Darolutamide in Addition to Standard Androgen Deprivation Therapy and Docetaxel in Metastatic Hormone-Sensitive Prostate Cancer (ARASENS)

• ClinicalTrials.gov Identifier: NCT02799602
• Recruitment Status: Completed
• First Posted: June 15, 2016
• Results First Posted: February 24, 2023
• Last Update Posted: April 16, 2024
• Sponsor: Bayer
• Collaborator: Orion Corporation, Orion Pharma
• Information provided by (Responsible Party): Bayer

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Metastatic Hormone-sensitive Prostate Cancer
• Interventions: Drug: BAY1841788 / darolutamide (ODM-201); Drug: Standard ADT (androgen deprivation therapy); Drug: Docetaxel; Drug: Placebo
• Enrollment: 1306

Participant Flow

Recruitment Details	This multinational study was conducted between 30-Nov-2016 First Participant First Visit and 11-Apr-2023 Last Participant Last Visit, in 23 countries/regions: Australia, Belgium, Brazil, Bulgaria, Canada, China, Czech Republic, Finland, France, Germany, Israel, Italy, Japan, Mexico, Netherlands, Poland, Russian Federation, South Korea, Spain, Sweden, Taiwan, UK, US
Pre-assignment Details	1306 were randomly assigned in a 1:1 ratio to study treatment and 1305 were considered valid for efficacy analyses. A total of 1302 participants started treatment and were included to safety analyses.

Arm/Group Title	Darolutamide (BAY1841788) + Docetaxel	Placebo + Docetaxel
Arm/Group Description	Participants received darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equivalent to a total daily dose of 1200 mg in addition to their standard treatment with docetaxel and androgen deprivation therapy (ADT). Docetaxel was administered for six cycles after randomization. The first cycle of docetaxel was administered within 6 weeks after start of study drug. ADT administration started ≤12 weeks before randomization.	Participants received matching placebo to darolutamide in addition to their standard treatment with docetaxel and androgen deprivation therapy (ADT). Docetaxel was administered for six cycles after randomization. The first cycle of docetaxel was administered within 6 weeks after start of study drug. ADT administration started ≤12 weeks before randomization.
Period Title: Overall Study
Started [1]	651	654
Started Treatment	651	651
Completed [2]	0	0
Not Completed	651	654
Reason Not Completed
Protocol Violation	1	0
Physician Decision	5	6
Lost to Follow-up	4	2
Additional primary malignancy	11	6
Non-compliance with study drug	14	12
Adverse event associated with clinical disease progression	24	26
Withdrawal by Subject	26	40
Progressive disease - clinical progression	131	276
Progressive disease - radiological progression	90	133
Adverse event not associated with clinical disease progression	49	27
Death	9	5
Other	287	118
Study drug never administered	0	3
[1] Randomized: 1306 patients were randomized. One patient was excluded from analysis due to a GCP violation; [2] Ongoing with treatment

Baseline Characteristics

Arm/Group Title		Darolutamide (BAY1841788) + Docetaxel	Placebo + Docetaxel	Total
Arm/Group Description		Participants received darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equivalent to a total daily dose of 1200 mg in addition to their standard treatment with docetaxel and androgen deprivation therapy (ADT). Docetaxel was administered for six cycles after randomization. The first cycle of docetaxel was administered within 6 weeks after start of study drug. ADT administration started ≤12 weeks before randomization.	Participants received matching placebo to darolutamide in addition to their standard treatment with docetaxel and androgen deprivation therapy (ADT). Docetaxel was administered for six cycles after randomization. The first cycle of docetaxel was administered within 6 weeks after start of study drug. ADT administration started ≤12 weeks before randomization.	Total of all reporting groups
Overall Number of Baseline Participants		651	654	1305
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	651 participants	654 participants	1305 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	243 37.3%	234 35.8%	477 36.6%
	>=65 years	408 62.7%	420 64.2%	828 63.4%
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	651 participants	654 participants	1305 participants
	Female	0 0.0%	0 0.0%	0 0.0%
	Male	651 100.0%	654 100.0%	1305 100.0%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	651 participants	654 participants	1305 participants
	Hispanic or Latino	40 6.1%	49 7.5%	89 6.8%
	Not Hispanic or Latino	561 86.2%	557 85.2%	1118 85.7%
	Unknown or Not Reported	50 7.7%	48 7.3%	98 7.5%
Race (NIH/OMB) [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	651 participants	654 participants	1305 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%
	Asian	231 35.5%	245 37.5%	476 36.5%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	26 4.0%	28 4.3%	54 4.1%
	White	345 53.0%	333 50.9%	678 52.0%
	More than one race	6 0.9%	2 0.3%	8 0.6%
	Unknown or Not Reported	43 6.6%	46 7.0%	89 6.8%
		[1] Measure Description: More than one race includes: "American Indian or Alaska Native", "Native Hawaiian or other Pacific Islander", and "Multiple"

Outcome Measures

1. Primary Outcome

Title	OS From Date of Randomization Until Death From Any Cause - Number of Events
Description	Overall survival (OS) was defined as the time from the date of randomization until death from any cause. Treatment period: treatment was provided for all patients, twice daily, until disease progression (symptomatic progressive disease, change of systemic antineoplastic therapy), unacceptable toxicity, consent withdrawal, withdrawal at the discretion of the investigator, death, or non-compliance. Active follow-up visits from the discontinuation of the darolutamide or placebo treatment period for up to 1 year or until the patient could no longer travel to the clinic, died, was lost to follow-up, or withdrew informed consent and actively objected to collection of further data. Long-term (Survival) follow-up period: After Active follow-up, patients continued to be contacted approximately every 12 weeks by phone. The end of the Survival follow-up period was defined as when the patient died, was lost to follow-up, withdrew consent, or at the end-of-study.
Time Frame	From randomization of the first participant until death from any cause up to 25 OCT 2021 cut-off date 533 OS events were reached (approximate 59 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Darolutamide (BAY1841788) + Docetaxel	Placebo + Docetaxel
Arm/Group Description:	Participants received darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equivalent to a total daily dose of 1200 mg in addition to their standard treatment with docetaxel and androgen deprivation therapy (ADT). Docetaxel was administered for six cycles after randomization. The first cycle of docetaxel was administered within 6 weeks after start of study drug. ADT administration started ≤12 weeks before randomization.	Participants received matching placebo to darolutamide in addition to their standard treatment with docetaxel and androgen deprivation therapy (ADT). Docetaxel was administered for six cycles after randomization. The first cycle of docetaxel was administered within 6 weeks after start of study drug. ADT administration started ≤12 weeks before randomization.
Overall Number of Participants Analyzed	651	654
Measure Type: Count of Participants; Unit of Measure: Participants
Number of patients with event	229 35.2%	304 46.5%
Number of patients censored	422 64.8%	350 53.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Darolutamide (BAY1841788) + Docetaxel, Placebo + Docetaxel
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	Hazard ratio < 1 indicates superiority of Darolutamide+docetaxel arm over Placebo+docetaxel arm. Hazard ratio and 95% CI was based on Cox Regression Model, stratified by EOD (Non-regional lymph nodes metastases only vs. Bone metastases with or without lymph node metastases vs. Visceral metastases with or without lymph node metastases or with or without bone metastases) and ALP (<ULN vs. >=ULN).
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	One-sided p-value.
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.675
	Confidence Interval	(2-Sided) 95%; 0.568 to 0.801
	Estimation Comments	[Not Specified]
Other Statistical Analysis		One-sided p-value from log-rank test, stratified by EOD (Non-regional lymph nodes metastases only vs. Bone metastases with or without lymph node metastases vs. Visceral metastases with or without lymph node metastases or with or without bone metastases) and ALP (<ULN vs. >=ULN).

2. Primary Outcome

Title	OS From Date of Randomization Until Death From Any Cause - Month
Description	Treatment period: treatment was provided for all patients, twice daily, until disease progression (symptomatic progressive disease, change of systemic antineoplastic therapy), unacceptable toxicity, consent withdrawal, withdrawal at the discretion of the investigator, death, or non-compliance. Active follow-up visits from the discontinuation of the darolutamide or placebo treatment period for up to 1 year or until the patient could no longer travel to the clinic, died, was lost to follow-up, or withdrew informed consent and actively objected to collection of further data. Long-term (Survival) follow-up period: After Active follow-up, patients continued to be contacted approximately every 12 weeks by phone. The end of the Survival follow-up period was defined as when the patient died, was lost to follow-up, withdrew consent, or at the end-of-study. Median, percentile and other 95% CIs were computed using Kaplan-Meier estimates. NA = Value cannot be estimated due to censored data
Time Frame	From randomization of the first participant until death from any cause up to 25 OCT 2021 cut-off date 533 OS events were reached (approximate 59 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Darolutamide (BAY1841788) + Docetaxel	Placebo + Docetaxel
Arm/Group Description:	Participants received darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equivalent to a total daily dose of 1200 mg in addition to their standard treatment with docetaxel and androgen deprivation therapy (ADT). Docetaxel was administered for six cycles after randomization. The first cycle of docetaxel was administered within 6 weeks after start of study drug. ADT administration started ≤12 weeks before randomization.	Participants received matching placebo to darolutamide in addition to their standard treatment with docetaxel and androgen deprivation therapy (ADT). Docetaxel was administered for six cycles after randomization. The first cycle of docetaxel was administered within 6 weeks after start of study drug. ADT administration started ≤12 weeks before randomization.
Overall Number of Participants Analyzed	651	654
Median (95% Confidence Interval); Unit of Measure: Month
	NA [1]; (NA to NA)	48.9 [1]; (44.4 to NA)

[1]

NA = Value cannot be estimated due to censored data

3. Secondary Outcome

Title	Number of Participants With TEAEs
Description	TEAEs = Treatment-emergent adverse events, were defined as any event(s) arising or worsening after the first dose of darolutamide or placebo, until 30 days after the last dose of darolutamide or placebo administration.
Time Frame	From the first dose of darolutamide or placebo until 30 days after the last dose of darolutamide or placebo administration up to cut-off date for the final completion analysis 11 APR 2023 (approximately 77 months)

Outcome Measure Data

Analysis Population Description

The number of patients who started treatment is presented based on the randomized treatment assignment. One patient was randomized to the placebo+docetaxel arm but received at least one dose of darolutamide. This patient was included in the darolutamide+docetaxel arm in the analysis of all safety variables.

Arm/Group Title	Darolutamide (BAY1841788) + Docetaxel	Placebo + Docetaxel
Arm/Group Description:	Participants received darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equivalent to a total daily dose of 1200 mg in addition to their standard treatment with docetaxel and androgen deprivation therapy (ADT). Docetaxel was administered for six cycles after randomization. The first cycle of docetaxel was administered within 6 weeks after start of study drug. ADT administration started ≤12 weeks before randomization.	Participants received matching placebo to darolutamide in addition to their standard treatment with docetaxel and androgen deprivation therapy (ADT). Docetaxel was administered for six cycles after randomization. The first cycle of docetaxel was administered within 6 weeks after start of study drug. ADT administration started ≤12 weeks before randomization.
Overall Number of Participants Analyzed	652	650
Measure Type: Count of Participants; Unit of Measure: Participants
Any TEAE	649 99.5%	643 98.9%
TESAE	306 46.9%	276 42.5%
TEAE leading to study drug dose modification	172 26.4%	112 17.2%
TEAE leading to permanent discontinuation of study drug	90 13.8%	69 10.6%
TEAE leading to docetaxel dose modification	216 33.1%	214 32.9%
TEAE leading to permanent discontinuation of docetaxel	52 8.0%	67 10.3%
Related to protocol-required procedure	69 10.6%	64 9.8%
Any study drug-related TEAE	344 52.8%	309 47.5%
Study drug-related TESAE	30 4.6%	24 3.7%
Study drug-related TEAE leading to study drug dose modification	75 11.5%	41 6.3%
Study drug-related TEAE leading to permanent discontinuation of study drug	25 3.8%	13 2.0%

4. Secondary Outcome

Title	Time to Castration-Resistant Prostate Cancer (CRPC) - Number of Events
Description	Time to castration-resistant prostate cancer was defined as the time from randomization to the first occurrence of one of the following events: PSA progression, Radiological progression by bone lesions, or Radiological progression by soft tissue and visceral lesions. Treatment period: until disease progression (symptomatic progressive disease, change of systemic antineoplastic therapy), unacceptable toxicity, consent withdrawal, withdrawal at the discretion of the investigator, death, or non-compliance. Active follow-up visits from the discontinuation of the darolutamide or placebo treatment period for up to 1 year or until the patient could no longer travel to the clinic, died, was lost to follow-up, or withdrew informed consent and actively objected to collection of further data.
Time Frame	From randomization of the first participant to the first occurrence of an CRPC event up to 25 OCT 2021 cut-off date approximately 59 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Darolutamide (BAY1841788) + Docetaxel	Placebo + Docetaxel
Arm/Group Description:	Participants received darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equivalent to a total daily dose of 1200 mg in addition to their standard treatment with docetaxel and androgen deprivation therapy (ADT). Docetaxel was administered for six cycles after randomization. The first cycle of docetaxel was administered within 6 weeks after start of study drug. ADT administration started ≤12 weeks before randomization.	Participants received matching placebo to darolutamide in addition to their standard treatment with docetaxel and androgen deprivation therapy (ADT). Docetaxel was administered for six cycles after randomization. The first cycle of docetaxel was administered within 6 weeks after start of study drug. ADT administration started ≤12 weeks before randomization.
Overall Number of Participants Analyzed	651	654
Measure Type: Count of Participants; Unit of Measure: Participants
Number of patients with event	225 34.6%	391 59.8%
Number of patients censored	426 65.4%	263 40.2%

5. Secondary Outcome

Title	Time to Castration-Resistant Prostate Cancer (CRPC) - Month
Description	Time to castration-resistant prostate cancer was defined as the time from randomization to the first occurrence of one of the following events: PSA progression, Radiological progression by bone lesions, or Radiological progression by soft tissue and visceral lesions. Treatment period: until disease progression (symptomatic progressive disease, change of systemic antineoplastic therapy), unacceptable toxicity, consent withdrawal, withdrawal at the discretion of the investigator, death, or non-compliance. Active follow-up visits from the discontinuation of the darolutamide or placebo treatment period for up to 1 year or until the patient could no longer travel to the clinic, died, was lost to follow-up, or withdrew informed consent and actively objected to collection of further data. NA = Value cannot be estimated due to censored data
Time Frame	From randomization of the first participant to the first occurrence of an CRPC event up to 25 OCT 2021 cut-off date approximately 59 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Darolutamide (BAY1841788) + Docetaxel	Placebo + Docetaxel
Arm/Group Description:	Participants received darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equivalent to a total daily dose of 1200 mg in addition to their standard treatment with docetaxel and androgen deprivation therapy (ADT). Docetaxel was administered for six cycles after randomization. The first cycle of docetaxel was administered within 6 weeks after start of study drug. ADT administration started ≤12 weeks before randomization.	Participants received matching placebo to darolutamide in addition to their standard treatment with docetaxel and androgen deprivation therapy (ADT). Docetaxel was administered for six cycles after randomization. The first cycle of docetaxel was administered within 6 weeks after start of study drug. ADT administration started ≤12 weeks before randomization.
Overall Number of Participants Analyzed	651	654
Median (95% Confidence Interval); Unit of Measure: Months
	NA [1]; (NA to NA)	19.1; (16.5 to 21.8)

[1]

NA = Value cannot be estimated due to censored data

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Darolutamide (BAY1841788) + Docetaxel, Placebo + Docetaxel
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	Hazard ratio < 1 indicates superiority of Darolutamide+docetaxel arm over Placebo+docetaxel arm. Hazard ratio and 95% CI was based on Cox Regression Model, stratified by EOD (Non-regional lymph nodes metastases only vs. Bone metastases with or without lymph node metastases vs. Visceral metastases with or without lymph node metastases or with or without bone metastases) and ALP (<ULN vs. >=ULN).
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	One-sided p-value.
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.357
	Confidence Interval	(2-Sided) 95%; 0.302 to 0.421
	Estimation Comments	[Not Specified]
Other Statistical Analysis		One-sided p-value from log-rank test, stratified by EOD (Non-regional lymph nodes metastases only vs. Bone metastases with or without lymph node metastases vs. Visceral metastases with or without lymph node metastases or with or without bone metastases) and ALP (<ULN vs. >=ULN).

6. Secondary Outcome

Title	Time to Pain Progression - Number of Events
Description	Time to pain progression was defined as the time from randomization to the first date a patient experienced pain progression. Treatment period: treatment was provided for all patients, twice daily, until disease progression (symptomatic progressive disease, change of systemic antineoplastic therapy), unacceptable toxicity, consent withdrawal, withdrawal at the discretion of the investigator, death, or non-compliance. Active follow-up visits from the discontinuation of the darolutamide or placebo treatment period for up to 1 year or until the patient could no longer travel to the clinic, died, was lost to follow-up, or withdrew informed consent and actively objected to collection of further data.
Time Frame	From randomization of the first participant to the first occurrence of a pain progression event up to 25 OCT 2021 cut-off date approximately 59 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Darolutamide (BAY1841788) + Docetaxel	Placebo + Docetaxel
Arm/Group Description:	Participants received darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equivalent to a total daily dose of 1200 mg in addition to their standard treatment with docetaxel and androgen deprivation therapy (ADT). Docetaxel was administered for six cycles after randomization. The first cycle of docetaxel was administered within 6 weeks after start of study drug. ADT administration started ≤12 weeks before randomization.	Participants received matching placebo to darolutamide in addition to their standard treatment with docetaxel and androgen deprivation therapy (ADT). Docetaxel was administered for six cycles after randomization. The first cycle of docetaxel was administered within 6 weeks after start of study drug. ADT administration started ≤12 weeks before randomization.
Overall Number of Participants Analyzed	651	654
Measure Type: Count of Participants; Unit of Measure: Participants
Number of patients with event	222 34.1%	248 37.9%
Number of patients censored	429 65.9%	406 62.1%

7. Secondary Outcome

Title	Time to Pain Progression - Month
Description	Time to pain progression was defined as the time from randomization to the first date a patient experienced pain progression. Treatment period: treatment was provided for all patients, twice daily, until disease progression (symptomatic progressive disease, change of systemic antineoplastic therapy), unacceptable toxicity, consent withdrawal, withdrawal at the discretion of the investigator, death, or non-compliance. Active follow-up visits from the discontinuation of the darolutamide or placebo treatment period for up to 1 year or until the patient could no longer travel to the clinic, died, was lost to follow-up, or withdrew informed consent and actively objected to collection of further data. NA = Value cannot be estimated due to censored data
Time Frame	From randomization of the first participant to the first occurrence of a pain progression event up to 25 OCT 2021 cut-off date approximately 59 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Darolutamide (BAY1841788) + Docetaxel	Placebo + Docetaxel
Arm/Group Description:	Participants received darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equivalent to a total daily dose of 1200 mg in addition to their standard treatment with docetaxel and androgen deprivation therapy (ADT). Docetaxel was administered for six cycles after randomization. The first cycle of docetaxel was administered within 6 weeks after start of study drug. ADT administration started ≤12 weeks before randomization.	Participants received matching placebo to darolutamide in addition to their standard treatment with docetaxel and androgen deprivation therapy (ADT). Docetaxel was administered for six cycles after randomization. The first cycle of docetaxel was administered within 6 weeks after start of study drug. ADT administration started ≤12 weeks before randomization.
Overall Number of Participants Analyzed	651	654
Median (95% Confidence Interval); Unit of Measure: Months
	NA [1]; (30.5 to NA)	27.5; (22.0 to 36.1)

[1]

NA = Value cannot be estimated due to censored data

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Darolutamide (BAY1841788) + Docetaxel, Placebo + Docetaxel
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	Hazard ratio < 1 indicates superiority of Darolutamide+docetaxel arm over Placebo+docetaxel arm. Hazard ratio and 95% CI was based on Cox Regression Model, stratified by EOD (Non-regional lymph nodes metastases only vs. Bone metastases with or without lymph node metastases vs. Visceral metastases with or without lymph node metastases or with or without bone metastases) and ALP (<ULN vs. >=ULN).
Statistical Test of Hypothesis	P-Value	0.0058
	Comments	One-sided p-value.
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.792
	Confidence Interval	(2-Sided) 95%; 0.660 to 0.950
	Estimation Comments	[Not Specified]
Other Statistical Analysis		One-sided p-value from log-rank test, stratified by EOD (Non-regional lymph nodes metastases only vs. Bone metastases with or without lymph node metastases vs. Visceral metastases with or without lymph node metastases or with or without bone metastases) and ALP (<ULN vs. >=ULN).

8. Secondary Outcome

Title	Symptomatic Skeletal Event Free Survival (SSE-FS) - Number of Events
Description	Symptomatic skeletal event-free survival (SSE-FS) was defined as the time from randomization to the first occurrence of an SSE or death from any cause, whichever occurred first. Treatment period: treatment was provided for all patients, twice daily, until disease progression (symptomatic progressive disease, change of systemic antineoplastic therapy), unacceptable toxicity, consent withdrawal, withdrawal at the discretion of the investigator, death, or non-compliance. Active follow-up visits from the discontinuation of the darolutamide or placebo treatment period for up to 1 year or until the patient could no longer travel to the clinic, died, was lost to follow-up, or withdrew informed consent and actively objected to collection of further data.
Time Frame	From randomization of the first participant to the first occurrence of an SSE event or death from any cause, whichever occurred first up to 25 OCT 2021 cut-off date approximately 59 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Darolutamide (BAY1841788) + Docetaxel	Placebo + Docetaxel
Arm/Group Description:	Participants received darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equivalent to a total daily dose of 1200 mg in addition to their standard treatment with docetaxel and androgen deprivation therapy (ADT). Docetaxel was administered for six cycles after randomization. The first cycle of docetaxel was administered within 6 weeks after start of study drug. ADT administration started ≤12 weeks before randomization.	Participants received matching placebo to darolutamide in addition to their standard treatment with docetaxel and androgen deprivation therapy (ADT). Docetaxel was administered for six cycles after randomization. The first cycle of docetaxel was administered within 6 weeks after start of study drug. ADT administration started ≤12 weeks before randomization.
Overall Number of Participants Analyzed	651	654
Measure Type: Count of Participants; Unit of Measure: Participants
Number of patients with event	257 39.5%	329 50.3%
Number of patients censored	394 60.5%	325 49.7%

9. Secondary Outcome

Title	Symptomatic Skeletal Event Free Survival (SSE-FS) - Month
Description	Symptomatic skeletal event-free survival (SSE-FS) was defined as the time from randomization to the first occurrence of an SSE or death from any cause, whichever occurred first. Treatment period: until disease progression (symptomatic progressive disease, change of systemic antineoplastic therapy), unacceptable toxicity, consent withdrawal, withdrawal at the discretion of the investigator, death, or non-compliance. Active follow-up visits from the discontinuation of the darolutamide or placebo treatment period for up to 1 year or until the patient could no longer travel to the clinic, died, was lost to follow-up, or withdrew informed consent and actively objected to collection of further data. NA = Value cannot be estimated due to censored data
Time Frame	From randomization of the first participant to the first occurrence of an SSE event or death from any cause, whichever occurred first up to 25 OCT 2021 cut-off date approximately 59 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Darolutamide (BAY1841788) + Docetaxel	Placebo + Docetaxel
Arm/Group Description:	Participants received darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equivalent to a total daily dose of 1200 mg in addition to their standard treatment with docetaxel and androgen deprivation therapy (ADT). Docetaxel was administered for six cycles after randomization. The first cycle of docetaxel was administered within 6 weeks after start of study drug. ADT administration started ≤12 weeks before randomization.	Participants received matching placebo to darolutamide in addition to their standard treatment with docetaxel and androgen deprivation therapy (ADT). Docetaxel was administered for six cycles after randomization. The first cycle of docetaxel was administered within 6 weeks after start of study drug. ADT administration started ≤12 weeks before randomization.
Overall Number of Participants Analyzed	651	654
Median (95% Confidence Interval); Unit of Measure: Months
	51.2 [1]; (47.2 to NA)	39.7; (36.0 to 42.3)

[1]

NA = Value cannot be estimated due to censored data

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Darolutamide (BAY1841788) + Docetaxel, Placebo + Docetaxel
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	Hazard ratio < 1 indicates superiority of Darolutamide+docetaxel arm over Placebo+docetaxel arm. Hazard ratio and 95% CI was based on Cox Regression Model, stratified by EOD (Non-regional lymph nodes metastases only vs. Bone metastases with or without lymph node metastases vs. Visceral metastases with or without lymph node metastases or with or without bone metastases) and ALP (<ULN vs. >=ULN).
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	One-sided p-value.
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.609
	Confidence Interval	(2-Sided) 95%; 0.516 to 0.718
	Estimation Comments	[Not Specified]
Other Statistical Analysis		One-sided p-value from log-rank test, stratified by EOD (Non-regional lymph nodes metastases only vs. Bone metastases with or without lymph node metastases vs. Visceral metastases with or without lymph node metastases or with or without bone metastases) and ALP (<ULN vs. >=ULN).

10. Secondary Outcome

Title	Time to First Symptomatic Skeletal Event (SSE) - Number of Events
Description	Time to the first SSE was defined as the time from randomization to the first occurrence of an SSE. Identical to the definition used for SSE-FS. Death was not considered as an event in this endpoint. Treatment period: treatment was provided for all patients, twice daily, until disease progression (symptomatic progressive disease, change of systemic antineoplastic therapy), unacceptable toxicity, consent withdrawal, withdrawal at the discretion of the investigator, death, or non-compliance. Active follow-up visits from the discontinuation of the darolutamide or placebo treatment period for up to 1 year or until the patient could no longer travel to the clinic, died, was lost to follow-up, or withdrew informed consent and actively objected to collection of further data.
Time Frame	From randomization of the first participant to the first occurrence of an SSE event up to 25 OCT 2021 cut-off date approximately 59 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Darolutamide (BAY1841788) + Docetaxel	Placebo + Docetaxel
Arm/Group Description:	Participants received darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equivalent to a total daily dose of 1200 mg in addition to their standard treatment with docetaxel and androgen deprivation therapy (ADT). Docetaxel was administered for six cycles after randomization. The first cycle of docetaxel was administered within 6 weeks after start of study drug. ADT administration started ≤12 weeks before randomization.	Participants received matching placebo to darolutamide in addition to their standard treatment with docetaxel and androgen deprivation therapy (ADT). Docetaxel was administered for six cycles after randomization. The first cycle of docetaxel was administered within 6 weeks after start of study drug. ADT administration started ≤12 weeks before randomization.
Overall Number of Participants Analyzed	651	654
Measure Type: Count of Participants; Unit of Measure: Participants
Number (%) of patients with event	95 14.6%	108 16.5%
Number (%) of patients censored	556 85.4%	546 83.5%

11. Secondary Outcome

Title	Time to First Symptomatic Skeletal Event (SSE) - Month
Description	Time to the first SSE was defined as the time from randomization to the first occurrence of an SSE. Identical to the definition used for SSE-FS. Death was not considered as an event in this endpoint. Treatment period: treatment was provided for all patients, twice daily, until disease progression (symptomatic progressive disease, change of systemic antineoplastic therapy), unacceptable toxicity, consent withdrawal, withdrawal at the discretion of the investigator, death, or non-compliance. Active follow-up visits from the discontinuation of the darolutamide or placebo treatment period for up to 1 year or until the patient could no longer travel to the clinic, died, was lost to follow-up, or withdrew informed consent and actively objected to collection of further data. NA = Value cannot be estimated due to censored data
Time Frame	From randomization of the first participant to the first occurrence of an SSE event up to 25 OCT 2021 cut-off date approximately 59 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Darolutamide (BAY1841788) + Docetaxel	Placebo + Docetaxel
Arm/Group Description:	Participants received darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equivalent to a total daily dose of 1200 mg in addition to their standard treatment with docetaxel and androgen deprivation therapy (ADT). Docetaxel was administered for six cycles after randomization. The first cycle of docetaxel was administered within 6 weeks after start of study drug. ADT administration started ≤12 weeks before randomization.	Participants received matching placebo to darolutamide in addition to their standard treatment with docetaxel and androgen deprivation therapy (ADT). Docetaxel was administered for six cycles after randomization. The first cycle of docetaxel was administered within 6 weeks after start of study drug. ADT administration started ≤12 weeks before randomization.
Overall Number of Participants Analyzed	651	654
Median (95% Confidence Interval); Unit of Measure: Months
	NA [1]; (NA to NA)	NA [1]; (NA to NA)

[1]

NA = Value cannot be estimated due to censored data

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Darolutamide (BAY1841788) + Docetaxel, Placebo + Docetaxel
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	Hazard ratio < 1 indicates superiority of Darolutamide+docetaxel arm over Placebo+docetaxel arm. Hazard ratio and 95% CI was based on Cox Regression Model, stratified by EOD (Non-regional lymph nodes metastases only vs. Bone metastases with or without lymph node metastases vs. Visceral metastases with or without lymph node metastases or with or without bone metastases) and ALP (<ULN vs. >=ULN).
Statistical Test of Hypothesis	P-Value	0.0081
	Comments	One-sided p-value.
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.712
	Confidence Interval	(2-Sided) 95%; 0.539 to 0.940
	Estimation Comments	[Not Specified]
Other Statistical Analysis		One-sided p-value from log-rank test, stratified by EOD (Non-regional lymph nodes metastases only vs. Bone metastases with or without lymph node metastases vs. Visceral metastases with or without lymph node metastases or with or without bone metastases) and ALP (<ULN vs. >=ULN).

12. Secondary Outcome

Title	Time to Initiation of Subsequent Antineoplastic Therapy - Number of Events
Description	Time to initiation of subsequent systemic antineoplastic therapy was defined as the time from randomization to the initiation of first subsequent systemic antineoplastic therapy. Treatment period: until disease progression (symptomatic progressive disease, change of systemic antineoplastic therapy), unacceptable toxicity, consent withdrawal, withdrawal at the discretion of the investigator, death, or non-compliance. Active follow-up visits from the discontinuation of the darolutamide or placebo treatment period for up to 1 year or until the patient could no longer travel to the clinic, died, was lost to follow-up, or withdrew informed consent and actively objected to collection of further data.
Time Frame	From randomization of the first participant to the initiation of first subsequent systemic antineoplastic therapy up to 25 OCT 2021 cut-off date approximately 59 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Darolutamide (BAY1841788) + Docetaxel	Placebo + Docetaxel
Arm/Group Description:	Participants received darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equivalent to a total daily dose of 1200 mg in addition to their standard treatment with docetaxel and androgen deprivation therapy (ADT). Docetaxel was administered for six cycles after randomization. The first cycle of docetaxel was administered within 6 weeks after start of study drug. ADT administration started ≤12 weeks before randomization.	Participants received matching placebo to darolutamide in addition to their standard treatment with docetaxel and androgen deprivation therapy (ADT). Docetaxel was administered for six cycles after randomization. The first cycle of docetaxel was administered within 6 weeks after start of study drug. ADT administration started ≤12 weeks before randomization.
Overall Number of Participants Analyzed	651	654
Measure Type: Count of Participants; Unit of Measure: Participants
Number (%) of patients with event	219 33.6%	395 60.4%
Number (%) of patients censored	432 66.4%	259 39.6%

13. Secondary Outcome

Title	Time to Initiation of Subsequent Antineoplastic Therapy - Month
Description	Time to initiation of subsequent systemic antineoplastic therapy was defined as the time from randomization to the initiation of first subsequent systemic antineoplastic therapy. Treatment period: until disease progression (symptomatic progressive disease, change of systemic antineoplastic therapy), unacceptable toxicity, consent withdrawal, withdrawal at the discretion of the investigator, death, or non-compliance. Active follow-up visits from the discontinuation of the darolutamide or placebo treatment period for up to 1 year or until the patient could no longer travel to the clinic, died, was lost to follow-up, or withdrew informed consent and actively objected to collection of further data. NA = Value cannot be estimated due to censored data
Time Frame	From randomization of the first participant to the initiation of first subsequent systemic antineoplastic therapy up to 25 OCT 2021 cut-off date approximately 59 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Darolutamide (BAY1841788) + Docetaxel	Placebo + Docetaxel
Arm/Group Description:	Participants received darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equivalent to a total daily dose of 1200 mg in addition to their standard treatment with docetaxel and androgen deprivation therapy (ADT). Docetaxel was administered for six cycles after randomization. The first cycle of docetaxel was administered within 6 weeks after start of study drug. ADT administration started ≤12 weeks before randomization.	Participants received matching placebo to darolutamide in addition to their standard treatment with docetaxel and androgen deprivation therapy (ADT). Docetaxel was administered for six cycles after randomization. The first cycle of docetaxel was administered within 6 weeks after start of study drug. ADT administration started ≤12 weeks before randomization.
Overall Number of Participants Analyzed	651	654
Median (95% Confidence Interval); Unit of Measure: Months
	NA [1]; (NA to NA)	25.3; (23.1 to 28.8)

[1]

NA = Value cannot be estimated due to censored data

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Darolutamide (BAY1841788) + Docetaxel, Placebo + Docetaxel
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	Hazard ratio < 1 indicates superiority of Darolutamide+docetaxel arm over Placebo+docetaxel arm. Hazard ratio and 95% CI was based on Cox Regression Model, stratified by EOD (Non-regional lymph nodes metastases only vs. Bone metastases with or without lymph node metastases vs. Visceral metastases with or without lymph node metastases or with or without bone metastases) and ALP (<ULN vs. >=ULN).
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	One-sided p-value.
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio, log
	Estimated Value	0.388
	Confidence Interval	(2-Sided) 95%; 0.328 to 0.458
	Estimation Comments	[Not Specified]
Other Statistical Analysis		One-sided p-value from log-rank test, stratified by EOD (Non-regional lymph nodes metastases only vs. Bone metastases with or without lymph node metastases vs. Visceral metastases with or without lymph node metastases or with or without bone metastases) and ALP (<ULN vs. >=ULN).

14. Secondary Outcome

Title	Time to Worsening of Disease-Related Physical Symptoms - Number of Events
Description	Time to worsening of disease-related physical symptoms was defined as the time from randomization to the first date a patient experienced an increase in disease-related physical symptoms based on the NCCN-FACT-FPSI-17 questionnaire. Treatment period: treatment was provided for all patients, twice daily, until disease progression (symptomatic progressive disease, change of systemic antineoplastic therapy), unacceptable toxicity, consent withdrawal, withdrawal at the discretion of the investigator, death, or non-compliance. Active follow-up visits from the discontinuation of the darolutamide or placebo treatment period for up to 1 year or until the patient could no longer travel to the clinic, died, was lost to follow-up, or withdrew informed consent and actively objected to collection of further data.
Time Frame	From randomization of the first participant to the first increase in disease-related physical symptoms based on the NCCN-FACT-FPSI-17 questionnaire up to 25 OCT 2021 cut-off date approximately 59 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Darolutamide (BAY1841788) + Docetaxel	Placebo + Docetaxel
Arm/Group Description:	Participants received darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equivalent to a total daily dose of 1200 mg in addition to their standard treatment with docetaxel and androgen deprivation therapy (ADT). Docetaxel was administered for six cycles after randomization. The first cycle of docetaxel was administered within 6 weeks after start of study drug. ADT administration started ≤12 weeks before randomization.	Participants received matching placebo to darolutamide in addition to their standard treatment with docetaxel and androgen deprivation therapy (ADT). Docetaxel was administered for six cycles after randomization. The first cycle of docetaxel was administered within 6 weeks after start of study drug. ADT administration started ≤12 weeks before randomization.
Overall Number of Participants Analyzed	651	654
Measure Type: Count of Participants; Unit of Measure: Participants
Number (%) of patients with event	351 53.9%	308 47.1%
Number (%) of patients censored	300 46.1%	346 52.9%

15. Secondary Outcome

Title	Time to Worsening of Disease-Related Physical Symptoms - Month
Description	Time to worsening of disease-related physical symptoms was defined as the time from randomization to the first date a patient experienced an increase in disease-related physical symptoms based on the NCCN-FACT-FPSI-17 questionnaire. Treatment period: treatment was provided for all patients, twice daily, until disease progression (symptomatic progressive disease, change of systemic antineoplastic therapy), unacceptable toxicity, consent withdrawal, withdrawal at the discretion of the investigator, death, or non-compliance. Active follow-up visits from the discontinuation of the darolutamide or placebo treatment period for up to 1 year or until the patient could no longer travel to the clinic, died, was lost to follow-up, or withdrew informed consent and actively objected to collection of further data.
Time Frame	From randomization of the first participant to the first increase in disease-related physical symptoms based on the NCCN-FACT-FPSI-17 questionnaire up to 25 OCT 2021 cut-off date approximately 59 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Darolutamide (BAY1841788) + Docetaxel	Placebo + Docetaxel
Arm/Group Description:	Participants received darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equivalent to a total daily dose of 1200 mg in addition to their standard treatment with docetaxel and androgen deprivation therapy (ADT). Docetaxel was administered for six cycles after randomization. The first cycle of docetaxel was administered within 6 weeks after start of study drug. ADT administration started ≤12 weeks before randomization.	Participants received matching placebo to darolutamide in addition to their standard treatment with docetaxel and androgen deprivation therapy (ADT). Docetaxel was administered for six cycles after randomization. The first cycle of docetaxel was administered within 6 weeks after start of study drug. ADT administration started ≤12 weeks before randomization.
Overall Number of Participants Analyzed	651	654
Median (95% Confidence Interval); Unit of Measure: Months
	19.3; (13.8 to 24.8)	19.4; (15.4 to 27.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Darolutamide (BAY1841788) + Docetaxel, Placebo + Docetaxel
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	Hazard ratio < 1 indicates superiority of Darolutamide+docetaxel arm over Placebo+docetaxel arm. Hazard ratio and 95% CI was based on Cox Regression Model, stratified by EOD (Non-regional lymph nodes metastases only vs. Bone metastases with or without lymph node metastases vs. Visceral metastases with or without lymph node metastases or with or without bone metastases) and ALP (<ULN vs. >=ULN).
Statistical Test of Hypothesis	P-Value	0.7073
	Comments	One-sided p-value.
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.043
	Confidence Interval	(2-Sided) 95%; 0.894 to 1.217
	Estimation Comments	[Not Specified]
Other Statistical Analysis		One-sided p-value from log-rank test, stratified by EOD (Non-regional lymph nodes metastases only vs. Bone metastases with or without lymph node metastases vs. Visceral metastases with or without lymph node metastases or with or without bone metastases) and ALP (<ULN vs. >=ULN).

16. Secondary Outcome

Title	Time to Initiation of Opioid Use for ≥7 Consecutive Days - Number of Events
Description	Time to the initiation of opioid use for ≥7 consecutive days was defined as the time from randomization to the date of the first opioid use for ≥7 consecutive days. Data of opioid use related to cancer pain was included in the analysis, and opioid use for non-malignant causes was excluded. Treatment period: until disease progression (symptomatic progressive disease, change of systemic antineoplastic therapy), unacceptable toxicity, consent withdrawal, withdrawal at the discretion of the investigator, death, or non-compliance. Active follow-up visits from the discontinuation of the darolutamide or placebo treatment period for up to 1 year or until the patient could no longer travel to the clinic, died, was lost to follow-up, or withdrew informed consent and actively objected to collection of further data.
Time Frame	From randomization of the first participant to the first opioid use for ≥7 consecutive days up to 25 OCT 2021 cut-off date approximately 59 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Darolutamide (BAY1841788) + Docetaxel	Placebo + Docetaxel
Arm/Group Description:	Participants received darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equivalent to a total daily dose of 1200 mg in addition to their standard treatment with docetaxel and androgen deprivation therapy (ADT). Docetaxel was administered for six cycles after randomization. The first cycle of docetaxel was administered within 6 weeks after start of study drug. ADT administration started ≤12 weeks before randomization.	Participants received matching placebo to darolutamide in addition to their standard treatment with docetaxel and androgen deprivation therapy (ADT). Docetaxel was administered for six cycles after randomization. The first cycle of docetaxel was administered within 6 weeks after start of study drug. ADT administration started ≤12 weeks before randomization.
Overall Number of Participants Analyzed	651	654
Measure Type: Count of Participants; Unit of Measure: Participants
Number of patients with event	92	117
Number of patients censored	559	537

17. Secondary Outcome

Title	Time to Initiation of Opioid Use for ≥7 Consecutive Days - Month
Description	Time to the initiation of opioid use for ≥7 consecutive days was defined as the time from randomization to the date of the first opioid use for ≥7 consecutive days. Data of opioid use related to cancer pain was included in the analysis, and opioid use for non-malignant causes was excluded. Treatment period: until disease progression (symptomatic progressive disease, change of systemic antineoplastic therapy), unacceptable toxicity, consent withdrawal, withdrawal at the discretion of the investigator, death, or non-compliance. Active follow-up visits from the discontinuation of the darolutamide or placebo treatment period for up to 1 year or until the patient could no longer travel to the clinic, died, was lost to follow-up, or withdrew informed consent and actively objected to collection of further data. NA = Value cannot be estimated due to censored data
Time Frame	From randomization of the first participant to the first opioid use for ≥7 consecutive days up to 25 OCT 2021 cut-off date approximately 59 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Darolutamide (BAY1841788) + Docetaxel	Placebo + Docetaxel
Arm/Group Description:	Participants received darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equivalent to a total daily dose of 1200 mg in addition to their standard treatment with docetaxel and androgen deprivation therapy (ADT). Docetaxel was administered for six cycles after randomization. The first cycle of docetaxel was administered within 6 weeks after start of study drug. ADT administration started ≤12 weeks before randomization.	Participants received matching placebo to darolutamide in addition to their standard treatment with docetaxel and androgen deprivation therapy (ADT). Docetaxel was administered for six cycles after randomization. The first cycle of docetaxel was administered within 6 weeks after start of study drug. ADT administration started ≤12 weeks before randomization.
Overall Number of Participants Analyzed	651	654
Median (95% Confidence Interval); Unit of Measure: Months
	NA [1]; (NA to NA)	NA [1]; (NA to NA)

[1]

NA = Value cannot be estimated due to censored data

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Darolutamide (BAY1841788) + Docetaxel, Placebo + Docetaxel
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	Hazard ratio < 1 indicates superiority of Darolutamide+docetaxel arm over Placebo+docetaxel arm. Hazard ratio and 95% CI was based on Cox Regression Model, stratified by EOD (Non-regional lymph nodes metastases only vs. Bone metastases with or without lymph node metastases vs. Visceral metastases with or without lymph node metastases or with or without bone metastases) and ALP (<ULN vs. >=ULN).
Statistical Test of Hypothesis	P-Value	0.0037
	Comments	One-sided p-value.
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.688
	Confidence Interval	(2-Sided) 95%; 0.523 to 0.906
	Estimation Comments	[Not Specified]
Other Statistical Analysis		One-sided p-value from log-rank test, stratified by EOD (Non-regional lymph nodes metastases only vs. Bone metastases with or without lymph node metastases vs. Visceral metastases with or without lymph node metastases or with or without bone metastases) and ALP (<ULN vs. >=ULN).

Adverse Events

Time Frame	From start of study drug administration until 30 days after the last administration, including adverse event of all-cause mortality at any time during the study, up to cut-off date for the final completion analysis 11 APR 2023 (approximately 77 months)
Adverse Event Reporting Description	Treatment-emergent AEs (TEAEs) were defined as any event(s) arising or worsening after the first dose of darolutamide or placebo, until 30 days after the last dose of darolutamide or placebo administration. Events causally related to treatment were considered as events causally related to either darolutamide / Docetaxel or Placebo / Docetaxel A total of 1305 patients were randomized for efficacy analysis, however 1302 patients only started treatment and were included to safety analyses.
Arm/Group Title	Darolutamide (BAY1841788) + Docetaxel		Placebo + Docetaxel
Arm/Group Description	Participants received darolutamide 600 mg (2 tablets of 300 mg) twice daily with food, equivalent to a total daily dose of 1200 mg in addition to their standard treatment with docetaxel and androgen deprivation therapy (ADT). Docetaxel was administered for six cycles after randomization. The first cycle of docetaxel was administered within 6 weeks after start of study drug. ADT administration started <=12 weeks before randomization.		Participants received matching placebo to darolutamide in addition to their standard treatment with docetaxel and androgen deprivation therapy (ADT). Docetaxel was administered for six cycles after randomization. The first cycle of docetaxel was administered within 6 weeks after start of study drug. ADT administration started <=12 weeks before randomization.
All-Cause Mortality
	Darolutamide (BAY1841788) + Docetaxel		Placebo + Docetaxel
	Affected / at Risk (%)		Affected / at Risk (%)
Total	231/652 (35.43%)		305/650 (46.92%)
Serious Adverse Events
	Darolutamide (BAY1841788) + Docetaxel		Placebo + Docetaxel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	306/652 (46.93%)		276/650 (42.46%)
Blood and lymphatic system disorders
Anaemia * 1	5/652 (0.77%)	6	4/650 (0.62%)	4
Febrile neutropenia * 1	40/652 (6.13%)	40	39/650 (6.00%)	44
Granulocytopenia * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Leukopenia * 1	0/652 (0.00%)	0	2/650 (0.31%)	2
Lymphadenopathy * 1	1/652 (0.15%)	2	0/650 (0.00%)	0
Myelosuppression * 1	1/652 (0.15%)	2	1/650 (0.15%)	1
Neutropenia * 1	12/652 (1.84%)	17	14/650 (2.15%)	17
Pancytopenia * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Thrombocytopenia * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Bicytopenia * 1	1/652 (0.15%)	1	1/650 (0.15%)	1
Bone marrow oedema syndrome * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Immune thrombocytopenia * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Cardiac disorders
Acute myocardial infarction * 1	4/652 (0.61%)	4	2/650 (0.31%)	2
Angina pectoris * 1	0/652 (0.00%)	0	1/650 (0.15%)	2
Angina unstable * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Aortic valve incompetence * 1	0/652 (0.00%)	0	1/650 (0.15%)	2
Atrial fibrillation * 1	1/652 (0.15%)	1	3/650 (0.46%)	3
Atrioventricular block complete * 1	3/652 (0.46%)	3	0/650 (0.00%)	0
Cardiac arrest * 1	1/652 (0.15%)	1	2/650 (0.31%)	2
Cardiac failure * 1	0/652 (0.00%)	0	2/650 (0.31%)	2
Cardiac failure acute * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Cardiac failure congestive * 1	1/652 (0.15%)	1	1/650 (0.15%)	1
Cardio-respiratory arrest * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Cardiomyopathy * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Coronary artery occlusion * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Left ventricular failure * 1	0/652 (0.00%)	0	2/650 (0.31%)	2
Mitral valve incompetence * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Myocardial infarction * 1	4/652 (0.61%)	4	1/650 (0.15%)	1
Myocardial ischaemia * 1	2/652 (0.31%)	2	0/650 (0.00%)	0
Sinus tachycardia * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Supraventricular tachycardia * 1	0/652 (0.00%)	0	2/650 (0.31%)	2
Ventricular extrasystoles * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Ventricular tachycardia * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Left ventricular dysfunction * 1	0/652 (0.00%)	0	2/650 (0.31%)	2
Acute coronary syndrome * 1	2/652 (0.31%)	2	1/650 (0.15%)	1
Congenital, familial and genetic disorders
Hydrocele * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Ear and labyrinth disorders
Vertigo * 1	2/652 (0.31%)	2	0/650 (0.00%)	0
Vestibular disorder * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Eye disorders
Cataract * 1	5/652 (0.77%)	6	1/650 (0.15%)	2
Diabetic retinopathy * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Macular oedema * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Retinal detachment * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Epiretinal membrane * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Gastrointestinal disorders
Abdominal discomfort * 1	1/652 (0.15%)	2	0/650 (0.00%)	0
Abdominal pain * 1	3/652 (0.46%)	3	0/650 (0.00%)	0
Anal fistula * 1	2/652 (0.31%)	2	1/650 (0.15%)	1
Colitis * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Constipation * 1	2/652 (0.31%)	2	1/650 (0.15%)	1
Dental caries * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Diarrhoea * 1	4/652 (0.61%)	4	3/650 (0.46%)	3
Dysphagia * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Gastric ulcer * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Gastric ulcer perforation * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Gastrooesophageal reflux disease * 1	1/652 (0.15%)	1	1/650 (0.15%)	1
Gastrointestinal haemorrhage * 1	1/652 (0.15%)	1	1/650 (0.15%)	1
Haematochezia * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Hiatus hernia * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Ileus * 1	1/652 (0.15%)	2	1/650 (0.15%)	2
Inguinal hernia * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Intestinal obstruction * 1	1/652 (0.15%)	1	1/650 (0.15%)	1
Large intestine perforation * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Nausea * 1	1/652 (0.15%)	1	1/650 (0.15%)	1
Oesophageal haemorrhage * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Oesophagitis * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Pancreatitis * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Pancreatitis acute * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Small intestinal obstruction * 1	2/652 (0.31%)	2	0/650 (0.00%)	0
Umbilical hernia * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Upper gastrointestinal haemorrhage * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Vomiting * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Large intestine polyp * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Gastrointestinal toxicity * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Intestinal strangulation * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Gastrointestinal polyp * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
General disorders
Asthenia * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Chest pain * 1	2/652 (0.31%)	2	2/650 (0.31%)	2
Death * 1	1/652 (0.15%)	1	2/650 (0.31%)	2
Fatigue * 1	2/652 (0.31%)	2	2/650 (0.31%)	2
Hernia * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Oedema peripheral * 1	2/652 (0.31%)	2	2/650 (0.31%)	2
Pain * 1	3/652 (0.46%)	4	0/650 (0.00%)	0
Pyrexia * 1	9/652 (1.38%)	9	15/650 (2.31%)	15
Sudden death * 1	2/652 (0.31%)	2	3/650 (0.46%)	3
General physical health deterioration * 1	1/652 (0.15%)	1	4/650 (0.62%)	4
Cardiac death * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Unevaluable event * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Non-cardiac chest pain * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Hepatobiliary disorders
Cholecystitis * 1	3/652 (0.46%)	3	0/650 (0.00%)	0
Cholecystitis acute * 1	2/652 (0.31%)	2	0/650 (0.00%)	0
Cholelithiasis * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Hepatic function abnormal * 1	1/652 (0.15%)	1	2/650 (0.31%)	2
Hyperbilirubinaemia * 1	0/652 (0.00%)	0	2/650 (0.31%)	2
Hypertransaminasaemia * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Drug-induced liver injury * 1	3/652 (0.46%)	3	1/650 (0.15%)	1
Biliary obstruction * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Immune system disorders
Anaphylactic reaction * 1	1/652 (0.15%)	1	1/650 (0.15%)	1
Hypersensitivity * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Infections and infestations
Appendicitis * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Bacteraemia * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Bronchitis * 1	3/652 (0.46%)	3	0/650 (0.00%)	0
Cellulitis * 1	0/652 (0.00%)	0	2/650 (0.31%)	2
Clostridium difficile colitis * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Cystitis * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Diverticulitis * 1	3/652 (0.46%)	4	2/650 (0.31%)	4
Epididymitis * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Epstein-Barr virus infection * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Erysipelas * 1	1/652 (0.15%)	1	2/650 (0.31%)	2
Fournier's gangrene * 1	1/652 (0.15%)	1	1/650 (0.15%)	1
Gastroenteritis * 1	2/652 (0.31%)	2	0/650 (0.00%)	0
Gastroenteritis clostridial * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Gingivitis * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Herpes zoster * 1	1/652 (0.15%)	1	2/650 (0.31%)	2
Infection * 1	2/652 (0.31%)	2	1/650 (0.15%)	1
Influenza * 1	2/652 (0.31%)	2	0/650 (0.00%)	0
Laryngitis * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Myelitis * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Nasopharyngitis * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Osteomyelitis * 1	2/652 (0.31%)	2	0/650 (0.00%)	0
Peritonitis * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Pneumonia * 1	16/652 (2.45%)	17	21/650 (3.23%)	22
Pneumonia aspiration * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Pyelonephritis * 1	2/652 (0.31%)	2	1/650 (0.15%)	1
Pyelonephritis acute * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Pyomyositis * 1	1/652 (0.15%)	2	0/650 (0.00%)	0
Sepsis * 1	6/652 (0.92%)	6	6/650 (0.92%)	6
Septic shock * 1	3/652 (0.46%)	3	2/650 (0.31%)	2
Sialoadenitis * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Sinusitis * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Skin infection * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Tonsillitis * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Upper respiratory tract infection * 1	1/652 (0.15%)	1	5/650 (0.77%)	5
Urinary tract infection * 1	7/652 (1.07%)	7	7/650 (1.08%)	11
Urosepsis * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Tooth infection * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Anal abscess * 1	3/652 (0.46%)	3	0/650 (0.00%)	0
Neutropenic sepsis * 1	3/652 (0.46%)	3	0/650 (0.00%)	0
Spinal cord infection * 1	2/652 (0.31%)	2	0/650 (0.00%)	0
Pulmonary sepsis * 1	0/652 (0.00%)	0	2/650 (0.31%)	2
Infective exacerbation of chronic obstructive airways disease * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
West Nile viral infection * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Enterocolitis infectious * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Abdominal abscess * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Pneumonia bacterial * 1	0/652 (0.00%)	0	2/650 (0.31%)	2
Arthritis infective * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Anorectal infection * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Respiratory tract infection * 1	1/652 (0.15%)	1	1/650 (0.15%)	1
Device related infection * 1	1/652 (0.15%)	2	0/650 (0.00%)	0
Vascular device infection * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
COVID-19 * 1	2/652 (0.31%)	2	0/650 (0.00%)	0
COVID-19 pneumonia * 1	7/652 (1.07%)	7	3/650 (0.46%)	3
Injury, poisoning and procedural complications
Anaesthetic complication cardiac * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Ankle fracture * 1	2/652 (0.31%)	2	2/650 (0.31%)	2
Extradural haematoma * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Fall * 1	2/652 (0.31%)	2	0/650 (0.00%)	0
Femoral neck fracture * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Femur fracture * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Fibula fracture * 1	2/652 (0.31%)	2	0/650 (0.00%)	0
Hip fracture * 1	1/652 (0.15%)	1	1/650 (0.15%)	1
Radius fracture * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Road traffic accident * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Snake bite * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Spinal compression fracture * 1	0/652 (0.00%)	0	2/650 (0.31%)	2
Spinal fracture * 1	0/652 (0.00%)	0	2/650 (0.31%)	2
Subdural haemorrhage * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Tendon rupture * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Tibia fracture * 1	2/652 (0.31%)	2	2/650 (0.31%)	2
Traumatic fracture * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Lumbar vertebral fracture * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Thoracic vertebral fracture * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Contusion * 1	1/652 (0.15%)	1	1/650 (0.15%)	1
Post laminectomy syndrome * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Skin laceration * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Pelvic fracture * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Limb injury * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Lower limb fracture * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Ligament rupture * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Investigations
Alanine aminotransferase increased * 1	6/652 (0.92%)	6	8/650 (1.23%)	10
Aspartate aminotransferase increased * 1	5/652 (0.77%)	5	4/650 (0.62%)	4
Biopsy lymph gland * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Blood bilirubin increased * 1	1/652 (0.15%)	2	0/650 (0.00%)	0
Blood glucose increased * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Haemoglobin decreased * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Lymphocyte count decreased * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Neutrophil count decreased * 1	18/652 (2.76%)	24	10/650 (1.54%)	10
Platelet count decreased * 1	1/652 (0.15%)	1	1/650 (0.15%)	1
White blood cell count decreased * 1	2/652 (0.31%)	3	4/650 (0.62%)	4
White blood cell count increased * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Prostatic specific antigen abnormal * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Metabolism and nutrition disorders
Cachexia * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Dehydration * 1	1/652 (0.15%)	1	2/650 (0.31%)	2
Diabetes mellitus * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Gout * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Hypercalcaemia * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Hyperglycaemia * 1	3/652 (0.46%)	5	3/650 (0.46%)	3
Hyperkalaemia * 1	1/652 (0.15%)	1	1/650 (0.15%)	1
Hypocalcaemia * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Hypoglycaemia * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Hyponatraemia * 1	1/652 (0.15%)	1	1/650 (0.15%)	1
Tumour lysis syndrome * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Vitamin B12 deficiency * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Decreased appetite * 1	0/652 (0.00%)	0	2/650 (0.31%)	2
Type 2 diabetes mellitus * 1	0/652 (0.00%)	0	3/650 (0.46%)	3
Hyperferritinaemia * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Musculoskeletal and connective tissue disorders
Arthralgia * 1	3/652 (0.46%)	3	3/650 (0.46%)	3
Arthritis * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Back pain * 1	6/652 (0.92%)	6	6/650 (0.92%)	6
Bone pain * 1	6/652 (0.92%)	6	6/650 (0.92%)	6
Groin pain * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Lumbar spinal stenosis * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Muscle spasms * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Muscular weakness * 1	2/652 (0.31%)	2	3/650 (0.46%)	3
Musculoskeletal pain * 1	0/652 (0.00%)	0	3/650 (0.46%)	3
Myalgia * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Neck pain * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Osteoarthritis * 1	3/652 (0.46%)	3	1/650 (0.15%)	1
Osteoporosis * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Pain in extremity * 1	1/652 (0.15%)	1	1/650 (0.15%)	1
Pathological fracture * 1	5/652 (0.77%)	5	1/650 (0.15%)	2
Periarthritis * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Rheumatoid arthritis * 1	1/652 (0.15%)	2	0/650 (0.00%)	0
Spinal osteoarthritis * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Trigger finger * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Pubic pain * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Intervertebral disc protrusion * 1	2/652 (0.31%)	2	2/650 (0.31%)	2
Osteonecrosis of jaw * 1	3/652 (0.46%)	3	0/650 (0.00%)	0
Spinal pain * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Spinal stenosis * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Brain neoplasm malignant * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Colon cancer * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Gastric cancer * 1	1/652 (0.15%)	1	1/650 (0.15%)	1
Laryngeal cancer * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Malignant melanoma in situ * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Medulloblastoma * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Metastases to lung * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Metastatic malignant melanoma * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Myelofibrosis * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Oesophageal adenocarcinoma * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Oesophageal carcinoma * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Pancreatic carcinoma * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Papillary thyroid cancer * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Phaeochromocytoma * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Rectal adenocarcinoma * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Rectal cancer * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Squamous cell carcinoma * 1	2/652 (0.31%)	2	0/650 (0.00%)	0
Squamous cell carcinoma of lung * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Squamous cell carcinoma of skin * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Transitional cell carcinoma * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Tumour pain * 1	4/652 (0.61%)	4	2/650 (0.31%)	5
Waldenstrom's macroglobulinaemia * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Cancer pain * 1	3/652 (0.46%)	4	1/650 (0.15%)	1
Lung neoplasm malignant * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Metastases to central nervous system * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Thyroid cancer * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Tumour compression * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Oral papilloma * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Sebaceous carcinoma * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Hepatocellular carcinoma * 1	0/652 (0.00%)	0	2/650 (0.31%)	2
Small intestine adenocarcinoma * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Nervous system disorders
Aphasia * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Carotid artery stenosis * 1	1/652 (0.15%)	2	0/650 (0.00%)	0
Carotid artery thrombosis * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Cerebellar syndrome * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Cerebral infarction * 1	5/652 (0.77%)	7	2/650 (0.31%)	2
Cerebrovascular accident * 1	3/652 (0.46%)	3	2/650 (0.31%)	2
Depressed level of consciousness * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Dizziness * 1	1/652 (0.15%)	1	1/650 (0.15%)	1
Epilepsy * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Haemorrhage intracranial * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Haemorrhagic stroke * 1	2/652 (0.31%)	2	0/650 (0.00%)	0
Headache * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Hypoaesthesia * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
IIIrd nerve paralysis * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Paraparesis * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Paraplegia * 1	1/652 (0.15%)	1	1/650 (0.15%)	1
Peripheral sensory neuropathy * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Presyncope * 1	0/652 (0.00%)	0	2/650 (0.31%)	2
Sciatica * 1	1/652 (0.15%)	2	0/650 (0.00%)	0
Seizure * 1	1/652 (0.15%)	2	0/650 (0.00%)	0
Spinal cord compression * 1	2/652 (0.31%)	2	7/650 (1.08%)	7
Subarachnoid haemorrhage * 1	2/652 (0.31%)	2	0/650 (0.00%)	0
Syncope * 1	3/652 (0.46%)	3	5/650 (0.77%)	5
Transient ischaemic attack * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Brain oedema * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Carotid artery occlusion * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Lacunar infarction * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Vagus nerve disorder * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Parkinson's disease * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Basal ganglia infarction * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Product Issues
Device dislocation * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Device occlusion * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Product contamination * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Device deposit issue * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Psychiatric disorders
Confusional state * 1	2/652 (0.31%)	2	0/650 (0.00%)	0
Insomnia * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Renal and urinary disorders
Calculus bladder * 1	3/652 (0.46%)	3	1/650 (0.15%)	1
Calculus urethral * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Calculus urinary * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Cystitis haemorrhagic * 1	1/652 (0.15%)	1	1/650 (0.15%)	1
Dysuria * 1	2/652 (0.31%)	3	0/650 (0.00%)	0
Haematuria * 1	3/652 (0.46%)	4	4/650 (0.62%)	5
Hydronephrosis * 1	3/652 (0.46%)	3	0/650 (0.00%)	0
Micturition disorder * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Nephrolithiasis * 1	2/652 (0.31%)	3	0/650 (0.00%)	0
Renal failure * 1	1/652 (0.15%)	2	3/650 (0.46%)	3
Urinary bladder haemorrhage * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Urinary incontinence * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Urinary retention * 1	2/652 (0.31%)	2	6/650 (0.92%)	6
Haemorrhage urinary tract * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Postrenal failure * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Urinary tract obstruction * 1	5/652 (0.77%)	8	3/650 (0.46%)	3
Urinary tract pain * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Renal impairment * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Bladder tamponade * 1	1/652 (0.15%)	3	0/650 (0.00%)	0
Urinary fistula * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Acute kidney injury * 1	5/652 (0.77%)	7	6/650 (0.92%)	6
Ureterolithiasis * 1	4/652 (0.61%)	5	1/650 (0.15%)	1
Malignant urinary tract obstruction * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Reproductive system and breast disorders
Benign prostatic hyperplasia * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Pelvic pain * 1	0/652 (0.00%)	0	2/650 (0.31%)	2
Prostatomegaly * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Prostatic obstruction * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Acute respiratory failure * 1	1/652 (0.15%)	2	1/650 (0.15%)	1
Bronchiectasis * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Bronchitis chronic * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Chronic obstructive pulmonary disease * 1	2/652 (0.31%)	2	0/650 (0.00%)	0
Dyspnoea * 1	1/652 (0.15%)	1	2/650 (0.31%)	2
Haemoptysis * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Hypoxia * 1	2/652 (0.31%)	2	2/650 (0.31%)	2
Interstitial lung disease * 1	1/652 (0.15%)	1	5/650 (0.77%)	6
Nasal polyps * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Pleural effusion * 1	1/652 (0.15%)	1	2/650 (0.31%)	2
Pneumonitis * 1	4/652 (0.61%)	4	3/650 (0.46%)	3
Pneumothorax * 1	2/652 (0.31%)	2	2/650 (0.31%)	2
Pneumothorax spontaneous * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Pulmonary embolism * 1	6/652 (0.92%)	6	4/650 (0.62%)	4
Respiratory distress * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Respiratory failure * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Obstructive airways disorder * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Skin and subcutaneous tissue disorders
Drug eruption * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Rash * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Skin ulcer * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Skin mass * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Social circumstances
Loss of personal independence in daily activities * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Surgical and medical procedures
Cardioversion * 1	1/652 (0.15%)	2	0/650 (0.00%)	0
Hip arthroplasty * 1	2/652 (0.31%)	2	0/650 (0.00%)	0
Inguinal hernia repair * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Orchidectomy * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Spinal laminectomy * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Bilateral orchidectomy * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Spinal fusion surgery * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Radical prostatectomy * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Cancer surgery * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Atrial appendage closure * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Vascular disorders
Aortic aneurysm * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Aortic dissection * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Arteriosclerosis * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Haematoma * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Hypertension * 1	1/652 (0.15%)	1	1/650 (0.15%)	1
Hypertensive crisis * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Lymphoedema * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Phlebitis * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
Deep vein thrombosis * 1	3/652 (0.46%)	3	0/650 (0.00%)	0
Hypertensive emergency * 1	1/652 (0.15%)	1	0/650 (0.00%)	0
Peripheral arterial occlusive disease * 1	1/652 (0.15%)	1	1/650 (0.15%)	1
Arterial occlusive disease * 1	0/652 (0.00%)	0	1/650 (0.15%)	1
1 Term from vocabulary, MedDRA (25.1); * Indicates events were collected by non-systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Darolutamide (BAY1841788) + Docetaxel		Placebo + Docetaxel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	636/652 (97.55%)		634/650 (97.54%)
Blood and lymphatic system disorders
Anaemia * 1	185/652 (28.37%)	276	164/650 (25.23%)	227
Neutropenia * 1	62/652 (9.51%)	108	67/650 (10.31%)	103
Eye disorders
Lacrimation increased * 1	38/652 (5.83%)	40	43/650 (6.62%)	47
Gastrointestinal disorders
Abdominal pain * 1	36/652 (5.52%)	40	37/650 (5.69%)	40
Constipation * 1	149/652 (22.85%)	202	132/650 (20.31%)	162
Diarrhoea * 1	168/652 (25.77%)	229	157/650 (24.15%)	225
Nausea * 1	117/652 (17.94%)	150	134/650 (20.62%)	174
Stomatitis * 1	67/652 (10.28%)	87	57/650 (8.77%)	69
Vomiting * 1	53/652 (8.13%)	63	58/650 (8.92%)	69
General disorders
Asthenia * 1	71/652 (10.89%)	89	65/650 (10.00%)	83
Fatigue * 1	222/652 (34.05%)	291	215/650 (33.08%)	287
Malaise * 1	58/652 (8.90%)	78	67/650 (10.31%)	97
Oedema peripheral * 1	175/652 (26.84%)	206	169/650 (26.00%)	194
Pain * 1	30/652 (4.60%)	36	42/650 (6.46%)	48
Pyrexia * 1	84/652 (12.88%)	104	83/650 (12.77%)	110
Infections and infestations
Nasopharyngitis * 1	46/652 (7.06%)	69	46/650 (7.08%)	56
Upper respiratory tract infection * 1	57/652 (8.74%)	73	46/650 (7.08%)	52
Urinary tract infection * 1	57/652 (8.74%)	91	63/650 (9.69%)	92
Injury, poisoning and procedural complications
Fall * 1	45/652 (6.90%)	64	33/650 (5.08%)	37
Investigations
Alanine aminotransferase increased * 1	99/652 (15.18%)	132	81/650 (12.46%)	103
Aspartate aminotransferase increased * 1	87/652 (13.34%)	120	66/650 (10.15%)	84
Neutrophil count decreased * 1	165/652 (25.31%)	432	151/650 (23.23%)	415
Weight decreased * 1	27/652 (4.14%)	32	37/650 (5.69%)	37
Weight increased * 1	116/652 (17.79%)	147	105/650 (16.15%)	130
White blood cell count decreased * 1	155/652 (23.77%)	395	142/650 (21.85%)	360
Blood alkaline phosphatase increased * 1	45/652 (6.90%)	53	43/650 (6.62%)	53
Metabolism and nutrition disorders
Hyperglycaemia * 1	77/652 (11.81%)	100	61/650 (9.38%)	74
Decreased appetite * 1	121/652 (18.56%)	157	86/650 (13.23%)	96
Musculoskeletal and connective tissue disorders
Arthralgia * 1	186/652 (28.53%)	270	173/650 (26.62%)	249
Back pain * 1	128/652 (19.63%)	154	121/650 (18.62%)	147
Bone pain * 1	80/652 (12.27%)	91	82/650 (12.62%)	96
Muscular weakness * 1	51/652 (7.82%)	59	48/650 (7.38%)	54
Myalgia * 1	74/652 (11.35%)	103	65/650 (10.00%)	84
Pain in extremity * 1	104/652 (15.95%)	148	78/650 (12.00%)	95
Nervous system disorders
Dizziness * 1	60/652 (9.20%)	69	52/650 (8.00%)	64
Dysgeusia * 1	71/652 (10.89%)	88	80/650 (12.31%)	84
Headache * 1	59/652 (9.05%)	72	49/650 (7.54%)	58
Hypoaesthesia * 1	38/652 (5.83%)	44	29/650 (4.46%)	40
Neuropathy peripheral * 1	77/652 (11.81%)	91	68/650 (10.46%)	72
Paraesthesia * 1	42/652 (6.44%)	45	55/650 (8.46%)	66
Peripheral sensory neuropathy * 1	65/652 (9.97%)	74	68/650 (10.46%)	72
Psychiatric disorders
Insomnia * 1	77/652 (11.81%)	85	80/650 (12.31%)	93
Renal and urinary disorders
Haematuria * 1	59/652 (9.05%)	73	36/650 (5.54%)	43
Pollakiuria * 1	31/652 (4.75%)	33	43/650 (6.62%)	47
Respiratory, thoracic and mediastinal disorders
Cough * 1	87/652 (13.34%)	103	73/650 (11.23%)	83
Dyspnoea * 1	62/652 (9.51%)	73	71/650 (10.92%)	78
Epistaxis * 1	38/652 (5.83%)	50	34/650 (5.23%)	38
Skin and subcutaneous tissue disorders
Alopecia * 1	267/652 (40.95%)	268	264/650 (40.62%)	265
Dry skin * 1	48/652 (7.36%)	54	35/650 (5.38%)	37
Nail discolouration * 1	50/652 (7.67%)	51	52/650 (8.00%)	52
Pruritus * 1	46/652 (7.06%)	54	52/650 (8.00%)	62
Rash * 1	53/652 (8.13%)	64	45/650 (6.92%)	58
Vascular disorders
Hypertension * 1	86/652 (13.19%)	112	61/650 (9.38%)	72
Hot flush * 1	128/652 (19.63%)	141	122/650 (18.77%)	136
1 Term from vocabulary, MedDRA (25.1); * Indicates events were collected by non-systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Bayer may recommend any changes to the Publication as deemed necessary for scientific purposes. If the Publication could hinder the ability to obtain patent protection for any Invention, Bayer may request a delay of the Publication for a reasonable period to be able to file the patent application, but not to exceed 6 months from the date publication is received for review. Bayer may request further delay in case the patent application has been filed and the priority application is incomplete.

Results Point of Contact

• Name/Title: Therapeutic Area Head
• Organization: Bayer AG
• Phone: 1-888-8422937
• EMail: clinical-trials-contact@bayer.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Smith MR, Hussain M, Saad F, Fizazi K, Sternberg CN, Crawford D, Manarite J, Muslin D, Farrington T, Tombal B. Darolutamide and survival in metastatic, hormone-sensitive prostate cancer: a patient and caregiver perspective and plain language summary of the ARASENS trial. Future Oncol. 2022 Jul;18(21):2585-2597. doi: 10.2217/fon-2022-0433. Epub 2022 Jun 3.

Smith MR, Hussain M, Saad F, Fizazi K, Sternberg CN, Crawford ED, Kopyltsov E, Park CH, Alekseev B, Montesa-Pino A, Ye D, Parnis F, Cruz F, Tammela TLJ, Suzuki H, Utriainen T, Fu C, Uemura M, Mendez-Vidal MJ, Maughan BL, Joensuu H, Thiele S, Li R, Kuss I, Tombal B; ARASENS Trial Investigators. Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer. N Engl J Med. 2022 Mar 24;386(12):1132-1142. doi: 10.1056/NEJMoa2119115. Epub 2022 Feb 17.

• Responsible Party: Bayer
• ClinicalTrials.gov Identifier: NCT02799602
• Other Study ID Numbers: 17777; 2015-002590-38 ( EudraCT Number )
• First Submitted: June 6, 2016
• First Posted: June 15, 2016
• Results First Submitted: October 25, 2022
• Results First Posted: February 24, 2023
• Last Update Posted: April 16, 2024