigator may predispose 
to seizure or treatment with drugs known to lower the seizure threshold within 4 weeks 
prior to starting treatment with apalutamide
6.
allergy or hypersensitivity to apalutamide, or excipients, unable or unwilling to take 
ADT
7.
history or presence of psoriasis, neurodermatitis, acneiform rashes or any 
dermatological condition that in the opinion of the investigator may predispose to 
confounding with the evaluation and management of study intervention related rash
8.
Criterion modified per Amendment 2
8.1
malignancies (ie, progressing or requiring treatment or treatment change in the 
last 24 months) other than prostate cancer. The only allowed exceptions are: non-muscle 
invasive bladder cancer; skin cancer (non-melanoma or melanoma) treated within the 
last 24 months that is considered completely cured. Malignancies considered cured for 
more than 24 months are allowed
9.
Criterion modified per Amendment 1
9.1
Criteria modified per Amendment 2
9.2
any of the following within 12 months prior to baseline: severe or unstable 
angina, myocardial infarction, symptomatic congestive heart failure, uncontrolled 
hypertension, long QT, arterial or venous thromboembolic events (eg, pulmonary 
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embolism, cerebrovascular accident including transient ischemic attacks), or clinically 
significant ventricular arrhythmias
10.
plans to father a child while enrolled in this study or within 12 weeks after the last dose 
of study intervention
11.
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
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 the participant no longer meets all eligibility criteria, then the participant should be 
excluded from participation in the study. The required source documentation to support meeting 
the enrollment criteria are noted in Section 10.3, Appendix 3, Regulatory, Ethical, and Study 
Oversight Considerations.
5.3.
Lifestyle Considerations
Potential participants must be willing and able to adhere to the following lifestyle restrictions 
during the course of the study to be eligible for participation:
1.
Refer to Section 6.8, Concomitant Therapy for details regarding prohibited and 
restricted 
therapy 
during 
the 
study, 
including 
chronic 
alcohol 
use, 
cytochrome P450 (CYP)3A4 interaction, and drugs known to lower the seizure 
threshold or cause seizures.
2.
Agree to follow all requirements that must be met during the study as noted in the 
Inclusion and Exclusion Criteria (eg, contraceptive requirements).
3.
Orchiectomy is prohibited during the entire study.
4.
A condom is required for all sexual activity during the study and for 3 months after 
completion of apalutamide. There is no sperm donation permitted during the study and 
within 3 months after completion of study treatment. See Section 10.5, Appendix 5, 
Contraceptive Guidance for further details.
5.
If the study participant is engaged in sexual activity with a female of childbearing 
potential, 2 forms of contraception, including condom use as described above, are 
required. These include:

Oral, injected or implanted methods of contraception including an intrauterine 
device (IUD) or intrauterine system (IUS)

Barrier methods with spermicide
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
Vasectomy
5.4.
Screening 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 enrolled into 
the study, the date seen and age at initial informed consent will be used.
Participants who do not meet the criteria for participation in this study (screen failure) will not be 
rescreened.
5.5.
Criteria for Temporary Delaying (Enrolment/Randomization/Administration 
of Study Intervention) (Not Applicable)
6.
STUDY INTERVENTION
6.1.
Study Intervention Administered
The study intervention apalutamide, 240 mg (four 60 mg tablets, slightly yellowish to greyish
green oblong film-coated tablets, debossed with “AR 60” on one side), will be provided as tablets 
for oral administration. The window for initiation of study intervention must occur between Day 
29 and Day 90 post-RP. Participants will be instructed to take their assigned dose of the study 
intervention orally once daily for 12 cycles per ERLEADA USPI. A treatment cycle is defined as 
28 days. Apalutamide can be taken with or without food. If a participant experiences a ≥Grade 3 
toxicity or an intolerable side effect, hold dosing until symptoms improve to ≤Grade 1 or original 
grade, then resume at the same dose or a reduced dose (180 mg or 120 mg), if warranted. If a 
participant remains off apalutamide for ≥4 weeks, the participant may be withdrawn from the 
study, after discussing with the sponsor. Participants experiencing treatment related seizure of any 
grade will have apalutamide permanently discontinued.
Description of Interventions
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 and the ERLEADA USPI.
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Investigator’s choice of a Food and Drug Administration (FDA)-approved and commercially 
available ADT, not provided by the sponsor, will be administered per the USPI for 12 months in 
total duration, during the treatment phase. Three-month depot is the preferred administration. For 
further information on ADT refer to the USPI.
For a definition of study intervention overdose, refer to Section 6.7, Treatment of Overdose.
6.2.
Preparation/Handling/Storage/Accountability
Preparation/Handling/Storage
Apalutamide must be stored at controlled temperatures ranging from 15°C to 30°C.
Refer to the ERLEADA USPI for additional guidance on apalutamide and ADT preparation, 
handling, and storage.
Accountability
The investigator is responsible for ensuring that all study intervention received at the site is 
inventoried and accounted for throughout the study. The study intervention administered to the 
participant must be documented on the intervention accountability form. 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.
Study intervention must be handled in strict accordance with the protocol and the container label, 
and must be stored at the study site in a limited-access area or in a locked cabinet under appropriate 
environmental conditions. Unused study 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.
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. 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. 
Further guidance and information for the final disposition of unused study interventions are 
provided in the Study Site Investigational Product and Procedures Manual.
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6.3.
Measures to Minimize Bias: Randomization and Blinding (Not Applicable)
6.4.
Study Intervention Compliance
Study-site personnel will maintain a log of all study intervention dispensed. Study intervention 
supplies for each participant will be inventoried and accounted for.
6.5.
Dose Modification
Any dose adjustment should be overseen by medically qualified study-site personnel (principal or 
subinvestigator unless an immediate safety risk appears to be present).
In case a dose modification is necessary, the study intervention will be administered per 
Section 10.9, Appendix 9, Recommendations for Management of Drug-related Rash.
6.6.
Continued Access to Study Intervention After the End of the Study (Not 
Applicable)
6.7.
Treatment of Overdose
For this study, any dose of apalutamide greater than 240 mg within a 24-hour time period will be 
considered an overdose. The sponsor does not recommend specific intervention for an overdose. 
There is no specific antidote and treatment should consist of general supportive measures.
In the event of an overdose, the investigator or treating physician should:

Contact the Medical Monitor immediately.

Closely monitor the participant for adverse event (AE)/serious adverse event (SAE).

Document the quantity of the excess dose as well as the duration of the overdosing in the 
eCRF.

Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant.
6.8.
Concomitant Therapy
Concomitant therapies must be recorded throughout the study from the time of first dose of study 
intervention to the last study visit. Concomitant therapies should also be recorded beyond 30 days 
after last study visit only in conjunction with new or worsening AEs and SAEs that meet the criteria 
outlined in Section 8.3.1, Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information.
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, or other specific categories of interest) 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.
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Modification of an effective preexisting therapy should not be made for the explicit purpose of 
entering a participant into the study.
Prohibited concomitant therapies, outlined in Section 10.6 Appendix 6, include treatment with any 
AR blocker or CYP17 inhibitor for the treatment of prostate cancer. Sipuleucel-T, pembrolizumab, 
radium-223, strontium-89, samarium-153, saw palmetto and any agent under investigation and not 
currently approved by the FDA for any indication are also prohibited. Concomitant therapy 
restrictions are outlined in Section 10.7, Appendix 7, Restricted Concomitant Medications.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1.
Discontinuation of Study Intervention
A participant's study intervention must be discontinued if:

The participant withdraws consent to receive study intervention

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

Noncompliance with study intervention administration

Participants experiencing treatment-related seizure of any grade will have apalutamide 
permanently discontinued
If a participant discontinues study intervention for any reason before the end of the study, then the
last scheduled study assessments should be obtained and scheduled assessments off study 
intervention should be continued. If a participant misses doses for >28 days, consult the sponsor 
regarding continuation in the study. If a participant discontinues study intervention due to disease 
progression, the subsequent treatment including radiation will be captured in the eCRF, if known. 
Additional participants will not be entered to ensure the protocol-specified number of participants 
complete the study.
7.1.1.
Rechallenge
If a participant experiences a ≥Grade 3 toxicity or an intolerable side effect, hold dosing until 
symptoms improve to ≤Grade 1 or original grade, then resume at the same dose or a reduced dose, 
if warranted per Section 10.9, Appendix 9, Recommendations for Management of Drug Related
Rash.
7.2.
Participant Discontinuation/Withdrawal From the Study
A participant will be withdrawn from the study for any of the following reasons:

Lost to follow-up

Withdrawal of consent
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
Investigator’s discretion

Seizure

Death
When a participant withdraws before study completion, the reason for withdrawal is to be 
documented in the eCRF and in the source document. If the reason for withdrawal from the study 
is withdrawal of consent, then no additional assessments are allowed.
Withdrawal of Consent
A participant declining to return for scheduled visits does not necessarily constitute withdrawal of 
consent. Alternate follow-up mechanisms that the participant agreed to when signing the consent 
form apply (eg, consult with family members, contacting the participant’s other physicians, 
medical records, database searches, use of locator agencies at study completion) as local 
regulations permit.
Prior to a participant withdrawing consent for follow-up, the investigator should offer the 
participant an opportunity for one of the alternative reduced follow-up mechanisms described 
below. Withdrawal of consent should be an infrequent occurrence in clinical studies, therefore, 
prior to the start of the study, the sponsor and the investigator should discuss and reach a clear 
understanding of what constitutes withdrawal of consent in the context of the available reduced 
follow-up mechanisms listed.
7.2.1.
Withdrawal From the Use of Research Samples
A participant who withdraws from the study will have the following options regarding the research 
samples:

The collected samples will be retained and used in accordance with the participant's original 
informed consent.

The participant may withdraw consent for research samples, in which case the samples will 
be destroyed, and no further testing will take place. To initiate the sample destruction process, 
the investigator must notify the sponsor study site contact of withdrawal of consent for the 
research samples and to request sample destruction. The sponsor study site contact will, in 
turn, contact the biomarker representative to execute sample destruction. If requested, the 
investigator will receive written confirmation from the sponsor that the sample has been 
destroyed.
Withdrawal From the Use of Samples in Future Research
The participant may withdraw consent for use of samples for research (refer to Long-term 
Retention of Samples for Additional Future Research in Section 10.3, Appendix 3, Regulatory, 
Ethical, and Study Oversight Considerations). In such a case, samples will be destroyed after they 
are no longer needed for the clinical study. Details of the sample retention for research are 
presented in the main informed consent form (ICF).
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7.3.
Lost to Follow-up
To reduce the chances of a participant being deemed lost to follow-up, prior to study entry, 
attempts should be made to obtain contact information from each participant, eg, home, work, and 
mobile telephone numbers and email addresses for both the participant as well as appropriate 
family members.
Participants will be considered lost to follow-up if they repeatedly fail to return for scheduled visits 
and is unable to be contacted by the study site. A participant cannot be deemed lost to follow-up 
until all reasonable efforts made by the study-site personnel to contact the participant are deemed 
futile. The following actions must be taken if a participant fails to return to the study site for a 
required study visit:

The study-site personnel must attempt to contact the participant to reschedule the missed visit 
as soon as possible, to counsel the participant on the importance of maintaining the assigned 
visit schedule, to ascertain whether the participant wishes to or should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee must make every 
reasonable effort to regain contact with the participant (where possible, 3 telephone calls, 
e-mails, fax, and, if necessary, a certified letter to the participant’s last known mailing address, 
or local equivalent methods). These contact attempts should be documented in the 
participant’s medical records.

Should the participant continue to be unreachable, they will be considered to have withdrawn 
from the study.
Should a study site close, eg, for operational, financial, or other reasons, and the investigator cannot 
reach the participant to inform them, their contact information will be transferred to another study 
site.
7.4.
National Disaster/Extra Ordinary Circumstances
If appropriate, site visits may be replaced with telephone visits during a national disaster or extra 
ordinary circumstances, with site visits resuming as soon as possible thereafter. Telephone visits 
will be recorded in the source documentation and eCRF. If a visit included blood collection, the 
collection and testing may be done at a facility closer to the participant. A copy of the laboratory 
report, along with the reference ranges must be obtained for the source documentation and 
provided with the eCRF. Study intervention may be dispensed by alternative methods (for example 
shipped to participants). Refer to Section 10.12, Appendix 12, Guidance on Study Conduct during 
the COVID-19 Pandemic, for details related to the COVID pandemic that may also be applied to 
other national disasters or extra ordinary circumstances.
8.
STUDY ASSESSMENTS AND PROCEDURES
Overview
The Schedule of Activities summarizes the frequency and timing of efficacy, biomarker, safety
measurements applicable to this study.
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The PSA assessments should be conducted/completed before any tests, procedures, or other 
consultations to prevent influencing participant perceptions.
Blood collections should be kept as close to the specified time as possible. 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.
The total blood volume for the main study is approximately 55 mL.
Repeat or unscheduled samples may be taken for technical issues with the samples.
Sample Collection and Handling
Refer to Section 1.3, Schedule of Activities for the timing and frequency of all sample collections.
Study-Specific Materials
The investigator will be provided with the following information:

IB and ERLEADA USPI for apalutamide and USPI for ADT

Pharmacy Manual/Study Site Investigational Product and Procedures Manual

National Cancer Institute Common- Terminology Criteria for Adverse Events (NCI-CTCAE)
Version 5.0

Response Evaluation Criteria in Solid Tumors (RECIST) guidelines Version 1.1

Electronic data capture (eDC) Manual

eSource Manual

ICF template
8.1.
Efficacy Assessments
Efficacy assessments include serum PSA and testosterone and will be assessed prior to first dose 
of study intervention and throughout the study per the SoA. A PSA level >0.2 ng/mL (confirmed 
within 3-4 weeks) will be considered an indicator of BCR.
8.2.
Safety Assessments
Participants will be monitored for safety from the beginning of the treatment and at each study 
visit. Events related to and associated with the recovery from the pre-planned RP will not be 
collected.
Details regarding the Steering Committee are provided in Committees Structure in Section 10.3
Appendix 3, 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 Section 10.4, Appendix 4, Adverse Events, 
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Serious Adverse Events, Product Quality Complaints, and Other Safety Reporting: 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 SoA.
8.2.1.
Physical Examinations
Focused physical examinations including skin assessment will be completed prior to treatment, 
and at 2, 3, 4, 7, 10, 13, and 14 months. Focused examinations are generally limited to the body 
systems or regions based on participant’s self-assessment and AE reporting. Any new complaints, 
symptoms reported by participants or adverse events noted by providers should guide the need and 
extent of physical examination.
8.2.2.
Vital Signs
Vital signs are to be assessed per standard of care or as warranted by AEs.
8.2.3.
Electrocardiograms
A 12-lead ECG will be conducted prior to treatment to assess for QT prolongation, if not available 
from pre-operative evaluation. 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.
8.2.4.
Clinical Safety Laboratory Assessments
Blood samples will be collected as noted in Section 10.2, Appendix 2, Clinical Laboratory Tests. 
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 only study-specified laboratory 
assessments are PSA and testosterone.
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 
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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 SAEs (Definitions and Classifications; Attribution Definitions; 
Severity Criteria; Special Reporting Situations; Procedures) as well as product quality complaints, 
refer to Section 10.4, Appendix 4, Adverse Events, Serious Adverse Events, Product Quality
Complaints, and Other Safety Reporting: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting.
8.3.1.
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information
All Adverse Events
Monitoring of AEs will be performed at 1, 2, 3, 4, 7, 10, 13, 14 months, at each follow-up visit, 
and during phone calls with the participants. All AEs and special reporting situations, whether 
serious or non-serious, will be reported from the time after the participant receives the first dose 
of apalutamide until completion of the participant's last study-related procedure, which may 
include contact for follow-up of safety. 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 SAE 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 signed by a physician from the study site, and transmitted to the sponsor within 
24 hours. The initial and follow-up reports of an SAE should be emailed to the to the appropriate 
sponsor contact person by study-site personnel.
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.
Participants who are not able to respond verbally, may be asked to write a brief description of 
how they have been feeling.
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 
Section 10.4, Appendix 4 Adverse Events, Serious Adverse Events, Product Quality Complaints, 
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and Other Safety Reporting: 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 AE 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.
The plan for monitoring and analyzing the anticipated events is specified in the IB.
The sponsor assumes responsibility for appropriate reporting of the listed anticipated events 
according to the United States requirements.
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. Follow-up information regarding the outcome of the pregnancy and 
any postnatal sequelae in the infant will be required.
8.3.6.
Cardiovascular and Death Events
Ischemic cardiovascular events, including events leading to death, occurred in patients receiving 
apalutamide. Monitor for signs and symptoms of ischemic heart disease. Optimize management of 
cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Consider 
discontinuation of apalutamide for Grade 3 and 4 events.
8.3.7.
Disease-Related Events and Disease-Related Outcomes not 
Qualifying as Adverse Events or Serious Adverse Events
All events that meet the definition of an SAE will be reported as SAEs, regardless of whether they 
are protocol-specific assessments.
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 
fulfil the SAE definition (refer to Adverse Event Definitions and Classifications in Section 10.4, 
Appendix 4, Adverse Events, Serious Adverse Events, Product Quality Complaints, and Other 
Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up, and 
Reporting). Expected progression of disease should not be considered an AE (or SAE). However, 
if determined by the investigator to be more likely related to the study intervention than the 
underlying disease, the clinical signs or symptoms of progression and the possibility that the study 
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intervention is enhancing disease progression, should be reported per the usual reporting 
requirements.
8.3.8.
Adverse Events of Special Interest
For apalutamide, there are no non-serious AEs of special interest identified.
Rash is an AE of special interest to be assessed by CTCAE criteria and following the specific rash 
management plan in Appendix 9, Recommendations for Management of Drug related Rash.
8.4.
Pharmacokinetics (Not Applicable)
8.5.
Genetics
Genetics will be evaluated by DNA repair deficient (DRD) germline testing using whole blood 
sample.
8.6.
Biomarkers
Biomarker samples may be collected as outlined in the SoA. Biomarker analysis is planned to 
retrospectively evaluate risk scores and other genomic markers and correlate with participants’ 
response to treatment and explore HRD status and efficacy of apalutamide in this subpopulation. 
To address these objectives, tumor tissue will be collected and sent to sponsor’s laboratory partner 
along with a copy of the full histopathology report of the specimen. Biopsy tissue is required for
risk scores (Prolaris) and is preferred for HRD testing Also, whole blood and plasma samples may
be collected at baseline, 12 months or end of treatment, and at 24 months or progression 
(whichever comes first).
Stopping Analysis
Biomarker analyses are dependent upon the availability of appropriate biomarker assays and 
clinical response rates. Biomarker analysis may be deferred or not performed, if during or at the 
end of the study, it becomes clear that the analysis will not have sufficient scientific value for 
biomarker evaluation, or if there are not enough samples or responders to allow for adequate 
biomarker evaluation. In the event the study is terminated early or shows poor clinical efficacy, 
completion of biomarker assessments is based on justification and intended utility of the data.
Additional Collections
If it is determined at any time before study completion that additional material is needed from a 
formalin-fixed, paraffin-embedded tumor sample for the successful completion of the protocol 
specified analyses, the sponsor may request that additional material be retrieved from existing 
samples. Also, based on emerging scientific evidence, the sponsor may request additional material 
from previously collected tumor samples during or after study completion for a retrospective 
analysis. In this case, such analyses would be specific to research related to the study 
intervention(s) or diseases being investigated.
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8.7.
Immunogenicity Assessments (Not Applicable)
8.8.
Health Economics (Not Applicable)
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.
9.1.
Statistical Hypotheses
The primary hypothesis of this study is that adjuvant treatment with apalutamide and ADT will 
improve the BCR-free rate at 24 months in the treatment-naïve, non-metastatic prostate cancer 
population who are at high risk for the development of metastases compared to historical data 
without adjuvant treatment (76%).14
9.2.
Sample Size Determination
It is assumed that BCR-free rate follows an exponential distribution with a constant hazard rate. It 
is estimated that approximately 94 participants accrued over approximately 1 year, treated for 
12 months and followed for an additional 12 months would be required to provide at least 
80% power in detecting a 10% absolute increase in BCR-free rate at 24 months of 76% to 86% at 
a 1-tailed significance level of 0.05. The null hypothesis of 76% BCR-free rate at 24 months for 
the historical data of no adjuvant treatment is an estimate based on published data.14 Sample size 
was calculated using PASS 15 (Power Analysis and Sample Size Software [2017]).20
9.3.
Populations for Analysis Sets
For analysis purpose, the following sets are defined:

All safety analyses will be performed using the Treated set. The Treated set will consist of all 
participants who received at least 1 dose of apalutamide.

All efficacy analyses will be performed using the Modified Intent-to-Treat set. The Modified 
Intent-to-Treat set consist of all participants who satisfy all of the following: 

Met all eligibility criteria and are enrolled in the study

Received at least 1 dose of apalutamide

Had a baseline PSA and at least 1 post-treatment PSA assessment.
9.4.
Statistical Analyses
The statistical analysis plan will be finalized prior to database lock (DBL) and it will include a 
more technical and detailed description of the statistical analyses described in this section. This 
section is a summary of the planned statistical analyses of the most important endpoints including 
primary and key secondary endpoints.
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9.4.1.
General Considerations
Primary endpoint test of hypothesis will be performed at 1-sided significant level 0.05; a 2-sided 
alpha level of 0.10 will be used to provide all confidence intervals.
9.4.2.
Primary Endpoint
Time to BCR (ie, PSA >0.2 ng/mL) will be analyzed using Kaplan-Meier method. The BCR -free 
rate at 24 months will be estimated with the 90% confidence interval. Null hypothesis of BCR
free- rate of 76% will be rejected if the lower limit of the 90% confidence interval exceeds 76%. 
Participants who do not have any occurrence of PSA >0.2 ng/mL, will be considered as censored 
at their last time of PSA measurement.
9.4.3.
Secondary Endpoint
The secondary endpoint of testosterone recovery will be analyzed similarly to the primary 
endpoint. The testosterone recovery, defined as a serum testosterone ≥150 ng/dL, will be analyzed 
using Kaplan-Meier method. The testosterone recovery at 24 months will estimated together with 
95% confidence interval.
9.4.4.
Exploratory Endpoint
Incidence of rash will be summarized descriptively.
9.4.5.
Safety Analyses
All safety analyses will be made on the Safety Population.
Adverse Events
The verbatim terms used in the eCRF by investigators to identify AEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). Any AE occurring at or after the initial 
administration of study intervention through the day of last dose plus 30 days is considered to be 
treatment emergent. All reported treatment 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.
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 
serious AE.
Parameters with predefined NCI-CTCAE toxicity grades will be summarized. Change from 
baseline to the worst AE grade experienced by the participant during the study will be provided as 
shift tables.
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9.4.6.
Other Analyses
Biomarkers Analyses
Participants with biomarker samples will be evaluated for high-risk genomic classifiers and HRD 
status. A subgroup analysis will be performed to assess the treatment effect in participants stratified 
by risk classifiers and HRD status.
The association of biomarkers with clinical response endpoints or survival may be assessed using 
appropriate statistical methods (eg, analysis of variance [ANOVA], categorical, or survival 
models) depending on the endpoints. Analyses may be performed within and between each 
intervention group. Other clinical covariates (such as baseline tumor characteristics and participant
demographics) may also be included in the model. Association of biomarkers with clinical 
response or relevant time-to-event endpoints will also be explored in the overall population. 
Results of these exploratory analyses will be presented in separate technical reports.
9.5.
Interim Analysis (Not Applicable)
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10.
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1.
Appendix 1: Abbreviations
ADT
androgen deprivation therapy
ADL
Activities of Daily Living
AE
adverse event
AR
androgen receptor
ANOVA
analysis of variance
BCR
biochemical recurrence
BCRP
breast cancer resistance protein
BSA
body surface area
COVID-19
coronavirus disease 2019
CSPC
castration-sensitive prostate cancer
CT
computed tomography
CYP
cytochrome P450
DBL
database lock
DES
diethylstilbestrol
DRD
DNA repair deficient
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
eDC
electronic data capture
EOS
end of study
FDA
Food and Drug Administration
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
GnRH
gonadotropin releasing hormone
HRD
homologous recombinant deficiency
HRT
hormonal replacement therapy
IB
investigator’s brochure
ICF
informed consent form
ICH
International Council for Harmonisation
ICMJE
International Committee of Medical Journal Editors
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
mCSPC
metastatic castration-sensitive prostate cancer
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
MFS
metastasis-free survival
NCCN
National Comprehensive Cancer Network
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
nmCRPC
non-metastatic castration-resistant prostate cancer
OATP1B1
organic anion transporter 1B1
PET
positron emission tomography
PASS
Power Analysis and Sample Size Software
P-gp
P-glycoprotein
PQC
product quality complaint
PSA
prostate-specific antigen
RECIST
Response Evaluation Criteria in Solid Tumors
RP
radical prostatectomy
rPFS
radiographic progression free survival
SAE
serious adverse event
SoA
Schedule of Activities
SUSAR
suspected unexpected serious adverse reaction
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UGT
uridine diphosphate glucuronosyl transferase
USPI
United States Package Insert
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 CRF as determined by the protocol. Data in this system may be 
considered source documentation.
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10.2.
Appendix 2: Clinical Laboratory Tests
Prostate-specific antigen and testosterone tests will be performed by the local laboratory.
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10.3.
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations
10.3.1.
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 Harmonization (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

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)

IB (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.
Approval for the collection of samples for research included in the ICF must be obtained from the 
IEC/IRB. Approval for the protocol can be obtained independent of this research component.
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 IB 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
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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 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).
Country Selection
This study will only be conducted in the US.
Other Ethical Considerations
For study-specific ethical design considerations, refer to Section 4.2.1, Participant Input Into 
Design.
10.3.2.
Financial Disclosure
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.
10.3.3.
Informed Consent Process
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 
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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 permission to obtain information about 
his survival status. It also denotes that the participant agrees to allow his or her 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.
10.3.4.
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 or her legally acceptable representative) 
includes explicit consent for the processing of personal data and for the investigator/institution to 
allow direct access to his or her 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 or her personal data 
and the right to request rectification of any data that are not correct or complete. Reasonable steps 
will be taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations.
Exploratory biomarker 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
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confidentiality of data generated in the future on stored samples will be protected by the same 
standards applicable to all other clinical data.
10.3.5.
Long-Term Retention of Samples for Additional Future Research
Samples collected in this study may be stored for up to 15 years (or according to local regulations) 
for additional research. Samples will only be used to understand apalutamide with ADT, to 
understand localized high-risk prostate cancer, to understand differential intervention responders, 
and to develop tests/assays related to apalutamide with ADT and localized high-risk prostate 
cancer. The research may begin at any time during the study or the post-study storage period. 
Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Participants may withdraw their consent for their samples to be 
stored for research (refer to Section 7.2.1, Withdrawal From the Use of Research Samples).
10.3.6.
Committee Structure
Steering Committee
A Steering Committee will be established to provide guidance and supervision for the study, 
including ensuring the continued safety of the participants enrolled in this study. The committee 
chair will have medical expertise in the relevant therapeutic area. Committee membership 
responsibilities, authorities, and procedures will be documented in its charter.
10.3.7.
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 biomarker research data, generated as a result of this 
study, are considered confidential and remain the sole property of the sponsor. The investigator 
agrees to maintain this information in confidence and use this information only to accomplish this 
study and will not use it for other purposes without the sponsor's prior written consent.
The investigator understands that the information developed in the study will be used by the 
sponsor in connection with the continued development of 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 biomarker 
analyses performed after the Clinical Study Report has been issued will be reported in a separate 
report and will not require a revision of the Clinical Study Report. 
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Status: Approved,  Date: 20 April 2021
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 (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 sub-study 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. The disclosure of the final study results will be performed after the end of study in order 
to ensure the statistical analyses are relevant.
10.3.8.
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 data base. 
Written instructions will be provided for collection, handling, storage, and shipment of samples. 
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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.
10.3.9.
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 
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 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 an 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.
10.3.10.
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.
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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:

Race

History of smoking, all nicotine use, eg, cigarettes (including e-cigarettes or the equivalent of 
e-cigarettes), cigars, chewing tobacco, patch, gum

History of alcohol intake, including type, usage, amount, and frequency.

Height and weight at baseline
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 thee
CRF.
10.3.11.
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. 
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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 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.
10.3.12.
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 investigators should immediately notify the sponsor if they have been 
contacted by a regulatory agency concerning an upcoming inspection.
10.3.13.
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.
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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.
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.
10.3.14.
Study and Site Start and Closure
First Act of Recruitment
The first site open is considered the first act of recruitment and it becomes the study start date.
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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10.4.
Appendix 4: Adverse Events, Serious Adverse Events, Product Quality 
Complaints, and Other Safety Reporting: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
10.4.1.
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 International Council for
Harmonisation [ICH]10)
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 from the time after the participant receives the first dose of 
apalutamide (refer to All Adverse Events 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
An 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 one of the other outcomes listed in the definition above. These 
should usually be considered serious.
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If a serious and unexpected AE occurs for which there is evidence suggesting a causal relationship 
between the study intervention and the event (eg, death from anaphylaxis), the event must be 
reported as a serious and unexpected suspected adverse reaction even if it is a component of the 
study endpoint (eg, all-cause mortality). 
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 IB.
10.4.2.
Attribution Definitions
Assessment of Causality
The causal relationship to study intervention is determined by the Investigator. The following 
selection should be used to assess all AE.
Related
There is a reasonable causal relationship between study intervention administration and the AE.
Not Related
There is not a reasonable causal relationship between study intervention administration and the 
AE.
The term "reasonable causal relationship" means there is evidence to support a causal relationship.
10.4.3.
Severity Criteria
An assessment of severity grade will be made using the Common Terminology Criteria for 
Adverse Events (CTCAE) Version 5.0, where ‘grade’ refers to the severity of the AE.
Grade 1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age 
appropriate instrumental Activities of Daily Living (ADL)
Grade 3
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care (ADL)
Grade 4
Life-threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE.
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For additional information, refer to Common Terminology Criteria for Adverse Events (CTCAE) 
Version 5.0 Published: November 27, 2017.
10.4.4.
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

Medication error, intercepted medication error, or potential medication error involving a 
Johnson & Johnson medicinal product (with or without participant exposure to the Johnson & 
Johnson medicinal product, eg, product name confusion, product label confusion, intercepted 
prescribing or dispensing errors)

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.
10.4.5.
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: 

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 personnel only)

Site number

Participant number
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Serious Adverse Events
All SAEs 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 an 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 an 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.
Expected progression of disease should not be considered an AE (or SAE). However, if determined 
by the investigator to be more likely related to the study intervention than the underlying disease, 
the clinical signs or symptoms of progression and the possibility that the study intervention is 
enhancing disease progression, should be reported per the usual reporting requirements.
10.4.6.
Product Quality Complaint Handling
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
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 
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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 an 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.
10.4.7.
Contacting Sponsor Regarding Safety, Including Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues, PQC, or questions regarding the study are listed in the Contact Information 
page(s), which will be provided as a separate document.
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10.5.
Appendix 5: Contraceptive Guidance
Participants’ female partners must follow contraceptive measures as outlined as below. Pregnancy 
information will be collected and reported as noted in Section 8.3.5, Pregnancy and Section 10.4, 
Appendix 4 Adverse Events, Serious Adverse Events, Product Quality Complaints, and Other 
Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up, and 
Reporting.
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below).
Woman Not of Childbearing Potential

premenarchal
A premenarchal state is one in which menarche has not yet occurred.

postmenopausal
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. A high follicle stimulating hormone (FSH) level (>40 IU/L or mIU/mL) in the 
postmenopausal range may be used to confirm a postmenopausal state in women not using 
hormonal contraception or hormonal replacement therapy (HRT), however in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient.

permanently sterile
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, bilateral tubal 
occlusion/ligation procedures, and bilateral oophorectomy.
Note: If the childbearing potential changes after start of the study (eg, a premenarchal woman
experiences menarche) or the risk of pregnancy changes (eg, a woman who is not heterosexually 
active becomes active), a woman must begin a highly effective method of contraception, as 
described throughout the inclusion criteria.
If reproductive status is questionable, additional evaluation should be considered.
Contraceptive (birth control) use by men or women should be consistent with local regulations 
regarding the acceptable methods of contraception for those participating in clinical studies.
Typical use failure rates may differ from those when used consistently and correctly. Use should 
be consistent with local regulations regarding the use of contraceptive methods for participants in 
clinical studies.
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Examples of Contraceptives
EXAMPLES OF CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:
USER INDEPENDENT
Highly Effective Methods That Are User Independent Failure rate of <1% per year when used 
consistently and correctly.

Implantable progestogen-only hormone contraception associated with inhibition of ovulationb

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

Bilateral tubal occlusion

Vasectomized partner
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the 
sole sexual partner of the woman of childbearing potential and the absence of sperm has been 
confirmed. If not, additional highly effective method of contraception should be used. 
Spermatogenesis cycle is approximately 74 days.)
USER DEPENDENT
Highly Effective Methods That Are User Dependent Failure rate of <1% per year when used 
consistently and correctly.

Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb
oral
intravaginal
transdermal
injectable

Progestogen-only hormone contraception associated with inhibition of ovulationb
oral
injectable

Sexual abstinence
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study intervention. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.)
NOT ALLOWED AS SOLE METHOD OF CONTRACEPTION DURING THE STUDY (not 
considered to be highly effective - failure rate of 1% per year)

Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary 
mode of action.

Male or female condom with or without spermicidec

Cap, diaphragm, or sponge with spermicide

A combination of male condom with either cap, diaphragm, or sponge with spermicide (double-
barrier methods)c

Periodic abstinence (calendar, symptothermal, post-ovulation methods)

Withdrawal (coitus-interruptus)

Spermicides alone

Lactational amenorrhea method
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a
Typical use failure rates may differ from those when used consistently and correctly. Use should be 
consistent with local regulations regarding the use of contraceptive methods for participants in 
clinical studies.
b
Hormonal contraception may be susceptible to interaction with the study intervention, which may 
reduce the efficacy of the contraceptive method. In addition, consider if the hormonal contraception 
may interact with the study intervention.
c
Male condom and female condom should not be used together (due to risk of failure with friction).
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10.6.
Appendix 6: Prohibited Concomitant Medications
Apalutamide
Drugs known to lower the seizure threshold or cause seizures are prohibited and a representative
list is included below:

Aminophylline/theophylline

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)
Other prohibited therapies include the following:

Investigational agents

Any other prior or current treatment for prostate cancer which includes but not limited to

Abiraterone acetate or other CYP17 inhibitors

Other hormonal agents for the treatment of prostate cancer

Other antineoplastic agents

Radiation therapy 

5-α-reductase inhibitors

Chemotherapy

Immunotherapy or vaccine therapy for cancer treatment

Other anti-androgens (eg, bicalutamide, nilutamide, flutamide, cyproterone acetate,
enzalutamide)

Bisphosphonates or denosumab unless for management of osteoporosis 

Systemic ketoconazole (or other azole drugs such as fluconazole or itraconazole)

Diethylstilbestrol (DES) or similar

Other preparations such as pomegranates or pomegranate juice or saw palmetto, which
are thought to have endocrine effects on prostate cancer

Radiopharmaceuticals such as strontium (89Sr) or samarium (153Sm) or similar analogs
such as radium-223 (223Ra)

Spironolactone
If the permissibility of a specific drug/treatment is in question, please contact the sponsor.
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10.7.
Appendix 7: Restricted Concomitant Medications

Investigators should refer to the IB (Sections 4.3.4 and 5.10) and associated addenda for
complete details on the drug interaction potential of 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 uridine 
diphosphate glucuronosyl transferase (UGT) can result in decreased exposure. Use caution if 
substrates of UGT must be co-administered with apalutamide and evaluate for loss of efficacy.

Effect of apalutamide on drug transporters: Apalutamide was clinically shown to be a weak 
inducer of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion 
transporter 1B1 (OATP1B1). Concomitant use of apalutamide with medications that are 
substrates of P-gp, BCRP, or OATP1B1 can result in lower exposure of these medications. 
Use caution if substrates of P-gp, BCRP, or OATP1B1 must be co-administered with 
apalutamide, and evaluate for loss of efficacy if medication is continued.

Long-term use of systemically administered corticosteroids during the study is not allowed. 
Short-term use (≤4 weeks, including taper) and locally administered steroids (eg, inhaled, 
topical, ophthalmic, and intra-articular) are allowed, if clinically indicated. 

See Section 10.8, Appendix 8, Medications with the Potential for Drug-drug Interactions, for 
a complete list of medications prohibited while on active treatment with apalutamide.

Because of the potential for drug-drug interaction, the concurrent use of all other drugs, over-
the-counter medications, and alternative therapies must be documented on the eCRF. The 
principal investigator should be alerted if the participant is taking any agent found in Appendix 
(a listing of medications with the potential for drug-drug interaction).
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10.8.
Appendix 8: Medications with the Potential for Drug-drug Interactions
Generic Name
Brand Name**
aminophylline
Aminocont; Aminomal; Diaphyllin; Filotempo; Neophyllin; 
Norphyl; Phyllocontin; Syntophyllin; Tefamin; Truphylline; Xing 
You Shan; 
aminophylline in 
combination
Asmeton; Cha Xin Na Min; Emergent-Ez; Fufang Dan An Pian; 
Ke Zhi
amitriptyline
Amirol; Amitrip; Amixide; Deprelio; Diapatol; Elatrol; cElatrolet; 
Elavil; Endep; Enovil; Emitrip; Klotriptyl; Laroxyl; Levate; 
Limbitrol; Limbitryl; Mutabase; Mutabon; Nobritol; Novo-Triptyn; 
Pertriptyl; Redomex; Saroten; Sarotex; Sedans; Syneudon; 
Teperin; Triptizol; Triptyl; Tryptizol
amitriptyline in 
combination
PMS-Levazine
bupropion
Aplenzin; Buproban; Contrave; Elontril; Forfivo; Fortivo XL; Le 
Fu Ting; Prexaton; Quomem; Voxra; Wellbutrin; Wellbutrin XL; 
Wellbutrin SR; Yue Ting; Zyban
chlorpromazine
Aminazin; Chlorazin; Hibernal; Klorproman; Largactil; Megaphen; 
Ormazine; Plegomazin; Solidon; Taroctyl;Thorazine; Vegetamin; 
Wintermin; Zuledin
Note: in Ireland also called “Clonazine” – very easy to confuse 
with clozapine.
clozapine
Azaleptin; Clopine; Closastene; Clozaril; CloZAPine; Denzapine; 
Elcrit; Fazacio ODT; Klozapol; Lanolept; Leponex; Lozapine; 
Nemea; Ozapim; Synthon, Versacloz; Zaponex
desipramine 
Deprexan; Norpramin; Nortimil; Pertofrane
doxepin
Adapin; Anten; Aponal; Deptran; Gilex; Li Ke Ning; Quitaxon; 
Silenor; Sinepin; Sinequan; Zonalon
imipramine
Impril; Melipramin; Mipralin; Norfranil; Novo-Pramine; 
Persamine; Pertofram; Pryleugan; Talendep; Tofranil; Tolerade
lithium
Arthriselect; Camcolit; Carbolith; Carbolithium; Eskolith; 
Hypnorex; Li-Liquid; Licarbium; Limas; Liskonum; Litarex; 
Lithane; Lithicarb; Lithioderm; Lithionit; Lithobid; Liticarb; 
Litiomal; Lito; Maniprex; Neurolepsin; Plenur; Priadel; 
Quilonorm; Quilonum; Saniquiet; Sedalit; Teralithe
lithium in combination
Boripharm No 23; Emser Salz; Girheulit HOM; Helidonium-Plus; 
Heweurat N; rheuma-loges; Rhus Toxicodendron Compose; Rhus-
Plus; Ricinus Compose
maprotiline
Cronmolin; Deprilept; Ludiomil; Mapromil; Melodil; Neuomil; 
Psymion
meperidine/pethidine
Alodan; Atropine and Demerol; Centralgine; Demerol; Dolantin ; 
Dolantina; Dolantine; Dolargan; Dolcontral,; Dolestine ; Dolosal ; 
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Generic Name
Brand Name**
Dolsin; Fada; Hospira; Liba; Mepergan ; Meprozine,; Mialgin,; 
Opystan; Pethidine ; Petigan Miro ; Psyquil compositum
meperidine/pethidine in
combination
Pamergan P100
mesoridazine
Serentil, Mesorin
mirtazapine
Arintapin; Avanza; Axit; Combar; Esprital; Mi Er Ning; Miro; 
Mirta TAD; Mirtabene; Mirtachem; Mirtadepi; Mirtagamma; 
Mirtalan; MirtaLich; Mirtamylan; Mirtaron; Mirtaz; Mirtazelon; 
Mirtazon; Mirtazonal; Mirtel; Mirtin; Mirtor; Mirzaten; Norset; 
Noxibel; Paidisheng; Psidep; Remergil; Remergon; Remeron; 
Remirta; Rexer; Yarocen; Zispin
olanzapine
Anzorin, Arenbil; Arkolamyl; Atyzyo; Bloonis; Clingozan; 
Egolanza; Lansyn; Lanzek; Lazapix; Nolian; Nykob; Olafid; 
Olanzaran; Olanzep; Olanzin; Olanzine; Olapin; Olasyn; Olazax; 
Olpinat; Olzapin; Olzin; Ou Lan Ning; Ozilormar; Parnassan; 
Ranofren; Sanza; Stygapon; Synza; Ximin; Zalasta; Zamil; Zappa; 
Zapris; Zerpi; Zolafren; Zolaxa; Zonapir; Zopridoxin; Zylap; 
Zypadhera; Zypine; Zyprexa; Zyprexa Relprew; Zydis
olanzapine in 
combination
Symbyax
risperidone
Aleptan; Apo-Risperid; Arketin; Calmapride; Diaforin; Doresol; 
Hunperdal; Jing Ping; Ke Tong; Leptinorm; Lergitec; Orizon; 
Ozidal; Perdox; Ranperidon; Resdone; Ridal; Ridonex; Rileptid; 
Ripedon; Risepro; Rispa; Rispaksole; Rispefar; Rispemylan; 
Rispen; Rispera; Risperanne; Risperdal; Risperdalconsta; 
Risperdaloro; Risperigamma; Risperon; Rispolept; Rispolux; 
Rispond; Rispons; Risset; Rixadone; Rorendo; Ryspolit; Si Li Shu; 
Sizodon; Speridan; Suo Le; Torendo; Zhuo Fei; Zhuo Fu; Ziperid; 
Zoridal
theophylline
Aerolate; Afonilum; Aminomal; An Fei Lin; Apnecut; Apo-Theo; 
Asmalix; Asmalon; Bi Chuan; Bronchoparat; Bronchoretard; 
Cylmin; Diffumal; Elixifilin; Elixophyllin; Etipramid; Euphyllin; 
Euphyllina; Euphylline; Euphylong; Frivent; Gan Fei Lin; Nuelin; 
Protheo; Pulmophylline; Quelesu; ratio-Theo-Bronc; Respicur; 
Retafyllin; Shi Er Ping; Slo-Bid; Slo-Phyllin; Telbans; Teotard; 
Terdan; Teromol; Theo-24; Theo-Dur; Theo; Theochron; Theodur; 
Theofol; Theolair; Theoplus; Theospirex; Theostat ; Theotard; 
Theotrim; Theovent; Tromphyllin; Unicon; Unicontin; Unifyl; 
Uniphyl; Uniphyllin Continus; Uniphyllin; UniXan; Xanthium; Xi 
Fu Li; Yan Er
theophylline in 
combination
Antong; Baladex; Bi Chuan; Binfolipase; Broncho-Euphyllin; 
Broncomar; Do-Do ChestEze; Elixophyllin-GG; Elixophyllin-KI; 
Insanovin; Marax ; Neoasma; Theofol Comp; Theophedrinum-N; 
Xu Hong; Yi Xi Qing
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Generic Name
Brand Name**
thioridazine
Detril; Elperil; Melleril; Ridazin; Ridazine; Thiodazine; Thioril; 
Sonapa
ziprasidone
Geodon; Li Fu Jun An; Pramaxima; Si Bei Ge; Ypsila; Zeldox; 
Zipwell; Zypsila; Zypsilan
**Note: This document is intended as an aid in identifying prohibited meds but may not be all inclusive.
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10.9.
Appendix 9: Recommendations for Management of Drug-related Rash

In the combined data of two randomized, placebo-controlled clinical studies, rash associated 
with apalutamide was most commonly described as macular or maculopapular. (Please refer 
to the current IB- for further details.)

Evaluate causality of the rash ie, Is it related to apalutamide? Or another form of rash such as 
shingles, sunburn, etc.

If not considered related to apalutamide, evaluate and treat according to the etiology.

If possibly related to apalutamide, grade the severity of rash per the 
NCI-CTCAE Version 5.0 below and treat according to Dose Modification and 
Management Guidelines.
Rash 
maculo-papular
A disorder characterized by the presence of macules (flat) and papules 
(elevated). Also known as morbilliform rash, it is one of the most 
common cutaneous adverse events, frequently affecting the upper trunk, 
spreading centripetally and associated with pruritis.
Grade 1 
Macules/papules covering <10% body surface area (BSA) with or without 
symptoms (eg, pruritus, burning, tightness) 
Grade 2 
Macules/papules covering 10 to 30% BSA with or without symptoms (eg, 
pruritus, burning, tightness); limiting instrumental Activities of Daily 
Living (ADL); rash covering >30% BSA with or without mild symptoms.
Grade 3
Macules/papules covering >30% BSA with moderate or severe symptoms; 
limiting self-care ADL.
NCI-CTCAE Version 5.0; Published: 27 November 2017.
Toxicity Severity Dose Modification and Management Guidelines
If there is blistering or mucosal involvement, stop apalutamide immediately and contact the sponsor.
Standardized photography to be undertaken by the study-site personnel. Educate on gentle skin care.
Initiate dermatological treatment.
Grade 1
or 
Grade 2
Continue apalutamide at the same dose:
o
High potency topical steroid lotion bid
eg, fluocinonide 0.05%, clobetasol 0.05%, or betamethasone 0.05% AND
o
Oral antihistamines hydroxyzine:
10 mg bid for Grade 1 or 25 mg bid for Grade 2, or equivalent.
Monitor for change in severity, contact the participant at minimum every 2 weeks:
o
If rash is stable or improves, continue current management and monitoring until rash 
resolves.
o
If rash worsens, follow guidance for Grade 3.
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Toxicity Severity Dose Modification and Management Guidelines
If there is blistering or mucosal involvement, stop apalutamide immediately and contact the sponsor.
Standardized photography to be undertaken by the study-site personnel. Educate on gentle skin care.
Initiate dermatological treatment.
Grade 3
Hold apalutamide until rash is Grade <1
o
Oral steroids Prednisone 0.5 to 1 mg/kg/day for 20 days or equivalent with maximum 
dose of 100 mg/day AND
o
High potency topical steroid lotion or solution bid
eg, fluocinonide 0.05%, clobetasol 0.05%, or betamethasone 0.05% AND
o
Oral antihistamines (hydroxyzine 25 mg bid or equivalent).
o
Reassess after 2 weeks (by site staff).
After 2 weeks of management (as above): 
If the rash is the same or has worsened
o
Continue to hold apalutamide and refer the participant to a dermatologist.
If rash improves to Grade 2: 
o
Continue to hold apalutamide, continue current management.
o
Reassess after 1 week (by site staff).
After 1 week:
o
If after 1-week rash is still Grade 2, continue to hold apalutamide and refer the 
participant to a dermatologist.
o
If rash has improved to Grade <1, see below. 
If rash is Grade <1: 
o
Reinitiate apalutamide at half the dose (120 mg) for 2 weeks 
o
Continue oral antihistamines for 1 week 
o
Start tapering oral steroids 
o
Continue topical treatment until rash resolves
o
Return to full dose after 2 weeks of half dose apalutamide and if rash remains <1
If the proposed total oral steroid use will exceed 28 days, contact the sponsor.
If after 28 days of starting the treatment, rash has not resolved to Grade ≤1, contact the 
sponsor
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10.10. Appendix 10: Phone calls with Participants
It is recommended to use a standardized questionnaire as noted below during phone calls. The 
questions serve as a guidance for documenting presence and severity of rash. All participants will 
receive a call weekly in the first month of treatment and then mid-cycle (ie, biweekly) after Visit 2 
through Visit 3 and thereafter if the participant has rash (per Section 10.9, Appendix 9, 
Recommendations for Management of Drug-related Rash). Participants should be encouraged to 
call the study site anytime they notice a rash or if the rash worsens.
Guide for discussion during phone calls:

Ask if the participant is willing to continue the study

Collect information on the participant’s compliance with oral administration of study 
intervention

Collect information on the participant’s current health status including discussion of 
concomitant medications and adverse events including any skin rash

Have you noticed any skin rash since the start of the treatment (or since the last site visit 
or phone call)? 
o
If this is the first occurrence of rash, please schedule a site visit for the participant as 
soon as possible

If yes, do you have any symptoms associated with the rash? (eg, pruritus, tingling, 
burning, tightness)

What is the severity of the symptoms? (none, mild, moderate, severe, very severe)

Are the symptoms improving or worsening?

(If applicable) Have you been regularly applying the skin lotion or solution prescribed to 
you for skin rash?

Remind the participant about the gentle skin care instructions

Schedule the next call (if applicable)
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10.11. Appendix 11: Instructions for Gentle Skin Care
1. Light emollient (lotion) applied daily as required after any other prescribed topical steroid 
lotion has had time to dry.
2. Use an antiseptic-containing soap substitute or a mild pH-neutral soap (eg, Cetaphil).
3. Avoid strong sun and weather extremes.
4. Use sunblock (SPF 50) when outdoors.
5. Avoid long, hot baths, showers and saunas. Use tepid water for bathing.
6. Avoid alcohol-based and fragranced skin-care products as these may exacerbate dry skin.
7. For participants with pre-existing eczema: intensify usual skin care routine.
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10.12. Appendix 12: Guidance on Study Conduct during the COVID-19 Pandemic
The measures outlined in this appendix are temporary, while access to sites may be 
restricted. As restrictions are lifted, the decision to revert back to the protocol specified 
procedures should be discussed and agreed with the sponsor.
It is recognized that the Coronavirus Disease 2019 (COVID-19) pandemic may have an impact on 
the conduct of this clinical study due to, for example, self-isolation/quarantine by participants and 
study-site personnel; travel restrictions/limited access to public places, including hospitals; study 
site personnel being reassigned to critical tasks.
In alignment with recent health authority guidance, the sponsor is providing options for study 
related participant management in the event of disruption to the conduct of the study. This guidance 
does not supersede any local or government requirements or the clinical judgment of the 
investigator to protect the health and well-being of participants and site staff. If, at any time, a 
participant’s safety is considered to be at risk, the study intervention will be discontinued, and 
study follow-up will be conducted.
If a potential participant had RP surgery delayed due to the COVID-19 situation and was given 
ADT as a bridging measure until the participant could be scheduled for surgery, the participant
may still be considered for the study, if all other inclusion/exclusion criteria are met. Each 
individual case will need to be discussed with the study sponsor for approval prior to entry into 
the study.
Scheduled visits that cannot be conducted in person at the study site will be performed to the extent 
possible remotely/virtually or delayed until such time that on-site visits can be resumed. At each 
contact, participants will be interviewed to collect safety data. Key efficacy endpoint assessments 
should be performed if required and as feasible. Participants will also be questioned regarding 
general health status to fulfill any physical examination requirement.
Every effort should be made to adhere to protocol-specified assessments for participants on study 
intervention, including follow-up. Modifications to protocol-required assessments may be 
permitted after consultation between the participant and investigator, and with the agreement of 
the sponsor. Missed assessments/visits will be captured in the clinical trial management system for 
protocol deviations. Discontinuations of study interventions and withdrawal from the study should 
be documented with the prefix “COVID-19-related” in the eCRF.
The sponsor will continue to monitor the conduct and progress of the clinical study, and any 
changes will be communicated to the sites and to the health authorities according to local guidance. 
If a participant has tested positive for COVID-19, the investigator should contact the sponsor’s 
responsible medical officer to discuss plans for study intervention and follow-up. Modifications 
made to the study conduct as a result of the COVID-19 pandemic should be summarized in the 
clinical study report.
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GUIDANCE SPECIFIC TO THIS PROTOCOL: 
To ensure participant safety and minimize disruption to completion of protocol scheduled visits, 
we recommend the following when it is not safe to complete a scheduled visit at the site due to the 
coronavirus pandemic: 

Arrange an appointment to conduct the visit as well as collect information on the participant
current health status, adverse events and concomitant medications over the phone or other 
remote technology (Facetime, WhatsApp etc) as allowed by local regulations. 

Document all communication with participants and protocol related activities completed 
remotely in the source and eDC as required. 

Document all missed assessments, discontinuations of study interventions and withdrawal 
from the study. Missed assessments will be captured in the clinical trial management system 
for protocol deviations, with the actual visit date documented or reason for withdrawals 
specified; discontinuations of study interventions and withdrawal from the study will be 
captured with the prefix “COVID-19-RELATED” in the eCRF.
Safety and Disease Evaluation Visits:
Protocol required laboratory tests may be performed at a nearby hospital or doctor´s office when 
they cannot be done at the site.

For participants who are unable or unwilling to leave their homes to complete protocol 
scheduled visits due to the coronavirus pandemic, the visits should be postponed until it is 
deemed safe to return to the site or local hospital. 

It is strongly recommended to schedule regular phone consultations to assess any new/ongoing 
adverse events including skin rash, fatigue, seizures, falls and fractures. Participants should 
be encouraged to check their blood pressure at home regularly and report any new symptoms 
to the study team urgently. Advise participants to seek immediate medical attention if any 
symptoms suggestive of a cardiovascular event occur.

If a participant is unable to visit study site or designated laboratory, serum PSA and 
testosterone testing can be done at a local laboratory. Protocol required biomarker and 
pharmacogenomics sampling can be done at the site as soon as the situation permits.

Please ensure any evaluations are documented in the source and eDC. Identify the assessments 
as “missed or delayed due to COVID-19”.
Changes in Study Intervention: 

Study intervention (apalutamide) should be continued in the protocol specified manner. If a 
participant is unable to receive the drug as specified in the protocol, please call the sponsor to 
discuss. 

Androgen Deprivation Therapy (ADT) which is administered concurrently should be 
continued (1-month or 3-month depot formulations given intramuscular or subcutaneously per 
the information in the package insert). If a participant is unable to visit the study site, please 
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arrange a visit to a nearby hospital or doctor´s office or a home visit by a trained provider to 
administer the ADT at home.
Keep Communications Open (within-site, sponsor-site, site-participant):

Please maintain up-to-date contact information for one another (site colleagues, sponsor 
contacts, participants) and keep communication channels open, including in circumstances 
where site staff/participants are experiencing restrictions in physical workplace or study visit 
attendance.
Source Data Verification/Monitoring: 

On-site monitoring visits may not be possible due to local regulations, restrictions and 
guidance. In these cases, the Site Manager will arrange to conduct site monitoring visits and 
activities remotely. Additional on-site monitoring visits may be needed in the future to catch 
up on source data verification.
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10.13. Appendix 13: Sub-Study Protocol
10.13.1.
Protocol Summary
A sub-study will be conducted assessing the coadministration of apalutamide and relugolix in 
treatment-naïve participants who have undergone radical prostatectomy (RP) for non-metastatic 
prostate cancer and who are at high risk for metastases.
Apalutamide (ERLEADA®) is an orally available, non-steroidal, small molecule, which acts as a 
potent and selective antagonist of androgen receptors (ARs). Apalutamide is indicated for the 
treatment of patients with non-metastatic castration-resistant prostate cancer (nmCRPC) and 
metastatic castration-sensitive prostate cancer (mCSPC). Patients should also receive a 
gonadotropin-releasing hormone (GnRH) analog concurrently or should have had a bilateral 
orchiectomy.
Relugolix (ORGOVYX™) is an orally available GnRH receptor antagonist approved by the FDA 
on December 18, 2020 for the treatment of adult patients with advanced prostate cancer.
Given the recent approval of relugolix and the fact that apalutamide is indicated in combination 
with a GnRH analog, there is a need to understand the effect of combining relugolix and 
apalutamide on testosterone suppression.
This is a single-arm, open-label, multi-center sub-study of apalutamide and relugolix in 
12 participants with high risk localized prostate cancer who are treatment naïve, documented to 
have no evidence of metastatic disease prior to study entry, who are between Day 29 and 
Day 90 post-RP, whose PSA is ≤0.2 ng/mL at study entry, and who have recovered from surgery, 
per the clinical judgment of the investigator. There will be one study intervention group receiving 
relugolix monotherapy for 2 weeks followed by coadministration with apalutamide for 1 cycle 
(28 days). Serum testosterone will be measured on Day –14 (ie, the day of starting relugolix 
administration), Day 1 (ie, the day of starting coadministration with apalutamide), and Day 28. 
The primary endpoint is the percentage of participants maintaining testosterone <50 ng/dL through 
Day 28, and the secondary endpoint is safety (adverse events) through Day 28. Upon completion 
of the sub-study, participants will be transitioned into the main ApaRP study protocol beginning 
at Cycle 2 Day 1.
Refer to subsequent sections for details on objectives and endpoints, hypothesis, overall design, 
number of participants, intervention groups and duration, efficacy evaluations, and safety 
evaluations.
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10.13.2.
Schema
Figure 2:
Schematic Overview of the Sub-Study
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b
The sub-study ICF must be signed before first study-related activity and will cover the sub-study and the main 
study.
c
Relugolix administered as 360 mg on first day of treatment (Day –14), followed by 120 mg on subsequent days.
d
If not occurring during an in-person visit, the study team should call the participant to ask about medication 
compliance.
e
Should be completed daily by the participant during sub-study treatment and provided to the study team at each 
sub-study visit (form located in Section 10.14, Appendix 14).
f
If participant's testosterone ≥50 ng/dL on Day 1 or Day 28, stop relugolix, switch to intramuscular ADT, and 
switch to main ApaRP study.
g
Focused examinations are generally limited to the body system or regions based on participant's self-assessment 
and AE reporting. Any new complaints, symptoms reported by participants or adverse events noted by providers 
should guide the need and extent of physical examination.
h
Collected at baseline, 12 months or end of treatment, and at 24 months or progression (whichever comes first) as 
part of the main ApaRP study.
i
Tissue sample to be collected and sent to sponsor's laboratory partner along with a copy of the full histopathology 
report of the specimen. See Section 8.6 for further details.
j
Collection of concomitant therapies does not begin until time of first dose of relugolix.
k
Collection of AEs does not begin until time of first dose of relugolix.
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10.13.4.
Introduction
10.13.4.1.
Study Rationale
Relugolix (ORGOVYX™) is an orally available gonadotropin-releasing hormone (GnRH) 
receptor antagonist approved by the FDA on December 18, 2020 for the treatment of adult patients 
with advanced prostate cancer. Relugolix is administered at a loading dose of 360 mg on the first 
day of treatment, followed by 120 mg taken orally once daily. Relugolix is metabolized primarily 
by CYP3A and is a substrate for intestinal P-glycoprotein (P-gp). Clinical studies with rifampin, a 
combined P-gp and strong CYP3A inducer, decreased the AUC and Cmax of relugolix by 55% and 
23%, respectively. Consequently, the relugolix label suggests avoiding coadministration with 
combined P-gp and strong CYP3A inducers and if unavoidable, to increase the dose of relugolix 
to 240 mg once daily.19
Apalutamide is a strong inducer of CYP3A4 and a weak inducer of P-gp. Concomitant use of 
apalutamide with medications that are primarily metabolized by CYP3A4 and/or a substrate of 
P-gp can result in lower exposure of these medications. Apalutamide has been shown to reach 
steady state concentrations at 4 weeks.7
Given relugolix is the first and only approved oral GnRH antagonist and apalutamide is indicated 
in combination with a GnRH analog, there is a need to understand the clinical implications of 
combining relugolix and apalutamide in the clinic. Achieving and maintaining a castrate level of 
serum testosterone (<50 ng/dL) while on ADT is considered the gold standard assessment of
achieving castration with GnRH analogs. Data from 899 participants (from Phase 1, 2, and 3 
studies) with both relugolix and testosterone concentration data were combined for PopPK and 
PopPK/PD analyses.18 In simulated testosterone concentrations, relugolix dosed as low as 40 mg 
once daily following a loading dose of 360 mg achieved a median testosterone <50 ng/dL within 
10 days.18 Relugolix dosed at 120 mg once daily following a loading dose of 360 mg achieved a 
testosterone <50 ng/dL in 90% of the simulations within 10 days.18 In the registrational Phase 3 
HERO study of relugolix dosed at 120 mg once daily after a loading dose of 360 mg, the 
cumulative probability of testosterone suppression to <50 ng/dL on Day 4 and Day 15 were 56% 
and 98.7%, respectively.24
As part of the Phase 3 HERO study, concomitant medications that could possibly affect 
testosterone were tracked. Seventeen (3%) participants received concomitant enzalutamide with 
relugolix.19 Similar to apalutamide, enzalutamide is a strong CYP3A4 inducer.30 In vitro, 
enzalutamide and N-desmethyl enzalutamide are inhibitors of P-gp.30 Despite the potential 
drug-drug interaction, no clinically significant differences in the pharmacokinetics of relugolix 
were observed when coadministered with enzalutamide.19 Additionally, no clinically relevant 
differences were noted in the incidence or types of adverse events (AE) before or after concomitant 
use of enzalutamide.18
Given the similarities in the metabolism of apalutamide and enzalutamide and the fact that 
relugolix achieved a median testosterone <50 ng/dL within 10 days dosed as low as 40 mg once 
daily following a loading dose of 360 mg, we hypothesize coadministration of apalutamide 240 mg 
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once daily with relugolix as indicated (120 mg once daily following a loading dose of 360 mg) 
will achieve and maintain castrate testosterone levels (<50 ng/dL) without the need to increase the 
relugolix dose.
For the most comprehensive nonclinical and clinical information regarding relugolix or 
apalutamide, refer to the latest version of their respective US Package Inserts (USPI). 
10.13.4.2.
Benefit-Risk Assessment
More detailed information about the known and expected benefits and risks of apalutamide may 
be found in the ERLEADA® USPI.7 More detailed information about the known and expected 
benefits and risks of relugolix may be found in the ORGOVYX™USPI.19
The perceived benefit of relugolix is the convenience of oral administration versus intramuscular 
injections that require supervision of a physician as indicated with other GnRH analogs.
Throughout the course of this 6-week sub-study, serum testosterone levels will be assessed on 
multiple occasions and participants will be removed from the sub-study if castrate levels of 
testosterone are not achieved. Safety will be monitored by AE reporting. With established safety 
profiles, close monitoring, and the low risk of short-term reduced relugolix effect on testosterone, 
the benefit of assessing the coadministration of apalutamide and relugolix outweighs the potential
risks associated with each intervention.
10.13.5.
Objectives and Endpoints
Objectives
Endpoints
Primary

To assess if the addition of apalutamide to relugolix 
is able to maintain castrate levels of testosterone.

Percentage of participants maintaining 
testosterone <50 ng/dL through Day 28.
Secondary

To evaluate the safety of coadministering 
apalutamide and relugolix at their indicated doses.

Adverse events through Day 28.
HYPOTHESIS
The primary hypothesis of this sub-study is that coadministration of apalutamide 240 mg once 
daily with relugolix 120 mg once daily (following a loading dose of 360 mg) will achieve and 
maintain castrate levels of testosterone (<50 ng/dL).
10.13.6.
SUB-Study Design
10.13.6.1.
Overall Design
This is a single-arm, open-label, multi-center sub-study of apalutamide and relugolix in 
12 participants with high risk localized prostate cancer who are treatment naïve, documented to 
have no evidence of metastatic disease prior to study entry, who are between Day 29 and Day 90
post-RP, whose PSA is ≤0.2 ng/mL at study entry, and who have recovered from surgery, per the 
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clinical judgment of the investigator. Upon completion of the sub-study, participants will be 
transitioned into the main ApaRP study protocol beginning at Cycle 2 Day 1. 
The sub-study will be conducted in approximately 6 urology practices already conducting the main 
ApaRP study. There will be one study intervention group receiving relugolix monotherapy for 
2 weeks followed by coadministration with apalutamide for 1 cycle (28 days). Treatment with 
relugolix will start following screening and completion of RP and no later than postoperative 
Day 90. Coadministration of apalutamide will start 14 days after initiation of relugolix 
monotherapy. Serum testosterone will be measured on Day –14 (ie, day of starting relugolix 
administration), Day 1 (ie, the day of starting coadministration with apalutamide), and Day 28. If 
a participant does not achieve a serum testosterone <50 ng/dL on Day 1 following 14 days of 
relugolix monotherapy, relugolix will be discontinued and the participant will switch to 
intramuscular ADT and the main ApaRP study and that participant will be replaced in the 
sub-study. If a participant achieves a serum testosterone <50 ng/dL on Day 1 following 14 days of 
relugolix monotherapy, coadministration with apalutamide will begin. As assessed on Day 28, if 
the coadministration of apalutamide and relugolix achieves and maintains a serum testosterone 
<50 ng/dL through Day 28 of the sub-study, participants will be given the opportunity to continue 
relugolix and apalutamide as part of the main ApaRP study. If the coadministration of apalutamide 
and relugolix does not achieve and maintain a testosterone <50 ng/dL through Day 28 of the 
sub-study in 2 or more participants, all participants on the sub-study will discontinue relugolix and 
switch to intramuscular ADT plus apalutamide as part of the main ApaRP study.
The sub-study will have 12 participants. If 2 or more participants have a testosterone ≥50 ng/dL
on Day 28, the sub-study will be considered negative and all participants will switch to 
intramuscular ADT in the main ApaRP protocol. If 0 or 1 participant has a testosterone ≥50 ng/dL, 
the sub-study will continue until all 12 participants have been enrolled.
If a participant ends the sub-study early (ie, due to treatment non-compliance or not achieving a 
testosterone <50 ng/dL on Day 1 after relugolix monotherapy), that participant will be replaced in 
order to enroll 12 participants total. If the sub-study is terminated early due to lack of efficacy (ie,
≥2 participants have a testosterone ≥50 ng/dL on Day 28) or safety (ie, ≥2 participants have 
prolonged QTc (>ULN) on Day 28), no further participants will be enrolled into the sub-study.
The timing and frequencies of study assessments are presented in the sub-study SoA 
(Section 10.13.3, Appendix 13). Efficacy assessments include serum testosterone and will be 
assessed at baseline (Day -14), after 14 days of relugolix monotherapy (Day 1), and after 28 days 
of coadministration of apalutamide and relugolix. A serum testosterone <50 ng/dL is considered 
castrate and the gold standard for indicating castration while on ADT. Study enrollment is defined 
as the day when the participant receives the first dose of relugolix monotherapy after having met 
all prescreening criteria. Adverse events will be assessed continuously from the time of enrollment 
and during treatment. A 12-lead electrocardiogram (ECG) will be conducted at screening, after 14 
days of relugolix monotherapy, and after 28 days of apalutamide and relugolix coadministration, 
to examine QT prolongation. If any participant has a prolonged QTc at either Day 1 or Day 28,
that participant will be removed from the study completely and replaced in the sub-study. If 
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2 participants have prolonged QTc at Day 28 the sub-study will terminated and any participants
currently on the combination of relugolix and apalutamide will be evaluated for potentially 
changing to intramuscular ADT.
A diagram of the study design is provided in Section 10.13.2, Appendix 13, Schema. 
10.13.6.2.
Scientific Rationale for Study Design
The single-arm, open-label design is appropriate to evaluate the pharmacodynamic effect of a new 
oral ADT medication with apalutamide. Additionally, stopping rules can be quickly implemented 
with this design (see Section 10.13.6.1, Appendix 13 Overall Design for stopping rules).
Scientific Rationale for the main ApaRP study design can be found in Section 4.2, Scientific 
Rationale of the main protocol.
10.13.6.3.
Justification for Dose
The dose of 240 mg once daily apalutamide and 120 mg once daily relugolix following a loading 
dose of 360 mg relugolix are approved doses per their respective USPIs.
10.13.6.4.
End of Study Definition
End of Study Definition
The sub-study EOS is defined as the date of the last participant’s enrollment in the sub-study 
+6 weeks or discontinuation of all study participants from the sub-study, whichever occurs first. 
All participants will be transitioned to the main ApaRP study following the sub-study EOS visit.
Study Completion Definition
Participants will be considered to have completed the sub-study if they have completed EOS 
assessments. Participants who prematurely discontinue sub-study intervention for any reason 
before sub-study completion will not be considered to have completed the sub-study. If a 
participant misses a dose for ≥3 days, the investigator should consult the sponsor regarding 
continuation of the sub-study.
10.13.7.
Study Population
The sub-study population will use the criteria of the main ApaRP study. Refer to Section 5 of the 
main ApaRP protocol for details of the study population. Participants must also be willing to 
participate in the sub-study and should not have any allergy, hypersensitivity, or contraindications
to the administration of relugolix per the ORGOVYX USPI.
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10.13.8.
Study Intervention
10.13.8.1.
Study Intervention Administered
Apalutamide
The sub-study intervention apalutamide, 240 mg (four 60 mg tablets, slightly yellowish to greyish
green oblong film-coated tablets, debossed with “AR 60” on one side), will be provided as tablets 
for oral administration. Participants will be instructed to take their assigned dose of the sub-study 
intervention orally once daily for 28 days per the ERLEADA USPI. Apalutamide can be taken 
with or without food. If a participant experiences a ≥Grade 3 toxicity or an intolerable side effect, 
hold dose until symptoms improve to ≤Grade 1 or original grade, then resume at the same dose or 
a reduced dose (180 mg or 120 mg), if warranted. If a participant remains off apalutamide for 
≥3 days, the participant may be withdrawn from the sub-study and switched to the main ApaRP 
study after discussing with the sponsor. Participants experiencing treatment related seizure of any 
grade will have apalutamide permanently discontinued.
Relugolix
The sub-study intervention relugolix, 120 mg with a loading dose of 360 mg (three 120 mg tablets, 
light red, almond-shaped, film-coated, debossed with “R” on one side and “120” on the other side), 
will be provided as tablets for oral administration. Participants will be instructed to take their 
assigned dose of the sub-study intervention orally once daily for 42 days per the ORGOVYX
USPI. Relugolix can be taken with or without food. If a participant misses relugolix for ≥3 days, 
the participant may be withdrawn from the sub-study and switched to the main ApaRP study after 
discussing with the sponsor. 
Description of Interventions
Sub-study interventions administration must be captured in the source documents and the 
electronic case report form (eCRF). Sub-study site personnel will instruct participants on how to 
store sub-study interventions for at-home use as indicated for this protocol.
Apalutamide will be manufactured and provided under the responsibility of the sponsor. Refer to 
the IB11 for a list of excipients and the ERLEADA USPI.
Relugolix, an FDA approved and commercially available oral ADT, not provided by the sponsor, 
will be administered per the ORGOVYX USPI during the sub-study and the main ApaRP study if 
participants continue relugolix coadministration (see Section 10.13.6.1, Appendix 13, Overall 
Design for details of relugolix continuation in the main ApaRP study). For further information on 
relugolix refer to the ORGOVYX USPI. For a definition of apalutamide overdose, refer to Section 
6.7, Treatment of Overdose, in the main ApaRP protocol.
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10.13.8.2.
Preparation/Handling/Storage/Accountability
Preparation/Handling/Storage
Refer to the respective USPIs for guidance on apalutamide and relugolix preparation, handling, 
and storage.
Accountability
The investigator is responsible for ensuring that all sub-study interventions received at the site are
inventoried and accounted for throughout the sub-study. The sub-study interventions administered 
to the participant must be documented on the intervention accountability form. All sub-study 
interventions will be stored and disposed of according to the sponsor’s instructions. Sub-study site 
personnel must not combine contents of the sub-study intervention containers.
Sub-study interventions must be handled in strict accordance with the protocol and the container 
labels, and must be stored at the sub-study site in a limited-access area or in a locked cabinet under 
appropriate environmental conditions. Unused sub-study interventions and sub-study interventions 
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 sub-study interventions, or 
used returned sub-study interventions for destruction, will be documented on the intervention 
return form. When the sub-study site is an authorized destruction unit and sub-study intervention 
supplies are destroyed on-site, this must also be documented on the intervention return form.
Sub-study interventions should be dispensed under the supervision of the investigator or a qualified 
member of the study-site personnel, or by a hospital/clinic pharmacist. Sub-study interventions 
will be supplied only to participants participating in the sub-study. Returned sub-study 
interventions must not be dispensed again, even to the same participant. Sub-study interventions 
may not be relabeled or reassigned for use by other participants. The investigator agrees neither to 
dispense the sub-study intervention from, nor store it at, any site other than the sub-study sites 
agreed upon with the sponsor. Further guidance and information for the final disposition of unused 
sub-study interventions are provided in the Study Site Investigational Product and Procedures 
Manual.
10.13.8.3.
Study Intervention Compliance
Sub-study site personnel will maintain a log of all sub-study interventions dispensed. Sub-study 
interventions supplied for each participant will be inventoried and accounted for.
10.13.8.4.
Dose Modification
Any dose adjustment should be overseen by medically qualified study-site personnel (principal or 
sub-investigator unless an immediate safety risk appears to be present).
In case a dose modification of apalutamide is necessary, apalutamide will be administered per
ApaRP main protocol Section 10.9, Appendix 9, Recommendations for Management of 
Drug-related Rash.
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10.13.8.5.
Treatment of Overdose
Refer to the main ApaRP protocol Section 6.7, Treatment of Overdose.
10.13.8.6.
Concomitant Therapy
Concomitant therapies must be recorded throughout the sub-study from the time of first dose of 
sub-study intervention (Day -14) to the last sub-study visit (Day 28). Concomitant therapies 
occurring after sub-study EOS will be captured as part of the main ApaRP protocol (Section 6.8, 
Concomitant Therapy).
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, or other specific categories of interest) different from the sub-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.
Prohibited concomitant medications are outlined as part of the main ApaRP study in Section 10.6, 
Appendix 6, Prohibited Concomitant Medications. Concomitant therapy restrictions are outlined 
in Section 10.7, Appendix 7, Restricted Concomitant Medications.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.
10.13.9.
Discontinuations of study intervention and Participant 
discontinuations/withdrawal
10.13.9.1.
Discontinuation of Study Intervention
A participant's sub-study interventions must be discontinued if:

The participant withdraws consent to receive sub-study interventions

The investigator believes that for safety reasons or tolerability reasons (eg, AE) it is in the 
best interest of the participant to discontinue sub-study interventions

Noncompliance with sub-study interventions administration

The sub-study is terminated (Refer to Section 10.13.6.1, Appendix 13, Overall Design for 
details)

Participants experiencing treatment-related seizure of any grade will have apalutamide 
permanently discontinued
If a participant discontinues sub-study interventions for any reason before the end of the sub-study, 
then the last scheduled sub-study assessments should be obtained. If a participant misses doses of 
either sub-study intervention for ≥3 days, the investigator should consult the sponsor regarding 
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continuation in the sub-study. If a participant discontinues sub-study interventions due to disease 
progression, the subsequent treatment including radiation will be captured in the eCRF, if known. 
10.13.9.2.
Rechallenge
Refer to the main ApaRP study protocol Section 7.1.1, Rechallenge for details.
10.13.9.3.
Participant Discontinuation/Withdrawal From the Study
A participant will be withdrawn from the sub-study for any of the following reasons:
•
Lost to follow-up
•
Withdrawal of consent
•
Investigator’s discretion
•
Seizure
•
Death
When a participant withdraws before sub-study completion, the reason for withdrawal is to be 
documented in the eCRF and in the source document. If the reason for withdrawal from the 
sub-study is withdrawal of consent, then no additional assessments are allowed. Refer to main 
ApaRP protocol Section 7.2, Participant Discontinuation/Withdrawal From the Study and Section 
7.2.1, Withdrawal From the Use of Research Samples for further details.
10.13.9.4.
Lost to Follow-up
To reduce the chances of a participant being deemed lost to follow-up, prior to study entry, 
attempts should be made to obtain contact information from each participant, eg, home, work, and 
mobile telephone numbers and email addresses for both the participant as well as appropriate 
family members.
Participants will be considered lost to follow-up if they fail to return for scheduled visits and are
unable to be contacted by the study site. A participant cannot be deemed lost to follow-up until all 
reasonable efforts made by the study-site personnel to contact the participant are deemed futile. 
Refer to main ApaRP protocol Section 7.3 Lost to Follow-up for further details.
10.13.9.5.
National Disaster/Extra Ordinary Circumstances
Refer to main ApaRP protocol Section 7.4, National Disaster/Extra Ordinary Circumstances for 
details.
10.13.10.
Study Assessments and Procedures
Overview
The sub-study Schedule of Activities summarizes the frequency and timing of efficacy and safety 
measurements applicable to this sub-study. Refer to Section 10.13.3, Appendix 13, Schedule of 
Activities for the timing and frequency of sample collections.
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Blood collections should be kept as close to the specified time as possible. Actual dates and times 
of assessments will be recorded in the source documentation and eCRF.
The total blood volume for the sub-study is approximately 30 mL.
Repeat of unscheduled samples may be taken for technical issues with the samples.
Sub-Study-Specific Materials
The investigator will be provided with the following information in addition to what is provided 
as part of the main ApaRP protocol (refer to Section 8, Study-Specific Materials for details):
•
ICF sub-study template
•
Sub-study pill diary (found in Section 10.14, Appendix 14)
10.13.10.1.
Efficacy Assessments
Efficacy assessments include serum testosterone and will be assessed prior to the first dose of 
relugolix monotherapy (Day -14), prior to starting apalutamide coadministration (Day 1), and 
following 28 days of apalutamide and relugolix coadministration, per the sub-study SoA. A 
testosterone level <50 ng/dL will be considered an indicator of castration.
10.13.10.2.
Safety Assessments
Participants will be monitored for safety from the beginning of the study treatment (Day -14) and 
at each sub-study visit. Events related to and associated with the recovery from the pre-planned 
RP will not be collected.
Adverse events will be reported and followed by the investigator as specified in the main ApaRP 
protocol Section 8.3, Adverse Events and Serious Adverse Events and Section 10.4, Appendix 4, 
Adverse Events, Serious Adverse Events, Product Quality Complaints, and Other Safety 
Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up, and Reporting.
Any clinically relevant changes occurring during the sub-study must be recorded on the AE section 
of the eCRF.
Any clinically significant abnormalities persisting at the end of the sub-study/early withdrawal 
will be followed by the investigator until resolution or until a clinically stable condition is reached.
The sub-study will include the evaluations of safety and tolerability included in the main ApaRP 
protocol as noted in Section 8.2.1, Physical Examinations, and 8.2.2, Vital Signs.
10.13.10.2.1. Electrocardiograms
A 12-lead ECG will be conducted at screening, after 14 days of relugolix monotherapy, and after 
28 days of apalutamide and relugolix coadministration, to examine QT prolongation. During the 
collection of ECGs, participants should be in a quiet setting without distractions (eg, television, 
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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.
10.13.10.2.2. Adverse Events and Serious Adverse Events
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 sub-study.
For further details on AEs and SAEs (Definitions and Classifications; Attribution Definitions; 
Severity Criteria; Special Reporting Situations; Procedures) as well as product quality complaints, 
refer to the main ApaRP protocol Section 8.3, Adverse Events and Serious Adverse Events, 
Section 10.4, Appendix 4, Adverse Events, Serious Adverse Events, Product Quality Complaints, 
and Other Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up, 
and Reporting.
10.13.11.
Statistical Considerations
Statistical analysis will be done by the sponsor or under the authority of the sponsor.
The primary hypothesis of this sub-study is that coadministration of apalutamide 240 mg once 
daily with relugolix 120 mg once daily (following a loading dose of 360 mg) will achieve and 
maintain castrate levels of testosterone (<50 ng/dL). Clinical decision rule is that if 2 or more 
participants have a testosterone ≥50 ng/dL on Day 28, the sub-study will be considered negative. 
The 95% 1-sided upper limit for the observed incidence of proportion of patients not able to 
maintain castrate levels is 22.1% if no participant out of 12 has a testosterone ≥50 ng/dL and 33.9% 
if 1 participant out of 12 has a testosterone ≥50 ng/dL. Percentage of participants maintaining 
testosterone <50 ng/dL through Day 28 will be summarized descriptively.
Once one cycle (28 days) of the coadministration of apalutamide and relugolix has completed, the 
participants will transition to the treatment schedule of the main ApaRP protocol beginning at 
Cycle 2 Day 1. Safety data collected during the coadministration of apalutamide and relugolix will 
be summarized descriptively. Data for participants transitioned to the main ApaRP protocol 
schedule will be summarized at the end of the study using methods similar to the main protocol 
analysis.
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10.15. Appendix 15: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC).
Amendment 1 (12 August 2020)
Overall Rationale for the Amendment: The main reason for the amendment is to add visit windows, 
administrative changes, and specify the unit for prostate-specific antigen (PSA) level for high risk 
population.
Section number
and Name
Description of Change
Brief Rationale
1.1 Synopsis Overall 
Design; 4.1 Overall 
Design; 4.4 End of 
Study Definition
Definition of end of study (EOS) is updated to:
“The EOS is defined as the date of last 
participant’s enrollment +24 months or 
discontinuation of all study participants from the 
study, whichever occurs first.”
Clarified the definition of EOS to 
allow some participants to have 
follow-up visits beyond 24 months 
from enrollment.
1.1 Synopsis Overall 
Design, Intervention 
Groups and 
Duration; 4.1 
Overall Design; 6.1 
Study Intervention 
Administration
Text is added to define treatment with apalutamide; 
text has been reworded to define treatment duration 
of 12 cycles for apalutamide.
To define treatment cycles and 
treatment duration.
1.1 Synopsis Overall 
Design, Intervention 
Groups and 
Duration; 6.1 Study 
Intervention 
Administration
Text is added to mention the use of study 
intervention (apalutamide) as per its United States 
Package Insert (USPI).
Added text to accommodate 
prospective changes in apalutamide 
label.
1.1 Synopsis 
Biomarker 
Evaluations; 8.6 
Biomarkers 
Text added to specify that full histopathology 
report will be sent along with the primary biopsy 
specimen to sponsor’s laboratory partner.
To clarify the steps in biomarker 
assessment.
1.3 Schedule of 
Activities (SoA)
Updated footnote j to: “Tissue sample to be 
collected from the primary biopsy and sent to 
sponsor’s laboratory partner along with a copy of 
the full histopathology report of the biopsy 
specimen.”
1.2 Schema; 5.1 
Inclusion criteria
Figure 1 and inclusion criterion 5 are updated to 
include the unit of PSA level as ng/mL.
Added the unit of PSA for clarity.
1.3. Schedule of 
Activities (SoA)
‘Focused physical examinations including skin 
assessment’ is added at Baseline.
Text added to be consistent with 
Inclusion criterion 4 have recovered 
from radical prostatectomy (RP) 
procedure, per the clinical 
judgement of the investigator.
1.3. Schedule of 
Activities (SoA)
Footnote is updated to add recording of alcohol 
intake directly in the eCRF.
Text added to record history of 
alcohol intake directly into the 
eCRF in alignment with lifestyle 
restrictions #1).
Appendix 3, 10.3.10 
Source Documents
Text to include history of alcohol intake including 
type, usage, amount, and frequency is added to the 
list of data that will be recorded directly into the 
electronic Case Report Form (eCRF).
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Section number
and Name
Description of Change
Brief Rationale
1.3 Schedule of 
Activities (SoA)
New footnotes a and b are added to allow a visit 
window of ±7 calendar days for Visits 2 through 8 
and a visit window of ±14 calendar days, Visit 9 
onwards for all follow-up visits. The subsequent 
footnotes are rearranged alphabetically and are 
updated in the SoA.
Visit windows are added to allow 
scheduling flexibility.
1.3 Schedule of 
Activities (SoA)
New footnote i added for plasma samples:
“Collected at baseline, 12 months or end of 
treatment, and at 24 months or progression 
(whichever comes first).”
Added to clarify the guidance of 
‘whichever comes first’
1.3. Schedule of 
Activities (SoA)
New footnotes k and l are added to start collection 
of concomitant therapies and adverse events (AEs) 
from the time of first dose of apalutamide.
Added the day of commencing 
concomitant therapy and AE 
collection to be consistent 
throughout the protocol and in 
agreement with Global Medical 
Safety (GMS) to collect AEs 
beginning with dosing (and not to 
collect AEs that could be associated 
with RP).
8.3.1 Time Period 
and Frequency for 
Collecting AE and 
SAE Information; 
Appendix 4, 10.4.1 
AE Definitions and 
Classifications
Reporting of AEs from the time after enrollment is 
changed to Reporting of AEs from the time after 
the participant receives the first dose of 
apalutamide. 
8.3.1 Time Period 
and Frequency for 
Collecting AE and 
SAE Information
Text added to mention that AEs will additionally 
be monitored during phone calls with the 
participants. 
To include all timepoints for AE 
monitoring.
5.2. Exclusion 
Criteria
Exclusion criterion 1 is updated to exclude 
presence of soft tissue/bone metastasis or 
metastasis in distant lymph nodes.
Exclusion Criteria 9 is updated with “any of the 
following within 6 months prior to baseline” at the 
beginning of the sentence.
To clarify the metastasis criterion.
Rearranged the wording to clarify 
that the 6 months period applies to 
all the conditions listed therein.
7.1. Discontinuation 
of Study 
Intervention
Text is added to record the subsequent therapy, if 
known, in the eCRF for participants discontinuing 
the study intervention due to disease progression.
Added instructions to record 
subsequent therapy.
Deleted the text: “Study intervention assigned to 
the participant who discontinued study intervention 
may not be assigned to another participant.”
To disallow reassignment of study 
intervention as this is not relevant 
for an open-label study.
7.2.1 Withdrawal 
From the Use of 
Research Samples; 
Appendix 3, 10.3.1 
Regulatory and 
Ethical 
Considerations
‘Optional research sample’ is changed to ‘research 
sample’ and the sentences are reworded 
accordingly.
The provision to keep research 
samples optional is deleted as this 
is not considered optional 
collection.
7.2.1 Withdrawal 
From the Use of 
Research Samples
Paragraph on "withdrawal from optional research 
samples while remaining in the main study" is 
deleted.
The paragraph is not applicable as 
the provision to keep research 
samples optional is deleted.
Provision of separate Informed Consent Form 
(ICF) for optional research is deleted.
Separate ICF is not applicable for 
research samples as the details are 
included in the main ICF.
8.3.8 Adverse 
Events of Special 
Interest
Added text:
“For apalutamide, there are no non-serious AEs of 
special interest identified.”
To provide background information 
on apalutamide AEs of special 
interest.
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Section number
and Name
Description of Change
Brief Rationale
“Rash is an AE of clinical interest” is changed to 
“Rash is an AE of special interest”.
Text is modified for consistency 
with the heading.
Appendix 4, 10.4.3 
Severity Criteria
Text to grade AEs as per Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 
is added.
Text to grade AEs into mild, moderate, and severe 
is deleted.
Changed the AE grading criteria to 
be consistent with the standard for 
oncology studies.
Appendix 10, 10.10 
Phone Calls With 
Participants
Added new bullet points to the ‘Guide for 
discussion during phone calls’
Added additional bullets for clarity 
on guidance for phone calls.
Throughout protocol
Minor grammatical, spelling, and formatting 
changes are made.
Minor errors were noted.
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Martini A, Gangdaglia G, Karnes RJ, et al. Defining the Most Informative Intermediate Clinical Endpoints for 
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National Comprehensive Cancer Network Guidelines for Treatment of Prostate Cancer; Version 4, 2019; 
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adjuvant radiotherapy after radical prostatectomy for prostate cancer with poor pathologic features. Int J Radiat 
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SAP_001.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Final Version, Date: 14-Dec-2023
Janssen Research & Development
Statistical Analysis Plan
A Multi-center, Open-label, Single-arm Phase 2 Study of the Adjuvant Treatment of 
Apalutamide and Androgen Deprivation Therapy (ADT) in Treatment-naïve Participants Who 
Have Undergone Radical Prostatectomy (RP) for Non-metastatic Prostate Cancer and Who Are 
at High Risk for Metastases
Protocol 56021927PCR2041; Phase 2
JNJ-56021927 (Apalutamide)
Status:
Final Version
Date:
14-Dec-2023
Prepared by:
Janssen Research & Development, LLC
Document No.: EDMS-RIM-140616
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company 
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or 
otherwise.
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JNJ-56021927 (Apalutamide)
Statistical Analysis Plan: 56021927PCR2041
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
2
Status: Final Version, Date: 14-Dec-2023
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
VERSION HISTORY..................................................................................................................................... 4
1.
INTRODUCTION.................................................................................................................................. 5
1.1.
Objectives and Endpoints ................................................................................................................ 5
1.2.
Study Design.................................................................................................................................... 5
2.
STATISTICAL HYPOTHESES............................................................................................................ 6
3.
SAMPLE SIZE DETERMINATION...................................................................................................... 6
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS....................................................................... 6
5.
STATISTICAL ANALYSES................................................................................................................. 7
5.1.
General Considerations ................................................................................................................... 7
5.1.1.
Visit Windows ............................................................................................................................... 7
5.2.
Participant Dispositions.................................................................................................................... 8
5.3.
Primary Endpoint(s) Analysis........................................................................................................... 8
5.3.1.
Definition of Endpoint(s) ............................................................................................................... 8
5.3.2.
Estimand....................................................................................................................................... 8
5.3.2.1.
Population:................................................................................................................................. 9
5.3.2.2.
Variables:................................................................................................................................... 9
5.3.2.3.
Intercurrent Events and Strategies:........................................................................................... 9
5.3.2.4.
Population level summary: ...................................................................................................... 10
5.3.3.
Analysis Methods........................................................................................................................ 10
5.4.
Secondary Endpoint(s) Analysis .................................................................................................... 11
5.4.1.
Analysis Methods........................................................................................................................ 11
5.5.
Exploratory Endpoint(s) Analysis ................................................................................................... 11
5.5.1.
Analysis Methods........................................................................................................................ 11
5.6.
Safety Analyses ............................................................................................................................. 11
5.6.1.
Extent of Exposure ..................................................................................................................... 11
5.6.2.
Adverse Events........................................................................................................................... 12
5.6.3.
Additional Safety Assessments (if applicable)............................................................................ 13
5.6.3.1.
Clinical Laboratory Tests......................................................................................................... 13
5.6.3.2.
Vital Signs and Physical Examination Findings....................................................................... 14
5.6.3.3.
Electrocardiogram ................................................................................................................... 14
5.7.
Other Analyses............................................................................................................................... 14
5.7.1.
Pharmacokinetics ....................................................................................................................... 14
5.7.2.
Immunogenicity........................................................................................................................... 14
5.7.3.
Pharmacodynamics .................................................................................................................... 14
5.7.4.
Pharmacokinetic/Pharmacodynamic Relationships ................................................................... 14
5.7.5.
Biomarkers.................................................................................................................................. 14
5.7.6.
Health Economics....................................................................................................................... 14
5.7.7.
Other Variables and/or Parameters............................................................................................ 14
5.7.8.
Definition of Subgroups .............................................................................................................. 14
5.8.
Interim Analyses............................................................................................................................. 15
5.8.1.
Data Monitoring Committee (DMC) or Other Review Board ...................................................... 15
6.
SUPPORTING DOCUMENTATION .................................................................................................. 15
6.1.
Appendix 1 List of Abbreviations.................................................................................................... 15
6.2.
Appendix 2 Changes to Protocol-Planned Analyses ..................................................................... 15
6.3.
Appendix 3 Demographics and Baseline Characteristics.............................................................. 15
6.4.
Appendix 4 Protocol Deviations ..................................................................................................... 16
6.5.
Appendix 5 Prior and Concomitant Medications............................................................................ 16
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6.6.
Appendix 6 Medical History ........................................................................................................... 16
6.7.
Appendix 7 Intervention Compliance ............................................................................................. 16
6.8.
Appendix 8 Adverse Events of Special Interest............................................................................. 17
6.9.
Appendix 9 Medications of Special Interest................................................................................... 17
6.10.
Appendix 10 Laboratory Toxicity Grading...................................................................................... 17
7.
REFERENCES................................................................................................................................... 17
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VERSION HISTORY
Table 1 – SAP Version History Summary
SAP Version
Approval Date
Change
Rationale
1.0
18-Aug-2020
Not Applicable
Pre-FPI Stable version
2.0
14-Dec-2023
Update general considerations 5.1
Provided a conservative approach 
for confidence intervals of 
survival function at specific time 
point in case no events have 
occurred by the given time point
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1.
INTRODUCTION
This statistical analysis plan (SAP) describes the definitions of analysis sets, derived variables,
and statistical methods for all planned statistical analyses for protocol 56021927PCR2041.
1.1.
Objectives and Endpoints
Objectives
Endpoints
Primary

To assess if the combination of apalutamide and ADT
in participants with high-risk localized prostate cancer
improves the BCR-free rate.

BCR-free rate at 24 months. BCR is
defined
as
a
confirmed
PSA
>0.2 ng/mL.
Secondary

To determine the BCR-free rate at 12 months.

BCR-free rate at 12 months.

To determine the time to serum testosterone recovery.

Testosterone recovery rate at 18 and
24 months.
Exploratory

To evaluate the incidence of rash.

Incidence of rash.
Key: ADT=androgen-deprivation therapy; BCR=biochemical recurrence; PSA=prostate-specific antigen
1.2.
Study Design
This is a  single-arm,  open-label,  multi-center  study  of  apalutamide  and  ADT  in  96
participants with high risk localized prostate cancer who are treatment naïve, documented to 
have no evidence of metastatic disease prior to study entry, who are no more than 60 days post 
radical prostatectomy (RP), whose prostate-specific antigen (PSA) is ≤0.2 ng/mL at study entry 
and who have recovered from surgery, per the clinical judgement of the investigator. 
There will be one intervention group receiving apalutamide with ADT of investigator’s choice 
(3-month depot preferred) for 12 months. Treatment with apalutamide and ADT will start 
following screening and completion of RP and no later than postoperative Day 60. 
Approximately 30 days post-treatment, a safety follow-up examination will be completed (end 
of treatment visit). There will be a follow-up period during which serum PSA and testosterone 
levels will be measured and clinical status monitored every 6 months after the completion of 
treatment until the end of the study (EOS). The EOS is defined as the date of last participant’s 
enrolment + 24 months or discontinuation of all study participants from the study, whichever 
occurs first. Study enrollment is defined as the day when the participant receives the first dose 
of apalutamide after having met all pre-screening criteria.
A diagram of the study design is provided below.
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Key: ADT=androgen deprivation therapy; EOS=end of study; N=number of participants; 
post-op=postoperative; PSA=prostate-specific antigen; RP=radical prostatectomy.
2.
STATISTICAL HYPOTHESES
The primary hypothesis of this study is that adjuvant treatment with apalutamide and ADT will
improve the BCR-free rate at 24 months in the treatment-naïve, non-metastatic prostate cancer
population who are at high risk for the development of metastases. The null hypothesis is that 
the BCR-free rate at 24 months is ≤ 76%.
3.
SAMPLE SIZE DETERMINATION
It is assumed that BCR-free rate follows an exponential distribution with a constant hazard rate.
It is estimated that approximately 94 participants accrued over approximately 1 year, treated for
12 months and followed for an additional 12 months would be required to provide at least
80% power in detecting a 10% absolute increase in BCR-free rate at 24 months of 76%1 to 86% 
at a 1-tailed significance level of 0.05. Sample size was calculated using PASS 15 (Power 
Analysis and Sample Size Software [2017]2 .
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS
Following analysis sets will be defined for analysis purposes.

Safety Analysis Set: The safety analysis set will consist of all participants who received at 
least 1 dose of apalutamide. All safety analyses will be performed using the safety 
analysis set.

Modified Intent-to-Treat Analysis Set: The Modified Intent-to-Treat set consist of all 
participants who satisfy all the following:

Met all eligibility criteria and are enrolled in the study
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
Received at least 1 dose of apalutamide

Had a baseline PSA and at least 1 post-treatment PSA assessment.
This analysis set will be used for efficacy analyses of endpoints and subject disposition,
unless otherwise specified.
5.
STATISTICAL ANALYSES
5.1.
General Considerations
Study Day will be calculated in reference to the date of first dose of study drug (apalutamide).
Positive study days will count forward from Study Day 1. Study Day -1 will be the day before
Study Day 1, and all subsequent negative study days will be measured backward from Study
Day -1. There will be no Study Day 0.
The first dose starts on Day 1 of Cycle 1.
Unless otherwise specified, baseline value is defined as the closest measurement prior to the first
dose of study drug. Change from baseline will be defined as (post-baseline value – baseline
value).
Treatment Duration will be calculated as the duration of time from the date of the first dose of
study drug (apalutamide) to the date of last dose of the study drug, i.e., date of last dose –
date of first dose + 1.
Time to Event endpoints will be calculated as the number of days from the start of the study drug
to the date of the event of interest, i.e., date of event of interest – date of first dose + 1. Time
to event or duration of event endpoints will be based on the actual date of the event, not visit 
number or visit label. Confidence intervals of survival function at specific time point will be 
calculated using Kaplan-Meier method. In case no events have occurred by the given time point, 
a conservative approach will be used by assuming one event at the time point among subjects 
still at risk.
Continuous/numerical variables will be summarized using mean, standard deviation (SD),
median, minimum, and maximum. Categorical variables will be summarized using count and
percentage. In general, means and other measures of central tendency will be displayed with one
more decimal digit than collected, and standard deviations and other measures of variability will
be displayed with two decimal digits more than collected. For frequency counts of categorical
variables, categories for which the counts are zero will be displayed for the sake of
completeness. For example, if no subject discontinued due to “withdrawal of consent”, this
reason would still be included in the table but with a count of 0.
5.1.1.
Visit Windows
The reference day is Cycle 1 Day 1 of the treatment. A visit window of ±7 calendar days for 
visits 2 through 8 and a visit window of ±14 calendar days for visit 9 onwards for all follow-up 
visits are set up for this study.
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5.2.
Participant Dispositions
The number of participants in the following disposition categories will be summarized during 
treatment period using safety analysis set:

Participants enrolled

Participants who received study treatment

Participants who completed the study

Participants who discontinued study treatment

Reasons for discontinuation of study treatment

Participants who terminated study prematurely

Reasons for termination of study
A listing of participants will be provided for the following categories:

Participants who discontinued study treatment

Participants who terminated study prematurely
5.3.
Primary Endpoint(s) Analysis
The primary endpoint of the study is BCR-free rate at 24 months. BCR is defined as a confirmed 
PSA > 0.2 ng/mL.
BCR-free rate will be estimated from primary efficacy variable (time to BCR) using Kaplan-Meier
method in modified intent-to-treat analysis set.
5.3.1.
Definition of Endpoint(s)
Time to confirmed BCR will be defined as the time between the date of the first dose of study 
drug (apalutamide) and the date of the first occurrence of confirmed PSA > 0.2 ng/mL. 
Confirmation of PSA value will be done within 3-4 weeks regardless of study visit and timing. 
Depending on timing, this may be captured as an unscheduled visit.
Subjects without confirmed PSA > 0.2 ng/mL (including subjects who are lost-to-follow up) will 
be censored on their last PSA date during treatment phase of the study. Additional censoring 
rules are provided in 5.3.3.
The time to unconfirmed BCR (from the first dose of the study drug to the first occurrence of 
PSA > 0.2 ng/mL) will be used for sensitivity analysis of the primary endpoint using similar 
methodology.
5.3.2.
Estimand
The primary estimand, the main clinical quantity of interest to be estimated in the study, is defined 
by the following 4 components -
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IE: Death
PSA value censored at the last 
PSA assessment prior to the 
time of death
Non-informative 
censoring as per 
censoring rule
End of study
(Administratively) censored at 
the last PSA assessment prior 
to the end of the study
Non-informative 
censoring as per 
censoring rule
5.4.
Secondary Endpoint(s) Analysis

BCR-free rate at 12 months

Testosterone recovery rate at 18 and 24 months. Serum testosterone ≥150 ng/dL is defined 
as testosterone recovery.
5.4.1.
Analysis Methods
Analyses of secondary efficacy endpoints will be performed using the methods similar to those
for the primary endpoint using modified intent-to-treat analysis set.
Time to testosterone recovery will be analyzed using Kaplan-Meier (KM) method. Quartiles of 
the distribution along with 95% CI will be estimated. Estimates of testosterone recovery rates at 
13-, 18-, and 24-month together with 95% CI will be estimated. Primary analysis censoring rule 
(5.3.3) as it relates to testosterone, will be used for these analyses.
5.5.
Exploratory Endpoint(s) Analysis

Incidence of rash
5.5.1.
Analysis Methods
Rash is an AE of clinical interest to be assessed by NCI-CTCAE Version 5.0 criteria. Incidence
of rash will be summarized descriptively using safety analysis set. Incidence rates will be
summarized with frequency and percentage by system organ class (SOC) and preferred term (PT),
with all subjects treated with study drug as the denominator. In addition, incidence rate will also
be summarized by severity and relationship to the study drug.
5.6.
Safety Analyses
The safety parameters to be evaluated are the incidence, intensity, and type of adverse events 
(AE), vital signs, ECG, and clinical laboratory results.
5.6.1.
Extent of Exposure
Treatment duration (in terms of cycles and in months) will be defined as the duration from the 
date of the first dose of study drug to the date of last dose of study drug. Descriptive summary 
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statistics for duration of apalutamide treatment (N, mean, SD, median, and range (minimum, 
maximum)) will be summarized using safety analysis set.
Treatment duration will be calculated as the number of days with dosing record divided by 28 (i.e.,
expected number of days in a cycle) and 30.4375 (i.e., number of days in a month calculated as 
365.25/12).
5.6.2.
Adverse Events
Subjects will be assessed for adverse events at each clinic visit (as specified in protocol Schedule 
of activities) while on the study. Adverse events (AEs) will be graded according to the NCI 
Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 (published on 27 
November 2017) and coded to preferred term and system organ class (SOC) using the MedDRA 
version 20.0 or later.
All AEs reported on or after the date of first dose until 30 days (inclusive) after the last dose
of study drug will be considered treatment-emergent and will be summarized.
AE incidence rates will be summarized with frequency and percentage by SOC and preferred
term, with all subjects treated as the denominator, unless otherwise specified. In addition, AE
incidence rates will also be summarized by severity and relationship to study drug. Treatment-
related AEs are those judged by the Investigator to be at least possibly related to the study
drug. AEs with missing severity or relationship to study drug will be classified as severe and
treatment-related, respectively. Subjects with multiple occurrences of events will only be counted
once at the maximum severity to study drug for each preferred team, SOC, and overall. Deaths
that occur within 30 days after the last dose of study drug are defined as on-study deaths.
Summary tables of the following AEs will be provided:

Overall summary of AEs: the number and percentage of subjects who experienced any
AE, number of subjects with Grade 3/4 AEs, any serious adverse event (SAE), any
treatment- related AE, treatment related Grade 3/4 AE, any treatment-related SAE,
AE
leading
to
treatment
discontinuation,
related
AE
leading
to
treatment
discontinuation, AE leading to death, related AE leading to death, and all deaths within 
30 days of last dose

All AEs by SOC and preferred term

Most frequent AEs by SOC and preferred term (reported in ≥5% of subjects in either
the investigational or control group)

All AEs by SOC, preferred term, and toxicity grade

Grades 3 or 4 AEs by SOC and preferred term

Grades 3 or 4 AEs by decreasing frequency of preferred term

Treatment-related AEs by SOC and preferred term

Treatment-related AEs by SOC, preferred term, and toxicity grade

Treatment-related AEs by decreasing frequency of preferred term
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
Treatment-related Grades 3 or 4 AEs by SOC and preferred term

Most frequent treatment-related Grades 3 and 4 AEs (reported in ≥5% of subjects in
either the investigational or control group)

Treatment-related Grades 3 or 4 AEs by decreasing frequency of preferred term

All AEs that led to death by SOC and preferred term

All AEs that led to study drug discontinuation by SOC and preferred term. Study
drug discontinuation will be determined from the End of Treatment CRF (where
reason for termination is “Adverse Event”) and the specific AE will be determined from
the AE eCRF page (where action taken is “Withdrawn from Study”)

All AEs that led to study drug discontinuation by SOC, preferred term, and toxicity grade

All AEs that lead to study drug dose modification by SOC and preferred term

All SAEs by SOC and preferred term

All SAEs by SOC, preferred term, and toxicity grade

Deaths by time period (Treatment Phase, Follow-up Phase) and cause of death
Subject listings of all Grades 3 or 4 AEs, all SAEs, AEs that led to study drug discontinuation,
dose modification, and all deaths will be provided as well. If there are any AEs attributed to
RP (e.g. lymphocele, intraoperative bleeding, postoperative bleeding, urinary incontinence),
listings of all AEs (or relevant tables if there is a large of proportion of these subjects)
will also be provided.
Narratives will be written for the following subjects in the final clinical study report:

Subjects who die due to treatment-related adverse events ≤30 days after the last dose
of study drug

Subjects who discontinue study drug due to adverse events

Subjects who have a treatment-related serious adverse event

Subjects who experience a seizure
Subjects who experience other Grade 3 or higher treatment-emergent adverse events of
special interest.
5.6.3.
Additional Safety Assessments (if applicable)
5.6.3.1.
Clinical Laboratory Tests
Study-specified laboratory assessments will be done only for PSA and testosterone (performed by 
local laboratory). Descriptive summary statistics of changes from baseline will be summarized at 
each scheduled time point. 
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5.6.3.2.
Vital Signs and Physical Examination Findings
N/A
5.6.3.3.
Electrocardiogram
Electrocardiograms (ECGs) (12-lead) will be recorded at Screening. Abnormalities noted at 
screening will be included in the medical history.
5.7.
Other Analyses
5.7.1.
Pharmacokinetics
N/A
5.7.2.
Immunogenicity
N/A
5.7.3.
Pharmacodynamics
N/A
5.7.4.
Pharmacokinetic/Pharmacodynamic Relationships
N/A
5.7.5.
Biomarkers
N/A
5.7.6.
Health Economics
N/A
5.7.7.
Other Variables and/or Parameters
N/A
5.7.8.
Definition of Subgroups
Consistency of apalutamide treatment effect will be evaluated across different subject 
subpopulations. Subgroup analyses for time to BCR and testosterone recovery endpoints will be 
conducted, contingent on the number of events, and will consider the following baseline 
characteristics.

Age

Baseline ECOG PS grade

Baseline Gleason score categories

Baseline Tumor stage (T; N)
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5.8.
Interim Analyses
No interim analysis is planned for this study.
5.8.1.
Data Monitoring Committee (DMC) or Other Review Board
No independent data monitoring committee (IDMC) is planned for this study.
A Steering Committee will be established to provide guidance and supervision for the study.
The committee chair will have medical expertise in the relevant therapeutic area.
6.
SUPPORTING DOCUMENTATION
6.1.
Appendix 1 List of Abbreviations
The list below will be updated as appropriate
ADT
androgen deprivation therapy
AE
adverse event
CI
confidence interval
CRF
case report form
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
DMC
Data Monitoring Committee
DPS
Data Presentation Specifications
ECG
electrocardiogram
eCRF
electronic case report form
IQ
interquartile
IVRS
interactive voice response system
IWRS
interactive web response system
MedDRA
Medical Dictionary for Regulatory Activities
PK
pharmacokinetic(s)
PP
per protocol
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
standard deviation
SMQs
standardized MedDRA queries
TEAE
treatment-emergent adverse event
WHO
World Health Organization
WHO-DD
World Health Organization Drug Dictionary
6.2.
Appendix 2 Changes to Protocol-Planned Analyses
To be updated as necessary and will be finalized before data base lock.
6.3.
Appendix 3 Demographics and Baseline Characteristics
The following parameters will be summarized using modified intent-to-treat analysis set:

Age, race, ethnicity, weight, height

Baseline ECOG PS grade
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
All classifications of Gleason score

Tumor stage (T; N)

Baseline value of PSA, testosterone
6.4.
Appendix 4 Protocol Deviations
Protocol deviations will be summarized using modified intent-to-treat analysis set. Protocol 
deviations will be reviewed on a case-by-case basis and major protocol deviations will be 
identified and summarized by the following example categories:

Deviation from inclusion/exclusion criteria that may affect efficacy endpoints

Administration of prohibited concomitant medication during the course of the study 
treatment period

Received disallowed concomitant treatments

Met withdrawal criteria but was not withdrawn

Any other deviation that impacts subject safety
The categories will be finalized prior to database lock.
6.5.
Appendix 5 Prior and Concomitant Medications
Prior and concomitant medications will be summarized using World Health Organization (WHO) 
Drug therapeutic class, and generic medication name using the safety analysis set. Prior
medications are those taken (with medication start date) prior to Cycle 1 Day 1. Concomitant
medications are those, other than study medication, taken during the Treatment Phase, i.e., with
medication start date on or prior to the End-of-Treatment visit and medication stop date on or after
Cycle 1 Day 1 or ongoing.
Subsequent prostate cancer therapies received after the Treatment Phase will be summarized by
treatment group using the safety analysis set. If the therapy is medication, then it will also be
summarized by WHO Drug therapeutic class and generic medication name.
6.6.
Appendix 6 Medical History
Ongoing general medical history will be summarized by system organ class and preferred term 
using the safety analysis set.
6.7.
Appendix 7 Intervention Compliance
Treatment compliance and dose modifications will be summarized using the safety analysis set.
Percent treatment compliance will be defined as the number of tablets taken during the study
divided by the expected number of tablets, multiplied by 100. The number of tablets taken will be 
calculated based on the number of tablets dispensed minus the number of returned tablets. A
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subject’s expected number of tablets will be calculated according to the planned treatment
regimen. For example, for subjects with no dose modification the expected number of tablets
equals the number of assigned tablets per day multiplied by treatment duration (defined in 
Section 5.6.1), however for subjects with dose reduction the expected number of tablets will be
smaller. Subjects with at least one dose modification or with dose interruption and the reason for
the dose modification will be summarized by treatment group. ADT is background therapy and
its dosing and modifications will be summarized by treatment group.
6.8.
Appendix 8 Adverse Events of Special Interest
No non-serious AEs of special interest has been identified in this study.
Rash is an AE of clinical interest to be assessed by CTCAE criteria and following the specific 
rash management plan in protocol (Appendix 9, Recommendations for Management of 
Drug-related Rash).
6.9.
Appendix 9 Medications of Special Interest
No concomitant medications of special interest have been identified in this study. Prohibited 
concomitant medications (listed in Appendix 6 of protocol) will be summarized using World 
Health Organization (WHO) Drug therapeutic class, and generic medication name using the 
safety analysis set.
6.10.
Appendix 10 Laboratory Toxicity Grading
The grading scale to be used for lab assessments will be based on ‘Common Terminology Criteria 
for Adverse Events (CTCAE Version 5.0) (3).
If a laboratory value falls within the grading as specified below but also within the local laboratory 
normal limits, the value is considered to be normal and will be reset to grade 0.
Pre-baseline measurements will use the same grading ranges as applied to baseline measurements. 
In case a test has two sets of ranges – one for baseline normal and one for baseline abnormal, the 
one for baseline normal will be applied for all measurements taken pre-baseline and on baseline.
7.
REFERENCES
1.
Martini, A., et al., Defining the Most Informative Intermediate Clinical Endpoints for Predicting 
Overall Survival in Patients Treated with Radical Prostatectomy for High-risk Prostate Cancer. Eur 
Urol Oncol, 2019. 2(4): p. 456-463.
2.
PASS 15 Power Analysis and Sample Size Software (2017). NCSS, LLC. Kaysville, Utah, USA. 
Available at https://www.ncss.com/software/pass. Accessed November 2019.
3.
Common Terminology Criteria for Adverse Events (CTCAE). Version 5.0; Published: November 27, 
2017
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