A Randomized, Open-label, Multicenter, Phase 2b Study to Evaluate Physical Function, Including Balance and Daily Activity, in Participants With Castration-resistant Prostate Cancer Treated With Darolutamide or Enzalutamide
Phase: PHASE2
Conditions: Prostatic Cancer, Castration-Resistant
Sponsor: Bayer

Document Type: 
Study protocol 
Official Title: 
A randomized, open-label, multicenter, phase 2b study to evaluate 
physical function, including balance and daily activity, in 
participants with castration-resistant prostate cancer treated with 
darolutamide or enzalutamide 
NCT Number: 
NCT04157088 
Document Date: 
06-Jun-2019

CONFIDENTIAL
Clinical Study Protocol 
BAY 1841788 / 20609
Title Page
Protocol Title: A randomized, open-label, multicenter, Phase 2b study to evaluate physical 
function, including balance and daily activity, in participants with castration-resistant prostate 
cancer treated with darolutamide or enzalutamide
Protocol Number: 20609
Compound Number: BAY 1841788 (ODM-201)
Study Phase: Phase 2b
Short Title: DaroAcT: darolutamide physical function and daily activity study
Acronym: DaroAcT
Sponsor Name: Bayer HealthCare Pharmaceuticals Inc. 
Legal Registered Address: Bayer HealthCare Pharmaceuticals Inc., 100 Bayer Boulevard, 
P.O. Box 915, Whippany NJ 07981-0915, USA
Regulatory Agency Identifier Number(s): Not applicable
Approval Date: 06 JUN 2019
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.

C O N FI D E N TI A L 
S p o ns o r Si g n at o r y 
 
Cli ni c al St u d y Pr ot o c ol 
B A Y 1 8 4 1 7 8 8 I 2 0 6 0 9 
D at e 
M e di c al M o nit or N a m e a n d C o nt a ct I nf or m ati o n will be pr o vi d e d s e p ar at el y. 
P a g e 2 of 5 9 
P P D
P P D
P P D

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Table of Contents
Title Page................................................................................................................................... 1
Sponsor Signatory .................................................................................................................... 2
Table of Contents ..................................................................................................................... 3
Table of Tables ......................................................................................................................... 5
Table of Figures........................................................................................................................ 5
1.
Protocol Summary ............................................................................................................ 6
1.1
Synopsis........................................................................................................................... 6
1.2
Schema............................................................................................................................. 9
1.3
Schedule of Activities (SoA) ......................................................................................... 10
1.3.1
Lead-in phase.............................................................................................................. 10
1.3.2
Randomized phase...................................................................................................... 13
2.
Introduction..................................................................................................................... 16
2.1
Study Rationale.............................................................................................................. 16
2.2
Background.................................................................................................................... 16
2.3
Benefit/Risk Assessment ............................................................................................... 18
3.
Objectives and Endpoints............................................................................................... 19
4.
Study Design .................................................................................................................... 20
4.1
Overall Design ............................................................................................................... 20
4.1.1
Randomization............................................................................................................ 21
4.2
Scientific Rationale for Study Design ........................................................................... 22
4.3
Justification for Dose..................................................................................................... 22
4.4
End of Study Definition................................................................................................. 22
4.4.1
Final evaluation of the randomized phase.................................................................. 22
4.4.2
End of assessments / follow-up .................................................................................. 22
4.4.3
End of study................................................................................................................ 23
5.
Study Population............................................................................................................. 23
5.1
Inclusion Criteria ........................................................................................................... 23
5.2
Exclusion Criteria .......................................................................................................... 24
5.3
Lifestyle Considerations ................................................................................................ 26
5.4
Screen Failures............................................................................................................... 26
6.
Study Intervention .......................................................................................................... 26
6.1
Study Intervention(s) Administered............................................................................... 26
6.1.1
Medical Devices ......................................................................................................... 27
6.2
Preparation/Handling/Storage/Accountability............................................................... 27
6.3
Measures to Minimize Bias: Randomization................................................................. 27
6.4
Study Intervention Compliance ..................................................................................... 27
6.5
Concomitant Therapy .................................................................................................... 28
6.6
Dose Modification ......................................................................................................... 29
6.6.1
Definitions .................................................................................................................. 29
6.6.2
Dose modifications..................................................................................................... 29
6.6.3
Dose reduction............................................................................................................ 30
6.6.4
Dose interruption........................................................................................................ 31
6.7
Intervention after the End of the Study.......................................................................... 31

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7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal.......................................................................................... 31
7.1
Discontinuation of Study Intervention........................................................................... 31
7.2
Participant Discontinuation/Withdrawal from the Study............................................... 32
7.3
Lost to Follow up........................................................................................................... 32
8.
Study Assessments and Procedures............................................................................... 32
8.1
Efficacy Assessments .................................................................................................... 33
8.2
Safety Assessments........................................................................................................ 33
8.2.1
Physical Examinations................................................................................................ 36
8.2.2
Vital Signs .................................................................................................................. 36
8.2.3
Clinical Safety Laboratory Assessments .................................................................... 36
8.3
Adverse Events and Serious Adverse Events ................................................................ 37
8.3.1
Time Period and Frequency for Collecting AE and SAE Information....................... 37
8.3.2
Method of Detecting AEs and SAEs.......................................................................... 38
8.3.3
Follow-up of AEs and SAEs ...................................................................................... 38
8.3.4
Regulatory Reporting Requirements for SAEs .......................................................... 38
8.3.5
Pregnancy ................................................................................................................... 39
8.3.6
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs....................................................................................................................... 39
8.4
Treatment of Overdose .................................................................................................. 39
8.5
Pharmacokinetics........................................................................................................... 40
8.6
Pharmacodynamics ........................................................................................................ 40
8.7
Genetics ......................................................................................................................... 40
8.8
Biomarkers..................................................................................................................... 40
8.9
Medical Resource Utilization and Health Economics ................................................... 40
9.
Statistical Considerations ............................................................................................... 40
9.1
Statistical Hypotheses.................................................................................................... 40
9.2
Sample Size Determination ........................................................................................... 40
9.3
Populations for Analyses ............................................................................................... 41
9.4
Statistical Analyses........................................................................................................ 41
9.4.1
Efficacy Analyses....................................................................................................... 42
9.4.2
Safety Analyses .......................................................................................................... 42
9.5
Interim Analyses............................................................................................................ 45
9.5.1
Data Monitoring Committee (DMC).......................................................................... 45
10. Supporting Documentation and Operational Considerations .................................... 45
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........................ 45
10.1.1
Regulatory and Ethical Considerations ...................................................................... 45
10.1.2
Financial Disclosure ................................................................................................... 46
10.1.3
Informed Consent Process.......................................................................................... 46
10.1.4
Data Protection ........................................................................................................... 46
10.1.5
Committees Structure ................................................................................................. 46
10.1.6
Data Quality Assurance.............................................................................................. 47
10.1.7
Source Documents...................................................................................................... 47
10.1.8
Study and Site Closure ............................................................................................... 47
10.1.9
Publication Policy....................................................................................................... 48
10.2
Appendix 2: Clinical Laboratory Tests.......................................................................... 50
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting.............................................................................................. 50

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10.3.1
Definition of AE......................................................................................................... 50
10.3.2
Definition of SAE....................................................................................................... 52
10.3.3
Recording and Follow-Up of AE and/or SAE............................................................ 53
10.3.4
Reporting of SAEs...................................................................................................... 54
10.4
Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information......... 56
10.5
Appendix 5: Abbreviations............................................................................................ 57
11. References ........................................................................................................................ 59
Table of Tables
Table 1–1 Schedule of Activities for the Lead-in Phase (darolutamide) ................................. 10
Table 1–2 Schedule of Activities for the Randomized Phase (darolutamide, enzalutamide).. 13
Table 6–1 Dose Interruption and/or Reduction for Toxicities Considered Related to 
Darolutamide Treatment........................................................................................ 30
Table 8–1: Study Assessments for Physical Ability and Cognitive Function.......................... 34
Table 9–1: Estimated Decline Rates and 2-sided 95% Confidence Intervals.......................... 41
Table 10–1 Protocol-Required Safety Laboratory Assessments.............................................. 50
Table of Figures
Figure 1–1:  Study Periods......................................................................................................... 9

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1.
Protocol Summary
1.1
Synopsis
Protocol Title:
A randomized, open-label, multicenter, Phase 2b study to evaluate physical function, 
including balance and daily activity, in participants with castration-resistant prostate cancer
treated with darolutamide or enzalutamide
Short Title:
DaroAcT: darolutamide physical function and daily activity study
Rationale:
There are multiple androgen receptor (AR) inhibitors indicated for prostate cancer with 
proven efficacy. However, these drugs are associated with adverse events including fatigue, 
cognitive dysfunctions, anorexia, sarcopenia, muscle weakness, and falls. There is an unmet 
medical need to improve patients’ daily function, quality of life, and safety with an AR
inhibitor with a better safety profile. Enzalutamide is the most frequently used AR inhibitor 
indicated for the treatment of patients with castration-resistant prostate cancer (CRPC).
The Phase 3 ARAMIS study of AR inhibitor darolutamide resulted in statistically significant 
improvement in metastasis-free survival compared to placebo (40.4 months vs. 22.0 months 
in the placebo arm) with a p-value of <0.001 and hazard ratio of 0.41 (95%CI: [0.34;0.50]). 
Treatment with darolutamide also resulted in a positive trend in overall survival and a delay in 
time to pain progression (Fizazi et al. 2019). The study also showed that darolutamide is well-
tolerated and has a differentiated safety profile from other AR inhibitors (enzalutamide and 
apalutamide). However, currently there has not been a study to assess physical functioning
and daily activities in patients treated with darolutamide.
The primary aim of this study is to evaluate the effects of treatment with darolutamide or 
enzalutamide on physical function as demonstrated by changes in balance, mobility, and 
cognitive function in participants with CRPC.

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Objectives and Endpoints:
Objectives
Endpoints
Primary
The primary objective of this study is to 
compare the effects of treatment with 
darolutamide vs. enzalutamide on physical
function as assessed by the Timed Up and 
Go (TUG) test in participants with castration-
resistant prostate cancer.
Proportion of participants with a worsening in TUG
time during the 24-week period from baseline.
Worsening is defined as an increase of at least 
1 second in TUG time from baseline. (The 
minimum clinically important difference [MCID] in 
TUG time is 1 second (Davies et al. 2016))
Secondary
The secondary objectives of this study are to:
Compare the effects of treatment with 
darolutamide vs. enzalutamide on physical 
function, as assessed by the TUG test at 
12 and 24 weeks, and by 52 weeks.
Compare the effects of treatment with 
darolutamide vs. enzalutamide on physical 
function as assessed by Short Physical 
Performance Battery (SPPB) test at 12 and 
24 weeks, and by 24 and 52 weeks.
Assess the effects of treatment with 
darolutamide vs. enzalutamide on daily 
activity as assessed by accelerometry at 
12 and 24 weeks, and by 24 and 52 weeks.
Compare the effects of treatment with 
darolutamide vs. enzalutamide on cognitive 
function as assessed by Hopkins Verbal 
Learning Test-Revised (HVLT-R), Trail 
Making Test (TMT), Controlled Oral Word 
Association (COWA), and Functional 
Assessment of Cancer Therapy – Cognitive 
questionnaire (FACT-Cog)
Compare the effects of treatment with 
darolutamide vs. enzalutamide on fatigue
as assessed by the Brief Fatigue Inventory 
(BFI)
Compare the effects of treatment with 
darolutamide vs. enzalutamide on 
depression as assessed by the Patient 
Health Questionnaire-9 (PHQ-9)
Evaluate safety, including adverse events 
(AEs) of interest, of participants treated with 
darolutamide vs. enzalutamide

Evaluate the effect of treatment with 
darolutamide or enzalutamide on 
prostate-specific antigen (PSA), 
survival status, and exposure
Physical Function:

Proportion of participants with an increase of at 
least 1 second in TUG time at 12 and 
24 weeks and during the 52 weeks from 
baseline.

Time to worsening (increase of at least
1 second) in TUG time 

Proportion of participants with a worsening in 
SPPB total score at 12 and 24 weeks and 
during the 24 weeks and 52 weeks from 
baseline. Worsening is defined as a decline of 
at least 0.5 points in SPPB total score. 
Daily Activity:

Mean change from baseline in daily physical 
activity at 12 and 24 weeks, and during the 
24 weeks and 52 weeks from baseline.

Mean change from baseline in accelerometer-
assessed proportion of time spent in light to 
vigorous physical activity based on a threshold 
of >100 activity counts per minute at 12 and 
24 weeks, and during the 24 weeks and 
52 weeks from baseline.
Cognitive Function:

Proportion of participants with a decline in 
cognitive function during the 24 weeks and 
52 weeks from baseline, as assessed by 
HVLT-R, TMT, and COWA. See Table 8–1 for 
the definition of decline for each test.

Proportion of participants with a decline using 
a selected domain of FACT-Cog. Decline is 
defined as a decrease of >10 points during the 
24 weeks and 52 weeks from baseline.
Fatigue:

Proportion of participants with a worsening of 
fatigue during the 24 weeks and 52 weeks 
from baseline. Worsening is defined as an 
increase of at least 1 point in worst level of 
fatigue from baseline by 24 weeks and 
52 weeks (based on item 3 of the BFI). 

Proportion of participants with an increase of at 
least 1 point in fatigue interference by 
24 weeks and 52 weeks from baseline (based 
on items 4A-F of the BFI).

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Objectives
Endpoints
Depression:

Proportion of participants with a worsening in 
scores in the PHQ-9 during the 24 weeks and 
52 weeks from baseline. Worsening is defined 
as an increase of at least 1 point in worst level 
of depression from baseline by 24 weeks and 
52 weeks.
Safety 

All treatment emergent AEs, SAEs, and AEs 
leading to study intervention discontinuation

AEs of interest, including falls, fractures, and 
hypothyroidism
Exposure and other:

Time to deterioration of KPS defined as at 
least a 10 point decline from baseline

Treatment exposure of the study intervention 
including time on treatment

Dose reductions of study intervention

Time to PSA progression (as per Prostate 
Cancer Working Group [PCWG3] criteria)

Survival status
Overall Design:
This randomized, open-label, multicenter, Phase 2b study is designed to evaluate 
darolutamide therapy in participants with CRPC who have not previously been treated with 
apalutamide, darolutamide, or enzalutamide. CRPC patients with a history of treatment with 
abiraterone may be eligible if they have not progressed and discontinued treatment within
6 months before signing the ICF for this study.
The study consists of two phases, a lead-in phase and a randomized phase. In the lead-in 
phase, approximately 30 participants will be treated with darolutamide. Following the 
evaluation of the lead-in phase, approximately 120 additional participants will be randomized 
in a 1:1 ratio to receive either darolutamide (600 mg twice daily) or enzalutamide (160 mg 
once daily) in the randomized phase of the study. Randomization will be stratified by age 
(<75, ≥75 years).
The endpoints used in this study are novel in a way that decline in physical function will be 
evaluated using objective measures such as TUG, SPPB, and accelerometry, therefore, the
lead-in phase has been added to be able to assess compliance and the variability of the 
endpoints and overall feasibility of the study execution. The randomized phase of the study 
will start only after the primary evaluation of the lead-in phase. Depending on the results of 
the lead-in phase, the primary endpoint of the study and/or sample size for the randomized 
phase may be changed.
The primary evaluation of the lead-in phase will occur when the last participant in the lead-in 
phase has been on the study for at least 24 weeks, unless the participant discontinued due to 
lost to follow-up, withdrawal, or death.

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Disclosure Statement:
This is an open-label treatment study consisting of a lead-in phase with one arm to be
followed by a randomized phase with two arms.
Number of Participants:

Lead-in phase: approximately 30 participants (darolutamide)

Randomized phase: approximately 120 participants (1:1 darolutamide or 
enzalutamide)
Intervention Groups and Duration:
The following treatment arms are defined for this study:

Darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equal to a total
daily dose of 1200 mg

Enzalutamide 160 mg (four 40 mg capsules) administered orally once daily. Capsules 
are to be swallowed whole. Enzalutamide can be taken with or without food.
All participants must continue to receive androgen deprivation therapy (ADT) of the 
investigator’s choice (luteinizing hormone-releasing hormone [LHRH] agonist/antagonists) as 
standard therapy or have had orchiectomy.
Data Monitoring Committee: No
1.2
Schema
Figure 1–1:  Study Periods
CRPC = castration-resistant prostate cancer; N = number of participants; R = randomization
Randomization will be stratified by age (<75 vs ≥75 years).

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1.3
Schedule of Activities (SoA)
1.3.1
Lead-in phase
Table 1–1 Schedule of Activities for the Lead-in Phase (darolutamide)
Assessment
Screening
Intervention + Observation Period 
End of 
treatment 
visit       
(30 days 
after last 
dose) m
Survival 
follow-up l,n
Week 1 
Day 1 i
Week 
4 j
Week 
8
Week 
12
Week 
24
Week 
38
Week 
52
from 
Week 53:
Active follow 
up every 
3 months k,l
Time window allowed
within 21 days 
prior to first 
dose
7
days
7 
days
7
days
7
days
14
days
7
days
1 month
+ 1 month
1 month
Informed consent
X
Inclusion and exclusion 
criteria 
X
Demography
X
Full physical examination 
including weight (height 
at screening only)
X
X
X
X
X
X
X
X
X
X
Medical & surgical history 
including past and 
current medical 
conditions, substance 
use of drugs, alcohol, 
tobacco and caffeine. 
X
Concomitant medication 
review
==============================================================================
Karnofsky Performance 
Scale
X
X
X
X
X
X
X
X
X
X
Laboratory assessments 
(including liver 
chemistries) a
X
X
X
X
X
X
X
X
X
Serum PSA a
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X

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Table 1–1 Schedule of Activities for the Lead-in Phase (darolutamide)
Assessment
Screening
Intervention + Observation Period 
End of 
treatment 
visit       
(30 days 
after last 
dose) m
Survival 
follow-up l,n
Week 1 
Day 1 i
Week 
4 j
Week 
8
Week 
12
Week 
24
Week 
38
Week 
52
from 
Week 53:
Active follow 
up every 
3 months k,l
Time window allowed
within 21 days 
prior to first 
dose
7
days
7 
days
7
days
7
days
14
days
7
days
1 month
+ 1 month
1 month
Treatment dispensing / 
accountability

X
======================================================
AE review b
========================================================================
AEs of interest review,
including fall c
========================================================================
Timed Up and Go 
assessment (TUG) d
X h
X h
X
X
X
X
Short Physical 
Performance Battery
(SPPB) d
X
X
X
X
X
Accelerometry 
assessment e
X
X
X
X
X
Cognitive function f
X
X
X
X
Brief Fatigue Inventory 
(BFI) g
X
X
X
X
X
X
Patient Health 
Questionnaire (PHQ-9)
X
X
X
X
X
X
X
Survival status
X
X = measure/action to be performed at the time point indicated
======== measure/action to be performed continually during the time period indicated

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AE = adverse event; BFI = Brief Fatigue Inventory; COWA = Controlled Oral Word Association; CRF = case report form; HVLT-R = Hopkins Verbal 
Learning Test - Revised; PHQ-9 = Patient health questionnaire-9; PSA = prostate-specific antigen; SPPB = Short Physical Performance Battery; 
TMT = Trail Making Test; TUG = Timed Up and Go
a    PSA will be assessed at the same time as other laboratory assessments. A time window of 14 days is allowed for laboratory and PSA
assessments.
b    Including survival, pain, radiographic progression, metastases, and skeletal events
c    AEs of interest are fractures, falls, and hypothyroidism
d    Physical function tests include SPPB and the TUG assessment. 
e    Accelerometry assessment will require the participant to wear an accelerometry device on the wrist or hip for a minimum of 7 days at each time 
point. The first accelerometry assessment is to be performed before the first dose (i.e. during screening).
f    Cognitive function tests include the HVLT-R, TMT, and COWA, as well as the patient-reported outcome questionnaire FACT-Cog.
g   BFI is a 5 minute self-assessment tool that identifies fatigue in cancer participants over a 24-hour period.
h    The first TUG assessment is to be performed before the first dose (either during screening or Week 1 Day 1).
i     Once the baseline procedures are completed, the first administration of study intervention will be provided at the study center and the participant 
will be provided with additional medication to take as scheduled through the Week 4 visit. (Each participant will be instructed to bring any 
remaining drug back to the center at the Week 4 visit.)
j     At this and each subsequent visit, the participant will return dispensed but unused study intervention to the investigator for recording on the 
CRF. Reasons for non-compliance will be recorded. A new supply of study drug sufficient to meet the dosing requirements of each participant 
will be dispensed.
k    Participants remaining on treatment beyond Week 52 will continue, where possible, to receive study intervention and assessments until the final
evaluation of the randomized phase (i.e. at Week 52 for the last participant, see Section 4.4.1).
l     Prior to the final evaluation of the randomized phase of the study, all participants will go into Week 53 active follow-up or survival follow-up as 
applicable.
m  Each participant should complete an end of treatment visit after discontinuation of study intervention for any reason. All anti-cancer treatments 
after discontinuation of study intervention in this study will be recorded on the CRF at the end of treatment visit. See Section 4.4.2 for more 
details once the date of the final evaluation of the randomized phase is determined.
n   Survival will be followed with contact with the participant and/or his caregiver every 3 months following the date of last treatment until the end of 
the study for participants treated with darolutamide (see Section 4.4.2). 

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1.3.2
Randomized phase
Table 1–2 Schedule of Activities for the Randomized Phase (darolutamide, enzalutamide)
Assessment
Screening
Randomization
Intervention + Observation Period 
Survival 
follow-up m,o
Week 1 
Day 1 i
Week 
4 k
Week 
8
Week 
12
Week 
24
Week 
38
Week 
52
from 
Week 53:
Active 
follow up
every 
3 months l,m
End of 
treatment 
visit       
(30 days 
after last 
dose) n
Time window allowed
within 21 days 
prior to 
randomization
within 21 
days after 
randomization
7 
days
7 
days
7 
days
7 
days
14 
days
7 
days
1 month
+ 1 month
1 month
Informed consent
X
Inclusion and exclusion 
criteria 
X
Demography
X
Full physical examination 
including weight (height 
at screening only)
X
X
X
X
X
X
X
X
X
X
Medical & surgical history 
including past and 
current medical 
conditions, substance 
use of drugs, alcohol, 
tobacco and caffeine. 
X
Concomitant medication 
review
==============================================================================
Karnofsky Performance 
Scale
X
X
X
X
X
X
X
X
X
X
Laboratory assessments 
(including liver 
chemistries) a
X
X j
X
X
X
X
X
X
X
Serum PSA a
X
X j
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X

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Table 1–2 Schedule of Activities for the Randomized Phase (darolutamide, enzalutamide)
Assessment
Screening
Randomization
Intervention + Observation Period 
Survival 
follow-up m,o
Week 1 
Day 1 i
Week 
4 k
Week 
8
Week 
12
Week 
24
Week 
38
Week 
52
from 
Week 53:
Active 
follow up
every 
3 months l,m
End of 
treatment 
visit       
(30 days 
after last 
dose) n
Time window allowed
within 21 days 
prior to 
randomization
within 21 
days after 
randomization
7 
days
7 
days
7 
days
7 
days
14 
days
7 
days
1 month
+ 1 month
1 month
Treatment dispensing / 
accountability

X
======================================================
AE review b
========================================================================
AEs of interest review,
including fall c
========================================================================
Timed Up and Go 
assessment (TUG) d
X h
X h
X
X
X
X
Short Physical 
Performance Battery
(SPPB) d
X
X
X
X
X
Accelerometry 
assessment e
X
X
X
X
X
Cognitive function f
X
X
X
X
Brief Fatigue Inventory 
(BFI) g
X
X
X
X
X
X
Patient Health 
Questionnaire (PHQ-9)
X
X
X
X
X
X
X
Survival status
X
X = measure/action to be performed at the time point indicated
======== measure/action to be performed continually during the time period indicated

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AE = adverse event; BFI = Brief Fatigue Inventory; COWA = Controlled Oral Word Association; CRF = case report form; HVLT-R = Hopkins Verbal 
Learning Test - Revised; PHQ-9 = Patient health questionnaire-9; PSA = prostate-specific antigen; SPPB = Short Physical Performance Battery; 
TMT = Trail Making Test; TUG = Timed Up and Go
a    PSA will be assessed at the same time as other laboratory assessments. A time window of 14 days is allowed for laboratory and PSA 
assessments.
b    Including survival, pain, radiographic progression, metastases, and skeletal events
c    AEs of interest are fractures, falls, and hypothyroidism
d    Physical function tests include SPPB and the TUG assessment.
e    Accelerometry assessment will require the participant to wear an accelerometry device on the wrist or hip for a minimum of 7 days at each time 
point. The first accelerometry assessment is to be performed before the first dose (i.e. during screening).
f    Cognitive function tests include the HVLT-R, TMT, and COWA, as well as the patient-reported outcome questionnaire FACT-Cog.
g   BFI is a 5 minute self-assessment tool that identifies fatigue in cancer participants over a 24-hour period.
h    The first TUG assessment is to be performed before the first dose (either during screening or Week 1 Day 1).
i     Once the baseline procedures are completed, the first administration of study intervention will be provided at the study center and the participant 
will be provided with additional medication to take as scheduled through the Week 4 visit. (Each participant will be instructed to bring any 
remaining drug back to the center at the Week 4 visit.)
j     Laboratory and PSA analyses and the physical examination will need to be repeated if they are not within 21 days from randomization. Week 1 
Day 1 cannot be longer than 3 weeks from randomization.
k    At this and each subsequent visit, the participant will return dispensed but unused study intervention to the investigator for recording on the 
CRF. Reasons for non-compliance will be recorded. A new supply of study drug sufficient to meet the dosing requirements of each participant 
will be dispensed.
l     Participants remaining on treatment beyond Week 52 will continue, where possible, to receive study intervention and assessments until the final
evaluation of the randomized phase (i.e. at Week 52 for the last participant, see Section 4.4.1). 
m   Prior to the final evaluation of the randomized phase of the study, all participants will go into Week 53 active follow-up or survival follow-up as 
applicable.
n    Each participant should complete an end of treatment visit after discontinuation of study intervention for any reason. All anti-cancer treatments 
after discontinuation study intervention in this study will be recorded on the CRF at the end of treatment visit. See Section 4.4.2 for more details 
once the date of the final evaluation of the randomized phase is determined.
o   Survival will be followed with contact with the participant and/or his caregiver every 3 months following the date of last treatment until the end of 
the study for participants treated with darolutamide, and until the final evaluation of the randomized phase for participants treated with 
enzalutamide (see Section 4.4.2).

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2.
Introduction
Prostate cancer is the second most common cancer and the fifth leading cause of cancer death 
among men worldwide (World Health Organization 2017). It is the most common 
non-cutaneous cancer and the second leading cause of cancer-related deaths in men in Europe
(World Health Organization 2008) and the United States (USA) (Hirsch et al. 2001). The 
most significant morbidity of prostate cancer is bone metastases.
2.1
Study Rationale
Most prostate cancer at diagnosis (in Europe and the USA) is localized disease. The majority 
of patients receive local treatment alone or with adjuvant androgen deprivation therapy 
(ADT). Many patients will eventually become resistant to ADT and develop 
castration-resistant prostate cancer (CRPC) (Dai et al. 2017). Contemporary research has led 
to the development of multiple active treatments for men with advanced disease, in addition to 
ADT. Management of CRPC involves the sequential use of these approaches, with the goals 
of prolonging survival and minimizing complications, but there is also a need to maintain 
quality of life.
There are multiple androgen receptor (AR) inhibitors indicated for prostate cancer with 
proven efficacy. However, these drugs are associated with adverse events including fatigue, 
cognitive dysfunctions, anorexia, sarcopenia, muscle weakness, and falls. There is an unmet 
medical need to improve patients’ daily function, quality of life, and safety with an AR
inhibitor with a better safety profile. Enzalutamide is the most frequently used AR inhibitor 
indicated for the treatment of patients with CRPC.
The Phase 3 ARAMIS study of AR inhibitor darolutamide showed clinically and statistically 
significant prolongation of time to metastasis in patients with non-metastatic CRPC treated 
with darolutamide as compared to placebo (Fizazi et al. 2019). The study also showed that 
darolutamide was well tolerated and has a differentiated safety profile from enzalutamide, 
which is why darolutamide-treated patients may have improved function for activities of daily 
living, less fatigue, and improved cognition. However, currently there has not been a study to 
assess physical function and daily activities in patients treated with darolutamide.
The primary aim of this study is to evaluate the effects of treatment with darolutamide or 
enzalutamide on physical function as demonstrated by changes in balance, mobility, and
cognitive function in participants with CRPC. Standardized assessments of physical function
including the Timed Up and Go (TUG) and Short Physical Performance Battery (SPPB) will 
be used to monitor participants’ physical function on treatment (Belch et al. 2003). Each 
participant will also use an accelerometry device to track daily physical activity. 
The cognitive function assessments included in this study are the Hopkins Verbal Learning 
Test, Revised (HVLT-R), Trail Making Test (TMT), Controlled Oral Word Association Test
(COWA), and Functional Assessment of Cancer Therapy-Cognitive (FACT-Cog). Fatigue 
and depression will be assessed using the Brief Fatigue Inventory (BFI) and Patient Health 
Questionnaire-9 (PHQ-9), respectively.
2.2
Background
Darolutamide (ODM-201/BAY 1841788) is a novel non-steroidal AR inhibitor that appears to 
negligibly cross the blood–brain barrier, reducing the occurrence of central side effects 
including seizures. Darolutamide has been found to block the activity of all tested/well-known 
mutant ARs in prostate cancer, including the recently identified clinically-relevant F876L 

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mutation that produces resistance to enzalutamide and apalutamide, and shows a higher 
binding affinity (9 nM) to AR compared with known second-generation antiandrogens and 
greater inhibitory efficacy (Eikelboom et al. 2017).
Darolutamide has been investigated in multiple Phase 1, 2, and 3 trials. Detailed information 
can be found in the Investigator’s Brochure (IB).
The Phase 1/2 ARADES study in patients with metastatic CRPC showed tolerability of 
darolutamide in the population with advanced prostate cancer with metastatic lesions. The 
Phase 1 component of ARADES was an open-label, uncontrolled, non-randomized, 
multicenter, dose-escalation safety study with single- and multiple-dose pharmacokinetic 
(PK) evaluation in 24 patients. No dose-limiting toxic effects were reported and the maximum 
tolerated dose was not reached (Derry and Loke 2000).
The Phase 2 part of the trial randomized 124 patients to one of three darolutamide doses, with 
a primary endpoint of proportion of patients with PSA response (≥50% decrease in serum 
PSA) at Week 12. PSA response was achieved by 11 patients (29%) in the 200 mg group, 
13 (33%) in the 400 mg group, and 11 (33%) in the 1400 mg group. The most common 
treatment-emergent adverse events (TEAEs) were fatigue or asthenia (12% of patients), hot 
flush (5%), and decreased appetite (4%) (Derry and Loke 2000).
The multinational, randomized, double-blind, placebo-controlled, Phase 3, efficacy and safety 
study of darolutamide in men with high-risk non-metastatic castration-resistant prostate 
cancer (ARAMIS) met the primary endpoint of metastasis-free survival (MFS). In total, 
1509 patients underwent randomization (955 to the darolutamide arm and 554 to the placebo 
arm). The median MFS was 40.4 months with darolutamide, as compared with 18.4 months 
with placebo (hazard ratio for metastasis or death in the darolutamide arm, 0.41; 
95% confidence interval, 0.34 to 0.50; p<0.001). Darolutamide was also associated with 
benefits with regard to all secondary endpoints, including overall survival, time to pain 
progression, time to cytotoxic chemotherapy, and time to a symptomatic skeletal event. 
Darolutamide treatment was well-tolerated with comparable incidence of the most common 
TEAEs and similar incidence of permanent discontinuations of treatment between the 
darolutamide and the placebo arms. Incidences of TEAEs were below 10% in both treatment 
arms, with the exception of fatigue (12.1% darolutamide vs. 8.7% placebo) (Fizazi et al. 
2019).
The median MFS with darolutamide in ARAMIS is similar to that in two other randomized 
controlled trials with enzalutamide and apalutamide in patients with non-metastatic CRPC. 
Median MFS was 36.6 months with enzalutamide (vs. 14.7 with placebo) in the PROSPER 
Phase 3 trial, and was 40.4 months with apalutamide (vs. 16.2 months with placebo) in the 
SPARTAN Phase 3 trial (Hussain et al. 2018, Smith et al. 2018). Rates of fatigue and asthenia, 
common adverse events for patients receiving hormone-targeted therapy for advanced 
prostate cancer, were lower in ARAMIS than in PROSPER and SPARTAN. In contrast to 
apalutamide and enzalutamide, darolutamide was not associated with increased rates of falls 
or fractures compared with placebo despite few patients using osteoclast-targeted therapies. 
Seizures were noted as a potential risk in the dose escalation and toxicity studies of 
enzalutamide (Scher et al. 2010). The incidence of seizure events was low and similar in the 
darolutamide and placebo arms; none of the patients with a medical history of seizure (12 in 
the darolutamide arm) experienced a seizure on study. Rates of rash and hypothyroidism, 
which were increased in patients receiving apalutamide compared with placebo, were low and 
similar between the darolutamide and placebo arms. Incidences of hypertension and central 
nervous system (CNS)-related adverse events were also low and similar between

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darolutamide and placebo arms in ARAMIS. In PROSPER and SPARTAN, rates of 
hypertension and CNS-related adverse effects, such as mental impairment disorders and 
dizziness, were more common in patients receiving enzalutamide or apalutamide compared 
with placebo. The similar incidence of seizures, dizziness, and cognitive impairment in the 
darolutamide and placebo arms of ARAMIS may be linked to darolutamide’s low blood–brain 
barrier penetration observed in preclinical studies (Zurth et al. 2018).
However, currently there has been no study to assess differences in physical function and the 
influence on quality of life of CRPC patients treated with these treatment options, and the
effect of the treatments on daily function, quality of life, and activities are unknown. This
study is designed to assess physical function, daily activity level, cognitive functions, and 
influence of secondary events in patients with CRPC treated with darolutamide and 
enzalutamide.
2.3
Benefit/Risk Assessment
The available clinical data suggest that darolutamide use is well-tolerated and safe for patients 
with non-metastatic CRPC. Darolutamide has been shown to significantly increase the time to 
metastasis compared to placebo while providing a favorable safety profile with low risk for 
adverse reactions that could deteriorate patients’ quality of life. Therefore, the benefit from 
darolutamide treatment is significantly greater than the risk imposed by the treatment.
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of darolutamide can be found in the IB. Information about the 
adverse events of enzalutamide is available in the prescription information of enzalutamide
(XTANDITM  Prescribing information).

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3.
Objectives and Endpoints
Objectives
Endpoints
Primary
The primary objective of this study is to 
compare the effects of treatment with 
darolutamide vs. enzalutamide on physical
function as assessed by the TUG test in 
participants with castration-resistant prostate 
cancer.
Proportion of participants with a worsening in TUG
time during the 24-week period from baseline. 
Worsening is defined as an increase of at least 
1 second in TUG time from baseline. (The MCID in 
TUG time is 1 second (Davies et al. 2016))
Secondary
The secondary objectives of this study are to:
Compare the effects of treatment with 
darolutamide vs enzalutamide on physical 
function, as assessed by the TUG test at 
12 and 24 weeks, and by 52 weeks.
Compare the effects of treatment with 
darolutamide vs enzalutamide on physical 
function as assessed by the SPPB test at 
12 and 24 weeks, and by 24 and 52 weeks.
Assess the effects of treatment with 
darolutamide vs. enzalutamide on daily 
activity as assessed by accelerometry at 
12 and 24 weeks, and by 24 and 52 weeks.
Compare the effects of treatment with 
darolutamide versus enzalutamide on 
cognitive function as assessed by 
HVLT-R, TMT, COWA, and FACT-Cog
Compare the effects of treatment with 
darolutamide versus enzalutamide on 
fatigue as assessed by the BFI
Compare the effects of treatment with 
darolutamide vs. enzalutamide on 
depression as assessed by the PHQ-9
Evaluate safety, including AEs of interest, 
of participants treated with darolutamide 
vs. enzalutamide

Evaluate the effect of treatment with 
darolutamide or enzalutamide on PSA, 
survival status, and exposure 
Physical Function:

Proportion of participants with an increase of at 
least 1 second in TUG time at 12 and 24 weeks 
and during the 52 weeks from baseline.

Time to worsening (increase of at least 
1 second) in TUG time 

Proportion of participants with a worsening in 
SPPB total score at 12 and 24 weeks and 
during the 24 weeks and 52 weeks from 
baseline. Worsening is defined as a decline of 
at least 0.5 points in SPPB total score.
Daily Activity:

Mean change from baseline in daily physical 
activity at 12 and 24 weeks, and during the 
24 weeks and 52 weeks from baseline.

Mean change from baseline in accelerometer-
assessed proportion of time spent in light to 
vigorous physical activity based on a threshold 
of >100 activity counts per minute at 12 and 
24 weeks, and during the 24 weeks and 
52 weeks from baseline.
Cognitive Function:

Proportion of participants with a decline in 
cognitive function during the 24 weeks and 
52 weeks from baseline, as assessed by 
HVLT-R, TMT, and COWA. See Table 8–1 for 
the definition of decline for each test.

Proportion of participants with a decline using a 
selected domain of FACT-Cog. Decline is 
defined as a decrease of >10 points during the 
24 weeks and 52 weeks from baseline.
Fatigue:

Proportion of participants with a worsening of 
fatigue during the 24 weeks and 52 weeks from 
baseline. Worsening is defined as an increase 
of at least 1 point in worst level of fatigue from 
baseline by 24 weeks and 52 weeks (based on 
item 3 of the BFI). 

Proportion of participants with an increase of at 
least 1 point in fatigue interference by 
24 weeks and 52 weeks from baseline (based 
on items 4A-F of the BFI).

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Objectives
Endpoints
Depression:

Proportion of participants with a worsening in 
scores in the PHQ-9 during the 24 weeks and 
52 weeks from baseline. Worsening is defined 
as an increase of at least 1 point in worst level 
of depression from baseline by 24 weeks and 
52 weeks.
Safety 

All treatment emergent AEs, SAEs, and AEs 
leading to discontinuation

AEs of interest, including falls, fractures, and 
hypothyroidism
Exposure and other:

Time to deterioration of KPS defined as at least 
a 10 point decline from baseline 

Treatment exposure of the study intervention
including time on treatment

Dose reductions of study intervention

Time to PSA progression (as per PCWG3
criteria)

Survival status
4.
Study Design
4.1
Overall Design
This is a randomized, open-label, multicenter, Phase 2b study to be conducted with a total of 
approximately 150 participants with CRPC who have not previously been treated with 
apalutamide, darolutamide, or enzalutamide. CRPC patients with a history of treatment with 
abiraterone may be eligible if they have not progressed and discontinued treatment within
6 months before signing the ICF for this study.
The study consists of two phases, a lead-in phase and a randomized phase (see 
Figure 1–1). In the lead-in phase, approximately 30 participants will be treated with 
darolutamide. Following the primary evaluation of the lead-in phase, approximately 
120 participants will be randomized in a 1:1 ratio to receive either darolutamide (600 mg 
twice daily) or enzalutamide (160 mg once daily) in the randomized phase of the study. 
Randomization will be stratified by age (<75, ≥75 years).
At the end of the lead-in phase of the study, the compliance and variability of the endpoints 
and overall feasibility of the study execution will be assessed. The randomized phase of the 
study will start only after the primary evaluation of the lead-in phase. Depending on the 
results of the evaluation, the primary endpoint for the randomized portion of the study may be 
changed. The final study design and endpoints for the randomized phase will be determined 
based on the lead-in cohort of 30 participants. The decision to move to the randomized phase 
of the study will involve reviewing the findings from the lead-in phase of the study with the 
members of the steering committee.

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The primary evaluation of the lead-in phase will occur when at least 30 participants in the 
lead-in phase have been on the study for at least 24 weeks, unless the participant discontinued 
due to lost to follow-up, withdrawal, or death. Additional participants may be enrolled in the 
lead-in phase if necessary.  
The following endpoints will be evaluated at the end of the lead-in phase: 

the proportion of participants with a worsening in TUG time at week 12 and 24 and 
during the 24-week and 52-week period from baseline. Worsening is defined as an 
increase of at least 1 second in TUG time from baseline.

the proportion of participants with a worsening in SPPB total score at week 12 and 24 
and during the 24-week and 52-week period from baseline. Worsening is defined as a 
decline of at least 0.5 points in SPPB total score.

the proportion of participants with a decline in cognitive function during the 24-week
period from baseline, as assessed by HVLT-R and TMT
The suggested sample size for the randomized phase is based on the assessment of TUG test 
as the primary endpoint; however, after the feasibility assessment, the appropriate endpoint 
and the time point and time frame of evaluation of the endpoint for this part of the study will 
be chosen and the sample size will be reassessed.
The study is designed to evaluate physical function, including balance and daily activity, in 
participants treated with darolutamide or enzalutamide. It will also evaluate, safety, cognitive 
function, fatigue, and survival in participants treated with darolutamide or enzalutamide.
Participants will receive treatment (darolutamide or enzalutamide) until toxicity or disease 
progression and receive assessments during treatment. The study will continue until at least 
52 weeks after the initial dose of the last participant, unless the participant discontinued due to
lost to follow-up, withdrawal, or death. All participants will be followed up for survival status 
until the end of the study unless participants withdraw their informed consent.
The primary analysis for the lead-in phase will be performed when the last participant in the 
lead-in phase has been on the study for at least 24 weeks, unless the participant discontinued 
due to lost to follow-up, withdrawal, or death.
The primary analysis for the randomized phase for the study will occur when last participant
in the randomized phase of the study has been on the study for at least 24 weeks, unless the 
participant discontinued due to lost to follow-up, withdrawal, or death. A final analysis for the 
randomized phase for the study will occur when last participant in the randomized phase of 
the study has been on the study for at least 52 weeks, unless the participant discontinued due
to lost to follow-up, withdrawal, or death.  
No data monitoring committee, dose escalation committee, or similar review group will be 
used for this study. The study will be conducted only in the USA at approximately 20 sites.
4.1.1
Randomization
This is an open-label study; however, the specific intervention to be taken by a participant 
will be assigned using an IWRS. The site will need to access the IWRS prior to the start of 
study intervention administration for each participant. The site will record the intervention 
assignment on the applicable case report form (CRF), if required. Randomization will be 
stratified by age (<75, ≥75 years). 

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4.2
Scientific Rationale for Study Design
This study is designed to assess physical function, daily activity level, cognitive functions, 
and influence of secondary events in participants with CRPC treated with darolutamide and 
enzalutamide. The primary aim of this study is to evaluate the effects of treatment with 
darolutamide or enzalutamide on physical function as demonstrated by changes in balance, 
mobility, and cognitive function in participants with CRPC. Standardized assessments of 
physical function including the TUG and SPPB will be used to monitor participants’ physical 
function on treatment (Belch et al. 2003). Each participant will also use an accelerometry 
device to measure daily physical activity. The cognitive function assessments included in this 
study are the HVLT-R, TMT, COWA, and FACT-Cog. Fatigue and depression will be 
assessed using the BFI and PHQ-9, respectively. Before the randomized phase, in the lead-in 
phase in participants treated with darolutamide, these parameters will be assessed for 
feasibility and clinical relevance. After assessment in approximately 30 evaluable 
participants, the parameters and endpoints will be assessed and selected accordingly. This will
allow a re-evaluation of the study design and endpoints before the randomized phase and
allow a re-estimation of the assumptions for the comparator and study arms.
4.3
Justification for Dose
In the ARAMIS Phase 3 study, it was demonstrated that a dose of 600 mg darolutamide bid is 
sufficient to achieve maximum decrease in PSA and to result in a significantly longer 
metastasis-free survival (MFS) compared to the placebo arm. Overall, a darolutamide dose of 
600 mg bid is considered to have an optimal benefit-risk profile.
The enzalutamide dose was based on approved dosing in the USA for enzalutamide in this 
population.
4.4
End of Study Definition
4.4.1
Final evaluation of the randomized phase
The final evaluation of the randomized phase will be at least 52 weeks from the initial dose of 
the study drug of the last participant randomized in the study, unless the participant 
discontinued due to lost to follow-up, withdrawal, or death.
If the trial is stopped but benefits are observed for ongoing participants, options for treatment 
continuation will be discussed and agreed between the investigator, sponsor and the 
participants.
4.4.2
End of assessments / follow-up
A participant is considered to have completed the study if he has completed all periods of the 
study including the last visit or evaluation at 52 weeks, unless the participant discontinued 
due to lost to follow-up, withdrawal, or death.
For participants treated with darolutamide, at the time of the final evaluation of the 
randomized phase:

If ongoing on study intervention, the participant can continue treatment until he meets 
the criteria for discontinuation (see Section 7). After discontinuation, the participant 
should complete an end-of-treatment visit and enter survival follow-up until the end of 
the study (defined in Section 4.4.3).

If in survival follow-up, the participant can continue in survival follow-up until the 
end of the study (defined in Section 4.4.3).

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For participants treated with enzalutamide, at the time of the final evaluation of the 
randomized phase:

These participants should complete an end-of-treatment visit or a final survival 
follow-up, as applicable. All participants treated with enzalutamide will reach their 
final assessment. No data will be collected for participants treated with enzalutamide 
beyond this time.
4.4.3
End of study 
The end of the study is defined as the time when the last participant treated with darolutamide
has completed the end of treatment visit or survival follow-up; however, participants may 
continue darolutamide treatment outside of the study.
In the event a roll-over study is established:

The last patient last visit (LPLV) date can be reached based on the last participant 
switching to a roll-over study or being switched to another drug supply.

The present study will end when all participants have transitioned into the roll-over
study or have discontinued from this study for another reason (e.g. consent withdrawn, 
lost to follow-up, death). 

Until the transition to a roll-over study, participants will continue to follow all the 
procedures and visits required in the current version of the protocol.
5.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1. Participant must be 18 years of age inclusive or older at the time of signing the 
informed consent.
Type of Participant and Disease Characteristics
2. Participants who have:
Histologically or cytologically confirmed adenocarcinoma of prostate, CRPC 
defined by disease progression despite ADT and may present as either a confirmed 
rise in serum PSA levels (as defined by PCWG3), the progression of pre-existing 
disease, and/or the appearance of new metastases. Metastatic and non-metastatic 
CRPC patients will be eligible.
KPS performance status of ≥80
Blood counts at screening: hemoglobin ≥9.0 g/dL, absolute neutrophil count 
≥1500/µL, platelet count ≥100,000/µL
Screening values of serum alanine aminotransferase (ALT) and/or aspartate 
aminotransferase (AST) ≤2.5 × upper limit of normal (ULN), total bilirubin 
≤1.5 × ULN, creatinine ≤2.0 × ULN
Life expectancy of at least 1 year

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Eligible for treatment with enzalutamide (only for the randomized phase)
Sex
3. Male
Contraceptive use by men should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
Sexually active participants, unless surgically sterile, must agree to use condoms as an 
effective barrier method and refrain from sperm donation during study treatment and 
for 3 months after the end of the study treatment. Participants who are sexually active 
with a female partner of childbearing potential, unless surgically sterile, must agree to 
ensure that an additional form of contraception is also used. See Appendix 4 
(Section 10.4) for contraceptive guidance for women of childbearing potential.
Informed Consent
4. Capable of giving signed informed consent as described in Appendix 1 (Section 10.1) 
which includes compliance with the requirements and restrictions listed in the 
informed consent form (ICF) and in this protocol
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Symptomatic local-regional disease that requires medical intervention including 
moderate/severe urinary obstruction or hydronephrosis with abnormal renal function 
due to prostate cancer. Participants with visceral metastasis will be excluded.
2. Severe or uncontrolled concurrent disease, infection, or comorbidity
3. Past (within 6 months before the start of study intervention) or concurrent stroke, 
myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery 
bypass graft, and/or congestive heart failure (New York Heart Association Class III or 
IV)
4. Uncontrolled clinically significant hypertension
5. Prior malignancy. Adequately treated basal cell or squamous cell carcinoma of the 
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 3 years before the start of study intervention and from 
which the participant has been disease free
6. Known metastatic brain or meningeal tumors
7. Prior or concurrent central nervous system disease, such as epilepsy, Parkinson’s 
disease, Alzheimer’s disease, dementia, or multiple sclerosis
8. Active viral hepatitis, active human immunodeficiency virus (HIV), or chronic liver 
disease
9. Gastrointestinal disorder or procedure that is expected to interfere significantly with 
absorption of study treatment
10. Major surgical procedure or significant traumatic injury within 28 days before the start 
of study intervention

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11. Seizure disorder requiring medication
12. Non-healing wound, ulcer, or bone fracture
13. Substance abuse, medical, psychological, or social conditions that may interfere with 
the participant’s participation in the study or evaluation of the study results
14. Non-ambulatory participants who need a wheelchair. Other assistive devices (e.g., 
cane or walker) are permitted.
15. Any illness or medical condition that is unstable or could jeopardize the safety of the 
participant and his compliance in the study
16. Clinically significant limitations in cognitive function and/or physical function, such 
as >20 seconds in the TUG assessment
Prior/Concomitant Therapy
17. Prior treatment with any of the following:
o
Second-generation AR inhibitors, such as enzalutamide, apalutamide, or 
darolutamide
o
Other investigational AR inhibitors
o
Progression on abiraterone acetate and discontinuation within 6 months before 
signing the ICF for the study
o
For mCRPC participants: any chemotherapy, and/or >2 prior lines of systemic 
anticancer treatment. Treatment with an LHRH agonist, LHRH antagonists, or 
orchidectomy is not counted as systemic treatment with regard to this exclusion 
criterion.
18. Use of estrogens or 5-α reductase inhibitors (finasteride, dutasteride) within 28 days 
before the start of study intervention and AR inhibitors (bicalutamide, flutamide, 
nilutamide, cyproterone acetate) within 28 days before screening
19. Use of immunotherapy within 28 days before the start of study intervention
20. Treatment with radiotherapy/radiopharmaceuticals within 12 weeks before the start of 
study intervention
21. Use of systemic corticosteroid with dose greater than the equivalent 10 mg of 
prednisone/day within 28 days before the start of study intervention
22. Acute toxicities of prior treatments and procedures not resolved to grade ≤1 or 
baseline before the start of study intervention
Prior/Concurrent Clinical Study Experience
23. Previous participation in other clinical studies within 28 days before the start of study 
treatment or 5 half-lives of the investigational treatment of the previous study, 
whichever is longer
Diagnostic assessments
24. Known hypersensitivity to any of the study interventions, study drug classes, or 
excipients in the formulation
25. Inability to swallow oral medications
Other Exclusions

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26. If, in the opinion of the investigator, the participant is unable to complete the different 
tests required for the study. 
5.3
Lifestyle Considerations
No restrictions are required.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently entered in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any serious adverse event (SAE).
During the screening period, if a participant has failed a test, the test may be repeated if the 
investigator has determined that the repeated screening test does not expose the participant to 
an unjustifiable health risk. The participant may be eligible for study participation if the 
repeated test meets the screening criteria and protocol window.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. A participant who is rescreened is required to sign another ICF. 
6.
Study Intervention
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
6.1
Study Intervention(s) Administered
Intervention Name
Darolutamide
Enzalutamide
Type
drug
drug
Dose formulation
film-coated tablet
soft tablet
Unit dose strengths
300 mg
40 mg
Dosage Level
600 mg twice daily
160 mg once daily
Route of administration
oral
oral
investigational 
medicinal product (IMP)
/ non- investigational 
medicinal product
(NIMP)
IMP
IMP
Sourcing
Provided centrally by the sponsor
Commercially available
Packaging and Labeling
Will be provided in white opaque 
wide-necked high density 
polyethylene (HDPE) bottles closed 
with white opaque screw cap 
polypropylene (PP) / PP with seal 
polyethylene child-resistant. Each 
container will be labeled as required 
per country requirement.
Will be supplied via prescription 
for those in the enzalutamide 
arm as commercially available 
from the pharmacy and will not 
be supplied by the sponsor.
Current/Former 
Name(s) or Alias(es)
Darolutamide (BAY 1841788 /
ODM-201)
Enzalutamide (Xtandi®)

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6.1.1
Medical Devices
All enrolled participants will perform accelerometry assessments as described in the SoA
(Section 1.3). Additional accelerometry details will be specified in a separate Operational Site 
User manual.
1. Accelerometry medical devices (not manufactured by or for the sponsor) are provided
for use in this study.
2. Medical device incidents, including those resulting from malfunctions of the device, 
must be detected, documented, and reported by the investigator throughout the study.
6.2
Preparation/Handling/Storage/Accountability
Darolutamide should be stored in the original container not above 30°C as indicated on the 
clinical supply label. 
1. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
2. Only participants enrolled in the study may receive study intervention and only authorized 
site staff may supply or administer study intervention. All study intervention must be 
stored in a secure, environmentally controlled, and monitored (manual or automated) area 
in accordance with the labeled storage conditions with access limited to the investigator 
and authorized site staff.
3. The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(i.e., receipt, reconciliation, and final disposition records).
4. Further guidance and information for the final disposition of unused study interventions 
will be made available to sites as required.
6.3
Measures to Minimize Bias: Randomization
This is an open-label study; however, all participants in the randomized phase will be 
centrally assigned to randomized study intervention using an Interactive Web Response 
System (IWRS). Before the study is initiated, the log in information & directions for the 
IWRS will be provided to each site.
The site will contact the IWRS prior to the start of study intervention administration for each 
participant. The site will record the intervention assignment in the participant’s source 
documents and on the applicable case report form, if required. Potential bias will be reduced 
by central randomization.
6.4
Study Intervention Compliance
Participant compliance with study intervention will be assessed at each visit. Compliance will 
be assessed by direct questioning, counting returned tablets/capsules, etc. The participant
should be asked about the reason for obvious non-compliance. Deviation(s) from the 
prescribed dosage regimen should be recorded in the source records and eCRF.

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6.5
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or 
receives during the study must be recorded along with:

Reason for use

Dates of administration including start and end dates

Dosage information including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy.
All participants must continue to receive ADT of the investigator’s choice (LHRH 
agonist/antagonists) as standard therapy or have had orchiectomy. Switching ADT to an 
LHRH antagonist is permitted during study treatment.
All concomitant treatments must be recorded in the participant’s source documents and on the 
CRFs, from the time of informed consent until the end of treatment visit at the time points 
specified in the SoA (Section 1.3). Once the participant has been withdrawn from treatment 
with the study intervention, subsequent systemic antineoplastic therapies for prostate cancer
also will be recorded. 
Palliative radiation therapy or surgical intervention as needed is allowed during study 
treatment. Treatment with biphosphonates and denosumab is allowed.
Darolutamide is a substrate of CYP3A4 and P-glycoprotein (P-gp). Repeated administration 
of rifampicin (600 mg), a strong CYP3A4 and a P-gp inducer, with a single dose of 
darolutamide (600 mg) together with food, resulted in a decrease of 72% in mean exposure 
[AUC(0‑72)] and a decrease of 52% in Cmax of darolutamide. Use of strong CYP3A4 
inducers and P-gp inducers (e.g. carbamazepine, phenobarbital, St. John's Wort) during 
treatment with darolutamide is not recommended, unless there is no therapeutic alternative. 
Selection of an alternate concomitant medicinal product, with no or weak potential to induce 
CYP3A4 or P-gp should be considered. 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 substrate, together with food resulted in a 5.2-fold
increase in mean exposure [AUC(0–24)] of rosuvastatin and a 4.9-fold increase in Cmax. 
These results indicate that co–administration of darolutamide can also increase the plasma 
concentrations of other concomitant BCRP substrates (e.g. methotrexate, sulfasalazine, 
fluvastatin, atorvastatin). Therefore, participants should be closely monitored for signs and 
symptoms of increased exposure to BCRP substrates. Dose modification of BCRP substrates 
should be considered based on the prescriber information.
For participants receiving enzalutamide in the study, the use of concomitant medications 
should follow the prescriber information for enzalutamide (XTANDITM  Prescribing 
information).
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.
Initiation of the following medications during the study treatment period is prohibited:

any investigational medicinal product

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
radiopharmaceuticals

radium-223

immunotherapy (e.g. sipuleucel–T)

cytotoxic chemotherapy 

apalutamide, 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 intervention

any medication that would affect the assessment of physical or cognitive function
For prohibited prior therapy, please refer to the exclusion criteria in Section 5.2.
6.6
Dose Modification
In case a dose reduction is necessary, the study intervention will be administered as described 
in the following sections.
The dose or dosing schedule of the study intervention may be modified following the 
occurrence of clinically significant AEs.
6.6.1
Definitions

Delay: Administration of study intervention is later than the planned schedule;
however, no planned doses of medication are actually missed. Delays can only occur 
in regimens with a drug holiday, or regimens consisting of individual doses. Dose 
delay does not apply to the first administration of drug at the start of the study.

Interruption: Unscheduled break in administration during which scheduled doses of 
study intervention are not received.
6.6.2
Dose modifications 
Doses of study intervention may be interrupted or reduced in case of clinically significant 
toxicities that are related to study treatment. All dose modifications regardless of relatedness 
should be recorded on the CRF. 
Study intervention may be interrupted for situations other than treatment-related AEs such as 
medical/surgical events or logistical reasons not related to study therapy. Participants should 
be placed back on study intervention within 28 days of the interruption, unless otherwise 
discussed with the sponsor. The reason for interruption should be documented in the 
participant's study record.
Darolutamide
A participant who experiences a darolutamide treatment-related grade 3 or 4 AE should 
interrupt study treatment until the AE improves to grade 2 or less. Darolutamide treatment is 
then to be restarted at 300 mg bid.
Additional details are provided in Table 6–1.

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Table 6–1 Dose Interruption and/or Reduction for Toxicities Considered Related to 
Darolutamide Treatment
Severity grade
(NCI-CTCAE v 5.0)
Dose modifications
Permanent discontinuation of 
darolutamide
Grade 0-2
Treat on time.
Per investigator’s decision to interrupt 
or reduce darolutamide a,b
-
Grade 3 or 4
Interrupt 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 
intervention is temporarily or 
permanently reduced to 300 mg 
bid and a grade 3 or higher 
treatment-related AE occurs 
while the participant is on a dose 
of 300 mg bid, the participant
must be withdrawn from 
treatment with darolutamide.
Excludes clinically non-significant and asymptomatic laboratory abnormalities
AE = adverse event; bid = twice daily; NCI-CTCAE v 5.0 = National Cancer Institute - Common 
Terminology Criteria for Adverse Events version 5.0
a   If darolutamide is interrupted for 28 consecutive days, darolutamide should be permanently 
discontinued.
b   When the AE improves or is resolved, dose escalation to 600 mg bid may be considered at the 
discretion of the investigator.
c   If the dose is re-escalated to 600 mg and any treatment-related AE with a severity grade 3 or 
higher occurs, a permanent dose reduction is required. A third occurrence of a grade 3 or higher 
treatment-related AE requires permanent discontinuation of darolutamide.
Enzalutamide
Dose modification and/or interruption for toxicities considered related to enzalutamide 
treatment can be made according to the prescription information (XTANDITM  Prescribing 
information). If a participant experiences a grade ≥3 toxicity or an intolerable adverse 
reaction, dosing should be withheld for one week or until symptoms improve to grade ≤2, 
then resumed at the same or a reduced dose (120 mg or 80 mg) if warranted.
6.6.3
Dose reduction
Darolutamide
If considered necessary for the participant’s safety, the dose of darolutamide may be reduced 
to 300 mg bid. The medical monitor must be notified of any dose reduction. 
Dosing of darolutamide below 300 mg bid is not allowed. If a grade 3 or higher treatment-
related AE occurs while the participant is on 300 mg bid, the participant must be withdrawn 
from darolutamide.
When an AE leading to dose reduction improves or is resolved, dose re-escalation to 600 mg 
bid may be considered at the discretion of the investigator.
Enzalutamide
Dose reduction of enzalutamide can be done according to the prescription information
(XTANDITM  Prescribing information). The medical monitor must be notified of any dose 
reduction.

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When an AE leading to dose reduction improves or is resolved, dose re-escalation may be 
considered at the discretion of the investigator.
6.6.4
Dose interruption
Participants should restart study intervention within 7 days of dose interruption, but the 
maximum time allowed for a dose interruption period is 28 consecutive days. Any participant 
requiring treatment interruption >28 consecutive days must be withdrawn from study 
intervention.
6.7
Intervention after the End of the Study
The study will continue until at least 52 weeks from the initial dose of the study intervention
of the last participant randomized in the study, unless the participant discontinued due to lost 
to follow-up, withdrawal, or death.
All anti-cancer treatments after discontinuation of treatment with study intervention in this 
study will be recorded on the CRF.
At the end of study intervention for the individual participant, further therapy is at the 
discretion of the investigator. Participants treated with darolutamide who are clinically 
benefitting can continue to receive treatment.
The sponsor reserves the right to terminate access to study intervention, in particular if any of 
the following occur: 
a) the study is terminated due to safety concerns
b) the participant can obtain medication used in this study as treatment from a government 
sponsored or private health program
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
All participants who enter the study should complete all applicable study periods. Participants 
can be withdrawn from any study period at any time. Withdrawal from the intervention period 
alone does not constitute withdrawal from the study.
Participants will be followed up for survival status unless they withdraw their informed 
consent.
Participants will continue study intervention until intolerable toxicity or progressive disease.
Participants who withdraw from the intervention period for any reason are to be encouraged 
to remain on the study for follow-up of primary, secondary and other objectives (i.e., continue 
in the active follow-up and survival follow-up periods). Participants are expected to 
participate in follow-up unless they explicitly object. Withdrawal of consent to the 
intervention period should be documented in the participant's medical record. If the 
participant does not wish to be followed up further, this additional consent withdrawal for 
follow-up must also be documented.
7.1
Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant will remain in 
the study to be evaluated for 52 weeks. 

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See the SoA (Section 1.3) for data to be collected at the time of intervention discontinuation 
and follow-up and for any further evaluations that need to be completed.
7.2
Participant Discontinuation/Withdrawal from the Study

A participant must be withdrawn from the study at any time at his/her own request.

A participant may be withdrawn from the study at any time at the discretion of the 
investigator for safety, behavioral, compliance, or administrative reasons. This is 
expected to be uncommon.

If the participant withdraws consent for disclosure of future information, the sponsor 
may retain and continue to use any data collected before such a withdrawal of consent.

If a participant withdraws from the study, and additionally requests destruction of 
her/his samples taken but not yet tested, the investigator must document this (either 
destruction by site or request to central lab, as applicable) in the site study records.
7.3
Lost to Follow up
A participant will be considered lost to follow-up if he repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as soon 
as possible and counsel the participant on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the participant wishes to and/or should 
continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing address 
or local equivalent methods). These contact attempts should be documented in the 
participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered lost to 
follow-up.
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1 
(Section 10.1).
8.
Study Assessments and Procedures

Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol
waivers or exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention.

Adherence to the study design requirements, including those specified in the SoA
(Section 1.3), is essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.

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
Procedures conducted as part of the participant’s routine clinical management (e.g., 
blood count) and obtained before signing of the ICF may be utilized for screening or 
baseline purposes provided the procedures met the protocol-specified criteria and were 
performed within the time frame defined in the SoA (Section 1.3).
8.1
Efficacy Assessments
Assessments specific to tumor burden will not be collected in this study. Participants will be 
followed for survival to assess the 1-year survival rate.
8.2
Safety Assessments
Planned time points for all safety assessments are provided in the SoA in Section 1.3.
Safety assessments in this study are AEs, as recorded by the investigator. Descriptive 
summary tables will be presented for all safety parameters by each treatment arm. 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
coding system and graded using NCI-CTCAE version 5.0. A TEAE is defined as any event 
arising or worsening after start of study drug administration until 30 days after the last study 
drug intake.
Fatigue, cognitive function and depression will be assessed as described below.
Other AEs of interest including fractures, falls, fractures, and hypothyroidism will be 
collected with specific questions on CRF.
Study assessments for physical ability and cognitive function are described in Table 8–1.

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Table 8–1: Study Assessments for Physical Ability and Cognitive Function
Test
Description
Possible range 
of score
MCID /
RCI from 
baseline
Physical ability tests
Timed Up & 
Go (TUG)
The TUG test is used to assess a 
person's mobility and requires both static 
and dynamic balance. It uses the time 
that a person takes to rise from a chair, 
walk three meters, turn around, walk 
back to the chair, and sit down.
Where possible, TUG time is to be 
measured by independent blinded 
assessors.
>1second
1 second
(Davies et al. 
2016)
Short 
Physical 
Performance 
Battery 
(SPPB)
The SPPB is a group of measures that 
combines the results of the gait speed, 
chair stand and balance tests.
0–12 points
0.5 points
(Davies et al. 
2016)
Cognitive Tests
Hopkins 
Verbal 
Learning 
Test-Revised
Total Recall
(HVLT-R TR)
The HVLT-R is a learning and memory 
test, in which the participant is asked to 
learn and recall a list of 12 words over 3 
trials. 
0–36 words
±5 words
(Wefel et al. 2011)
Hopkins 
Verbal 
Learning 
Test-Revised
Delayed 
Recall
(HVLT-R DR)
Spontaneous recall is assessed before 
and after a delay.
0–12 words
±3 words
(Wefel et al. 2011)
Hopkins 
Verbal 
Learning 
Test-Revised
Delayed 
Recognition
(HVLT-R 
RECOG)
Recognition discriminability is also 
assessed after a delay. Four alternate 
versions of the test are used to minimize 
practice effects over time.
-12–+12 words
±2 words
(Wefel et al. 2011)
Trail Making 
Test (TMT)
Part A (TMTA)
Part B (TMTB)
The TMT Part A (TMTA) assesses visual 
scanning and motor tracking requiring 
focused attention. Participants are 
required to sequentially connect 
numbered dots in ascending order that 
are randomly scattered across the test 
page. 
Part B (TMTB) includes a divided 
attention component requiring mental 
flexibility (i.e., executive function). On 
this subtest, dots with numbers and 
1–2750 seconds
1–3750 seconds
±12 seconds
±26 seconds
(Wefel et al. 2011)

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Test
Description
Possible range 
of score
MCID /
RCI from 
baseline
letters are randomly scattered on the 
test page. Participants are required to 
alternate between connecting numbers 
and letters in an ascending sequential 
order. 
Both tests require the participants to 
complete the sequence as fast as 
possible. TMTA is discontinued after 
3 minutes and TMTB is discontinued 
after 5 minutes for participants who have
difficulty in order to reduce participant
burden.
Controlled 
Oral Word 
Association 
(COWA)
The COWA test assesses lexical 
fluency. Given a specific letter of the 
alphabet, participants are required to 
produce as many words as possible that 
begin with that letter. There are two 
alternate forms of the COWA, each with 
three unique letter exemplars.
0 – unlimited
words
±12 words
(Wefel et al. 2011)
Cognitive tests – Patient-reported outcomes
Functional 
Assessment 
of Cancer 
Therapy-
Cognitive 
(FACT-Cog)
The FACT-Cog questionnaire was 
developed to assess perceived cognitive 
function and impact on quality of life 
(QOL) in cancer patients. It is a patient-
reported outcome measure used to 
assess cognitive function in patients 
undergoing cancer therapy. 
0–28 points
6.9-10.6 points 
(Cheung et al. 
2014, Costa et al. 
2018)
COWA = Controlled Oral Word Association; FACT-Cog = Functional Assessment of Cancer 
Therapy-Cognitive; HVLT-R DR = Hopkins Verbal Learning Test-Revised Delayed Recall; HVLT-R 
RECOG = Hopkins Verbal Learning Test-Revised Delayed Recognition; HVLT-R TR = Hopkins 
Verbal Learning Test-Revised Total Recall; MCID = minimal clinically important difference; QOL = 
quality of life; RCI = reliable change index; SPPB = Short Physical Performance Battery; 
TMTA/TMTB = Trail Making Test Part A/B; TUG = Timed up & Go
In addition, fatigue will be assessed using BFI. BFI is a validated tool and consists of three 
questions assessing the severity of fatigue and six questions assessing the impact of fatigue on 
the participant’s mood, social functioning and physical functioning. The BFI is a 9-item scale 
developed to assess subjective fatigue. Each question is asked in relation to the last 24 hours 
and is scored on an 11-point numerical rating scale, with higher scores indicating greater 
fatigue and interference with functionality. The first three questions measure fatigue severity 
at current, usual, and worst levels from 0 to 10, with 0 indicating “no fatigue,” and 10 
indicating “as bad as you can imagine”. The following six questions assess fatigue 
interference with daily activities including general activity, mood, walking ability, normal 
work (both inside and outside the home), relations with other people, and enjoyment of life. 
Response options range from 0 to 10 with 0 indicating “does not interfere” and 10 indicating 
“completely interferes.” Higher scores on the BFI correspond to greater self-reported levels of 
fatigue.
Depression will be assessed using PHQ-9. It is a self-administered version of the Primary 
Care Evaluation of Mental Disorders (PRIME-MD) diagnostic instrument for common mental 

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disorders. The PHQ-9 is the depression module, which scores each of the 9 Diagnostic and 
Statistical Manual of Mental Disorders (DSM-IV) criteria as “0” (not at all) to “3” (nearly 
every day) (Kroenke et al. 2001). As a severity measure, the PHQ-9 score can range from 0 to 
27, since each of the 9 items can be scored from 0 (not at all) to 3 (nearly every day). Major 
depression is diagnosed if 5 or more of the 9 depressive symptom criteria have been present at 
least “more than half the days” in the past 2 weeks, and 1 of the symptoms is depressed mood 
or anhedonia. Other depression is diagnosed if 2, 3, or 4 depressive symptoms have been 
present at least “more than half the days” in the past 2 weeks, and 1 of the symptoms is 
depressed mood or anhedonia. One of the 9 symptom criteria (“thoughts that you would be 
better off dead or of hurting yourself in some way”) counts if present at all, regardless of 
duration.
8.2.1
Physical Examinations
A complete routine physical examination will be conducted at the time points outlined in the 
SoA (Section 1.3). Height (only baseline) and weight will also be measured and recorded.
Investigators should pay special attention to clinical signs related to previous serious illnesses.
8.2.2
Vital Signs
Vital signs will be measured and will include temperature, systolic and diastolic blood 
pressure, and pulse.
8.2.3
Clinical Safety Laboratory Assessments
The laboratory safety assessments will be performed at the time points outlined in the SoA 
(Section 1.3).
Laboratory values will be classified by NCI-CTCAE severity grade.
Additional or repeated laboratory safety assessments may also be obtained according to the 
investigator’s judgment.

See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed 
and to the SoA (Section 1.3) for the timing and frequency.
o
The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the CRF. The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which 
are not associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant's condition.

If laboratory values from non-protocol specified laboratory assessments performed at 
the institution’s local laboratory are considered clinically significant by the 
investigator, then these also need to be reported as SAE or AE.

All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 28 days after the last dose of study intervention 
should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the investigator or medical monitor.
o
If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.

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o
All protocol-required laboratory assessments, as defined in Appendix 2 
(Section 10.2), must be conducted in accordance with the laboratory manual and 
the SoA (Section 1.3).
o
If laboratory values from non-protocol specified laboratory assessments 
performed at the institution’s local laboratory require a change in participant 
management or are considered clinically significant by the investigator (e.g., SAE 
or AE or dose modification), then the results must be recorded in the CRF. 
8.3
Adverse Events and Serious Adverse Events
New lesions or disease progression per se should not be regarded as an AE. Instead, the 
associated signs and symptoms should be recorded as AEs.
The intensity of AEs should be documented using the National Cancer Institute’s Common 
Terminology Criteria for Adverse Events (NCI-CTCAE, version 5.0).
If a participant experiences several study intervention-related toxicities with different grading, 
the recommendation of the worst grading should be used.
An isolated laboratory abnormality that meets the criteria for a CTCAE Grade 4 classification 
is not reportable as an SAE, unless the investigator assesses that the event meets standard ICH 
criteria for an SAE (Section 10.3.2).
The study intervention action should be recorded as detailed in the CRF.
- Drug withdrawn
- Drug interrupted
- Dose reduced
- Dose not changed
- Dose increased
- Not applicable
- Unknown
The definitions of an AE or SAE can be found in Appendix 3 (Section 10.3).
An AE will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or 
the participant's legally authorized representative or health care professional not involved in 
the study).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE. They remain responsible for 
following up SAEs, or AEs, considered related to the study intervention or study procedures, 
or those that caused the participant to discontinue the study (see Section 7). AEs of interest 
have to be followed up regardless of causality or relationship to study intervention.
8.3.1
Time Period and Frequency for Collecting AE and SAE Information
An AE (irrespective of causal relationship) not completely resolved at the end of the
pre-defined collection period must be followed up until resolution (defined as chronicity, 
baseline grade or complete resolution) or until the investigator considers the event will not 
improve further.
All SAEs will be collected from the signing of the informed consent form (ICF) until 30 days 
after the last dose, at the time points specified in the SoA (Section 1.3).

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All AEs will be collected from the signing of the ICF until the follow-up visit(s) at the time 
points specified in the SoA (Section 1.3).
Medical occurrences that begin before obtaining informed consent will be recorded on the 
medical history section of the case report form (CRF).
Medical occurrences that begin before the start of study intervention but after obtaining 
informed consent will be recorded on the AE section of the CRF.
Medical occurrences that started before but deteriorated after obtaining informed consent will 
be recorded as AEs. 
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Appendix 3 (Section 10.3). The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it being 
available.
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the investigator must 
promptly notify the sponsor.
8.3.2
Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3 
(Section 10.3).
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.3.3
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs and non-serious AEs of interest will be 
followed until resolution, stabilization, the event is otherwise explained, or the participant is 
lost to follow-up (as defined in Section 7.3). Further information on follow-up procedures is 
given in Appendix 3 (Section 10.3).
8.3.4
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of an SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators.

Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary.

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
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor will 
review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements.
8.3.5
Pregnancy

Details of all pregnancies in female partners of male participants will be collected after 
the start of study intervention and until at least 30 days after the last dose.

If a pregnancy is reported, the investigator should inform the sponsor within 24 hours 
of learning of the pregnancy and should follow the procedures outlined in Appendix 4 
(Section 10.4).

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.
8.3.6
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs
Not applicable. For details on AEs and SAEs, refer to Section 10.3.
8.4
Treatment of Overdose
Darolutamide
For this study, any dose of darolutamide greater than 600 mg (2 tablets of 300 mg) twice daily
within a 24-hour time period will be considered an overdose.
The highest dose of darolutamide studied clinically was 900 mg twice daily, equal to a total 
daily dose of 1800 mg. No dose limiting toxicities were observed with this dose.
Considering the saturable absorption and the absence of evidence for acute toxicity, an intake 
of a higher than recommended dose of darolutamide is not expected to lead to toxicity.
Therefore, in the event of intake of a higher than recommended dose, it is suggested that 
darolutamide treatment be continued with the next dose as scheduled.
For detailed guidance on overdosing, please refer to the most current version of the IB for
darolutamide.
Enzalutamide
For detailed guidance on overdosing please refer to the prescribing information for 
enzalutamide (XTANDITM  Prescribing information).
In the event of an overdose of study intervention
In the event of an overdose, the investigator should:
1. Closely monitor the participant for any AE/SAE and laboratory abnormalities.
2. Obtain a plasma sample for PK analysis within 3 days from the date of the last dose 
of study intervention if requested by the Medical Monitor (determined on a 
case-by-case basis).
3. Any overdose or incorrect administration of study drug should be noted in the 
participant’s source documents and on the Study Drug Administration eCRF.

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4. AEs associated with an overdose or incorrect administration of study drug should be 
recorded on the AE eCRF.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant.
8.5
Pharmacokinetics
PK parameters are not evaluated in this study.
8.6
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.7
Genetics
Genetics are not evaluated in this study.
8.8
Biomarkers
Biomarkers are not evaluated in this study.
8.9
Medical Resource Utilization and Health Economics
Medical resource utilization and Health Economics parameters are not evaluated in this study.
9.
Statistical Considerations
9.1
Statistical Hypotheses
There is no formal statistical hypothesis testing for the lead-in part of the study.
For the randomized portion of the study, this study will test the null hypothesis of no 
difference in the proportion of participants with a worsening in physical function as assessed 
by the TUG test in the two arms against the alternative hypothesis that there is a difference.
9.2
Sample Size Determination
Lead-in phase 
Approximately 30 participants will receive study intervention in the lead-in phase of the 
study. The example point estimates of decline rates (physical or cognitive function) and the 
corresponding 2-sided 95% CI (based on exact binomial distribution) are shown in Table 9–1. 
For instance, decline/worsening for TUG test is defined as an increase of at least 1 second in 
TUG time from baseline. The definition of decline in cognitive functions is provided in 
Section 9.4.2. The values are provided as a reference rather than a basis for decision making.

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Table 9–1: Estimated Decline Rates and 2-sided 95% Confidence Intervals
95% CI
Number of participants 
with a decline
Observed 
Decline Rate
Lower limit
Upper Limit
Width (%)
0
0
0.00
11.57
11.57
6
20%
7.71
38.57
30.85
12
40%
22.66
59.40
36.74
18
60%
40.60
77.34
36.74
24
80%
61.43
92.29
30.85
30
100%
88.43
100.00
11.57
CI: confidence interval
Randomized phase
The sample size calculation for the randomized phase of the study is based on the primary 
endpoint of physical decline (using TUG test as an example). In the event that the primary 
endpoint or the assumed rate of decline changes based on results from the lead-in phase of the 
study, the sample size will be adjusted accordingly.
Approximately 120 participants in the randomized phase of the study will provide 85% power 
to detect a difference of 20% in the two arms using one-sided alpha of 10%. This is assuming 
that 20% of participants in the darolutamide arm and 40% of participants in the enzalutamide 
arm will have a worsening in physical function at 24 weeks as measured by the TUG test. 
Worsening is defined as an increase of at least 1 second in TUG time from baseline. A 10% 
drop-out rate is assumed.
9.3
Populations for Analyses
For the purposes of the analysis, the following populations are defined:
Population
Description
Enrolled
All participants who sign the ICF
Full analysis set (FAS)
All enrolled participants or all randomized patients (for the 
randomized portion of the study). This population will be used for 
baseline and disposition summaries as well as for the analysis of 
secondary endpoints related to efficacy.
Safety population
All enrolled (or randomized for the randomized portion of the study) 
participants who received any quantity of study intervention, 
regardless of their eligibility for the study. The safety evaluation will 
be performed based on the intervention actually received.
The safety population will be used for all baseline, exposure, 
physical function, cognitive function, daily function, and safety
analyses. For the evaluation of each endpoint using an instrument 
or questionnaire, participants with baseline and at least one post-
baseline assessment will be included.
9.4
Statistical Analyses
The statistical analysis plan (SAP) will be developed and finalized before database lock and 
will describe the participant populations to be included in the analyses and procedures for 
accounting for missing, unused, and spurious data. This section is a summary of the planned 
statistical analyses of the primary and secondary endpoints. Additional exploratory analyses 
of the data will be conducted as deemed appropriate.

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All variables will be analyzed with appropriate statistical methods: categorical variables by 
frequency tables (absolute and relative frequencies) and continuous variables by sample 
statistics (i.e., mean, standard deviation, minimum, median, quartiles, and maximum). 
Continuous variables will be described by absolute value and as change from baseline per 
analysis time point, if applicable.
The primary analysis for the lead-in phase of the study will occur when the last participant has 
been on the study for at least 24 weeks, unless the participant discontinued due to lost to 
follow-up, withdrawal, or death. The primary analysis for the randomized phase of the study 
will occur when the last participant has been on the study for at least 24 weeks, unless the 
participant discontinued due to lost to follow-up, withdrawal, or death. The final analysis for 
the randomized phase of the study will occur when the last participant has been on the study
for at least 52 weeks after the start of study intervention, unless the participant discontinued 
due to lost to follow-up, withdrawal, or death. Separate analyses will be performed for the 
lead-in phase and the randomized phase of the study. Participants will not be pooled across 
the two phases of the study.
9.4.1
Efficacy Analyses
Endpoint
Statistical Analysis
Primary
There is no primary efficacy endpoint in this study.
Secondary
The study is not powered to test a specific hypothesis for efficacy, therefore, 
the two arms will not be formally compared for efficacy.

The time to PSA progression will be calculated as the time from 
randomization (or the date of the first dose for participants in the lead-in 
phase) to the time when the criteria for PSA progression according to 
PCWG3. The PCWG3 guideline defines PSA progression as the date 
that an increase of 25% or more and absolute increase of 2 ng/mL or 
more from the nadir are documented. For participants who had an initial 
PSA decline during treatment, this must be confirmed by a second 
value 3 or more weeks later. Kaplan-Meier methods will be used to 
estimate the median time to PSA progression and 95% CIs for each 
treatment arm.

Overall survival is defined as the time from the date of randomization 
(or the date of the first dose for participants in the lead-in phase) to 
death due to any cause. Participants who did not die will be censored at 
the date known to be alive. The Kaplan-Meier method will be used to 
estimate the median survival and survival rate at the 1-year time-point 
along with the 95% CI for each treatment arm. 
Other pre-specified
Will be described in the statistical analysis plan 
9.4.2
Safety Analyses
All safety analyses will be performed on the Safety population.
Endpoints measuring physical function, cognitive function, and daily activity will also be 
performed on the Safety population.

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Endpoint
Statistical Analysis Methods
Primary
The primary variable in this study is the proportion of participants with a 
worsening in TUG time during the 24-week period from baseline. 
Worsening is defined as an increase of at least 1 second in TUG time 
from baseline by 24 weeks.

At each assessment, change in TUG test time (seconds) from 
baseline will be calculated, and the status will be categorized as: 
improved, stable, or declined using the MCID of 1 second. Decline in 
physical function is defined as at least a 1-second increase from 
baseline in TUG time in each arm by 24 weeks. The proportion of 
participants with a decline and the 95% CIs will be summarized for 
each treatment arm. This rate will be compared between the two
arms using Cochran-Mantel-Haenszel test adjusting for stratification 
factors as captured by IWRS.
Secondary
Physical Function

Proportion of participants with an increase of at least 1 second in the 
TUG time from baseline at 12 and 24 weeks, and by 52 weeks will 
be summarized similar to the primary endpoint.

Time to worsening (increase of at least 1 second) in TUG time will be 
defined as time from randomization (or time from first dose for 
participants in the lead-in phase) to the first date a participant had an 
increase of at least 1 second or more from baseline. Time to 
worsening in TUG time will be summarized using Kaplan-Meier 
methodology, and a comparison between the two arms will be made 
using a two-sided, stratified log-rank test, stratified by IWRS strata. 
The hazard ratio as well as its 95% CI will be presented using a 
stratified Cox regression model. An unstratified analysis will also be 
performed.

Similar to the primary endpoint, the proportion of participants with a 
decline of at least 0.5 points in SPPB total score at 12 and 24 weeks 
and by 24 and 52 weeks will be summarized.
Daily Activity

Mean change from baseline in daily activity will be calculated for 
each treatment arm at 12 and 24 weeks, and by 24 weeks and 
52 weeks and will be compared using two sample t-test. 95% CI will 
be presented.

Mean change from baseline in accelerometer-assessed proportion of 
time spent in light to vigorous physical activity based on a threshold 
of >100 activity counts per minute at 12 and 24 weeks and by 24 and 
52 weeks will be summarized.
Additional daily activity parameters based on accelerometry data may be 
explored and details will be provided in the SAP.
Cognitive Function

The proportion of participants with a decline in cognitive function by 
24 and 52 weeks as assessed by HVLT-R, TMT, and COWA, will be 
summarized similar to the primary endpoint. At each assessment, 
the change in score from baseline will be calculated and the status of 
cognitive function will be categorized as improved, stable, or 
declined using the Reliable Change Index (RCI) as shown below. 
Each test will be assessed individually.

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Endpoint
Statistical Analysis Methods
Test
Reliable Change Index 
threshold (from baseline)
Hopkins Verbal Learning Test -
Revised Total Recall
(HVLT-R TR)
±5 words
Hopkins Verbal Learning Test -
Revised Delayed Recall
(HVLT-R DR)
±3 words
Hopkins Verbal Learning Test -
Revised Delayed Recognition
(HVLT-R RECOG)
±2 words
Trail Making Test: Part A (TMTA)
±12 seconds
Trail Making Test: Part B (TMTB)
±26 seconds
Controlled Oral Word
Association (COWA)
±12 words

The proportion of participants with a decline of >10 points from 
baseline in the FACT-Cog domain by 24 and 52 weeks will be 
summarized.
Fatigue

The proportion of participants with an increase of at least 1 point in 
worst level of fatigue from baseline during the past 24 hours (item 3 
of BFI) by 24 and 52 weeks will be summarized.

Similarly, the proportion of participants with an increase of at least 
1 point in in fatigue interference from baseline during the past 
24 hours (items 4A through F of BFI) by 24 and 52 weeks will be 
summarized. The proportion of participants with a decline and the 
95% CIs will be summarized for each treatment arm. This rate will be 
compared between the two arms using Cochran-Mantel-Haenszel 
test adjusting for stratification factors as captured by IWRS.
Depression

The proportion of participants with a worsening of scores by PHQ-9 
during the 24 and 52 week period from baseline will be summarized. 
Worsening is defined as an increase of at least 1 point in worst level 
of depression from baseline by 24 weeks and 52 weeks.
AE, Exposure, other

AEs, drug-related AEs, and SAEs will be summarized by MedDRA 
coding system and NCI-CTCAE version 5.0 worst grade. 

AE of interest (fall, fracture, hypothyroidism) will be summarized 
descriptively.

Time to deterioration of KPS will be calculated as the time from 
randomization (or time from first dose for participants in the lead-in 
phase) to the first date the participant had a decline in KPS score of 
at least 10 points. Data will be summarized using the Kaplan-Meier 
method.

Treatment exposure of the study intervention, including time on 
treatment and dose reductions, will be summarized. 

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9.5
Interim Analyses
No formal interim analyses are planned in this study. However, this study will be conducted
in two phases and the primary analysis for the lead-in phase will be performed when the last 
participant in the lead-in phase has been on the study for at least 24 weeks, unless the 
participant discontinued due to lost to follow-up, withdrawal, or death. The decision to move 
to the randomized phase of the study will involve reviewing the findings from the lead-in 
phase of the study with the members of the steering committee.
The primary analysis for the randomized phase for the study will occur when last participant 
in the randomized phase of the study has been on the study for at least 24 weeks, unless the 
participant discontinued due to lost to follow-up, withdrawal, or death. A final analysis for the 
randomized phase for the study will occur when last participant in the randomized phase of 
the study has been on the study for at least 52 weeks, unless the participant discontinued due 
to lost to follow-up, withdrawal, or death.
9.5.1
Data Monitoring Committee (DMC)
Not applicable.
10.
Supporting Documentation and Operational Considerations
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the investigator 
and reviewed and approved by the IRB/IEC before the study is initiated.

Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study participants.

The investigator will be responsible for the following:
o
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC
o
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures
o
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations

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10.1.2
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
All relevant documentation will be filed in the trial master file.
10.1.3
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions 
regarding the study.

Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed 
consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
Health Insurance Portability and Accountability Act (HIPAA) requirements, where 
applicable, and the IRB/IEC or study center.

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must also 
sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study.

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.

A participant who is rescreened is required to sign another ICF.
10.1.4
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier only; 
participant names or any information that would make the participant identifiable will 
not be transferred.

The participant must be informed that his personal study-related data will be used by 
the sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the participant.

The participant must be informed that his medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities.
10.1.5
Committees Structure
A steering committee will provide strategic direction, guidance and oversight for the study. 
This committee will meet approximately once a year or as required to keep track of issues and 
the progress of the study’s implementation and activity.
No data monitoring committee, dose escalation committee, or similar review group will be 
used for this study.

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10.1.6
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the sponsor or designee electronically (e.g., laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.

The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.

The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.

Monitoring details describing strategy (e.g., risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-
Based Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the Monitoring Plan.

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data.

The sponsor assumes accountability for actions delegated to other individuals (e.g., 
Contract Research Organizations).

Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements.

Records and documents should be retained for the longer of the two periods prescribed 
below: 
o
Records and documents, including signed ICFs, pertaining to the conduct of 
this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer 
retention period. No records may be destroyed during the retention period 
without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor.
10.1.7
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available.

Definition of what constitutes source data can be found in the monitoring plan.
10.1.8
Study and Site Closure
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 

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completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development

If risk-benefit ratio becomes unacceptable owing to, for example,
Safety findings from this study (e.g. SAEs) 
Results of parallel clinical Bayer studies or emerging data from literature
Results of parallel animal studies (on e.g. toxicity, teratogenicity, carcinogenicity 
or reproduction toxicity).

If the study conduct (e.g. recruitment rate; dropout rate; protocol compliance) does not 
suggest a proper completion of the trial within a reasonable time frame.

strategic reasons (e.g. the clinical development of the drug is stopped)
The site is entitled to end its participation in the study if necessary due to medical or ethical 
reasons.
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 study closure, participants on treatment and those in post-study follow-up 
must be taken care of in an ethical manner.
10.1.9
Publication Policy
The sponsor adheres to Good Publication Practice and authorship established by the 
International Committee of Medical Journal Editors (ICMJE). A Publication Roles and 
Responsibilities letter will be sent from Datavision, a publication management platform, to all 
authors for acknowledgement for each publication related to this study. For reference, the 
content of the letter can be found below. These roles and responsibilities are aligned with the 
sponsor’s corporate publication policy.
Publication Roles and Responsibilities Letter:

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Bayer is committed to adhering to the prevailing standards for Good Publication Practice 
(GPP3) (Battisti et al. 2015) as well as the criteria for authorship established by the 
International Committee of Medical Journal Editors (ICMJE). 
The purpose of this letter is to inform you about the roles and responsibilities of you, as an 
author, and Bayer, as sponsor: 
Author Responsibilities 
1. In accordance with the ICMJE authorship criteria, you must meet all of the following 
criteria to be considered an author of the publication: 
a. Substantial contributions to the conception or design of the work; or the 
acquisition, analysis, or interpretation of data for the work; AND 
b. Drafting the work or revising it critically for important intellectual content; 
AND 
c. Final approval of the version to be published; AND 
d. Agreement to be accountable for all aspects of the work in ensuring that 
questions related to the accuracy or integrity of any part of the work are 
appropriately investigated and resolved. 
Authorship will be rescinded if you fail to meet all of the above requirements. 
2. Contributors who do not meet the above criteria but who contributed to the 
publication, e.g., those who provided editorial assistance, writing support, statistical 
support, or study support, may be listed in the acknowledgements, with their 
permission. 
3. You will develop publications which are accurate, objective and complete, in a 
timely and responsible manner. 
4. You will comply with all applicable disclosure requirements, and will disclose any 
potential conflicts of interest. 
5. You (and any other author) retain full editorial control over the content of the 
manuscript. 
6. You (and any other author) accept full responsibility for final approval of the 
manuscript prior to submission. 
7. You agree to comply with all applicable laws, regulations, industry codes and 
professional standards. 
8. You represent that you have obtained all necessary approvals including from your 
institution or employer in connection with this publication. 
9. You represent that you have not been debarred, disqualified, blacklisted or banned or 
to the best of your knowledge currently under investigations or threat of 
investigation by any regulatory authority for debarment, disqualification, 
blacklisting or any similar regulatory action in any jurisdiction anywhere in the 
world. During the term of this Agreement, you shall promptly notify Bayer should
you become subject of such debarment, disqualification, blacklisting or banning 
proceeding.
      Bayer Responsibilities 
1. Bayer, upon request, will provide data, documents, and materials necessary for 
development of the manuscript/publication (under a standard confidentiality 
agreement). 

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2. Bayer may review the draft publication for scientific and medical accuracy. You 
(and any other author) will consider any comments made by Bayer in good faith, but 
may accept or reject revisions suggested by Bayer.
10.2
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 10–1 will be performed by the local laboratory.

Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.

Pregnancy Testing: not applicable 
Table 10–1 Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet count
RBC indices:
MCV
MCH
% reticulocytes
WBC count with differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC count
Hemoglobin
Hematocrit
Clinical 
Chemistry
BUN
Potassium
AST/SGOT
Total and direct 
bilirubin
Creatinine
Sodium
ALT/SGPT
Total protein
Glucose 
(non-fasting)
Calcium
Alkaline 
phosphatase
Routine 
urinalysis

Specific gravity

pH, glucose, protein, blood, ketones, by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 
screening tests

Testosterone

PSA

TSH
The results of each test must be entered into the CRF.
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; 
CRF = case report form; MCV = mean corpuscular volume; MCH = mean corpuscular hemoglobin; 
PSA = prostate-specific antigen; RBC = red blood cell; SGOT = serum glutamic-oxaloacetic 
transaminase; SGPT = serum glutamic-pyruvic transaminase; TSH = thyroid-stimulating hormone; 
WBC = white blood cell
Investigators must document their review of each laboratory safety report.
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study 

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AE Definition
participant, temporally associated with the use of study intervention, whether or 
not considered related to the study intervention.

Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., electrocardiogram, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not related to 
progression of underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.

The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as an AE or SAE if they fulfil the definition of an AE or SAE. Also, “lack 
of efficacy” or “failure of expected pharmacological action” also constitutes an AE 
or SAE.
Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.

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10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease).
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually involving 
at least an overnight stay) at the hospital or emergency ward for observation and/or 
treatment that would not have been appropriate in the physician’s office or outpatient 
setting. Complications that occur during hospitalization are AEs. If a complication prolongs 
hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to 
whether “hospitalization” occurred or was necessary, the AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.

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10.3.3
Recording and Follow-Up of AE and/or SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to the sponsor in lieu of completion of the AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by the sponsor. In this case, all participant identifiers, with the exception 
of the participant number, will be redacted on the copies of the medical records 
before submission to the sponsor.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
coding system and graded using NCI-CTCAE version 5.0.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the IB and/or Product Information, for marketed 
products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is 
very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to the sponsor.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 

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Assessment of Causality
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
sponsor to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide the sponsor with a copy of any 
post-mortem findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to the sponsor within 24 hours 
of receipt of the information.
10.3.4
Reporting of SAEs
SAE Reporting to the Sponsor via an Electronic Data Collection Tool

The primary mechanism for reporting an SAE to the sponsor will be the electronic 
data collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to safety at the vendor by telephone.

Contacts for SAE reporting can be found in the Investigator site file.
SAE Reporting to the Sponsor via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to safety at the vendor.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by 
overnight mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 

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SAE Reporting to the Sponsor via Paper CRF
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in the Investigator site file.

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10.4
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information
Contraception Guidance for women of childbearing potential: (see Inclusion criterion 3, 
Section 5.1)
The investigator or a designated associate is requested to advise the participant how to 
achieve highly effective birth control in women of childbearing potential. Highly effective 
(failure rate of less than 1% per year) contraception methods include:

Combined (estrogen and progesterone containing: oral, intravaginal, transdermal) and 
progesterone-only (oral, injectable, implantable) hormonal contraception associated 
with inhibition of ovulation.

Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS).

Bilateral tubal occlusion or vasectomized partner (provided that the partner is the sole 
sexual partner and has received medical assessment of the surgical success).

Sexual abstinence (reliability to be evaluated in relation to the duration of the clinical 
trial and the preferred and usual lifestyle of the participant). 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and 
withdrawal are not acceptable methods of contraception.
Collection of Pregnancy Information
Male participants with partners who become pregnant:

The investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant is in 
this study. This applies only to male participants who receive study intervention.

After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the appropriate 
form and submit it to the sponsor within 24 hours of learning of the partner’s 
pregnancy. The female partner will also be followed to determine the outcome of the 
pregnancy. Information on the status of the mother and child will be forwarded to the 
sponsor. Generally, the follow-up will be no longer than 6 to 8 weeks following the 
estimated delivery date. Any termination of the pregnancy will be reported regardless 
of fetal status (presence or absence of anomalies) or indication for the procedure. 

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10.5
Appendix 5: Abbreviations
ADT
Androgen deprivation therapy
AE
Adverse event
ALT
Alanine aminotransferase
AR
Androgen receptor
AST
Aspartate aminotransferase
AUC(0–24)
Area under the curve from time zero to 24 hours after dosing
BCRP
Breast cancer resistance protein
BFI
Brief Fatigue Inventory
bid
Twice daily
BUN
Blood urea nitrogen
CFR
Code of federal regulations
CI
Confidence interval
CIOMS
Council for International Organizations of Medical Sciences
Cmax
Maximal plasma exposure
CNS
Central nervous system
CONSORT
Consolidated Standards of Reporting Trials
COWA
Controlled Oral Word Association
CPM
Counts per minute
CRF
Case report form
CRPC
Castration-resistant prostate cancer 
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
Cytochrome P450
DMC
Data monitoring committee
DRE
Disease-related event
DSM-IV
Diagnostic and Statistical Manual of Mental Disorders
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
F876L
Mutation of phenylalanine at position 876 to leucine
FACT-Cog
Functional Assessment of Cancer Therapy – Cognitive
FAS
Full analysis set 
GCP
Good clinical practice 
GMP
Good manufacturing practice
GnRH
Gonadotropin-releasing hormone 
GPP3
Good publication practice 3
HDPE
High density polyethylene
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human immunodeficiency virus
HVLT-R
Hopkins Verbal Learning Test – Revised
HVLT-R DR
Hopkins Verbal Learning Test – Revised   Delayed Recall
HVLT-R RECOG
Hopkins Verbal Learning Test – Revised   Delayed Recognition
HVLT-R TR
Hopkins Verbal Learning Test – Revised   Total Recall
IB
Investigator’s brochure
ICF
Informed consent form
ICH
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use
ICMJE
International Committee of Medical Journal Editors
IEC
Independent Ethics Committee

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IMP
Investigational medicinal product
IRB
Institutional Review Board
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
IWRS
Interactive web response system 
KPS
Karnofsky Performance Scale 
LHRH
Luteinizing hormone-releasing hormone
LPLV
Last patient last visit
MCH
Mean corpuscular hemoglobin
MCID
Minimal clinically important difference
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MFS
Metastasis-free survival
MRI
Magnetic resonance imaging
NCI
National Cancer Institute
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for 
Adverse Events
NIMP
Non-investigational medicinal product
NJ
New Jersey
OS
Overall survival 
PCWG
Prostate Cancer Working Group 
PE
Polyethylene
PFS
Progression-free survival
PHQ-9
Patient Health Questionnaire-9
PK
Pharmacokinetic
PP
Polypropylene
PRIME-MD
Primary Care Evaluation of Mental Disorders
PSA
Prostate-specific antigen
QOL
Quality of life
RBC
Red blood cell
RCI
Reliable change index
SAE
Serious adverse event
SAP
Statistical analysis plan
SGOT
Serum glutamic-oxaloacetic transaminase
SGPT
Serum glutamic-pyruvic transaminase
SID
Subject identification
SmPC
Summary of product characteristics
SoA
Schedule of activities
SPPB
Short Physical Performance Battery
SSE-FS
Symptomatic skeletal event-free survival
SUSAR
Suspected unexpected serious adverse reactions
TEAE
Treatment-emergent adverse event
TMT
Trail-Making Test
TMTA/TMTB
Trail Making Test Part A/B
TSH
Thyroid-stimulating hormone
TUG
Timed Up & Go 
ULN
Upper limit of normal
USA
United States of America
WBC
White blood cell

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11.
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