A 2-stage, Lead-in and Randomized, Phase 2, Open-label Study of Darolutamide Versus Enzalutamide as Monotherapy on Testosterone Levels Change in Men With Hormone-Naïve Prostate Cancer
Phase: PHASE2
Conditions: Biochemically Recurrent Prostate Cancer
Sponsor: Bayer

 
Document Type: 
Protocol 
Official Title: 
A 2-stage, Lead-In and Randomized, Phase 2, Open-label study of 
Darolutamide versus Enzalutamide as Monotherapy on 
Testosterone Levels Change in Men with Hormone-Naïve Prostate 
Cancer (ARAMON) 
NCT Number: 
NCT05526248 
Document Date: 
24 AUG 2023 
 

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Clinical Study Protocol Global Amendment 1 
BAY 1841788 / 21953 
 
Title Page 
 
Protocol Title: 
A 2-stage, Lead-in and Randomized, Phase 2, 
Open-label study of Darolutamide versus Enzalutamide 
as Monotherapy on Testosterone Levels Change in Men 
with Hormone-Naïve Prostate Cancer (ARAMON) 
Protocol Number: 
21953 
Version Number: 
2.0 
Compound [Number or Name]: 
BAY 1841788 / Darolutamide 
Study Phase: 
II 
Short Title: 
ARAMON: Evaluation of darolutamide versus 
enzalutamide monotherapy in men with hormone 
naïve Prostate Cancer 
Acronym: 
ARAMON 
Sponsor Name and Legal 
Registered Address: 
Bayer HealthCare Pharmaceuticals, Inc., 
100 Bayer Boulevard, 
P.O. Box 915, Whippany, NJ 07981-0915, USA 
Regulatory Agency Identifying 
Number: 
IND: 114769 
NCT: 05526248 
 
This is an electronically generated document that does not bear any sponsor signatures. The 
signature of the Sponsor’s medically responsible person is filed in the Trial Master File 
(TMF) and available on request. 
 
Medical Monitor Name and Contact Information will be provided separately. 
The information provided in this document is strictly confidential and is intended solely for the use in the 
performance of the clinical investigation. Reproduction or disclosure of this document, whether in part or in full, 
to parties not associated with the clinical investigation or its use for any other purpose without the prior written 
consent of the Sponsor, is not permitted. 
 
Throughout this document, symbols indicating proprietary names (®, TM) may not be displayed. Hence, the 
appearance of product names without these symbols does not imply that these names are not protected. 
 
 

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Summary of protocol changes 
 
Affected 
sections 
Summary of revisions made 
Rationale 
1, Table 1–1 
Primary endpoint 
Old text: To evaluate the effect of treatment 
with darolutamide on serum testosterone 
level. 
New text: To evaluate the impact of 
darolutamide monotherapy on serum 
testosterone level over a 12-week 
intervention period. 
 
Secondary endpoint 
Old text 
… on testosterone level  
New text 
… on serum testosterone level 
Modification following PRC-CT comment 
- 
New wording uses "evaluate the 
impact". 
Agree with the fact that it is not a relative 
effect as is the usual interpretation but an 
effect versus baseline. 
Alignment of the wording between primary 
and secondary endpoints. 
1, Table 1–2 
Primary endpoint 
Old text: To compare the effects of 
treatment with darolutamide vs. 
enzalutamide on serum testosterone level. 
New text: To compare the effects of 
treatment with darolutamide vs. 
enzalutamide monotherapy on serum 
testosterone level over a 12-week 
intervention 
 
Secondary endpoint 
Old text 
To compare the impact of darolutamide or 
enzalutamide monotherapy on testosterone 
level over the course of a 52-week 
intervention period  
New text 
To compare the effect of darolutamide vs. 
enzalutamide monotherapy on serum 
testosterone level over the course of a 52-
week intervention period 
For consistency with Table 1–1 
1.3 
Figure 1-1 was moved up from 
section 1.4.1.3 (Data Monitoring Committee) 
to section 1.3 (Overall design) 
Previous insertion of Figure 1-1 was not 
relevant 
1.5 
Tables 1-3 and 1-4 
The Active follow-up column was deleted. An 
Active follow-up period SoA Table was 
added (new Table 1-5) 
Inclusion and none of the exclusion criteria: 
collected during screening only (consistent in 
Lead In and Randomized phases SoA 
PSMA-PET imaging was added as a 
possible technique for bone scans (Table 1–
3 and 1–4). 
Full physical examination is now scheduled 
at EOT visit (instead of 52W visit), consistent 
in Table 1–3 and 1–4. 
Last lines of Tables 1-3 and 1-4 were 
removed (Exploratory assessments and 
CPET) 
Footnotes were adjusted 
According to comments and for consistency 
with the course of the study 
2.2 
Rewording of last sentence  
Old text: the patients with an elevated PSA 
and/or a shorter PSADT and an otherwise 
Rewording to avoid "encouraged" 

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long-life expectancy should be encouraged 
to consider ADT earlier. 
New text: ADT should be considered earlier 
in patients with an elevated PSA and/or a 
shorter PSADT and an otherwise long-life 
expectancy.  
 
2.3 
Reference Fizazi et al. 2020 was inserted 
(end of §4) 
Reference Smith et al. 2021 was inserted 
(end §5 and list of references) 
References Smith et al. 2022 and Haresh et 
al. 2022 were inserted (§7 and list of 
references)  
Referencing the data described. 
3, Table 3-1 
Abbreviations were added in footnote 
 
3, Table 3–1 
Primary endpoint 
Old text: To evaluate the effect of treatment 
with darolutamide on serum testosterone 
level. 
New text: To evaluate the impact of 
darolutamide monotherapy on serum 
testosterone level over a 12-week 
intervention period. 
 
Secondary endpoint 
Old text 
… on testosterone level  
New text 
… on serum testosterone level 
Modification following PRC-CT comment 
- 
New wording uses "evaluate the 
impact". 
Agree with the fact that it is not a relative 
effect as is the usual interpretation but an 
effect versus baseline. 
Alignment of the wording between primary 
and secondary endpoints. 
3, Table 3–2 
Primary endpoint 
Old text: To compare the effects of 
treatment with darolutamide vs. 
enzalutamide on serum testosterone level. 
New text: To compare the effects of 
treatment with darolutamide vs. 
enzalutamide monotherapy on serum 
testosterone level over a 12-week 
intervention 
 
Secondary endpoint 
Old text 
To compare the impact of darolutamide or 
enzalutamide monotherapy on testosterone 
level over the course of a 52-week 
intervention period  
New text 
To compare the effect of darolutamide vs. 
enzalutamide monotherapy on serum 
testosterone level over the course of a 52-
week intervention period 
For consistency with Table 3–1 
4.1, 3rd paragraph 
Old text 
A steering comittee including external 
prostate cancer experts will review… 
New text 
The study team will review 
 
The following sentence was removed: 
Details on the responsability and operations 
oft he steering commitee will be provided i 
the steering committee charters 
 
Old text: The Sponsor withholds the right to 
conduct or stop the lead-in phase in case 
data … 
Consistency with the absence of steering 
committee in the study 
 
 
 
 
 
 
 
 
 
Comment from the PRC-CT review: please 
check whether the Sponsor should have the 
right to stop the lead-in phase or start the 

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New text: The Sponsor withholds the right to 
conduct or stop the lead-in phase or start the 
randomized phase in case data 
randomized phase (currently written: start 
the lead-in phase) if data on testosterone 
levels become available from other studies. 
4.1.1 
"Darolutamide" was changed for study 
intervention" 
 
 
 
 
 
 
 
 
 
Old text: met all inclusion and none of the 
exclusion criteria 
New text: met all inclusion/exclusion criteria 
Comment from the PRC-CT review: 4.1.1 
and 4.1.2 – these sections relate to both the 
lead in and the randomized phase. Please 
consider changing “darolutamide 
administration” to “administration of 
darolutamide or, for the randomized phase, 
darolutamide or enzalutamide)” or similar. 
 
The new wording applies to both lead-in and 
randomized phase. 
 
According to PRC-CT review (this change 
was reported in section 9.3, Table 9–1, 9–2) 
4.1.3 
This sentence was added to define the 
Active Follow-up period: 
When the patient's treatment is discontinued 
before completing week 52 treatment, the 
patient will continue assessments until week 
52 for both Lead In and Randomized 
phases. This follow-up period is defined as 
the Active Follow-up period (see Table 1–5, 
Active-follow-up SoA). 
 
Sentence deleted from 4.1.3 and moved 
in the relevant section 9.3. “No data 
monitoring committee, dose escalation 
committee, or similar review group will be 
used for this study.”  
Clarification 
4.3 
§1, Sentence 2 was changed 
LPLV of the study is reached when all 
participants have completed the last 
scheduled procedure shown in the Schedule 
of Activities including Active follow up period. 
Clarification 
5.1, Incl criteria 4 
Old text 
Patients must have PSA of 2 ng/ml or 
greater at screening. 
New text  
PSA ≥0.2 ng/mL after ART or SRT post-RP 
or after RP in participants who are unfit for 
ART or SRT, OR PSA ≥2 ng/mL above the 
nadir after primary RT only. 
(RP, radical prostatectomy; ART, adjuvant 
radiotherapy; SRT salvage radiotherapy; RT, 
primary radiotherapy) 
As per discussion at ASCO-GU 2023 with 
the co-primary investigators 
 and 
 to adapt the PSA value for 
inclusion based on treatment to the prostate 
cancer. 
 
5.1, Incl criteria 10 
More stringent condition related to birth 
control, and „placebo“ removed because not 
applicable. 
Old text 
Sexually active male […] and/or their female 
partners of reproductive potential to use a 
method of effective birth control, during the 
treatment with study intervention/placebo 
and for 1 weeks after treatment with study 
intervention/placebo. 
New text 
Sexually active male […] and/or their female 
partners of reproductive potential to use a 
method of effective birth control, during the 
treatment with study intervention and for 3 
Safety lead suggested to modify the 
language for effective birth control to be 
consistent with the more stringent language 
from ARASENS and ARAMIS. 
PPD
PPD

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months after treatment with study 
intervention. 
5.1, Incl criteria 12 
Old text 
Able to speak and comprehend languages 
validated on included surveys. 
New text 
Able to speak and comprehend languages 
validated on FACT-P. 
Clarification 
6.2.2.1 
Old text 
A participant who experiences a Grade 3 or 
4 study treatment-related AE should interrupt 
darolutamide until the AE improves to Grade 
≤2 or baseline status. Treatment with 
darolutamide is then to be restarted at 300 
mg bid.  
New text 
A participant who experiences a Grade 3 or 
4 TEAE that is thought to be related to study 
intervention, should interrupt study 
intervention until the TEAE improves to < 
Grade 2 or to baseline status. 
Cases of idiosyncratic drug-induced liver 
injury (DILI) with increases in ALT and/or 
AST to ≥5 and ≥20 x ULN, including with 
concomitant bilirubin elevation > 2x ULN, 
have been reported with darolutamide. Liver 
function tests abnormalities were reversible 
upon darolutamide discontinuation. 
Participants who experience hepatic 
transaminase elevations suggestive of 
idiosyncratic DILI considered to be causally 
related to study intervention, should 
discontinue study intervention.  
Additional lab tests monitoring is 
recommended for Grade 2 or higher ALT 
and/or AST increase (ALT/AST >3 x ULN). 
Please see the below. 
Table 6–1 was changed. Dose modification 
and study treatment withdrawal are detailed 
for ALT/AST increase AE and other AEs.  
DILI-Language was updated 
6.5 
Old text 
Enzalutamide should be stored at 20°C to 
25°C (68°F to 77°F) in a dry place and keep 
the container tightly closed. Excursions 
permitted from 15°C to 30°C (59°F to 86°F). 
 
New text 
Enzalutamide should be stored as indicated 
on the outer package and/ or the clinical 
supply label. 
Clarification 
6.7 
The 3 last § describing a particular case 
from Japan were deleted 
This case is already described in the IB 
7. 
Old text 
Participants who discontinue the study 
treatment for any reason are to be 
encouraged to remain on the study for 
follow-up of primary 
New text 
Participants who discontinue the study 
treatment for any reason are to remain on 
the study for follow-up of primary 
Rewording to avoid “encouraged” 
9.4.2 
9.4.2.1 old text 
Comment oft he PRC-CT review: 
For the secondary endpoints, it is stated that 
the proc mixed procedure (with an estimate 

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Clinical Study Protocol Global Amendment 1 
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… with 95% confidence intervals using SAS 
PROC MIXED with the ESTIMATE 
statement. 
9.4.2.1 new text 
… with 95% confidence intervals using SAS 
PROC MIXED with the ESTIMATE 
statement and a Toeplitz covariance 
structure. 
 
9.4.2.2 old text 
with 95% Confidence Intervals using SAS 
PROC MIXED with the SLICE option. 
9.4.2.2 new text 
…with 95% Confidence Intervals using SAS 
PROC MIXED with the SLICE option and a 
Toeplitz covariance structure. 
statment) will be used. However, this is not a 
very clear description: It can refer to 
statistical models from a simple t-test (like it 
is done for the primary analysis) and up to 
complicated models considering time as a 
covariate (and with a multitude of possible 
covariance matrices applied). While a full 
specification of the mixed model can be 
saved for the SAP, it would be very helpful to 
get at least a partial description what model 
is planned to be evaluated with the mixed 
procedure (for evaluation time points beyond 
week 12). 
 
Response: We are using a more efficient 
and simpler Toeplitz covariance structure 
rather than an unstructured covariance. 
Agree that this can be specified through the 
following changes. 
10.1.6 
EU Clinical Trials Register was replaced by 
Clinical Trials Information System  
As of 31 January 2023, all initial clinical trial 
applications in the EU/EEA must be 
submitted through the Clinical Trials 
Information System  
www.clinicaltrialsregister.eu 
European clinical trials information system 
(CTIS) 
10.4 
A Section Questionnaires was created: 
(PROMIS Fatigue, PROMIS Physical, Godin 
and Self Efficacy questionnaires were 
inserted) 
10.4.1 (section # updated) Questionnaire 
FACT-P  
10.4.2 Questionnaire PROMIS Fatigue 
10.4.3 Questionnaire PROMIS Physical 
function 
10.4.4 Godin-4 questions 
10.4.5 Self Efficacy 9 questions 
 
DILI language 
impacts the following 
sections: 
2.3 Benefit/Risk 
assessment 
6.2 Dose modification 
7.1 Discontinuation 
Appendix: AE 10.3.5 
10.6 Appendix and 
Abbreviations 
ToC 
2.3 Benefit/Risk assessment 
A sentence was added at the end of this 
section:  
Cases of idiosyncratic drug-induced liver 
injury (DILI) with increases in ALT and/or 
AST to ≥5 and ≥20 x ULN, including with 
concomitant bilirubin elevation > 2x ULN, 
have been reported with darolutamide. Liver 
function tests abnormalities were reversible 
upon darolutamide discontinuation. Please 
see sections 6.2 and 7.1. 
6.2 Dose modification 
Sentence was added (last §): 
Participants who experience hepatic 
transaminase elevations suggestive of 
idiosyncratic drug induced liver injury (DILI) 
considered to be causally related to study 
intervention, should discontinue study 
intervention. Please see section 7.1. 
7.1 Discontinuation of study treatment 
Sentence was added at the end of §2: 
Drug-induced liver injury (DILI): Participants 
who experience hepatic transaminase 
elevations suggestive of idiosyncratic drug 
induced liver injury (DILI) considered to be 
causally related to study intervention, should 
discontinue study intervention. (See 
appendix number 10.3.5). 
Safety 
Description of change: Addition of newly 
identified safety data for darolutamide. Text 
added to provide guidance on criteria for 
study intervention discontinuation in the 
event of suspected drug-induced liver injury 
(DILI). 
Brief rationale: Newly identified safety data 
across darolutamide clinical trials, including 
cases of idiosyncratic hepatic reactions that 
were reversible upon treatment 
discontinuation. 
FDA. 2009. Guidance for Industry. Drug-
Induced Liver Injury: Premarketing Clinical 
Evaluation. 

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This § was reorganized in 2 bullet points. 
10.3.5 Identify a potential drug induced 
liver injury (DILI)  
This section was added, with the following 
text: 
This appendix describes the recommended 
work up to be followed in order to identify a 
potential drug induced liver injury (DILI). It is 
not intended to be a comprehensive guide 
for the management of elevated liver 
function tests. During the study the 
investigator should remain vigilant for 
increases in liver function tests. The 
investigator is responsible for determination 
of the liver function test alterations nature at 
any point during the study. In case 
Investigator suspects DILI, the Sponsor 
Medical Representative has to be informed 
as soon as possible. 
And following § and steps of the work up. 
10.6 Appendix and abbreviations 
The DILI acronym was added. 
ToC was updated. 
All 
Punctuation  
The entire document was proofread to 
ensure punctuation accuracy and 
harmonization without changing the scientific 
content. 
All 
Acronyms 
The entire document was proofread to 
ensure acronyms consistency without 
changing the scientific content. The list of 
acronyms was updated. 
All 
"Study drug" replaced by "study intervention" 
Consistency, according to protocole 
template 
 

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Table of Contents 
TITLE PAGE 
1 
SUMMARY OF PROTOCOL CHANGES 
2 
TABLE OF CONTENTS 
8 
TABLE OF TABLES 
12 
TABLE OF FIGURES 
12 
1. 
PROTOCOL SUMMARY 
13 
1.1 
Synopsis 
13 
1.1.1 
Protocol Title: 
13 
1.2 
Rationale 
13 
1.2.1 
Objectives and Endpoints: 
15 
1.3 
Overall Design 
16 
1.4 
Number of Participants: 
18 
1.4.1 
Treatment Groups and Duration: 
18 
Study Intervention Lead-in phase 
19 
Study Interventions Randomized phase 
19 
1.4.1.1 
Lead-in phase: 
19 
1.4.1.2 
Randomized phase: 
20 
1.4.1.3 
Data Monitoring Committee 
20 
1.5 
Schedule of Activities (SoA), Sampling and Assessments 
21 
2. 
INTRODUCTION 
26 
2.1 
Study Rationale 
26 
2.2 
Background 
26 
2.2.1 
Therapeutic options in BCR prostate cancer patients 
29 
2.2.1.1 
Combined Androgen Blockade (CAB) and continuous ADT 
29 
2.2.1.2 
Intermittent ADT (IADT) 
30 
2.2.1.3 
Peripheral Androgen Blockade (PAB) 
30 
2.2.1.4 
Second generation AR inhibitors in BCR hormone-sensitive prostate cancer 
31 
2.2.2 
Markers of endocrine Metabolisms 
31 
2.2.2.1 
Markers of Insulin Resistance and Metabolic Syndrome 
31 
2.2.2.2 
Bone Mineral Density (BMD) 
32 
2.3 
Benefit/Risk Assessment 
32 
3. 
OBJECTIVES AND ENDPOINTS 
34 
4. 
STUDY DESIGN 
36 
4.1 
Overall Design 
36 
4.1.1 
Screening period 
37 
4.1.2 
Treatment period 
37 
4.1.3 
Active Follow–up period 
37 
4.2 
Participants and Study Completion 
37 
4.2.1 
Participant completion of study 
38 
4.3 
End of Study Definition 
38 
4.3.1 
Early Study Termination 
38 
4.4 
Scientific Rationale for the Study Design 
38 
5. 
STUDY POPULATION 
40 
5.1 
Inclusion Criteria 
41 
5.2 
Exclusion Criteria 
42 

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5.3 
Lifestyle Restrictions 
43 
5.4 
Screen Failures 
43 
6. 
TREATMENTS 
43 
6.1 
Treatments Administered 
44 
6.2 
Dose Modification 
44 
6.2.1 
Definitions 
44 
6.2.2 
General requirements for dose modifications of study treatment 
45 
6.2.2.1 
Darolutamide 
45 
6.2.2.2 
Enzalutamide 
47 
6.2.3 
Dose reduction 
47 
6.2.3.1 
Darolutamide 
47 
6.2.3.2 
Enzalutamide 
47 
6.3 
Method of Treatment Assignment 
47 
6.4 
Blinding 
48 
6.5 
Preparation/Handling/Storage/Accountability 
48 
6.6 
Treatment Compliance 
48 
6.7 
Concomitant Therapy 
48 
6.7.1 
Prohibited concomitant therapy 
49 
6.7.2 
Permitted concomitant therapy 
49 
6.8 
Treatment After the End of the Study 
50 
7. 
DISCONTINUATION/WITHDRAWAL CRITERIA 
50 
7.1 
Discontinuation of Study Treatment 
50 
7.2 
Withdrawal from the Study 
51 
7.3 
Lost to Follow-up 
51 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
51 
8.1 
Imaging Time-Points 
52 
8.2 
Serum Hormone Levels 
52 
8.3 
PSA Measurement 
52 
8.4 
Bone Health Assessment 
53 
8.5 
Fasting Lipid Panel 
53 
8.6 
Markers of Insulin Resistance 
53 
8.7 
Safety Assessments 
53 
8.7.1 
Time Period and Frequency for Collecting AE and SAE Information 
53 
8.7.2 
Method of Detecting AEs and SAEs 
54 
8.7.3 
Follow-up of AEs and SAEs 
54 
8.7.4 
Regulatory Reporting Requirements for SAEs 
54 
8.7.5 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs or SAEs 
55 
8.7.6 
Pregnancy 
55 
8.7.7 
Adverse Events of Special Interest 
55 
8.7.8 
Management of Overdose 
56 
8.7.8.1 
Darolutamide 
56 
8.7.8.2 
Enzalutamide 
56 
8.7.9 
In the event of an overdose of study intervention 
56 
8.8 
Physical Examinations 
56 
8.8.1 
Vital Signs 
56 
8.8.2 
Electrocardiograms 
57 
8.8.3 
Clinical Safety Laboratory Assessments 
57 
8.9 
Pharmacokinetics 
57 
8.10 
Pharmacodynamics 
57 

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8.11 
Genetics 
57 
8.12 
Biomarkers 
57 
9. 
STATISTICAL CONSIDERATIONS 
57 
9.1 
Statistical Hypotheses 
57 
9.1.1 
Lead-in Phase 
57 
9.1.2 
Randomized Phase 
58 
9.2 
Sample Size Determination 
58 
9.2.1 
Lead-in Phase 
58 
9.2.2 
Randomized Phase 
58 
9.3 
Populations for Analyses 
59 
9.4 
Statistical Analyses 
59 
9.4.1 
Primary endpoints 
59 
9.4.1.1 
Lead-in Phase 
60 
9.4.1.2 
Randomized Phase 
60 
9.4.2 
Secondary Endpoints 
60 
9.4.2.1 
Lead-in Phase 
60 
9.4.2.2 
Randomized Phase 
60 
9.4.3 
Other Pre-Specified Endpoints 
61 
9.4.4 
Safety Analyses 
61 
9.5 
Interim Analyses 
61 
9.6 
Data Monitoring Committee (DMC) 
61 
10. 
APPENDICES 
61 
10.1 
Appendix 1: Study Governance Considerations 
61 
10.1.1 
Regulatory and Ethical Considerations 
61 
10.1.2 
Financial Disclosure 
62 
10.1.3 
Informed Consent Process 
62 
10.1.4 
Data Protection 
62 
10.1.5 
Publication Policy 
62 
10.1.6 
Dissemination of Clinical Study Data 
63 
10.1.7 
Data Quality Assurance 
63 
10.1.8 
Source Documents 
63 
10.1.9 
Study and Site Closure 
64 
10.2 
Appendix 2: Clinical Laboratory Tests 
65 
10.3 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up, and 
Reporting 
67 
10.3.1 
Definition of AE 
67 
10.3.2 
Definition of SAE 
68 
10.3.3 
Recording and Follow-up of AE and/or SAE 
69 
10.3.4 
Reporting of SAEs 
71 
10.3.5 
Identify a potential drug induced liver injury (DILI) 
71 
10.4 
Appendix 4: Questionnaires 
73 
10.4.1 
FACT-P (Version 4) 
73 
10.4.2 
PROMIS Fatigue 
76 
10.4.3 
PROMIS Physical 
77 
10.4.4 
Godin-4 questions 
78 
10.4.5 
Self Efficacy 9 questions 
79 
10.5 
Appendix 5: Contraceptive Guidance and Collection of Pregnancy Information 
80 
10.5.1 
Definitions 
80 
10.5.1.1 
Woman of Childbearing Potential (WOCBP) 
80 
10.5.1.2 
Premenopausal female with 1 of the following: 
80 

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10.5.1.3 
Fertile Man 
80 
10.5.2 
Contraception Guidance 
80 
10.5.2.1 
Male participants 
80 
10.6 
Appendix 6: Abbreviations 
82 
11. 
REFERENCES 
84 

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Table of Tables 
Table 1–1: Lead-in Phase Objectives and Endpoints ................................................................ 13 
Table 1–2: Randomized Phase Objectives and Endpoints ........................................................ 14 
Table 1–3: Schedule of Activities Lead-In Phase ..................................................................... 19 
Table 1–4: Schedule of Activities Randomized Phase.............................................................. 21 
Table 1–5: Schedule of Activities Active follow-up period ..................................................... 23 
Table 3–1: Lead-in phase Objectives and Endpoints ................................................................ 32 
Table 3–2: Randomized Phase Objectives and Endpoints ........................................................ 33 
Table 6–1: Study Treatment Dose Modifications ..................................................................... 44 
Table 9–1: Populations for Analyses: Lead-in Phase................................................................ 57 
Table 9–2: Populations for Analyses: Randomized Phase ........................................................ 57 
Table 10–1: Protocol-Required Safety Laboratory Assessments .............................................. 64 
Table 10–2: Highly Effective Contraceptive Methods ............................................................. 79 
 
Table of Figures 
Figure 1–1: Study Schema ........................................................................................................ 15 
Figure 4–1: Overall Design ....................................................................................................... 35 
 
 
 

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1. 
Protocol Summary 
1.1 
Synopsis 
1.1.1 
Protocol Title: 
Full Title: A 2-stage, Lead-in and Randomized, Phase 2, Open-label study of Darolutamide 
versus Enzalutamide as Monotherapy on Testosterone Levels Change in Men with Hormone- 
Naïve Prostate Cancer (ARAMON) 
 
Short Title: ARAMON: Evaluation of darolutamide or enzalutamide monotherapy in men 
with hormone naïve PC. 
 
1.2 
Rationale 
Biochemical recurrence (BCR) in hormone-naïve prostate cancer is characterized by a rising 
prostate-specific antigen (PSA) after curative therapy, radical prostatectomy, or radiotherapy 
without recurrent or metastatic cancer on conventional imaging studies. It occurs in 
approximately 20-40% of post-prostatectomy patients and 30-50% of post-radiation patients 
within 10 years (Artibani et al. 2018). While many patients with BCR do well clinically for 
years, proper adequate treatment of BCR is important as BCR precedes the appearance of 
clinical metastasis by 8 years after radical prostatectomy (RP) and by 7 years after primary 
definitive radiotherapy (RT) (Artibani et al. 2018). Various management options are acceptable 
for prostate cancer with BCR, including observation, intermittent or continuous use of androgen 
deprivation therapy (ADT), non-steroidal anti androgen (NSAA) therapy, and salvage 
radiotherapy or radical prostatectomy with pelvic lymph node dissection, depending on the prior 
definitive therapy (National Comprehensive Cancer Network 2021). 
Androgen deprivation therapy (ADT) currently constitutes the current first line systemic 
treatment for prostate cancer, resulting in marked suppression of serum testosterone levels and 
associated loss of libido and sexual function (DiBlasio et al. 2008). ADT also has well 
documented metabolic adverse effects including decreased bone mineral density, loss of muscle 
mass, increased lipid levels, and insulin resistance leading to a higher risk of diabetes and 
contributing to an increased risk of cardiovascular disease (Jespersen et al. 2014, Taylor et al. 
2009). Attempts to reduce the morbidity of systemic prostate cancer treatments with less 
adverse effects have largely focused on non-testosterone lowering strategies using first 
generation NSAA monotherapies, an approach that is supported by EAU Guidelines on Prostate 
cancer (Mottet et al. 2020) and largely based on benefits in health-related quality of life 
(HRQoL) and tolerability. In contrast to ADT, NSAAs are associated with increased bone 
mineral density and reduced risks of fat accumulation, hyperglycemia, anemia, fatigue, loss of 
libido, and vasomotor flushing. NCCN guidelines for prostate cancer (National Comprehensive 
Cancer Network 2021) do not recommend the use of NSAA monotherapies due to lack of 
adequate follow up. 
Although the approach with NSAA does result in reduced loss of bone density and a lesser 
effect on libido and potency (Boccardo et al. 1999, Garg et al. 2013, Iversen et al. 1998, Smith 
et al. 2004, Tyrrell et al. 1998) its use is limited by specific feminization side effects like 
gynecomastia and breast tenderness/pain. Those side effects result from upregulation of 
luteinizing hormone signaling which is the product of androgen receptor (AR) antagonism in 
the central nervous system which increases serum testosterone concentrations, which in turn, 
are peripherally converted to estrogens (Fagerlund et al. 2015, Scher et al. 1997). 
 
 

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First generation anti androgen monotherapy has also been associated with lower overall survival 
rates when compared to castration (Seidenfeld et al. 2000). 
Second generation antiandrogens (darolutamide, enzalutamide and apalutamide) have 
demonstrated increased efficacy compared to first generation antiandrogens in castration 
resistant prostate cancer (CRPC) (Rice et al. 2019). Such agents to date constitute the standard 
of care (SOC) for men for almost all disease stages of prostate cancer. 
For prostate cancer patients with BCR who are at significant risk for the development of 
metastases and prostate cancer-specific mortality, treatment with second generation androgen 
receptor inhibitors (ARIs) as monotherapy may mitigate the potential impact of systemic 
treatment on QoL, and clinically significant metabolic derangements observed with ADT or 
NSAAs, addressing an important unmet medical need. 
The effect of monotherapy with enzalutamide and apalutamide in patients with hormone- naïve 
prostate cancer has been explored and reported. A single arm phase 2 study by Tombal et al 
evaluating enzalutamide monotherapy in men with biochemically recurrent and hormone-
sensitive metastatic prostate cancer showed similar PSA level reduction by enzalutamide 
monotherapy compared to testosterone suppression treatment with luteinizing hormone-
releasing hormone (LHRH) analogues. Enzalutamide alone, however, resulted in a mean 
increase of testosterone levels of 114% at week 25 with frequent side effects of grades 1-2 such 
as gynecomastia (36%), fatigue (33%), nipple pain (20%), and hot flush (18%) (Tombal et al. 
2014). In this enzalutamide study, peak serum testosterone rise plateaued at around 10 to 13 
weeks of treatment. At ASCO 2020, (Maluf et al. 2018) presented data of LACOG 0415, a 
three-arm phase 2 study exploring efficacy of the ADT-free alternatives in a patient population 
with advanced hormone-sensitive prostate cancer and biochemical recurrence. The apalutamide 
monotherapy arm demonstrated similar PSA decline level to the other two arms, however, it 
too resulted in a high mean increase in levels of serum testosterone of 134.3% at week 25 with 
high incidences of any grade side effects such as gynecomastia (55%), rash (26%), fatigue 
(21%), pruritus (17%) and breast pain (14%). In this apalutamide study, peak serum testosterone 
rise plateaued at around 10 to 13 weeks of treatment. 
The increased serum testosterone levels are peripherally converted to estrogens (Fagerlund et 
al. 2015, Scher et al. 1997) and are suspected to be the cause for the specific feminization side 
effects like gynecomastia and breast tenderness observed in the above mentioned two trials. 
The increase in serum testosterone level observed with enzalutamide and apalutamide is thought 
to result from the ability of these compounds to penetrate the blood-brain-barrier (BBB), 
resulting in upregulation of luteinizing hormone signaling due to blockage of the androgen 
receptor in hypothalamus and pituitary gland which increases testosterone production. 
Unfortunately, it is not fully established whether this negative feedback loop occurs entirely 
within the central nervous system (CNS) or whether parts of it may be situated outside of the 
BBB. 
Beyond the potential effect on testosterone production, the penetration of apalutamide and 
enzalutamide into the CNS may also be responsible for CNS related adverse events observed 
in the phase 3 clinical trials such as fatigue, falls and cognitive impairment. 
Darolutamide (Daro) does not appear to have the above-mentioned limitations given that due 
to its distinct chemical structure, darolutamide exhibits a high binding affinity to the androgen 
receptor with a low blood brain barrier penetration (Zurth et al. 2018, Zurth et al. 2019). 
Darolutamide is structurally distinct from the other second-generation anti-androgens, 
enzalutamide and apalutamide (Moilanen et al. 2015). The ARAMIS phase 3 trial in nmCRPC 
showed a low incidence of CNS related adverse events (AEs) (i.e., fatigue, falls, cognitive and 
memory impairment, depression) with less than 2% difference between the Daro DB (double 
blind) and placebo (PBO) DB arms, with the exception of fatigue which was the only AE with 
incidence of more than 10% (13.2% Daro vs 8.3% Placebo in the DB period). Evidence from 
clinical studies including ARAMIS also suggests a reduction of the incidence of AEs commonly 

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seen with other ARIs like fatigue and rash (Fizazi et al. 2019, Moilanen et al. 2015). 
Darolutamide has demonstrated significantly lower penetration of the BBB compared to 
enzalutamide and apalutamide in preclinical models. Additionally, it was demonstrated in a 
neuro-imaging study conducted in healthy volunteers that enzalutamide but not darolutamide 
reduced blood flow in brain areas related to cognitive function (Williams et al. 2020). 
Darolutamide is hypothesized to lead to a reduced reactive testosterone rise via the 
hypothalamic-pituitary gland-gonadal axis, which in turn is expected to result in significantly 
less peripheral conversion of testosterone to estrogen and related feminization side effects. In 
consequence darolutamide used as monotherapy may have a high efficacy against prostate 
cancer, coupled with a favorable short- and long-term side effect profile and therefore may 
potentially disrupt the dogma of testosterone reduction as foundational therapy in prostate 
cancer, and provide benefits to patients experiencing biochemical recurrence of their disease. 
1.2.1 
Objectives and Endpoints: 
 
 
Table 1–1: Lead-in Phase Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
To evaluate the impact of darolutamide 
monotheray on serum testosterone level 
over a 12-week intervention period 
Change in serum testosterone level from baseline 
to week 12 
Secondary 
To evaluate the impact of darolutamide 
monotherapy on serum testosterone level 
over the course of a 52-week intervention 
period 
Change in serum testosterone level from baseline 
at week 24 and 52 
Assess PSA response rate 
Serum PSA Week 4, 12, 24, 36, 52 
To assess safety of darolutamide monotherapy 
in patients with hormone-naïve prostate cancer 
with BCR 
AE assessments using NCI CTCAE (v.5.0) 
Abbreviations: BCR-Biochemical Recurrence, NCI CTCAE-National Cancer Institute Common Terminology Criteria for Adverse Events, 
PSA Prostate Specific Antigen.  

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Table 1–2: Randomized Phase Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
To compare the effects of treatment with 
darolutamide 
vs. 
enzalutamide 
monotherapy on serum testosterone 
level over a 12-week intervention period 
Change in serum testosterone level from baseline 
to week 12 
Secondary 
To compare the effect of darolutamide vs. 
enzalutamide monotherapy on serum 
testosterone level over the course of a 52-
week intervention period 
Change in serum testosterone level from baseline 
at week 24 and 52 
Measure changes in markers of endocrine 
function related to sex hormones 
Assess changes in the blood levels of sex 
hormones (DHT, DHEA, SHBG, LH, FSH, 
Androstenedione, Prolactin, Estradiol) 
Measure changes in markers of components of 
fat and glucose metabolism 
Assess changes blood levels of Total cholesterol, 
High-density and low-density lipoproteins, 
Triglycerides, Hemoglobin A1C, Fasting insulin, 
Fasting glucose, Fat body mass, Lean body 
mass 
Assess PSA response rate 
Serum PSA Week 4, 12, 24, 36, 52 
To assess safety and QoL of darolutamide 
vs. enzalutamide monotherapy in patients 
with hormone-naïve prostate cancer with 
BCR 
AE assessments using NCI CTCAE (v.5.0) and 
FACT-P 
Exploratory 
Evaluate changes in Bone turnover 
Markers of bone turnover: 
BSAP, CTX, DEXA scan 
Physical function* 
Subjective physical function: 
Godin – 4 questions, PROMIS Fatigue – 8 
questions, PROMIS Physical – 6 questions, Self- 
Efficacy – 9 questions 
Abbreviations: A1C-glycated (hemoglobin), AE adverse events, BCR-Biochemical Recurrence, BSAP bone specific 
alkaline phosphatase, CTX C-telopeptid, DHEA-dehydroepiandrosterone, DHT-dihydrotestosterone, DEXA dual 
energy x-ray absorptiometry, FACT-P Functional Assessment of Cancer Therapy – Prostate Cancer, FSH-follicle-
stimulating hormone, LH-luteinizing hormone, NCI CTCAE-National Cancer Institute-Common Terminology Criteria 
for Adverse Events, PSA-Prostate-specific antigen, QoL Quality of life, SHBG- sex hormone-binding globulin, 
PROMIS Patient-Reported Outcomes Measurement Information System. 
*the physical function assessments might be modified. 
 
1.3 
Overall Design 
This is a two-stage phase 2 open label study, with a lead-in phase and randomized phase to 
assess the impact of darolutamide or enzalutamide as a monotherapy treatment on serum 
testosterone levels in men with hormone-naïve prostate cancer experiencing biochemical 
recurrence (BCR) after failure of treatment with curative intent for localized prostate cancer. 
Secondary endpoints to be evaluated include the impact of darolutamide or enzalutamide 
monotherapy on energy metabolism and the metabolism of sex hormones as well as PSA 
response and safety. 
Exploratory endpoints will evaluate changes in bone metabolism and physical function. 
 

 
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Figure 1–1: Study Schema 
 
 
 
 
 
 
Abbreviations: ECOG Eastern cooperative oncology group, PC prostate cancer, PSADT PSA doubling time. 

 
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1.4 
Number of Participants: 
During the lead-in phase 25 participants will be assigned in a single cohort to darolutamide to 
ensure that 20 participants treated with darolutamide for 12 weeks are evaluable for serum 
testosterone level at week 12. 
The conduct of the randomized phase is dependent on the results of the lead-in phase. Further 
details follow later in the protocol. If the study proceeds into the randomized phase, it is planned 
that 40 patients (20 per arm) are enrolled in the randomized phase to have 34 evaluable 
participants for the final analysis. The projected number of total participants for this study is 
65. Nevertheless, the sample size of the randomized phase might be adjusted according to the 
results obtained in the lead-in phase. Participants will only take part in one of the phases of the 
study. 
1.4.1 
Treatment Groups and Duration: 
The treatments to be administered during the study: 
In the lead-in phase participants will receive darolutamide 600 mg bid for a total duration of 52 
weeks until unacceptable toxicity, PSA progression, withdrawal of consent, investigator’s or 
patient’s decision to stop therapy for the patient, Sponsor’s decision to terminate the study, or 
death. The Sponsor withholds the right to conduct or stop the lead-in phase in case data on 
testosterone levels from patients treated with darolutamide alone would become available from 
other ongoing studies. 
The conduct of the randomized phase is contingent on the results of the lead-in phase unless 
data from other ongoing studies could provide similar evidence. Participants will receive 
darolutamide 600 mg bid or enzalutamide 160 mg once daily for a total duration of 52 weeks 
until unacceptable toxicity, PSA progression, withdrawal of consent, investigator’s or patient’s 
decision to stop therapy, Sponsor’s decision to terminate the study, or death. Following the 52-
week intervention, all participants will be offered to continue the treatment with darolutamide 
as per investigator decision, including patients randomized to enzalutamide who would switch 
to treatment with darolutamide. 
 
 

 
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Study Intervention Lead-in phase 
 
Study Intervention 
Darolutamide 
Dosage Level(s) 
Darolutamide 600 mg (2 tablets of 300 mg) will be administered twice 
daily with food, equivalent to a total daily dose of 1200 mg 
Route of Administration 
Oral (p.o.) 
Use 
Experimental 
 
Study Interventions Randomized phase 
 
Study Intervention 
Darolutamide 
Dosage Level(s) 
Darolutamide 600 mg (2 tablets of 300 mg) will be administered twice 
daily with food, equivalent to a total daily dose of 1200 mg 
Route of Administration 
Oral (p.o.) 
Use 
Experimental 
 
Study Intervention 
Enzalutamide 
Dosage Level(s) 
Enzalutamide 160 mg will be administered once daily with or without 
food 
Route of Administration 
Oral (p.o.) 
Use 
Experimental 
 
The expected study duration for the lead-in phase is 18 months assuming 20 evaluable 
participants are enrolled within an enrollment period of 6 months and treated for 12 months (52 
weeks). The expected study duration for the randomized phase is 25 months assuming 40 
participants are enrolled within an enrollment period of 12 months. For each phase the primary 
analysis will be at 12 weeks. The final analysis for both phases will be conducted after all 
subjects have completed the 52 weeks of treatment and will analyze the long-term results of 
the secondary endpoints. 
 
1.4.1.1 
Lead-in phase: 
During the lead-in phase 25 participants will be assigned in a single cohort to darolutamide to 
ensure that 20 participants treated with darolutamide for 12 weeks are evaluable for serum 
testosterone level at week 12. This sample size will help estimate the mean percent change in 
serum testosterone level from baseline at 12 weeks within at most +/- 25%, assuming a true 
mean percent increase of less than 45%. This assessment uses a log normal distribution for 
percent change. 
The conduct of the randomized phase is binding to a condition of obtaining an estimated mean 
percent increase from baseline in serum testosterone level at 12 weeks of less than 45%, and 
non-binding to a condition that the incidence of feminizing side effects observed is below that 
previously reported (
 
).  
The Sponsor reserves the right to conduct or stop the lead-in phase in case data on testosterone 
levels from patients treated with darolutamide alone would become available from other 
ongoing studies. 
 
 
CCI

 
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1.4.1.2 
Randomized phase: 
A maximum of 40 participants (20 per arm) will be randomly assigned to study treatment 
(darolutamide or enzalutamide) such that approximately 34 evaluable participants complete the 
study. The randomized stage will require a sample size of 20 per group to provide 85% power 
to test the null hypothesis of no-difference between groups on mean percent change at two-
sided 0.05 level. This assessment is based on a mean percent change in serum testosterone from 
baseline and Standard Deviation for the darolutamide arm of 45% and 65% versus 110% and 
75% respectively for enzalutamide. The final sample size and time of testosterone assessments 
may be modified according to the results of the lead-in phase. 
 
1.4.1.3 
Data Monitoring Committee 
None.  
 
 

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1.5 
Schedule of Activities (SoA), Sampling and Assessments 
Table 1–3: Schedule of Activities Lead-In Phase 
 
STUDY 
 
TREATMENT Period 
 
STUDY ELEMENT/PERIOD 
Screening 
Baseline 
Treatment Period: Weeks 
 
VISIT 
acceptable time window (days) 
(Up to 28 
days before 
Week 1 Day 
1) 
(Up to 
7 days 
before 
Week
1 Day 
1) 
2 
[± 7 d] 
4 
[± 7 d] 
8 
[± 7 
d] 
12 
[± 7 d] 
16 
[± 7 d] 
24 
[± 7 d] 
36 
[± 7 d] 
52 
[± 7 d] 
EOT Visit 
30 days (+7 days) after last dose) c 
PROCEDURE 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
General 
 
 
 
 
 
 
 
 
 
 
 
Demography 
 
x 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
x 
 
 
 
 
 
 
 
 
 
 
Relevant medical history 
(Includes substance use) 
 
x 
 
 
 
 
 
 
 
 
 
PC history, classification 
(diagnosis, staging) including 
pre-treatments 
 
x 
 
 
 
 
 
 
 
 
 
Prior/Concomitant medicationsd 
x 
 
xg 
 
CT/ MRI/ PSMA-PET bone scana 
x 
 
 
 
 
 
 
 
 
 
 
Physical examination 
 
 
 
 
 
 
 
 
 
 
 
Full physical examination  
 
x 
 
 
 
 
 
 
 
 
x 
Safety 
 
 
 
 
 
AE /SAE/Discontinuations due to 
AE b 
 
xg 
x 
ECOG performance status 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
Fasting glucose, fasting insulin, 
hemoglobin A1C, lipid profile, lean 
body massf, fat massf, weight 
 
x 
 
x 
 
x 
 
x 
x 
x 
x 
Clinical chemistry (liver), 
hematology 
xh 
x 
 
x 
 
x 
 
x 
x 
x 
x 
DHT, DHEA, SHBG, 
androstenedione, prolactin, 
estradiol 
 
x 
 
x 
 
x 
 
x 
x 
x 
x 
12-lead ECGj 
 
x 
 
x 
 
 
 
 
 
x 
x 
Vital signs 
x 
x 
 
x 
 
x 
 
x 
x 
x 
x 
Bone specific alkaline 
phosphatase (BSAP) and CTX 
 
x 
 
x 
 
x 
 
x 
x 
x 
x 

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STUDY 
 
TREATMENT Period 
 
STUDY ELEMENT/PERIOD 
Screening 
Baseline 
Treatment Period: Weeks 
 
VISIT 
acceptable time window (days) 
(Up to 28 
days before 
Week 1 Day 
1) 
(Up to 
7 days 
before 
Week
1 Day 
1) 
2 
[± 7 d] 
4 
[± 7 d] 
8 
[± 7 
d] 
12 
[± 7 d] 
16 
[± 7 d] 
24 
[± 7 d] 
36 
[± 7 d] 
52 
[± 7 d] 
EOT Visit 
30 days (+7 days) after last dose) c 
Efficacy 
 
 
 
 
 
 
 
 
 
 
 
Testosterone, free testosterone 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Serum PSA 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Gonadotropins, LH, FSH 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
24 DEXA scan 
 
x 
 
 
 
 
 
 
 
x 
 
Darolutamide dispensinge 
 
x 
 
x 
 
x 
 
x 
x 
 
 
Patient reported outcomes 
 
 
 
 
 
 
 
 
 
 
 
FACT-P 
 
x 
 
x 
 
x 
 
x 
x 
x 
x 
Surveys: physical functioni 
 
x 
 
 
 
x 
 
x 
 
x 
 
a Radiological tumor assessments will be conducted only at screening to exclude presence of visceral metastases, and because these are not considered standard of care, will only be done at other times 
based on treating physician discretion and based on PSA progression. Investigators are encouraged to provide the results of PSMA-PET CT scans in the eCRF if performed (optional at baseline or during the 
study). 
b Safety assessments should be continued as per SOC at time of progression. After the 30-day short term follow-up period, only SAEs that are considered related to study intervention or study participation, 
with concomitant medications used to treat the event, should be reported by the investigator. Documentation of progression should be provided to the Sponsor (in CRF). 
c During the treatment period and up to 30 days following study intervention discontinuation, all (S)AEs are collected, regardless of causality. 
d For anti-cancer therapies, also collect prior to 28 days. 
e Treatment compliance will also be assessed at each visit when study intervention is dispensed. 
f Bioelectrical impedance scale to be used. 
g To be collected and updated as needed, not visit dependent. Eligibility assessments need to be completed prior to the patient being enrolled to the study. 
h Tests related to inclusion exclusion criteria should be performed at screening visit. Neutrophil count, Platelet count, Total bilirubin, ALT, AST, Creatinine, Creatinine clearance, PTT, PT, INR. All the other 
clinical chemistry and hematology are mentioned in Section 10.2, Table 10-1. 
i PROMIS, Self-Efficacy Assessment, and GODIN survey are not mandatory if translated version in not available. Questionnaires required are detailed in Section 10.4. 
j Assessment to be done in triplicate. 
If patient treatment discontinued BEFORE completing the full 52-week treatment, please refer to the Active Follow Up Period SoA Table 1–5. 
Bayer will provide questionnaires wherever validated version is available in the said language. 
Abbreviations: A1C (hemoglobin) Glycated, AE adverse event, ALT Alanine aminotransferase, AST Aspartate aminotransferase, BSAP bone-specific alkaline phosphatase, CT computerized tomography, 
CTX C-terminal telopeptide, DEXA dual energy x-ray absorptiometry, DHEA dehydroepiandrosterone, DHT dihydrotestosterone, ECG Electrocardiogram, ECOG Eastern Cooperative Oncology Group, 
EOT end of treatment, FACT-P Functional Assessment of Cancer Therapy – Prostate Cancer, FSH-follicle-stimulating hormone, INR international normalized ratio, LH-luteinizing hormone, MRI magnetic 
resonance imaging, PC prostate cancer, PSA Prostate-specific antigen, PSMA-PET Prostate-specific membrane antigen positron emission tomography, PT prothrombin time, PTT partial thromboplastin 
time, SAE serious adverse event, SHBG sex hormone-binding globulin, SOC standard of care. 

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Table 1–4: Schedule of Activities Randomized Phase 
 
STUDY 
 
TREATMENT Period 
 
STUDY 
ELEMENT/PERIOD 
Screening 
Baseline 
Treatment Period: Weeks 
 
VISIT 
acceptable time window 
(days) 
(Up to 28 
days before 
Week 1 Day 
1) 
(up to 7 
days 
beforeW
eek1 
Day 1) 
2 
[± 7 d] 
4 
[± 7 d] 
8 
[± 7 d] 
12 
[± 7 d] 
16 
[± 7 d] 
24 
[± 7 d] 
36 
[± 7 d] 
52 
[± 7 d] 
EOT 
30 days (+7 
days) after 
last dose c 
PROCEDURE 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
General 
 
 
 
 
 
 
 
 
 
 
 
Demography 
 
x 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion 
criteria 
x 
 
 
 
 
 
 
 
 
 
 
Relevant medical history 
(Includes substance use) 
 
x 
 
 
 
 
 
 
 
 
 
PC history, classification 
(diagnosis, staging) 
including pre-treatments 
 
x 
 
 
 
 
 
 
 
 
 
Prior/Concomitant 
medicationsd 
x 
 
xg 
 
CT/ MRI/ PSMA-PET bone 
scana 
x 
 
 
 
 
Randomization 
 
x 
 
 
 
 
 
 
 
 
 
Physical examination 
 
 
 
 
 
 
 
 
 
 
 
Full physical examination  
 
x 
 
 
 
 
 
 
 
 
x 
Safety 
 
 
 
 
 
AE /SAE/ discontinuation 
due to AEs b 
 
xg 
x 
ECOG performance status 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
Fasting glucose, fasting 
insulin, hemoglobin A1C, 
lipid profile, lean body 
massf, fat massf, weight 
 
x 
 
x 
 
x 
 
x 
x 
x 
x 
Clinical chemistry (liver), 
hematology 
xh 
x 
 
x 
 
x 
 
x 
x 
x 
x 
DHT, DHEA, SHBG, 
androstenedione, prolactin, 
estradiol 
 
x 
 
x 
 
x 
 
x 
x 
x 
x 
12-lead ECGj 
 
x 
 
x 
 
 
 
 
 
x 
x 
Vital signs 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 

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STUDY 
 
TREATMENT Period 
 
STUDY 
ELEMENT/PERIOD 
Screening 
Baseline 
Treatment Period: Weeks 
 
VISIT 
acceptable time window 
(days) 
(Up to 28 
days before 
Week 1 Day 
1) 
(up to 7 
days 
beforeW
eek1 
Day 1) 
2 
[± 7 d] 
4 
[± 7 d] 
8 
[± 7 d] 
12 
[± 7 d] 
16 
[± 7 d] 
24 
[± 7 d] 
36 
[± 7 d] 
52 
[± 7 d] 
EOT 
30 days (+7 
days) after 
last dose c 
Bone specific alkaline 
phosphatase (BSAP) and 
CTX 
 
x 
 
x 
 
x 
 
x 
x 
 
 
Efficacy 
 
 
 
 
 
 
 
 
 
 
 
Testosterone, free 
testosterone 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Serum PSA 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Gonadotropins, LH, FSH 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
24 DEXA scan 
 
x 
 
 
 
 
 
 
 
x 
 
Study treatment dispensinge 
 
x 
 
x 
 
x 
 
x 
x 
 
 
Patient reported 
outcomes 
 
 
 
 
 
 
 
 
 
 
 
FACT-P 
 
x 
 
x 
 
x 
 
x 
x 
x 
x 
Surveys: physical functioni 
 
x 
 
 
 
x 
 
x 
 
x 
 
a Radiological tumor assessments will be conducted only at screening to exclude presence of visceral metastases, and because these are not considered standard of care, will only be done at other times based on 
treating physician discretion and based on PSA progression. Investigators are encouraged to provide the results of PSMA-PET CT scans in the eCRF if performed (optional at baseline or during the study). 
b Safety assessments should be continued as per SOC at time of progression. After the 30-day short term follow-up period, only SAEs that are considered related to study intervention or study participation, 
with concomitant medications used to treat the event, should be reported by the investigator. Documentation of progression should be provided to the Sponsor (in CRF). 
c During the treatment period and up to 30 days following study intervention discontinuation, all (S)AEs are collected, regardless of causality. 
d For anti-cancer therapies, also collect prior to 28 days. 
e Treatment compliance will also be assessed at each visit when study intervention is dispensed. 
f Bioelectrical impedance scale to be used. 
g To be collected and updated as needed, not visit dependent. Eligibility assessments need to be completed prior to the patient being enrolled to the study. 
h Tests related to inclusion exclusion criteria should be performed at screening visit. Neutrophil count, Platelet count, Total bilirubin, ALT, AST, Creatinine, Creatinine clearance, PTT, PT, INR. All the other 
clinical chemistry and hematology are mentioned in Section 10.2, Table 10-1. 
i PROMIS, Self-Efficacy Assessment, and GODIN survey are not mandatory if translated version in not available. Questionnaires required are detailed in Section 10.4. 
j Assessment to be done in triplicate. 
If patient treatment discontinued BEFORE completing the full 52-week treatment, please refer to the Active Follow Up Period SoA Table 1–5.  
Bayer will provide questionnaires wherever validated version is available in the said language.  
Abbreviations: A1C (hemoglobin) Glycated, AE adverse event, ALT Alanine aminotransferase, AST Aspartate aminotransferase, BSAP bone-specific alkaline phosphatase, CT computerized tomography, 
CTX C-telopeptide, DEXA dual energy x-ray absorptiometry, DHEA dehydroepiandrosterone, DHT dihydrotestosterone, ECG Electrocardiogram, ECOG Eastern Cooperative Oncology Group, EOT end of 
treatment, FACT-P Functional Assessment of Cancer Therapy – Prostate Cancer, FSH follicle-stimulating hormone, INR international normalized ratio, LH-luteinizing hormone, MRI magnet resonance 
imaging, PC prostate cancer, PSA Prostate-specific antigen, PSMA-PET Prostate-specific membrane antigen positron emission tomography, PT prothrombin time, PTT partial thromboplastin time, SAE 
serious adverse event, SHBG sex hormone-binding globulin, SOC standard of care. 
 

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Table 1–5: Schedule of Activities Active Follow-up period 
STUDY ELEMENT/PERIOD 
ACTIVE FOLLOW UP PERIOD 
For Patients who discontinue treatment BEFORE completing week 52 treatment for both Lead-in and Randomized 
Phases: Weeks 
VISIT (acceptable time window: 
days) 
2 [± 7 d] 
4 [± 7 d] 
8 [± 7 d] 
12 [± 7 d] 
16 [± 7 d] 
24 [± 7 d] 
36 [± 7 d] 
52 [± 7 d] 
Fasting glucose, fasting insulin, 
hemoglobin A1C, lipid profile, 
lean body massa, fat massa, 
weight 
 
x 
 
x 
 
x 
x 
x 
Clinical chemistry (liver), 
hematologye 
 
x 
 
x 
 
x 
x 
x 
DHT, DHEA, SHBG, 
androstenedione, prolactin, 
estradiol 
 
x 
 
x 
 
x 
x 
x 
Vital signs 
 
x 
 
x 
 
x 
x 
x 
Bone specific alkaline 
phosphatase (BSAP) and CTX 
 
x 
 
x 
 
x 
x 
x 
Efficacy 
 
 
 
 
 
 
 
 
Testosterone, free testosterone 
x 
x 
x 
x 
x 
x 
x 
x 
Serum PSA 
x 
x 
x 
x 
x 
x 
x 
x 
Gonadotropins, LH, FSH 
x 
x 
x 
x 
x 
x 
x 
x 
24 DEXA scan 
 
 
 
 
 
 
 
x 
Patient reported outcomes 
 
 
 
 
 
 
 
 
FACT-P 
 
x 
 
x 
 
x 
x 
x 
Surveys: physical functionb 
 
 
 
x 
 
x 
 
x 
Safety 
 
 
 
 
 
 
 
 
AE/SAE assessmentc 
xd 
a Bioelectrical impedance scale to be used. 
b PROMIS, Self-Efficacy Assessment, and GODIN survey are not mandatory if translated version in not available. 
c Concomitant medications used to treat related AEs that were unresolved at EOT will be capture in Active Follow-up period. 
d To be collected and updated as needed, not visit dependent. 
e Tests related to inclusion exclusion criteria should be performed at screening visit. Neutrophil count, Platelet count, Total bilirubin, ALT, AST, Creatinine, Creatinine clearance, PTT, PT, INR. All the other 
clinical chemistry and hematology are mentioned in Section 10.2, Table 10-1. 
Bayer will provide questionnaires wherever validated version is available in the said language. 
 
Abbreviations: A1C (hemoglobin) Glycated, AE adverse event, ALT Alanine aminotransferase, AST Aspartate aminotransferase, BSAP bone-specific alkaline phosphatase, CT computerized tomography, 
CTX C-telopeptide, DEXA dual energy x-ray absorptiometry, DHEA dehydroepiandrosterone, DHT dihydrotestosterone, FACT-P Functional Assessment of Cancer Therapy – Prostate Cancer, FSH follicle-
stimulating hormone, INR international normalized ratio, LH-luteinizing hormone, PSA Prostate-specific antigen, PT prothrombin time, PTT partial thromboplastin time, SAE serious adverse event, SHBG 
sex hormone-binding globulin. 
.

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2. 
Introduction 
Darolutamide is a next-generation nonsteroidal androgen receptor inhibitor (ARI) for the 
treatment of prostate cancer, which binds with a high affinity and selectivity to the androgen 
receptor (AR) with potent and improved antagonism for AR. 
 
Darolutamide has shown a very low blood-brain barrier penetration in rodents (Zurth et al. 
2019) compared to enzalutamide and apalutamide. First data in humans also suggest that 
darolutamide has a favorable impact on brain blood flow compared to enzalutamide and that 
this might be attributable to difference in blood brain barrier penetration (BBB). Differences in 
BBB penetration of treatment and therefore, the effect on the central nervous system (CNS) 
may reduce the risk of CNS related side effects such as cognitive function, fatigue falls, 
dizziness, and depressed mood disorders. 
 
Darolutamide plus androgen deprivation therapy (ADT) demonstrated significant improvement 
of metastasis-free survival (MFS) and overall survival (OS) in patients with non-metastatic 
castration resistant prostate cancer (nmCRPC) compared to ADT alone in the phase III 
ARAMIS study (Fizazi et al. 2019). The primary analysis in ARAMIS showed a median MFS 
improvement of 22 months (40.4 months in darolutamide compared with to 18.4 months in 
placebo arms HR of 0.41; 95% CI 0.34 to 0.50). 
 
The final analysis showed a statistically significant benefit in overall survival (HR 0.69; 95% 
CI 0.53 to 0.88) and all other secondary end points such as time to pain progression, time to 
cytotoxic chemotherapy, and time to a symptomatic skeletal event. 
 
Safety results of pivotal phase 3 study ARAMIS in nmCRPC showed ≤2% difference between 
the darolutamide and placebo groups for most AEs of interest, including CNS related AEs (i.e., 
falls, cognitive and mental impairment, depression), with fatigue as the only AE with a more 
that 10% incidence in the darolutamide arm (13.2% vs 8.3% in the placebo arm in the DB 
period). 
 
2.1 
Study Rationale 
The study of care for men with biochemically relapsed prostate cancer in the United States 
annually, is an estimated 40,000 – 50,000, with treatment of these subjects with this disease 
state being far from standardized. 
 
2.2 
Background 
Prostate cancer is the second most common cancer in men worldwide, with an estimated 
incidence of 900,000 cases and 258,000 deaths in 2008 (Fizazi et al. 2020). In the United States, 
approximately 222,000 cases were diagnosed in 2010 (Jemal et al. 2011), of which an estimated 
two-thirds undergo radical prostatectomy or definitive radiation therapy (RT). Approximately 
25%-35% of patients treated with definitive surgical or radiation therapy for localized 
adenocarcinoma of the prostate will recur in the form of rising serum PSA without overt 
metastatic disease, termed biochemical recurrence (BCR) (Jemal et al. 2010, Zietman et al. 
2004). An estimated 40,000 - 50,000 men in the U.S. develop biochemically relapsed prostate 
cancer each year, yet treatment of men in this disease state is far from standardized. The optimal 
time to initiate treatment and the choice of specific therapy for such patients remains 
controversial and highly variable in clinical practice. This may be due to several potential 
reasons, including (1) absence of prospective randomized trial data demonstrating an overall 
survival advantage for one therapeutic approach and (2) a biologically heterogeneous 
population with a variable natural disease course. 
 
Biochemical recurrence (BCR) of prostate cancer, characterized by a rising prostate-specific 

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antigen (PSA) after definitive primary therapy, occurs in approximately 20-40% of post- 
prostatectomy patients and 30-50% of post-radiation patients within 10 years (Artibani et al. 
2018). While many patients with BCR do well clinically for years, proper treatment of BCR is 
important as BCR precedes the appearance of clinical metastasis by 8 years after radical 
prostatectomy (RP) and by 7 years after primary definitive RT (Artibani et al. 2018). 
 
The kinetics of PSA change over time has emerged as an important independent prognostic 
factor for patients with BCR, both with respect to time to development of metastases as well as 
the risk of prostate cancer-specific mortality. In a cohort study of 8,669 men treated with 
localized therapy, of the 1,451 men with PSA recurrence, a PSA doubling time (PSADT) less 
than 3 months was associated with an approximately 50% chance of prostate-cancer specific 
mortality at 5 years; in contrast, those with a PSADT greater than 12 months had less than 10% 
prostate cancer-specific mortality during the same time interval (Han et al. 2003). In another 
study of 1,650 patients previously treated with external beam radiotherapy, at the time of PSA 
recurrence, the 3-year risk of distant metastases for a PSADT of 0-3 months, 3-6 months, 6-12 
months, and > 12 months was 49%, 41%, 20%, and 7%, respectively (P <0.001) (D'Amico 
et al. 2004). 
 
Risk stratifying patients with biochemical recurrence may allow for more optimal and 
individualized selection of treatment (Zelefsky et al. 2005). 
 
Various management options are acceptable for prostate cancer with BCR, including 
observation, intermittent or continuous use of androgen deprivation therapy (ADT), 
nonsteroidal antiandrogen (NSAA) therapy, and salvage radiotherapy or surgery. 
 
A prolonged PSADT, as well as other factors such as low Gleason grade, positive surgical 
margins, and pre-treatment PSA level < 2.0 ng/mL, may help to predict which patients may 
benefit from localized salvage therapy such as radiotherapy after prior prostatectomy (Ryan and 
Small 2006). 
 
For those patients with a PSADT greater than 12 months, active surveillance may be the optimal 
treatment approach, especially in elderly patients with other potentially life-limiting co-
morbidities who are not candidates for locally directed salvage therapy. For patients with a 
shorter PSADT, who are at significant risk of prostate-cancer specific mortality over the next 
5-10 years, early treatment with continuous androgen deprivation therapy (ADT), in the form 
of luteinizing hormone releasing hormone (LHRH) antagonists or agonists (e.g., goserelin, 
leuprolide acetate) with or without a first generation androgen receptor (AR) antagonist (e.g., 
flutamide, bicalutamide), has been a standard approach. In that patient population, intermittent 
ADT is also considered an alternative approach, which showed non-inferiority to continuous 
ADT with respect to survival and improved quality of life (National Comprehensive Cancer 
Network 2021). 
 
 

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Androgen deprivation therapy (ADT) constitutes the current first line systemic treatment for 
prostate cancer, resulting in marked suppression of serum testosterone levels and associated 
loss of libido and sexual function (DiBlasio et al. 2008). ADT also has well documented 
metabolic adverse effects including decreased bone mineral density, loss of muscle mass, 
increased lipid levels, and insulin resistance leading to a higher risk of diabetes and contributing 
to an increased risk of cardiovascular disease (Jespersen et al. 2014, Taylor et al. 2009). 
Attempts to reduce the morbidity of advanced prostate cancer treatments with less adverse 
effect have largely focused on non-testosterone lowering strategies using first generation non-
steroidal anti-androgen (NSAA) monotherapies, an approach that is supported by EAU 
Guidelines on Prostate cancer (Mottet et al. 2020) and largely based on benefits in health-related 
quality of life (HRQoL) and tolerability. 
 
For patients who are treated with systemic therapy, NSAAs serve as an alternative to ADT by 
providing a potentially more favorable side effect profile. In contrast to ADT, NSAAs are 
associated with increased bone mineral density and reduced risks of fat accumulation, 
hyperglycemia, anemia, fatigue, loss of libido, and vasomotor flushing. 
 
Second generation antiandrogens (enzalutamide, apalutamide and darolutamide) have 
demonstrated increased efficacy compared to first generation antiandrogens (Rice et al. 2019). 
Such agents to date remain a part of the SOC for men with advanced prostate cancer. 
 
The effect of monotherapy with ARIs enzalutamide and apalutamide in patients with 
biochemical recurrence has been explored and reported. A single arm, phase 2 study by Tombal 
et al evaluating enzalutamide monotherapy in biochemically recurrent and metastatic patients 
showed similar PSA level reduction by enzalutamide monotherapy compared to testosterone 
suppression by LHRH analogues. Enzalutamide alone, however, resulted in a mean increase of 
testosterone levels at week 25 of 114% with very frequent side effects of grades 1-2 such as 
gynecomastia (36%), fatigue (31%), nipple pain (19%), and hot flush (18%) (Tombal et al. 
2014). In this enzalutamide study, peak serum testosterone rise plateaued at around 10 to 13 
weeks of treatment. 
 
(Maluf et al. 2018) presented data of LACOG 0415, a three-arm phase 2 study exploring 
efficacy of the ADT-free alternatives in a patient population with advanced hormone-sensitive 
prostate cancer and biochemical recurrence. The apalutamide monotherapy arm demonstrated 
similar PSA decline level to the other two arms, however, it too resulted in a high mean increase 
in levels of testosterone of 134.3% at week 25 with high incidences of any grade side effects 
such as gynecomastia (55%), rash (26%), fatigue (21%), pruritus (17%) and breast pain (14%). 
In this apalutamide study, peak serum testosterone rise plateaued at around 10 to 13 weeks of 
treatment. 
 
The increase in serum testosterone level observed with enzalutamide and apalutamide is thought 
to result from the ability of these compounds to penetrate the blood-brain-barrier (BBB), 
resulting in negative feedback on the luteinizing hormone (LH)-testosterone axis and 
subsequent rise in testosterone. Unfortunately, it is not fully established whether this negative 
feedback loop occurs entirely within the central nervous system (CNS) or whether parts of it 
may be situated outside of the BBB. 
 
 

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Penetration of the BBB by apalutamide and enzalutamide may also result in added CNS related 
side effects, including fatigue, falls, cognitive impairment, and impaired balance, as evidenced 
in phase 3 clinical studies. 
 
Darolutamide does not appear to experience the above-mentioned pharmacokinetic limitations, 
given that it has a distinct chemical structure with high binding affinity to the androgen receptor 
with a low blood brain barrier penetration (Zurth et al. 2018, Zurth et al. 2019). Evidence from 
clinical studies including the ARAMIS phase 3 trial in nmCRPC suggests a reduction in CNS 
related side effects like fatigue, falls, cognitive decline and memory impairment, as well as 
other side effects commonly seen with other ARIs like fractures, rash and hypertension (Fizazi 
et al. 2019, Moilanen et al. 2015). 
 
Darolutamide has demonstrated lower penetration of the BBB compared to enzalutamide and 
apalutamide in preclinical models (Zurth et al. 2018, Zurth et al. 2019). Additionally, 
enzalutamide but not darolutamide reduced blood flow in brain areas related to cognitive 
function in an imaging study conducted in healthy volunteers (Williams et al. 2020). 
 
Due to the low BBB, darolutamide is expected to lead to a reduced reactive testosterone rise 
via the hypothalamic-pituitary gland-gonadal axis, which in turn is expected to result in 
significantly less peripheral conversion of testosterone to estrogen and the related feminization 
side effects. In consequence darolutamide used as monotherapy may have high efficacy against 
prostate cancer, coupled with a favorable short- and long-term side effect profile and therefore 
may potentially disrupt the dogma of testosterone reduction as foundational therapy in prostate 
cancer. 
 
Earlier use of ADT may be better than delayed therapy, although the definitions of early and 
late (i.e., what level of PSA) remain controversial (National Comprehensive Cancer Network 
2021). The multicenter phase 3 TROG 03.06/VCOG PR01-03 (TOAD) trial randomized 293 
men with PSA relapse after operation or radiation (n=261) or who were not considered for 
curative treatment (n=32) to immediate ADT or ADT delayed by a recommended interval of 
more than 2 years (National Comprehensive Cancer Network 2021). Five-year OS was 
improved in the immediate therapy arm compared with the delayed therapy arm (91.2% vs 
86.4%, log-rank P=0.047) (National Comprehensive Cancer Network 2021). However, the 
hormone-treatment related symptoms were higher in the immediate ADT group compared with 
the delayed ADT group (National Comprehensive Cancer Network 2021). Hence, the current 
NCCN guidelines v2.2021 for prostate cancer state that the benefit of early ADT must be 
balanced against the risk of ADT related side effects and ADT should be considered earlier in 
patients with an elevated PSA and/or a shorter PSADT and an otherwise long-life expectancy. 
2.2.1 
Therapeutic options in BCR prostate cancer patients 
2.2.1.1 
Combined Androgen Blockade (CAB) and continuous ADT 
Combined androgen blockade (CAB) refers to the combination of medical castration with an 
LHRH agonist (LHRHa) and a first-generation antiandrogen such as flutamide or bicalutamide. 
There are currently no completed randomized clinical trials comparing CAB with LHRHa 
monotherapy in men with biochemically relapsed prostate cancer. In the metastatic hormone-
sensitive prostate cancer (mHSPC) disease population, several meta- analyses demonstrate a 
small 5-year overall survival benefit with the addition of a first-generation antiandrogen to 
LHRHa therapy, with a slim absolute 5-year survival benefit of 2-3% (Prostate Cancer Trialists' 
Collaborative Group 2000, Samson et al. 2002). In the non- metastatic BCR disease setting, the 
use of CAB is quite variable across clinical practices, ranging from no use to temporary use at 
the time of initiation of ADT, and continuous use. 
 
While continuous, long-term treatment with ADT is effective in terms of decreasing PSA levels, 
disease progression in the setting of castrate levels of testosterone is a near universal event. 

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Furthermore, over the past decade, there has been a growing appreciation for the significant 
short-term and longer-term toxicities of continuous ADT, in which serum testosterone is 
maintained at a castrate level. Side effects developing shortly after the initiation of ADT include 
fatigue, gynecomastia, decreased libido, impotence, decreased physical capacity, mood 
changes, and hot flashes. Over the long term, serious metabolic side effects can often emerge, 
including decreased bone mineral density and risk for osteoporotic fractures, anemia, increased 
risk of insulin resistance and overt diabetes mellitus, dyslipidemia, and an increased risk of 
cardiovascular mortality (Basaria et al. 2006, Braga- Basaria et al. 2006, Dockery et al. 2003, 
Keating et al. 2006, Smith et al. 2001, Smith et al. 2002, Smith et al. 2006). 
2.2.1.2 
Intermittent ADT (IADT) 
Given the toxicities of long term, continuous ADT, more contemporary treatment strategies 
involving intermittent ADT (IADT) have emerged for men with BCR. The threshold at which 
to stop and start ADT during the course of IADT is variable in prior clinical trials and clinical 
practice (Albrecht et al. 2003, Bruchovsky et al. 2006, Da Silva et al. 2006, Peyromaure et al. 
2005). Nevertheless, numerous Phase 2 and 3 trials comparing IADT to continuous ADT, 
though not adequately powered for non-inferiority, have shown comparable overall and 
prostate-cancer specific survival and improved quality of life (QoL) (Albrecht et al. 2003, 
Bruchovsky et al. 2006, Da Silva et al. 2006, Peyromaure et al. 2005). More recently, a 
randomized Phase 3, non-inferiority trial of continuous vs. IADT in 1,386 patients with BCR 
after prior definitive radiation treatment was conducted by the National Cancer Institute of 
Canada (NCIC) Clinical Trials Group. There was no difference in overall survival after a 
median follow up of 6.9 years (HR = 1.02, 95% CI 0.86 – 1.21) and significantly better QoL 
with IADT (Crook et al. 2011). The results of this trial could provide further justification to 
consider treatment alternatives to continuous ADT in the BCR disease setting. 
2.2.1.3 
Peripheral Androgen Blockade (PAB) 
Peripheral androgen blockade, utilizing an androgen receptor antagonist (e.g., flutamide or 
bicalutamide), with or without a 5-alpha reductase inhibitor, inhibits intra-tumoral activation of 
the AR, thereby potentially slowing disease progression. Yet in contrast to ADT, PAB does not 
decrease serum testosterone levels to a castrate state. In theory, this may lead to an improvement 
in quality of life and the metabolic profile of patients treated with PAB versus traditional ADT, 
while preserving response to treatment. In one contemporary study, monotherapy with 
bicalutamide was compared to LHRHa therapy in patients with prostate cancer without bone 
metastases. After 1 year of therapy, bicalutamide was shown to improve bone density (increase 
of 2.5% vs. decrease of 2.5% with leuprolide) in the posterior-anterior lumbar spine, lessen 
increase in fat mass (6.4% vs. 11.1% increase with leuprolide), and diminish fatigue, loss of 
sexual interest and vasomotor flushing (Smith et al. 2004). Although the earlier studies signal 
to efficacy benefit with less AEs with first generation ARIs, efficacy and safety evidence with 
second generation ARIs became a more compelling data generating approach. 
 
 

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2.2.1.4 
Second generation AR inhibitors in BCR hormone-sensitive prostate 
cancer 
First generation AR inhibitors such as flutamide and bicalutamide have relatively low AR 
binding affinity relative to dihydrotestosterone (DHT) and may exhibit partial agonist activity 
and may eventually lead to disease progression through putative activation of the AR. To 
overcome the potential deficiencies of first-generation antiandrogens, second generation 
antiandrogens (darolutamide, enzalutamide and apalutamide) have been developed which 
potently inhibit AR activation, nuclear translocation, binding to co-activators, and AR- 
mediated gene expression. Furthermore, these second-generation antiandrogens do not have any 
agonist activity. 
 
The effect of monotherapy with ARI’s enzalutamide and apalutamide in patients with 
biochemical recurrence has been explored and reported. A single arm, phase 2 study by Tombal 
et al. 2014 evaluating enzalutamide monotherapy in biochemically recurrent and metastatic 
patients showed similar PSA level reduction by enzalutamide monotherapy compared to 
testosterone suppression by LHRH analogues. Enzalutamide alone, however, resulted in a mean 
increase of testosterone levels of 114% at week 25 with very frequent side effects of grades 1--2 
such as gynecomastia (36%), fatigue (31%), nipple pain (19%), and hot flush (18%) (Tombal 
et al. 2014). In this enzalutamide study, peak serum testosterone rise plateaued at around 10 to 
13 weeks of treatment. 
 
(Maluf et al. 2018) presented data of LACOG 0415, a three-arm phase 2 study with 
apalutamide alone exploring efficacy of the ADT-free alternatives in a patient population with 
advanced hormone-sensitive prostate cancer and biochemical recurrence. The apalutamide 
monotherapy arm demonstrated similar PSA decline levels to the other two arms, however, it 
too resulted in a high mean increase in levels of testosterone of 134.3% at week 25 with high 
incidences of side effects of all grades: gynecomastia (55%), rash (26%), fatigue (21%), 
pruritus (17%) and breast pain (14%). In this apalutamide study, peak serum testosterone rise 
plateaued at around 10 to 13 weeks of treatment. 
2.2.2 
Markers of endocrine Metabolisms 
2.2.2.1 
Markers of Insulin Resistance and Metabolic Syndrome 
Androgen deprivation therapy has numerous effects on the metabolic profile, including 
increased insulin resistance, development of obesity and increased waist circumference, 
unfavorable changes in the lipid panel, and ultimately increased risk of diabetes and potentially 
cardiovascular mortality (Basaria et al. 2006, Braga-Basaria et al. 2006, Dockery et al. 2003, 
Keating et al. 2006, Smith et al. 2001, Smith et al. 2002, Smith et al. 2006). To detect differences 
in the incidence rate of new diabetes or cardiovascular events between treatment arms, studies 
in the BCR disease setting would require large numbers of patients and long term follow up, 
given the low annual incidence rate of these co-morbidities for men on ADT. Measuring 
changes in metabolic risk factors for these processes, including surrogate markers of insulin 
resistance such as fasting glucose and insulin, body mass index, hemoglobin A1C, along with 
changes in the fasting lipid panel, may serve as intermediate, exploratory endpoints in initial 
phase 2 trials. Favorable results with respect to these metabolic parameters may then serve as 
the basis for larger trials of new therapeutic agents, in which the incidence rate for diabetes or 
cardiovascular disease could serve as more quantifiable endpoints. 
 
 

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2.2.2.2 
Bone Mineral Density (BMD) 
Bone mineral density, as measured by dual energy x-ray absorptiometry (DEXA) scan, remains 
the standard method of diagnosing osteoporosis and estimating osteoporotic fracture risk, 
defined as vertebral compression fractures or fractures after a fall from a standing height or less 
in the absence of other significant trauma. In general, for each standard deviation decrease in 
BMD by DEXA scan, the risk of osteoporotic fracture doubles (Cauley et al. 2007). Prior studies 
have shown that continuous treatment with ADT decreases BMD. For example, in a prior study 
of 65 men who had proximal femur BMD measured at baseline and again after 12 months of 
ADT with LHRHa therapy, the mean BMD decreased by 1.9 ± 2.7% (p < 0.001) (Lee et al. 
2005), demonstrating that even 1 year of ADT can adversely affect BMD. In addition, patients 
on ADT appear to be at increased risk for osteoporotic fracture. In a prior retrospective cohort 
study of the 50,613 men who were listed in the linked database of the Surveillance, 
Epidemiology, and End Results program and Medicare as having received a diagnosis of 
prostate cancer in the period from 1992 through 1997, of those men surviving at least 5 years 
after diagnosis, 19.4% of those receiving ADT sustained a fracture, compared with 12.6% of 
those not receiving ADT (p< 0.001) (Shahinian et al. 2005). 
 
Other methods applied in this trial are bone specific alkaline phosphatase (BSAP) and C- 
telopeptide (CTX). 
 
Measuring changes in BMD may serve as an intermediate, exploratory endpoint for a 
therapeutic agent tested in the BCR disease population. Favorable results with respect to better 
preservation of BMD over time compared to traditional ADT would then serve as the basis for 
larger trials with longer follow up using a more definitive endpoint such as incidence of 
osteoporotic fractures. 
 
2.3 
Benefit/Risk Assessment 
Darolutamide has undergone an extensive clinical development program and the data have 
demonstrated efficacy and effectiveness in the treatment of patients with nmCRPC. 
Darolutamide treatment was well tolerated demonstrating a favorable benefit risk balance, 
hence approved for the treatment of patients with nmCRPC. 
 
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 dose-escalation ARADES study in patients with metastatic CRPC showed no 
dose-limiting toxic effects. Based on ARADES and Phase 1 ARAFOR studies, no dose– related 
trends were noted in the AE profile. Early phase studies demonstrated that antitumor activity 
was seen at all dose levels as evaluated by PSA, Circulating tumor cell (CTC) counts, and soft 
and bone lesion imaging. In these 2 studies, patients who were naïve to treatment with 
chemotherapy or cytochrome P450 17 inhibitor (CYP17i) have responded best to darolutamide 
treatment (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 and all secondary endpoints. In total, 1509 patients underwent 
randomization (955 to the darolutamide arm and 554 to the placebo arm). Darolutamide was 
associated with a statistically significant 31% reduction in the risk of death compared with 
placebo (HR 0.69; 95% CI 0.53 to 0.88, p=0.003) and statistically significant improvement in 
MFS compared to placebo with a p-value of <0.000001 and a hazard ratio of 0.413. 
Darolutamide was also associated with statistically significant improvement in all other 
secondary endpoints (Fizazi et al. 2020). 
 

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Darolutamide treatment was well-tolerated, with incidences of treatment emergent AEs 
(TEAEs) below 10% in both DB treatment arms, and with ≤2% difference between the 
darolutamide and placebo groups for most AEs of interest, except for fatigue which was the 
only AE with a more that 10% incidence in the darolutamide arm (13.2% vs 8.3% in both DB 
period). The rate of permanent treatment discontinuation due to the AEs was similar in both 
treatment arms at the final overall survival analysis (8.9% darolutamide and 8.7% placebo). 
Importantly, patient quality of life was maintained throughout the duration of treatment (Smith 
et al. 2021). 
 
Results from the ARAMIS study led to the Food and Drug Administration (FDA), European 
Medicine Agency (EMA) and other regulatory authorities’ approval of darolutamide for the 
treatment of men with nmCRPC. 
 
Darolutamide is also being investigated in the metastatic hormone-sensitive prostate cancer. 
ARASENS is a randomized phase 3 study assessing the combination of ADT and docetaxel 
with or without darolutamide in mHSPC that has completed enrollment (Smith et al. 2022). 
ARANOTE is an ongoing study comparing the efficacy and safety of darolutamide and ADT 
versus ADT alone in mHSPC (Haresh et al. 2022). 
 
Men in early stage of prostate cancer are concerned about the side-effects related to the ADT, 
therefore, optimizing treatment is of high importance to patients and caregivers. Drug induced 
adverse events may lead to a reduced quality of life, hence, treatments with favorable safety 
profiles could fulfill a medical need by providing an alternative to treatment with ADT. 
 
Due to the fact that darolutamide is potent antiandrogen with strong efficacy and favorable 
safety and tolerability, there is rationale to study darolutamide in men with experiencing BCR 
prostate cancer. The available safety and efficacy data suggest that patients who participate in 
this trial are not placed at undue risk. Overall, the benefit/risk assessment for darolutamide 
monotherapy for hormone-naïve PC patients is favorable. 
 
Cases of idiosyncratic drug-induced liver injury (DILI) with increases in ALT and/or AST to 
≥5 and ≥20 x ULN, including with concomitant bilirubin elevation > 2x ULN, have been 
reported with darolutamide. Liver function tests abnormalities were reversible upon 
darolutamide discontinuation. Please see Section 6.2 and Section 7.1. 
 
 
 
 

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3. 
Objectives and Endpoints 
Table 3–1: Lead-in Phase Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
To evaluate the impact of  darolutamide 
monotherapy on serum testosterone level 
over a 12-week intervention period 
Change in serum testosterone level from baseline 
to week 12 
Secondary 
To evaluate the impact of darolutamide 
monotherapy on serum testosterone level 
over the course of a 52-week intervention 
period 
Change in serum testosterone level from baseline 
at week 24 and 52 
Assess PSA response rate 
Serum PSA Week 4, 12, 24, 36, 52 
To assess safety of darolutamide monotherapy 
in patients with hormone-naïve prostate Cancer 
with BCR 
AE assessments using NCI CTCAE (v.5.0) 
Abbreviations: AE adverse events, BCR biochemical recurrent, NCI CTCAE National cancer institute common terminology criteria for 
adverse events, PSA prostate specific antigen. 
 
 

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Table 3–2: Randomized Phase Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
To compare the effects of treatment with 
darolutamide 
vs. 
enzalutamide 
monotherapy on serum testosterone 
level over a 12-week intervention period 
Change in serum testosterone level from baseline 
to week 12 
Secondary 
To compare the effect of darolutamide vs. 
enzalutamide monotherapy on serum 
testosterone level over the course of a 52-
week intervention period 
Change in serum testosterone level from baseline 
at week 24 and 52 
Measure changes in markers of endocrine 
function related to sex hormones 
Assess changes in the blood levels of sex 
hormones (DHT, DHEA, SHBG, LH, FSH, 
Androstenedione, Prolactin, Estradiol) 
Measure changes in markers of components of 
fat and glucose metabolism 
Assess changes blood levels of Total cholesterol, 
High-density and low-density lipoproteins, 
Triglycerides, Hemoglobin A1C, Fasting insulin, 
Fasting glucose, Fat body mass, Lean body 
mass 
Assess PSA response rate 
Serum PSA Week 4, 12, 24, 36, 52 
To assess safety and QoL of darolutamide 
vs. enzalutamide monotherapy in patients 
with hormone-naïve prostate Cancer with 
BCR 
AE assessments using NCI CTCAE (v.5.0) and 
FACT-P 
Exploratory 
Evaluate changes in Bone turnover 
Markers of bone turnover: 
BSAP, CTX, DEXA scan 
Physical function* 
Subjective physical function: 
Godin – 4 questions, PROMIS Fatigue – 8 
questions, PROMIS Physical – 6 questions, Self- 
Efficacy – 9 questions 
Abbreviations: A1C-glycated (hemoglobin), AE adverse events, BCR-Biochemical Recurrence, BSAP bone specific alkaline 
phosphatase, CPET Cardiopulmonary Exercise Test, CTX C-telopeptid, DHEA-dehydroepiandrosterone, DHT-
dihydrotestosterone, DEXA dual energy x-ray absorptiometry, FACT-P Functional Assessment of Cancer Therapy – Prostate 
Cancer, FSH-follicle-stimulating hormone, LH-luteinizing hormone, NCI CTCAE-National Cancer Institute-Common Terminology 
Criteria for Adverse Events, PROMIS Patient-Reported Outcomes Measurement Information System., PSA-Prostate-specific 
antigen, QoL Quality of life, SHBG- sex hormone-binding globulin. 
*the physical function assessments might be modified. 
 
 

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4. 
Study Design 
4.1 
Overall Design 
This is a two-stage open label phase 2 study with a lead-in single-arm phase and the randomized 
phase, to assess the impact of ARI darolutamide or enzalutamide as a monotherapy treatment 
on serum testosterone levels in men with hormone-naïve prostate cancer experiencing 
biochemical recurrence (BCR) after failure of treatment with curative intent for localized 
prostate cancer. Secondary endpoints to be evaluated include the impact of ARI monotherapy 
on energy metabolism and the metabolism of sex hormones as well as PSA response and safety. 
Exploratory endpoints will evaluate changes in bone metabolism, physical function, and quality 
of life profiles. The study design is shown in the Figure 4-1. 
 
In the lead-in phase, approximately 25 participants will be treated with darolutamide for 52 
weeks. The primary endpoint analysis of the lead-in phase will occur when all participants in 
the lead-in phase have been on treatment for 12 weeks, unless the participant discontinued due 
to lost to follow-up, withdrawal, or death. The secondary endpoint analysis of lead-in phase 
(see Table 3-1) will occur after patients have been treated for 52 weeks. 
 
The study team will review the findings form the lead-in phase of the study, to provide input on 
interpretation of the results from the lead-in phase which will help guide a decision on the 
conduct or not of the randomized phase as well as potential changes in the study design for the 
randomized phase by the Sponsor. In any case, the conduct of the randomized phase is 
conditional on obtaining a mean percent change in serum testosterone from baseline for the 
darolutamide arm of less than 45%. Additional non-binding thresholds to help with the decision 
on the conduct of, or changes in the randomized phase, are that the incidence of feminizing side 
effects observed is below than that previously reported 
 
). Depending on the results of the 
evaluation and in case of the decision to proceed with the randomized phase, the primary 
endpoint may be modified, and the statistical assumptions revised. The Sponsor withholds the 
right to conduct or stop the lead-in phase or start the randomized phase in case data on 
testosterone levels from patients treated with darolutamide alone would become available from 
other ongoing studies. 
 
In case of the decision to proceed in the randomized phase, approximately 40 participants will 
be randomized in a 1:1 ratio to receive either darolutamide (600 mg twice daily) or enzalutamide 
(160 mg once daily). The randomized phase will have primary and final analysis. The primary 
analysis will be conducted when all the participants in the randomized phase have been on the 
treatment for at least 12 weeks and the final analysis for the randomized phase of the study will 
occur when last participant in the randomized phase has been on the treatment for at least 52 
weeks, unless the participant discontinued due to lost to follow-up, withdrawal, or death. The 
overall sample size across the two phases is expected to be about 65 participants. 
CCI

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Figure 4–1: Overall Design 
 
 
Abbreviations: ECOG Eastern cooperative oncology group, PC prostate cancer, PSADT PSA doubling 
time. 
 
The study is designed to evaluate the effect of ARI treatment on the serum testosterone levels, 
PSA levels, hormonal changes derived from the androgen axis including markers of endocrine 
and energy metabolism, changes in bone mineral density, adverse events, and quality of life 
profiles. 
 
The study will be conducted only in the USA at approximately 4-6 sites. 
 
The study will comprise the following consecutive periods: Screening, Treatment period, 
Active Follow–up period. 
4.1.1 
Screening period 
After the participant has signed the Informed Consent Form (ICF), the screening period will 
begin from the date of signed ICF to up to 28 days before start of study intervention (date of 
first dose). Enrolled participants include those who signed the informed consent form, met all 
inclusion and none of the exclusion criteria and are eligible for the first dose of study 
intervention. The interactive web response system (IWRS) will assign a unique participant 
identification (ID) number to an enrolled participant. 
4.1.2 
Treatment period 
Eligible participants (eligibility documented and confirmed) will start study intervention 
administration twice daily. 
The treatment period is defined as the time from the administration of first dose of study 
treatment until 52 weeks or unacceptable toxicity, withdrawal of consent, investigator’s 
decision to stop therapy for the participant, participant decision to stop therapy, Sponsor’s 
decision to terminate the study, or death. 
End of treatment (EOT) visit takes place 30 days (+7 days) after the last dose. 
4.1.3 
Active Follow–up period 
When the patient's treatment is discontinued before completing week 52 treatment, the patient 
will continue assessments until week 52 for both Lead In and Randomized phases. This follow-
up period is defined as the Active Follow-up period (see Table 1–5, Active-follow-up SoA). 
 
 
4.2 
Participants and Study Completion 
Approximately 25 participants will be assigned to darolutamide to achieve 20 evaluable 
participants in the lead-in phase. 

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The conduct of the randomized phase is dependent on the results of the lead in phase. If the 
study proceeds into the randomized phase, it is planned to randomly assign 40 patients (20 per 
arm) to study intervention to have 34 evaluable participants for the final analysis in the 
randomized phase. 
4.2.1 
Participant completion of study 
A participant is considered to have completed the study if he has completed all periods of the 
study (see Table 1–3 for lead-in phase, Table 1–4 for randomized phase and Table 1–5 for 
Active Follow-up period), unless the participant discontinued due to lost to follow-up, 
withdrawal, or death. 
 
4.3 
End of Study Definition 
The end of the study is defined as the date of the last patient last visit (LPLV) in the study. 
LPLV of the study is reached when all participants have completed the last scheduled procedure 
shown in the Schedule of Activities including Active follow up period. 
If the study 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. 
Completion of the study is required in order to provide sufficient participants as defined in 
Section 9.2 Sample Size Determination. 
4.3.1 
Early Study Termination 
The Sponsor has the right to close this study or individual sections of this study at any time. 
Any participant requiring treatment interruption >28 consecutive days must be withdrawn from 
study intervention. 
Reasons for closure may include: 
• If risk-benefit ratio becomes unacceptable; 
• Safety findings from this study. (e.g., SAEs); 
o Unacceptable toxicity; 
o Darolutamide dosing below 300 mg bid; 
o Occurrence of Grade ≥3 study intervention related TEAE while the participant 
is on 300 mg bid. 
• Results of parallel clinical 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; 
• For strategic reasons (e.g., the clinical development of the darolutamide monotherapy 
in the BCR patient population is stopped); 
• Should this be necessary, the patient should be seen as soon as possible. 
The same assessments should be performed as described in Section 7 and Section 8 for a 
discontinued or withdrawn patient. The investigator may be informed of additional procedures 
to be followed to ensure that adequate consideration is given to the protection of the patients’ 
interests. The investigator will be responsible for informing institutional review boards (IRBs) 
and/or independent ethics committee (IECs) of the early termination of the trial. 
 
4.4 
Scientific Rationale for the Study Design 

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ARAMON is designed to evaluate the efficacy and safety of treatment of men with hormone 
sensitive prostate cancer experiencing BCR with darolutamide or enzalutamide monotherapy. 
Efficacy outcomes measured will include serum testosterone levels, PSA levels and hormonal 
changes derived from the androgen axis including endocrine and energy metabolism markers 
and changes in bone mineral density. Study will also evaluate safety and quality of life, as well 
as fitness and physical function. 
Proper adequate treatment of BCR is important as BCR precedes the appearance of clinical 
metastasis by 8 years after RP and by 7 years after primary definitive RT (Artibani et al. 2018). 
 
Androgen deprivation therapy (ADT), the current first line systemic treatment for prostate 
cancer, is associated with loss of libido and sexual function (DiBlasio et al. 2008), and has well 
documented metabolic adverse effects including decreased bone mineral density, loss of muscle 
mass, increased lipid levels, and insulin resistance leading to a higher risk of diabetes and 
contributing to an increased risk of cardiovascular disease (Jespersen et al. 2014, Taylor et al. 
2009). Attempts to reduce the adverse effects using first generation NSAA monotherapies is 
limited by specific feminization side effects like gynecomastia and breast tenderness. 
 
Second generation antiandrogens (darolutamide, enzalutamide and apalutamide) have 
demonstrated increased efficacy compared to first generation antiandrogens (Rice et al. 2019). 
 
For prostate cancer patients with BCR who are at significant risk for the development of 
metastases and prostate cancer-specific mortality, treatment with second generation androgen 
receptor inhibitors ARIs as monotherapy may mitigate the potential impact of systemic 
treatment on QoL, and clinically significant metabolic derangements observed with ADT or 
NSAAs, addressing an important unmet medical need. 
 
The effect of monotherapy with enzalutamide in patients with biochemical recurrence has been 
explored and reported, a mean increase of testosterone levels of 114% at week 25 with very 
frequent side effects of grades 1-2 such as gynecomastia (36%), fatigue (33%), nipple pain 
(20%), and hot flush (18%) (Tombal et al. 2014). Similar results have been reported with 
apalutamide monotherapy. 
 
The increased serum testosterone levels are peripherally converted to estrogens (Fagerlund et 
al. 2015, Scher et al. 1997) and are suspected to be the cause for the specific feminization side 
effects like gynecomastia and breast tenderness observed in the above mentioned two trials. 
 
The increase in serum testosterone level observed with enzalutamide and apalutamide is thought 
to result from the ability of these compounds to penetrate the blood-brain-barrier (BBB), 
resulting in upregulation of luteinizing hormone signaling due to blockage of the androgen 
receptor in hypothalamus and pituitary gland which increases testosterone production. 
 
 
 

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Beyond the potential effect on testosterone production, the penetration of apalutamide and 
enzalutamide into the CNS may also be responsible for CNS related adverse events observed 
in the phase 3 clinical trials such as fatigue, falls and cognitive impairment. 
 
Darolutamide does not appear to suffer from the above-mentioned limitations given that due to 
its distinct chemical structure darolutamide exhibits a high binding affinity to the androgen 
receptor with a low blood brain barrier penetration (Zurth et al. 2018, Zurth et al. 2019). 
Darolutamide is structurally distinct from the other second-generation anti-androgens, 
enzalutamide and apalutamide (Moilanen et al. 2015). The ARAMIS phase 3 trial in nmCRPC 
showed a low incidence of CNS related AEs (i.e., fatigue, falls, cognitive and memory 
impairment, depression) with less than 2% difference with the placebo arm, with the exception 
of fatigue which was the only AE with incidence of more than 10% (13.2% Daro vs 8.3% 
placebo in the DB period). 
 
Darolutamide has demonstrated significantly lower penetration of the BBB compared to 
enzalutamide and apalutamide in preclinical models. Additionally, it was demonstrated in a 
neuro-imaging study conducted in healthy volunteers that enzalutamide but not darolutamide 
reduced blood flow in brain areas related to cognitive function (Williams et al. 2020). 
 
Darolutamide is hypothesized to lead to a reduced reactive testosterone rise via the 
hypothalamic-pituitary gland-gonadal axis, which in turn is expected to result in significantly 
less peripheral conversion of testosterone to estrogen and related feminization side effects. In 
consequence darolutamide used as monotherapy may have a high efficacy against prostate 
cancer, coupled with a favorable short- and long-term side effect profile and therefore may 
potentially disrupt the dogma of testosterone reduction as foundational therapy in prostate 
cancer. 
Intermittent ADT (IADT) has become an acceptable treatment strategy to minimize the toxicity 
associated with long term continuous ADT. In previously reported IADT studies, the initial 
ADT was given 8-12 months, followed by an off-therapy observation period (Boccon- Gibod 
et al. 2007, Shaw et al. 2007). In this study, patients will be treated with darolutamide (lead-in 
phase and randomized phase) or enzalutamide (randomized phase) for 52 weeks (~12 months). 
As discussed previously, a randomized Phase 3 trial of continuous ADT vs. IADT in 1,386 
patients with BCR after prior definitive radiation treatment showed no difference in overall 
survival after a median follow up of 6.9 years (HR = 1.02, 95% CI 0.86 – 1.21) and significantly 
better QoL with IADT (Crook et al. 2011). The results of the trial provide further justification 
of using IADT approach for this study in the BCR disease setting. 
 
5. 
Study Population 
The study population includes men with hormone-naïve prostate cancer experiencing 
biochemical recurrence (BCR) after failure of treatment with curative intent for localized 
prostate cancer. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted. 
The investigator or designee must ensure that only patients who meet all of the following 
inclusion and none of the exclusion criteria are offered treatment in the study: 
 
 

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5.1 
Inclusion Criteria 
1. Male of ≥ 18 years of age. 
2. Patients must have histologically or cytologically confirmed adenocarcinoma of the 
prostate. 
3. Prior treatment with primary radical prostatectomy or definitive RT for localized 
prostate cancer. 
4. Patients must have PSA ≥0.2 ng/mL after ART or SRT post-RP or after RP in participants 
who are unfit for ART or SRT, OR PSA ≥2 ng/mL above the nadir after primary RT only. 
(RP, radical prostatectomy; ART, adjuvant radiotherapy; SRT, salvage radiotherapy; RT 
primary radiotherapy) 
5. The presence of < 5 asymptomatic (symptomatic lesions should be excluded) metastatic 
lesions (except for visceral metastases), and including extra-pelvic lymph nodes, and > 
2 cm pelvic lymph nodes, on conventional or PSMA-PET based imaging methods is 
permitted. Lesions that need treatment with any opioid based analgetic are considered 
symptomatic. 
6. PSADT ≤ 20 months calculated per PCWG3 + RECIST 1.1 per Scher et al. (Scher et al. 
2016) and MSKCC nomogram. 
7. ECOG PS of 0 - 1. 
8. Serum testosterone >150 ng/dl. 
9. Patients must have adequate organ function within 4 weeks before the first dose of 
study intervention and evidenced by: 
a. Absolute Neutrophil Count ≥ 1500/mm3 
b. Platelet count ≥ 100,000/mm3 
c. Total bilirubin ≤ 1.5 x ULN 
d. ALT and AST ≤ 1.5 x ULN 
e. Creatinine ≤ 2.0 X ULN 
f. Creatinine clearance (CrCl) of ≥ 30 mL/min. CrCl should be calculated at 
screening using the Cockcroft-Gault formula: Creatinine clearance for males 
(mL/min) = (140 – age in years) x (body weight in kg)/[72 x (serum creatinine 
in mg/dl)]. 
g. PTT, PT, INR ≤ 1.5 x ULN (except if on therapeutic anticoagulation in which 
case the patient can be enrolled if stable and anti-coagulation levels are 
appropriate for their condition per good clinical practice). 
NOTE: All values must be obtained within 4 weeks prior to first dose of 
darolutamide. 
NOTE: Participants must not have received any growth factor within 4 weeks 
or a blood transfusion within 7 days prior to the hematology laboratory sample 
obtained at Screening. 
10. Sexually active male participants must agree to use condoms as an effective barrier 
method and refrain from sperm donation, and/or their female partners of reproductive 
potential to use a method of effective birth control, during the treatment with study 
intervention and for 3 months after treatment with study intervention. 
11. More than 30 days (or 5 half-lives) (whichever is longer) since prior participation in 
another clinical trial with an investigational medicinal product. 
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13. Ability to comply with the current protocol and to sign informed consent form by 
the participant or legal representative. 
 
5.2 
Exclusion Criteria 
Any potential subject who meets any of the following criteria will be excluded from 
participating in the study: 
1. Prior treatment with ADT of up to 6 months for localized disease is permitted but not if 
during the prior 6 months before first dose of study intervention. Plan to initiate ADT during 
the trial period is not allowed. 
2. RT or major surgery within 4 weeks of screening. 
3. Systemic glucocorticoids within 3 months prior to the first dose of study intervention or was 
expected to require systemic glucocorticoids during the study period. 
4. Had any of the following within 6 months before the first dose of study intervention: stroke, 
myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass 
graft, congestive heart failure (New York Heart Association Class III or IV). 
5. Uncontrolled hypertension as indicated by a resting systolic BP ≥160 mmHg or diastolic 
BP ≥100 mmHg despite medical management. 
6. A gastrointestinal (GI) disorder or procedure which is expected to interfere significantly 
with absorption of study intervention. 
7. An active viral hepatitis (defined as Hepatitis B surface antigen [HBsAg] reactive or 
detectable [qualitative] HBV DNA defined as HCV Ribonucleic Acid [RNA] [qualitative] 
is detected), known human immunodeficiency virus infection with detectable viral load, or 
chronic liver disease with a need of treatment. 
NOTE: No testing for Hepatitis B and Hepatitis C is required unless mandated by local 
authority. No HIV testing is required unless mandated by local authority. 
8. Patients have participated in another clinical trial within 30 days prior to the first dose of 
study intervention. Patients may participate in nontherapeutic trials. 
9.  Prior history of a clinically significant malignancy with the exception of basal cell, 
squamous cell carcinoma of the skin, and superficial bladder cancer (Ta, Tis and T1) 
10. Prior treatment with: 
• Second–generation androgen receptor (AR) inhibitors such as enzalutamide, 
apalutamide, darolutamide other investigational AR inhibitors. 
• Cytochrome P17 enzyme inhibitor such as abiraterone acetate as antineoplastic 
treatment for prostate cancer. 
11. Known hypersensitivity to the study intervention, study intervention class, or excipients in 
the formulation of the study intervention. 
 
 

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12. Any other serious or unstable illness, or medical, social, or psychological condition, that 
could jeopardize the safety of the subject and/or his compliance with study procedures or 
may interfere with the subject’s participation in the study or which in the opinion of the 
investigator, will interfere with the patient’s participation in this study or evaluation of study 
results. 
13. Prior history of gynecomastia. 
14. Use of herbal products that may have had hormonal anti-prostate cancer activity or were 
known to decrease prostate-specific antigen (PSA) levels (e.g., saw palmetto) within 4 
weeks of before the first dose of study intervention. 
15. Inability to swallow oral medications. 
 
5.3 
Lifestyle Restrictions 
No lifestyle restrictions are required for this study. 
 
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 and 
any serious adverse event (SAE). 
 
Participants who do not meet the criteria for participation in this study (screen failure) may be 
rescreened within 2 weeks from the prior screen failure date. Rescreened participants will be 
assigned a new participant ID via the IWRS. 
 
Re-screening of screen failed participants may only be allowed once, after discussion with the 
Bayer-designated medical representative or Sponsor and after approval by the Sponsor. Sponsor 
approval of re-screening for a screen failed participant must be documented. The participants 
who need to repeat the screening procedures will be re-consented. Investigator must ensure that 
the repeated screening procedures do not expose the participant to an unjustifiable health risk. 
 
6. 
Treatments 
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo, or 
medical device(s), intended to be administered to a study participant according to the study 
protocol. 
 
 
 
 

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6.1 
Treatments Administered 
 
Study Treatment Name 
darolutamide 
enzalutamide 
Dose Formulation 
Film-coated tablet 
Solid oral dosage form  
Unit Dose Strength 
300 mg 
40 mg 
Route of Administration 
Oral (p.o.) 
Oral (p.o.) 
Dosing instructions 
600 mg (2 tablets of 300 mg) twice 
daily with food, equivalent to a 
total daily dose of 1200 mg 
160 mg once daily 
Packaging and Labeling 
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 
For local sourcing by Clinical Sites: 
yellow, round, film-coated tablets 
debossed with E 40, and are 
available in the bottles of 120 tablets 
with child resistant closures (NDC 
0469-0625-99) 
For central sourcing:  
Depending on Manufacturer and 
sourcing country. 
Manufacturer 
Bayer/ Orion 
For local sourcing by Clinical Sites: 
Astellas Pharma US. 
For central sourcing: to be defined. 
 
6.2 
Dose Modification 
6.2.1 
Definitions 
Interruption: Unscheduled break in administration during which scheduled doses of study 
medication are not received. 
For toxicities considered by the investigator to be not related to study treatment, but clinically 
significant, the decision to interrupt or reduce the dose is left to investigator’s decision. 
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. 
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. 
For dose modifications, refer to the US package insert for darolutamide and enzalutamide. 
Toxicities will be graded using the National Cancer Institute–Common Terminology Criteria 
for Adverse Events (NCI–CTCAE) v. 5.0. All dose modifications regardless of relatedness 
should be recorded on the eCRF. 
If a participant experiences several study treatment-related toxicities with different grading, the 
recommendation of the worst grading should be used. 
Participants who experience hepatic transaminase elevations suggestive of idiosyncratic drug 
induced liver injury (DILI) considered to be causally related to study intervention, should 
discontinue study intervention. Please see Section 7.1. 
 
 

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6.2.2 
General requirements for dose modifications of study treatment 
6.2.2.1 
Darolutamide 
A participant who experiences a Grade 3 or 4 TEAE that is thought to be related to study 
intervention, should interrupt study intervention until the TEAE improves to < Grade 2 or to 
baseline status. 
Cases of idiosyncratic drug-induced liver injury (DILI) with increases in ALT and/or AST to 
≥5 and ≥20 x ULN, including with concomitant bilirubin elevation > 2x ULN, have been 
reported with darolutamide. Liver function tests abnormalities were reversible upon 
darolutamide discontinuation. Participants who experience hepatic transaminase elevations 
suggestive of idiosyncratic DILI considered to be causally related to study intervention, should 
discontinue study intervention.  
Additional lab tests monitoring is recommended for Grade 2 or higher ALT and/or AST 
increase (ALT/AST >3 x ULN). Please see the below. Table 6–1. 
 
For participants who experience a decreased renal function to severe renal impairment (eGFR 
of 15 to 29 mL/min/1.73m2), the dose adjustment to 300 mg twice daily of darolutamide is 
recommended. 
If a dose of darolutamide is delayed, the dose can be taken up to 6 hours later with food to make 
up for the missed one. 
 

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Table 6–1: Study Treatment Dose Modifications 
 
Type of AE and  
Severity grade 
(NCI-CTCAE v 5.0) 
Dose modification 
Study treatment withdrawal 
All AE except ALT/AST increase 
Grade 0-2 
Treat on time. Per investigator’s decision whether to reduce or interrupt 
the study intervention. a,b 
 
Grade 3 or 4 
Interrupt until ≤Grade 2 or baseline. a 
When the severity is ≤ Grade 2 or baseline, restart a reduced dose of 
300 mg bid. b,c 
If Grade ≥3 study intervention-related TEAE occurs while the participant is on 
a dose of 300 mg bid (following temporary or permanent dose reduction) the 
participant must be withdrawn from treatment with study intervention 
AE: ALT/AST increase 
Grade 0-1 
Treat on time. Per investigator’s decision whether to reduce or interrupt 
the study interventiona 
 
Grade 2-3-4 
If ALT or AST rise to >3 ULN: 
Per investigator’s decision whether to reduce or interrupt the study 
intervention. a 
Monitor LFT (ALT, AST, total and direct bilirubin, ALP) and INR within 72 
hours after the onset and then as frequently as needed according to 
Investigator’s clinical judgment, until ALT and/or AST returns to baseline 
or normal values. 
If ALT or AST rise to >3 ULN: 
Participants must be discontinued from the study treatment in case of hepatic 
transaminase elevations suggestive of idiosyncratic DILI considered to be 
causally related to study intervention. DILI should be suspected after other 
causes of liver injury, have been excluded. Please see Section 10.3.5 for 
further guidance. 
Criteria for study treatment discontinuation (FDA 2009): 
• ALT or AST >8 x ULN 
• ALT or AST >5 x ULN for more than 2 weeks 
• ALT or AST >3 x ULN and (TBL >2 x ULN or INR >1.5) 
• ALT or AST >3 x ULN with the appearance of fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia 
(>5%) 
All grades 
Further recommendations 
• If ALT and AST return to normal values or to baseline after study intervention interruption, study intervention may be restarted at the reduced dose of 
300 mg bid  
• If, at the reduced dose, there is no increase of ALT or AST in the subsequent two weeks, full dose may be resumed. 
• If, at the reduced or full dose, ALT or AST values rise again, study intervention should be permanently discontinued. Monitor LFTs until ALT and/or 
AST return to baseline or normal values. 
 
Abbreviation: AE, Adverse events; bid, Twice daily; NCI-CTCAE v 5.0, National cancer institute-Common terminology criteria for adverse events version 5.0; TEAE, 
Treatment emergent adverse event. 
a If there is no recovery after 28 consecutive days, treatment with study intervention should be permanently discontinued. 
b When AE returns to baseline or is resolved, re-escalation to 600 md bid may be considered by the investigator. 
c If, following a re-escalation to 600 md bid a second Grade ≥3 study intervention TEAE occurs, a permanent dose reduction to 600 mg bid is required. A third 
occurrence of a Grade ≥3 study intervention related TEAE requires permanent discontinuation of treatment with study intervention. 
Note : table excludes clinically non-significant and asymptomatic laboratory abnormalities. 

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6.2.2.2 
Enzalutamide 
Dose modification and/or interruption for toxicities considered related to enzalutamide 
treatment can be made according to the enzalutamide prescription 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. 
 
6.2.3 
Dose reduction 
6.2.3.1 
Darolutamide 
If considered necessary for the participant’s safety, the dose of darolutamide may be reduced to 
300 mg bid.  
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. 
6.2.3.2 
Enzalutamide 
Dose reduction of enzalutamide can be done according to the enzalutamide prescription 
information. The medical monitor must be notified of any dose reduction. 
When an AE leading to dose reduction improves or is resolved, dose re-escalation may be 
considered at the discretion of the investigator. 
 
6.3 
Method of Treatment Assignment 
This study is planned for a lead-in phase followed by a randomized phase (conditions described 
above). The lead-in phase of the study is open-label and all participants will be treated with 
darolutamide. 
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. 
 
Study using 
IWRS 
All participants will be centrally assigned to randomized study treatment using an 
Interactive Web Response System (IWRS). Before the study is initiated, the telephone 
number and the log in information & directions for the IWRS will be provided to each 
site. 
Study treatment will be dispensed at the study visits summarized in the SoA 
(Section 1.5). 
 
 
 

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6.4 
Blinding 
 
Open label, No 
blinding at site level 
This is an open-label study; blinding is not applicable due to nature of the 
primary endpoint assessment (serum testosterone level) which won’t 
change due to potential bias. In the randomized phase, potential bias will 
also be reduced by central randomization 
Open label using 
This is an open-label study; however, the specific treatment to be taken by a 
central 
participant will be assigned using an IWRS. The site will contact the IWRS 
randomization via 
prior to the start of study treatment administration for each participant. The 
(IWRS) 
site will record the treatment assignment on the applicable case report form, 
if required. Potential bias will be reduced by central randomization. 
6.5 
Preparation/Handling/Storage/Accountability 
Darolutamide should be stored in the original container at 20°C to 25°C (68°F to 77°F); 
excursions permitted between 15°C and 30°C (59°F and 86°F), as indicated on the clinical 
supply label. 
Enzalutamide should be stored as indicated on the outer package and/ or the clinical supply 
label. 
1. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported 
and resolved before use of the study treatment. 
2. Only participants meeting the eligibility criteria may receive study treatment and only 
authorized site staff may supply or administer study treatment. All study treatment 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, or the head of the medical institution (where applicable) is responsible for 
study treatment accountability, reconciliation, and record maintenance (e.g., receipt, 
reconciliation, and final disposition records). 
4. Further guidance and information for the final disposition of unused study treatment are 
provided in the Study Reference Manual. 
5. Drug receipt, reconciliation and destruction information on the study sites will be captured 
in the IWRS. 
 
6.6 
Treatment Compliance 
Participant compliance with study intervention will be assessed at each visit. Compliance will 
be assessed by the designated study staff by direct questioning, counting returned tablets 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. 
Drug accountability will be performed on a patient basis. Drug returns, reconciliation and 
destruction information will be captured in the IWRS. 
 
6.7 
Concomitant Therapy 
Any concomitant medication or vaccine (including over the counter or prescription medicines, 
vitamins, and/or herbal supplements) or other specific categories of interest, that the participant 
is receiving at the time of enrollment or receives during the study must be recorded along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency. 
 

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The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
Other concomitant medication may be considered on a case-by-case basis by the investigator in 
consultation with the Medical Monitor if required. 
All concomitant treatments from the time of informed consent (IC) until the end–of–study 
treatment visit must be recorded on the CRFs. Once the participant has been withdrawn from 
the study treatment, follow–up treatments will be recorded if used to treat new study treatment-
related SAEs or unresolved related AEs or if being used as a systemic antineoplastic therapy 
for prostate cancer. Non-anticancer concomitant medication should be handled as 
recommended by the valid professional information for darolutamide unless otherwise specified 
in this protocol or the investigator brochure. 
For details of drug-drug interactions please refer to United States prescribing 
information (USPI) for both darolutamide and enzalutamide. 
6.7.1 
Prohibited concomitant therapy 
Concomitant treatment with another systemic anticancer therapy or another investigational 
medicinal product is prohibited throughout the study after enrollment. 
Initiation of the following medications during the study treatment period is prohibited: 
• 
Any investigational medicinal product 
• 
Radiopharmaceuticals 
• 
Immunotherapy and immune-oncology agents 
• 
Cytotoxic chemotherapy 
• 
Apalutamide, bicalutamide, flutamide, nilutamide 
• 
Abiraterone acetate, TAK–700, or other CYP17 inhibitors 
• 
LHRH antagonist, LHRH agonist 
• 
Hormonal treatment that is intended for cancer treatment such high dose 
testosterone. Substitutive hormone treatments are permitted. 
 
For details of drug-drug interactions please refer to USPI for both darolutamide and 
enzalutamide. 
 
6.7.2 
Permitted concomitant therapy 
In general, concomitant medications and therapies deemed necessary for the supportive care 
(e.g., such as anti-emetics, anti-diarrhea) and safety of the patient are allowed except those 
prohibited in Section 6.7.1. 
All medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that may affect the efficacy, toxicity or taken for any concurrent 
medical conditions at the time of enrollment or 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 
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Analgesic use will be captured in eCRF. Investigators or designees are to record which opioid 
and non-opioid medications were used since the last visit, and Investigators or designees are to 
record exact daily doses of each analgesic consumed. 
Participants should be evaluated by investigators for presence of osteoporosis according to 
local guidelines and be provided with bone treatment support per local standard of care. 
Participants receiving treatment with osteoclast-targeted therapy at a dose and schedule 
indicated for osteoporosis prior to study entry may continue treatment at the same dose and 
schedule. 
 
6.8 
Treatment After the End of the Study 
After completion of the last visit in Treatment period (evaluation at 52 weeks), all participants 
will be offered to continue with the treatment of darolutamide as long as they derived benefit, 
at the discretion of the investigator. All patients having been randomized to enzalutamide will 
be given the option to discontinue enzalutamide or offered to switch to treatment with 
darolutamide in this period.  
For safety assessments, please refer to Section 8.7. The Sponsor reserves the right to terminate 
access to study intervention, in particular if the study is terminated due to safety concerns. 
 
7. 
Discontinuation/Withdrawal Criteria 
All participants who enter the study should complete all applicable study periods. Participants 
can be withdrawn from any study period at any time. Discontinuation of study treatment alone 
does not constitute withdrawal from the study. 
Participants who discontinue the study treatment for any reason are to remain on the study for 
follow-up of primary, secondary and other objectives until week 52 (e.g., continue in the active 
follow-up periods, Table 1–5). Participants are expected to participate in active follow-up 
unless they explicitly object. Withdrawal of consent to the study treatment 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 Treatment 
In some instances, it may be necessary for a participant to permanently discontinue (definitive 
discontinuation) study treatment (i.e., disease progression, unacceptable toxicity, study 
intervention interruption > 28 days, need for dose reduction below 300 mg bid). If study 
treatment is definitively discontinued, the participant is expected to participate in the active 
follow-up unless he explicitly objects. See the SoA (Section 1.5) for data to be collected at the 
time of intervention discontinuation and active follow-up and for any further evaluations that 
need to be completed. If the participant does not agree to active follow-up until week 52, he 
undergoes the EOT visit (within 30 days after last dose of study intervention).  
If a clinically relevant finding is identified, including, but not limited to:  
• Changes from baseline in QT interval corrected using Fridericia’s formula (QTcF) after 
enrollment: the investigator or qualified designee will determine if the participant can 
continue in the study and if any change in participant management is needed. This 
review of the electrocardiogram (ECG) printed at the time of collection must be 
documented.  
• Drug-induced liver injury (DILI): Participants who experience hepatic transaminase 
elevations suggestive of idiosyncratic drug induced liver injury (DILI) considered to be 
causally related to study intervention, should discontinue study intervention. (See 
appendix number 10.3.5). 

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Any new clinically relevant finding should be reported as an AE. 
 
7.2 
Withdrawal from the Study 
A participant must be withdrawn from the study at any time at his 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 and can do so (a) without giving 
reasons and (b) without suffering any disadvantages as a result. 
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 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. 
See the SoA (Section 1.5) for data to be collected at the time of study discontinuation and 
follow-up and for any further evaluations that need to be completed. 
 
7.3 
Lost to Follow-up 
A participant will be considered lost to follow-up if he repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the participant and reschedule the missed visit* as soon 
as possible and counsel the participant on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the participant wishes to and/or should 
continue in the study. 
• Before a participant is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• Should the participant continue to be unreachable, he will be considered lost to follow- 
up with a primary reason of lost to follow-up. 
 
Discontinuation of specific sites or of the study as a whole are handled as part of the Appendices 
(Section 10.1.9). 
 
*Note: Rescheduled visits may be performed using the remote visit option (see Section 8). 
 
8. 
Study Assessments and Procedures 
Study procedures and their timing are summarized in the SoA (Section 1.5). 
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 treatment. 
Adherence to the study design requirements, including those specified in the SoA (Section 1.5), 
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 
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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 informed consent form (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 1.5). 
Note: If the study participant is not able to come to the investigational site for protocol specific 
visits, alternative methods for assessments (e.g., phone contact, virtual visit, alternative location 
for laboratory tests and imaging, provided that the imaging modality is consistent for a 
particular subject throughout the study) should be implemented when necessary and feasible as 
per local health authority and ethic committees. Darolutamide, typically distributed for self-
administration, is also amenable to alternative secure delivery methods from the site pharmacy. 
 
8.1 
Imaging Time-Points 
Radiological tumor assessments will be conducted only at screening to exclude presence of 
visceral metastases, and because these are not considered SOC, will only be done at other times 
based on treating physician discretion and/or based on PSA progression. Scans performed prior 
to the participant signing informed consent may be used for screening tumor assessments 
provided: 
• CT/MRI/ PSMA-PET bone scans were conducted within 42 days prior to day 1 (D1) 
• There has been no intervening therapy between the scans and D1 
 
8.2 
Serum Hormone Levels 
Peripheral blood for measurement of serum hormone levels, including testosterone, free 
testosterone, DHT, DHEA, SHBG, androstenedione, prolactin, estradiol, LH, FSH and 
gonadotropins, will be collected. Collection of peripheral blood for measurement of serum 
hormone should coincide with fasting lipid panel. Refer to SoA (Section 1.5) for timing of 
sample collection. 
 
8.3 
PSA Measurement 
For PSA response rate, serum PSA will be measured according to the study schedule (see SoA 
Section 1.5) using local laboratory’s ultrasensitive assay. It is preferable that each subject has 
serial laboratory measurements of PSA at the same laboratory while on study. 
 
 
 

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8.4 
Bone Health Assessment 
DEXA scans, CTX and BSAP will be completed according to the study schedule (see SoA 
Section 1.5). The mean percent change in bone mineral density as measured at the spine, hip 
(total hip and femoral neck), and forearm (radius and ulna) will be compared between treatment 
arms. 
 
8.5 
Fasting Lipid Panel 
The fasting lipid panel (total cholesterol, LDL, HDL, and triglycerides) will be measured 
according to the study schedules (see SoA Section 1.5). Subjects must be fasting for 9 to 12 
hours prior to collection of blood for accurate measure of fasting lipid panel. If the subject is 
not in a fasting state at a particular study time point, the lipid panel will not be collected on that 
date and omitted from these exploratory statistical analyses. 
 
8.6 
Markers of Insulin Resistance 
Fasting plasma glucose, fasting serum insulin, lean body mass, fat body mass and hemoglobin 
A1C will be measured according to the study schedules (See SoA Section 1.5). Subjects must 
be fasting for at least 8 hours prior to collection of blood for fasting glucose and insulin 
measurement. If the subject is not in a fasting state at the time point, the fasting glucose and 
insulin tests will be omitted from the analysis. 
 
8.7 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA in Section 1.5. 
Safety assessments in this study are AEs, as recorded by the investigator. 
Changes in study visit schedules, missed visits, or participant discontinuations may lead to 
missing information (e.g., for protocol-specified procedures). The specific information (e.g., 
explanation of the basis of the missing data) will be captured in the case report form and the 
information will be summarized in the clinical study report. In all cases, existing regulatory 
requirements for maintaining investigational product accountability remain and should be 
addressed and documented. 
Missing information will be recorded as protocol deviations and summarized in the Clinical 
Study Report. 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Section 10.3. 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study treatment or study procedures, or those 
that caused the participant to discontinue the study treatment (see Section 7). 
QoL will be assessed with the FACT-P questionnaire (Section 10.4) during the visit, prior to 
any procedures or examination by physician. 
 
8.7.1 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs will be collected from the signing of the ICF until the EOT visit or end of active follow 
up.  
Medical occurrences that begin before obtaining informed consent will be recorded on the 
medical history section of the case report form (CRF). Information on major diseases that have 
occurred in the study subject that might affect function of critical organs (e.g., renal failure, 
hepatic insufficiency, heart disease) should be collected at screening. Collection of additional 
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intervention/disease under study or deemed relevant by the investigator should also be included. 
Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the AE section of the case report form (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 within 24 hours if 
investigator awareness, as indicated in Appendix 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 in former study participants. 
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 considers the event to be reasonably related to the 
study treatment or study participation, the investigator must promptly notify the Sponsor. 
 
8.7.2 
Method of Detecting AEs and SAEs 
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. 
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). 
8.7.3 
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 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 provided in Appendix 3, 
(Section 10.3). 
8.7.4 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study treatment under clinical investigation are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting 
to the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics Committees 
(IEC), and investigators. 
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 a SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the Sponsor will review and then 
file it along with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate, 
according to local requirements. 
8.7.5 
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. 
8.7.6 
Pregnancy 
Sexually active male participants must agree to use condoms as an effective barrier method and 
refrain from sperm donation, and/or their female partners of reproductive potential to use a 
method of effective birth control, during the study treatment and for 1 week after the end of the 
treatment with darolutamide or enzalutamide. 
Pregnancies inadvertently fathered by study participants during the study should be reported 
and followed up by the investigator using the Bayer Pregnancy Monitoring Forms, if 
permissible by local legislation.  
Pregnancies will be collected from the date of IC signature until 30 days after the last dose of 
darolutamide is administered. 
If an adverse outcome of pregnancy is suspected to be related to study treatment exposure, this 
should be reported regardless of the length of time that has passed since the exposure to the 
study treatment. 
An induced or a spontaneous abortion is considered to be SAE and should be reported in the 
same timeframe and in the same manner as all other SAEs. 
For all reports, the forms provided are to be used. The report should be submitted within the 
same timelines as an SAE, although a pregnancy per se is not considered an SAE. 
The female partner will also be followed to determine the outcome of the pregnancy, delivery, 
postpartum recovery and the clinical condition of the offspring during the neonatal period. 
Information on the status of the mother and child will be forwarded to the Sponsor. Generally, 
the follow-up will be no longer than 6 to 8 weeks following the estimated delivery date. Any 
termination of the pregnancy will be reported regardless of fetal status (presence or absence of 
anomalies) or indication for the procedure. 
 
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. 
 
8.7.7 
Adverse Events of Special Interest 
There are no adverse events of special interest in this study. 
 
 
 

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8.7.8 
Management of Overdose 
8.7.8.1 
Darolutamide 
For this study, any dose of darolutamide greater than 600 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. 
There is no specific antidote for darolutamide, and symptoms of overdose are not established. 
No specific information is available on the treatment of overdose of darolutamide. In the event 
of overdose, the participant should be observed closely for signs of toxicity. Appropriate 
supportive treatment should be provided if clinically indicated. 
Clarification as to intentional or accidental overdose should be reported. 
For detailed guidance on overdosing, please refer to the most current version of the IB for 
darolutamide. 
8.7.8.2 
Enzalutamide 
For detailed guidance on overdosing please refer to the prescribing information for 
enzalutamide (enzalutamide prescribing information). 
8.7.9 
In the event of an overdose of study intervention 
In the event of an overdose, the investigator should: 
• Contact the Medical Monitor immediately. 
• Closely monitor the participant for any AE/SAE and laboratory abnormalities for at least 
3 days. 
• 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). 
• Document the quantity of the excess dose and duration of the overdose as well as the 
circumstances (e.g., intentional, accidental/administration error) in the CRF. 
• Any overdose or incorrect administration of study intervention should be noted on the 
Study intervention Administration Electronic Case Report Form (eCRF). 
• Adverse events associated with an overdose or incorrect administration of study 
intervention should be recorded on the Adverse Event 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. 
 
8.8 
Physical Examinations 
A complete routine physical examination will be conducted at baseline and at EOT visit. Weight 
will also be measured and recorded. 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
 
8.8.1 
Vital Signs 

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Vital signs will be measured and will include temperature, systolic and diastolic blood pressure, 
and pulse. Please refer to Section 1.5 Schedule of Activities (SoA), Sampling and Assessments. 
 
8.8.2 
Electrocardiograms 
Triplicate 12-lead ECG will be obtained as outlined in the SoA (see Section 1.5) using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc 
intervals. Refer to Section 7 for QTc withdrawal criteria and any additional QTc readings that 
may be necessary. 
At each time point at which triplicate ECG are required, 3 individual ECG tracings should be 
obtained as closely as possible in succession, but no more than 2 minutes apart. The full set of 
triplicates should be completed in less than 4 minutes. 
8.8.3 
Clinical Safety Laboratory Assessments 
See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and refer 
to the SoA (Section 1.5) for the timing and frequency. 
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 relevant abnormal 
laboratory values or test results must be identified through a review of values outside of normal 
ranges/clinical notable ranges, significant changes from baseline or the previous visit, or values 
which are considered to be non-typical in patient with underlying disease. 
All laboratory tests with values considered clinically relevant abnormal during participation in 
the study or within 30 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. All protocol-required laboratory assessments, as defined in 
Appendix 2, Section 10.2, must be conducted in accordance with the SoA (Section 1.5). 
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 relevant by the investigator (e.g., SAE or AE or dose modification), then the results 
must be recorded in the CRF. 
 
8.9 
Pharmacokinetics 
PK parameters are not evaluated in this study. 
 
8.10 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
 
8.11 
Genetics 
Genetics are not evaluated in this study. 
 
8.12 
Biomarkers 
Biomarkers are not evaluated in this study. 
 
9. 
Statistical Considerations 
9.1 
Statistical Hypotheses 
9.1.1 
Lead-in Phase 
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The findings from the lead-in phase of the study will be reviewed by the Sponsor to interpret 
the results from the lead-in phase and guide a decision on the conduct or not of the randomized 
phase as well as potential changes in the study design. The conduct of the randomized phase is 
contingent on conditions described in Section 4.1. 
 
9.1.2 
Randomized Phase 
The randomized phase will test the Null Hypothesis of no difference between the darolutamide 
arm and the enzalutamide arm on the primary endpoint of mean percent change in Testosterone 
from baseline to week 12, against the alternative hypothesis of a difference between arms at a 
two-sided 0.05 level. For mean percent changes of ΔD and ΔE in the darolutamide and 
enzalutamide arms these hypotheses can be expressed as 
H0: ΔD = ΔE vs. H1: ΔD ≠ ΔE 
 
9.2 
Sample Size Determination 
9.2.1 
Lead-in Phase 
Approximately 25 participants will be assigned to darolutamide to achieve at least 20 evaluable 
participants. This sample size will help estimate the mean percent change in serum testosterone 
level at 12 weeks with a 95% confidence interval having a half-width of no more than 25%, 
assuming a true mean percent increase of less than 45% and a standard deviation of 65%. This 
assessment uses a log normal distribution for percent change. 
9.2.2 
Randomized Phase 
Contingent on the results of the evaluation in Section 9.1, the randomized phase statistical 
assumptions may be revised, or the study could be terminated after lead-in. 
Should the study continue to the randomized phase unmodified, a maximum of 40 participants 
(20 per arm) will be randomly assigned to study treatment (darolutamide or enzalutamide) such 
that approximately 34 evaluable participants complete the study. The randomized stage will 
require a sample size of 20 per group to provide 85% power to test the null hypothesis of no-
difference between groups on mean percent change at two-sided 0.05 level. This assessment is 
based on a mean percent change in testosterone from baseline and standard deviation for the 
darolutamide arm of 45% and 65% versus 110% and 75% respectively for enzalutamide and 
assumes a log normal distribution for percent change. 
 
 
 

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9.3 
Populations for Analyses 
For purposes of analysis, the following populations are defined: 
 
Table 9–1: Populations for Analyses: Lead-in phase 
 
Population 
Description 
Screened 
All participants who sign the informed consent form 
Evaluable 
All enrolled subjects having testosterone data at baseline and week 12. 
Enrolled subjects include those who signed informed consent and met all 
inclusion and none of the exclusion criteria. 
Safety 
All enrolled participants who received any darolutamide post-enrollment 
regardless of their eligibility for the study. 
 
 
Table 9–2: Populations for Analyses: Randomized Phase 
 
Population 
Description 
Screened 
All participants who sign the informed consent form 
Evaluable 
All randomized subjects having testosterone data at baseline and Week 12 
who signed informed consent and met all inclusion and none of the exclusion 
criteria. 
Safety 
All randomized 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 
 
9.4 
Statistical Analyses 
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. 
All baseline variables will be reported using the appropriate statistics: categorical variables by 
frequency tables (frequencies and percentages) and continuous variables by sample statistics 
(i.e., mean, standard deviation, minimum, median, quartiles, and maximum). The number of 
patients screened will be summarized for both the lead-in and randomized cohorts. 
The primary analysis for the lead-in phase of the study will occur when the last participant has 
been on the treatment for at least 12 weeks, unless the participant discontinued due to lost to 
follow-up, withdrawal, or death. The primary analysis for the randomized phase will occur 
when all the patients in the randomized phase have been on the treatment for at least 12 weeks. 
Final analysis for both phases of the study will occur when the last participant on randomized 
phase has been on the treatment 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. 
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. 
 
9.4.1 
Primary endpoints 
The primary endpoint for both phases will be analyzed using a natural logarithm 
transformation consistent with sample size assessments in Section 9.2 given a distribution for 
the endpoint which is skewed right. Further, the percent change endpoint is a re-scaled fold 
change from baseline statistic for which such a transformation is often conducted. The mean 
fold change and percent change estimates are interpretable as geometric means given the 
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9.4.1.1 
Lead-in Phase 
The patient testosterone levels at baseline and week 12 in the evaluable population will be 
transformed to natural logarithm values. The mean and 95% confidence interval of the 
differences between week 12 and baseline values will be computed and back transformed by 
exponentiation to obtain the mean fold change MF with its 95% confidence interval [LF, UF]. 
The mean percent change Δ can be obtained as Δ = 100*(MF-1) with confidence interval [ 
100*(LF-1), 100*(UF-1)]. In addition to the estimated mean percent change and its confidence 
interval, summary statistics will include the mean fold change with confidence intervals, and 
the range, minimum, maximum and quartiles of percent change computed from the raw week 
12 and baseline testosterone values. 
9.4.1.2 
Randomized Phase 
The patient level differences between natural log transformed testosterone values at week 12 
and baseline will be computed. These differences will be compared across the darolutamide 
and enzalutamide arms using a two-sample t-test. Two-sided p-values from this t-test will be 
reported to assess whether the null hypothesis can be rejected in favor of the alternate 
hypothesis in Section 9.1. Additionally, the estimated difference between darolutamide and 
enzalutamide and the 95% confidence limits from the t-test will be back transformed by 
exponentiation to obtain the ratio of the fold change in testosterone values from baseline for 
darolutamide, to that for enzalutamide and the confidence limits for this estimate. Within 
treatment group mean percent change and confidence intervals as well as other summary 
statistics described for the lead-in phase will also be reported. 
9.4.2 
Secondary Endpoints 
All secondary endpoints will be analyzed in the evaluable population with the exception of 
the AEs, which will be analyzed in the safety population. 
9.4.2.1 
Lead-in Phase 
For testosterone at the visits at week 24 and 52, the differences between the log transformed 
data at the visit and that at baseline will be estimated with 95% confidence intervals using SAS 
PROC MIXED with the ESTIMATE statement and a Toeplitz covariance structure. 
These are to be transformed to mean percent change and 95% confidence intervals using the 
same steps as for the primary analysis in the lead-in phase. Results will be summarized in a 
similar manner to the primary endpoint for testosterone at week 24 and 52. PSA response 
rates will be summarized at week 4, 12, 24, 36 and 52 using frequencies and percentages. 
Response levels to be summarized will be 30%, 50% and 90% decreases.  
Feminizing side effects of gynecomastia, breast tenderness/pain, nipple pain, and hot flush 
will be summarized using frequencies and percentages. 
9.4.2.2 
Randomized Phase 
For testosterone at the visits at week 24 and 52, and for each of the sex hormones, and for each 
of the components of fat and glucose metabolism at weeks 4, 12, 24 and 52, the differences 
between the log transformed data at the visit and that at baseline will be compared across 
treatment groups with 95% Confidence Intervals using SAS PROC MIXED with the SLICE 
option and a Toeplitz covariance structure. These are to be transformed to the ratio of the fold 
change from baseline for darolutamide to that for enzalutamide and 95% confidence intervals 
using the same steps as for the primary analysis in the randomized phase. Results will be 
analyzed in a similar manner to the primary endpoint for testosterone at week 24 and 52 and for 
the other sex hormones and the metabolic endpoints. These analyses will be summarized 
graphically using the mean percent change over time with 95% confidence intervals at each 
visit by treatment group, flagging visits where differences are significant at the nominal 0.05 
and 0.01 levels. 

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PSA response rates will be compared descriptively across treatments at week 4, 12, 24, 36 and 
52 using frequencies and percentages. Response levels to be summarized will be 30%, 50% and 
90% decreases. 
Differences in the FACT-P prostate cancer subscale will be summarized at each visit using 
PROC Mixed with the SLICE option and the mean subscale score will be depicted graphically 
over time with 95% confidence intervals at each visit by treatment group, flagging visits where 
differences are significant at the nominal 0.05 and 0.01 levels. 
 
Feminizing side effects of gynecomastia, breast tenderness/pain, nipple pain, and hot flush 
will be summarized using frequencies and percentages by treatment group. 
9.4.3 
Other Pre-Specified Endpoints 
Details on the analyses of exploratory endpoints, including markers of bone turnover and 
physical function, will be described in the statistical analysis plan. 
9.4.4 
Safety Analyses 
All safety analyses will be descriptive and will be performed on the safety population. Safety 
data will be summarized descriptively for the lead-in phase and by treatment group for the 
randomized phase. 
All AEs will be coded using the latest version prior to data base lock of the Medical 
Dictionary for Regulatory Activities (MedDRA). 
Further details on safety analyses will be described in the SAP. 
NOTE: AEs and safety lab parameters will be presented with their worst NCI-CTCAE grade. 
 
9.5 
Interim Analyses 
No interim analysis is planned. 
 
9.6 
Data Monitoring Committee (DMC) 
No data monitoring committee, dose escalation committee, or similar review group will be used for 
this study.  
10. 
Appendices 
10.1 
Appendix 1: Study Governance 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 approval by IRB/IEC as well as by regulatory 
authorities (as applicable) 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: 

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• 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. 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
• Providing oversight of the conduct of the study at the site and adherence to requirements 
of ICH guidelines, the IRB/IEC, and all other applicable local regulations. 
10.1.2 
Financial Disclosure 
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and 
for 1 year after completion of the study. 
10.1.3 
Informed Consent Process 
• The investigator or his representative will explain the nature of the study to the 
participant or his legally authorized representative* (if acceptable by local law) and 
answer all questions regarding the study. 
• Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative* 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) in a timely 
manner if new information becomes available that may be relevant to the participant’s 
willingness to continue participation in the trial. 
• A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative*. 
*Participants who are rescreened are required to sign a new ICF. 
10.1.4 
Data Protection 
• Participants will be assigned a unique identifier by the Sponsor. Any participant records 
or datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred. 
• The participant must be informed that his 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 
Publication Policy 
• The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission. This allows the Sponsor to protect proprietary information and to 
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• The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual site 
data. In this case, a coordinating investigator will be designated by mutual agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
10.1.6 
Dissemination of Clinical Study Data 
Result summaries of Bayer's sponsored clinical trials in drug development Phases 2, 3 and 4 
and Phase 1 studies in patients are provided in the Bayer Trial Finder application after marketing 
authorization approval, in line with the position of the global pharmaceutical industry 
associations laid down in the "Joint Position on the Disclosure of Clinical Trial Information via 
Clinical Trial Registries and Databases". In addition, results of clinical drug trials will be 
provided on the publicly funded websites www.ClinicalTrials.gov (US National Library of 
Medicine) and www.clinicaltrialsregister.eu (the European clinical trials information system, 
CTIS) in line with the applicable regulations. 
Bayer commits to sharing upon request from qualified scientific and medical researchers 
patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials 
in participants for medicines and indications approved in the United States (US) and European 
Union (EU) on or after 01 JAN 2014 as necessary for conducting legitimate research. 
All Bayer-sponsored clinical trials are considered for publication in the scientific literature 
irrespective of whether the results of the clinical trials are positive or negative. 
10.1.7 
Data Quality Assurance 
• All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the Sponsor or designee electronically (e.g., laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
• The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
• The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• Study monitors may 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. They will review source data to ensure that the safety and rights 
of participants are being protected 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 good clinical practice (GCP), 
and all applicable regulatory requirements. 
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator after study completion for the retention period as 
set forth in the Investigator Agreement unless local regulations or institutional policies 
require a longer retention period. No records may be destroyed during the retention 
period without the written approval of the Sponsor. No records may be transferred to 
another location or party without written notification to the Sponsor. 
 
10.1.8 
Source Documents 
• Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site. 

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• Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
• Definition of what constitutes source data can be found in the Source Data Location 
List. 
 
10.1.9 
Study and Site Closure 
The Sponsor reserves the right to close the study site or terminate the study or individual 
sections of this study (e.g., treatment arms, dose cohorts, centers) at any time for any reason at 
the sole discretion of the Sponsor. Study sites will be closed upon study completion. A study 
site is considered closed when all required documents and study supplies have been collected 
and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or investigator may include but are 
not limited to: 
• Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor's procedures, or GCP guidelines; 
• Inadequate recruitment of participants by the investigator; 
• Discontinuation of further study treatment development; 
• If the study is prematurely terminated or suspended, the Sponsor shall promptly inform 
the Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified 
by the applicable regulatory requirements. The Investigator shall promptly inform the 
participant and should assure appropriate therapy and/or follow-up. 
• If the risk-benefit ratio becomes unacceptable owing to, for example: 
o Safety findings from this study (e.g., SAEs); 
o Results of parallel clinical Bayer studies or emerging data from literature; 
o 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 period. 
• 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); regulatory authority(ies); study center; 
head of study center) must be informed as applicable according to local law. 
• All study materials (except documentation that must remain stored at site) must be 
returned to the Sponsor. The investigator will retain all other documents until 

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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. 
Details for individual participant's withdrawal can be found in Section 7. 
 
10.2 
Appendix 2: Clinical Laboratory Tests 
• The tests detailed in Table 1–1 will be performed by the local laboratory. 
• Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5.1 and Section 5.2 of the protocol. 
• Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations. 
 
 

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Table 10–1: Protocol-Required Safety Laboratory Assessments 
 
Laboratory 
Assessments 
Parameters 
Hematology 
Hemoglobin 
Hematocrit 
RBC count 
WBC Count with Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Platelet Count 
Clinical 
chemistry1 
BUN or Urea 
Potassium 
Aspartate 
Aminotransferase (AST) / 
Serum Glutamic- 
Oxaloacetic Transaminase 
(SGOT) 
Creatinine 
Sodium 
Alanine Aminotransferase 
(ALT)/ Serum Glutamic- 
Pyruvic Transaminase 
(SGPT) 
Alkaline Phosphatase 
(ALP) 
Glucose (non-fasting)2 
Calcium (Total Calcium) 
Total protein 
Total and direct bilirubin 
Albumin 
Other 
screening tests 
Testosterone 
PSA 
NOTES: 
1 Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or monitoring 
event are given in Section 7.1 and Section 6. All events of ALT ≥3 × upper limit of normal (ULN) and bilirubin ≥2 × ULN (>35% 
direct bilirubin) or ALT ≥3 × ULN and international normalized ratio (INR) >1.5, if INR measured, may indicate severe liver injury 
(possible Hy’s Law) and must be reported as an SAE (excluding studies of hepatic impairment or cirrhosis). 
2 In case of fasting glucose is required, Daro should be taken after blood drawn with food as recommended. 
Abbreviations: BUN blood urea nitrogen, PSA prostate specific antigen, RBC red blood cells, WBC white blood cells. 
Investigators must document their review of each laboratory safety report. 

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10.3 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
10.3.1 
Definition of AE 
AE Definition 
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study treatment, whether or not considered related to 
the study treatment. 
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 treatment. 
 
 
Events Meeting the AE Definition 
1. Any abnormal laboratory test results or other safety assessments (e.g., ECG, 
radiological scans, vital signs measurements), including those that worsen from 
baseline, considered clinically relevant in the medical and scientific judgment of the 
investigator. 
2. Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
3. New conditions detected or diagnosed after signature of the ICF even though it may 
have been present before the start of the study. 
4. Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
5. Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment 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. 
6. For efficacy studies, include: 
7. “Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfil the definition of an AE 
or SAE. 
8. For non-efficacy studies involving marketed products in established indications, 
include: 
9. The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfil the definition of an AE or SAE. Also, “lack of 
efficacy” or “failure of expected pharmacological action” also constitutes an AE or 
SAE. 

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Events NOT Meeting the AE Definition 
1. Any laboratory findings outside of the normal range 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. 
2. 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. 
3. Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
4. Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
5. Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
10.3.2 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease). 
 
An SAE is defined as any untoward medical occurrence that, at any dose: 
Results in death 
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. 
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. 
Results in persistent disability/incapacity 
1. The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions. 
2. 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. 

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Is a congenital anomaly/birth defect 
Other situations: 
1. 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. 
2. Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
10.3.3 
Recording and Follow-up of AE and/or SAE 
AE and SAE Recording 
1. 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. 
2. The investigator will then record all relevant AE/SAE information in the CRF. 
3. 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. 
4. 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 CRO/Sponsor. 
5. 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 
1. The intensity of AEs should be documented using the National Cancer Institute’s 
Common Terminology Criteria for Adverse Events (NCI-CTCAE, v.5.0). 
2. The intensity of AEs is classified according to the following categories for events not 
listed in the CTCAE v.5.0: 
3. Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
4. Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL (ADL: Activities of Daily Living; instrumental ADL 
refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc.). 
5. Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL (Self-care ADL refer to bathing, dressing and undressing, feeding self, using 
the toilet, taking medications, and not bedridden). 
6. Grade 4: Life-threatening consequences; urgent intervention indicated. 

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Assessment of Causality 
1. The investigator is obligated to assess the relationship between study treatment and 
each occurrence of each AE/SAE. 
2. 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. 
3. The investigator will use clinical judgment to determine the relationship. 
4. Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated. 
5. The investigator will also consult the Investigator’s Brochure (IB) and/or 
Product Information, for marketed products, in his assessment. 
6. For each AE/SAE, the investigator must document in the medical notes that he 
has reviewed the AE/SAE and has provided an assessment of causality. 
7. 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 especially important that the investigator always assesses causality for every 
event before the initial transmission of the SAE data to the Sponsor. 
8. The investigator may change his opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality assessment. 
9. The causality assessment is one of the criteria used when determining 
regulatory reporting requirements. 
 
Follow-up of AEs and SAEs 
1. 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. 
2. 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. 
3. New or updated information will be recorded in the originally completed CRF. 
4. The investigator will submit any updated SAE data to the Sponsor within 24 hours 
of receipt of the information. 

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10.3.4 
Reporting of SAEs 
SAE Reporting to the Sponsor via an Electronic Data Collection Tool 
1. The primary mechanism for reporting a SAE to the Sponsor will be the electronic data 
collection tool. 
2. If the electronic system is unavailable for more than 24 hours, then the site will use the 
paper SAE data collection tool (see below). 
3. The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
4. 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. 
5. If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see next 
section) or to the Sponsor by telephone. 
6. Contacts for SAE reporting can be found in Investigator site file. 
 
SAE Reporting to the Sponsor via Paper CRF 
1. Paper reports via confidential email (pdf) or facsimile transmission of the SAE paper 
CRF is the preferred method to transmit this information to the Sponsor. 
2. In rare circumstances if none of the above is available, notification by telephone is 
acceptable with a copy of the SAE data collection tool sent by overnight mail or courier 
service. 
3. Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames. 
4. Contacts for SAE reporting can be found in Investigator site file. 
10.3.5 
Identify a potential drug induced liver injury (DILI) 
This appendix describes the recommended work up to be followed in order to identify a potential 
drug induced liver injury (DILI). It is not intended to be a comprehensive guide for the management 
of elevated liver function tests. During the study the investigator should remain vigilant for increases 
in liver function tests. The investigator is responsible for determination of the liver function test 
alterations nature at any point during the study. In case Investigator suspects DILI, the Sponsor 
Medical Representative has to be informed as soon as possible. 
 
DILI is a diagnosis of exclusion. In case of liver enzyme alterations, please consider the following 
comprehensive work-up and report results in the eCRF (under “unscheduled visits/unscheduled labs” 
page): 
 
• Please obtain, and report in the eCRF, a detailed, “liver-focused” medical history including liver 
metastasis/ liver cancer, alcohol-related liver disease, non-alcoholic steatohepatitis, liver cirrhosis, 
viral 
hepatitis, 
ischemic/congestive 
hepatic 
injury, 
vaccination, 
biliary 
obstruction, 
hemochromatosis, pancreatitis, recent systemic infection/sepsis, COVID-19 Infection, autoimmune 
disease, alcohol abuse or drug abuse and any other clinically relevant information. 
 
 

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• Please investigate and report in the eCRF a complete list of concomitant medications, prior 
chemotherapy or hormonal therapy, antineoplastic drugs, herbal substances, nutritional supplements, 
complementary and alternative medicines, or exposure to any hepatotoxic agents.  
 
• Imaging 
 Abdominal imaging (e.g., Ultrasound, CT, and MRI) 
 
• Serological tests 
 Hepatitis A testing: lgM Anti-HAV 
 Hepatitis B testing: anti-HBc lgG, lgM, HBsAg, HBV DNA 
 Hepatitis C testing: anti HCV, HCV RNA (PCR) 
 Hepatitis E testing: anti-HEV (lgG, lgM); HEV RNA 
 Alcoholic hepatitis: carbohydrate-deficient transferrin 
 Anti‐Cytomegalovirus (CMV) IgM Antibodies 
 Anti‐Epstein Barr Virus (EBV) IgM Antibodies 
 Herpes Simplex IgG, IgM 
 Autoantibody and immunoglobulin testing: ANA, ASMA, ANCA, p-ANCA, AMA 
 Quantitative Ig G, IgM and IgA (optional) 
 Metabolic disease: Alpha-1-antitripsin, ceruloplasmin, iron, ferritin, GGT, LDH, PT, INR, 
transferrin, transferrin saturation 
 
• Other tests 
 PT-INR 
 Serum albumin 
 CK Values 
 Amylase, lipase 
 

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10.4 
Appendix 4: Questionnaires 
10.4.1 
FACT-P (Version 4) 
 

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10.4.2 
PROMIS Fatigue 
 
 
 

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10.4.3 
PROMIS Physical 
 
 
 

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10.4.4 
Godin-4 questions 
 
 
 

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10.4.5 
Self Efficacy 9 questions 
 
(Resnick et al. 2000) 
 
 
 
 

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10.5 
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information 
10.5.1 
Definitions 
10.5.1.1 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below). 
Women in the following categories are not considered WOCBP: 
• 
Premenarchal. 
10.5.1.2 
Premenopausal female with 1 of the following: 
• 
Documented hysterectomy. 
• 
Documented bilateral salpingectomy. 
• 
Documented bilateral oophorectomy. 
Note: Documentation can come from the site personnel’s: review of the participant’s medical 
records, medical examination, or medical history interview. 
• 
Postmenopausal female. A postmenopausal state is defined as no menses for 12 months 
without an alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in women not 
using hormonal contraception or hormonal replacement therapy (HRT). However, in the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient. 
Females on HRT and whose menopausal status is in doubt will be required to use one of the 
non-estrogen hormonal highly effective contraception methods if they wish to continue their 
HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment. 
10.5.1.3 
Fertile Man 
A man is considered fertile after puberty, unless permanently sterile by bilateral 
orchidectomy. 
10.5.2 
Contraception Guidance 
The investigator or a designated associate is requested to advise the patient how to achieve 
highly effective birth control. 
10.5.2.1 
Male participants 
Male participants with female partners of childbearing potential are eligible to participate if 
they agree to the following (as applicable) during the protocol-defined time frame in 
Section 5.1: 
• Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent. 
• Agree to use a male condom plus partner use of a contraceptive method with a failure 
rate of <1% per year as described in Table 10–2 when having penile-vaginal intercourse 
with a WOCBP who is not currently pregnant. 

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• 
Men with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom during each episode of penile 
penetration during the protocol-defined time frame in Section 5.1; 
• 
Refrain from donating sperm for the duration of the study and during the protocol- 
defined time frame in Section 5.1. 
 
Table 10–2: Highly Effective Contraceptive Methods 
 
Highly Effective Contraceptive Methods That Are User Dependent a 
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulationb 
Oral 
Intravagi
nal 
Transder
mal 
Progestogen only hormonal contraception associated with inhibition of 
ovulation: Oral 
Injectable 
Highly Effective Methods of Low User Dependencya 
Implantable progestogen only hormonal contraception associated with inhibition of ovulation:b 
Intrauterine device (IUD) 
Intrauterine hormone-releasing system 
(IUS) Bilateral tubal occlusion 
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner is the 
sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an 
additional highly effective method of contraception should be used. 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant. 
NOTES: 
a) Typical use failure rates may differ from those when used consistently and correctly. Use should 
be consistent with local regulations regarding the use of contraceptive methods for participants 
participating in clinical studies. 
b) Hormonal contraception may be susceptible to interaction with the study treatment, which may 
reduce the efficacy of the contraceptive method. As a general rule, use of hormonal contraception is 
not recommended if a clinically relevant interaction with contraceptive steroids has been observed 
or is suspected. If an interaction with contraceptive steroids has been observed or is suspected, but 
the effect is considered to be of limited clinical significance, the hormonal contraception method must 
be supplemented with a barrier method (preferably male condom). 

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10.6 
Appendix 6: Abbreviations 
 
A1C (hemoglobin) 
Glycated (hemoglobin) 
ADT 
Androgen deprivation therapy 
AE 
Adverse events 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AR 
Androgen receptor 
ART 
Adjuvant radiotherapy 
ARI 
Androgen receptor inhibitor 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate aminotransferase 
BBB 
Blood-brain-barrier 
BCR 
Biochemical recurrence 
BCRP 
Breast cancer resistance protein 
Bid (b.i.d) 
twice (two times) a day (bis in die) 
BMD 
Bone mineral density 
BMI 
Body mass index 
CAB 
Combined androgen blockade 
CI 
Confidence interval 
CNS 
Central nervous system 
CONSORT 
Consolidated standards of reporting trials 
eCRF 
Electronic case report form 
CRPC 
Castrate-resistant prostate cancer 
nmCRPC 
Non-metastatic castration resistant prostate cancer 
CT 
Computerized tomography 
CTC 
Circulating tumor cell 
CTCAE 
Common terminology criteria for adverse events 
CYP17i 
Cytochrome P450 17 inhibitor 
DEXA 
Dual energy x-ray absorptiometry 
DHT 
Dihydrotestosterone 
DILI 
Drug induced liver injury 
IEC 
Independent ethics committee 
ECG 
Electrocardiogram 
ECOG (PS) 
Eastern cooperative oncology group (performance score) 
EMA 
European medicine agency 
EORTC 
European Organization for Research and Treatment of Cancer 
EOT 
End of treatment 
FACT-P 
Functional assessment of cancer therapy – prostate 
FDA 
Food and drug administration 
FFPE 
Formalin-fixed paraffin-embedded 
FSH 
Follicle-stimulating hormone 
HDL 
High-density lipoprotein 
HIV 
Human immunodeficiency virus 
HR 
Hazard ratio 
HRQoL 
Health related quality of life 
mHSPC 
Metastatic hormone sensitive prostate cancer 
IADT 
Intermittent androgen deprivation therapy 
IC 
Informed consent 
ICF 
Informed consent form 

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ICH 
International council for harmonization of technical requirements for 
pharmaceuticals for human use 
ID 
Identification 
INR 
International normalized ratio 
IRB 
Institutional review boards 
ITT 
Intent-to-treat 
IWRS 
Interactive web response system 
LDL 
Low-density lipoprotein 
LH 
Luteinizing hormone 
LHRH 
Luteinizing hormone-releasing hormone 
LHRHa 
LHRH agonist 
LPLV 
Last patient last visit 
MedDRA 
Medical dictionary for regulatory activities 
MFS 
Metastatic free survival 
MRI 
Magnetic resonance imaging 
MSKCC 
Memorial Sloan Kettering cancer center 
NCI 
National cancer institute 
NCIC 
National Cancer Institute of Canada 
NSAA 
Non-steroidal anti androgen 
OATP1B1/OATP1B3 
Organic anion-transporting polypeptide 1B1/1B3 
OS 
Overall survival 
PAB 
Peripheral androgen blockade 
PC 
Prostate cancer 
PCWG3 
Prostate cancer working group 3 
PET 
Positron emission tomography 
PSA 
Prostate-specific antigen 
PSADT 
PSA doubling time 
PSMA 
Prostate-specific membrane antigen 
PT/PPT 
Prothrombin time / partial thromboplastin time 
q.d. 
Once a day (quaque die) 
QoL 
Quality of life 
RECIST 
Response evaluation criteria in solid tumours 
RP 
Radical prostatectomy 
RT 
Radiation therapy (primary radiotherapy) 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SoA 
Schedule of activities 
SOC 
Standard of care 
SRT 
Salvage radiotherapy 
SUSAR 
Suspected unexpected serious adverse reactions 
TEAE 
Treatment emergent adverse event 
ULN 
Upper limit of normal 
USPI 
United States prescribing information 

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