A Study of Enzalutamide Plus Androgen Deprivation Therapy (ADT) Versus Placebo Plus ADT in Patients With Metastatic Hormone Sensitive Prostate Cancer (mHSPC) (ARCHES)

• ClinicalTrials.gov Identifier: NCT02677896
• Recruitment Status: Active, not recruiting
• First Posted: February 9, 2016
• Results First Posted: January 21, 2020
• Last Update Posted: April 19, 2024
• Sponsor: Astellas Pharma Global Development, Inc.
• Collaborator: Medivation LLC, a wholly owned subsidiary of Pfizer Inc.
• Information provided by (Responsible Party): Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. )

• 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: Enzalutamide; Drug: Placebo
• Enrollment: 1150

Participant Flow

Recruitment Details	Participants with metastatic hormone sensitive prostate cancer (mHSPC) were enrolled in 204 study sites worldwide.
Pre-assignment Details	The randomization was stratified by volume of disease (low vs high) and prior docetaxel therapy for prostate cancer (no prior docetaxel, 1 to 5 cycles, 6 cycles).

Arm/Group Title	Enzalutamide + Androgen Deprivation Therapy (ADT)	Placebo + Androgen Deprivation Therapy (ADT)
Arm/Group Description	Participants received 160 mg of enzalutamide orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide during double-blind treatment period and provided informed consent to take part in open-label period continued to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or luteinizing hormone-releasing hormone (LHRH) agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.	Participants received enzalutamide matching placebo orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide matching placebo during double-blind treatment period and provided informed consent to take part in open-label period switched to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.
Period Title: Double Blind Period (up to 35 Months)
Started	574	576
Treated	572	574
Completed	0	0
Not Completed	574	576
Reason Not Completed
Death	113	189
Lost to Follow-up	12	12
Progressive disease	3	4
Withdrawal by Subject	41	69
Miscellaneous	9	14
Continued in OLE	365	180
Followed-up for OS	31	108
Period Title: Open-Label Extension (up to 25 Months)
Started	365 [1]	180 [1]
Completed	0	0
Not Completed	365	180
Reason Not Completed
Death	40	14
Lost to Follow-up	2	1
Progressive disease	3	1
Withdrawal by Subject	10	9
Miscellaneous	0	1
OLE treatment ongoing	261	136
Followed up for OS	49	18
[1] Eligible participants who provided consent took part in open-label period

Baseline Characteristics

Arm/Group Title		Enzalutamide + Androgen Deprivation Therapy (ADT)	Placebo + Androgen Deprivation Therapy (ADT)	Total
Arm/Group Description		Participants received 160 mg of enzalutamide orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide during double-blind treatment period and provided informed consent to take part in open-label period continued to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.	Participants received enzalutamide matching placebo orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide matching placebo during double-blind treatment period and provided informed consent to take part in open-label period switched to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.	Total of all reporting groups
Overall Number of Baseline Participants		574	576	1150
Baseline Analysis Population Description		All Randomized Participants
Age, Continuous; Mean (Standard Deviation); Unit of measure: Year
	Number Analyzed	574 participants	576 participants	1150 participants
		69.5 (8.0)	69.5 (8.4)	69.5 (8.2)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	574 participants	576 participants	1150 participants
	Female	0 0.0%	0 0.0%	0 0.0%
	Male	574 100.0%	576 100.0%	1150 100.0%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	574 participants	576 participants	1150 participants
	Hispanic or Latino	46 8.0%	37 6.4%	83 7.2%
	Not Hispanic or Latino	504 87.8%	514 89.2%	1018 88.5%
	Unknown or Not Reported	24 4.2%	25 4.3%	49 4.3%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	574 participants	576 participants	1150 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%
	Asian	75 13.1%	80 13.9%	155 13.5%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	8 1.4%	8 1.4%	16 1.4%
	White	466 81.2%	460 79.9%	926 80.5%
	More than one race	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	25 4.4%	28 4.9%	53 4.6%
Volume of Disease [1] [2]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	574 participants	576 participants	1150 participants
	Low	220 38.3%	203 35.2%	423 36.8%
	High	354 61.7%	373 64.8%	727 63.2%
		[1] Measure Description: High volume of disease was defined as metastases involving the viscera or, in the absence of visceral lesions, 4 or more bone lesions, at least 1 of which was in a bony structure beyond the vertebral column and pelvic bone. Low volume was anything that wasn't considered high volume by definition provided.; [2] Measure Analysis Population Description: Intent-to-Treat (ITT)
Prior Docetaxel Therapy Use [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	574 participants	576 participants	1150 participants
	None	471 82.1%	474 82.3%	945 82.2%
	1 to 5 cycles	14 2.4%	11 1.9%	25 2.2%
	6 cycles	89 15.5%	91 15.8%	180 15.7%
		[1] Measure Analysis Population Description: ITT

Outcome Measures

1. Primary Outcome

Title	Radiographic Progression-Free Survival (rPFS) Based on Independent Central Review (ICR) of Bone Scan According to Prostate Cancer Clinical Trials Working Group 2 (PCWG2) Criteria
Description	rPFS was calculated as the time from the date of randomization to the first objective evidence of radiographic progression disease (rPD) at any time or death up to 24 weeks after study drug discontinuation without documented radiographic progression, whichever occurred first. rPD was defined as progressive disease by Response Evaluation Criteria in Solid Tumors version 1.1 for soft tissue disease or by appearance of 2 or more new lesions on bone scan compared to baseline or week 13 according to PCWG2 criteria, as assessed by ICR or death. In participants with no rPFS event, rPFS was censored on the date of last evaluable radiographic assessment prior to the data analysis cutoff date. In participants with no baseline radiographic assessment, participants with no postbaseline radiographic assessments and participants with all postbaseline radiographic assessments documented as "not evaluable (NE)," rPFS was censored on the date of randomization.
Time Frame	From randomization until the data cut-off date of 14 October 2018; maximum duration of treatment was 26.6 months

Outcome Measure Data

Analysis Population Description

ITT population is defined as all participants who were randomized in this study.

Arm/Group Title	Enzalutamide + Androgen Deprivation Therapy (ADT)	Placebo + Androgen Deprivation Therapy (ADT)
Arm/Group Description:	Participants received 160 mg of enzalutamide orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide during double-blind treatment period and provided informed consent to take part in open-label period continued to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.	Participants received enzalutamide matching placebo orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide matching placebo during double-blind treatment period and provided informed consent to take part in open-label period switched to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.
Overall Number of Participants Analyzed	574	576
Median (95% Confidence Interval); Unit of Measure: months
	NA [1]; (NA to NA)	19.4 [1]; (16.59 to NA)

[1]

Not reached. Data was not reached due to low number of events.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enzalutamide + Androgen Deprivation Therapy (ADT), Placebo + Androgen Deprivation Therapy (ADT)
	Comments	rPFS Treatment Comparison
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Stratified by volume of disease (low vs high) and prior docetaxel use (yes vs no) during screening period.
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Cox hazard ratio
	Estimated Value	0.39
	Confidence Interval	(2-Sided) 95%; 0.30 to 0.50
	Estimation Comments	Stratified by volume of disease (low vs high) and prior docetaxel use (yes vs no) during screening period.

2. Primary Outcome

Title	rPFS Based on ICR of Bone Scan According to Protocol Assessment Criteria
Description	rPFS was calculated as the time from the date of randomization to the first objective evidence of radiographic progression disease (rPD) at any time or death up to 24 weeks after study drug discontinuation without documented radiographic progression, whichever occurred first. rPD was defined as progressive disease by Response Evaluation Criteria in Solid Tumors version 1.1 for soft tissue disease or by appearance of 2 or more new lesions on bone scan compared to baseline for week 13 or the best response on treatment for week 25 or later assessments, as assessed by ICR or death. In participants with no rPFS event, rPFS was censored on the date of last evaluable radiographic assessment prior to the data analysis cutoff date. In participants with no baseline radiographic assessment, participants with no postbaseline radiographic assessments and participants with all postbaseline radiographic assessments documented as "not evaluable (NE)," rPFS was censored on the date of randomization.
Time Frame	From randomization until the data cut-off date of 14 October 2018; maximum duration of treatment was 26.6 months.

Outcome Measure Data

Analysis Population Description

ITT

Arm/Group Title	Enzalutamide + Androgen Deprivation Therapy (ADT)	Placebo + Androgen Deprivation Therapy (ADT)
Arm/Group Description:	Participants received 160 mg of enzalutamide orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide during double-blind treatment period and provided informed consent to take part in open-label period continued to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.	Participants received enzalutamide matching placebo orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide matching placebo during double-blind treatment period and provided informed consent to take part in open-label period switched to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.
Overall Number of Participants Analyzed	574	576
Median (95% Confidence Interval); Unit of Measure: months
	NA [1]; (NA to NA)	19.0; (16.59 to 22.24)

[1]

Not reached. Data was not reached due to low number of events.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enzalutamide + Androgen Deprivation Therapy (ADT), Placebo + Androgen Deprivation Therapy (ADT)
	Comments	rPFS Treatment Comparision
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Cox proportional hazards model
	Estimated Value	0.39
	Confidence Interval	(2-Sided) 95%; 0.30 to 0.50
	Estimation Comments	[Not Specified]

3. Secondary Outcome

Title	Overall Survival (OS)
Description	OS was defined as the time from randomization to death due to any cause. In participants still alive at the date of the analysis cutoff point, OS was censored on the last date the participant was known to be alive. OS was analyzed using Kaplan-Meier estimates.
Time Frame	From date of randomization to OS final analysis (28 May 2021); Maximum treatment duration was 58.6 months

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Enzalutamide + Androgen Deprivation Therapy (ADT)	Placebo + Androgen Deprivation Therapy (ADT)
Arm/Group Description:	Participants received 160 mg of enzalutamide orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide during double-blind treatment period and provided informed consent to take part in open-label period continued to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.	Participants received enzalutamide matching placebo orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide matching placebo during double-blind treatment period and provided informed consent to take part in open-label period switched to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.
Overall Number of Participants Analyzed	574	576
Median (95% Confidence Interval); Unit of Measure: months
	NA [1]; (NA to NA)	NA [1]; (49.74 to NA)

[1]

Not reached. Data was not reached due to low number of events.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enzalutamide + Androgen Deprivation Therapy (ADT), Placebo + Androgen Deprivation Therapy (ADT)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Log Rank
	Comments	P-value from stratified log-rank test.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.66
	Confidence Interval	(2-Sided) 95%; 0.53 to 0.81
	Estimation Comments	Significance level is 0.04. Hazard ratio and 95 % CI are estimated by cox proportional hazards model.

4. Secondary Outcome

Title	Time to Prostate Specific Antigen (PSA) Progression
Description	Time to PSA progression was calculated as the time from the date of randomization to the first observation of PSA progression. A PSA progression was defined as a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL above the nadir, which was confirmed by a second consecutive value at least 3 weeks later. In participants with no PSA progression, time to PSA progression was censored on the date of the last PSA sample taken (or last value prior to 2 or more consecutive missed PSA assessments).
Time Frame	From randomization until the data cut-off date of 14 October 2018; maximum duration of treatment was 26.6 months

Outcome Measure Data

Analysis Population Description

ITT

Arm/Group Title	Enzalutamide + Androgen Deprivation Therapy (ADT)	Placebo + Androgen Deprivation Therapy (ADT)
Arm/Group Description:	Participants received 160 mg of enzalutamide orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide during double-blind treatment period and provided informed consent to take part in open-label period continued to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.	Participants received enzalutamide matching placebo orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide matching placebo during double-blind treatment period and provided informed consent to take part in open-label period switched to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.
Overall Number of Participants Analyzed	574	576
Median (95% Confidence Interval); Unit of Measure: months
	NA [1]; (NA to NA)	NA [1]; (16.59 to NA)

[1]

Not reached. Data was not reached due to low number of events.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enzalutamide + Androgen Deprivation Therapy (ADT), Placebo + Androgen Deprivation Therapy (ADT)
	Comments	Time to PSA Progression Treatment Comparison
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Stratified by volume of disease (low vs high) and prior docetaxel use (yes vs no) during screening period.
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Cox hazard ratio
	Estimated Value	0.19
	Confidence Interval	(2-Sided) 95%; 0.13 to 0.26
	Estimation Comments	Stratified by volume of disease (low vs high) and prior docetaxel use (yes vs no) during screening period.

5. Secondary Outcome

Title	Time to Start of New Antineoplastic Therapy
Description	In participants with a new antineoplastic therapy initiated for prostate cancer after randomization, time to start of a new antineoplastic therapy was defined as the time interval from randomization to the date of the first dose administration of the first antineoplastic therapy. In participants with no new antineoplastic therapy initiated for prostate cancer after randomization, time to start of new antineoplastic therapy was censored on the last visit date or the date of randomization, whichever occurred last. Time to start of new antineoplastic therapy was analyzed using Kaplan-Meier estimates.
Time Frame	From date of randomization to data cut-off date (28 May 2021); Maximum treatment duration was 58.6 months

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Enzalutamide + Androgen Deprivation Therapy (ADT)	Placebo + Androgen Deprivation Therapy (ADT)
Arm/Group Description:	Participants received 160 mg of enzalutamide orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide during double-blind treatment period and provided informed consent to take part in open-label period continued to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.	Participants received enzalutamide matching placebo orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide matching placebo during double-blind treatment period and provided informed consent to take part in open-label period switched to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.
Overall Number of Participants Analyzed	574	576
Median (95% Confidence Interval); Unit of Measure: months
	NA [1]; (NA to NA)	40.5 [1]; (26.25 to NA)

[1]

Not reached. Data was not reached due to low number of events.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enzalutamide + Androgen Deprivation Therapy (ADT), Placebo + Androgen Deprivation Therapy (ADT)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.38
	Confidence Interval	(2-Sided) 95%; 0.31 to 0.48
	Estimation Comments	Hazard ratio and 95 % CI are estimated by cox proportional hazards model.

6. Secondary Outcome

Title	PSA Undetectable Rate
Description	The PSA undetectable rate was defined as the percentage of participants with undetectable (< 0.2 ng/mL) PSA values at any time during study treatment, of those participants with detectable (≥ 0.2 ng/mL) PSA values at baseline.
Time Frame	Up to the data cut-off date of 14 October 2018; maximum duration of treatment was 26.6 months

Outcome Measure Data

Analysis Population Description

ITT with detectable PSA at baseline

Arm/Group Title	Enzalutamide + Androgen Deprivation Therapy (ADT)	Placebo + Androgen Deprivation Therapy (ADT)
Arm/Group Description:	Participants received 160 mg of enzalutamide orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide during double-blind treatment period and provided informed consent to take part in open-label period continued to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.	Participants received enzalutamide matching placebo orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide matching placebo during double-blind treatment period and provided informed consent to take part in open-label period switched to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.
Overall Number of Participants Analyzed	511	506
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	68.1; (63.9 to 72.1)	17.6; (14.4 to 21.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enzalutamide + Androgen Deprivation Therapy (ADT), Placebo + Androgen Deprivation Therapy (ADT)
	Comments	PSA Undetectable Rate Treatment Comparison
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Stratified by volume of disease (low vs high) and prior docetaxel use (yes vs no) during screening period.
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in rate
	Estimated Value	50.5
	Confidence Interval	(2-Sided) 95%; 45.3 to 55.7
	Estimation Comments	[Not Specified]

7. Secondary Outcome

Title	Objective Response Rate (ORR)
Description	The ORR was calculated as the percentage of participants who achieved a completed response (CR) or a partial response (PR) (unconfirmed responses) in their soft tissue disease using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 assessed by ICR.
Time Frame	Up to the data cut-off date of 14 October 2018; maximum duration of treatment was 26.6 months

Outcome Measure Data

Analysis Population Description

ITT participants with measurable disease at baseline

Arm/Group Title	Enzalutamide + Androgen Deprivation Therapy (ADT)	Placebo + Androgen Deprivation Therapy (ADT)
Arm/Group Description:	Participants received 160 mg of enzalutamide orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide during double-blind treatment period and provided informed consent to take part in open-label period continued to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.	Participants received enzalutamide matching placebo orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide matching placebo during double-blind treatment period and provided informed consent to take part in open-label period switched to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.
Overall Number of Participants Analyzed	177	182
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	83.1; (76.7 to 88.3)	63.7; (56.3 to 70.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enzalutamide + Androgen Deprivation Therapy (ADT), Placebo + Androgen Deprivation Therapy (ADT)
	Comments	ORR Treatment Comparison
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	Stratified by volume of disease (low vs high) and prior docetaxel use (yes vs no) during screening period.
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in rate
	Estimated Value	19.3
	Confidence Interval	(2-Sided) 95%; 10.4 to 28.2
	Estimation Comments	[Not Specified]

8. Secondary Outcome

Title	Time to Deterioration in Urinary Symptoms
Description	In participants with deterioration, the time to deterioration was calculated as the time interval between randomization and the first deterioration in urinary symptoms at any postbaseline visit. A deterioration in urinary symptoms was defined as an increase in the Quality of Life Prostate-specific Questionnaire (QLQ-PR25) modified urinary symptoms. Subscale score by ≥ 50% of the standard deviation observed in the QLQ-PR25 modified urinary symptoms subscale score at baseline. Modified urinary symptoms subscale score consisted of 3-items (Q31 - Q33) from the QLQ-PR25, each scored from 1 (not at all) to 4 (very much). The total modified urinary symptoms subscale score ranges from 0-100, with higher scores represents a higher level of symptomatology/problems. In participants without deterioration in urinary symptoms, the time to deterioration in urinary symptoms was censored on the date the last urinary symptoms QLQ-PR25 score was calculable.
Time Frame	From randomization to the data cut-off date of 14 October 2018; maximum duration of treatment was 26.6 months

Outcome Measure Data

Analysis Population Description

ITT

Arm/Group Title	Enzalutamide + Androgen Deprivation Therapy (ADT)	Placebo + Androgen Deprivation Therapy (ADT)
Arm/Group Description:	Participants received 160 mg of enzalutamide orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide during double-blind treatment period and provided informed consent to take part in open-label period continued to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.	Participants received enzalutamide matching placebo orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide matching placebo during double-blind treatment period and provided informed consent to take part in open-label period switched to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.
Overall Number of Participants Analyzed	574	576
Median (95% Confidence Interval); Unit of Measure: months
	NA [1]; (19.35 to NA)	16.8 [1]; (14.06 to NA)

[1]

Not reached. Data was not reached due to low number of events.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enzalutamide + Androgen Deprivation Therapy (ADT), Placebo + Androgen Deprivation Therapy (ADT)
	Comments	Time to Deterioration of Urinary Symptoms Treatment Comparison
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2162
	Comments	Stratified by volume of disease (low vs high) and prior docetaxel use (yes vs no) during screening period.
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Cox hazard ratio
	Estimated Value	0.88
	Confidence Interval	(2-Sided) 95%; 0.72 to 1.08
	Estimation Comments	Stratified by volume of disease (low vs high) and prior docetaxel use (yes vs no) during screening period.

9. Secondary Outcome

Title	Time to First Symptomatic Skeletal Event (SSE)
Description	Time to first SSE was calculated as the time from randomization to the occurrence of the first SSE prior to the data analysis cut-off date. An SSE was defined as radiation to bone, surgery to bone, clinically apparent pathological bone fracture, or spinal cord compression. In participants with no SSE by the time of the data cut-off point, time to SSE was censored on the last visit date or the date of randomization, whichever occurred last.
Time Frame	From randomization to the data cut-off date of 14 October 2018; maximum duration of treatment was 26.6 months

Outcome Measure Data

Analysis Population Description

ITT

Arm/Group Title	Enzalutamide + Androgen Deprivation Therapy (ADT)	Placebo + Androgen Deprivation Therapy (ADT)
Arm/Group Description:	Participants received 160 mg of enzalutamide orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide during double-blind treatment period and provided informed consent to take part in open-label period continued to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.	Participants received enzalutamide matching placebo orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide matching placebo during double-blind treatment period and provided informed consent to take part in open-label period switched to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.
Overall Number of Participants Analyzed	574	576
Median (95% Confidence Interval); Unit of Measure: months
	NA [1]; (NA to NA)	NA [1]; (NA to NA)

[1]

Not reached. Data was not reached due to low number of events.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enzalutamide + Androgen Deprivation Therapy (ADT), Placebo + Androgen Deprivation Therapy (ADT)
	Comments	Time to SSE Treatment Comparison
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0026
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Cox hazard ratio
	Estimated Value	0.52
	Confidence Interval	(2-Sided) 95%; 0.33 to 0.80
	Estimation Comments	[Not Specified]

10. Secondary Outcome

Title	Time to Castration Resistance
Description	Time to castration resistance was calculated as the time from randomization to the first castration-resistant event. A castration resistance event was defined as any of the following in the presence of castrate levels of testosterone (< 50 ng/dL): radiographic disease progression, PSA progression or SSE, whichever occurred first. In participants with no documented castration resistance event, the time to castration resistance was censored on the latest date from: the date of last radiologic assessment, the last PSA sample taken prior to the start of any new prostate cancer therapy and prior to 2 or more consecutive missed PSA assessments (if applicable), and the last visit date performed.
Time Frame	From randomization to the data cut-off date of 14 October 2018; maximum duration of treatment was 26.6 months

Outcome Measure Data

Analysis Population Description

ITT

Arm/Group Title	Enzalutamide + Androgen Deprivation Therapy (ADT)	Placebo + Androgen Deprivation Therapy (ADT)
Arm/Group Description:	Participants received 160 mg of enzalutamide orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide during double-blind treatment period and provided informed consent to take part in open-label period continued to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.	Participants received enzalutamide matching placebo orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide matching placebo during double-blind treatment period and provided informed consent to take part in open-label period switched to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.
Overall Number of Participants Analyzed	574	576
Median (95% Confidence Interval); Unit of Measure: months
	NA [1]; (NA to NA)	13.9; (11.40 to 17.18)

[1]

Not reached. Data was not reached due to low number of events.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enzalutamide + Androgen Deprivation Therapy (ADT), Placebo + Androgen Deprivation Therapy (ADT)
	Comments	Time to Castration Resistance Treatment Comparison
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Cox hazard ratio
	Estimated Value	0.28
	Confidence Interval	(2-Sided) 95%; 0.22 to 0.36
	Estimation Comments	[Not Specified]

11. Secondary Outcome

Title	Time to Deterioration of Quality of Life (QoL) in Functional Assessment of Cancer Therapy-Prostate (FACT-P)
Description	Time to deterioration of QoL was calculated as the time interval from the date of randomization to the first date a decline from baseline of 10 points or more in the FACT-P total score was recorded. The FACT-P consists of 27 core items that assess participant function in 4 domains and 12 prostate cancer-related items grouped into 5 subscales as follows: physical wellbeing, social/family wellbeing, emotional wellbeing, functional wellbeing and prostate cancer subscale. Each item is rated on a 0 to 4 Likert-type scale. The FACT-P total score is the sum of all 5 subscale scores of the FACT-P questionnaire and ranges from 0 to 156), where high score represent better quality of life. In participants without FACT-P progression, the time to deterioration of QoL was censored on the date of the last FACT-P total score was calculable.
Time Frame	From randomization to the data cut-off date of 14 October 2018; maximum duration of treatment was 26.6 months

Outcome Measure Data

Analysis Population Description

ITT

Arm/Group Title	Enzalutamide + Androgen Deprivation Therapy (ADT)	Placebo + Androgen Deprivation Therapy (ADT)
Arm/Group Description:	Participants received 160 mg of enzalutamide orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide during double-blind treatment period and provided informed consent to take part in open-label period continued to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.	Participants received enzalutamide matching placebo orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide matching placebo during double-blind treatment period and provided informed consent to take part in open-label period switched to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.
Overall Number of Participants Analyzed	574	576
Median (95% Confidence Interval); Unit of Measure: months
	11.3; (11.04 to 13.83)	11.1; (8.48 to 13.83)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enzalutamide + Androgen Deprivation Therapy (ADT), Placebo + Androgen Deprivation Therapy (ADT)
	Comments	Time to Deterioration of QoL in FACT-P Treatment Comparison
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.6548
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Cox hazard ratio
	Estimated Value	0.96
	Confidence Interval	(2-Sided) 95%; 0.81 to 1.14
	Estimation Comments	[Not Specified]

12. Secondary Outcome

Title	Time to Pain Progression Based on Brief Pain Inventory-Short Form (BPI-SF)
Description	Time to pain progression was defined as time from randomization to the first pain progression event. Pain progression was defined as an increase of ≥ 30% from baseline in the average BPI-SF pain severity score. BPI-SF contains 9 questions with rating scales from 0 (no pain/no interference) to 10 (worst pain/interferes completely). Total score was calculated as the average of each question. Higher scores represent a higher level of pain or interference. In participants with no pain progression event, time to pain progression was censored on the last visit date where BPI-SF was collected.
Time Frame	From randomization to the data cut-off date of 14 October 2018; maximum duration of treatment was 26.6 months

Outcome Measure Data

Analysis Population Description

ITT

Arm/Group Title	Enzalutamide + Androgen Deprivation Therapy (ADT)	Placebo + Androgen Deprivation Therapy (ADT)
Arm/Group Description:	Participants received 160 mg of enzalutamide orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide during double-blind treatment period and provided informed consent to take part in open-label period continued to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.	Participants received enzalutamide matching placebo orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide matching placebo during double-blind treatment period and provided informed consent to take part in open-label period switched to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.
Overall Number of Participants Analyzed	574	576
Median (95% Confidence Interval); Unit of Measure: months
	8.3; (8.25 to 10.91)	8.3; (5.65 to 8.38)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enzalutamide + Androgen Deprivation Therapy (ADT), Placebo + Androgen Deprivation Therapy (ADT)
	Comments	Time to Pain Progression Based on BPI-SF Treatment Comparison
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2715
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Cox hazard ratio
	Estimated Value	0.92
	Confidence Interval	(2-Sided) 95%; 0.78 to 1.07
	Estimation Comments	[Not Specified]

Adverse Events

Time Frame	From first dose of study drug up to 30 days after last dose of study or prior to initiation of new therapy for prostate cancer, whichever occurred first. Maximum duration of treatment to the data cut-off date of 28 May 2021 was 58.6 months
Adverse Event Reporting Description	Safety Analysis Set (SAF) consisted of all randomized participants who received at least one dose of study drug.
Arm/Group Title	Enzalutamide + Androgen Deprivation Therapy (ADT)		Placebo + Androgen Deprivation Therapy		Placebo Cross-over Enzalutamide
Arm/Group Description	Participants received 160 mg of enzalutamide orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide during double-blind treatment period and provided informed consent to take part in open-label period continued to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.		Participants received enzalutamide matching placebo orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. This arm represents only double blind period.		Eligible participants who received enzalutamide matching placebo during double-blind treatment period and provided informed consent to take part in open-label period switched to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock. This arm represents only the open-label extension period.
All-Cause Mortality
	Enzalutamide + Androgen Deprivation Therapy (ADT)		Placebo + Androgen Deprivation Therapy		Placebo Cross-over Enzalutamide
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	154/572 (26.92%)		189/574 (32.93%)		14/180 (7.78%)
Serious Adverse Events
	Enzalutamide + Androgen Deprivation Therapy (ADT)		Placebo + Androgen Deprivation Therapy		Placebo Cross-over Enzalutamide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	197/572 (34.44%)		128/574 (22.30%)		36/180 (20.00%)
Blood and lymphatic system disorders
Anaemia † 1	5/572 (0.87%)	5	2/574 (0.35%)	4	1/180 (0.56%)	1
Blood loss anaemia † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Febrile neutropenia † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Immune thrombocytopenia † 1	1/572 (0.17%)	6	0/574 (0.00%)	0	0/180 (0.00%)	0
Iron deficiency anaemia † 1	1/572 (0.17%)	2	0/574 (0.00%)	0	0/180 (0.00%)	0
Lymphadenopathy † 1	2/572 (0.35%)	2	0/574 (0.00%)	0	0/180 (0.00%)	0
Pancytopenia † 1	3/572 (0.52%)	3	1/574 (0.17%)	1	0/180 (0.00%)	0
Cardiac disorders
Acute coronary syndrome † 1	2/572 (0.35%)	2	2/574 (0.35%)	2	0/180 (0.00%)	0
Acute myocardial infarction † 1	3/572 (0.52%)	3	1/574 (0.17%)	1	2/180 (1.11%)	2
Angina pectoris † 1	2/572 (0.35%)	3	0/574 (0.00%)	0	0/180 (0.00%)	0
Angina unstable † 1	1/572 (0.17%)	1	1/574 (0.17%)	1	0/180 (0.00%)	0
Aortic valve incompetence † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Arteriosclerosis coronary artery † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Atrial fibrillation † 1	8/572 (1.40%)	10	7/574 (1.22%)	10	1/180 (0.56%)	1
Atrial flutter † 1	1/572 (0.17%)	1	2/574 (0.35%)	2	0/180 (0.00%)	0
Atrioventricular block † 1	1/572 (0.17%)	1	1/574 (0.17%)	1	0/180 (0.00%)	0
Atrioventricular block complete † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	1/180 (0.56%)	1
Atrioventricular block second degree † 1	1/572 (0.17%)	1	1/574 (0.17%)	1	0/180 (0.00%)	0
Bradycardia † 1	1/572 (0.17%)	1	1/574 (0.17%)	1	0/180 (0.00%)	0
Cardiac arrest † 1	2/572 (0.35%)	2	1/574 (0.17%)	1	0/180 (0.00%)	0
Cardiac failure † 1	3/572 (0.52%)	3	1/574 (0.17%)	1	1/180 (0.56%)	1
Cardiac failure chronic † 1	1/572 (0.17%)	2	0/574 (0.00%)	0	0/180 (0.00%)	0
Cardio-respiratory arrest † 1	1/572 (0.17%)	1	1/574 (0.17%)	1	0/180 (0.00%)	0
Cardiopulmonary failure † 1	2/572 (0.35%)	2	0/574 (0.00%)	0	0/180 (0.00%)	0
Coronary artery disease † 1	2/572 (0.35%)	2	0/574 (0.00%)	0	1/180 (0.56%)	1
Coronary artery stenosis † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	1/180 (0.56%)	1
Myocardial infarction † 1	3/572 (0.52%)	3	2/574 (0.35%)	2	2/180 (1.11%)	2
Myocardial ischaemia † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Sinus node dysfunction † 1	2/572 (0.35%)	2	0/574 (0.00%)	0	0/180 (0.00%)	0
Supraventricular tachycardia † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Trifascicular block † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Ventricular fibrillation † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Ear and labyrinth disorders
Deafness † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Deafness neurosensory † 1	0/572 (0.00%)	0	0/574 (0.00%)	0	1/180 (0.56%)	1
Endocrine disorders
Goitre † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Hyperparathyroidism † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Eye disorders
Cataract † 1	0/572 (0.00%)	0	0/574 (0.00%)	0	1/180 (0.56%)	1
Eye haemorrhage † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Retinal detachment † 1	1/572 (0.17%)	1	1/574 (0.17%)	1	0/180 (0.00%)	0
Ulcerative keratitis † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Gastrointestinal disorders
Abdominal pain † 1	3/572 (0.52%)	3	2/574 (0.35%)	2	0/180 (0.00%)	0
Colitis ischaemic † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Constipation † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	1/180 (0.56%)	1
Diarrhoea † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Diverticulum intestinal haemorrhagic † 1	1/572 (0.17%)	3	0/574 (0.00%)	0	0/180 (0.00%)	0
Duodenal ulcer haemorrhage † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Duodenal ulcer perforation † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Duodenitis † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Dyspepsia † 1	1/572 (0.17%)	2	2/574 (0.35%)	2	1/180 (0.56%)	1
Dysphagia † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Epiploic appendagitis † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Gastritis † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Gastritis erosive † 1	1/572 (0.17%)	2	0/574 (0.00%)	0	0/180 (0.00%)	0
Gastrointestinal haemorrhage † 1	1/572 (0.17%)	1	1/574 (0.17%)	1	0/180 (0.00%)	0
Impaired gastric emptying † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Incarcerated inguinal hernia † 1	2/572 (0.35%)	3	0/574 (0.00%)	0	0/180 (0.00%)	0
Inguinal hernia † 1	1/572 (0.17%)	1	1/574 (0.17%)	1	1/180 (0.56%)	1
Large intestinal obstruction † 1	2/572 (0.35%)	2	0/574 (0.00%)	0	0/180 (0.00%)	0
Large intestine perforation † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Large intestine polyp † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Nausea † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Pneumoperitoneum † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Proctalgia † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Retroperitoneal fibrosis † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Retroperitoneal haematoma † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Small intestinal obstruction † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Subileus † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Upper gastrointestinal haemorrhage † 1	2/572 (0.35%)	4	1/574 (0.17%)	2	1/180 (0.56%)	1
General disorders
Asthenia † 1	1/572 (0.17%)	1	2/574 (0.35%)	2	0/180 (0.00%)	0
Chills † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Death † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Drowning † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Euthanasia † 1	1/572 (0.17%)	1	1/574 (0.17%)	1	0/180 (0.00%)	0
Fatigue † 1	3/572 (0.52%)	4	0/574 (0.00%)	0	0/180 (0.00%)	0
General physical health deterioration † 1	3/572 (0.52%)	3	2/574 (0.35%)	3	0/180 (0.00%)	0
Implant site dehiscence † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Malaise † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Pyrexia † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Sudden cardiac death † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Sudden death † 1	0/572 (0.00%)	0	2/574 (0.35%)	2	0/180 (0.00%)	0
Hepatobiliary disorders
Cholecystitis † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Cholecystitis acute † 1	1/572 (0.17%)	1	1/574 (0.17%)	2	0/180 (0.00%)	0
Cholelithiasis † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Hepatic function abnormal † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	3/180 (1.67%)	4
Jaundice cholestatic † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Infections and infestations
Anorectal infection † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Appendicitis † 1	2/572 (0.35%)	2	1/574 (0.17%)	1	0/180 (0.00%)	0
Bronchitis † 1	1/572 (0.17%)	1	1/574 (0.17%)	1	0/180 (0.00%)	0
Bronchopulmonary aspergillosis † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
COVID-19 † 1	2/572 (0.35%)	2	0/574 (0.00%)	0	2/180 (1.11%)	3
COVID-19 pneumonia † 1	3/572 (0.52%)	4	0/574 (0.00%)	0	1/180 (0.56%)	1
Cellulitis † 1	2/572 (0.35%)	3	1/574 (0.17%)	1	0/180 (0.00%)	0
Cholecystitis infective † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Cystitis † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Device related infection † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Diverticulitis † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Endocarditis † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Erysipelas † 1	1/572 (0.17%)	1	2/574 (0.35%)	2	1/180 (0.56%)	1
Escherichia pyelonephritis † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Escherichia urinary tract infection † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	1/180 (0.56%)	1
Gangrene † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Gastroenteritis † 1	2/572 (0.35%)	2	0/574 (0.00%)	0	0/180 (0.00%)	0
Genital abscess † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Groin abscess † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Infected lymphocele † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Infection † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Influenza † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Osteomyelitis † 1	1/572 (0.17%)	2	0/574 (0.00%)	0	0/180 (0.00%)	0
Otitis media chronic † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Pneumonia † 1	5/572 (0.87%)	8	5/574 (0.87%)	6	1/180 (0.56%)	1
Pyelonephritis † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Sepsis † 1	4/572 (0.70%)	5	3/574 (0.52%)	3	2/180 (1.11%)	3
Septic shock † 1	1/572 (0.17%)	2	0/574 (0.00%)	0	0/180 (0.00%)	0
Spinal cord infection † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Subcutaneous abscess † 1	1/572 (0.17%)	2	0/574 (0.00%)	0	0/180 (0.00%)	0
Systemic candida † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Urinary tract infection † 1	1/572 (0.17%)	1	2/574 (0.35%)	2	0/180 (0.00%)	0
Urinary tract infection bacterial † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Urinary tract infection staphylococcal † 1	0/572 (0.00%)	0	0/574 (0.00%)	0	1/180 (0.56%)	1
Urosepsis † 1	2/572 (0.35%)	2	1/574 (0.17%)	1	0/180 (0.00%)	0
Injury, poisoning and procedural complications
Accidental overdose † 1	2/572 (0.35%)	2	1/574 (0.17%)	1	0/180 (0.00%)	0
Bone fissure † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Brain contusion † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Cervical vertebral fracture † 1	0/572 (0.00%)	0	2/574 (0.35%)	2	0/180 (0.00%)	0
Clavicle fracture † 1	1/572 (0.17%)	2	1/574 (0.17%)	1	0/180 (0.00%)	0
Comminuted fracture † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Concussion † 1	2/572 (0.35%)	2	0/574 (0.00%)	0	0/180 (0.00%)	0
Coronary artery restenosis † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Craniocerebral injury † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Fall † 1	8/572 (1.40%)	8	4/574 (0.70%)	4	1/180 (0.56%)	1
Femoral neck fracture † 1	2/572 (0.35%)	2	3/574 (0.52%)	3	0/180 (0.00%)	0
Femur fracture † 1	4/572 (0.70%)	4	1/574 (0.17%)	1	0/180 (0.00%)	0
Fracture displacement † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Head injury † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Hip fracture † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Humerus fracture † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Infusion related reaction † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Jaw fracture † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Limb injury † 1	1/572 (0.17%)	1	1/574 (0.17%)	1	0/180 (0.00%)	0
Lumbar vertebral fracture † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Multiple fractures † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Overdose † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Patella fracture † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	1/180 (0.56%)	2
Peripheral artery restenosis † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Radius fracture † 1	1/572 (0.17%)	1	1/574 (0.17%)	1	0/180 (0.00%)	0
Rib fracture † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Road traffic accident † 1	1/572 (0.17%)	1	1/574 (0.17%)	1	0/180 (0.00%)	0
Scapula fracture † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Skull fractured base † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Spinal compression fracture † 1	2/572 (0.35%)	2	0/574 (0.00%)	0	0/180 (0.00%)	0
Stenosis of vesicourethral anastomosis † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Subdural haematoma † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Thermal burn † 1	1/572 (0.17%)	2	0/574 (0.00%)	0	0/180 (0.00%)	0
Thoracic vertebral fracture † 1	2/572 (0.35%)	2	1/574 (0.17%)	1	0/180 (0.00%)	0
Ulna fracture † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Urinary retention postoperative † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Urinary tract stoma complication † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Wound † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Wound haemorrhage † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Wrong dose † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	1/180 (0.56%)	1
Investigations
Alanine aminotransferase increased † 1	2/572 (0.35%)	3	0/574 (0.00%)	0	0/180 (0.00%)	0
Antineutrophil cytoplasmic antibody increased † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Aspartate aminotransferase increased † 1	2/572 (0.35%)	3	0/574 (0.00%)	0	0/180 (0.00%)	0
Blood alkaline phosphatase increased † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Blood bilirubin increased † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Blood creatinine increased † 1	2/572 (0.35%)	3	1/574 (0.17%)	1	0/180 (0.00%)	0
Blood testosterone increased † 1	0/572 (0.00%)	0	1/574 (0.17%)	2	0/180 (0.00%)	0
Intraocular pressure increased † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Liver function test abnormal † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Transaminases increased † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Metabolism and nutrition disorders
Adult failure to thrive † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Cachexia † 1	1/572 (0.17%)	1	1/574 (0.17%)	1	0/180 (0.00%)	0
Dehydration † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	1/180 (0.56%)	1
Hypercalcaemia † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Hypoglycaemia † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Musculoskeletal and connective tissue disorders
Arthralgia † 1	0/572 (0.00%)	0	0/574 (0.00%)	0	1/180 (0.56%)	1
Arthritis † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Back pain † 1	3/572 (0.52%)	3	2/574 (0.35%)	2	1/180 (0.56%)	1
Bone pain † 1	2/572 (0.35%)	2	0/574 (0.00%)	0	0/180 (0.00%)	0
Compartment syndrome † 1	0/572 (0.00%)	0	0/574 (0.00%)	0	1/180 (0.56%)	1
Flank pain † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Groin pain † 1	0/572 (0.00%)	0	0/574 (0.00%)	0	1/180 (0.56%)	1
Muscle spasms † 1	0/572 (0.00%)	0	0/574 (0.00%)	0	1/180 (0.56%)	1
Muscular weakness † 1	1/572 (0.17%)	1	2/574 (0.35%)	2	0/180 (0.00%)	0
Musculoskeletal chest pain † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Neck pain † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Osteoarthritis † 1	3/572 (0.52%)	3	2/574 (0.35%)	2	0/180 (0.00%)	0
Osteonecrosis of jaw † 1	2/572 (0.35%)	2	0/574 (0.00%)	0	0/180 (0.00%)	0
Osteoporotic fracture † 1	0/572 (0.00%)	0	0/574 (0.00%)	0	1/180 (0.56%)	2
Pain in extremity † 1	1/572 (0.17%)	1	1/574 (0.17%)	1	1/180 (0.56%)	1
Pathological fracture † 1	1/572 (0.17%)	1	1/574 (0.17%)	1	0/180 (0.00%)	0
Spinal osteoarthritis † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Adenocarcinoma gastric † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
B-cell lymphoma † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Basal cell carcinoma † 1	4/572 (0.70%)	5	5/574 (0.87%)	5	1/180 (0.56%)	2
Benign pancreatic neoplasm † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Bladder cancer † 1	3/572 (0.52%)	3	0/574 (0.00%)	0	0/180 (0.00%)	0
Bone cancer † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Bowen's disease † 1	1/572 (0.17%)	2	0/574 (0.00%)	0	1/180 (0.56%)	1
Bronchial carcinoma † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Cancer pain † 1	2/572 (0.35%)	2	1/574 (0.17%)	1	0/180 (0.00%)	0
Colon cancer † 1	2/572 (0.35%)	2	3/574 (0.52%)	5	1/180 (0.56%)	2
Colorectal adenocarcinoma † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Diffuse large B-cell lymphoma † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Gastric cancer † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Laryngeal squamous cell carcinoma † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Lung adenocarcinoma † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Lung adenocarcinoma stage 0 † 1	1/572 (0.17%)	1	1/574 (0.17%)	1	0/180 (0.00%)	0
Lung adenocarcinoma stage I † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Lung neoplasm malignant † 1	3/572 (0.52%)	6	1/574 (0.17%)	1	0/180 (0.00%)	0
Malignant melanoma † 1	2/572 (0.35%)	3	0/574 (0.00%)	0	1/180 (0.56%)	1
Malignant melanoma in situ † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Malignant neoplasm progression † 1	11/572 (1.92%)	12	3/574 (0.52%)	4	2/180 (1.11%)	4
Meningioma † 1	0/572 (0.00%)	0	0/574 (0.00%)	0	1/180 (0.56%)	1
Metastases to adrenals † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Metastases to central nervous system † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Metastases to liver † 1	2/572 (0.35%)	2	0/574 (0.00%)	0	1/180 (0.56%)	1
Monoclonal gammopathy † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Neuroendocrine carcinoma † 1	2/572 (0.35%)	2	1/574 (0.17%)	1	0/180 (0.00%)	0
Non-small cell lung cancer † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	1/180 (0.56%)	1
Oesophageal squamous cell carcinoma † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Paraproteinaemia † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Penile cancer † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Plasmacytoma † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Squamous cell carcinoma † 1	1/572 (0.17%)	1	1/574 (0.17%)	1	0/180 (0.00%)	0
Squamous cell carcinoma of head and neck † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Squamous cell carcinoma of lung † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Squamous cell carcinoma of skin † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Transitional cell carcinoma † 1	0/572 (0.00%)	0	1/574 (0.17%)	4	0/180 (0.00%)	0
Tumour pain † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Nervous system disorders
Altered state of consciousness † 1	0/572 (0.00%)	0	0/574 (0.00%)	0	1/180 (0.56%)	1
Aphasia † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Brain stem haemorrhage † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Carotid arteriosclerosis † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Cerebellar infarction † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Cerebral haemorrhage † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Cerebral infarction † 1	2/572 (0.35%)	2	0/574 (0.00%)	0	0/180 (0.00%)	0
Cerebral ischaemia † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Cerebrovascular accident † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	1/180 (0.56%)	1
Cervicobrachial syndrome † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Cognitive disorder † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Dementia † 1	1/572 (0.17%)	1	1/574 (0.17%)	1	1/180 (0.56%)	1
Dementia Alzheimer's type † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Dizziness † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	1/180 (0.56%)	1
Facial paralysis † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Guillain-Barre syndrome † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Headache † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	1/180 (0.56%)	1
Hemianopia † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Hypoglycaemic seizure † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Ischaemic stroke † 1	1/572 (0.17%)	1	1/574 (0.17%)	1	0/180 (0.00%)	0
Lethargy † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Loss of consciousness † 1	0/572 (0.00%)	0	0/574 (0.00%)	0	1/180 (0.56%)	1
Lumbar radiculopathy † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Memory impairment † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Monoparesis † 1	1/572 (0.17%)	1	1/574 (0.17%)	1	0/180 (0.00%)	0
Paraparesis † 1	1/572 (0.17%)	1	1/574 (0.17%)	1	0/180 (0.00%)	0
Seizure † 1	3/572 (0.52%)	3	2/574 (0.35%)	2	0/180 (0.00%)	0
Spinal cord compression † 1	3/572 (0.52%)	3	7/574 (1.22%)	7	1/180 (0.56%)	1
Subarachnoid haemorrhage † 1	1/572 (0.17%)	1	1/574 (0.17%)	1	0/180 (0.00%)	0
Syncope † 1	5/572 (0.87%)	5	0/574 (0.00%)	0	0/180 (0.00%)	0
Thalamus haemorrhage † 1	0/572 (0.00%)	0	0/574 (0.00%)	0	1/180 (0.56%)	1
Toxic encephalopathy † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Transient global amnesia † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Transient ischaemic attack † 1	4/572 (0.70%)	4	2/574 (0.35%)	3	0/180 (0.00%)	0
Product Issues
Device occlusion † 1	0/572 (0.00%)	0	0/574 (0.00%)	0	1/180 (0.56%)	1
Psychiatric disorders
Completed suicide † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Confusional state † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Delirium † 1	2/572 (0.35%)	2	2/574 (0.35%)	2	1/180 (0.56%)	1
Renal and urinary disorders
Acute kidney injury † 1	6/572 (1.05%)	9	3/574 (0.52%)	3	1/180 (0.56%)	3
Bladder mass † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Bladder perforation † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Calculus bladder † 1	1/572 (0.17%)	1	1/574 (0.17%)	1	0/180 (0.00%)	0
Dysuria † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Haematuria † 1	8/572 (1.40%)	12	2/574 (0.35%)	2	1/180 (0.56%)	1
Hydronephrosis † 1	4/572 (0.70%)	4	3/574 (0.52%)	4	1/180 (0.56%)	1
Nephrolithiasis † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	1/180 (0.56%)	1
Renal colic † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Renal failure † 1	2/572 (0.35%)	2	0/574 (0.00%)	0	0/180 (0.00%)	0
Renal impairment † 1	1/572 (0.17%)	1	1/574 (0.17%)	1	0/180 (0.00%)	0
Ureterolithiasis † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	1/180 (0.56%)	1
Urethral obstruction † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Urethral stenosis † 1	0/572 (0.00%)	0	1/574 (0.17%)	2	0/180 (0.00%)	0
Urinary bladder haemorrhage † 1	0/572 (0.00%)	0	0/574 (0.00%)	0	1/180 (0.56%)	1
Urinary incontinence † 1	2/572 (0.35%)	2	0/574 (0.00%)	0	0/180 (0.00%)	0
Urinary retention † 1	7/572 (1.22%)	7	4/574 (0.70%)	4	2/180 (1.11%)	2
Urinary tract obstruction † 1	2/572 (0.35%)	2	0/574 (0.00%)	0	1/180 (0.56%)	1
Reproductive system and breast disorders
Benign prostatic hyperplasia † 1	2/572 (0.35%)	2	1/574 (0.17%)	1	0/180 (0.00%)	0
Pelvic pain † 1	1/572 (0.17%)	1	1/574 (0.17%)	1	0/180 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	1/180 (0.56%)	1
Chronic obstructive pulmonary disease † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Diaphragmatic paralysis † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Dyspnoea † 1	0/572 (0.00%)	0	2/574 (0.35%)	2	0/180 (0.00%)	0
Eosinophilic pneumonia † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Epistaxis † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Hypoxia † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Interstitial lung disease † 1	2/572 (0.35%)	2	0/574 (0.00%)	0	0/180 (0.00%)	0
Pneumonia aspiration † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Pneumonitis † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Pneumothorax † 1	3/572 (0.52%)	3	0/574 (0.00%)	0	1/180 (0.56%)	2
Pulmonary embolism † 1	5/572 (0.87%)	6	3/574 (0.52%)	3	1/180 (0.56%)	1
Pulmonary haemorrhage † 1	1/572 (0.17%)	4	0/574 (0.00%)	0	0/180 (0.00%)	0
Respiratory distress † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Respiratory failure † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Surgical and medical procedures
Bone lesion excision † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Vascular disorders
Aortic aneurysm † 1	2/572 (0.35%)	2	1/574 (0.17%)	1	0/180 (0.00%)	0
Aortic dissection † 1	2/572 (0.35%)	2	0/574 (0.00%)	0	0/180 (0.00%)	0
Aortic dissection rupture † 1	1/572 (0.17%)	2	0/574 (0.00%)	0	0/180 (0.00%)	0
Circulatory collapse † 1	1/572 (0.17%)	2	0/574 (0.00%)	0	1/180 (0.56%)	1
Deep vein thrombosis † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	1/180 (0.56%)	4
Embolism † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Essential hypertension † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Granulomatosis with polyangiitis † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Haematoma † 1	2/572 (0.35%)	3	0/574 (0.00%)	0	1/180 (0.56%)	1
Hypertensive crisis † 1	1/572 (0.17%)	1	1/574 (0.17%)	1	0/180 (0.00%)	0
Hypotension † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Hypovolaemic shock † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Lymphoedema † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Peripheral arterial occlusive disease † 1	0/572 (0.00%)	0	0/574 (0.00%)	0	1/180 (0.56%)	1
Peripheral embolism † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Peripheral ischaemia † 1	1/572 (0.17%)	1	1/574 (0.17%)	1	0/180 (0.00%)	0
Phlebitis † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Thrombosis † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
Vena cava thrombosis † 1	0/572 (0.00%)	0	1/574 (0.17%)	1	0/180 (0.00%)	0
Venous thrombosis † 1	1/572 (0.17%)	1	0/574 (0.00%)	0	0/180 (0.00%)	0
1 Term from vocabulary, MedDRA v23.0; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Enzalutamide + Androgen Deprivation Therapy (ADT)		Placebo + Androgen Deprivation Therapy		Placebo Cross-over Enzalutamide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	443/572 (77.45%)		396/574 (68.99%)		110/180 (61.11%)
Blood and lymphatic system disorders
Anaemia † 1	38/572 (6.64%)	55	28/574 (4.88%)	39	4/180 (2.22%)	5
Gastrointestinal disorders
Constipation † 1	52/572 (9.09%)	60	34/574 (5.92%)	34	8/180 (4.44%)	8
Diarrhoea † 1	48/572 (8.39%)	60	34/574 (5.92%)	35	6/180 (3.33%)	7
Nausea † 1	51/572 (8.92%)	62	34/574 (5.92%)	35	12/180 (6.67%)	16
General disorders
Asthenia † 1	49/572 (8.57%)	70	28/574 (4.88%)	35	4/180 (2.22%)	5
Fatigue † 1	141/572 (24.65%)	180	92/574 (16.03%)	103	39/180 (21.67%)	45
Oedema peripheral † 1	46/572 (8.04%)	60	40/574 (6.97%)	48	7/180 (3.89%)	7
Infections and infestations
Nasopharyngitis † 1	48/572 (8.39%)	57	33/574 (5.75%)	39	13/180 (7.22%)	17
Injury, poisoning and procedural complications
Fall † 1	52/572 (9.09%)	78	16/574 (2.79%)	16	12/180 (6.67%)	18
Investigations
Weight increased † 1	46/572 (8.04%)	83	45/574 (7.84%)	51	2/180 (1.11%)	2
Metabolism and nutrition disorders
Decreased appetite † 1	39/572 (6.82%)	41	18/574 (3.14%)	20	12/180 (6.67%)	13
Musculoskeletal and connective tissue disorders
Arthralgia † 1	104/572 (18.18%)	136	65/574 (11.32%)	78	11/180 (6.11%)	14
Back pain † 1	74/572 (12.94%)	98	67/574 (11.67%)	70	19/180 (10.56%)	22
Bone pain † 1	34/572 (5.94%)	42	31/574 (5.40%)	34	2/180 (1.11%)	2
Musculoskeletal pain † 1	50/572 (8.74%)	59	26/574 (4.53%)	30	7/180 (3.89%)	10
Pain in extremity † 1	37/572 (6.47%)	45	27/574 (4.70%)	28	7/180 (3.89%)	7
Nervous system disorders
Dizziness † 1	44/572 (7.69%)	47	22/574 (3.83%)	24	7/180 (3.89%)	7
Headache † 1	46/572 (8.04%)	52	22/574 (3.83%)	27	5/180 (2.78%)	6
Psychiatric disorders
Insomnia † 1	29/572 (5.07%)	31	20/574 (3.48%)	21	4/180 (2.22%)	4
Reproductive system and breast disorders
Gynaecomastia † 1	33/572 (5.77%)	37	8/574 (1.39%)	8	3/180 (1.67%)	3
Vascular disorders
Hot flush † 1	171/572 (29.90%)	196	131/574 (22.82%)	137	15/180 (8.33%)	16
Hypertension † 1	75/572 (13.11%)	87	35/574 (6.10%)	37	13/180 (7.22%)	15
1 Term from vocabulary, MedDRA v23.0; † Indicates events were collected by 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.

Institute and/or Principal Investigator may publish trial data generated at their specific study site after Sponsor publication of the multi-center data. Sponsor must receive a site's manuscript prior to publication for review and comment as specified in the Investigator Agreement.

Results Point of Contact

• Name/Title: Clinical Trial Disclosure
• Organization: Astellas Pharma Inc.
• Phone: +81 3-3244-0512
• EMail: astellas.resultsdisclosure@astellas.com

Publications of Results:

Armstrong AJ, Szmulewitz RZ, Petrylak DP, Holzbeierlein J, Villers A, Azad A, Alcaraz A, Alekseev B, Iguchi T, Shore ND, Rosbrook B, Sugg J, Baron B, Chen L, Stenzl A. ARCHES: A Randomized, Phase III Study of Androgen Deprivation Therapy With Enzalutamide or Placebo in Men With Metastatic Hormone-Sensitive Prostate Cancer. J Clin Oncol. 2019 Nov 10;37(32):2974-2986. doi: 10.1200/JCO.19.00799. Epub 2019 Jul 22.

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

Cella D, Ganguli A, Turnbull J, Rohay J, Morlock R. US Population Reference Values for Health-Related Quality of Life Questionnaires Based on Demographics of Patients with Prostate Cancer. Adv Ther. 2022 Aug;39(8):3696-3710. doi: 10.1007/s12325-022-02204-3. Epub 2022 Jun 22.

Armstrong AJ, Azad AA, Iguchi T, Szmulewitz RZ, Petrylak DP, Holzbeierlein J, Villers A, Alcaraz A, Alekseev B, Shore ND, Gomez-Veiga F, Rosbrook B, Zohren F, Yamada S, Haas GP, Stenzl A. Improved Survival With Enzalutamide in Patients With Metastatic Hormone-Sensitive Prostate Cancer. J Clin Oncol. 2022 May 20;40(15):1616-1622. doi: 10.1200/JCO.22.00193. Epub 2022 Apr 14.

Stenzl A, Dunshee C, De Giorgi U, Alekseev B, Iguchi T, Szmulewitz RZ, Flaig TW, Tombal B, Morlock R, Ivanescu C, Ramaswamy K, Saad F, Armstrong AJ. Effect of Enzalutamide plus Androgen Deprivation Therapy on Health-related Quality of Life in Patients with Metastatic Hormone-sensitive Prostate Cancer: An Analysis of the ARCHES Randomised, Placebo-controlled, Phase 3 Study. Eur Urol. 2020 Oct;78(4):603-614. doi: 10.1016/j.eururo.2020.03.019. Epub 2020 Apr 23.

• Responsible Party: Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. )
• ClinicalTrials.gov Identifier: NCT02677896
• Other Study ID Numbers: 9785-CL-0335; 2015-003869-28 ( EudraCT Number )
• First Submitted: February 5, 2016
• First Posted: February 9, 2016
• Results First Submitted: January 8, 2020
• Results First Posted: January 21, 2020
• Last Update Posted: April 19, 2024