Conditions: Prostate Cancer Non-Metastatic Castration-Resistant
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1509
Healthy volunteers: no

Brief summary:
The purpose of this study is to assess the safety and efficacy of BAY1841788 (ODM-201) in patients with non-metastatic castration-resistant prostate cancer.

Detailed description:

Arms:
arm 1: Participants received Darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equal to a total daily dose of 1200 mg. arm 2: Participants received matching placebo 2 tablets twice daily with food.

Interventions: intervention 1: Darolutamide (Nubeqa, BAY1841788) intervention 2: Placebo
Intervention descriptions: intervention 1: Darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equivalent to a total daily dose of 1200 mg. intervention 2: Matching placebo 2 tablets twice daily with food.

Protocol document:
Prot_002.pdf: 
 
 
 
Document Type: 
Study Protocol 
Official Title: 
A multinational, randomised, double-blind, placebo-controlled, 
Phase III efficacy and safety study of darolutamide (ODM-201) in 
men with high-risk non-metastatic castration-resistant prostate 
cancer 
NCT Number: 
NCT02200614 
Document Date: 
06 July 2019 
 


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COVER PAGE OF THE INTEGRATED PROTOCOL 
A multinational, randomised, double-blind, placebo-controlled, Phase III efficacy and 
safety study of darolutamide (ODM-201) in men with high-risk non-metastatic 
castration-resistant prostate cancer
This protocol version is an integration of the following documents / sections:
Original protocol, Version 1.0, dated 10 MAR 2014
Amendment 01 (global amendment described in Section 11.1)
forming integrated protocol Version 2.0, dated 24 NOV 2014
Amendment 02 (global amendment described in Section 11.2)
forming integrated protocol Version 3.0, dated 19 JUL 2016
Amendment 03 (global amendment described in Section 11.3)
forming integrated protocol Version 4.0, dated 26 FEB 2018
Amendment 04 (global amendment described in Section 11.4)
forming integrated protocol Version 5.0, dated 06 JUL 2019
NOTE:
On 02 JUN 2014 Orion Corporation and Bayer entered into a global agreement for the 
development and commercialization of the investigational novel oral androgen receptor 
inhibitor compound ODM-201. As a result of this agreement Orion transferred sponsorship 
of the ARAMIS trial (Orion trial no. 3104007) to Bayer HealthCare AG (Bayer trial no. 
17712) on a country-by-country basis during 2015-2016. Effective 01 JUL 2016, Bayer 
HealthCare AG merged with its affiliated company Bayer AG. Thereby, Bayer HealthCare 
AG ceased to exist and Bayer AG became its legal successor and assumed the role of 
sponsor for this trial.  With the approval of the international nonproprietary name (INN) 
darolutamide, the Orion drug nomenclature (ODM-201) was replaced with darolutamide 
throughout the protocol. The Bayer nomenclature (BAY 1841788) continues to be 
included for reference. These terms are interchangeable, and BAY 1841788 appears on the 
drug labels.


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TITLE PAGE
A multinational, randomised, double-blind, placebo-controlled, Phase III efficacy and 
safety study of darolutamide (ODM-201) in men with high-risk non-metastatic 
castration-resistant prostate cancer
Efficacy and Safety Study of Darolutamide (ODM-201) in Men With High-risk Non-
metastatic Castration-resistant Prostate Cancer (ARAMIS)
Test drug:
BAY 1841788 / darolutamide / ODM-201
Study purpose:
Efficacy and safety of BAY 1841788 (darolutamide)
Clinical study phase:
III
Date:
06 JUL 2019
Registration:
EudraCT no.: 2013-003820-36
Version no.:
5.0
Sponsor’s study no.:
17712
Sponsor:
Non-US: Bayer AG, 
US territory: Bayer HealthCare Pharmaceuticals Inc., 
 
Sponsor’s medical expert:
Bayer HealthCare Pharmaceuticals, Inc.
Whippany, NJ 07981-0915, USA
Telephone no.: 
Mobile: 
The study will be conducted in compliance with the protocol, ICH-GCP and any applicable 
regulatory requirements.
Confidential
The information provided in this document is strictly confidential and is intended solely for 
the guidance 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.
PPD
PPD
PPD
PPD
PPD
PPD
PPD


PPD
PPD


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TABLE OF CONTENTS
COVER PAGE OF THE INTEGRATED PROTOCOL ............................................................................. 1
TITLE PAGE.................................................................................................................................. 2
SIGNATURE OF THE SPONSOR’S MEDICALLY RESPONSIBLE PERSON ............................................. 3
TABLE OF CONTENTS................................................................................................................... 4
SYNOPSIS .................................................................................................................................. 11
ABBREVIATIONS AND DEFINITION OF TERMS ............................................................................. 16
1.
INTRODUCTION ................................................................................................................ 19
1.1
Background ................................................................................................................ 19
1.2
Pharmacology............................................................................................................. 20
1.3
Nonclinical pharmacokinetics and metabolism ......................................................... 20
1.4
Safety pharmacology and toxicology......................................................................... 21
1.5
Clinical studies with darolutamide............................................................................. 23
1.6
Rationale of the clinical phase III study..................................................................... 24
1.6.1
Rationale of the study design ................................................................................ 24
1.6.2
Rationale for selection of dose.............................................................................. 26
1.6.3
Benefit-risk assessment ......................................................................................... 26
2.
STUDY OBJECTIVES.......................................................................................................... 27
2.1
Primary objective ....................................................................................................... 27
2.2
Secondary objectives.................................................................................................. 27
2.3
Additional objectives ................................................................................................. 27
3.
OVERALL STUDY DESIGN AND PLAN................................................................................. 28
4.
SELECTION OF STUDY POPULATION.................................................................................. 29
4.1
Number of patients..................................................................................................... 29
4.2
Inclusion criteria ........................................................................................................ 29
4.3
Exclusion criteria ....................................................................................................... 30
4.4
Screening log and subject identification list .............................................................. 31
4.5
Recruitment procedures ............................................................................................. 32
4.6
Information to be collected on screening failures...................................................... 32
4.7
Discontinuation of study and withdrawal from study treatment................................ 32
4.7.1
Reasons for discontinuation of study .................................................................... 32
4.7.2
Reasons for withdrawal from study treatment ...................................................... 33
4.7.2.1
Confirmed metastasis ....................................................................................... 33


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4.7.2.2
Intolerable adverse event.................................................................................. 35
5.
STUDY TREATMENTS........................................................................................................ 36
5.1
Investigational product............................................................................................... 36
5.2
Reference product ...................................................................................................... 37
5.3
Selection and timing of doses .................................................................................... 37
5.4
Method of assigning patients to treatment groups ..................................................... 38
5.4.1
Randomisation method.......................................................................................... 38
5.4.2
Implementation of randomisation ......................................................................... 38
5.5
Blinding...................................................................................................................... 38
5.6
Emergency procedures............................................................................................... 39
5.6.1
Breaking of treatment code ................................................................................... 39
5.6.2
Treatment of emergencies ..................................................................................... 39
5.7
Prior, concomitant and follow-up treatments............................................................. 39
5.7.1
Prior and concomitant treatments.......................................................................... 39
5.7.2
Prohibited treatments............................................................................................. 39
5.7.3
Drug-drug interactions .......................................................................................... 40
5.8
Treatment compliance and exposure.......................................................................... 41
5.9
Availability of investigational product after termination of study............................. 42
6.
VISIT SCHEDULE, METHODS OF ASSESSMENT AND VARIABLES ......................................... 42
6.1
Visit schedule............................................................................................................. 42
6.1.1
Procedures during the screening period (-28 to -1 days)....................................... 47
6.1.2
Procedures during the study treatment period....................................................... 48
6.1.2.1
Day 1 (visit 1)................................................................................................... 49
6.1.2.2
Day 15 (± 3 days) (Visit 2)............................................................................... 49
6.1.2.3
Day 29 (± 5 days) (Visit 3)............................................................................... 50
6.1.2.4
Week 16 (± 7 days) (Visit 4) and every subsequent 16 weeks (± 7 days) 
thereafter........................................................................................................... 51
6.1.2.5
Start of open-label treatment visit .................................................................... 51
6.1.2.6
End-of-study treatment visit, and in transition to the roll-over study .............. 53
6.1.3
Follow-up period ................................................................................................... 54
6.1.4
Unscheduled visits................................................................................................. 55
6.1.5
Roll-over study...................................................................................................... 55
6.1.6
End of study........................................................................................................... 56
6.2
PK assessments during double-blind treatment ......................................................... 56
6.3
Assessment of efficacy variables ............................................................................... 58


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6.3.1
Primary efficacy variable ...................................................................................... 58
6.3.2
Secondary efficacy variables................................................................................. 59
6.3.2.1
Overall survival ................................................................................................ 59
6.3.2.2
Time to first symptomatic skeletal event (SSE) ............................................... 59
6.3.2.3
Time to initiation of first cytotoxic chemotherapy........................................... 60
6.3.2.4
Time to pain progression .................................................................................. 60
6.3.3
Additional efficacy variables................................................................................. 60
6.3.3.1
Progression-free survival.................................................................................. 60
6.3.3.2
Time to first prostate cancer-related invasive procedure.................................. 60
6.3.3.3
Time to initiation of subsequent antineoplastic therapy................................... 60
6.3.3.4
Time to PSA progression.................................................................................. 61
6.3.3.5
Percent of patients with PSA response............................................................. 61
6.3.3.6
Percent of patients with ECOG performance status deterioration.................... 61
6.3.3.7
Time to ECOG performance status deterioration............................................. 61
6.3.3.8
Health-related quality of life............................................................................. 61
6.4
Pharmacokinetic assessments .................................................................................... 63
6.4.1
Blood sampling...................................................................................................... 63
6.4.2
Determination of (S,R)-darolutamide, (S,S)-darolutamide and keto-
darolutamide concentrations in plasma................................................................. 64
6.5
Pharmacogenetic and tumour-related biomarker assessments................................... 64
6.5.1
Assessment of pharmacogenetic polymorphisms.................................................. 64
6.5.2
Assessment of tumour-related biomarkers............................................................ 64
6.6
Assessment of safety and tolerability variables ......................................................... 65
6.6.1
Adverse events ...................................................................................................... 65
6.6.1.1
Definitions of adverse events ........................................................................... 65
6.6.1.2
Assessment of adverse events........................................................................... 66
6.6.1.3
Reporting of serious adverse events ................................................................. 68
6.6.1.4
Special situations .............................................................................................. 69
6.6.1.5
Pregnancy during a clinical study..................................................................... 69
6.6.2
Clinical safety assessments ................................................................................... 70
6.6.2.1
12-lead ECG ..................................................................................................... 70
6.6.2.2
Vital signs......................................................................................................... 70
6.6.2.3
Physical examination........................................................................................ 70
6.6.3
Laboratory safety assessments .............................................................................. 70
6.6.4
Reporting of medical device failures..................................................................... 72


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7.
EVALUATIONS AND STATISTICS........................................................................................ 72
7.1
Estimation of sample size .......................................................................................... 72
7.2
Statistical hypotheses ................................................................................................. 73
7.3
Data sets to be analysed ............................................................................................. 73
7.3.1
Intent-to-treat dataset............................................................................................. 73
7.3.2
Per-protocol dataset............................................................................................... 73
7.3.3
Safety dataset......................................................................................................... 73
7.4
General statistical considerations............................................................................... 73
7.5
Demographic and other baseline characteristics........................................................ 74
7.6
Evaluation of treatment compliance and exposure .................................................... 74
7.7
Evaluation and analysis of efficacy ........................................................................... 75
7.7.1
Primary efficacy evaluation................................................................................... 75
7.7.2
Secondary efficacy evaluations............................................................................. 75
7.7.3
Additional efficacy evaluations............................................................................. 76
7.7.4
Evaluation of pharmacokinetics............................................................................ 77
7.7.5
Evaluation of pharmacogenetics and tumour-related biomarkers......................... 77
7.8
Evaluation and analysis of safety and tolerability ..................................................... 77
7.8.1
Evaluation of adverse events................................................................................. 77
7.8.2
Clinical safety evaluations..................................................................................... 78
7.8.3
Laboratory safety evaluations ............................................................................... 78
7.8.4
Other safety evaluations ........................................................................................ 78
7.9
Interim analyses ......................................................................................................... 78
7.10
Execution of statistical analyses ................................................................................ 78
7.11
Software ..................................................................................................................... 78
8.
FURTHER REQUIREMENTS AND GENERAL INFORMATION .................................................. 79
8.1
Quality control of data handling ................................................................................ 79
8.2
Insurance .................................................................................................................... 79
8.3
Financial disclosure.................................................................................................... 79
8.4
Study centre team information................................................................................... 79
8.5
Protocol reviews......................................................................................................... 80
8.6
Amendments to the study protocol ............................................................................ 80
8.7
Case report forms....................................................................................................... 81
8.8
Data management....................................................................................................... 81
8.8.1
Database design..................................................................................................... 81
8.8.2
Data entry .............................................................................................................. 81


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8.8.3
Data validation and query management ................................................................ 81
8.8.4
Data lock................................................................................................................ 82
8.8.5
Database lock ........................................................................................................ 82
8.8.6
Opening of the treatment code .............................................................................. 82
8.8.7
Hardware and software.......................................................................................... 82
8.9
Record retention......................................................................................................... 82
8.10
Monitoring, quality assurance and inspection............................................................ 82
8.11
Steering committee .................................................................................................... 83
8.12
Data and safety monitoring board.............................................................................. 83
8.13
Reports, publications and communication of results ................................................. 83
8.14
Study schedule ........................................................................................................... 84
8.15
Qualification documentation...................................................................................... 84
8.15.1
Curriculum vitae.................................................................................................... 84
8.16
Study termination....................................................................................................... 85
8.16.1
Study completion................................................................................................... 85
8.16.2
Premature study termination ................................................................................. 85
9.
ETHICAL REQUIREMENTS ................................................................................................. 85
9.1
Ethics committee........................................................................................................ 85
9.2
Ethical conduct of the study....................................................................................... 85
9.3
Subject information and consent................................................................................ 85
9.3.1
Subject data protection .......................................................................................... 86
10.
REFERENCE LIST .............................................................................................................. 86
11.
PROTOCOL AMENDMENTS ................................................................................................ 88
11.1
Amendment 1............................................................................................................. 88
11.1.1
Overview of adjustments....................................................................................... 88
11.1.2
Overview of clarifications and corrections ........................................................... 92
11.2
Amendment 2............................................................................................................. 97
11.2.1
Overview of changes to the study ......................................................................... 97
11.2.1.1
Modification 1: Sponsorship change ................................................................ 97
11.2.1.2
Modification 2: Introductory information updated........................................... 97
11.2.1.3
Modification 3: Entry criteria updated ............................................................. 97
11.2.1.4
Modification 4: List of prohibited treatments revised...................................... 98
11.2.1.5
Modification 5: Requirements for monitoring drug-drug interactions 
revised............................................................................................................... 98
11.2.1.6
Modification 6: Site’s role in the confirmation of metastasis clarified ............ 99


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11.2.1.7
Modification 7: Collection of the optional PG IC revised................................ 99
11.2.1.8
Modification 8: Clarification of PSA values used to confirm patient 
eligibility........................................................................................................... 99
11.2.1.9
Modification 9: Clarification of re-testing and re-screening procedures ......... 99
11.2.1.10
Modification 10: Two study event schedules for follow-up period 
combined ........................................................................................................ 100
11.2.1.11
Modification 11: Study drug accountability emphasized............................... 100
11.2.1.12
Modification 12: EQ-5D-3L assessment adjusted.......................................... 100
11.2.1.13
Modification 13: PK data collection and vital sign measurements 
revised............................................................................................................. 101
11.2.1.14
Modification 14: Unblinding instructions revised.......................................... 101
11.2.1.15
Modification 15: Number of study centres increased..................................... 101
11.2.1.16
Modification 16: Non-osseous metastasis need central read 
confirmation.................................................................................................... 101
11.2.1.17
Modification 17: Adverse event reporting instructions revised for 
clarity and consistency.................................................................................... 102
11.2.1.18
Modification 18: Other clarifications and corrections.................................... 102
11.2.2
Changes to the protocol text................................................................................ 103
11.3
Amendment 3........................................................................................................... 103
11.3.1
Overview of changes to the study ....................................................................... 103
11.3.1.1
Modification 1: Modified plan for the statistical analysis.............................. 103
11.3.1.2
Modification 2: Possibility to receive open-label darolutamide 
treatment ......................................................................................................... 104
11.3.1.3
Modification 3: New in vitro data related to drug-drug interaction 
potential .......................................................................................................... 104
11.3.1.4
Modification 4: New data from drug-drug interaction clinical studies .......... 105
11.3.1.5
Modification 5: Reporting of medical device failures of imported and 
non-approved third-party device .................................................................... 105
11.3.1.6
Modification 6: Clarification to the collection of concomitant 
treatments........................................................................................................ 105
11.3.1.7
Modification 7: Clarification related to additional efficacy variables............ 105
11.3.1.8
Modification 8: Assessments for patients who continue on open-label 
darolutamide treatment................................................................................... 106
11.3.1.9
Modification 9: Additional language added to perform survival sweep ........ 106
11.3.1.10
Modification 10: Modification of dosing language........................................ 106
11.3.1.11
Modification 11: Nomenclature change ......................................................... 106
11.3.1.12
Modification 12: Personnel change ................................................................ 107


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11.3.1.13
Modification 13: Other clarifications and corrections.................................... 107
11.3.2
Changes to the protocol text................................................................................ 107
11.4
Amendment 4........................................................................................................... 107
11.4.1
Overview of changes to the study ....................................................................... 108
11.4.2
Changes to the protocol text................................................................................ 109
12.
APPENDICES................................................................................................................... 109


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SYNOPSIS
Sponsor/Company
Bayer AG
Individual Study Table referring to a 
specific Part of the dossier
Volume:
Page
(for National Regulatory Authority 
use only)
Finished product:
Not applicable
Active ingredient:
BAY 1841788 (darolutamide)
Study code: 17712 (former Orion Pharma study code 3104007)
Study title: A multinational, randomised, double-blind, placebo-controlled, Phase III efficacy and safety study 
of darolutamide (ODM-201) in men with high-risk non-metastatic castration-resistant prostate cancer
Study centres:
Approximately 480 global study centres
Development phase: III
Objectives:
The primary objective of this study is to demonstrate superiority of darolutamide over placebo in metastasis-
free survival (MFS) in patients with high-risk non-metastatic castration-resistant prostate cancer (nmCRPC).
The secondary objectives of this study are to demonstrate benefit of darolutamide compared with placebo on
overall survival (OS), time to first symptomatic skeletal event (SSE), time to initiation of first cytotoxic 
chemotherapy, time to pain progression, and to characterise the safety and tolerability of darolutamide.
The additional objectives of this study are to determine benefit of darolutamide in progression-free survival
(PFS), time to first prostate cancer-related invasive procedure, time to initiation of subsequent antineoplastic 
therapy, prostate-specific antigen (PSA) progression and response, Eastern Cooperative Oncology Group 
(ECOG) performance status deterioration and quality of life (QoL), and to evaluate pharmacokinetics (PK) of 
darolutamide and keto-darolutamide, and to explore possible relationships between exposure and safety and 
efficacy responses.
Methodology:
This is a randomised, phase III, multicentre, double-blind, placebo-controlled efficacy and safety study of oral 
darolutamide in patients with nmCRPC who are at high risk for developing metastatic disease. The study has a 
design of 2 parallel groups and consists of 2 periods: a study treatment period and a follow-up period. 
All eligible patients will be randomised to receive darolutamide 600 mg twice daily or placebo in a 2:1 ratio in 
a double-blind manner. Randomisation will be stratified by PSA doubling time (PSADT; 6 months vs. 
> 6 months) and use of osteoclast-targeted therapy (yes vs. no).
All patients will visit the study centre at day 1, day 15, day 29, week 16, and every 16 weeks thereafter. 
CT/MRI and bone scans will be obtained at baseline and every 16 weeks until metastasis. Absence or presence 
of metastasis will be confirmed at baseline and during the double-blind treatment phase by a blinded 
independent central reading. Changes identified by central reading must be confirmed with anatomic imaging 
(CT/MRI or x-ray). Upon central confirmation of metastasis, the patient must be withdrawn from the study 
treatment and the patient will be followed every 16 weeks for secondary and additional variables (OS, first 
SSE, pain progression, first prostate cancer-related invasive procedure, initiation of subsequent antineoplastic 
therapy, initiation of cytotoxic chemotherapy, initiation of opioid use for pain, and changes in ECOG
performance status and QoL) until the end of the study by visit or telephone contact.
Patients initiating a prohibited therapy before confirmation of the metastasis during the double-blind part 
should discontinue study treatment and patients will be followed only for survival status until the end of the 
study. 
The double-blind part is planned to be continued until the total number of MFS events have been reached at 
approximately 385 events. 


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Once the study results are available, and if they support a positive benefit/risk assessment for darolutamide in 
the study by judgment of the Sponsor (considering feedback from the study steering committee and/or health 
authorities), those patients who are on study treatment (darolutamide or placebo) will be offered the 
opportunity to receive darolutamide through open-label treatment in this study. 
At the time of study treatment code unblinding, patients who choose to receive open-label darolutamide will 
have a start of open-label treatment visit and will visit the study centre every 16 weeks until metastasis is seen 
by local reading. After occurrence of metastasis, the patients should discontinue study treatment and will be 
followed thereafter every 16 weeks for secondary and additional variables until the end of the study. Patients 
initiating a prohibited therapy before metastasis confirmed by local reading must discontinue study treatment 
and will be followed for survival status until the end of the study.
Patients will be contacted to assess survival status every 16 weeks during follow-up. Survival data will be 
collected through an additional survival sweep. All patients considered alive shortly after the database cut-off 
date for the MFS analysis and prior to any subsequent analysis of OS will be contacted for survival status.
The estimated maximum total duration of the study per an individual patient is 72 months (6 years). 
A separate roll-over study has been set up to allow patients who received darolutamide in the course of 
Bayer-sponsored clinical trials to continue receiving treatment with darolutamide at the time of study 
discontinuation. All study patients who are ongoing on treatment and eligible to enter the roll-over study will 
transition as soon as it has been approved by local ethics committee/independent review board/health 
authority. Patients who will transition to the roll-over study will perform the end-of-study treatment visit in the 
current study, after which they may be transitioned. All patients who transition into this separate study will 
require a separate signed informed consent.
The follow-up period will end at each site when all patients at the site who are ongoing on treatment have 
transitioned into the roll-over study or have discontinued from the study for another reason (e.g., consent 
withdrawn, lost to follow-up). Patients who are in follow-up at the site will end follow-up.
This study will end when all patients on treatment have transitioned into the roll-over study or have
discontinued from this study for another reason (e.g., death, consent withdrawn [with no further data 
collection], lost to follow-up).
Sample size:
The planned number of patients is approximately 1500 randomised to darolutamide or placebo in a 2:1 ratio.
Diagnosis and main criteria for inclusion and exclusion: 
Men with nmCRPC who are at high risk for developing metastases.
Inclusion criteria:
1.
Written informed consent obtained.
2.
Males aged 18 years.
3.
Histologically or cytologically confirmed adenocarcinoma of prostate
without neuroendocrine 
differentiation or small cell features. 
4.
Castration-resistant prostate cancer (CRPC) defined as 3 rising PSA levels after the nadir taken at least 1 
week apart during androgen deprivation therapy (ADT). If the patient has a history of antiandrogen use,
the most recent PSA value must be obtained at least 4 weeks after antiandrogen withdrawal. See Section 0
for further details.
5.
Castrate level of serum testosterone (< 1.7 nmol/l [50 ng/dl]) on gonadotropin releasing hormone (GnRH) 
agonist or antagonist therapy or after bilateral orchiectomy. Patients who have not undergone bilateral 
orchiectomy must continue GnRH therapy during the study.
6.
PSADT of 10 months and PSA 2 ng/ml at screening. See Section 0 for further details.
7.
Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
8.
Blood counts at screening: haemoglobin 9.0 g/dl, absolute neutrophil count 1500/µl (1.5x109/l), 
platelet count 100,000/µl (100x109/l ) (patient must not have received any growth factor or blood 
transfusion within 7 days of the haematology laboratory obtained at screening).
9.
Screening values of serum alanine aminotransferase (ALT) and aspartate transaminase (AST) 2.5 x 
upper limit of normal (ULN), total bilirubin 1.5 x ULN (except patients with a diagnosis of Gilbert’s 


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disease), creatinine 2.0 x ULN.
10. Sexually active patients, unless surgically sterile, must agree to use condoms as an effective barrier 
method and refrain from sperm donation during the study treatment and for 3 months after the end of the 
study treatment.
Exclusion criteria:
1.
History of metastatic disease at any time or presence of detectable metastases by blinded central reading
within 42 days prior to start of study treatment. Presence of pelvic lymph nodes < 2 cm in short axis below 
the aortic bifurcation is allowed. See Section 0 for further details.
2.
Symptomatic local-regional disease that requires medical intervention including moderate/severe urinary 
obstruction or hydronephrosis due to prostate cancer.
3.
Acute toxicities of prior treatments and procedures not resolved to grade 1 or baseline before 
randomisation.
4.
Prior treatment with:

second generation androgen receptor (AR) inhibitors such as enzalutamide, ARN-509, 
darolutamide, other investigational AR inhibitors,

CYP17 enzyme inhibitor such as abiraterone acetate, TAK-700 or

oral ketoconazole longer than for 28 days.
5.
Use of estrogens or 5-α reductase inhibitors (finasteride, dutasteride) within 28 days before randomisation
and AR inhibitors (bicalutamide, flutamide, nilutamide, cyproterone acetate) at least 28 days before 
screening.
6.
Prior chemotherapy or immunotherapy for prostate cancer, except adjuvant/neoadjuvant treatment 
completed > 2 years before randomisation. 
7.
Use of systemic corticosteroid with dose greater than the equivalent 10 mg of prednisone/day within 
28 days before randomisation. 
8.
Radiation therapy (external beam radiation therapy [EBRT], brachytherapy, or radiopharmaceuticals) 
within 12 weeks before randomisation.
9.
Severe or uncontrolled concurrent disease, infection or co-morbidity that, in the opinion of the 
investigator, would make the patient inappropriate for enrolment.
10. Treatment with an osteoclast-targeted therapy (bisphosphonate or denosumab) to prevent skeletal-related 
events within 12 weeks before randomisation. Patients receiving osteoclast-targeted therapy to prevent 
bone loss at a dose and schedule indicated for osteoporosis may continue treatment at the same dose and 
schedule.
11. Known hypersensitivity to the study treatment or any of its ingredients.
12. Major surgery within 28 days before randomisation.
13. Any of the following within 6 months before randomisation: stroke, myocardial infarction, severe/unstable 
angina pectoris, coronary/peripheral artery bypass graft; congestive heart failure New York Heart 
Association (NYHA) Class III or IV.
14. Uncontrolled hypertension as indicated by a systolic blood pressure (BP) 160 mmHg or diastolic BP 
100 mmHg at screening.
15. Prior malignancy. Adequately treated basal cell or squamous cell carcinoma of skin or superficial bladder 
cancer that has not spread behind the connective tissue layer (i.e. pTis, pTa, and pT1) is allowed, as well 
as any other cancer for which treatment has been completed 5 years ago and from which the patient has 
been disease-free.
16. Gastrointestinal disorder or procedure which expects to interfere significantly with absorption of study 
treatment.
17. Active viral hepatitis, active human immunodeficiency virus (HIV) or chronic liver disease.
18. Treatment with any investigational drug within 28 days before randomisation.
19. Any condition that in the opinion of the investigator would impair the patients’ ability to comply with the 
study procedures.


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20. Unable to swallow study medications and comply with study requirements.
Investigational product, dose and mode of administration: BAY 1841788 (darolutamide) 600 mg (2 tablets 
of 300 mg) twice daily with food, equivalent to a total dose of 1200 mg.
Duration of treatment: Until confirmed metastasis or until death up to 72 months (6 years).
Reference product, dose and mode of administration:
Matching placebo for
BAY 1841788
(darolutamide) (2 tablets) twice daily with food.
Variables 
Efficacy variable:
The primary efficacy variable is MFS defined as time between randomisation and evidence of metastasis or 
death from any cause, whichever comes first.
Secondary variables:

OS

Time to first SSE defined as external beam radiation therapy (EBRT) to relieve skeletal symptoms, new 
symptomatic pathologic bone fracture, occurrence of spinal cord compression, or tumour-related 
orthopaedic surgical intervention

Time to initiation of first cytotoxic chemotherapy for prostate cancer 

Time to pain progression, as assessed with Brief Pain Inventory – short form and first opioid use 
Additional variables:

PFS

Time to first prostate cancer-related invasive procedure 

Time to initiation of subsequent antineoplastic therapy

Time to PSA progression

Percent of patients with PSA response

Percent of patients with ECOG performance status deterioration

Time to ECOG performance status deterioration

Changes in health-related QoL assessed by Functional Assessment of Cancer Therapy-Prostate (FACT-P), 
European Organization for Research and Treatment of Cancer Quality of life Questionnaire - Prostate 
Cancer Module (EORTC-QLQ-PR25) and European QoL 5-domain scale (EQ-5D-3L) questionnaire
Population PK of darolutamide and its major metabolite keto-darolutamide will be evaluated in study centres 
participating in PK sample collection.
Safety variables:

Adverse events (AEs) until the end-of-study treatment visit

Vital signs: BP and heart rate (HR)

12-lead electrocardiogram (ECG)

Physical examination

Laboratory safety assessments (haematology, clinical chemistry, urinalysis)
Evaluation and statistical methods
The intention-to-treat (ITT) population, defined as all randomised patients, will be used as the primary analysis 
population for all efficacy variables.
Eligible patients will be randomised and stratified by PSADT (6 months vs. > 6 months) and use of 
osteoclast-targeted therapy (yes vs. no) at randomisation. All efficacy analyses will incorporate the 
stratification.
Primary efficacy endpoint
The primary efficacy endpoint is MFS defined as time between randomisation and evidence of metastasis or 
death from any cause, whichever comes first. Approximately 385 events will be collected for the 
MFS analysis. A stratified log rank test will be used to compare the darolutamide group and the placebo group. 
This comparison will be 2-sided at the 0.05 level of significance.


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For the primary efficacy endpoint no formal interim analysis is planned.
Secondary efficacy endpoints
The secondary endpoints are OS, time to first SSE, time to initiation of first cytotoxic chemotherapy for 
prostate cancer and time to pain progression. Secondary endpoints will be evaluated for statistical significance 
at the time of the MFS analysis and at a later time point. Similar to the primary endpoint, a stratified log rank 
test will be used to compare the darolutamide group and the placebo group for secondary endpoints.
For secondary efficacy variables the analysis done at the time of the MFS analysis is considered as interim 
analysis and the subsequent analysis is considered as final analysis for statistical significance. Further updates 
of secondary endpoint analyses without testing for statistical significance may be done.
The safety population will include all patients who have taken at least 1 dose of study medication. Safety will 
be assessed through summaries of AEs, vital signs, physical examinations, ECGs and laboratory safety data. 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) coding system. 
Descriptive statistics will be used rather than inferential statistics. 
The independent Data and Safety Monitoring Board (DSMB) will periodically review the benefit-risk profile 
of darolutamide for patients’ safety.


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ABBREVIATIONS AND DEFINITION OF TERMS
ADT
Androgen deprivation therapy
AE
Adverse event 
AR
Androgen receptor
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
bid
Twice a day
BP
Blood pressure
BPI-SF
Brief pain inventory – short form
Cmax
Maximum concentration
CRF
Case report form
CRO
Contract research organisation
CRPC
Castration-resistant prostate cancer
CT
Computed tomography
CTC
Circulating tumour cell
CTCAE
Common Terminology Criteria For Adverse Events
CYP
Cytochrome P450
DSMB
Data and Safety Monitoring Board
EBRT
External beam radiation therapy
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EDC
Electronic data capture
EMA
European Medicines Agency
EORTC-QLQ-
PR25
European Organization for Research and Treatment of Cancer 
Quality of life Questionnaire - Prostate Cancer Module
EQ-5D-3L
European Quality of Life 5-Domain Scale 
EU
European Union
FACT-P
Functional Assessment of Cancer Therapy-Prostate
FDA
US Food and Drug Administration


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GCP
Good clinical practice
GnRH
Gonadotropin releasing hormone
HR
Heart rate
HTA
Health Technology Assessment
IB
Investigator’s brochure
IC
Informed consent
IC50
Concentration required for < 50% inhibition
IEC
Independent Ethics Committee
INN
International nonproprietary name
INR
International normalised ratio
IRB
Independent Review Board
IRT
Interactive response technology
ITT
Intent-to-treat
Ki
Inhibition constant
mCRPC
Metastatic castration-resistant prostate cancer
MedDRA
Medical Dictionary for Regulatory Activities
MFS
Metastasis-free survival
MRI
Magnetic resonance imaging
nmCRPC
Non-metastatic castration-resistant prostate cancer
OATP
Organic anion transporting polypeptide
OS
Overall survival
PCS
Prostate-cancer related symptoms
PFS
Progression-free survival
PG
Pharmacogenomics
P-gp
P-glycoprotein
PK
Pharmacokinetic(s)
PMDA
Pharmaceuticals and Medical Devices Agency (Japan)
PP
Per-protocol
PSA
Prostate-specific antigen
PSADT
Prostate-specific antigen doubling time
QoL
Quality of life


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OS
Overall survival
QTc
Corrected QT
QTcB
Corrected QT (Bazett's formulae)
QTcF
Corrected QT (Fridericia's formulae)
RECIST
Response Evaluation Criteria in Solid Tumours
rPFS
Radiographic progression-free survival
SAE
Serious adverse event
SAP 
Statistical analysis plan
SOP
Standard operating procedure
SSE
Symptomatic skeletal event
SUSAR
Suspected unexpected serious adverse reaction
ULN
Upper limit of normal
US
The United States
VCaP
Vertebral Cancer of the Prostate cell line
Definition of terms
With the approval of the INN darolutamide, the Orion drug nomenclature (ODM-201) was 
replaced with darolutamide throughout the protocol. In addition, the Orion codes for 
darolutamide diastereomers and metabolite were replaced with trivial names in the entire 
document as shown in the table below.
Orion name
INN/trivial name
Drug substance and drug product
ODM-201
Darolutamide (INN)
Diastereomer
ORM-16497
(S,R)-darolutamide
Diastereomer
ORM-16555
(S,S)-darolutamide
Metabolite
ORM-15341
Keto-darolutamide


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1.
INTRODUCTION
1.1
Background
Prostate cancer is the second most common cancer and the 5th leading cause of cancer death 
among men worldwide (Ferlay J et al., 2012). It is the most common non-cutaneous cancer 
and the 2nd leading cause of cancer-related deaths in men in Europe (Ferlay J et al., 2010) and 
the United States (US) (Jemal A et al., 2008). The most significant morbidity of prostate 
cancer is bone metastases. 
At the time of initial prostate cancer diagnosis, most men in Europe and the US are found to 
have localised disease. A majority of patients receive local treatment alone or with adjuvant 
androgen deprivation therapy (ADT). Some patients appear to receive ADT based only on an 
isolated prostate-specific antigen (PSA) failure. Many of these patients will eventually 
become resistant to ADT and develop castration-resistant prostate cancer (CRPC). Usually, 
the earliest sign of resistance to ADT is a rising serum PSA level before metastases are 
detectable. Currently, there is no standard treatment for castrated patients with rising PSA and 
no evidence of metastases. 
Non-metastatic CRPC (nmCRPC) is defined as a rise in PSA in a man with castrate levels of
testosterone in the absence of radiographic or clinical evidence of metastases. Approximately 
30% of patients with nmCRPC will develop bone metastases within 2 years (Tombal B, 2012)
with a median overall survival (OS) of approximately 4 years. Men at high-risk of developing 
metastases can be identified either by a short PSA doubling time (PSADT) or by a minimum 
absolute value of PSA (Smith MR et al., 2005). For example, in a recent phase III clinical 
study with denosumab in which men were selected on the basis of a minimum PSA level and 
a short PSADT, the median OS in the placebo group was 44 months (Smith MR et al., 2011).
The prevention of the development of metastases in men with nmCRPC is a major unmet 
medical need. The development of metastases can cause symptoms such as bone pain, add 
morbidity and may require additional treatments that may result in increased toxicity and 
additional supportive care measures. Metastases also increase the risk of skeletal-related 
events, such as spinal cord compression, pathologic fracture, or surgery or radiotherapy to a 
bone lesion, which are serious complications of advanced prostate cancer and increase the risk 
of death (Fizazi K et al., 2011, Smith MR et al., 2012). Therefore a delay in the development 
of metastases will have clinical benefits for men with prostate cancer.
The androgen receptor (AR) signalling pathway plays an important role in prostate cancer.
(Massard C et al., 2012). Prostate cancer growth is dependent on androgen stimulating 
proliferation. CRPC remains mainly driven by the AR signalling pathway and overexpression 
of AR is common in CRPC (Linja MJ et al., 2001, Scher HI et al., 2005). Therefore, treatment 
with an AR inhibitor is expected to delay development of metastases as manifestation of 
disease progression.


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1.2
Pharmacology
Darolutamide is a novel nonsteroidal AR inhibitor with excellent selectivity and superior 
binding affinity (9 nM) to AR when compared to known 2nd generation antiandrogens. In AR 
overexpressing cells, darolutamide functions as an antagonist unlike bicalutamide which 
shows significant agonism. In addition, darolutamide
was observed to decrease 
testosterone-mediated nuclear localisation of AR in AR overexpressing cells. In Vertebral 
Cancer of the Prostate cell line (VCaP; cell line derived from a bone metastasis of a patient 
with CRPC) with endogenous AR gene amplification and AR overexpression, darolutamide
suppressed dose-dependently androgen-induced VCaP cell proliferation whereas bicalutamide 
was able to antagonise growth only partially.
Darolutamide
is 
a 
1:1 
mixture 
of 
2
pharmacologically 
active 
diastereomers: 
(S,R)-darolutamide and (S,S)-darolutamide. Diastereomers show no major differences in 
pharmacological activity. The main circulating metabolite, keto-darolutamide, is also 
pharmacologically active and functions as an antagonist in AR overexpressing cells.
In the immature rat assay darolutamide showed antiandrogenic activity, by dose-dependently 
and significantly antagonising testosterone-induced growth of androgen sensitive tissues 
ventral prostate and seminal vesicles after 6-day oral dosing, with maximal inhibition at 
100 mg/kg/day.
In the castration-resistant VCaP xenograft model, darolutamide showed significant antitumour
activity. VCaP tumours were observed to grow significantly more slowly in mice treated with 
50 mg/kg of darolutamide orally once daily for 37 days compared with castrated untreated 
mice. After a twice a day (bid) oral dosing of 50 mg/kg, tumour regression was observed in 
treated mice.
In the orthotopic prostate cancer model, where VCaP cells were inoculated into prostate of 
nude intact male mice, tumour regression and a slower increase in serum PSA level were 
observed in mice treated with 50 mg/kg of darolutamide orally bid for 3 weeks compared with
vehicle controls. Darolutamide did not have any effect on serum testosterone levels.
1.3
Nonclinical pharmacokinetics and metabolism
Darolutamide is rapidly absorbed in mice and rats from preclinical formulations. Dog studies 
show that fasted and fed states differ in darolutamide absorption with fed states showing 
higher total exposure than fasted states. Upon repeated dosing, no accumulation was 
observed. Systemic exposure to darolutamide increased less than dose-proportionally, 
suggesting solubility limited absorption at the high dose levels.
Darolutamide consists of diastereomers (S,R)-darolutamide and (S,S)-darolutamide, which
have different pharmacokinetics (PK) in animals. Rat has a diastereomer ratio of about 1:1 but 
mice and dog show higher exposure to (S,R)-darolutamide, i.e. (S,S)-darolutamide is 
eliminated more rapidly than (S,R)-darolutamide in these species. (S,S)-darolutamide is the 
main human diastereomer (about 85%).
The main circulating metabolite keto-darolutamide is formed by oxidation of a secondary 
alcohol to form a ketone. The diastereomers (S,R)-darolutamide and (S,S)-darolutamide are 


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able to interconvert via keto-darolutamide.
In 
rats and dogs, the metabolite 
keto-darolutamide/the parent darolutamide ratio is close to unity, while in mice and human 
the ratios are around 2-3. No human specific disproportionate metabolites have been found so 
far.
Systemic clearance of darolutamide in nonclinical species is low (0.2 l/h/kg in dogs) which is 
in agreement with the results obtained in vitro in hepatocyte incubations. Terminal volume of 
distribution of darolutamide in dogs is 1.8 l/kg.
Based on in vitro data, darolutamide is a substrate and inhibitor of P–glycoprotein (P–gp) and 
Breast Cancer Resistance Protein (BCRP). According to additional in vitro data, darolutamide
is also an inhibitor of the uptake transporters OATP1B1 and OATP1B3. Interactions with 
P-gp or BCRP are expected in vivo based on these in vitro data, and also on preliminary 
clinical study results (please refer to Section 5.7.3).
In general, the potential for darolutamide to inhibit CYP reaction pathways in vitro in human 
liver microsomes is low. The lowest concentration required for < 50% inhibition (IC50) of 
30 μM was observed for CYP2C9. For its pharmacologically active metabolite 
keto-darolutamide, a Ki value of 27 μM was determined. Applying a mechanistic static 
model, no inhibition potential towards CYP2C9 in vivo is expected.
The CYP450 induction potential of darolutamide and keto-darolutamide was evaluated in 
vitro in primary cultures of human hepatocytes from three individual donors. Based on these 
data, a risk to observe weak to moderate CYP3A4 induction by darolutamide in the clinic 
cannot be ruled out.
In vitro darolutamide has a free fraction of 4.5-8% in the plasma of human, rat and mouse. 
The free fraction in dog plasma is dependent of darolutamide concentration (range 0.3-11%). 
The major binding protein is serum albumin. There are no differences in plasma protein 
binding between the diastereomers. The major metabolite keto-darolutamide has free fraction 
< 1% in most species.
Tissue distribution studies in rodents suggest that darolutamide and its metabolite 
keto-darolutamide have a very limited access to brain (brain/plasma ratio < 0.05). Prostate and 
heart have clearly higher tissue/plasma ratios of darolutamide. Kidney/plasma ratio of 
darolutamide is around 1 and liver/plasma ratio is around 3. The results from a whole body 
autoradiography study in rats confirm that the 14C-darolutamide related radioactivity 
concentrations in tissues except in the liver are lower than those in plasma.
In vivo mass balance study in rat suggests that about 2/3 of darolutamide related radioactivity 
is excreted to faeces and the rest to urine. Maximally 45% of darolutamide is excreted as 
unchanged. The similar excretion pattern after intravenous and per os route supports complete 
oral absorption at the studied low dose (11 mg/kg).
1.4
Safety pharmacology and toxicology
The repeat dose toxicity studies with darolutamide have been conducted up to 26 weeks in the 
rat and up to 13 weeks in the dog. Darolutamide has been well tolerated up to the highest dose 
levels 
in 
both 
species. 
The 
no 
observable 
adverse 
effect 
level 
(NOAEL) 


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was > 2 x 500 mg/kg/day in the rat and > 2 x 200 mg/kg/day in the dog. All the observed 
effects were directly related to the antiandrogenic mechanism of action of darolutamide and 
no off-target toxicity could be identified in either species. The effects were also shown to be 
reversible after discontinuation of administration of darolutamide. Increase of exposure to 
darolutamide was less than dose-proportional both in rats and dogs, and no accumulation was 
observed. The exposure multiples of darolutamide at the highest dose level in the rat and dog 
were approximately up to 3-fold and 1.8-fold, respectively, compared with AUC0-24 at 700 mg 
bid dose level in patients with metastatic CRPC (mCRPC) in the clinical phase I/II ARADES 
study (3104001). The corresponding exposure multiples of the metabolite ORM-15341 in the 
rat and dog were approximately up to 1.5-fold and 0.7-fold, respectively.
No stand-alone developmental and reproductive toxicity studies have been conducted with 
darolutamide. Based on the known pharmacologic effects of antiandrogens (Iswaran TJ et al., 
1997, Assessment Report for Zytiga (abiraterone), 2011, Schneider S et al., 2011, Assessment 
Report for Xtandi (enzalutamide), 2013), decreased fertility in males and developmental 
toxicity would be expected. Also it has to be taken into account that the patients in this 
clinical study use gonadotropin releasing hormone (GnRH) agonist or antagonist treatment or 
have bilateral orchiectomy, which also affects fertility.
Based on the results from the completed in vitro and in vivo genotoxicity studies, 
darolutamide is not considered to represent any significant genotoxic risk for man. Although 
both darolutamide and its metabolite keto-darolutamide absorb light in the UVB wavelength 
range of 290-320 nm with the absorption maximum at 290 nm, an in vitro 3T3 neutral red 
uptake phototoxicity study demonstrated that darolutamide is not phototoxic.
Cardiovascular safety evaluation of darolutamide, integrated into the 28-day and 13-week 
toxicity studies in dogs, did not reveal any significant cardiovascular effects up to the highest 
dose levels tested after oral dosing. The mean maximum concentrations (Cmax) of 
darolutamide in dog plasma at the highest dose levels in the 28-day and 13-week toxicity 
studies were 9990 and 6030-8350 ng/ml, respectively. 
In an anaesthetised dog model using bolus intravenous administration, darolutamide and its 
main human diastereomer (S,S)-darolutamide at observed mean Cmax of > 9300 ng/ml and 
> 4000 mg/ml in plasma, respectively, induced vasodilatation, especially at the peripheral 
level, leading to decreased arterial blood pressure (BP). In the study with(S,S)-darolutamide, 
1 dog out of 4 displayed a reversible complete atrioventricular (AV) block at the highest bolus 
dose. At this dose, the mean Cmax of (S,S)-darolutamide in dog plasma was 27200 ng/ml, 
indicating that (S,S)-darolutamide may affect AV conduction at very high systemic exposure 
level. The mechanism and aetiology of vasodilatation and AV block are not known, but they 
might be multifactorial and at least partly related to synergistic effect of the anaesthetic agents 
used and secondary pharmacodynamic effects of darolutamide and its main human 
diastereomer (S,S)-darolutamide. Based on in vitro human ether-a-go-go-related gene (hERG)
and calcium channel inhibition and in vivo dog studies, the risk for QT interval prolongation 
appears low.
Functional in vitro studies evaluating secondary pharmacodynamic effects showed that 
darolutamide inhibits 5-hydroxytryptamine (5-HT) uptake and GABAA (-aminobutyric acid) 
receptors. However, due to the low brain/plasma ratio, central nervous system (CNS) effects 
via 5-HT uptake and GABAA inhibition are not expected. In vivo safety pharmacology 


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evaluations confirmed that darolutamide has no remarkable effects on CNS or respiratory 
function. At high local doses/concentrations in the gastro-intestinal (GI) tract, darolutamide
may affect gastric emptying and intestinal transit.
1.5
Clinical studies with darolutamide
Over 160 patients have been treated to date with darolutamide in clinical phase I and II 
studies, with approximately 70 patients at the 600 mg bid dose level or higher (up to 900 mg
bid). 
In an open-label phase I dose escalation study with phase II expansion (ARADES, 3104001),
134 patients with mCRPC were treated with darolutamide. During the phase I dose escalation,
patients were treated with darolutamide doses of 100 to 900 mg bid whilst the phase II 
expanded doses were 100, 200 and 700 mg bid. A long-term safety extension study for this 
study is ongoing (3104002). By October 2013 approximately 70 patients had received 
darolutamide for more than 6 months and approximately 20 patients for more than 12 months
(Massard C et al., 2012, Fizazi K, 2013, Fizazi K et al., 2013).
In a bioavailability bridging study (ARAFOR, 3104003), 30 chemotherapy-naïve patients
with mCRPC have been treated with darolutamide at 600 mg bid.
Darolutamide was absorbed quite rapidly after oral administration with breakfast, with the 
median time to maximum concentration (tmax) for darolutamide ranging between 2 and 
5 hours after a single dose. The mean elimination half-life was approximately 10-30 hours at 
steady state; steady state concentration was reached in 1 week. The inter- and intra-subject 
variability in darolutamide plasma concentrations was low. The plasma concentrations and 
exposures (AUCt and Cmax) of darolutamide increased linearly at doses 100-700 mg bid. 
Plasma exposure after 900 mg bid was similar to that observed after 700 mg bid.
A food effect was observed when darolutamide was administered after a standardised 
breakfast. Food had an effect on absorption of darolutamide. AUC and Cmax values were about 
50% higher when darolutamide was taken in the fed state compared with the fasting state.
The antitumour activity of darolutamide was studied in the extension component of ARAFOR 
study (3104003) at week 12 by change in serum PSA, soft tissue and bone disease. 
PSA declines of 50% were observed in 83% of all the 30 patients; 30% of these patients had 
a PSA reduction ≥90%. Improved or stable bone disease was observed in 78% of evaluable 
patients. Complete, partial or stable response by Response Evaluation Criteria in Solid 
Tumours (RECIST) criteria was seen in soft tissue lesions in 91% of patients.
No statistically significant changes (p = 0.5) were observed in median serum testosterone 
level between baseline and week 12, suggesting negligible brain penetration of darolutamide
and lack of effect on the hypothalamic-pituitary-gonadal axis.
Darolutamide was well tolerated in this study. Similar to the ARADES study, most AEs were 
grade 1–2, all treatment-related AEs were grade 1, and no dose reductions were required for 
any patient (Massard C et al., 2015).
No dose-limiting toxicities were observed in the dose escalation part of the study 3104001. By 
30 Oct 2013 all deaths and all other serious adverse events (SAEs) have been assessed as not 


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related to darolutamide by the investigator and the sponsor and no apparent relationship 
between dose and incidence of adverse events (AEs) has been observed. The most common 
AEs have been fatigue/asthenia, back pain and arthralgia.
The antitumour activity of darolutamide was studied in the ARADES study (3104001) at 
week 12 by change in serum PSA, soft tissue and bone disease, as well as change in blood 
circulating tumour cells (CTCs). PSA declines of 50% were observed in 65% of 
chemotherapy-naïve cytochrome P450 (CYP) 17i-naïve patients and in 32% of post-
chemotherapy CYP17i-naïve patients. The highest PSA responses were seen at 700 mg bid in 
chemotherapy-naïve CYP17i-naïve patients (85% of patients). Improved or stable bone 
disease was observed in 84% of chemotherapy-naïve CYP17i-naïve evaluable patients and in 
65% of post-chemotherapy CYP17i-naïve evaluable patients. Complete, partial or stable 
response by Response Evaluation Criteria in Solid Tumours (RECIST) criteria was seen in 
soft tissue lesions in 84% of chemotherapy-naïve CYP17i-naïve and 60% of post-
chemotherapy CYP17i-naïve patients.
CTCs count was studied in the ARADES study (3104001). 53% of chemotherapy-naïve 
CYP17i-naïve and 60% of post-chemotherapy CYP17i-naïve evaluable patients converted 
from unfavourable pre-treatment counts (5 CTCs/7.5 ml of blood) to favourable counts 
(< 5 CTCs/7.5 ml of blood) during treatment. 90% of chemotherapy-naïve CYP17i-naïve and 
69% of post-chemotherapy CYP17i-naïve evaluable patients with favourable pre-treatment 
counts maintained favourable counts during treatment.
Further details can be found in the latest available version of the Investigator's Brochure (IB), 
which contains comprehensive information on the study drug (including human data from the 
completed study 3104001 and the ongoing studies with darolutamide).
1.6
Rationale of the clinical phase III study
1.6.1
Rationale of the study design
There is no standard treatment for CRPC patients who have rising PSA during ADT and no 
detectable metastases. In men with progressive nmCRPC, a short PSADT has been 
consistently associated with reduced time to first metastasis and death (Smith MR et al., 2005, 
Smith MR et al., 2011). This randomised, double-blind, phase III study aims to confirm that 
treatment with darolutamide significantly prolongs metastasis-free survival (MFS) over
placebo in nmCRPC patients having rising PSA and short PSADT. As the randomisation ratio 
is 2:1, the majority of patients will be allocated to active arm. 
The primary hypothesis of this study is that patients receiving darolutamide will demonstrate 
prolonged MFS compared with placebo. MFS is considered a clinically relevant endpoint in 
this patient population. Bone metastasis can result in serious complicated skeletal events and 
pain, and an increased risk of death. Often painful bone metastasis requires additional 
treatments such as radiation and chemotherapy. Prevention of progression in pelvic area
reduces risk for urinary tract obstruction and invasive procedures.
In this study, evidence of metastasis is defined by 1 or more new lesions in bone or new 
distant pathologic lymph nodes (M1a) or other pathological lesion (M1c) according to 


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RECIST 1.1. New or progressive regional (below the aortic bifurcation) pathologic lymph 
nodes (N1) will not be defined as metastasis. 
A nuclear medicine bone scan and CT/MRI will be performed every 16 weeks until first 
metastasis. 16 weeks interval between imaging sessions should provide appropriate follow-up 
for patients at high risk for developing metastasis while limiting the amount of radiation that 
patients are exposed to during imaging.
A nuclear medicine bone scan is more sensitive for detecting early bone metastases than 
anatomic imaging (CT, MRI or x-ray). However, bone scan is not specific for bone metastases 
and can result in false positive findings caused by non-malignant processes such as 
degenerative changes, infection and trauma. The aim of the study is to enable the detection of 
bone metastases as early as possible, and bone scan is the primary tool for this purpose. 
Before declaring new metastasis based on bone scan, findings must be confirmed to truly 
represent metastasis. Confirmation of findings on bone scan is presented in detail in 
Section 4.7.2.1.
Confirmation of absence or presence of metastasis will be based on blinded independent 
central reading during the double-blind treatment phase, also at baseline (screening). MFS, as 
defined in the study, is considered an objective and verifiable measurement.
The secondary variables of this study plan to support the clinical benefit of darolutamide. The 
risk of death from prostate cancer increases with metastasis. Considering the relatively early 
stage of the prostate cancer disease in the study population, it is likely that OS and other 
secondary endpoint data will not be mature at the time of the MFS analysis. For secondary 
efficacy variables the analysis done at the time of the MFS analysis is considered as interim 
analysis and the subsequent analysis is considered as final analysis for statistical significance. 
Further updates of secondary endpoint analyses without testing for statistical significance may 
be done. Because of the relatively early stage of the disease, it is expected that not all the 
observed benefits of darolutamide in prolongation of MFS will be carried over to the 
secondary endpoints.
The time to first symptomatic skeletal event (SSE) will be assessed, as it is considered a
clinically relevant endpoint in patients with prostate cancer. Time to initiation of cytotoxic 
chemotherapy, and time to pain progression (assessed as first use of opioids for pain or time 
to pain progression) will also be collected. Delaying cytotoxic chemotherapy and opioid use is 
considered a major treatment benefit for patients. Time to pain progression will be assessed 
by the Brief Pain Inventory - Short Form (BPI-SF), which is a validated tool.


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Quality of life (QoL) will be measured using the Functional Assessment of Cancer Therapy-
Prostate (FACT-P) and Prostate-Cancer Specific (PCS) subscale of FACT-P questionnaire
and the European Quality of Life 5-Domain Scale version with 3 response levels (EQ-5D-3L). 
FACT-P was selected to be used in the study, because it is validated and clinically meaningful 
changes have been determined (Pickard AS et al., 2007, Cella D et al., 2009). In addition, 
QoL and prostate cancer specific symptoms will also be measured using the European 
Organization for Research and Treatment of Cancer Quality of life Questionnaire - Prostate 
Cancer Module (EORTC-QLQ-PR25), but only until the end-of-study treatment visit, because 
the questionnaire was developed and validated in a predominately non-metastatic prostate 
cancer patient population (van Andel G et al., 2008).
1.6.2
Rationale for selection of dose 
A dose of 600 mg bid was selected for this study. Plateau in darolutamide plasma exposure 
was seen from 700 mg bid dose in the ARADES study (3104001) and darolutamide plasma 
exposure after 600 mg in the ARAFOR study (3104003) was similar to what was observed 
after 700 mg bid in the ARADES study. Significant PSA declines were seen at 700 mg and 
600 mg bid dose levels in chemotherapy-naïve patients. In this population, PSA declines were 
greater at higher dose levels compared to the lower dose levels of 100 and 200 mg bid. No 
differences in safety and tolerability between the higher and lower doses were observed. The 
dose of 600 mg bid is expected to have optimal benefit-risk profile.
1.6.3
Benefit-risk assessment
The available nonclinical data suggest that treatment with darolutamide at doses up to 900 mg 
bid does not carry significant risk. The available clinical data suggest that darolutamide use is 
well tolerated and safe for patients with CRPC. Darolutamide has been shown to significantly 
decrease serum PSA at least in the same level as marketed drugs with similar mechanism of 
action (e.g. enzalutamide). Treatment with darolutamide has antitumour effects on bone and 
soft tissue lesions, thus providing a clinical benefit to the patients. Overall, it is considered 
that a benefit from darolutamide treatment is significantly greater than the risk imposed by the 
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2.
STUDY OBJECTIVES
2.1
Primary objective
The primary objective of this study is to demonstrate the superiority of darolutamide vs.
placebo in MFS in patients with high-risk nmCRPC.
2.2
Secondary objectives
The secondary objectives of this study are to demonstrate the benefit of darolutamide for:

OS, 

time to first SSE,

time to initiation of first cytotoxic chemotherapy for prostate cancer and

time to pain progression,
and to characterise the safety and tolerability of darolutamide.
2.3
Additional objectives
The additional objectives of this study are to determine benefit of darolutamide for 

progression-free survival (PFS),

time to first prostate cancer-related invasive procedure,

time to initiation of first subsequent antineoplastic therapy,
and to determine effect of darolutamide on 

PSA progression and PSA response,

ECOG performance status deterioration and

health-related QoL
and to evaluate PK of darolutamide and keto-darolutamide, and to explore possible 
relationships between exposure and safety and efficacy response.


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3.
OVERALL STUDY DESIGN AND PLAN
This is a randomised, phase III, multicentre, double-blind, placebo-controlled efficacy and 
safety study of oral darolutamide (600 mg bid) in patients with nmCRPC who are at high risk 
for developing metastatic disease. 
Approximately 1500 patients will be randomised to receive darolutamide or placebo in a 2:1 
ratio in a double-blind manner. Randomisation will be stratified by PSADT (6 months vs. 
> 6 months) and use of osteoclast-targeted therapy (yes vs. no).
Randomised patients will receive study treatment until confirmed metastasis or intolerable 
AE.
The study has a design of 2 parallel groups. For each patient, the study may involve 1 to 2
variable length periods: a study treatment period (a double-blind part for darolutamide or 
placebo arms and an open-label darolutamide treatment phase) and a follow-up period.
The length of the periods for each patient will depend on the absence or presence of 
metastasis – after confirmed metastasis, the patient must be withdrawn from study treatment.
During the double-blind part, patients may be on study treatment (darolutamide or placebo 
arm) or at follow-up. After the double-blind part, patients who are on study treatment may 
continue open-label darolutamide treatment under the conditions outlined in Section 5.9.
Assessments will depend on the period the patient is in (see Table 3 and Table 4 for more 
details) and as described below.
The double-blind treatment (darolutamide or placebo arm) is planned to be continued until the 
total number of events for the MFS analysis have been reached (planned at approximately
385 events). During this part the treatment code will remain blinded. 
Patients in the darolutamide arm at the time of unblinding may continue open-label
darolutamide treatment according to Section 5.9 and will visit the study centre as outlined in
Table 3 until the end of the study.
Patients in the placebo arm at the time of unblinding may cross over to open-label 
darolutamide treatment according to Section 5.9, or will receive subsequent treatment at the 
discretion of the investigator, and will visit the study centre as outlined in Table 4 until the 
end of the study.
After confirmed metastasis in the double-blind treatment phase or after metastasis is identified
by local reading in the open-label treatment phase, the patient will be withdrawn from study 
treatment and will be followed as outlined in Table 4 until the end of the study.
Patients withdrawing from study treatment before metastasis during the double-blind or open-
label darolutamide treatment phase (e.g., toxicity, clinical progression, judgment of the 
investigator) but not initiating any subsequent prohibited antineoplastic therapy will be 
followed as outlined in Table 4 until the end of the study.


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Patients initiating any prohibited treatment (see Section 5.7.2) before metastasis must 
discontinue the study treatment. These patients will be followed only for survival status until 
the end of the study.
Patients who discontinue darolutamide during the open-label darolutamide treatment phase 
without metastases and who withdraw consent to study procedures but agree to follow-up for 
survival will be followed via phone for survival status until the end of the study.
Throughout the study, an independent Data and Safety Monitoring Board (DSMB) will 
periodically review the benefit-risk profile of darolutamide.
4.
SELECTION OF STUDY POPULATION
4.1
Number of patients
Approximately 1500 patients are planned to be randomised in a 2:1 ratio to receive 
darolutamide or placebo at approximately 480 global centres. 
Patients who discontinue the study will not be replaced. Statistical calculations for the 
selected number of patients are presented in Section 7.1.
4.2
Inclusion criteria
To be included in the study, patients must meet all of the following criteria:
1. Written informed consent (IC) obtained.
2. Males aged 18 years.
3. Histologically or cytologically confirmed adenocarcinoma of prostate
without 
neuroendocrine differentiation or small cell features.
4. CRPC defined as 3 rising PSA levels after the nadir taken at least 1 week apart during 
ADT. If the patient has a history of antiandrogen use, the most recent PSA value must be 
obtained at least 4 weeks after antiandrogen withdrawal. See Section 0 for further details.
5. Castrate level of serum testosterone (< 1.7 nmol/l [50 ng/dl]) on GnRH agonist or 
antagonist therapy or after bilateral orchiectomy. Patients who have not undergone 
bilateral orchiectomy must continue GnRH therapy during the study.
6. PSADT of 10 months and PSA ≥2 ng/ml at screening. See Section 0 for further details.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
8. Blood counts at screening: haemoglobin ≥ 9.0 g/dl, absolute neutrophil count ≥ 1500/µl 
(1.5x109/l), platelet count ≥ 100,000/µl (100x109/l ) (patient must not have received any 
growth factor or blood transfusion within 7 days of the haematology laboratory obtained 
at screening).


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9. Screening values of serum alanine aminotransferase (ALT) and aspartate transaminase 
(AST) 2.5 x upper limit of normal (ULN), total bilirubin 1.5 x ULN (except patients 
with a diagnosis of Gilbert’s disease), creatinine 2.0 x ULN.
10. Sexually active patients, unless surgically sterile, must agree to use condoms as an 
effective barrier method and refrain from sperm donation during the study treatment and 
for 3 months after the end of the study treatment.
4.3
Exclusion criteria
Patients will not be entered into this study if they meet any of the following criteria:
1. History of metastatic disease at any time or presence of detectable metastases by blinded 
central reading within 42 days prior to start of study treatment. Presence of pelvic lymph 
nodes < 2 cm in short axis below the aortic bifurcation is allowed. See Section 0 for 
further details.
2. Symptomatic local-regional disease that requires medical intervention including 
moderate/severe urinary obstruction or hydronephrosis due to prostate cancer. 
3. Acute toxicities of prior treatments and procedures not resolved to grade 1 or baseline 
before randomisation.
4. Prior treatment with:

second generation AR inhibitors such as enzalutamide, ARN-509, darolutamide,
other investigational AR inhibitors,

CYP17 enzyme inhibitor such as abiraterone acetate, TAK-700 or

oral ketoconazole longer than for 28 days.
5. Use of estrogens or 5-α reductase inhibitors (finasteride, dutasteride) within 28 days 
before randomisation and AR inhibitors (bicalutamide, flutamide, nilutamide, cyproterone 
acetate) at least 28 days before screening.
6. Prior chemotherapy or immunotherapy for prostate cancer, except adjuvant/neoadjuvant 
treatment completed > 2 years before randomisation. 
7. Use of systemic corticosteroid with dose greater than the equivalent 10 mg of 
prednisone/day within 28 days before randomisation. 
8. Radiation therapy (external beam radiation therapy
[EBRT], brachytherapy, or 
radiopharmaceuticals) within 12 weeks before randomisation. 
9. Severe or uncontrolled concurrent disease, infection or co-morbidity that, in the opinion of 
the investigator, would make the patient inappropriate for enrolment.
10. Treatment with an osteoclast-targeted therapy (bisphosphonate or denosumab) to prevent 
skeletal-related events within 12 weeks before randomisation. Patients receiving 


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osteoclast-targeted therapy to prevent bone loss at a dose and schedule indicated for 
osteoporosis may continue treatment at the same dose and schedule.
11. Known hypersensitivity to the study treatment or any of its ingredients.
12. Major surgery within 28 days before randomisation.
13. Any of the following within 6 months before randomisation: stroke, myocardial infarction, 
severe/unstable angina pectoris, coronary/peripheral artery bypass graft; congestive heart 
failure New York Heart Association (NYHA) Class III or IV.
14. Uncontrolled hypertension as indicated by a systolic BP 160 mmHg or diastolic 
BP 100 mmHg at screening.
15. Prior malignancy. Adequately treated basal cell or squamous cell carcinoma of skin or 
superficial bladder cancer that has not spread behind the connective tissue layer (i.e. pTis, 
pTa, and pT1) is allowed, as well as any other cancer for which treatment has been 
completed 5 years ago and from which the patient has been disease-free.
16. Gastrointestinal disorder or procedure which expects to interfere significantly with 
absorption of study treatment.
17. Active viral hepatitis, active human immunodeficiency virus (HIV) or chronic liver 
disease.
18. Treatment with any investigational drug within 28 days before randomisation.
19. Any condition that in the opinion of the investigator would impair the patients’ ability to 
comply with the study procedures.
20. Unable to swallow study medications and comply with study requirements.
4.4
Screening log and subject identification list
The investigator will keep appropriate source records to detail patients.
Patient’s full identity including name and address is captured in a log named e.g. subject 
identification list, which is filed in an Investigator’s study file and never shared outside. The 
screening log captures patient’s subject number, year of birth, screening date, randomisation 
date and reason for screen failure where applicable. Patient’s initials and full date of birth will
not be captured on the screening log.
No identifying information will be collected on the pre-screening log on patients who were 
considered for the study but did not consent.
4.5
Recruitment procedures
Detailed recruitment procedures will be presented in a separate document.
From the local study centre’s patient population, the investigator will identify and approach 


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potential candidates for screening and possible enrolment. In addition to this, patients will be 
invited to participate in the study during routine follow-up visits or telephone contacts by 
physicians. In countries where advertisements are permitted, patients will be invited via such
advertisements in local newspapers, patient newsletters (or related publications) or 
appropriate websites. Only text as accepted by independent ethics committees (IECs) or 
independent review boards (IRBs) will be used in any advertisement media.
Patients who are not eligible for the study will be informed and the reason for their exclusion 
will be explained, including information on which eligibility criterion led to their exclusion
from the study.
If patients discontinue their participation in the study, they are not allowed to re-enter the 
study. 
4.6
Information to be collected on screening failures
The minimum information to be collected on patients who have been screened but not 
randomised will include completion of the following case report form (CRF) fields: IC, 
demography (date of birth and sex), the inclusion/exclusion criteria causing the exclusion,
decision of entry, AEs related to study procedures and all SAEs (including all information 
related to these events, such as concomitant treatments, medical history and other relevant 
information).
4.7
Discontinuation of study and withdrawal from study treatment 
4.7.1
Reasons for discontinuation of study
Patients are free to discontinue the study at any time for any reason. Investigators should try 
to find out the reason and document it on the corresponding CRF (study 
completion/discontinuation). Additionally, the investigator may withdraw a patient at any
time if he/she considers this to be medically necessary and in the patient’s best interest.
In case the patient will initiate any prohibited treatment (see Section 5.7.2) before confirmed 
metastasis during the double-blind treatment, the patient must discontinue the study treatment 
and they will be followed for survival until the end of the study.
In case the patient will initiate any prohibited treatment (see Section 5.7.2) during the 
open-label treatment phase before metastasis confirmed by local reading, the patient must 
discontinue the study treatment and they will be followed for survival until the end of the 
study.
Patients will be invited to the end-of-study treatment visit 28 days after the last dose of study 
treatment. Another systemic antineoplastic therapy may be initiated no sooner than 7 days 
after the last dose of study treatment.
4.7.2
Reasons for withdrawal from study treatment 
Patients must be withdrawn from study treatment for the following reasons:


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
Confirmed metastasis (in the double-blind treatment phase) (see Section 4.7.2.1)

Metastasis identified by local reading (in the open-label treatment phase) (see
Section 4.7.2.1)

Intolerable AE (see Section 4.7.2.2)
The study monitor and medical monitor should be notified about study treatment withdrawals 
by email/phone/fax within 24 hours in the event of discontinuation due to an SAE or within 
7 days in the event of discontinuation due to another reason.
Patients will be invited to the end-of-study treatment visit 28 days after the last dose of study 
treatment. 
Patients withdrawing from study treatment before metastasis during the double-blind or 
open-label darolutamide treatment phase (e.g., toxicity, clinical progression, judgment of the 
investigator) with or without receiving subsequent prohibited antineoplastic therapy will be 
followed as outlined in Table 4 until the end of the study.
Patients who discontinue darolutamide during the open-label darolutamide treatment phase 
without metastases and who withdraw consent to study procedures but agree to follow-up for 
survival will be followed via phone for survival status until the end of the study.
Patients, after confirmed metastasis or receiving subsequent treatment after unblinding, will 
be followed as outlined in Table 4 until the end of the study.
After the end-of-study treatment visit, the patients will be followed every 16 weeks by visit or 
telephone contact until the end of study as outlined in Table 4 and Sections 6.1.2.6 and 6.1.3.
4.7.2.1
Confirmed metastasis
Patient must be withdrawn from the study treatment after confirmed metastasis. Evidence of 
metastasis and the subsequent actions are presented in Table 1. Central confirmation of 
metastasis is not required for metastasis determined by local reading that occurs during the 
open-label darolutamide treatment phase.


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Table 1.
Actions upon confirmation of metastasis
Double-blind treatment phase
Appearance of metastasis
Confirmation of metastasis
Action
Bone lesion
Appearance of 1 or more lesions
on bone scan by central reading.
New lesion(s) on bone scan must 
be confirmed by central reading. 
Confirmation requires CT/MRI 
scan or x-ray of the area in question 
performed up to 2 weeks prior to 
bone scan or later.
Study treatment should continue 
until radiographic metastasis is
confirmed by central reading.
After confirmed metastasis, the
patient must be withdrawn from 
study treatment.
Non-osseous lesion
New distant pathologic lymph 
nodes (M1a) or other pathological
lesion (M1c) according to 
RECIST 1.1.
New or progressive regional
pathologic lymph nodes (N1) will 
not be defined as metastasis.
New lesion(s) on CT/MRI scan
must be confirmed by central 
reading.
Study treatment should continue 
until radiographic metastasis is 
confirmed by central reading.
After confirmed metastasis, the 
patient must be withdrawn from 
study treatment.
Patients with new or progressive 
regional pathologic lymph nodes 
will continue study treatment.
Open-label treatment phase
Appearance of metastasis
Confirmation of metastasis
Action
Bone lesion
Appearance of 1 or more lesions 
on bone scan by local reading.
New lesion(s) on bone scan must 
be confirmed, by CT/MRI scan or 
x-ray of the area in question 
performed up to 2 weeks prior to 
bone scan or later.
After confirmed metastasis, the 
patient must be withdrawn from 
study treatment.
Non-osseous lesion
New distant pathologic lymph 
nodes (M1a) or other pathological 
lesion (M1c) according to 
RECIST 1.1.
New or progressive regional 
pathologic lymph nodes (N1) will 
not be defined as metastasis. 
New lesion(s) on CT/MRI scan
must be confirmed by local
reading.
Study treatment should continue 
until radiographic metastasis is 
confirmed by local reading.
After confirmed metastasis, the 
patient must be withdrawn from 
study treatment.
Patients with new or progressive 
regional pathologic lymph nodes 
will continue study treatment.
Study treatment will continue in the absence of metastasis independent of PSA values or new 
or progressive regional pathologic lymph nodes. Although serial PSA measurements will be 


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performed in the study, progression (see Section 6.3.3.4) or change in PSA values should not 
be used as an indication for withdrawal of patient from study treatment.
Instructions on image acquisition and submission of scans for central reading will be provided 
in the imaging manual.
4.7.2.2
Intolerable adverse event
4.7.2.2.1
Dose modifications and delays
Doses of study treatment may be delayed or reduced in case of clinically significant toxicities 
that are related to study treatment. Toxicities will be graded using the NCI-CTCAE v 4.03. 
All dose modifications regardless of relatedness should be recorded on the CRF. If a patient 
experiences several study treatment related toxicities with different grading, the 
recommendation of the worst grading should be used.
4.7.2.2.1.1
Dose interruption
The maximum time for a dose interruption period is 28 consecutive days. Any patient 
requiring treatment interruption > 28 consecutive days must be withdrawn from study 
treatment. 
4.7.2.2.1.2
Dose reduction
If considered necessary for patient’s safety, the dose of study treatment may be reduced to 
300 mg bid. Any dose reduction must be notified to the medical monitor.
Dosing of the study treatment below 300 mg bid is not allowed. If a grade 3 or higher 
treatment-related AE occurs while the patient is on 300 mg bid, the patient must be withdrawn 
from study treatment.
4.7.2.2.1.3
General recommendations for dose modifications
A patient who experiences a treatment-related grade 3 or 4 AE should interrupt study 
treatment until AE improves to grade 2 or less. Treatment is then to be restarted at 300 mg 
bid. Additional details are provided in Table 2.


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Table 2.
Dose modification and/or delay for toxicities considered related to study treatment 
Severity grade 
(NCI-CTCAE v 
4.03)
Dose modifications
Study treatment withdrawal
Grade 0-2
Treat on time.
Per investigator’s decision to interrupt 
or reduce study treatment a, b
-
Grade 3 or 4
Delay until grade 2 a
When the severity is grade 2, restart 
at a reduced dose of 300 mg bid. b, c
If the dosing of the study treatment is 
temporally or permanently reduced to 
300 mg bid and a grade 3 or higher 
treatment-related AE occurs while the 
patient is on a dose of 300 mg bid, the 
patient must be withdrawn from study
treatment.
Excludes clinically nonsignificant and asymptomatic laboratory abnormalities 
Abbreviations: NCI-CTCAE v 4.03 = National Cancer Institute-Common Terminology Criteria for Adverse Events 
version 4.03.
a If there is no recovery after 28 consecutive days, treatment should be permanently discontinued. 
b When AE returns to baseline or is resolved, dose escalation to 600 mg bid may be considered at the discretion of the 
investigator.
c If dose is escalated to 600 mg and a second treatment-related AE with a severity of grade 3 or higher occurs, a permanent 
dose reduction is required. A third occurrence of a grade 3 or higher treatment-related AE requires permanent 
discontinuation of study treatment.
5.
STUDY TREATMENTS
Manufacturing, packaging and labelling of the study treatments will comply with good 
manufacturing practice (GMP) regulations (Annex 13 of the European Union [EU] guide to 
GMP).
All inactive ingredients comply with the current monographs relevant for the territory where 
the drug products are distributed, i.e. the European Pharmacopoeia, the US Pharmacopoeia
and the Japanese Pharmacopoeia.
The study treatments should be stored at room temperature. The detailed instructions are 
given in the label of the study treatment containers.
The study centre personnel will be provided with detailed instructions for the handling, 
storage and return of used and unused study treatment containers.
5.1
Investigational product
The active ingredient BAY 1841788 (darolutamide) will be provided as 300 mg film-coated 
tablets for oral administration. The tablets are blue oval-shaped tablets embossed with a code 
‘OR-300’. Each tablet contains approximately 180 mg lactose.


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5.2
Reference product
Placebo BAY 1841788 (darolutamide) film-coated tablets will be provided as a reference 
product. The tablets are blue oval-shaped tablets embossed with a code ‘OR-300’. Each tablet 
contains approximately 180 mg lactose. The placebo tablets will be indistinguishable from the 
darolutamide tablets.
5.3
Selection and timing of doses
Patients will be instructed to take 2 tablets of study treatment orally bid at about 12-h intervals 
as close to the same time each day as possible. If dosing is delayed, dosing can be taken up to 
6 hours to make up for the missed one.
The tablets should be taken with food and a glass (about 250 ml) of water, milk or juice. The 
tablets should be swallowed whole.
Patients will take the blinded study treatment (darolutamide or placebo) until confirmation of 
metastasis.
After unblinding of the study treatment codes and under the conditions outlined in 
Section 5.9, patients in the darolutamide arm who are on treatment when the target number of 
events for the MFS analysis has been reached may continue open-label darolutamide 
treatment until occurrence of metastasis.
Patients in the placebo arm who are on treatment when the target number of MFS has been 
reached may cross over to open-label darolutamide treatment under the conditions outlined in 
Section 5.9, or will receive subsequent treatment according to standard of care at the 
discretion of the investigator.
Patients will be instructed to take their morning dose of study treatment on study visit days at 
home. 
Patients participating in the pharmacokinetic (PK) procedures will be instructed to take their 
morning dose of study treatment at the visit days for trough and early PK sampling windows 
at the study centre after the trough (i.e. pre-dose) blood samples have been drawn. For the late 
PK sampling windows, patients will be instructed to take their morning dose of study 
treatment at home and to arrive at the study centre in time for blood sampling between 4 and 
8 hours after the dose (See Section 6.2).
Dose interruption and reduction due to related AEs are described in Section 4.7.2.2. For 
reduced dose, patients will be instructed to take 1 tablet of study treatment orally bid at about 
12-h intervals as close to the same time every day as possible. If dosing is delayed, it can be 
taken up to 6 hours from the planned dosing time to make up for the missed one.


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5.4
Method of assigning patients to treatment groups
5.4.1
Randomisation method
Randomisation, i.e. random allocation of treatments to subject numbers, will be performed 
centrally blocking by centre according to the design of the study using a 2-step procedure. 
Firstly, a separate master randomisation schedule and study treatment package list will be 
created using randomly permuted blocks.
Secondly, randomly permuted blocks from the master randomisation schedule are assigned to 
the centres and study subjects using an interactive response technology (IRT) to receive either 
darolutamide or matching placebo using allocation ratio 2:1, respectively. The package 
numbers are assigned to the unique subject number previously allocated by the investigator. 
The randomisation will be stratified by the following:

PSADT is (6 months vs. > 6 months)

Osteoclast-targeted therapy at randomisation (yes vs. no).
Details of the randomisation method will be given in the user requirements of IRT vendor and 
detailed description of the randomly permuted blocks will be stored by the sponsor.
5.4.2
Implementation of randomisation
When the signed IC has been received, the investigator has confirmed that the patient fulfils 
all the inclusion and none of the exclusion criteria, and the medical monitor has reviewed and 
approved the eligibility form, the patient will be allocated the next available randomisation
number at that study centre.
Thereafter, the investigator or study nurse will obtain the study treatment package numbers 
via IRT to be allocated to the patient. The following information will be given: subject 
number, patient’s date of birth, PSADT and use of osteoclast-targeted therapy. On receipt of 
the requested information, the IRT will provide the study treatment package numbers 
allocated to the patient. The point at which randomisation is considered to have occurred is 
when the study treatment package numbers have been allocated to the patient. In case the start 
of study treatment is not logistically feasible on the same day as randomisation, randomisation 
can be performed 1 day before the initiation of study treatment.
The treatment codes will be stored in the randomisation system of the sponsor and the IRT 
vendor. The codes will be listed by an independent randomisation expert and the list delivered 
to the sponsor.
5.5
Blinding
The reference for this study will be placebo tablets that match the darolutamide tablets.
All patients, study personnel and sponsor’s personnel directly involved in the conduct of the 
study will remain blinded to treatment assignments during the double-blind part of the study.
Also, patient’s treatment assignment will remain blinded at the time of metastasis during the 
double-blind part.


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After completing the double-blind part, the study will be unblinded for the primary analyses. 
The study will have an independent DSMB that will safeguard patients randomised to the 
study. As part of the process DSMB may perform unblinded analyses on the data.
5.6
Emergency procedures
The investigator is responsible for ensuring adequate medical expertise and facilities to handle 
possible emergency situations during the study.
5.6.1
Breaking of treatment code
The treatment code may only be broken in the case of an emergency requiring immediate 
knowledge of the study treatment. A request of unblinding should be discussed with the 
medical monitor. For urgent safety reasons, the investigator can unblind the patient’s study 
treatment assignment and inform the medical monitor as soon as possible. Unblinding is 
performed via the IRT system and the procedure is described in detail in a separate instruction 
manual.
5.6.2
Treatment of emergencies
Emergencies may be treated according to the decision of the physician in charge or the 
investigator when available.
5.7
Prior, concomitant and follow-up treatments
5.7.1
Prior and concomitant treatments
History of all prostate cancer treatments, including radiotherapy, before the time of IC must 
be recorded on the CRFs. 
All concomitant treatments from the time of IC until the end-of-study treatment visit must be 
recorded on the CRFs. 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). Once the 
patient has been withdrawn from study treatment, follow-up treatments will be recorded if 
used to treat new related or unresolved related AEs or if it is a systemic antineoplastic 
therapy.
Patients who have not undergone bilateral orchiectomy must continue GnRH agonist or 
antagonist therapy during the study.
The patient must not have been administered another investigational drug within 28 days 
before randomisation.
5.7.2
Prohibited treatments 
Initiation of the following medications before the first metastasis, either during or after the 
study treatment period is prohibited: 


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
Any investigational medicinal product

Radiopharmaceuticals

Immunotherapy (e.g. sipuleucel-T)

Cytotoxic chemotherapy and any other systemic antineoplastic therapy 

Enzalutamide, ARN-509, bicalutamide, flutamide, nilutamide

Cyproterone acetate, estrogen

5 α-reductase inhibitor

Abiraterone acetate, TAK-700 or other CYP17 inhibitors

Systemic ketoconazole (as antineoplastic therapy) 

Osteoclast-targeted therapy such as bisphosphonate or denosumab. Patients 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.

Continuous use of systemic corticosteroid with dose greater than the equivalent 10 mg 
of prednisone/prednisolone per day. Short-term use of systemic corticosteroids with 
higher doses up to 28 days during the study treatment period is allowed, but treatment 
should be kept as short as possible.
Another systemic antineoplastic therapy may be initiated no sooner than 7 days after the last 
dose of study treatment.
5.7.3
Drug-drug interactions
In vitro data hint that darolutamide is a substrate of P-gp and BCRP. Therefore administration 
of strong inhibitors of P-gp (e.g. verapamil, dronedarone) and BCRP (e.g. pantoprazole, 
eltrombopaq) may increase the plasma concentrations of darolutamide and should be used 
with caution.
Plasma concentration of drugs that are sensitive P-gp or BCRP substrates might be increased 
by darolutamide. Medicinal products that are sensitive substrates for P-gp (e.g. digoxin) 
should be used with caution when co-administered with darolutamide.


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Based on data from a drug-drug interaction study (Study 17723), administration of 600 mg 
darolutamide bid over 4 days prior to administration of a single dose of 5 mg rosuvastatin, 
a BCRP substrate, together with food resulted in a 5.2–fold increase in mean exposure 
AUC0-24 of rosuvastatin and a 4.9–fold increase in Cmax. This indicates that co–administration 
of darolutamide can also increase the plasma concentrations of other concomitant BCRP 
substrates (e.g. methotrexate, sulfasalazine, fluvastatin, atorvastatin). Therefore, the patients 
should be closely monitored for signs and symptoms of increased exposure to BCRP 
substrates. 
Dose modification of BCRP substrates should be considered based on the prescriber 
information or such compounds should be avoided.
Based on in vitro CYP induction data in human hepatocytes, darolutamide may decrease the 
plasma concentrations of concomitantly given drugs which are mainly metabolized via 
CYP3A4 enzyme (e.g. simvastatin, verapamil, dronedarone). The clinical significance of 
these potential interactions is not known. Patients receiving such drugs should be monitored 
for signs of decreased efficacy.
In a drug-drug interaction study (Study 17726), the effect of a strong CYP3A4 inducer 
(rifampicin) on darolutamide was evaluated. Rifampicin (600 mg) was given once daily for 
10 days and on Day 8, a single dose of 600 mg (2 tablets of 300 mg) darolutamide together 
with food. An approximately 3-fold decrease of mean exposure (AUC0-72) of darolutamide to 
28% and an approximately 2-fold decrease of mean Cmax to 48% were observed. This 
indicates that repeated co-administration of strong CYP3A4 inducers (see listing of drugs in 
Appendix 8) with darolutamide is expected to reduce darolutamide plasma concentrations. 
Therefore, concomitant intake of strong CYP3A4 inducers should be avoided. It is strongly 
recommended to use alternative treatments. Concomitant short term use is allowed.
Administration of 200 mg itraconazole, a strong CYP3A4 and P-gp inhibitor, twice daily on 
Day 1 and once daily on the following days for 7 days and administration of a single dose of 
600 mg (2 tablets of 300 mg) darolutamide together with food on Day 5 resulted in a 1.7-fold 
increase in mean exposure (AUC0-72) of darolutamide and a 1.4-fold increase of Cmax. This 
indicates that co-administration of darolutamide with a strong CYP3A4 or P-gp inhibitor does 
not result in a clinically relevant increase of darolutamide plasma concentrations. 
Oral ketoconazole as a prior (longer than for 28 days) or concomitant treatment is excluded in 
the study because of its effect on steroidogenesis and not because of pharmacokinetic drug-
drug interaction.
5.8
Treatment compliance and exposure
Any deviation from the treatment regimen defined in the protocol must be documented on the 
corresponding CRF. The patient should be asked about the reason for obvious non-
compliance.


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Drug accountability records will be kept. The investigator must maintain accurate records 
demonstrating the date and amount of drug received, to whom and by whom dispensed (drug 
dispensing list) and accounts of drugs accidentally or deliberately destroyed. All remaining
study drugs and study drug containers will be returned to the study centre at the start of open-
label treatment visit and at the end-of-study treatment visit. Study drug tablets not returned 
will be considered to have been taken unless otherwise specified. At the end of the study, any 
remaining drugs will be collected and returned to the sponsor. Any discrepancies between the 
returned and expected returned study drugs should be explained.
5.9
Availability of investigational product after termination of study
There is no option to continue study treatment once the patient has completed the study. 
Subsequent treatments of the patient will be at the discretion of the investigator. In case of 
premature site closure or termination of the study, the sponsor will comply with regulatory 
requirements in a given country.
Once the study results are available, and if they support a positive benefit/risk assessment for 
darolutamide in the study by judgment of the Sponsor (considering feedback from the study 
steering committee and/or health authorities), those patients who are on study treatment 
(darolutamide or placebo) will be offered the opportunity to receive darolutamide through 
open-label treatment in this study.
6.
VISIT SCHEDULE, METHODS OF ASSESSMENT AND VARIABLES
6.1
Visit schedule
The schedule of procedures is provided for the double-blind study treatment period and for 
the patients in the darolutamide arm continuing open-label darolutamide treatment in Table 3.
For the follow-up period and for the patients in the placebo arm crossing over to open-label 
darolutamide treatment, see Table 4.
The schedule of procedures at centres participating in PK sample collection is provided in
Figure 1.


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Table 3.
Study event schedule during the double-blind study treatment period, and for 
darolutamide patients continuing on open-label darolutamide treatment
Protocol activities
Screening 
period
Double-blind study treatment period 
(darolutamide or placebo)
For darolutamide patients 
continuing on open-label 
treatment
Visit 1
Visit 2
Visit 3
Visit 4 and 
subsequent 
visits
Start of 
open-label 
treatment 
visit *
EOS
treatment visit
or in 
transition to 
roll-over 
study **
Within 
28 days 
before
randomisation
Day 11
Day 
15
(±3 
days)
Day 
29
(±5 
days)
Week 16
(±7 days) 
and every 
subsequent 
16 weeks 
and 
subsequent 
visits every
16 weeks 
(±7 days)
EOS
treatment
visit: 28 days 
(+7 days) 
after last dose
IC
x
Demography
x
Medical history
x
Prostate cancer history, incl. 
treatments and procedures
x
Eligibility criteria and randomisation
x
BPI-SF
x
x
x
x
EORTC-QLQ-PR25 
x
x
x
x
x
FACT-P or 
PCS of FACT-P
x
(FACT-P)
x 
(FACT-P)
x2
x2
x 
(FACT-P)
EQ-5D-3L
x
x
x3
x3
x3
Physical examination, weight 
x4
x
x
x
x
x
12-lead ECG and vital signs
x5
x5
x5
x5
x5
x17
Laboratory safety assessments
x
x
x
x
x
x
x
Serum PSA14
x
x
x
x
x
Testosterone
x
x
x
PK samples at participating centres6
x5, 6
x5, 6
x5, 6
PK diary dispensing6
x
x
x
PK diary collection
x
x
x 
ECOG performance status
x
x
x
x
Pain diary dispensing
x
x
x
x
x
Pain diary collection7
x
x
x
x
Chest, abdomen and pelvic CT/MRI
x8
x8
x8
Bone scan9
x8
x8
x8
First SSE
x
x
x
x
x
First prostate cancer-related invasive 
procedure 
x
x
x
x
x
Survival status18
x
x
x
x
x
Adverse events10
x
x
x
x
x
x
x
Concomitant treatments11
x
x
x
x
x
x
x
Study drug dispensing and 
accountability
x
x
x
x
x15
PG IC 
x12
PG sample
x16
Tumour-related biomarker blood 
sample13
x
x13
x


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Abbreviations: IC = informed consent; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOS = 
end-of-study; OS = overall survival; PG = pharmacogenomics; HR = heart rate; PK = pharmacokinetic; PSA = prostate-
specific antigen; SSE = symptomatic skeletal event
*
Under the conditions outlined in Section 5.9, patients who choose to receive open-label darolutamide will have a start of 
open-label treatment visit at the time of study treatment code unblinding.
Patients in the darolutamide arm continuing open-label darolutamide treatment will have subsequent visits every 
16 weeks according to Table 3 until metastasis is seen by local reading.
Patients in the placebo arm crossing over to open-label darolutamide treatment will have subsequent visits every 
16 weeks according to Table 4 until metastasis is seen by local reading.
Those patients who do not choose to continue with open-label darolutamide treatment, will have an end-of-study 
treatment visit at the time of unblinding.
** Procedures for the end-of-study treatment visit or in transition to a roll-over study are for patients in the darolutamide arm 
continuing on open-label darolutamide treatment. Procedures for the end-of-study treatment visit or in transition to a 
roll-over study for placebo patients crossing over to open-label darolutamide treatment are described in Table 4.
1
In case the start of study treatment is not logistically feasible on the same day as randomisation, randomisation can be 
performed 1 day before the initiation of study treatment.
2
FACT-P (Appendix 5a) will be assessed at the week 16 visit only, and PCS subscale of FACT-P (Appendix 5b) will be 
assessed at the subsequent 16-week visits thereafter. For placebo patients crossing over to open-label darolutamide, 
FACT-P will be assessed at the start of open-label treatment visit; whereas for patients in the darolutamide arm 
continuing open-label treatment, PCS subscale of FACT-P will continue to be assessed at this visit and at subsequent
16-week visits thereafter.
3
EQ-5D-3L (Appendix 6) will be assessed at the week 16 visit only, and end-of-study treatment visit. For placebo patients
crossing over to open-label darolutamide, EQ-5D-3L will be assessed at the start of open-label treatment instead of end-
of-study treatment visit. If the end of the double-blind treatment period occurs less than 16 weeks from the start of study
treatment, the EQ-5D-3L assessment is required in the first 16 weeks of open-label darolutamide treatment.
4
Also height will be recorded at the screening visit.
5
A triplicate 12-lead ECG including HR in a supine position after at least 10 minutes rest will be performed at screening 
and on day 1 for all patients. For patients participating to PK sampling, a triplicate 12-lead ECG will be also performed 
before PK samplings. The 3 consecutive recordings will be performed within approximately 5 minutes. BP and HR
(unless recorded by ECG) in a supine position after at least 10 minutes rest. The assessments will be done in the 
following order: ECGs and vital signs before any type of blood draw. For those patients who do not participate to PK 
sampling, 12-lead ECG will be obtained once on visits after day 1. See Section 6.6.2.1 for further details.
6
See Section 6.2 for PK procedures (blood sampling and recording of 12-lead ECG and vital signs) at study centres 
participating in PK sample collection. If PK sampling is not feasible during these visits, later visits may be used for PK 
procedures.
7
Patients will be instructed to complete the diary for 6 days (-6 to -1 day) before day 1 and every 16-week visits until 
documented pain progression.
8
CT/MRI and bone scans are acceptable if performed within 42 days prior to start of study treatment. A local qualified site 
physician (e.g. site radiologist or PI, at the PI’s discretion) must first review the screening scans and confirm the patient is 
non-metastatic before submitting the scans to central review to confirm eligibility. If the local qualified site physician 
detects metastasis, the scans should not be submitted to central review. For guidance on CT/MRI and bone scans 
performed at Week 16 and subsequent visits during double-blind treatment, see Section 6.1.2.4. Scans are acceptable if 
performed within 42 days prior to the start of open-label treatment visit. Imaging will be conducted every 16 weeks 
(±7 days) during the open-label darolutamide treatment after the start of open-label treatment visit (see Section 6.1.2.5). 
Patients continuing open-label darolutamide will only have local imaging, central confirmation is not required.
9
New lesion(s) in bone scan must be confirmed by CT/MRI (whichever imaging was conducted at screening for soft 
tissue) or x-ray. If confirmatory scan is negative (does not confirm progression), the patient will continue study treatment 
and visit study centre as specified in the study event table.
10
All AEs including SAEs will be recorded from the date of signing IC and continuing until the end-of-study treatment visit
(including open-label darolutamide treatment phase). Any AEs or SAEs that occur after the end-of-study treatment visit 
and which are considered to be related to the study treatment or any study procedures have to be reported and entered into 


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the eCRF. When the eCRF is not available anymore, all SAEs considered study treatment related should be reported to 
Bayer using a paper SAE form. AEs related to study procedures and all SAEs will be recorded for screening failures.
11
Once the patient has been withdrawn from study treatment, concomitant treatments will be recorded if used to treat new 
related or unresolved related AEs or if it is an antineoplastic therapy.
12
An optional PG IC for pharmacogenetic research study will be obtained at screening visit (or later during the study if 
feasible) unless precluded by local guidelines, e.g. IEC/IRB or regulatory authorities.
13
Blood (plasma) sampling for tumour-related biomarker evaluation will be collected on day 1 visit before study treatment 
administration, at the start of open-label treatment visit, and at the end-of-study treatment visit unless precluded by local 
guidelines, e.g. IEC/IRB or regulatory authorities. For placebo patients crossing over to open-label darolutamide
treatment, sampling will not be performed at the end-of-study treatment visit (see Table 4).
14
The local PSA result taken at screening should be used to confirm the patient has CRPC (inclusion criterion 4) and meets 
inclusion criterion 6.
15
Only study drug accountability performed at the end-of-study treatment visit.
16
A blood sample for DNA extraction will be taken at day 1 visit (or later during the study if feasible) only from patients 
who have signed the PG IC unless precluded by local guidelines, e.g. IEC/IRB or regulatory authorities.
17
12-lead ECG will be performed only at the start of open-label visit. ECG is not required on subsequent visits during the 
open-label darolutamide treatment.
18
Survival data will also be collected through an additional survival sweep. All patients considered alive shortly after the 
database cut-off date for the MFS analysis and prior to any subsequent analysis of OS will be contacted for survival 
status.


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Table 4.
Study event schedule after withdrawal of study treatment or during the follow-up 
period; and study event schedule for placebo patients crossing over to open-label 
darolutamide treatment
Protocol activities
For patients 
discontinuing study 
drug before confirmed 
metastasis and not 
initiating any 
prohibited treatment *
For patients 
after confirmed 
metastasis, or 
receiving 
subsequent 
treatment after 
unblinding *
For placebo patients 
crossing over to open-label 
darolutamide 
Visits
Every 16 weeks 
(±7 days) 
from end-of-study 
treatment visit1
Visits or phone 
contacts
Every 16 weeks 
(±7 days) 
from end-of-
study treatment 
visit2
Visits
Every 16 weeks
(±7 days) 
from start of 
open-label 
treatment visit1
End-of-study 
treatment visit
28 days 
(+7 days)
after last dose
or in transition
to roll-over 
study
BPI-SF
X
X
X
X
Dispensing of pain diary
X
X
X
X
Collection of pain diary and pain medications
X3
X3
X3
X
PCS subscale of FACT-P
X
X
X
X
ECOG performance status
X
X
X
X
Use of subsequent antineoplastic therapies
X
X
X
X
Laboratory safety assessments
X
X
Collection of AEs and SAEs considered to be 
related to study treatment or procedures
X
X
X5
X5
Collection of concomitant treatments used to 
treat new related or unresolved related AEs
X
X
X
X
Darolutamide dispensing and accountability
X
X7
First SSE
X
X
X
X
First prostate cancer-related invasive procedure 
for prostate cancer
X
X
X
X
Survival status8
X
X
X
X
Serum PSA 
X
X6
Chest, abdomen, and pelvic CT/MRI
X
X6
Bone scan4
X
X6
Abbreviations: ECOG = Eastern Cooperative Oncology Group; EOS = end-of-study; PSA = prostate-specific antigen; SSE = 
symptomatic skeletal event
*   Note: In case a patient initiates a prohibited treatment during the open-label treatment phase before metastasis confirmed 
by local reading, the patient must discontinue study treatment and will be followed for survival until the end of the study 
(see Section 4.7.1 for additional details).
1
Until  metastasis, death, transition to a roll-over study, or the end of the study 
2
Until death or the end of the study
3
Patients will be instructed to complete the diary for 6 days before each 16-week visit until documented pain progression. 
Pain medications will be recorded on CRFs at each 16-week visit until documented pain progression.
4
New lesion(s) in bone scan must be confirmed by CT/MRI (whichever imaging was conducted at screening for soft 
tissue) or x-ray. If confirmatory scan is negative (does not confirm progression), the patient will continue to visit study 
centre as specified in the study event table. 


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5
For placebo patients crossing over to open-label darolutamide, all AEs and SAEs irrespective of relatedness will be 
captured.
6
Placebo patients crossing over to open-label darolutamide will have central PSA testing and local imaging,radiology .
7
Only drug accountability performed at the end-of-study treatment visit.
8
Survival data will also be collected through an additional survival sweep. All patients considered alive shortly after the 
database cut-off date for the MFS analysis and prior to any subsequent analysis of OS will be contacted for survival 
status.
Patients initiating a prohibited treatment before confirmed metastasis will be followed only 
for survival status every 16 weeks until the end of the study.
6.1.1
Procedures during the screening period (-28 to -1 days)
A prospective study subject will receive both written and verbal information about the study,
and will have an opportunity to ask questions and sufficient time to decide whether or not to 
participate in the study. The original signed and dated IC must be retained in the 
Investigator’s study file and a copy must be provided to the patient.
All patients for whom the IC procedure is completed successfully will be assigned a subject 
number.
In addition to central laboratory sample collection, a local PSA value should be obtained at 
screening and used to confirm the patient has CRPC (inclusion criterion 4) and meets 
inclusion criterion 6.
To define CRPC and fulfil inclusion criterion 4, 3 subsequent PSA values rising after the 
nadir must be taken when the patient was on androgen deprivation therapy (ADT) that started 
at least 4 weeks before each PSA sampling, or at least 4 weeks after a bilateral orchiectomy.
PSA values used in calculation of PSADT should preferably have been obtained using the 
same assay, preferably at the same laboratory. PSADT should not be calculated using PSA 
values obtained when testosterone is rebounding after ADT (started at least 4 weeks before 
each PSA sampling, or at least 4 weeks after a bilateral orchiectomy). At least 3 PSA values 
need to be available and measured over the last 12 months before randomisation, at least 
4 weeks apart. Screening PSA from local laboratory must be included in the PSADT 
calculation. The PSA values used for the calculation must be > 0.2 ng/ml and the screening 
value ≥ 2 ng/ml. The PSA values used for the calculation of PSADT will be recorded on the 
CRF.
PSADT will be calculated using a linear regression model of the normal logarithm of PSA and 
time (Pound CR et al., 1999). Medical monitor must review the PSA and PSADT values 
submitted on the eligibility form before randomisation.
Patient screening must occur within 28 days before the first study treatment dosing at visit 1 
(day 1). For practical reasons, screening procedures can be performed on separate occasions 
during the screening period. Re-testing is allowed during the 28-day window only, if there is a 
medical or logistical reason. Re-testing of the safety laboratory assessments, testosterone and 
PSA may be allowed after consulting with the medical monitor. It is estimated that it will take 
7 to 14 days to obtain results from the safety laboratory assessments, testosterone and PSA 
(including PSADT).


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Screening procedures that fall outside of the 28-day window must be repeated. Re-screening 
of a patient who did not fulfil the eligibility criteria is allowed after at least 30 days from last 
screening decision. If a patient is re-screened, a new screening number will be allocated and a 
link will be made between the screening numbers of the same patient. Only one re-screening 
for each patient is allowed, after consultation with medical monitor.
The following procedures will be performed during the screening period:

Signed and dated IC

An optional PG IC signed and dated at screening (or later during the study if feasible) 
for pharmacogenetic research study unless precluded by local guidelines, e.g. IEC/IRB 
or regulatory authorities.

FACT-P, EORTC-QLQ-PR25 and EQ-5D-3L questionnaires

Demographic data (date of birth, age, racial group)

Medical history and current medical condition

Prostate cancer history including prior treatments and procedures

Physical examination including weight and height

A triplicate 12-lead ECG in a supine position after at least 10 minutes rest. The
3 consecutive recordings will be performed within approximately 5 minutes. An ECG 
with a QTcF > 500 ms should be confirmed by a second ECG taken 1-2 hours later.

BP and HR (unless recorded by ECG) in a supine position after at least 10 minutes 
rest.

ECOG performance status

Laboratory safety assessments (haematology, chemistry and urinalysis), testosterone,
and PSA.

Chest, abdomen and pelvic CT or MRI and bone scan.
CT/MRI and bone scans performed within 42 days prior to start of study treatment are 
acceptable as screening scans. A local qualified site physician (e.g. site radiologist or 
PI, at the PI’s discretion) must first review the screening scans and confirm the patient 
is non-metastatic before submitting the scans to central review to confirm eligibility. If 
the local qualified site physician detects metastasis, the scans should not be submitted 
to central review.

AEs and concomitant treatments

Dispensing pain diary
6.1.2
Procedures during the study treatment period
PK assessments at study centres participating in PK sample collection are described in 
Section 6.2.


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6.1.2.1
Day 1 (visit 1)
The patient will arrive at the study centre in the morning of day 1. The first study treatment 
will be administered with breakfast at the study centre. The following procedures will be 
performed before administration of study treatment: 

Confirmation of the patient’s eligibility

The patient will be randomised using IRT. In case the start of study treatment is not 
logistically feasible on the same day as randomisation, randomisation can be 
performed 1 day before the initiation of study treatment.

BPI-SF, FACT-P, EORTC-QLQ-PR25 and EQ-5D-3L questionnaires

Physical examination including weight

A triplicate 12-lead ECG in a supine position after at least 10 minutes rest. The
3 consecutive recordings will be performed within approximately 5 minutes. An ECG 
with a QTcF > 500 ms should be confirmed by a second ECG taken 1-2 hours later.

BP and HR (unless recorded by ECG) in a supine position after at least 10 minutes 
rest.

Laboratory safety assessments (haematology, chemistry, and urinalysis), testosterone,
and PSA

A blood sample for DNA extraction taken from patients who have signed the PG IC
(or later during the study if feasible) unless precluded by local guidelines, e.g.
IEC/IRB or regulatory authorities

A blood (plasma) sample for tumour-related biomarker analysis unless precluded by 
local guidelines, e.g. IEC/IRB or regulatory authorities (see Section 6.5)

Current medical condition, AEs and concomitant treatments

Study drug will be dispensed for 28 days and accountability performed

Collection of pain diary
Patients will continue taking study treatment at home throughout the study treatment period.
6.1.2.2
Day 15 (± 3 days) (Visit 2)
Patients will arrive at the study centre in the morning of day 15 after having taken study 
treatment at home in the morning. The following procedures will be performed:

A 12-lead ECG in a supine position after at least 10 minutes rest. An ECG with a 
QTcF > 500 ms should be confirmed by a second ECG taken 1-2 hours later.

BP and HR (unless recorded by ECG) in a supine position after at least 10 minutes rest

Laboratory safety assessments (haematology, chemistry and urinalysis)

Date of first SSE


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
Date of first prostate cancer-related invasive procedure

Status of survival

Current medical condition, AEs and concomitant treatments
Patients will continue taking study treatment at home until day 29 visit (visit 3).
6.1.2.3
Day 29 (± 5 days) (Visit 3)
The patient will arrive at the study centre in the morning of day 29 after having taken study 
treatment at home in the morning. The following procedures will be performed:

Physical examination including weight

A 12-lead ECG in a supine position after at least 10 minutes rest. An ECG with a 
QTcF > 500 ms should be confirmed by a second ECG taken 1-2 hours later.

BP and HR (unless recorded by ECG) in a supine position after at least 10 minutes rest

Laboratory safety assessments (haematology, chemistry and urinalysis)

Date of first SSE

Date of first prostate cancer-related invasive procedure

Status of survival

Current medical condition, AEs and concomitant treatments

Study drug will be dispensed for 12 weeks and accountability performed

Dispensing pain diary
Patients will continue taking study drug at home until week 16 visit (visit 4).


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6.1.2.4
Week 16 (± 7 days) (Visit 4) and every subsequent 16 weeks (± 7 days) thereafter
The patient will arrive at the study centre in the morning of week 16 (and every subsequent 
16 weeks) after having taken study treatment at home in the morning. The following 
procedures will be performed:

BPI-SF and EORTC-QLQ-PR25 questionnaires at each visit 

EQ-5D-3L and FACT-P at week 16 only, and PCS subscale of FACT-P every 
16 weeks thereafter

Physical examination including weight

A 12-lead ECG in a supine position after at least 10 minutes rest. An ECG with a 
QTcF > 500 ms should be confirmed by a second ECG taken 1-2 hours later

BP and HR (unless recorded by ECG) in a supine position after at least 10 minutes rest

ECOG performance status

Laboratory safety assessments (haematology, chemistry and urinalysis), and 
testosterone and PSA

Chest, abdomen and pelvic CT/MRI and bone scan
Local review should always be completed as soon as possible. All scans should then 
be submitted for independent blinded central reading during the double-blind 
treatment phase, on an ongoing basis, according to the timelines described in the 
imaging manual. All patient scans will undergo central imaging review during the 
double-blind treatment phase. If the local qualified physician (e.g. site radiologist or 
PI, at the PI’s discretion) suspects the presence of metastasis, this should be recorded 
in the CRF. The presence or absence of metastasis will need to be confirmed by 
independent blinded central reading. Patients should remain on treatment until deemed 
metastatic by central review.

Date of first SSE

Date of first prostate cancer-related invasive procedure

Status of survival

Current medical condition, AEs and concomitant treatments.

Study drug will be dispensed for 16 weeks and accountability performed

Collection of pain diary and dispensing a new pain diary
Patients will continue taking study drug at home until next visit.
6.1.2.5
Start of open-label treatment visit
Under the conditions outlined in Section 5.9, patients who choose to receive open-label 
darolutamide will have a start of open-label treatment visit at the time point of study treatment 


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code unblinding. Those patients who do not choose to continue with open-label darolutamide
treatment, will have an end-of-study treatment visit at this point of time (see Section 6.1.2.6).
The following procedures will be performed during the start of open-label treatment visit:

QoL:
o
BPI-SF and EORTC-QLQ-PR25: all patients
o
FACT-P and EQ-5D-3L: placebo patients crossing over to open-label 
darolutamide treatment
o
PCS-subscale of FACT-P: patients in the darolutamide arm continuing 
open-label darolutamide treatment
If the end of the double-blind treatment period occurs less than 16 weeks from 
the start of study treatment, the EQ-5D-3L assessment is required in the first 
16 weeks of open-label darolutamide treatment.

Physical examination including weight

A 12-lead ECG in a supine position after at least 10 minutes rest. An ECG with a 
QTcF > 500 ms should be confirmed by a second ECG taken 1-2 hours later. 
12-lead ECG will be performed only at the start of open-label visit. ECG is not 
required on subsequent visits during the open-label darolutamide treatment.

BP and HR (unless recorded by ECG) in a supine position after at least 10 minutes rest

Laboratory safety assessments (haematology, chemistry and urinalysis) and PSA

Chest, abdomen and pelvic CT/MRI and bone scan. Scans are acceptable if performed 
within 42 days prior to the start of open-label treatment visit. Imaging will be
conducted every 16 weeks (±7 days) during the open-label darolutamide treatment 
after the start of open-label treatment visit. Central confirmation of local imaging is 
not required during the open-label darolutamide treatment.

A blood (plasma) sample for tumour-related biomarker analysis unless precluded by 
local guidelines, e.g. IEC/IRB or regulatory authorities (see Section 6.5)

ECOG performance status

Date of first SSE

Date of first prostate cancer-related invasive procedure

Status of survival

Current medical condition, AEs and concomitant treatments

Collection of pain diary and dispensing a new pain diary


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
Return of all remaining study drugs and study drug containers and drug accountability 
performed. Study drug for the open-label treatment phase will be dispensed for 
16 weeks.
Patients in the darolutamide arm continuing open-label darolutamide treatment will have 
subsequent visits every 16 weeks according to Table 3 until metastasis is seen by local 
reading. After occurrence of metastasis, the patients should discontinue study treatment and 
will be followed thereafter every 16 weeks for secondary and additional variables (see Table 
4).
Patients in the placebo arm crossing over to open-label darolutamide treatment will have 
subsequent visits every 16 weeks according to Table 4 until metastasis is seen by local 
reading. After occurrence of metastasis, the patients should discontinue study treatment and 
will be followed every 16 weeks for secondary and additional variables (see Table 4).
6.1.2.6
End-of-study treatment visit, and in transition to the roll-over study
Patients will have an end-of-study treatment visit 28 days (+7 days) after the last dose of 
study treatment or before transition to the roll-over study. Another systemic antineoplastic 
therapy may be initiated no sooner than 7 days after the last dose of study treatment.
Note: the end-of-study treatment visit procedures for placebo patients crossing over to open-
label darolutamide treatment are described in Table 4 instead.
The following procedures will be performed during the end-of-study treatment visit:

BPI-SF, FACT-P, EORTC-QLQ-PR25 and EQ-5D-3L questionnaires

Physical examination including weight

Only for the double-blind treatment period: A 12-lead ECG in a supine position after 
at least 10 minutes rest. An ECG with a QTcF > 500 ms should be confirmed by a 
second ECG taken 1-2 hours later

BP and HR (unless recorded by ECG) in a supine position after at least 10 minutes rest

Laboratory safety assessments (haematology, chemistry and urinalysis) and PSA

A blood (plasma) sample for tumour-related biomarker analysis unless precluded by 
local guidelines, e.g. IEC/IRB or regulatory authorities (see Section 6.5)

ECOG performance status

Date of first SSE

Date of first prostate cancer-related invasive procedure

Status of survival

Current medical condition, AEs and concomitant treatments

Collection of pain diary and dispensing a new pain diary. No pain diary will be 
dispensed when a patient is transitioning to the roll-over study.


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
Return of all remaining study drugs and study drug containers and drug accountability 
performed
6.1.3
Follow-up period
Patients with MFS events (double-blind treatment phase) or metastasis by local reading 
(open-label treatment phase) will enter the follow-up period and will be contacted every 
16 weeks until death or the end of the study. Follow-up contact will be performed by visit or 
telephone. The following data will be captured during the follow-up contacts:

BPI-SF and PCS subscale of FACT-P questionnaires. If the patient is contacted 
through physician visit, a paper questionnaire will be completed by the patient prior to 
meeting with the physician in the office. If the patient is contacted by phone, the caller 
will read each item from the questionnaires to the patient and record the responses on 
a paper questionnaire.

ECOG performance status

Any AEs or SAEs that occur after the end-of-study treatment visit and which are 
considered to be related to the study treatment or any study procedures have to be
reported and entered into the CRF.

Collection of concomitant treatments used to treat new related or unresolved related 
AEs, if applicable)

Status of survival

Date of first SSE

Date of first prostate cancer-related invasive procedure

Use of systemic antineoplastic therapies

Collection of pain diary and dispensing a new pain diary, and collection of pain 
medications. If the patient is contacted by phone, the pain diary will be mailed back to 
the clinic. No pain diary will be dispensed when a patient is transitioning to the roll-
over study.
In case the patient discontinues study treatment before confirmed metastasis in the double-
blind treatment phase or metastasis by local reading in the open-label treatment phase without 
initiating any prohibited treatment, these patients will be followed as outlined in Table 4 until 
the end of the study.
The follow-up period will end at each site when all patients at the site who are ongoing on 
treatment have transitioned into the roll-over study or discontinued from the study for another 
reason (e.g., consent withdrawn - with no further data collection, lost to follow-up). Patients 
who are in follow-up at the site will end follow-up.


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6.1.4
Unscheduled visits
In the event that there are significant abnormal safety findings or suspected disease 
progression, control assessments may be performed at any time during the study treatment 
period according to the judgment of the investigator. The following procedures (one or more) 
may be performed at the unscheduled visit, if indicated:

Physical examination including weight

12-lead ECG

BP and HR

Laboratory safety assessments (haematology, chemistry, urinalysis)

Status of survival

AEs, current medical condition, concomitant treatments

Chest, abdomen and pelvic CT/MRI or x-ray

Bone scan 
Survival data will be collected through an additional survival sweep. All patients considered 
alive shortly after the database cut-off date for the MFS analysis and prior to any subsequent 
analysis of OS will be contacted for survival status.
6.1.5
Roll-over study
A separate roll-over study (study 20321) has been set up to allow patients who received 
darolutamide in the course of Bayer-sponsored clinical trials to continue receiving treatment 
with darolutamide at the time of study discontinuation.
The roll-over study is subject to approval by the competent health authority and ethics 
committee. The roll-over study protocol will be available to patients as long as darolutamide 
is not approved and reimbursed in a specific country.
All study patients who are ongoing on treatment and eligible to enter the roll-over study will 
transition as soon as it has been approved by local ethics committee/independent review 
board/health authority and the site is ready to receive patients. Patients who will transition to 
the roll-over study will perform the end-of-study treatment visit in the current study as 
outlined in Table 3 and Table 4, after which they may be transitioned. When the last patient at 
a given site has transitioned into the roll-over study, all other patients in follow-up at that site 
will perform the end-of-study visit.
All patients who transition into this separate study will require a separate signed informed 
consent.
If approval and reimbursement of darolutamide becomes available after a patient has been 
enrolled in the roll-over study, patients have 2 months to be transitioned to commercial 
supplies.


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6.1.6
End of study
For each participating EU country, the end of the study according to the EU Clinical Trial 
Directive will be reached when the last patient last visit date has been reached in the 
respective country.This study will end when all patients on treatment have transitioned into 
the roll-over study or have discontinued from this study for another reason (e.g., death, 
consent withdrawn - with no further data collection, lost to follow-up). Until the transition to 
the roll-over study, patients will continue to follow all the protocol required procedures and 
visits in the current protocol.
At each site, when all patients on treatment are moved to a roll-over study or have 
discontinued, all ongoing patients (i.e. in follow-up) will be discontinued, as the current study 
will be terminated.
Once the roll-over study 20321 is available for patients to move to, study treatment in the 
current study will no longer be available.
6.2
PK assessments during double-blind treatment
No samples for PK will be collected during the open-label treatment period.
The following PK-related procedures will be performed at study centres participating in PK 
sample collection, to ensure evaluable samples are collected in approximately 600 patients:

In total, four sparse PK samples (one trough, two early and one late sample) will be 
collected at different visits (see Figure 1 for details). The samples will be collected 
within 3 sampling windows:

Trough: at least 10 hours after the evening dose on the preceding day and before 
morning dosing on the day of PK sampling

Early: between 1 and 6 hours after the morning dose on the day of PK sampling

Late: between 4 and 12 hours after the morning dose and before the next dosing on the 
day of PK sampling. 
Samples taken on the same occasion will be separated by at least 2 hours. If PK sampling is 
not feasible during the proposed visits, later visits may be used to obtain PK samples. 
Sampling times outside the suggested time windows will not be considered as protocol 
deviations. It is of importance that the actual date and time of blood sampling are documented 
in the eCRF because PK calculations will be based on the actual sampling times relative to 
dosing times.


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An example order of sampling is given below:
o
Visit 2 – Trough sample + Early sample
o
Visit 3 – Early sample
o
Visit 4 – Late sample
On occasions when trough and early PK samples are to be collected at the same day, patients 
will be instructed to take their morning dose of study treatment at the study site after the 
trough PK sample has been collected. Dosing will be witnessed by the study personnel.
On the occasion when only early or late PK samples are to be collected, the patient will be 
instructed to take study treatment at home in the morning. Exact date and time of dosing and 
each PK sample collection will be recorded. Patient will use the PK diary to record the 
required date and time of home dosing.
Additional PK samples may be collected in the event of early study treatment discontinuation. 
When additional PK samples are collected, the dates and times of sample collection and the 
2 doses of study treatment preceding sample collection will be recorded.
The following 12-lead ECG and vital sign measurements will be performed before each PK 
sampling:

A triplicate 12-lead ECG including HR in a supine position after at least 10 minutes 
rest. The 3 consecutive recordings will be performed within approximately 5 minutes.

BP and HR (unless recorded by ECG) in a supine position after at least 10 minutes 
rest. 


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Early PK Sampling
Morning Dose
at home1
Triplicate ECG and 
HR, single BP2
Early PK sample
1-6 hours later
Morning Dose 
Evening Dose
at home (prior day)1
Trough and Early PK Sampling
Morning Dose 
Evening Dose
at home (prior day)1
Triplicate ECG and 
HR, single BP2
Triplicate ECG and 
HR, single BP2
separated by 
≥2 hours
≥10 hours 
later
2-6 hours 
later
Trough PK 
sample
Early PK sample
Morning Dose
at study centre1
Late PK Sampling
Morning Dose
at home1
Triplicate ECG and 
HR, single BP2
Late PK sample
4-12 hours later,
before next dosing
Morning Dose 
Evening Dose
at home (prior day)1
Figure 1.
Overview of study treatment dosing and PK blood sampling
1
Record the date and time for the 2 doses of study treatment on the day prior to PK sampling. On the day of PK sampling 
record the time for the morning dosing at the study centre or at home, as applicable.
2
Before each PK sampling, triplicate 12-lead ECG including HR and a single BP will be recorded in a supine position 
after at least 10 minutes rest. The 3 consecutive (triplicate) recordings will be performed within approximately 5 minutes.
6.3
Assessment of efficacy variables
6.3.1
Primary efficacy variable
The primary efficacy variable is MFS, defined as time between randomisation and evidence 
of metastasis or death from any cause, whichever occurs first.
Chest, abdomen, and pelvic CT/MRI and nuclear medicine bone scan will be performed at 
screening (baseline) and every 16 weeks until confirmed metastasis. Absence or presence of 
metastasis will be confirmed by the independent blinded central reading during the double-
blind treatment phase.
Conventional CT and MRI should be used with cuts of 10 mm or less in slice thickness 
contiguously. Spiral CT should be performed using 5 mm contiguous reconstruction, and 
both reconstructions should be done using both a bone (edge-enhancing) and a soft tissue 
algorithm.


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Metastasis in bone is defined as appearance of 1 or more lesions that are confirmed by the 
central reading according to the one of the methods described below. If the central reading 
identifies changes on bone scan, confirmatory anatomic imagine CT/MRI or x-ray, of the area 
in question needs to be obtained. Anatomic imaging performed up to 2 weeks prior to bone 
scan or later may be used as a confirmatory scan. Appearance of bone metastasis is assigned
to the date of the bone scan at which the lesion was first identified.
Metastasis in non-osseous tissue is defined as new distant pathologic lymph nodes (M1a) or 
other pathological lesion (M1c) according to RECIST 1.1. New or progressive regional 
pathologic lymph nodes will not be defined as metastasis.
Upon central confirmation of metastasis (local reading during open-label darolutamide
treatment), the patient must be withdrawn from study treatment. If the reading does not
confirm metastasis, the patient will continue study treatment as specified in Table 3. Patients 
with new or progressive regional pathologic lymph nodes will continue study treatment.
Status of metastasis will be assessed from randomisation until first metastasis throughout the 
study treatment period.
Patients withdrawing from study treatment before metastasis during the double-blind 
treatment but not initiating any subsequent prohibited antineoplastic therapy will be followed 
as outlined in Table 4.
Instructions on image acquisition and submission of scans for central reading will be provided 
in the imaging manual.
6.3.2
Secondary efficacy variables
6.3.2.1
Overall survival
OS is defined as time from randomisation to date of death from any cause. Date of death and 
primary cause of death will be recorded.
Survival status will be assessed from randomisation until the end of follow-up period.
6.3.2.2
Time to first symptomatic skeletal event (SSE)
Time to first SSE is defined as time from randomisation to the first occurrence of SSE. Date 
of the first SSE will be recorded.
SSE is defined as EBRT to relieve skeletal symptoms, new symptomatic pathologic bone 
fracture, or occurrence of spinal cord compression or tumour-related orthopaedic surgical 
intervention, whichever comes first.
SSE will be assessed from randomisation until the first occurrence of SSE.


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6.3.2.3
Time to initiation of first cytotoxic chemotherapy
Time to cytotoxic chemotherapy is defined as time from randomisation to initiation of the first
cytotoxic chemotherapy. Name and start date of cytotoxic chemotherapy treatment will be 
recorded.
Use of cytotoxic chemotherapy will be assessed from randomisation until the first use of 
cytotoxic chemotherapy. 
6.3.2.4
Time to pain progression
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, or initiation of short or long-acting opioids for pain, whichever comes first.
Pain will be assessed with the BPI-SF questionnaire (Appendix 4) during the visit, pain diary 
entries from 6 days preceding the visit and opioid use from baseline until documented pain 
progression. The pain diary consists of 6 copies of BPI-SF questionnaire.
Initiation or change in the use of other non-opioid analgesics is not used in the analysis of 
pain progression.
6.3.3
Additional efficacy variables
6.3.3.1
Progression-free survival
PFS is defined as time between randomisation and evidence of any radiographic disease 
progression, including new pathologic lymph nodes identified above or below the aortic 
bifurcation or death from any cause, whichever occurs first.
Status of PFS will be assessed from randomisation until the first evidence of radiographic 
disease progression.
6.3.3.2
Time to first prostate cancer-related invasive procedure
Time to first prostate cancer-related invasive procedure is defined as time from randomisation 
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 (e.g. catheterisation 
of the bladder, percutaneous drainage of hydronephrosis, palliative electroresection of the 
prostate, etc.).
Status of prostate cancer-related invasive procedures will be assessed from randomisation 
until the first prostate cancer-related invasive procedure.
6.3.3.3
Time to initiation of subsequent antineoplastic therapy
Time to initiation of subsequent antineoplastic therapy is defined as time from randomisation 
to initiation of first antineoplastic therapy.


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Subsequent antineoplastic therapy will be assessed from the first follow-up visit until the first 
use of such therapy.
6.3.3.4
Time to PSA progression
PSA progression is defined according to the Consensus Guidelines of the Prostate Cancer 
Clinical Trials Working Group 2 (PCWG2).

For patients with declines from baseline at week 16, the PSA progression is defined as 
the date that a 25% PSA increase and an absolute increase of 2 ng/ml above the 
nadir is documented, which is confirmed by a second consecutive value obtained 3 or 
more weeks later. 

For patients with no decline from baseline at week 16, the PSA progression is defined 
as the date that a 25% PSA increase in PSA along with an absolute increase of 
2 ng/ml above the baseline is documented, which is confirmed by a second 
consecutive value obtained 3 or more weeks later.
Early increases in PSA values before the 16 weeks are not considered as PSA progression.
PSA values will be collected from randomisation until the end-of-study treatment visit.
6.3.3.5
Percent of patients with PSA response
The percentage change of PSA from baseline will be calculated and the proportion of patients 
achieving a decline of 50% from baseline will be determined.
PSA values will be collected from randomisation until the end-of-study treatment visit.
6.3.3.6
Percent of patients with ECOG performance status deterioration
ECOG performance status (Appendix 3) will be assessed at screening and every 16 weeks
until the end of follow-up period. ECOG performance status deterioration is defined as an 
increase to grade 3 or higher, with an increase of at least 2 from baseline.
6.3.3.7
Time to ECOG performance status deterioration
Time to ECOG performance status deterioration is defined as time from randomisation to 
ECOG performance status deterioration (an increase to grade 3 or higher, with an increase of 
at least 2 from baseline).
6.3.3.8
Health-related quality of life
The mean of the screening and day 1 (pre-treatment) values will serve as baseline for QoL.
6.3.3.8.1
FACT-P 
QoL will be assessed using a disease-specific FACT-P questionnaire completed by the patient
(Appendix 5a). FACT-P will be assessed at screening, day 1, week 16, and at the end-of-study 
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FACT-P will be assessed at the start of open-label treatment instead of end-of-study treatment 
visit.
Patients will be defined as having total QoL deterioration, if they experience a decrease
of 10 points in FACT-P total score compared with baseline (Cella D et al., 2009).
The percent of patients experiencing deterioration in QoL from baseline based on the FACT-P 
total score at week 16 will be determined.  
6.3.3.8.2
PCS subscale of FACT-P 
QoL will be assessed using prostate cancer-specific subscale of the FACT-P questionnaire 
(PCS subscale of FACT-P) completed by the patient (Appendix 5b). 
PCS subscale will be assessed at screening, day 1 and every 16 weeks until the end of the 
follow-up period, and at the end-of-study treatment visit. The PCS subscale measurements at 
screening, day 1, week 16 and end-of-study treatment visit will be obtained from the FACT-P 
questionnaire completed by patients at those visits (see Section 6.3.3.8.1). For placebo 
patients crossing over to open-label darolutamide treatment, FACT-P will be assessed at the 
start of open-label treatment instead of end-of-study treatment visit. 
Patients will be defined as having QoL deterioration, if they experience a change of 3 points 
in PCS compared with baseline (Cella D et al., 2009).
Time to deterioration in prostate cancer-specific subscale of the FACT-P questionnaire (PCS 
subscale of FACT-P) will be determined.  
6.3.3.8.3
EQ-5D-3L
QoL will also be assessed using a generic EQ-5D-3L questionnaire completed by the patient. 
Mobility, self-care, usual activities, pain/discomfort, and anxiety/depression are each assessed 
on 3-point categorical scales ranging from “no problem” to “severe problem” (Appendix 6).
EQ-5D-3L will be assessed at screening, day 1, week 16, and at the end-of-study treatment 
visit to explore the impact of potential adverse effects on overall QoL. For placebo patients
crossing over to open-label darolutamide, EQ-5D-3L will be assessed at the start of open-
label treatment instead of end-of-study treatment visit. If the end of the double-blind treatment 
period occurs less than 16 weeks from the start of study treatment, the EQ-5D-3L assessment 
is required in the first 16 weeks of open-label darolutamide treatment.
Patients will be considered to have deterioration in overall QoL, if they experience a 
deterioration of 0.06 points compared with baseline. 
The percent of patients experiencing deterioration in QoL from baseline based on the PCS 
score at week 16 will be determined.  
The mean change in utility score (QoL) for on treatment period (end-of-study treatment –
baseline) will be calculated per treatment arm.


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6.3.3.8.4
EORTC-QLQ-PR25
The EORTC-QLQ-PR25 questionnaire (Appendix 7) will be completed at screening, day 1, 
and every 16 weeks until the end-of-study treatment visit, except for placebo patients crossing 
over to open-label darolutamide treatment for whom the questionnaire will be completed only 
until the start of open-label treatment visit. 
6.3.3.8.5
Time to worsening in prostate cancer-related urinary symptoms
Patients will be defined as having a worsening in prostate cancer-related urinary symptoms if 
they experience an increase from baseline of greater or equal to 8 points in urinary symptom 
scale/score (PRURI) measured by the EORTC-QLQ-PR25 questionnaire (Norman GR et al., 
2003). Patients will be defined as having improvement in cancer-related urinary symptoms if 
they experience a decrease from baseline of greater or equal to 8 points in urinary symptom 
scale/score (PRURI). The 8-point cut-off is based half the expected standard deviation for this 
scale.
The patients’ status in terms of change of urinary symptoms will be determined every 
16 weeks from baseline until the end-of-study-treatment visit using the urinary symptom 
score (PRURI) that is part of the EORTC-QLQ-PR25 questionnaire. For placebo patients
crossing over to open-label darolutamide treatment, the questionnaire will be completed only 
until the start of open-label treatment visit.
Time to worsening of prostate cancer related urinary symptoms will be determined.
6.4
Pharmacokinetic assessments
6.4.1
Blood sampling
PK samples will be collected from approximately 600 patients at study centres participating in 
PK sample collection. PK samples will be collected from all patients at the participating study 
centres to maintain blinding; however PK samples from the placebo arm will not be analysed.
Venous 
blood 
samples 
will 
be 
collected 
for 
determination 
of 
diastereomers 
(S,R)-darolutamide
and 
(S,S)-darolutamide
and 
the 
metabolite 
keto-darolutamide
concentrations in plasma.
PK blood samples will be collected as outlined in Section 6.2 and Figure 1. On the PK sample 
collection day, accurate information on dosing and timing of the 2 doses of study treatment on 
the day prior to PK collection day and on the day of PK sampling will be recorded from the 
PK diaries.
Instruction on sample collection, handling, labelling, storage and shipment will be provided in 
the laboratory manual. 
Full details of the modelling will be provided in a separate Modelling & simulation analysis 
plan.


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6.4.2
Determination of (S,R)-darolutamide, (S,S)-darolutamide and keto-darolutamide
concentrations in plasma
Concentrations of diastereomers (S,R)-darolutamide and (S,S)-darolutamide, and metabolite 
keto-darolutamide in plasma will be determined by liquid chromatography-tandem mass 
spectrometry (LC-MS/MS). The concentration of darolutamide will be calculated as the sum 
of concentrations of diastereomers (S,R)-darolutamide and (S,S)-darolutamide.
Bioanalytical issues and the criteria for acceptance of the results will be described in a 
bioanalytical plan and reported in a bioanalytical report. 
6.5
Pharmacogenetic and tumour-related biomarker assessments
Blood (plasma) samples will be collected for tumour-related biomarker assessments and a 
whole blood sample for pharmacogenetic (PG) assessments.
Instruction on sample collection, handling, labelling, storage and shipment will be provided in 
the laboratory manual.
6.5.1
Assessment of pharmacogenetic polymorphisms
The PG assessment may be done as exploratory research with the objective to assess whether 
genetic polymorphisms relate to the absorption, distribution, metabolism, excretion, 
pharmacodynamics or safety of darolutamide. A whole blood sample for DNA extraction will 
be collected on day 1 visit (or later during the study if feasible) from patients who have signed 
the PG IC unless precluded by local guidelines, e.g. IEC/IRB or regulatory authorities.
6.5.2
Assessment of tumour-related biomarkers
Exploratory biomarker studies will be performed to assess whether genetic alterations of the 
androgen receptor (AR) relate to potential primary or acquired resistance to darolutamide. 
These gene alterations may include AR amplification, point mutations and AR gene 
rearrangements leading to expression of truncated, constitutively active AR splice variants. 
Each of these alterations are proposed mechanisms for continued AR signalling in CRPC and 
potentially linked to disease progression and mechanisms of resistance to AR targeting 
therapies such as enzalutamide and abiraterone. Genetic biomarkers of interest may be 
analysed using circulating tumour DNA obtained from plasma.
In addition to the markers mentioned above, other biomarkers deemed relevant to gain further 
knowledge about the pathomechanism of the disease or about the study treatment (i.e. mode 
of action or safety of the treatment) may be measured, based on newly emerging data from 
other ongoing studies of these investigational drugs and/or literature data.
Blood samples for the preparation of plasma will be collected at baseline (day 1 before study 
treatment administration), at the start of open-label treatment visit, and at the end-of-study 
treatment visit (upon disease progression or study treatment discontinuation). For placebo 
patients crossing over to open-label darolutamide treatment, sampling will not be performed 
at the end-of-study treatment visit.


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6.6
Assessment of safety and tolerability variables
6.6.1
Adverse events
6.6.1.1
Definitions of adverse events
6.6.1.1.1
Adverse event
An AE is any untoward medical occurrence in a study subject which does not necessarily 
have a causal relationship with this treatment. AE can therefore be any unfavourable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an investigational medicinal product, whether or not related to the 
investigational medicinal product. The definition covers also treatment errors and uses outside 
those foreseen in the protocol, including misuse and abuse of the product.
Thus, an AE may be an appearance or worsening of any undesirable sign or symptom, any 
worsening of the current medical conditions or onset of a new disease, compared with the 
previous observations or clinically significant adverse change in a laboratory variable or other 
diagnostic finding (e.g. ECG).
A surgical procedure that was planned prior to the start of the study by any physician treating 
the subject should not be recorded as an AE (however, the condition for which the surgery is 
required may be an AE).
In the following differentiation between medical history and AEs, the term “condition” may 
include abnormal symptoms, diseases, laboratory or vital sign findings.

Conditions that started before signing of IC form and for which no symptoms or 
treatment are present until signing of IC form are recorded as medical history (e.g.
seasonal allergy without acute complaints).

Conditions that started before signing of IC form and for which symptoms or 
treatment are present after signing of IC form, at unchanged intensity, are recorded as 
medical history (e.g. allergic pollinosis).

Conditions that started or deteriorated after signing of IC form will be documented as 
AEs if it is considered clinically relevant.
A laboratory test abnormality should be reported as an AE if it is consi dered clinically 
relevant (e.g. causing the subject to withdraw from the study), requires treatment, causes 
apparent clinical manifestations, or is judged as relevant by the investigator.
Disease progression, per se, should not be reported as an AE. 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.
6.6.1.1.2
Serious adverse event
A SAE is any untoward medical occurrence that at any dose:

results in death,


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
is immediately life-threatening,

requires inpatient hospitalisation or prolongation of existing hospitalisation,

results in persistent or significant disability/incapacity,

is a congenital anomaly/birth defect,
or

is an important medical event: Medical and scientific judgment should be exercised in 
deciding whether an AE may be considered serious (due to an important medical 
event) because it jeopardizes the health of the patient or may require intervention to 
prevent another serious condition (death, a life-threatening condition, hospitalisation, 
persistent or significant disability or congenital anomaly). Examples of such events are 
invasive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasia or convulsions that do not result in hospitalisation; development of any drug 
dependency or drug abuse.
6.6.1.1.3
Other significant adverse event
AEs (other than those meeting the definition of serious) that are of clinical importance and 
lead to:

a diagnostic or therapeutic intervention,

withdrawal of the investigational medicinal product,

reduction of its dose,

significant additional concomitant treatment,

marked haematological and other laboratory abnormalities,
should be considered as other significant AEs.
6.6.1.2
Assessment of adverse events
All AEs must be elicited, documented and reported by the investigator to the sponsor from the 
time that a study subject signs the IC form until the end-of-study treatment visit. See 
Section 4.6 for guidance on adverse event reporting for screening failures.
Any AEs or SAEs that occur after the end-of-study treatment visit and which are considered 
to be related to the study treatment or any study procedures have to be reported until the end-
of-study. Additionally, SAEs considered study treatment related even beyond study end 
should also be reported.
SAEs and other significant AEs should be followed-up until resolved or until the event is 
considered chronic and/or stable outcome.
AEs may be notified to the investigator by the study subject, observed by the investigator 
clinically, or be an adverse change in laboratory assessment results. The investigator will 


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evaluate the subject’s AEs by asking a standard question, such as “Since you were last asked, 
have you felt unwell or different from usual in any way?”
The investigator will assess and record the causality and severity of the AEs. Causality should 
be assessed in relation to the investigational product (see criteria for causality and severity 
below).
Causality criteria:
Related: The temporal relationship of the AE onset to the administration of the investigational 
product makes a causal relationship possible, and other drugs, therapeutic interventions or 
underlying conditions do not provide a sufficient explanation for the AE.
Not related: The temporal relationship of the AE onset to the administration of the 
investigational product makes a causal relationship unlikely, or other drugs, therapeutic 
interventions or underlying conditions provide a sufficient explanation for the AE.
Severity criteria:
All AEs will be graded with National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE) version 4.03: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf.
The severity of the adverse event and the CTCAE term should be recorded in the appropriate 
section of the AE CRF. Severity is included in this grading and there is no separate severity 
assessment. 
In case a patient experiences an AE that is not presented in NCI CTCAE, the severity will be 
assessed according to following criteria:
Grade 1 = Mild AE, transient in nature and generally not interfering with normal activities
Grade 2 = Moderate AE, sufficiently discomforting to interfere with normal activities
Grade 3 = Severe AE, prevents normal activities
Grade 4 = Potentially life-threatening (subject was at risk of death at the time of the event) 
and/or disabling AE
Grade 5 = Results in death (fatal)
From the time that a study subject candidate signs the IC form newly appearing diagnosed 
diseases will be recorded on the AE CRF.
The investigator must report all AEs to the sponsor on a specific AE CRF irrespective of 
his/her assessment of the causal relationship of the investigational medicinal product to the 
event.
SAEs are also by definition AEs and should be elicited in the same way, and also reported on 
the AE CRF.


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6.6.1.3
Reporting of serious adverse events
The investigator must report all SAEs within 24 hours of becoming aware of an SAE (see
Appendix 2) regardless of the time that may have elapsed since the time the event occurred 
and regardless of the causal relationship of investigational medicinal product to the event.
In this study, the following events will not be reported as SAEs:

hospitalisation and elective surgery for treatment of pre-existing condition that has not 
exacerbated during the study

planned hospitalisation to simplify procedure or treatments
Disease progression per se should not be recorded as an SAE. If disease progression leads to 
clinical signs and symptoms that meet the criteria for seriousness, these events - not the 
underlying cause - should be reported as SAE (i.e. “disease progression” should not be 
recorded as SAE). In this case, disease progression should be mentioned on the SAE form as 
the likely cause, and the event causality assessment be “not related”, unless the investigator 
considers the study treatment to be the cause.
All SAEs should be reported on an electronic SAE form which must be completed by the 
investigator or other relevant study centre personnel and signed by the investigator. 
Optionally, if the investigator is not able to complete the SAE form electronically, the paper 
version of the SAE form can be completed and sent by e-mail or fax (in case of internet 
issues) within the standard SAE reporting timeline. SAE reporting contact information will be 
filed in the Investigator study file. If an SAE is sent to Bayer in the paper form then it is 
mandatory and essential for the site to enter all the relevant data into the electronic CRF 
(eCRF) as soon as possible. This information will need to be signed by the investigator in the 
eCRF system.
If the initial report is reported by telephone or e-mail to a clinical research associate (CRA) or 
other CRO personnel and the study centre personnel are unable to fill in the SAE form within 
24 hours, a paper SAE form will be initiated by the person receiving the report. The 
investigator must report the SAE on the SAE eCRF as soon as possible.
Minimum criteria for SAE reporting are: the event or outcome meets the SAE definition, the 
event happens to an identifiable study subject, and the event is reported by an identifiable and 
qualified reporter (usually an investigator or other qualified study centre personnel).
A follow-up report to an SAE should be prepared if any relevant change in the condition of 
the study subject occurs after the initial report. The follow-up report should be documented as 
an update to the initial report.
SAEs that occur after the end-of-study treatment visit and which are considered to be related 
to the study treatment or any study procedures have to be reported and entered into the eCRF
until the end-of-study. When the eCRF is not available anymore, all SAEs considered study 
treatment related should be reported to Bayer using a paper SAE form.
The sponsor will expedite all suspected unexpected serious adverse reactions (SUSARs) as 
well as other safety issues requiring expedited reporting to the relevant authorities within 
applicable timelines.


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Notification of the IECs/IRBs about all relevant events (SUSARs, other relevant safety 
information) will be performed by the sponsor’s designee, the CRO (as delegate of the 
responsible sponsor) and/or by the investigator according to applicable regulations.
The sponsor’s designee, the CRO will inform all investigators about relevant safety events 
(SUSARs, other safety issues) in accordance with applicable regulations (as delegate of the 
responsible sponsor).
The expectedness evaluation is needed for regulatory reporting and the sponsor or its designee
is responsible for performing this evaluation. The expectedness in this study is evaluated 
against the current version of darolutamide IB.
6.6.1.4
Special situations
The special situations with study treatment are defined as: 

medication error

overdose

abuse

misuse

interaction
These special situations with study treatment are reported on a separate CRF even if there is 
no accompanying AE. All clinical manifestations in relation to these special situations will be 
reported as AEs or SAEs at the same time using the corresponding section of the CRF.
6.6.1.5
Pregnancy during a clinical study
Any case of pregnancy inadvertently fathered by study subjects during a clinical study should 
be reported and followed up by the investigator in the same way and within the same 
timelines as an SAE, if permissible by local legislation, although a pregnancy per se is not 
considered an SAE.
Whenever it becomes known that the partner of a study subject was pregnant during the 
exposure to study treatments, the outcome of the pregnancy, delivery, postpartum recovery 
and the clinical condition of the offspring during the neonatal period should be reported, 
subject to the partner’s consent. For all reports, the forms provided are to be used. A 
pregnancy follow-up form will be provided to the investigator for completion after the 
sponsor has received the initial report.


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6.6.2
Clinical safety assessments
Whenever a study procedure coincidences with a scheduled time point for ECG, the study 
procedures should be undertaken in the following order: ECGs and vital signs before any type 
of blood draw (see also Section 6.2). 
6.6.2.1
12-lead ECG
All 12-lead ECG will be recorded in a supine position after at least 10 minutes rest.

In patients who do not participate in the PK sampling, triplicate (3 consecutive) 12-lead 
ECG recordings will be performed within approximately 5 minutes at screening and on 
day 1 visit before the first study treatment administration. At other visits, 12-lead ECG 
will be obtained once. 

In patients who participate in the PK sampling, triplicate 12-lead ECG recordings will be 
performed within approximately 5 minutes at screening, on day 1 visit before the first 
study treatment administration and before each PK sampling. At later visits, where PK 
samples are not collected, 12-lead ECG will be obtained once.
Corrected QT (QTc) will be calculated using Bazett’s (QTcB) and Fridericia’s (QTcF)
formula. Fridericia’s correction will be used when assessing the eligibility of patients at 
screening.
An ECG with a QTcF > 500 ms should be confirmed by a second ECG taken 1-2 hours later.
All 12-lead ECG recordings will be read by a central ECG laboratory. The investigator will 
assess the clinical significance of abnormal ECG findings.
6.6.2.2
Vital signs
All vital sign assessments will be recorded in a supine position after at least 10 minutes rest.
BP and HR (unless recorded by ECG) measurements will be obtained once in all visits.
6.6.2.3
Physical examination
Physical examination will be performed and weight will be measured at all visits except at
day 15 visit. Height will be recorded at screening only.
6.6.3
Laboratory safety assessments
Local laboratory will be used to provide results for screening PSA. All other samples will be 
sent to the central laboratory for analysis.
Instruction on sample collection, handling, labelling, storage and shipment will be provided in 
the laboratory manual. 
The following laboratory safety assessments will be performed during the screening period, 
study treatment period and at the end-of-study treatment visit. 


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Haematology:

Haemoglobin

Haematocrit

Erythrocyte count

Leukocyte count

Differential count (lymphocytes, monocytes, eosinophils, neutrophils, basophils)

Mean corpuscular haemoglobin (MCH)

Mean corpuscular volume (MCV)

Mean corpuscular haemoglobin concentration (MCHC)

Thrombocytes
Clinical chemistry:

Albumin 

Alanine aminotransferase (ALT)

Aspartate aminotransferase (AST)

Alkaline phosphatase

Bilirubin total (+ direct and indirect bilirubin if total bilirubin is > 1.5 x ULN)

Calcium

Blood urea nitrogen

Creatinine

Total protein

Lactate dehydrogenase

Potassium

Sodium

Testosterone

PSA (total)

Chromogranin A (only at visit 1)
Urinalysis:

Glucose

Protein

Erythrocytes

Leukocytes


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6.6.4
Reporting of medical device failures
The investigator must report immediately all non-approved medical device failures which 
could cause health damage, as well as any health damage that may be causally associated with 
a non-approved medical device failure. For this reporting, the forms provided are to be used
and sent to the designated recipient. This requirement is specific to Japan.
7.
EVALUATIONS AND STATISTICS
This protocol describes the statistical principles for this confirmatory phase III study. A 
complete description of the methodology will be detailed in a statistical analysis plan (SAP), 
which will be approved before database lock and opening the treatment code.
7.1
Estimation of sample size
The assumptions used in determining the sample size for this study are as follows. The 
median MFS for placebo is based on denosumab phase III study results (Smith MR et al., 
2012). The imaging assessment process includes an Independent Efficacy Review in order to 
provide an objective assessment of all relevant imaging to determine the presence or absence 
of metastases and the date of metastasis for the primary endpoint of MFS. In order to account 
for patients with metastases at baseline that are identified as part of the  independent efficacy 
review process, the number of events has been adjusted to account for the non-informative 
character of baseline metastases events and the dilution impact to the estimated MFS hazard 
ratio due to the inclusion of baseline metastases events.

Overall type I error rate: 0.05

Statistical power at the final analysis: 91%

Primary endpoint: MFS

Median MFS for placebo: 25 months

Assumed hazard ratio of 0.65

Diluted hazard ratio of 0.71

Randomisation: 2:1
385 MFS events will provide approximately 91% power to detect a statistically significant 
difference in MFS times, using a log-rank test with a two-sided 0.05 level of significance. 
Assuming 40 months accrual time and a dropout rate of 40%, the study will require 
approximately 1500 patients (1000 darolutamide patients, 500 placebo patients) to achieve 
approximately 385 MFS events within a reasonable time. This sample size calculation was 
performed with a simulation based algorithm.


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7.2
Statistical hypotheses
The primary objective of this phase III confirmatory study is to demonstrate efficacy of 
darolutamide over placebo in delaying the development of metastases in patients with high-
risk CRPC using MFS as a primary endpoint.
Survival distribution function will be used as basis for statistical hypothesis. Hypothesis will 
be 2-sided, although superiority over placebo is anticipated. The 2-sided hypothesis is 
formulated as follows:
H0: SDAROLUTAMIDE(t) = SPBO(t), for all t > 0 and
H1: SDAROLUTAMIDE(t) ≠ SPBO(t), for some t > 0,
where S(t) represent estimated survival distribution at time t for MFS. Estimation will be 
performed using Kaplan-Meier method. The hypothesis will be tested using the stratified log 
rank test.
7.3
Data sets to be analysed
Subject classification will be completed during the blind review before the database lock and 
opening the treatment code.
7.3.1
Intent-to-treat dataset
All randomised patients will be included in the intent-to-treat (ITT) dataset. All efficacy 
variables will be analysed using the ITT dataset.
7.3.2
Per-protocol dataset
All patients with no major protocol violations will be included in the per-protocol (PP)
analysis dataset. Criteria for eligibility for PP analyses will be presented in detail in the SAP
prior to unblinding the treatment code.
7.3.3
Safety dataset
All randomised patients who received any study treatment will be included in the evaluation 
of safety.
7.4
General statistical considerations
Statistical analysis will be performed using the datasets defined above. 
Primary efficacy will be evaluated at the end of double-blind part when targeted number of 
primary endpoint events is collected. 
To determine whether demographic or baseline characteristics influence the response to 
treatment, subgroup analyses will be performed on the efficacy variables by the treatment and 
the relevant subgroup variable in question e.g., disease characteristics and previous therapies. 
Subgroups will be specified in the SAP. The stratification factors PSADT and use of 


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osteoclast-targeted therapy at randomisation will be used to adjust primary and all secondary 
efficacy analyses.
Incomplete event occurrence dates will be imputed as the earliest possible date. Missing event 
dates e.g., due to withdrawal of consent, lost to follow up or not known to have died at the 
analysis cut-off date, will be right censored. Detailed methods will be described in the SAP.
All efficacy and safety data will be tabulated using appropriate descriptive statistics. Detailed 
description of all statistical methods will be defined in the SAP.
Data from patients who are transferred to a roll-over study may be pooled and analyzed 
together with the data from the study in which the patient was initially included. The results 
from these analyses will be reported separately.
7.5
Demographic and other baseline characteristics
All relevant demographic and disease baseline characteristics will be summarised by 
treatment arm using descriptive statistics. Comparability of the treatment groups may be 
examined using statistical models appropriate for the type of the variable. The disposition and 
number, as well as reasons for withdrawal and discontinuations will be listed and tabulated.
7.6
Evaluation of treatment compliance and exposure
Treatment duration, total cumulative dose (mg) and percent of planned dose will be calculated 
and summarised by treatment arm as treated. Number of tablets taken will be calculated using 
information on the number of tablets dispensed and the number of tablets returned. Study drug
tablets not returned will be considered to have been taken, unless otherwise specified in CRF.
Percent of planned dose will be defined as the number of tablets taken during the study 
divided by the expected number of tablets. Patients with at least 1 dose modification 
(including dose reduction and dose interruption) and the reason for dose modifications will be 
summarised by treatment arm as treated.


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7.7
Evaluation and analysis of efficacy
7.7.1
Primary efficacy evaluation
The primary endpoint is MFS - defined as time from randomisation to confirmed evidence of 
metastasis or death from any cause, whichever occurs first. The MFS analysis will be 
performed when approximately 385 MFS events are observed. A log rank test stratified by
stratification factors will be used to compare the darolutamide treated and placebo groups. 
This comparison will be a 2-sided test at the 0.05 level of significance. Kaplan-Meier curves, 
including median survival times and their 95% confidence intervals, the hazard ratio 
calculated with Cox model, will be used for statistical description. Detailed censoring 
methods and additional supporting analyses will be described in the SAP.
7.7.2
Secondary efficacy evaluations
Secondary endpoints including OS will be evaluated for statistical significance at the time of 
the MFS analysis and at a later time point. Further details will be described in the SAP. 
An overall 2-sided 0.05 significance level will be allocated for the analyses of secondary 
variables. If the primary analysis of MFS is considered unmet, each of the secondary 
objectives will be considered unmet. Details how overall significance level will be controlled 
across the secondary efficacy endpoints and the evaluation time points will be given in the 
SAP.
The secondary outcomes are:

OS 

Time to first SSE 

Time to cytotoxic chemotherapy 

Time to pain progression 
These secondary efficacy variables will be analysed with the same methods as the primary 
variable. A log rank test stratified by stratification factors will be used to compare the 
darolutamide treated and placebo groups. Kaplan-Meier curves, including median survival 
times and their 95% confidence intervals, and the hazard ratio calculated with the Cox model 
will be used for statistical description. Detailed censoring methods and additional supportive 
analyses, including established methods to adjust for the expected crossover effects on 
secondary endpoints, will be described in the SAP.


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7.7.3
Additional efficacy evaluations
Additional endpoints include:

PFS 

Time to first cancer-related invasive procedures 

Time to initiation of subsequent antineoplastic therapy 

Time to PSA progression 

Percent of patients with PSA response

Percent of patients with ECOG performance status deterioration

Time to ECOG performance status deterioration

QoL
o
Percent of patients with deterioration of FACT-P total score at 16 weeks
o
Time to deterioration in PCS subscale score
o
Percent of patients with improvement of EORTC-QLQ-PR25 urinary 
symptoms 
o
Time to worsening of EORTC-QLQ-PR25 urinary symptom score
o
Percent of patients with deterioration of EQ-5D-3L utility score at 16 weeks
o
Mean change in utility score (QoL) for on treatment period (end-of-study 
treatment – baseline)
The efficacy variables PFS, time to first prostate cancer-related invasive procedures, time to 
initiation of subsequent antineoplastic therapy, time to PSA progression and time to ECOG 
performance status deterioration will be analysed with the same methods as the primary 
variable. A log rank test stratified by stratification factors will be used to compare the 
darolutamide treated and placebo groups. Kaplan-Meier curves, including median survival 
times and their 95% confidence intervals, and the hazard ratio calculated with the Cox model 
will be used for statistical description. Detailed censoring methods and additional supportive 
analyses will be described in the SAP. 
The efficacy variables percent of patients with PSA response and percent of patients with
ECOG performance status deterioration will be analysed with the Cochran-Mantel-Haenszel 
test stratified by stratification factors.
Descriptive statistics for the QoL variables will be produced. The details of the QoL analyses 
will be described in the SAP.
Details regarding additional analyses will be specified in the SAP.


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7.7.4
Evaluation of pharmacokinetics
The PK samples obtained during this study will be subjected to population-based nonlinear, 
mixed effects modelling. Individual measures of exposure will be derived from the PK model 
and will be used to explore exposure-response relationships with safety and efficacy 
endpoints.
Full details of the modelling will be provided in a separate Modelling & simulation analysis 
plan. 
PK sampling will be undertaken at centres participating in PK sample collection. It is 
estimated that approximately 600 patients will participate in the PK sampling, resulting in 
approximately 400 patients randomised to receive darolutamide being included in the 
population PK analysis. Such a sample size should be sufficient to accurately characterise the 
PK of darolutamide in this patient population including the extent to which factors such as 
age, body weight, renal and hepatic function affect darolutamide PK. Effects on concomitant 
treatments on darolutamide plasma concentrations will also be evaluated.
7.7.5
Evaluation of pharmacogenetics and tumour-related biomarkers
Genetic polymorphisms may be analysed in relation to significant variation or specific 
scientific question in PK, pharmacodynamics or safety of darolutamide.
Exploratory biomarker analysis may be performed related to primary or acquired resistance to 
darolutamide.
If such analyses are performed, the results will be reported in separate reports.
7.8
Evaluation and analysis of safety and tolerability
Safety will be assessed through summaries of AEs, the frequency of discontinuation of study 
treatment due to AEs, laboratory evaluations, vital signs, ECGs and physical examination. 
Safety analyses will include all randomised patients who receive at least 1 dose of study drug 
(safety analysis set). For all safety analyses descriptive statistics will be used rather than 
inferential statistics.
7.8.1
Evaluation of adverse events
AEs will be summarised. Treatment emergent AEs are defined as AEs with an onset date on 
or after the first dose of study treatment and up to the end-of-study treatment visit. For all 
AEs, CTCAE v4.03 terminology should be recorded in the appropriate section of the AE 
CRF. All AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) coding system. The incidence of AEs will be presented by MedDRA system 
organ class and preferred term, relationship to study drug treatment, and severity. A patient 
reporting the same AE more than once is counted only once when evaluating incidence, 
maximum severity or strongest relationship to study treatment. To adjust for unequal lengths 
of study treatment period among patients, and potentially between treatment groups, an 
additional summary based on event rate per patient year will be performed for all AEs and all 
SAEs occurring after the first dose of study treatment.


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7.8.2
Clinical safety evaluations
The actual values and corresponding changes from baseline for supine HR and BP, 12-lead 
ECG variables (HR, RR, PR, QT, QRS, QTcB and QTcF) will be summarised using 
descriptive statistics. All HR and 12-lead ECG will be mean of 3 separate recordings unless 
HR is measured separately from ECG. The number of patients with QTc interval prolongation 
will be classified and tabulated. The frequencies of normal and abnormal physical 
examination findings will be summarised.
7.8.3
Laboratory safety evaluations
Laboratory safety variables will be summarised using descriptive statistics; the absolute 
values and the changes from baseline will be shown. Laboratory values will be classified by 
the National Cancer Institute’s CTCAE severity grade. Laboratory shift tables of the baseline 
results to each of the subsequent visits will be produced. The laboratory values will be also 
categorised into low, normal and high according to their reference ranges. Clinically 
significant increases or decreases from baseline will be tabulated for some specific laboratory 
assessments, if applicable.
7.8.4
Other safety evaluations
Baseline and concomitant medications will be coded using the WHO-DD with preferred name 
and therapeutic use. In summaries of baseline and concomitant medication use, each patient 
will be counted once per class and once per preferred name. Concomitant medications include 
all medications that are used on or after the date of initial study drug administration until end-
of-study treatment visit. Concomitant medications will be summarised by treatment and dose 
for the safety analysis set.
7.9
Interim analyses
For the primary efficacy endpoint no formal interim analysis is planned. For secondary 
efficacy variables the analysis done at the time of the MFS analysis is considered as interim 
analysis and the subsequent analysis is considered as final analysis for statistical significance. 
Further updates of secondary endpoint analyses without testing for statistical significance may 
be done. The DSMB will review the benefit-risk profile of darolutamide periodically 
according to the separate DSMB charter.
7.10 Execution of statistical analyses
Statistical analysis will be performed by or under the supervision of the sponsor.
7.11 Software
Statistical analysis, tables and subject data listings will be performed with SAS® for Windows 
(SAS Institute Inc., Cary, NC, the US).


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8.
FURTHER REQUIREMENTS AND GENERAL INFORMATION
8.1
Quality control of data handling
The clinical conduct of the study will be performed according to good clinical practice (GCP) 
and standard operating procedures (SOPs) of the CRO, except for AE reporting, which will be 
performed according to the SOPs of the sponsor.
A central laboratory will be used for the analysis of safety laboratory measurements 
(haematology, clinical chemistry and urinalysis), imaging and ECG assessments.
Monitoring is the responsibility of the CRO and will be performed according to the SOPs of 
the CRO.
Bioanalytics will be performed according to the principles of good laboratory practice (GLP) 
and GCP using validated methods.
The investigators will ensure that appropriate training relevant to the study is given to the 
medical, nursing and other personnel involved in the study. Any information relevant to the 
performance of the study is to be forwarded to the co-investigators and other personnel 
involved.
An investigators’ meeting will be arranged for the investigators and other relevant study 
personnel. The meeting includes a detailed review of the protocol, CRFs and all study 
procedures.
8.2
Insurance
The sponsor will provide clinical trial liability insurance for study subjects in all participating 
countries according to the local regulations.
8.3
Financial disclosure 
The investigator will be required to disclose any financial arrangement whereby the value of 
the compensation for conducting the study could be influenced by the outcome of the stu dy; 
any significant payments of other sorts from the sponsor, such as a grant to fund on-going 
research, compensation in the form of equipment, retainer for on-going consultation, or 
honoraria; any proprietary interest in darolutamide; any significant equity interest in the 
sponsor as defined in the US Code of Federal Regulations [21 CFR 54 2(b)].
In consideration of participation in the study, the sponsor will pay the investigator, or 
nominated payee the sums set out in the payment schedule attached to the Investigator 
Agreement.
8.4
Study centre team information
The investigator must ensure that all study centre team members involved in the study are 
fully informed of all relevant aspects of the study, including detailed knowledge and training 
in all procedures to be adhered to.


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Should the investigator transfer one of his/her responsibilities to other member(s) of the study 
centre team, after the initial completion and approval of the Site Delegation of Responsibility 
Log, he/she must have this change approved by the CRO and documented.
In the event of changes in key study centre team members the responsible investigator must
ensure that the successor is fully informed and capable of following the procedures.
The Study Coordinating Investigator is
.
8.5
Protocol reviews
The study shall not be initiated until approvals of the clinical study protocol including its 
appendices have been obtained from the responsible IEC/IRB and regulatory authority.
It is the responsibility of the investigator to provide a copy of the written approval and a list of 
the IEC/IRB members, their titles or occupations and institutional affiliations to the sponsor. 
The approval should include an unambiguous identification of the study (study code, study 
title) and the date.
8.6
Amendments to the study protocol
Any change or addition to the protocol can only be made in a written protocol amendment 
that must be approved by the sponsor, and when required by the IEC/IRB or regulatory 
authority. Only in the event of a need to eliminate an immediate hazard(s) to study subjects, 
the investigator may implement deviation from the protocol without prior approval.
Any new investigator must also sign the consent of approval for the valid original or amended 
clinical study protocol (Appendix 1). In addition, he/she must sign all the consents of 
approval for any valid amendments issued after that.
Appendix 1 (the sample investigator consent page) may be modified as necessary without 
protocol amendment.
Any change or addition to the approved study protocol may lead to suspension of the study or 
its results.
Any changes to the study protocol are subject to prior discussion with, and approval by, the 
sponsor and the study coordinating investigator. As a general rule, protocol amendments 
should be approved according to the same procedures as the study protocol.
Amendments are regarded as substantial, where they are likely to have a significant impact on 
the safety, physical or mental integrity of the study subjects, or the scientific value of the 
study. An approval of the responsible IEC/IRB or regulatory authority shall be obtained 
before substantial amendments may be implemented, unless local regulations are different.
If an amendment contains only minor changes (typically administrative) not affecting the 
safety, physical or mental integrity of the study subjects, or the scientific value of the study, 
the IEC/IRB or regulatory authority need not to be notified and in-house approval (including 
approval by the study coordinating investigator) is adequate.
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8.7
Case report forms
Data to be collected according to the study protocol (and its amendments, if any) shall be 
recorded on study-specific CRFs provided by the sponsor. All data on the CRFs must be 
verifiable in the hospital or patient records unless declared as source data in the monitoring 
manual.
The data will be recorded with electronic data capture (EDC) using electronic CRFs at study 
centre.
CRFs are required for each study subject. They will be completed in English by the 
investigator or other authorised study personnel. The investigator is required to confirm the 
content of the CRF by an electronic signature.
Corrections to the CRFs can be made by the investigator or other authorised study personnel.
An audit trail within the system will track all changes/corrections made.
Instructions and training for completing the CRFs will be provided. These instructions will 
cover content and technical issues of EDC.
The EDC database is the joint property of Orion Corporation and Bayer and should not be 
made available in any form to third parties without written permission from both Orion
Corporation and Bayer, except to authorised representatives of responsible regulatory 
authorities.
8.8
Data management
8.8.1
Database design
The study characteristics of the protocol will be defined into an EDC system by designing the 
eCRFs.
8.8.2
Data entry
Study centre personnel will be trained in the use of the CRFs. After successful completion of 
the training, they are provided with authorised access to enter and handle data on the CRFs.
Authorised persons from or under the supervision of the sponsor will code medical history 
and current medical conditions, AEs and concomitant treatments using standard coding 
dictionaries.
Externally produced electronic data may be uploaded or integrated directly into the EDC 
system or transferred to sponsor Data Management at agreed time intervals.
8.8.3
Data validation and query management
Edit checks will be defined and programmed in the EDC system to reveal possible 
discrepancies (missing, misleading, incomplete or illogical data).


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During data entry by study centre personnel, electronic queries within the EDC system will be 
opened and displayed on the computer screen.
Externally produced electronic data must be verified and validated.
8.8.4
Data lock
Individual data fields in the EDC system may be locked on an on-going basis during the 
study. A field may be locked after all necessary actions defined for that particular field have
been completed. The fields may be unlocked if further updates are needed.
8.8.5
Database lock
When all data for the double-blind period of the study have been entered and all queries 
resolved the data will be locked. Entire database will be locked after all data for the follow-up 
period of the study have been entered and queries resolved. Only authorised and well-
documented updates to the study data are possible after the database locks. The locked data 
will be used in the statistical analyses for study reporting.
8.8.6
Opening of the treatment code
The treatment code will be opened after the double-blind data are locked. The treatment codes 
will be available in the EDC after code opening.
8.8.7
Hardware and software
The study data will be managed and stored using Medidata Rave (Medidata Inc.) EDC system 
hosted by Medidata Solutions, Inc. There will be no special hardware requirements at the 
study centres, as the EDC application runs with standard web browsers.
The MedDRA coding dictionary is maintained in the coding system. 
8.9
Record retention
The investigator agrees to keep study subject records, including a subject screening log, 
subject identification list, all original signed IC forms, CRFs on PDF-CD/DVD and detailed 
records of drug dispensing in the Investigator’s study file to enable the follow-up assessments 
or audits by the quality assurance of the sponsor, or inspections by the regulatory authorities.
The study files will be stored in the respective archives for 15 years, after which the sponsor 
will be contacted and the possible future archiving mutually agreed.
8.10 Monitoring, quality assurance and inspection
The study monitor will visit the study centre regularly, as agreed by the investigator and the 
representative of the sponsor. The study monitor will ensure that the study complies with GCP 
and applicable regulatory requirements and that the protocol is followed in all aspects, 
including the randomisation procedure, accurate recording of results, reporting of AEs, drug 
accountability and record keeping.


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Furthermore, it will be verified that the clinical facilities remain accurate, and that the CRFs 
correspond with source data. For this purpose, the study monitor will be allowed direct access
to hospital or patient records of the study subjects, original laboratory data etc., as far as they 
are related to the study.
The study may be audited by the sponsor’s study-independent representative(s) or inspected 
by the regulatory authorities.
It is essential that the investigator and other relevant members of the study centre team a re 
available during the monitoring visits, possible audits and inspections, and that they devote 
sufficient time to these processes.
More detailed instructions are provided in a separate monitoring manual.
8.11 Steering committee
A Steering Committee will be established for the study. The Steering Committee will review 
the protocol and oversee the conduct, analyses, and publication of the study. The Steering 
Committee will consist of experts in prostate cancer and members of the sponsor’s personnel.
The Steering Committee will remain blinded to subjects’ study treatment assignment until the 
database is locked and unblinded.
8.12 Data and safety monitoring board
An independent DSMB will be established for the study. The DSMB will monitor the study 
periodically for safety and patient benefit-risk and perform other functions according to a 
charter that defines its roles and responsibilities. The committee will consist of individuals 
with extensive multicentre clinical study experience drawn from the fields of clinical 
oncology (specifically, prostate cancer) and biostatistics. These individuals will be entirely 
independent of the conduct of the study.
Periodically, the DSMB will be provided with tables summarising all adverse events and 
laboratory toxicities and a listing of patient deaths by treatment arm. The DSMB will review 
the data provided to them and make a recommendation to the sponsor to either continue the 
trial or suspend enrollment pending further evaluation. The DSMB may also request 
additional data or analyses. Since this is a safety evaluation with no intent of stopping for 
positive efficacy, there will be no adjustments to the overall alpha level of the efficacy 
analysis from these safety reviews. 
Meetings will be convened by conference call or in person. The appointed CRO will prepare 
all materials for DSMB evaluations.
Further details of the committee procedures and policies, including table displays, will be 
described in a DSMB charter.
8.13 Reports, publications and communication of results
The main clinical study report will be prepared when target number of MFS events have been 
analysed. 


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The follow-up clinical study report will be prepared when the study has been completed.
The study reports will be prepared by, or under supervision of, the sponsor. The final reports
will be approved by the study coordinating investigator and the appropriate representatives of
the sponsor. The sponsor remains the exclusive owner of the study data defined by the 
protocol.
The sponsor wishes to collaborate with investigator(s) to publish clinical study results in 
scientific journals and other arenas as promptly as possible without compromising accuracy or 
industrial property rights.
The first publication should be a joint publication based on data from all participating centres, 
analysed according to the protocol and the SAP by the sponsor’s statisticians or appointed 
CRO. Investigators are responsible for data analysis to support their own subsequent 
publications.
All manuscripts, including abstracts for oral or poster presentation, should be made available 
to the sponsor for review prior to submission for publication. Within agreed time periods, the 
sponsor will review manuscripts and abstracts for content and accuracy and will ensure that 
no confidential information is being inadvertently disclosed, and that the information does not 
become public until appropriate industrial property rights are secured. The sponsor will 
provide written comments, supply any relevant additional material and may, in case of 
discrepancies found in an investigator’s own analysis, request a new or repeat analysis prior to 
publication. If the clinical study report has not been completed within 24 months after last 
subject last visit (LSLV), an investigator may send a manuscript for review to the sponsor.
The sponsor and Steering Committee will determine the authorship of publications using the 
criteria defined by the International Committee of Medical Journal Editors.
This clinical study will be registered in one of the approved registries.
8.14 Study schedule
The study is estimated to start in Q3 2014 and to be completed in 2020 when the last subject’s 
last contact is estimated to take place.
A decision to continue the study beyond the time covered by the study protocol must be based 
on a mutual agreement between the investigator and the sponsor.
8.15 Qualification documentation
8.15.1 Curriculum vitae
A curriculum vitae in English must be obtained from all investigators who sign the protocol, 
and from other relevant persons. It should include name, title, occupation, education, research 
experience, present and past positions, and be signed and dated.


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8.16 Study termination
8.16.1 Study completion
When the last subject has completed the study, the remaining issues with CRFs, study 
treatments, other study materials delivered to the study centre, as well as archiving of study 
documents by the investigator, will be dealt with.
8.16.2 Premature study termination
The sponsor reserves the right to prematurely terminate the study for valid scientific or 
administrative reasons. After such a decision, the investigator must be informed within 7 days 
and call in all participating study subjects for a final study (termination) visit. On this visit, all 
delivered study materials must be collected and all CRFs completed up to the termination 
date.
9.
ETHICAL REQUIREMENTS
9.1
Ethics committee
The study protocol, subject information sheet and IC forms will be submitted to an IEC/IRB
for evaluation and approval. The protocol will be submitted to the regulatory authority, in 
accordance with local regulations. The study will not be initiated before the prescribed time 
required by the regulatory authority has elapsed or the regulatory authority has given its 
permission to start the study.
The investigator is responsible for obtaining the favourable opinion/approval for the study
from the IEC/IRB, submitting any amendment(s) and communicating study-related safety 
issues to the IEC/IRB as requested by the IEC/IRB. The investigator should file all 
correspondence with the IEC/IRB in the Investigator’s study file. 
9.2
Ethical conduct of the study
The study will be conducted in accordance with the Declaration of Helsinki which guides 
physician in biomedical research involving human subjects.
The study will be conducted in compliance with the protocol, GCP (ICH/135/95) and the 
applicable regulatory requirements.
For benefit-risk consideration of the study, see Section 1.6.3
9.3
Subject information and consent
The investigator is responsible for providing each study subject candidate with full and 
adequate verbal and written information regarding the objectives and procedures of the study.
The investigator should also explain any possible risks and benefits involved before asking for 
the subject's IC. The information given to the study subjects may not be changed without prior 


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written approval from both the sponsor and the IEC/IRB. Any questions that a study subject 
candidate may have should be answered satisfactorily. After this, the study subject candidate 
should be allowed sufficient time to make up his mind concerning participation in the study.
The study subject candidate must also be informed of his right to withdraw from the study at 
any time without any penalty or loss of benefits to which the subject is otherwise entitled to 
and about the possibility of audits and inspections of relevant parts of the study subject 
records by representatives of the sponsor and local or foreign regulatory authority.
It is the responsibility of the investigator to obtain a signed and dated IC from all study 
subject candidates before recruitment. Each study subject should receive a copy of his signed 
and dated IC.
The investigator should confirm the receipt of each IC by entering the date of the consent both
on the subject’s CRF and also on the source data. The signed IC forms should be filed in the 
Investigator’s study file.
9.3.1
Subject data protection
Information collected during the course of the study will be stored in a database and use d in 
the further development of darolutamide and thereafter, for as long as the information is 
relevant to patient care. The use includes the transfer of data to regulatory authorities in the 
EU or its member states, the US or other countries for the purpose of obtaining, maintaining 
and processing marketing authorisations. All information is handled confidentially and 
according to current laws and regulations.
Records identifying the subject will be kept confidential and, to the extent permitted by the
applicable laws and/or regulations, will not be made publicly available. If the results of the 
trial are published, the subjects’ identity will remain confidential.
The investigator must ensure that subjects' anonymity will be maintained. On the CRFs or 
other documents submitted to the CRO and/or sponsor, subjects should NOT be identified by 
their names, but by the assigned subject number, date of birth and sex (see Section 8.9).
If subject names are included on copies of documents submitted to the CRO and/or the 
sponsor, the names will be obliterated and the assigned subject number added to the 
document. The investigator should keep a separate log of subject's codes, names, addresses, 
telephone numbers and hospital numbers (if applicable). Documents not for submission to the 
CRO and/or sponsor (e.g. signed ICs) should be maintained by the investigator in strict 
confidence. Source data will be stored at the study centres.
Confidentiality of pharmacogenetic data will be preserved according to local laws and 
regulations.
10. REFERENCE LIST
Assessment Report for Xtandi (enzalutamide). (2013) 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Public_assessment_report/human/002639/WC500144998.pdf.


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Assessment Report for Zytiga (abiraterone). (2011) 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Public_assessment_report/human/002321/WC500112860.pdf.
Cella D et al. (2009) Estimating clinically meaningful changes for the Functional Assessment 
of Cancer Therapy--Prostate: results from a clinical trial of patients with metastatic 
hormone-refractory prostate cancer. Value Health. 12 (1): 124-9.
Ferlay J et al. (2010) Estimates of cancer incidence and mortality in Europe in 2008. Eur J 
Cancer. 46 (4): 765-81.
Ferlay J et al. (2012) GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: 
IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research 
on Cancer; 2013. Available from: 
http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx, accessed on 24 March 2014.
Fizazi K. (2013) An open-label, phase I/II safety, pharmacokinetic, and proof-of concept 
study of ODM-201 in patients with progressive metastatic castration-resistant prostate 
cancer. ECCO 2013. September, 2013. Amsterdam, The Netherlands.
Fizazi K et al. (2011) Denosumab versus zoledronic acid for treatment of bone metastases in 
men with castration-resistant prostate cancer: a randomised, double-blind study. 
Lancet. 377 (9768): 813-22.
Fizazi K et al. (2013) ODM-201, a new generation antiandrogen for castration resistant 
prostate cancer: preclinical and phase I data ACSO, Genitourinary Cancers 
Symposium. February 14-16. Rosen Shingle Creek, Orlando, FL.
Iswaran TJ et al. (1997) An overview of animal toxicology studies with bicalutamide (ICI 
176,334). J Toxicol Sci. 22 (2): 75-88.
Jemal A et al. (2008) Cancer statistics, 2008. CA Cancer J Clin. 58 (2): 71-96.
Linja MJ et al. (2001) Amplification and overexpression of androgen receptor gene in 
hormone-refractory prostate cancer. Cancer Res. 61 (9): 3550-5.
Massard C et al. (2012) ARADES trial: A first-in-man, open-label, phase I/II safety, 
pharmacokinetic, and proof-of-concept study of ODM-201 in patients with 
progressive metastatic castration-resistant prostate cancer. ESMO. Vienna, Austria.
Massard C et al. (2015) Pharmacokinetics, Antitumor Activity, and Safety of ODM-201 in 
Patients with Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer: An 
Open-label Phase 1 Study. Eur Urol: http://dx.doi.org/10.1016/j.eururo.2015.09.046.
Norman GR et al. (2003) Interpretation of changes in health-related quality of life: the 
remarkable universality of half a standard deviation. Med Care. 41 (5): 582-92.
Penson DF et al. (2016) Enzalutamide Versus Bicalutamide in Castration-Resistant Prostate 
Cancer: The STRIVE Trial. J Clin Oncol. 34 (18): 2098-106.
Pickard AS et al. (2007) Estimation of minimally important differences in EQ-5D utility and 
VAS scores in cancer. Health Qual Life Outcomes. 5: 70.
Pound CR et al. (1999) Natural history of progression after PSA elevation following radical 
prostatectomy. JAMA. 281 (17): 1591-7.


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Scher HI et al. (2005) Biology of progressive, castration-resistant prostate cancer: directed 
therapies targeting the androgen-receptor signaling axis. J Clin Oncol. 23 (32): 8253-
61.
Schneider S et al. (2011) Vinclozolin: a feasibility and sensitivity study of the ILSI-HESI F1-
extended one-generation rat reproduction protocol. Regul Toxicol Pharmacol. 59 (1): 
91-100.
Smith MR et al. (2016) Phase 2 Study of the Safety and Antitumor Activity of Apalutamide 
(ARN-509), a Potent Androgen Receptor Antagonist, in the High-risk Nonmetastatic 
Castration-resistant Prostate Cancer Cohort. Eur Urol. 70 (6): 963-70.
Smith MR et al. (2011) Disease and host characteristics as predictors of time to first bone 
metastasis and death in men with progressive castration-resistant nonmetastatic 
prostate cancer. Cancer. 117 (10): 2077-85.
Smith MR et al. (2005) Natural history of rising serum prostate-specific antigen in men with 
castrate nonmetastatic prostate cancer. J Clin Oncol. 23 (13): 2918-25.
Smith MR et al. (2012) Denosumab and bone-metastasis-free survival in men with castration-
resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. 
Lancet. 379 (9810): 39-46.
Tombal B. (2012) Non-metastatic CRPC and asymptomatic metastatic CRPC: which 
treatment for which patient? Ann Oncol. 23 Suppl 10: x251-8.
van Andel G et al. (2008) An international field study of the EORTC QLQ-PR25: a 
questionnaire for assessing the health-related quality of life of patients with prostate 
cancer. Eur J Cancer. 44 (16): 2418-24.
11. PROTOCOL AMENDMENTS
11.1 Amendment 1
The adjustments incorporated in this amended protocol from the original protocol dated 
10 Mar 2014 are summarised in Section 11.1.1.
Clarifications and corrections are summarised in Section 11.1.2. 
11.1.1 Overview of adjustments
Modification 1: Definition of progression in soft tissue
It is clarified that progression in soft tissue excludes progression in lymph nodes in the pelvis 
below the aortic bifurcation. 
Justification: Progression in soft tissue below the aortic bifurcation is more consistent with 
loco-regional progression; therefore progression in lymph nodes in the pelvis below the aortic 
bifurcation will not be defined as metastases. Patients with new pathologic lymph nodes 
identified in the pelvis below the aortic bifurcation can continue study treatment.
Protocol sections affected: 1.6.1, 4.7.2.1, 6.3.1


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Modification 2: Eligibility related to PSA 
Inclusion criterion 4 was amended to allow patients with CRPC defined as 3 rising PSA 
values at least 1 week apart during ADT to enter the study. The observation period of PSA 
values that can be used in the calculation of PSADT was prolonged from 6 to 12 months.
Justification: Inclusion criterion 4 was amended to remove overlapping requirements with 
inclusion criterion 6 and to align it with the common patterns of PSA testing in the target 
study population. Notably, inclusion criterion 6 (PSADT of 10 months and PSA > 2 ng/ml 
at screening) assures that eligible patients have CRPC. 
The period for PSA sampling used for calculation of PSADT was amended to align the 
requirement with routine intervals for PSA testing in clinical practice in the target study 
population. Common patterns of clinical follow-up and PSA testing in the target study 
population would not allow collection of 3 PSA samples within 6 months.
Protocol sections affected: Synopsis (inclusion criterion 4), 4.2, 6.1.1
Modification 3: Progression-free survival (PFS) 
Progression-free survival was added as an additional endpoint.
Justification: Progression in lymph nodes in the pelvis below the aortic bifurcation will not be 
defined as metastasis. Therefore, to capture loco-regional disease progression, the secondary 
endpoint PFS has been added. 
Protocol sections affected: Synopsis (objectives, variables), 1.6.1, 2.3, 6.3.3, 7.7.3
Modification 4: Collection period of pain data and collection of pain medications
The collection of pain data was corrected to continue until documented pain progression 
instead of the end of the follow-up period. Question 7 “What treatments or medications are 
you receiving for your pain?” of Appendix 4 BPI-SF was deleted to avoid collection of pain 
data in 2 different places as the pain medication data will be collected using CRFs. 
Justification: The unintended inconsistency in the assessment period of pain data was 
corrected to align with the evaluation and statistical analysis of this endpoint, and the pain 
medication data was corrected to be collected using only CRFs.
Protocol sections affected: 6.1 (Tables 3, 4, 5), 6.1.3, 6.3.2.4, Appendix 4
Modification 5: Bilirubin measurements
If total bilirubin is > 1.5 x ULN, direct and indirect bilirubin values are obtained.
Justification: Determination of the direct and indirect bilirubin will be performed to 
understand better the reasons for high bilirubin.
Protocol sections affected: 6.6.3
Modification 6: Time between consecutive BP, HR and ECG recordings


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The 3 consecutive BP, HR and ECG recordings were amended to be performed within 
approximately 5 minutes instead of at least 5 minutes apart.
Justification: 5 minutes between measurements is considered too long interval, representing 3 
separate time points rather than a triplicate of a single time point. A mean of 3 measurements 
made within approximately 5 minutes would more closely represent a single time point 
measurement.
Protocol sections affected: 6.1, 6.1.1, 6.1.2.1, 6.2, 6.6.2.1, 6.6.2.2
Modification 7: Dose modifications
More information on dose modifications was provided and a new in-text table (Table 2) was 
created.
Justification: To provide better instructions for investigators how to decrease, interrupt and 
re-escalate study drug dose.
Protocol sections affected: 4.7.2.2.1, 4.7.2.2.1.1, 4.7.2.2.1.2, 4.7.2.2.1.3
Modification 8: Unscheduled visits
Suspected disease progression was added as a reason for an unscheduled visit. Chest, 
abdomen and pelvic CT/MRI or x-ray and bone scan were added as options for assessments 
that may be performed at the unscheduled visit, if indicated.
Justification: Symptomatic disease may progress between visits and may require further 
evaluation.
Protocol sections affected: 6.1.4
Modification 9: Tumour-related biomarker assessment
Blood (plasma) samples for analysis of tumour-related biomarkers will be taken in the study.
Justification: Exploratory biomarker studies may be performed to assess whether genetic 
alterations of the androgen receptor (AR) or other tumour genetic modifications relate to 
potential primary or acquired resistance to ODM-201.
Protocol sections affected: 6.1, 6.1.2.1, 6.1.2.5, 6.5 and 7.7.5 
Modification 10: EORTC-QLQ-PR25 and EQ-5D-3L
A new QoL questionnaire, EORTC-QLQ-PR25, was added and EQ-5D-3L will not be 
assessed after the week 16 visit.
Justification: EORTC-QLQ-PR25 has been developed and validated in a predominately non-
metastatic prostate cancer patient population and therefore supports other questionnaires used 
in this study.
EQ-5D-3L assessments were reduced to be done only at start of study treatment and week 16 
to assess the impact of potential adverse effects on overall QoL. The QoL impact of later 


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disease progression is measured by the EORTC-QLQ-PR25 scale and PCS subscale of 
FACT-P which should be more sensitive to the expected changes.
Protocol sections affected: Synopsis (Variables), 1.6.1, 6.1 (Tables 3, 4 and 5), 6.1.1, 6.1.2.1, 
6.1.2.4, 6.1.2.5, 6.1.3, 6.3.3.7.4, 6.3.3.7.5, 7.7.3, Appendix 7
Modification 11: Data collection from screening failure patients
AEs related to study procedures and SAEs, and relevant information related to these events 
from patients who signed the IC but did not fulfil eligibility criteria will also be collected. 
Justification: Since AEs related to study procedures and SAEs may happen during screening 
period, this information will be collected for screening failure patients.
Protocol sections affected: 4.6
Modification 12: Use of antineoplastic therapies
Follow-up treatments were clarified to cover collection of systemic antineoplastic therapies.
Justification: Missing information was added to align with Section 6.1.3.
Protocol sections affected: 5.7.1, 6.1 (Table 3: footnote 11)
Not only initiation date and name but also other details of use of systemic antineoplastic 
therapies will be collected. Initiation date and name of first cytotoxic chemotherapy were 
deleted as they are included in systemic antineoplastic therapies.
Initiation date and name of first cytotoxic chemotherapy was removed as redundant 
information from study procedures sections as these and other systemic antineoplastic 
therapies are collected together with other concomitant treatments.
Justification: More details of systemic antineoplastic therapies will be collected to allow 
evaluation of the potential effects of these therapies on the secondary endpoints.
Protocol sections affected: 6.1 (Tables 3, 4 and 5), 6.1.2.2, 6.1.2.3, 6.1.2.4, 6.1.2.5, 6.1.3
An instruction was added that another systemic antineoplastic therapy may be initiated no 
sooner than 7 days after the last dose of study treatment.
Justification: To be able to better evaluate treatment-related AEs while the study drug is still 
in the body.
Protocol sections affected: 4.7.1, 5.7.2, 6.1.2.5
The end-of-study treatment visit was changed to take place 28 days after the last dose (instead 
of 7 days) for patients that permanently discontinue study treatment and start subsequent 
antineoplastic therapy.
Justification: The end-of-study treatment visit was set to be the same for all patients to allow 
collection of AEs until 28 days after withdrawal of study treatment.
Protocol sections affected: 4.7.1, 4.7.2, 6.1 (Table 3), 6.1.2.5


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Modification 13: Reporting severity of AEs not presented in NCI CTCAE 
Severity grading of AEs not presented in NCI CTCAE was changed by replacing the 
mild/moderate/severe classification with a 5-point grading scale.
Justification: The change was done to harmonise the grading with the AEs that are presented 
in the NCI CTCAE.
Protocol sections affected: 6.6.1.2
Modification 14: CTCAE term
Collection of CTCAE terms to CRFs was added.
Justification: Collection of CTCAE terms was added to allow cross-checking between 
CTCAE severity grade and CTCAE term.
Protocol sections affected: 6.6.1.2, 7.8.1.
Modification 15: Pregnancy during a clinical study
Whenever it becomes known that the partner of a study subject was pregnant during the 
exposure to study treatments, the outcome of the pregnancy, delivery, postpartum recovery 
and the clinical condition of the offspring during the neonatal period should be reported,
subject to the partner’s consent.
Justification: It was added that the partner’s consent is needed for reporting the details and 
outcome of the possible pregnancy during a clinical study.
Protocol sections affected: 6.6.1.5
Modification 16: Number of study centres
Number of centres will be increased from about 350 to about 400 sites.
Justification: Re-evaluation of recruitment projections suggested that about 400 centres will 
be required to accomplish enrolment of about 1500 patients within the recruitment period.
Protocol sections affected: Synopsis (centre number) and 4.1
11.1.2 Overview of clarifications and corrections
Modification 17: Drug-drug interactions
More information about drug-drug interactions was added.
Justification: To give the investigators more information and instructions about drug-drug 
interactions.
Protocol sections affected: 5.7.3
Modification 18: Randomisation
Centre as a blocking factor was added to the method of randomisation. 


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Justification: This modification was made to align with the IRT procedures and 
specifications.
Protocol sections affected: 5.4.1
Modification 19: Re-screening
A clarification about the option for re-screening and the period of 30 days between screenings 
was added.
Justification: To give the investigators clear instructions related to the option of patient re-
screening.
Protocol sections affected: 6.1.1
Modification 20: Reporting disease progression as an SAE
Reporting disease progression as an SAE was further clarified.
Justification: To give the investigators clear instructions on how disease progressions should 
be reported, if they fulfil the criteria for seriousness.
Protocol sections affected: 6.6.1.3
Modification 21: AE/SAE reporting
Life-threatening in the definition of a SAE was clarified to be immediately life-threatening.
Protocol sections affected: 6.6.1.1.2
The mistake in the collection period for related SAEs was corrected by replacing the end -of-
study visit with the end-of-study treatment visit. 
Protocol sections affected: 6.6.1.3
The details (fax number) in SAE reporting process related to contact information for paper 
SAE forms were corrected; the paper SAE forms will not be sent to the CRO but to a fax 
number provided in the Investigator study file.
Protocol sections affected: 6.6.1.3
Responsibilities regarding expectedness evaluation were clarified by adding the word 
“performing” to the sentence “The expectedness evaluation is needed for regulatory reporting 
and the sponsor or its designee is responsible for performing this evaluation”.
Protocol sections affected: 6.6.1.3
Responsibilities between different parties for notification of relevant safety information to the 
relevant authorities, IECs/IRBs and investigators were clarified.
Protocol sections affected: 6.6.1.3, Appendix 2.
Modification 22: Detailed statistical evaluation of secondary and additional efficacy 
endpoints


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Details of the statistical evaluation of the secondary and additional efficacy endpoints were 
moved from the protocol to the statistical analysis plan.
Justification: Statistical evaluation in the protocol will be more focused on primary efficacy 
endpoint and safety evaluations.
Protocol sections affected: Synopsis (evaluations and statistical methods), 7.4, 7.7.2, 7.7.3
Modification 23: FACT-P and PCS of FACT-P
Collection of PCS of FACT-P in the footnote 2 was clarified to continue every 16 weeks after 
the week 16 visit: the words “until the end-of-study treatment visit” was removed as PCS of 
FACT-P will be assessed until the end of the follow-up period. FACT-P will be assessed at 
screening, day 1, week 16, and at the end-of-study treatment visit.
Justification: A mistake in footnote 2 of Table 3 was corrected.
Protocol sections affected: 6.1: Table 3 (Table 2 in the original protocol)
Assessments and evaluations of FACT-P and PCS of FACT-P were clarified.
Justification: More information was added.
Protocol sections affected: 6.3.3.7.1, 6.3.3.7.2, 7.7.3
Modification 24: Prohibited therapy 
Any prohibited therapy instead of only antineoplastic therapy leads to discontinuation of 
study treatment. Prohibited therapy is defined in Section 5.7.2.
Justification: The mistake in defining any antineoplastic therapy leading to discontinuation of 
study treatment was corrected to align with Sections 3 and 4.7.1, which specify that patients 
initiating any prohibited treatment before metastasis must discontinue the study treatment. 
These patients will be followed only for survival status until the end of the study.
Protocol section affected: Synopsis (methodology), 6.1, 6.1.3
Modification 25: Osteoclast-targeted therapy
The exclusion criterion for osteoclast-targeted therapy was clarified to exclude patients using 
this therapy for prevention of skeletal-related events and allow those using this therapy for 
osteoporosis at a dose and schedule indicated for osteoporosis. The minimum duration of this 
therapy for osteoporosis indication was deleted.
It was clarified that patients on osteoclast-targeted therapy indicated for osteoporosis may 
continue their treatment at the same dose and schedule during the study. 
Justification: The wording of exclusion criterion 10 was considered by some as unclear. The 
amended wording provides better guidance that is based on clinical practice that is familiar to 
investigators.
Protocol sections affected: Synopsis (exclusion criterion 10), 4.3, 5.7.2


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Modification 26: Unblinding in emergency situations
The following sentence was added to this section to clarify the process for emergency code 
breaks: For urgent safety reasons, the investigator can unblind the patient’s study treatment 
assignment and inform the medical monitor as soon as possible.
Justification: This clarification was made to ensure that the process for emergency code 
breaks is clear to the investigators and thus avoid any unnecessary delays in emergency 
situations. 
Protocol sections affected: Section 5.6.1
Modification 27: Central reading
A mistake in the time point concerning blinded independent central reading at baseline was 
corrected by replacing “day 1” with “screening”.
Justification: A mistake was corrected.
Protocol section affected: Section 1.6.1
Modification 28: Exclusion criterion 6
An unintended colon was removed between the words “treatment” and “completed” from the 
exclusion criterion 6 in Section 4.3. This criterion was correct in the synopsis.
Justification: A typographical error was corrected.
Protocol sections affected: 4.3
Modification 29: Details about Ferlay et al. reference
Ferlay et al. 2010 reference was updated to Ferlay et al. 2012.
Justification: Details related to Ferlay et al. reference were updated to reflect the most recent 
data available.
Protocol sections affected: 1.1 and 10
Modification 30: Screening laboratory assessments, PSA and testosterone
A clarifying sentence was added that it will take 7 to 14 days to obtain results from the safety 
laboratory assessments, testosterone and PSA (including PSADT).
Justification: As decision of entry cannot be done until all information needed for evaluation 
of eligibility is available, the estimated time needed for laboratory assessments, testosterone 
and PSA was added.
Protocol sections affected: 6.1.1
Modification 31: Corrections related to terminology or addition of clarifying text
The following changes related to terminology were corrected throughout the document:


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
Grape was replaced by grapefruit.

Biostatistics and Support Functions and Clinical Trial Supplies of Orion were replaced 
by sponsor.

Cancer related was replaced by prostate cancer-related.

Patient pain diary was replaced by pain diary.
The following additions were made to increase clarity.

“and refrain from sperm donation” was added to inclusion criterion 10 to increase 
clarity that sperm donation is not allowed during the study treatment and for 3 months 
after the end of the study treatment.

Address of the sponsor was added to the title page.

ECOG was added as an additional variable for consistency to synopsis (Methodology).

A sentence “Additionally, the investigator may withdraw a patient at any time if 
he/she considers this to be medically necessary and in the patient’s best interest” was 
added to Section 4.7.1.

Eastern Cooperative Oncology Group [ECOG] was added for consistency to the 
Methodology section in Synopsis.

New abbreviations were added to Table 3.

Table 3: Footnotes 8 and 10 were added to increase clarity.

“unless precluded by local guidelines, e.g. IEC/IRB or regulatory authorities” was 
added to blood samplings for PG.

The sentence “Instructions on image acquisition and submission of scans for central 
reading will be provided in the imaging manual” was added to Section 6.3.1.

HR and BP measurements were re-written in Section 6.6.2.2 to align the 12-ECG 
recordings in Section 6.6.2.1.

HR and BP were added to Section 7.8.2 as baseline will be mean of 3 separate 
recordings also for these variables.

It was clarified that EQ-5D-3L version will be used as there are 2 versions of EQ-5D 
available.
In addition,

corrections of obvious typing errors are not highlighted in this amendment.

the table of contents and numbering of in-text tables were updated to reflect the headings, 
pagination and in-text table numbering of the current document. 


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
the title page, header and footer sections were updated to reflect the version details of the 
current document.
11.2 Amendment 2
Amendment 2 is a global amendment dated 19 JUL 2016.
11.2.1 Overview of changes to the study
11.2.1.1 Modification 1: Sponsorship change
The original clinical study protocol and global protocol amendment 1 were prepared by the 
Orion Corporation, a company that Bayer entered into a global agreement with for the 
development and commercialization of the compound ODM-201. Additionally, effective 
01 JUL 2016, Bayer HealthCare AG merged with its affiliated company Bayer AG. Thereby, 
Bayer HealthCare AG ceased to exist and Bayer AG became its legal successor and assumed 
the role of sponsor for this trial.
The global protocol amendment 2 was updated to reflect the sponsorship change from Orion 
Pharma to Bayer with respect to information on study number and study drug nomenclature. 
The protocol structure continues to follow the Orion template, with a few exceptions. Bayer
specific Title page and Signature page of the sponsor’s medically responsible person were 
added. Section 11 was additionally modified to accommodate Bayer requirement for the 
amendment descriptions. The page header was modified to reflect the Bayer style.
The information on study coordinating investigator was repositioned as it is not included in 
Bayer specific Title page.
The EDC database was amended to be the joint property of both Orion Corporation and 
Bayer.
Protocol sections affected: Cover page for integrated clinical study protocol, Title page, 
Signature of the sponsor’s medically responsible person, Synopsis, 5.1 Investigational 
product, 5.2 Reference product, 8.4 Study centre team information, 8.7 Case report forms, 
11. Protocol amendments, 12. Appendices
11.2.1.2 Modification 2: Introductory information updated
The results from the extension component of the ARAFOR study (Orion Pharma study 
number 3104003) were briefly reviewed to provide the most recent data on the study drug.
Protocol sections affected: 1.5 Clinical studies with ODM-201, 10. Reference list
11.2.1.3 Modification 3: Entry criteria updated
Inclusion criterion 4 was modified for clarity. The protocol section providing additional 
details on the assessment requirements was additionally given for reference.


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Inclusion criterion 6 was modified to correct an error with regards to the required PSA value 
at screening: a value of 2 ng/ml is required. The protocol section providing additional 
details on the assessment requirements was additionally given for reference.
Inclusion criterion 9 was modified to correct an error. Both ALT and AST values at screening 
must be 2.5 x ULN, not only one of them.
Exclusion criterion 1 was modified for clarification purposes: The time periods for detecting 
metastases by blinded central reading or a metastatic disease are now specified. The protocol 
section providing additional details on the assessment requirements was additionally given for 
reference.
Exclusion criterion 5 was revised to make it consistent with inclusion criterion 4 where a 
withdrawal period of 4 weeks before screening (instead of before randomisation) is requested.
Exclusion criterion 14 was modified to make it consistent with the rest of the protocol on how 
to perform the blood pressure measurements.
Exclusion criterion 18 was modified to allow participation of subjects taking part in another 
interventional clinical trial but who are no longer on study treatment (i.e. subjects in follow-
up period). This change is made to clarify that only a wash-out period after any previous 
investigational treatment is required. 
Protocol sections affected: Synopsis, 4.2 Inclusion criteria, 4.3 Exclusion criteria, 5.7.1 Prior 
and concomitant treatments, 6.1.1 Procedures during the screening period (-28 to -1 days)
11.2.1.4 Modification 4: List of prohibited treatments revised
The list of prohibited treatments was amended to include other systemic antineoplastic 
therapies besides cytotoxic chemotherapy. The reason for the addition is that there are other 
systemic antineoplastic therapies, different than cytotoxic chemotherapy, used as standard of 
care or local practice. Information on the prohibited treatments was updated to align with 
current standard of care.
Systemic ketoconazole was clarified to be prohibited treatment as antineoplastic therapy only.
Protocol sections affected: 5.7.2 Prohibited treatments
11.2.1.5 Modification 5: Requirements for monitoring drug-drug interactions revised
The requirement for monitoring the prothrombin time (expressed as INR) in patients under 
vitamin K antagonist therapy was removed. Based on an additional evaluation of the potential 
of ODM-201 to inhibit CYP2C9, the interaction potential is not of any clinical relevance. The 
evaluation was performed using a model-based approach in accordance with the European 
Medicines Agency (EMA) and the US Food and Drug Administration (FDA) guidelines on 
drug-drug interaction. This conclusion has been confirmed by EMA and FDA based on 
scientific requests.


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New in vitro data on CYP enzyme induction has become available and was reflected in the 
protocol. Some wording adaptation was also performed for clarity.
Protocol sections affected: 5.7.3 Drug-drug interactions, 6.6.3 Laboratory safety assessments
11.2.1.6 Modification 6: Site’s role in the confirmation of metastasis clarified
The protocol text was revised to emphasize the need for a qualified site physician to locally 
review all the CT/MRI and bone scans prior to submitting the scans to an independent blinded 
central review. It was also clarified that at screening the scans should not be submitted for 
central review in accordance to the imaging manual if the local qualified site physician has 
determined the patient to be metastatic.
Protocol sections affected: 6.1 Visit schedule (Table 3: footnote 8), 6.1.1 Procedures during 
the screening period (-28 to -1 days), 6.1.2.4 Week 16 (± 7 days) (Visit 4) and every 
subsequent 16 weeks (± 7 days) thereafter, 6.3.1 Primary efficacy variable
11.2.1.7 Modification 7: Collection of the optional PG IC revised
The collection of the optional PG IC for the pharmacogenetic research study will be permitted
unless precluded by local guidelines already from the screening visit onwards to give an 
option to complete the consenting procedures during the same visit, if preferred. PG sample 
will remain to be taken at Day 1 visit or later during the study if feasible.
Protocol sections affected: 6.1 Visit schedule (Table 3: footnotes 12 and 16), 6.1.1 Procedures 
during the screening period (-28 to -1 days), 6.1.2.1 Day 1 (visit 1), 6.5.1 Assessment of 
pharmacogenetic polymorphisms
11.2.1.8 Modification 8: Clarification of PSA values used to confirm patient eligibility 
Additional instructions were provided for investigators on the criteria for PSA values used to 
confirm that the patient has CRPC and fulfils the PSADT criterion. It was clarified that a PSA 
value from a local laboratory must be obtained and used in calculations. It was additionally 
emphasized that all PSA values used to confirm patient’s eligibility need to be taken while the 
patient was on ADT that started at least 4 weeks before each PSA sampling, or at least 
4 weeks after a bilateral orchiectomy. Furthermore, it was clarified that 3 subsequent rising 
PSA levels obtained after the nadir are needed to define CRPC. The need for medical monitor 
to review the PSA and PSADT values submitted on patient eligibility form and to approve the 
form before randomisation was highlighted.
Protocol sections affected: 5.4.2 Implementation of randomisation, 6.1 Visit schedule 
(Table 3: footnote 14), 6.1.1 Procedures during the screening period (-28 to -1 days)
11.2.1.9 Modification 9: Clarification of re-testing and re-screening procedures
A clarification to minimize number of missed subjects otherwise eligible was added about 
permitting re-testing of screening procedures during the 28-day window only if there is a 
medical or logistical reason and after consultation with medical monitor to avoid unnecessary 


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re-testing. One re-screening attempt is allowed per subject after consultation with medical 
monitor.
Protocol sections affected: 6.1.1 Procedures during the screening period (-28 to -1 days)
11.2.1.10 Modification 10: Two study event schedules for follow-up period combined
The two separate study event schedules for the follow-up period after withdrawal of study 
treatment (Table 4 and Table 5) were combined into a single Table (Table 4) for clarification 
purposes. Additionally, the new Table 4 was amended to make it consistent with the protocol 
text with regards to the procedures during the follow-up period. Cross-references throughout
the protocol were updated to reflect this change. 
Protocol sections affected: 3. Overall study design and plan, 4.7.2 Reasons for withdrawal 
from study treatment, 6.1 Visit schedule (Table 4, Table 5), 6.1.3 Follow-up period, 
6.3.1 Primary efficacy variable
11.2.1.11 Modification 11: Study drug accountability emphasized
The importance of study drug accountability was emphasized in the protocol to ensure proper 
documentation for the receipt, distribution, return and destruction of the study drug.
Protocol sections affected: 6.1 Visit schedule (Table 3: footnote 15), 6.1.2.1 Day 1 (visit 1), 
6.1.2.3 Day 29 (± 5 days) (Visit 3), 6.1.2.4 Week 16 (± 7 days) (Visit 4) and every subsequent 
16 weeks (± 7 days) thereafter, 6.1.2.5 End-of-study treatment visit
11.2.1.12 Modification 12: EQ-5D-3L assessment adjusted
The EQ-5D-3L assessment was added to be done also at the end-of-study treatment visit. This 
is determined necessary after the consultation with Health Technology Assessment 
(HTAs)/Payers. The added measurement in conjunction with the baseline measurement will 
allow for calculating an average utility score (QoL) for the on treatment period (end-of-study 
treatment – baseline) per treatment arm.
The week 16 assessment is intended to capture changes in utility score (QoL) due to the initial 
onset of AEs.
The criterion for deterioration in overall QoL was corrected by removing the need for a 
patient to experience deterioration of 0.06 points at 2 consecutive assessments in 
comparison to the baseline. The reason for this is that there are no 2 consecutive EQ-5D-3L 
assessments during the on-treatment period – only week 16 and end-of study treatment.
Because the time period between week 16 and end-of study treatment will be highly variable, 
these two assessments cannot be used.
Protocol sections affected: 6.1 Visit schedule (Table 3: footnote 3), 6.1.2.5 End-of-study 
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11.2.1.13 Modification 13: PK data collection and vital sign measurements revised
In order to allow collection of the required PK data in a more convenient way and to reduce 
the number of protocol deviations, the PK sample collection intervals were widened. Due to 
the flat PK profile of ODM-201 this does not have a relevant impact on the outcome of this 
evaluation. This also applies to the simplification having only BP measurement only once 
during the triplicate ECG collection. It is clinically not necessary to collect BP three times 
within a period of less than 5 minutes which was based on the original protocol when the 
ECG collection was planned at least 5 minutes apart.
The above changes are reflected in a new flow chart (Figure 1) which replaces Table 6.
The protocol language was modified to allow flexibility in the number of centres taking part 
in PK sample collection. Additional centres may be required to participate to ensure collection 
of evaluable samples from approximately 600 patients.
Protocol sections affected: Synopsis, 5.3 Selection and timing of doses, 6.1 Visit schedule
(Table 3: footnote 6), 6.1.1 Procedures during the screening period (-28 to -1 days), 
6.1.2 Procedures during the study treatment period, 6.1.2.1 Day 1 (Visit 1), 6.1.2.2 Day 15 
(± 3 days) (Visit 2), 6.1.2.3 Day 29 (± 5 days) (Visit 3), 6.1.2.4 Week 16 (± 7 days) (Visit 4) 
and every subsequent 16 weeks (± 7 days) thereafter, 6.1.2.5 End-of-study treatment visit, 
6.2 PK assessments during double-blind treatment, 6.4 Pharmacokinetic assessments,
6.4.1 Blood sampling, 6.6.2 Clinical safety assessments, 6.6.2.1 12-lead ECG, 6.6.2.2 Vital 
signs, 7.7.4 Evaluation of pharmacokinetics, 7.8.2 Clinical safety evaluations
11.2.1.14 Modification 14: Unblinding instructions revised
Instructions on unblinding were revised to remove incorrect information: medical monitor is 
not able to unblind a patient’s study treatment assignment via the IRT. Additionally, a 
reference to a separate IRT instruction manual for unblinding guidance was added.
Protocol sections affected: 5.6.1 Breaking of treatment code
11.2.1.15 Modification 15: Number of study centres increased
The protocol was amended to be conducted at approximately 480 study centres to reflect the 
higher number of study centres needed to ensure timely recruitment.
Protocol sections affected: Synopsis, 4.1 Number of patients
11.2.1.16 Modification 16: Non-osseous metastasis need central read confirmation
The erroneous information in Table 1 of not needing to confirm new metastasis appearing in 
distant pathologic lymph nodes (M1a) or other pathological lesion (M1c) according to 
RECIST 1.1 was rectified. Detection of all new suspected metastases on CT/MRI scan at soft 
tissues/visceral level should be confirmed by central review as is done for bone lesions.
Protocol sections affected: 4.7.2.1 Confirmed metastasis (Table 1)


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11.2.1.17 Modification 17: Adverse event reporting instructions revised for clarity and 
consistency
Instructions on AE reporting for randomised patients and for screening failure patients were
clarified and made consistent throughout the protocol.
General description and differences for medical history findings, AEs and laboratory values 
were clarified to minimize incorrect interpretation on how to report AEs.
The Grade 4 severity criterion for an AE was revised to clarify that potentially life-threatening 
means the subject was at risk of death at the time of the event.
The definition of the SAE criterion important medical event was clarified in order to reduce 
misinterpretation of the criterion.
SAE reporting guidance was clarified for occasions when paper SAE form is used as a back-
up reporting system during the study conduct period. At such circumstances, the SAE form is 
to be sent to Bayer by e-mail or fax (in case of internet issues) within the standard SAE 
reporting timeline and the relevant study centre personnel is required to enter and the 
investigator to sign the data in the electronic CRF as soon as possible.
When the electronic CRF is not available anymore, all SAEs considered study treatment 
related were instructed be reported to Bayer using a paper SAE form. Collection of possible 
late toxicities is a required sponsor activity.
Appendix 2 containing a flow chart that describes the routing and time frames of serious 
adverse event reporting was updated to increase accuracy and clarity of the flow chart.
Protocol sections affected: 4.6 Information to be collected on screening failures, 6.1 Visit 
schedule (Table 3: footnote 10, Table 4), 6.1.3 Follow-up period, 6.6.1.1.1 Adverse event, 
6.6.1.1.2 Serious adverse event, 6.6.1.2 Assessment of adverse events, 6.6.1.3 Reporting of 
serious adverse events, 12. Appendices
11.2.1.18 Modification 18: Other clarifications and corrections
In addition to the modifications specified above there have been minor corrections for better 
clarity and consistency.
The collection of secondary and additional variables during the follow-up period was 
made consistent throughout the protocol: Time to PSA progression and PSA response are 
not followed after the patient is withdrawn from study treatment.
The erroneous wording for allocation of next consecutive subject number instead of next 
available randomisation number upon confirmation of subject eligibility was corrected in 
Section 5.4.2. The subject number is allocated when the subject signs the IC.
The instruction to record concomitant treatments used in the treatment of new related or 
unresolved related AEs after the patient has withdrawn from study treatment was 
included to the appropriate sections of the protocol for better guidance and consistency.


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The guidance from Section 6.6.2.1 to confirm an ECG with a QTcF > 500 ms by a 
second ECG taken 1-2 hours later was repeated in all applicable visit descriptions to 
emphasize this requirement and to avoid missing the instruction at the time of visits.
The procedures for capturing data from the BPI-SF and PCS subscale of FACT-P 
questionnaires and from the pain diaries for follow-up visits performed either on-site or 
via telephone contacts were clarified.
The process for collecting information on pregnancies inadvertently fathered by study 
subjects was modified for clarification purposes.
New or progressive regional pathologic lymph nodes are not considered metastases 
although they constitute radiographic progression. For clarity and consistency, the 
primary endpoint metastasis-free survival (MFS) was revised in Section 7.7.1 to be 
consistent with the actual definition of MFS i.e. the time between randomisation and 
evidence of metastasis or death from any cause.
Protocol sections affected: Synopsis, 5.4.2 Implementation of randomisation, 6.1 Visit 
schedule (Table 4), 6.1.1 Procedures during the screening period (-28 to -1 days), 6.1.2.1 Day 
1 (visit 1), 6.1.2.3 Day 29 (± 5 days) (Visit 3), 6.1.2.4 Week 16 (± 7 days) (Visit 4) and every 
subsequent 16 weeks (± 7 days) thereafter, 6.1.2.5 End-of-study treatment visit, 6.1.3 Follow-
up period, 6.6.1.5 Pregnancy during a clinical study, 6.6.2.1 12-lead ECG, 7.7.1 Primary 
efficacy evaluation
11.2.2 Changes to the protocol text
Changes to the protocol text done in Amendment 2 are provided in Section 11.2.2 of 
Amendment 2.
11.3 Amendment 3
Amendment 3 is a global amendment dated 26 FEB 2018.
11.3.1 Overview of changes to the study
11.3.1.1 Modification 1: Modified plan for the statistical analysis
The STRIVE trial examined enzalutamide versus bicalutamide in metastatic castration-
resistant prostate cancer patients. The hazard ratio for the primary endpoint PFS and rPFS was 
0.24 in the subgroup of patients with non-metastatic CRPC (Penson DF et al., 2016). In an 
uncontrolled study of apalutamide with one cohort in non-metastatic castration-resistant 
prostate cancer patients, at a median follow-up of 28.0 months, the median time of MFS was 
not reached (Smith MR et al., 2016).
The above data suggest that the currently assumed treatment effect size of a hazard ratio of 
0.75 is likely too conservative. Therefore, the statistical assumptions have been changed to a 
larger assumed treatment effect size of 0.65 requiring 385 MFS events for the primary 
analysis instead of 572 as calculated under the assumption of a hazard ratio of 0.75.


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The language related to statistical analyses of primary and secondary endpoints was also 
modified. The analysis of the primary efficacy endpoint was referred as MFS analysis 
throughout the protocol. It was also clarified that secondary endpoints including OS will be 
evaluated for statistical significance at the time of the MFS analysis and at a later time point, 
and that the further details will be described in the SAP.
It was clarified that details regarding additional analyses will be included in the SAP. 
Regarding secondary endpoints, it was also specified that established methods to adjust for 
the expected crossover effects on secondary endpoints will be described in the SAP.
Protocol sections affected: Synopsis, 1.6.1 Rationale of the study design, 3 Overall study 
design and plan, 5.3 Selection and timing of doses, 7.1 Estimation of sample size, 7.4 General 
statistical considerations, 7.7.1 Primary efficacy evaluation, 7.7.2 Secondary efficacy 
evaluations, 7.9 Interim analyses
11.3.1.2 Modification 2: Possibility to receive open-label darolutamide treatment
The protocol was modified to allow patients who are on darolutamide/placebo treatment at the 
time of study treatment code unblinding to continue open-label darolutamide treatment at the 
discretion of the investigator, given that study results support a positive benefit/risk 
assessment for darolutamide in the study by judgment of the Sponsor (considering feedback 
from the study steering committee and/or health authorities).
This modification was implemented to address in case of a positive benefit/risk ratio the 
possibility, also for ethical reasons, to provide access to darolutamide treatment to patients 
after the blinded study treatment period as long as they could derive clinical benefit.
Protocol sections affected: Synopsis, 3 Overall study design and plan, 5.3 Selection 
and timing of doses, 5.9 Availability of investigational product after termination of study, 
6.1 Visit schedule, 6.1.2.6 End-of-study treatment visit, 6.1.3 Follow-up period
11.3.1.3 Modification 3: New in vitro data related to drug-drug interaction potential
The protocol was modified to mention the in vitro results of darolutamide drug–drug 
interaction potential. The information regarding BCRP and P-gp inhibition potential was 
aligned based on newly available in vitro information and a drug–drug interaction clinical 
study (see also Modification 4). The changes were included following an IB revision.
The protocol text regarding CYP3A4 induction potential by darolutamide was added based on 
new in vitro results. The clinical relevance of these results is unknown. The restriction to use 
grapefruit fruit was also removed from the protocol. The results from the mass balance study 
and in vitro metabolism evaluation suggest that there is no strong CYP3A4 interaction 
expected by a CYP3A4 inhibitor. Furthermore, darolutamide is a well-tolerated compound 
which has not shown any dose limiting toxicity in the dose escalation study up to 900 mg 
twice daily or in any other trial. Thus, based on the current knowledge there is no need to 
restrict the co-administration of a CYP3A4 inhibitor such as grapefruit juice together with 
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The CYP450 and OATP inhibition potential was added to complete the information on new in 
vitro data. No drug-drug interaction potential in vivo is expected.
Protocol sections affected: 1.3 Nonclinical pharmacokinetics and metabolism, 5.3 Selection 
and timing of doses
11.3.1.4 Modification 4: New data from drug-drug interaction clinical studies
Based on clinical study results, strong CYP3A4 and P-gp inhibitors and strong CYP3A4 
inducers affect the PK of darolutamide. Text was modified to mention the results of drug–
drug interaction clinical studies, and to provide the Investigators with suggestions how to 
manage relevant concomitant medications. The list of strong and moderate CYP3A4 inducers 
was included as an appendix.
Protocol section affected: 5.7.3 Drug-drug interactions, 12 Appendices (Appendix 8 was 
added)
11.3.1.5 Modification 5: Reporting of medical device failures of imported and non-
approved third-party device
According to a new regulatory requirement in Japan, Bayer Japan has to report medical device 
failures of imported and non-approved third-party device used in Bayer-sponsored clinical 
trials in Japan to PMDA, IECs/IRBs and investigators. A new section was added to include 
this requirement.
Protocol section affected: 6.6.4 Reporting of medical device failures (new section)
11.3.1.6 Modification 6: Clarification to the collection of concomitant treatments
A standard guidance text related to contrast media collection was added.
Protocol section affected: 5.7.1 Prior and concomitant treatments
11.3.1.7 Modification 7: Clarification related to additional efficacy variables
The language regarding additional efficacy variables was modified. The change was done to 
clarify that both “percent of patients with ECOG performance status deterioration” and “time 
to ECOG performance status deterioration” will be evaluated as additional efficacy variables. 
The definition of ECOG performance status deterioration was also added to the protocol.
For consistency, the language was also modified to clarify that “percent of patients with PSA 
response” will be evaluated as an efficacy variable.
Protocol sections affected: Synopsis, 2.3 Additional objectives, 6.3.3.5 Percent of patients 
with PSA response, 6.3.3.6 Percent of patients with ECOG performance status deterioration,
6.3.3.7 Time to ECOG performance status deterioration (new section), 7.7.3 Additional 
efficacy evaluations


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11.3.1.8 Modification 8: Assessments for patients who continue on open-label 
darolutamide treatment
To clarify the transition to open-label treatment phase, a start of open-label treatment visit and 
subsequent visit schedule were added for those patients who choose to receive open-label 
darolutamide after unblinding. The schedule of procedures (e.g. QoL, biomarker sampling, 
drug dispensing and accountability) was updated accordingly.
Four-monthly imaging will be continued to ensure to follow-up patients in the darolutamide 
open-label arm for MFS. Local reading is considered to be adequate during the open-label 
treatment phase, no central confirmation is required. 
In addition, it was added that ECG and PK sampling are not required during the open-label 
darolutamide treatment.
Protocol sections affected: Synopsis, 1.6.1 Rationale of the study design, 4.7.2.1 Confirmed 
metastasis, 5.8 Treatment compliance and exposure, 6.1 Visit schedule, 6.1.2.4 Week 16 
(± 7 days) (Visit 4) and every subsequent 16 weeks (± 7 days) thereafter, 6.1.2.5 Start of 
open-label treatment visit (new section), 6.1.2.6 End-of-study treatment visit, 6.3.1 Primary 
efficacy variable, 6.3.3.8 Health-related quality of life, 6.5.2 Assessment of tumour-related 
biomarkers
11.3.1.9 Modification 9: Additional language added to perform survival sweep
Language was added to include additional survival sweeps shortly after the database cut-off 
date for the MFS analysis and prior to any subsequent analysis of OS to ensure that OS data is 
current.
Protocol sections affected: Synopsis, 6.1 Visit schedule, 6.1.4 Unscheduled visits
11.3.1.10 Modification 10: Modification of dosing language
The wording for the study drug dose to be administered was modified: 600 mg (2 tablets of 
300 mg) twice daily with food, equivalent to a total daily dose of 1200 mg.
The change was done to align darolutamide dosing wording across the development program.
Protocol sections affected: Synopsis
11.3.1.11 Modification 11: Nomenclature change
With the approval of the INN darolutamide, the Orion drug nomenclature (ODM-201) was 
replaced with darolutamide throughout the protocol. In addition, the Orion codes for
darolutamide diastereomers and metabolite were replaced with trivial names in the entire 
document.
Protocol sections affected: Abbreviations and definition of terms (new subsection added), the 
entire document (amended sections are not indicated in the protocol body)


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11.3.1.12 Modification 12: Personnel change
The sponsor’s medically responsible person was changed as a result of personnel change.
Protocol section affected: Signature of the sponsor’s medically responsible person
11.3.1.13 Modification 13: Other clarifications and corrections
The wording of exclusion criterion 15 was harmonised between synopsis and Section 4.3.
PFS was removed from the list of follow-up assessments in the synopsis since PFS 
cannot be assessed/reported by site and unless a previous local/regional progression (not 
evaluated as metastasis) MFS and PFS would be coincidental.
The wording was harmonised throughout the protocol to state that approximately 1500 
patients will be randomised and approximately 600 patients will participate in the PK 
sampling. 
The guidance for ECG and vital signs measurements was further clarified in Table 3 and 
in Section 6.6.2.
An error was corrected: a footnote referring to pain diary completion was removed from
the PK diary collection row in Table 3.
The definition of the pain progression was corrected in section 6.3.2.4 since the data will 
not be collected at screening (day 1 is considered baseline).
Since the data related to clinical studies with darolutamide was not updated in the 
introduction section, it was clarified that more detailed information is available in the 
latest available version of the IB.
The abbreviation for AUC0-X was corrected in the list of abbreviations.
The sentence related to local amendments was removed from the cover page since there 
are no local amendments for this study.
Protocol sections affected: Cover page of the integrated protocol, Synopsis, Abbreviations and 
definitions of terms, 1.5 Clinical studies with darolutamide, 4.1 Number of patients,
4.3 Exclusion criteria, 6.1 Visit schedule, 6.3.2.4 Time to pain progression, 6.6.2 Clinical 
safety assessments, 7.7.4 Evaluation of pharmacokinetics
11.3.2 Changes to the protocol text
Changes to the protocol text are provided in a separate track changes version.
11.4 Amendment 4
Amendment 4 is a global amendment dated 06 JUL 2019.


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11.4.1 Overview of changes to the study
Section # and name
Description of change
Rationale
Synopsis
6.1 Visit schedule
6.1.2.6 End-of-study 
treatment visit
6.1.3 Follow-up period
6.1.5 Roll-over study (new 
section)
6.1.6 End of study (new 
section)
7.4 General statistical 
considerations
The option for patients 
currently receiving treatment 
in this study to continue 
treatment in a roll-over study 
was added. Statistical 
considerations were 
described.
The end of the study was 
defined.
To enable patients who are 
receiving darolutamide treatment 
in the current study to continue 
to receive darolutamide 
treatment when the study is 
completed.
The section for the end of the 
study was added for 
completeness and clarity. 
5.7.3 Drug-drug 
interactions
The recommendation to 
avoid concomitant use of 
moderate CYP3A4 inducers 
was deleted (while strong 
CYP3A4 inducers should still 
be avoided).
Recent results have established
the darolutamide exposure-
response relationship which 
showed a flat relationship 
(maximum PSA response) over 
the entire exposure range of 
600 mg BID and also at 
exposures below that range. 
Thus, even with a darolutamide
exposure decrease of 50%
(potentially driven by a CYP3A4 
inducer), there would still be 
sufficient effect on PSA.
Therefore the modification 
allows the use of moderate 
CYP3A4 inducers.
Synopsis
3 Overall study design 
and plan
4.7.1 Reasons for 
discontinuation of study
4.7.2 Reasons for 
withdrawal from study 
treatment
4.7.2.1 Confirmed 
metastasis
Open-label study wording 
was updated to: 
describe the endpoint of 
the study visits and 
follow-up
describe the local and 
central reading 
requirements for 
metastasis assessments
add guidance related to 
discontinuation of study 
Modifications were made for 
clarity for the open-label part of 
the study, and to correct an 
inconsistency related to ECG 
requirements.


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Section # and name
Description of change
Rationale
6.1 Visit schedule
6.1.2.6 End-of-study 
treatment visit
6.1.3 Follow-up period
6.2 PK assessments 
during double-blind 
treatment
treatment
clarify the time points of 
ECG collection
Title page
Signature of the sponsor’s 
medically responsible 
person
The sponsor’s medical 
expert / medically 
responsible person was 
changed.
Administrative change
11.2.2 Changes to the 
protocol text
The old/new text detailed 
comparison from protocol 
amendment 2 was removed 
and a reference to 
amendment 2 was added.
For brevity, to improve 
readability, and to reduce 
complexity of the protocol.
5.7.2 Prohibited 
treatments
The sentence “Concomitant 
treatment with another 
systemic antineoplastic 
therapy (except GnRH) or 
another investigational 
medicinal product” was 
removed.
To reduce redundancy within the 
section. 
11.4.2 Changes to the protocol text
Changes to the protocol text are provided in a separate track changes version.
12. APPENDICES
Appendix 1.
Investigator consent page
Appendix 2.
Routing and time frames of serious adverse event reporting
Appendix 3.
ECOG performance status
Appendix 4.
Brief Pain Inventory – Short Form
Appendix 5a.
FACT-P


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Appendix 5b.
PCS subscale of FACT-P
Appendix 6.
EQ-5D-3L
Appendix 7.
EORTC-QLQ-PR25
Appendix 8.
  List of strong and moderate CYP3A4 inducers


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APPENDIX 1. INVESTIGATOR CONSENT PAGE
STUDY COORDINATING INVESTIGATOR
SIGNATURE AND CONSENT
TO THE INTEGRATED CLINICAL STUDY PROTOCOL
(AMENDMENT 04)
Study title:
A multinational, randomised, double-blind, placebo-
controlled, Phase III efficacy and safety study of 
darolutamide (ODM-201) in men with high-risk non-
metastatic castration-resistant prostate cancer
Study code:
17712 (former Orion Pharma study code 3104007)
I have carefully read the protocol (version 5.0) and agree to its terms. I am also aware of 
content of The Declaration of Helsinki, the principles of which are followed in this study.
Centre number:
Study coordinating 
investigator:
Signature:
Date:
.


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INVESTIGATOR
SIGNATURE AND CONSENT
TO THE INTEGRATED CLINICAL STUDY PROTOCOL
(AMENDMENT 04)
Study title:
A multinational, randomised, double-blind, placebo-
controlled, Phase III efficacy and safety study of 
darolutamide (ODM-201) in men with high-risk non-
metastatic castration-resistant prostate cancer
Study code:
17712 (former Orion Pharma study code 3104007)
I have carefully read the protocol (version 5.0) and agree to its terms. I am also aware of 
content of The Declaration of Helsinki, the principles of which are followed in this study.
Centre number:
Investigator:
Signature:
Date:


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Appendix 2. ROUTING AND TIME FRAMES OF SERIOUS ADVERSE EVENT 
REPORTING


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Appendix 3. ECOG performance status
Grade
ECOG performance status
0
Fully active, able to carry on all pre-disease 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 house work, 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 selfcare, confined to bed or chair more than 50% of waking 
hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
5
Dead


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Appendix 4. Brief Pain Inventory – Short Form
CCI


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CCI


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Appendix 5a. FACT-P
CCI


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CCI


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CCI


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Appendix 5b. PCS subscale of FACT-P
CCI


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Appendix 6. EQ-5D
CCI


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CCI


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CCI


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Appendix 7. EORTC-QLQ-PR25
CCI


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CCI


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Appendix 8. List of strong and moderate CYP3A4 inducers
Strong
Ajmaline phenobarbital
Carbamazepine
Enzalutamide
Fosphenytoin
Hypericum perforatum (St. John’s Wort)
Lumacaftor
Methylphenobarbital
Mitotane
Phenobarbital
Phenytoin
Primidone
Propranolol phenobarbital
Rifabutin
Rifampicin
Rifamycin
Rifapentin
Moderate
Bosentan
Efavirenz
Etravirine
Lopinavir
Mephenytoin
Modafinil
Nafcillin

SAP_003.pdf: 
 
 
 
Document Type: 
Statistical Analysis Plan 
Official Title: 
A multinational, randomised, double-blind, placebo-controlled, 
Phase III efficacy and safety study of darolutamide (ODM-201) in 
men with high-risk non-metastatic castration-resistant prostate 
cancer 
NCT Number: 
NCT02200614 
Document Date: 
12 March 2021 
 


Statistical Analysis Plan - Supplement7
Protocol No.: BAY 1841788 / 17712
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Title page
A multinational, randomized, double-blind, placebo-controlled, Phase III 
efficacy and safety study of darolutamide (ODM-201) in men with high-risk 
non-metastatic castration-resistant prostate cancer
Bayer study drug
BAY 1841788 / darolutamide
Clinical study 
phase:
III
Date:
12 MAR 2021
Study No.:
17712
Version:
1.0
Author:
Confidential
The information provided in this document is strictly confidential and is intended solely 
for the guidance 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) are not displayed.  Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.
This Statistical Analysis Plan is produced on a word-processing system and bears no signatures.
The approval of the Statistical Analysis Plan is documented in a separate Signature Document.
PPD


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Table of Contents
Title page................................................................................................................................... 1
Table of Contents...................................................................................................................... 2
Table of Tables.......................................................................................................................... 2
List of Abbreviations................................................................................................................ 3
1.
Introduction ....................................................................................................................... 3
2.
Study Objectives................................................................................................................ 3
3.
Study Design ...................................................................................................................... 4
4.
General Statistical Considerations .................................................................................. 4
5.
Analysis Sets....................................................................................................................... 4
6.
Statistical Methodology..................................................................................................... 4
6.1
Population characteristics ................................................................................................ 4
6.1.1
Disposition of patients.................................................................................................. 4
6.1.2
Demographic and Baseline Characteristics .................................................................. 4
6.1.3
Medical history............................................................................................................. 5
6.1.4
Prior and concomitant medications .............................................................................. 5
6.2
Efficacy............................................................................................................................ 5
6.3
Pharmacokinetics/pharmacodynamics............................................................................. 5
6.4
Biomarker evaluation....................................................................................................... 5
6.5
Safety ............................................................................................................................... 5
6.5.1
Extent of exposure........................................................................................................ 6
6.5.2
Adverse events.............................................................................................................. 6
6.5.3
Deaths and Serious Adverse events............................................................................ 13
6.5.4
Clinical laboratory data............................................................................................... 13
6.5.5
12-Lead ECG, QTc..................................................................................................... 15
6.5.6
Other safety measures................................................................................................. 15
6.5.7
Physical examinations ................................................................................................ 16
7.
Document history and changes in the planned statistical analysis:............................ 16
8.
References ........................................................................................................................ 16
9.
Appendices ....................................................................................................................... 16
Table of Tables
Table 6–1: MedDRA search criteria for special topics .............................................................. 8
Table 6–2: TEAEs grouped by data driven approach: ............................................................. 10


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List of Abbreviations
AE
Adverse Event
BMI
Body Mass Index
CI
Confidence Interval
CRF
Case Report Form
ECG
Electrocardiogram 
FAS
Full Analysis Set
HLGT
High level group term
HLT
High level term
MedDRA
Medical Dictionary for Regulatory Activities
MLG
MedDRA Labelling Grouping
n
Number of non-missing values
N/A
Not Applicable
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse 
Events
nmCRPC
Non-metastatic castration-resistant prostate cancer
PT
Preferred Term
QTc
Corrected QT
SAE
Serious Adverse Event
SAF
Safety Analysis Set
SAP
Statistical Analysis Plan
SOC
System organ class
TEAE
Treatment-Emergent AE
TESAE
Treatment-Emergent SAE
WHO-DD
World Health Organization Drug Dictionary
1.
Introduction
Study 17712 (ARAMIS) is a multinational, randomized, double-blind, placebo-controlled, 
phase III efficacy and safety study of darolutamide in men with high-risk non-metastatic 
castration-resistant prostate cancer (nmCRPC).
This supplement to the statistical analysis plan (SAP) describes the analyses and data 
presentations for final clinical study report addendum when all patients have discontinued the 
trial.
This SAP Supplemental 7 version 1.0 is based on integrated protocol version 5.0
(amendment 4) dated 06 JUL 2019, on Supplemental 4 SAP version 1.0 dated 04 DEC 2019 
and SAP v4.2 dated 20 SEP 2018.
2.
Study Objectives
Refer to main SAP v4.2 dated 20 SEP 2018.


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3.
Study Design
Refer to main SAP v4.2 dated 20 SEP 2018.
4.
General Statistical Considerations
Refer to main SAP v4.2 dated 20 SEP 2018.
5.
Analysis Sets
Refer to main SAP v4.2 dated 20 SEP 2018.
6.
Statistical Methodology
The statistical analyses will be descriptive. Summaries will be provided for both treatment 
groups, darolutamide and placebo. 
For disposition tables, concomitant medications, concurrent procedures, study-drug exposure 
tables and adverse events tables, the patients who switched from placebo to darolutamide 
during the open-label period will be displayed. These following treatment groups will be 
shown: darolutamide total (double-blind and open-label periods), darolutamide double-blind 
period, placebo double-blind period, placebo-darolutamide cross-over patients.
6.1
Population characteristics
6.1.1
Disposition of patients
A summary table will be presented for the number of patients enrolled and the number and 
percentage of patients in each of the defined populations. Re-screened patients will only be 
counted once.
The reasons for patients excluded from each of the patient populations will also be tabulated. 
The reasons for discontinuation of study treatment will be tabulated.
6.1.2
Demographic and Baseline Characteristics
No demographics and baseline characteristics analyses will be performed in this addendum.


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6.1.3
Medical history
No medical history analysis will be performed.
6.1.4
Prior and concomitant medications
The following concomitant medications and procedures tables will be created:

Concurrent diagnostic and therapeutic procedures: frequency of patients by procedure 

Concomitant medications: frequency of patients for each drug category 

Concurrent diagnostic and therapeutic procedures related to adverse event (AE): 
frequency of patients by procedure 
The dictionary used for coding medications is the WHO Drug Dictionary.
Concomitant medications, subsequent treatment and concurrent procedures will be displayed 
for darolutamide total (double-blind and open-label periods), darolutamide double-blind 
period, placebo double-blind period, placebo-darolutamide cross-over patients.
If the start date of the concomitant medications or concurrent procedures is missing, the 
respective medications or procedures will be considered under the double-blind period.
In addition to the full analysis set (FAS) population, concomitant medication will also be 
summarized for the safety analysis set (SAF) population.
6.2
Efficacy
No efficacy analyses will be performed, only follow-up time will be presented.
The duration of follow-up, defined as time from randomization to last contact or death at the 
database cut-off date, will be summarised using descriptive statistics (number of 
observations, mean, standard deviation, minimum, median and maximum).
6.3
Pharmacokinetics/pharmacodynamics
No pharmacokinetic analyses will be performed.
6.4
Biomarker evaluation 
No biomarker analyses will be performed.
6.5
Safety
All data including the open-label period will be summarized.
For patients randomized to darolutamide, safety events will be displayed separately for:

the double-blind period


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
the double-blind and open-label periods (total)
For patients randomized to placebo, safety events will be displayed separately for:

the double-blind period

the open-label period after cross-over to darolutamide treatment 
The double-blind period of the study only will be considered for risk difference, risk ratio, 
interval-specific incidence and prevalence.
If the start date of the AE is missing then the event will be considered occurring during the 
double-blind period.
No formal statistical tests will be done for the safety endpoints. All analyses for safety will be 
performed in the SAF population.
6.5.1
Extent of exposure
Extent of exposure will be summarized for the SAF by treatment group, using descriptive 
statistics. Patients who switched from placebo to darolutamide during the open-label period
will be described.
Duration of study treatment will be calculated in days and presented in months as the date of 
the last dose of any study treatment – date of the first dose of any study treatment + 1.
Dose modifications will be summarized.
6.5.2
Adverse events
All adverse events (AE) whether considered drug-related or not, will be reported on the case 
report form (CRF) with diagnosis, start/stop dates, dates of any grade change, action taken, 
whether treatment was discontinued, any corrective measures taken, and outcome. For all 
events, the relationship to treatment and the severity of the event will be determined by the 
Investigator. AEs will be classified and coded using the National Cancer Institute (NCI) 
Common Terminology Criteria Adverse Event (CTCAE), version 4.03.
The treatment period for this study, for purposes of safety analyses, extends from the 
initiation of study treatment until 30 days after the last administration of study treatment.
Each change in AE grade was entered as a separate record with no automatic link to the 
original AE record, which may lead to variations of the verbatim for the same AE. This 
makes a correct grouping of AE grades, which actually belong together, not always possible. 
An AE is considered as treatment-emergent (TEAE) if there is an AE record which starts 
during treatment or within the post-treatment time window of 30 days.


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For further definitions of the terms AE, SAE, seriousness, intensity, causal relationship with
treatment, causal relationship to protocol-required procedures, action taken, and outcome; 
see Protocol Section 6.6.1.
Descriptive summary tables (frequency and percentage of patients, not of events) will be 
presented by treatment group and MedDRA version 24.0, or the most recent version for the 
following:

Pre-treatment AEs

TEAEs

TEAEs with grade 3, 4, or 5

TEAEs occurring in at least 1% of patients

TEAEs occurring in at least 5% of patients

TEAEs leading to study drug withdrawal

TEAEs leading to dose reduction

TEAEs leading to drug interruption

TEAEs leading to dose reduction and/or drug interruption

Drug-related TEAEs

Drug-related TEAEs with grades 3, 4, or 5

Drug-related TEAEs occurring in at least 5% of patients in any treatment group

Drug-related TEAEs leading to study drug withdrawal

Drug-related TEAEs leading to dose reduction

Drug-related TEAEs leading to drug interruption

Drug-related TEAEs leading to dose reduction and/or drug interruption

Interval specific and cumulative event rates for TEAEs (for TEAEs with at least a 5% 
total incidence rate (any grade)).

Post-treatment non-treatment-emergent AEs
Listings of non-treatment-emergent AEs and treatment-emergent AEs not coded per NCI-
CTCAE dictionary will be created.
No subgroup analyses will be performed.


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Grouped AE terms defined as special topics
Following TEAEs are considered as special topics, Table 6–1:
Table 6–1: MedDRA search criteria for special topics 
Grouped term
MedDRA search criteria
Bone fractures
HLT: Fractures and dislocations NEC (without PTs: Joint dislocation, Joint 
dislocation pathological)
HLT: Limb fractures and dislocations (without PT: Radial head dislocation)
HLT: Pelvic fractures and dislocations
HLT: Skull fractures, facial bone fractures and dislocations
HLT: Spinal fractures and dislocations (without PT: Dislocation of vertebra)
HLT: Thoracic cage fractures and dislocations (without PT: Dislocation of 
sternum))
Fall
PT: Fall
PT: Accident
Seizure
MLG: Seizures
Fatigue
MLG: Decreased general strength and energy
PT: Lethargy; PT Chronic fatigue syndrome; PT Malaise
Weight 
decreased
MLG: Weight decreased
MLG: MedDRA Labeling Grouping; PT: Preferred Term; HLT: High Level Term
Following tables will be created for the TEAE of special topics as defined above

TEAEs

TEAEs leading to study drug withdrawal

TEAEs leading to dose reduction

TEAEs leading to drug interruption

Exposure adjusted special topics TEAEs per 100 patient years

Prevalence rates for most common TEAEs

Risk ratio for TEAEs

Treatment-emergent SAEs (TESAEs)
Fracture events will be described by a cumulative incidence plot of fracture. A summary of 
treatment-emergent fracture by bone sparing agent use (bone sparing agent will be selected in 
CM dataset using ATC codes M05B drugs affecting bone structure and mineralization, 
A11CC Vitamin D and analogues, A12A Calcium, A12CD Fluoride and H05BA Calcitonins)
at study entry will be provided. Association with weight decrease will be presented by 
histogram of fracture events by patient weight change (the weight collected closest to the start 
of fracture will be considered and compared to baseline weight).


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A listing will be generated for patients with fall treatment-emergent events with syncope 
and/or loss of consciousness (using the MLG Syncope).
Timing of occurrence of fracture events based on first dose of study drug will be presented. A 
detailed summary of patients with fall and fracture events will be presented, in addition, a 
graph will be created to display the time to fall and time to fracture.
An overview of patients at risk for developing an AE seizure will be tabulated by displaying 
medical history.
To adjust for unequal lengths of study treatment period among patients, and potentially 
between treatment groups, an additional summary based on event rate per 100 patient years
will be performed for all TEAEs, special topics TEAEs and all TESAEs occurring during the 
double-blind treatment. The event rate per patient is calculated as the total number of events 
divided by the total treatment duration in years. The treatment duration in years will be 
calculated as treatment duration in days divided by 365.25.
Additional AE groupings
The following additional tables for treatment-emergent adverse events (TEAEs) will be 
created. In all tables, results will be shown by treatment group. The double-blind part of the 
study will be considered only for risk difference, risk ratio, interval-specific incidence and 
prevalence.
To increase the sensitivity of the analysis, the synonymous or pathophysiologically related 
TEAEs were grouped using following approaches: 

Utilization of MedDRA hierarchy – i.e. using grouping on the level of system organ 
class (SOC) or high level group term (HLGT) or high level term (HLT),

Utilization of predefined customized MedDRA queries denoted as MedDRA Labeling 
Groupings (MLG). These MLG are created and centrally maintained by Bayer 
internal coding experts,

Data driven approach was used for grouping of TEAEs, for which the mentioned 
above predefined grouping were not available/suitable. For this purpose, a customized 
MedDRA query was created by selection of MedDRA terms after the review of safety 
data, as shown in Table 6–2.
Incidence proportions will be calculated as number of patients experiencing an event per 
number of patients exposed. Incidence proportions will be presented by worst CTCAE grade 
(grade 1 to grade 5, missing grade, any grade)

by MedDRA SOC, HLGT, HLT, preferred term (PT) and worst CTCAE grade,

by MLG, PT and worst CTCAE grade,

by data driven grouping, PT and worst CTCAE grade.
A separate table will be created for PTs not covered by MLG or data driven grouping. 
A definition table for the groupings will be provided, showing the AE grouping, the type of 
grouping entity used for definition (e.g. MLG, combination of MLGs, MLG + PT, data 


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driven), the corresponding preferred terms, and the reported terms. Preferred terms which 
occurred in the data are marked with preceding asterisk (***).
The risk difference ‘Darolutamide – Placebo’ and risk ratio ‘Darolutamide/Placebo’ will be 
calculated together with 95% confidence intervals (CIs). No zero-cell correction will be 
applied for calculation of the risk ratio, i.e. in case of no events in the placebo arm the risk 
ratio will not be calculated. The incidence rate ratio for Darolutamide/Placebo will also be 
calculated with 95% CI.
Risk difference, risk ratio, incidence rate ratio with 95% CIs will also be calculated for the 
predefined grouped terms defined as special topics, see Table 6–1.
Interval specific and cumulative incidence proportions will be created for grouped TEAEs
(i.e. HLGT/HLT, MLG, data driven grouping) with a 5% incidence proportion of at least 5% 
in either treatment group. The prevalence of these events will also be displayed for the same 
intervals. Prevalence will be calculated as the number patients with the respective TEAE 
starting or ongoing in the specific time interval, divided by the number of patients still being 
in the study at the beginning of the time interval.
Table 6–2: TEAEs grouped by data driven approach: 
Grouped term
MedDRA search criteria
Pneumonia and 
Pneumonitis
PT:
Lower respiratory tract infection; Lung infection; Pneumonia; Pneumonia 
pneumococcal; Pneumonia staphylococcal; Lower respiratory tract 
inflammation; Pneumonitis
Diabetes mellitus 
and 
Hyperglycaemia 
MLG plus
MLG: Hyperglycaemia
PT: Diabetes mellitus; Diabetes mellitus inadequate control; Diabetic 
metabolic decompensation; Type 2 diabetes mellitus; Diabetic ketoacidosis
Renal impairment
MLG combo plus
MLG: Laboratory tests related to reduced renal function
MLG: Renal impairment
PT: Blood urea increased
Rash
MLG combo plus
MLG: Rash
MLG: Skin erythema
PT: Dermatitis
Dizziness
MLG plus
MLG: Dizziness
PT: Vertigo
Cerebral ischaemia 
MLG combo plus
MLG: Cerebral infarction and stroke not specified as hemorrhagic or 
ischemic
MLG: Cerebral ischemic infarction and stroke
PT: Cerebral ischaemia: Transient ischaemic attack
MLG: MedDRA Labeling Grouping; PT: Preferred Term; HLT: High Level Term
The following tables will be created:


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Incidence proportions by worst CTCAE grade: These tables are company standard tables 
showing the absolute and relative frequencies in each treatment group, by worst CTCAE 
grade.

TEAEs by MedDRA (SOC/ HLGT/ HLT/ PT) and worst CTCAE grade,

Treatment-emergent grouped adverse events by MedDRA labeling grouping (MLG), 
PT and worst CTCAE grade,

Treatment-emergent grouped adverse events by data driven grouping, PT and worst 
CTCAE grade,

Definition of adverse events MedDRA labeling groupings (MLG),

Definition of adverse events data driven groupings,

TEAEs - PTs not covered by MLG or data driven grouping and worst CTCAE grade.
Risk difference, risk ratio, exposure-adjusted rates and incidence rate ratio: These tables show 
columns for AE grouping, incidence proportion darolutamide, incidence proportion placebo, 
risk difference with 95% confidence interval (CI), risk ratio with 95% CI, exposure-adjusted 
incidence rate darolutamide, exposure-adjusted incidence rate placebo, incidence rate ratio 
with 95% CI.

Incidence rates and overall risk ratio for grouped terms defined as special topics –
double-blind treatment period

Incidence rates and overall risk ratio for TEAEs by MedDRA SOC, HLGT and HLT
– double-blind treatment period. All numbers will be shown on the HLGT and HLT 
level, not on the SOC level. The SOC is used for sorting only.

Incidence rates and overall risk ratio for TEAEs by MLG – double-blind treatment 
period

Incidence rates and overall risk ratio for TEAEs by data driven grouping – double-
blind treatment period
TEAEs over time for common TEAEs (frequency > 5% in any treatment group)

Interval-specific and cumulative event rates for most common TEAEs by HLGT/HLT 
grouping – double-blind treatment period

Interval-specific and cumulative event rates for most common TEAEs by MLG
grouping – double-blind treatment period

Interval-specific and cumulative event rates for most common TEAEs by data driven 
grouping – double-blind treatment period

Prevalence over time for most common TEAEs by HLGT/HLT grouping – double-
blind treatment period

Prevalence over time for most common TEAEs by MLG grouping – double-blind 
treatment period


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
Prevalence over time for most common TEAEs by data driven grouping – double-
blind treatment period
Adverse events within SOC Cardiac disorders 
The following additional tables for TEAEs by history of cardiac disorders will be created:

for the subgroup of patients with present medical history in the SOC ‘Cardiac
history’,

for the subgroup of patients without present medical history in the SOC ‘Cardiac 
history’.
In all tables, results will be shown by treatment group.
Incidence proportions of the TEAEs in the system organ class (SOC) ‘Cardiac disorders’ will 
be presented by HLGT, HLT, PT and worst CTCAE grade.
Interval specific and cumulative incidence proportions for TEAEs will be presented for the 
HLGTs Cardiac arrhythmias, Coronary artery disorders, and Heart failures.
In addition, Exposure adjusted treatment-emergent AE (fracture, weight decrease, cardiac 
disorders, fall) per 100 patient years will be created for the treatment groups:

Darolutamide – double-blind period

Darolutamide – double-blind and open-label periods

Placebo – double-blind period
Below selection will be used:

Bone fractures: HLT: Fractures and dislocations NEC (without PTs: Joint dislocation, 
Joint dislocation pathological), HLT: Limb fractures and dislocations (without PT: 
Radial head dislocation), HLT: Pelvic fractures and dislocations, HLT: Skull 
fractures, facial bone fractures and dislocations, HLT: Spinal fractures and 
dislocations (without PT: Dislocation of vertebra), HLT: Thoracic cage fractures and 
dislocations (without PT: Dislocation of sternum)

Weight decrease: MLG weight decrease

Cardiac arrhythmia: HLGT cardiac arrhythmias

Coronary artery disorders: HLGT coronary artery disorders

Heart failures: HLGT Heart failures

Fall: PT Fall and PT Accident


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6.5.3
Deaths and Serious Adverse events
Serious adverse events (SAE) will be classified using the National Cancer Institute (NCI) 
Common Terminology Criteria Adverse Event (CTCAE), version 4.03 and MedDRA version 
24.0 or most recent version

TESAEs

TESAEs leading to study drug withdrawal

TESAEs leading to dose reduction

TESAEs leading to drug interruption

TESAEs leading to dose reduction and/or drug interruption

Drug-related TESAEs

Listing of TESAEs

Listing of non-treatment-emergent SAEs
The incidence of deaths in the study and especially deaths up to 30 days of last dose of study 
drug will be summarized by each treatment group and cause of death. All deaths up to 30 
days of last dose of study drug will be listed by patient with start and stop date of study 
medication, date of death, and cause of death. All deaths beyond 30 days after last dose of 
study drug will be displayed in a separate listing.
6.5.4
Clinical laboratory data
Descriptive statistics (number of observations, mean, standard deviation, minimum, median 
and maximum values) will be presented for clinical laboratory tests (hematology, clinical
biochemistry and urinalysis), their changes from baseline (including baseline value), and their 
percent changes from baseline by treatment group at applicable visits.
Hematological and biochemical laboratory values will be graded based on NCI CTCAE 
version 4.03. CTCAE severity grading for laboratory abnormalities are based on applicable 
laboratory threshold values outlined in NCI CTCAE v4.03. It should be noted that in the 
present analysis of those laboratory parameters for which additional clinical information 
potentially can also influence the toxicity grade, this clinical information is in general not 
available and only the laboratory measurements are used for grading.
Any additional specific handling of the NCI CTCAE v4.03 toxicity grading assignments will 
be noted in the footnotes of the corresponding tables as applicable per the data collection in 
the study.

In the event of overlapping CTCAE criteria ranges for specific lab tests, the algorithm 
assigns the worst grade 

If calcium type is not recorded (i.e. only “calcium” is recorded), then grading is done 
as if the calcium is total calcium.  “Calcium corrected” is computed from total 


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calcium and serum albumin (if ≤4.0 g/dl) from the same time point based on CTCAE 
v3.0 guidance. If serum albumin (if ≤4.0 g/dl) from the same time point is not 
available or if “calcium, unspecified” was collected then grading is done as if the 
calcium is ”corrected calcium.”

Results with special characters (such as “>” and “<”) are not graded.
The frequency of laboratory abnormalities regarding hematology, coagulation panel, clinical 
chemistry, and urinalysis will be tabulated by treatment group. Worst grades for 
hematological and biochemical toxicities will be calculated according to CTCAE, version 
4.03 based on laboratory measurements, and will be summarized by treatment group and NCI 
CTCAE v4.03 category and worst grade.
Clinical laboratory toxicities during treatment including a period of 30 days after last dose of
treatment will be considered as “treatment-emergent.
The last non-missing value before or on the first day of study drug will be retained as 
“baseline” data. If several assessments are performed on the same day (without timing 
information) the average of the values will be considered.
Incidence tables (frequency and percentage of patients) as well as tables with change in NCI 
CTCAE v4.03 worst grade from baseline will be presented as following:

Treatment-emergent hematological and biochemical toxicity.

Treatment-emergent hematological and biochemical toxicities with incidence rate 
above 5% in any treatment group.

Change in worst grade for hematological and biochemical toxicity from baseline.
The laboratory values will be also categorized into low, normal and high according to their 
reference ranges.
Descriptive statistics will be calculated by treatment group and time interval. 16-week time 
intervals will be used.
A listing will be provided for all patients possibly fulfilling Hy’s Law criteria, i.e. patients 
with elevated AST and / or ALT > 3xULN, alkaline phosphatase < 2xULN and bilirubin 
≥2xULN. For possible Hy’s Law cases relevant laboratory data will also be displayed 
graphically within actual patient profiles (presenting total bilirubin, ALT, AST and ALP 
values in terms of ULN over time) by treatment group. Below example of Hy’s law plot will 
be provided for peak total bilirubin vs ALT. If a patient has any total bilirubin ≥ 2xULN then 
peak bilirubin will be plotted versus the maximum ALT amongst the total bilirubin ≥ 2xULN. 
Otherwise, peak bilirubin will be plotted versus peak ALT.
Example for Hy’s law plot:


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Unscheduled laboratory data will be included in the descriptive tables.
6.5.5
12-Lead ECG, QTc
No analyses of ECG will be performed.
6.5.6
Other safety measures
For each treatment group, vital signs (i.e. blood pressure, heart rate, weight and BMI) will be 
tabulated and summarized by visit for observed values and changes from baseline using 
descriptive statistics, as appropriate. If more than one baseline assessment was collected, the 
most recent one will be used. If several assessments are performed on the same day (without 
timing information) the average of the values will be considered.
Outlier analyses will be conducted using the following limits: 

low systolic blood pressure:
90 mmHg and a decrease of 20 mmHg

high systolic blood pressure: >190 mmHg and an increase of 20 mmHg

low diastolic blood pressure: 50 mmHg and a decrease of 20 mmHg

high diastolic blood pressure: > 105 mmHg and an increase of 20 mmHg 
Cholestasis range
Hy's Law range
Normal range
Temple's Corollary range
TREATMENT A: n= &n1.
TREATMENT B: n= &n2.
TREATMENT A: n= &n3.
TREATMENT B: n= &n4.
TREATMENT A: n= &n5.
TREATMENT B: n= &n6.
TREATMENT A: n= &n7.
TREATMENT B: n= &n8.
Treatment
TREATMENT A
TREATMENT B
Peak TBL/ULN 
0.1
1.0
10.0
100.0
Peak ALT/ULN
0.1
1.0
10.0
100.0


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
low heart rate:
< 50 bpm and a decrease of 15 bpm

high heart rate:
> 120 bpm and an increase of 15 bpm
The number and percentage of patients with outlying values will be tabulated by treatment 
group and time interval.
No subgroup analyses will be performed.
Unscheduled vital signs data will be included in the summary tables.
6.5.7
Physical examinations
The number and percent of patients with physical examination abnormalities will be 
summarized based on the safety analysis set for each treatment group and overall. Physical 
examination findings will be presented in a data listing.
No subgroup analyses will be performed.
7.
Document history and changes in the planned statistical analysis:
SAP Version 4.2 dated 20 SEP 2018
Supplemental 4 SAP version 1.0 dated 04DEC2019
Supplemental 5 SAP version 1.0 dated 27JAN2020.
8.
References
Refer to main SAP v4.2 dated 20 SEP 2018.
9.
Appendices
Not applicable.


 
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A multinational, randomised, double-blind, placebo-controlled, Phase III 
efficacy and safety study of darolutamide (ODM-201) in men with high-risk 
non-metastatic castration-resistant prostate cancer 
 
 
Bayer study drug 
BAY 1841788 / darolutamide  
 
Clinical study 
phase: 
III 
Date: 
20 SEP 2018 
Study No.: 
 
17712 
Version: 
4.2 
Author: 
 
 
 
 
Confidential 
The information provided in this document is strictly confidential and is intended solely 
for the guidance 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) are not displayed.  Hence, the 
appearance of product names without these symbols does not imply that these names are not protected. 
 
This Statistical Analysis Plan is produced on a word-processing system and bears no signatures. 
The approval of the Statistical Analysis Plan is documented in a separate Signature Document. 
 
 
PPD


 
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Table of Contents 
Table of Tables .......................................................................................................................... 3 
List of Abbreviations ................................................................................................................ 5 
1. 
Introduction ........................................................................................................................ 7 
2. 
Study Objectives ................................................................................................................ 7 
3. 
Study Design ....................................................................................................................... 8 
3.1 
Determination of Sample Size .......................................................................................... 9 
4. 
General Statistical Considerations ................................................................................. 10 
4.1 
General Principles .......................................................................................................... 10 
4.2 
Handling of Dropouts ..................................................................................................... 10 
4.3 
Handling of Missing Data .............................................................................................. 11 
4.4 
Interim Analyses and Data Monitoring .......................................................................... 12 
4.5 
Data Rules ...................................................................................................................... 13 
4.6 
Blinded Review, Validity Findings, and Protocol Deviations ....................................... 13 
4.6.1 
Blinded Review ........................................................................................................... 14 
4.6.2 
Validity Findings ......................................................................................................... 14 
4.6.3 
Protocol Deviations ..................................................................................................... 14 
5. 
Analysis Sets ..................................................................................................................... 14 
6. 
Statistical Methodology ................................................................................................... 15 
6.1 
Population characteristics ............................................................................................... 15 
6.1.1 
Disposition of patients ................................................................................................. 15 
6.1.2 
Demographic and Baseline Characteristics ................................................................. 16 
6.1.3 
Medical history ............................................................................................................ 18 
6.1.4 
Prior and concomitant medications ............................................................................. 18 
6.2 
Efficacy ........................................................................................................................... 19 
6.2.1 
Primary Efficacy Analysis .......................................................................................... 19 
 
Metastasis-free survival (MFS) ................................................................................ 19 
6.2.2 
Analysis of secondary efficacy endpoints ................................................................... 28 
 
Overall survival (OS) ............................................................................................... 31 
 
Time to pain progression ......................................................................................... 33 
 
Time to initiation of first cytotoxic chemotherapy .................................................. 34 
 
Time to first symptomatic skeletal event (SSE) ...................................................... 35 
6.2.3 
Tertiary or additional efficacy analysis ....................................................................... 37 
 
Progression-free Survival (PFS) .............................................................................. 37 
 
Time to first prostate cancer-related invasive procedures ....................................... 39 
 
Time to initiation of subsequent antineoplastic therapy .......................................... 40 
 
Time to PSA progression ......................................................................................... 41 
 
Percent of patients with PSA response .................................................................... 42 
 
Percent of patients with ECOG performance status deterioration ........................... 43 
 
Time to ECOG performance status deterioration .................................................... 43 


 
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Time to first opioid use for cancer pain ................................................................... 44 
 
Health related Quality of Life and utility values. .................................................... 44 
6.2.3.9.1 
Percent of patients with deterioration of FACT-P total score at 16 weeks .......... 48 
6.2.3.9.2 
Time to deterioration in PCS subscale score ........................................................ 48 
6.2.3.9.3 
Percent of patients with improvement of EORTC-QLQ-PR25 urinary 
symptoms .............................................................................................................. 49 
6.2.3.9.4 
Time to worsening of EORTC-QLQ-PR25 urinary symptom score .................... 49 
6.2.3.9.5 
Percent of patients with deterioration of EQ-5D-3L utility score at 16 weeks .... 50 
6.2.4 
Subgroup analysis ....................................................................................................... 50 
6.3 
Pharmacokinetics/pharmacodynamics ........................................................................... 51 
6.4 
Biomarker evaluation ..................................................................................................... 51 
6.5 
Safety .............................................................................................................................. 52 
6.5.1 
Extent of exposure ....................................................................................................... 52 
6.5.2 
Adverse events ............................................................................................................ 52 
6.5.3 
Deaths and Serious Adverse events ............................................................................ 55 
6.5.4 
Clinical laboratory data ............................................................................................... 55 
6.5.5 
12-Lead ECG, QTc ..................................................................................................... 57 
6.5.6 
Other safety measures ................................................................................................. 58 
6.5.7 
Physical examinations ................................................................................................. 59 
7. 
Document history and changes in the planned statistical analysis: ............................ 59 
8. 
References ......................................................................................................................... 60 
9. 
Appendices ........................................................................................................................ 61 
9.1 
Study event schedule ...................................................................................................... 61 
9.2 
Brief pain Inventory – Short Form (BPI-SF) questionnaire and scoring information ... 67 
9.3 
FACT-P questionnaire and scoring information ............................................................ 69 
9.4 
EORTC-QLQ-PR25 questionnaire and scoring information ......................................... 77 
9.5 
EQ-5D-3L questionnaire and scoring information ......................................................... 80 
9.6 
Prohibited medication: metastasis-free survival ............................................................. 81 
9.7 
Cytotoxic chemotherapy: time to cytotoxic chemotherapy ............................................ 82 
9.8 
Antineoplastic therapy: time to initiation of subsequent antineoplastic therapy ............ 82 
9.9 
Statins medications ......................................................................................................... 83 
9.10 Opioid for cancer pain .................................................................................................... 83 
9.11 Antiandrogen (AR inhibitors) therapy ............................................................................ 83 
9.12 GnRH agonist/antagonist therapy ................................................................................... 83 
9.13 Hormonal therapy ........................................................................................................... 83 
9.14 Bone sparing agent ......................................................................................................... 84 
 
Table of Tables 
Table 1: Definition of primary and secondary analyses of MFS – handling of baseline 
metastasis ............................................................................................................... 20 
Table 2: Censoring Rules for MFS Based on independent blinded central reading Data ........ 20 


 
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Table 3: Censoring Rules .......................................................................................................... 24 
Table 4: Censoring Rules .......................................................................................................... 24 
Table 5: Example for calculated α significance levels and standard normal thresholds (z) for 
OS........................................................................................................................... 29 
Table 6: Interim analysis for significance; number of OS events and standard normal 
thresholds are illustrating the example from Table 5 ............................................. 29 
Table 7: Final Analysis for significance, scenario 1; number of OS events and standard 
normal thresholds are illustrating the example from Table 5 ................................ 30 
Table 8: Final analysis for significance, scenario 2; number of OS events and standard normal 
thresholds are illustrating the example from Table 5 ............................................. 30 
Table 9: Censoring Rules for OS .............................................................................................. 31 
Table 10: Censoring Rules for Pain Progression ...................................................................... 33 
Table 11: Censoring Rules for Cytotoxic Chemotherapy ......................................................... 34 
Table 12: Censoring Rules for SSE .......................................................................................... 35 
Table 13: Censoring Rules for SSE-free survival ..................................................................... 36 
Table 14: Censoring Rules for PFS Based on independent blinded central reading Data ........ 37 
Table 15: Censoring Rules for prostate cancer-related invasive procedure ............................. 39 
Table 16: Censoring Rules for antineoplastic therapy .............................................................. 40 
Table 17: Censoring Rules for PSA progression ...................................................................... 42 
Table 18: Censoring Rules for ECOG performance status deterioration ................................. 43 
Table 19: Censoring Rules for Time to first opioid for cancer pain ......................................... 44 
Table 20: Censoring Rules for time to deterioration in PCS .................................................... 48 
Table 21: Censoring Rules for time to worsening of EORTC-QLQ-PR25 urinary symptoms 49 


 
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List of Abbreviations 
AE 
Adverse Event 
ADT 
Androgen Deprivation Therapy 
ANCOVA 
Analysis of covariance 
AUC 
Area under the curve 
BMI 
Body Mass Index 
BPI-SF 
Brief Pain Inventory – Short form 
CYTOC 
Cytotoxic Chemotherapy 
CI 
Confidence Interval 
CRF 
Case Report Form 
DMC 
Data Monitoring Committee 
EBRT 
External beam radiation therapy 
ECG 
Electrocardiogram  
ECOG 
Eastern Cooperative Oncology Group 
EORTC-QLQ-
PR25 
European Organization for Research and Treatment of Cancer quality of 
Life Questionnaire- Prostate Cancer Module 
EQ-5D-3L 
European Quality of Life 5 – Domain scale 
EWB 
Emotional well being 
FACT-P 
Functional assessment of cancer therapy Prostate 
FAS 
Full Analysis Set 
FWB 
Functional well being 
HRQoL 
Health Related Quality of Life 
HLT 
High level term 
IRT 
Interactive response technology 
ITT 
Intent-to-treat 
IPE 
Iterative Parametric Estimation 
IVRS 
Interactive voice response system 
MedDRA 
Medical Dictionary for Regulatory Activities 
MFS 
Metastasis-Free Survival 
MLG 
MedDRA Labelling Grouping 
n 
Number of non-missing values 
N/A 
Not Applicable 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
nmCRPC 
Non-metastatic castration-resistant prostate cancer 
OM 
Operational manual  
OS 
Overall Survival 
PCS 
Prostate cancer subscale 
PCWG2 
Prostate Cancer Trials Working Group2 
PDD 
Protocol Deviations Document 
PFS 
Progression-free Survival 


 
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PK 
Pharmacokinetics 
PPS 
Per-Protocol Set 
PRO 
Patient Reported Outcome 
PSA 
Prostate-specific antigen 
PSADT 
PT 
Prostate-specific antigen doubling time 
Preferred Term 
PWB 
Physical well being 
QoL 
Quality of Life 
QTc 
Corrected QT 
QTcB 
Corrected QT Bazaett’s formula 
QTcF 
Corrected QT Fredericia’s formula 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RPSFT 
Rank-Preserving Structural Failure Time 
SAE 
Serious Adverse Event 
SAC 
Statistical Analysis Center 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SDG 
Standardized Drug Grouping 
SSE 
Symptomatic skeletal event 
SOC 
System organ class 
SWB 
Social family well being 
TEAE 
Treatment-Emergent AE 
TOI 
Trial Outcome Index 
US 
United States 
WHO-DD 
World Health Organization Drug Dictionary 
 


 
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1. 
Introduction 
Study 17712 (ARAMIS) is a multinational, randomized, double-blind, placebo-controlled, 
phase III efficacy and safety study of darolutamide in men with high-risk non-metastatic 
castration-resistant prostate cancer (nmCRPC). 
This statistical analysis plan (SAP) describes the analyses and data presentations for final 
primary efficacy endpoint (metastasis-free survival) and the final overall survival analysis at 
the end of double-blind part when targeted number of primary endpoint events is collected. 
The SAP contains definitions of analysis sets, derived variables, and statistical methods for 
the analysis of efficacy and safety. 
This SAP version 4.2 is an updated of SAP version 4.1 dated 13SEP2018 which was an 
update of version 4.0 dated 10AUG2018 and version 3.0 dated 12MAR2018. SAP v3.0 is 
based on the integrated protocol version 4.0 (amendment 3), dated 26 FEB 2018, is an 
amendment of the abbreviated SAP version 2.1 dated 22 JUN2017, based on protocol version 
3.0 (amendment2), dated 19 JUL 2016. 
 
2. 
Study Objectives 
The primary objective of the study is to demonstrate superiority of darolutamide over placebo 
in metastasis-free survival (MFS) in patients with high-risk non-metastatic castration-
resistant prostate cancer (nmCRPC). 
The secondary objectives of the study are: 
• Overall survival (OS), 
• Time to pain progression,  
• Time to first symptomatic skeletal event (SSE), 
• Time to initiation of first cytotoxic chemotherapy for prostate cancer, 
• Characterize the safety and tolerability of darolutamide. 
The additional objectives of the study are: 
• Progression free survival (PFS), 
• Time to first prostate cancer related invasive procedure, 
• Time to initiation of first subsequent antineoplastic therapy, 
• determine effect of darolutamide on prostate-specific antigen (PSA) progression and 
PSA response 
• ECOG performance status deterioration 


 
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• Health-related quality of life (QoL) 
• Evaluate pharmacokinetics (PK) of darolutamide and keto-darolutamide 
• Explore possible relationships between exposure and safety and efficacy response. 
 
3. 
Study Design 
This is a randomized, phase III, multi-center, double-blind, placebo-controlled efficacy and 
safety study of oral darolutamide (600 mg twice a day [bid]) in patients with nmCRPC who 
are at high risk for developing metastatic disease.  
Approximately 1500 patients will be randomized to receive darolutamide or placebo in a 2:1 
ratio in a double-blind manner. Randomization will be stratified by prostate-specific antigen 
doubling time (PSADT) (≤ 6 vs. > 6 months) and use of osteoclast-targeted therapy (yes vs. 
no). Randomized patients will receive study treatment until confirmed metastasis or 
intolerable adverse event (AE). 
The study has a design of 2 parallel groups. For each patient, the study may involve 1 to 2 
variable length periods: a study treatment period (a double-blind part for darolutamide or 
placebo arms and an open-label darolutamide treatment phase) and a follow-up period.  
The length of the periods for each patient will depend on the absence or presence of 
metastasis – after confirmed metastasis, the patient must be withdrawn from study treatment. 
During the double-blind part, patients may be on study treatment (darolutamide or placebo 
arm) or at follow-up. After the double-blind part, patients may be on open-label study 
treatment if they are in the darolutamide arm or if they have received double-blind placebo 
treatment and have started open-label darolutamide treatment in case of positive study results. 
Once the study results are available, and if they support a positive benefit/risk assessment for 
darolutamide in the study by the judgment of the sponsor, also considering feedback from the 
study steering committee and/or health authorities, those patients who are on study treatment 
(darolutamide or placebo) will be offered the opportunity to receive darolutamide through 
open-label treatment in this study. 
The double-blind treatment (darolutamide or placebo arm) is planned to be continued until 
the total number of events for the primary efficacy analysis (MFS analysis) had been reached 
(approximately 385 events). During this part the treatment code will remain blinded.  
Randomization and blinding: 
Randomization will be performed centrally blocking by center according to the design of the 
study using a 2-step procedure. Firstly, a separate master randomization schedule and study 
treatment package list will be created using randomly permuted blocks. Secondly, randomly 
permuted blocks from the master randomization schedule are assigned to the study centers. 
An interactive response technology (IRT) (also called interactive voice response system 
[IVRS]) system assigns patients to receive either darolutamide or matching placebo using 
allocation ratio 2:1, respectively. 


 
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The numbers are assigned to the unique patient number previously allocated by the 
investigator. The randomization will be stratified by: 
• PSADT ( 6 months vs. > 6 months), 
• Osteoclast-targeted therapy at randomization (yes vs. no). 
Details of the randomization method will be given in the IRT user requirements. 
The reference for this study will be placebo tablets that match the darolutamide tablets. 
During the double-blind part of the study at the time of radiographic metastasis patient’s 
treatment assignment will remain blinded. 
All patients, study personnel, and sponsor’s personnel directly involved in the conduct of the 
study will be blinded to treatment assignments during the double-blind part of the study. 
After completing the double-blind part the study will be unblinded for the primary analyses.  
Schedule of procedures: 
Efficacy and safety measurements obtained during the course of the study are summarized in 
the schedule of assessments, see Appendix 9.1. 
3.1 
Determination of Sample Size 
Several clinical publications were used as basis for the sample size calculation. The median 
MFS for placebo is based on denosumab phase III study results [8] at the time the ARAMIS 
protocol was designed, no data were available on the expected treatment effect size for 
androgen-receptor inhibitors in high-risk nmCRPC patients. Data published in 2016 and 
recently published data from SPARTAN and PROSPER phase III trials indicate, that the 
treatment effect of the class of novel androgen receptor inhibitors (enzalutamide, 
apalutamide) is stronger than initially assumed  
Given the results from PROSPER and SPARTAN, the initial assumption for the treatment 
effect size of a hazard ratio of 0.75 was considered as too conservative.  
 
All patients had to have an independent evaluation of radiological images for no baseline 
metastases at baseline to be eligible for randomization. However, for the central efficacy 
review, the baseline scans were again reviewed. During this review some patients were 
identified with metastases at baseline; to calculate sample size these patients are considered 
as having a MFS event on the date of randomization. 
The number of events has been adjusted to account for the non-informative character of 
baseline metastases events and the dilution impact to the estimated MFS hazard ratio. 
 
The assumptions used in determining the sample size for this study are as follows:  
• Overall 2-sided type I error rate: 0.05, 
• Assumed hazard ratio of 0.65, 


 
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• Accounting for 5% of the patients with baseline metastasis, diluted hazard ratio of 
0.71, 
• Randomization ratio: 2:1 
• Statistical power at the final analysis: 91%, 
• Median MFS for placebo: 25 months, 
385 MFS events will provide approximately 91% power to detect a statistically significant 
difference in MFS times, with a two-sided log-rank test with a 0.05 level of significance. 
With 40 months accrual time and a dropout rate of 40%, the study will require approximately 
1500 patients (1000 darolutamide patients, 500 placebo patients) to achieve the targeted 385 
MFS events. The MFS analysis will be performed when the targeted number of 
approximately 385 MFS events has been observed. 
This sample size calculation was performed with a simulation based algorithm. 
 
4. 
General Statistical Considerations 
4.1 
General Principles 
The statistical evaluation will be performed by using the software package SAS release 9.2 or 
higher (SAS Institute Inc., Cary, NC, USA). 
All variables will be analyzed by descriptive statistical methods. 
In general, continuous variables will be summarized using number of non-missing values (n), 
number of missing values, means, standard deviations, medians, maximum, minimum, and 
interquartile range. 
Ordinal variables will be summarized using n, number of missing values, medians, 
maximum, minimum, and interquartile range. 
Categorical variables will be summarized using n, number of missing values, and 
percentages. 
Time-to-event variables will be summarized using Kaplan-Meier estimates. 
Frequency tables will be generated for categorical data. 
 
4.2 
Handling of Dropouts 
Patients withdrawn from study treatment will not be replaced. Refer to section 4.7 in the 
study protocol for withdrawal of patients from study. 
All primary efficacy analyses are based on the Full Analysis Set (FAS) that comprises all 
randomized patients, including patients who withdraw regardless of the reason for 
withdrawal. The intent-to –treat (ITT) population set mentioned in the protocol is identical to 


 
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the FAS. See following chapters for more details on deriving efficacy endpoints in case of 
missing data. 
 
4.3 
Handling of Missing Data 
All missing or partial data will be presented in the patient data listing as they are recorded on 
the Case Report Form (CRF). 
When appropriate, the following rules will be implemented so as not to exclude patients from 
statistical analyses due to missing or incomplete data. 
Missing or unevaluable tumor assessments “including scheduled assessments that were not 
done and incomplete assessments that did not result in an unambiguous occurrence of first 
metastasis or evaluation of local regional disease progression” will not be used in the 
calculation of derived efficacy variables related to tumor assessments unless a new lesion 
occurred or the lesions that were evaluated already showed metastasis. No imputation will be 
performed for unevaluable or missing tumor assessment. For example, if a patient misses a 
scan visit and metastasis is documented at the next available scan visit, the actual visit date of 
the first documented metastasis will be used to calculate MFS. 
If a date is incomplete, (e.g. only year and month of date of tumor assessment or date of death 
is available), then day 15 of the month will be used for the calculation of, for example, MFS, 
OS. 
If the actual scan date of the radiological metastasis is missing and radiological metastasis has 
been documented based on criteria specified in the protocol, the scheduled scan date will be 
used to calculate the time to metastasis. 
If date for QoL questionnaire is not documented, then the corresponding visit date will be 
used. 
Safety variables, Medical history, and Concomitant medications: 
Treatment emergent AEs, treatment phases, period and relative days will be derived 
according to data management programming, the operational manual document and standard 
guidelines. 
 
 


 
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Missing Patient report Outcome (PRO) data 
In case of missing responses for one or more items, subscale scores can be prorated (see 
scoring of FACT-P, EORTC-QLQ-PR25, Brief Pain Inventory – Short form (BPI-SF) and of 
EQ-5D-3L in Appendices 9.2 to 9.5). 
For FACT-P this is done by multiplying the sum of the subscale by the number of items in 
the scale, then dividing the number of items actually answered. Prorating of scores is 
acceptable as long as more than 50% of the items are answered (assuming that the score of 
missing items are similar to those of non-missing items). If less than or equal to 50% of the 
items are answered for any domain, then the score of that domain is set to missing. The total 
score is then calculated as the sum of the un-weighted subscale scores. Moreover, the FACT-
P total score is set to missing if the related overall item response rate is less than or equal to 
80%. 
For EQ-5D-3L, if there is a missing or ambiguous answer (i.e. marking of more than one 
answer) on the 5-dimension questions, then the index score is missing. 
For BPI-SF 2 scores will be derived: 1/ for the pain severity score if one missing answer then 
scoring will be set to missing, 2/ for the pain interference score if 4 or more missing answers 
out of the seven questions then the score will be set to missing. 
For EORTC-QLQ-PR25, six scales are created, if less than or equal to 50% of the items are 
answered for any scales, then the score of that scale is set to missing. 
 
4.4 
Interim Analyses and Data Monitoring 
No formal interim analysis will be performed for primary endpoint MFS. 
A formal interim analysis for secondary endpoints will be performed by the sponsor at the 
same time as the primary endpoint analysis. See more details in Section 6.2. 
A Data Monitoring Committee (DMC) (also called Data and safety monitoring board 
(DSMB)) was instituted in order to ensure the ongoing safety of the patients. The operation of 
the DMC is guided by a DMC charter. 
The DMC includes 3 independent disease experts (physicians) and one independent 
statistician. The DMC will operate independently of the Sponsor and Investigators. Data 
review meetings will be held periodically as per separate DMC charter. Enrollment into the 
study is to continue throughout the scheduled meetings of the DMC. The Statistical Analyst 
Center (SAC) is scheduled to receive the randomization list for their unblinding. Data which 
may compromise the integrity of the study (e.g., comparative data and/or any unblinded data) 
are to be analyzed and discussed only in the closed session of the DMC meetings. The closed 
session will be restricted to the DMC members and a non-voting facilitator (biostatistician 
from the SAC). Closed session minutes will be maintained by the DMC in confidence. All 


 
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data provided to the DMC and all deliberations of the DMC are to be considered privileged 
and confidential. DMC members signed confidentiality agreements. 
 
4.5 
Data Rules 
Generally, for each date stored in the database, a set of organizational variables will be 
derived in order to describe the temporal context of that date in the specific study: phase of 
treatment (pre, during or post study treatment), day relative to the start of study treatment, 
day relative to the end of study treatment. 
Additional contextual variables may be created in analysis datasets. 
Refer to Section 4.3 for handling of missing data, as well as to Section 6, for specific 
endpoints data rules, for example censoring patients or definition of treatment-emergent 
adverse events (TEAEs). 
All derived variables will be stored in analyses data sets (ADS) created by the statistician and 
/ or the statistical analyst. 
Since differences may occur between the values of the stratification variables entered by the 
investigator at the time of randomization (IVRS) and those collected on the CRF, the analysis 
will be performed using both assignments to the strata. However, the primary stratified 
analyses for the efficacy endpoints will be based on the information collected in the IVRS 
whereas stratification information entered in the CRF (considered the ‘true’ information) will 
be used for sensitivity analyses. In rare circumstances, if CRF data cannot be documented, 
then IVRS data will be used. 
Baseline data for stratification will be taken from the last non-missing observation on or 
before the randomization date. 
Baseline data for demographics and characteristics, PRO questionnaires and safety will be 
taken from the last non-missing observation on or before the first day of study drug intake. 
Reported outcome questionnaires dates of completion were not collected therefore the dates 
of corresponding visit will be used for analyses.  
Unscheduled visits will be considered in analyses, excepted for analyses of health-related 
QoL. 
A data cut-off date for the final and the interim efficacy analyses will be chosen. 
Time to event variables values will be displayed in months. Months will be calculated 
dividing days by 30.44. 
 
4.6 
Blinded Review, Validity Findings, and Protocol Deviations 
Protocol deviations and validity review will be performed as described in the sponsor’s 
operational instruction on conducting blind review meetings, cleaning, and reviewing study 


 
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data, in addition to detailed guidance on important deviations and validity findings. Any 
unscheduled assessments prior to randomization will be included in the determination of the 
baseline value. 
4.6.1 
Blinded Review 
Blinded review will be conducted prior to database lock for each analysis, as described in the 
sponsor’s operational instruction on conducting blinded review meetings. Reviewers will be 
tasked with evaluating the overall quality and reliability of the study data and its suitability 
for the planned statistical analysis. Blinded review will also assess protocol deviations and 
validity findings. 
4.6.2 
Validity Findings 
Criteria for validity, i.e. eligibility for each analysis set, are described in Section 5. Details 
may be further described in a separate document. Validity findings will be obtained as 
described in both the sponsor’s operational instruction on cleaning and reviewing study data, 
and the sponsor’s detailed guidance on important deviations and validity findings, and 
includes major protocol deviations as described in Section 4.6.3 and the separate Protocol 
Deviations Document (PDD). The blinded review will review and finalize the validity 
findings prior to the database lock for each analysis. 
4.6.3 
Protocol Deviations 
Protocol deviations will be classified as major or important. Major protocol deviations are 
deviations affecting analysis set eligibility or treatment group assignment and constitute 
validity findings as described in Section 4.6.2. 
Major protocol deviations will be identified based on the criteria described in the sponsor’s 
operational instruction on cleaning and viewing study data. Assessment criteria, deviation 
definitions, methods of evaluation, and further details will be described in a separate PDD. 
 
5. 
Analysis Sets 
All patients who were randomized are included in the Full Analysis Set (FAS). Following 
the intent-to-treat (ITT) principle, the patients in this set will be grouped according to the 
treatment they were allocated to receive at randomization, irrespective of actual treatment. 
The FAS is the primary analysis set for the efficacy analyses. 
In contrast to wording from the protocol, a Per Protocol data Set (PPS) will not be specified 
and any per protocol analysis will not be performed as its additional value is minor. 
All patients who were randomized and received at least one dose of study treatment will be 
included in the Safety Analysis Set (SAF). This set of patients will be grouped for analysis 
according to the treatment they actually received, as opposed to the treatment they were 
allocated to receive at randomization. Only patients who solely received placebo treatment 
will be analyzed under the placebo arm. Patients who received at least one dose of 


 
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darolutamide treatment will be analyzed under the darolutamide arm. The SAF will be used 
for all safety analyses. 
 
6. 
Statistical Methodology 
The formal statistical analyses will be both descriptive and inferential. Summaries will be 
provided for each of the treatment groups, darolutamide, and placebo. In addition, descriptive 
summaries of population characteristics will be provided for the total study population. 
Stratification factors are: 
• PSADT ( 6 months vs. > 6 months) 
• use of osteoclast-targeted therapy (yes vs. no) 
CRF baseline data are closely monitored and corrected if necessary therefore IVRS 
stratification variable data may differ from CRF data in some instances. For the purpose of 
stratified analyses per this SAP, IVRS data will be used. For the primary endpoint MFS, a 
sensitivity analysis using CRF stratification data will be created. For other purposes, like 
analysis of baseline patient information, CRF data will be used. 
Patient’s characteristics tables will be displayed by the subgroups: 
Geographical region (North America, Asia Pacific, and Rest of the World (ROW)). 
North America region is defined by countries: 
• Canada, United States. 
Asia Pacific region is defined by countries/regions:  
• Japan, South Korea, and Taiwan. 
ROW region is defined as all countries that are neither included in the North America region 
nor in the Asia Pacific region. 
 
6.1 
Population characteristics 
 
6.1.1 
Disposition of patients 
The number of patients enrolled and included in each population will be tabulated by region, 
country, and center. A summary table will also be presented for the number of patients 
enrolled and the number and percentage of patients in each of the defined populations. Re-
screened patients will only be counted once. 
The reasons for patients excluded from each of the patient populations will also be tabulated. 
The reasons for discontinuation of study treatment will be tabulated. 


 
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The number of patients who discontinued study treatment due to PSA increased without 
documented metastasis per independent central reading will be displayed. 
 
6.1.2 
Demographic and Baseline Characteristics 
Descriptive summaries of demographics and baseline characteristics will be presented by 
treatment group and overall for the FAS and SAF populations. Comparability of the treatment 
groups with respect to demographics and baseline characteristics will be assessed using 
descriptive summaries. 
The following demographic data will be summarized: 
• Age (years), calculated at the date of randomization using date of birth 
• Age (years) (<65, 65 - 74, 75 - 84, ≥85) 
• Sex (Male) 
• Race (White, Asian, Black or African American, Other)  
• Ethnicity (Hispanic or Latino) 
• Height (cm) 
• Weight (kg)  
• Body Mass Index (BMI) (kg/cm2) (< 20, 20 to < 25, 25 to < 30, ≥ 30) 
• Geographical region (North America, Asia Pacific, ROW). 
The following baseline characteristics will be summarized: 
• PSADT (≤6, >6 months) - IVRS 
• PSADT (≤6, >6 months) - CRF 
• PSADT (months) 
• Osteoclast-Targeted Therapy (yes, no) - IVRS 
• Osteoclast-Targeted Therapy (yes, no) - CRF 
• ECOG Performance status 
• Gleason Score 
• Primary tumor classification 
• Regional lymph node classification 
• Time since start of castration-resistant (months) 
• Time since initial diagnosis (capture under clinical staging) (months) 


 
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• Time from start of first prior GnRH agonist/antagonist to start of study-drug (months) 
(for selection, see 9.12) 
• Time from prior orchiectomy to start of study-drug (months) 
• Time from start of first prior antiandrogen (AR inhibitors) to start of study-drug 
(months) (for selection, see 9.11) 
• Time from the first prior ADT to start of study drug (months) (ADT is defined by 
GnRH agonist/antagonist, orchiectomy, antiandrogen (AR inhibitors)) 
• Renal function - eGFR at baseline: 
o Normal: eGFR ≥ 90 mL/min 
o Mildly impaired: 60 ≤ eGFR < 90 mL/min 
o Moderately impaired: 30 ≤ eGFR < 60 mL/min 
o Severely impaired: 15 ≤ eGFR < 30 mL/min 
o End stage renal disease: eGFR < 15 mL/min and not on dialysis, or requiring 
dialysis 
 
eGFR will be calculated according to the Modification of Diet in Renal Disease 
(MDRD) Formula: 
eGFR (mL/min/1.73m2) = 186 x SCR-1.154 x age-0.203 x (0.742, if female) x 
(1.212 if blacks or African American) x (0.881 if Japanese) x (1.227 for 
Chinese (mainland China, Taiwan and Hongkong), where SCR= serum 
creatinine measured in mg/dL 
• Hepatic impairment at baseline: 
o Normal: Total bilirubin and AST ≤ upper limit of normal (ULN) 
o Mild hepatic impairment: Total bilirubin > ULN to 1.5 x ULN or (Total 
bilirubin ≤ ULN and AST > ULN) 
o Moderate impairment: Total bilirubin > 1.5 to 3 x ULN, any AST 
o Severe impairment: Total bilirubin > 3 x ULN, any AST. 
• Baseline PSA from central laboratory (≤ 10, >10 to ≤20, >20 ng/mL)  
• Baseline hemoglobin (g/dL) 
• Baseline lactate dehydrogenase (U/L) 
• Baseline alkaline phosphatase (U/L) 
• Baseline testosterone (nmol/L) 
• Prior hormonal therapies (1, ≥2) (for definition of hormonal therapies, refers to 
Section 9.13). 


 
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In case date is not completed the following rules will be applied for calculation: 
- 
-if only year is documented, 1st January will be applied, 
- 
-if month and year are available, day 1of the month will be used. 
Demographic and baseline characteristics tables will be provided for the subgroups:  
- 
patients with presence of baseline metastasis and absence of baseline metastasis, 
per independent blinded central reading for efficacy assessment, 
- 
patients from United States (US) and non-US countries. 
 
6.1.3 
Medical history 
Medical history will be summarized by Medical Dictionary for Regulatory Activities 
(MedDRA) version 20.0 or the most recent version terminology.  
Summary statistics (frequency and percentage) will be provided by body system organ class 
(SOC), high level term (HLT) and preferred term (PT) for the FAS population, by treatment 
group. 
Past and present finding will be displayed. 
 
6.1.4 
Prior and concomitant medications 
Concomitant medications and procedures are: 
• Prior prostate cancer therapy: frequency of patients for each drug category 
• Radiotherapy (prior) 
• Opioid treatment (prior, concurrent, and follow-up): frequency of patients – patient 
listings 
• Diagnostic and therapeutic procedures: frequency of patients by procedure (prior, 
concurrent) 
• Concomitant medications: frequency of patients for each drug category  
• Concomitant statin medications: frequency of patients  
• Diagnostic and therapeutic procedures related to AE: frequency of patients by 
procedure (concurrent) 
The dictionary used for coding medications is the WHO Drug dictionary.  
 
In addition to the FAS population, concomitant medication will also be summarized on the 
SAF population. 


 
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For selection of statins medications, please refer to Appendix 9.9. 
 
6.2 
Efficacy 
After the end of randomization of patients into the study, it will be reviewed if all 
stratification factors are represented by a sufficient number of patients. In case at least one of 
the stratification factors does not have sufficient number of patients (less than 3%) and the 
inferential analyses would be negatively impacted, the stratification factor will not be 
included as a stratification factor in this analysis. 
Efficacy analyses will be performed in the FAS population. 
 
6.2.1 
Primary Efficacy Analysis 
The primary efficacy variable is MFS, as determined by the independent blinded central 
reading. 
 
Metastasis-free survival (MFS) 
MFS is defined as time from randomization to confirmed evidence of metastasis or death 
from any cause, whichever occurs first. The MFS analysis will be performed when 
approximately 385 events are observed. Patients not experiencing death or metastasis will be 
censored at the last tumor assessment. 
Survival distribution function will be used as basis for statistical hypothesis. Hypothesis will 
be two sided, although superiority over placebo is anticipated. The two-sided hypothesis is 
formulated as follows: 
H0: SDAROLUTAMIDE(t) = SPBO(t), for all t > 0 and 
H1: SDAROLUTAMIDE(t) ≠ SPBO(t), for some t > 0, 
Where S(t) represents estimated survival distribution at time t for MFS. 
Metastasis in bone is defined as appearance of 1 or more lesions that are confirmed by the 
central reading according to the one of the methods described below. If the central reading 
identifies changes on bone scan, confirmatory anatomic imagine CT/MRI or x-ray, of the 
area in question needs to be obtained. Anatomic imaging performed up to 2 weeks prior to 
bone scan or later may be used as a confirmatory scan. Appearance of bone metastasis is 
assigned to the date of the bone scan at which the lesion was first identified. 
Metastasis in non-osseous tissue is defined as new distant pathologic lymph nodes (M1a) or 
other pathological lesion (M1c) according to Response Evaluation Criteria in Solid Tumors 
(RECIST) version 1.1. New or progressive regional pathologic lymph nodes will not be 
defined as metastasis. 
 
As part of the blinded central imaging review for the efficacy assessment to determine distant 
metastases, the baseline scans, which were classified as metastasis free by the eligibility read, 


 
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were reviewed again, together with all later scans. During this review some patients were 
classified with metastases already at baseline. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Censoring Rules 
Time of MFS is calculated as time to MFS = End Date-Date of randomization +1. 
Table 2: Censoring Rules for MFS Based on independent blinded central reading 
Data 
Situation 
End Date on or prior to cut-off date 
Censored 
Documented metastasis 
Date of documented metastasis 
No 
Documented metastasis at baseline 
Date of randomization 
No /
 
 
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Situation 
End Date on or prior to cut-off date 
Censored 
 ) 
Documented metastasis after two or more 
consecutively missed tumor assessments, 
i.e. metastasis later than last evaluable 
scan + (32 +1) weeks 
Date of last tumor assessment that 
the patient was known to be 
metastasis-free 
Yes 
Death before documented metastasis and 
not later than last evaluable scan + (32+1) 
weeks 
Date of death 
No 
Death before documented metastasis  
and after two or more consecutively 
missed tumor assessments, i.e. death 
later than last evaluable scan + (32+1) 
weeks 
Date of last tumor assessment that 
the patient was known to be 
metastasis-free 
Yes 
Discontinued the study before any post-
baseline tumor assessments 
Date of randomization 
Yes 
Discontinued the study before any post-
baseline tumor assessments and died 
within (32+1) weeks after randomization 
Date of death 
No 
Discontinued the study before any post-
baseline tumor assessments and died 
later than (32+1) weeks after 
randomization 
Date of randomization 
Yes 
Discontinued the study, but no 
documented metastasis 
Date of last tumor assessment before 
discontinuation 
Yes 
Prohibited new anticancer treatment 
started prior to documented metastasis 
Date of last tumor assessment before 
start of prohibited new treatment 
Yes 
Patients still on treatment without 
documented metastasis as of data cut-off 
Date of last tumor assessment  
Yes 
 
MFS will be compared between the treatment arms using a two-sided stratified log-rank test, 
stratified by PSADT (≤6 vs. >6 months) and use of osteoclast-targeted therapy (yes vs. no) at 
randomization. A two-sided overall alpha of 0.05 will be used for the efficacy analysis of 
MFS. 
The analysis will be performed according to treatment groups as randomized, with 
stratification as recorded in the IVRS data. 
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For the baseline metastasis non-censored primary analysis, this endpoint is selected from the 
ADTTE dataset using variable PARAMCD equal to ‘MFS’ (primary analysis) and 
‘SAMFSBAS’ (secondary analysis). 
For the baseline metastasis censored primary analysis, this endpoint is selected from the 
ADTTE dataset using variable PARAMCD equal to ‘MFS’ (secondary analysis) and 
‘SAMFSBAS’ (primary analysis). 
 
Sample code to produce stratified log rank test: 
proc lifetest data=data; 
time prog_time*cnsr(1); 
strata psa_double ot_therapy / group=treat test=(logrank); 
run; 
Where:  
 
prog_time contains metastasis free survival time for the patient, cnsr contains a value of one 
for censored records and zero otherwise, psa_double contains PSA doubling time category at 
randomization, ot_therapy contains category for osteoclast-targeted therapy use at 
randomization,  treat contains assigned treatment group. 
The hazard ratio as well as its 95% confidence interval (CI) will be presented based on fitting 
a Cox regression model with treatment as factor and stratified by PSA doubling time (≤6 vs. 
>6 months) and use of osteoclast-targeted therapy (yes vs. no) at randomization.  
Sample code to produce hazard ratio: 
proc phreg data=data; 
model prog_time *cnsr(1) = trtpn; 
strata psa_double ot_therapy / missing; 
run; 
Where:  
 
prog_time contains metastasis free survival time for the patient, cnsr contains a value of one 
for censored records and zero otherwise, psa_double contains PSA doubling time category at 
randomization, ot_therapy contains category for osteoclast-targeted therapy use at 
randomization, treat contains assigned treatment group. 
The Kaplan-Meier estimate of the median survival time and first and third quartiles will be 
presented with 95% CI. The survival curves will also be plotted. 4, 8, 12, months MFS rate 
time-points will also be provided with 95% CI. Greenwood's formula will be used for the 
standard error of the Kaplan-Meier estimate in the calculation of these confidence limits. The 
number and percentage of patients in each treatment group who have progressed or died at 4, 
8, 12 months will be summarized along with the number and percentage of censored patients. 


 
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Sample code to produce Kaplan Meier curves: 
proc lifetest data=data method=km outsurv=outsurv; 
time prog_time *cnsr(1); 
strata treat; 
run; 
Where: 
Prog_time contains metastasis free survival time for the patient, cnsr contains a value of one 
for censored records and zero otherwise, treat contains assigned treatment group. 
 
If the complete date of the scan is not known, but the year and month are available, Day 15 of 
the month will be used for the calculation. 
If the complete date of the death is not known, but the year and month are available, Day 15 
of the month will be used for the calculation. 
Per protocol, following medications are considered prohibited:  
- 
Radiopharmaceuticals, 
- 
Immunotherapy (e.g. sipuleul T), 
- 
Cytotoxic chemotherapy and any other systemic antineoplastic therapy, 
- 
Enzalutamide, ARN-509, bicalutamide, flutamide, nilutamide, 
- 
Cyproterone acetate estrogen, 
- 
5 α-reductase inhibitor, 
- 
Abiraterone acetate, TAK-700 or other CYP17 inhibitors, 
- 
Systemic ketoconazole (as antineoplastic therapy), 
- 
Osteoclast-targeted therapy such as bisphosphonate or denosumab given for 
preventing skeletal-related events. These drugs are allowed for treatment of 
osteoporosis, 
- 
Continuous use of systemic corticosteroid. 
Selection and list of these prohibited treatments are available in Appendix 9.6. 
 
Description of the MFS events will be provided, ie number of metastasis with location 
(distant lymph nodes, bone lesions, and/or visceral and/or other soft tissue) and number of 
death. 
 
Sensitivity analyses: 


 
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Sensitivity analysis 1: Analysis of time to metastasis will be conducted using only the 
appearance of documented metastases as event. In particular, deaths are not counted as 
events. Patients who died before documented metastasis will be censored. See Table 3 below 
with this change. 
Table 3: Censoring Rules 
Situation 
End Date on or prior to cut-off date 
Censored 
Documented metastasis 
Date of documented metastasis 
No 
Documented metastasis at baseline 
Date of randomization 
No 
 
 
  
Documented metastasis after two or more 
consecutively missed tumor assessments, 
i.e. metastasis later than last evaluable 
scan + (32 +1) weeks 
Date of last tumor assessment that 
the patient was known to be 
metastasis-free 
Yes 
Death before documented metastasis 
Date of last tumor assessment that 
the patient was known to be 
metastasis-free 
Yes  
Discontinued the study before any post-
baseline tumor assessment 
Date of randomization 
Yes 
Discontinued the study with at least one 
post-baseline tumor assessment and no 
documented metastasis 
Date of last tumor assessment before 
discontinuation 
Yes 
Prohibited new anticancer treatment 
started prior to documented metastasis 
Date of last tumor assessment before 
start of prohibited new treatment 
Yes 
Patients still on treatment without 
documented metastasis as of data cut-off 
Date of last tumor assessment  
Yes 
This endpoint is selected from the ADTTE dataset using variable PARAMCD equal to 
‘SAMFS1’ (baseline metastasis non-censored) and ‘SAMFS2’ (baseline metastasis 
censored). 
 
Sensitivity analysis 2: Analysis of MFS will be conducted with all prohibited new treatment 
started prior to documented metastasis considered as an event. See Table 4 below with this 
change. 
Table 4: Censoring Rules 
Situation 
End Date on or prior to cut-off date 
Censored 
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Situation 
End Date on or prior to cut-off date 
Censored 
Documented metastasis 
Date of documented metastasis 
No 
Documented metastasis at baseline 
Date of randomization 
No 
 
 
  
Documented metastasis after two or more 
consecutively missed tumor assessments, 
i.e. metastasis later than last evaluable 
scan + (32 +1) weeks 
Date of last tumor assessment that 
the patient was known to be 
metastasis-free 
Yes 
Death before documented metastasis and 
not later than last evaluable scan + (32+1) 
weeks 
Date of death 
No 
Death before documented metastasis and 
after two or more consecutively missed 
tumor assessments, i.e. death later than 
last evaluable scan + (32+1) weeks 
Date of last tumor assessment that 
the patient was known to be 
metastasis-free 
Yes 
Discontinued the study before the post-
baseline tumor assessments 
Date of randomization 
Yes 
Discontinued the study before the post-
baseline tumor assessments but died later 
than (32+1) weeks after randomization 
Date of randomization 
Yes 
Discontinued the study before the post-
baseline tumor assessments but died 
within (32+1) weeks after randomization 
Date of death 
No 
Discontinued the study, but no 
documented metastasis 
Date of last tumor assessment before 
discontinuation 
Yes 
Prohibited new anticancer treatment 
started prior to documented metastasis 
Date of start of prohibited new 
treatment 
No 
Patients still on treatment without 
documented metastasis as of data cut-off 
Date of last tumor assessment  
Yes 
This endpoint is selected from the ADTTE dataset using variable PARAMCD equal to 
‘SAMFSPT1’ (baseline metastasis non-censored) and ‘SAMFSPT2’ (baseline metastasis 
censored). 
If the complete date of the prohibited treatment is not known, but the year and month are 
available, Day 15 of the month will be used for the calculation. 
 
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Sensitivity analysis 3: similar analysis to the one created for the primary analysis for MFS 
with a two-sided model stratified by the stratification data from CRF. This endpoint is 
selected from the ADTTE dataset using variable PARAMCD equal to ‘MFS’ (baseline 
metastasis non-censored) and ‘SAMFSBAS’ (baseline metastasis censored). 
Sensitivity analysis 4: similar analysis to the one created for the primary analysis for MFS 
with a two-sided log rank test without including stratification factors in the model. This 
endpoint is selected from the ADTTE dataset using variable PARAMCD equal to ‘MFS’ 
(baseline metastasis non-censored) and ‘SAMFSBAS’ (baseline metastasis censored). 
Sensitivity analysis 5: similar analysis to the one created for the primary analysis for MFS, 
but using investigator assessment of radiological imaging. This endpoint is selected from the 
ADTTE dataset using variable PARAMCD equal to ‘SAMFSIA1’ (baseline metastasis non-
censored) and ‘SAMFSIA2’ (baseline metastasis censored). 
Sensitivity analysis 6: similar analysis to the one created for the primary analysis for MFS 
with all deaths independent when it occurred considered as an event. This endpoint is 
selected from the ADTTE dataset using variable PARAMCD equal to ‘SAMFSDH1’ 
(baseline metastasis non-censored) and ‘SAMFSDH2’ (baseline metastasis censored). 
Sensitivity analysis 7: similar analysis to the one created for the primary analysis for MFS 
with event at date of first post baseline scan with metastasis instead of event at randomization 
for patients with baseline metastasis. If no metastasis documented in post baseline scans such 
patient will be censored at last available scan date. In case such a patient did not have any 
post baseline scan, the patient will be censored at randomization. This endpoint is selected 
from the ADTTE dataset using variable PARAMCD equal to SAMFSPB1’ (baseline 
metastasis non-censored) and ‘SAMFSPB2’ (baseline metastasis censored). 
 
Discordance of metastasis between independent blinded central reading and investigator 
assessment will be displayed. 
Summary of baseline metastasis per independent blinded central reading and per charter 
version will be created. 
Summary of eligibility read and efficacy read per charter version will be displayed. 
Summary of adjudication reading will also be displayed. 
The following flags will be available in the central imaging related datasets providing more 
detailed information on some specificities of the central reading process and versions of the 
imaging charter: 
• Flags for charter version (flag_ch1, flag_ch2, flag_ch3), 
• Flags for adjudication (flag_ad1, flag_ad2, flag_ad3), 
• Flags for discordances between reviewers sets: eligibility, efficacy and confirmation 
of metastasis (flag_dc, flag_dc1, flag_dc2), 
• Flags for change of metastasis determination after final read (flag_fb1, flag_fb2). 


 
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Description  
Value  
Flag name 
Charter version flag for eligibility (Charter cut-off 01 
FEB 2017) 
• v1.0 
• v4.0 
flag_ch1 
Eligibility review adjudication 
0 = no adjudication 
1 = adjudication  
• 0 
• 1 
flag_ad1 
Charter version flag for confirmation of metastasis review • v1.0 
flag_ch2 
Confirmation of Metastasis adjudication 
0 = no adjudication 
1 = adjudication 
• 0 
• 1 
flag_ad2 
Charter version flag for efficacy 
v4.0 
flag_ch3 
Independent Efficacy Review Adjudication 
0 = no adjudication 
1 = adjudication 
• 0 
• 1  
flag_ad3 
Change of baseline response per Independent Efficacy 
Review triggered at final visit evaluation 
0 = no change  
1 = change from no metastasis to metastasis 
2 = change from metastasis to no metastasis  
• 0 
• 1 
• 2 
flag_fb1 
Change of metastasis progression per Independent 
Efficacy Review triggered at final visit evaluation 
0 = no change 
1 = change 
• 0 
• 1 
flag_fb2 
Metastasis at baseline per efficacy review 
0 = no metastasis 
1 = metastasis 
• 0 
• 1 
flag_dc 
Discordance of metastasis at baseline (Eligibility Review 
vs. Independent Efficacy Review) 
0 = same result 
1 = different results 
• 0 
• 1 
flag_dc1 
Comparison of confirmation of metastasis under Charter 
v1.0 where metastasis confirmed to the same time point 
as efficacy. 
0 = same result 
1 = different results 
• 0 
• 1 
flag_dc2 
Initial date of metastasis per before final visit  evaluation 
(can be missing if no metastasis seen) 
 
DDM
MMY
YYY 
IMETSDT 
Final date of metastasis per independent efficacy review 
before final visit  evaluation (can be missing if no 
metastasis seen) 
DDM
MMY
YYY 
FMETSDT 


 
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6.2.2 
Analysis of secondary efficacy endpoints 
Secondary endpoints will be tested with the hierarchical gatekeeping procedure. The order of 
secondary endpoints is 
• (1) Overall survival (OS), 
• (2) Time to pain progression (PP), 
• (3) Time to cytotoxic chemotherapy (CYTOC), 
• (4) Time to first symptomatic skeletal event (SSE). 
 
Secondary endpoints are tested only if the primary endpoint MFS is significant. They will be 
tested according to the sequence given above. If significance of the primary analysis of MFS 
is considered unmet, each of the secondary objectives will be considered unmet. The same 
overall two-sided significance level of 0.05 as used for the primary endpoint will be used for 
the secondary endpoints. 
All secondary endpoints OS, PP, CYTOC and SSE will be tested sequentially two times, in 
case the previous endpoint in the hierarchical order was significant. The first test for 
statistical significance will occur at the time of the MFS analysis and the final test for 
statistical significance will occur when approximately 240 OS events have been observed. 
A rho-family spending function with parameter rho=10 will be used for OS, time to pain 
progression, time to cytotoxic chemotherapy and time to first SSE to determine the two 
stopping boundaries for efficacy at the interim and final analyses. The OS information 
fraction will be used for determining the alpha spending and significance threshold also for 
the other secondary endpoints at the interim analysis. For the final analysis the remaining 
alpha available and the actually observed numbers of events at interim and final for each 
endpoint will be used to determine the significance thresholds of secondary endpoints. 
This rho spending function is slightly more conservative at the first test compared to the 
O’Brien-Fleming spending function and assigns slightly more alpha at the second test 
compared to the O’Brien-Fleming spending function. This choice is motivated by the low 
likelihood to achieve a significant result for the hierarchically first secondary endpoint OS at 
the first test for both spending functions. 
The significance boundaries will be calculated with the EAST software package based on 
number of events actually observed in the analyzed data sets. 
As an example for the planned sequential testing of the secondary endpoint OS, the table 
shows calculated alpha significance levels (α) and standard normal significance thresholds 
(z), assuming numbers of OS events of 140 at interim and 240 at final analysis. See Table 5 
for details. 


 
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Table 5: Example for calculated α significance levels and standard normal thresholds 
(z) for OS 
 
O’Brien-Fleming 
Rho family, rho=10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The schema of testing the secondary endpoints is illustrated in Table 6 to Table 8. 
 
Table 6: Interim analysis for significance; number of OS events and standard normal 
thresholds are illustrating the example from Table 5  
 
140 OS events 
 
Interim analysis 
OS 
interim dataset 
test at z1 
 
 
if positive  
PP 
interim dataset 
test at z1 
 
 
if positive  
CYTOC 
interim dataset 
test at z1 
 
 
if positive  
SSE 
interim dataset 
test at z1 
 
 
 
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Table 7: Final Analysis for significance, scenario 1; number of OS events and 
standard normal thresholds are illustrating the example from Table 5 
Assuming OS interim analysis was not positive: 
 
 
240 OS events 
 
 
Final analysis 
OS 
final dataset 
OS interim  
not positive 
test at z2 
 
 
 
if positive  
PP 
interim dataset* 
 
test at z2 
 
 
 
if positive  
CYTOC 
final dataset 
 
test at z2 
 
 
 
if positive  
SSE 
final dataset 
 
test at z2 
 
 
*PP is a more subjective endpoint, therefore an analysis of PP which includes a large portion 
of data collected under open-label conditions is not considered meaningful. In case PP would 
be tested in the final analysis, the interim dataset would be used also for this test procedure. 
 
Table 8: Final analysis for significance, scenario 2; number of OS events and 
standard normal thresholds are illustrating the example from Table 5 
Assuming OS interim analysis was positive and PP interim analysis was not positive: 
 
 
240 OS events 
 
 
final analysis 
OS 
final dataset 
OS interim  
was positive 
no test  
 
PP 
interim dataset* 
PPR interim 
not positive 
test at z2 
 
 
 
if positive  


 
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CYTOC 
final dataset 
 
test at z2 
 
 
 
if positive  
SSE 
final dataset 
 
test at z2 
 
 
In further scenarios where in the interim analysis after OS also PP was positive or where in 
the interim analysis after OS and after PP also CYTOC was positive, accordingly modified 
testing sequences would be applied. 
 
The above testing schema is following the testing strategy 2 which is discussed in the 
publication of Hung et al. [10]. 
 
 
Overall survival (OS) 
OS is defined as time from randomization to death due to any cause. OS of patients not 
known to have died will be censored at their last date of being known to be alive or at the 
database cutoff date, whichever comes first. OS will be analyzed on the FAS population. 
If a patient died and the date of death is completely or partially missing, but there is an AE 
with the outcome as ‘Death’, the date of death will be replaced by the end date of the AE. 
If the complete date of death is not known, but the year and month are available and there is 
no AE with outcome as ‘Death’, Day 15 of the month will be used for the calculation of the 
time to death. 
Table 9 will be used for calculating the OS; time to death = End Date – Date of 
Randomization+1. 
Table 9: Censoring Rules for OS 
Situation 
End Date on or prior to cut-
off date 
Censored 
Death during study 
Date of death 
No 
Patient still alive at data cut-off 
Date of data cut-off 
Yes 
Patient lost to follow-up before data cut-off 
Date last known to be alive 
Yes 
Patient lost to follow-up without contact 
after randomization 
Date of randomization 
Yes  
This endpoint is selected from the ADTTE dataset using variable PARAMCD equal to 
‘DEATH’. 


 
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The Last Known Alive Date (LKAD) is derived from the main data sources. The last 
available date across all selected data panels listed below will be picked as the LKAD by 
patient. Information from selected data, i.e. visit dates, exposure information, demographics, 
laboratory measurements, tumor assessment dates, MFS dates, SSE dates, survival status 
date, and disposition events or follow up assessments will be used to determine survival 
status. Within all the dates from the selected data panels, identify the latest available date as 
the LKAD for each patient. 
A log rank test stratified by stratification factor of PSADT (≤6 vs. >6 months) and use of 
osteoclast-targeted therapy (yes vs. no) at randomization (i.e. from IVRS) will be used to 
compare the darolutamide treated and placebo groups. 
The hazard ratio as well as its 95% CI will be presented based on fitting a Cox regression 
model with treatment as factor and stratified by PSADT (≤6 vs. >6 months) and use of 
osteoclast-targeted therapy (yes vs. no) at randomization. 
Kaplan-Meier survival curves (product-limit estimates) will be presented by treatment arm 
(including display of numbers at risk at various time points). The Kaplan-Meier estimate of 
the median survival time and first and third quartiles will be presented with 95% CI. 
Greenwood's formula will be used for the standard error of the Kaplan-Meier estimate in the 
calculation of these confidence limits. 
The number and percentage of patients in each treatment group who have died will be 
summarized at yearly time points along with the number and percentage of censored patients. 
Summaries by cause of death will be provided too. 
Descriptive statistics of survival follow-up time will be calculated by treatment arm and total. 
Follow-up time (days) is the time to death as described for the OS endpoint for censored and 
uncensored patients. 
Once the study results are available, and if they support a positive benefit/risk assessment for 
darolutamide in the study by judgment of the Sponsor (considering feedback from the study 
steering committee and/or health authorities), those patients who are on study treatment 
(darolutamide or placebo) will be offered the opportunity to receive darolutamide through 
open-label treatment in this study. This may dilute the effect size for the secondary endpoints 
as the placebo arm outcomes will become more similar to the darolutamide arm outcomes. 
The amount of this bias can be approximately assessed by established crossover adjustment 
methods like Rank-Preserving Structural Failure Time (RPSFT) [7] or Iterative Parametric 
Estimation (IPE) [5]. These methods construct a placebo arm Kaplan-Meier curve which is 
expected to resemble the Kaplan-Meier (KM) curve which would be observed if placebo to 
darolutamide crossover would not had occurred. The data of the second analysis of OS will 
be analyzed in addition with the RPSFT and IPE methods. Only the unadjusted OS data will 
be used for testing for a statistically significant treatment effect. 
 


 
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Time to pain progression 
Time to pain progression (PP) is defined as time from randomization to pain progression, 
where progression is defined as an increase of 2 or more points from baseline in question 3 of 
the Brief Pain Inventory-Short Form questionnaire (BPI-SF) related to the worst pain in the 
last 24 hours taken as a 7-day average for post-baseline scores, or initiation of short or long-
acting opioids for pain, whichever comes first. Initiation or change in the use of other non-
opioid analgesics is not used in the analysis of pain progression. 
List of opioids for cancer pain is available in Appendix 9.10. 
Questionnaire BPI-SF is detailed in Appendix 9.2. 
A minimum number of 4 completed daily reports at each reporting time point out of the 7 
days required per protocol are needed to consider valid the assessment. 
If the complete date of the assessment is not known, but the year and month are available, 
day 15 of the month will be used for the calculation. 
Table 10 will be used for calculating the time to first pain progression. Time to Pain 
progression = End Date – Date of Randomization +1. 
 
Table 10: Censoring Rules for Pain Progression 
Situation 
End Date on or prior to cut-off date 
Censored 
Recorded pain progression during the 
study 
Date of the first assessment that 
qualified as pain progression  
No 
No baseline BPI-SF assessments 
Date of randomization  
Yes 
Discontinued the study before the post-
baseline BPI-SF assessments 
Date of randomization  
Yes 
Death during the study before pain 
progression 
Date of last visit the patient was 
known not to have progressed or 
randomization date whatever comes 
later 
Yes 
Patient has no recorded pain progression 
at data cut-off  
Date of last visit the patient was 
known not to have progressed or 
randomization date whatever comes 
later 
Yes 
Patient lost to follow-up before data cut-off 
Date of last visit the patient was 
known not to have progressed or 
randomization date whichever comes 
later 
Yes 
Patient taking opioids for any reason 
Date of randomization 
Yes 


 
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within 4 weeks prior to randomization 
This endpoint is selected from the ADTTE dataset using variable PARAMCD equal to ‘PP’. 
A log rank test stratified by stratification factor of PSADT (≤6 vs. >6 months) and use of 
osteoclast-targeted therapy (yes vs. no) at randomization will be used to compare the 
darolutamide treated and placebo groups. 
The hazard ratio as well as its 95% CI will be presented based on fitting a Cox regression 
model with treatment as factor and stratified by PSADT (≤6 vs. >6 months) and use of 
osteoclast-targeted therapy (yes vs. no) at randomization. 
Kaplan-Meier survival curves (product-limit estimates) will be presented by treatment arm. 
The Kaplan-Meier estimate of the median survival time and first and third quartiles will be 
presented with 95% CI. Greenwood's formula will be used for the standard error of the 
Kaplan-Meier estimate in the calculation of these confidence limits. 
 
 
Time to initiation of first cytotoxic chemotherapy 
The time to cytotoxic chemotherapy (CYTOC) is defined as time from randomization to the 
start of the first cytotoxic chemotherapy cycle. Patients who have not taken cytotoxic 
chemotherapy will be right censored at their last visit.  
Cytotoxic chemotherapy drugs are defined with ATC code L01A, L01B, L01C, L01D and 
L01X. The list of all cytotoxic chemotherapy is available under Appendix 9.7. 
If the complete date of the cytotoxic chemotherapy is not known, but the year and month are 
available, day 15 of the month will be used for the calculation. 
Table 11 will be used for calculating the time to first cytotoxic chemotherapy. Time to 
cytotoxic chemotherapy = End Date – Date of Randomization +1.  
 
Table 11: Censoring Rules for Cytotoxic Chemotherapy 
Situation 
End Date on or prior to cut-off date 
Censored 
Recorded cytotoxic chemotherapy during 
the study 
Date of the first assessment that 
qualified as cytotoxic chemotherapy  
No 
Death during the study before cytotoxic 
chemotherapy 
Date of last visit at which cytotoxic 
chemotherapy question was 
collected or randomization date 
whatever comes later 
Yes 
Patient has no recorded cytotoxic 
chemotherapy at data cut-off  
Date of last visit at which cytotoxic 
chemotherapy question was 
collected or randomization date 
whatever comes later 
Yes 


 
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Patient lost to follow-up before data cut-off 
Date of last visit at which cytotoxic 
chemotherapy question was 
collected or randomization date 
whatever comes later 
Yes 
Cytotoxic chemotherapy is a specific antineoplastic therapy and therefore the CRF question 
“Has the patient taken any new antineoplastic therapy since previous visit?” implies the 
question for cytotoxic chemotherapy. 
This endpoint is selected from the ADTTE dataset using variable PARAMCD equal to 
‘CYTOC’. 
A log rank test stratified by stratification factor of PSADT (≤6 vs. >6 months) and use of 
osteoclast-targeted therapy (yes vs. no) at randomization will be used to compare the 
darolutamide treated and placebo groups. 
The hazard ratio as well as its 95% CI will be presented based on fitting a Cox regression 
model with treatment as factor and stratified by PSADT (≤6 vs. >6 months) and use of 
osteoclast-targeted therapy (yes vs. no) at randomization. 
Kaplan-Meier survival curves (product-limit estimates) will be presented by treatment arm. 
The Kaplan-Meier estimate of the median survival time and first and third quartiles will be 
presented with 95% CI. Greenwood's formula will be used for the standard error of the 
Kaplan-Meier estimate in the calculation of these confidence limits. 
 
 
Time to first symptomatic skeletal event (SSE) 
The time to first SSE is defined as time from randomization to the occurrence of the first 
SSE. SSE is defined as external beam radiation therapy (EBRT) to relieve skeletal symptoms, 
new symptomatic pathologic bone fracture, occurrence of spinal cord compression, or tumor-
related orthopedic surgical intervention.  
Patients who do not reach the SSE event will be censored at their last visit (SSE assessment).  
If the complete date of the assessment is not known, but the year and month are available, 
Day 15 of the month will be used for the calculation. 
Table 12 will be used for calculating the time to first SSE. Time to first SSE = End Date – 
Date of Randomization +1. 
Table 12: Censoring Rules for SSE 
Situation 
End Date on or prior to cut-off date 
Censored 
Recorded SSE event during the study 
Date of the first assessment that 
qualified as SSE 
No 
Patient has no recorded SSE event at 
data cut-off  
Date of last SSE assessment before 
data cut-off 
Yes 


 
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Patient lost to follow-up before data cut-off 
Date of last SSE assessment or 
randomization date, whichever 
comes later 
Yes 
This endpoint is selected from the ADTTE dataset using variable PARAMCD equal to 
‘SSEFS’.  
A log rank test stratified by stratification factor of PSADT (≤6 vs. >6 months) and use of 
osteoclast-targeted therapy (yes vs. no) at randomization will be used to compare the 
darolutamide treated and placebo groups. 
The hazard ratio as well as its 95% CI will be presented based on fitting a Cox regression 
model with treatment as factor and stratified by PSADT (≤6 vs. >6 months) and use of 
osteoclast-targeted therapy (yes vs. no) at randomization.  
Kaplan-Meier survival curves (product-limit estimates) will be presented by treatment arm. 
The Kaplan-Meier estimate of the median survival time and first and third quartiles will be 
presented with 95% CI. Greenwood's formula will be used for the standard error of the 
Kaplan-Meier estimate in the calculation of these confidence limits. 
The data of the second analysis of SSE will be analyzed in addition with the RPSFT and IPE 
methods for the same reasons as described for the analyses of OS. Only the unadjusted SSE 
data will be used for testing for a statistically significant treatment effect. 
Sensitivity analysis 1: SSE-free survival will be analyzed like time to first SSE event, death 
will be considered as an event. See Table 13 describe censoring rules (SSE-free survival = 
End Date – Date of Randomization +1). 
 
Table 13: Censoring Rules for SSE-free survival 
Situation 
End Date on or prior to cut-off date 
Censored 
Recorded SSE event during the study 
Date of the first assessment that 
qualified as SSE 
No 
Death during the study before SSE 
assessment 
Date of death 
No 
Patient has no recorded SSE at data cut-
off  
Date of last SSE assessment or 
randomization date whichever comes 
later 
Yes 
Patient lost to follow-up before data cut-off 
Date of last SSE assessment or at 
the data cut-off, whichever occurs 
first 
Yes 
This endpoint is selected from the ADTTE dataset using variable PARAMCD equal to 
‘SASSEDTH’. 


 
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A summary description of skeletal events will be tabulated. 
 
6.2.3 
Tertiary or additional efficacy analysis 
Calculating the p-value for tertiary endpoints has informative character only. These efficacy 
endpoints are: 
 
Progression-free Survival (PFS) 
PFS is defined as the time (days) from the date of randomization to the date of radiological 
disease progression based on independent blinded central reading, including progressing 
pelvic lymph nodes and new pathologic lymph nodes identified above or below the aortic 
bifurcation or death due to any cause, whichever occurs first. The radiological progression 
component of PFS will be derived by taking all distant metastasis events as determined for 
the MFS endpoint, adding all local radiological progression events per RECIST evaluation 
and choosing whatever comes first, in cases where both types of radiological progression 
were observed. 
Censoring rules for PFS are derived from the rules used for MFS as in Table 14. 
 
Censoring Rules 
Time of PFS is calculated as time to PFS = End Date-Date of randomization +1. 
Table 14: Censoring Rules for PFS Based on independent blinded central reading 
Data 
Situation 
End Date on or prior to cut-off date 
Censored 
Documented metastasis or local 
progression 
Date of documented metastasis 
No 
Documented metastasis at baseline 
Date of randomization 
No 
 
 
  
Documented metastasis or local 
progression after two or more 
consecutively missed tumor assessments, 
i.e. metastasis later than last evaluable 
scan + (32 +1) weeks 
Date of last tumor assessment that 
the patient was known to be 
metastasis-free 
Yes 
Death before documented metastasis or 
local progression and not later than last 
evaluable scan + (32+1) weeks 
Date of death 
No 
Death before documented metastasis or 
Date of last tumor assessment that 
Yes 
CCI


 
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Situation 
End Date on or prior to cut-off date 
Censored 
local progression and after two or more 
consecutively missed tumor assessments, 
i.e. death later than last evaluable scan + 
(32+1) weeks 
the patient was known to be 
metastasis-free 
Discontinued the study before any post-
baseline tumor assessments 
Date of randomization 
Yes 
Discontinued the study before any post-
baseline tumor assessments and died 
within (32+1) weeks after randomization 
Date of death 
No 
Discontinued the study before any post-
baseline tumor assessments and died 
later than (32+1) weeks after 
randomization 
Date of randomization 
Yes 
Discontinued the study, but no 
documented metastasis or local 
progression 
Date of last tumor assessment before 
discontinuation 
Yes 
Prohibited new anticancer treatment 
started prior to documented metastasis or 
local progression 
Date of last tumor assessment before 
start of prohibited new treatment 
Yes 
Patients still on treatment without 
documented metastasis or local 
progression as of data cut-off 
Date of last tumor assessment  
Yes 
If the complete date of the scan is not known, but the year and month are available, Day 15 of 
the month will be used for the calculation. 
The date used for the calculation of PFS is the actual (rather than scheduled) date of 
assessment (i.e. actual scan date); incomplete scans are not considered unless they showed 
progression. 
This endpoint is selected from the ADTTE dataset using variable PARAMCD equal to ‘PFS’ 
(baseline metastasis non-censored) and ‘SAPFSBAS’ (baseline metastasis censored). 
 
The two treatment groups will be compared using a stratified two-sided log-rank test with an 
alpha of 0.05 stratified by the same stratification factors used in the MFS analysis. 
The product-limit estimates of the survival distribution functions (Kaplan-Meier) will be 
presented for each treatment group: N, total censored, total failed, time to progression 
(median and its 95% CI, first and third quartiles, range), rate of patients who did not yet 
progressed at 4,8, 12, etc. months, KM curves. 


 
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The hazard ratio (darolutamide over placebo) and its 95% CI will be generated with the Cox 
model as for MFS. 
 
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. 
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.). 
Status of prostate cancer-related invasive procedures will be assessed from randomization 
until the first prostate cancer-related invasive procedure, i.e. until end of follow-up period. 
Patient with no prostate cancer-related invasive procedure will be censored. 
Table 15 will be used for calculating the time to first prostate cancer-related invasive 
procedure. Time Cancer-related invasive procedure = End Date-Date of randomization +1. 
 
Table 15: Censoring Rules for prostate cancer-related invasive procedure 
Situation 
End Date on or prior to cut-off date 
Censored 
Recorded prostate cancer-related 
invasive procedure during the study 
Date of the first assessment that 
qualified as prostate cancer-related 
invasive procedure 
No 
Death during the study before prostate 
cancer-related invasive procedure 
Date of the last visit at which prostate 
cancer-related invasive procedure  
question was collected or 
randomization date whatever comes 
later 
Yes 
Patient has no recorded prostate cancer-
related invasive procedure at data cut-off  
Date of last visit at which prostate 
cancer-related invasive procedure  
question or randomization date 
whatever comes later 
Yes 
Patient lost to follow-up before data cut-off 
Date of last visit at which prostate 
cancer-related invasive procedure  
question or at the data cut-off, 
whichever occurs first 
Yes 
This endpoint is selected from the ADTTE dataset using variable PARAMCD equal to 
‘CRIP’. 
A log rank test stratified by same stratification factors used in the MFS analysis will be used 
to compare the darolutamide treated and placebo groups. 


 
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The hazard ratio as well as its 95% CI will be generated with a Cox regression model as for 
MFS. 
Kaplan-Meier survival curves (product-limit estimates) will be presented by treatment arm. 
The Kaplan-Meier estimate of the median time to first prostate cancer-related invasive 
procedure and first and third quartiles will be presented with 95% CI. 
 
 
Time to initiation of subsequent antineoplastic therapy 
Time to initiation of subsequent antineoplastic therapy is defined as time from randomization 
to initiation of first antineoplastic therapy. 
Subsequent antineoplastic therapy will be assessed from the first follow-up visit until the first 
use of such therapy. Patients who do not reach the endpoint or died will be censored. 
Antineoplastic therapy will be selected using: 
-ATC code class L (antineoplastic and immunodulating agents): L01 Antineoplastic agents 
(except cytotoxic chemotherapy L01A, L01B, L01C, L01D and L01X), L02 endocrine 
therapy and L03 immunostimulants, 
-ATC code class H: H02Corticosteroids for systemic use. 
The list of antineoplastic therapy is available in Appendix 9.8. 
Table 16 will be used for calculating the time to initiation of subsequent antineoplastic 
therapy. Time to initiation of subsequent antineoplastic therapy event = End Date-Date of 
randomization +1. 
Table 16: Censoring Rules for antineoplastic therapy 
Situation 
End Date on or prior to cut-off date 
Censored 
Recorded antineoplastic therapy during 
the study 
Date of the first assessment that 
qualified as antineoplastic therapy 
No 
Death during the study before 
antineoplastic therapy 
Date of last visit at which 
antineoplastic therapy question was 
collected or randomization date 
whatever comes later 
Yes 
Patient has no recorded antineoplastic 
therapy at data cut-off  
Date of last visit at which 
antineoplastic therapy question was 
collected or randomization date 
whatever comes later 
Yes 
Patient lost to follow-up before data cut-off 
Date of last visit at which 
antineoplastic therapy question was 
collected or at the data cut-off, 
whichever occurs first 
Yes 


 
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This endpoint is selected from the ADTTE dataset using variable PARAMCD equal to 
‘ISAT’. 
A log rank test stratified by same stratification factors used in the MFS analysis will be used 
to compare the darolutamide treated and placebo groups. 
The hazard ratio as well as its 95% CI will be generated with a Cox regression model as for 
MFS. 
Kaplan-Meier survival curves (product-limit estimates) will be presented by treatment arm. 
The Kaplan-Meier estimate of the median time to initiation of subsequent antineoplastic 
therapy and first and third quartiles will be presented with 95% CIs. 
A summary of first subsequent antineoplastic therapy will be provided. 
 
 
Time to PSA progression 
Time to PSA progression is defined as the time (days) from the date of randomization to the 
date of first PSA progression. 
PSA progression is defined according to the Consensus Guidelines of the Prostate Cancer 
Trials Working Group2 (PCWG2) as: 
For patients with no decline from baseline at week 16, the PSA progression is defined as the 
date that a  25% PSA increase in PSA along with an absolute increase of  2 ng/ml above 
the baseline is documented, which is confirmed by a second consecutive value obtained 3 or 
more weeks later, 
Or 
For patients with declines from baseline at week 16, the PSA progression is defined as the 
date that a  25% PSA increase and an absolute increase of  2 ng/ml above the nadir is 
documented, which is confirmed by a second consecutive value obtained 3 or more weeks 
later.  
The above PSA definition deviate from PCWG2, as confirmation by a second value is 
requested here for a patient with no decline from baseline. 
Early increases in PSA values before the 16 weeks are not considered as PSA progression. 
PSA documented post end of study-treatment visit will not be considered. Central laboratory 
assessment will be considered. 
Baseline PSA value is the last non-missing observation on or before the first day of study 
drug intake. 
Table 17will be used for calculating the time to PSA progression. Time to PSA progresion 
=End Date-Date of randomization +1. 
 
 


 
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Table 17: Censoring Rules for PSA progression 
Situation 
End Date on or prior to cut-off date 
Censored 
No baseline or post-baseline PSA 
assessment 
Date of randomization 
Yes 
No PSA progression  
Last PSA assessment date  
Yes 
Patient  had an PSA progression  
The date of first observation of PSA 
progression  
No 
PSA progression after two or more 
consecutive missed  PSA assessments  
Date of last PSA assessment before 
missed assessments 
Yes  
 
This endpoint is selected from the ADTTE dataset using variable PARAMCD equal to 
‘TTCPP’. 
Time to PSA progression will be analyzed with the same methods as the primary variable 
MFS. A log rank test stratified by the same factors as used for randomization will be used to 
compare the darolutamide treated and placebo groups. Kaplan-Meier curves, median survival 
times, and their 95% CI will be presented. Hazard ratios will be calculated with the Cox 
model. 
 
 
Percent of patients with PSA response 
The percentage change of PSA from baseline at any time point will be calculated and the 
proportion of patients achieving a decline of  50% from baseline will be determined. 
PSA values will be collected until the end-of-study treatment visit. 
PSA response rate will be compared between treatment groups using Cochran-Mantel-
Haenszel test adjusting for same stratification factors as for primary endpoint. Estimates and 
the 95% CI will be computed for each treatment group. 
Sample code for Cochran-Mantel-Haenszel test: 
proc freq data=data; 
tables psa_double*ot_therapy*PSA_Response*trtpn /CMH; 
run; 
Where:  
PSA_Response contains corresponding PSA Response values, trtpn contains assigned 
treatment group, psa_double contains PSA doubling time category at randomization, 
ot_therapy contains category for osteoclast-targeted therapy use at randomization. 
 


 
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In addition, descriptive statistics will be provided for PSA at baseline, 16 weeks, change from 
16 weeks to baseline, maximum percent decline from baseline at any time on study. 
 
 
Percent of patients with ECOG performance status deterioration 
ECOG performance status (PS) is assessed at screening and every 16 weeks until the end of 
follow-up period. 
ECOG PS will be tabulated and summarized by visit for observed values and changes from 
baseline using descriptive statistics, as appropriate. If more than one baseline assessment was 
collected, the most recent one will be used. If several assessments were performed on the 
same day (without timing information) the most severe score will be used. 
ECOG performance status deterioration is defined as an increase to grade 3 or higher, with an 
increase of at least 2 from baseline. 
Deterioration will be compared between treatment groups using Cochran-Mantel-Haenszel 
test adjusting for same stratification factors as for primary endpoint. Estimates and the 95% 
CI will be computed for each treatment group. 
 
 
Time to ECOG performance status deterioration 
Time from randomization to ECOG performance status deterioration is defined as time from 
randomization to ECOG PS deterioration.  
Table 18 will be used for calculating the time to ECOG performance status deterioration. 
Time to ECOG performance status deterioration event = End Date-Date of randomization +1. 
Table 18: Censoring Rules for ECOG performance status deterioration  
Situation 
End Date on or prior to cut-off date 
Censored 
Recorded ECOG PS deterioration during 
the study 
Date of the first ECOG PS 
deterioration 
No 
No ECOG PS deterioration during study  
Date of last ECOG PS assessment  
Yes 
Patient has no post baseline ECOG PS 
assessment at data cut-off  
Date of randomization  
Yes 
This endpoint is selected from the ADTTE dataset using variable PARAMCD equal to 
‘ECOGDET’.  
A log rank test stratified by same stratification factors used in the MFS analysis will be used 
to compare the darolutamide treated and placebo groups.  
The hazard ratio as well as its 95% CI will be generated with a Cox regression model as for 
MFS. 


 
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Kaplan-Meier survival curves (product-limit estimates) will be presented by treatment arm. 
The Kaplan-Meier estimate of the median time to ECOG PS deterioration and first and third 
quartiles will be presented with 95% CIs. 
 
 
Time to first opioid use for cancer pain 
Time to first opioid use for cancer pain is defined as time from randomization to first opioid 
use for cancer pain. 
List of opioids for cancer pain is available in Appendix 9.10. 
Table 19 will be used for calculating the time to Time to first opioid use for cancer pain. 
Time to first opioid use for cancer pain = End Date-Date of randomization +1. 
Table 19: Censoring Rules for Time to first opioid for cancer pain 
Situation 
End Date on or prior to cut-off date 
Censored 
Recorded opioid use for cancer pain 
during the study 
Date of first opioid use 
No 
No opioid use for cancer pain during study  Date of last visit   
Yes 
Patient has no post baseline assessment 
at data cut-off  
Date of randomization  
Yes 
This endpoint is selected from the ADTTE dataset using variable PARAMCD equal to 
‘OCP’. 
A log rank test stratified by same stratification factors used in the MFS analysis will be used 
to compare the darolutamide and placebo groups. 
The hazard ratio as well as its 95% CI will be generated with a Cox regression model as for 
MFS. 
Kaplan-Meier survival curves (product-limit estimates) will be presented by treatment arm. 
Kaplan-Meier estimates of the median time and first and third quartiles times will be 
presented with 95% CIs. 
 
 
Health related Quality of Life and utility values. 
1) The EQ-5D-3L is a generic quality of life preference based instrument which has been 
validated in cancer population to measure both utility and health status. 
The EQ-5D-3L contains a descriptive system which measures 5 health dimensions: mobility, 
self-care, usual activity, pain/discomfort, and anxiety/depression. Each dimension contains 3 
levels of response to reflect the degree of problems patients have experienced: no problem 
(level 1), some problems (level 2), and extreme problems (level 3). These five health 


 
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dimensions are summarized into a single score, the EQ-5D-3L index score. The EQ-5D-3L 
index score ranges -0.59 to 1 with higher scores representing better health states. 
The EQ-5D-3L also contains a visual analog scale (EQ-VAS), which records the 
respondents’ self-rated health status on a vertical graduated visual analogue scale ranging 
from 0 (worst imaginable health state) to 100 (best imaginable health state). 
For details on scoring, please refer to the EQ-5D-3L user guide Appendix 9.5. 
Since EQ-5D-3L is a descriptive system based on five independent dimensions, a missing 
answer or ambiguous answer (i.e. marking of more than one level on scale) will lead to 
complete rejection of the questionnaire, but the VAS score will be retained if available. 
2) The FACT-P questionnaire assesses prostate cancer-related quality of life and has been 
validated in the prostate cancer population. 
This questionnaire contains 5 domains: Physical Well-Being (PWB), Social/Family Well-
Being (SWB), Emotional Well-Being (EWB), Functional Well-Being (FWB), and Additional 
Concerns (also called Prostate cancer subscale [PCS]). 
According to the FACT-P scoring guide, all subscale items are summed to a total which is the 
subscale (=domain) score. The FACT-P total score is the sum of the scores of 39 items of the 
questionnaire and ranges from 1 to 156; the higher the score, the better the quality of life of 
prostate cancer patients. 
Each item can be answered on a 5-point (0–4) scale. 
The sum of the scores on the first four domains (PWB, SWB, EWB, and FWB) constitutes 
the FACT-G (General). The sum of the scores on all five domains constitutes the FACT-P. 
The trial outcome index (TOI) is derived by the sum of PWB, FWB, and PCS scores. 
For details on scoring, please refer to the FACT-P user guide Appendix 9.3. 
In case of missing responses for one or more items, subscale scores can be prorated. This is 
done by multiplying the sum of the subscale by the number of items in the scale, then 
dividing the number of items actually answered. Prorating of scores is acceptable as long as 
more than 50% of the items are answered (assuming that the score of missing items are 
similar to those of non-missing items). If less than or equal to 50% of the items are answered 
for any domain, then the score of that specific domain is set to missing. The FACT-P total 
score is then calculated as the sum of the un-weighted subscale scores. Moreover, the FACT-
P total score is set to missing if the related overall item response rate is less than or equal to 
80%. 
The total score is then calculated as the sum of the un-weighted subscale scores. A total score 
is calculated if all of the component subscales have a valid score. 
Rate of the question GS7 ‘I am satisfied with my sex life’ in the SWB domain will be used 
independent of the answer documented in the question Q1 “Regardless of your current level 
of sexual activity, please answer the following question. If you prefer not to answer it, please 
check this box and go to the next section”. 


 
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3) The BPI-SF questionnaire assesses clinical pain related to cancer, it is a validated tool. 
Two scores will be derived: the pain severity and the pain interference. 
Questionnaire is completed daily over a 7-day period. Averages during the period of 
reporting are calculated. If fewer than 4 reports out of the 7 days are available at the planned 
time point for assessment, this would constitute missing data. 
The BPI assesses pain at its “worst” “least” “average” and “right now” (current pain). To 
derive the “pain severity” score a mean score of the 4 questions (questions 3 to 6 from the 
BPI-SF) related to pain will be created. In case of one or more missing information the “pain 
severity” score will be assessed to missing. 
The BPI measures how much pain has interfered with seven daily activities, including general 
activity, walking ability, normal work, mood, enjoyment of life, relations with others, and 
sleep (question 9 from the BPI-SF). BPI “pain interference” is scored as the mean of the 
seven interference items. This mean can be used if more than 50% or four of seven, of the 
total items have been completed on a given administration. 
Rate of pain entered in questions 3 to 9 will be used independent of the answer documented 
in the question 1 (have you had pain other than these everyday kinds of pain today) of the 
BPI-SF. 
For details on scoring, please refer to the BPI-SF user guide Appendix 9.2. 
4) The EORTC-QLQ-PR25 questionnaire assesses prostate cancer-related quality of life and 
has been validated in the prostate cancer population. 
The prostate cancer module is a 25-item questionnaire designed for use among patients with 
localized and metastatic prostate cancer. It includes subscales assessing urinary symptoms (8 
items), bowel symptoms (4 items), hormonal treatment-related symptoms (6 items), 
incontinence aid (1 item), sexual activity (2 items) and sexual functioning (4 items). The 
sexual activity and sexual functioning scales constitute the functional scales. The urinary 
symptoms, bowel symptoms, hormonal treatment-related symptoms, and incontinence aid 
constitute the symptom scales. 
If less than or equal to 50% of the items are answered for any subscales, then the score of that 
specific subscale is set to missing. 
For details on scoring, please refer to the EORTC-QLQ-PR25 user guide Appendix 9.4. 
PRO analyses: 
PRO data as measured by the FACT-P, the EQ-5D-3L , the EORTC-QLQ-PR25 and the BPI-
SF will be analyzed to assess differences in HRQoL and health utility values between 
treatment arms based on time-adjusted area under the curve (AUC) using all available data. 
The PRO analyses will be performed for the patients in the FAS. Statistical tests will be 
performed with a 2 sided type I error of 5%. 
Descriptive statistics on observed data will be presented for the FACT-P questionnaire (each 
domain score including the PCS and the FACT-P total score), for the EQ-5D-3L index score 


 
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(utility value) and visual analog scale score (VAS), for the EORTC-QLQ-PR25 questionnaire 
(each subscale score) and for BPI-SF questionnaire (pain severity and pain interference 
scores) at each assessment time and for change from baseline by treatment group. 
Questionnaires under unscheduled visits and not planned visits per protocol will not be 
displayed in the descriptive tables. Analyses will be done for patients with baseline 
assessments. 
The frequency for missing health related quality of life (HRQoL) assessment by treatment 
group will be summarized. 
An analysis of covariance (ANCOVA) model will be used to estimate the mean difference in 
the time-adjusted Area under Curve (AUC) between the two treatment groups, with 
covariates for baseline PRO scores and stratification factors as recorded in the IVRS data. 
Least-square mean estimates, standard errors and 95% CIs will be estimated for each 
treatment group and for the treatment group difference. 
Calculation of Time (AUC): 
AUC will not be calculated if baseline data is missing. 
The trapezoidal rule will be used to derive the AUC for a patient for the FACT-P total and 
subscale score, EQ-5D-3L index score, VAS score, BPI-SF pain severity and interference 
scores and EORTC-QLQ-PR25 urinary symptoms score. The time-adjusted AUC will be 
calculated by dividing the AUC by the duration (in days) over the treatment period. When 
calculating the AUC, the exact date of completion of the questionnaires should be plotted and 
the duration will be calculated in days. The time adjusted AUC for the FACT-P subscale 
scores and total score, EQ-5D-3L index score, VAS score, BPI-SF pain severity and 
interference scores and EORTC-QLQ-PR25 urinary symptoms score for an individual patient 
over a period of time [Ta,Tb] will be calculated as follows: 
 
Where PROi is the PRO measurement at time Ti (i=a… b). 
To test the treatment effect, a mixed linear model (random coefficient model) will be used for 
the EQ-5D-3L index score and VAS score, and for the FACT-P total score, BPI-SF pain 
severity and interference scores and the subscale scores and the EORTC-QLQ-PR25 urinary 
symptoms score. 
For patients with missing baseline FACT-P, PCS, EORTC-QLQ-PR25 urinary symptoms, 
EQ-5D-3L scores, time to deterioration will not be calculated. 
 


 
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6.2.3.9.1 Percent of patients with deterioration of FACT-P total score at 16 
weeks 
Patients will be defined as having total QoL deterioration, if they experience a decrease of ≥ 
10 points in FACT-P total score at 16 weeks compared with baseline. 
Deterioration from baseline in FACT-P total score will be compared between treatment arms 
using a Cochran-Mantel-Haenszel test stratified by stratification factor of PSADT (≤6 vs. >6 
months) and use of osteoclast-targeted therapy (yes vs. no) at randomization. 
Analysis will be created on both sub-sets of patients: 
• FAS, 
• FAS excluding patients with no visit at week16. 
 
6.2.3.9.2 Time to deterioration in PCS subscale score 
Time to deterioration for the FACT-P PCS score: a deterioration being defined as a 3 point or 
more decline in the PCS score. 
A patient’s time to deterioration will be defined as the time from randomization to the 
deterioration date. For patients with no symptomatic deterioration at the time of the analysis, 
the time to deterioration will be censored at the date of the last FACT-P PCS valid 
assessment. 
Table 20 will be used for calculating the time to deterioration in PCS. Time to Deterioration 
in PCS = End Date - Date of randomization + 1 
 
Table 20: Censoring Rules for time to deterioration in PCS 
Situation 
End Date on or prior to cut-off date 
Censored 
No baseline or post-baseline PCS 
assessment 
Date of randomization  
Yes 
No deterioration in PCS  
Last PCS assessment date  
Yes 
Patient had a deterioration in PCS 
The date of first observation of 
deterioration in PCS 
No 
This endpoint is selected from the ADTTE dataset using variable PARAMCD equal to 
‘FACTDETP’. 
Times to deterioration will be displayed by the product-limit estimates of the survival 
distribution functions (Kaplan-Meier) for each treatment group: N, total censored, total failed, 
survival time (median and its 95% CI, range), deterioration-free rate at 12, 24, 36 etc., 


 
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months, KM curves. The hazard ratio darolutamide over placebo, its 95% CI will be 
generated from the Cox model. 
 
6.2.3.9.3 Percent of patients with improvement of EORTC-QLQ-PR25 urinary 
symptoms 
Patients will be defined as having EORTC-QLQ-PR25 urinary improvement, if they 
experience a decrease of ≥ 8 points in EORTC-QLQ-PR25 urinary symptoms score, scale 
(PRURI), from baseline. 
Improvement from baseline in EORTC-QLQ-PR25 urinary symptoms score will be 
compared between treatment arms using a Cochran-Mantel-Haenszel test stratified by 
stratification factor of PSADT (≤6 vs. >6 months) and use of osteoclast-targeted therapy (yes 
vs. no) at randomization. 
 
6.2.3.9.4 Time to worsening of EORTC-QLQ-PR25 urinary symptom score 
A patient’s time to worsening of EORTC-QLQ-PR25 urinary symptoms will be defined as 
the time from randomization to the deterioration date. For patients with no symptomatic 
deterioration at the time of the analysis, the time to deterioration will be censored at the date 
of the last EORTC-QLQ-PR25 (PRURI) valid assessment. 
Patients will be defined as having EORTC-QLQ-PR25 urinary symptoms deterioration if 
they experience an increase of greater or equal to 8 points in EORTC-QLQ-PR25 urinary 
symptoms score, scale (PRURI), from baseline. 
Table 21 will be used for calculating the time to worsening of EORTC-QLQ-PR25 urinary 
symptoms. Time to worsening of EORTC-QLQ-PR25 urinary symptoms = End Date - Date 
of randomization +1. 
 
Table 21: Censoring Rules for time to worsening of EORTC-QLQ-PR25 urinary 
symptoms  
Situation 
End Date on or prior to cut-off date 
Censored 
No baseline or post-baseline EORTC-
QLQ-PR25 urinary assessment 
Date of randomization 
Yes 
No worsening in EORTC-QLQ-PR25 
urinary symptoms score  
Last EORTC-QLQ-PR25 urinary 
symptoms assessment date  
Yes 
Patient had a worsening in EORTC-QLQ-
PR25 urinary symptoms 
The date of first observation of 
worsening in EORTC-QLQ-PR25 
urinary symptoms  
No 


 
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This endpoint is selected from the ADTTE dataset using variable PARAMCD equal to 
‘EORTCWOR’. 
Times to worsening will be displayed by the product-limit estimates of the survival 
distribution functions (Kaplan-Meier) for each treatment group: N, total censored, total failed, 
survival time (median and its 95% CI, range), deterioration-free rate at 12, 24, and 36 etc.… 
months, KM curves. The hazard ratio darolutamide over placebo, its 95% CI will be 
generated from the Cox model. 
 
6.2.3.9.5 Percent of patients with deterioration of EQ-5D-3L utility score at 16 
weeks 
Patients will be defined as having a deterioration in EQ-5D-3L index if they experience a 
deterioration of greater or equal 0.06 points compared to baseline at 16 weeks after start of 
treatment. 
Deterioration from baseline in EQ-5D-3L index score will be compared between treatment 
arms using a Cochran-Mantel-Haenszel test stratified by stratification factor of PSADT (≤6 
vs. >6 months) and use of osteoclast-targeted therapy (yes vs. no) at randomization. 
Analysis will be created on both sub-sets of patients: 
• FAS, 
• FAS excluding patients with no visit at week16. 
 
6.2.4 
Subgroup analysis 
There are specific subgroup analyses of interest which will be performed for the primary 
endpoint (MFS) and the secondary endpoints (OS). 
Subgroup analyses will be based on FAS analysis set. 
Descriptive statistics and hazard ratio with 95% CI will be provided within each category, 
provided there are a sufficient number of patients in total within the subgroup across the 
treatment arms. All subgroups analyses will be done on non-stratified Cox model and log-
rank test. 
Subgroup analyses of interest: 
• Baseline CRF PSADT (≤6 and >6 months), 
• Baseline CRF osteoclast-targeted therapy (yes vs. no), 
• Baseline PSA (ng/mL) (≤10; >10 to ≤20; >20) from central laboratory, 
• Baseline PSA (ng/mL) (at or below median vs. above the median [median of all 
patients]) from central laboratory, 
• Gleason score at diagnosis (≥7 vs. <7), 


 
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• Age (years) (<65, 65- 74, 75 - 84, ≥85), 
• Geographical region (North America, Asia Pacific, ROW), 
• Baseline presence of regional pathological lymph nodes (yes vs. no) by central 
imaging review, 
• Baseline ECOG performance status (0, 1), 
• Race: White, Asian, Black or African American, Other; ethnicity ‘Hispanic or Latino’ 
will be shown as well as it cannot be mapped to the Bayer race subgroups, 
• Number of prior hormonal therapies (1, ≥2) (for definition of hormonal therapies, 
refers to Section 9.13). 
Further important baseline cancer characteristics may also be considered. 
Subgroup analyses will not be performed for the sensitivity analyses. 
 
6.3 
Pharmacokinetics/pharmacodynamics 
PK sampling will be undertaken at centers participating in PK sample collection. It is 
estimated that approximately 600 patients will participate in the PK sampling, resulting 
in approximately 400 patients randomized to receive darolutamide being included in the 
population PK analysis. 
Venous blood samples will be collected for determination of darolutamide, the diastereomers 
(S,R)-darolutamide and (S,S)-darolutamide and the metabolite keto-darolutamide 
concentrations in plasma. 
 
Pharmacokinetics of darolutamide: PK data will be analyzed using a population PK model to 
explore possible relationships between selected demographics and clinical covariates and 
drug/metabolite exposure. 
Pharmacokinetic analyses and results will be provided in a separate report. Full details of the 
modelling will be provided in a separate Modelling & simulation analysis plan. 
 
6.4 
Biomarker evaluation  
Blood (plasma) samples will be collected for tumour-related biomarker assessments and a 
whole blood sample for pharmacogenetic (PG) assessments. Patients’ biomarker status will 
be correlated with clinical treatment effect to explore which targets may be important in 
defining the appropriate therapeutic population for the agent.  
Since this clinical study is not powered to specifically address biomarker questions, and since 
the analysis will be conducted retrospectively, these biomarker analyses are considered 
exploratory. 


 
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Biomarker analyses and results will be provided in a separate report. 
 
6.5 
Safety 
No formal statistical tests will be done for the safety endpoints. All analyses for safety will be 
performed in the SAF population. 
An updated analysis of safety events will be performed as of the final OS analysis. 
Specific tables of adverse events will be displayed by following subgroups: 
• Age (years) :<65, 65 - 74, 75 - 84, ≥85, 
• Geographical region (North America, Asia Pacific, ROW). 
• Renal function - eGFR at baseline (normal vs.mildly impaired vs. moderately 
impaired, severely impaired and end stage renal disease) (for calculation see Section 
6.1.2), 
• Hepatic impairment at baseline (normal vs mild vs moderate and severe impairment) 
(for calculation see section 6.1.2), 
• Concomitant statin use (no vs. yes), to be determined by concomitant medication (see 
Appendix 9.9). 
 
6.5.1 
Extent of exposure 
Extent of exposure will be summarized for the SAF by treatment group, using descriptive 
statistics. 
Duration of study treatment will be calculated in days and presented in months as the date of 
the last dose of any study treatment – date of the first dose of any study treatment + 1. 
Dose modification will be summarized. 
Extent of exposure will be described by age groups and geographical regions. 
 
6.5.2 
Adverse events 
All adverse events (AE) whether considered drug-related or not, will be reported on the CRF 
with diagnosis, start/stop dates, dates of any grade change, action taken, whether treatment 
was discontinued, any corrective measures taken, and outcome. For all events, the 
relationship to treatment and the severity of the event will be determined by the Investigator. 
AEs will be classified and coded using the National Cancer Institute (NCI) Common 
Terminology Criteria Adverse Event (CTCAE), version 4.03. 
The treatment period for this study, for purposes of safety analyses, extends from the 
initiation of study treatment until 30 days after the last administration of study treatment. 


 
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Each change in AE grade was entered as a separate record with no automatic link to the 
original AE record, which may lead to variations of the verbatim for the same AE. This 
makes a correct grouping of AE grades, which actually belong together, not always possible. 
An AE is considered as treatment-emergent (TEAE) if there is an AE record which starts 
during treatment or within the post-treatment time window of 30 days. 
 
For further definitions of the terms AE, SAE, seriousness, intensity, causal relationship with 
treatment, causal relationship to protocol-required procedures, action taken, and outcome; see 
Protocol Section 6.6.1. 
Descriptive summary tables (frequency and percentage of patients, not of events) will be 
presented by treatment group and MedDRA version 20.0, or the most recent version 
terminology, for the following: 
• AEs during screening 
• Treatment-emergent AEs 
• Treatment-emergent AEs with grade 3, 4, or 5 
• Treatment-emergent AEs occurring in at least 1% of patients  
• Treatment-emergent AEs occurring in at least 5% of patients  
• Treatment-emergent AEs leading to study drug withdrawal 
• Treatment-emergent AEs leading to dose reduction 
• Treatment-emergent AEs leading to drug interruption 
• Treatment-emergent AEs leading to dose reduction and/or drug interruption 
• Treatment-emergent drug-related AEs 
• Treatment-emergent drug-related AEs with grades 3, 4, or 5 
• Treatment-emergent drug-related AEs occurring in at least 5% of patients in any 
treatment arm 
• Treatment-emergent drug-related AEs leading to study drug withdrawal 
• Treatment-emergent drug-related AEs leading to dose reduction 
• Treatment-emergent drug-related AEs leading to drug interruption 
• Treatment-emergent drug-related AEs leading to dose reduction and/or drug 
interruption 
Interval specific and cumulative event rates for treatment-emergent adverse events (for AE 
with at least a 5% total incidence rate (any grade)). 
Subgroup analyses will be performed for TEAEs. Tables showing differences of at least 5% 
points in incidence proportions between any of the subgroup categories will be produced. 


 
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Following treatment-emergent adverse events are considered as special topics: 
- 
Bone fracture (selected using HLT: Fractures and dislocations NEC (without PTs: 
Joint dislocation, Joint dislocation pathological), Limb fractures and dislocations 
(without PT: Radial head dislocation), Pelvic fractures and dislocations, Skull 
fractures, facial bone fractures and dislocations, Spinal fractures and dislocations 
(without PT: Dislocation of vertebra),Thoracic cage fractures and dislocations 
(without PT: Dislocation of sternum)) 
- 
Fall (selection of MLG Fall (only PT Fall)) 
- 
Seizure (selection of MLG Seizures) 
- 
Fatigue (selection of MLG decreased general strength and energy, selection of PT 
Lethargy, Malaise, Chronic fatigue syndrome) 
- 
Weight decreased (selection of MLG Weight decreased) 
Following tables will be created for the TEAE of special topics 
• Treatment-emergent AEs 
• Treatment-emergent AEs leading to study drug withdrawal 
• Treatment-emergent AEs leading to dose reduction 
• Treatment-emergent AEs leading to drug interruption 
• Treatment-emergent SAEs 
Incidence of TEAEs of special topics will be displayed for the subgroup of concomitant statin 
use. 
Fracture events will be described by a cumulative incidence plot of fracture. A summary of 
treatment-emergent fracture by bone sparing agent use (for selection of bone sparing agent 
see Appendix 9.14) at study entry will be provided. Association with weight decrease will be 
presented by histogram of fracture events by patient weight change (the weight collected 
closest to the start of fracture will be considered and compared to baseline weight). 
A listing will be generated for patients with fall treatment-emergent events with syncope 
and/or loss of consciousness (using the MLG Syncope). 
An overview of patients at risk for developing an AE seizure will be tabulated by displaying 
medical history. 
 
Listing of non-treatment-emergent AEs will be created. 
Incidence of post treatment non-treatment-emergent AEs will be tabulated. 
To adjust for unequal lengths of study treatment period among patients, and potentially 
between treatment groups, an additional summary based on event rate per 100 patient year 
will be performed for all AEs, special topics AEs and all SAEs occurring after the first dose 


 
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of study treatment. The event rate per patient is calculated as the total number of events 
divided by the total treatment duration in years. 
 
6.5.3 
Deaths and Serious Adverse events 
Serious adverse events (SAE) will be classified using the National Cancer Institute (NCI) 
Common Terminology Criteria Adverse Event (CTCAE), version 4.03 and MedDRA version 
20.0 or most recent version 
• Treatment-emergent SAEs 
• Treatment-emergent SAEs leading to study drug withdrawal 
• Treatment-emergent SAEs leading to dose reduction 
• Treatment-emergent SAEs leading to drug interruption 
• Treatment-emergent SAEs leading to dose reduction and/or drug interruption 
• Treatment-emergent drug-related SAEs 
• Listing of treatment-emergent SAEs 
• Listing of non-treatment-emergent SAEs 
The incidence of deaths in the study and especially deaths up to within 30 days of last dose of 
study drug will be summarized by each treatment group and cause of death. All deaths up to 
within 30 days of last dose of study drug will be listed by patient with start and stop date of 
study medication, date of death, and cause of death. All deaths beyond 30 days after last dose 
of study drug will be displayed in a separate listing. 
 
6.5.4 
Clinical laboratory data 
Descriptive statistics (number of observations, mean, standard deviation, minimum, median 
and maximum values) will be presented for clinical laboratory tests (hematology, clinical 
biochemistry and urinalysis), their changes from baseline (including baseline value), and their 
percent changes from baseline by treatment group at applicable visits. 
Hematological and biochemical laboratory values will be graded based on NCI CTCAE 
version 4.03. CTCAE severity grading for laboratory abnormalities are based on applicable 
laboratory threshold values outlined in NCI CTCAE v4.03. It should be noted that in the 
present analysis of those laboratory parameters for which additional clinical information 
potentially can also influence the toxicity grade, this clinical information is in general not 
available and only the laboratory measurements are used for grading. 
Any additional specific handling of the NCI CTCAE v4.03 toxicity grading assignments will 
be noted in the footnotes of the corresponding tables as applicable per the data collection in 
the study. 


 
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• 
In the event of overlapping CTCAE criteria ranges for specific lab tests, the 
algorithm assigns the worst grade  
• 
If calcium type is not recorded (i.e. only “calcium” is recorded), then grading is 
done as if the calcium is total calcium.  “Calcium corrected” is computed from 
total calcium and serum albumin (if ≤ 4.0 g/dl) from the same time point based on 
CTCAE v3.0 guidance. If serum albumin (if ≤ 4.0 g/dl) from the same time point 
is not available or if “calcium, unspecified” was collected then grading is done as 
if the calcium is ”corrected calcium.” 
• 
Results with special characters (such as “>” and “<”) are not graded. 
The frequency of laboratory abnormalities regarding hematology, coagulation panel, clinical 
chemistry, and urinalysis will be tabulated by treatment group. Worst grades for 
hematological and biochemical toxicities will be calculated according to CTCAE, version 
4.03 based on laboratory measurements, and will be summarized by treatment group and NCI 
CTCAE v4.03 category and worst grade. 
Clinical laboratory toxicities during treatment including a period of 30 days after last dose of 
treatment will be considered as “treatment-emergent. 
The last non-missing value before or on the first day of study drug will be retained as 
“baseline” data. If several assessments are performed on the same day (without timing 
information) the average of the values will be considered. 
Incidence tables (frequency and percentage of patients) as well as tables with change in NCI 
CTCAE v4.03 worst grade from baseline will be presented as following: 
• Hematological and biochemical toxicity during screening (the last evaluation 
available before assignment to treatment is taken into account). 
• Treatment-emergent hematological and biochemical toxicity. 
• Treatment-emergent hematological and biochemical toxicities with incidence rate 
above 5% in any treatment arm. 
• Change in worst grade for hematological and biochemical toxicity from baseline. 
The laboratory values will be also categorized into low, normal and high according to their 
reference ranges. 
Descriptive statistics will be calculated by treatment group and time interval. 16-week time 
intervals will be used. 
Only for ALT, descriptive statistics will be displayed for subgroups of statin users and non-
statin users. Clinical laboratory tables will not be described by subgroups. 
The data will also be displayed graphically using box plots and laboratory shift plots. These 
will show the baseline value and post baselines values up-to end of treatment. 
A listing will be provided for all patients possibly fulfilling Hy’s Law criteria, i.e. patients 
with elevated AST and / or ALT > 3xULN, alkaline phosphatase < 2xULN and bilirubin 


 
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≥2xULN (ref. 9). For possible Hy’s Law cases relevant laboratory data will also be displayed 
graphically within actual patient profiles (presenting total bilirubin, ALT, AST and ALP 
values in terms of ULN over time) by treatment group. Below example of Hy’s law plot will 
be provided for peak total bilirubin vs ALT. If a patient has any total bilirubin ≥ 2xULN then 
peak bilirubin will be plotted versus the maximum ALT amongst the total bilirubin ≥ 2xULN. 
Otherwise, peak bilirubin will be plotted versus peak ALT. 
Example for Hy’s law plot: 
 
 
Unscheduled laboratory data will be listed (Section 16 of the CSR) but will be included in the 
descriptive tables. 
 
6.5.5 
12-Lead ECG, QTc 
Analyses of ECG and QTc will be performed on the SAF population; no subgroup tables will 
be created. 
Corrected QT (QTc) will be calculated using Bazett’s (QTcB) and Fridericia’s (QTcF) 
formula. 
Standard 12-lead ECGs will be performed in a supine position after at least 10 minutes rest. 
Three consecutive 12-lead ECG recordings will be performed within approximately 5 
Cholestasis range
Hy's Law range
Normal range
Temple's Corollary range
TREATMENT A: n= &n1.
TREATMENT B: n= &n2.
TREATMENT A: n= &n3.
TREATMENT B: n= &n4.
TREATMENT A: n= &n5.
TREATMENT B: n= &n6.
TREATMENT A: n= &n7.
TREATMENT B: n= &n8.
Treatment
TREATMENT A
TREATMENT B
Peak TBL/ULN 
0.1
1.0
10.0
100.0
Peak ALT/ULN
0.1
1.0
10.0
100.0


 
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minutes at screening and on day 1 visit before the first study treatment administration, at 
other visits, 12-lead ECG will be obtained once. 
An ECG with a QTcF > 500 ms should be confirmed by a second ECG taken 1-2 hours later. 
Descriptive statistics including arithmetic mean, SD, median, minimum, and maximum will 
be presented for the following ECG parameters: HR, RR, PR, QT, QRS, QTcB and QTcF. 
Parameters will be summarized for actual results and the change from baseline for the safety 
analysis set by treatment group at each scheduled visit. Baseline for 12-lead ECG will be 
mean of separate recordings. Similarly, post baseline values of 12-lead ECG for patients will 
be mean of separate recordings. 
Mean time courses +/- one standard deviation will be displayed graphically. 
The last non-missing average value before the first study drug intake will be considered as 
“baseline” data.  
If several assessments are performed on the same day (without timing information) the 
average of the values will be considered. 
In case, timing of ECG is missing at day1 then screening assessment will be considered as 
baseline data. 
The number and percent of patients with absolute QTc interval prolongation or QTc increase 
from baseline will be defined and summarized by treatment arms. The criteria are: 
QTc prolongation: QTc interval > 450 msec, QTc interval > 480 msec and QTc interval > 
500 msec. 
Increase from baseline in QTc interval: QTc interval increases from baseline > 30 msec and 
QTc interval increases from baseline > 60 msec. 
The number and percent of patients with new clinically significant abnormalities on ECGs 
per the investigator’s assessment at post-baseline time points will be summarized by 
treatment arms. 
ECG data will be presented in a listing. Values with QTc interval > 450 msec,> 480 msec, 
and >500 msec, and change from baseline in QTc interval >30 msec and >60 msec will be 
flagged. In addition, abnormalities or clinically significant abnormalities found in the 12-lead 
ECGs at each scheduled time point will be provided in a listing.   
ECG data collected under unscheduled visit will be included in the analyses. 
 
6.5.6 
Other safety measures 
For each treatment group, vital signs (i.e. blood pressure, heart rate, weight and BMI) will be 
tabulated and summarized by visit for observed values and changes from baseline using 
descriptive statistics, as appropriate. If more than one baseline assessment was collected, the 
most recent one will be used. If several assessments are performed on the same day (without 
timing information) the average of the values will be considered. 


 
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In addition to descriptive analysis box plots will be created. 
For weight parameter a graph representing mean changes in weight from baseline by visit 
will be created. 
Outlier analyses will be conducted using the following limits:  
• 
low systolic blood pressure: 
 90 mmHg and a decrease of  20 mmHg 
• 
high systolic blood pressure: 
>190 mmHg and an increase of  20 mmHg 
• 
low diastolic blood pressure: 
 50 mmHg and a decrease of 20 mmHg 
• 
high diastolic blood pressure: 
> 105 mmHg and an increase of  20 mmHg  
• 
low heart rate: 
 
 
< 50 bpm and a decrease of  15 bpm 
• 
high heart rate: 
 
 
> 120 bpm and an increase of  15 bpm 
The number and percentage of patients with outlying values will be tabulated by treatment 
group and time interval. 
No subgroup analyses will be performed. 
Unscheduled vital signs data will be listed (Section 16 of the CSR) but will be included in the 
summary tables. 
 
6.5.7 
Physical examinations 
The number and percent of patients with physical examination abnormalities will be 
summarized based on the safety analysis set for each treatment group and overall. Physical 
examination findings will be presented in a data listing. 
No subgroup analyses will be performed. 
 
7. 
Document history and changes in the planned statistical analysis: 
Abbreviated SAP Version 1.0 dated 14 MAY 2015 
Abbreviated SAP Version 2.1 dated 22 JUN 2017 
SAP Version 3.0 dated 12 MAR 2018 
SAP Version 4.0 dated 10 AUG 2018 
SAP Version 4.1 dated 13 SEP 2018 
 


 
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8. 
References 
1. FACT-P guideline refers to the Administration and Scoring Guidelines in the manual 
or on-line at www.facit.org. 
2. BPI user guide, 2009Charles S. Cleveland. 
3. EORTC QLQ-C30 scoring manual - Third edition, 2001. 
4. Pain Palliation Measurement in Cancer Clinical Trials – the US Food and Drug 
Administration Perceptive. Ethan Basch. Cancer, March 1, 2014. 
5. Branson M, Whitehead J: Estimating a Treatment Effect in Survival Studies in Which 
Patients Switch Treatment. Statistics in Medicine 2002, 21:2449-2463. 
6. Penson DF et al. (2016) Enzalutamide versus Bicalutamide in Castration-Resistant 
Prostate Cancer: The STRIVE Trial. J Clin Oncol. 34 (18): 2098-106. 
7. Robins JM, Tsiatis AA Correcting For Non-Compliance in Randomized Trials Using 
Rank Preserving Structural Failure Time Models. Commun. Statist.-Theory 
Meth. 1991; 20(8):2609-2631. 
8. Smith MR et al. (2012) Denosumab and bone-metastasis-free survival in men with 
castration-resistant prostate cancer: results of a phase 3, randomised, placebo-
controlled trial. Lancet. 379 (9810): 39-46. 
9. U.S. Department of Health and Human Services, Food and Drug Administration, 
Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation, 
July 2009. 
10. Hung HM et al. Statistical considerations for testing multiple endpoints in group 
sequential or adaptive clinical trials. J Biopharm Stat. 2007; 17(6):1201-10. 
 


 
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9. 
Appendices 
9.1 
Study event schedule 
Study event schedule during the double-blind study treatment period  
Protocol activities 
Screening period 
Study treatment period (Darolutamide (ODM-201) or placebo) 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 and subsequent 
visits 
End-of-study treatment 
visit 
 
Within 28 days before 
randomization 
Day 11 
Day 15 
(±3 days) 
Day 29 
(±5 days) 
Week 16 
(±7 days) and every 
subsequent  
16 weeks  
28 days  
(+7 days) after last dose 
FACT-P or PCS of FACT-P 
x (FACT-P) 
x (FACT-P) 
 
 
x2 
x (FACT-P) 
EQ-5D-3L 
x 
x 
 
 
x3 
x3 
Physical examination, weight  
x4 
x 
 
x 
x 
x 
12-lead ECG and vital signs 
x5 
x5 
x 
x 
x 
x 
Laboratory safety assessments 
x 
x 
x 
x 
x 
x 
Serum PSA14  
x 
x 
 
 
x 
x 
Testosterone 
x 
x 
 
 
x 
 
PK samples at participating 
centres6 
 
 
x 
x 
x 
 


 
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Protocol activities 
Screening period 
Study treatment period (Darolutamide (ODM-201) or placebo) 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 and subsequent 
visits 
End-of-study treatment 
visit 
PK diary dispensing6 
 
x 
x 
x 
 
 
PK diary collection7 
 
 
x 
x 
x  
 
ECOG performance status 
x 
 
 
 
x 
x 
Pain diary dispensing 
x 
 
 
x 
x 
x 
Pain diary collection7 
 
x 
 
 
x 
x 
Chest, abdomen and pelvic 
CT/MRI 
x8 
 
 
 
x8 
 
Bone scan9 
x8 
 
 
 
x8 
 
First SSE 
 
 
x 
x 
x 
x 
First prostate cancer-related 
invasive procedure  
 
 
x 
x 
x 
x 
Survival status 
 
 
x 
x 
x 
x 
Adverse events10 
x 
x 
x 
x 
x 
x 
Concomitant treatments11 
x 
x 
x 
x 
x 
x 
Study drug dispensing and 
accountability 
 
x 
 
x 
x 
x15 


 
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Protocol activities 
Screening period 
Study treatment period (Darolutamide (ODM-201) or placebo) 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 and subsequent 
visits 
End-of-study treatment 
visit 
PG IC 
x12 
 
 
 
 
 
PG sample 
 
x16 
 
 
 
 
Tumor-related biomarker blood 
sample13 
 
x 
 
 
 
x 
Abbreviations: IC = informed consent; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; PG = pharmacogenomics; HR = heart rate; PK 
= pharmacokinetic; PSA = prostate-specific antigen; SSE = symptomatic skeletal event 
1) In case the start of study treatment is not logistically feasible on the same day as randomization can be performed 1 day before the initiation of study treatment. 
2) FACT-P (Appendix 5a) will be assessed at the week 16 visit only, and PCS subscale of FACT-P (Appendix 5b) will be assessed at the subsequent 16-week 
visits thereafter.  
3) EQ-5D-3L (Appendix 6) will be assessed at the week 16 visit only, and end-of-study treatment visit.  
4) Also height will be recorded at the screening visit.  
5) A triplicate 12-lead ECG including HR in a supine position after at least 10 minutes rest. The 3 consecutive recordings will be performed within approximately 5 
minutes. BP and HR (unless recorded by ECG) in a supine position after at least 10 minutes rest. The assessments will be done in the following order: ECGs, 
vital signs, and any type of blood draw as the last assessment.  
6) See Section 6.2 for PK procedures (blood sampling and recording of 12-lead ECG and vital signs) at study centers participating in PK sample collection. If PK 
sampling is not feasible during these visits, later visits may be used for PK procedures.  
7) Patients will be instructed to complete the diary for 6 days (-6 to -1 day) before day 1 and every 16-week visits until documented pain progression.  
8) CT/MRI and bone scans are acceptable if performed within 42 days prior to start of study treatment. A local qualified site physician (e.g. site radiologist or PI, at 
the PI’s discretion) must first review the screening scans and confirm the patient is non-metastatic before submitting the scans to central review to confirm 
eligibility. If the local qualified site physician detects metastasis, the scans should not be submitted to central review. For guidance on CT/MRI and bone scans 
performed at Week 16 and subsequent visits see Section 6.1.2.4. 
9) New lesion(s) in bone scan must be confirmed by CT/MRI (whichever imaging was conducted at screening for soft tissue) or x-ray. If confirmatory scan is 
negative (does not confirm progression), the patient will continue study treatment and visit study center as specified in the study event table.  


 
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10) All AEs including SAEs will be recorded from the date of signing IC and continuing until the end-of-study treatment visit. Any AEs or SAEs that occur after the 
end-of-study treatment visit and which are considered to be related to the study treatment or any study procedures have to be reported and entered into the 
eCRF. When the eCRF is not available anymore, all SAEs considered study treatment related should be reported to Bayer using a paper SAE form. AEs related 
to study procedures and all SAEs will be recorded for screening failures. 
11) Once the patient has been withdrawn from study treatment, concomitant treatments will be recorded if used to treat new related or unresolved related AEs or if 
it is an antineoplastic therapy.  
12) An optional PG IC for pharmacogenetics research study will be obtained at screening visit (or later during the study if feasible) unless precluded by local 
guidelines, e.g. IEC/IRB or regulatory authorities.  
13) Blood (plasma) sampling for tumor-related biomarker evaluation will be collected on day 1 visit before study treatment administration and at the end-of-study 
treatment visit unless precluded by local guidelines, e.g. IEC/IRB or regulatory authorities.  
14) The local PSA result taken at screening should be used to confirm the patient has CRPC (inclusion criterion 4) and meets inclusion criterion 6.  
15) Only study drug accountability performed at the end-of-study treatment visit.  
16) A blood sample for DNA extraction will be taken at day 1 visit (or later during the study if feasible) only from patients who have signed the PG IC unless 
precluded by local guidelines, e.g. IEC/IRB or regulatory authorities. 
 


 
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Study event schedule during the follow-up period after withdrawal of study treatment 
Protocol activities 
For patients during double-blind period 
before confirmed metastasis and not 
initiating any prohibited treatment 
For patients after confirmed metastasis or 
for patients in the placebo arm at 
unblinding 
 
Visits 
Every 16 weeks (±7 days)  
from end-of-study treatment visit1 
Visits or phone contacts 
Every 16 weeks (±7 days)  
from end-of-study treatment visit2 
BPI-SF 
X 
X 
Dispensing of pain diary 
X 
X 
Collection of pain diary and pain medications 
X3 
X3 
PCS subscale of FACT-P 
X 
X 
ECOG performance status 
X 
X 
Use of subsequent antineoplastic therapies 
X 
X 
Collection of AEs and SAEs considered to be related to study 
treatment or procedures 
X 
X 
Collection of concomitant treatments used to treat new related or 
unresolved related AEs 
X 
X 
First SSE 
X 
X 
First prostate cancer-related invasive procedure for prostate 
cancer 
X 
X 


 
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Protocol activities 
For patients during double-blind period 
before confirmed metastasis and not 
initiating any prohibited treatment 
For patients after confirmed metastasis or 
for patients in the placebo arm at 
unblinding 
 
Visits 
Every 16 weeks (±7 days)  
from end-of-study treatment visit1 
Visits or phone contacts 
Every 16 weeks (±7 days)  
from end-of-study treatment visit2 
Survival status 
X 
X 
Serum PSA  
X 
 
Chest, abdomen, and pelvic CT/MRI 
X 
 
Bone scan4 
X 
 
1) Until confirmed metastasis, death or the end of the study  
2) Until death or the end of the study 
3) Patients will be instructed to complete the diary for 6 days before each 16-week visit until documented pain progression. Pain medications will be recorded on 
CRFs at each 16-week visit until documented pain progression.  
4) New lesion(s) in bone scan must be confirmed by CT/MRI (whichever imaging was conducted at screening for soft tissue) or x-ray. If confirmatory scan is 
negative (does not confirm progression), the patient will continue to visit study center as specified in the study event table.  


 
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9.2 
Brief pain Inventory – Short Form (BPI-SF) questionnaire and scoring 
information  
 


 
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Scoring:  
Pain Severity Score = mean of items 3-6 
(pain at its worst, pain at its least, pain on the average, pain for right now) 
Pain Interference Score = mean of items 9A-9G (interference of pain with: general activity, 
mood, walking ability, normal work, relations with other people, sleep, and enjoyment of 
life). 
 
9.3 
FACT-P questionnaire and scoring information 
PCS subscale of FACT-P concerns the “additional concerns” questions. 
 


 
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FACT-P Scoring Guidelines (Version 4)  
Instructions: 
1. Record answers in "item response" column. If missing, mark with an X 
2. Perform reversals as indicated, and sum individual items to obtain a score. 
3. Multiply the sum of the item scores by the number of items in the subscale, and then divide 
by the number of items answered. This produces the subscale score. 
4. Add subscale scores to derive total scores (TOI, FACT-G & FACT-P).  
5. The higher the score, the better the QOL. 
Subscale 
Item Code 
Reverse item? 
Item response 
Item Score  
 
PHYSICAL  
GP1 
 
4 
- 
________ 
 
=________ 
WELL-BEING 
GP2 
 
4 
- 
________ 
 
=________ 
(PWB) 
 
GP3 
 
4 
 
________ 
 
=________ 
 
 
 
GP4 
 
4 
- 
________ 
 
=________ 
 
 
 
GP5 
 
4 
- 
________ 
 
=________ 
GP6 
 
4 
- 
________ 
 
=________ 
GP7 
 
4 
- 
________ 
 
=________ 
 
Sum individual item scores: ________ 
Multiply by 7: ________ 
Divide by number of items answered: ________=  
 
PWB subscale score 
SOCIAL/FAMILY GS1 
 
0 
+ 
________ 
 
=________ 
WELL-BEING 
GS2 
 
0 
+ 
________ 
 
=________ 
(SWB)  
 
GS3 
 
0 
+ 
________ 
 
=________ 
GS4 
 
0 
+ 
________ 
 
=________ 
GS5 
 
0 
+ 
________ 
 
=________ 
GS6 
 
0 
+ 
________ 
 
=________ 
GS7 
 
0 
+ 
________ 
 
=________ 
Sum individual item scores: ________  
Multiply by 7: ________ 
Divide by number of items answered: ________=  
 
SWB  subscale score 
Score range: 0-28 
Score range: 0-28 


 
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EMOTIONAL 
GE1 
4 
- 
________ 
 
=________ 
WELL-BEING 
GE2 
0 
+ 
________ 
 
=________ 
(EWB) 
 
GE3 
4 
- 
________ 
 
=________ 
GE4 
4 
- 
________ 
 
=________ 
GE5 
4 
- 
________ 
 
=________ 
GE6 
4 
- 
________ 
 
=________ 
 
Sum individual item scores: ________ 
Multiply by 6: ________ 
Divide by number of items answered: ________=  
EWB subscale score 
 
FUNCTIONAL   
GF1 
 
0 
+ 
________ 
 
=________ 
WELL-BEING  
GF2 
 
0 
+ 
________ 
 
=________ 
(FWB) 
 
GF3 
 
0 
+ 
________ 
 
=________ 
GF4 
 
0 
+ 
________ 
 
=________ 
GF5 
 
0 
+ 
________ 
 
=________ 
GF6 
 
0 
+ 
________ 
 
=________ 
GF7 
 
0 
+ 
________ 
 
=________ 
 
Sum individual item scores: ________ 
Multiply by 7: ________ 
Divide by number of items answered: ________=  
FWB  subscale score 
 
Score range: 0-24 
Score range: 0-28 


 
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FACT-P Scoring Guidelines (Version 4) – Page 2 
Subscale 
 
Item Code 
Reverse item? 
Item responds  Item Score  
PROSTATE  
C2 
 
4 
- 
________ 
 
=________ 
CANCER 
 
C6 
 
0 
+ 
________ 
 
=________ 
SUBSCALE  
P1 
 
4 
- 
________ 
 
=________ 
(PCS)  
 
P2 
 
4 
- 
________ 
 
=________ 
P3 
 
4 
- 
________ 
 
=________ 
P4 
 
0 
+ 
________ 
 
=________ 
P5 
 
0 
+ 
________ 
 
=________ 
P6 
 
4 
- 
________ 
 
=________ 
P7 
 
4 
- 
________ 
 
=________ 
BL2 
 
4 
- 
________ 
 
=________ 
P8 
 
4 
- 
________ 
 
=________ 
BL5 
 
0 
+ 
________ 
 
=________ 
Sum individual item scores: ________ 
Multiply by 12: ________ 
Divide by number of items answered: ________=PC Subscale score 
 
Score range: 0-48 


 
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To derive a FACT-P Trial Outcome Index (TOI): 
  __________ + __________ + __________ =________=FACT-P TOI 
(PWB score) (FWB score) (PCS score) 
To Derive a FACT-G total score: 
__________ + __________ + __________ + __________=________=FACT-G Total score 
(PWB score)    (SWB score) (EWB score) (FWB score) 
 
To Derive a FACT-P total score: 
 
_________ + __________ + __________ + __________ + __________ =________=FACT-
P Total score 
(PWB score) (SWB score) (EWB score) (FWB score) (PCS score) 
*For guidelines on handling missing data and scoring options, please refer to the 
Administration and Scoring Guidelines in the manual or on-line at www.facit.org. 
Score range: 0-104 
Score range: 0-108 
Score range: 0-156 


 
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9.4 
EORTC-QLQ-PR25 questionnaire and scoring information 
 


 
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Questions are re-numbered from 1 to 25. 


 
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Scoring 
 
 
Item range is the difference between the possible maximum and the minimum response to 
individual items. Values from 1 to 4 gives range=3. 
 
Remarks 
• Items 20 and 21 can be completed by all patients 
• Items 22-25 are conditional on being sexually active, and thus will only be completed by a 
subgroup of patients. This will require reversing the response categories of questions 23-25 
but not of 22. 
For all scales, the RawScore, RS, is the mean of the component items:  
RawScore = RS = (I1 + I2 +...+ In) n  
Then for Functional scales:  
Score = 1− ((RS− 1) /range) x 100 
and for Symptom scales / items:  
Score = {(RS − 1) range} x 100  
Missing items are simply ignored when making the calculations for scores, the above 
equations for multi-item scales can be used whenever at least half of the items are completed. 
All of the scales and single-item measures range in score from 0 to 100. A high scale score 
represents a higher response level. 
 


 
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9.5 
EQ-5D-3L questionnaire and scoring information 
 
 
 


 
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Values for the 243 health states defined by the EuroQol classification have been calculated 
using a regression model. The following worked example indicates how these coefficients are 
to be used so as to compute the estimated values for each state. 
Calculating EQ-5D-3L state scores - a worked example 
 
EuroQol dimension 
Level 2 
Level 3 
Mobility 
0.069 
  0.314 
Self-care 
0.104 
  0.214 
Usual activity 
0.036 
  0.094 
Pain / discomfort 
0.123 
  0.386 
Anxiety / depression 
0.071 
  0.236 
 
Constant = 0.081 
  N3 = 0.269 
 
The arithmetic needed to recover the estimated value for any health state from this table of 
decrements is given by the following example:  
• Taking health state 1 1 2 2 3 
• Full health (1 1 1 1 1) = 1.0 
• Constant term (for any dysfunctional state)(subtract 0.081) 
• Mobility. level 1 (subtract 0) 
• Self-care. level 1 (subtract 0) 
• Usual activity. level 2 (subtract 0.036) 
• Pain / discomfort. level 2 (subtract 0.123) 
• Anxiety / depression. level 3 (subtract 0.236) 
• Level 3 occurs within at least 1 dimension (subtract N3 parameter 0.269)  
• Hence the estimated value for state 1 1 2 2 3 is given by 
1.0- 0.081 - 0.036 - 0.123 - 0.236 - 0.269 = .25 
 
9.6 
Prohibited medication: metastasis-free survival 
Following medications considered prohibited was selected in CM dataset: 


 
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- 
Radiopharmaceuticals (ATC codes V10BX, V10XX03), 
- 
Immunotherapy (e.g. sipuleul T) (ATC code L03), 
- 
Cytotoxic chemotherapy and any other systemic antineoplastic therapy (ATC code 
class L: antineoplastic and immunodulating agents , with the exception of L02AE 
(Gonadotropin-releasing hormone analogues)), 
- 
Enzalutamide, ARN-509, bicalutamide, flutamide, nilutamide (ATC code L02B), 
- 
Cyproterone acetate estrogen (ATC codes G03H, G03C), 
- 
5 α-reductase inhibitor (ATC code G04CB), 
- 
Abiraterone acetate, TAK-700 or other CYP17 inhibitors (ATC code L02B), 
- 
Systemic ketoconazole (as antineoplastic therapy) (ATC codes D01AC08; G01AF11, 
J02AB02), 
- 
Osteoclast-targeted therapy such as bisphosphonate or denosumab (ATC code M05B) 
given for preventing skeletal-related events. These drugs are allowed for treatment of 
osteoporosis, 
- 
Continuous use of systemic corticosteroid (ATC code H02). 
Sponsor’s assessment of prohibited medication is presented in a supplementary 
document. 
 
9.7 
Cytotoxic chemotherapy: time to cytotoxic chemotherapy 
The cytotoxic chemotherapy was selected in CM dataset (ATC code L01A, L01B, L01C, 
L01D, and L01X). ). Sponsor’s assessment of cytotoxic chemotherapy is presented in a 
supplementary document. 
 
9.8 
Antineoplastic therapy: time to initiation of subsequent antineoplastic 
therapy 
• Antineoplastic therapy treatment was selected in CM dataset 
• ATC code class L (antineoplastic and immunodulating agents): L01 Antineoplastic 
agents (except cytotoxic chemotherapy L01A, L01B, L01C, L01D and L01X), L02 
endocrine therapy and L03 immunostimulants 
• ATC code class H: H02Corticosteroids for systemic use. 
Sponsor’s assessment of antineoplastic therapy is presented in a supplementary document. 
 


 
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9.9 
Statins medications 
Statins will be identified using the Standardized Drug Grouping (SDG) classification 
‘Statins’. 
 
9.10 
Opioid for cancer pain 
The opioid treatments were selected in CM dataset (ATC code starting with N02A). 
Sponsor’s assessment of opioid treatments is presented in a supplementary document. 
 
9.11 
Antiandrogen (AR inhibitors) therapy 
The antiandrogen (AR inhibitors) therapy treatments were selected in CM dataset (ATC code 
starting with L02BB and G03HA01). 
L02BB antiandrogens (L02BB01 flutamide, L02BB02 nilutamide, L02BB03 bicalutamide, 
L02BB04 enzalutamide), G03HA antiandrogens plain (G03HA01 cyproterone). 
 
9.12 
GnRH agonist/antagonist therapy 
The GnRH antagonist treatments were selected in CM dataset (ATC code starting with L02AE, 
H01CA and L02BX). 
L02AE Gonadotropin releasing hormone analogues (L02AE01 buserelin, L02AE02 
leuprorelin, L02AE03 goserelin, L02AE04 triptorelin, L02AE05 histrelin), H01CA 
Gonadotropin releasing hormones, L02BX Other hormone antagonists and related agents 
(L02BX01 abarelix, L02BX02 degarelix, L02BX03 abiraterone (except if used as previous 
therapy). 
 
9.13 
Hormonal therapy 
Hormonal therapy will be were selected in CM dataset: 
The GnRH antagonist treatments (ATC code starting with L02AE, H01CA and L02BX). 
L02AE Gonadotropin releasing hormone analogues (L02AE01 buserelin, L02AE02 
leuprorelin, L02AE03 goserelin, L02AE04 triptorelin, L02AE05 histrelin), H01CA 
Gonadotropin releasing hormones, L02BX Other hormone antagonists and related agents 
(L02BX01 abarelix, L02BX02 degarelix, L02BX03 abiraterone (except if used as previous 
therapy). 
The antiandrogen (AR inhibitors) therapy treatments (ATC code starting with L02BB and 
G03HA01). 


 
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L02BB antiandrogens (L02BB01 flutamide, L02BB02 nilutamide, L02BB03 bicalutamide, 
L02BB04 enzalutamide), G03HA antiandrogens plain (G03HA01 cyproterone). 
 
9.14 
Bone sparing agent 
Bone sparing agent will be were selected in CM dataset, using ATC codes: 
M05B drugs affecting bone structure and mineralization, A11CC Vitamin D and analogues, 
A12A Calcium, A12CD Fluoride, H05BA Calcitonins.