A Randomized, Double-blind, Placebo-controlled Phase 3 Study of Darolutamide in Addition to Androgen Deprivation Therapy (ADT) Versus Placebo Plus ADT in Men With Metastatic Hormone-sensitive Prostate Cancer (mHSPC)
Phase: PHASE3
Conditions: Prostatic Neoplasms
Sponsor: Bayer

 
Document Type: 
Clinical Study Protocol  
Official Title: 
A randomized, double-blind, placebo-controlled Phase 3 
study of darolutamide in addition to androgen deprivation 
therapy (ADT) versus placebo plus ADT in men with 
metastatic hormone-sensitive prostate cancer (mHSPC) 
NCT Number: 
NCT04736199 
Document Date: 
28-Jun-2022 
 

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Title Page
Protocol Title: A randomized, double-blind, placebo-controlled Phase 3 study of 
darolutamide in addition to androgen deprivation therapy (ADT) versus placebo plus ADT in 
men with metastatic hormone-sensitive prostate cancer (mHSPC)
Protocol Number: 21140 Clinical Study Protocol
Amendment Number: Amendment 1 (Global)
Protocol Version: 2.0
Compound: Darolutamide (BAY 1841788)
Study Phase: 3
Short Title: Phase 3 study of darolutamide in addition to ADT versus placebo plus ADT in 
men with mHSPC
Acronym: ARANOTE
Sponsor Name and Legal Registered Address:
Sponsor (Non-US):
Bayer Consumer Care AG, Peter-Merian-Strasse 84, 4052 Basel, Switzerland
Sponsor (US territory):
Bayer HealthCare Pharmaceuticals Inc., 100 Bayer Boulevard, P.O. Box 915, 
Whippany, NJ 07981-0915, USA
Regulatory Agency Identifier Numbers
IND: 114769
EudraCT: 2020-003093-48
Medical Monitor Name and Contact Information: Will be provided separately.
This is an electronically generated document that does not bear any sponsor signatures. The 
signature of the Sponsor’s medically responsible person is filed in the Trial Master File 
(TMF) and available on request.
Confidential
The information provided in this document is strictly confidential and is intended solely for the performance of 
the clinical investigation. Reproduction or disclosure of this document, whether in part or in full, to parties not 
associated with the clinical investigation or its use for any other purpose without the prior written consent of the 
sponsor is not permitted.
Throughout this document, symbols indicating proprietary names (®, TM) may not be displayed. Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.

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Document History Table
DOCUMENT HISTORY
Document
Version
Date
Comments (if applicable)
Amendment 1 (Global)
2.0
28 JUN 2022
Local Amendment (Canada) CAN-1
CAN-1
22 DEC 2020
Original Clinical Study Protocol
1.0
24 SEP 2020
No versioning applied to the 
original protocol as per 
company convention at the 
time of protocol generation. 
The original protocol is 
technically considered as 
document version 1.0.
Protocol Amendment Summary of Changes Table
Overall Rationale for the Amendment:
The rationale for Amendment 1 was to add the open-label phase to the study design and to 
update the sample size. In addition, text was added to provide guidance on criteria for study 
drug discontinuation in the event of suspected drug-induced liver injury (DILI). Changes were 
also added to the other pre-specified endpoints for clarification, as well as a new endpoint
added for time to first prostate cancer-related invasive procedure. Futility Interim Analysis 
was removed.
Section # and Name
Description of Change
Brief Rationale
1.1 Synopsis
1.2 Schema (Figure 1-1 
Study Design)
1.3 Schedule of Activities 
(SoA)
4.1 Overall Design
4.1.1 Screening Period
4.1.2 Treatment Period
4.1.3 Active Follow-up 
Period
4.1.4 Long-term (survival) 
Follow-up Period
4.2 Scientific Rationale for 
Study Design
4.4 End of Study 
Definition
7.1 Discontinuation of 
Study Intervention
Added open-label phase to 
the study design.
New guidance on the 
management of radiological 
scans and study periods.
Added new Table 1-3: 
Schedule of Activities for 
open-label phase.
To grant patients access to the 
active drug, in case of positive 
results at the primary 
completion. Therefore, text was 
modified in these sections.
New guidance on the 
management of radiological 
scans and study periods entered 
to decrease the risk of data loss 
for the primary and key 
secondary endpoints.

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Section # and Name
Description of Change
Brief Rationale
8.1 Efficacy Assessments
9.4.2.2 Secondary 
Endpoints
9.6 Data Monitoring 
Committee (DMC) or 
other Review Board
1.1 Synopsis (Overall 
Design:
Number of Participants:)
1.2 Schema (Figure 1-1 
Study Design)
4.1 Overall Design
4.2 Scientific Rationale for 
Study Design
9.2 Sample Size
Determination
Updated increased sample 
size numbers.
Compared to the original 
protocol version, a higher 
dropout rate is expected, 
mainly due to unpredictable 
geopolitical situation in some 
participating countries. 
Therefore, sample size has 
been updated.
2.3.1 Risk Assessment
6.6.3 General 
Requirements for Dose 
Modifications of Study 
Drug
7.1 Discontinuation of 
Study Intervention
10.4 Appendix 4: 
Participant 
Discontinuation
11. References
Addition of newly 
identified safety data for 
darolutamide. Text added to 
provide guidance on criteria 
for study drug 
discontinuation in the event 
of suspected drug-induced 
liver injury (DILI).
Note: numbering change as 
Appendix 4 was newly 
added.
New reference (FDA, 2009) 
was added.
Newly identified safety data 
across darolutamide clinical 
trials, including cases of 
idiosyncratic hepatic reactions 
that were reversible upon 
treatment discontinuation.
3. Objectives and 
Endpoints
3. Objectives and 
Endpoints (Table 3-1: 
Objectives and Endpoints)
4.1.3 Active Follow-up
Added text clarifying that 
all objectives listed in Table 
3-1 will be analyzed at the 
primary completion, and 
only limited analyses will 
be conducted in the final 
analysis.
Added patient relevant 
objective and endpoint/text 
to other pre-specified 
objectives and endpoints 
For alignment and clarification.

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Section # and Name
Description of Change
Brief Rationale
Period
4.1.4 Long-term (survival) 
Follow-up Period
8.1 Efficacy Assessments
9.4.2.2 Secondary 
Endpoints
9.4.2.3 Other Pre-specified 
Endpoints
(which are reflected 
throughout the listed 
sections).
9.6 Data Monitoring 
Committee (DMC) or 
other Review Board
Removed futility analysis.
Futility analysis considered not 
needed in light of additional 
data from study 17777 
(ARASENS), where 
darolutamide demonstrated 
benefit in mHSPC setting.
3. Objectives and 
Endpoints (Table 3-1)
9.4.2.3 Other Pre-specified 
Endpoints
Removed “radiological” 
from radiological 
progression-free survival 2 
(rPFS2).
For alignment and clarification.
6.3.2 Emergency 
unblinding by the 
Investigator
Removed text referring to 
“Emergency” unblinding in 
heading and section.
Further, added text that 
unblinding may also be 
performed after participant 
discontinues from the 
treatment phase.
To allow unblinding for 
subsequent anti-cancer 
treatment choice under specific 
circumstances.
8.4 Treatment of Overdose
Removed PK analysis text 
as PK parameters are not 
evaluated in this study.
Clarification.
1.1 Synopsis
4.1 Overall Design
5.1 Inclusion Criteria 
(criterion #5)
5.2 Exclusion Criteria 
(criterion #3)
6.1 Study Interventions 
Administered
Updated background 
treatment start time wording 
(“not earlier than 12 
weeks”) for consistency.
To harmonize.
5.1 Inclusion Criteria 
(criterion #4)
Added a note to clarify 
participants with bone scan 
showing a diffuse, intense, 
For clarification.

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Section # and Name
Description of Change
Brief Rationale
skeletal uptake of the tracer 
with absent renal and 
background activity are 
considered ineligible.
5.1 Inclusion Criteria 
(criterion #10)
8.3.5 Pregnancy
Modified wording for 
clarity.
For clarification.
5.2 Exclusion Criteria
(criterion #3)
Added two new bullet 
points to criterion #3.
For clarity.
6.5.2 Prohibited 
Concomitant Therapy
Added new bullet point 
(“Any other anti-cancer
treatment for prostate 
cancer, excluding local 
therapies and ADT”).
Use of other treatments with 
anti-cancer effect may bias 
efficacy and safety endpoints; 
therefore, they are considered 
prohibited concomitant 
treatments.
1.3 Schedule of Activities 
(SoA) Table 1-2 Schedule 
of Activities for double-
blind period
Modified and updated Table 
1-2 footnotes c, i, k, m, n, q, 
v, and x.
Added prostate cancer 
related invasive procedure 
with respective footnote y.
For clarity and correction.
2.1 Study Rationale
Removed text to clarify 
where the study is planned 
to be conducted.
For clarity.
2.1 Study Rationale
2.3 Benefit/Risk 
Assessment
2.3.1 Risk Assessment
2.3.2 Benefit Assessment
2.3.3 Overall Benefit: Risk 
Conclusion
Added study 17777 
(ARASENS) data.
New efficacy and safety data 
are available for darolutamide 
in mHSPC setting.
3. Objectives and 
Endpoints (Table 3-1)
8.8.1 Potential Predictive 
Biomarkers
8.8.2 Pharmacodynamic 
Biomarkers
Removed footnote ** from 
Table 3-1, which was 
referring to biomarker 
analyses text for China.
Updated biomarker analyses 
text for China.
Clarification of the strategy for 
biomarker analysis.

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Section # and Name
Description of Change
Brief Rationale
9.4.2.3 Other Pre-specified 
Endpoints
5.1 Inclusion Criteria
(criteria #9 and #11)
6.6.3 General 
Requirements for Dose 
Modifications of Study 
Drug
11. References
For Canada sites: 
Added wording to criterion 
#9 indicating screening 
values for ALT, AST and 
total bilirubin. In addition, 
criterion #11 was added 
with eGFR values at 
screening.
Added text recommending 
dose adjustment for 
participants experiencing 
decreased to severe renal 
impairment.
Reference for the eGFR 
formula was added.
Health Authority for Canada 
request.
5.2 Exclusion Criteria
Removed 
radiopharmaceuticals from 
criterion #4 and added it to 
criterion #3. Further added 
use of any anti-cancer
treatments as exclusion 
criterion.
Previous use of 
radiopharmaceuticals or any 
other treatments with anti-
cancer effect may bias efficacy 
and safety endpoints; therefore, 
they are considered prohibited 
prior treatments. 
6.5.1 Permitted 
Concomitant Therapy
Added text permitting 
vaccines for COVID-19 and 
flu during study treatment.
For clarity.
6.5.2 Prohibited 
Concomitant Therapy
Added text not permitting 
“use of live, attenuated, 
replication-competent 
vaccines”.
For clarity.
6.1 Study Interventions 
Administered
6.5.1 Permitted 
Concomitant Therapy
9.2 Sample Size 
Determination
Removed text.
Redundant.
6.1 Study Interventions 
Administered
Removed documented 
radiological disease 
progression assessed by 
For clarity.

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Section # and Name
Description of Change
Brief Rationale
7.1 Discontinuation of 
Study Intervention
central review.
6.2 Preparation/Handling/ 
Storage/Accountability
6.4 Study Intervention 
Compliance
Removed IWRS text.
Correction.
7.1.2 Rechallenge
Removed first sentence in 
last paragraph.
Correction.
8.1 Efficacy Assessments
Added paper forms for 
administered questionnaires 
(in second to last paragraph 
of this section).
To allow the use of paper forms 
in absence of the ePRO 
devices.
4.1.4 Long-term (survival) 
Follow-up Period
7.1 Discontinuation of 
Study Intervention
8.2.3 Electrocardiogram 
(ECG)
9.4 Statistical Analyses
9.4.2.1 Primary Endpoint
9.4.3 Safety Analyses
Changes were added for 
clarity:
indicating double-blind 
and/or open-label study 
phase
describing QTc intervals 
will be calculated by 
eCRF system
Modifications were made for 
clarity and completeness.
9.4.3 Safety Analyses
Removed “(+7 days)” from 
safety assessment period for 
TEAE starting after the first 
dose of study drug until 30 
days after the last treatment 
with darolutamide/placebo.
Correction.
3. Objectives and 
Endpoints (Table 3-1)
4.1.2 Treatment Period
4.1.3 Active Follow-up 
Period
4.1.4 Long-term (survival) 
Follow-up Period
5.4 Screen Failures
6.5.1 Permitted 
Concomitant Therapy
6.6.3 General 
Requirements for Dose 
Modifications of Study 
Minor text modifications.
For clarity and correction.

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Section # and Name
Description of Change
Brief Rationale
Drug (Table 6-3: Study 
drug dose modifications)
9.4.2.2 Secondary 
Endpoints
9.4.2.3 Other Pre-specified 
Endpoints
10.11 Appendix 11: 
Abbreviations
Made updates and 
corrections.
For completeness.
2.3 Benefit/Risk 
Assessment
11. References
Added reference in Section 
2.3 (Smith et al. 2022).
Update.
1.1 Synopsis (Secondary 
objectives)
1.2 Schema (Figure 1-1 
Study Design)
1.3 Schedule of Activities 
(SoA, Table 1-2)
3. Objectives and 
Endpoints (Secondary and 
other pre-specified 
objectives)
4.1.3 Active Follow–up 
Period
4.1.4 Long–term (survival) 
Follow–up Period
5.2 Exclusion Criteria
6.5 Concomitant Therapy
6.5.2 Prohibited 
Concomitant Therapy
7.1 Discontinuation of 
Study Intervention
8.1 Efficacy Assessments
9.4.2.2 Secondary 
Endpoints
Terminology changed from 
“antineoplastic” to “anti-
cancer” at all occurrences.
For consistency.
Throughout
Minor editorial and 
document formatting 
revisions
Minor, therefore, have not been 
summarized.
A tracked changes version of the document will be provided separately.

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Table of Contents
Title Page................................................................................................................................... 1
Document History Table.......................................................................................................... 2
Protocol Amendment Summary of Changes Table............................................................... 2
Table of Tables ....................................................................................................................... 12
Table of Figures...................................................................................................................... 12
1.
Protocol Summary .......................................................................................................... 13
1.1
Synopsis......................................................................................................................... 13
1.2
Schema........................................................................................................................... 17
1.3
Schedule of Activities (SoA) ......................................................................................... 18
2.
Introduction..................................................................................................................... 23
2.1
Study Rationale.............................................................................................................. 23
2.2
Background.................................................................................................................... 24
2.3
Benefit/Risk Assessment ............................................................................................... 25
2.3.1
Risk Assessment......................................................................................................... 26
2.3.2
Benefit Assessment .................................................................................................... 27
2.3.3
Overall Benefit: Risk Conclusion............................................................................... 27
3.
Objectives and Endpoints............................................................................................... 28
4.
Study Design .................................................................................................................... 30
4.1
Overall Design ............................................................................................................... 30
4.1.1
Screening Period......................................................................................................... 31
4.1.2
Treatment Period ........................................................................................................ 32
4.1.3
Active Follow–up Period............................................................................................ 32
4.1.4
Long–term (survival) Follow–up Period.................................................................... 33
4.2
Scientific Rationale for Study Design ........................................................................... 34
4.2.1
Participant Input into Design...................................................................................... 35
4.3
Justification for Dose..................................................................................................... 35
4.4
End of Study Definition................................................................................................. 35
5.
Study Population............................................................................................................. 36
5.1
Inclusion Criteria ........................................................................................................... 36
5.2
Exclusion Criteria .......................................................................................................... 37
5.3
Lifestyle Considerations ................................................................................................ 38
5.3.1
Meals and Dietary Restrictions .................................................................................. 38
5.3.2
Activity....................................................................................................................... 38
5.4
Screen Failures............................................................................................................... 39
6.
Study Intervention .......................................................................................................... 39
6.1
Study Interventions Administered ................................................................................. 40
6.2
Preparation/Handling/Storage/Accountability............................................................... 41
6.3
Measures to Minimize Bias: Randomization and Blinding........................................... 42
6.3.1
SUSAR Unblinding.................................................................................................... 43
6.3.2
Unblinding by the Investigator................................................................................... 43
6.4
Study Intervention Compliance ..................................................................................... 43
6.5
Concomitant Therapy .................................................................................................... 44
6.5.1
Permitted Concomitant Therapy................................................................................. 44

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6.5.2
Prohibited Concomitant Therapy................................................................................ 45
6.6
Dose Modification ......................................................................................................... 46
6.6.1
Dose Interruption........................................................................................................ 46
6.6.2
Dose Reduction .......................................................................................................... 46
6.6.3
General Requirements for Dose Modifications of Study Drug.................................. 46
6.7
Intervention after the End of the Study.......................................................................... 47
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal.......................................................................................... 48
7.1
Discontinuation of Study Intervention........................................................................... 48
7.1.1
Temporary Discontinuation........................................................................................ 49
7.1.2
Rechallenge ................................................................................................................ 49
7.2
Participant Discontinuation/Withdrawal from the Study............................................... 49
7.3
Lost to Follow-up........................................................................................................... 50
8.
Study Assessments and Procedures............................................................................... 50
8.1
Efficacy Assessments .................................................................................................... 51
8.2
Safety Assessments........................................................................................................ 53
8.2.1
Physical Examinations................................................................................................ 54
8.2.2
Vital Signs .................................................................................................................. 54
8.2.3
Electrocardiogram (ECG)........................................................................................... 54
8.2.4
Clinical Safety Laboratory Assessments .................................................................... 54
8.2.5
ECOG Performance Status......................................................................................... 55
8.2.6
Population characteristics........................................................................................... 55
8.2.6.1 Demographic .............................................................................................................. 55
8.3
Adverse Events and Serious Adverse Events ................................................................ 56
8.3.1
Time Period and Frequency for Collecting AE and SAE Information....................... 56
8.3.2
Method of Detecting AEs and SAEs.......................................................................... 57
8.3.3
Follow-up of AEs and SAEs ...................................................................................... 57
8.3.4
Regulatory Reporting Requirements for SAEs .......................................................... 57
8.3.5
Pregnancy ................................................................................................................... 58
8.3.6
Adverse Events of Special Interest............................................................................. 58
8.4
Treatment of Overdose .................................................................................................. 58
8.5
Pharmacokinetics........................................................................................................... 59
8.6
Pharmacodynamics ........................................................................................................ 59
8.7
Genetics ......................................................................................................................... 59
8.8
Biomarkers..................................................................................................................... 59
8.8.1
Potential Predictive Biomarkers................................................................................. 60
8.8.2
Pharmacodynamic Biomarkers................................................................................... 61
8.8.3
Other Biomarkers (not applicable for China)............................................................. 61
8.9
Immunogenicity Assessments........................................................................................ 61
8.10
Medical Resource Utilization and Health Economics ................................................... 61
9.
Statistical Considerations ............................................................................................... 61
9.1
Statistical Hypotheses.................................................................................................... 61
9.2
Sample Size Determination ........................................................................................... 61
9.3
Populations for Analyses ............................................................................................... 62
9.4
Statistical Analyses........................................................................................................ 62
9.4.1
General Considerations............................................................................................... 62
9.4.2
Efficacy analyses........................................................................................................ 62
9.4.3
Safety Analyses .......................................................................................................... 65

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9.4.4
Other Analyses ........................................................................................................... 65
9.5
Interim Analyses............................................................................................................ 65
9.6
Data Monitoring Committee (DMC) or other Review Board........................................ 65
10. Supporting Documentation and Operational Considerations .................................... 66
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........................ 66
10.1.1
Regulatory and Ethical Considerations ...................................................................... 66
10.1.2
Financial Disclosure ................................................................................................... 66
10.1.3
Informed Consent Process.......................................................................................... 67
10.1.4
Data Protection ........................................................................................................... 67
10.1.5
Committees Structure ................................................................................................. 67
10.1.6
Dissemination of Clinical Study Data ........................................................................ 67
10.1.7
Data Quality Assurance.............................................................................................. 68
10.1.8
Source Documents...................................................................................................... 68
10.1.9
Study and Site Start and Closure................................................................................ 69
10.1.10 Publication Policy....................................................................................................... 70
10.2
Appendix 2: Clinical Laboratory Tests.......................................................................... 70
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting.............................................................................................. 72
10.3.1
Definition of AE......................................................................................................... 72
10.3.2
Definition of SAE....................................................................................................... 73
10.3.3
Recording and Follow-up of AE and/or SAE............................................................. 74
10.3.4
Reporting of SAEs...................................................................................................... 76
10.4
Appendix 4: Participant Discontinuation....................................................................... 76
10.5
Appendix 5: Contraceptive Guidance and Collection of Pregnancy Information......... 77
10.6
Appendix 6: Genetics..................................................................................................... 78
10.7
Appendix 7: BPI-SF....................................................................................................... 79
10.8
Appendix 8: FACT-P (Version 4) ................................................................................. 81
10.9
Appendix 9: RECIST 1.1 Criteria.................................................................................. 84
10.10 Appendix 10: Prostate Cancer Working Group 3 Criteria for Bone Metastases........... 88
10.11 Appendix 11: Abbreviations.......................................................................................... 89
11. References ........................................................................................................................ 94

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Table of Tables
Table 1–1 Objectives and Endpoints...................................................................................... 14
Table 1–2 Schedule of Activities for double-blind period ..................................................... 18
Table 1–3 Schedule of Activities for open-label phase.......................................................... 22
Table 3–1 Objectives and Endpoints...................................................................................... 29
Table 6–1 Administration of study drug ................................................................................ 41
Table 6–2 Randomization and Blinding by using Interactive Web Response System (IWRS)42
Table 6–3 Study drug dose modifications.............................................................................. 47
Table 8–1 Definitions for ECOG PS Grading........................................................................ 55
Table 9–1 Populations for analyses........................................................................................ 62
Table 10–1 Protocol-Required Safety Laboratory Assessments.............................................. 71
Table 10–2 RECIST 1.1 - Time Point Response for participants with target and non-target 
lesions.................................................................................................................... 86
Table of Figures
Figure 1–1 Study Design ......................................................................................................... 17

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1.
Protocol Summary
1.1
Synopsis
Protocol Title: A randomized, double-blind, placebo-controlled Phase 3 study of 
darolutamide in addition to androgen deprivation therapy (ADT) versus placebo plus ADT in 
men with metastatic hormone-sensitive prostate cancer (mHSPC)
Short Title: Phase 3 study of darolutamide in addition to ADT versus placebo plus ADT in 
men with mHSPC
Rationale:
For decades, the treatment of mHSPC was ADT; however, resistance ultimately occurs, and 
patients progress to metastatic castration-resistant prostate cancer (mCRPC) from which they
eventually die (Shevach et al. 2019).
Pivotal trials confirmed that adding docetaxel, abiraterone acetate, enzalutamide or 
apalutamide to ADT result in improvement of overall survival (OS) and/or radiological 
progression-free survival (rPFS) for patients with mHSPC (Di Nunno et al. 2020). Despite the 
efficacy benefits reported with all combinations in mHSPC, the safety profile is an important 
factor to be considered for treatment acceptance together with patients’ comorbidities who 
require chronic treatments (Cattrini et al. 2019).
Darolutamide is a potent androgen receptor inhibitor (ARi) with low blood-brain barrier 
penetration and low potential for drug-drug interactions (Moilanen et al. 2015, Shore et al. 
2019, Williams et al. 2020). Considering the unique safety profile of darolutamide, the 
present study will evaluate darolutamide in addition to ADT in mHSPC patients.

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Objectives and Endpoints
The purpose of this study is to evaluate the efficacy and safety of darolutamide in addition to
ADT versus placebo plus ADT in participants with mHSPC.
Table 1–1
Objectives and Endpoints
Objectives
Endpoints
Primary

To determine if darolutamide in addition to
ADT is superior to placebo plus ADT by 
improving rPFS in participants with mHSPC

rPFS assessed by central review based on 
RECIST v. 1.1 criteria for soft tissue
metastases and PCWG3 criteria for bone 
metastases
Secondary

To evaluate efficacy of darolutamide in 
addition to ADT compared to placebo plus 
ADT by improving OS, time to progress to 
CRPC, time to initiation of subsequent anti-
cancer therapy, time to PSA progression, and 
undetectable PSA rates

OS – key secondary endpoint

Time to CRPC

Time to initiation of subsequent anti-cancer
therapy

Time to PSA progression

PSA undetectable rates (<0.2 ng/mL)

To estimate the participant’s quality of life 
benefit of darolutamide in addition to ADT 
compared to placebo plus ADT by improving 
symptomatic time to pain progression

Time to pain progression (BPI-SF)

To assess the safety of darolutamide in 
addition to ADT compared to placebo plus
ADT in participants with mHSPC

AE assessments using NCI-CTCAE (v.5.0)
Abbreviations: ADT = Androgen Deprivation Therapy; AE = Adverse event; BPI-SF = Brief Pain Inventory-Short 
Form; CRPC = Castration-resistant prostate cancer; mHSPC = Metastatic hormone-sensitive prostate 
cancer; NCI-CTCAE = National Cancer Institute–Common Terminology Criteria for Adverse Events
(version 5.0); OS = Overall survival; PCWG3 = Prostate Cancer Working Group 3; PSA = Prostate-specific 
antigen; RECIST = Response Evaluation Criteria in Solid Tumours; rPFS = Radiological progression-free 
survival

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Overall Design:
Disclosure Statement: This is a randomized, double-blind, placebo-controlled Phase 3 study 
to determine if darolutamide in addition to ADT is superior to placebo plus ADT by 
improving radiological progression-free survival (rPFS) in participants with mHSPC
Number of Participants:
Approximately 665 participants who meet the eligibility criteria will be randomly assigned to 
study drug (darolutamide or placebo), at the ratio of 2:1. All participants who were 
randomized are included in the Full Analysis Set (FAS). The participants in this set will be 
grouped according to the treatment they were allocated to receive at randomization, 
irrespective of actual treatment. Eligibility requirement of metastatic disease by radiologic 
assessment will be confirmed by central review during screening. 
Participants will by stratified at randomization as follows:

Presence of visceral metastases versus absence of visceral metastases assessed by 
central review

Prior local therapy versus no prior local therapy 
Intervention Groups and Duration:
In the double-blind period, the study  comprises 4 consecutive periods: Screening, Treatment, 
Active Follow–up, and Long–term (survival) Follow–up. Open-label phase will start in case 
of positive benefit/risk assessment for darolutamide, based on data from primary analysis.
After an up to 28-day screening period, participants who satisfy all eligibility criteria (see 
Section 5.1 and Section 5.2) will be randomized in a 2:1 ratio to receive one of the following 
study drugs:

Darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equivalent to a total 
daily dose of 1200 mg 

Placebo darolutamide matched tablets in appearance, twice daily with food
Background treatment: All participants must receive ADT of investigator’s choice 
(luteinizing hormone-releasing hormone [LHRH] agonist/antagonists or orchiectomy) as 
standard therapy, not earlier than 12 weeks before randomization, on a continuous basis.
For participants receiving LHRH agonists, treatment in combination with a first generation 
anti–androgen for at least 14 days prior to randomization is recommended. First generation 
anti–androgen will be discontinued before study treatment start.
During Treatment period, participants will be evaluated with regular clinic visits for efficacy 
and safety as described in the SoA (Section 1.3). The dose or dosing schedule of the study 
drug may be modified following the occurrence of adverse events (AEs) as described in 
Section 6.6. Participants will receive study drug until documented radiological disease 
progression assessed by central review, unacceptable toxicity or until any other withdrawal 
criteria specified in Section 7.1 is met.

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After discontinuation of study drug, participants will enter the Active Follow-up period where
clinic visits will continue for approximately 1 year (12 ±1 months), and then will be contacted 
by telephone in the Long-term Follow-up period, unless central imaging and PSA evaluations 
have to be continued, in which case participants should continue with clinic visits. Please 
refer to Section 4.1 for further details on study design. Please refer to Section 4.1.4 for further 
details on the need to continue imaging assessments in the Long-term Follow-up period.
Data Monitoring Committee: Yes

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1.2
Schema
Figure 1–1
Study Design
Abbreviations: ADT = Androgen Deprivation Therapy; CRPC = Castration-resistant prostate cancer; mHSPC = Metastatic hormone-sensitive prostate cancer; OS = Overall 
survival; PCWG3 = Prostate Cancer Working Group 3; PSA = Prostate-specific antigen; RECIST = Response Evaluation Criteria in Solid Tumours; rPFS = Radiological
progression-free survival; vs. = versus

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1.3
Schedule of Activities (SoA)
Table 1–2
Schedule of Activities for double-blind period
ProceduresX
Screening Period
Treatment Perioda
Follow–up Period
Active Follow–up Period
Long–term Follow–
up Period
Visit 1
Visit 2 and 
subsequent 
visits
EOT Visit
Active 
Follow–up 
Visits
Within 28 days before 
randomization
Within 7 days 
before 
randomization
Day 1
(+3 days)
Week 12
Every 
12 weeks
(±7 days)u
EOT Visit: 
30 days
(+7 days) 
after last 
dose of 
study drugv
Approximately 
every 
12 weeks from 
discontinuation 
of treatment 
for 
approximately 
1 year
(12 ±1 months)
Approximately every 
12 weeks after Active 
Follow–up, until 
death, lost to follow–
up, consent 
withdrawal, or end–
of–study
Signed and dated informed consent
X
Informed consent for WGS (optional)
(not applicable for China)
X
Demography
X
Medical history
X
Prostate cancer historyb
X
Eligibility criteria 
X
X
Symptom/QoL by FACT-P 
questionnairec
X
(X)d
X
X
X
Pain questionnaire BPI–SFc, e
X
X
X
X
X
Analgesic 24 hour consumption log –
eCRF (physician recording analgesic 
pain meds consumed over last 
24 hours)c, e
X
Xd
X
X
X
Randomizationf
Xf
Physical examinationg
X
Xh
X
X
12–lead ECG 
X
(X)o
X
X
Vital signs (BT, HR, BP)
X
Xh
X
X
Laboratory safety assessments 
(hematology, general chemistry and 
X
X
X

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Table 1–2
Schedule of Activities for double-blind period
ProceduresX
Screening Period
Treatment Perioda
Follow–up Period
Active Follow–up Period
Long–term Follow–
up Period
Visit 1
Visit 2 and 
subsequent 
visits
EOT Visit
Active 
Follow–up 
Visits
Within 28 days before 
randomization
Within 7 days 
before 
randomization
Day 1
(+3 days)
Week 12
Every 
12 weeks
(±7 days)u
EOT Visit: 
30 days
(+7 days) 
after last 
dose of 
study drugv
Approximately 
every 
12 weeks from 
discontinuation 
of treatment 
for 
approximately 
1 year
(12 ±1 months)
Approximately every 
12 weeks after Active 
Follow–up, until 
death, lost to follow–
up, consent 
withdrawal, or end–
of–study
urinalysis)i
Serum PSAi
X
X
X
(X)
(X)
Testosteronei
X
X
X
(X)
(X)
Biomarker plasma
X
Xj
X
Biomarker whole blood for 
pharmacogenetic analysis
(not applicable for China)
Xw
(X)o
Biomarker tumor tissue (e.g. biopsy)
(not applicable for China)
Xk
Xl
ECOG PS
X
X
X
X
CT/MRIn
Xm
Xn
Xn
Xn
Xn
Bone scann
Xm
Xn
Xn
Xn
Xn
First SSEp
X
X
X
Prostate cancer related invasive 
procedurey
X
X
X
X
X
Post–study anti-cancer therapyq
X
X
AEs/SAEs
X
X
X
X
X
Xs
Xs
Concomitant treatmentsr
X
X
X
X
X
Xs
Xs
Study drug dispensing
X
X
Survival statust
X
X
Abbreviations: ADT = Androgen deprivation therapy; AE = Adverse events; AR = Androgen receptor; BHA = Bone health agents; BP = Blood pressure; BPI–SF = Brief Pain 
Inventory–Short Form; BT = Body temperature; CNS = Central nervous system; CT = Computed tomography; EBRT = External beam radiation therapy; ECG =

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Electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group Performance Status; eCRF = Electronic case report form; EOT = End of treatment; FACT-P = 
Functional Assessment of Cancer Therapy-Prostate Cancer questionnaire; HR = Heart rate; ICF = Informed consent form; LHRH = Luteinizing hormone releasing 
hormone; MRI = Magnetic resonance imaging; OS = Overall survival; PI = Principal Investigator; PSA = Prostate–specific antigen; QoL = Quality of life; SAE = Serious 
adverse event; SSE = Symptomatic skeletal event; WGS = Whole genome sequencing; (X) = (the X in parenthesis) indicates optional assessment.
Participants will receive study drug (darolutamide or placebo) in addition to ongoing ADT (LHRH agonist/antagonist at the investigator discretion; prior therapy with 
first-generation AR inhibitors given with LHRH agonist must be discontinued within 1 day before study treatment start).
a.
The study treatment will be administered until documented radiological disease progression assessed by central review, unacceptable toxicity or until any other 
withdrawal criteria specified in Section 7.1 is met.
b.
Including prior treatments and procedures.
c.
Questionnaires should be administered at the start of the visit prior to any study–related procedure or other clinical activities. In screening 7 days prior to 
randomization: daily record completion (7 copies), 7th day may correspond to Visit 1 Day 1 (V1D1).
d.
If not collected at the Screening visit. The (X) indicates optional assessment.
e.
Analgesic consumption and pain assessment questionnaires must be collected on the same day.
f.
Randomization must occur within 28 days from ICF signature.
g.
Physical examination including assessments of the cardiovascular, respiratory, gastrointestinal, neurological, and skin systems; height (at screening only) and 
weight will also be measured.
h.
If not previously done within 7 days prior study treatment start.
i.
PSA and testosterone values are to be assessed by a central laboratory during the study treatment period. PSA and testosterone for participants who discontinue 
the study treatment before radiological progression must be continued to be assessed by central laboratory also in Active Follow-up visits and Long-term Follow-up 
periods until radiological progression is assessed by central review or change of anti-cancer therapy. Other laboratory assessments are to be performed by local 
laboratories. The (X) indicates optional assessment.
j.
To be performed at Visit 2 only.
k.
Provision of archival tumor tissue at Screening is optional if available. Archival tumor tissue (blocks or predefined number of slides) has to be provided, if available 
and unless precluded by local regulations. All efforts should be undertaken to collect primary or metastatic tumor if biopsies were taken outside the treating hospital. 
Participants for whom archival tissue is not available or collection from locations outside the treating hospitals may still be eligible to participate in the study. No 
fresh biopsies are required to participate. Provision of archival tumor tissue is not applicable for China.
l.
Tissue sample from a tumor biopsy at progression is highly encouraged to be taken as per investigator’s decision, if technically feasible unless precluded by local 
guidelines (optional collection). Not applicable for China.
m.
99mTc-phosphonate bone scan, contrast–enhanced chest, abdomen, and pelvic CT or MRI performed within 42 days prior to start of study treatment are acceptable 
as screening scans if the standard acquisition procedure according to the Imaging Manual and Section 8.1 was followed.
Baseline CT/MRI and bone scans must first be reviewed by a local qualified site physician (e.g. site radiologist or PI, at the PI’s discretion) to confirm presence of 
metastases before submitting the scans to central review to confirm eligibility and provide stratification group (visceral disease present vs. absent). If the local 
qualified site physician detects metastases of only local lymph nodes (below aortic bifurcation) or determines that the screening bone scan is a superscan 
(Section 5.1, inclusion criterion 4), the scans should not be submitted to central review and participants should not be randomized.
n.
In addition to planned study visits, tumor assessment imaging, (99mTc-phosphonate bone scan, chest, abdomen and pelvic CT or MRI) can be performed at any 
time in case of PSA progression, symptomatic progressive disease, or change of anti-cancer therapy or if considered appropriate in the investigator’s judgment; 
Brain/CNS CT scan or MRI will be performed in case of symptoms as appropriate. Such unscheduled imaging must be sent for central review and radiological 
progression assessment. Participants who discontinue study drug without radiological disease progression assessed by central review should continue the 
schedule of imaging assessments until radiological disease progression is assessed by central review or change of anti-cancer therapy. This also applies to 
participants who enter the Long-term Follow-up. Once the participant experiences radiological progression assessed by central review, imaging will continue to be 
performed according to local clinical practice. In the active and long-term follow-up periods, if allowed by local regulations, participants without centrally-assessed 

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radiological disease progression, for whom start of a subsequent anti-cancer therapy is planned before the next follow-up visit/contact, should perform a tumor 
assessment (contrast enhanced CT/MRI and bone scan) and submit it to the core imaging laboratory for central radiology review. Note that this tumor assessment 
is not required if the prior tumor assessment was performed within the previous 30 days.
o.
Only if missed at Visit 1. The (X) indicates optional assessment.
p.
SSE defined as EBRT to relieve skeletal symptoms, or new symptomatic pathologic bone fracture, or occurrence of spinal cord compression or tumor–related 
orthopedic surgical intervention.
q.
Documentation of post–study anti-cancer therapies must include the start and stop dates of each treatment and reason for treatment changes (PSA progression, 
clinical progression, radiological progression, toxicity, other).
r.
Including bone health agents (BHA) according to local guidelines for participants with risk of bone fracture.
s.
Only SAEs that are considered related to study drug or study participation, with concomitant medications used to treat the event. Also, concomitant medications 
used to treat related AEs that were unresolved at EOT will be captured in Active and Long-term Follow-up.
t.
Survival data will be collected through an additional survival sweep. All participants considered alive shortly after the database cut-off date for the primary analysis 
and prior to any subsequent analysis of OS will be contacted for survival status.
u.
Date of visit is to be calculated based on the previous visit date.
v.
The EOT visit will be completed before starting a new anti-cancer therapy if it starts sooner than 30 days (+7 days) after the last dose of study drug.
w.
This should be collected pre-dose on Visit 1.
x.
Some screening visit procedures and Active Follow-up visit procedures may be conducted using eTools where applicable with the exception of CT/MRI and bone
scan.
y.
Prostate cancer-related invasive procedure is defined as any procedure needed for alleviation of symptoms, signs or findings caused by progression of prostate 
cancer (e.g., catheterization of the bladder, percutaneous drainage of hydronephrosis, palliative electro resection of the prostate, etc.). Prostate cancer-related 
procedure will be collected at every visit/contact until change of anti-cancer therapy.

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Table 1–3
Schedule of Activities for open-label phase
Procedures
Follow–up Period
Active Follow–up Period
Long–term Follow–up Period
Visit 2 and 
subsequent visits
EOT Visit
Active Follow–up 
Visits
Week 12
Every 12 weeks 
(±7 days)
EOT Visit: 30 days
(+7 days) after last 
dose of study drug
Approximately every 
12 weeks from 
discontinuation of 
treatment for 
approximately 1 year 
(12 ±1 months)
Approximately every 12 weeks 
after Active Follow–up, until death, 
lost to follow–up, consent 
withdrawal, or end–of–study
Signed and dated informed consent
Xa
12–lead ECG 
X
X
Vital signs (BT, HR, BP)
X
X
Laboratory safety assessments (hematology, general chemistry 
and urinalysis)
X
X
ECOG PS
X
X
AEs/SAEs
X
X
Xc
Xc
Concomitant treatmentsb, c
X
X
Xc
Xc
Study drug dispensing
X
Survival status
X
X
Abbreviations: AEs = Adverse events; BP = Blood pressure; BT = Body temperature; EOT = End of treatment; ECG = Electrocardiogram; ECOG PS = Eastern Cooperative 
Oncology Group Performance Status; HR = Heart rate; ICF = Informed consent form; SAEs = Serious adverse events; PSA = Prostate–specific antigen
a.
At the moment of unblinding and if participant is eligible to continue the study treatment, participant will be offered to enter the open-label phase. Open-label phase ICF 
must be signed before any study-related intervention.
b.
Including bone health agents (BHA) according to local guidelines for participants with risk of bone fracture.
c.
Only SAEs that are considered related to study drug or study participation, with concomitant medications used to treat the event. Also, concomitant medications used 
to treat related AES that were unresolved at EOT will be captured in Active and Long-term Follow-up.

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2.
Introduction
2.1
Study Rationale
For decades, the treatment of metastatic hormone sensitive prostate cancer (mHSPC) was 
androgen deprivation therapy (ADT); however, resistance ultimately occurs, and patients 
progress to metastatic castration-resistant prostate cancer (mCRPC) from which they 
eventually die (Shevach et al. 2019). Various approaches have been tested to enhance disease 
control and to prolong patient’s survival by adding docetaxel, abiraterone/prednisone or next 
generation androgen receptor inhibitors (ARi), enzalutamide and apalutamide to ADT (Kinsey 
et al. 2020).
Pivotal trials confirmed that adding docetaxel, abiraterone acetate, enzalutamide or 
apalutamide to ADT in addition to placebo result in improvement of overall survival (OS)
and/or radiological progression-free survival (rPFS) for patients with mHSPC (Di Nunno et al. 
2020). The placebo plus ADT (ADT alone) as comparator arm in this trial is therefore 
consistent with other pivotal studies conducted in the same population.
Additionally, based on the ICH E17 guidance, the comparator(s) in a study should be in 
principle the same in all participating regions. The study is therefore planned to be conducted 
in Europe, North America (Ex-US), Asia, and Latin America in locations where ADT alone is 
a standard of care for these patients. 
The safety analyses of the pivotal Phase 3 studies 17712 (ARAMIS) in non-metastatic 
castration-resistant prostate cancer (nmCRPC), and 17777 (ARASENS) in mHSPC in 
combination with docetaxel, showed that darolutamide combined with ADT treatment was 
well-tolerated compared to the placebo arm. Also, the overall TEAE profile in the mCRPC 
phase 1/2 pool was consistent with that observed in ARAMIS study supporting the favorable 
safety profile of darolutamide.
As patients with mHSPC are generally asymptomatic, more intensive hormonal therapy could 
negatively affect the quality of life (QoL) of patients treated. It is noteworthy that 
darolutamide has shown a favorable safety profile, since mHSPC patients are often on 
treatment for prolonged periods of time.
Despite the efficacy benefits reported with all combinations in mHSPC for treatment decision, 
physicians should consider the safety profiles including treatment-induced morbidities related 
to the long treatment exposure of abiraterone acetate, apalutamide, and enzalutamide.
Abiraterone, apalutamide or enzalutamide in addition to ADT were given for long time 
periods in patients with mHSPC, leading to long-term exposure morbidities. 
Mineralocorticoid-associated side effects including hypertension, hypokalemia, 
hyperglycemia, weight gain and hepatic toxicity have been seen with abiraterone treatment. 
Patients with co-morbidities such as osteoporosis or diabetes mellitus might be at higher risk 
for a treatment with abiraterone. Higher rates of fatigue, hypertension, fractures and falls were 
reported with treatment of enzalutamide and for apalutamide AEs such as rash, pruritus, hot 
flushes and hypothyroidism. In addition, the risk of seizures should be taken into 
consideration if patients are planned to receive treatment with either enzalutamide or 
apalutamide (Cattrini et al. 2019, Chi et al. 2019, Davis et al. 2019, Fizazi et al. 2017). 
Additionally, potential drug-drug interactions of enzalutamide or apalutamide may be 
challenging in this patient population with co-morbidities where polypharmacy is the norm. 

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An analysis of real-world prescription, potential drug-drug interactions were noted in up to 
85% of patients receiving treatment with enzalutamide for mCRPC (Benoist et al. 2018).
Darolutamide is a potent ARi with low blood-brain barrier penetration and low potential for 
drug-drug interactions. Preclinical studies of darolutamide have shown a low blood-brain 
barrier penetration compared to that of available therapies, which may indicate an improved 
safety profile with respect to CNS related events. Darolutamide also exhibited low potential 
for drug-drug interaction, allowing a greater flexibility for the use of concomitant medications 
without compromising therapeutic efficacy or safety of therapy. (Moilanen et al. 2015, Shore 
et al. 2019, Williams et al. 2020)
Chemo–hormonal therapy with docetaxel in addition to ADT was the first combination that 
was integrated in the clinical guidelines for patients with mHSPC (EAU 2020, National 
Comprehensive Cancer Network 2020). Not all patients with mHSPC may receive or are 
willing to undergo treatment with chemotherapy. As the clinical practice continues to evolve 
with new strategies and criteria to be considered for treatment decisions the overall treatment 
paradigm of mHSPC is currently under modification aiming to propose the most appropriate 
therapeutic options to different subgroups of patients with mHSPC including those who are 
not planned for chemotherapy. Darolutamide added to ADT has demonstrated a significant 
benefit and a favorable safety profile in nmCRPC and therefore, it is expected that 
darolutamide in addition to ADT will enhance disease control and will provide a significant 
benefit in patients with mHSPC compared to placebo plus ADT without compromising 
patient’s quality of life.
Therefore, considering the unique safety profile of darolutamide, the present study will 
evaluate darolutamide in addition to ADT in mHSPC participants.
2.2
Background
Prostate cancer is the second most frequent cancer diagnosed in men and the fifth leading 
cause of death in the world. Based on GLOBOCAN 2018 estimates, 1,276,106 new cases of 
prostate cancer were reported worldwide in 2018, with higher prevalence in developed 
countries (Rawla 2019). In 2019, an estimated 174,650 new diagnoses of prostate cancer are 
expected in the US, with 31,620 expected deaths (Siegel et al. 2019). In the US, the incidence 
of mHSPC, defined as metastatic disease in patients who have not yet received or are 
continuing to respond to hormone therapy, has increased by approximately 72% between 
2004 and 2013, with age-standardized incidence rates having significantly risen from 1.45% 
to 2.74% annually since 2012, most prominently among men aged ≤ 69-year (Chen et al. 
2014, Jack et al. 2010, Norgaard et al. 2010). Based on European country-specific registries, 
approximately 6% to 30% of newly diagnosed prostate cancer are mHSPC and more than 
50% of patients in regions such as Indonesia have metastatic disease at diagnosis (Kelly et al. 
2018, Scher et al. 2015, Weiner et al. 2019).
Metastatic hormone-sensitive prostate cancer is the disease stage where patients have 
metastatic prostate cancer and are responsive to ADT including patients who develop 
metastatic recurrence after local treatment (surgery and / or radiotherapy) and patients with de 
novo metastatic disease who did not benefit from prior radical procedures.
Newly diagnosed mHSPC is recognized as an aggressive form of the disease with rapid 
progression to the metastatic castration-resistant state in virtually all patients (Fizazi et al. 
2019, Vale et al. 2016). Historically, androgen deprivation, achieved by surgical or medical 
castration, has been the standard of care for mHSPC (Rydzewska et al. 2017). Although 

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almost all men with mHSPC initially experience a response to ADT, most will develop 
mCRPC within 1 to 3 years of their diagnosis (Fizazi et al. 2015, Gravis et al. 2013, Sweeney 
et al. 2015). Metastatic castration-resistant prostate cancer has poor prognosis and high 
lethality.
Metastatic hormone-sensitive prostate cancer has a well-documented course, and the 
treatment landscape has rapidly evolved over the last five years. Several randomized trials 
have demonstrated significant clinical benefit with the addition of docetaxel, abiraterone plus 
prednisone, enzalutamide or apalutamide to ADT (Cattrini et al. 2019, Hahn et al. 2018). 
However, the addition of those agents to ADT may induce acute and chronic morbidities. 
Strategies to avoid and/or diminish these morbidities should be considered, as the choice 
between ADT alone and ADT combined with docetaxel, abiraterone acetate, enzalutamide or 
apalutamide remains challenging (Cattrini et al. 2019, EAU 2020, Eliasson et al. 2017). 
Factors that are related to the tumor, patient condition, drug side effects or potential drug-drug 
interactions (DDI) together with patient preferences currently guide these clinical decisions 
(Cattrini et al. 2019). As an example, one discrete choice study that evaluated preferences of 
men with mCRPC and mHSPC in France, Germany and the UK found that they expressed a 
strong preference for treatment(s) that delays the initiation of chemotherapy (odds ratio [OR]: 
1.727; 95% CI: 1.548-1.927) (National Comprehensive Cancer Network 2020). 
Chemo–hormonal therapy with docetaxel in addition to ADT was the first combination that 
was integrated in the clinical guidelines for patients with mHSPC (James et al. 2016, Sweeney 
et al. 2015). As the clinical practice continues to evolve with new strategies and criteria to be 
considered for treatment decisions the overall treatment paradigm of mHSPC is currently 
under modification aiming to propose the most appropriate therapeutic options to different 
subgroups of patients with mHSPC.
2.3
Benefit/Risk Assessment
Darolutamide has undergone an extensive clinical development program and the data have 
demonstrated efficacy and effectiveness in the treatment of patients with mCRPC and 
nmCRPC.
Darolutamide’s efﬁcacy and tolerability have been demonstrated in two Phase 3 studies, 
17712 (ARAMIS) and 17777 (ARASENS) (Smith et al. 2022).
In the randomized, double-blind placebo-controlled Phase 3 study 17712 (ARAMIS), 
including 1509 patients, darolutamide demonstrated an improvement in metastasis-free 
survival (MFS) and overall survival (OS) compared to placebo for nmCRPC patients with a 
rapid PSA doubling time (MFS: active arm median 40.4 vs 18.4 months in placebo arm, HR 
0.41; 95% CI 0.34–0.50; P<0.0001; OS: at the time of primary analysis, darolutamide showed 
statistically significant OS benefit corresponding to a 31% reduction in the risk of death 
compared with placebo). Darolutamide showed a favorable safety profile, with similar 
incidence of most common treatment-emergent adverse events (TEAEs) and similar incidence 
of permanent discontinuations of treatment between the darolutamide and the placebo arms. 
No evidence was found that darolutamide would add any clinically relevant toxicity when 
administered with ADT. Importantly, patient quality of life was maintained throughout the 
duration of treatment. Based on the results of ARAMIS study, darolutamide was approved for 
the treatment of patients with nmCRPC.
In the randomized, double-blind, Phase 3 study 17777 (ARASENS), including 1306 patients, 
darolutamide, in combination with docetaxel and ADT treatment, showed survival benefit, 

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compared to placebo in combination with docetaxel and ADT, in mHSPC patients. The risk of 
death was significantly lower, by 32.5%, in the darolutamide group than in the placebo group 
(hazard ratio 0.68; 95% confidence interval, 0.57 to 0.80; P<0.001). Also, secondary 
endpoints favored darolutamide treatment arm. Adverse events were similar in the two 
groups, and the incidences of the most common adverse events (occurring in ≥10% of the 
patients) were highest during the overlapping docetaxel treatment period in both groups. The 
most commonly reported AEs were known toxic effects related to the docetaxel therapy. As 
AE of interest for the antiandrogen therapeutic class, in 17777 (ARASENS) trial only rash 
and hypertension showed a difference of incidence between the 2 arms which was >2 percent 
(rash was reported in 16.6% of the patients in the darolutamide group and 13.5% of those in 
the placebo group; hypertension was reported in 13.7% and 9.2%, respectively).
In the pooled analysis of safety in mCRPC patients from Phase 1/2 studies, the overall 
incidences of individual TEAEs were higher than seen in nmCRPC patients. This was 
expected considering that the mCRPC patients have more advanced disease with 
comorbidities. Despite the differences in the patient populations, the overall TEAE profile in 
the mCRPC pool was consistent with that observed in ARAMIS study supporting the 
favorable safety profile of darolutamide.
With its potent anti–androgenic and favorable safety profile, there is a strong rationale to 
study darolutamide in participants with mHSPC to delay disease progression and death. The 
available safety and efficacy data suggest that participants who participate in this trial are not 
placed at undue risk.
2.3.1
Risk Assessment
The safety profile of darolutamide therapy is well characterized based on the data from the 
ARAMIS and ARASENS studies in nmCRPC and mHSPC patients, respectively, as well as 
on integrated data from Phase 1 and 2 studies including patients with mCRPC. safety issues. 
Overall, the data show that darolutamide is well tolerated and has a favorable safety profile.
The overall safety profile of darolutamide is based on data from 1508 patients of whom 954 
received at least one dose of darolutamide in the ARAMIS study, plus 1306 patients of whom 
651 took at least one dose of darolutamide in the ARASENS study.
In ARAMIS, the good tolerability of darolutamide treatment was demonstrated by similar 
incidences of TEAEs leading to permanent treatment discontinuation between the treatment 
arms (8.9% darolutamide vs. 8.7% placebo) during the double-blind phase. The incidence of 
adverse events was low and generally similar in the darolutamide and placebo treatment arms; 
with the exception of fatigue, which was the only event reported in >10% of patients (13.2% 
darolutamide vs. 8.3% placebo). Rash, pain in extremity and fatigue adverse drug reactions 
were identified as adverse drug reactions; neutrophil count decreased, bilirubin and aspartate 
aminotransferase (AST) increased as laboratory test abnormalities for darolutamide.
The laboratory abnormalities were predominantly of grade 1 or 2 in intensity and not 
associated with any clinically relevant signs and symptoms and were either transient or 
reversible after treatment discontinuation. There was no incremental risk with the addition of 
darolutamide to ADT for events such as fall, seizure, hypertension. No evidence was found 
that darolutamide would add any clinically relevant toxicity when administered with ADT.
In ARASENS, incidence of TEAEs were similar in both treatment arms. The incidences of 
the commonly reported TEAEs (occurring in ≥10% of the participants), were highest in both 
treatment groups during the period when the participants received both docetaxel and either 

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darolutamide or placebo, and progressively decreased thereafter. The most commonly 
reported TEAE with grade 3 and grade 4 as worst grade, were white blood cell count 
decreased and neutrophil count decreased, respectively. Hypertension and rash were identified 
as adverse drug reactions, blood bilirubin increase, alanine aminotransferase (ALT) and AST 
increased as lab test abnormalities.
More detailed information about the known and expected risks and expected adverse events 
can be found in the Investigator’s Brochure of darolutamide and Patient Information Leaflet, 
Package Insert of ADTs.
Cases of idiosyncratic hepatic reactions with increases in ALT and AST to ≥5 and ≥20 x 
upper limit of normal (ULN) have been reported in darolutamide clinical trials. Time to onset 
ranged from 1 month to 10.5 months after initiation of darolutamide. The ALT and AST 
elevations were reversible upon darolutamide discontinuation. Please see Sections 6.6.3 and 
7.1.
2.3.2
Benefit Assessment
Darolutamide is a potent ARi with low blood–brain barrier penetration and low potential for 
drug–drug interactions. The present study will evaluate darolutamide in addition to ADT in 
mHSPC participants.
Darolutamide has a favorable safety profile based on the data from two the Phase 3 
randomized, double-blind studies, i.e., ARAMIS study in nmCRPC and ARASENS in 
mHSPC patients, supported by the integrated safety data from studies in mCRPC patients.
In ARAMIS, most of the adverse events were generally mild and manageable. In ARASENS, 
incidence of the adverse events occurred in the period of concomitant treatment with 
chemotherapy.
In addition, in the ARAMIS study, darolutamide effect on cardiac repolarization was studied 
in a subset of 500 participants. There was no clinically significant effect on cardiac 
repolarization (QTc) detected. Treatment with darolutamide will allow greater flexibility for 
concomitant use with medication typically used in the elderly patient population. This overall 
good tolerability was further demonstrated by the fact that in mCRPC patients (ARAMIS) no 
increase in permanent treatment discontinuations due to TEAEs has been observed in the 
darolutamide arm as compared to the placebo arm.
In ARASENS, where patients received up to 6 cycles of chemotherapy, the combination of 
darolutamide and docetaxel did not result in more toxic effects than the combination of 
androgen-deprivation therapy and docetaxel alone.
With its potent anti–androgenic and favorable safety profile, there is a strong rationale to 
study darolutamide in participants with mHSPC to delay disease progression and death. The 
available safety and efficacy data suggest that participants who participate in this trial are not 
placed at undue risk.
2.3.3 Overall Benefit: Risk Conclusion
Taking into account the measures taken to minimize risk to participants in this study, and 
regular evaluation of risk benefit by an independent DMC, the potential risks identified in 
association with darolutamide in addition to ADT are justified by the anticipated benefits that 
may be afforded to participants with mHSPC.

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Based on ARAMIS study, darolutamide provided a significant improvement in MFS and OS, 
as well as a significant benefit in extending time to pain progression, time to cytotoxic 
chemotherapy and time to first symptomatic skeletal event (SSE) in patients with nmCRPC.
Patients treated with darolutamide maintained their quality of life.
Based on ARASENS data, darolutamide provided a significant improvement in OS and other 
clinically relevant endpoints such as time to development of CRPC, time to pain progression, 
time to the first SSE, time to initiation of subsequent anticancer therapy in the mHSPC 
setting, when given in association with docetaxel.
The benefits of darolutamide treatment outweigh the risks arising from its use. The risks are 
well understood and are appropriately managed with product labeling and routine 
pharmacovigilance. Taking into account the seriousness of the disease as well as the medical 
need for additional therapy in this population, the overall benefit-risk balance of darolutamide 
is considered favorable.
Darolutamide offers an effective treatment option without the addition of clinically relevant 
toxicity when administered with ADT. The compelling safety and DDI profile of 
darolutamide will positively impact clinical practice by improving the management of 
prostate cancer treatment in an elderly population with co-morbidities where polypharmacy is 
the norm.
3.
Objectives and Endpoints
The purpose of this study is to evaluate the efficacy and safety of darolutamide in addition to 
ADT versus placebo plus ADT in participants with mHSPC. All the objectives listed in Table 
3–1 will be analyzed at the primary completion. Only limited analyses will be conducted in 
the final analysis, i.e. OS and safety.

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Table 3–1
Objectives and Endpoints
Objectives
Endpoints
Primary

To determine if darolutamide in addition to ADT is 
superior to placebo plus ADT by improving rPFS in 
participants with mHSPC

rPFS assessed by central review based on 
RECIST v. 1.1 criteria for soft tissue 
metastases and PCWG3 criteria for bone 
metastases
Secondary

To evaluate efficacy of darolutamide in addition to 
ADT compared to placebo plus ADT by improving 
OS, time to progress to CRPC, time to initiation of 
subsequent anti-cancer therapy, time to PSA 
progression, and undetectable PSA rates

OS – key secondary endpoint

Time to CRPC

Time to initiation of subsequent anti-cancer
therapy

Time to PSA progression

PSA undetectable rates (<0.2 ng/mL)

To estimate the participant’s quality of life benefit of 
darolutamide in addition to ADT compared to 
placebo plus ADT by improving symptomatic time 
to pain progression

Time to pain progression (BPI-SF)

To assess the safety of darolutamide in addition to 
ADT compared to placebo plus ADT in participants 
with mHSPC

AE assessments using NCI CTCAE (v.5.0)
Other pre-specified

To further evaluate efficacy of darolutamide in 
addition to ADT compared to placebo plus ADT by 
progression-free survival 2 as assessed by the 
investigator (PFS2)

Progression-free survival 2 (PFS2) as assessed 
by the investigator, is defined as time from 
randomization to clinical, biochemical, or 
radiological disease progression under first 
subsequent anti-cancer therapy or death,
whichever occurs first

To estimate the participant’s quality of life benefit of 
darolutamide in addition to ADT compared to 
placebo plus ADT by improving time to first SSE

Time to symptomatic skeletal event, defined as 
time from date of randomization to the date of 
first SSE

To investigate tumor* and circulating biomarkers 
with the aim of elucidating the molecular profile of 
the participants potentially related to response to 
darolutamide

To assess changes in tumor molecular status in 
circulating tumor DNA obtained before, during 
treatment and after progression on darolutamide, 
with the aim of elucidating the molecular profile, 
modifiers of response and acquired resistance to 
darolutamide

Alterations of markers related to prostate 
cancer and androgen receptor inhibition such 
as androgen receptor (AR) alterations, 
alternative AR splice variants (e.g. AR V7), 
PTEN loss

To further investigate the study drug and similar 
drugs (e.g. mode-of-action-related effects, safety)
and to further investigate pathomechanisms 
deemed relevant to cancer and associated health 
problems*

Various biomarkers (e.g. diagnostic, safety, 
pharmacodynamic, monitoring, or potentially 
predictive biomarkers)*

To estimate the participant’s quality of life benefit of 
darolutamide in addition to ADT compared to 
placebo plus ADT by improving time to 
deterioration in FACT-P total score

To estimate the benefit of darolutamide in addition 
to ADT compared to placebo plus ADT by 
improving time to first prostate cancer- related 
invasive procedures

Time to deterioration in FACT-P total score
During the double-blind period: Time to first 
prostate cancer-related invasive procedures

Time to first prostate cancer-related invasive 
procedure is defined as time from
randomization to date of first prostate cancer-
related invasive procedure

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Abbreviations: ADT = Androgen Deprivation Therapy; AE = Adverse event; AR = Androgen receptor; ARi = 
Androgen receptor inhibitor; BPI-SF = Brief Pain Inventory-Short Form; CRPC = Castration-resistant 
prostate cancer; CT = Computed tomography; EBRT = External beam radiation therapy; FACT-P = 
Functional Assessment of Cancer Therapy-Prostate; mHSPC = Metastatic hormone-sensitive prostate 
cancer; MRI = Magnetic resonance imaging; NCI CTCAE = National Cancer Institute–Common 
Terminology Criteria for Adverse Events (version 5.0); OS = Overall survival; PCWG3 = Prostate Cancer 
Working Group 3; PSA = Prostate-specific antigen; PTEN = Phosphatase and tensin homolog;
QoL = Quality of life; RECIST = Response Evaluation Criteria in Solid Tumours; rPFS = Radiological
progression-free survival; PFS2 as assessed by the investigator = Time from randomization to radiological 
disease progression under first subsequent anti-cancer therapy or death, whichever occurs first; SSE = 
Symptomatic skeletal event; TEAE = Treatment-emergent adverse event
* Not applicable for China.
4.
Study Design
4.1
Overall Design
This is a randomized, double-blind, placebo-controlled Phase 3 study to determine if 
darolutamide in addition to ADT is superior to placebo plus ADT by improving rPFS in 
participants with mHSPC. The study schema and SoA are provided in Section 1.1 and 
Section 1.3, respectively.
Approximately 665 participants who meet the eligibility criteria including confirmation of 
metastatic disease by central review (see Section 5.1 and Section 5.2) will be randomized in a 
2:1 ratio to receive one of the following study drugs:

Darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equivalent to a total 
daily dose of 1200 mg or

Placebo darolutamide matched tablets in appearance, twice daily with food
Participants will be stratified at randomization as follows:

Presence of visceral metastases versus absence of visceral metastases assessed by 
central review

Prior local therapy versus no prior local therapy
Background treatment: All participants must receive ADT of investigator’s choice (LHRH 
agonist/antagonists or orchiectomy) as standard therapy, started not earlier than 12 weeks 
before randomization, on a continuous basis.
For participants receiving LHRH agonists, treatment in combination with a first generation 
anti–androgen for at least 14 days prior to randomization is recommended. First generation 
anti–androgen will be discontinued before study treatment start.
The study will comprise 4 consecutive periods: Screening, Treatment, Active Follow–up, and 
Long–term (survival) Follow–up.
Once results of the primary analysis are available, if they support a positive benefit/risk 
assessment for darolutamide considering feedback from the study Steering Committee and/or 
health authorities, an open-label phase may start. Following the unblinding, those participants
who are on study treatment (darolutamide or placebo) will be offered the opportunity to 
receive darolutamide through open-label period in this study, at the discretion of the 
investigator. Those participants who do not choose to continue with open-label darolutamide 
treatment, will have an end-of-study treatment visit at the time of unblinding.

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At the moment of unblinding, if participant qualifies to continue the study treatment, 
participant will be offered to enter the open-label phase. Open-label phase ICF must be signed 
before any study-related intervention. Participants in the open-label phase will continue to be 
assessed according to the SoA in Section 1.3. 
To transition from the double-blind to open-label phase, participants who are on placebo arm 
will undergo an unscheduled visit to confirm they qualify to continue the study treatment, 
sign ICF and dispense open-label active drug. Participants who are on active arm will undergo 
subsequent scheduled regular study visit to, sign ICF and dispense open-label drug. 
In the open-label phase, tumor assessments, including radiology assessments, PSA and 
testosterone will continue according to local practice and evaluated by local 
radiologists/laboratories. Scans will no longer be collected for the central radiology review. 
Upon discontinuation of the study drug, participant will continue the study in the active and 
subsequently Long-term Follow-up phase for collection of data relevant for selected endpoints
(i.e., OS and safety).
4.1.1
Screening Period
The start of the screening period is defined by signing of the informed consent form (ICF).
Participant screening must occur within 28 days prior to randomization, during which all 
study-related procedures and evaluations will be performed in order to establish participant
eligibility. Baseline computed tomography (CT)/magnetic resonance imaging (MRI) scans 
and bone scans should be submitted for central review as soon as possible during the 
screening period in order to complete confirmation of metastatic disease for eligibility and 
assess stratification for presence/absence of visceral metastases during the screening period. 
Screening procedures can be performed on separate occasions within the allowed 28-day 
timeframe. It is estimated that it will take 7 to 14 days to obtain results from the safety 
laboratory assessments, testosterone, and PSA.
Each participant’s eligibility will be double-checked by the Bayer–designated medical 
representative (contract research organization [CRO] Medical Monitor) in writing. The 
investigator will complete a paper eligibility form confirming the key inclusion and exclusion 
criteria. This form will be forwarded to the Bayer–designated medical representative for 
review and eligibility double-check, which will take into account the results of the central 
image review for eligibility. Central review imaging will also provide stratification (visceral 
disease present vs. visceral disease absent). The responsibility of a participant’s enrollment 
remains with the investigator.
Timing for sending the scans to the imaging core laboratory, central review of images, 
sending the eligibility form and its review will have to be taken into account when planning 
the screening procedures.
Screening will take place in the Interactive Web Response System (IWRS), where the 
participant will receive a unique identification (ID).
At the end of the screening period, eligible participants (eligibility documented and 
confirmed) will be randomized to receive study drug as described in Section 4.1.
The screening period only applies to the double-blind phase of the study.

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4.1.2
Treatment Period
The start of the treatment period is defined by the first administration of study drug, which 
has to occur within 3 days since randomization and after all activities described in the SoA 
(Section 1.3) Visit 1, Day 1 have been conducted.
During treatment period, participants will be evaluated with regular clinic visits every 
12 weeks (±7 days) for efficacy and safety as described in the SoA (Section 1.3). Date of visit 
is to be calculated based on the previous visit date.
The dose or dosing schedule of the study drugs may be modified following the occurrence of 
adverse events (AEs) according to the guidance provided in Section 6.6.
The treatment period can take place either in the double-blind or both in the double-blind and 
open-label phases.
In the double-blind period, participants will receive study drug until documented radiological
disease progression assessed by central review, unacceptable toxicity or until any other 
withdrawal criteria specified in Section 7.1 is met. In the open-label phase same 
discontinuation criteria apply, but radiological tumor assessments will continue according to 
local practice and will be evaluated by local radiologists. 
An independent Data Monitoring Committee (DMC) will monitor the unblinded safety data 
on a regular basis throughout the trial, until primary completion. Participants will have a 
safety follow-up visit 30 days (+7 days) after last dose of study drug or prior to initiating of 
new anti-cancer therapy for prostate cancer whichever occurs first.
After final OS analysis of the current study participants ongoing on darolutamide treatment 
may continue to receive darolutamide in the current study or in a separate access program 
(roll-over study or any other mechanism to supply drug post-study). This is subject to 
approval by the competent health authority and ethics committee.
The treatment period will end at each site when all participants at the site who are ongoing on 
darolutamide treatment have transitioned into a separate access program (roll-over study or 
any other mechanism to supply drug post-study) to continue receiving darolutamide (see 
Section 6.7) or have discontinued from the study treatment.
4.1.3
Active Follow–up Period
The Active Follow–up period is the interval from the end–of–study drug intake to the end of 
all protocol–specified post–treatment interventions.
In both the double-blind and open-label phases of the study, End of Treatment (EOT) visit
will be conducted 30 days (+7 days) after the last dose of study drug.
For the participants who, at the start of open-label period, do not qualify or refuse to enter the 
open-label phase of the study, EOT will be performed.
Another systemic anti-cancer therapy may be initiated no sooner than 7 days after the last 
dose of study drug. For participants for whom another systemic anti-cancer therapy is planned 
to start sooner than 30 days (+7 days) after the last dose of the study drug, the EOT visit must 
be conducted before the new anti-cancer therapy starts.
During the EOT visit, procedures to monitor participant’s health, to identify potential 
toxicities, and to assess efficacy will be performed as described in the SoA tables (Section 
1.3).

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Active Follow–up visits will start after completion of the EOT evaluation: 
approximately 5 Active Follow–up visits will occur as standard of care clinic visits 
approximately every 12 weeks, for approximately 1 year (12 ±1 months).
In the double-blind phase, Active Follow-up visits are meant to record survival status, SSEs,
efficacy (CT/MRI and bone scan), PSA and testosterone for participants who discontinue the 
study treatment before radiological progression assessed by central review, prostate cancer-
related invasive procedure until change of anti-cancer therapy, QoL, pain assessment, 
subsequent anti-cancer treatments for prostate cancer, and study drug-related SAEs with
concomitant medication received. 
Instructions for imaging in the Active Follow-up phase in the double-blind phase of the study, 
for participants who discontinued study drug before radiological progression assessed by 
central radiology review: 

Contrast enhanced CT/MRI and bone scan will be performed every 12 weeks until
radiological disease progression is assessed by central review.

If allowed by local regulations, participants without centrally-assessed radiological 
disease progression, for whom start of a subsequent anti-cancer therapy is planned 
before the next follow-up visit/contact, should perform a tumor assessment (contrast 
enhanced CT/MRI and bone scan) and submit it to the core imaging laboratory for 
central radiology review. Note that this tumor assessment is not required if the prior 
tumor assessment was performed within the previous 30 days.
Participants for whom radiological disease progression was already assessed by central 
review, will continue imaging as per local practice.
In the open-label phase of the study, Active Follow-up visits are meant to record survival 
status and study drug-related SAEs with concomitant medication received.
Date of clinical, biochemical, or radiological disease progression under first subsequent 
anticancer therapy, as assessed by the investigator, will be reported in the electronic case 
report form (eCRF).
The Active Follow–up period extends from the discontinuation of treatment period for 
approximately 1 year (12 ±1 months) or until the participant can no longer travel to the clinic, 
dies, is lost to follow–up, or withdraws informed consent and actively objects to collection of 
further data.
4.1.4
Long–term (survival) Follow–up Period
In both double-blind and open-label study phases, after completing the Active Follow–up
period, participants will enter the Long–term Follow-up period and will be contacted 
approximately every 12 weeks (by telephone) to record survival status, subsequent anti-cancer
treatments for prostate cancer and prostate cancer-related invasive procedure until change of 
anti-cancer therapy, (only applicable to the double-blind phase), and study drug-related SAEs
with concomitant medications received until death, lost to follow-up, consent withdrawal, or
the sponsor terminates the study.
Limited to the double-blind phase of the study, in case that a participant did not experience 
radiological disease progression assessed by central review or did not start a subsequent anti-
cancer treatment within the end Active Follow-up, radiological assessments by CT/MRI and 
bone scan must continue in the Long-term Follow-up. If allowed by local regulations, 
participants without centrally-assessed radiological disease progression, for whom start of a 

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subsequent anti-cancer therapy is planned before the next follow-up visit/contact, should
perform a tumor assessment (contrast enhanced CT/MRI and bone scan) and submit it to the 
core imaging laboratory for central radiology review. Note that this tumor assessment is not 
required if the prior tumor assessment was performed within the previous 30 days.
Also, PSA and testosterone central assessments should continue in long term follow-up for 
participants not experiencing radiological disease progression by central review, until it
occurs, or a new anti-cancer treatment is started. Therefore, in that case participants should 
continue with clinic visits during long term follow-up.
The information will be collected as described in the SoA (Section 1.3).
Pertaining to the information that will be collected over the telephone from the participant, it 
is the clinical site’s responsibility to obtain and make available the source documentation for 
the information collected from the participant and documented it in the source data and 
recorded in the eCRF.
Survival Sweep
For the primary analysis and subsequent overall survival (OS) analyses, the survival data will 
be collected through additional survival sweeps. All participants considered alive shortly after 
the database cut-off date for the primary analysis and prior to any subsequent analysis of OS 
will be contacted for survival status.
4.2
Scientific Rationale for Study Design
This is a randomized, placebo-controlled, double-blind Phase 3 study to determine if 
darolutamide in addition to ADT is superior to placebo plus ADT by improving rPFS in 
participants with mHSPC.
Despite the recent combinations approved for patients with mHSPC, the ADT alone still to be 
standard of care in many countries. The ADT alone as comparator arm is consistent with other 
pivotal study designs conducted in mHSPC, and therefore important to study in this patient 
populations who are often on these medications for a significant period.
Darolutamide, added to ADT has demonstrated a significant benefit and a favorable safety 
profile in nmCRPC and therefore, it is expected that darolutamide in addition to ADT will 
enhance the disease control and will provide a significant benefit in patients with mHSPC 
compared to ADT while preserving patient’s quality of life without increasing the incidence 
of adverse events.
The primary endpoint of this study will be radiological progression-free survival (rPFS)
utilizing conventional imaging methods 99mTc-bone scan for bone metastases according to 
Prostate Cancer Working Group 3 (PCWG3) (Scher et al. 2016) [Appendix 10, Section 10.10]
criteria and CT/MRI for soft tissue/visceral metastases based on Response Evaluation Criteria 
in Solid Tumors version 1.1 (RECIST v. 1.1) (Eisenhauer et al. 2009) [Appendix 9, 
Section 10.9] criteria. In the recently reported pivotal trials in mHSPC, rPFS has been used as 
the sole primary endpoint or as part of a dual endpoint (Armstrong et al. 2019, Fizazi et al. 
2017).
Metastatic hormone-sensitive prostate cancer is a complex disease and trials that make use of 
OS as a primary outcome in mHSPC can take close to a decade to complete and are subject to 
issues with crossover. Therefore, rPFS as the primary endpoint may be used as a surrogate 
endpoint to OS that is available earlier and that can be measured more frequently than OS. For 
patients with localized prostate cancer it has been shown that MFS is a strong surrogate for 

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OS based on an analysis of 20 trials and 13,000 men with localized prostate cancer conducted 
by the Intermediate Clinical Endpoints in Cancer of the Prostate program (ICECaP M0) and is 
currently accepted for nmCRPC (Xie et al. 2017).
Based on the positive outcome of ICECaP M0, the STOPCAP M1 program aims to identify 
whether other endpoints could be potential surrogate endpoints for OS in mHSPC (Tierney et 
al. 2019). Besides, recently enzalutamide was approved in addition to ADT for patients 
mHSPC based on rPFS improvement reported in ARCHES trial (Armstrong et al. 2019).
Overall, this study will evaluate approximately 665 participants randomized 2:1. Overall 
survival will be the key secondary endpoint and the interim analysis of OS will occur at the 
time of the rPFS analysis. The stopping boundaries for the two OS analyses will be calculated 
with an O’Brien-Fleming alpha-spending function based on the actual number of events 
observed up to the cut-off dates.
Once results of the primary analysis are available, if they support a positive benefit/risk 
assessment for darolutamide considering feedback from the study Steering Committee and/or 
health authorities, an open-label phase may start.
4.2.1 Participant Input into Design
For this study participant input into design was not assessed.
4.3
Justification for Dose
The recommended oral dose was determined based on non-clinical results and clinical results 
from studies 17829 (ARADES), 17830 (ARAFOR) and 17712 (ARAMIS).
Clinically, darolutamide has been studied in dose range from 100 mg to 900 mg bid in the 
dose-escalation and dose finding study 17829 (ARADES). Dose-linearity of the 
pharmacokinetic parameters was observed after single and repeated administration in the dose
range of 100 mg and 700 mg darolutamide bid. At higher dose (900 mg bid), no further 
increase in exposure or maximum concentration of darolutamide was observed, indicating that 
saturation of absorption occurs at doses higher than 700 mg of darolutamide bid.
Study 17830 (ARAFOR) was conducted using a dose of 600 mg darolutamide bid, a dose 
selected based on non-clinical efficacy data in mice showing maximum PSA suppression at an 
exposure level of unbound darolutamide to be expected at a dose of 600 mg darolutamide bid. 
Based on biopharmaceutical characteristics, antitumor activity and safety profile, the dose of 
600 mg bid was selected for subsequent clinical studies.
In a randomized, double-blinded, placebo-controlled Phase 3 study 17712 (ARAMIS), this 
recommended dose of 600 mg darolutamide bid demonstrated statistically significant clinical 
benefits in nmCRPC patients as mentioned above (see Section 2.3).
4.4
End of Study Definition
The study starts with a double-blind phase. Primary completion will be reached when the 
planned number of events for the primary endpoint is reached (see Section 9.4.2.1). Once 
results of the primary analysis are available, if they support a positive benefit/risk assessment 
for darolutamide considering feedback from the study Steering Committee and/or health 
authorities, an open-label phase may start.
The end of the study as a whole will be reached as soon as the last visit of the last participant
has been reached in all centers in all participating countries.

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A participant is considered to have completed the study if he has undergone all periods of the 
study described in Section 4.1, and has transitioned into a separate access program (roll-over 
study or any other program to supply drug post-study, where possible) or has discontinued the 
study for another reason (e.g., death, lost to follow–up, consent withdrawal with no further 
data collection).
Until transition to a separate access program, participants will continue to follow all the 
protocol-required procedures and visits in the current protocol. Once a separate access 
program is available for participants to move to, study treatment in the current study will no 
longer be available.
At each site, when all participants on darolutamide treatment have transitioned into the 
separate access program or have discontinued the study for another reason (e.g. lost to 
follow–up, consent withdrawal), those participants who are in follow-up will discontinue as 
the current study will be terminated.
If the trial is stopped but benefits are observed for ongoing participants, options for treatment 
continuation will be discussed and agreed between the investigator, sponsor and the 
participants.
5.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted.
The study population includes participants with a diagnosis of mHSPC.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
1. Written informed consent obtained.
Capable of giving signed informed consent as described in Appendix 1 (Section 10.1)
which includes compliance with the requirements and restrictions listed in the ICF and in 
this protocol.
2. Males ≥18 years of age.
3. Histologically or cytologically confirmed adenocarcinoma of prostate.
4. Documented metastatic disease by conventional imaging method either by a positive 
99mTc-phosphonate bone scan, or soft tissue or visceral metastases, either by contrast-
enhanced abdominal/pelvic/chest CT or MRI scan assessed by central review. Note: 
participants with a baseline “superscan” (bone scan showing a diffuse, intense, skeletal 
uptake of the tracer with absent renal and background activity) are considered ineligible.
Note: Metastatic disease is defined as either malignant lesions in bone scan or measurable 
lymph nodes above the aortic bifurcation or soft tissue/visceral lesions according to 
RECIST version 1.1. Lymph nodes are measurable if the short axis diameter is ≥15 mm, 
soft tissue/visceral lesions are measurable if the long axis diameter is ≥10 mm.
Regional lymph node metastases only (N1, below the aortic bifurcation) will not be 
considered as metastases eligible for the study. Only participants with non-regional lymph 
node metastases (M1a) and/or bone metastases (M1b) and/or other sites of metastases 
with or without bone disease (M1c), assessed according to National Comprehensive 

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Cancer Network (NCCN) classification, will be eligible. (National Comprehensive Cancer 
Network 2020)
5. Started ADT (LHRH agonist/antagonist or orchiectomy) with or without first generation 
anti–androgen, but not earlier than 12 weeks before randomization. For participants 
receiving LHRH agonists, treatment in combination with a first generation anti–androgen 
for at least 14 days prior to randomization is recommended.
6. First generation anti–androgen must be discontinued at least 1 day before study treatment 
start.
7. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0, 1 or 2.
8. Blood counts at Screening: hemoglobin ≥9.0 g/dL, absolute neutrophil count ≥1.5x109/L, 
platelet count ≥100x109/L (participant must not have received any growth factor within 
4 weeks or a blood transfusion within 7 days of the hematology laboratory sample 
obtained at Screening).
9. Screening values of serum alanine aminotransferase (ALT) and aspartate aminotransferase
(AST) ≤1.5 x ULN, total bilirubin ≤1.5 x ULN, creatinine ≤2.0 x ULN (for Canada: 
Screening values of serum alanine aminotransferase (ALT) and aspartate aminotransferase 
(AST) ≤1.5 x ULN, total bilirubin ≤1.5 x ULN).
10. Sexually active male participants must agree to use condoms as an effective barrier 
method and refrain from sperm donation, and/or their female partners of reproductive 
potential to use a method of effective birth control, during the treatment with study drug
and for 4 weeks after the last dose of the study treatment with study drug.
11. For Canada: At Screening; estimated glomerular filtration rate (eGFR) 
eGFR ≥30 mL/min/1.73 m2 (calculated by the CKD-EPI formula, (Levey et al. 2009).
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
1. Pathological finding consistent with small cell, ductal or neuroendocrine carcinoma of the 
prostate.
2. Known brain/ leptomeningeal metastases
Note: Brain CT/MRI scan should be performed only in case of symptoms.
3. Prior treatment with:

LHRH agonist/antagonists started >12 weeks before randomization starts except 
neoadjuvant and /or adjuvant therapy for a duration ≤24 months and completed 
≥12 months prior to randomization

Second–generation androgen receptor (AR) inhibitors such as enzalutamide, 
darolutamide, apalutamide or other investigational AR inhibitors

Cytochrome P 17 enzyme inhibitor such as abiraterone acetate or oral ketoconazole as 
anti-cancer treatment for prostate cancer

Chemotherapy including docetaxel or immunotherapy for prostate cancer

Use of systemic corticosteroid with dose greater than the equivalent 10 mg of 
prednisone/day within 28 days prior to randomization

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
Radiopharmaceuticals

Any other anti-cancer treatment for prostate cancer, excluding local therapies and 
ADT
4. Treatment with radiotherapy (external beam radiation therapy [EBRT], brachytherapy) 
within 2 weeks before randomization.
5. Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the 
formulation of the study drugs.
6. Contraindication to iodinated CT and gadolinium chelate MRI intravenous contrast 
agent(s).
7. Any prior malignancy (other than adequately treated basal cell or squamous cell skin 
cancer, superficial bladder cancer, or any other cancer in situ currently in complete 
remission) within 5 years prior to randomization.
8. An active viral hepatitis (defined as Hepatitis B surface antigen [HBsAg] reactive or 
detectable [qualitative] hepatitis B virus [HBV] DNA or defined as hepatitis C virus 
[HCV] ribonucleic acid [RNA] [qualitative] is detected), known human 
immunodeficiency virus (HIV) infection with detectable viral load, or chronic liver 
disease with a need of treatment.
Note: No testing for Hepatitis B and/or Hepatitis C is required unless mandated by local 
authority. No HIV testing is required unless mandated by local authority.
9. Had any of the following within 6 months before randomization: stroke, myocardial 
infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, 
congestive heart failure (New York Heart Association Class III or IV).
10. Uncontrolled hypertension as indicated by a resting systolic BP ≥ 160 mmHg or diastolic 
BP ≥ 100 mmHg despite medical management.
11. A gastrointestinal (GI) disorder or procedure which is expected to interfere significantly 
with absorption of study drug.
12. Previous (within 28 days before the start of study drug or 5 half–lives of the 
investigational treatment of the previous study, whichever is longer) or concomitant 
participation in another clinical study with investigational medicinal product(s).
13. Any other serious or unstable illness, or medical, social, or psychological condition, that 
could jeopardize the safety of the participant and/or his/her compliance with study 
procedures or may interfere with the participant’s participation in the study or evaluation 
of the study results.
14. Inability to swallow oral medications.
5.3
Lifestyle Considerations
There are no lifestyle considerations for participant’s eligibility for the study.
5.3.1
Meals and Dietary Restrictions
There are no meals and dietary restrictions for participants participating in this study.
5.3.2
Activity
There are no specific activity restrictions for participants participating in this study.

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5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomly assigned to study drug. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details and any serious adverse event (SAE).
A participant who, for any reason (e.g., failure to fulfill the eligibility criteria), terminates the 
study at any time prior to randomization is regarded a “screen failure”. The reason will be 
documented in the source documentation and the eCRF and the participant will discontinue 
participation in study with no further follow–up required. Screen failure must be completed in 
the IWRS.
Re–testing is allowed during the 28-day window only if there is a medical or logistical reason. 
In case screening procedures need to be repeated outside the allowed 28-day timeframe of the 
screening period, participant should be considered a screen failure.
Participants who do not meet the criteria for participation in this study (screen failure) may be 
re-screened within 2 weeks from the prior screen failure date.
The participants who need to repeat the screening procedures will be re-consented.
The investigator must ensure that the repeated screening procedures do not expose the 
participant to an unjustifiable health risk.
Re–screening of a participant who did not fulfill the eligibility criteria is allowed within 
2 weeks from the prior screen failure date. If the participant meets criteria for re-screening, 
then this step must be completed in the IWRS, and the participant will be assigned a new ID.
Re–screening of screen failed participants may only be allowed once after discussion with the 
Bayer–designated medical representative. Sponsor approval may be required on case by case 
evaluation. Approval of re–screening for a screen failed participant must be documented.
6.
Study Intervention
Study drug is defined as any investigational drugs, marketed product(s), placebo, or medical 
device(s) intended to be administered to a study participant according to the study protocol.

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6.1
Study Interventions Administered
Study drugs
The following study drugs are administered in this study: 

Darolutamide (BAY 1841788) or

Placebo matching darolutamide
The term “study drug” used in this protocol refers to either of these drugs. If either only 
darolutamide or placebo is described, the respective drug name will be used. Details on study 
drugs are provided in Table 6–1.
Background treatment
In both double-blind and open-label periods, all participants must receive ADT of 
investigator’s choice (LHRH agonist/antagonists or orchiectomy) as standard therapy, not
earlier than 12 weeks before randomization, on a continuous basis.
For participants receiving LHRH agonists, treatment in combination with a first generation 
anti–androgen for at least 14 days prior to randomization is recommended. First generation 
anti–androgen will be discontinued 1 day before study treatment start. 
The concurrent treatment with a LHRH agonist/ antagonists will be provided by the local/ site 
pharmacy and the dose and schedule of administration will be consistent with the local 
prescribing information approved. 
The concurrent therapy with LHRH agonist/ antagonists or orchiectomy must be documented 
in the source data and recorded in the eCRF.

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Table 6–1
Administration of study drug
Study Drug Name
Darolutamide 
Placebo 
Type 
Drug 
Drug
Dose Formulation
Coated tablet
Coated tablet
Unit Dose Strength(s)
300 mg / tablet
Not applicable
Dosage Levels
600 mg twice daily
Twice daily
Route of Administration
Oral
Oral
Additional administrative information
Use
Active test drug
Inactive comparator
IMP and NIMP
IMP
IMP
Sourcing
Provided centrally by the 
sponsor
Provided centrally by the 
sponsor
Packaging and Labeling
Study drug will be provided in 
150ml HDPE bottles with child 
resistant closure, each 
containing 140 tablets. Each 
bottle will be labeled as required 
per country requirement.
Study drug will be provided in 
150ml HDPE bottles with child 
resistant closure, each 
containing 140 tablets. Each 
bottle will be labeled as required 
per country requirement.
Current/Former Name(s) 
or Alias(es)
Darolutamide (INN), 
BAY 1841788
Placebo to darolutamide
Abbreviations: HDPE = High density polyethylene, IMP = Investigational medicinal product; 
INN = International nonproprietary name; NIMP = Non-investigational medicinal product.
Participants will be instructed to take 2 tablets of study drug orally twice daily at 
approximately 12 hour intervals as close to the same time each day as possible.
The tablets should be taken with food and a glass (about 250 ml) of water. The tablets should 
be swallowed whole.
The first dose of study drug will be administered with breakfast at the study center. 
Participants will continue taking study drug at home throughout the study treatment period 
and will be instructed to take their morning dose of study drug at home on further visit days.
Participants will receive study drug until any withdrawal criteria specified in Section 7.1 is 
met.
Dose modifications (interruption or reduction) due to study drug-related AEs are described in 
Section 6.6. For reduced dose, participants will be instructed to take 1 tablet of study drug 
orally twice daily with food at approximately 12 hour intervals as close to the same time 
every day as possible. If dosing is missed, it can be taken up to 6 hours from the planned 
dosing time to make up for the missed one.
6.2
Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study drugs received and any discrepancies are 
reported and resolved before use of the study drugs.
2. Only participants enrolled in the study may receive study drugs and only authorized 
site staff may supply or administer study drugs. All study drugs must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in 

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accordance with the labeled storage conditions with access limited to the investigator 
and authorized site staff.
3. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study drug accountability, reconciliation, and record maintenance 
(i.e., receipt, reconciliation, and final disposition records). Study drug returns, 
reconciliation, and destruction may be captured in study drug reconciliation and 
destruction logs.
4. Further guidance and information for the final disposition of unused study drugs are 
provided in the Study Reference Manual or other specified location.
6.3
Measures to Minimize Bias: Randomization and Blinding
Table 6–2
Randomization and Blinding by using Interactive Web Response 
System (IWRS)
Study using IWRS
All participants will be centrally assigned to randomized study drug using an 
Interactive Web Response System (IWRS). Before the study is initiated, the 
log in information & directions for the IWRS will be provided to each site.
Study drug will be dispensed at the study visits summarized in SoA (Section 
1.3). 
Returned study drugs should not be re-dispensed to the participants. 
Potential bias will be reduced by central randomization.
Blind Break (IWRS)
The IWRS will be programmed with blind-breaking instructions. In case of an 
emergency, the investigator has the sole responsibility for determining if 
unblinding of a participant’s treatment assignment is warranted. Participant’s 
safety must always be the first consideration in making such a determination. 
If the investigator decides that unblinding is warranted, the investigator 
should make every effort to contact the sponsor prior to unblinding a 
participant’s treatment assignment unless this could delay emergency 
treatment of the participant. If a participant’s treatment assignment is 
unblinded, the sponsor must be notified within 24 hours after breaking the 
blind. The date and reason that the blind was broken must be recorded in the 
source documentation and case report form, as applicable.
Abbreviations: IWRS = Interactive Web Response System; SoA = Schedule of Activities
Participants will be randomized in a 2:1 allocation ratio to receive study drug (darolutamide 
or matching placebo) in a double–blind fashion such that neither the investigator/study site 
personnel nor the sponsor, nor the participant will know which study drug is being 
administered. 
Treatment assignments of participants randomized to study drug will be done centrally using 
IWRS. A computer-generated randomization list will be generated by the sponsor or delegate 
for random assignments and provided to the IWRS vendor. The randomization number will be 
assigned to the participant through the IWRS based on information supplied by the 
investigator at the time of randomization.
Darolutamide and placebo will be identical in appearance in order to preserve blinding. To
maintain the blind, study drugs will be packaged in bottles labelled with a unique kit number. 
The study kit number will be assigned to the participant through the IWRS.

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Participants will be stratified as follows:

Presence of visceral metastases versus absence of visceral metastases assessed by 
central review

Prior local therapy versus no prior local therapy
The DMC will regularly review in an unblinded manner the safety data of participants who 
were randomized and have received at least 1 dose of study drug. The investigators, the 
participants and the sponsor will remain blinded.
6.3.1
SUSAR Unblinding
In the event of a Suspected Unexpected Serious Adverse Reaction (SUSAR) (see Section 
10.3) related to the blinded treatment, the participant’s treatment code will usually be broken 
before reporting to health authorities and central ethics committees in an unblinded fashion. In 
compliance with the European Commission’s Detailed Guidance on the collection and 
verification of presentation of AE/reaction reports arising from clinical trials on medicinal
products for human use, investigators and persons responsible for the ongoing conduct of the
study will not usually receive unblinded copies of SUSAR reports, unless unblinded
information is judged necessary for safety reasons.
6.3.2
Unblinding by the Investigator
Investigators may only unblind participants under following unblinding rules. 
If a participant is unblinded by the investigator, they must discontinue study drug.
Investigators should note that emergency unblinding is reserved for emergency situations
where lack of knowledge about the actual study drug treatment interferes with appropriate
emergency management. The occurrence of an SAE should not routinely precipitate the 
immediate unblinding of the label. 
If emergency unblinding is necessary for the treatment of a participant for an SAE, the 
treatment with study drug can be unblinded via the IWRS system (refer to the IWRS manual 
for instructions). The participating site has unrestricted and immediate access to break the
treatment code in IWRS. Should the blinded code be broken for a participant for emergency, 
the Medical Monitor or designee should be contacted by the principal investigator (PI) within 
24 hours of unblinding to discuss the rationale.
Unblinding may also be performed after the participant discontinues study treatment because 
of radiological progression assessed by central review, and the investigator feels this 
information is essential to determine the next course of therapy. Unblinding a participant for 
this situation may only take place after discussion with the sponsor’s medical monitor or 
designee.
6.4
Study Intervention Compliance
Participants will self-administer study drug (study intervention) at home, compliance with 
study drug will be assessed at each visit. Compliance will be assessed by direct questioning, 
counting returned tablets/capsules, etc. Study site personnel will instruct participants to report 
the time when study drug is self-administered. Participant compliance with study drug will be 
assessed at each visit. Deviation(s) from the prescribed dosage regimen should be documented 
in the source data and recorded in the eCRF. Compliance will be assessed during the site 
visits and documented in the source documents.

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A record of the number of tablets dispensed to and taken by each participant must be 
maintained and reconciled with study treatment and compliance records. An adequate record 
of receipt, distribution, and return/destruction of all study treatment must be captured on the 
dispensing log and drug accountability form.
Study drug tablets not returned will be considered to have been taken unless otherwise 
specified. At the end of the study, any remaining study drugs will be collected and returned to 
the sponsor, destruction depot, or destroyed at the site. Any discrepancies between the 
returned and expected returned study drugs should be explained.
6.5
Concomitant Therapy
Any concomitant medication or vaccine (including over-the-counter or prescription 
medicines, vitamins, and/or herbal supplements) or other specific categories of interest, that 
the participant is receiving at the time of enrollment or receives during the study must be 
recorded along with:

Reason for use

Dates of administration including start and end dates

Dosage information including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy.
Other concomitant medication may be considered on a case-by-case basis by the investigator 
in consultation with the Medical Monitor if required.
All concomitant treatments from the time of informed consent (IC) until the end–of–study 
treatment visit must be recorded on the CRFs. Once the participant has been withdrawn from 
the treatment with study drug, follow–up treatments will be recorded if used to treat new 
study drug–related SAEs or unresolved related AEs or if being used as a systemic anti-cancer
therapy for prostate cancer.
Contrast media do not need to be recorded as concomitant medication unless there is an 
adverse event related to its administration (e.g., allergic reaction).
6.5.1
Permitted Concomitant Therapy
Analgesic use will be captured via eCRF. Investigators or designees are to record which 
opioid and non-opioid medications were used since the last visit, and investigators or 
designees are to record exact daily doses of each analgesic consumed in the last 24 hours prior 
to the visit (Analgesic 24-hour consumption log – eCRF). Note that analgesic medication 
should be recorded via eCRF for each visit that pain is assessed via the Brief Pain Inventory-
Short Form (BPI–SF) (Section 8.1).
Palliative radiation therapy or surgical intervention as needed are allowed during study
treatment.
Vaccines for COVID-19, and flu are permitted during study treatment (see Section 6.5.2).
All participants must receive ADT of investigator’s choice (LHRH agonist/antagonists or
orchiectomy) as standard therapy, on a continuous basis. Switching ADT to an LHRH 
agonist/antagonist is permitted during study treatment, the reason and the time of LHRH 
treatment modification must be documented in the source data and recorded in the eCRF.

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Administration of 600 mg darolutamide bid over 4 days prior to administration of a single 
dose of 5 mg rosuvastatin, a breast cancer resistance protein (BCRP), OATP1B1 and 
OATP1B3 substrate, together with food resulted in a 5.2–fold increase in mean exposure 
[AUC(0–24)] and a 4.9–fold increase in Cmax of rosuvastatin in study 17723. This indicates 
that co–administration of darolutamide may also increase the plasma concentrations of other 
concomitant BCRP, OATP1B1 and OATP1B3 substrates (e.g., methotrexate, sulfasalazine, 
fluvastatin, atorvastatin). Therefore, the participants should be closely monitored for signs and 
symptoms of increased exposure to BCRP, OATP1B1 or OATP1B3 substrates. Dose 
modification of these substrates should be considered based on the prescriber information, or 
such compounds should be avoided.
Participants should be evaluated by investigators for presence of osteoporosis according to 
local guidelines and be provided with bone treatment support per local standard of care. 
Participants receiving treatment with osteoclast-targeted therapy at a dose and schedule 
indicated for osteoporosis prior to study entry may continue treatment at the same dose and 
schedule.
Contrast agents for radiological assessments are not required to be recorded in the 
Concomitant Medication CRF page, unless there is an adverse event related to the 
administration of contrast (e.g., contrast media allergic reaction) or the procedure is 
experimental and/or using an experimental contrast material (e.g., contrast enhanced 
ultrasound to determine vascularity).
6.5.2
Prohibited Concomitant Therapy
Concomitant treatment with another systemic anti-cancer therapy or another investigational
medicinal product is prohibited with the exception of ADT throughout the study after 
randomization.
Initiation of the following medications during the study treatment period is prohibited

Any investigational medicinal product

Radiopharmaceuticals

Immunotherapy (e.g. sipuleucel–T)

Cytotoxic chemotherapy including docetaxel

Enzalutamide, apalutamide, bicalutamide, flutamide, nilutamide

Abiraterone acetate or other CYP17 inhibitors

Systemic ketoconazole as anti-cancer treatment for prostate cancer

Any other anti-cancer treatment for prostate cancer, excluding local therapies and 
ADT
Any new systemic anti-cancer therapy may be initiated no sooner than 7 days after the last 
dose of study drug.
Use of live, attenuated, replication-competent vaccines is not permitted.
Darolutamide is a substrate of CYP3A4 and P-glycoprotein (P-gp). Repeated administration 
of rifampicin (600 mg), a strong CYP3A4 and a P-gp inducer, with a single dose of 
darolutamide (600 mg) together with food, resulted in a decrease of 72% in mean exposure 
[AUC(0-72)] and a decrease of 52% in Cmax of darolutamide. Use of strong CYP3A4 inducers 

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and P-gp inducers (e.g., carbamazepine, phenobarbital, St. John's Wort) during treatment with 
darolutamide is not recommended, unless there is no therapeutic alternative. Selection of an 
alternate concomitant medicinal product, with no or weak potential to induce CYP3A4 or P-
gp should be considered.
6.6
Dose Modification
The dose or dosing schedule of the study drug may be modified following the occurrence of
AEs. Doses of study drug may be interrupted or reduced in case of clinically significant 
toxicities that are considered by the investigator to be related to study drug.
For toxicities considered by the investigator to be not related to study drug, but clinically 
significant, the decision to interrupt or reduce the dose is left to investigator’s decision.
Toxicities will be graded using the National Cancer Institute–Common Terminology Criteria
for Adverse Events (NCI–CTCAE) v 5.0. All dose modifications regardless of relatedness
should be recorded on the eCRF.
If a participant experiences several study drug-related toxicities with different grading, the 
recommendation of the worst grading should be used. If a dose of study drug is delayed, dose 
can be taken up to 6 hours later with food to make up for the missed one.
6.6.1
Dose Interruption
The maximum time for a dose interruption period is 28 consecutive days. Any participant
requiring dose interruption >28 consecutive days must be withdrawn from treatment with
study drug.
6.6.2
Dose Reduction
If considered necessary for participant’s safety, the dose of study drug may be reduced to
300 mg bid.
Dosing of the study drug below 300 mg bid is not allowed. If a Grade ≥3 study drug-related 
TEAE occurs while the participant is on 300 mg bid, the participant must be withdrawn from 
the treatment with study drug.
6.6.3
General Requirements for Dose Modifications of Study Drug
A participant who experiences a Grade 3 or 4 study drug-related TEAE should interrupt study 
drug until the TEAE improves to Grade ≤2 or baseline status. Treatment with study drug is 
then to be restarted at 300 mg bid.
For Canada: For participants who experience a decreased renal function to severe renal 
impairment (eGFR of 15 to 29 mL/min/1.73 m2, calculated by the CKD-EPI formula, (Levey 
et al. 2009), the dose adjustment to 300 mg twice daily of darolutamide is recommended.
Participants who experience hepatic transaminase elevations suggestive of idiosyncratic drug 
induced liver injury (DILI) considered to be causally related to study drug, should discontinue 
study drug. Please see Section 7.1.
Additional details are provided in Table 6–3.

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Table 6–3
Study drug dose modifications
Severity grade
(NCI–CTCAE v 5.0)
Dose modifications
Study treatment withdrawal
Grade 0–2
Treat on time.
Per investigator’s decision to 
interrupt or reduce study drug a,b
–––
Grade 3 or 4
Interrupt until ≤ Grade 2 or 
baseline a
When the severity is Grade ≤2 or 
baseline, restart at a reduced 
dose of 300 mg bid b,c
If Grade ≥3 study drug-related TEAE occurs 
while the participant is on a dose of 300 mg bid
(following temporary or permanent dose 
reduction) the participant must be withdrawn 
from treatment with study drug
Excludes clinically nonsignificant and asymptomatic laboratory abnormalities. 
Abbreviations: AE = Adverse event; bid = Twice daily; NCI–CTCAE v 5.0 = National Cancer Institute–Common 
Terminology Criteria for Adverse Events version 5.0; TEAE = Treatment-emergent adverse event
a: If there is no recovery after 28 consecutive days, treatment with study drug should be permanently 
discontinued.
b: When AE returns to baseline or is resolved, re-escalation to 600 mg bid may be considered by the investigator.
c: If, following a re-escalation to 600 mg bid a second Grade ≥3 study drug-related TEAE occurs, a permanent 
dose reduction to 300 mg bid is required. A third occurrence of a Grade ≥3 study drug-related TEAE requires 
permanent discontinuation of treatment with study drug.
6.7
Intervention after the End of the Study
If the study is stopped for any reasons but benefits are observed for participants, treatment 
options will be discussed and agreed between the investigators, the sponsor and the 
participants.
They may receive further treatment, assessments and/or be followed via a roll-over study or 
any other mechanism to supply drug post-study. This applies to participants on treatment and 
in follow-up.
In the event that a roll-over study or any other mechanism to supply drug post-study is 
established, the present study will end when all participants have transitioned or discontinued 
from this study for another reason (e.g. consent withdrawn, lost to follow-up, death, sponsor 
decision). Until the transition, participants will continue to follow all the procedures and visits 
required in the current version of the protocol.
However, the sponsor reserves the right to terminate access to study drug, in particular if any 
of the following occur: 
a.
the study is terminated due to safety concerns or lack of proven efficacy; 
b. the marketing application is rejected by a health authority; 
c.
the participant can obtain medication used in this study as treatment from a 
government sponsored or private health program; 
d. the clinical development of the drug is stopped, no marketing authorization is pursued,
and therapeutic alternatives are available in the local market.
In case participants are transferred to a roll-over study or any other mechanism to supply drug 
post-study, drug formulation and / or dosage might change compared to the present study 
depending on the course of the clinical development. 

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7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
All participants who enter the study should complete all applicable study periods, however, 
participants can be withdrawn from any study period at any time. Withdrawal from the 
treatment period alone does not constitute withdrawal from the study.
7.1
Discontinuation of Study Intervention
In some instances, it may be necessary for a participant to permanently discontinue (definitive 
discontinuation) study drug. If study drug is definitively discontinued, the participant will 
remain on the study for follow-up of primary, secondary, and other pre-specified endpoints. 
See the SoA (Section 1.3) for data to be collected at the time of discontinuation of study drug, 
in follow-up, and for any further evaluations that need to be completed.
Participants must be discontinued from the study treatment if any of the following occurs:
In the double-blind period:

Radiological disease progression assessed by central review; 
Note: participants who experience a clinical benefit may continue the study treatment 
beyond radiological progression, according to PCWG3 guidelines, after agreement 
between the investigator and the sponsor or designee.

If, in the investigator’s opinion, continuation of the study drug would be harmful to 
the participant’s wellbeing. If a participant experiences a clinical progression by 
worsening of disease signs/symptoms leading to study treatment discontinuation, 
radiological evaluations must be continued until radiological progression is assessed 
by central review or subsequent anti-cancer therapy is started.

Start of new anti-cancer therapy

Unacceptable toxicity

Study drug interruption >28 consecutive days

Darolutamide dosing below 300 mg bid

Occurrence of Grade ≥3 study drug-related TEAE while the participant is on 
300 mg bid

Participants must be discontinued from the study treatment in case of hepatic 
transaminase elevations suggestive of idiosyncratic DILI considered to be causally 
related to study drug. (See Appendix 4, Section 10.4).
PSA increase or PSA progression should not trigger discontinuation of study treatment unless,
radiological progression was assessed by central review.
In the open-label phase:

Radiological disease progression assessed by local review or clinical progression 
assessed by the investigator.
Note: participants who experience a clinical benefit may continue the study treatment 
beyond radiological progression, according to PCWG3 guidelines, after agreement 
between the investigator and the sponsor or designee.

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
If, in the investigator’s opinion, continuation of the study drug would be harmful to 
the participant’s wellbeing.

Start of new anti-cancer therapy

Unacceptable toxicity

Study drug interruption >28 consecutive days

Darolutamide dosing below 300 mg bid

Occurrence of Grade ≥3 study drug-related TEAE while the participant is on 
300 mg bid
Note: Study drug discontinuation (i.e., discontinuation during the treatment period) does not 
constitute withdrawal from the study. Every effort should be made to retain participants who 
discontinue the treatment period for any reason. These participants are to be encouraged to 
remain on the study for follow-up of primary endpoint (i.e., until radiological progression is 
assessed by central review) and also secondary and other pre-specified endpoints (i.e., 
continue in the Active Follow–up period or Long–term Follow–up period). Participants are 
expected to participate in follow–up unless they explicitly object. Withdrawal of consent 
should be documented in the participant medical file.
7.1.1
Temporary Discontinuation
For a guidance on dose modifications, see Section 6.6.
7.1.2
Rechallenge
Participants who experienced TEAE requiring temporary discontinuation of study treatment 
may be rechallenged to the reduced dose (300 mg bid) or the full dose (600 mg bid) at 
discretion of the investigator. After a temporary dose reduction, rechallenge to the full dose 
(600 mg bid) can be considered if appropriate in investigator’s opinion.
For further details regarding dose modifications for study drug-related TEAEs dose 
modifications and rechallenge, please see Section 6.6.3.
All dose modifications should be reported with start and stop dates in the eCRF.
7.2
Participant Discontinuation/Withdrawal from the Study
Participants must withdraw from the study if any of the following occurs

At their own request or at the request of their legally acceptable representative. At any 
time during the study and without giving reasons, a participant may decline to 
participate further. The participant will not suffer any disadvantage as a result.

At the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons. This is expected to be uncommon.

Sponsor terminates the study.
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
If a participant withdraws from the study, and additionally requests destruction of her/his 
samples taken but not yet tested, the investigator must document this (either destruction by 
site or request to central lab, as applicable) in the site study records.

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7.3
Lost to Follow-up
A participant will be considered lost to follow-up if he repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as soon 
as possible and counsel the participant on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the participant wishes to and/or should 
continue in the study.

Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls 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 record.

Should the participant continue to be unreachable, he will be considered lost to follow-
up.
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1, 
Section 10.1.
8.
Study Assessments and Procedures

Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol 
waivers or exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study drug.

Adherence to the study design requirements, including those specified in the SoA
(Section 1.3), is essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participant meet all eligibility criteria. The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management (e.g.,
CT/MRI/bone scan) performed within 42 days prior to start of treatment and obtained 
before signing of the ICF may be utilized for screening or baseline purposes provided 
the procedures meet the protocol-specified criteria and were performed within the time 
frame defined in the SoA (Section 1.3).

Randomization must occur within 28 days from ICF signature. The participant will 
arrive at the study center on the morning of Day 1 (+3 days). The first dose of study 
drug will be administered with breakfast at the study center. Participants will continue 
taking study drug at home throughout the study treatment period and will be instructed 
to take their morning dose of study drug at home on further visit days.

Control assessments (unscheduled visits) may be performed at any time during the 
study treatment period according to the judgment of the investigator.

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8.1
Efficacy Assessments
Participants in the double-blind period will be evaluated every 12 weeks for:

Disease progression by conventional imaging methods (CT/MRI and bone scan)

Castration–resistant prostate cancer (CRPC), initiation of subsequent anti-cancer
therapy, symptomatic skeletal events (SSEs), pain progression (BPI-SF questionnaire), 
first prostate cancer-related invasive procedure

PSA assessment until confirmed radiological progression of the disease or change of 
anti-cancer therapy.

Survival status

In the open-label phase, the efficacy assessment will continue with recording of 
survival status. Tumor assessments, including radiology assessments, PSA and 
testosterone will continue according to local practice and evaluated by local 
radiologists/laboratories. Scans will no longer be collected for the central radiology 
review. Also, collection of data related to other prespecified endpoints will stop.
Refer to the SoA (Section 1.3) for detailed timing of efficacy assessments, and to Section 
9.4.2 for definitions and analyses of efficacy endpoints. RECIST 1.1 will be utilized for tumor 
response assessment of metastatic soft tissue lesions (lymph nodes and visceral lesions) and 
metastatic bone lesions will be assessed according the PCWG3 criteria for bone lesions 
(Eisenhauer et al. 2009, Scher et al. 2016) (Appendix 9, Section 10.9 and Appendix 10, 
Section 10.10). This study will utilize both tumor assessments by the local investigator and by 
central review as described below.
Imaging during the double-blind phase of the study:
The preferred and recommended imaging modality for soft tissue tumor assessments is multi-
detector CT with both oral and intravenous (i.v.) contrast. Anatomic coverage should be chest, 
abdomen and pelvis at all timepoints. MRI with i.v. gadolinium chelate-based contrast may be 
performed in lieu of contrast-enhanced CT when institutional policy does not recommend the 
use of CT or there is a contraindication to i.v. iodinated CT contrast. It is recommended that, 
when MRI is used, the abdomen and pelvis be performed with MRI. The chest should still be 
assessed with CT (with i.v. contrast if no contrast allergy, otherwise without contrast). If a 
participant develops a contraindication to CT contrast media during the course of the study 
after the baseline imaging, contrast enhanced MRI may be used in lieu of abdominal and 
pelvic CT and a non-contrast chest CT may performed in lieu of a contrast-enhanced chest 
CT. At screening, a participant suspected of having brain/ leptomeningeal metastases, should 
undergo brain CT or MRI with contrast to exclude such lesions.
The imaging modality for assessment of metastatic bone lesions is 99mTc-phophonate whole 
body bone planar scans acquired in anterior and posterior projections. The preferred 
radiotracer is 99mTc-methylene diphosphonate (99mTc-MDP) but other commercially available 
99mTc-phosphonate radiotracers such as hydroxymethylene diphosphonate (HMDP) or 
hydroxyethylene diphosphonate (HDP) or 2,3-dicarboxypropane-1, 1-diphosphonate (DPD) 
may also be used in accord with local site practice.
For consistency, the same imaging modality and equivalent technique (e.g., slice thickness, 
field of view for CT/MRI; same 99mTc-phosphonate tracer for bone scans) should be used for 
all scans and tumor assessments across all time points performed on an individual participant, 

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including screening / baseline scans. Slice thickness for CT and MRI is strongly 
recommended to be ≤ 5mm.
The time points for chest, abdomen and pelvic CT/MRI scans and bone scans are described in 
the SoA (Section 1.3).
The baseline radiological tumor assessment will be conducted within 28 days before start of 
study treatment. Note that CT/MRI scans or bone scans performed as standard of care within 
42 days prior to start of treatment are acceptable as screening scans provide that they meet the 
imaging requirements of this study (see Section 8.1 and the Imaging Guidelines that will be 
provided to the sites).
Subsequent CT/MRI and bone scans should then be performed every 12 weeks until 
radiological progression as assessed by central review or start of subsequent anti-cancer 
therapy. Participants who discontinued the study drug without radiological disease 
progression will continue the schedule of imaging assessment until radiological disease 
progression is assessed by central review or start of subsequent anti-cancer therapy. This will 
also happen in the Long-term Follow-up period for participants who did not have radiological 
progression assessed by central review or did not start subsequent anti-cancer therapy within 
the end of Active Follow-up. After radiological progression has been confirmed by central 
review or subsequent anti-cancer therapy has started, imaging will be performed according to 
local clinical practice. Date of clinical, biochemical, or radiological disease progression under 
subsequent anti-cancer therapy assessed by local reviewer will be reported. 
During the study, CTs or MRIs and bone scans may be performed at any time in case of PSA 
progression, symptomatic progressive disease, change of anti-cancer therapy or if considered 
appropriate in the investigator’s judgment. (Section 1.3). Such unscheduled imaging must be 
sent for central review and radiological progression assessment.
Tumor measurements and assessments of malignant soft tissue lesions (visceral lesions and 
malignant lymph nodes) will be based on RECIST 1.1 and, separately, malignant bone lesions 
are to be assessed in accord the PCWG3 criteria (Eisenhauer et al. 2009, Scher et al. 2016)
(Appendix 9, Section 10.9 and Appendix 10, Section 10.10). Local site assessments are to be 
entered in the eCRFs and scans should be interpreted by the same radiologist/nuclear 
medicine physician/investigator. Any soft tissue lesion that has been previously treated with 
radiotherapy should be considered as a non-target lesion. However, if a soft tissue lesion 
previously treated with radiotherapy has clearly progressed on the baseline/ screening scan, it 
can be considered as a measurable lesion.
For assessment of eligibility criterion of metastatic disease, baseline CT/MRI and bone scans 
must first be reviewed by a local qualified site physician to confirm presence of metastases 
before submitting the scans to central review to confirm eligibility. If the local qualified site 
physician detects metastases of only local lymph nodes (below aortic bifurcation), the scans 
should not be submitted to central review and participants should not be randomized. The 
presence or absence of visceral metastases at baseline will be assessed by central review to 
establish stratification of randomized participants. Tumor response assessments following 
baseline will be also performed by central review. If/when local review determines 
radiological progression has occurred, that finding must be confirmed by central review 
before response imaging is discontinued and study treatment is stopped.
Further guidance on the acquisition of CT/MRIs and bone scans as well as information on 
how to transmit image files to the imaging core laboratory will be provided in the Imaging 
Guidelines for this study. Further information on RECIST 1.1 criteria for assessment of soft 

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tissue lesions and on PCWG3 criteria for assessment of bone metastases is provided in 
Appendix 9, Section 10.9 and Appendix 10, Section 10.10 respectively.
For PSA related endpoints (please refer to Section 9.4.2.2 for definition of time to CRPC, 
time to PSA progression and PSA undetectable rates), PSA values obtained by central 
laboratory will be used.
For time to initiation of the subsequent anti-cancer therapy, all new anti-cancer therapies have 
to be reported with start date and reason to start.
Pain progression is defined as an increase of ≥ 2 points from baseline (day 1 score) in
question 3 of BPI-SF (related to the worst pain in the last 24 hours) taken as a 7-day average. 
Pain will be assessed with the BPI-SF questionnaire (Appendix 7 in Section 10.7) during the 
visit, pain diary entries from 6 days preceding the visit and on the day of the visit from 
baseline until documented pain progression. The pain diary consists of 7copies of BPI-SF 
questionnaire. Initiation or change in the use of other non-opioid analgesics is not used in the 
analysis of pain progression.
For time to first prostate cancer-related invasive procedures, only procedures needed for 
alleviation of symptoms, signs or findings caused by progression in prostate will be collected 
until the first prostate-cancer invasive procedure occurs or change of anti-cancer treatment, 
whichever occurs first. See Section 9.4.2.3 for further explanations.
Analgesic 24–hour consumption log–eCRF should be collected on the same day as pain 
assessment questionnaires. Physician should record whether or not the participant has initiated 
opioid therapy since last visit and to record analgesic pain medications consumed by the 
participant over last 24 hours. To facilitate assessment of analgesic use, at each visit, 
participants should be requested to list all the pain medications consumed since the last visit, 
therefore based on the investigator’s preference blister packs or written notes or any other 
applicable methods may be needed.
For all visits where questionnaires are administered either via electronic patient-reported 
outcome (ePRO) device, or paper forms, the questionnaires should be administered at the start 
of the visit prior to any study–related procedure or other clinical activities.
Survival status will be assessed until death or lost to follow-up. An additional survival sweep 
will be performed for primary analysis and prior to any subsequent analysis of OS.
8.2
Safety Assessments
Safety will be assessed by monitoring and recording all AEs and SAEs, vital signs, ECG,
ECOG PS, cardiac, hematologic, and blood chemistry parameters, and any abnormal findings 
observed during the performance of physical examinations.
Planned time points for all safety assessments are provided in the SoA (see Section 1.3).
In a potential state of pandemic, if the study participant is not able to come to the 
investigational site for protocol-specific visits, alternative methods for safety assessments 
(phone contact, virtual visit, alternative location for laboratory tests and imaging) could be
implemented when necessary and feasible, to assure the safety of study participants. 
Darolutamide, typically distributed for self-administration, is also amenable to alternative 
secure delivery methods.
Changes in study visit schedules, missed visits, or participant discontinuations may lead to 
missing information (e.g. for protocol-specified procedures). The specific information (e.g. 

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explanation of the basis of the missing data) will be captured in the case report form and the 
information will be summarized in the clinical study report. In all cases, existing regulatory 
requirements for maintaining investigational product accountability remain and should be 
addressed and documented.
8.2.1
Physical Examinations

A physical examination will include, at a minimum, assessments of the 
Cardiovascular, Respiratory, Gastrointestinal, Neurological and Skin systems. Height 
(at Screening only) and weight will also be measured and recorded as outlined in the 
SoA (see Section 1.3).

Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.2.2
Vital Signs

Body temperature, heart rate, and blood pressure will be assessed as outlined in the 
SoA (see Section 1.3).

Vital signs will be measured after 10 minutes of rest in supine position and will 
include temperature, systolic and diastolic blood pressure, and pulse.
8.2.3
Electrocardiogram (ECG)

12-lead ECG will be obtained as outlined in the SoA (see Section 1.3) using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT. The
QTc intervals (QTcF by Fridericia formula and QTcB by Bazett formula) will be 
calculated by eCRF system.
8.2.4
Clinical Safety Laboratory Assessments

See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed 
and to the SoA (Section 1.3) for the timing and frequency.
o
The investigator must review the laboratory report, document this review, and 
record any clinically significant changes occurring during the study in the AE 
section of the eCRF. The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which are 
not associated with the underlying disease, unless judged by the investigator to be 
more severe than expected for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 days (+7 days) (EOT visit) after the last dose of 
study drug should be repeated until the values return to normal or baseline or are no 
longer considered clinically significant by the investigator.
o
If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified, and the sponsor 
notified.
o
All protocol-required laboratory assessments, as defined in Appendix 2 
(Section 10.2), must be conducted in accordance with the protocol and the 
SoA (Section 1.3).
o
If laboratory values from non-protocol specified laboratory assessments performed 
at the institution’s local laboratory are considered clinically significant by the 

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investigator, (e.g., SAE or AE or dose modification), then the results must be 
recorded in the CRF.
8.2.5
ECOG Performance Status

An ECOG PS score of 0, 1 or 2 is required for study inclusion (see Section 5.1). 
During the study, assessment of ECOG PS is carried out as indicated in the SoA 
(Section 1.3).

Grading definitions for ECOG PS are given in Table 8–1 below.
Table 8–1
Definitions for ECOG PS Grading
Grade
Description
0
Fully active, able to carry on all pre-diseases performance without restriction.
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of 
a light or sedentary nature (e.g., light housework, office work).
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up 
and about more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours.
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.
5
Dead.
Abbreviations: ECOG = Eastern Cooperative Oncology Group; PS = Performance status
8.2.6
Population characteristics
8.2.6.1
Demographic
Demographic characteristics of date of birth (age), sex, and race/ethnicity should be entered in 
the eCRF.
8.2.6.2
Medical history
Medical history findings (i.e., previous diagnoses, diseases, or surgeries) meeting all criteria 
listed below will be collected and recorded in the CRF:

Not pertaining to the study indication

Start before signing of the ICF
Detailed instructions on the differentiation between medical history and AEs can be found in 
Section 10.3.
History of prostate cancer will be collected separately from the general medical history. This 
includes, but is not limited to:

Date of diagnosis

Staging (performed at diagnosis)

Prostate cancer history

Disease status at study entry

Prior diagnostic and therapeutic procedures

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
Prior prostate cancer treatments (any therapy that is ongoing should be reported as 
concomitant medication. Prior radiotherapy on primary tumor and/or metastatic sites
will be reported including the sites, the dose and date of completion of radiation.
8.2.6.3
Other baseline characteristics
Baseline characteristics relating to disease factors include:

QoL assessment (FACT-P and BPI-SF)

ECOG PS

Cancer pain assessment

All medications and significant non–drug therapies ongoing during the screening 
period (28 days prior to randomization) must be entered in the eCRF, including:
o
Medication trade name and dose
o
Reason for medication
o
Start date and end date, or if continuing at time of study entry
8.3
Adverse Events and Serious Adverse Events
The definitions of an AE or SAE can be found in Appendix 3 (Section 10.3).
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant’s legally authorized representative or health care professional not involved in the 
study).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE. They remain responsible for 
following up on SAEs, or AEs, considered related to the study drug or study procedures, or 
those that caused the participant to discontinue the study drug or the study (see Section 7).
Investigators should refer to the current darolutamide Investigator’s Brochure and LHRH 
agonists/antagonists product information for the expected adverse reactions. As with any 
agent, there is always the potential for unexpected AEs, including hypersensitivity reactions.
8.3.1
Time Period and Frequency for Collecting AE and SAE Information
All AEs/SAEs will be collected from the signing of the informed consent form (ICF) until the 
EOT visit after 30 days (+7 days) since the last dose of the study drug as per the SoA 
(Section 1.3).
Medical occurrences that begin before signing informed consent will be recorded on the 
medical history section of the case report form (CRF).
Medical occurrences that begin before the start of study drug but after obtaining informed 
consent will be recorded on the AE section of the case report form (CRF).
Medical occurrences that started or deteriorated after signing informed consent will be 
recorded as adverse events.

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All SAEs must be immediately (within 24 hours of the investigator’s awareness) reported to 
the sponsor or designee, as indicated in Appendix 3 (Section 10.3). The investigator will 
submit any updated SAE data to the sponsor within 24 hours of it being available.
If the investigator learns of any SAE, at any time and he/she considers the event to be 
reasonably related to the study drug or study participation, the investigator must promptly 
notify the sponsor.
In addition, during the Follow-up period participants will be followed for:

Study drug-related SAEs

Any anti-cancer treatment
8.3.2
Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3 
(Section 10.3).
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
Once data regarding survival and remission status are no longer required by the protocol, only 
additional primary tumors regarded as related to study treatment should be reported.
Recurrence or disease progression should not be reported as AE/SAE. If there are separate 
identifiable clinical consequences that result from the disease progression (for example bone 
pain), the clinical consequence is to be reported as an AE/SAE.
8.3.3
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. A follow-up report to an SAE should be prepared if 
any relevant change in the condition of the study participant occurs after the initial report. The 
follow-up report should be documented as an update to the initial report. A SAE follow-up 
form should be forwarded within 24 hours of the investigator’s awareness and if the follow-up 
information changes the investigator’s assessment of the causality, this should also be noted 
on the follow-up SAE form All SAEs must be followed to resolution, or if resolution is 
unlikely, to stabilization (as defined in Section 7.3). Further information on follow-up 
procedures is provided in Appendix 3 (Section 10.3).
8.3.4
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study treatment under clinical investigation are met.

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators.

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
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor will 
review and then file it along with the Investigator’s Brochure and local product 
information for LHRH agonists /antagonists and will notify the IRB/IEC, if 
appropriate according to local requirements.
8.3.5
Pregnancy
Sexually active male participants must agree to use condoms as an effective barrier method 
and refrain from sperm donation, and/or their female partners of reproductive potential to use 
a method of effective birth control, during the study drug treatment and for 4 weeks after the 
last dose of the study treatment with darolutamide, (inclusion criterion).
Pregnancies inadvertently fathered by study participants during the study should be reported 
and followed up by the investigator using the Bayer Pregnancy Monitoring Forms, if 
permissible by local legislation.
For a pregnancy in the partner of a male study participant in the active treatment of the study, 
all efforts will be made to obtain similar information on course and outcome of the pregnancy, 
delivery, postpartum recovery and the clinical condition of the offspring during the neonatal 
period, subject to the partner’s consent.
Pregnancies will be collected from the date of IC signature until 30 days after the last dose of 
study drug administered.
If an adverse outcome of pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to the 
study drug.
An induced or a spontaneous abortion is considered to be SAE and should be reported in the 
same timeframe and in the same manner as all other SAEs.
For all reports, the forms provided are to be used. The report should be submitted within the 
same timelines as an SAE, although a pregnancy per se is not considered an SAE.
8.3.6
Adverse Events of Special Interest
There are no adverse events of special interest.
8.4
Treatment of Overdose
The highest dose of darolutamide studied clinically was 900 mg twice daily, equivalent to a 
total daily dose of 1800 mg. No dose limiting toxicities were observed with this dose.
Considering the saturable absorption and the absence of evidence for acute toxicity, an intake 
of a higher than recommended dose of darolutamide is not expected to lead to toxicity.
In the event of intake of a higher than recommended dose, treatment with darolutamide can be 
continued with the next dose as scheduled.
There is no specific antidote for darolutamide, and symptoms of overdose are not established.

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No specific information is available on the treatment of overdose of darolutamide. In the 
event of overdose, the participant should be observed closely for signs of toxicity. 
Appropriate supportive treatment should be provided if clinically indicated.
In the event of an overdose, the investigator should:
1. Closely monitor the participant for any signs of toxicity and appropriate supportive 
treatment should be provided if clinically indicated.
2. Any overdose (intentional or accidental) or incorrect administration of study drug 
should be noted on the Study Drug Administration electronic Case Report Form 
(eCRF).
3. Adverse events associated with (or resulted from) an overdose or incorrect 
administration of study drug should be reported as Serious Adverse Event.
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.
For detailed guidance on overdosing please refer to the most current version of the IB for 
darolutamide.
8.5
Pharmacokinetics
PK parameters are not evaluated in this study.
8.6
Pharmacodynamics
Refer to Section 8.8 for pharmacodynamic biomarkers.
8.7
Genetics
Genetic as well as non-genetic analyses will be part of the biomarker investigations in this 
study if approved by local ECs / IRBs and competent authorities. See Section 8.8 for details.
Optional whole genome sequencing will be offered to all participants (not applicable for 
China). See Appendix 6 (Section 10.6) for details.
8.8
Biomarkers

In this study, genetic as well as non-genetic biomarkers will be investigated. Genetic 
investigations may be of any kind, except for whole genome sequencing.

Timing – see SoA (Section 1.3) for planned time points of sample collection.

Sample handling and storage – Details on the collection, processing, shipment and 
storage of samples will be provided in separate documents (e.g. sample handling 
sheets or lab manual). Samples may be stored for a maximum of 15 years (or 
according to local regulations) following the end of the study at a facility selected by
the sponsor to enable further analyses.

Medical history information – If any additional molecular information about the 
tumor was collected in the course of treatment prior to entry of the participant in the 
study, the results may be collected in order to include this data in biomarker analyses.

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
Data analysis and Reporting – Details of the biomarker analyses may be described 
in a separate statistical analysis plan (SAP) and the results of these analyses may be 
provided as a separate biomarker report.

In exceptional circumstances, if permission for specific biomarker samples collection 
is not obtained from local authority, Chinese sites will be instructed not to collect 
these samples until permission is granted.
8.8.1
Potential Predictive Biomarkers
Biomarker status will be correlated with clinical outcome to explore whether any molecular 
characteristics appear to define participant populations that are particularly sensitive or 
resistant to darolutamide.
Plasma analysis:
Candidates of genes for the evaluation from circulating tumor deoxyribonucleic acid (ctDNA)
are AR, phosphatase and tensin homolog (PTEN). The types of analyses may comprise the 
identification of mutations, gene amplifications or splice variants. Furthermore, the plasma 
samples may serve as source for non-coding microRNA, as possible markers describing 
treatment response. (For China, only analyses as granted by local authorities will be 
performed.)
Tumor biopsy analysis (not applicable for China):
The analysis of tumor genetic markers by tumor DNA sequencing and/or gene expression 
studies with tissue samples taken from the primary tumor and metastases will support 
identification of biomarkers that characterize molecular subtypes contributing to clinical 
benefit to therapy.
Tumor specific biomarker analyses are intended to be used for the following purposes: (1) to 
evaluate mutations, copy numbers or gene rearrangements in known oncogenes such as AR, 
TMPRSS, cMYC, PI3K, and CYP17 extracted from tumor tissue specimens; (2) to analyze 
the gene expression of genes of interest such as AR, cMYC, PTEN, PI3K, and AR–regulated 
genes in RNA extracted from tumor tissue specimens; (3) to evaluate expression of non-
coding tumor relevant RNAs such as microRNAs.
Provided sufficient tissue quality and quantity, tumor tissue specimens are also intended to be 
used to quantify the expression of proteins of interest, to attempt to identify a protein 
signature that correlates with drug response.
As per investigator’s discretion, and if technically feasible, biopsy at the time of disease 
recurrence is highly encouraged to be taken. This sample would allow generation of 
information about the identification of tumor biomarkers playing a role in therapy resistance 
for which the participant may benefit for further guidance. Note, however, that this is not 
considered to be mandatory by this study protocol.
Whole blood analysis (not applicable for China):
Biomarkers related to drug safety, efficacy, or mechanism of action may be analyzed from 
whole blood and involve targeted genetic testing. Targeted genetic testing will focus on single 
gene polymorphisms of genes involving, but not limited to, hepatotoxicity, metabolism, or 
targets involved in drug activity. Identified gene variants aim to predict the best individuals to 
treat, either selecting for toxicity avoidance or for positive benefit.

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8.8.2
Pharmacodynamic Biomarkers
Pharmacodynamic biomarkers will be evaluated in samples collected before and during 
treatment in order to determine the impact of darolutamide on these biomarkers. Candidate 
markers will be analyzed from plasma samples to quantify various proteins of interest, to 
attempt to identify a protein signature that correlates with drug response, and/or assessment of 
variations in allelic fractions by analysis of ctDNA to investigate tumor evolution under 
treatment and potentially monitor treatment response. (For China, only analyses as granted by 
local authorities will be performed.)
8.8.3
Other Biomarkers (not applicable for China)
In addition to the biomarkers described above, further biomarkers related to, e.g., the mode of 
action or the safety of the study drug and similar drugs may be investigated. The same applies 
to further biomarkers deemed relevant to cancer and associated health problems. These 
investigations may include e.g., diagnostic, safety, pharmacodynamic, monitoring, or 
potentially predictive biomarkers.
8.9
Immunogenicity Assessments
Not applicable.
8.10
Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics parameters are not evaluated in this 
study.
9.
Statistical Considerations
9.1
Statistical Hypotheses
The null hypothesis that there is no difference in rPFS between treatment arms, which is 
equivalent to a hazard ratio (HR) of 1, will be tested against the alternative hypothesis that the 
HR of darolutamide over placebo is below 1.
9.2
Sample Size Determination
Assuming a one-sided alpha of 0.025 for rPFS, a power of 90%, and a randomization ratio of 
2:1 between the experimental and control arms, 214 events are required to detect a 60% 
increase in median time of rPFS (HR 0.625).
Assuming an exponential distribution of rPFS events and a control arm median time of 
20 months, the active arm median would be approximately 32 months, which is a 60% 
increase in median time.
The expected study duration is approximately 36 months assuming approximately
665 participants are randomized at a rate of 45 participants per month, an enrollment ramp-up 
time of 6 months, approximately 18 months until randomization is complete, a dropout rate of 
33% for rPFS follow-up, exponentially distributed event times, and 20-month median time of 
rPFS for the control group.
Assuming a 25% screening failure rate, approximately 886 screened participants would lead 
to 665 randomized participants.

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9.3
Populations for Analyses
Populations for analyses are defined in Table 9–1.
Table 9–1
Populations for analyses
Population
Description
Enrolled 
All participants who sign the ICF.
Full Analysis Set (FAS)
All participants who were randomized are included in the Full 
Analysis Set. The participants in this set will be grouped 
according to the treatment they were allocated to receive at 
randomization, irrespective of actual treatment.
Safety analysis set (SAF)
All participants who were randomized and took at least 1 
dose of study drug. Participants will be analyzed according to 
the study drug they actually received.
Abbreviations: ICF = Informed consent form
If there are participants who received the wrong study drug, safety data should be analyzed as 
treated. For example, if a placebo participant received at least one dose of the active test drug, 
this participant should be included in the test drug group for safety analysis. However, if a 
participant randomized to the test drug group received at least one dose of placebo and also at 
least one dose of test drug, this participant should be included in the test drug group. A 
participant should be included in the placebo group only if he received exclusively placebo 
(i.e. not any dose of test drug).
9.4
Statistical Analyses
This section is a summary of the planned statistical analyses of the most important endpoints 
including primary and key secondary endpoints for double-blinded phase.
The SAP which includes a more technical and detailed description of the statistical analyses 
described in this section will be developed and finalized before database release.
For any planned analyses for the open-label phase, a supplementary SAP will be developed. 
9.4.1
General Considerations
Statistical analysis will be performed using SAS; the version used will be specified in the 
SAP.
9.4.2
Efficacy analyses
9.4.2.1
Primary Endpoint
The primary endpoint is radiological progression-free survival (rPFS) using conventional 
imaging method (99mTc-phosphonate bone scan, CT/MRI scan), assessed by central review
based on RECIST v. 1.1 criteria for soft tissue metastases and PCWG3 criteria for bone 
metastases. rPFS is defined as the time from the date of randomization to the date of first 
documentation of radiological progressive disease or death due to any cause, whichever 
occurs first. Additional definition details and censoring rules will be provided in the SAP.

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Analysis of rPFS
All randomized participants (FAS) will be included in the primary analysis of rPFS by central 
review. The analysis will be performed when approximately 214 events of rPFS are observed. 
The primary analysis will be a stratified log–rank test with the same stratification factors as 
used for randomization (from IWRS).
The HR (darolutamide group/placebo) for rPFS and its 95% confidence interval will be 
calculated using the Cox model, stratified by the same factors as stated above. Kaplan–Meier 
(KM) estimates for rPFS will be presented for each treatment group. The KM estimates at 
time points such as 3 months, 6 months, etc., together with corresponding 95% confidence 
intervals (CIs) and the differences of these estimates between the darolutamide group and the 
placebo group will be presented.
The overall 1–sided type I error rate for the analysis of rPFS is 0.025. No interim analyses of 
rPFS are planned.
9.4.2.2
Secondary Endpoints

Overall survival (OS) is planned to be a key secondary endpoint and is defined as the 
time from the date of randomization to the date of death from any cause.
Other secondary endpoints are:

Time to castration–resistant prostate cancer (CRPC), defined as the time from the 
date of randomization to the date of first castration resistant event (radiological
progression, PSA progression or symptomatic skeletal events, whichever occurs first).

Time to initiation of subsequent anti-cancer therapy, defined as the time from the 
date of randomization to initiation of first subsequent antineoplastic therapy for 
prostate cancer.

Time to PSA progression, defined as the time from the date of randomization to the 
date of first PSA progression. Participants without PSA progression as of database 
cut–off, whether or not surviving, will be censored at the last total PSA laboratory
assessment date.
PSA progression is defined as a ≥25% increase above the nadir (lowest at or after 
baseline) value, which is confirmed by a second value 3 or more weeks later, and an 
increase in absolute value of ≥ 2 ng/mL above nadir, at least 12 weeks from baseline.

PSA undetectable rates (<0.2 ng/mL), defined as the percentage of participants with 
detectable PSA values (≥0.2 ng/mL) at baseline which become undetectable 
(<0.2 ng/mL) during the period between randomization and the earlier of 30 days after 
last dose of study drug or change of anti-cancer therapy.

Time to pain progression, defined as the time from the date of randomization to pain 
progression, where progression is defined as an increase of 2 or more points from 
baseline in question 3 of the BPI-SF questionnaire related to the worst pain in the last 
24 hours taken as a 7-day average for post-baseline scores.
For asymptomatic participants (worst pain subscale [WPS] 0 at baseline), pain 
progression is defined as an increase of 2 or more points in the “worst pain in 
24 hours” (i.e. 2 or more points increase in WPS score) score from baseline observed 
at 2 consecutive evaluations ≥4 weeks apart.
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increase of 2 or more points in the “worst pain in 24 hours” (i.e. 2 or more points 
increase in WPS score) score from baseline observed at 2 consecutive evaluations 
≥4 weeks apart and a WPS of ≥4.
Pain will be assessed with the BPI–SF questionnaire (Appendix 7, Section 10.7) 
during the visit, prior to any procedures or examination by physician. Participants who 
have not experienced pain progression at the time of analysis will be censored on the 
last date the participant was known to have not progressed. Participants with no on 
study assessment or no baseline assessment will be censored at the date of 
randomization.
Analysis of secondary endpoints
The secondary efficacy endpoints will be analyzed in the FAS population at the time of 
primary analysis unless otherwise specified in SAP. Time–to–event endpoints will be 
analyzed using same method as the primary efficacy variable. The stratified log–rank test with 
randomization stratification factors will be used to compare treatment effect. Hazard ratio and 
95% CI will be provided using the Cox model stratified by the same factors as stated above. 
Detailed analysis methods and the plan for type 1 error control for secondary endpoints will 
be specified in SAP.
Only overall survival will be tested at the final analysis time point, when the open-label phase 
is ended. Therefore, during the open-label period, data collection will continue with recording 
of survival status.
9.4.2.3
Other Pre-specified Endpoints

Progression-free survival 2 (PFS2) as assessed by the investigator, is defined as the 
time from randomization to first occurrence of clinical, biochemical, or radiological 
disease progression under first subsequent anti-cancer therapy or death, whichever 
occurs first.

Time to symptomatic skeletal event (SSE), defined as the time from the date of 
randomization to the date of first occurrence of SSE. An SSE is defined as EBRT to 
relieve skeletal symptoms, or new symptomatic pathologic bone fracture, or 
occurrence of spinal cord compression or tumor–related orthopedic surgical 
intervention, whichever comes first.

Biomarkers. Analysis of biomarkers will be described in a separate analysis plan.
(For China, only analyses as granted by local authorities will be performed.)

Time to deterioration in the Functional Assessment of Cancer Therapy – Prostate 
Cancer (FACT-P) total score, is defined as the interval from the date of 
randomization to the first date a participant experiences a decrease of 10 points in the 
FACT-P total score. Symptoms and QoL will be assessed with the FACT-P
questionnaire (Appendix 8, Section 10.8) during the visit, prior to any procedures or 
examination by physician.

Time to first prostate cancer-related invasive procedure is defined as time from
randomization to date of first prostate cancer-related invasive procedure.
Prostate cancer-related invasive procedure is defined as any procedure needed for 
alleviation of symptoms, signs or findings caused by progression of prostate cancer 

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(e.g., catheterization of the bladder, percutaneous drainage of hydronephrosis, 
palliative electro resection of the prostate, etc.). Status of cancer-related invasive 
procedure will be assessed from randomization until the first cancer-related invasive 
procedure or change of anti-cancer therapy, whatever occurs first.
9.4.3
Safety Analyses
All safety analyses will be performed in the SAF population based on actual treatment 
received.
The safety variables include:

TEAEs until the EOT visit

TESAEs until the EOT visit

Study drug–related TESAEs should be reported to sponsor regardless of the length of 
time from the study completion

Physical examinations including weight

Vital signs and body temperature: BP and heart rate (HR)

12–lead electrocardiogram (ECG)

Clinical laboratory safety assessments (hematology, clinical chemistry, urinalysis)

ECOG PS
Safety analysis
AE/SAE collection will start after signing the IC. AEs will be coded using Medical 
Dictionary for Regulatory Activities (MedDRA). Descriptive summary tables will be 
presented on all safety parameters by treatment group. The safety assessment period for 
TEAE will start after the first dose of study drug until 30 days after the last treatment with 
darolutamide/placebo. Participants will be monitored for AEs using the NCI–CTCAE v. 5.0.
The AEs and safety laboratory parameters will be presented with their worst NCI–CTCAE 
v. 5.0 grade.
9.4.4
Other Analyses 
The details of the analysis for the exploratory biomarker variables may be provided in the 
SAP or a separate Biomarker evaluation plan.
9.5
Interim Analyses
For this study no formal interim analysis for the primary endpoint is planned. At the time of 
primary analysis an interim analysis for secondary endpoint OS will be conducted. A second 
final OS analysis will be conducted later. Additional details regarding the statistical plan for 
the interim and final analysis of OS will be provided in the SAP.
9.6
Data Monitoring Committee (DMC) or other Review Board
An independent Data Monitoring Committee (DMC) will be instituted for this study in order 
to ensure ongoing safety of study participants. The DMC will conduct risk/benefit assessment 
during periodic data review meetings, and provide a formal recommendation for 

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continuation/termination of the study. The DMC will operate independently of the sponsor 
and investigators. The DMC will review safety data as per a separate DMC charter.
A Steering Committee including prostate cancer experts and oncologists, familiar with the 
existing treatment paradigm in mHSPC and are involved in current development research in 
this disease area will review, monitor and provide advice regarding the progress of the study 
in order to ensure alignment between the study conduct plan and the study protocol. Feedback 
from Steering Committee will be considered for the start of open-label phase, once primary 
analysis results are available.
Details on the responsibilities and operations of the DMC and Steering Committee will be 
provided in the respective committee charters.
10.
Supporting Documentation and Operational Considerations
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the following:
o
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines
o
Applicable International Council for Harmonization (ICH) Good Clinical Practice 
(GCP) Guidelines
o
Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the investigator 
and reviewed and approved by the IRB/IEC before the study is initiated.

Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study participants.

The investigator will be responsible for the following:
o
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC
o
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures
o
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the 
IRB/IEC, European regulation 536/2014 for clinical studies (if applicable), and all 
other applicable local regulations
10.1.2
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested 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.

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10.1.3
Informed Consent Process

Participants will receive both written and verbal information about the study and will 
have an opportunity to ask questions and should have sufficient time to decide 
whether or not to participate in the study. The original signed and dated ICF must be 
retained in the investigator’s study file and a copy must be provided to the participant.

The investigator or his/her representative will explain the nature of the study to the 
participant or his legally authorized representative (if acceptable by local law) and
answer all questions regarding the study.

Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative (if acceptable per local law) will be required to sign a 
statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
(HIPAA) requirements, where applicable, and the IRB/IEC or study center.

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must also 
sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study as applicable.

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.
Participants who are rescreened are required to sign a new ICF.
10.1.4
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant
records or datasets that are transferred to the sponsor will contain the identifier only; 
participant names or any information which would make the participant identifiable 
will not be transferred.

The participant must be informed that his/her personal study-related data will be used 
by the sponsor in accordance with local data protection law. The level of disclosure 
must also be explained to the participant who will be required to give consent for their 
data to be used as described in the informed consent.

The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities.
10.1.5
Committees Structure
For details see Section 9.6.
10.1.6
Dissemination of Clinical Study Data
Result Summaries of Bayer’s sponsored clinical trials in drug development Phases 2, 3 and 4 
and Phase 1 trials in participants are provided in the Bayer Trial Finder application after 
marketing authorization approval in line with the position of the global pharmaceutical 
industry associations laid down in the “Joint Position on the Disclosure of Clinical Trial 
Information via Clinical Trial Registries and Databases”. In addition, results of clinical drug 

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trials will be provided on the publicly funded website www.ClinicalTrials.gov and EU 
Clinical Trials Register in line with the applicable regulations.
Bayer commits to sharing upon request from qualified scientific and medical researchers,
participant-level clinical trial data, study-level clinical trial data, and protocols from clinical 
trials in participants for medicines and indications approved in the United States (US) and 
European Union (EU) on or after 01 JAN 2014 as necessary for conducting legitimate 
research.
All Bayer-sponsored clinical trials are considered for publication in the scientific literature 
irrespective of whether the results of the clinical trials are positive or negative.
10.1.7
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the sponsor or designee electronically (e.g., laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.

The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.

The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.

Monitoring details describing strategy (e.g., risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-
Based Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the Monitoring Plan.

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data.

The sponsor assumes accountability for actions delegated to other individuals (e.g.,
Contract Research Organizations).

Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements.

Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator after study completion for the retention period as 
set forth in the investigator agreement unless local regulations or institutional policies 
require a longer retention period. No records may be destroyed during the retention 
period without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor.
10.1.8
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

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
Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available.

Definition of what constitutes source data can be found in Source Data Identification 
(SDI) Form.
10.1.9
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The sponsor designee 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 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study drug development
The sponsor has the right to close this study (or, if applicable, individual segments thereof 
[e.g. treatment arms; dose steps; centers]) at any time, which may be due, but not limited to, 
the following reasons:

If risk–benefit ratio becomes unacceptable owing to, for example,
o
Safety findings from this study (e.g. SAEs)
o
Results of any interim analysis
o
Results of parallel clinical studies
o
Results of parallel animal studies (e.g. toxicity, teratogenicity, carcinogenicity, 
or reproduction toxicity).

If the study conduct (e.g. recruitment rate; dropout rate; data quality; protocol 
compliance) does not suggest a proper completion of the trial within a reasonable time 
frame.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The investigator shall promptly inform the participant 
and should assure appropriate participant therapy and/or follow-up.

Closures should occur only after consultation between involved parties. Final decision 
on the closure must be in writing.

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
All affected institutions (e.g. IEC[s]/IRB[s]; competent authority[ies]; study center; 
head of study center) must be informed as applicable according to local law.

All study materials (except documentation that has to remain stored at site) must be 
returned to the sponsor. The investigator will retain all other documents until 
notification is given by the sponsor for destruction.
10.1.10
Publication Policy

The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual 
site data. In this case, a coordinating investigator will be designated by mutual 
agreement.

Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.

Investigators may publish or present individual study data (including case reports) 
obtained in the course of this study but only after the primary report and/or publication 
of the study results in their entirety. If publishing individual site data is foreseen, the 
investigator agrees to submit all manuscripts or abstracts to the sponsor before 
submission. This allows the sponsor to protect proprietary information and to provide 
comments.
10.2
Appendix 2: Clinical Laboratory Tests

The protocol-required safety laboratory assessments detailed in Table 10–1 will be 
performed by the local laboratory at each site.

Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.

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Table 10–1
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
MCV
MCH
%Reticulocytes
White blood cell (WBC) 
count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Red blood cell (RBC) 
Count
Hemoglobin
Hematocrit
Clinical 
Chemistry
Blood urea 
nitrogen (BUN)
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT)
Total Protein
Glucose (fasting)
Calcium
Alkaline 
phosphatase
Albumin
Routine 
Urinalysis
Specific gravity
pH, glucose, protein, blood, ketones, by dipstick
Microscopic examination (if blood or protein is abnormal)
Other Screening 
Tests
The results of each test must be entered into the CRF.
Abbreviations: ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; CRF = Case report form; 
MCH = Mean corpuscular hemoglobin; MCV = Mean corpuscular volume; pH = Power of hydrogen; RBC = 
Red blood cell; SGOT = Serum Glutamic-Oxaloacetic Transaminase; SGPT = Serum Glutamic-Pyruvic 
Transaminase; WBC = White blood cell 
Investigators must document their review of each laboratory safety report.
Laboratory/analyte results that could unblind the study will not be reported to investigative 
sites or other blinded personnel until the study has been unblinded.

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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study participant, 
after providing written IC for participation in the study, may or may not be
temporally associated with the use of study drug, whether or not considered related 
to the study drug.

Treatment-emergent AE (TEAE) is defined as any event arising or worsening after 
the first dose of study drug until 30 days after the last dose of study drug.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study drug.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant (e.g. requiring treatment intervention, study dose interruption/ 
discontinuation, dose reduction) in the medical and scientific judgment of the 
investigator (i.e., not related to progression of underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study drug administration even though it 
may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
drug or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.
For efficacy studies, include: 

“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfil the definition of an AE 
or SAE.
For non-efficacy studies involving marketed products in established indications, include:

The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 

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Events Meeting the AE Definition
reported as AE or SAE if they fulfil the definition of an AE or SAE. Also, “lack of 
efficacy” or “failure of expected pharmacological action” also constitutes an AE or 
SAE.
Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy); however, the 
condition that leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually involving 
at least an overnight stay) at the hospital or emergency ward for observation and/or 
treatment that would not have been appropriate in the physician’s office or outpatient 
setting. Complications that occur during hospitalization are AEs. If a complication prolongs 
hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to 
whether “hospitalization” occurred or was necessary, the AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

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
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is 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 medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3
Recording and Follow-up of AE and/or SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to the CRO/sponsor in lieu of completion of the AE/SAE CRF 
page.

There may be instances when copies of medical records for certain cases are
requested by the CRO/sponsor. In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to the CRO/sponsor.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported during 
the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated and transient in nature by the participant, 
causing minimal discomfort and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.

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
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study drug and each 
occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study drug 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the CRO/sponsor. However, it 
is very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to the
sponsor/CRO.

The investigator may change his/her opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
CRO/sponsor to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide the cause of death with a copy of any 

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Follow-up of AEs and SAEs
post-mortem findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to CRO/sponsor within 24 hours 
of receipt of the information.
10.3.4
Reporting of SAEs
SAE Reporting to the CRO/sponsor via an Electronic Data Collection Tool

The primary mechanism for reporting a SAE to the CRO/sponsor will be the 
electronic data collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the CRO/sponsor by telephone.

Contacts for SAE reporting can be found in Investigator Site File.
SAE Reporting to the CRO/sponsor via Paper CRF (when the electronic system is 
unavailable)

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the CRO/sponsor.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by 
overnight mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in Investigator Site File.
10.4
Appendix 4: Participant Discontinuation
Participants must be discontinued from the study treatment in case of hepatic transaminase 
elevations suggestive of idiosyncratic DILI considered to be causally related to study drug. 
DILI should be suspected after other causes of liver injury have been excluded.
Criteria for study treatment discontinuation (FDA 2009):

ALT or AST >8 x ULN 

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
ALT or AST >5 x ULN for more than 2 weeks 

ALT or AST >3 x ULN and (TBL >2 x ULN or INR >1.5) 

ALT or AST >3 x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
It is recommended to monitor and report in eCRF liver function tests (ALT, AST, ALP and 
total bilirubin) until recovery, according to your local clinical practice.
10.5
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information
Contraception Guidance is specified in Section 5.1.
Collection of Pregnancy Information
Male participants with partners who become pregnant

The investigator will make all efforts to collect pregnancy information regarding the 
pregnancy in the partner of a male study participant’s female partner who becomes 
pregnant while the male participant is in this study. This applies only to male 
participants who receive study intervention.

After obtaining the necessary signed informed consent from both the study participant
and the pregnant female partner, the investigator will record pregnancy information on 
the appropriate form and submit it to the sponsor within 24 hours of learning of the 
partner’s pregnancy. The female partner will also be followed to determine the 
outcome of the pregnancy, delivery, postpartum recovery and the clinical condition of 
the offspring during the neonatal period. Information on the status of the mother and 
child will be forwarded to the sponsor. Generally, the follow-up will be no longer than 
6 to 8 weeks following the estimated delivery date. Any termination of the pregnancy 
will be reported regardless of fetal status (presence or absence of anomalies) or 
indication for the procedure. 

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10.6
Appendix 6: Genetics
Genetic as well as non-genetic analyses will be part of the biomarker investigations in this 
study. See Section 8.8 for details.
Whole genome sequencing (WGS) will be offered to all participants. The WGS analysis will 
only be carried out in samples from those participants who have provided respective optional 
informed consent. Participants who do not wish to have their sample(s) analysed for WGS 
may still participate in the study (not applicable for China).
Details on sample handling will be provided separately.

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10.7
Appendix 7: BPI-SF

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10.8
Appendix 8: FACT-P (Version 4)

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10.9
Appendix 9: RECIST 1.1 Criteria 
This study will use RECIST 1.1 criteria (Eisenhauer et al. 2009) for assessment of extra-
skeletal malignant lesions. Metastatic bone lesions will be assessed in accord with PCWG3 
criteria (Scher et al. 2016); see Appendix 10, Section 10.10).
RECIST 1.1 criteria: 
Definition of Measurable disease: 

Soft tissue/ visceral tumor lesions: Must be accurately measured in at least one 
dimension (longest diameter in the plane of measurement is to be recorded) with a 
minimum size of 10 mm by CT scan. If scans with slice thicknesses greater than 5 mm 
are used, the minimum size should be twice the slice thickness.

Malignant lymph nodes: To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in short axis when assessed by CT scan (for CT scan 
slice thickness of 5 mm). At baseline and in follow-up, only the short axis will be 
measured and followed.
Non-measurable disease
All other lesions are considered non-measurable. This includes small lesions (longest 
diameter < 10 mm or pathological lymph nodes with ≥ 10 to < 15 mm short axis) and also 
truly non-measurable lesions, such as: leptomeningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung.
Bone lesions, cystic lesions and lesions previously treated with local therapy require particular 
comment:
Bone lesions: (Note: not assessed by RECIST 1.1 in the current study)

Lytic bone lesions, with an identifiable soft-tissue component, (e.g., lytic bone lesions 
in renal cell carcinoma) evaluated by CT or MRI can be considered as measurable 
lesions if the soft-tissue component otherwise meets the definition of measurability.

Blastic bone lesions are considered as non-measurable.
Cystic lesions:

Lesions that meet radiographic criteria for simple cysts should not be considered 
malignant lesions (neither measurable nor non-measurable).

“Cystic lesions” thought to be cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability. However, if non-cystic lesions are 
present in the same participants, these should be preferably selected for assessment.
Lesions with prior local treatment:

Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable. Previously treated 
lesions can only be selected as target lesions when they have progressed prior to 
baseline.
Target lesions
When more than one measurable lesion is present at baseline, all lesions up to a maximum of 
5 lesions total (and a maximum of 2 lesions per organ) representative of all involved organs 

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should be identified as target lesions and will be recorded and measured at baseline (this 
means in instances where participants have only 1 or 2 organ sites involved a maximum of 2 
and 4 lesions respectively will be recorded). Target lesions should be selected on the basis of 
their size (lesions with the longest diameter), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated measurements. It may 
be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected. A sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and reported as the baseline 
sum diameters. If lymph nodes are to be included in the sum, then as noted above, only the 
short axis is added into the sum. The baseline sum diameters will be used as reference to 
further characterize any objective change in the measurable dimension of the disease.
Optimally, lesions selected as target (measurable) lesions should not be biopsied. Additional 
guidance will be provided to the site on decisions about performing biopsies on potential 
target lesions when only one potential target lesion exists at baseline.
Non-target lesions
All other lesions (or sites of disease) including pathological lymph nodes (with short axis 
≥10 mm and < 15 mm) not considered as target should be identified as non-target lesions and 
should also be recorded at baseline. Measurements are not required, and these lesions should 
be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ (more details to 
follow). Please note that some non-target lesions may actually be measurable, but if they were 
chosen to be followed as non-target lesions, they should be assessed only qualitatively. In 
addition, it is possible to record multiple non-target lesions involving the same organ as a 
single item on the case record form (e.g. ‘multiple enlarged pelvic lymph nodes’ or ‘multiple 
liver metastases’).
Best Response: The best overall response for a participant is the best response recorded from 
the start of the study intervention until the end of treatment or Active Follow-up (A-FU), if 
applicable, taking into account any requirement for confirmation. The participant’s best 
overall response assignment will depend on the findings of both target and non-target disease 
and will also take into consideration the appearance of new lesions.
Complete Response (CR): Disappearance of all non-nodal target lesions. Any pathological 
lymph nodes (whether target or non-target) must have decreased in size to have a short axis of 
< 10 mm. In addition, there must be normalization of any applicable tumor marker.
Since lymph nodes are normal body structures, it is not expected that they disappear. Lymph 
nodes identified as target lesions should always have the short axis measurement recorded 
(measured in the same anatomical plane as the baseline examination), even if the nodes 
regress to below 10 mm on study. This means that when lymph nodes are included as target 
lesions, the ‘sum’ of lesions may not be zero even if complete response criteria are met, since 
a lymph node is defined as normal when having a short axis of < 10 mm.
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions 
taking as reference the baseline sum diameters.
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for progressive disease (PD), taking as reference the smallest sum diameters while on 
study.

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Non-CR/Non-PD (to be used for participants with non-target lesions only): Persistence of 
one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal 
limits.
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. Unequivocal progression of existing non-target lesions 
(see comments below), or the appearance of one or more new lesions, also constitutes 
progressive disease.
To achieve unequivocal progression in participants with measurable disease on the basis of 
the non-target disease, there must be an overall level of substantial worsening in non-target 
disease such that, even in presence of SD or PR in target disease, the overall tumor burden has 
increased sufficiently to merit discontinuation of therapy. A modest ‘increase’ in the size of 
one or more non-target lesions is usually not sufficient to qualify for unequivocal.
In the absence of measurable disease, the same general concepts apply here as noted above.
The above text descriptions of the visit/time point response are logically equivalent to Table 
10–2 below.
Table 10–2
RECIST 1.1 - Time Point Response for participants with target and non-
target lesions
Target 
Lesions
Non-Target 
Lesions
New 
Lesions
Overall Time 
Point Response
Best Response for this
category also requires
CR
CR
No
CR
-
CR
Non-CR/Non-PD
No
PR
-
CR
Not evaluated
No
PR
-
PR
Non-PD or not all 
evaluated
No
PR
-
SD
Non-PD or not all 
evaluated
No
SD
documented at least 6 weeks 
from treatment allocation 
Not all 
evaluated
Non-PD
No
NE
-
PD
Any
Yes or No
PD
-
Any
PD
Yes or No
PD
-
Any
Any
Yes
PD
-
Abbreviations: CR = Complete response; NE = Not evaluated; PD = Progressive disease; PR = Partial response; 
RECIST = Response Evaluation Criteria in Solid Tumours; SD = Stable disease.
Participants with a global deterioration of health status requiring discontinuation of 
intervention without objective evidence of disease progression at that time should be reported 
as “symptomatic deterioration”. Every effort should be made to document the objective 
progression even after discontinuation of intervention.
Response duration
The duration of overall response is measured from the time measurement criteria are first met 
for CR/PR (whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented.

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The duration of overall complete response is measured from the time measurement criteria are 
first met for CR until the first date that recurrent disease is objectively documented.
Stable disease duration
Stable disease is measured from the start of the intervention until the criteria for progression 
are met, taking as reference the smallest sum on study (if the baseline sum is the smallest, this 
is the reference for calculation of PD).

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10.10
Appendix 10: Prostate Cancer Working Group 3 Criteria for Bone 
Metastases
In this study, the PCWG3 criteria will be used for bone metastases only. All extra-skeletal 
metastatic disease will be assessed by RECIST 1.1 (Appendix 9, Section 10.9).
Details of the Prostate Cancer Working Group 3 Criteria may be found:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872347/pdf/JCO642702.pdf 
99mTc-phophonate whole body planar bone scans are to be used for assessment of bone 
disease.
Bone lesion response types per PCWG3:
Bone scans will be used to assess that there are no new lesions (stable) or worse (new lesions)
Changes in intensity of uptake alone do not constitute progression or regression.
No new lesions would indicate continuation of therapy in the absence of other signs of 
progression (e.g., soft tissue progression by RECIST 1.1 above).
For new lesions and progression, the 2x2 rule is used: at least two new lesions on the first 
post-treatment scan, with at least two additional lesions on the next scan. If at least two 
additional new lesions are seen on the next (confirmatory) scan, the date of progression is the 
date of the first post-treatment scan. For scans after the first post-treatment scan, at least two 
new lesions relative to the first post-treatment scan and confirmed on a subsequent scan [see 
Figure 2 in (Scher et al. 2016)] provide a confirmed progression status.

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10.11
Appendix 11: Abbreviations
ADT
Androgen deprivation therapy
AE
Adverse event 
A-FU
Active Follow-up
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AR
Androgen receptor
ARi
Androgen receptor inhibitor
AST
Aspartate aminotransferase
AUC0–24
The area under the concentration–time curve from time zero to 24 h
AUC0–72
The area under the concentration–time curve from time zero to 72 h
BCRP
Breast Cancer Resistance Protein
BHA
Bone health agents
bid
Twice daily
BP
Blood pressure
BPI-SF
Brief Pain Inventory–Short Form
BT
Body temperature
BUN
Blood urea nitrogen
CFR
Code of Federal Regulations
CI
Confidence interval
CIOMS
Declaration of Helsinki and Council for International Organizations 
of Medical Sciences
Cmax
Maximum concentration
CNS
Central nervous system
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
Coronavirus disease 2019
CR
Complete response
CRF
Case report form
CRO
Contract research organization
CRPC
Castration-resistant prostate cancer
CT
Computed tomography
CTCAE
Common Terminology Criteria For Adverse Events

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ctDNA
Circulating tumor deoxyribonucleic acid
CYP
Cytochrome P450 enzyme
CYP3A4
Cytochrome P450 family 3 subfamily A member 4
DDI
Drug-drug interaction
DILI
Drug-induced liver injury
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
DPD
1-diphosphonate
EBRT
External beam radiation therapy
ECG
Electrocardiogram
ECOG PS
Eastern Cooperative Oncology Group Performance Status
eCRF
Electronic case report form
e.g.
For example (exempli gratia)
eGFR
Estimated glomerular filtration rate
EOT
End of treatment
ePRO
Electronic patient-reported outcome
EU
European Union
FACT-P
Functional Assessment of Cancer Therapy-Prostate
FAS
Full analysis set
GCP
Good Clinical Practice
GI
Gastrointestinal
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HDP
Hydroxyethylene diphosphonate
HDPE
High density polyethylene
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human immunodeficiency virus
HMDP
Hydroxymethylene diphosphonate
HR
Heart rate
IB
Investigator’s Brochure
IC
Informed consent
ICECaP
Intermediate Clinical Endpoints in Cancer of the Prostate

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ICF
Informed consent form
ICH
International Council for Harmonization
ID
Identification
i.e.
That is (id est)
IEC
Independent Ethics Committee
IMP
Investigational medicinal product
IND
Investigational New Drug
INN
International nonproprietary name
IRB
Independent Review Board
i.v.
Intravenous(ly)
IWRS
Interactive Web Response System
KM
Kaplan–Meier
LHRH
Luteinizing hormone-releasing hormone
MCH
Mean corpuscular hemoglobin
mCRPC
Metastatic castration-resistant prostate cancer
MCV
Mean corpuscular volume
MDP
Methylene diphosphonate
MedDRA
Medical Dictionary for Regulatory Activities
MFS
Metastasis-free survival
mHSPC
Metastatic hormone-sensitive prostate cancer
MRI
Magnetic resonance imaging
NCCN
National Comprehensive Cancer Network
NCI-CTCAE
National Cancer Institute–Common Terminology Criteria for 
Adverse Events
NE
Not evaluated
NIMP
Non-investigational medicinal product
nmCRPC
Non-metastatic castration-resistant prostate cancer
OATP
Organic anion transporting polypeptide
OR
Odds ratio
OS
Overall survival
PCWG3
Prostate Cancer Working Group 3
PD
Progressive disease
PFS
Progression-free survival
P-gp
P-glycoprotein

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pH
Power of hydrogen
PI
Principal Investigator
PI3K
Phosphatidylinositol-3-kinase
PK
Pharmacokinetic(s)
PR
Partial response (except in Section 8.2.3)
PR
PR interval in ECG (in Section 8.2.3)
PS
Performance status
PSA
Prostate-specific antigen
PTEN
Phosphatase and tensin homolog
QoL
Quality of life
QRS
QRS interval in ECG
QT
QT interval in ECG
QTc
Corrected QT
QTcB
Corrected QT (Bazett's formulae)
QTcF
Corrected QT (Fridericia's formulae)
RBC
Red blood cell
RECIST 1.1
Response Evaluation Criteria in Solid Tumours, version 1.1
RNA
Ribonucleic acid
rPFS
Radiological progression-free survival
PFS2 as assessed 
by the investigator
Time from randomization to clinical, biochemical, or radiological 
disease progression under first subsequent anti-cancer therapy or 
death, whichever occurs first
SAE
Serious adverse event
SAF
Safety analysis set
SAP
Statistical analysis plan
SAS
Statistical Analysis Software
SD
Stable disease
SDI Form
Source Data Identification Form
SGOT
Serum glutamic-oxaloacetic transaminase
SGPT
Serum glutamic-pyruvic transaminase
SoA
Schedule of Activities
SSE
Symptomatic skeletal event
SUSAR
Suspected unexpected serious adverse reaction
99mTc
Technetium 99m radionuclide

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TEAE
Treatment-emergent adverse event
TMF
Trial Master File
UK
The United Kingdom
ULN
Upper limit of normal
US
The United States
USA
The United States of America
V1D1
Visit 1 Day 1
WBC
White blood cell
WGS
Whole genome sequencing
WPS
Worst pain subscale

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11.
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