Conditions: Metastatic Hormone-sensitive Prostate Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1306
Healthy volunteers: no

Brief summary:
The purpose of the study is to assess the efficacy and safety of BAY1841788 (darolutamide (ODM-201)) in combination with standard androgen deprivation therapy (ADT) and docetaxel in patients with metastatic hormone sensitive prostate cancer.

Detailed description:
This is a randomized, double-blind, placebo-controlled, multicenter phase III study. The study population will consist of approximately 1300 subjects with metastatic hormone sensitive prostate cancer (mHSPC), who will be randomized (1:1 ratio) to receive 600 mg (2 x 300 mg tablets) of darolutamide (ODM-201)/placebo twice daily with food, equivalent to a total daily dose of 1200 mg, in addition to standard androgen deprivation therapy (ADT) and docetaxel. Subjects will be stratified at randomization for the extent of disease and for Alkaline Phosphatase levels. All subjects will be treated with ADT as standard therapy. Six cycles of docetaxel will be administered after randomization.

The subjects considered for inclusion in the study will have metastatic prostate cancer and will be candidates for ADT and docetaxel.

Treatment with darolutamide (ODM-201)/placebo will be administered until symptomatic progressive disease, change of antineoplastic therapy, unacceptable toxicity, until subject withdraws consent, withdrawal from the study at the discretion of the investigator or his/her designated associate(s), death, non-compliance, or if sponsor terminates the study.

Arms:
arm 1: Co-administration of BAY 1841788 / darolutamide (ODM-201), standard ADT and docetaxel arm 2: Co-administration of Placebo matching BAY 1841788 / darolutamide (ODM-201) tablets, standard ADT and docetaxel

Interventions: intervention 1: BAY1841788 / darolutamide (ODM-201) intervention 2: Standard ADT (androgen deprivation therapy) intervention 3: Docetaxel intervention 4: Placebo
Intervention descriptions: intervention 1: 600mg (2 tablets of 300 mg) of darolutamide (ODM-201)/placebo twice daily with food, equivalent to a total a daily dose of 1200 mg in addition to standard ADT (luteinizing hormone releasing hormone (LHRH) agonist/antagonist or orchiectomy) and 6 cycles of docetaxel intervention 2: As prescribed by the treating physician. intervention 3: As prescribed by the treating physician. intervention 4: Placebo matching darolutamide (ODM-201) tablets in appearance, bid orally with food, in addition to standard ADT (luteinizing hormone releasing hormone \[LHRH\] agonist/antagonist or orchiectomy) and 6 cycles of docetaxel.

Protocol document:
Prot_002.pdf: 
 
Document Type: 
Study protocol 
Official Title: 
A randomized, double–blind, placebo–controlled Phase III study 
of darolutamide (ODM–201) versus placebo in addition to 
standard androgen deprivation therapy and docetaxel in patients 
with metastatic hormone–sensitive prostate cancer 
NCT Number: 
NCT02799602  
Document Date: 
26-May-2020 
 


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Cover page of the integrated protocol
A randomized, double–blind, placebo–controlled Phase III study of darolutamide 
(ODM–201) versus placebo in addition to standard androgen deprivation therapy and 
docetaxel in patients with metastatic hormone–sensitive prostate cancer
This protocol version is an integration of the following documents / sections:

Original protocol, Version 1.0, dated 25 MAY 2016

Amendment 2 (global amendment described in Section 15.1),
forming integrated protocol, Version 2.0, dated 04 OCT 2016

Amendment 5 (global amendment described in Section 15.2),
forming integrated protocol, Version 3.0, dated 12 FEB 2018

Amendment 6 (global amendment described in Section 15.3),
forming integrated protocol, Version 4.0, dated 10 DEC 2019

Amendment 7 (global amendment described in Section 15.4),
forming integrated protocol, Version 5.0, dated 26 MAY 2020
Amendments not included in the consecutive numbering of amendments are 
local amendments not forming part of this integrated global protocol. 

Amendment 1, dated 20 SEP 2016
(local amendment valid for China only)

Amendment 3, dated 04 NOV 2016
(local amendment valid for UK only)

Amendment 4, dated 31 JAN 2017
(local amendment valid for Japan only)


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1.
Title page
A randomized, double–blind, placebo–controlled Phase III study of darolutamide
(ODM–201) versus placebo in addition to standard androgen deprivation therapy and 
docetaxel in patients with metastatic hormone–sensitive prostate cancer 
Darolutamide in addition to standard androgen deprivation therapy and docetaxel in 
metastatic hormone–sensitive prostate cancer
Acronym: ARASENS
Test drug:
BAY 1841788 / darolutamide / ODM–201 
Study purpose:
Efficacy and Safety
Clinical study phase:
III
Date:
26 MAY 2020
EudraCT: no:
2015–002590–38
Version no.:
5.0
Sponsor’s study no.:
17777
Sponsor:
a)
Non–US: Bayer AG, D–51368 Leverkusen, Germany
b)
US territory: Bayer HealthCare Pharmaceuticals Inc., 
100 Bayer Boulevard, P.O. Box 915, Whippany NJ 
07981–0915, USA
Sponsor’s medical expert:
Muellerstrasse 178
13353 Berlin, Germany
Telephone no.: 
This document is electronically signed. The eSignature is archived in the trial master file 
(TMF) and can be provided upon request.
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


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Signature of the sponsor’s medically responsible person
This document is electronically signed. The eSignature is archived in the trial master file 
(TMF) and can be provided upon request.
The signatory agrees to the content of the final integrated clinical study protocol as presented.
Name:
Role: 
Date:
Signature:
PPD
PPD


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Signature of principal investigator
The signatory agrees to the content of the final integrated clinical study protocol as presented.
Name:
Affiliation:
Date:
Signature:
Signed copies of this signature page are stored in the sponsor’s study file and in the respective 
center’s Investigator site file.


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2.
Synopsis
Title
A randomized, double–blind, placebo–controlled Phase III study of 
darolutamide (ODM–201) versus placebo in addition to standard 
androgen deprivation therapy and docetaxel in patients with 
metastatic hormone–sensitive prostate cancer
Short title
Darolutamide in addition to standard androgen deprivation therapy (ADT)
and docetaxel in metastatic hormone–sensitive prostate cancer
Acronym
ARASENS
Clinical study phase
III
Study objective(s)
The primary objective of this study is:

To demonstrate the superiority in overall survival (OS) of 
darolutamide in addition to standard ADT and docetaxel over placebo 
in addition to standard ADT and docetaxel
The secondary objectives of this study are to evaluate:

Time to castration–resistant prostate cancer

Time to initiation of subsequent antineoplastic therapy

Symptomatic skeletal event free survival (SSE–FS) 

Time to first symptomatic skeletal event (SSE)

Time to initiation of opioid use for ≥7 consecutive days

Time to pain progression

Time to worsening of physical symptoms of disease based on 
functional assessment of cancer therapy / National Comprehensive 
Cancer Network prostate cancer symptom index 17 item questionnaire 
(NCCN–FACT FPSI–17)

Safety
The exploratory objectives of this study include:

Quality of life

Medical resource use

Prostate–specific antigen (PSA) assessments

Pharmacokinetics and exposure–response analysis

Evaluate biomarkers to investigate the drug (i.e. mode–of–action–
related effect and / or safety) and / or the pathomechanism of the 
disease
Test drug
Darolutamide (BAY 1841788)


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Name of active ingredient
Darolutamide (BAY 1841788)
Dose(s)
Darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, 
equivalent to a total daily dose of 1200 mg.
Route of administration
Oral
Duration of treatment
Until symptomatic progressive disease, change of antineoplastic therapy, 
unacceptable toxicity, until subject withdraws consent, withdrawal from the 
study at the discretion of the Investigator or his/her designated associate(s), 
death, or non–compliance.
Reference drug(s)
Matching placebo
Name of active ingredient
Not applicable
Dose(s)
The dosing of placebo is the same as for darolutamide (BAY 1841788), 
please see above.
Route of administration
Oral
Duration of treatment
Until symptomatic progressive disease, change of antineoplastic therapy, 
unacceptable toxicity, until subject withdraws consent, withdrawal from the 
study at the discretion of the Investigator or his/her designated associate(s), 
death, or non–compliance.
Background treatment
ADT (luteinizing hormone–releasing hormone [LHRH] agonist/antagonist 
or orchiectomy) and 6 cycles of docetaxel.
Indication
Metastatic hormone–sensitive prostate cancer (mHSPC)
Diagnosis and main criteria for 
inclusion /exclusion
Inclusion criteria

Written informed consent

Males ≥18 years of age

Histologically or cytologically confirmed adenocarcinoma of prostate

Metastatic disease documented either by a positive bone scan, or for 
soft tissue or visceral metastases, either by contrast–enhanced 
abdominal/pelvic/chest computed tomography (CT) or magnetic 
resonance imaging (MRI) scan assessed by Investigator and confirmed 
by central radiology review. Metastatic disease is defined as either 
malignant lesions in bone scan or measurable lymph nodes above the 
aortic bifurcation or soft tissue/visceral lesions according to Response 
Evaluation Criteria In Solid Tumors (RECIST) 1.1. Lymph nodes are 
measurable if the short axis diameter is ≥15 mm, soft tissue/visceral 
lesions are measurable if the long axis diameter is ≥10 mm.
Subjects with regional lymph node metastases only (N1, below the 
aortic bifurcation) will not be eligible for the study. Only subjects 
with non–regional lymph node metastases (M1a) and/or bone 
metastases (M1b) and/or other sites of metastases with or without 


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bone disease (M1c) will be eligible.

Subjects must be candidates for ADT and docetaxel therapy per 
Investigator’s judgment

Started ADT (LHRH agonist/antagonist or orchiectomy) with or 
without first generation anti–androgen, but no longer than 12 weeks 
before randomization. For subjects receiving LHRH agonists, 
treatment in combination with a first generation anti–androgen for at 
least 4 weeks, prior to randomization is recommended. First generation 
anti–androgen has to be stopped prior to randomization.

An Eastern Cooperative Oncology Group performance status of 0 or 1

Blood counts at Screening: hemoglobin 9.0 g/dL, absolute neutrophil 
count 1.5x109/L, platelet count 100x109/L (subject must not have 
received any growth factor within 4 weeks or a blood transfusion 
within 7 days of the hematology laboratory sample obtained at 
Screening)

Screening values of serum alanine aminotransferase and/or aspartate 
transaminase 1.5 x upper limit of normal (ULN), total bilirubin 
≤ULN, creatinine 2.0 x ULN

Sexually active male subjects must agree to use condoms as an 
effective barrier method and refrain from sperm donation, and/or their 
female partners of reproductive potential to use a method of effective 
birth control, during the treatment with darolutamide/placebo and for 
3 months after the end of the treatment with darolutamide/placebo and 
6 months after treatment with docetaxel.
Exclusion criteria

Prior treatment with:
o
LHRH agonist/antagonists started more than 12 weeks before 
randomization
o
Second–generation androgen receptor (AR) inhibitors such as 
enzalutamide, ARN–509, darolutamide, other investigational 
AR inhibitors
o
Cytochrome P 17 enzyme inhibitor such as abiraterone acetate 
or oral ketoconazole as antineoplastic treatment for prostate 
cancer
o
Chemotherapy or immunotherapy for prostate cancer prior to 
randomization

Treatment with radiotherapy (external beam radiation therapy, 
brachytherapy, or radiopharmaceuticals) within 2 weeks before 
randomization

Known hypersensitivity to any of the study drugs, study drug classes, 
or excipients in the formulation of the study drugs

Contraindication to both CT and MRI contrast agent

Had any of the following within 6 months before randomization: 
stroke, myocardial infarction, severe/unstable angina pectoris, 


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coronary/peripheral artery bypass graft, congestive heart failure (New 
York Heart Association Class III or IV)

Uncontrolled hypertension as indicated by a resting systolic blood 
pressure (BP) 160 mmHg or diastolic BP 100 mmHg despite 
medical management

Had a 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 before randomization and from which the subject has been 
disease–free

A gastrointestinal disorder or procedure which is expected to interfere 
significantly with absorption of study drug

An active viral hepatitis, known human immunodeficiency virus 
infection with detectable viral load, or chronic liver disease with a 
need for treatment

Previous (within 28 days before the start of study drug or 5 half–lives 
of the investigational treatment of the previous study, whichever is 
longer) or concomitant participation in another clinical study with 
investigational medicinal product(s)

Any other serious or unstable illness, or medical, social, or 
psychological condition, that could jeopardize the safety of the subject
and/or his/her compliance with study procedures, or may interfere with 
the subject’s participation in the study or evaluation of the study 
results

Inability to swallow oral medications

Close affiliation with the investigational site (e.g., a close relative of 
the Investigator, dependent person [e.g., employee or student of the 
investigational site])

Previous assignment to treatment in this study
Study design
Randomized, double–blind, placebo–controlled, multicenter phase III 
study. Approximately 1,300 subjects will be randomized (1:1 ratio) to 
receive one of the following study drugs:

Darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, 
equivalent to a total daily dose of 1200 mg

Placebo matching darolutamide tablets in appearance, twice daily
with food
All subjects must receive ADT of Investigator’s choice (LHRH 
agonist/antagonists or orchiectomy) as standard therapy, started ≤12 weeks 
before randomization. For subjects receiving LHRH agonists, treatment in 
combination with a first generation anti–androgen for at least 4 weeks prior 
to randomization is recommended.
Six cycles of docetaxel will be administered after randomization.
Docetaxel can be administered in combination with 


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prednisone/prednisolone at the discretion of the Investigator.
Subjects will be stratified at randomization as follows:

Extent of disease
o
Non–regional lymph nodes metastases only
o
Bone metastases with or without lymph node metastases
o
Visceral metastases with or without lymph node metastases or 
with or without bone metastases

Alkaline Phosphatase (ALP)
o
ALP<ULN
o
ALP≥ULN
Note: Blood samples to measure ALP levels for stratification will be 
analyzed in a central laboratory.
Methodology
The study will comprise 4 consecutive periods: Screening, Treatment, 
Active Follow–up, and Long–term (survival) Follow–up.
Screening period:
All trial–related procedures and evaluations will only be performed after 
the subject has agreed to participate and has signed the informed consent 
form. The Screening period will consist of multiple evaluations that will 
take place within 28 days prior to randomization to ensure that all 
eligibility criteria are met.
Once eligibility is confirmed and documented, eligible subjects will be 
randomized in a ratio of 1:1 to treatment with darolutamide or placebo.
Treatment period:
Study treatment will be provided for all subjects bid until symptomatic 
progressive disease, change of antineoplastic therapy, unacceptable 
toxicity, until subject withdraws consent, withdrawal from the study at the 
discretion of the Investigator or his/her designated associate(s), death, and 
non–compliance.
Subjects will be evaluated every 12 weeks for castration–resistant prostate 
cancer, initiation of subsequent antineoplastic therapy, SSEs, opioid use for 
≥7 consecutive days, pain progression, worsening of physical symptoms of 
disease based on NCCN–FACT FPSI–17, adverse events (AEs) and serious
adverse events (SAEs), Quality of life (QoL) and PSA assessment.
Active Follow–up period:
After treatment discontinuation, subjects will enter the Active Follow–up
period, which includes:

End of Treatment Visit
An End of Treatment (EOT) Visit will be conducted 30 (+7) days after the 
last dose of study drug. The following assessments will be performed at the 
EOT Visit: QoL, pain assessment, analgesic consumption, subsequent 
antineoplastic treatments for prostate cancer (which should be provided 
with start and stop dates and reason for change: PSA progression, clinical 


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progression, radiological progression, toxicity, or other), SSEs, and all AEs 
and SAEs regardless of causality.

Active Follow–up visits
During the Active Follow–up period, the following assessments will be 
performed during standard of care clinic visits approximately every 
12 weeks for up to 1 year: QoL, pain assessment, analgesic consumption, 
survival status, subsequent antineoplastic treatments for prostate cancer
(which should be provided with start and stop dates and reason for change: 
PSA progression, clinical progression, radiological progression, toxicity, or 
other), SSEs, and study drug–related SAEs. After approximately 1 year of 
Active Follow–up, subjects will be transitioned to Long–term (survival) 
Follow–up. The Active Follow–up period extends from the discontinuation 
of treatment period for up to 1 year or until the subject can no longer travel 
to the clinic, dies, is lost to follow–up, or withdraws informed consent and 
actively objects to collection of further data.
Long–term (survival) Follow–up period:
After Active Follow–up, subjects will continue to be contacted 
approximately every 12 weeks (by phone) to capture all antineoplastic 
treatments for prostate cancer with start and stop date and reasons for 
change (PSA progression, clinical progression, radiological progression, 
toxicity, other), study drug–related SAEs and survival status. The end of 
Long–term Follow–up period is death, lost to follow–up, consent 
withdrawal, or end–of–study.
Survival sweep:
For every formal analysis of OS, survival data will be collected through 
additional survival sweeps. All subjects considered alive at the database 
cut-off date and prior to any subsequent additional analysis will be 
contacted for survival status.
After primary analysis of the study:
For subjects who are ongoing with darolutamide treatment, the sponsor will 
continue to provide darolutamide via a separate program at least until 
darolutamide is approved and reimbursed in a specific country.
Type of control
Placebo
Data Monitoring Committee
Yes
Number of subjects
Approximately 1,300 subjects in total are to be randomized
Primary variable(s)
Overall survival, defined as the time (in days) from date of randomization 
until death from any cause.
Time point/frame of 
measurement for primary 
variable(s)
The primary analysis will be performed when approximately 509 deaths
occur in the 2 treatment arms combined. The expected study duration for 
509 deaths is approximately 70 months. 
Plan for statistical analysis
All randomized subjects will be included in the analysis of overall survival 
(OS), the primary efficacy endpoint.


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The primary efficacy endpoint of OS will be analyzed using a one–sided 
stratified log–rank test with an overall alpha of 0.025. Analysis will be 
according to treatment groups as randomized, with stratification factors 
extent of disease and alkaline phosphatase level. The hazard ratio (HR)
(darolutamide/placebo) and its 95% confidence interval will be calculated 
using the Cox model, stratified by the same randomization factors. 
Kaplan-Meier estimates and plots will be presented for each treatment 
group.
The secondary efficacy time–to–event endpoints will be analyzed using 
stratified log–rank test with randomization stratification factors. HR and 
95% confidence intervals will be provided using Cox model.
Interim analysis for futility at approximately 30% of total planned events 
will be conducted.


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Table of Contents
Cover page of the integrated protocol.................................................................................... 1
1.
Title page............................................................................................................................ 2
Signature of the sponsor’s medically responsible person..................................................... 3
Signature of principal investigator......................................................................................... 4
2.
Synopsis.............................................................................................................................. 5
Table of Contents ................................................................................................................... 12
Table of Tables ....................................................................................................................... 16
Table of Figures...................................................................................................................... 16
List of abbreviations............................................................................................................... 17
Definitions of terms ................................................................................................................ 20
3.
Introduction..................................................................................................................... 21
3.1
Background.................................................................................................................... 21
3.2
Overview of darolutamide (BAY 1841788) .................................................................. 22
3.2.1
Pharmacology............................................................................................................. 22
3.2.2
Nonclinical pharmacokinetics and metabolism.......................................................... 23
3.2.3
Safety pharmacology and toxicology......................................................................... 24
3.2.4
Drug–drug interactions............................................................................................... 25
3.2.5
Clinical studies with darolutamide ............................................................................. 26
3.3
Rationale of the study .................................................................................................... 27
3.4
Benefit–risk assessment................................................................................................. 29
4.
Study objectives............................................................................................................... 29
5.
Study design..................................................................................................................... 30
6.
Study population ............................................................................................................. 34
6.1
Inclusion criteria ............................................................................................................ 34
6.2
Exclusion criteria ........................................................................................................... 35
6.3
Justification of selection criteria.................................................................................... 36
6.4
Withdrawal of subjects from study................................................................................ 36
6.4.1
Withdrawal ................................................................................................................. 36
6.4.2
Replacement ............................................................................................................... 38
6.5
Subject identification ..................................................................................................... 38
7.
Treatment(s) .................................................................................................................... 38
7.1
Treatments to be administered....................................................................................... 38
7.2
Identity of study treatment............................................................................................. 39
7.2.1
Darolutamide and placebo.......................................................................................... 39
7.2.2
Background docetaxel treatment ................................................................................ 40
7.3
Treatment assignment.................................................................................................... 41


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7.4
Dosage and administration of study treatment .............................................................. 41
7.4.1
Dose modifications of study drug............................................................................... 41
7.4.1.1
Dose interruption..................................................................................................... 42
7.4.1.2
Dose reduction......................................................................................................... 42
7.4.1.3
General recommendations for dose modifications of study drug ........................... 42
7.4.2
Dosage and administration for background treatment................................................ 43
7.4.3
Dose modifications of docetaxel background treatment ............................................ 43
7.5
Blinding ......................................................................................................................... 43
7.6
Drug logistics and accountability................................................................................... 44
7.7
Treatment compliance.................................................................................................... 45
8.
Non–study therapy.......................................................................................................... 45
8.1
Prior and concomitant therapy....................................................................................... 45
8.1.1
Prior therapy ............................................................................................................... 45
8.1.2
Permissible concomitant medications and treatments................................................ 46
8.1.3
Prohibited concomitant medications and treatments.................................................. 46
8.2
Post–study therapy......................................................................................................... 47
9.
Procedures and variables ............................................................................................... 48
9.1
Tabular schedule of evaluations .................................................................................... 48
9.2
Visit description............................................................................................................. 52
9.2.1
Screening period......................................................................................................... 52
9.2.2
Study treatment period ............................................................................................... 54
9.2.2.1
Day 1 (Visit 1)......................................................................................................... 54
9.2.2.2
Visit 2 and subsequent visits (every 12 weeks ± 7 days)........................................ 55
9.2.2.3
Requirement for chest, abdomen and pelvic CT/MRI and bone scan during the 
study treatment period............................................................................................. 57
9.2.3
Active Follow–up period............................................................................................ 58
9.2.4
Long–term (survival) Follow–up period .................................................................... 60
9.2.5
Unscheduled visits...................................................................................................... 60
9.3
Population characteristics .............................................................................................. 61
9.3.1
Demographic .............................................................................................................. 61
9.3.2
Medical history........................................................................................................... 61
9.3.3
Other baseline characteristics..................................................................................... 61
9.4
Efficacy.......................................................................................................................... 61
9.5
Pharmacokinetics/pharmacodynamics........................................................................... 62
9.5.1
Drug measurements.................................................................................................... 62
9.5.2
Pharmacokinetic evaluation........................................................................................ 63
9.6
Safety ............................................................................................................................. 64
9.6.1
Adverse events............................................................................................................ 64
9.6.1.1
Definitions............................................................................................................... 64
9.6.1.2
Classifications for adverse event assessment.......................................................... 66
9.6.1.3
Assessments and documentation of adverse events ................................................ 68
9.6.1.4
Reporting of serious adverse events........................................................................ 68
9.6.1.5
Expected adverse events.......................................................................................... 70
9.6.1.6
Adverse events of special safety interest................................................................. 70


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9.6.2
Pregnancies................................................................................................................. 70
9.6.3
Further safety.............................................................................................................. 70
9.6.3.1
Laboratory safety assessments ................................................................................ 70
9.6.3.2
Physical examination............................................................................................... 72
9.6.3.3
12–lead ECGs.......................................................................................................... 72
9.6.3.4
Vital signs................................................................................................................ 72
9.7
Other procedures and variables...................................................................................... 72
9.7.1
Biomarker investigations............................................................................................ 73
9.7.1.1
Plasma–based biomarker analysis........................................................................... 73
9.7.1.2
Circulating tumor cells............................................................................................ 74
9.7.1.3
Tumor–based biomarker analysis............................................................................ 74
9.7.1.4
Genetic biomarker analysis from whole blood ....................................................... 75
9.7.2
Medical resource use .................................................................................................. 75
9.7.3
Subject–reported outcomes......................................................................................... 75
9.8
Appropriateness of procedures / measurements ............................................................ 76
10. Statistical methods and determination of sample size ................................................. 77
10.1
General considerations................................................................................................... 77
10.2
Analysis sets .................................................................................................................. 77
10.3
Variables and planned statistical analyses..................................................................... 77
10.3.1
Primary efficacy variable............................................................................................ 77
10.3.2
Secondary efficacy variables...................................................................................... 78
10.3.3
Safety variables........................................................................................................... 79
10.3.4
Other exploratory variables ........................................................................................ 80
10.3.5
Pharmacokinetics........................................................................................................ 81
10.3.6
Biomarker analyses..................................................................................................... 81
10.3.7
Medical Resource use................................................................................................. 82
10.3.8
Subject–reported outcomes......................................................................................... 82
10.3.9
Baseline and demographic characteristics.................................................................. 82
10.4
Determination of sample size......................................................................................... 82
10.5
Planned interim analyses ............................................................................................... 82
11. Data handling and quality assurance ............................................................................ 83
11.1
Data recording................................................................................................................ 83
11.2
Monitoring ..................................................................................................................... 84
11.3
Data processing.............................................................................................................. 85
11.4
Missing data................................................................................................................... 85
11.5
Audit and inspection ...................................................................................................... 85
11.6
Archiving ....................................................................................................................... 85
12. Premature termination of the study .............................................................................. 86
13. Ethical and legal aspects................................................................................................. 87
13.1
Investigator(s) and other study personnel...................................................................... 87
13.1.1
Independent data monitoring committee.................................................................... 88
13.2
Funding and financial disclosure ................................................................................... 88
13.3
Ethical and legal conduct of the study........................................................................... 89


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13.4
Subject information and consent.................................................................................... 89
13.5
Publication policy and use of data ................................................................................. 90
13.6
Compensation for health damage of subjects / insurance.............................................. 91
13.7
Confidentiality ............................................................................................................... 91
14. Reference list.................................................................................................................... 92
15. Protocol amendments...................................................................................................... 94
15.1
Amendment 2................................................................................................................. 94
15.1.1
Overview of changes to the study............................................................................... 94
15.1.1.1
Modification 1: New drug–drug interaction data available .................................... 94
15.1.1.2
Modification 2: Clarification of PK analysis .......................................................... 94
15.1.1.3
Modification 3: Addition of non–protein–bound (free) testosterone analysis ........ 95
15.1.1.4
Modification 4: Administrative changes................................................................. 95
15.1.1.5
Modification 5: Other clarifications and corrections .............................................. 95
15.1.2
Changes to the protocol text....................................................................................... 95
15.2
Amendment 5................................................................................................................. 95
15.2.1
Overview of changes to the study............................................................................... 95
15.2.1.1
Modification 1: New drug-drug interaction data available ..................................... 95
15.2.1.2
Modification 2: Modification of the dosing language............................................. 96
15.2.1.3
Modification 3: Clarification of docetaxel dosage and administration................... 96
15.2.1.4
Modification 4: Guidance on laboratory tests before each docetaxel cycle............ 97
15.2.1.5
Modification 5: Clarification related to soft tissue/visceral lesions........................ 97
15.2.1.6
Modification 6: Time windows for randomization and Visit 1............................... 97
15.2.1.7
Modification 7: Switch of ADT to LHRH agonist prohibited ................................ 97
15.2.1.8
Modification 8: Collection of whole blood sample for pharmacogenetics test 
allowed at other visits if missed at Visit 1 .............................................................. 98
15.2.1.9
Modification 9: Unblinding in non-emergency situations not permitted................ 98
15.2.1.10 Modification 10: Clarification of PK sampling....................................................... 98
15.2.1.11 Modification 11: Clarification of laboratory safety assessments............................ 98
15.2.1.12 Modification 12: Nomenclature change.................................................................. 99
15.2.1.13 Modification 13: Personnel change......................................................................... 99
15.2.1.14 Modification 14: Other clarifications and corrections ............................................ 99
15.2.2
Changes to the protocol text....................................................................................... 99
15.3
Amendment 6............................................................................................................... 100
15.3.1
Overview of changes to the study............................................................................. 100
15.3.2
Changes to the protocol text..................................................................................... 102
15.4
Amendment 7............................................................................................................... 103
15.4.1
Overview of changes to the study............................................................................. 103
15.4.2
Changes to the protocol text..................................................................................... 103
16. Appendices..................................................................................................................... 104
16.1
Eastern Cooperative Oncology Group performance status.......................................... 104
16.2
National Cancer Institute–Common Terminology Criteria for Adverse Events ......... 104
16.3
NCCN–FACT FPSI–17 ............................................................................................... 105
16.4
BPI–SF......................................................................................................................... 106


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16.5
List of strong CYP3A4 inducers.................................................................................. 108
Table of Tables
Table 7–1 Study drug identifiers ............................................................................................ 40
Table 7–2 Study drug dose modifications.............................................................................. 42
Table 9–1 Schedule of assessments........................................................................................ 49
Table of Figures
Figure 5–1 Study periods schematic........................................................................................ 31


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List of abbreviations
5–HT
5–hydroxytryptamine
ADT
Androgen deprivation therapy
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
AR
Androgen receptor
AST
Aspartate aminotransferase
AUC
The area under the concentration–time curve
AUC(0–tlast)
The area under the concentration–time curve from time zero to the last 
sample with the quantifiable concentration
AUC(0–8)
The area under the concentration–time curve from time zero to 8 h
AUC(0–12)
The area under the concentration–time curve from time zero to 12 h
AUC(0–24)
The area under the concentration–time curve from time zero to 24 h
AUC(0–72)
The area under the concentration–time curve from time zero to 72 h
AV
Atrioventricular
bid
Twice daily
BCRP
Breast cancer resistance protein
BP
Blood pressure
BPI–SF
Brief Pain Inventory – Short Form
CAB
Complete androgen blockade
CI
Confidence interval
Cmax
Maximum concentration
CNS
Central nervous system
CRF
Case report form
CRO
Contract research organization
CRPC
Castration–resistant prostate cancer
CT
Computed tomography
CTC
Circulating tumor cell
ctDNA
Circulating tumor DNA
CV
Coefficient of variation
CYP
Cytochrome P
dL
Deciliter
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
EBRT
External beam radiation therapy
ECG
Electrocardiogram
ECOG PS
Eastern Cooperative Oncology Group Performance Status


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eCRF
Electronic case report form
EDC
Electronic data capture
EOT
End of treatment
ePRO
Electronic patient reported outcome
ESMO
European Society of Medical Oncology
EU
European Union
FAS
Full analysis set
FPSI–DRS–P
FACT/NCCN FPSI–17 disease–related symptoms – physical
g
Gram
GABAA
Type–A γ–aminobutyric acid
GCP
Good Clinical Practice
GI
Gastrointestinal
GMP
Good Manufacturing Practice
HDPE
High density polyethylene
HR
Hazard ratio, heart rate
IB
Investigator’s brochure
IC
Informed consent
IC50
Half maximal inhibitory concentration
ICF
Informed consent form
IEC
Independent Ethics Committee
INN
International nonproprietary name
IRB
Institutional Review Board
IV
Intravenous
IXRS
Interactive Voice/Web Response System
KM
Kaplan–Meier
LC–MS/MS
Liquid chromatography–tandem mass spectrometry
LHRH
Luteinizing hormone releasing hormone
LLOQ
Lower limit of quantification
M&S
Modeling & Simulation
mCRPC
Metastatic castration–resistant prostate cancer
mCSPC 
Metastatic castration–sensitive prostate cancer
mHSPC
Metastatic hormone–sensitive prostate cancer
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
mL
Milliliter
mmHg
Millimeter of mercury
MRI
Magnetic resonance imaging
NCCN
National Comprehensive Cancer Network
NCCN–FACT FPSI–17
Functional assessment of cancer therapy / National Comprehensive 
Cancer Network prostate cancer symptom index 17 item questionnaire


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NCI–CTCAE v 4.03
National Cancer Institute–Common Terminology Criteria for Adverse 
Events; version 4.03
ng
Nanogram
nM
Nanomolar
OS
Overall survival
P–gp
P–glycoprotein
PCWG3
Prostate Cancer Clinical Trials Working Group
PD
Pharmacodynamic
PI
Principal investigator
PI3K
Phosphatidylinositol 3–kinase
PIK3CA
Phosphatidylinositol–4,5–bisphosphate 3–kinase, catalytic subunit 
alpha
PK
Pharmacokinetics
PKS
Pharmacokinetic Analysis Set
PRO
Subject–reported outcomes
PSA
Prostate–specific antigen
PTEN
Phosphatase and tensin homolog
QoL
Quality of life
RECIST
Response Evaluation Criteria In Solid Tumors
RNA
Ribonucleic acid
SAE
Serious adverse event
SAP
Statistical analysis plan
SAS
Statistical Analysis Software
SD
Standard deviation
SHBG
Sex hormone–binding globulin
SNP
Single gene polymorphism
SSE
Symptomatic skeletal event
SSE–FS
Symptomatic skeletal event free survival 
SUSAR
Suspected unexpected serious adverse reaction
tlast
Time to the last quantifiable concentration
tmax
Time to the maximum plasma concentration
TMF
Trial master file
ULN
Upper limit of normal
UVB
Ultraviolet B
VCaP
Vertebral cancer of the prostate
WPS
Worst pain subscale


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Definitions 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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3.
Introduction
3.1
Background
Prostate cancer is the second most common cancer and the fifth leading cause of cancer death 
among men worldwide (1). It is the most common non–cutaneous cancer and the second 
leading cause of cancer–related deaths in men in Europe (2) and the United States (3).
At the time of initial diagnosis, most men are found to have localized disease and can be 
treated with curative surgery or radiotherapy. However, a proportion of subjects will recur 
either locally or in distant sites. In addition, approximately 5% of new diagnoses present with 
de novo hormone–sensitive metastatic disease. The most common site of metastases is bone. 
However, soft tissue and visceral metastases can also occur (4). Upon development of 
metastatic disease, treatment is palliative, with the goal of prolonging quantity and 
maintaining quality of life (QoL) (5; 6; 7).
The mainstay of therapy for newly diagnosed metastatic hormone–sensitive prostate cancer 
(mHSPC), also known as metastatic castration–sensitive prostate cancer (mCSPC), remains 
androgen deprivation therapy (ADT), as recommended by the prostate cancer guidelines from 
the American Society of Clinical Oncology, the National Comprehensive Cancer Network 
(NCCN), and the European Association of Urology (8; 9; 10). Androgen deprivation therapy 
can be accomplished either by surgical orchiectomy (castration) or medical castration (using 
either a luteinizing hormone releasing hormone [LHRH] agonist or an LHRH antagonist). 
When LHRH therapy is initiated, a transient rise in luteinizing hormone can cause a surge in 
serum testosterone, which may stimulate prostate cancer growth. The flare phenomenon can 
be effectively prevented with the addition of an anti–androgen therapy to ADT, a complete 
androgen blockade (CAB), which blocks the effect of the increased serum testosterone 
(8; 9; 10).
Over the years, efforts have been made to improve upon ADT by modified timing (early 
versus deferred) and schedule (intermittent versus continuous) or by adding adjunctive agents, 
but the optimal management of this disease state is still not defined. Combined androgen 
blockade using both an LHRH agonist and an anti–androgen has been extensively studied as 
upfront therapy in mHSPC (6; 7; 11). Several meta–analyses have shown a modest 2% to 5% 
improvement in 5–year survival with CAB over castration, although with increased toxicity. 
One of the largest meta–analyses included the individual level data of 8,275 subjects from 
27 trials. Although there was an overall trend toward improved 5–year survival with CAB 
over castration, this did not reach statistical significance (P=0.11) (12; 13; 14). According to 
NCCN prostate cancer guidelines 2014, CAB provides modest to no benefit over castration 
alone in metastatic subjects.
While ADT demonstrates antitumor activity in mHSPC with prolonged disease control, 
unfortunately resistance ultimately occurs and subjects die of castration–resistant prostate 
cancer (CRPC). Approximately 10% to 20% of prostate cancer subjects develop CRPC within 
5 years, with a median time of 12–24 months (15), and have a poor median survival 
expectancy of 9 to 30 months (16). In the setting of metastatic castration–resistant prostate 
cancer (mCRPC), new therapeutic agents with different mechanisms of action have recently 


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become available and have significantly improved clinical outcomes, including 
chemotherapeutic agents (cabazitaxel), androgen–receptor targeted agents (abiraterone and 
enzalutamide), immunotherapies (sipuleucel–T), and radiopharmaceuticals (radium–223) 
(17; 18; 19; 20; 21; 22; 23). Conversely, the overall treatment paradigm of mHSPC has 
remained substantially stable and has not been strongly challenged until more recently, when 
the randomized controlled CHAARTED trial examined the addition of chemotherapy to 
standard ADT for metastatic hormone–sensitive disease, thus bringing chemotherapy to an 
arena historically dominated by hormone therapy only. The CHAARTED study demonstrated 
that combining 6 cycles of docetaxel chemotherapy with standard ADT was associated with a 
statistically significant overall survival (OS) benefit in metastatic hormone–sensitive disease 
compared with ADT alone, particularly in subjects with high volume disease (24; 25). Recent 
data from another ongoing study in Europe, the Medical Research Council STAMPEDE trial, 
confirm a significant OS benefit for docetaxel combined with ADT compared with ADT 
alone in subjects with high risk locally advanced or newly diagnosed metastatic disease 
(26; 27).
Chemo–hormonal therapy is currently recommended by the NCCN as first–line therapy for 
high volume mHSPC (11) and is recommended by ESMO Clinical guidelines as first–line 
treatment of metastatic, hormone–naïve disease in men fit enough for chemotherapy (33).
3.2
Overview of darolutamide (BAY 1841788)
3.2.1
Pharmacology
Darolutamide is a novel non–steroidal androgen receptor (AR) inhibitor which binds with 
high selectivity and binding affinity (9 nM) to AR when compared to known 
second-generation anti–androgens. Darolutamide is a 1:1 mixture of 2 pharmacologically 
active diastereomers: (S,R)-darolutamide and (S,S)-darolutamide. Diastereomers as well as the 
main circulating metabolite from darolutamide, keto-darolutamide, show no major differences 
in pharmacological activity and function as antagonists in AR–overexpressing cells.
In the vertebral cancer of the prostate (VCaP) cell line (derived from a bone metastasis of a 
subject with CRPC) with endogenous AR gene amplification and AR overexpression, 
darolutamide suppressed dose dependently androgen–induced VCaP cell proliferation more 
efficiently than bicalutamide.
W741L (tryptophan to leucine) mutation of AR has been shown to have a role in the 
mechanism of bicalutamide resistance. In this mutation, darolutamide functioned as an
antagonist, whereas bicalutamide was a pure agonist, as previously shown.
In addition, darolutamide inhibits testosterone–mediated nuclear translocation of AR in AR 
overexpressing cells. Darolutamide and keto-darolutamide were found to decrease 0.3 nM 
testosterone–induced nuclear translocation at concentrations ≥100 nM and ≥300 nM, 
respectively; whereas bicalutamide failed to block testosterone–induced AR nuclear 
translocation at all tested concentrations.
In the immature rat assay, darolutamide showed anti–androgenic activity, by dose 
dependently and significantly antagonizing testosterone–induced growth of 


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androgen-sensitive tissues in 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 anti-tumor 
activity. The VCaP tumors grew significantly more slowly in mice treated with 50 mg/kg of 
darolutamide orally once daily for 37 days compared with untreated castrated mice, whereas 
tumor growth was fully inhibited after orally twice daily (bid) dosing at 50 mg/kg.
In the orthotopic prostate cancer model, where VCaP cells were inoculated into prostate of 
nude intact male mice, inhibition of tumor growth and reduced increase in serum 
prostate-specific antigen (PSA) level were observed in mice treated with 50 mg/kg of 
darolutamide orally twice daily for 3 weeks compared with vehicle controls. Darolutamide did 
not have any effect on serum testosterone levels.
3.2.2
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 1:1 ratio of diastereomers (S,R)-darolutamide and 
(S,S)-darolutamide, which are able to interconvert and exhibit different ratios in animals. In 
rat plasma the diastereomer ratio remains about 1:1, but mice and dogs 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 
able to interconvert via keto-darolutamide. In rats and dogs, the metabolite/parent 
darolutamide ratio is close to unity, while in mice and humans the ratio is around 2 to 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 3.2.4).
In general, the potential for darolutamide to inhibit CYP reaction pathways in vitro in human 
liver microsomes is low. The lowest 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.


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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% to 8% in the plasma of human, rat, and 
mouse. The free fraction in dog plasma is dependent on darolutamide concentration (range:
0.3% to 11%). The major binding protein is serum albumin. There are no differences in 
plasma protein binding between the diastereomers. The main circulating metabolite 
keto-darolutamide has a free fraction <1% in most species.
Tissue distribution studies in rodents suggest that darolutamide and its metabolite 
keto-darolutamide have very limited access to brain (brain/plasma ratio <0.05). Prostate and 
heart have clearly higher tissue/plasma ratios of darolutamide. The kidney/plasma ratio of 
darolutamide is around 1 and the 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 rats suggests that about two–thirds of darolutamide–related 
radioactivity is excreted to feces and the rest to urine. Maximally, 45% of darolutamide is 
excreted unchanged. The similar excretion pattern after intravenous (IV) and oral
administration supports complete oral absorption at the studied low dose (11 mg/kg). 
Excretion is almost complete by 48 hours post–dose.
3.2.3
Safety pharmacology and toxicology
The repeat–dose toxicity studies with darolutamide have been conducted up to 26 weeks in 
the rat and up to 39 weeks in the dog. Darolutamide has been well tolerated up to the highest 
dose levels in both species. The no observable adverse effect level 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 anti–androgenic 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 AUC(0–24) at the 700–mg bid dose level 
in subjects with mCRPC in the clinical phase I/II ARADES study (17829 / 3104001). The 
corresponding exposure multiples of the metabolite keto-darolutamide 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 anti–androgens (11; 12; 13; 14), 
decreased fertility in males and developmental toxicity would be expected. Also it has to be 
taken into account that the subjects in this clinical study use gonadotropin releasing hormone 
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 


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both darolutamide and its metabolite, keto-darolutamide, absorb light in the UVB wavelength 
range of 290 to 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 investigated within the frame of systemic 
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, 13–week and 39–week 
toxicity studies were 9,990, 6,030 to 8,350 and 12070–12440 ng/mL, respectively. 
In an anesthetized dog model using bolus IV administration, darolutamide and its main human 
diastereomer (S,S)-darolutamide, at observed mean Cmax values of >9,300 ng/mL and 
>4,000 mg/mL in plasma, respectively, induced vasodilatation, especially at the peripheral 
level, leading to decreased arterial blood pressure (BP). This is not regarded to be of 
biological relevance as this was observed at free peak plasma concentrations of ≥3–fold
higher than the plasma free peak concentrations observed at 700 mg bid dose level in the 
Phase I/II clinical study in mCRPC subjects.
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 27,200 ng/mL, indicating that (S,S)-darolutamide may 
affect AV conduction at very high systemic exposure levels. The mechanism and etiology of 
vasodilatation and AV block are not known, but they might be multifactorial and at least 
partly related to a synergistic effect of the anesthetic agents used and secondary 
pharmacodynamic (PD) effects of darolutamide and its main human diastereomer 
(S,S)-darolutamide. Based on in vitro human ether-a-go–go– related gene and calcium channel 
inhibition and in vivo dog studies, the risk for QT interval prolongation appears low.
Functional in vitro studies evaluating secondary PD effects showed that darolutamide inhibits 
5-hydroxytryptamine (5–HT) uptake and type–A γ–aminobutyric acid (GABAA) 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 evaluations 
confirmed that darolutamide has no remarkable effects on CNS or respiratory function. At 
high local doses/concentrations in the gastrointestinal (GI) tract, darolutamide may affect 
gastric emptying and intestinal transit.
3.2.4
Drug–drug interactions
The information on darolutamide drug-drug interactions is provided in the latest available 
version of the Investigator's Brochure (IB) for darolutamide.
Docetaxel will be administered after randomization according to standard treatment practice. 
Docetaxel is mainly metabolized by CYP3A4. Thus, inducers or inhibitors of CYP3A4 may 
alter the PK of docetaxel. Darolutamide has no inhibitory but may have some inducing effect 
on CYP3A4 substrates. Docetaxel is also a substrate of P–gp and OATP1B3. An effect of 
darolutamide on the PK of docetaxel could, therefore, not be excluded. The potential impact 
of darolutamide on docetaxel PK, and the respective impact on safety was investigated on the 
day of the first docetaxel administration in the first 20 subjects who were randomized and 


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have received at least 1 cycle of docetaxel. The data did not reveal any significant impact of 
darolutamide on the PK of docetaxel.
3.2.5
Clinical studies with darolutamide
As of 02 OCT 2015, 173 subjects with mCRPC have been treated with darolutamide.
Darolutamide has been studied in 7 clinical trials: a first–in–man study with cohort expansion 
(Study 17829 / 3104001, ARADES), a long–term safety extension study for the first–in–man 
study (Study 18035 / 3104002, ARADES–EXT), and a bioavailability study (Study 17830 / 
3104003, ARAFOR). Additionally, there is a phase III efficacy and safety study of 
darolutamide in men with high risk non–metastatic ongoing CRPC (Study 17712 / 3104007, 
ARAMIS), a Phase I mass balance and bioavailability study in healthy male subjects (Study 
17831 / 3104005, ARIADME), a phase I study in Japanese subjects with mCRPC (Study 
17719) and a phase I drug–drug interaction study in healthy male and female subjects (Study 
17723).
Darolutamide treatment has been well tolerated up to the highest pre–specified dose of 900 
mg bid. The maximum tolerated dose was not reached, and no dose–limiting toxicities were 
observed in the phase I dose–escalation. Escalation of doses in the phase I study was 
discontinued because a plateau in bioavailability of darolutamide was observed.
Following oral administration of darolutamide at doses of 100, 200, 300, 500, 700, and 
900 mg bid, both diastereomers, (S,R)-darolutamide and (S,S)-darolutamide, were slowly 
absorbed after administration with a light breakfast, the median tmax was 2–5 h.
AUC and Cmax of darolutamide, (S,R)-darolutamide, and (S,S)-darolutamide increased in a 
nearly dose–proportional manner at doses 100–700 mg bid. At the 900 mg bid dose level, 
there was no further increase of Cmax or AUC observed compared to 700 mg dose bid. The 
concentration of the active metabolite keto-darolutamide was 1.6–2.4 times higher than of the 
parent compound darolutamide. This ratio was dose–independent. After repeated oral 
administration of darolutamide, steady–state conditions seemed to be reached after 7 days at 
the latest. The diastereomer ratio of (S,R)-darolutamide to (S,S)-darolutamide was about 
1:6 under steady–state conditions. The terminal half–life of darolutamide was in the range of 
11.5–16.1 hours after single oral administration of a tablet formulation. 
A food effect was observed when darolutamide was administered after a standardized 
high-fat, high–calorie breakfast. The exposure and Cmax were about 50% lower when 
darolutamide was administered under fasting conditions. 


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Considering the 164 mCRPC patients as of 02 OCT 2015 treated with darolutamide in the 
Studies 17829 / 3104001, ARADES, 17830 / 3104003, ARAFOR, and 18035 / 3104002, 
ARADES–EXT, the integrated safety data showed 93.3% of subjects developed at least 
1 adverse event (AE) and Grade 3 or higher AEs were reported in 28% of subjects. The most 
common AEs have been fatigue in 26.8% of subjects, back pain (22%). The most common 
AEs considered related to study treatment by the Investigator have been fatigue (9.8%) and 
hot flush (4.3%). The majority of AEs (91%) were classified as Grade 1 to 2. No dose–related 
trends were noted for the occurrence of any AEs.
Forty–five subjects (27.4%) have experienced a total of 125 serious adverse events (SAEs) 
from the start of study treatment and 7 subjects (4%) have died. None of these events was 
considered related to the study treatment by the Investigator or by the Sponsor.
Eleven subjects (6.7%) have withdrawn from the studies due to an AE. Only 1 of these AEs 
(fatigue, Grade 2) was considered related to the study treatment by the Investigator.
No events of seizure have been reported during darolutamide treatment period.
Seven patients (7/164) experienced falls or accidental falls. Two out of those seven patients 
who had a fall or accidental fall experienced SAEs. All SAEs were resolved/improved after 
treatment. Nine patients (9/164) experienced non–pathological fractures. Four patients 
experienced SAEs. All serious events of fractures were secondary to a fall, an accidental 
wound, or syncope. Among the other five patients who experienced non–serious fractures, 
only one patient had a fall. None of those events were assessed as related to darolutamide or 
resulted in permanent discontinuation from the study due to the events.
No safety concerns were raised from the ongoing Studies. In Japanese Phase I study, one SAE 
of grade 3 nausea was reported as related to darolutamide by Investigator, however, due to 
preexisting confounding factors, the sponsor assessed the event as not related with 
darolutamide treatment.
Efficacy results show that darolutamide has substantial antitumor activity in subjects with 
metastatic CRPC for time to PSA progression and for 12–week changes from baseline in 
serum PSA, soft tissue and bone lesions, and circulating tumor cell (CTC) count. Anti–tumor 
effects were observed at all dose levels. Anti–tumor activity was better in chemotherapy-naïve 
CYP17i–naïve subjects compared to post–chemotherapy CYP17i–naïve subjects and 
post-CYP17i subjects. The higher doses seemed to have a better response than the lower 
doses, particularly in chemotherapy–naïve CYP17i–naïve subjects.
Further details can be found in the latest available version of the IB, which contains 
comprehensive information on the study drug.
3.3
Rationale of the study
Management of advanced prostate cancer has evolved considerably in recent years and new 
therapeutic agents with diverse mechanisms of action have dramatically changed the 
paradigm of treatment. However, the vast majority of advances have been made in subjects 
with metastatic castration–resistant disease. Fewer advances have been made in the earlier, 
hormone–responsive stage of metastatic disease.


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ADT remains the mainstay of treatment in metastatic hormone–sensitive prostate cancer. 
However, despite the demonstrated antitumor activity of ADT in mHSPC, subjects ultimately 
progress and die of CRPC (5; 6; 7).
The variations upon ADT timing and schedule have not resulted in substantial changes in 
clinical outcome. Similarly, combined androgen blockade using both an LHRH agonist and an 
anti–androgen has shown a modest survival benefit over castration, with higher toxicity and 
costs (12; 13; 14).
The treatment scenario of mHSPC has only recently been challenged, when the randomized 
controlled CHAARTED trial showed improved survival with upfront chemotherapy 
(docetaxel) combined with ADT compared to standard ADT in men with metastatic 
hormone–sensitive prostate cancer, with a 17–month median OS benefit in those with high 
volume disease (25). Recent data from the STAMPEDE trial confirm the role of upfront 
chemo–hormonal therapy in mHSPC, showing a significant improvement in OS for subjects 
with metastatic disease treated with docetaxel in addition to ADT (26; 27).
Docetaxel combined with ADT is, therefore, anticipated to become a new standard for 
subjects with mHSPC.
It is clear that while ADT is the backbone of treatment, and upfront chemotherapy combined 
with ADT considerably improves survival, hormone–sensitive disease remains an area of 
active investigations. Novel treatment approaches are needed to improve disease control and 
survival and delay castration resistance.
Darolutamide is a novel non–steroidal AR inhibitor lacking a significant agonist action on 
AR, unlike first generation anti–androgens. It has high binding affinity to AR and a distinctive 
ability to decrease testosterone–mediated nuclear localization of AR in AR overexpressing 
cells. In phase I–II clinical studies, darolutamide has demonstrated a very favorable safety 
profile, with no dose–limiting toxicities observed, and substantial antitumor activity in 
mCRPC, with effect on both serum PSA and soft tissue and bone lesions. A phase III trial is 
ongoing to compare darolutamide versus placebo in men with non–metastatic CRPC.
The excellent tolerability and the clinical activity demonstrated so far in phase I/II in mCRPC 
provide the rationale to explore the efficacy of darolutamide in the earlier stages of metastatic 
hormone–sensitive prostate cancer, where novel therapeutic strategies are needed to improve 
the outcome of subjects before castration resistance occurs.
This randomized phase III study aims to demonstrate that the addition of darolutamide to 
ADT and docetaxel chemotherapy significantly prolongs OS over placebo in mHSPC 
subjects.
Based on in vitro transporter inhibition and in vitro CYP3A4 induction results with 
darolutamide, a small effect on docetaxel exposure during concomitant treatment with
darolutamide cannot be excluded. It is, therefore, planned to investigate the potential impact 
of darolutamide on docetaxel PK and the respective impact on safety on the day of the first 
docetaxel administration in the first 20 subjects who were randomized and have received at 
least 1 cycle of docetaxel (see Section 13.1.1). Based on the mechanisms described above as 
well as known safety profiles from darolutamide and docetaxel, the toxicities from the 


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combination therapy are expected to be well managed. Therefore, the study will continue 
subject accrual during this PK and safety review period.
3.4
Benefit–risk assessment
Darolutamide treatment has been well tolerated in clinical studies in mCRPC subjects. There 
is no important risk identified. Fall and non–pathological fractures are currently considered 
important potential risks. No dose–limiting toxicities were observed in the phase I dose 
escalation. The AE profile observed reflects a profile that is expected in a population of 
subjects with advanced prostate cancer. Most AEs were Grade 1 to 2 and assessed by the 
investigators as not related to the study treatment. No dose–related trends were noted in the 
AE profile. Antitumor activity was seen at all dose levels as evaluated by PSA, CTC counts, 
and soft and bone lesion imaging. Subjects who were naïve to treatment with chemotherapy or 
CYP17i have responded best to darolutamide treatment.
With its potent anti–androgenic profile, there is a strong rationale to study darolutamide in 
subjects with mHSPC to delay disease progression and death. The available safety and 
efficacy data suggest that subjects who participate in this trial are not placed at undue risk.
As presented in the previous section, ADT and docetaxel have demonstrated significant 
survival benefits with the tolerable toxicities and is anticipated to become a new standard for 
subjects with mHSPC.
Overall, the benefit/risk assessment for darolutamide in addition to standard ADT and 
docetaxel therapy for mHSPC subjects is positive.
4.
Study objectives
The primary objective of this study is:

To demonstrate the superiority in OS of darolutamide in addition to standard ADT
and docetaxel over placebo in addition to standard ADT and docetaxel
The secondary objectives of this study are to evaluate:

Time to castration–resistant prostate cancer

Time to initiation of subsequent antineoplastic therapy

Symptomatic skeletal event free survival (SSE–FS)

Time to first symptomatic skeletal event (SSE)

Time to initiation of opioid use for ≥7 consecutive days

Time to pain progression

Time to worsening of physical symptoms of disease based on NCCN–FACT FPSI–17

Safety


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The exploratory objectives of this study include:

Quality of life

Medical resource use

Prostate–specific antigen (PSA) assessments

Pharmacokinetics and exposure–response analysis

Evaluate biomarkers to investigate the drug (i.e. mode–of–action–related effect and / 
or safety) and / or the pathomechanism of the disease
5.
Study design
Design overview
This is an international, randomized, double–blind, placebo–controlled phase III study of 
darolutamide in subjects with mHSPC.
The estimated sample size is approximately 1,300 subjects (see Section 10.4).
The start of the study period is defined by signing of the informed consent form (ICF). After 
an up to 28–day Screening period, subjects meeting the eligibility criteria (i.e. all of the 
inclusion criteria and none of the exclusion criteria [see Sections 6.1 and 6.2]) will be 
randomly assigned in a 1:1 ratio to treatment with one of the study drugs (darolutamide or 
placebo):

Darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equivalent to a total
daily dose of 1200 mg

Placebo matching darolutamide tablets in appearance, twice daily with food
All subjects must receive ADT of Investigator’s choice (LHRH agonist/antagonists or 
orchiectomy) as standard therapy, started ≤12 weeks before randomization. For subjects 
receiving LHRH agonists, treatment in combination with a first generation anti–androgen for 
at least 4 weeks prior to randomization is recommended.
Six cycles of docetaxel will be administered after randomization.
Docetaxel can be administered in combination with prednisone/prednisolone at the discretion 
of the Investigator.
For the first 20 subjects who were randomized and have received at least 1 cycle of docetaxel,
and for whom a detailed mandatory PK analysis will be performed, docetaxel should be 
administered at least 14 days after randomization (i.e. start of study drug).


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Subjects will be stratified at randomization as follows:

Extent of disease
o
Non–regional lymph nodes metastases only
o
Bone metastases with or without lymph node metastases
o
Visceral metastases with or without lymph node metastases or with or without 
bone metastases

Alkaline Phosphatase (ALP)
o
ALP<upper limit of normal (ULN)
o
ALP≥ULN
Note: Blood samples to measure ALP levels for stratification will be analyzed in a central 
laboratory.
A schematic of the study periods is presented in Figure 5–1.
Figure 5–1
Study periods schematic
On study
Off study
Screening /
Baseline
Treatment period
Active Follow–up
Long–term
Follow–up
Informed
consent
First dose of 
study drug
Last dose of 
study drug
Last protocol–
stipulated 
procedure
The study will comprise 4 consecutive periods: Screening, Treatment, Active Follow–up, and 
Long–term (survival) Follow–up.
Screening period:
All trial–related procedures and evaluations will only be performed after the subject has 
agreed to participate and has signed the ICF. The Screening period will consist of multiple 
evaluations that will take place within 28 days prior to randomization to ensure that all 
eligibility criteria are met.
Once eligibility is confirmed and documented, eligible subjects will be randomized in a ratio 
of 1:1 to treatment with darolutamide or placebo.


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Treatment period:
The start of the treatment period is defined by the first administration of study drug. 
Treatment will be provided for all subjects twice daily until disease progression (symptomatic
progressive disease, change of antineoplastic therapy), unacceptable toxicity, consent 
withdrawal or withdrawal from the study at the discretion of the Investigator or his/her 
designated associate(s), death, or non–compliance.
Subjects will be evaluated every 12 weeks for CRPC, initiation of subsequent antineoplastic 
therapy, SSEs, opioid use for ≥7 consecutive days, pain progression, worsening of physical 
symptoms of disease based on NCCN–FACT FPSI–17, AEs and SAEs, QoL and PSA 
assessment.
Active Follow–up period:
The Active Follow–up period is the interval from the end–of–study drug intake to the end of 
all protocol–specified post–treatment interventions.
It includes:

End of Treatment Visit (EOT)
An EOT Visit will be conducted 30 (+7) days after the last dose of study drug. The following 
assessment will be performed: QoL, pain assessment, analgesic consumption, subsequent 
antineoplastic treatments for prostate cancer, which should be provided with start and stop 
dates and reason for change (PSA progression, clinical progression, radiological progression, 
toxicity, other), SSEs, and all AEs and SAEs regardless of causality.

Active Follow–up visits
During the Active Follow–up period, the following assessment will be performed during 
standard of care clinic visits approximately every 12 weeks for up to 1 year: QoL, pain 
assessment, analgesic consumption, survival status, subsequent antineoplastic treatments for 
prostate cancer, which should be provided with start and stop dates and reason for change 
(PSA progression, clinical progression, radiological progression, toxicity, other), SSEs, and 
study drug–related SAEs with concomitant medications received. After approximately 1 year 
of Active Follow–up, subjects will be transitioned to Long–term (survival) Follow–up. The 
Active Follow–up period extends from the discontinuation of treatment period for up to 1 year 
or until the subject can no longer travel to the clinic, dies, is lost to follow–up, or withdraws 
informed consent and actively objects to collection of further data.


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Long–term Follow–up period:
After Active Follow–up, subjects will continue to be contacted approximately every 12 weeks 
(by phone) to capture all antineoplastic treatments for prostate cancer with start and stop date 
and reasons for change (PSA progression, clinical progression, radiological progression, 
toxicity, other), study drug–related SAEs with concomitant medications received, and 
survival status. The end of Long–term Follow–up period is death, lost to follow–up, consent 
withdrawal, or end–of–study.
Survival sweep:
For every formal analysis of OS, survival data will be collected through additional survival 
sweeps. All subjects considered alive at the database cut-off date and prior to any subsequent 
additional analysis will be contacted for survival status.
End–of–study
The end of the study as a whole will be reached as soon as the last visit of the last subject has 
been reached in all centers in all participating countries (European Union [EU] and non–EU).
This study will end when all subjects on darolutamide treatment have transitioned into a 
separate program to continue receiving darolutamide (see Section 8.2) or have discontinued 
the study for any other reason (e.g. death, lost to follow-up, consent withdrawal with no 
further data collection), and all subjects on placebo have discontinued treatment. 
Until transition to the separate program, subjects on darolutamide treatment will continue to 
follow all the protocol required procedures and visits in the current protocol. Once the 
separate program is available for subjects to move to, study treatment in the current study will 
no longer be available.
Primary completion
The first analysis of OS will be performed as an interim futility analysis when approximately 
153 deaths have occurred. In case the study continues after the futility analysis, a final 
efficacy analysis of OS will be performed when approximately 509 deaths have occurred and 
will be considered the primary completion. The database cut–off date for this analysis will be 
the date of primary completion.


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6.
Study population
6.1
Inclusion criteria
Subjects must meet the following criteria at the time of Screening:
1. Written informed consent.
2. Males ≥18 years of age.
3. Histologically or cytologically confirmed adenocarcinoma of prostate.
4. Metastatic disease documented either by a positive bone scan, or for soft tissue or visceral 
metastases, either by contrast–enhanced abdominal/pelvic/chest computed tomography 
(CT) or magnetic resonance imaging (MRI) scan assessed by Investigator and confirmed 
by central radiology review. Metastatic disease is defined as either malignant lesions in 
bone scan or measurable lymph nodes above the aortic bifurcation or soft tissue/visceral 
lesions according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 (31). 
Lymph nodes are measurable if the short axis diameter is ≥15 mm, soft tissue/visceral 
lesions are measurable if the long axis diameter is ≥10 mm.

Subjects with regional lymph node metastases only (N1, below the aortic bifurcation) 
will not be eligible for the study. Only subjects with non–regional lymph node 
metastases (M1a) and/or bone metastases (M1b) and/or other sites of metastases with 
or without bone disease (M1c) will be eligible.
5. Subjects must be candidates for ADT and docetaxel therapy, per Investigator’s judgment.
6. Started ADT (LHRH agonist/antagonist or orchiectomy) with or without first generation 
anti–androgen, but no longer than 12 weeks before randomization. For subjects receiving 
LHRH agonists, treatment in combination with a first generation anti–androgen for at 
least 4 weeks prior to randomization is recommended. First generation anti–androgen has 
to be stopped prior to randomization.
7. An Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1.
8. Blood counts at Screening: hemoglobin 9.0 g/dL, absolute neutrophil count 1.5x109/L, 
platelet count 100x109/L (subject must not have received any growth factor within 
4 weeks or a blood transfusion within 7 days of the hematology laboratory sample 
obtained at Screening).
9. Screening values of serum alanine aminotransferase (ALT) and/or aspartate transaminase 
(AST) ≤1.5 x ULN, total bilirubin ≤ULN, creatinine ≤2.0 x ULN.


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10. Sexually active male subjects must agree to use condoms as an effective barrier method 
and refrain from sperm donation, and/or their female partners of reproductive potential to 
use a method of effective birth control, during the treatment with darolutamide/placebo
and for 3 months after treatment with darolutamide/placebo and 6 months after treatment 
with docetaxel.
6.2
Exclusion criteria
Subjects who meet any of the following criteria at the time of Screening will be excluded:
1. Prior treatment with:

LHRH agonist/antagonists started more than 12 weeks before randomization

Second–generation AR inhibitors such as enzalutamide, ARN–509, darolutamide, 
other investigational AR inhibitors

CYP17 enzyme inhibitor such as abiraterone acetate or oral ketoconazole as 
antineoplastic treatment for prostate cancer

Chemotherapy or immunotherapy for prostate cancer prior to randomization
2. Treatment with radiotherapy (external beam radiation therapy [EBRT], brachytherapy, or 
radiopharmaceuticals) within 2 weeks before randomization.
3. Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the 
formulation of the study drugs.
4. Contraindication to both CT and MRI contrast agent.
5. Had any of the following within 6 months before randomization: stroke, myocardial 
infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, 
congestive heart failure (New York Heart Association Class III or IV).
6. Uncontrolled hypertension as indicated by a resting systolic BP 160 mmHg or diastolic 
BP 100 mmHg despite medical management.
7. Had a 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 before randomization and from which the subject has been 
disease-free.
8. A GI disorder or procedure which is expected to interfere significantly with absorption of 
study drug.
9. An active viral hepatitis, known human immunodeficiency virus infection with detectable 
viral load, or chronic liver disease with a need of treatment.
10. Previous (within 28 days before the start of study drug or 5 half–lives of the 
investigational treatment of the previous study, whichever is longer) or concomitant 
participation in another clinical study with investigational medicinal product(s).


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11. Any other serious or unstable illness, or medical, social, or psychological condition, that 
could jeopardize the safety of the subject and/or his/her compliance with study 
procedures, or may interfere with the subject’s participation in the study or evaluation of 
the study results.
12. Inability to swallow oral medications.
13. Close affiliation with the investigational site (e.g., a close relative of the Investigator, 
dependent person [e.g., employee or student of the investigational site]).
14. Previous assignment to treatment in this study.
For prohibited concomitant therapy, please refer to Section 8.1.3.
6.3
Justification of selection criteria
The inclusion/exclusion criteria used in this study, including concomitant conditions and 
medications as outlined above and in Section 8.1 are based upon knowledge of the known 
toxicity profile of the agent under investigation and the understanding of the concomitant 
conditions associated with prostate cancer. To ensure that subjects are in the earliest stages of 
mHSPC, before castration resistance occurs, ADT initiation within 12 weeks before 
randomization was selected as an inclusion criterion.
The selection criteria were chosen to ensure, to the best of the Sponsor’s ability, the safety of 
the subjects who may participate in this study.
6.4
Withdrawal of subjects from study
6.4.1
Withdrawal
Withdrawal criteria
General procedures
In all cases, the reason for withdrawal must be recorded in the case report form (CRF) and in 
the subject’s medical records.
The subject may object to the generation and processing of post–withdrawal data as specified 
in Section 13.4.
Details for the premature termination of the study as a whole (or components thereof) are 
provided in Section 12.


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Withdrawal from the treatment with study drug
Subjects must be withdrawn from the treatment with study drug if any of the following 
occurs:

If, in the Investigator’s opinion, continuation of the study drug would be harmful to 
the subject’s well–being

Disease progression (symptomatic progressive disease, change of antineoplastic 
therapy)

Unacceptable toxicity

Any subject requiring study drug interruption >28 consecutive days

Any subject requiring dosing of the study drug below 300 mg bid

Occurrence of Grade 3 or higher treatment–related AE while the subject is on 
300 mg bid
Note: Study drug discontinuation (i.e., discontinuation during the treatment period) does not 
constitute withdrawal from the study. Every effort should be made to retain subjects who 
discontinue the treatment period for any reason. These subjects are to be encouraged to 
remain on the study for follow–up of primary, secondary, and exploratory endpoints (i.e., 
continue in the Active Follow–up period or Long–term Follow–up period). Subjects are 
expected to participate in follow–up unless they explicitly object. Withdrawal of consent 
should be documented in the subject’s medical file. For guidance on docetaxel background 
treatment, see Section 7.4.3.
Withdrawal from study
Subjects must be withdrawn from the study if any of the following occurs:

At their own request or at the request of their legally acceptable representative. At any 
time during the study and without giving reasons, a subject may decline to participate 
further. The subject will not suffer any disadvantage as a result.

At the specific request of the Sponsor and in liaison with the Investigator (e.g. obvious 
non–compliance, safety concerns)

Sponsor terminates the study
Depending on the time point of withdrawal, a withdrawn subject is referred to as either 
“screening failure” or “dropout” as specified below:
Screening failure
A subject who, for any reason (e.g. failure to satisfy the selection criteria), terminates the 
study before the time point used for the definition of “dropout” (see below) is regarded a 
“screening failure”. The reason will be documented in the source documentation and the 
electronic case report form (eCRF) and the subject will discontinue participation in study with 
no further follow–up required.


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Re–screening of a subject who did not fulfill the eligibility criteria is allowed within 2 weeks 
from the prior screen failure date. If a subject is re–screened, a new screening number will be 
allocated and a link will be made between the screening numbers of the same subject.
Re–screening of screen failed subjects may only be allowed once after discussion with the 
Bayer–designated medical representative or Sponsor and after approval by the Sponsor. 
Sponsor approval of re–screening for a screen failed subject must be documented.
The subjects who need to repeat the screening procedures will be re–consented.
In any case, the Investigator has to ensure that the repeated screening procedures do not 
expose the subject to an unjustifiable health risk.
Dropout
A subject who discontinues study participation prematurely for any reason is defined as a 
“dropout” if the subject has already been randomized.
6.4.2
Replacement
A subject withdrawn from the treatment with study drug will not be replaced.
6.5
Subject identification
The subject number is a 9–digit number consisting of:
Digits 1 to 2 = Country code
Digits 3 to 5
= Center number within the country
(Digits 1 to 5
= Trial unit)
Digits 6 to 9
= Current subject number within the center
7.
Treatment(s)
7.1
Treatments to be administered
Study drugs
The following treatment groups are defined for this study:

Darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equivalent to a total
daily dose of 1200 mg

Placebo matching darolutamide tablets in appearance, twice daily orally with food


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Background treatment
All subjects must receive ADT of Investigator’s choice (LHRH agonist/antagonists or 
orchiectomy) as standard therapy.
Six cycles of docetaxel will be administered after randomization. Docetaxel can be 
administered in combination with prednisone/prednisolone at the discretion of the 
Investigator. The first cycle of docetaxel should be administered within 6 weeks after start of 
study drug. For the first 20 subjects who were randomized and have received at least 1 cycle 
of docetaxel, and for whom a detailed mandatory PK analysis will be performed, docetaxel 
should be administered at least 14 days after randomization (i.e. start of study drug). 
Docetaxel should be prepared at the study centers in accordance with the product information
and/or local standards and it should only be administered under the supervision of a physician 
qualified in the use of anticancer chemotherapy following within one hour after the 
administration of study drug. Administration of study drug in these 20 subjects should come 
before docetaxel administration.
7.2
Identity of study treatment
7.2.1
Darolutamide and placebo
All study drugs will be labeled according to the requirements of local law and legislation. 
Label text will be approved according to the Sponsor’s agreed procedures, and a copy of the 
labels will be made available to the study site upon request.
For all study drugs, a system of numbering in accordance with all requirements of Good 
Manufacturing Practice (GMP) will be used, ensuring that each dose of study drug can be 
traced back to the respective bulk batch of the ingredients. Lists linking all numbering levels 
will be maintained by the Sponsor’s clinical supplies Quality Assurance group.
A complete record of batch numbers and expiry dates of all study drugs as well as the labels 
will be maintained in the Sponsor’s study file.
Darolutamide and matching placebo tablets will be provided by Bayer AG.
The items in Table 7–1 describe the elements used to identify each study drug.


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Table 7–1
Study drug identifiers
Name
Darolutamide
Placebo
Formulation
Film coated tablets for oral 
administration
Film coated tablets for oral 
administration
Appearance
Blue oval shaped tablets embossed 
with ‘OR–300’
Blue oval shaped tablets embossed 
with ‘OR–300’
Galencial form
Film coated tablet
Film coated tablet
Composition
Drug substance:
300 mg BAY1841788
Excipients:
Lactose monohydrate
Calcium hydrogen phosphate 
anhydrous
Croscarmellose sodium
Povidone
Magnesium stearate
Laquer blue
Excipients:
Lactose monohydrate
Cellulose microcrystalline
Calcium hydrogen phosphate 
anhydrous
Croscarmellose sodium
Povidone
Magnesium stearate
Laquer blue
Strength
300 mg
Not applicable
Bayer number
BAY 1841788
Not applicable
Packaging
White plastic bottles of HDPE each 
containing 140 tablets
White plastic bottles of HDPE each 
containing 140 tablets
Abbreviations: HDPE = high density polyethylene.
7.2.2
Background docetaxel treatment
Docetaxel is commercially available. The participating investigators are required to consult 
the product information for docetaxel.
All treatment provided by the Sponsor will be labeled according to the requirements of local 
law and legislation. Label text will be approved according to the Sponsor’s agreed procedures, 
and a copy of the labels will be made available to the study site upon request. For all study 
treatment provided by the Sponsor, a system of numbering in accordance with all 
requirements of GMP will be used, ensuring that each dose of study treatment can be traced 
back to the respective bulk ware of the ingredients. Lists linking all numbering levels will be 
maintained by the Sponsor’s clinical supplies Quality Assurance group. A complete record of 
batch numbers and expiry dates as well as the labels of all study treatments provided by the 
Sponsor will be maintained in the Sponsor study file.


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7.3
Treatment assignment
At the end of the screening period, all subjects meeting all of the inclusion criteria and none 
of the exclusion criteria will be randomly assigned on a 1:1 basis in a blinded fashion to 
treatment with darolutamide or matching placebo plus ADT and docetaxel. In addition, 
randomization will be stratified by:

Extent of disease
o
Non–regional lymph nodes metastases only
o
Bone metastases with or without lymph node metastases
o
Visceral metastases with or without lymph node metastases or with or without 
bone metastases

Alkaline Phosphatase
o
ALP<ULN
o
ALP≥ULN
Note: Blood samples to measure ALP levels for stratification will be analyzed in a central 
laboratory.
A computer–generated randomization list will be prepared by the Bayer Randomization
Manager. The randomization number will be used to link the subject to a treatment group and 
to a medication package.
The Investigator (or designated associate) will obtain the randomization number and the 
medication package numbers assigned to a subject by accessing the Interactive Voice/Web 
Response System (IXRS) after confirming that the subject meets all the inclusion criteria and 
does not meet any of the exclusion criteria.
An IXRS description and handbook will be provided to each investigational site.
7.4
Dosage and administration of study treatment
7.4.1
Dose modifications of study drug
The study drug will be administered as oral 300 mg tablets. The dose of study drug to be 
administered is 600 mg (2 tablets of 300 mg) twice daily with food, equivalent to a total daily 
dose of 1200 mg. Placebo matching darolutamide tablets in appearance will be administered 
twice daily with food. 
The dose or dosing schedule of the study drug may be modified following the occurrence of 
clinically significant AEs. Doses of study drug may be delayed or reduced in case of clinically 
significant toxicities that are considered by the Investigator to be related to study drug. 
Toxicities will be graded using the National Cancer Institute–Common Terminology Criteria 
for Adverse Events (NCI–CTCAE) v 4.03. All dose modifications regardless of relatedness 
should be recorded on the eCRF. If a subject experiences several study drug–related toxicities 
with different grading, the recommendation of the worst grading should be used.


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If a dose of study drug is delayed, dose can be taken up to 6 hours later with food to make up 
for the missed one.
7.4.1.1
Dose interruption
The maximum time for a dose interruption period is 28 consecutive days. Any subject
requiring treatment interruption >28 consecutive days must be withdrawn from treatment with 
study drug.
7.4.1.2
Dose reduction
If considered necessary for subject’s safety, the dose of study drug may be reduced to 
300 mg bid. The medical monitor must be notified of any darolutamide dose reduction.
Dosing of the study drug below 300 mg bid is not allowed. If a Grade 3 or higher 
treatment-related AE occurs while the subject is on 300 mg bid, the subject must be 
withdrawn from the treatment with study drug.
7.4.1.3
General recommendations for dose modifications of study drug
A subject who experiences a treatment–related Grade 3 or 4 AE should interrupt study drug
until the AE improves to Grade 2 or less. Treatment with study drug is then to be restarted at 
300 mg bid.
Additional details are provided in Table 7–2.
Table 7–2
Study drug dose modifications
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 drug 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 drug is 
temporally or permanently reduced to 
300 mg bid and a Grade 3 or higher 
treatment–related AE occurs while the 
subject is on a dose of 300 mg bid, the 
subject must be withdrawn from 
treatment with study drug
Excludes clinically nonsignificant and asymptomatic laboratory abnormalities.
Abbreviations: AE = adverse event; bid = twice daily; NCI–CTCAE v 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 with study drug 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, following a dose reduction, dose is escalated to 600 mg bid and a second treatment–related AE with a severity of Grade 3 or 
higher occurs, a permanent dose reduction to 300 mg bid is required. A third occurrence of a Grade 3 or higher treatment–
related AE requires permanent discontinuation of treatment with study drug.


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7.4.2
Dosage and administration for background treatment
All subjects must receive ADT of Investigator’s choice (LHRH agonist/antagonists or 
orchiectomy) as standard therapy.
The docetaxel dose to be administered is 75 mg/m2 Day 1 as 1 hour IV infusion every 
21 days, in line with the summary of products characteristics. At Investigator’s discretion, 
longer infusions are allowed for medical reasons. The cycle should be repeated every 3 weeks 
for 6 cycles. Docetaxel can be administered in combination with prednisone/prednisolone at 
the discretion of the Investigator. To prevent hypersensitivity reactions and fluid retention, the 
recommended pre–medication regimen is oral dexamethasone 8 mg, 12 hours, 3 hours and 1 
hour before the docetaxel infusion. Anti-emetic regimens are recommended as per local 
clinical practice.
7.4.3
Dose modifications of docetaxel background treatment
Dose adjustments of docetaxel should be made based on the specific types of toxicities 
observed, graded using NCI–CTCAE v4.03.
Docetaxel should be administered when the neutrophil count is ≥1,500 cells/mm3. In order to 
monitor the occurrence of neutropenia, which may be severe and result in infection, frequent 
blood cell counts should be performed on all subjects receiving docetaxel.
Docetaxel should not be given to subjects with bilirubin >ULN, or to subjects with AST 
and/or ALT >1.5 x ULN. Bilirubin, AST and ALT values should be obtained prior to each 
cycle of docetaxel. In subjects who experienced either febrile neutropenia, neutrophil count 
<500 cells/mm3 for more than one week, severe or cumulative cutaneous reactions or severe 
peripheral neuropathy during docetaxel therapy, the dose of docetaxel should be reduced from 
75 to 60 mg/m2. If the subject continues to experience these reactions at 60 mg/m2, the
docetaxel treatment should be discontinued. Should treatment with docetaxel be discontinued 
for any reason before completion of 6 cycles, the treatment with study drug may be continued.
7.5
Blinding
Subjects will be randomized to receive darolutamide or matching placebo in a double–blind 
fashion such that neither the Investigator, nor the Sponsor, nor the subject will know which 
agent is being administered. The randomization number will be assigned through the IXRS 
based on information supplied by the Investigator at the time of randomization.
Darolutamide and placebo will be identical in appearance in order to preserve blinding. To 
maintain the blind, study drugs (either darolutamide or matching placebo) will be packaged in 
a drug pack labeled with a unique drug pack number. The study drug pack number will be 
assigned to the subject through the IXRS.
The DMC will review in an unblinded manner the safety data and PK of the first 20 subjects
who were randomized and have received at least 1 cycle of docetaxel. However, the 
investigators, subjects and the Sponsor will remain blinded.
Bioanalytic analysis of darolutamide and docetaxel PK samples will be performed by an 
unblinded bioanalyst at an external laboratory.


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SUSAR unblinding
In the event of a Suspected Unexpected Serious Adverse Reaction (SUSAR) (see 
Section 9.6.1.4) related to the blinded treatment, the subject’s treatment code will usually be 
broken before reporting to health authorities and central ethics committees in an unblinded 
fashion. In compliance with the European Commission’s Detailed Guidance on the collection 
and verification of presentation of AE/reaction reports arising from clinical trials on medicinal 
products for human use, investigators and persons responsible for the ongoing conduct of the 
study will not usually receive unblinded copies of SUSAR reports, unless unblinded 
information is judged necessary for safety reasons.
Emergency unblinding by the Investigator
Investigators may only unblind subjects under emergency unblinding rules. If a subject is 
unblinded by the Investigator, they must discontinue study drugs.
Investigators should note that emergency unblinding is reserved for emergency situations 
where lack of knowledge about the actual study drug treatment interferes with appropriate 
emergency management. 
The occurrence of an SAE should not routinely precipitate the immediate unblinding of the 
label. Progressive disease itself does not routinely constitute an emergency situation, therefore 
unblinding the label only for subsequent treatment decision is not allowed.
If emergency unblinding is necessary for the treatment of a subject for an SAE, the treatment 
with study drug can be unblinded via the IXRS system (refer to the IXRS manual for 
instructions). The participating site has unrestricted and immediate access to break the 
treatment code in IXRS. Should the blinded code be broken for a subject, the medical monitor 
or designee should be contacted by the principal investigator (PI) within 1 working day of 
unblinding to discuss the rationale for the premature unblinding.
7.6
Drug logistics and accountability
All study drugs will be stored at the investigational site in accordance with Good Clinical 
Practice (GCP) and GMP requirements and the instructions given by the clinical supplies 
department of the Sponsor (or its affiliate/contract research organization [CRO]), and will be 
inaccessible to unauthorized personnel. Special storage conditions and a complete record of 
batch numbers and expiry dates can be found in the Sponsor’s study file; the site–relevant 
elements of this information will be available in the Investigator site file. On the day of 
receipt, the responsible site personnel will confirm receipt of study drug via IXRS. The 
personnel will use the study drug only within the framework of this clinical study and in 
accordance with this protocol. Receipt, distribution, return, and destruction (if any) of the 
study drug must be properly documented according to the Sponsor’s agreed and specified 
procedures.
Written instructions on medication destruction will be made available to affected parties as 
applicable.
The Investigator or designated associate(s) are responsible for dispensing the study drugs 
(darolutamide or placebo).


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The Investigator is responsible for control of the distribution and use of the study drug. 
Bottles must be returned to the Investigator with all unused medication. Throughout the study, 
all unused study drug must be accounted for. This information will be recorded in the drug 
dispensing log.
Study subjects should be instructed to return all unused tablets to the study site at their 
next study visit for drug accountability and proper disposal. Study subjects must be instructed 
not to dispose of unused tablets on their own. Drug accountability should be done at the time 
bottles are returned by the subject. Any discrepancies should be reported immediately upon 
discovery.
7.7
Treatment compliance
Any discrepancies between actual and expected amount of returned study medication must be 
discussed with the subject at the time of the visit, and any explanation must be documented in 
the source records.
8.
Non–study therapy
8.1
Prior and concomitant therapy
All subjects must receive an ADT of the Investigator’s choice (LHRH agonist/antagonists or 
orchiectomy) as standard therapy started ≤12 weeks before randomization (if combined with a 
first–generation anti–androgen, such as bicalutamide, flutamide, nilutamide, or cyproterone 
acetate, it must be stopped before randomization). For subjects receiving LHRH agonists, 
treatment in combination with a first generation anti–androgen for at least 4 weeks prior to 
randomization is recommended.
Six cycles of docetaxel will be administered after randomization.
Docetaxel can be administered in combination with prednisone/prednisolone at the discretion 
of the Investigator.
8.1.1
Prior therapy
All medications taken in the first 28 days prior to randomization (including start/stop dates, 
dose frequency, route of administration, and indication) must be recorded in the subject’s 
source documentation, as well as entered in the appropriate pages of the eCRF. Prior local 
treatment for prostate cancer (surgery and/or radiation) before the time of informed consent 
(IC) is allowed and should be recorded in the medical record and in the appropriate eCRF. 
Prior treatment with LHRH agonist/antagonists started more than 12 weeks before 
randomization, second–generation AR inhibitors, other investigational AR inhibitors, CYP17 
enzyme inhibitor such as abiraterone acetate or oral ketoconazole as antineoplastic treatment 
for prostate cancer is not allowed. Prior chemotherapy or immunotherapy for prostate cancer 
is not allowed. Treatment with radiotherapy (EBRT, brachytherapy, or radiopharmaceuticals) 
within 2 weeks before randomization is not allowed. Blood transfusions are not allowed 
within 7 days and growth factors are not allowed within 4 weeks of the hematology laboratory 
sample obtained at Screening. For a detailed list of prohibited medications and treatments, see 
Sections 6.2 and 8.1.3.


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8.1.2
Permissible concomitant medications and treatments
All concomitant treatments from the time of IC until the end–of–study treatment visit must be 
recorded on the CRFs. Once the subject has been withdrawn from the treatment with study 
drug, follow–up treatments will be recorded if used to treat new study drug–related SAEs or 
unresolved related AEs or if being used as a systemic antineoplastic therapy for prostate 
cancer.
Analgesic use will be captured via eCRF. Physicians are to record which opioid and non–
opioid medications were used since the last visit, and physicians are to record exact daily 
doses of each analgesic consumed in the last 24 hours prior to the visit (Analgesic 24 hour 
consumption log –eCRF). Note that analgesic medication should be recorded via eCRF for 
each visit that pain is assessed via the Brief Pain Inventory short form (BPI–SF).
Palliative radiation therapy or surgical intervention as needed are allowed during study 
treatment. Treatment with biphosphonates and denosumab is allowed.
All subjects must receive ADT of Investigator’s choice (LHRH agonist/antagonists or 
orchiectomy) as standard therapy. Switching ADT to an LHRH antagonist is permitted during 
study treatment.
For docetaxel pre–medication please refer to Section 7.4.2. Supportive care in case of toxicity 
related to docetaxel including use of biologic response modifiers such as granulocyte
colony-stimulating factor or granulocyte–macrophage colony–stimulating factor, should be 
applied according to standard practice.
Based on results from a drug–drug interaction study (Study 17726), repeated 
co-administration of strong CYP3A4 inducers (see listing of drugs in Appendix 16.5) 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 600 mg darolutamide bid over 4 days prior to administration of a single 
dose of 5 mg rosuvastatin, a BCRP, OATP1B1 and OATP1B3 substrate, together with food 
resulted in a 5.2–fold increase in mean exposure [AUC(0–24)] and a 4.9–fold increase in Cmax
of rosuvastatin in Study 17723. This indicates that co–administration of darolutamide can also 
increase the plasma concentrations of other concomitant BCRP, OATP1B1 and OATP1B3
substrates (e.g. methotrexate, sulfasalazine, fluvastatin, atorvastatin). Therefore, the patients 
should be closely monitored for signs and symptoms of increased exposure to BCRP, 
OATP1B1 or OATP1B3 substrates. Dose modification of these substrates should be 
considered based on the prescriber information or such compounds should be avoided.
8.1.3
Prohibited concomitant medications and treatments
Concomitant treatment with another systemic antineoplastic therapy or another investigational 
medicinal product is prohibited with the exception of ADT throughout the study and 6 cycles 
of docetaxel after randomization.
Initiation of the following medications during the study treatment period is prohibited:


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
Any investigational medicinal product

Radiopharmaceuticals

Immunotherapy (e.g. sipuleucel–T)

Cytotoxic chemotherapy other than docetaxel for 6 cycles after randomization

Enzalutamide, ARN–509, bicalutamide, flutamide, nilutamide

Abiraterone acetate, TAK–700, or other CYP17 inhibitors

Systemic ketoconazole as antineoplastic treatment for prostate cancer

ADT switch to LHRH agonist

Another systemic antineoplastic therapy may be initiated no sooner than 7 days after 
the last dose of study drug
For prohibited prior therapy, please refer to Section 6.2.
8.2
Post–study therapy
After treatment discontinuation, subjects will enter the Active Follow–up period and then the 
Long–term (Survival) Follow–up period. Therapy after discontinuation of study treatment 
will be collected as follows:
During Active Follow–up (includes EOT Visit and Active Follow–up visits):

EOT Visit: collection of medications related to pain and QoL, and collection of 
medications for study drug–related SAEs.

Active Follow–up Visit: collection of all subsequent antineoplastic treatments for 
prostate cancer (which should be provided with start and stop dates and reason for 
change PSA progression, clinical progression, radiological progression, toxicity, or 
other); collection of medications related to pain and QoL, and collection of 
medications for study drug–related SAEs.


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During Long–term (Survival) Follow–up period:

Long–term Follow–up visits: collection of subsequent antineoplastic treatments for 
prostate cancer which should be provided with start and stop dates and reason for 
change (PSA progression, clinical progression, radiological progression, toxicity, or 
other), and collection of medications for study drug–related SAEs.
After primary analysis of the study:

For subjects who are ongoing with darolutamide treatment, the sponsor will continue 
to provide darolutamide via a separate program at least until darolutamide is approved 
and reimbursed in a specific country.

Subjects receiving placebo will discontinue the treatment and complete the study. 
Further treatment is at the discretion of the Investigator.

Subjects in the Active or Long-term follow-up will complete the study.
9.
Procedures and variables
9.1
Tabular schedule of evaluations
All procedures, including efficacy and safety measurements obtained during the course of the 
study, are summarized in the schedule of assessments (Table 9–1).


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Table 9–1
Schedule of assessments
Procedures
Screening Period
Treatment Perioda
Follow–up Period
Active Follow–up Period
Long–term Follow–up Period
Visit 1
Visit 2 and 
subsequent 
visits
EOT Visit
Active 
Follow–up 
Visits
Within 28 days 
before 
randomization
Within 7 days 
before 
randomization
Day 1
(+3 days)
Week 12
(±7 days) and 
every 12 weeks
30 days
(+7 days)u
after last 
dose of 
study drug
Approximately 
every 
12 weeks from 
discontinuation 
of treatment 
up to 1 year
Approximately every 12 weeks 
after Active Follow–up, until 
death, lost to follow–up, 
consent withdrawal, or end–of–
study
Informed consent 
X
Pharmacogenetic consent 
(whole blood only)
X
Demography
X
Medical history
X
Prostate cancer historyb
X
Eligibility criteria 
X
X
Medical resource use
X
X
X
X
Symptom/QoL questionnaire 
NCCN–FACT–FPSI–17c
X
Xd
X
X
X
Pain questionnaire BPI–SF c,e
X
Xd
X
X
X
Analgesic 24 hour consumption log –
eCRF (physician recording analgesic 
pain meds consumed over last 
24 hours)c,e
X
Xd
X
X
X
Randomization
Xs
Physical examination 
including weight and heightf
X
Xg
X
X
12–lead ECG 
X
Xg
X
X
Vital signs (BP, HR)
X
Xg
X
X
Laboratory safety assessments 
(hematology, general chemistry and 
urinalysis)h
X
X
X


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Procedures
Screening Period
Treatment Perioda
Follow–up Period
Active Follow–up Period
Long–term Follow–up Period
Visit 1
Visit 2 and 
subsequent 
visits
EOT Visit
Active 
Follow–up 
Visits
Within 28 days 
before 
randomization
Within 7 days 
before 
randomization
Day 1
(+3 days)
Week 12
(±7 days) and 
every 12 weeks
30 days
(+7 days)u
after last 
dose of 
study drug
Approximately 
every 
12 weeks from 
discontinuation 
of treatment 
up to 1 year
Approximately every 12 weeks 
after Active Follow–up, until 
death, lost to follow–up, 
consent withdrawal, or end–of–
study
Serum PSAh
X
X
X
Testosterone
Xh
Xh
Xh
Alkaline Phosphatase for screeningh
X
PK samplesi 
X
X
Plasma collection for genetic 
biomarkers
X
X
X
X
Plasma collection for non–genetic 
biomarkers
X
X
X
X
Whole blood for CTC analyses
X
Xj
X
Whole blood collection for 
pharmacogenetic analysis – only if 
pharmacogenetic consent is signed
X
(X)t
Collection of tumor tissue (e.g. biopsy)
Xk
Xk
ECOG PS
X
X
X
X
CT/MRI l
X m
(X)n
Bone scanl
X o
(X)p
First SSE
X
X
X
SSE–FS
X
X
X
Post–study antineoplastic therapyq
X
X
Survival statusv
X
X
AEs/SAEs
X
X
X
X
X
Xr
Xr
Concomitant treatments
X
X
X
X
X
Xr
Xr
Study drug dispensing
X
X
AE=adverse events, BP=blood pressure, BPI–SF=Brief Pain Inventory – Short Form; CT=computed tomography, CTC=circulating tumor cells, ECG=electrocardiogram, ECOG 
PS=Eastern Cooperative Oncology Group Performance Status, eCRF=electronic case report form, HR=heart rate, MRI=magnetic resonance imaging, NCCN–FACT FPSI–
17=Functional assessment of cancer therapy / National Comprehensive Cancer Network prostate cancer symptom index 17–item questionnaire; PK=pharmacokinetics, 
PSA=prostate–specific antigen, QoL=quality of life, SAE=serious adverse event, SSE=symptomatic skeletal event, SSE–FS=symptomatic skeletal event free survival


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a Subjects will receive 6 cycles of docetaxel every 21 days after check of the routine hematology and biochemistry blood tests (see Section 9.6.3.1). The first cycle of docetaxel 
should be administered within 6 weeks after start of study drug. For the first 20 subjects who were randomized and have received at least 1 cycle of docetaxel, and for whom a 
detailed mandatory PK analysis will be performed, docetaxel should be administered at least 14 days after randomization (i.e. start of study drug).
b Including treatments and procedures.
c Questionnaires should be administered at the start of the visit prior to any study–related procedure or other clinical activities.
d If not collected at the Screening visit.
e Analgesic consumption and pain assessment questionnaires must be collected on the same day.
f Height to be measured at Screening only.
g If not previously done.
h PSA and testosterone values are to be assessed by a central laboratory during the study period. In a subset of approximately 300 subjects, additional determination of total and free 
testosterone will be performed at Screening and repeated every 6 months (Visit 3, Visit 5, etc.), and at the EOT Visit using a liquid chromatography–tandem mass spectrometry
method for the analysis of total testosterone. The non–protein–bound (free) testosterone will be analyzed and also calculated with the sex hormone–binding globulin and albumin 
concentrations, both of which will also be determined. Blood samples to test alkaline phosphatase for stratification purpose will be analyzed in a central laboratory and thereafter by a
local laboratory. Other laboratory assessments are to be performed by local laboratories. Specific laboratory assessments are detailed in Section 9.6.3.1.
i In the first 20 subjects who were randomized and have received at least 1 cycle of docetaxel, several blood samples will be collected on the day of first docetaxel administration, 
which should be at least 14 days after start of study drug. On this day, blood samples will be collected at the following time points: Pre–Dose (prior to the administration of 
darolutamide and docetaxel), 20±10 minutes after start of docetaxel infusion, 1 hour (within 5 minutes before the end of the infusion), 90 minutes, 2,3, 4, 6, and 8 hours following the 
start of docetaxel infusion. For planned time points between 90 minutes and 8 hours, blood samples should be collected within ±15 minutes of the planned time. For all other 
randomized subjects, 2 blood samples for PK will be collected at least one hour apart on the first day of study drug administration independent of docetaxel administration. The first 
sample should be taken at least 30 minutes after the first study drug dose. In all randomized subjects, two additional blood samples will be collected at 2 subsequent docetaxel cycles 
(one sample per docetaxel cycle), at any time relative to study drug administration and after docetaxel administration on the same day. For the first 20 subjects who were randomized 
and have received at least 1 cycle of docetaxel, the first additional blood sample must be taken from docetaxel cycle 2 onwards. Please refer to Section 9.5.1 for further guidance.
j To be performed at Visit 2 only.
k Collection of tumor tissue at Screening is only if available. Biopsy at disease progression is optional and if available.
l Chest, abdomen and pelvic CT or MRI and bone scan should be performed at the end of docetaxel treatment (within 30 days from last cycle of docetaxel) and yearly thereafter.
m Contrast–enhanced chest, abdomen, and pelvic CT or MRIs performed within 42 days prior to start of treatment with study drug are acceptable as screening scans if the standard 
acquisition procedure according to the Imaging Manual was followed.
n Chest, abdomen and pelvic CT or MRI can be performed at any time in case of PSA progression, symptomatic progressive disease, or change of antineoplastic therapy or if 
considered as appropriate in the Investigator’s judgment; (X) indicates optional assessment.
o Bone scan performed within 42 days prior to start of treatment with study drug are acceptable as screening scan if the standard acquisition procedure according to the Imaging 
Manual was followed.
p Bone scan can be performed at any time in case of PSA progression, symptomatic progressive disease, change of antineoplastic therapy or if considered as appropriate in the 
Investigator’s judgment; (X) indicates optional assessment.
q Please note that documentation of post–study antineoplastic therapy must include the start and stop dates of each treatment and reason for treatment changes (PSA progression, 
clinical progression, radiological progression, toxicity, other).
r Only study drug–related SAEs with concomitant medication received.
s Randomization must occur within 28 days from ICF signature.
t If missed at Visit 1.
u For further details, see Section 9.2.3.
v For every formal analysis of OS, survival data will be collected through additional survival sweeps. All subjects considered alive at the database cut-off date and prior to any 
subsequent additional analysis will be contacted for survival status.


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9.2
Visit description
Subject study visits are to occur every 12 weeks (±7 days) starting from randomization. The 
EOT Visit should occur within a minimum of 30 days (+7 days) after last dose of study drug.
The details of these visits are listed in Table 9–1.
9.2.1
Screening period
A prospective study subject will receive both written and verbal information about the study, 
and will have an opportunity to ask questions and should have sufficient time to decide 
whether or not to participate in the study. The original signed and dated ICF must be retained 
in the Investigator’s study file and a copy must be provided to the subject.
All subjects for whom the IC procedure is completed successfully will be assigned a
subject number.
Subject screening must occur within 28 days prior to randomization. Screening procedures 
can be performed on separate occasions within the allowed 28 day timeframe. Re–testing is 
allowed during the 28–day window only if there is a medical or logistical reason. In case 
screening procedures need to be repeated outside the allowed 28 day timeframe of the 
screening period, subject should be considered a screen failure. It is estimated that it will take
7 to 14 days to obtain results from the safety laboratory assessments, testosterone, and PSA.
Each subject’s eligibility will be confirmed by the Bayer–designated medical representative’s 
written agreement. The Investigator will complete a paper eligibility form confirming the 
inclusion and exclusion criteria, this will be forwarded to the Bayer–designated medical 
representative for review and eligibility confirmation which will take into account the results 
of the central image review for eligibility. The subject will be identified only by their 
study-specific subject number.
A subject who, for any reason (e.g. failure to satisfy the selection criteria), terminates the 
study at any time prior to randomization is regarded a “screening failure”.
Please refer to Section 6.4.1 for guidance on re–screening procedures.
The following procedures will be performed during the Screening period:
Within 28 days before randomization:

Signed and dated ICF

Informed consent for pharmacogenetic consent (whole blood only)

Demographic data (date of birth, age, racial group)

Medical history and current medical condition

Prostate cancer history including prior treatments and procedures


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
Assess eligibility criteria
o Eligibility must be confirmed by written agreement of the Bayer–designated 
medical representative

ECOG PS

Physical examination including weight and height

PSA

Testosterone
o
Note for testosterone: In a subset of approximately 300 subjects, additional 
determination of total and free testosterone will be performed at Screening and 
repeated every 6 months (Visit 3, Visit 5, etc.), and at the EOT Visit using a 
liquid chromatography-tandem mass spectrometry (LC–MS/MS) method for 
the analysis of total testosterone. The non–protein–bound (free) testosterone 
will be analyzed and calculated with the sex hormone–binding globulin 
(SHBG) and albumin concentrations, both of which will also be determined 

Alkaline phosphatase for screening (stratification)
o
Note for alkaline phosphatase test during Screening: blood samples to test 
alkaline phosphatase for stratification purpose will be analyzed in central 
laboratory and during treatment period by local laboratory

Contrast–enhanced chest, abdomen, and pelvic CT or MRI. CT/MRI performed
within 42 days prior to start of treatment with study drug are acceptable as screening 
scans if fulfilling the requirements of the Imaging Manual.
Radiologic tumor assessments will include, chest, abdomen and pelvis, and will be 
evaluated locally at the study site and by the central review. The first radiological 
assessment must be comprised of an IV (and oral, if indicated, per Imaging Manual) 
contrast enhanced CT/MRI scans of chest, abdomen and pelvis. Scans done up to 
42 days prior to first dose can be used as baseline scans fulfilling the requirements in 
the Imaging Manual. Contrast–enhanced MRI shall be performed instead of CT when 
local regulations or allergy to CT contrast media do not permit the use of CT as 
requested per protocol schedule. Copies of scans should be forwarded to the central 
imaging facility for independent assessment. Subjects with a contraindication to both, 
CT and MRI contrast agent, should not be enrolled in this study (see exclusion 
criterion 4).

Bone scan. Bone scan performed within 42 days prior to start of treatment with 
study drug is acceptable as screening scan if performed according to the Imaging 
Manual. Copies of scans should be forwarded to the central imaging facility for 
independent assessment

AEs/SAEs and concomitant treatments, including opioid use for pain

Optional collection of archival tissue – if available– for tissue biomarker analyses
unless precluded by local guidelines, e.g. Independent Ethics Committee (IEC)/
Institutional Review Board (IRB) or regulatory authorities


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Within 7 days before randomization:

Functional assessment of cancer therapy/National Comprehensive Cancer Network 
prostate cancer symptom index (NCCN–FACT FPSI–17) questionnaire (collected via 
electronic patient reported outcome [ePRO] device)

Pain questionnaire – BPI–SF (collected via ePRO device)

Analgesic 24–hour consumption log –eCRF (Physician to record whether or not the 
subject has initiated opioid therapy since last visit and to record analgesic pain meds 
consumed by the subject). Should be collected on the same day as pain assessment 
questionnaires

A 12–lead ECG

Vital signs (BP and HR)

Laboratory safety assessments (hematology, chemistry and urinalysis) (see
Section 9.6.3.1)

A blood (plasma) sample for tumor–related biomarker analysis (genetic and non–
genetic) unless precluded by local guidelines, e.g. IEC/IRB or regulatory authorities if 
eligibility has been confirmed (see Section 13)

AEs/SAEs

Concomitant treatments, including opioid use for pain

Confirmation of eligibility
Note: For all visits where questionnaires are administered, the questionnaires should be 
administered at the start of the visit prior to any study–related procedure or other clinical 
activities.
At the end of the screening period, the subject will be randomized.
9.2.2
Study treatment period
9.2.2.1
Day 1 (Visit 1)
Randomization must occur within 28 days from ICF signature. The subject will arrive at the
study center on the morning of Day 1 (+3 days). The first dose of study drug will be
administered with breakfast at the study center. The following procedures will be 
performed:

Medical resource use

Blood draw for 2 PK samples, which are collected at least 1 hour apart, and the first 
sample should be taken at least 30 minutes after the first darolutamide dose
In the first 20 subjects who were randomized and have received at least one cycle of 
docetaxel, detailed mandatory blood sampling for PK analysis of darolutamide, 
(S,S)-darolutamide, (S,R)-darolutamide, keto-darolutamide, and docetaxel will be collected on 
the day of the first docetaxel administration which should be at least 14 days after 
randomization (i.e. start of study drug; see Section 9.5).


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
A blood (plasma) sample for tumor–related biomarker analysis (genetic and 
non-genetic) unless precluded by local guidelines, e.g. IEC/IRB or regulatory 
authorities (see Section 13)

Whole blood draw for CTC

Whole blood draw for pharmacogenomics analysis if PI/ICF Pharmacogenetic consent 
is signed unless precluded by local guidelines, e.g., IEC/IRB or regulatory authorities 
(see Section 13)

ECOG PS

Current medical condition, AEs, SAEs, and concomitant treatments

Study drug will be dispensed for 12 weeks
If not performed at Screening:

Functional assessment of cancer therapy/National Comprehensive Cancer Network 
prostate cancer symptom index (NCCN–FACT– FPSI–17) questionnaire (collected 
via ePRO device)

Pain questionnaire – BPI–SF (collected via ePRO device)

Analgesic 24–hour consumption log –eCRF (Physician to record whether or not the 
subject has initiated opioid therapy since last visit and to record analgesic pain meds 
consumed by the subject over last 24 hours). Should be collected on the same day as
pain assessment questionnaires
o
To facilitate assessment of analgesic use, subjects should be requested to bring 
all pain medication consumed to each visit

Physical examination including weight

A 12–lead ECG

Vital signs (BP and HR)
Subjects will continue taking study drug at home throughout the study treatment period.
Note: For all visits where questionnaires are administered, the questionnaires should be 
administered at the start of the visit prior to any study–related procedure or other clinical 
activities.
Note for docetaxel administration: Subjects will receive 6 cycles of docetaxel every 21 days
after check of the routine hematology and biochemistry blood tests (see Section 9.6.3.1). The
first cycle of docetaxel should be administered within 6 weeks after start of study drug. For 
the first 20 subjects who were randomized and have received at least 1 cycle of docetaxel, and 
for whom a detailed mandatory PK analysis will be performed, docetaxel should be 
administered at least 14 days after randomization (i.e. start of study drug).
9.2.2.2
Visit 2 and subsequent visits (every 12 weeks ± 7 days)
The following procedures will be performed:

Medical resource use

Symptom / QoL questionnaire NCCN–FACT–FPSI–17


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
Pain questionnaire – BPI–SF

Analgesic 24–hour consumption log –eCRF (Physician to record whether or not the 
subject has initiated opioid therapy since last visit and to record analgesic pain meds 
consumed by the subject over last 24 hours). Should be collected on the same day as
pain assessment questionnaires
o
To facilitate assessment of analgesic use, subjects should be requested to bring 
all pain medication consumed to each visit

Physical examination including weight

A 12–lead ECG

Vital signs (BP, HR)

Laboratory safety assessments (hematology, chemistry and urinalysis) (see 
Section 9.6.3.1)

PSA

Testosterone
o
Note for testosterone: In a subset of approximately 300 subjects, additional 
determination of total and free testosterone will be performed at Screening and 
repeated every 6 months (Visit 3, Visit 5, etc.), and at the EOT Visit using a 
LC–MS/MS method for the analysis of total testosterone. The non–protein–
bound (free) testosterone will be analyzed and calculated with the SHBG and 
albumin concentrations, both of which will also be determined 

At 2 visits, an additional blood draw for PK analysis (see Section 9.5)

A blood (plasma) sample for tumor–related biomarker analysis (genetic and non–
genetic) unless precluded by local guidelines, e.g. IEC/IRB or regulatory authorities 
(see Section 13)

Collect whole blood sample for CTC (at Visit 2 only)

ECOG PS

Chest, abdomen and pelvic CT/MRI: (please refer to Section 9.2.2.3)

Bone scan: (please refer to Section 9.2.2.3)

Date of first SSE (if applicable)

Current medical condition, AEs, SAEs, and concomitant treatments

Study drug will be dispensed for 12 weeks

If missed at Visit 1, whole blood collection for pharmacogenetic analysis – only if 
pharmacogenetic consent is signed
Note: For all visits where questionnaires are administered, the questionnaires should be 
administered at the start of the visit prior to any study–related procedure or other clinical 
activities.


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The treatment period will end at each site when all subjects at the site who are ongoing on 
darolutamide treatment have transitioned into the separate program to continue receiving 
darolutamide (see Section 8.2) or have discontinued from the study for any other reason 
(e.g. lost to follow-up, consent withdrawal), and all subjects on placebo have discontinued the 
treatment.
9.2.2.3
Requirement for chest, abdomen and pelvic CT/MRI and bone scan 
during the study treatment period
Contrast–enhanced chest, abdomen and pelvic CT or MRI for the assessment of soft 
tissue/visceral lesions and bone scan for the assessment of bone lesions should be performed 
at the end of docetaxel treatment (within 30 days from last cycle of docetaxel) and yearly 
thereafter.
In addition, contrast–enhanced chest, abdomen and pelvic CT or MRI and bone scan can be 
performed at any time in case of PSA progression, symptomatic progressive disease, change 
of antineoplastic therapy or if considered as appropriate in the Investigator’s judgment.
(Section 9.2.5).
If a subject develops contraindication to CT contrast media during the course of the study 
after the baseline imaging, contrast enhanced MRI shall be performed. In rare cases where the 
subject develops contraindication to both CT and MRI contrast media, the post–baseline 
imaging examination could continue without contrast media.
The method chosen at the baseline should be the same throughout the study. The same 
technique (e.g., slice thickness, field of view) should be used for all scans during the study 
treatment period. Preferably all scans should be interpreted by the same 
investigator/radiologist during the study whenever possible.
Radiological progression by soft tissue/visceral lesions is determined according to RECIST
criteria, version 1.1 (31), based on MRI / CT scans of the chest, abdomen, and pelvis 
performed by the Investigator, as recommended by Prostate Cancer Clinical Trials Working 
Group (PCWG3) (32). 
Bone lesions will be recorded separately from soft tissue/visceral lesions. Radiological 
progression by bone lesions is determined according to PCWG3 criteria based on whole body 
99mTc methylene diphosphonate bone scans performed by the Investigator.
Further guidance for acquisition of images and assessment rules will be provided in the 
Imaging Manual.


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9.2.3
Active Follow–up period
End–of–study treatment visit
Subjects will have an EOT Visit 30 days (+7 days) after the last dose of study drug. Another
systemic antineoplastic therapy may be initiated no sooner than 7 days after the last dose of 
study drug.
After primary analysis of the study:

Subjects in the darolutamide arm, who decide to continue darolutamide treatment in a 
separate program, will have their EOT Visit for the current study at the same time as 
their first treatment visit in the separate program. 

Subjects in the darolutamide arm, who then do not decide to continue treatment, will 
have their EOT visit 30 days (+7 days) after the last dose.

Subjects in the placebo arm will discontinue treatment and will have their EOT Visit at 
their earliest convenience, and at the latest 30 days (+7 days) after the last dose. 
The following procedures will be performed during the EOT Visit:

Medical resource use

Symptom / QoL questionnaire NCCN–FACT–FPSI–17

Pain questionnaire – BPI–SF

Analgesic consumption log –eCRF (Physician to record whether or not the subject has
initiated opioid therapy since last visit and to record analgesic pain meds consumed by 
the subject over last 24 hours). Should be collected on the same day as pain 
assessment questionnaires

Physical examination including weight

A 12–lead ECG

Vital signs (BP, HR)

Laboratory safety assessments (hematology, chemistry, and urinalysis) (see 
Section 9.6.3.1)

PSA

Testosterone
o
Note for testosterone: In a subset of approximately 300 subjects, additional 
determination of total and free testosterone will be performed at screening and 
repeated every 6 months (Visit 3, Visit 5, etc.), and at the EOT Visit using a 
LC–MS/MS method for the analysis of total testosterone. The non–protein–
bound (free) testosterone will be analyzed and calculated with the SHBG and 
albumin concentrations, both of which will also be determined 

A blood (plasma) sample for tumor–related biomarker analysis (genetic and non–
genetic) unless precluded by local guidelines, e.g. IEC/IRB or regulatory authorities

Whole blood draw sample for CTC analysis


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
Optional collection of biopsy tissue taken at disease progression, if available, for 
tissue biomarker analyses unless precluded by local guidelines, e.g. IEC/IRB or 
regulatory authorities

ECOG PS

Date of first SSE (if applicable)

Current medical condition, AEs, SAEs and concomitant treatments
Note: For all visits where questionnaires are administered, the questionnaires should be 
administered at the start of the visit prior to any study–related procedure or other clinical 
activities.
Active Follow–up Visits
After treatment discontinuation, subjects will begin the Active Follow–up period. Active 
Follow–up visits occur as standard of care clinic visits approximately every 12 weeks for up 
to 1 year to collect the following:

Medical resource use

Review handheld device or tablet and ensure subjects complete the following:
o
Symptom / QoL questionnaire NCCN–FACT–FPSI–17
o
Pain questionnaire – BPI–SF
o
Analgesic consumption log –eCRF (Physician to record whether or not the 
subject has initiated opioid therapy since last visit and to record analgesic pain 
meds consumed by the subject over last 24 hours). Should be collected on the 
same day as pain assessment questionnaires
o
To facilitate assessment of analgesic use, subjects should be requested to bring 
all pain medication consumed to each visit

Record SSEs if applicable

Subsequent antineoplastic treatments for prostate cancer which should be provided 
with start and stop dates and reason for treatment change (PSA progression, clinical 
progression, radiological progression, toxicity, other)

Record survival status

Study drug–related SAEs with concomitant medications received
Note: For all visits where questionnaires are administered, the questionnaires should be 
administered at the start of the visit prior to any study–related procedure or other clinical 
activities.
After approximately 1 year of Active Follow–up, subjects will be transitioned to Long–term
(survival) Follow–up. The Active Follow–up period extends from the discontinuation of 
treatment period for up to 1 year or until the subject can no longer travel to the clinic, dies, is 
lost to follow–up, or withdraws IC and actively objects to collection of further data.
After primary analysis of the study, all subjects in the Active Follow-up will complete the 
study.


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9.2.4
Long–term (survival) Follow–up period
After completing the Active Follow–up period, subjects will enter the Long–term Follow–up
period. Subjects will be contacted approximately every 12 weeks by phone, and additional
contacts may be required for overall (survival assessment). The following information will be 
collected:

Record subsequent antineoplastic treatments for prostate cancer with start and stop 
dates and reason for treatment change (PSA progression, clinical progression, 
radiological progression, toxicity, other)

Record survival status

Study drug–related SAEs with concomitant medications received
As this information will be collected over the telephone from the subject, it is the clinical 
site’s responsibility to obtain and make available the source documentation for the 
information collected from the subject and document it in the eCRF.
After primary analysis of the study, all subjects in the Long-term Follow-up will complete the 
study.
9.2.5
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

Vital signs (BP, HR)

Laboratory safety assessments (hematology, chemistry, urinalysis)

Status of survival

AEs, SAEs, current medical condition, concomitant treatments

Chest, abdomen, and pelvic CT/MRI

Bone scan
Other unscheduled procedures may be performed, as per Investigator’s judgment.
The laboratory tests routinely obtained before each cycle of docetaxel must be reported in the 
unscheduled hematology and biochemistry eCRF.
For every formal analysis of OS, survival data will be collected through additional survival 
sweeps. All subjects considered alive at the database cut-off date and prior to any subsequent 
additional analysis will be contacted for survival status.


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9.3
Population characteristics
9.3.1
Demographic
Demographic characteristics of date of birth (age), sex, and race/ethnicity should be entered in 
the eCRFs.
9.3.2
Medical history
Medical history findings (i.e. previous diagnoses, diseases, or surgeries) meeting all criteria 
listed below will be collected:

Not pertaining to the study indication

Start before signing of the ICF

Considered relevant to the study
Detailed instructions on the differentiation between medical history and AEs can be found in 
Section 9.6.1.1.
History of prostate cancer will be collected separately from the general medical history. This 
includes, but is not limited to:

Date of diagnosis

Staging (performed at diagnosis)

Prostate cancer history

Disease status at study entry

Prior diagnostic and therapeutic procedures

Prior prostate cancer treatments (any therapy that is ongoing should be reported as 
concomitant medication)
9.3.3
Other baseline characteristics
Baseline characteristics relating to disease factors include:

QoL assessment (NCCN–FACT FPSI–17)

ECOG PS

Cancer pain assessment
All medications and significant non–drug therapies ongoing during the screening period
(28 days prior to randomization) must be entered in the eCRF, including:

Medication trade name and dose

Reason for medication

Start date and end date, or if continuing at time of study entry
9.4
Efficacy
The primary efficacy variable is OS.


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Survival status will be assessed from randomization until the end of the Long–term Follow-up
period. Date of death and primary cause of death will be recorded.
For definition and analysis of primary variable, and for description of secondary and 
exploratory variables, please refer to Section 10.3.
9.5
Pharmacokinetics/pharmacodynamics
9.5.1
Drug measurements
The concentrations of diastereomers (S,R)-darolutamide (BAY 1896951) and 
(S,S)-darolutamide (BAY 1896952), metabolite keto-darolutamide (BAY 1896953) and 
docetaxel in plasma will be determined by a validated method, e.g. liquid chromatography–
tandem mass spectrometry (LC–MS/MS). Darolutamide (BAY 1841788) concentration will 
be calculated as the sum of diastereomers (S,R)-darolutamide and (S,S)-darolutamide
concentrations.
PK samples will be collected from all subjects to maintain blinding. However PK samples 
from the placebo arm will not be analyzed.
In the first 20 subjects who were randomized and have received at least 1 cycle of docetaxel, 
detailed mandatory blood sampling for PK analysis of darolutamide, (S,S)-darolutamide, 
(S,R)-darolutamide, keto-darolutamide, and docetaxel will be collected on the day of the first 
docetaxel administration which should be at least 14 days after randomization (i.e. start of 
study drug).
On this day blood samples will be collected at the following time points:
Pre–dose (prior to the administration of study drug and docetaxel), 20±10 minutes after start 
of docetaxel infusion, 1 hour (within 5 minutes before the end of infusion), 90 minutes, 2, 3,
4, 6, and 8 hours following the start of docetaxel infusion. For planned time points between 
90 minutes and 8 hours, blood samples should be collected within ±15 minutes of the planned 
time.
Two additional samples will be taken at 2 subsequent docetaxel cycles (i.e. one sample per
docetaxel cycle, at any time relative to study drug administration and after docetaxel
administration on the same day), from docetaxel cycle 2 onwards. These samples will be used 
to provide information on variability at steady state for darolutamide and to explore any 
potential effect of darolutamide on the PK of docetaxel.
It is of importance that the actual date and time of blood sampling and study drug 
administration as well as docetaxel administration are documented in the eCRF because PK 
calculations will be based on the actual sampling times relative to dosing times.


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In all other randomized subjects, sparse sampling for population PK will be collected to 
determine the exposure (i.e. area under the curve over the dosing interval at steady state) of 
darolutamide, the diastereomers (S,S)-darolutamide and (S,R)-darolutamide, the metabolite 
keto-darolutamide, and docetaxel and to quantify its variability in the target subject
population. 
Two samples will be taken on the day of first study drug intake (Visit 1 Day 1), at least 
30 minutes after the first dose of study drug, approximately 1 hour apart to determine
darolutamide absorption data. 
Two additional samples will be taken at 2 docetaxel cycles (i.e. one sample per docetaxel 
cycle from the first cycle onwards, at any time relative to study drug administration and after 
docetaxel administration on the same day). These samples will be used to provide information 
on variability at steady state for darolutamide and to explore any potential effect of 
darolutamide on the PK of docetaxel. The first additional sample in this subset of subjects can 
be taken on the day of first docetaxel cycle, as long as the subject has already received at least 
one dose of study drug on the day before. 
Drug intake and sampling times have to be accurately documented.
The instructions for sample collection, processing, storage and shipment will be detailed in a 
separate document (e.g., sample handling sheet or lab manual).
9.5.2
Pharmacokinetic evaluation
Non–compartment approach PK analysis
In the first 20 subjects who were randomized and have received at least 1 cycle of docetaxel:
Pharmacokinetic parameters will be calculated using a non–compartment approach according 
to the current Bayer guidelines, using Win–Nonlin software. Details of the used version will 
be given in the clinical study report.
Based on the plasma concentration–time data, the following PK parameters are planned to be 
estimated for darolutamide, (S,S)-darolutamide, (S,R)-darolutamide, keto-darolutamide, and 
docetaxel.
Main parameter:
Darolutamide, (S,S)-darolutamide, (S,R)-darolutamide, keto-darolutamide: 
AUC(0–12) 1)
1) : Using the predose plasma sample also as 12 hour sample
Docetaxel:  
AUC(0–tlast)


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Additional parameters:
Darolutamide, (S,S)-darolutamide, (S,R)-darolutamide, keto-darolutamide: 
AUC(0–8), AUC(0–tlast), Cmax, tmax, tlast
Docetaxel:  
Cmax, tmax, tlast
To ensure the blinding of the PK–evaluator during preliminary PK evaluation for DMC 
review, concentration data with masked subject IDs will be provided by Bioanalytics. The 
evaluation results will then be transferred to an unblinded statistician at the DMC.
Population PK evaluation
In all other randomized subjects:
Individual concentration–time data of darolutamide, (S,S)-darolutamide, (S,R)-darolutamide,
and keto-darolutamide will be provided in a clinical study report appendix. The concentration 
data from this study, which might be augmented with PK data from other studies, will be 
analyzed to evaluate the variability of the PK of darolutamide, of the respective diastereomers 
(S,S)-darolutamide and (S,R)-darolutamide, and of the metabolite keto-darolutamide in this 
phase III population. The possible effect of relevant covariates on the PK of these compounds 
might also be evaluated. In addition, exploratory exposure–response analyses of efficacy, PD 
or safety parameters, e.g. OS, PSA response rate, etc., are planned. In addition, the docetaxel 
exposure in the two treatment groups will be compared. A population PK approach will be 
applied for these evaluations, which will be described in detail in a separate Modeling & 
Simulation (M&S) Plan and the results will be reported separately in the M&S Report.
9.6
Safety
9.6.1
Adverse events
9.6.1.1
Definitions
Definition of adverse event
In a clinical study, an AE is any untoward medical occurrence (i.e. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom, or disease) in a subject
or clinical investigation subject after providing written IC for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
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 physical examination findings, symptoms, diseases, laboratory, or ECG 
results.


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
Conditions that started before signing of IC and for which no symptoms or treatment 
are present until signing of IC will be recorded as medical history (e.g. seasonal 
allergy without acute complaints).

Conditions that started before signing of IC and for which symptoms or treatment are 
present after signing of IC, at unchanged intensity, will be recorded as medical history 
(e.g. allergic pollinosis).

Conditions that started or deteriorated after signing of the ICF including those 
recorded as medical history will be documented as AEs. This includes intercurrent 
illnesses.
Definition of a serious adverse event
An SAE is classified as any untoward medical occurrence that, at any dose, meets any of the 
following criteria:
a.
Results in death
b. Is life threatening
The term ‘life threatening’ in the definition refers to an event during which the subject
was at risk of death at the time of the event. It does not refer to an event that, 
hypothetically, might have caused death if it were more severe.
c.
Requires in–subject hospitalization or prolongation of existing hospitalization
A hospitalization or prolongation of hospitalization will not be regarded as an SAE if at 
least one of the following exceptions is met:
-
The admission results in a hospital stay of less than 12 hours
-
The admission is pre–planned 
(i.e. elective or scheduled surgery arranged prior to the start of the study)
-
The admission is not associated with an AE 
(e.g. social hospitalization for purposes of respite care)
However, it should be noted that invasive treatment during any hospitalization may fulfill 
the criterion of ‘medically important’ and as such may be reportable as an SAE, 
dependent on clinical judgment. In addition, where local regulatory authorities 
specifically require a more stringent definition, the local regulation takes precedence.
d. Results in persistent or significant disability/incapacity
Disability means a substantial disruption of a person’s ability to conduct normal life 
functions.
e.
Is a congenital anomaly/birth defect
f.
Is another medically important serious event as judged by the Investigator


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9.6.1.2
Classifications for adverse event assessment
All AEs will be assessed and documented by the Investigator according to the categories 
detailed below.
9.6.1.2.1
Seriousness
For each AE, the seriousness must be determined according to the criteria given in 
Section 9.6.1.1.
9.6.1.2.2
Intensity
The severity (or intensity) of AEs should be documented using NCI–CTCAE v 4.03. If no 
exact matching code is available in NCI–CTCAE v 4.03, the following guide should be used:
-
CTC 1 = Mild AE: Transient in nature and generally not interfering with normal 
activities
-
CTC 2 = Moderate AE: Sufficiently discomforting to interfere with normal activities
-
CTC 3 = Severe AE: Prevents normal activities
-
CTC 4 = Life threatening (subject was at risk of death at the time of the event)
-
CTC 5 = Results in death (fatal)
9.6.1.2.3
Causal relationship
The assessment of the causal relationship between an AE and the administration of treatment 
is a clinical decision based on all available information at the time of the completion of the 
eCRF. The causal relationship should be assessed to darolutamide/placebo as well as the 
background docetaxel treatment independently.
The assessment is based on the question whether there was a “reasonable causal relationship” 
to darolutamide/placebo or docetaxel in question.
Possible answers are “yes” or “no.”
An assessment of “no” should include either:
1. The existence of a clear alternative explanation (e.g. mechanical bleeding at surgical site)
or
2. A lack of plausibility (e.g. the subject is struck by an automobile without evidence that 
darolutamide/placebo or docetaxel caused disorientation that may have led to the event, or 
cancer develops a few days after the first administration of a darolutamide/placebo or 
docetaxel.
An assessment of “yes” indicates that there is a reasonable suspicion that the AE is associated 
with the use of darolutamide/placebo or docetaxel.
Important factors to be considered in assessing the relationship of the AE to 
darolutamide/placebo or docetaxel include:


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
The temporal sequence relating the event to drug administration. The event should 
occur after the drug is given. The length of time from drug exposure to event should 
be evaluated in the clinical context of the event.

Recovery on drug discontinuation (dechallenge) and recurrence on drug re–
introduction (rechallenge). The subject’s response after dechallenge or the subject’s 
response after rechallenge should be considered in the view of the usual clinical 
course of the event in question.

Underlying, concomitant, intercurrent diseases: Each event should be evaluated in the 
context of the natural history and course of the disease being treated and any other 
disease the subject may have.

Concomitant medication or treatment: The other drugs the subject is taking or the 
treatment the subject receives should be examined to determine whether any of these 
may be suspected as a cause for the event in question.

Known response pattern for this class of drug: Clinical/preclinical.

Exposure to physical and/or mental stresses: The exposure to stress might induce 
adverse changes in the recipient and provide a logical and better explanation for the 
event.

The pharmacology and PK of the study treatment: The PK properties (absorption, 
distribution, metabolism and excretion) of the study treatment, coupled with the 
individual subject’s PD should be considered.

The assessment is not possible.
Causal relationship to protocol–required procedure(s)]
The assessment of a possible causal relationship between the AE and protocol–required 
procedure(s) is based on the question whether there was a “reasonable causal relationship” to 
protocol–required procedure(s).
Possible answers are “yes” or “no”
9.6.1.2.4
Action taken with study treatment
Any action on study treatment to resolve the AE is to be documented using the categories 
listed below:

Drug withdrawn

Drug interrupted

Dose reduced

Dose not changed

Not applicable

Unknown
9.6.1.2.5
Other specific treatment(s) of adverse events

None


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
Remedial drug therapy

Other
9.6.1.2.6
Outcome
The outcome of the AE is to be documented using the following categories:

Recovered/resolved

Recovering/resolving

Recovered/resolved with sequelae

Not recovered/not resolved

Fatal

Unknown
9.6.1.3
Assessments and documentation of adverse events
All AEs occurring from the time the subject has signed the ICF until 30 (+7) days after the 
last dose of study drug must be entered in the subject’s eCRF. All treatment–emergent AEs 
must be followed until resolution or stabilization, wherever feasible.
The type of information that should be assessed and recorded by the Investigator for each AE 
is listed in Section 9.6.1.2.
Disease progression per se should not be regarded as an AE. Instead, the associated signs and 
symptoms should be recorded as AEs.
“Death” should not be recorded as an AE on the AE page. Instead, “death” is the outcome of 
underlying AE(s).
For all SAEs, the Sponsor has to carry out a separate assessment for expectedness, 
seriousness, and causal relationship to study drug.
A laboratory test abnormality that is considered to have a clinically relevant effect on the 
subject (e.g. causing the subject to withdraw from the study, requiring treatment or causing 
apparent clinical manifestations, or judged relevant by the Investigator) should be reported as 
an AE.
Documentation of an AE must be supported by an entry in the subject’s medical file.
Each event should be described in detail, along with start and stop dates, severity, relationship 
to investigational product, action taken, and outcome.
9.6.1.4
Reporting of serious adverse events
The definition of SAEs is given in Section 9.6.1.1. Each SAE must be followed up until 
resolution or stabilization by submission of updated reports to the designated recipient.


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Investigator’s notification of the Sponsor
All investigators will be thoroughly instructed and trained on all relevant aspects of the 
Investigator’s reporting obligations for SAEs. This information, including all relevant contact 
details, is summarized in the Investigator site file. This information will be updated as needed.
All SAEs occurring during the observation period defined in Section 9.6.1.1 must 
immediately (within 24 hours of the Investigator’s awareness) be reported to the recipient 
detailed in the Investigator’s file. An SAE form must also be completed within 24 hours of 
the Investigator awareness and forwarded to the designated recipient. Each SAE must be 
followed up until resolution or stabilization by submission of updated reports to the 
designated recipient.
Serious AEs that occur 30 (+7) days after the last dose of study drug during Active Follow–up
or Long–term Follow–up should be reported on the SAE form, if the Investigator feels that 
there is a reasonable possibility for the event to have been caused by the study subject’s 
participation in the study. In such cases, the SAEs will be processed by the Sponsor according 
to all applicable regulations.
If disease progression leads to signs and symptoms that meet the criteria for seriousness 
(e.g. hospitalization), the associated signs and symptoms may be reported as an SAE, but the 
underlying cause (that is, “recurrent disease” or “metastatic disease”) should not be reported 
as an SAE. In this case, recurrent or metastatic disease should be mentioned on the SAE form 
as an “alternative explanation.”
An isolated laboratory abnormality that is assigned a severity rating of Grade 4, as defined in 
NCI–CTCAE v 4.03, is not reportable as an SAE unless the Investigator assesses that the 
event meets standard International Conference on Harmonization criteria for an SAE. 
Similarly, a baseline laboratory abnormality that is part of the disease profile should not be 
reported as an SAE when assigned a severity rating of Grade 4, as defined in NCI–CTCAE 
v 4.03, specifically when this abnormality is allowed (or not excluded) by the protocol 
inclusion/exclusion criteria (see Sections 6.1 and 6.2). If an Investigator is in doubt about the 
applicable reporting obligations, he/she should consult with the study monitor for the 
Sponsor. The NCI–CTCAE version 4.03 Grade 4 laboratory abnormalities will be 
documented and will be reviewed on a regular basis.
Notification of the IECs / IRBs
Notification of the IECs/IRBs about all relevant events (e.g. SAEs or SUSARs) will be 
performed by the Sponsor/delegate and/or by the Investigator according to all applicable 
regulations.


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Notification of the authorities
The Sponsor will expedite all suspected unexpected SAEs and SUSARs as well as other 
safety issues requiring expedited reporting to the relevant authorities within applicable 
timelines.
Sponsor’s notification of the investigational site
The Sponsor/delegate will inform all investigational sites about reported relevant events 
(e.g. SUSARs) according to all applicable regulations.
9.6.1.5
Expected adverse events
For this study, the applicable reference document is the most current version of the IB.
Overview listings of frequent events that have occurred so far in the clinical development are 
shown in the current IB. If relevant new safety information is identified, the information will 
be integrated into an update of the IB and distributed to all participating sites.
The expectedness of AEs will be determined by the Sponsor according to the applicable 
reference document and according to all local regulations.
9.6.1.6
Adverse events of special safety interest
None.
9.6.2
Pregnancies
Sexually active male subjects must agree to use condoms as an effective barrier method and 
refrain from sperm donation, and/or their female partners of reproductive potential to use a 
method of effective birth control, during the study treatment and for 3 months after the end of 
the treatment with darolutamide, and 6 months after treatment with docetaxel (inclusion 
criterion).
Pregnancies inadvertently fathered by study subjects during the study should be reported and 
followed up using the Bayer Pregnancy Monitoring Forms, if permissible by local legislation.
For a pregnancy in the partner of a male study subject, all efforts will be made to obtain 
similar information on course and outcome, subject to the partner’s consent.
For all reports, the forms provided are to be used. The report should be submitted within the 
same timelines as an SAE, although a pregnancy per se is not considered an SAE.
9.6.3
Further safety
9.6.3.1
Laboratory safety assessments
The PSA and testosterone values are to be assessed by a central laboratory during the study 
period. Blood samples to test alkaline phosphatase for stratification purpose will be analyzed
in central laboratory and thereafter by local laboratory. Other laboratory assessments are to be 
performed by local laboratories.
Instruction on sample collection, handling, labeling, storage, and shipment will be provided
in the laboratory manual.


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The following laboratory safety assessments will be performed during the screening
period, study treatment period and at the end–of–study treatment visit.
At screening, all the following assessments are to be taken within 7 days prior to 
randomization, but PSA.
Hematology:

Hemoglobin

Hematocrit

Erythrocyte count

Leukocyte count

Differential count (lymphocytes, monocytes, eosinophils, neutrophils, basophils)

Mean corpuscular hemoglobin

Mean corpuscular volume

Mean corpuscular hemoglobin concentration

Thrombocytes
Chemistry:

Albumin

Alanine aminotransferase (ALT)

Aspartate aminotransferase (AST)

Alkaline phosphatase
o
Note: Blood samples to test alkaline phosphatase for stratification purpose will 
be analyzed in central laboratory and thereafter by local laboratory

Bilirubin total (+ direct and indirect bilirubin if total bilirubin is >1.0 x ULN)

Calcium

Blood urea nitrogen

Creatinine

Serum glucose

Total protein

Lactate dehydrogenase

Potassium

Sodium

Testosterone
o
Note for testosterone: In a subset of approximately 300 subjects, additional 
determination of total and free testosterone will be performed at Screening and 
repeated every 6 months (Visit 3, Visit 5, etc.), and at the EOT Visit using a 
LC–MS/MS method for the analysis of total testosterone. This method allows 
precise quantification of low testosterone levels in subjects during ADT 


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treatment. The non–protein–bound (free) testosterone will be analyzed and 
calculated with the sex hormone–binding globulin (SHBG) and albumin 
concentrations, both of which will also be determined

PSA (total) (at screening, blood sample for PSA is to be taken within 28 days prior to 
randomization)

Chromogranin A (only at Screening)

Prothrombin time, expressed as international normalized ratio, in subjects under 
vitamin K antagonist therapy (local assessment)
Urinalysis:

Glucose

Protein

Erythrocytes

Leukocytes
Safety assessments for docetaxel: Hematology (for ANC check), ALT, AST, bilirubin total 
(+ direct and indirect bilirubin if total bilirubin is >1.0 x ULN) are mandatory safety 
assessments to be checked before each cycle of docetaxel. Further laboratory safety 
assessments may also be checked according to Investigator’s judgment. 
In the event of implausible results, the laboratory may measure additional parameters to 
assess the quality of the sample (e.g. clotted or hemolyzed) and to verify the results. The 
results from such additional analyses may neither be included in the clinical database of this 
study nor evaluated further. If the results are relevant, the Investigator will be informed to 
determine follow–up activities outside of this protocol.
9.6.3.2
Physical examination
Physical examination will be performed and weight will be measured at all visits (except at 
Day 1 Visit if already performed at Screening). Height will be recorded at Screening only.
Abnormal physical examination findings are recorded either as medical history or as AEs (see 
Section 9.6.1.1).
9.6.3.3
12–lead ECGs
All 12–lead ECGs will be recorded in a supine position after at least 10 minutes rest.
9.6.3.4
Vital signs
All vital sign assessments will be recorded in a supine position after at least 10 minutes rest.
9.7
Other procedures and variables
Other exploratory variables in this study are pain intensity and pain interference scores from 
the BPI–SF, medical resource use, and assessment of biomarkers.


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In addition to calculating a pain score based on the worst pain question (i.e., worst pain 
subscale [WPS] score) on the BPI–SF (Appendix 16.4), the subject’s responses on the BPI-SF 
can be used to calculate a pain score intensity and a pain interference score (29).
9.7.1
Biomarker investigations
Biomarker status will be correlated with clinical outcome to explore whether any biological 
targets appear to define subject populations that are particularly sensitive or resistant to 
darolutamide. Details of the biomarker analyses may be described in a separate statistical 
analysis plan (SAP) and the results of these analyses may be provided as a separate biomarker 
report.
Tumor biomarker studies will be performed to investigate the mechanisms by which 
darolutamide may work in subjects with mHSPC and will use tumor biomarkers circulating in 
plasma or, if available, biopsies either collected prior to study entry or at disease progression.
Tumor biomarkers may be categorized as “non–genetic” (involving protein) or “genetic” 
(involving ribonucleic acid [RNA] or deoxyribonucleic acid [DNA]). In the current study, 
analyses of both non–genetic and genetic biomarkers are planned. The analysis of tumor 
genetic markers by tumor DNA sequencing and/or gene expression studies with tissue 
samples taken from the primary tumor and metastases will support identification of 
biomarkers contributing to clinical benefit to therapy. Utmost care will be taken to protect 
subject identity during biomarker analyses.
Biomarkers related to drug safety, efficacy, or mechanism of action will be analyzed from 
whole blood and involve targeted genetic testing. Targeted genetic testing will focus on single
gene polymorphisms of genes involving, but not limited to, hepatotoxicity, metabolism, or 
targets involved in drug activity. Identified gene variants aim to predict the best individuals to 
treat, either selecting for toxicity avoidance or for positive benefit.
In addition to the biomarkers listed above, other biomarkers deemed relevant to gain further
knowledge about the pathomechanism of the disease or about the drug (i.e. mode of action
related effect or safety of the drug) may be measured, based on newly emerging data from
other ongoing studies and / or literature data.
Details on the collection, processing, storage and shipment of biomarker samples will be
provided in separate documents (e.g. sample handling sheets or lab manual).
9.7.1.1
Plasma–based biomarker analysis
Subjects will be asked to provide blood samples for biomarker analyses, which will be 
obtained during regular study visits in which blood will be drawn for other scheduled but 
unrelated laboratory tests.
Genetic biomarkers from plasma: 
These samples are intended to isolate plasma to study tumor markers circulating in blood such 
as circulating tumor DNA (ctDNA) or circulating tumor RNA. Candidates of genes for the 
evaluation from ctDNA are AR, PIK3CA, and phosphatase and tensin homolog (PTEN). The 
types of analyses may comprise the identification of mutations or splice variants. 


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Furthermore, these plasma samples will serve as source for non–coding microRNA, as 
possible markers describing treatment response.
Non–genetic biomarkers from plasma: 
Plasma samples will also be used to quantify the circulating levels of various proteins of 
interest, to attempt to identify a protein signature that correlates with drug response.
Plasma samples for the analyses of tumor biomarkers (genetic and non–genetic biomarkers) 
will be prepared from blood samples obtained at the following time points:

Screening visit and on Day 1, Visit 1 (pre–dose) once eligibility criteria have been 
confirmed

Visit 2 and subsequent Visits

End of Treatment Visit
On treatment days, blood will be drawn for preparation of plasma samples prior to drug 
administration, if possible.
In addition to the proteins and genes listed above, other biomarkers deemed relevant to this 
study will be measured.
Data from the biomarker analyses may be correlated with measures of clinical efficacy or 
toxicity obtained in this study.
9.7.1.2
Circulating tumor cells
CTCs may serve as source of tumor metastases circulating in blood and may reflect the tumor 
phenotype or genotype. Enumeration of CTCs may serve as description of tumor burden.
Circulating tumor cells will be analyzed in detail from whole blood samples collected at 
various time points to assess the effect of darolutamide in decreasing numbers of CTCs as 
well as to characterize the phenotype and genotype of CTCs such as presence of AR 
mutations, AR splice variants, and other genomic markers.
A whole blood sample for CTC analysis will be obtained at Visit 1 (once eligibility criteria 
have been confirmed), Visit 2 and EOT.
9.7.1.3
Tumor–based biomarker analysis
From subjects for which tumor tissue specimens (e.g. from biopsy) are available, tumor 
specific biomarker analyses are intended to be used for the following purposes: (1) to evaluate 
mutations, copy numbers or gene rearrangements in known oncogenes such as AR, TMPRSS, 
cMYC, PI3K, and CYP17 extracted from tumor tissue specimens; (2) to analyze the gene 
expression of genes of interest such as AR, cMYC, PTEN, PI3K, and AR–regulated genes in 
RNA extracted from tumor tissue specimens; (3) to evaluate expression of non–coding tumor 
relevant RNAs such as microRNAs.
Provided sufficient tissue quality and quantity, tumor tissue specimens are also intended to be 
used to quantify the expression of proteins of interest, to attempt to identify a protein 
signature that correlates with drug response.


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As per Investigator’s discretion, and if technically feasible, biopsy at the time of disease 
recurrence is highly encouraged to be taken. This sample would allow generation of 
information about the identification of tumor biomarkers playing a role in therapy resistance 
for which the subject may benefit for further guidance. Note, however, that this is not 
considered to be mandatory by this study protocol.
9.7.1.4
Genetic biomarker analysis from whole blood
Biomarkers related to drug safety, efficacy, or mechanism of action may be analyzed from 
whole blood and involve targeted pharmacogenetic testing. These studies will conducted 
aiming to find gene variants associated with responses to darolutamide treatment and to 
predict the best individuals to treat, either selecting for toxicity avoidance or for positive 
benefit.
Targeted pharmacogenetic testing will focus on single gene polymorphisms (SNPs) on genes 
involved but not limited to hepatotoxicity, metabolism, or targets involved in drug activity. 
Unless precluded by local guidelines, subjects will be asked to sign a separate 
pharmacogenetic ICF. A whole blood sample for pharmacogenetic testing will be obtained 
preferably at Visit 1 (once eligibility criteria have been confirmed) or alternatively at any 
other visit during the treatment period, regardless of the time of study drug intake. Samples 
can only be collected from subjects who have signed a separate pharmacogenetic ICF. From 
these blood samples, DNA will be isolated which will be used for the analysis SNP candidates 
such as CYP17.
9.7.2
Medical resource use
Information on medical resource use (e.g. hospitalization visits, physician visits etc.) that is 
associated with the management of AEs as well as non–protocol–driven subject monitoring 
will be collected by e–CRF that is completed by the physician at each visit.
9.7.3
Subject–reported outcomes
For this study, health–related QoL will be measured using the NCCN–FACT FPSI–17 
questionnaire.
The NCCN–FACT FPSI–17 is a validated instrument that was developed to assess symptoms 
of prostate cancer, symptoms of treatment of prostate cancer, and health related QoL of 
prostate cancer subjects. The instrument was developed in accordance with recent Food and 
Drug Administration guidance for development of instruments for ePRO. The instrument 
contains 17 items, each of which utilizes a Likert scale with 5 possible responses (30). The 
10 items reflect disease–related physical symptoms of disease and the responses on the items 
are to be summed to calculate a disease–related physical symptom subscale score. One item 
represents emotional symptoms of disease and the response to that item is used to calculate 
a disease–related emotional symptom subscale score. Four items represent treatment–related 
symptoms and the responses to these items are summed to calculate a treatment side effect 
subscale score. Finally, 2 items represent functional well–being and responses to those items 
are summed to calculate a functions / well–being subscale score. The NCCN–FACT FPSI–17 
will be self–administered by the subject via ePRO device. Some subjects may skip an item 


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altogether if they feel that it is not applicable to them. The questionnaire is to be completed at 
baseline either within 7 days before randomization or at Visit 1 (Day 1), at all treatment visits 
(at Visit 2 and subsequent visits), at the End of Treatment (EOT), and approximately every 
12 weeks during Active Follow–up.
Brief Pain Inventory – Short form is a validated instrument totaling 15 items to assess 
subject–reported levels of pain that has a precedent of being used in clinical trials with the 
goal of obtaining label claims based on the results captured with this instrument. A reduced 
set of 11 items is used in this trial. This reduced questionnaire is self–administered and
designed to evaluate the intensity of, and the impairment caused by, pain. All BPI–SF items 
are scored using rating scales. Four items measure pain intensity (pain now, average pain, 
worst pain, and least pain) using 0 (“no pain”) to 10 (“pain as bad as you can imagine”) 
numeric rating scales, and 7 items measure the level of interference with function caused by 
pain (general activity, mood, walking ability, normal work, relations with other people, sleep, 
and enjoyment of life) using 0 (no interference) to 10 (complete interference) rating scales.
The items are aggregated into 2 dimensions: (1) Pain severity index, using the mean of the 
4 items on the pain intensity, and (2) Function interference index, using the mean of the 
7 pain interference items. All 4 severity items must be completed for aggregating the pain 
severity index. The function interference index is scored as the mean of the item scores 
multiplied by 7, given that more than 50% or 4 of 7, of the items have been completed.
The questionnaire is to be completed via ePRO at Baseline (Screening or Visit 1), at treatment 
visits (at Visit 2 and subsequent visits), at EOT, and approximately every 12 weeks during 
Active Follow–up.
For each questionnaire, a subject–reported outcome (PRO) information sheet must be 
completed by the study nurse/Investigator at each visit at which the questionnaires are 
scheduled to be administered regardless of whether or not the questionnaires were completed, 
in order to document information on questionnaire assessment such as completion status, date 
of administration, and reasons for non–completed questionnaires, missing assessments, etc.
9.8
Appropriateness of procedures / measurements
All efficacy and safety parameters, as well as the methods to measure them, are standard
variables /methods in clinical studies and/or clinical practice. They are widely used and
generally recognized as reliable, accurate, and relevant.
The NCCN–FACT FPSI–17 is a validated instrument that was developed to assess symptoms 
of prostate cancer, symptoms of treatment of prostate cancer, and health related QoL of 
prostate cancer subjects (28).
Brief Pain Inventory – Short form is validated to assess subject–reported levels of pain that 
has a precedent of being used in clinical trials with the goal of obtaining label claims based on 
the results captured with this instrument.
The NCI–CTCAE v 4.03 is a list of AE terms harmonized with the Medical Dictionary for 
Regulatory Activities (MedDRA) Terminology at the AE term level and associated with a 
severity grading scale that is widely used within the oncology research community as the 


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standard for documentation and analysis of AEs occurring in cancer research. This tool is 
useful in defining the maximum tolerated dose of study drugs, in making recommendations 
concerning modification of dose and dose schedule of study drugs, and in comparing safety 
profiles of therapeutic interventions.
10.
Statistical methods and determination of sample size
10.1
General considerations
Statistical analysis will be performed using SAS; the version used will be specified in the 
SAP.
10.2
Analysis sets
Full analysis set (FAS): All randomized subjects. The FAS will be used in the analysis of all 
efficacy endpoints. Subjects will be included in FAS according to the treatment to which they 
are randomized.
Safety analysis set (SAF): All randomized subjects who have received at least 1 dose of 
study drug. This safety population will be used in the analyses of all safety endpoints. 
Subjects will be included in the analyses according to the treatment they actually received.
Pharmacokinetic Analysis Set (PKS): The first 20 subjects who were randomized and have 
received at least 1 cycle of docetaxel, and for whom mandatory dense PK sampling will be 
done, will be included in the Pharmacokinetic Analysis Set, as long as they have received at 
least 3 days of uninterrupted study drug treatment as well as one cycle of docetaxel and have 
at least one post dose PK measurement.
10.3
Variables and planned statistical analyses
The complete list of variables to be analyzed for this study will be provided in the SAP.
10.3.1
Primary efficacy variable
The primary efficacy variable is OS, defined as the time (in days) from date of randomization 
until death from any cause.
Analysis of OS
All randomized subjects (FAS) will be included in the primary analysis of OS, the primary 
efficacy endpoint. The analysis will be performed when approximately 509 deaths are 
observed. The primary analysis of OS will be a stratified log–rank test with the same 
stratification factors as used for randomization.
The null hypothesis that there is no difference in OS between treatment arms, which is 
equivalent to a hazard ratio (HR) of 1, will be tested against the alternative hypothesis that the 
HR of darolutamide over placebo is below 1.
The HR (darolutamide group/placebo) for OS and its 95% confidence interval will be 
calculated using the Cox model, stratified by the same factors as stated above. Kaplan–Meier 


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(KM) estimates for OS will be presented for each treatment group. The KM estimates at time 
points such as 3 months, 6 months, etc., together with corresponding 95% confidence 
intervals (CIs) and the differences of these estimates between the darolutamide group and the 
placebo group will be presented.
The overall one–sided type I error rate for the analysis of OS is 0.025. One formal interim 
analysis of OS for futility was planned. A DMC was overseeing the interim analysis. For 
further details on the interim analysis, see Section 10.5.
10.3.2
Secondary efficacy variables
The secondary efficacy variables include:

Time to castration–resistant prostate cancer, defined as the time to PSA 
progression (Section 10.3.4) with serum testosterone being at castrate level <0.50 
ng/mL, or the time to progression by soft tissue/visceral lesions (as described in 
Section 9.2.2.3) or time to progression by bone lesions (as described in 
Section 9.2.2.3), whatever comes first.

Time to initiation of subsequent antineoplastic therapy, defined as the time from 
randomization to initiation of first subsequent antineoplastic therapy for prostate 
cancer.

Symptomatic skeletal event free survival, defined as the time from randomization to 
the first occurrence of SSE or death from any cause, whichever comes first. An SSE is 
defined as EBRT to relieve skeletal symptoms, or new symptomatic pathologic bone 
fracture, or occurrence of spinal cord compression or tumor–related orthopedic 
surgical intervention, whichever comes first.

Time to first SSE, defined as the time from randomization to the first occurrence of 
SSE. An SSE is defined as EBRT to relieve skeletal symptoms, or new symptomatic 
pathologic bone fracture, or occurrence of spinal cord compression or tumor–related 
orthopedic surgical intervention, whichever comes first.

Time to initiation of opioid use for ≥7 consecutive days, defined as the time from 
date of randomization to the date of first opiate use for ≥7 consecutive days. Time to 
opiate use will be determined by opioid use captured via eCRF (recorded opioid, see 
schedule of assessments).

Time to pain progression is defined as the interval from randomization to the first
date a subject experiences a pain progression. Pain will be assessed with the BPI–SF 
questionnaire (Appendix 16.4) during the visit, prior to any procedures or examination 
by physician. Subjects who have not experienced pain progression at the time of 
analysis will be censored on the last date the subject was known to have not 
progressed. Subjects with no on study assessment or no baseline assessment will be 
censored at the date of randomization.


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For asymptomatic subjects (WPS 0 at baseline), pain progression is defined as an increase 
of 2 or more points in the “worst pain in 24 hours” (i.e. 2 or more point increase in WPS 
score) score from baseline observed at 2 consecutive evaluations ≥4 weeks apart
OR
initiation of short– or long–acting opioid use for pain.
For symptomatic subjects (WPS >0 at baseline), pain progression is defined as an increase 
of 2 or more points in the “worst pain in 24 hours” (i.e. 2 or more point increase in WPS 
score) score from baseline observed at 2 consecutive evaluations ≥4 weeks apart and a WPS 
of ≥4
OR
initiation of short– or long–acting opioid use for pain.

Time to worsening of physical symptoms of disease is defined as the interval from 
randomization to the first date a subject experiences an increase in physical symptoms 
based on the NCCN–FACT–FPSI–17 questionnaire. Symptoms and QoL will be 
assessed with the NCCN–FACT–FPSI–17 questionnaire (Appendix 16.3) during the 
visit, prior to any procedures or examination by physician. An increase in physical 
symptoms of disease is defined as 3–point decrease (a lower score = higher symptom 
burden) from baseline in the physical symptoms of disease subscale (FPSI–DRS–P 
subscale of the NCCN–FACT–FPSI–17 questionnaire) observed at 2 consecutive 
evaluations ≥4 weeks apart.
Secondary efficacy variables analysis
The secondary efficacy variables will be analyzed for the FAS population unless otherwise 
specified in the SAP. Time–to–event endpoints will be analyzed using stratified log–rank test 
with randomization stratification factors. Hazard ratio and 95% CI will be provided using the 
Cox model stratified by the same factors as stated above. Detailed analysis methods and the 
plan for type 1 error control for secondary endpoints, including ranking of secondary 
endpoints, will be specified in the SAP.
10.3.3
Safety variables
The safety variables include:

AEs until the end–of–study treatment visit

SAEs until the end–of–study treatment visit

Study drug–related SAEs until the end of Long–term Follow–up

Vital signs: BP and heart rate (HR)

12–lead electrocardiogram (ECG)

Physical examination

Laboratory safety assessments (hematology, clinical chemistry, urinalysis)


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Safety analysis
AEs will be coded using MedDRA. Descriptive summary tables will be presented on all 
safety parameters by treatment group. The safety assessment period is from the first dose of 
study drug until 30 days (+7 days) after the last treatment with darolutamide/placebo. Subjects 
will be monitored for AEs using the NCI–CTCAE v 4.03.
The AEs and safety laboratory parameters will be presented with their worst NCI–CTCAE 
v 4.03 grade (Section 16.2).
10.3.4
Other exploratory variables

Rate of absolute PSA response at 6 and 12 months
Absolute PSA response is defined as blood PSA level <0.2 ng/mL, confirmed by a 
second subsequent PSA value <0.2 ng/mL 3 or more weeks later. Rate of absolute 
PSA response is defined as the number of subjects with absolute PSA response, 
divided by the total number of subjects evaluable for absolute PSA response. Rate of 
absolute PSA response will be evaluated on subject data up to 6 months and 
12 months after randomization.

Rate of relative PSA response at 3, 6 and 12 months
Relative PSA response is defined as a ≥30% reduction of the blood PSA level 
compared to the screening value, confirmed by a second subsequent PSA value with a 
≥30% reduction from Screening 3 or more weeks later. Rate of relative PSA response 
is defined as the number of subjects with relative PSA response, divided by the total 
number of subjects evaluable for relative PSA response. Rate of relative PSA 
response will be evaluated on subject data up to 3 months, 6 months, and 12 months 
after randomization.

Time to PSA progression
Prostate–specific antigen progression is defined as a ≥25% increase above the nadir 
(lowest Screening or baseline) value, which is confirmed by a second value 3 or more 
weeks later, and an increase in absolute value of ≥2 ng/mL above nadir, at least 
12 weeks from baseline.
The time to PSA progression is defined as the time (in days) from the date of 
randomization to the date of first PSA progression. Subjects without PSA progression 
as of database cut–off, whether or not surviving, will be censored at the last total PSA 
lab assessment date.

Changes in symptom burden and QoL based on the NCCN–FACT FPSI–17 
questionnaire (see Section 10.3.8)

Medical resource use (see Section 9.7.2)

Pharmacokinetics (see Section 9.5.2)

Biomarker evaluations (see Section 9.7.1)


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The details of the analysis for the exploratory variables to be analyzed for this study will be 
provided in the SAP.
Missing data / drop outs
Every effort should be made to retain subjects who discontinue the treatment period for any 
reason. These subjects are to be encouraged to remain on the study for follow–up of primary, 
secondary, and exploratory endpoints.
The method used for imputation of missing data will be described in the SAP (see 
Section 11.4).
10.3.5
Pharmacokinetics
Pharmacokinetics in the first 20 subjects who were randomized and have received at 
least 1 cycle of docetaxel
The concentration–time courses of all substances will be tabulated separated by treatment. 
The following statistics will be calculated for each of the sampling points: arithmetic mean, 
standard deviation (SD), and coefficient of variation (CV); geometric mean, geometric SD 
(re–transformed SD of the logarithms), and CV; minimum, median, maximum value, and the 
number of measurements.
Means at any time will only be calculated if at least 2/3 of the individual data were measured 
and were above the lower limit of quantification (LLOQ). For the calculation of the mean 
value, a data point below LLOQ will be substituted by one–half of this limit. In tables 
showing mean values, where values below LLOQ are included in the calculation of mean 
values, these means will be marked.
Individual and geometric mean concentration versus time curves of all substances (using the 
actual sampling times for individual plots and the planned sampling times for mean plots) will
be plotted by treatment using both a linear and semilogarithmic scale.
Pharmacokinetic characteristics (tmax, tlast excluded) will be summarized by the statistics 
mentioned above. The tmax, tlast will be described utilizing minimum, maximum, and median as
well as frequency counts.
Pharmacokinetics in all subjects
Individual concentration–time data of darolutamide, (S,S)-darolutamide, (S,R)-darolutamide,
and keto-darolutamide will be provided in a clinical study report appendix. All other 
parameters will be described in detail in a separate M&S report.
10.3.6
Biomarker analyses
Results from exploratory biomarker studies will be reported in a separate biomarker report.


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10.3.7
Medical Resource use
Medical resource use is described in Section 9.7.2.
10.3.8
Subject–reported outcomes
Subject–reported outcome procedures are described in Section 9.7.3.
10.3.9
Baseline and demographic characteristics
Baseline and demographic characteristics will be summarized by descriptive statistics by 
treatment group darolutamide for the FAS population.
In addition, exploratory exposure–response analyses of efficacy, PD, or safety parameters, 
e.g. OS, PSA response rate, etc., are planned.
10.4
Determination of sample size
The sample size of the study is based on the primary endpoint of OS. The study is designed to 
have 90% power to detect a 33% increase in median time of OS with darolutamide compared 
to placebo (from 60 to 80 months, corresponding to a HR of 0.75) with a 1–sided alpha of 
0.025. The OS data will be considered as mature when approximately 509 deaths are 
observed.
With the additional assumptions that subjects will enroll at a rate of 50 subjects per month, 
exponential distributions of the OS event times, median time of OS in the control group of 
60 months, 5% dropout rate of subjects, and a 6–months enrollment ramp–up period, it 
follows that approximately 1,300 subjects must be enrolled to observe 509 deaths after 
approximately 70 months.
10.5
Planned interim analyses
One formal interim analysis of OS was planned. This interim analysis for futility was to be 
performed after approximately 153 deaths were observed. The DMC (see Section 13.1.1) was 
overseeing the interim analysis. Detailed analysis methods and stopping rules will be 
specified in the SAP and the DMC charter.
For the futility interim and final analyses together, a one–sided overall beta of 0.1 will be 
used. Stopping boundaries will be calculated with an O’Brien–Fleming beta–spending 
function based on the actual number of events observed up to the cut–off date. The interim 
futility analysis was planned to be performed when approximately 153 deaths were observed 
(information fraction=0.3). 
A DMC (see Section 13.1.1) will be instituted for independent review of ongoing data from 
this study in accordance with a separate DMC charter. The DMC will operate independently 
of the Sponsor and Investigators.
The DMC will review safety data as per a separate DMC charter.


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11.
Data handling and quality assurance
11.1
Data recording
The data collection tool for this study will be an eCRF; a validated electronic data capture 
system called RAVE. Subject data necessary for analysis and reporting will be 
entered/transmitted into a validated database or data system (CIE/TOSCA; SAS).
Data required according to this protocol will be recorded by investigational site personnel via 
data entry into the internet based electronic data capture (EDC) software system RAVE, 
which Bayer has licensed from Medidata Solutions Worldwide. RAVE has been validated by 
Medidata Solutions Worldwide and Bayer for use in its clinical studies. RAVE allows for the 
application of software logic to set up data entry screens and data checks to ensure the 
completeness and accuracy of the data entered by the site personnel. Bayer extensively 
applies the logic to ensure data are complete and reflect the clinical data requirements of the 
study. Data queries resulting from the application of the software logic are resolved by the site 
personnel. The data are stored at a secure host facility maintained by Medidata Solutions 
Worldwide and transferred on a periodic basis to Bayer's internal computer system via a 
secure Virtual Private Network.
All access to the RAVE system is through a password–protected security system that is part 
of the RAVE software. All internal Bayer and external Investigator site personnel seeking 
access must go through a thorough RAVE training process before they are granted access to 
RAVE for use in Bayer's clinical studies. Training records are maintained.
All personnel with access to the RAVE system are supported by a Service Desk staffed with 
trained personnel to answer questions and ensure access is maintained such that data entry can 
proceed in a timely manner.
The RAVE system contains a system–generated audit trail that captures any changes made to 
a data field, including who made the change, why the change was made and the date and time 
it was made. This information is available both at the Investigator’s site and at Bayer. Data 
entries made in the RAVE EDC screens are supported by source documents maintained for all 
subjects enrolled in this study.
Source documentation
It is the expectation of the Sponsor that key data entered into the CRF has source 
documentation available at the site. Study–specific data not needed for the subject’s routine 
medical care (QoL–related data: NCCN–FACT FPSI–17 and BPI–SF questionnaires) may be 
entered directly into the validated database or data system, without availability of 
corresponding source documentation.
The site must implement processes to ensure availability of all required source 
documentation. A source document checklist will be used at the site to identify the source 
data for key data points collected and the monitor will work with the site to complete this.


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Data recorded from screening failures
Data of 'only screened subjects' will be recorded at least as source data, as far as the reason for 
the premature discontinuation is identifiable. At a minimum, the following data should be 
recorded in the eCRF:

Demographic information (subject number; year of birth / age; sex; if applicable,
race/ethnicity)

Relevant Inclusion and/or Exclusion criteria

Date of IC

Reason for premature discontinuation

Date of last visit.
These data will be transferred to the respective database.
For screening failures with an SAE, the following data should be collected in the CRF in 
addition to the data specified above:

All information related to the SAE such as:
o
Concomitant medication
o
Medical history
o
Other information needed for SAE complementary page
11.2
Monitoring
In accordance with applicable regulations, GCP, and Sponsor’s/CRO’s procedures, monitors 
will contact the site prior to the start of the study to review with the site staff the protocol, 
study requirements, and their responsibilities to satisfy regulatory, ethical, and Sponsor’s 
requirements. When reviewing data collection procedures, the discussion will also include 
identification and documentation of source data items.
The Sponsor/designee will monitor the site activity to verify that the:

Data are authentic, accurate, and complete. 
Supporting data may be requested (example: blood glucose readings to support a 
diagnosis of diabetes).

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol 
(including study treatment being used in accordance with the protocol).

Any other study agreements, GCP, and all applicable regulatory requirements are met.
The Investigator and the head of the medical institution (where applicable) agrees to allow the 
monitor direct access to all relevant documents.


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11.3
Data processing
Data will be collected as described in Section 11.1. Clinical data management will be 
performed in accordance with applicable Sponsor’s/CRO’s standards and data cleaning 
procedures. This is applicable for data recorded on CRF as well as for data from other sources 
(e.g. IXRS, laboratory, ECG, ePRO, adjudication committees).
For data coding (e.g. AEs, medication), internationally recognized and accepted dictionaries 
will be used.
After its initial release for biometrical analysis, the clinical database is planned to be re–
opened for the inclusion of the following additional data: PK data, antibody data.
11.4
Missing data
The analysis of the primary endpoint is based on the intent to treat population. Subjects who 
discontinue the treatment prematurely or leave the study prematurely will not be replaced.
Handling of missing data, which in this context are events not observed for the time–to–event 
endpoints (primary variable and secondary variables), is implicitly handled in the statistical 
methods applied (log–rank test, Cox model) by censoring these subjects. Further aspects of 
handling of missing data will be discussed in the SAP.
11.5
Audit and inspection
To ensure compliance with GCP and regulatory requirements, a member of the Sponsor’s (or 
a designated CRO’s) quality assurance unit may arrange to conduct an audit to assess the 
performance of the study at the study site and of the study documents originating there. The 
Investigator/institution will be informed of the audit outcome.
In addition, inspections by regulatory health authority representatives and IEC(s)/IRB(s) are 
possible. The Investigator should notify the Sponsor immediately of any such inspection.
The Investigator/institution agrees to allow the auditor or inspector direct access to all 
relevant documents and allocate his/her time and the time of his/her staff to the 
auditor/inspector to discuss findings and any issues. Audits and inspections may occur at any 
time during or after completion of the study.
11.6
Archiving
Essential documents shall be archived safely and securely in such a way that ensures that they 
are readily available upon authorities’ request.
Subject (hospital) files will be archived according to local regulations and in accordance with 
the maximum period of time permitted by the hospital, institution, or private practice. Where 
the archiving procedures do not meet the minimum timelines required by the Sponsor, 
alternative arrangements must be made to ensure the availability of the source documents for 
the required period.
The Investigator/institution notifies the Sponsor if the archival arrangements change (e.g. 
relocation or transfer of ownership).


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The Investigator site file is not to be destroyed without the Sponsor’s approval.
The contract with the Investigator/institution will contain all regulations relevant for the study 
center.
12.
Premature termination of the study
The Sponsor has the right to close this study (or, if applicable, individual segments thereof 
[e.g. treatment arms; dose steps; centers]) at any time, which may be due, but not limited to,
the following reasons:

If risk–benefit ratio becomes unacceptable owing to, for example,
o
Safety findings from this study (e.g. SAEs)
o
Results of any interim analysis
o
Results of parallel clinical studies
o
Results of parallel animal studies 
(e.g. toxicity, teratogenicity, carcinogenicity, or reproduction toxicity).

If the study conduct (e.g. recruitment rate; dropout rate; data quality; protocol 
compliance) does not suggest a proper completion of the trial within a reasonable time 
frame.
The Investigator has the right to close his/her center at any time.
For any of the above closures, the following applies:

Closures should occur only after consultation between involved parties. Final decision 
on the closure must be in writing.

All affected institutions (e.g. IEC[s]/IRB[s]; competent authority[ies]; study center; 
head of study center) must be informed as applicable according to local law.

All study materials (except documentation that has to remain stored at site) must be 
returned to the Sponsor. The Investigator will retain all other documents until 
notification is given by the Sponsor for destruction.

In the event of a partial study closure, ongoing subjects, including those in post–study 
follow–up, must be taken care of in an ethical manner.
Details for an individual subject's withdrawal can be found in Section 6.4.1.


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13.
Ethical and legal aspects
13.1
Investigator(s) and other study personnel
Sponsor’s medical expert 
Name: 
Address: 
Muellerstrasse 178
13353 Berlin, Germany
Telephone no.: 
Co–ordinating investigators 
Name: 
Address: 
United States
Name: 
Address: 
 Belgium
All other study personnel not included in this section are identified in a separate personnel list 
(not part of this clinical study protocol) as appropriate. This list will be updated as needed; an 
abbreviated version with personnel relevant for the centers will be available in each center’s 
Investigator site file.
Whenever the term ‘Investigator’ is noted in the protocol text, it may refer to either the PI at 
the site, or an appropriately qualified, trained and delegated individual of the investigational 
site.
The PI of each center must sign the protocol signature page and must receive all required 
external approvals (e.g. health authority, ethics committee, Sponsor) before subject
recruitment may start at the respective center. Likewise, all amendments to the protocol must 
be signed by the PI and must have received all required external approvals before coming into 
effect at the respective center.
A complete list of all participating centers and their investigators, as well as all required 
signature documents, will be maintained in the Sponsor’s study file.
The global Sponsor of this study is identified on the title page of this protocol. If required by 
local law, local co–sponsors will be nominated; they will be identified on the respective 
country–specific signature pages.
PPD
PPD
PPD
PPD
PPD
PPD


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13.1.1
Independent data monitoring committee
A DMC will be instituted to ensure ongoing safety of study subjects with respect to a 
risk/benefit assessment during periodic data review meetings, review results from the planned 
interim analysis and provide a formal recommendation for continuation/termination of the 
study and monitor study conduct to ensure the overall integrity of trial is maintained. 
Recommendation for trial continuation will be guided by safety evaluations at all safety data 
reviews. The committee will include at least 3 independent oncologists and one independent 
statistician. Data review meetings will be held periodically as per separate DMC charter. 
Enrollment in the study will continue throughout the scheduled meetings of the DMC. 
Decisions on trial termination, protocol amendment, on hold of subject recruitment, or 
cessation of subject recruitment based on risk/benefit assessments will be made after 
recommendations from the DMC have been assessed by the Sponsor. Safety review meetings 
will be held in accordance with the DMC charter. Decisions on study termination or cessation 
of subject recruitment based on safety or OS outcomes will be made after recommendations 
from the DMC have been assessed by Bayer AG.
The DMC will also review the safety assessment, including PK, which will be performed after 
the first 20 subjects were randomized and have received at least 1 cycle of docetaxel. Blinding 
of Investigators, subjects and the Sponsor will be maintained during this assessment based on 
the preclinical mechanisms and known safety profiles for the darolutamide and docetaxel (see 
Section 3.3), the toxicities from the combination are expected to be manageable. Therefore, 
enrollment will continue during this 20–subject safety review unless unexpected or excessive 
toxicities related to darolutamide in addition to docetaxel plus ADT compared to the treatment 
of docetaxel plus ADT alone are reported, in which case subject enrollment will be placed on 
hold until completion of the DMC safety review. Further safety reviews to ensure subjects’ 
safety may be implemented for different subject populations following the first 20 subjects
who were randomized and have received at least one cycle of docetaxel, due to lack of 
experience in treatment of darolutamide in addition to docetaxel plus ADT. The details of the 
evaluations will be described in the DMC charter. 
13.2
Funding and financial disclosure
Funding
This study will be funded by its Sponsor.
Financial disclosure
Each Investigator (including principal and/or any sub–investigators) who is directly involved 
in the treatment or evaluation of research subjects has to provide a financial disclosure 
according to all applicable legal requirements. All relevant documentation will be filed in the 
trial master file.


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13.3
Ethical and legal conduct of the study
The procedures set out in this protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the Sponsor and Investigator abide by 
GCP guidelines and the guiding principles detailed in the Declaration of Helsinki. The study 
will also be carried out in keeping with applicable local law(s) and regulation(s).
Documented approval from appropriate IEC(s)/IRBs will be obtained for all participating 
centers/countries before start of the study, according to GCP, local laws, regulations, and 
organizations. When necessary, an extension, amendment or renewal of the IEC/IRB approval 
must be obtained and also forwarded to the Sponsor. The responsible unit (e.g. IEC/IRB, head 
of the study center/medical institution) must supply to the Sponsor, upon request, a list of the 
IEC/IRB members involved in the vote and a statement to confirm that the IEC/IRB is 
organized and operates according to GCP and applicable laws and regulations.
Strict adherence to all specifications laid down in this protocol is required for all aspects of 
study conduct; the Investigator may not modify or alter the procedures described in this 
protocol.
Modifications to the study protocol will not be implemented by either the Sponsor or the 
Investigator without agreement by both parties. However, the Investigator or the Sponsor may 
implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) 
to the trial subjects without prior IEC/IRB/Sponsor approval/favorable opinion. As soon as 
possible, the implemented deviation or change, the reasons for it and if appropriate the 
proposed protocol amendment should be submitted to the IEC/IRB/head of medical 
institution/Sponsor. Any deviations from the protocol must be explained and documented by 
the Investigator.
Details on discontinuation of the entire study or parts thereof can be found in Section 12.
13.4
Subject information and consent
All relevant information on the study will be summarized in an integrated subject information 
sheet and ICF provided by the Sponsor or the study center. A sample subject information and 
ICF is provided as a document separate to this protocol.
Based on this subject information sheet, the Investigator or designee will explain all relevant 
aspects of the study to each subject/legal representative or proxy consenter (if the subject is 
under legal protection) prior to his/her entry into the study (i.e. before any examinations and 
procedures associated with the selection for the study are performed or any study–specific 
data is recorded on study–specific forms).
The Investigator will also mention that written approval of the IRB/IEC has been obtained.
Each subject/legal representative or proxy consenter will be informed about the following 
aspects of premature withdrawal:

Each subject has the right to withdraw from the study at any time without any 
disadvantage and without having to provide reasons for this decision.


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
The subject’s consent covers end–of–study examinations as specified in the visit 
description described in Section 9.2 to be conducted after withdrawal of consent.

The subject’s data that have been collected until the time of withdrawal will be 
retained and statistically analyzed in accordance with the SAP.

Subject–specific data on the basis of material obtained before withdrawal may be 
generated after withdrawal (e.g. image reading, analysis of biological specimen such 
as blood, urine or tissues); these data would also be retained and statistically analyzed 
in accordance with the SAP. The subject has the right to object to the generation and 
processing of this post–withdrawal data. For this, he/she needs to sign a corresponding 
declaration of objection; alternatively, the subject’s oral objection may be documented 
in the subject’s source data.
If at any time during the study the subject would like to withdraw consent, the Investigator 
must discuss with the subject the active and Long–term Follow–up period parts of the study. 
Withdrawal of consent should be documented in the subject’s medical file.
Each subject/legal representative or proxy consenter will have ample time and opportunity to 
ask questions.
Only if the subject/legal representative or proxy consenter voluntarily agrees to sign the ICF
and has done so, may he/she enter the study. Additionally, the Investigator will personally 
sign and date the form. The subject/legal representative or proxy consenter will receive a copy 
of the signed and dated form.
The signed IC statement is to remain in the Investigator site file or, if locally required, in the 
subject’s note/file of the medical institution.
In the event that IC is obtained on the date that baseline study procedures are performed, the 
study record or subject´s clinical record must clearly show that IC was obtained prior to these 
procedures.
If the subject is not capable of providing a signature, a verbal statement of consent can also be 
given in the presence of an impartial witness (independent of the Sponsor and the 
Investigator). This is to be documented by a signature from the informing physician as well as 
by a signature from the witness.
The ICF and any other written information provided to subjects/legal representatives or proxy 
consenters will be revised whenever important new information becomes available that may 
be relevant to the subject’s consent, or there is an amendment to the protocol that necessitates 
a change to the content of the subject information and/or the written ICF. The Investigator 
will inform the subject/legal representative or proxy consenter of changes in a timely manner 
and will ask the subject to confirm his/her participation in the study by signing the revised 
ICF. Any revised written ICF and written information must receive the IEC/IRB`s 
approval/favorable opinion in advance of use.
13.5
Publication policy and use of data
The Sponsor has made the information regarding the study protocol publicly available on the 
internet at www.clinicaltrials.gov.


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All data and results and all intellectual property rights in the data and results derived from the 
study will be the property of the Sponsor who may utilize them in various ways, such as for 
submission to government regulatory authorities or disclosure to other investigators.
Regarding public disclosure of study results, the Sponsor will fulfill its obligations according 
to all applicable laws and regulations. The Sponsor is interested in the publication of the 
results of every study it performs.
The Sponsor recognizes the right of the Investigator to publish the results upon completion of 
the study. However, the Investigator, while free to utilize study data derived from his/her 
center for scientific purposes, must obtain written consent of the Sponsor on the intended 
publication manuscript before its submission. To this end, the Investigator must send a draft 
of the publication manuscript to the Sponsor within a time period specified in the contract. 
The Sponsor will review the manuscript promptly and will discuss its content with the 
Investigator to reach a mutually agreeable final manuscript.
13.6
Compensation for health damage of subjects / insurance
The Sponsor maintains clinical trial insurance coverage for this study in accordance with the 
laws and regulations of the country in which the study is performed.
13.7
Confidentiality
All 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.
Subject names will not be supplied to the Sponsor. Only the subject number will be recorded 
in the CRF, and if the subject name appears on any other document (e.g. pathologist report), it 
must be obliterated before a copy of the document is supplied to the Sponsor. Study findings 
stored on a computer will be stored in accordance with local data protection laws. As part of 
the IC process, the subjects will be informed in writing that representatives of the Sponsor, 
IEC/IRB, or regulatory authorities may inspect their medical records to verify the information 
collected, and that all personal information made available for inspection will be handled in 
strictest confidence and in accordance with local data protection laws.
If the results of the study are published, the subject’s identity will remain confidential.
The Investigator will maintain a list to enable subjects to be identified.


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14.
Reference list
1. Ferlay J, Steliarova–Foucher E, Lortet–Tieulent J, Rosso S, Coebergh JW, Comber H, et 
al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. 
Eur J Cancer. 2013;49(6):1374–403.
2. Ferlay J, Parkin DM, Steliarova–Foucher E. Estimates of cancer incidence and mortality 
in Europe in 2008. Eur J Cancer. 2010;46(4):765–81.
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nation on the status of cancer, 1975–2005, featuring trends in lung cancer, tobacco use, 
and tobacco control. J Natl Cancer Inst. 2008;100(23):1672–94.
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blockade for subjects with advanced prostate carcinoma. Cancer. 2002;95(2):361–76.
15. Vis AN, Schroder FH. Key targets of hormonal treatment of prostate cancer. Part1: the 
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in metastatic prostate cancer without previous chemotherapy. N Engl J Med.
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with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187–
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immunotherapy for castration–resistant prostate cancer. N Engl J Med. 2010;363:411–22.
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STAMPEDE Trial (MRC PR08, CRUK/06/019). European Urology. 2015;67(6):1028–
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30. Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, et al. Design and end points 
of clinical trials for subjects with progressive prostate cancer and castrate levels of 
testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J 
Clin Oncol. 2008;26:1148–59.
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response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). 
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32. Scher HI, Morris MJ, Stadler WM, Higano C, Basch E, Fizazi K, et al. Trial Design and 
Objectives for Castration–Resistant Prostate Cancer: Updated Recommendations From the 
Prostate Cancer Clinical Trials Working Group 3. J Clin Oncol. 2016;34(12):1402–18.
33. Parker C, Gillessen S, Heidenreich A, Horwich A, on behalf of the ESMO Guidelines 
Committee. Annals of Oncology 26 (Supplement 5): v69–v77, 2015.
34. Lolli C, De Lisi D, Conteduca V, Gurioli G, Scarpi E, Schepisi G, et al. Testosterone 
levels and androgen receptor copy number variations in castration-resistant prostate 
cancer treated with abiraterone or enzalutamide. Prostate. 2019;79(11):1211–1220.
15.
Protocol amendments
15.1
Amendment 2
Amendment 2 is a global amendment dated 04 OCT 2016.
15.1.1
Overview of changes to the study
15.1.1.1
Modification 1: New drug–drug interaction data available 
It was clarified that interaction between ODM–201 and P–gp or BCRP are expected in vivo
based on in vitro data and preliminary clinical study results. Text in the protocol was revised, 
to mention the preliminary results of a drug–drug interaction clinical study, and to provide the 
Investigators with suggestions how to manage relevant concomitant medications.
Rationale: based on newly available information from a drug–drug interaction clinical study
and following IB revision, the protocol text has been revised and aligned.
Sections affected by this modification: 3.2.2 Nonclinical pharmacokinetics and metabolism, 
3.2.4 Drug–drug interactions, 3.2.5 Clinical studies with ODM–201, 8.1.2 Permissible 
concomitant medications and treatments.
15.1.1.2
Modification 2: Clarification of PK analysis
Wording defining the patient population for the detailed PK analysis was revised and clarified 
throughout the protocol. Wording about docetaxel analysis for the sparse PK sampling in all 
randomized subjects was also revised and clarified throughout the protocol.
Rationale: Modification was done to clarify that the patients participating to the detailed PK 
analysis must have received at least one cycle of docetaxel, and to clarify the timing of the 
sparse PK sampling as well as the additional analysis of docetaxel in all the randomized 
subjects.
Sections affected by this modification: 3.2.4 Drug–drug interactions, 3.3 Rationale of the 
study, 5 Study design, 7.1 Treatments to be administered, 7.5 Blinding, 9.1 Tabular schedule 
of evaluations, 9.2.2.1 Day 1 (Visit 1), 9.5.1 Drug measurements, 9.5.2 Pharmacokinetic 
evaluation, 10.2 Analysis sets, 10.3.5 Pharmacokinetics, 13.1.1 Independent data monitoring 
committee.


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15.1.1.3
Modification 3: Addition of non–protein–bound (free) testosterone 
analysis
Wording throughout the protocol was revised to add the non–protein–bound (free) 
testosterone analysis in a subset of 300 subjects. 
Rationale: Low testosterone levels are expected in subjects during ADT treatment, therefore 
the sex hormone–binding globulin and albumin concentrations will be determined to calculate 
the non–protein–bound (free) testosterone in a subset of approximately 300 patients. 
Non-protein–bound (free) testosterone analysis results will be compared to the results from 
the calculation. In case non–protein–bound (free) testosterone is not measurable in all the 
subjects of that subset of approximately 300 patients, the calculation will be used.
Sections affected by this modification: 9.1 Tabular schedule of evaluations, 9.2.1 Screening 
period, 9.2.2.2 Visit 2 and subsequent visits (every 12 weeks ± 7 days), 9.2.3 Active 
Follow-up period, 9.6.3.1 Laboratory safety assessments 
15.1.1.4
Modification 4: Administrative changes
Sponsor’s study medical expert was updated due to a change in sponsor’s personnel. The 
contact information was also added to Section 13.1 as per template. The contact details of 
Co-ordinating investigators were also added.
Sections affected by this modification: Title page, 13.1 Investigator(s) and other study 
personnel.
15.1.1.5
Modification 5: Other clarifications and corrections

Scheme of study periods was updated: “treatment with study drug” was changed to 
“treatment period” to clarify that also docetaxel is given during treatment period.

Subheading “Further safety” was added as per template, content was not changed.
Sections affected by this modification: 5 Study design, 9.6.3 Further safety
15.1.2
Changes to the protocol text
Changes to the protocol text done in Amendment 2 are provided in Section 15.1.2 of 
Amendment 2.
15.2
Amendment 5
Amendment 5 is a global amendment dated 12 FEB 2018.
15.2.1
Overview of changes to the study
15.2.1.1
Modification 1: New drug-drug interaction data available
Text was modified to include the results of drug–drug interaction clinical study, and to 
provide the Investigators with guidance how to manage relevant concomitant medications: 
Concomitant treatment with strong and moderate CYP3A4 inducers should be avoided. The
list of strong and moderate CYP3A4 inducers was also included as an appendix.


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Rationale: Based on clinical study results (Study 17726), strong CYP3A4 and P-gp inhibitors 
and strong CYP3A4 inducers affect the PK of darolutamide. Results indicate 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. Results also indicate that 
repeated co-administration of strong or moderate CYP3A4 inducers with darolutamide is 
expected to reduce darolutamide plasma concentrations. Therefore, concomitant intake of 
strong or moderate CYP3A4 inducers should be avoided.
Sections affected by this modification: List of abbreviations, 3.2.4 Drug-drug interactions, 
8.1.2 Permissible concomitant medications and treatments, 16.5 List of strong and moderate 
CYP3A4 inducers (new appendix added)
15.2.1.2
Modification 2: Modification of the dosing language
The wording for the study drug dose to be administered was modified and harmonized 
throughout the protocol: 600 mg (2 tablets of 300 mg) twice daily with food, equivalent to a 
total daily dose of 1200 mg.
A guidance text in the event of a missed dose was added: if a dose of study drug is delayed, 
dose can be taken up to 6 hours to make up for the missed one.
Rationale: The change was done to align darolutamide dosing wording across the 
development program. In addition, instructions for handling a missed dose were missing from 
the protocol.
Sections affected by this modification: 2 Synopsis, 5 Study design, 7.1 Treatments to be 
administered, 7.4.1 Dose modifications of study drug
15.2.1.3
Modification 3: Clarification of docetaxel dosage and administration
The possibility to administer docetaxel as per local practice (if different from the regimen 
described in the summary of product characteristics) was removed from the protocol, and also 
the guidance to refer to the local prescribing information was deleted. Docetaxel should be 
administered at 75 mg/m2 as 1 hour IV infusion every 3 weeks for 6 cycles. Infusions longer 
than 1 hour are acceptable for medical reasons at Investigator’s discretion. It was also 
clarified that the first cycle of docetaxel should be administered within 6 weeks after start of 
study drug instead of 6 weeks after randomization. Rationale for pre–medication instructions 
was also clarified.
Rationale: The change was done to clarify that pre–medication, docetaxel dose and infusion 
schedule must be in accordance with the label and that docetaxel can only be administered 
after the patient has started study drug. 
Sections affected by this modification: 7.1 Treatments to be administered, 7.4.2 Dosage and 
administration for background treatment, 7.4.3 Dose modifications of docetaxel background 
treatment 9.1 Tabular schedule of evaluations, 9.2.2.1 Day 1 (Visit 1)


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15.2.1.4
Modification 4: Guidance on laboratory tests before each docetaxel 
cycle
The list of laboratory assessments that should be performed before each docetaxel cycle was 
added to the protocol. It was also clarified that docetaxel can only be infused after routine
hematology and biochemistry laboratory tests have been obtained and that the results must be 
reported in the unscheduled hematology and biochemistry eCRF.
Rationale: The modification was done to give further guidance on laboratory safety 
assessments and to be in line with docetaxel label requirements.
Sections affected by this modification: 7.4.3 Dose modifications of docetaxel background 
treatment, 9.1 Tabular schedule of evaluations, 9.2.2.1 Day 1 (Visit 1), 9.2.5 Unscheduled 
visits, 9.6.3.1 Laboratory safety assessments
15.2.1.5
Modification 5: Clarification related to soft tissue/visceral lesions
It was clarified that the evaluation of soft tissue and visceral lesions is done with the same 
radiological methods and assessed by RECIST criteria.
Rationale: The change was done for clarity and for consistency throughout the protocol.
Sections affected by this modification: 9.2.2.3 Requirement for chest, abdomen and pelvic 
CT/MRI and bone scan during the study treatment period, 10.3.2 Secondary efficacy variables 
15.2.1.6
Modification 6: Time windows for randomization and Visit 1
Protocol was modified to state that randomization must occur within 28 days from ICF 
signature and that the patient will be randomized at the end of the screening period. In 
addition, the time window for Day 1 (Visit 1) procedures was adjusted to clarify that 
procedures scheduled for Visit 1 can occur +3 days after randomization instead of ±3 days.
The modification was done for clarification.
Sections affected by this modification: 9.1 Tabular schedule of evaluations, 9.2 Visit 
description, 9.2.1 Screening period, 9.2.2.1 Day 1 (Visit 1), 9.5.1 Drug measurements 
15.2.1.7
Modification 7: Switch of ADT to LHRH agonist prohibited
ADT switch to LHRH agonist was added to the list of prohibited concomitant medications 
and treatments. It was also clarified that ADT switch to an antagonist is allowed during study 
treatment.
Rationale: Switch of ADT to LHRH agonist may cause flare reactions, impacting subject's 
safety and radiological assessments, therefore it is prohibited. Opposite a switch to an LHRH 
antagonist is permitted.


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Sections affected by this modification: 8.1.2 Permissible concomitant medications and 
treatments, 8.1.3 Prohibited concomitant medications and treatments
15.2.1.8
Modification 8: Collection of whole blood sample for pharmacogenetics 
test allowed at other visits if missed at Visit 1
A whole blood sample for pharmacogenetic testing will be collected preferably at Visit 1 from 
subjects who have signed pharmacogenetic consent. However, the protocol was modified to 
allow the collection at any other visit during the treatment period if missed at Visit 1
Rationale: To ensure completeness of sample collection for pharmacogenetics, more 
flexibility was added to the timing of collecting the respective blood samples. 
Sections affected by this modification: 9.1 Tabular schedule of evaluations, 9.2.2.2 Visit 2 
and subsequent visits (every 12 weeks ± 7 days), 9.7.1.4 Genetic biomarker analysis from 
whole blood
15.2.1.9
Modification 9: Unblinding in non-emergency situations not permitted
It was clarified that progressive disease does not routinely constitute an emergency situation, 
therefore unblinding the label only for subsequent treatment decision is not allowed.
Rationale: The modification was done to clarify that unblinding in non-emergency situations 
is not permitted.
Sections affected by this modification: 7.5 Blinding
15.2.1.10 Modification 10: Clarification of PK sampling
It was clarified that two additional blood samples for sparse PK analysis can be taken from 
docetaxel cycle 1 onwards from patients who do not belong to the dense PK subset.
Rationale: To provide clear instructions to the sites regarding collection of blood samples for 
sparse PK analysis.
Sections affected by this modification: 9.1 Tabular schedule of evaluations, 9.5.1 Drug 
measurements
15.2.1.11 Modification 11: Clarification of laboratory safety assessments
It was clarified in the protocol text that PSA at screening can be taken within 28 days before 
randomization. 
Rationale: To provide clear instructions about timing of the safety laboratory assessments in 
the screening period.
Section affected by this modification: 9.6.3.1 Laboratory safety assessments


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15.2.1.12 Modification 12: 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 as shown in the table under “definitions of terms”.
Sections affected by this modification: Definition of terms (new section added), the entire 
document (amended sections are not indicated in the protocol body)
15.2.1.13 Modification 13: Personnel change
The sponsor’s medically responsible person was changed as a result of personnel change.
Section affected by this modification: Signature of the sponsor’s medically responsible person
15.2.1.14 Modification 14: Other clarifications and corrections

A typo was corrected in Section 9.7.1.4 (incomplete sentence).

The abbreviation for AUC(0-x) was corrected in the list of abbreviations.
The word “approval” was changed to “agreement” in Section 9.2.1 to clarify that the 
Bayer–designated medical representative provides written agreement to each subject’s 
eligibility. The modification was done to harmonize the language with other study 
documents.
The wording related to medical resource use was harmonized (“resource utilization” 
was changed to “medical resource use”) for consistency.
The statement “not part of this protocol” was removed from the language related to 
source document checklist to avoid confusion.
Section affected by this modification: List of abbreviations, 9.2.1 Screening period, 9.2.3
Active Follow-up period, 9.7.1.4 Genetic biomarker analysis from whole blood, 9.7.2 Medical 
resource use, 11.1 Data recording
15.2.2
Changes to the protocol text
Changes to the protocol text done in Amendment 5 are provided in a separate track changes 
version.


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15.3
Amendment 6
Amendment 6 is a global amendment dated 10 DEC 2019.
15.3.1
Overview of changes to the study
Section(s)
Description of change
Rationale
2 Synopsis
8.2 Post-study 
therapy
9.1 Tabular schedule 
of evaluations
9.2.2.2 Visit 2 and 
subsequent visits 
(every 12 weeks ± 7 
days)
9.2.3 Active Follow-
up period
9.2.4 Long–term 
(survival) Follow–up 
period
The option to continue 
darolutamide treatment in a 
separate program was added for 
those subjects who are ongoing 
on darolutamide treatment at the 
time of the primary analysis of the 
current study. 
Subjects receiving placebo will 
discontinue the treatment and 
complete the study. 
To enable subjects who are receiving 
darolutamide treatment in the current 
study to continue to receive 
darolutamide treatment when the study 
is completed. 
Subjects in the placebo arm have 
received standard of care with 6 cycles 
docetaxel after randomization. Upon 
disease progression, it will be at the 
Investigator’s discretion to decide on 
further treatment in the best interest of 
the patient.
2 Synopsis
5 Study design
9.1 Tabular schedule 
of evaluations
9.2.5 Unscheduled 
visits
Additional survival sweeps were
added to be performed in all
subjects considered alive at the 
database cut-off date for the 
second interim analysis and prior 
to any subsequent additional 
analysis.
To ensure that survival data is current.
3.2.4 Drug-drug 
interactions
Detailed information on 
darolutamide drug-drug 
interactions were removed and a 
reference to the latest available 
version of darolutamide IB was 
provided instead.
The section was updated to 
reflect that the data from the 
present study did not reveal any 
significant impact of darolutamide 
on the PK of docetaxel.
The most up to date data on drug-drug 
interactions can be found from the 
darolutamide IB.
The information on the effect of 
darolutamide on the PK of docetaxel 
was updated based on the availability of 
blinded results and the DMC
assessment.
8.1.2 Permissible
concomitant 
medications and 
treatments
16.5 List of strong 
CYP3A4 inducers
a) The guidance to use strong 
inhibitors of P-gp and BCRP 
with caution was removed.
b) The guidance to use medicinal 
products that are sensitive 
substrates for P-gp or BCRP 
with caution when 
co-administered with 
darolutamide was removed.
a) The results of study 17726 with 
itraconazole, a strong CYP3A4, P-gp 
and BCRP inhibitor, did not indicate 
a clinically relevant impact on the PK 
of darolutamide.
b) Based on the results of study 18860 
using dabigatran etexilate as a 
sensitive P-gp substrate, there is no 
effect of darolutamide on P-gp 


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c) The guidance to monitor 
subjects receiving concomitant
drugs which are mainly 
metabolized via CYP3A4 
enzyme for signs of decreased 
efficacy was removed. 
d) The recommendation to avoid 
concomitant use of moderate 
CYP3A4 inducers was 
removed (while strong 
CYP3A4 inducers should still 
be avoided).
e) The guidance to closely 
monitor patients for signs and 
symptoms of increased 
exposure was updated to 
include also OATP1B1 and
OATP1B3 substrates.
transporter. The effect of 
darolutamide on BCRP is described 
in detail based on study 17723 with 
rosuvastatin.
c) Based on the results of study 18860 
using midazolam as a sensitive 
CYP3A4 substrate, darolutamide 
has only a minor inducing effect on 
CYP3A4 which is not considered to 
be clinically relevant.
d) 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% (driven by a 
CYP3A4 inducer), there would still 
be a strong effect on PSA.
Therefore, the modification allows 
the use of moderate CYP3A4 
inducers.
e) New in vitro data on OATP1B1 and 
OATP1B3 indicated that the effect of 
darolutamide on such substrates 
may be clinically relevant.
9.6.1.3 Assessments 
and documentation 
of adverse events
The guidance on AE reporting 
was modified to clarify that 
disease progression should not 
be reported as an AE. Instead, 
the associated signs and 
symptoms should be recorded as 
AEs.
The change was done for clarification.
9.1 Tabular schedule 
of evaluations
9.2.1 Screening 
period
9.2.2.2 Visit 2 and 
subsequent visits 
(every 12 weeks ± 7 
days)
9.2.3 Active Follow-
up period
9.6.3.1 Laboratory 
safety assessments
In a subset of subjects, additional 
determination of total and free 
testosterone was added to be 
performed also at the EOT Visit 
Emerging scientific data suggest that 
investigating free testosterone at the 
time of disease progression (which likely 
will lead to stopping study treatment) will 
be worth analyzing in relation to the 
efficacy endpoints (34)
9.8 Appropriateness 
of procedures / 
Clarifications and corrections 
Modifications were done for clarification 


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measurements
10.3.2 Secondary 
efficacy variables
10.3.4 Other 
exploratory variables
were done:
MedDRA version number 
removed
“Analgesic use” changed to 
“opioid use”
Definition of “time to PSA 
progression” clarified
Typos corrected
and consistency.
Title page
Signature of the 
sponsor’s medically 
responsible person
13.1 Investigator and 
other study 
personnel
Sponsor’s medical expert and 
medically responsible person 
were changed.
Administrative changes.
15.1.2 Changes to 
the protocol text
The detailed old vs. new text 
comparison for protocol 
amendment 2 was replaced with a 
reference to the respective 
protocol amendment.
To improve readability, and to reduce 
complexity of the protocol.
15.3.2
Changes to the protocol text
Changes to the protocol text done in Amendment 6 are provided in a separate track changes 
version.


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15.4
Amendment 7
Amendment 7 is a global amendment dated 26 MAY 2020.
15.4.1
Overview of changes to the study
Section(s)
Description of change
Rationale
1 Title page
New e-signature text added.
New e-signature process implemented 
at Bayer.
2 Synopsis
5 Study design
9.1 Tabular schedule 
of evaluations
(footnote v)
9.2.5 Unscheduled 
visits
10.3.1 Primary 
efficacy variable
10.5 Planned interim 
analyses
13.1.1 Independent 
data monitoring 
committee
Planned second interim analysis 
will not be performed.
Due to the implications of the COVID-19 
pandemic on the conduct of study 
procedures and data collection at the 
study sites, the risk for not achieving the 
needed quality of data for a formal 
analysis is considered to be too high. 
Therefore, the second interim analysis, 
which was expected to be conducted in 
the second half of 2020, will not be 
performed. 
As a consequence, there is no splitting 
of alpha for efficacy between the now 
dropped second interim analysis and the 
final analysis. This change does not 
affect the regular DMC for safety.
9.7.1 Biomarker 
investigations
Clarification added for biomarker 
analysis and reporting.
To allow for inclusion of biomarker 
analysis in the main study SAP and to 
be consistent with other parts of the 
protocol.
10.3.2 Secondary 
efficacy variables
Added text regarding ranking of 
secondary endpoints.
To clarify that type 1 error control will 
include the ranking of secondary 
endpoints.
10.5 Planned interim 
analyses
Stopping boundaries for the futility 
interim and final analyses 
together will use a beta-spending 
function based on the actual 
number of events.
Due to removal of interim analysis 2, the 
sentence regarding alpha-spending has 
been removed. 
Added a statement about beta-spending 
for clarification.
15.4.2
Changes to the protocol text
Changes to the protocol text done in Amendment 7 are provided in a separate track changes 
version.


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16.
Appendices
16.1
Eastern Cooperative Oncology Group performance status
Grade
Description
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 housework, office work)
2
Ambulatory and capable of all self–care but unable to carry out any work activities. 
Up and about more than 50% of waking hours.
3
Capable of only limited self–care, confined to bed or chair more than 50% of 
waking hours 
4
Completely disabled. Cannot carry on any self–care. Totally confined to bed or 
chair. 
5
Death 
16.2
National Cancer Institute–Common Terminology Criteria for Adverse 
Events
This study will utilize the NCI–CTC for Adverse Events Version 4.03 for toxicity and serious 
AEs reporting. A copy of the CTC Version 4.03 can be downloaded in PDF form from 
http://evs.nci.hin.gov/ftp1/CTCAE/About.html.
All appropriate treatment areas should have access to a copy of the NCI–CTC Version 4.03.


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16.3
NCCN–FACT FPSI–17
Below is a list of statements that other people with your illness have said are important. 
Please circle or mark one number per line to indicate your response as it applies to 
the past 7 days.
Not at 
all
A 
little 
bit
Some
what
Quite
a bit
Very 
much
GP1
I have a lack of energy...............................
0
1
2
3
4
GP4
I have pain .................................................
0
1
2
3
4
P7
I have difficulty urinating..........................
0
1
2
3
4
C2
I am losing weight .....................................
0
1
2
3
4
BP1
I have bone pain.........................................
0
1
2
3
4
HI7
I feel fatigued.............................................
0
1
2
3
4
NCCN3
I have weakness in my legs .......................
0
1
2
3
4
P3
My pain keeps me from doing things I 
want to do ..................................................
0
1
2
3
4
C6
I have a good appetite................................
0
1
2
3
4
GF5
I am sleeping well......................................
0
1
2
3
4
GE6
I worry that my condition will get worse ..
0
1
2
3
4
GP2
I have nausea .............................................
0
1
2
3
4
P6
I have trouble moving my bowels .............
0
1
2
3
4
GS7
I am satisfied with my sex life...................
0
1
2
3
4
GP5
I am bothered by side effects of 
treatment....................................................
0
1
2
3
4
GF3
I am able to enjoy life................................
0
1
2
3
4
GF7
I am content with the quality of my life 
right now....................................................
0
1
2
3
4
DRS–P=Disease–Related Symptoms Subscale – Physical
DRS–E=Disease–Related Symptoms Subscale – Emotional
TSE=Treatment Side Effects Subscale
FWB=Function and Well–Being Subscale
English (Universal), Copyright 2001
03 March 2010
D
R
S
–
P
D
R
S
–
E
T
S
E
F
W
B


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16.4
BPI–SF


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16.5
List of strong 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

SAP_003.pdf: 
Document Type: 
Statistical Analysis Plan 
Official Title: 
A randomized, double–blind, placebo–controlled Phase III study 
of darolutamide (ODM–201) versus placebo in addition to 
standard androgen deprivation therapy and docetaxel in patients 
with metastatic hormone–sensitive prostate cancer 
NCT Number: 
NCT02799602 
Document Date: 
11-Nov-2021


Statistical Analysis Plan
Protocol No.: BAY 1841788 / 17777
Page: 1 of 48
Title page
A randomized, double-blind, placebo-controlled Phase III study of 
darolutamide (ODM-201) versus placebo in addition to standard androgen 
deprivation therapy and docetaxel in patients with metastatic hormone-
sensitive prostate cancer
Darolutamide in addition to standard androgen deprivation therapy and docetaxel in 
metastatic hormone-sensitive prostate cancer
Acronym: ARASENS
Bayer study drug
BAY 1841788 / Darolutamide
Study purpose:
Efficacy and Safety
Clinical study 
phase:
III
Date:
11 NOV 2021
Study No.:
17777
Version:
4.1
Author:
 Bayer Pharmaceuticals
Whippany, NJ  07981
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
PPD
PPD


Statistical Analysis Plan
Protocol No.: BAY 1841788 / 17777
Page: 2 of 48
Table of Contents
Title page................................................................................................................................... 1
Table of Contents...................................................................................................................... 2
Table of Tables.......................................................................................................................... 3
Table of Figures........................................................................................................................ 3
List of Abbreviations................................................................................................................ 4
1.
Introduction ....................................................................................................................... 6
2.
Study Objectives................................................................................................................ 6
3.
Study Design ...................................................................................................................... 7
4.
General Statistical Considerations .................................................................................. 9
4.1
General Principles............................................................................................................ 9
4.2
Handling of Dropouts ...................................................................................................... 9
4.3
Handling of Missing Data................................................................................................ 9
4.4
Determination of Sample Size ....................................................................................... 10
4.5
Interim Analyses and Data Monitoring.......................................................................... 10
4.5.1
Interim Analyses......................................................................................................... 10
4.5.2
Independent Data Monitoring Committee.................................................................. 11
4.6
Data Rules...................................................................................................................... 11
5.
Analysis Sets..................................................................................................................... 12
5.1
Assignment of Analysis Sets ......................................................................................... 12
6.
Statistical Methodology................................................................................................... 12
6.1
Population characteristics .............................................................................................. 12
6.1.1
Disposition.................................................................................................................. 12
6.1.2
Demographic and Other Baseline Characteristics ...................................................... 13
6.1.3
Medical History .......................................................................................................... 15
6.1.4
Prior and Concomitant Medication and Procedures ................................................... 15
6.1.5
Extent of Exposure ..................................................................................................... 16
6.2
Efficacy.......................................................................................................................... 16
6.2.1
Primary Efficacy Endpoint ......................................................................................... 17
6.2.2
Secondary Efficacy Endpoints.................................................................................... 18
6.2.3
Exploratory Efficacy Endpoints ................................................................................. 25
6.2.4
Subgroup Analyses for Efficacy Endpoints................................................................ 27
6.3
Safety ............................................................................................................................. 27
6.3.1
Adverse Events........................................................................................................... 28
6.3.2
Deaths and Serious Adverse events............................................................................ 31
6.3.3
Additional Primary Malignancies............................................................................... 31
6.3.4
Laboratory Safety Assessments.................................................................................. 32
6.3.5
Other Safety Measures................................................................................................ 34
6.4
Other Exploratory Variables .......................................................................................... 36
6.5
Pharmacokinetics ........................................................................................................... 36
7.
Document History and Changes in the Planned Statistical Analysis ......................... 38
8.
References ........................................................................................................................ 39


Statistical Analysis Plan
Protocol No.: BAY 1841788 / 17777
Page: 3 of 48
9.
Appendix .......................................................................................................................... 39
9.1
Imputation rule for partial missing Adverse Event/ Concomitant medication dates ..... 39
9.2
Systemic antineoplastic therapy: time to initiation of subsequent systemic 
antineoplastic therapy .................................................................................................... 40
9.3
Brief Pain Inventory – Short Form (BPI-SF) questionnaire and scoring information... 41
9.4
NCCN-FACT FPSI-17 questionnaire and scoring information..................................... 43
9.5
Statins medications ........................................................................................................ 46
9.6
Special topic AE definition............................................................................................ 47
9.7
Bone health agent (BHA)............................................................................................... 48
9.8
Concomitant statins (BCRP substrates) of interest........................................................ 48
9.9
Pre-defined adverse events for analysis of statin (BCRP substrates) ............................ 48
Table of Tables
Table 4–1 Example of stopping boundaries for interim analyses ............................................ 10
Table 6–1 Censoring rules for OS............................................................................................ 17
Table 6–2 Censoring rules for time to castration-resistant prostate cancer ............................. 19
Table 6–3 Censoring rules for time to pain progression .......................................................... 21
Table 6–4 Censoring rules for SSE-FS .................................................................................... 22
Table 6–5 Censoring rules for first SSE................................................................................... 22
Table 6–6 Censoring rules for time to initiation of subsequent systemic antineoplastic therapy
............................................................................................................................... 23
Table 6–7 Censoring rules for time to worsening of disease-related physical symptoms ....... 24
Table 6–8 Censoring rules for time to initiation of opioid use for ≥7 consecutive days ......... 24
Table 6–9 Censoring rules for PSA progression...................................................................... 26
Table 9–1 Imputation rule for partial missing dates................................................................. 39
Table 9–2 Special topic AE definitions.................................................................................... 47
Table of Figures
Figure 6–1 Example for Hy’s law plot..................................................................................... 34


Statistical Analysis Plan
Protocol No.: BAY 1841788 / 17777
Page: 4 of 48
List of Abbreviations
ADT
Androgen deprivation therapy
AE
Adverse event
AEE
Actual extent of exposure
ALP
Alkaline phosphatase
ATC
Anatomical-Therapeutic-Chemical
bid
Twice daily
BHA
Bone health agent
BPI-SF
Brief Pain Inventory – Short Form
CI
Confidence interval
CT
Computed tomography
CV
Coefficient of variation
DMC
Data Monitoring Committee
EBRT
External beam radiation therapy
ECG
Electrocardiogram
ECOG PS
Eastern Cooperative Oncology Group Performance Status
EOT
End of treatment
FAS
Full analysis set
FPSI-DRS-P
FACT/NCCN FPSI-17 disease-related symptoms - physical
GCP
Good Clinical Practice
HR
Hazard ratio
ICF
Informed consent form
KM
Kaplan-Meier
LHRH
Luteinizing hormone releasing hormone
LKAD
Last known alive date
LLOQ
Lower limit of quantification
M&S
Modeling & Simulation
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
mHSPC
Metastatic hormone-sensitive prostate cancer
mL
Milliliter
MRI
Magnetic resonance imaging
NCCN
National Comprehensive Cancer Network
NCCN-FACT FPSI-17
Functional assessment of cancer therapy / National Comprehensive Cancer Network 
prostate cancer symptom index 17 item questionnaire
NCI-CTCAE v4.03
National Cancer Institute-Common Terminology Criteria for Adverse Events; 
version 4.03
ng
Nanogram
OEE
Overall extent of exposure
OS
Overall survival
PCWG3
Prostate Cancer Clinical Trials Working Group
PK
Pharmacokinetics
PKS
Pharmacokinetic Analysis Set
PRO
Patient-reported outcomes
PSA
Prostate-specific antigen
PT
Preferred Term
QoL
Quality of life
RECIST
Response Evaluation Criteria In Solid Tumors
SAE
Serious adverse event
SAF
Safety analysis set
SAP
Statistical Analysis Plan
SD
Standard deviation
SOC
System Organ Class
SSE
Symptomatic skeletal event
SSE-FS
Symptomatic skeletal event free survival
TEAE
Treatment emergent adverse events


Statistical Analysis Plan
Protocol No.: BAY 1841788 / 17777
Page: 5 of 48
TESAE
Treatment emergent serious adverse events
tlast
Time to the last quantifiable concentration
tmax
Time to the maximum plasma concentration
ULN
Upper limit of normal
WHO
World Health Organization
WHO-DD
WHO Drug Dictionary
WPS
Worst pain subscale


Statistical Analysis Plan
Protocol No.: BAY 1841788 / 17777
Page: 6 of 48
1.
Introduction
Study 17777 (ARASENS) is an international, randomized, double-blind, placebo-controlled, 
Phase III efficacy and safety study of darolutamide in addition to standard androgen 
deprivation therapy (ADT) and docetaxel in patients with metastatic hormone-sensitive 
prostate cancer (mHSPC).
This statistical analysis plan (SAP) describes the pre-specified analyses and data presentations 
for the primary completion analyses, which will be performed when the targeted number of 
death events for the primary efficacy endpoint of overall survival (OS) is reached.
The SAP contains definitions of analysis sets, derived variables, and statistical methods for 
the analysis of efficacy and safety.
For SAP version history and changes in the planned statistical analysis, please refer to Section 
7.
2.
Study Objectives
The primary objective of this study is:

To demonstrate the superiority in overall survival (OS) of darolutamide in addition to 
standard androgen deprivation therapy (ADT) and docetaxel over placebo in addition 
to standard ADT and docetaxel
The secondary objectives of this study are to evaluate:

Time to castration-resistant prostate cancer

Time to pain progression

Symptomatic skeletal event free survival (SSE-FS)

Time to first symptomatic skeletal event (SSE)

Time to initiation of subsequent systemic antineoplastic therapy

Time to worsening of disease-related physical symptoms based on functional 
assessment of cancer therapy / National Comprehensive Cancer Network prostate 
cancer symptom index 17 item questionnaire (NCCN-FACT FPSI-17)

Time to initiation of opioid use for ≥7 consecutive days 

Safety
The secondary objective of the efficacy endpoints will be tested in the hierarchical order as 
given above, except for safety.
The exploratory objectives of this study include the evaluation of:

Quality of life (QoL), measured using the NCCN-FACT FPSI-17 questionnaire

Medical resource use

Prostate-specific antigen (PSA) assessments

PK and exposure-response analysis

Evaluate biomarkers to investigate the drug (i.e. mode-of-action-related effect and / or
safety) and / or the pathomechanism of the disease


Statistical Analysis Plan
Protocol No.: BAY 1841788 / 17777
Page: 7 of 48
3.
Study Design
Design overview
This is an international, randomized, double-blind, placebo-controlled, multicenter Phase III 
study of darolutamide in patients with mHSPC. Approximately 1,300 patients will be 
randomized (1:1 ratio) to receive one of the following study drugs:

Darolutamide, 600 mg (2 x 300 mg tablets) bid orally with food

Placebo matching darolutamide tablets in appearance, bid orally with food
All patients must receive ADT of Investigator’s choice (LHRH agonist/antagonists or 
orchiectomy) as standard therapy, started ≤12 weeks before randomization. Six cycles of 
docetaxel will be administered as background treatment after randomization. The first cycle of 
docetaxel should be administered within 6 weeks after start of study drug.
For at least the first 20 randomized patients who have received at least 1 cycle of docetaxel,
and for whom a detailed mandatory PK analysis will be performed, docetaxel should be
administered at least 14 days after randomization.
Patients will be stratified at randomization as follows:

Extent of disease
o
Non-regional lymph nodes metastases only
o
Bone metastases with or without lymph node metastases
o
Visceral metastases with or without lymph node metastases or with or without 
bone metastases

Alkaline Phosphatase (ALP)
o
ALP < upper limit of normal (ULN)
o
ALP ≥ULN
Note: Blood samples to measure ALP levels for stratification will be analyzed in a central 
laboratory.
The study will comprise 4 consecutive periods: Screening, Treatment, Active Follow-up, and 
Long-term (survival) Follow-up.
Screening period:
All trial-related procedures and evaluations will only be performed after the patient has agreed 
to participate and has signed the informed consent form (ICF).
The Screening period will consist of multiple evaluations that will take place within 28 days 
prior to randomization to ensure that all eligibility criteria are met.
Once eligibility is confirmed and documented, eligible patients will be randomized in a ratio 
of 1:1 to treatment with darolutamide or placebo.
Treatment period:
The start of the treatment period is defined by the first administration of study drug
(darolutamide or placebo). Study treatment will be provided for all patients to be taken twice 


Statistical Analysis Plan
Protocol No.: BAY 1841788 / 17777
Page: 8 of 48
daily until disease progression (symptomatic progressive disease, change of systemic 
antineoplastic therapy), unacceptable toxicity, consent withdrawal or withdrawal from the 
study at the discretion of the Investigator or his/her designated associate(s), death, or non-
compliance.
Patients will be evaluated every 12 weeks for castration-resistant prostate cancer, initiation of 
subsequent systemic antineoplastic therapy, SSEs, opioid use for ≥7 consecutive days, pain 
progression, worsening of physical symptoms of disease based on NCCN-FACT FPSI-17, 
adverse events (AEs) and serious adverse events (SAEs), QoL and PSA assessment.
Active Follow-up period:
The Active Follow–up period is the interval from the end of darolutamide or placebo intake to 
the end of all protocol–specified post–treatment interventions. 
It includes the End of Treatment Visit (EOT). An EOT Visit will be conducted 30 (+ window 
of 7) days after the last dose of darolutamide or placebo. The following assessments will be 
performed at the EOT Visit: QoL, pain assessment, analgesic consumption, subsequent 
systemic antineoplastic treatments for prostate cancer, SSEs, and all AEs and SAEs regardless 
of causality.
During the Active Follow-up period, the following assessments will be performed during 
standard of care clinic visits approximately every 12 weeks for up to 1 year: QoL, pain 
assessment, analgesic consumption, survival status, subsequent systemic antineoplastic 
treatments for prostate cancer (which should be provided with start and stop dates and reason 
for change, SSEs, and study drug-related SAEs. After approximately 1 year of Active Follow-
up, patients will be transitioned to Long-term (survival) Follow-up. The Active Follow-up 
period extends from the discontinuation of darolutamide or placebo treatment period for up to 
1 year or until the patient can no longer travel to the clinic, dies, is lost to follow-up, or 
withdraws informed consent and actively objects to collection of further data.
Long-term (survival) Follow-up period:
After Active Follow-up, patients will continue to be contacted approximately every 12 weeks 
(by phone) to capture all systemic antineoplastic treatments for prostate cancer with start and 
stop date and reasons for change (PSA progression, clinical progression, radiological 
progression, toxicity, other), study drug-related SAEs and survival status. The end of Long-
term Follow-up period is death, lost to follow-up, consent withdrawal, or end-of-study.
Survival sweep:
For every analysis of OS, survival data will be collected through additional survival sweeps. 
All patients considered alive at the database cut-off date and prior to any subsequent 
additional analysis will be contacted for survival status.
Primary completion
The first analysis of OS will be performed as an interim futility analysis when approximately 
153 deaths have occurred. In case the study continues after the futility analysis, a final 
efficacy analysis of OS will be performed when approximately 509 deaths have occurred and 
will be considered the primary completion. The database cut–off date for this analysis will be 
the date of primary completion.


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Protocol No.: BAY 1841788 / 17777
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4.
General Statistical Considerations
4.1
General Principles
Statistical analyses will be performed by using the software package SAS® Version 9.2 or 
higher (SAS Institute Inc., Cary, NC, USA). 
All variables will be analyzed by descriptive statistical methods by treatment arm and overall, 
unless otherwise specified. The number of data available and missing data, mean, standard 
deviation (SD), minimum, quartiles, median, and maximum will be calculated for continuous 
variables. Frequency tables will be generated for categorical variables. 
4.2
Handling of Dropouts
A patient who discontinues study participation prematurely for any reason is defined as a
“dropout” if the patient has already been randomized. Patients who discontinue treatment or 
study will not be replaced.
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. Except as noted, missing data will not be estimated or carried forward 
in any statistical analysis.
When appropriate, the following rules will be implemented so as not to exclude patients from 
statistical analyses due to missing or incomplete data:
Overall survival and other time-to-event endpoints:
Every effort should be made to resolve incomplete or missing dates during the course of the 
study (i.e. edit checks, data cleaning/monitoring etc.). However, in rare circumstances, 
missing parts of either the censoring date or the event date may occur where an imputation 
algorithm has to be defined. In general the following rule should be followed: Missing month 
or year is not acceptable. To impute a value for day, day 15 of the month will be used for the 
calculation. This applies to all OS and time-to-event endpoints dates if the dates are partially
missing in the selected data panels.
AE and Concomitant Medication (CM) partial or missing dates
Refer to SAP appendix 9.1 imputation rule for incomplete AE/CM dates.
Laboratory Assessments
If laboratory assessment results contain an inequality sign “<” or “>”, then the lower or higher 
detection limit will be used as the imputed laboratory assessment value for both safety and 
efficacy analyses.
ePRO Questionnaire
Two scores will be derived for Brief Pain Inventory-Short Form (BPI-SF): (1) for the pain 
severity score if one answer is missing then scoring will be set to missing, (2) for the pain 
interference score if four or more answers are missing out of the seven questions then the 
score will be set to missing (see scoring of BPI-SF in Appendix 9.3).


Statistical Analysis Plan
Protocol No.: BAY 1841788 / 17777
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For NCCN-FACT FPSI-17, total scores and subscales scores (disease-related physical 
symptoms, disease–related emotional symptoms, treatment side-effects, function/well-being) 
will be assessed. Where there are missing items, subscale scores can be prorated if >50% of 
items on subscale are completed. If ≤50% of the items are answered for any domain, then the 
score of that domain is set to missing. The total score is set to missing if the related overall 
item response rate is less than or equal to 80% (see scoring of NCCN-FACT FPSI-17 in 
Appendix 9.4). In addition, a total score should only be calculated if all of the component 
subscales have valid scores.
4.4
Determination of Sample Size
The sample size of the study is based on the primary endpoint of OS. The study is designed to
have 90% power to detect a 25% decrease in risk of death with darolutamide compared to
placebo, corresponding to a HR of 0.75 with a one-sided test with a type I error of 0.025
(equivalent a two-sided test with a type I error 0.05). The OS data will be considered mature 
when approximately 509 deaths are observed.
With the additional assumptions that patients will enroll at a rate of 50 patients per month,
exponential distributions of the OS event times, median time of OS in the control group of
60 months, 5% dropout rate of patients, and a 6-months enrollment ramp-up period, it follows
that approximately 1,300 patients need to be randomized to observe 509 deaths after 
approximately 70 months.
4.5
Interim Analyses and Data Monitoring
4.5.1
Interim Analyses
For the futility interim and final analyses together, a one-sided overall beta of 0.1 will be 
used. Stopping boundaries will be calculated with an O’Brien-Fleming beta-spending function 
using the actual number of events observed up to the cut-off date. The interim futility analysis 
is planned when approximately 153 deaths were observed (information fraction=0.3). The 
critical boundary for the futility analysis will be calculated separately from the efficacy 
boundary, in order to not interfere with the type I error of the efficacy analysis.
The following scenario in Table 4–1 serves as an example.
Table 4–1 Example of stopping boundaries for interim analyses
Analysis
Time 
# Events
Stopping Boundaries
Hazard Ratio Scale
(darolutamide+docetaxel arm vs. placebo+docetaxel arm)
(% Improvement) / Z Score
Cumulative
Alpha Spent
Cumulative
Beta Spent
Crossing 
Lower Bound
(efficacy)
Crossing
Upper Bound
(futility - lack of efficacy)
1st
Interima
153
-
1.166 (-14.2 %)
/ 0.952 
-
0.003
Final
509
0.841 (19.0%)
/ 1.96
0.841 (19.0%)
/ 1.96
0.025
0.100
Software ADDPLAN neo V10.0.4 was used for this design 
a: the 1st interim analysis was completed and its stopping boundaries were calculated before the decision was 
made to remove the 2nd interim analysis, which was originally planned but removed with version 3.0 of the 
SAP. Please refer to Section 7 for additional details.


Statistical Analysis Plan
Protocol No.: BAY 1841788 / 17777
Page: 11 of 48
If the estimated hazard ratio (darolutamide over placebo) is greater than or equal to 1.166 at 
the interim analysis, stopping the trial for lack of efficacy (i.e. futility) would be considered. 
Otherwise, i.e. if the estimated hazard ratio is less than 1.166, the trial would continue to the 
final analysis, providing there were no other safety considerations to warrant discontinuation 
of patient treatment.
4.5.2
Independent Data Monitoring Committee
A DMC will be instituted to ensure ongoing safety of study patients with respect to a
risk/benefit assessment during periodic data review meetings, review results from planned
interim analyses and provide a formal recommendation for continuation/termination of the
study and monitor study conduct to ensure the overall integrity of study is maintained. The 
DMC will operate independently of the Sponsor and Investigators.
4.6
Data Rules
Baseline
Baseline is defined as the last measurements performed in Screening or Visit 1 (regardless the 
scheduled or the unscheduled visits), unless otherwise specified prior to the first study drug 
administration.
Repeated measures
If there are repeated measurements per time point on the same day (e.g. laboratory values, 
vital signs, etc.), the following rules will be used (unless otherwise specified):

Before the start of the study drug administration (i.e., for screening and baseline 
value), the latest measurement at scheduled visits will be used. Unscheduled visits will 
be used if there are no measurements at scheduled visits. If the latter is the case, the 
last unscheduled visit will be used.

In case of repeated measurements at any post baseline time point, the first 
measurement at scheduled visits will be used. Unscheduled visits will be used if there 
are no measurements at scheduled visits. If the latter is the case, the first unscheduled 
visit will be used.
Stratification variables
Since differences may occur between the values of the stratification factors entered by the 
investigator at the time of randomization into IxRS and those collected on the eCRF, the 
stratified analysis of OS will be performed using both assignments to the strata. The primary 
stratified analysis for OS will be based on the information collected in the IxRS whereas 
stratification information entered in the eCRF (considered the ‘true’ information) will be used 
for the sensitivity analysis. In rare circumstances, if eCRF data cannot be documented, then 
IxRS data will be used.


Statistical Analysis Plan
Protocol No.: BAY 1841788 / 17777
Page: 12 of 48
5.
Analysis Sets
5.1
Assignment of Analysis Sets
Patients will be excluded from all below-mentioned analysis set if they are related to or 
associated with any critical GCP violations that result in fraudulent patient data (please refer 
to Section 7 for rationale). The FAS will be used for the analysis of all efficacy endpoints and 
all other endpoints. The SAF will be used for the analyses of all safety endpoints. The 
pharmacokinetic data will be analyzed in the PKS. Patients who signed the informed consent
but for any reasons did not proceed to randomization will be considered screening failures. 
They will be listed separately.
Full analysis set (FAS) 
All patients who were randomized are included in the Full Analysis Set, except for cases with 
critical GCP violations. Following the intent-to-treat (ITT) principle, the patients in this set 
will be grouped according to the planned treatment they were allocated to receive at 
randomization, irrespective of actual treatment.
Safety analysis set (SAF)
All randomized patients who have received at least 1 dose of darolutamide or placebo 
represent the SAF, except for cases with critical GCP violations. This safety population will 
be used in the analyses of all safety endpoints. Patients will be included in the analyses 
according to the treatment they actually received. Patients will be included in the 
darolutamide+docetaxel arm if they have received any dose of darolutamide, otherwise they 
will be included in the placebo+docetaxel arm if they only received placebo.
Pharmacokinetic Analysis Set (PKS) 
At least the first 20 randomized patients who have received at least 1 cycle of docetaxel, and 
for whom mandatory dense PK sampling was done, will be included in the PKS, as long as 
they have received at least 3 days of uninterrupted study drug treatment as well as one cycle 
of docetaxel and have at least one post dose PK measurement, except for cases with critical 
GCP violations.
In addition, a subset of Chinese patients who were randomized and have received at least 1 
dose of darolutamide, and for whom mandatory dense PK sampling was done prior to the first
dose of docetaxel, will also be included in the PK analysis set.
6.
Statistical Methodology
6.1
Population characteristics
6.1.1
Disposition
The number of patients enrolled and included in each population will be tabulated by region, 
country, and center. The number of patients starting, completing, and discontinuing together 
with the primary reason (including COVID-19 pandemic related reason) for discontinuing of 
the Screening, Treatment, Active Follow-up, and Long-term Follow-up periods will be 
presented overall and by treatment arm (except for the Screening period). The number of 
patients currently on treatment at primary completion analysis cut-off will also be summarized 
by treatment arm. Disposition of Screening will be summarized for all enrolled patients, and 


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disposition of other study periods for the FAS. Patients who enter Active Follow-up are
defined as patients who discontinued study treatment not due to death or lost to follow-up and 
had Active Follow-up visits after the end of treatment visit. The number of patients affected 
by COVID-19 pandemic related study disruptions (protocol deviations, premature 
discontinuations, and AEs) will be summarized in a separate table.
In addition, the number of patients with important protocol deviations will be presented by
treatment arm and overall. The frequencies of each important protocol deviation will be 
presented by treatment arm and overall. All COVID-19 pandemic related protocol deviations 
are considered important protocol deviations and will be presented by treatment arm and 
overall. Listings of important protocol deviations associated with COVID-19 pandemic will 
be presented as well. The number of patients with missed visits or assessments in the key 
assessments will be presented for each treatment arm and overall.  
6.1.2
Demographic and Other Baseline Characteristics
Descriptive summaries of demographics and baseline characteristics are presented by 
treatment arm and overall, for the FAS. Comparability of the treatment arms with respect to 
demographics and baseline characteristics is assessed using descriptive summaries.
The following demographic data will be summarized:

Age at screening (years)

Age category (<65, 65-74, 75-84, ≥85 years)

Geographical region (North America, Asia Pacific, Rest of the World)1

Race (White, Asian, Black or African American, Other, Not Reported) and 
ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not Reported)

Weight at baseline

Body Mass Index (BMI) (kg/cm2) (<20, 20 to <25, 25 to <30, ≥30)

Renal function - eGFR at baseline:
o Normal: eGFR ≥ 90 mL/min
o Mild impairment: 60 ≤ eGFR < 90 mL/min
o Moderate impairment: 30 ≤ eGFR < 60 mL/min
o Severe impairment: 15 ≤ eGFR < 30 mL/min
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 function at baseline:
                                                
1 Geographic region: North America (Canada and United States), Asia Pacific (China, Japan, South Korea, and 
Taiwan) and the rest of the world (Australia, Belgium, Bulgaria, Brazil, Czech Republic, Germany, Spain, 
Finland, France, United Kingdom, Israel, Italy, Mexico, Netherlands, Poland, Russian Federation, and Sweden).


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o Normal: Total bilirubin and AST ≤ upper limit of normal (ULN)
o Mild 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.
The following baseline characteristics will be summarized:

Extent of metastatic disease at study entry (Non-regional lymph nodes metastases 
only, Bone metastases with or without lymph node metastases, Visceral metastases 
with or without lymph node metastases or with or without bone metastases), from 
both IxRS and eCRF

ALP (U/L) at baseline (<ULN, ≥ULN) - central laboratory, from both IxRS and 
eCRF

PSA (ug/L) at baseline (<median of overall population, ≥median of overall 
population) - central laboratory

Eastern Cooperative Oncology Group Performance Status (ECOG PS) at baseline

Stage of prostate cancer (TNM Classification) at initial diagnosis (Stage I, IIA, 
IIB, III, IV (M1, M0))
The study used AJCC 7 and therefore the stage 4 M0 and M1 were not captured in 
the eCRF. As the CRFs captured the date of initial diagnosis and the date of initial 
diagnosis of metastases, the following assumptions will be used to estimate the M0 
or M1 status at initial diagnosis:
o
Patients who have a time interval > 3 months between initial diagnosis and 
initial metastases diagnosis will be assumed to be M0.
o
Patients who have a time interval of ≤ 3 months between initial diagnosis and 
initial metastases diagnosis will be assumed to be M1.

Gleason score of prostate cancer (<8, ≥8) at initial diagnosis

Time from initial diagnosis to the date of the first actual dose of darolutamide or 
placebo (months)

Time from initial diagnosis of metastases to the date of the first actual dose of 
darolutamide or placebo (months)

Time from initial diagnosis to initial diagnosis of metastases (months)

Stage of prostate cancer (TNM Classification) at study entry

Testosterone (<0.5, ≥0.5 ng/mL) at baseline - central laboratory

Chromogranin A (ug/L) at baseline – local laboratory.

The disease-related physical symptoms subscale of the NCCN-FACT FPSI-17 at 
baseline

Worst pain subscale, average pain subscale of the BPI-SF (0: no pain, 1-3: mild 
pain, 4-7: moderate pain, 8 to 10: severe pain)


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
Pain severity score of the BPI-SF
Demographic and baseline characteristics tables will be presented by geographical regions 
(North America, Asia Pacific, Rest of the World).
6.1.3
Medical History
For data coding, the Medical Dictionary for Regulatory Activities (MedDRA) will be used for 
medical history. Medical history findings (i.e. previous diagnoses, diseases or surgeries) not 
pertaining to the study indication, start before signing of the ICF and considered relevant to 
the study will be presented for each MedDRA Primary System Organ Class (SOC), and 
Preferred Term (PT) by treatment arm and overall for the FAS. 
6.1.4
Prior and Concomitant Medication and Procedures
Prior therapy is defined as all medications taken before the start of darolutamide or placebo
treatment. Concomitant therapy is defined as all medications taken between the start of 
darolutamide or placebo treatment and the last dose date of darolutamide or placebo.

Prior and concomitant medications excluding ADT, systemic antineoplastic therapies
captured in the anti-cancer therapy eCRF page: frequency of patients for each drug 
category

Concomitant statin medications: frequency of patients 

Prior systemic antineoplastic therapy, including ADT by preferred drug name: 
frequency of patients for each drug category. The prior systemic antineoplatic therapy, 
including ADT, are selected in CM dataset using ATC codes: L02BX, L02BB, 
H01CC, V98, G03HB, L02AE, H01CA.

A summary of subsequent systemic antineoplastic therapy will be presented by 
preferred drug name based on WHO-DD drug record number.

A summary of life-prolonging subsequent systemic antineoplastic therapy will be
presented by preferred drug name based on WHO-DD drug record number. The 
following medications after the study treatment period are life-prolonging subsequent 
therapies for prostate cancer: Abiraterone, Apalutamide, Enzalutamide, Docetaxel, 
Cabazitaxel, Radium 223, Sipuleucel-T, Lutetium-177.

Hormonal theray and orchiectomy at study entry (by LHRH agonist/antagonist only,
orchiectomy only, LHRH agonist/antagonist and orchiectomy).

Prior local treatment for prostate cancer at study entry (by prostatectomy, surgery, 
TURP, other, radiation, no surgical treatment and no radiation).

Concurrent prostate cancer related-invasive procedures (e.g. procedures for urinary 
symptoms, surgical procedures for prostate cancer): frequency of patients by grouped 
term and 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.).


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The dictionary used for coding medications was the ATC Class/Subclass and the World 
Health Organization Drug Dictionary (WHO-DD). For selection of statins medications, please 
refer to Appendix 9.5.
6.1.5
Extent of Exposure
Study drug is defined as darolutamide or placebo. Six cycles of docetaxel will be administered 
as background treatment after randomization and is not considered as study drug. As a general 
rule, trailing “0 mg” records, which are not followed by any positive amount of drug, will not 
be included in the calculation of any drug duration or amount. Similarly, trailing “drug 
interruptions” will not be used in statistical tables. Interruption becoming permanent study 
treatment discontinuation is not accounted as an interruption.
Descriptive statistical summaries will be provided for darolutamide or placebo and docetaxel 
separately by treatment arm in the SAF population for the following variables:

Overall time under treatment (or treatment duration)
Including time off drug and dose interruptions. It will be calculated in days and 
presented in months as (date of the last dose of any study treatment – date of the first 
dose of any study treatment + 1) / 30.44.

Actual dose per day 
Actual dose per day = total amount of dose / number of days with intake > 0

Total amount of dose 
Total amount of dose = sum of dose received over total time under treatment

Percent of planned dose received.
Percent of planned dose received = total amount of dose [mg] / planned dose [mg] * 
100%; planned dose is sum of the intended initial dose according to protocol over total 
time under treatment.

From 1 day after the last dose of docetaxel to the last dose of darolutamide or placebo.
Including time off drug and dose interruptions. It will be calculated in days and 
presented in months as (date of the last dose of darolutamide or placebo – date of the 
last dose of docetaxel + 1) / 30.44. If the last dose of docetaxel date is after the last 
dose of darolutamide or placebo, then 0 day of duration will be included in the 
calculation.
For patients with dose reduction, interruption, or delay, the number of dose reductions, 
re-escalations, interruptions, or delays per patient and their reasons will be summarized. Only 
dose modifications after start of treatment and before end of treatment are included in the dose 
modification summary table. For example, dose interruption or delay documented without 
further dose resumption afterwards.
Extent of exposure will be described by age groups (<65, 65 - 74, 75 - 84, ≥85 years) and 
geographical regions (North America, Asia Pacific, Rest of the World).
6.2
Efficacy
For time-to-event analyses the censoring mechanism is assumed to be non-informative.
Patients without events will be handled as right-censored in time-to-event analyses. Time to 


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event will be calculated in days as date of event or censoring minus date of randomization and 
presented in months (=days/30.44). If event or censoring date is on date of the randomization, 
then time to event =1 (or day 1).
6.2.1
Primary Efficacy Endpoint
Definition of OS
The primary efficacy variable is OS, defined as the time from date of randomization until 
death from any cause. 
The following censoring rules in Table 6–1 will be applied:
Table 6–1 Censoring rules for OS
Situation
End Date
Censored
Documented death during study
before or at data cut-off date
Death date
No
No documented death with no 
contacts after randomization and
before or at data cut-off date
Date of randomization (Day 1)
Yes
No documented death before or
at data cut-off date
Last known alive date (LKAD) or at 
the data cut-off date, whichever 
comes earlier
Yes
Last Known Alive Date
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 used as the LKAD by patient.
Information from selected data, i.e. visit dates, exposure information, laboratory 
measurements, tumor assessment dates, SSE dates, demographics, survival status date, vital 
signs and disposition events or follow up assessments will be used to determine survival 
status.
Analysis of OS
All randomized patients (FAS) will be included in the primary analysis of OS. 
The primary analysis of OS will be a stratified log-rank test with the same IxRS stratification 
factors as used for randomization. The null hypothesis that there is no difference in OS 
between treatment arms, which is equivalent to a hazard ratio (HR) of 1, will be tested against 
the alternative hypothesis that the HR of darolutamide over placebo is below 1. If the p-value 
from the one-sided log-rank test is less than 0.025 (corresponding to a two-sided log-rank test  
less than 0.05) with the HR (darolutamide+docetaxel arm vs. placebo+docetaxel arm) less 
than 1, the null hypothesis will be rejected in favor of the alternative hypothesis.  


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The SAS code will be similar to the following:
PROC LIFETEST DATA=<DATASET>;
TIME EFFVAL * CENSORNY;
STRATA {strata variables} / GROUP=TREATMGR test=(logrank);
RUN;
The HR (darolutamide or placebo) for OS and its 95% confidence interval (CI) will be 
calculated using the Cox model, stratified by the same factors as were used for randomization. 
The SAS code similar to the following will be used:
PROC PHREG DATA = <DATASET>;
MODEL EFFVAL * CENSORNY = TREATMGR;
STRATA {strata variables};
RUN;
Kaplan-Meier (KM) estimates for the median time of OS (including 95% CI) and 25% and 
75% percentiles will be presented for each treatment arm. The KM estimates at time points 
such as 12 months, 24 months, etc., together with corresponding 95% CIs and the differences 
of these estimates between the darolutamide+docetaxel arm and the placebo+docetaxel arm
will be presented. The SAS code will be similar to the following:
PROC LIFETEST DATA = <DATASET>;
TIME EFFVAL * CENSORNY;
STRATA TREATMGR;
RUN;
Descriptive statistics of survival follow-up time will be calculated by treatment arm and total. 
Follow-up time is the time to LKAD or death as described for the OS endpoint for censored 
and uncensored patients.
Sensitivity analyses
OS will be evaluated with the unstratified log-rank test and Cox model for the FAS population
(OS sensitivity analysis 1 – unstratified analysis). 
OS will also be evaluated with the stratified log-rank test and Cox model for the FAS 
population using stratification factors collected from the eCRF, in case there are more than 
5% of patients with different values in any stratification variable between IxRS and eCRF (OS 
sensitivity analysis 2 – eCRF-variables stratified analysis).
In addition, OS will also be evaluated with the stratified log-rank test and Cox model for the 
FAS population using extent of disease stratification factors collected from the central 
imaging review (OS sensitivity analysis 3 – central imaging review extent of disease as 
stratification factor).
6.2.2
Secondary Efficacy Endpoints
If the primary endpoint OS is significant, secondary efficacy endpoints will be tested with the 
hierarchical gatekeeping procedure. The order of secondary endpoints is as follows:
1) Time to castration-resistant prostate cancer 
2) Time to pain progression 
3) Symptomatic skeletal event free survival (SSE-FS) 


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4) Time to first symptomatic skeletal event (SSE) 
5) Time to initiation of subsequent systemic antineoplastic therapy
6) Time to worsening of disease-related physical symptoms based on functional 
assessment of cancer therapy / National Comprehensive Cancer Network prostate 
cancer symptom index 17 item questionnaire (NCCN-FACT FPSI-17) 
7) Time to initiation of opioid use for ≥ 7 consecutive days
If the primary endpoint OS is statistically significant at a 0.025 level (one-sided), the 
secondary endpoints will be tested using a hierarchical test procedure in the order as described 
above at the same nominal significance level. If the OS or a secondary endpoint is not 
statistically significant, the hierarchical procedure is stopped and all subsequent analyses of 
the secondary endpoints will be considered exploratory.
6.2.2.1
Time to castration-resistant prostate cancer
Time to castration-resistant prostate cancer is defined as the time from randomization to the 
time of the occurrence of the following events, whatever comes first (date of first occurrence 
of castration-resistant prostate cancer minus date of randomization): 

PSA progression, according to PCWG3 criteria, with serum testosterone being at 
castrate level <0.50 ng/mL, is defined as the date that a 25% or greater increase and an 
absolute increase of 2 ng/mL or more from the nadir (lowest at or after baseline) is 
documented, which both are confirmed by a second value obtained at least 3 weeks 
later, including all potential PSA values ≥2 ng/mL above nadir and ≥25% increase 
above nadir between initial assessment date and confirmation assessment date. This 
definition requires serum testosterone at castrate levels <0.50 ng/mL and a first 
assessment date at least 12 weeks from randomization.

Radiological progression by soft tissue and visceral lesions, is defined according to 
Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 (1), based on 
MRI / CT scans of the chest, abdomen, and pelvis performed by the Investigator, as 
recommended by Prostate Cancer Clinical Trials Working Group (PCWG3) (2).

Radiological progression by bone lesions, is defined according to PCWG3 criteria 
based on whole body 99mTc methylene diphosphonate bone scans performed by the 
Investigator. Bone lesions will be recorded separately from soft tissue and visceral 
lesions. 
The following censoring rules in Table 6–2 will be applied:
Table 6–2 Censoring rules for time to castration-resistant prostate cancer
Situation
End Date
Censored
Castration-resistant prostate cancer due to 
any component event during study
The earliest event date among the three 
components
No
No baseline or post-baseline event 
assessment for all three components #
Date of randomization (Day 1)
Yes
PSA progression event immediately after 
two or more consecutive missing 
assessments, without any prior radiological 
Date of the last PSA assessment before 
the consecutive missing PSA 
assessments or date of last radiological 
Yes


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progression event and before or at data 
cut-off
assessment, whichever comes later
No castration-resistant prostate cancer (or 
no event among the three components) 
before or at data cut-off date
Date of the latest date among the three 
components’ last assessment before 
discontinuation or randomization date 
(censored at Day 1 if there is no follow-up 
available), whichever is later
Yes
Subsequent systemic antineoplastic
therapy without any prior components
event, without post PSA progression event 
and before or at data cut-off
Date of last radiological assessment 
before or on subsequent systemic 
antineoplastic therapy start date or the 
last PSA assessment date or 
randomization date (censored at Day 1 if 
there is no follow-up available), whichever 
comes later
Yes
# This includes subjects with superscan at baseline for radiological bone lesion assessment
A summary of first castration-resistant prostate cancer events will be provided. Patients with 
multiple events are only counted for the category in which the first event occurred. If multiple 
CRPC events (component events) occur on the same date for one subject, the subject is only 
counted into one category in the order of: radiological soft tissue/ visceral lesion progression 
> radiological bone progression > PSA progression.
The primary analysis of time to castration-resistant prostate cancer will be based on central 
PSA assessments only. The sensitivity analysis of time to castration-resistant prostate cancer 
will be based on both central and local PSA laboratory data.
6.2.2.2
Time to pain progression
Time to pain progression is defined as the time from randomization to the first date a patient 
experiences pain progression (first date of pain progression minus date of randomization).
Pain will be assessed with the BPI-SF questionnaire. The main analysis is based on the ePRO 
device questionnaire data only. Pain progression is defined as follows:

For asymptomatic patients (worst pain subscale [WPS] 0 at baseline), pain progression 
is defined as 
o
an increase of 2 or more points in the “worst pain in 24 hours” score (i.e. 2 or 
more point increase in WPS score) from nadir (i.e. zero) observed at 2 
consecutive evaluations ≥4 weeks apart, or
o
initiation of short- or long-acting opioid use for pain.

For symptomatic patients (WPS >0 at baseline), pain progression is defined as 
o
an increase of 2 or more points in the “worst pain in 24 hours” (i.e. 2 or more 
point increase in WPS score) from nadir observed at 2 consecutive evaluations 
≥4 weeks apart and a WPS of ≥4, or
o
initiation of short- or long-acting opioid use for pain.


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The following censoring rules in Table 6–3 will be applied:
Table 6–3 Censoring rules for time to pain progression
Situation
End Date
Censored
Pain progression during study
Start date of pain progression 
No
No baseline or post-baseline event 
assessment
Date of randomization (censored at 
Day 1 if there is no follow-up available)
Yes
No pain progression before or at data 
cut-off date
The last BPI-SF assessment date or 
randomization date (censored at Day 
1 if there is no follow-up available), 
whichever comes later
Yes
Opioids taken for any reason within 4 
weeks before or on randomization
Date of randomization (Day 1)
Yes
Sensitivity analysis for time to pain progression

Pain progression will be evaluated with an increase of 2 or more points in the “worst 
pain in 24 hours” score (i.e. 2 or more point increase in WPS score) from baseline.

Pain progression will be evaluated with an increase of 2 or more points in the “worst 
pain in 24 hours” score (i.e. 2 or more point increase in WPS score) from nadir after 
completion of docetaxel.

Pain progression will be evaluated with an increase of 2 or more points in the “worst 
pain in 24 hours” score (i.e. 2 or more point increase in WPS score) from baseline 
after completion of docetaxel.

The main analysis is based on the ePRO device questionnaire data only. Pain 
progression will be evaluated in this sensitivity analysis with source data from both the 
ePRO device and the paper questionnaire, based on the main analysis definition 
(change from nadir).
6.2.2.3
Symptomatic skeletal event free survival
Symptomatic skeletal event free survival (SSE-FS) is defined as the time from randomization 
to the first occurrence of an SSE or death from any cause, whichever comes first (date of first 
occurrence of an SSE or death minus date of randomization). 
An SSE is defined as the occurrence of one of the followings, whichever comes first:

external beam radiation therapy (EBRT) to relieve skeletal symptoms, or 

new symptomatic pathologic bone fracture, or 

occurrence of spinal cord compression, or 

tumor-related orthopaedic surgical intervention.
The following censoring rules in Table 6–4 will be applied:


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Table 6–4 Censoring rules for SSE-FS
Situation
End Date
Censored
SSE during study
Date of the first assessment reporting 
event
No
Death during study without SSE event
Date of death
No
No SSE before or at data cut-off date
Last SSE assessment before or at 
data cut-off
Yes
Patient lost to follow-up before or at 
data cut-off date
Date of last SSE assessment or 
randomization date (censored at Day 1
if there is no follow-up available), 
whichever comes later
Yes
A summary of SSE-FS events will be provided. Patients with multiple events are only counted 
for the category in which the first event occurred. If multiple SSEs (component events) occur 
on the same date for one patient, the patient is only counted into one category in the order of: 
spinal cord compression > bone fracture > orthopedic surgery > EBRT.
6.2.2.4
Time to first SSE
Time to first SSE is defined as the time from randomization to the first occurrence of an SSE. 
Death is not considered as event in this endpoint (date of first SSE minius date of 
randomization); otherwise the same rules as for SSE-FS apply. 
The following censoring rules in Table 6–5 will be applied:
Table 6–5 Censoring rules for first SSE
Situation
End Date
Censored
SSE during study
Date of the first assessment reporting 
event
No
No SSE before or at data cut-off date
Last SSE assessment before or at 
data cut-off
Yes
Patient lost to follow-up before or at 
data cut-off
Date of last SSE assessment or 
randomization date (censored at Day 1
if there is no follow-up available), 
whichever comes later
Yes
A summary of first SSE will be provided. Patients with multiple events are only counted for 
the category in which the first event occurred. If multiple SSEs (component events) occur on 
the same date for one patient, the patient is only counted into one category in the order of: 
spinal cord compression > bone fracture > orthopedic surgery > EBRT.


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6.2.2.5
Time to initiation of subsequent systemic antineoplastic therapy
Time to initiation of subsequent systemic antineoplastic therapy2 is defined as the time from 
randomization to initiation of the first subsequent systemic antineoplastic therapy  (first 
subsequent systemic antineoplastic therapy date minus date of randomization).
Systemic antineoplastic therapy treatment was selected in CM dataset, which includes 
“SYSTEMIC ANTI-CANCER THERAPY (MEDICATION) DURING FOLLOW-UP” eCRF
pages and CONCOMITANT MEDICATION” and “PRIOR AND CONCOMITANT 
MEDICATION” eCRF pages. Docetaxel administrated concomitantly with study drug that 
continued after study drug stopped will not be counted as subsequent systemic antineoplastic
therapy.
From above 3 eCRF pages, subsequent systemic antineoplastic therapy is identified with
criteria available in Appendix 9.2. The sponsor’s assessment of systemic antineoplastic 
therapy is presented in a supplementary document. The final list of systemic antineoplastic 
therapy will be based on the sponsor’s assessment and medical review before database lock.
The following censoring rules in Table 6–6 will be applied:
Table 6–6 Censoring rules for time to initiation of subsequent systemic antineoplastic 
therapy
Situation
End Date
Censored
Initiation of first subsequent systemic 
antineoplastic therapy during study
Start date of first subsequent systemic 
antineoplastic therapy 
No
No subsequent systemic antineoplastic 
therapy before or at data cut-off date
The last know alive date or death date 
or randomization date (censored at 
Day 1 if there is no follow-up 
available), whichever comes later
Yes
6.2.2.6
Time to worsening of disease-related physical symptoms 
Time to worsening of disease-related physical symptoms is defined as the time from 
randomization to the first date a patient experiences an increase in disease-related physical 
symptoms based on the NCCN-FACT-FPSI-17 questionnaire (date of first worsening of 
disease-related physical symptoms minus date of randomization). An increase in disease-
related physical symptoms is defined as 3-point decrease of FPSI-DRS-P subscale (a lower 
score = higher symptom burden, a score of “0” is a severely symptomatic patient and the 
highest possible score is an asymptomatic patient) from baseline in the disease-related 
physical symptoms subscale (FPSI-DRS-P subscale of the NCCN-FACT-FPSI-17 
questionnaire) observed at 2 consecutive evaluations ≥4 weeks apart. 
                                                
2 Antineoplastic therapy is the same as “anti-cancer therapy” in this study.


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The following censoring rules in Table 6–7 will be applied:
Table 6–7 Censoring rules for time to worsening of disease-related physical 
symptoms 
Situation
End Date
Censored
Worsening of disease-related physical 
symptoms during study
Start date of worsening of disease-
related physical symptoms
No
No baseline or post-baseline event 
assessment
Date of randomization (censored at 
Day 1 if there is no follow-up available)
Yes
No worsening of disease-related 
physical symptoms before or at data 
cut-off date
Date of last assessment, or 
randomization date (censored Day 1 if 
there is no follow-up available), 
whichever comes later
Yes
The main analysis is based on the ePRO device questionnaire data only. In addition, time to 
worsening of disease-related physical symptoms will be evaluated as a sensitivity analysis 
with source data from both the ePRO device and the paper questionnaire.
6.2.2.7
Time to initiation of opioid use for ≥7 consecutive days 
Time to initiation of opioid use for ≥7 consecutive days is defined as the time from 
randomization to the date of first opioid use for ≥7 consecutive days (date of first opioid use 
for ≥7 consecutive days minus date of randomization). Data of opioid use related to prostate 
cancer pain will be included. Opioid use for non-malignant cause will be excluded. Time to 
opioid use will be determined by opioid use captured via electronic case report form. 
The following censoring rules in Table 6–8 will be applied:
Table 6–8 Censoring rules for time to initiation of opioid use for ≥7 consecutive days
Situation
End Date
Censored
Opioid use for ≥7 consecutive days 
after randomization during study
Start date of initiation of opioid use for 
≥7 consecutive days for prostate 
cancer
No
No opioid use for ≥7 consecutive days 
before or at data cut-off date
Date of last visit at which analgesic
consumption question was collected or 
randomization date (censored at Day 1
if there is no follow-up available), 
whichever comes later.
Yes
Opioid use for ≥7 consecutive days 
at/before randomization date
Date of randomization (Day 1)
Yes
A summary of initiation of opioid use for ≥7 consecutive days will be provided.
6.2.2.8
Analyses of Secondary efficacy endpoints
The secondary efficacy variables will be analyzed for the FAS population unless otherwise 
specified. Time-to-event endpoints will be analyzed using stratified log-rank test with 


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randomization stratification factors using IxRS data. Hazard ratio and 95% CI will be 
provided using the Cox model stratified by the same factors as were used for randomization. 
Median time, the 25th and 75th percentiles and associated 95% CI of KM estimates will be 
presented by treatment arm as well as the number and percentage of censored observations. A 
KM curve will be generated for each treatment arm.
6.2.3
Exploratory Efficacy Endpoints
6.2.3.1
Rate of absolute PSA response at 6 and 12 months
Absolute PSA response is defined as baseline PSA value above the detection limit and a post 
baseline PSA level below 0.2 ng/mL, confirmed by a second subsequent PSA value below  
0.2 ng/mL 3 or more weeks later, with all potential PSA values between initial date and 
confirmation date below 0.2 ng/mL. 
Rate of absolute PSA response is defined as the number of patients with absolute PSA 
response, divided by the total number of patients randomized. Rate of absolute PSA response 
will be evaluated on patient data up to 6 months and 12 months after randomization.
6.2.3.2
Rate of relative PSA response at 3, 6 and 12 months
Relative 30% PSA response is defined as baseline PSA value above the detection limit and a 
post baseline ≥30% reduction of the PSA level compared to the baseline value, confirmed by 
a second subsequent PSA value with a ≥30% reduction from baseline 3 or more weeks later, 
with all potential PSA values between initial date and confirmation date showing a ≥30% 
reduction from baseline. Relative 50% and 90% PSA response is defined in the same way.
Rate of relative PSA response is defined as the number of patients with relative PSA response, 
divided by the total number of patients randomized. Rate of relative PSA response will be 
evaluated on patient data up to 3 months, 6 months, and 12 months after randomization.
The comparison of absolute PSA response at 6 and 12 months between two treatment arms 
will be done using the Cochran-Mantel-Haenszel test stratified by the IxRS stratification 
factors. Same comparison will be performed for relative PSA response at 3, 6 and 12 months.
In addition, descriptive statistics and frequency distribution (no decline, < 30%, 30% − < 
50%, 50% − < 90%, ≥90%) will be provided for PSA maximum percent decline from 
baseline at any time on study.
6.2.3.3
Time to PSA progression
The time to PSA progression is defined as the time from the date of randomization to the date 
of first PSA progression with testosterone at castrate level < 0.5 ng/mL. The same definition 
of PSA progression with testosterone at castrate level < 0.5 ng/mL and censoring rules applied 
to time to castration-resistant prostate cancer in Section 6.2.2 will be applied here. Baseline 
PSA value is the last non-missing observation on or before the first day of study drug intake
for treated patients. For not treated patients the baseline value will be the last non-missing 
observation on or before the randomization date . Time to PSA progression will be 
descriptively evaluated using KM estimates for quantiles, including 95% two-sided CIs. The 
following censoring rules in Table 6–9 will be applied:


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Table 6–9 Censoring rules for PSA progression
Situation
End Date
Censored
PSA progression event during study
Event assessment date
No
No baseline or post-baseline event 
assessment 
Date of randomization (censored at 
Day 1 if there is no follow-up available)
Yes
PSA progression event immediately
after two or more consecutive missing 
assessments
Date of the last PSA assessment 
before the consecutive missing ones
Yes
No PSA progression before or at data 
cut-off date
Date of last PSA assessment before 
discontinuation or randomization date
(censored at Day 1 if there is no follow-
up available), whichever comes later
Yes
The primary analysis of PSA response and progression will be based on central PSA 
assessments only. A sensitivity analysis of PSA response and progression will be based on 
both central and local laboratory data. 
6.2.3.4
ECOG PS
ECOG PS will be summarized with descriptive statistics and frequency tables. Changes from 
baseline to worst post-baseline ECOG PS score during treatment will be summarized in a shift 
tables by treatment arm. In addition, changes from worst post-baseline ECOG PS score during 
treatment to EOT score will be summarized in a shift table by treatment arm.
Baseline ECOG value is the last non-missing observation on or before the randomization date.
6.2.3.5
Quality of life 
PRO data as measured by the NCCN-FACT FPSI-17 and the BPI-SF will be analyzed.
Quality of Life and PRO data analyses specified in this section are based on the ePRO device 
questionnaire data only.
The PRO analyses will be performed for the patients in the FAS. Statistical tests will be 
performed with a one-sided test with type I error 0.025 (equivalent a two-sided test with type I 
error 0.05). The p-values are for descriptive purposes only.
Descriptive statistics on observed data will be presented for the NCCN-FACT FPSI-17
questionnaire (total score and each domain subscale score), and for BPI-SF questionnaire 
(pain severity and pain interference scores) at each assessment time and for change from 
baseline by treatment arm. 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 arm
will be summarized.
An analysis of covariance (ANCOVA) model (a mixed linear model, with a random 
coefficient) for BPI-SF pain severity or interference scores in the time-adjusted Area under 
Curve (AUC) will be used to estimate the mean difference and treatment effect between the 
two treatment arms.


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Least-square mean estimates, standard errors and 95% CIs will be estimated for each 
treatment arm and for the treatment arm 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 BPI-SF pain severity and 
interference scores. 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 BPI-SF pain severity and interference scores 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).
6.2.4
Subgroup Analyses for Efficacy Endpoints 
Subgroup analyses will be conducted for the primary efficacy endpoint OS, based on the FAS 
population. Descriptive statistics and HR estimates with 95% CI will be provided at least for 
the subgroups listed below, provided that at least 10 total events are observed within the 
subgroup across the treatment arms. HRs will be presented in forest plots. All subgroups 
analyses will be performed using an unstratified Cox model. Number of patients, number of 
events and KM estimates for the median per arm for all planned subgroups will be presented 
in the forest plot.

Stratification Factor based on eCRF: Extent of disease (non-regional lymph nodes 
metastases only, bone metastases with or without lymph node metastases, or visceral 
metastases with or without lymph node metastases or with or without bone metastases)

Stratification Factor based on eCRF: ALP at baseline (<ULN, ≥ULN) 

Age category (<65, 65-74, 75-84, ≥85 years)

Race (White, Asian, Black or African American, Other) 

Geographical region (North America, Asia Pacific, Rest of the World)

PSA values (<median of overall population, ≥median of overall population) at baseline

ECOG PS at baseline (0, 1)

Gleason score (<8, ≥8) at initial diagnosis

Metastases at initial diagnosis (Yes: Stage IV-M1, No: Stage I, IIA, IIB, III, IV-M0)
Further important baseline cancer characteristics may also be considered.
Subgroup analyses will not be performed for the sensitivity analyses.
6.3
Safety
The safety endpoints include:


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
AEs until the End of Treatment visit

SAEs until the End of Treatment visit

Study drug-related SAEs in Active Follow-up for up to one year

Study drug-related SAEs until the end of Long-term Follow-up

Laboratory safety assessments (hematology, clinical chemistry, urinalysis)

Vital signs: blood pressure and heart rate

12-lead electrocardiogram (ECG)
6.3.1
Adverse Events
AEs will be coded using MedDRA 24.0 or most recent version. The severity (or intensity) of 
AEs will be documented using the National Cancer Institute-Common Terminology Criteria 
for Adverse Event version 4.03 (NCI-CTCAE v 4.03). Descriptive summary tables will be 
presented on all safety parameters by treatment arm. 
The AEs will be presented with their worst NCI-CTCAE v 4.03 grade CTC 1 = mild,
CTC 2 = moderate, CTC 3 = Severe, CTC 4 = life threatening, CTC 5 = fatal. The causal 
relationship is based on whether there was a reasonable causal relationship to darolutamide or 
placebo and docetaxel. AEs will be classified by the investigator as related or not related to 
darolutamide or placebo and docetaxel separately.
Treatment-emergent AE (TEAE) is defined as any event arising or worsening after the first 
dose of darolutamide or placebo until 30 days after the last dose of darolutamide or placebo.
An overview of TEAEs will be summarized by treatment arm in the overall treatment period.
The following summaries will be created separately for study drug-related (darolutamide or 
placebo-related) and docetaxel-related TEAEs, by treatment arm: TEAEs leading to 
permanent discontinuation of study treatment, TEAEs leading to dose reduction and/or dose
interruption, and drug-related TEAEs. Summary statistics (frequency and percentage of 
patients, not of events) will be presented by treatment arm, MedDRA SOC and PT, and NCI-
CTCAE worst grade for the following:

Incidence of all TEAEs 

Incidence of TEAEs of NCI-CTCAE grade 3, 4 or 5

Incidence of TEAEs leading to permanent discontinuation of darolutamide or placebo
and docetaxel separately

Incidence of TEAEs leading to dose reduction

Incidence of TEAEs leading to dose interruption

Incidence of TEAEs with incidence of at least 5%

Incidence of all drug-related TEAEs 

Incidence of drug-related TEAEs of NCI-CTCAE grade 3, 4 or 5

Incidence of drug-related TEAEs leading to permanent discontinuation of 
darolutamide or placebo and docetaxel separately


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
Incidence of drug-related TEAEs leading to dose reduction

Incidence of drug-related TEAEs leading to dose interruption

Incidence of drug-related TEAEs with incidence of at least 5%

Incidence of pre-treatment AEs and post-treatment AEs (after 30 days from the last 
dose of study drug).

Incidence and prevalence of most common TEAEs ≥10% incidence in either 
treatment arm, analyzed within pre-specified time intervals. The same summary will 
be presented by geographical regions (North America, Asia Pacific, Rest of the World)
as well.

Incidence of COVID-19 related TEAEs   

The following subgroup analyses will be performed for overview of TEAEs and for 
TEAEs showing at least 5% point differences in incidence proportions between any of 
the subgroup categories .
o
Age category (<65, 65–74, 75–84, ≥85 years)
o
Geographical region (North America, Asia Pacific / Rest of the World
o
Renal function – eGFR at baseline (normal, mild impairment, moderate 
impairment, severe impairment)
o
Hepatic function at baseline (normal, mild, moderate, severe impairment)
o
Concomitant statin use (no, yes) to be determined by concomitant medication 
with any medication in the Standardized Drug Grouping (SDG) ‘Statins’.

Incidence of the TEAEs in the following will be presented by groupings and worst 
CTCAE grade.
o
Patients with present medical history of cardiac disorder (SOC).
o
Patients with present medical history of renal impairment (SMQ Acute renal 
failure; SMQ Chronic kidney disease).
o
Patients with present TEAE interstitial lung disease (not meidcal history, SMQ 
interstitial lung disease (narrow search)).
o
Patients with present TEAE neutropenia (SMQ of Haematopoietic leukopenia 
(narrow search)), by concomitant G-CSF use, where G-CSF is defined by ATC 
code: L03AA. The same summary will be presented by geographical regions 
(North America, Asia Pacific, Rest of the World) as well.
TEAE Groupings Considered as Special Topics
The following TEAE groupings are considered as special topics and shown in Appendix 9.6, 
Table 9–2:

Bone fractures excluding pathological fractures

Diabetes mellitus and hyperglycemia

Fall

Fatigue/ asthenic conditions


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
Weight decreased

Rash

Seizure

Hypertension 

Vasodilatation and flushing 

Mental impairment disorders 

Depressed mood disorders 

Breast disorders/gynecomastia 

Cardiac disorders

Cerebral ischaemia

Cerebral and intracranial hemorrhage
The following tables will be created for TEAEs of special topics:

Incidence of TEAEs

Incidence of TEAEs leading to permanent discontinuation of (darolutamide or placebo
and docetaxel separately) 

Incidence of TEAEs leading to dose reduction

Incidence of TEAEs leading to dose interruption

Incidence of treatment-emergent SAEs (TESAEs)

Incidence and prevalence of most common TEAEs of special topics ≥5% incidence in 
either treatment arm, analyzed within pre-specified time intervals. The same summary 
will be presented by geographical regions (North America, Asia Pacific, Rest of the 
World) as well.
Fracture events will be described by a cumulative incidence plot of fracture. A summary of 
treatment-emergent fracture by bone health agent use (for selection of bone health agent see 
Appendix 9.7) 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 
of patients with fracture events breakdown by relevant events occurring within 7 days 
window: fall, accident, syncope and/or loss of consciousness, dizziness will be presented.
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 summary of time to fall and 
fractures events will be presented in descriptive and inferential statistics, respectively. In 
addition, Kaplan-Meier plots 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 (darolutamide or placebo and docetaxel)
between the treatment arm, additional summaries based on event rate per 100 patient year will 
be performed for all TEAEs, special topics TEAEs, and all TESAEs occurring after the first 


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dose of darolutamide or placebo. The exposure adjusted incidence rate is calculated as the 
total number of patients with a given TEAE divided by the total darolutamide or placebo
treatment duration of all patients in years. The rate is expressed in 100 patient years. 
The treatment duration in years will be calculated as treatment duration in days divided by 
365.25. The risk difference ‘darolutamide+docetaxel arm – placebo+docetaxel arm’ and risk 
ratio ‘darolutamide+docetaxel arm vs. placebo+docetaxel arm’ 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+docetaxel arm the risk ratio will not be 
calculated. The incidence rate ratio for darolutamide+docetaxel arm vs. placebo+docetaxel 
arm will also be calculated.
6.3.2
Deaths and Serious Adverse events
Serious adverse events (SAEs) will be classified using the NCI-CTCAE version 4.03 and 
MedDRA version 24.0 or most recent version.

Treatment-emergent SAEs

Treatment-emergent SAEs leading to permanent discontinuation of study treatment

Treatment-emergent SAEs leading to dose reduction

Treatment-emergent SAEs leading to drug interruption

Treatment-emergent drug-related SAEs

COVID-19 related treatment-emergent SAEs

Listing of treatment-emergent SAEs

Listing of non-treatment-emergent SAEs
The incidence of deaths in the study: within 30 days after first dose of study drug / docetaxel, 
during study treatment from first to last dose of study drug / docetaxel, within 30 days after 
last dose of study drug/ docetaxel, later than 30 days after last dose of study drug/ docetaxel, 
will be summarized by each treatment arm and cause of death. All deaths before treatment 
start, during treatment and within 30 days after last dose of study drug, and later than 30 days 
after 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. 
6.3.3
Additional Primary Malignancies
Summary statistics (frequency and percentage of patients, not of events) will be presented by 
treatment arm, MedDRA SOC and PT for additional primary malignancies. A listing will be 
generated for patients with additional primary malignancies.
The additional primary malignancies are defined by:  SMQ Malignant tumors, excluding: the 
following terms: 

PT: Prostate cancer

PT: Prostate cancer metastatic

PT: Prostate cancer recurrent


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
PT: Prostate cancer stage 0

PT: Prostate cancer stage I

PT: Prostate cancer stage II

PT: Prostate cancer stage III

PT: Prostate cancer stage IV

PTs from HLGT: Metastases

PT: Cancer in remission

LLT: Progression of pre-existing cancer
6.3.4
Laboratory Safety Assessments
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 arm 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 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 “<”) will be imputed with the lower
or higher detection limit (refer to Section 4.3).
The frequency of laboratory abnormalities regarding hematology, international normalized 
ratio (INR),clinical chemistry, and urinalysis will be tabulated by visit and treatment arm. 
Worst grades for hematological and biochemical toxicities will be calculated according to 
CTCAE, v4.03 based on laboratory measurements, and will be summarized by treatment arm
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.


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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 either 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 arm and visit. 
Only for ALT, AST and creatinine, 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.
In addition, the mean of lab values (from both scheduled and unscheduled assessments) for 
ALT, AST, Bilirubin, Hemoglobin, Neutrophils and Platelets will be displayed in line plots by 
treatment arm and time interval (1 week or less) relative to the first concomitant docetaxel 
treatment date, from baseline up-to Visit 6 (EOT visit will be included if the last visit number 
before EOT visit is < 7) for safety patients who had concomitant docetaxel with darolutamide 
or placebo. In the line plots, if one patient has the repeated measures within the same interval, 
the mean of the repeated measures for the same patient will be used in the mean calculation.
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 (ref. 3). 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 arm. 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.


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Figure 6–1 Example for Hy’s law plot
Unscheduled laboratory data will be listed (in Section 14 listings and Section 16 of the 
CSR),but will not be displayed in the descriptive tables.
6.3.5
Other Safety Measures
12-lead ECG
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 as below:

Fridericia’s correction: QTc = QT/RR
0.33

Bazett’s correction: QTc =QT/RR
0.5
where RR interval = 60 / Ventricular Rate
Standard 12-lead ECGs were performed at screening and at each visit in a supine position 
after at least 10 minutes rest.
Descriptive statistics including arithmetic mean, SD, median, minimum, and maximum will
be presented for the following ECG parameters: Ventricular rate, PR, QRS, RR (derived), QT, 
QTcB (derived) and QTcF (derived). Parameters will be summarized for actual results and the 
change from baseline for the safety analysis set by treatment arm at each scheduled visit. 
Baseline for 12-lead ECG will be the mean of separate recordings. Similarly, post baseline 
values of 12-lead ECG for patients will be the mean of separate recordings.
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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Mean time courses +/- one standard deviation will be displayed graphically.
The last non-missing 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 the timing of ECG is missing at day 1 then the 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 451-480 msec, QTc interval 481-
500 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 of patients with QTC interval (max value) ≤450 msec, 451-480 msec, 481-500
msec and > 500 msec data will also be displayed graphically using a bar chart.
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, 451-480 msec, 
481-500 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.  
Unscheduled ECG data will be listed (in Section 14 listings and Section 16 of the CSR), but 
will not be displayed in the summary tables.
Vital signs
For each treatment arm, 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 is 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.
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


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Protocol No.: BAY 1841788 / 17777
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
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 
arm and time interval.
Unscheduled vital signs data will be listed (in Section 14 listings and Section 16 of the CSR),
but will not be displayed in the summary tables.
Concomitant statins (BCRP substrates) of interest
The number of patients reported with the below concomitant statins which are BCRP
substrates will be described with frequency and percentage for the SAF population.
Concomitant statins (BCRP substrates) of interest are defined as:
Atorvastatin (ATC code C10AA05)
Fluvastatin (ATC code C10AA04)
Rosuvastatin (ATC code C10AA07)
Simvastatin (ATC code C10AA01).
More details are available in Appendix 9.8.
A listing with intervals will be created for these subjects when above statins were taken
concomitantly with the study-treatment.
Interval will be created as follow: number of days when statins and study-treatment were
concomitantly taken plus 14 days.
For partial dates of concomitant statins, the imputation rules in Appendix 9.1will be applied. 
If the end date is completely missing it will be assumed that the concomitant medication is 
ongoing at study treatment end. If the start date is completely missing it is assumed that 
concomitant medication was taken before the start of study treatment.
The frequency of pre-defined adverse events (see Appendix 9.9) will be detailed if occurring 
during the interval defined above, for the subset of patients taking statins that are BCRP 
substrates. 
6.4
Other Exploratory Variables

Medical resource use 
Summary statistics (descriptive statistics and frequency) will be presented by treatment arm
for days in hospital and equivalent facility, and days in ICU (intensive care unit) facility,  
separately. Location/place of healthcare visit will be presented in frequency. Listings of 
patients with healthcare resource use will be provided. 

Biomarker evaluations 
Biomarker analyses will be described in a separate biomarker analysis plan. Results from 
exploratory biomarker analyses will be reported in a separate biomarker report.
6.5
Pharmacokinetics
Pharmacokinetics in two sub-groups: 1) at least the first 20 randomized patients who 
have received at least 1 cycle of docetaxel and 2) Chinese patients in the PK substudy


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Protocol No.: BAY 1841788 / 17777
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The concentration-time courses of all analytes will be tabulated separated by treatment and 
subgroup. The following statistics will be calculated for each of the sampling points: 
arithmetic mean, SD, and coefficient of variation (CV); geometric mean, geometric SD (re-
transformed SD of the logarithms), and CV; minimum, median, maximum value, and the
number of measurements.
Means at any time will only be calculated if at least 2/3 of the individual data were measured
and were above the lower limit of quantification (LLOQ). For the calculation of the mean
value, a data point below LLOQ will be substituted by one-half of this limit. 
In tables showing mean values, where values below LLOQ are included in the calculation of 
mean values, these means will be marked.
Individual and geometric mean concentration versus time curves of all analytes (using the
actual sampling times for individual plots and the planned sampling times for mean plots) will
be plotted by treatment using both a linear and semilogarithmic scale. For darolutamide and 
its diastereomers and metabolite all analytes will be plotted together.
Pharmacokinetic parameters (tmax, tlast and parameters listed under ‘other parameters’ 
excluded) will be summarized by the statistics mentioned above. The tmax, tlast will be 
described utilizing minimum, maximum, and median as well as frequency counts.
The diastereomer/darolutamide ratios will be calculated using the following equation:
Diastereomer/darolutamide ratios = 
AUC(0-tlast) (S,R)-darolutamide / AUC(0-tlast) darolutamide and
AUC(0-tlast) (S,S)-darolutamide / AUC(0-tlast) darolutamide
Metabolite keto-darolutamide to parent darolutamide AUC(0-tlast) ratios will be calculated 
using the following equation:
Metabolite Ratio = 
(AUC(0-tlast) metabolite / MW metabolite) / (AUC(0-tlast) parent / MW parent) 
Molecular weight (MW) keto-darolutamide = 396.8 g/mol
Molecular weight (MW) darolutamide =398.8 g/mol
Individual data points of docetaxel PK parameters Cmax and AUC(0-tlast) for treatments of 
treatments of docetaxel in combination with darolutamide and docetaxel with placebo will be 
compared with a scatter plot.   
Only dense PK sampling data from the first Visit (as well as Day 15 for the Chinese 
subgroup) will be used for statistical analysis. Sparse PK samples from later visits will only be 
listed.
Pharmacokinetics in all patients
Individual concentration-time data of darolutamide (BAY 1841788), (S,S)-darolutamide
(BAY 1896952), (S,R)-darolutamide (BAY 1896951), keto-darolutamide (BAY 1896953),
and docetaxel will be provided in a clinical study report appendix. The PK data will be used 
for population PK data anlaysis that will be described in detail in a separate M&S report.


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Protocol No.: BAY 1841788 / 17777
Page: 38 of 48
7.
Document History and Changes in the Planned Statistical Analysis

Approval of SAP v1.0, dated 07 APR 2017, was based on the integrated clinical study 
protocol v2.0 (amendment 1), dated 04 OCT 2016.

Approval of interim futility SAP v1.0, 11 MAR 2019 was based on SAP v1.0, dated 
07 APR 2017 and the integrated clinical study protocol v2.0 (amendment 1), dated 04 
OCT 2016.

Approval of SAP v2.0, dated 03 JUL2019, was mainly an update of the efficacy 
censoring rules from SAP v1.0 and was based on the integrated clinical study protocol 
v3.0 (amendment 5), dated 12 FEB 2018

Approval of interim futility SAP v2.0, 03 JUL 2019, was mainly an update of the 
efficacy censoring rules from SAP v1.0 and was based on SAP v2.0, dated 03 
JUL2019 and the integrated clinical study protocol v3.0 (amendment 5), dated 12 FEB 
2018.

Approval of SAP v3.0, dated 26 MAY 2020, describes the changes of removing 
interim analysis 2 for futility and efficacy from the testing plan due to data collection
limitations during the COVID-19 pandemic and was based on the integrated clinical 
study protocol v5.0 (amendment 7), dated 26 MAY 2020.

Approval of SAP v4.0, dated 22 SEP 2021, based on the SAP v3.0, dated 26 MAY 
2020, describes the changes as a result of the following: 
o
Efficacy changes included applying a hierarchical gatekeeping procedure to the 
secondary efficacy endpoints, inclusion of a summary of ECOG PS, additional 
relative 50% and 90% PSA response rate and PSA maximum percent decline 
from baseline and
o
Safety changes included the analysis of special topics adverse events,
additional primary malignancies, liver function laboratory test, 12-lead ECG, 
etc.

Approval of SAP v4.1, dated 11 NOV 2021, based on the SAP v4.0, dated 22 SEP 
2021, describes the changes as a result of the following: 
o
Analysis set changes with an additional statement: Patients will be excluded 
from all FAS, SAF and PKS if they are related to or associated with any 
critical GCP violations that result in fraudulent patient data.
Rationale: After detection of issues with investigator fraud at one site, it was 
decided to exclude one affected patient from all analysis sets as these data 
cannot be trusted.
o
Efficacy change included a sensitivity analysis of OS with central imaging 
review extent of disease as stratification factor.
o
Safety changes included summary of incidence and prevalence of most 
common TEAEs and special topics TEAEs by geographical regions, and 
incidence of TEAE neutropenia by concomitant G-CSF use and geographical 
regions.


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Protocol No.: BAY 1841788 / 17777
Page: 39 of 48
8.
References
1.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. 
New response evaluation criteria in solid tumours: Revised RECIST guideline 
(version 1.1). Eur J Cancer. 2009;45:228-47.
2.
Scher HI, Morris MJ, Stadler WM, Higano C, Basch E, Fizazi K, et al. Trial 
Design and Objectives for Castration-Resistant Prostate Cancer: Updated 
Recommendations From the Prostate Cancer Clinical Trials Working Group 3. J 
Clin Oncol. 2016;34(12):1402-18.
3.
U.S. Department of Health and Human Services, Food and Drug Administration, 
Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical 
Evaluation, July 2009.
9.
Appendix
9.1
Imputation rule for partial missing Adverse Event/ Concomitant 
medication dates
Table 9–1 Imputation rule for partial missing dates
Partial Dates 
Imputation 
Rule
Impute partial AE/CM Start Date
Impute partial AE/CM Stop 
Date
The day missing 
only
IF AESTDT year and months is same as TRTSDT 
year and months, 
then impute AESTDT= TRTSDT
IF AEENDT year and months is same 
as last known alive date (LKAD) year 
and months,
then impute AEENDT= LKAD
ELSE IF AESTDT year and month is before 
TRTSDT year and months, 
then AESTDT= last date of the months
ELSE impute AEENDT= last date of 
the months
ELSE IF AESTDT year and month is after 
TRTSDT year and months, 
then AESTDT= first date of the months
Both day and 
months missing
IF AESTDT year is same as TRTSDT year, 
then impute AESTDT=TRTSDT
IF AEENDT year is same as last 
known alive date (LKAD) year, 
then impute AEENDT= LKAD
ELSE IF AESTDT year is before TRTSDT year, 
then impute AESTDT=31DECYYYY
ELSE impute 
AEENDT=31DECYYYY
ELSE IF AESTDT year is after TRTSDT year , 
then impute AESTDT=01JANYYYY
Completely 
missing
No need to impute, try to query the sites by DM
No need to impute, try to query the 
sites by DM
Additional criteria 
to meet
1.
AE/CM start date <= AE/CM stop date
2.
The imputed dates <= last known alive date 
(LKAD)
3.
If TRTSDT is missing, use RANDDT as 
reference date


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9.2
Systemic antineoplastic therapy: time to initiation of subsequent 
systemic antineoplastic therapy
1. Systemic antineoplastic therapy treatment was selected from eCRF page in 2 and 3 
below in CM dataset
2. From “SYSTEMIC ANTI-CANCER THERAPY (MEDICATION) DURING 
FOLLOW-UP” eCRF pages
o
ATC code class L (antineoplastic and immunomodulating agents): L01 
Antineoplastic agents, L02 endocrine therapy, L03 immunostimulants and L04 
immunosuppressants. 
o
ATC code class V10.
o
ATC code: G03CA, G03CB, V03AX, V, V98.
3. From “SYSTEMIC ANTI-CANCER THERAPY (MEDICATION) DURING 
FOLLOW-UP” eCRF pages or CONCOMITANT MEDICATION” or “PRIOR AND 
CONCOMITANT MEDICATION” eCRF pages
o
If the WHO-DD drug record number is 062951(ABIRATERONE), 900315
(ANTINEOPLASTIC AGENTS), 012711 (BICALUTAMIDE), 082361
(RADIUM RA 223 DICHLORIDE.
o
If ATC code or code class is same as any above, but the WHO-DD drug record 
number is 093203 (MARSDENIA TENACISSIMA STEM), 000826
(MEGESTROL ACETATE), 007269 (LEUPRORELIN ACETATE), 007321
(GOSERELIN ACETATE), 009759 (TRIPTORELIN EMBONATE), 017648
(DEGARELIX ACETATE), 010277 (UBENIMEX), 017660
(THYMALFASIN), 901166 (OTHER THERAPEUTIC PRODUCTS), then do 
not consider as antineoplastic therapy.
The sponsor’s assessment of antineoplastic therapy is presented in a supplementary document.


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9.3
Brief Pain Inventory – Short Form (BPI-SF) questionnaire and scoring 
information 


Statistical Analysis Plan
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Page: 42 of 48
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).


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9.4
NCCN-FACT FPSI-17 questionnaire and scoring information
Below is a list of statements that other people with your illness have said are 
important. 
Please circle or mark one number per line to indicate your response as it applies 
to the past 7 days.


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NCCN/FACT Prostate Symptom Index-17 (FPSI-17) Scoring Guidelines
(Version 2) 
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, then divide by 
the number of items answered.  This produces the symptom index score.
4. As with all FACIT questionnaires, a high score is good. Therefore, a score of “0” is a 
severely symptomatic patient and the highest possible score is an asymptomatic patient.


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Statistical Analysis Plan
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Page: 46 of 48
Missing data: 
For NCCN-FACT FPSI-17, total scores and subscales scores (disease-related physical 
symptoms, disease–related emotional symptom, treatment side-effects, function/well-being) 
will be assessed. Where there are missing items, subscale scores can be prorated if >50% of 
items on subscale are completed. If ≤50% of the items are answered for any domain, then the 
score of that domain is set to missing. The total score is set to missing if the related overall 
item response rate is ≤80%. (e.g., at least 14 of 17 FACT-G items completed). This is not to 
be confused with individual subscale item response rate, which allows a subscale score to be 
prorated for missing items if >50% of items are answered. In addition, a total score should 
only be calculated if ALL of the component subscales have valid scores.
9.5
Statins medications
Statins will be identified using the Standardized Drug Grouping (SDG) classification 
‘Statins’.


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9.6
Special topic AE definition
Table 9–2 Special topic AE definitions
Grouped term
MedDRA search criteria for special topics
Bone fractures
excluding 
pathological 
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))
Exclude PT pathological fractures
Diabetes 
mellitus and 
hyperglycemia
MLG Hyperglycemia
PT: Diabetes mellitus; Diabetes mellitus inadequate control; Diabetic metabolic 
decompensation; Type 2 diabetes mellitus; Diabetic ketoacidosis
Fall*
PT Fall
PT Accident
Fatigue/ 
asthenic 
conditions
MLG Decreased general strength and energy
PT: Lethargy; Chronic fatigue syndrome; Malaise
Weight 
decreased
MLG: Weight decreased
Rash
MLG: Rash
MLG: Skin erythema
PT: Dermatitis
Seizure
MLG Seizures
Hypertension 
MLG: Hypertension
Vasodilatation 
and flushing 
MLG: Vasodilatation and flushing
Mental 
impairment 
disorders 
HLGT: Mental impairment disorders
Depressed 
mood disorders 
HLGT: Depressed mood disorders and disturbance
Breast 
disorders/gynec
omastia 
HLGT: Breast disorders
Cardiac 
disorders
HLGT Cardiac arrhythmias 
HLGT Coronary artery disorders 
HLGT Heart failures
Cerebral 
ischaemia
MLG: Cerebral infarction and stroke not specified as hemorrhagic or ischemic
MLG: Cerebral ischemic infarction and stroke
PT: Cerebral ischaemia, Transient ischaemic attack
Cerebral and 
intracranial 
hemorrhage
MLG: Cerebral and intracranial hemorrhage
MLG: MedDRA Labeling Grouping; PT: Preferred Term; HLT: High Level Term; HLGT: High Level 
Group Term
* Based on review of verbatims the search criteria for “Fall” was extended by the PT “Accident”.


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9.7
Bone health agent (BHA)
Bone health agent were selected in CM dataset, using ATC codes:
M05BA, M05BB: Bisphosphonates 
M05BX: Denosumab
9.8
Concomitant statins (BCRP substrates) of interest
Concomitant statins (BCRP substrates) of interest
The co-medication statins (BCRP substrates) were selected in CM dataset using 
ATC codes:
Atorvastatin - ATC code C10AA05
Fluvastatin -ATC code C10AA04
Rosuvastatin -ATC code C10AA07
Simvastatin -ATC code C10AA01
As in CM dataset, ATC code (variable CM5CL01) contains only 5 digits, the first 5 digits of
the above ATCs with 7 digits will be used.
In addition, the drug name below will be selected from “standardized medication name”
variable (variable CMDECOD). This list was validated per medical team based on the output
from the prior selection of ATC.
CMDECOD to select:
ATORVASTATIN
ATORVASTATIN CALCIUM
FLUVASTATIN
FLUVASTATIN SODIUM
ROSUVASTATIN
ROSUVASTATIN CALCIUM
SIMVASTATIN
9.9
Pre-defined adverse events for analysis of statin (BCRP substrates)
Pre-defined adverse events of special interest were selected from AE dataset using below 
MedDRA PT code:
Alanine aminotransferase increased (PT 10001551)
Aspartate aminotransferase increased (PT 10003481)
Blood alkaline phosphatase increased (PT 10059570)
Blood bilirubin increased (PT 10005364)
Blood creatinine increased (PT 10005483)
Blood lactate dehydrogenase increased (PT 10005630)
Hyperbilirubinaemia (PT 10020578)
Muscular weakness (PT 10028372)
Renal failure (PT 10038435)
Renal impairment (PT 10062237)
Transaminases increased (PT 10054889).


 
Document Type: 
Additional Statistical Analysis Plan 
Official Title: 
A randomized, double–blind, placebo–controlled Phase III study 
of darolutamide (ODM–201) versus placebo in addition to 
standard androgen deprivation therapy and docetaxel in patients 
with metastatic hormone–sensitive prostate cancer 
NCT Number: 
NCT02799602  
Document Date: 
04-Feb-2022 
 


CONFIDENTIAL
Additional Statistical Analysis Plan
BAY 1841788 / 17777
IND 114769
Page: 1 of 8
Title Page
A randomized, double-blind, placebo-controlled Phase III study of darolutamide (ODM-
201) versus placebo in addition to standard androgen deprivation therapy and docetaxel 
in patients with metastatic hormone-sensitive prostate cancer
Protocol Number:  17777
SAP Supplement 1 (incl. version and date): V1.0, 04 FEB 2022
Compound Number: BAY 1841788
Sponsor Name and Legal Registered Address:
Non-US: Bayer AG, 51368 Leverkusen, Germany 
US territory: Bayer HealthCare Pharmaceuticals Inc., 100 Bayer Boulevard, P.O. Box 915, 
Whippany NJ 07981-0915, USA
Regulatory Agency Identifier Number(s):
Registry
ID
IND
114769
Date: 4 FEB 2022
Version: 1.0
Confidential
The information provided in this document is strictly confidential and is intended solely for the performance of 
the clinical investigation. Reproduction or disclosure of this document, whether in part or in full, to parties not 
associated with the clinical investigation or its use for any other purpose without the prior written consent of the 
sponsor is not permitted. 
Throughout this document, symbols indicating proprietary names (®, TM) may not be displayed. Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.
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.


CONFIDENTIAL
Additional Statistical Analysis Plan
BAY 1841788 / 17777
IND 114769
Page: 2 of 8
Table of Contents
Title Page................................................................................................................................... 1
Table of Contents ..................................................................................................................... 2
1.
Introduction....................................................................................................................... 3
2.
Study Objectives................................................................................................................ 3
3.
Study Design ...................................................................................................................... 3
4.
General Statistical Considerations .................................................................................. 3
5.
Analysis Sets ...................................................................................................................... 3
6.
Statistical Methodology .................................................................................................... 3
6.1
Population characteristics ................................................................................................ 3
6.1.1
Disposition.................................................................................................................... 3
6.1.2
Demographic and Other Baseline Characteristics........................................................ 3
6.1.3
Medical History............................................................................................................ 3
6.1.4
Prior and Concomitant Medication and Procedures..................................................... 3
6.1.5
Extent of Exposure ....................................................................................................... 4
6.2
Efficacy............................................................................................................................ 4
6.2.1
Primary Efficacy Endpoint........................................................................................... 4
6.2.2
Secondary Efficacy Endpoint....................................................................................... 4
6.2.3
Exploratory Efficacy Endpoint..................................................................................... 5
6.3
Safety ............................................................................................................................... 5
6.3.1
Adverse Events............................................................................................................. 5
6.3.2
Deaths and Serious Adverse events.............................................................................. 7
6.3.3
Additional Primary Malignancies................................................................................. 7
6.3.4
Laboratory Safety Assessments.................................................................................... 7
6.3.5
Other Safety Measures.................................................................................................. 7
6.4
Other Exploratory Variables............................................................................................ 8
6.5
Pharmacokinetics/pharmacodynamics............................................................................. 8
7.
Document history and changes in the planned statistical analysis............................... 8
8.
References .......................................................................................................................... 8


CONFIDENTIAL
Additional Statistical Analysis Plan
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IND 114769
Page: 3 of 8
1.
Introduction
This Supplemental Statistical Analysis Plan (SAP) describes analyses that were not included 
in the main SAP but may be used for Clinical Study Report (CSR) and marketing 
authorization / NDA. 
This Supplemental SAP version 1.0 is based on main SAP version 4.1 dated 11 NOV 2021.
2.
Study Objectives
Refer to main SAP V4.1 dated 11 NOV 2021.
3.
Study Design
Refer to main SAP V4.1 dated 11 NOV 2021.
4.
General Statistical Considerations
Refer to main SAP V4.1 dated 11 NOV 2021.
5.
Analysis Sets
Refer to main SAP V4.1 dated 11 NOV 2021. All tables, figures and listings as described in 
this supplemental SAP will be based on the safety analysis set (SAF).
6.
Statistical Methodology
6.1
Population characteristics
6.1.1
Disposition
Patients with treatment unblinded during double-blind study period will be listed.
6.1.2
Demographic and Other Baseline Characteristics
Not applicable.
6.1.3
Medical History
Not applicable.
6.1.4
Prior and Concomitant Medication and Procedures
A summary of duration of start of prior ADT within 12 weeks from randomization to 
randomization by geographical region based on WHO-DD drug record number. Patients who 
started ADT prior to 12 weeks before randomization will be listed. ADT is defined by WHO-
DD drug record number: 1. Gonadotropin-releasing hormone agonist: Buserelin or Buserelin 


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IND 114769
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acetate (007716), Gonadorelin (004865), Leuprorelin or Leuprorelin acetate (007269), 
Goserelin or Goserelin acetate (007321), Histrelin acetate (012465), Triptorelin or Triptorelin 
acetate or Triptorelin embonate (009759); 2. Gonadotropin-releasing hormone antagonist: 
Degarelix or Degarelix acetate (017648).
Patients with prior ADT, based on WHO-DD drug record number, before 12 weeks prior to 
randomization will be listed.
6.1.5
Extent of Exposure
Patients with actual dose of darolutamide >1800 mg per day will be listed.
Patients with darolutamide/placebo dose interruption > 28 consecutive days during study 
treatment will be listed.
6.2
Efficacy
6.2.1
Primary Efficacy Endpoint
Sensitivity analyses
The following OS sensitivity analyses by docetaxel cycles and including patients with 
violation of GCP are planned, respectively:

OS analyses by 6 cycles versus 5 and less cycles (including 26 patients who did not 
receive any docetaxel, based on full analysis set).

OS analyses by 6 and 5 cycles versus 4 and less cycles (including 26 patients who did 
not receive any docetaxel, based on full analysis set).

OS analysis including one patient with violation of GCP, based on all the randomized 
patients.
Refer to main SAP V4.1 dated 11 NOV 2021 for analysis of OS.
Number of patients, number of events and KM estimates for the median per arm for OS 
sensitivity analyses by docetaxel cycles will be presented in the forest plot.
6.2.2
Secondary Efficacy Endpoint
6.2.2.2
Time to pain progression 
Time to pain progression is defined as the time from randomization to the first date a patient 
experiences pain progression (first date of pain progression minus date of randomization). 
Pain will be assessed with the BPI-SF questionnaire. The main analysis is based on the ePRO 
device questionnaire data only. Additional sensitivity analyses for time to pain progression 
are defined as following:
Pain progression including unconfirmed worst pain score is defined as follows:

For asymptomatic patients (worst pain subscale [WPS] 0 at baseline), pain progression 
is defined as 
o
an increase of 2 or more points in the “worst pain in 24 hours” score (i.e. 2 or 
more point increase in WPS score) from nadir (i.e. zero), or
o
initiation of short- or long-acting opioid use for pain.


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
For symptomatic patients (WPS >0 at baseline), pain progression is defined as 
o
an increase of 2 or more points in the “worst pain in 24 hours” (i.e. 2 or more 
point increase in WPS score) from nadir and a WPS of ≥4, or
o
initiation of short- or long-acting opioid use for pain.
Pain progression based on 4 or more-point increase is defined as follows:

For asymptomatic patients (worst pain subscale [WPS] 0 at baseline), pain progression 
is defined as 
o
an increase of 4 or more points in the “worst pain in 24 hours” score (i.e. 4 or 
more point increase in WPS score) from nadir (i.e. zero) observed at 2 
consecutive evaluations ≥4 weeks apart, or
o
initiation of short- or long-acting opioid use for pain.

For symptomatic patients (WPS >0 at baseline), pain progression is defined as 
o
an increase of 4 or more points in the “worst pain in 24 hours” (i.e. 4 or more 
point increase in WPS score) from nadir observed at 2 consecutive evaluations 
≥4 weeks apart and a WPS of ≥4, or
o
initiation of short- or long-acting opioid use for pain.
The censoring rule in Table 6-3 of main SAP V4.1 will be applied.
6.2.3
Exploratory Efficacy Endpoint
Not applicable.
6.3
Safety
6.3.1
Adverse Events
The following additional tables for treatment-emergent adverse events (TEAEs) will be 
created. In all tables, results will be shown by treatment group.
Adverse events will be analyzed by using of predefined customized MedDRA queries denoted 
as MedDRA Labeling Groupings (MLG). These MLG are created and centrally maintained by 
Bayer internal coding experts.
Incidence proportions will be calculated as number of subjects experiencing an event per 
number of subjects exposed. Incidence proportions will be presented by MLG, PT and worst 
CTCAE grade (grade 1 to grade 5, missing grade, any grade). A separate table will be created 
for PTs not covered by MLG or special topic adverse events 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 name), and the corresponding preferred terms. Preferred terms which 
occurred in the data are marked with preceding asterisks (***).
To adjust for potential differences in study drug treatment duration (darolutamide or placebo) 
between treatment arms, additional summaries based on event rate per 100 patient years (PY) 
will be performed for the MLGs occurring after the first dose of darolutamide or placebo. 
This additional table will show columns for AE grouping, incidence proportion darolutamide, 
incidence proportion placebo, risk difference ‘Darolutamide – placebo’ with 95% confidence 
interval (CI), risk ratio ‘Darolutamide/placebo’ with 95% CI, exposure-adjusted incidence 


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rate darolutamide, exposure-adjusted incidence rate placebo, incidence rate ratio. No zero-
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 exposure-adjusted event rate is 
calculated as the total number of patients with a given TEAE divided by the total 
darolutamide or placebo treatment duration of all patients in years. The treatment duration in 
years will be calculated as treatment duration in days divided by 365.25. 
Incidence and prevalence of most common MLGs will be created for the MLGs with an 
incidence proportion of at least 10% in any treatment arm. The worst grade per MLG will be 
considered within each time interval. The incidence proportion of the MLGs by time interval
is defined as number of patients with any TEAE within the MLG arising (new onset) or 
worsening in a specific interval divided by number of patients in that time interval of the 
treatment-emergent period.  The prevalence of the MLGs by time interval is defined as 
number of patients with any TEAE within the MLG starting or ongoing in the specific time 
interval divided by the number of patients in that time interval of the treatment-emergent 
period.
The above described tables will also be created for the data driven grouping of the MLG 
hypertension plus the PTs ‘Hypertensive crisis’ and ‘Hypertensive emergency’.
A listing will be generated of all adverse events for a patient (patient ID
) who was 
assigned to placebo+docetaxel arm but took both darolutamide and placebo treatment during 
the study.
Incidence of the TEAEs by MedDRA SOC, PT and worst CTCAE grade for subgroup of 
patients with medical history of hepatic impairment present (PT: Alcoholic liver disease, 
Cirrhosis alcoholic, Drug-induced liver injury, Endoscopic retrograde 
cholangiopancreatography, Hemangioma of liver, Hepatic cirrhosis, Hepatic function 
abnormal, Hepatic steatosis, Hepatitis, Hepatitis alcoholic, Hepatobiliary disease, 
Hepatomegaly, Liver abscess, Liver disorder, Liver transplant, Steatohepatitis) will be 
summarized by treatment arm.
Incidence of the TEAEs by MedDRA MLG hypertension, PT and worst CTCAE grade for 
subgroup of patients with medical history of MLG hypertension present will be summarized 
by treatment arm.
Per EMA guidance an overview of treatment-emergent adverse events (TEAE) according to 
specific categories by age classes (<65, 65-74, 75-84 and > 85) created in the main set of 
tables per SAP v4.1 dated 11 NOV 2021 will be updated in order to add the two following 
categories:
-
Anticholinergic syndrome
-
Sum of postural hypotension, falls, black outs, syncope, dizziness, ataxia, fractures
The following selections will be used:
-
Anticholinergic syndrome: SMQ ‘Anticholinergic syndrome’,
-
Postural hypotension: PT Orthostatic hypotension,
-
Falls: PT Fall and PT Accident,
-
Black outs: PT Loss of consciousness,
-
Syncope: MLG Syncope,
-
Dizziness: MLG Dizziness and PT Vertigo,
-
Ataxia: MLG Gait disturbance and gait inability,
PPD


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-
Fractures: 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)).
6.3.2
Deaths and Serious Adverse events
Not applicable.
6.3.3
Additional Primary Malignancies
A listing will be generated for patients with additional primary malignancies who had 
subsequent systemic antineoplastic therapies.
6.3.4
Laboratory Safety Assessments
The mean of lab values (from both scheduled and unscheduled assessments) for ALT, AST, 
Bilirubin, Hemoglobin, Neutrophils and Platelets will be displayed in line plots by treatment 
arm and new grouped time interval relative to the first concomitant docetaxel treatment date, 
from baseline up-to Visit 6 (EOT visit will be included if the last visit number before EOT 
visit is < 7) for safety patients who had concomitant docetaxel with darolutamide or placebo.

Week 0 – 15, mean values are presented by each week.

Week 16 (grouped with week 16-23), 

Week 24 (grouped with week 24-35),

Week 36 (grouped with week 36-47), 

Week 48 (grouped with week 48-59), 

Week 60(grouped with week 60-83).
If a patient had multiple measurements of a lab parameter in a specific interval defined above, 
mean value of a lab parameter will be calculated for a patient in that interval. In the line plots, 
the mean value of available patients’ multiple (or single) measures mean, will be presented for 
each interval defined above, by treatment arm and lab parameters.
To provide clearer presentation of the data, the selected lab parameters: ALT, AST, Bilirubin, 
Hemoglobin, Neutrophils, Platelets, PSA and Testosterone will also be displayed graphically 
using laboratory shift plots within the ranges of the majority of the data, including both 
scheduled and unscheduled assessments. These plots will show the baseline value and mean 
post baselines values up-to end of treatment. Clinical laboratory data for patients not 
displayed in the post-hoc shift plots will be provided in a patient listing.
6.3.5
Other Safety Measures
Incidence of ECG QTc > 500 msec occurring between the first dose of darolutamide or 
placebo and last dose of darolutamide or placebo plus 30 days will be summarized. To adjust 
for potential differences in study drug treatment duration (darolutamide or placebo) between 
the treatment arms, additional summaries based on event rate per 100 patient years (PYs) 
were performed for ECG QTc > 500 msec occurring between the first dose of darolutamide or 
placebo and the last dose of darolutamide or placebo plus 30 days. The exposure-adjusted 
incidence rate was calculated as the total number of patients with an event of ECG QTc > 500 


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msec divided by the total darolutamide or placebo treatment duration of all patients in years. 
The rate is expressed in number of patients with events per 100 PYs. 
6.4
Other Exploratory Variables 
Not applicable.
6.5
Pharmacokinetics/pharmacodynamics
Not applicable.
7.
Document history and changes in the planned statistical analysis

Supplemental SAP version 1.0 dated 04 FEB 2022 without attachments 
8.
References
Refer to main SAP v4.1 dated 11 NOV 2021.


 
Document Type: 
Additional Statistical Analysis Plan for CSR addendum 
Official Title: 
A randomized, double-blind, placebo-controlled Phase III study of 
darolutamide (ODM-201) versus placebo in addition to standard 
androgen deprivation therapy and docetaxel in patients with 
metastatic hormone-sensitive prostate cancer 
NCT Number: 
NCT02799602 
Document Date: 
25 APR 2023 
 


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Title Page 
A randomized, double-blind, placebo-controlled Phase III study of darolutamide 
(ODM-201) versus placebo in addition to standard androgen deprivation therapy and 
docetaxel in patients with metastatic hormone-sensitive prostate cancer 
 
Protocol Number:  17777 
SAP Supplement 2 (incl. version and date): V1.0, 25 APRIL 2023 
Compound Number: BAY 1841788 
Sponsor Name and Legal Registered Address: 
 
Non-US: Bayer AG, 51368 Leverkusen, Germany  
US territory: Bayer HealthCare Pharmaceuticals Inc., 100 Bayer Boulevard, P.O. Box 915, 
Whippany NJ 07981-0915, USA 
 
Regulatory Agency Identifier Number(s): 
Registry 
ID 
IND 
114769 
EudraCT 
2015–002590–38 
 
 
Date: 25 APRIL 2023 
Version: 1.0 
 
 
 
 
 
 
 
Confidential 
The information provided in this document is strictly confidential and is intended solely for the performance of 
the clinical investigation. Reproduction or disclosure of this document, whether in part or in full, to parties not 
associated with the clinical investigation or its use for any other purpose without the prior written consent of the 
sponsor is not permitted.  
Throughout this document, symbols indicating proprietary names (®, TM) may not be displayed. Hence, the 
appearance of product names without these symbols does not imply that these names are not protected. 
 
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. 
 
 


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Table of Contents 
Title Page ............................................................................................................................... 1 
Table of Contents ................................................................................................................. 2 
List of Abbreviations ............................................................................................................ 3 
1. 
Introduction ................................................................................................................... 4 
2. 
Study Objectives ............................................................................................................ 4 
3. 
Study Design .................................................................................................................. 4 
4. 
General Statistical Considerations .............................................................................. 4 
5. 
Analysis Sets .................................................................................................................. 4 
6. 
Statistical Methodology ................................................................................................ 4 
6.1 
Population characteristics ............................................................................................ 5 
6.1.1 
Disposition ................................................................................................................ 5 
6.1.2 
Demographic and Other Baseline Characteristics .................................................... 5 
6.1.3 
Medical History ........................................................................................................ 5 
6.1.4 
Prior and Concomitant Medication........................................................................... 5 
6.1.5 
Extent of Exposure ................................................................................................... 5 
6.2 
Efficacy ........................................................................................................................ 6 
6.2.1 
Primary Efficacy Endpoint ....................................................................................... 6 
6.2.2 
Secondary Efficacy Endpoint ................................................................................... 6 
6.2.3 
Exploratory Efficacy Endpoint ................................................................................. 6 
6.3 
Safety ........................................................................................................................... 7 
6.3.1 
Adverse Events ......................................................................................................... 7 
6.3.2 
Deaths and Serious Adverse events ........................................................................ 11 
6.3.3 
Additional Primary Malignancies ........................................................................... 12 
6.3.4 
Laboratory Safety Assessments .............................................................................. 12 
6.3.5 
Other Safety Measures............................................................................................ 12 
6.4 
Other Exploratory Variables ...................................................................................... 12 
6.5 
Pharmacokinetics/pharmacodynamics ....................................................................... 13 
7. 
Document history and changes in the planned statistical analysis ......................... 13 
8. 
References .................................................................................................................... 13 
9. 
Appendix ...................................................................................................................... 13 
9.1 
The selection criteria for EMA guidance on TEAEs are: .......................................... 13 
9.2 
Special topic AE definition ........................................................................................ 14 
9.3 
The selection criteria for additional safety AE analysis ............................................ 15 
9.4 
Bone health agent (BHA)........................................................................................... 16 
 
 
 


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List of Abbreviations 
 
ADT 
Androgen deprivation therapy 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ATC 
Anatomical-Therapeutic-Chemical 
BHA 
Bone health agent 
CI 
Confidence interval 
FAS 
Full analysis set 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mHSPC 
Metastatic hormone-sensitive prostate cancer 
NCI-CTCAE v4.03 
National Cancer Institute-Common Terminology Criteria for Adverse Events; 
version 4.03 
PSA 
Prostate-specific antigen 
PT 
Preferred Term 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
TEAE 
Treatment emergent adverse events 
TESAE 
Treatment emergent serious adverse events 
ULN 
Upper limit of normal 
WHO 
World Health Organization 
WHO-DD 
WHO Drug Dictionary 
 
 
 


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1. 
Introduction 
Study 17777 (ARASENS) is an international, randomized, double-blind, placebo-controlled, 
Phase III efficacy and safety study of darolutamide in addition to standard androgen 
deprivation therapy (ADT) and docetaxel in patients with metastatic hormone-sensitive 
prostate cancer (mHSPC). 
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 2 version 1.0 is based on integrated protocol version 5.0 
(amendment 7) dated 26 MAY 2020, on SAP version 4.1 dated 11 NOV 2021 and 
Supplemental 1 SAP version 1.0 dated 04 FEB 2022. 
 
2. 
Study Objectives 
Refer to main SAP V4.1 dated 11 NOV 2021. 
 
3. 
Study Design 
Refer to main SAP V4.1 dated 11 NOV 2021. 
 
4. 
General Statistical Considerations 
Refer to main SAP V4.1 dated 11 NOV 2021. 
 
5. 
Analysis Sets 
Refer to main SAP V4.1 dated 11 NOV 2021. All tables, figures and listings as described in 
this supplemental SAP will be based on either the full analysis set (FAS) or the safety analysis 
set (SAF). 
 
6. 
Statistical Methodology 
The statistical analyses will be descriptive. Summaries will be provided for both treatment 
arms, darolutamide+docetaxel arm and placebo+docetaxel arm by period of “At Primary 
completion cut-off - from FPFV to 25OCT2021” and “Whole Study - from FPFV to LPLV”.  
The number of patients will be summarized in disposition tables, concomitant medications, 
study-drug exposure tables and adverse events tables.  


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6.1 
Population characteristics 
6.1.1 
Disposition 
The number of patients starting, completing, and discontinuing together with the primary 
reason for discontinuing of the Treatment, Active Follow-up, and Long-term Follow-up 
periods will be presented   by treatment arm. 
In addition, the number of patients with important protocol deviations will be presented by 
period and treatment arm. The frequencies of each important protocol deviation will be 
presented by period and treatment arm. All COVID-19 pandemic related protocol deviations 
are considered important protocol deviations and will be presented by period and treatment 
arm. Median follow-up time during study will be summarized. 
6.1.2 
Demographic and Other Baseline Characteristics 
Refer to main SAP V4.1 dated 11 NOV 2021. Only changed data will be summarized and 
listed overall and by treatment arm for whole study period. No subgroup analysis will be 
presented for demographic and baseline characteristics tables. 
6.1.3 
Medical History 
Refer to main SAP V4.1 dated 11 NOV 2021. 
6.1.4 
Prior and Concomitant Medication  
The following tables and listing will be created:  
• Concomitant medications excluding ADT, systemic antineoplastic therapies captured 
in the anti-cancer therapy eCRF page: frequency of patients for each drug category. 
• A summary of subsequent systemic antineoplastic therapy will be presented by 
preferred drug name based on WHO-DD drug record number. 
• A summary of life-prolonging subsequent systemic antineoplastic therapy will be 
presented by preferred drug name based on WHO-DD drug record number or by 
number of regimens . The following medications after the study treatment period are 
life-prolonging subsequent therapies for prostate cancer: Abiraterone, Apalutamide, 
Enzalutamide, Docetaxel, Cabazitaxel, Radium 223, Sipuleucel-T, Lutetium-177. 
• Concurrent prostate cancer related-invasive procedures (e.g. procedures for urinary 
symptoms, surgical procedures for prostate cancer): frequency of patients by grouped 
term and 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.). 
The dictionary used for coding medications was the ATC Class/Subclass and the World 
Health Organization Drug Dictionary (WHO-DD). All tables will be presented with the most 
recent version (version 2022SEP) of the dictionary.  
 
6.1.5 
Extent of Exposure 
After primary completion (25 OCT 2021 cut-off), all patients on darolutamide treatment have 
transitioned into a separate program to continue receiving darolutamide or have discontinued 


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the study for any other reason (e.g. death, lost to follow-up, consent withdrawal with no 
further data collection), and all patients on placebo have discontinued treatment. Extent of 
exposure will be summarized for the SAF by treatment arm and by period of “At Primary 
completion cut-off - from FPFV to 25OCT2021” and “Whole Study - from FPFV to LPLV”, 
using descriptive statistics. for the following variables:  
• Overall time under treatment (or treatment duration)  
Including time off drug and dose interruptions. It will be calculated in days and 
presented in months as (date of the last dose of any study treatment – date of the first 
dose of any study treatment + 1) / 30.44. 
• Actual dose per day(or average daily dose received)  
Actual dose per day (or average daily dose received) = total amount of dose / number 
of days with intake > 0 
• Total amount of dose  
Total amount of dose = sum of dose received over total time under treatment 
• Percent of planned dose received. 
Percent of planned dose received = total amount of dose [mg] / planned dose [mg] * 
100%; planned dose is sum of the intended initial dose according to protocol over total 
time under treatment. 
• From 1 day after the last dose of docetaxel to the last dose of darolutamide or placebo. 
Including time off drug and dose interruptions. It will be calculated in days and 
presented in months as (date of the last dose of darolutamide or placebo – date of the 
last dose of docetaxel + 1) / 30.44. If the last dose of docetaxel date is after the last 
dose of darolutamide or placebo, then 0 day of duration will be included in the 
calculation. 
Patients with actual dose of darolutamide >1800 mg per day will be listed. Patients with 
darolutamide/placebo dose interruption > 28 consecutive days during study treatment will be 
listed. No subgroup analysis will be presented for extent of exposure. 
6.2 
Efficacy 
6.2.1 
Primary Efficacy Endpoint 
Not applicable. 
 
6.2.2 
Secondary Efficacy Endpoint 
Not applicable. 
 
6.2.3 
Exploratory Efficacy Endpoint 
Not applicable. 


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6.3 
Safety 
6.3.1 
Adverse Events 
6.3.1.1 
Treatment-emergent Adverse Events 
AEs will be coded using MedDRA 25.1 or most recent version. The severity (or intensity) of 
AEs will be documented using the National Cancer Institute-Common Terminology Criteria 
for Adverse Event version 4.03 (NCI-CTCAE v 4.03). Descriptive summary tables will be 
presented on all safety parameters by treatment arm.  
The AEs will be presented with their worst NCI-CTCAE v 4.03 grade CTC 1 = mild, 
CTC 2 = moderate, CTC 3 = Severe, CTC 4 = life threatening, CTC 5 = fatal. The causal 
relationship is based on whether there was a reasonable causal relationship to darolutamide or 
placebo and docetaxel. AEs will be classified by the investigator as related or not related to 
darolutamide or placebo and docetaxel separately. 
Treatment-emergent AE (TEAE) is defined as any event arising or worsening after the first 
dose of darolutamide or placebo until 30 days after the last dose of darolutamide or placebo.  
An overview of TEAEs will be summarized by treatment arm in the overall treatment period. 
The following summaries will be created separately for study drug-related (darolutamide or 
placebo-related) and docetaxel-related TEAEs, by treatment arm: TEAEs leading to 
permanent discontinuation of study treatment, TEAEs leading to dose reduction and/or dose 
interruption, and drug-related TEAEs. Summary statistics (frequency and percentage of 
patients, not of events) will be presented by treatment arm, MedDRA SOC and PT, and NCI-
CTCAE worst grade for the following: 
• Incidence of all TEAEs  
• Incidence of TEAEs of NCI-CTCAE grade 3, 4 or 5 
• Incidence of TEAEs leading to permanent discontinuation of darolutamide or placebo 
and docetaxel separately 
• Incidence of TEAEs leading to dose reduction  
• Incidence of TEAEs leading to dose interruption  
• Incidence of TEAEs with incidence of at least 5%  
• Incidence of all drug-related TEAEs  
• Incidence of drug-related TEAEs of NCI-CTCAE grade 3, 4 or 5 
• Incidence of drug-related TEAEs leading to permanent discontinuation of 
darolutamide or placebo and docetaxel separately  
• Incidence of drug-related TEAEs leading to dose reduction 
• Incidence of drug-related TEAEs leading to dose interruption 
• Incidence of drug-related TEAEs with incidence of at least 5%  
• Incidence of post-treatment AEs (after 30 days from the last dose of study drug). 
• Incidence and prevalence of most common TEAEs ≥10% incidence in either treatment 
arm, analyzed within pre-specified time intervals. The same summary will be 
presented by geographical regions (North America, Asia Pacific, Rest of the World) as 
well. 


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• Incidence of COVID-19-related TEAEs 
• Incidence of TEAEs by MedDRA SOC, HLGT, HLT, PT and worst CTCAE grade 
 
Subgroup analyses of TEAEs 
The following subgroup analyses will be performed for overview of TEAEs and for TEAEs 
showing at least 5%-point differences in incidence proportions between any of the subgroup 
categories: 
• Age category (<65, 65–74, 75–84, ≥85 years) 
• Age category (<65, 65–74, 75–84, ≥85 years) per EMA guidance for following 
categories: Psychiatric disorders (SOC), Nervous system disorders (SOC), Accidents 
and injuries (SMQ), Cardiac disorders (SOC), Vascular disorders (SOC), Central 
nervous system vascular disorders (SMQ), Anticholinergic syndrome (SMQ), 
Infections and infestations (SOC), Quality of life decreased (PT), Sum of postural 
hypotension, falls, black outs, syncope, dizziness, ataxia, fractures. The selection 
criteria of the grouped terms are defined in Appendix 9.1. 
• Geographical region (North America, Asia Pacific / Rest of the World 
 
TEAEs by medical conditions 
The incidence of TEAEs will be presented by groupings and worst CTCAE grade for the 
following: 
• Patients with present medical history of cardiac disorder (SOC). 
• Patients with present medical history of renal impairment (SMQ Acute renal failure; 
SMQ Chronic kidney disease). 
• Patients with present TEAE interstitial lung disease (not medical history, SMQ 
interstitial lung disease (narrow search)). 
• Patients with present medical history of hepatic impairment (PT: Alcoholic liver 
disease, Cirrhosis alcoholic, Drug-induced liver injury, Endoscopic retrograde 
cholangiopancreatography, Hemangioma of liver, Hepatic cirrhosis, Hepatic function 
abnormal, Hepatic steatosis, Hepatitis, Hepatitis alcoholic, Hepatobiliary disease, 
Hepatomegaly, Liver abscess, Liver disorder, Liver transplant, Steatohepatitis) will be 
summarized by treatment arm. 
• Patients with present medical history of MLG hypertension will be summarized by 
treatment arm. 
 
 


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Exposure-adjusted incidence rates of TEAEs  
To adjust for unequal lengths of study treatment (darolutamide or placebo and docetaxel) 
between the treatment arms, additional summaries based on event rate per 100 patient years 
(PYs) will be performed for all TEAEs, special topics TEAEs (Section 6.3.1.2), and all 
TESAEs occurring after the first dose of darolutamide or placebo. The exposure-adjusted 
incidence rate is calculated as the total number of patients with a given TEAE divided by the 
total darolutamide or placebo treatment duration of all patients in years. The rate is expressed 
in 100 PYs).  
The treatment duration in years will be calculated as treatment duration in days divided by 
365.25. The risk difference ‘darolutamide+docetaxel arm – placebo+docetaxel arm’ and risk 
ratio ‘darolutamide+docetaxel arm vs. placebo+docetaxel arm’ 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+docetaxel arm the risk ratio will not be 
calculated. The incidence rate ratio for darolutamide+docetaxel arm vs. placebo+docetaxel 
arm will also be calculated. 
6.3.1.2 
Treatment-emergent Adverse Events Groupings Considered as Special 
Topics 
The following TEAE groupings are considered as special topics (see definitions in 
Appendix 9.2): 
• Bone fractures excluding pathological fractures 
• Diabetes mellitus and hyperglycemia 
• Fall 
• Fatigue/ asthenic conditions 
• Weight decreased 
• Rash 
• Seizure 
• Hypertension  
• Vasodilatation and flushing  
• Mental impairment disorders  
• Depressed mood disorders  
• Breast disorders/gynecomastia  
• Cardiac disorders 
• Cerebral ischaemia 
• Cerebral and intracranial hemorrhage 
The following tables will be created for TEAEs of special topics: 
• Incidence of TEAEs  
• Incidence of TEAEs leading to permanent discontinuation of (darolutamide or placebo 
and docetaxel separately)   
• Incidence of TEAEs leading to dose reduction  
• Incidence of TEAEs leading to dose interruption  


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• Incidence of treatment-emergent SAEs (TESAEs) 
• Incidence and prevalence of most common TEAEs of special topics ≥ 5% incidence in 
either treatment arm, analyzed within pre-specified time intervals. The same summary 
will be presented by geographical regions (North America, Asia Pacific, Rest of the 
World) as well. 
Fracture events will be described by a cumulative incidence plot of fracture. A summary of 
treatment-emergent fracture by bone health agent use (for selection of bone health agent see 
Appendix 9.3) 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 
of patients with fracture events breakdown by relevant events occurring within 7 days 
window: fall, accident, syncope and/or loss of consciousness, dizziness will be presented. 
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 summary of time to fall and 
fractures events will be presented in descriptive and inferential statistics, respectively. In 
addition, Kaplan-Meier plots 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. 
 
6.3.1.3 
MedDRA Labeling Groupings  
The following additional tables for treatment-emergent adverse events (TEAEs) will be 
created. In all tables, results will be shown by treatment group. 
Adverse events will be analyzed by using predefined customized MedDRA queries denoted as 
MedDRA Labeling Groupings (MLG). These MLG are created and centrally maintained by 
Bayer internal coding experts. 
Incidence proportions will be calculated as number of subjects experiencing an event per 
number of subjects exposed. Incidence proportions will be presented by MLG, PT and worst 
CTCAE grade (grade 1 to grade 5, missing grade, any grade). A separate table will be created 
for PTs not covered by MLG or special topic adverse events 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 name), and the corresponding preferred terms. Preferred terms which 
occurred in the data are marked with preceding asterisks (***). 
To adjust for potential differences in study drug treatment duration (darolutamide or placebo) 
between treatment arms, additional summaries based on event rate per 100 PYs will be 
performed for the MLGs occurring after the first dose of darolutamide or placebo. This 
additional table will show columns for AE grouping, incidence proportion darolutamide, 
incidence proportion placebo, risk difference ‘Darolutamide – placebo’ with 95% confidence 
interval (CI), risk ratio ‘Darolutamide/placebo’ with 95% CI, exposure-adjusted incidence 
rate darolutamide, exposure-adjusted incidence rate placebo, incidence rate ratio. No zero- 
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.  


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Incidence and prevalence of most common MLGs will be created for the MLGs with an 
incidence proportion of at least 10% in any treatment arm. The worst grade per MLG will be 
considered within each time interval. The incidence proportion of the MLGs by time interval 
is defined as number of patients with any TEAE within the MLG arising (new onset) or 
worsening in a specific interval divided by number of patients in that time interval of the 
treatment-emergent period. The prevalence of the MLGs by time interval is defined as 
number of patients with any TEAE within the MLG starting or ongoing in the specific time 
interval divided by the number of patients in that time interval of the treatment-emergent 
period. 
The above-described tables: incidence and prevalence by time intervals, exposure-adjusted 
incidence rate and risk ratio will also be created for the data-driven grouping of Hypertension 
(MLG hypertension plus the PTs ‘Hypertensive crisis’ and ‘Hypertensive emergency’). 
6.3.1.4 
Additional safety AE analyses 
The additional safety AE analyses will be performed for AE grouped term of Interstitial lung 
disease, data-driven grouping Hypertension, and Hepatic disorders by treatment arm. The 
selection criteria of the grouped terms are defined in Appendix 9.3. 
• Exposure-adjusted treatment-emergent Interstitial lung disease (SMQ [narrow]), data-
driven grouping Hypertension, Hepatic disorders by Grouping and PT per 100 subject 
years  
• Treatment-emergent Interstitial lung disease (SMQ [narrow]), data-driven grouping 
Hypertension, Hepatic disorders by AE grouping, PT and worst CTCAE grade. 
6.3.2 
Deaths and Serious Adverse events 
Serious adverse events (SAEs) will be classified using the NCI-CTCAE version 4.03 and 
MedDRA version 25.1 or most recent version. 
• Treatment-emergent SAEs 
• Treatment-emergent SAEs leading to permanent discontinuation of study treatment 
• Treatment-emergent SAEs leading to dose reduction 
• Treatment-emergent SAEs leading to drug interruption 
• Treatment-emergent drug-related SAEs 
• COVID-19 related treatment-emergent SAEs 
• Listing of treatment-emergent SAEs 
• Listing of non-treatment-emergent SAEs 
• Non-treatment-emergent drug-related SAEs 
The incidence of deaths in the study: within 30 days after first dose of study drug / docetaxel, 
during study treatment from first to last dose of study drug / docetaxel, within 30 days after 
last dose of study drug/ docetaxel, later than 30 days after last dose of study drug/ docetaxel, 
will be summarized by each treatment arm and cause of death. All deaths before treatment 
start, during treatment and within 30 days after last dose of study drug, and later than 30 days 
after 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.  
 


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6.3.3 
Additional Primary Malignancies 
Summary statistics will be presented by treatment arm, MedDRA SOC, HLGT, HLT and PT 
for additional primary malignancies.  
• Exposure-adjusted additional primary malignancies during treatment and follow-up 
per 100 PYs by MedDRA HLGT, HLT, and PT. 
• Additional primary malignancies during treatment and follow-up by MedDRA HLGT, 
HLT, PT and worst CTCAE grade. 
• Incidence proportion and exposure adjusted incidence rate for data-driven grouping 
additional primary malignancies excluding superficial skin cancers during treatment or 
follow-up. 
A listing will be generated for patients with additional primary malignancies and subsequent 
systemic antineoplastic medications used for additional primary malignancy.  
The additional primary malignancies are defined Appendix 9.3. 
 
6.3.4 
Laboratory Safety Assessments 
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 arm 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.The lab parameters will be 
displayed graphically using laboratory shift plots within the ranges of the majority of the data, 
including both scheduled and unscheduled assessments. These plots will show the baseline 
value and mean post baselines values up-to end of treatment. Clinical laboratory data for 
patients not displayed in the shift plots will be provided in a patient listing. 
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 (ref. 3). 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 arm. 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. Liver function values for patients 
with a medical history of Gilbert' syndrome will be listed. 
6.3.5 
Other Safety Measures 
Not applicable. 
6.4 
Other Exploratory Variables  
Not applicable. 


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6.5 
Pharmacokinetics/pharmacodynamics 
Not applicable. 
7. 
Document history and changes in the planned statistical analysis 
• Supplemental SAP version 1.0 dated 04 FEB 2022 
• Main SAP version 4.1 dated 11 NOV 2021 
 
8. 
References 
Refer to main SAP v4.1 dated 11 NOV 2021. 
9. 
Appendix 
9.1 
The selection criteria for EMA guidance on TEAEs are: 
• Anticholinergic syndrome: SMQ ‘Anticholinergic syndrome’, 
• Postural hypotension: PT Orthostatic hypotension, 
• Falls: PT Fall and PT Accident, 
• Black outs: PT Loss of consciousness, 
• Syncope: MLG Syncope, 
• Dizziness: MLG Dizziness and PT Vertigo, 
• Ataxia: MLG Gait disturbance and gait inability, 
• Fractures: 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). 
 
 


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9.2 
Special topic AE definition 
Table 9–1 Special topic AE definitions 
Grouped term 
MedDRA search criteria for special topics 
Bone fractures 
excluding pathological 
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)) 
Exclude PT pathological fractures 
Diabetes mellitus and 
hyperglycemia 
MLG: Hyperglycemia 
PT: Diabetes mellitus; Diabetes mellitus inadequate control; Diabetic 
metabolic decompensation; Type 2 diabetes mellitus; Diabetic 
ketoacidosis 
 
Fall* 
PT: Fall 
PT: Accident 
Fatigue/ asthenic 
conditions 
MLG: Decreased general strength and energy 
PT: Lethargy; Chronic fatigue syndrome; Malaise 
Weight decreased 
MLG: Weight decreased 
 
Rash 
MLG: Rash 
MLG: Skin erythema 
PT: Dermatitis 
 
Seizure 
MLG: Seizures 
Hypertension  
MLG: Hypertension 
Vasodilatation and 
flushing  
MLG: Vasodilatation and flushing 
Mental impairment 
disorders  
HLGT: Mental impairment disorders 
Depressed mood 
disorders  
HLGT: Depressed mood disorders and disturbance 
Breast 
disorders/gynecomastia  
HLGT: Breast disorders 
Cardiac disorders 
HLGT: Cardiac arrhythmias  
HLGT: Coronary artery disorders  
HLGT: Heart failures 
Cerebral ischaemia 
MLG: Cerebral infarction and stroke not specified as hemorrhagic or 
ischemic 
MLG: Cerebral ischemic infarction and stroke 
PT: Cerebral ischaemia, Transient ischaemic attack 
Cerebral and 
intracranial 
hemorrhaege 
MLG: Cerebral and intracranial hemorrhage 
MLG: MedDRA Labeling Grouping; PT: Preferred Term; HLT: High Level Term; HLGT: High Level 
Group Term 
* Based on review of verbatims the search criteria for “Fall” was extended by the PT “Accident”. 
 
 


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9.3 
The selection criteria for additional safety AE analysis 
• Interstitial lung disease: SMQ Interstitial lung disease (SMQ narrow) 
• Data-driven grouping Hypertension: data-driven grouping of the MLG hypertension 
plus the PTs ‘Hypertensive crisis’ and ‘Hypertensive emergency’. 
• Hepatic disorders: 
Five MLGs: 
• MLG Increase in bilirubin, 
• MLG Increase in transaminases, 
• MLG Hepatic impairment, 
• MLG Hepatic failure acute, 
• MLG Hepatic failure unspecified,  
plus selected PTs per MedDRA v25.1 from the SMQ Drug related hepatic disorders - 
comprehensive search (SMQ) as follows 
• AST/ALT ratio abnormal 
• Alanine aminotransferase abnormal 
• Aspartate aminotransferase abnormal 
• Cholestasis 
• Cholestatic liver injury 
• Coma hepatic 
• Drug-induced liver injury 
• Hepatitis 
• Hepatitis acute 
• Hepatitis cholestatic 
• Hepatic encephalopathy 
• Hepatitis fulminant 
• Hepatitis toxic 
• Hepatorenal failure 
• Hyperammonaemia 
• International normalised ratio increased 
• Jaundice 
• Jaundice cholestatic 
• Jaundice hepatocellular 
• Liver disorder 
• Non-alcoholic steatohepatitis 
• Non-cirrhotic portal hypertension 
• Prothrombin time prolonged 
• Prothrombin time ratio increased 
• Additional primary malignancy (per PSUR):  


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• SMQ Malignant tumors (SMQ) excluding: PT: Hormone-dependent 
prostate cancer; PT: Hormone-refractory prostate cancer, PT: Prostate 
cancer, PT: Prostate cancer metastatic, PT: Prostate cancer recurrent, PT: 
Prostate cancer stage 0, PT: Prostate cancer stage I, PT: Prostate cancer 
stage II, PT: Prostate cancer stage III, PT: Prostate cancer stage IV, PTs 
from HLGT: Metastases, PT: Cancer in remission, LLT: Progression of 
pre-existing cancer 
 
9.4 
Bone health agent (BHA) 
Bone health agent were selected in CM dataset, using ATC codes: 
M05BA, M05BB: Bisphosphonates  
M05BX: Denosumab 


 
Document Type: 
Additional Statistical Analysis Plan for CSR addendum 
Official Title: 
A randomized, double-blind, placebo-controlled Phase III study of 
darolutamide (ODM-201) versus placebo in addition to standard 
androgen deprivation therapy and docetaxel in patients with 
metastatic hormone-sensitive prostate cancer 
NCT Number: 
NCT02799602 
Document Date: 
20 JUL 2023 
 


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Title Page 
A randomized, double-blind, placebo-controlled Phase III study of darolutamide 
(ODM-201) versus placebo in addition to standard androgen deprivation therapy and 
docetaxel in patients with metastatic hormone-sensitive prostate cancer 
 
Protocol Number:  17777 
SAP Supplement 3 (incl. version and date): V1.0, 20 JULY 2023 
Compound Number: BAY 1841788 
Sponsor Name and Legal Registered Address: 
 
Non-US: Bayer AG, 51368 Leverkusen, Germany  
US territory: Bayer HealthCare Pharmaceuticals Inc., 100 Bayer Boulevard, P.O. Box 915, 
Whippany NJ 07981-0915, USA 
 
Regulatory Agency Identifier Number(s): 
Registry 
ID 
IND 
114769 
EudraCT 
2015–002590–38 
 
 
Date: 20 JULY 2023 
Version: 1.0 
 
 
 
 
 
 
 
Confidential 
The information provided in this document is strictly confidential and is intended solely for the performance of 
the clinical investigation. Reproduction or disclosure of this document, whether in part or in full, to parties not 
associated with the clinical investigation or its use for any other purpose without the prior written consent of the 
sponsor is not permitted.  
Throughout this document, symbols indicating proprietary names (®, TM) may not be displayed. Hence, the 
appearance of product names without these symbols does not imply that these names are not protected. 
 
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. 
 
 


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Table of Contents 
Title Page ............................................................................................................................... 1 
Table of Contents ................................................................................................................. 2 
List of Abbreviations ............................................................................................................ 3 
1. 
Introduction ................................................................................................................... 4 
2. 
Study Objectives ............................................................................................................ 4 
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 ................................................................................................................ 4 
6.1.2 
Demographic and Other Baseline Characteristics .................................................... 4 
6.1.3 
Medical History ........................................................................................................ 4 
6.1.4 
Prior and Concomitant Medication........................................................................... 5 
6.1.5 
Extent of Exposure ................................................................................................... 5 
6.2 
Efficacy ........................................................................................................................ 5 
6.2.1 
Primary Efficacy Endpoint ....................................................................................... 5 
6.2.2 
Secondary Efficacy Endpoint ................................................................................... 5 
6.2.3 
Exploratory Efficacy Endpoint ................................................................................. 5 
6.3 
Safety ........................................................................................................................... 5 
6.3.1 
Adverse Events ......................................................................................................... 5 
6.3.2 
Laboratory Safety Assessments ................................................................................ 6 
6.3.3 
Other Safety Measures.............................................................................................. 6 
6.4 
Other Exploratory Variables ........................................................................................ 6 
6.5 
Pharmacokinetics/pharmacodynamics ......................................................................... 6 
7. 
Document history and changes in the planned statistical analysis ........................... 6 
8. 
References ...................................................................................................................... 6 
9. 
Appendix ........................................................................................................................ 6 
 
 
 


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List of Abbreviations 
 
AE 
Adverse event 
ATC 
Anatomical-Therapeutic-Chemical 
CI 
Confidence interval 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI-CTCAE v4.03 
National Cancer Institute-Common Terminology Criteria for Adverse Events; 
version 4.03 
PT 
Preferred Term 
SAP 
Statistical Analysis Plan 
TEAE 
Treatment emergent adverse events 
WHO 
World Health Organization 
WHO-DD 
WHO Drug Dictionary 
 
 
 


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1. 
Introduction 
This Supplemental 3 Statistical Analysis Plan (SAP) describes post-hoc analyses that were not 
included in the pre-defined Supplemental 2 SAP but may be used for Clinical Study Report 
(CSR) addendum and marketing authorization / NDA.  
This Supplemental 3 SAP version 1.0 is based on integrated protocol version 5.0 
(amendment 7) dated 26 MAY 2020, Supplemental 2 SAP version 1.0 dated 25 APR 2023, 
Supplemental 1 SAP version 1.0 dated 04 FEB 2022 and main SAP version 4.1 dated 
11 NOV 2021. 
 
2. 
Study Objectives 
Refer to Supplemental 2 SAP V1.0 dated 25 APR 2023. 
 
3. 
Study Design 
Refer to Supplemental 2 SAP V1.0 dated 25 APR 2023. 
 
4. 
General Statistical Considerations 
Refer to Supplemental 2 SAP V1.0 dated 25 APR 2023. 
 
5. 
Analysis Sets 
Refer to Supplemental 2 SAP V1.0 dated 25 APR 2023.  
 
6. 
Statistical Methodology 
Refer to Supplemental 2 SAP V1.0 dated 25 APR 2023.  
6.1 
Population characteristics 
6.1.1 
Disposition 
Refer to Supplemental 2 SAP V1.0 dated 25 APR 2023.  
 
6.1.2 
Demographic and Other Baseline Characteristics 
Refer to Supplemental 2 SAP V1.0 dated 25 APR 2023.  
 
6.1.3 
Medical History 
Refer to Supplemental 2 SAP V1.0 dated 25 APR 2023. 


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6.1.4 
Prior and Concomitant Medication  
A summary of prior systemic antineoplastic therapy will be presented by preferred drug name 
based on WHO-DD drug record number. 
The dictionary used for coding medications was the ATC Class/Subclass and the World 
Health Organization Drug Dictionary (WHO-DD). All tables will be presented with version 
2022SEP of the dictionary.  
 
6.1.5 
Extent of Exposure 
Refer to Supplemental 2 SAP V1.0 dated 25 APR 2023.  
 
6.2 
Efficacy 
6.2.1 
Primary Efficacy Endpoint 
Not applicable. 
 
6.2.2 
Secondary Efficacy Endpoint 
Not applicable. 
 
6.2.3 
Exploratory Efficacy Endpoint 
Not applicable. 
6.3 
Safety 
6.3.1 
Adverse Events 
6.3.1.1 
Treatment-emergent Adverse Events 
The following additional tables for treatment-emergent adverse events (TEAEs) will be 
created. In all tables, results will be shown by treatment group. 
Adverse events will be analyzed by using of predefined customized MedDRA queries denoted 
as MedDRA Labeling Groupings (MLG). These MLG are created and centrally maintained by 
Bayer internal coding experts. AEs will be coded using MedDRA 25.1 or most recent version. 
The severity (or intensity) of AEs will be documented using the National Cancer Institute-
Common Terminology Criteria for Adverse Event version 4.03 (NCI-CTCAE v 4.03). 
Descriptive summary tables will be presented on all safety parameters by treatment arm.  
 
6.3.1.2 
MedDRA Labeling Groupings  
Adverse events will be analyzed by using predefined customized MedDRA queries denoted as 
MedDRA Labeling Groupings (MLG). These MLG are created and centrally maintained by 
Bayer internal coding experts. 


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Incidence proportions will be calculated as number of subjects experiencing an event per 
number of subjects exposed. Incidence proportions, overall risk ratio, risk difference 
‘Darolutamide – placebo’ with 95% confidence interval (CI), risk ratio 
‘Darolutamide/placebo’ with 95% CI, exposure-adjusted incidence rate darolutamide, 
exposure-adjusted incidence rate placebo, incidence rate ratio will be presented by MedDRA 
Labeling Groupings (MLG), PT for darolutamide/placebo-related and docetaxel-related 
treatment-emergent adverse events, separately. No zero-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.  
 
6.3.2 
Laboratory Safety Assessments 
Refer to Supplemental 2 SAP V1.0 dated 25 APR 2023.  
 
6.3.3 
Other Safety Measures 
Vital signs data, ECG measurements and ECG findings data based on whole study period will 
be listed in Section 16. 
6.4 
Other Exploratory Variables  
Not applicable. 
6.5 
Pharmacokinetics/pharmacodynamics 
Not applicable. 
7. 
Document history and changes in the planned statistical analysis 
• Supplemental 2 SAP version 1.0 dated 25 APR 2023. 
• Supplemental 1 SAP version 1.0 dated 04 FEB 2022 
• Main SAP version 4.1 dated 11 NOV 2021 
 
8. 
References 
Refer to Supplemental 2 SAP V1.0 dated 25 APR 2023. 
 
9. 
Appendix 
Refer to Supplemental 2 SAP V1.0 dated 25 APR 2023.