Trial Outcomes & Findings for A Study to Assess the Efficacy and Safety of Enzalutamide in Subjects With Advanced Hepatocellular Carcinoma (NCT NCT02528643)

Last Updated: 2024-12-06

Results Overview

OS was defined as the time from the date of randomization until the documented date of death from any cause. Participants who were still alive at the time of the data cut-off date was censored on the last date known to be alive or at the data cutoff date, whichever occurs first. Results based on Kaplan-Meier estimates.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

165 participants

Primary outcome timeframe

From date of randomization up to data cut-off date 02 Oct 2017 (approximately 22 months); median follow-up time was 14.65 months for enzalutamide and 13.83 for placebo.

Results posted on

2024-12-06

Participant Flow

Participants were enrolled from 37 sites in 9 countries in Europe, Asia, and North America. Participants with hepatocellular carcinoma (HCC) of any etiology whose disease had progressed on or who were intolerant to sorafenib or other antivascular endothelial growth factor (VEGF) therapy in the advanced setting were enrolled. Double blind treatment (DB) Open label (OL).

Eligible participants were stratified by geographic region (Asia vs other) and Eastern Cooperative Oncology Group (ECOG) performance (0 vs 1) and randomized in a 2:1 ratio. Participants who discontinued treatment entered a follow-up period .

Participant milestones

Participant milestones
Measure	Placebo Participants received enzalutamide matching placebo orally, once daily (QD) during double blind treatment period until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Median treatment duration was 64 days.	Enzalutamide Participants received enzalutamide 160 milligrams (mg) capsules, orally QD during double blind treatment period until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Eligible participants received enzalutamide 160 mg capsules, orally QD during open label period until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Median treatment duration was 64 days.
DB (Median Duration up to 14.65 Months) STARTED	55	110
DB (Median Duration up to 14.65 Months) Treated	55	107
DB (Median Duration up to 14.65 Months) COMPLETED	0	0
DB (Median Duration up to 14.65 Months) NOT COMPLETED	55	110
OL (Median Duration up to 27.56 Months) STARTED	0	1
OL (Median Duration up to 27.56 Months) COMPLETED	0	0
OL (Median Duration up to 27.56 Months) NOT COMPLETED	0	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Participants received enzalutamide matching placebo orally, once daily (QD) during double blind treatment period until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Median treatment duration was 64 days.	Enzalutamide Participants received enzalutamide 160 milligrams (mg) capsules, orally QD during double blind treatment period until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Eligible participants received enzalutamide 160 mg capsules, orally QD during open label period until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Median treatment duration was 64 days.
DB (Median Duration up to 14.65 Months) Adverse Event	5	8
DB (Median Duration up to 14.65 Months) Death	1	6
DB (Median Duration up to 14.65 Months) Lost to Follow-up	0	1
DB (Median Duration up to 14.65 Months) Progressive Disease	44	82
DB (Median Duration up to 14.65 Months) Withdrawal by Subject	2	8
DB (Median Duration up to 14.65 Months) Miscellaneous	3	5
OL (Median Duration up to 27.56 Months) Progressive Disease	0	1

Baseline Characteristics

A Study to Assess the Efficacy and Safety of Enzalutamide in Subjects With Advanced Hepatocellular Carcinoma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Enzalutamide n=110 Participants Participants received enzalutamide 160 mg capsules, orally QD during double blind treatment period until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Median treatment duration was 64 days.	Total n=165 Participants Total of all reporting groups	Placebo n=55 Participants Participants received enzalutamide matching placebo orally, QD during double blind treatment period until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Median treatment duration was 64 days.
Age, Continuous	63.7 Years STANDARD_DEVIATION 10.9 • n=7 Participants	63.3 Years STANDARD_DEVIATION 11.5 • n=5 Participants	62.6 Years STANDARD_DEVIATION 12.5 • n=5 Participants
Sex: Female, Male Female	15 Participants n=7 Participants	21 Participants n=5 Participants	6 Participants n=5 Participants
Sex: Female, Male Male	95 Participants n=7 Participants	144 Participants n=5 Participants	49 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	3 Participants n=7 Participants	3 Participants n=5 Participants	0 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	107 Participants n=7 Participants	162 Participants n=5 Participants	55 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized White	52 Participants n=7 Participants	78 Participants n=5 Participants	26 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	5 Participants n=7 Participants	8 Participants n=5 Participants	3 Participants n=5 Participants
Race/Ethnicity, Customized Asian	52 Participants n=7 Participants	77 Participants n=5 Participants	25 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	1 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized Other	0 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=5 Participants
Geographic Region Asia	48 Participants n=7 Participants	72 Participants n=5 Participants	24 Participants n=5 Participants
Geographic Region Other	62 Participants n=7 Participants	93 Participants n=5 Participants	31 Participants n=5 Participants
Eastern Cooperative Oncology Group (ECOG) PS (0,1) ECOG PS = 0	43 Participants n=7 Participants	66 Participants n=5 Participants	23 Participants n=5 Participants
Eastern Cooperative Oncology Group (ECOG) PS (0,1) ECOG PS = 1	67 Participants n=7 Participants	99 Participants n=5 Participants	32 Participants n=5 Participants

PRIMARY outcome

Timeframe: From date of randomization up to data cut-off date 02 Oct 2017 (approximately 22 months); median follow-up time was 14.65 months for enzalutamide and 13.83 for placebo.

Population: The analysis population was the FAS.

Outcome measures

Outcome measures
Measure	Placebo n=55 Participants Participants received enzalutamide matching placebo orally, QD during double blind treatment period until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Median treatment duration was 64 days.	Enzalutamide n=110 Participants Participants received enzalutamide 160 mg capsules, orally QD during double blind treatment period until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Median treatment duration was 64 days.
Overall Survival (OS)	7.69 months Interval 5.82 to 13.77	7.75 months Interval 6.05 to 9.92

SECONDARY outcome

Timeframe: From first dose of study drug up to 30 days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo

Population: The analysis population was the safety analysis set (SAF), which consisted of all participants who have received at least 1 or partial capsule of study drug.

Safety was assessed by AEs, which included abnormalities identified during a medical test (e.g. laboratory tests, vital signs, electrocardiogram, etc.) if the abnormality induced clinical signs or symptoms, needed active intervention, interruption or discontinuation of study medication or was clinically significant. A treatment-emergent AE (TEAE) was defined as an AE observed after starting administration of the study drug up to 30 days after last dose of study drug or initiation of new treatment, whichever comes first. AEs were considered as serious if resulted in in death, was life-threatening resulted in persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions, resulted in congenital anomaly or birth defect, required inpatient hospitalization or led to prolongation of hospitalization and other medically important events.

Outcome measures

Outcome measures
Measure	Placebo n=55 Participants Participants received enzalutamide matching placebo orally, QD during double blind treatment period until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Median treatment duration was 64 days.	Enzalutamide n=107 Participants Participants received enzalutamide 160 mg capsules, orally QD during double blind treatment period until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Median treatment duration was 64 days.
Number of Participants With Adverse Events (AEs) TEAE	50 Participants	105 Participants
Number of Participants With Adverse Events (AEs) Drug-related TEAEs	24 Participants	69 Participants
Number of Participants With Adverse Events (AEs) Deaths	45 Participants	82 Participants
Number of Participants With Adverse Events (AEs) TEAE Leading to Death	6 Participants	12 Participants
Number of Participants With Adverse Events (AEs) Drug-related TEAEs Leading to Death	0 Participants	0 Participants
Number of Participants With Adverse Events (AEs) Serious TEAEs	22 Participants	47 Participants
Number of Participants With Adverse Events (AEs) Drug-related Serious TEAEs	3 Participants	7 Participants
Number of Participants With Adverse Events (AEs) TEAEs Leading to Treatment Withdrawal	14 Participants	34 Participants
Number of Participants With Adverse Events (AEs) Drug-related TEAEs Leading to Treatment Withdrawal	4 Participants	7 Participants

SECONDARY outcome

Timeframe: Predose at weeks 5, 9 and 13

Population: The analysis population was the pharmacokinetics analysis set (PKAS), consisted of the subset of the SAF population for whom at least 1 quantifiable enzalutamide and N-desmethyl enzalutamide concentration value was available. Participants who had available concentration data were included in the analysis.

Blood samples were collected for analysis.

Outcome measures

Outcome measures
Measure	Placebo n=96 Participants Participants received enzalutamide matching placebo orally, QD during double blind treatment period until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Median treatment duration was 64 days.	Enzalutamide Participants received enzalutamide 160 mg capsules, orally QD during double blind treatment period until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Median treatment duration was 64 days.
Plasma Trough Concentrations of Enzalutamide Week 5	14.29 μg/mL Standard Deviation 4.15	—
Plasma Trough Concentrations of Enzalutamide Week 9	12.15 μg/mL Standard Deviation 4.68	—
Plasma Trough Concentrations of Enzalutamide Week 13	12.45 μg/mL Standard Deviation 5.44	—

SECONDARY outcome

Timeframe: Predose at weeks 5, 9 and 13

Population: The analysis population was the PKAS, with participants who had available concentration data.

Blood samples were collected for analysis.

Outcome measures

Outcome measures
Measure	Placebo n=96 Participants Participants received enzalutamide matching placebo orally, QD during double blind treatment period until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Median treatment duration was 64 days.	Enzalutamide Participants received enzalutamide 160 mg capsules, orally QD during double blind treatment period until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Median treatment duration was 64 days.
Plasma Trough Concentrations N-desmethyl Enzalutamide (M2 Metabolite) Week 5	11.01 μg/mL Standard Deviation 3.63	—
Plasma Trough Concentrations N-desmethyl Enzalutamide (M2 Metabolite) Week 9	12.65 μg/mL Standard Deviation 3.89	—
Plasma Trough Concentrations N-desmethyl Enzalutamide (M2 Metabolite) Week 13	12.21 μg/mL Standard Deviation 4.94	—

SECONDARY outcome

Timeframe: Predose at weeks 5, 9 and 13

Population: The analysis population was the PKAS, with participants who had available concentration data.

Blood samples were collected for analysis.

Outcome measures

Outcome measures
Measure	Placebo n=96 Participants Participants received enzalutamide matching placebo orally, QD during double blind treatment period until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Median treatment duration was 64 days.	Enzalutamide Participants received enzalutamide 160 mg capsules, orally QD during double blind treatment period until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Median treatment duration was 64 days.
Plasma Trough Concentrations of MDPC0001 (M1 Metabolite) Week 5	4.70 μg/mL Standard Deviation 3.86	—
Plasma Trough Concentrations of MDPC0001 (M1 Metabolite) Week 9	5.60 μg/mL Standard Deviation 5.63	—
Plasma Trough Concentrations of MDPC0001 (M1 Metabolite) Week 13	6.12 μg/mL Standard Deviation 4.24	—

SECONDARY outcome

Timeframe: From date of randomization up to data cut-off date 02 Oct 2017 (approximately 22 months); median follow-up time was 14.65 months for enzalutamide and 13.83 for placebo.

Population: The analysis population was the FAS.

PFS was defined as the time from the date of randomization until the date of documented radiographic disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as determined by the investigator or death from any cause on study, whichever occurred first. The earliest of the censoring times was used: Participants with (1) no evaluable postbaseline imaging assessments or did not die were censored at the randomization date; (2) no radiographical progression or did not die before analysis cutoff date were censored at the last radiological assessment date before analysis cutoff date; (3) with no radiographical progression or did not die before new HCC treatment was censored at the last radiological assessment date before start of new HCC treatment. Based on Kaplan-Meier.

Outcome measures

Outcome measures
Measure	Placebo n=55 Participants Participants received enzalutamide matching placebo orally, QD during double blind treatment period until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Median treatment duration was 64 days.	Enzalutamide n=110 Participants Participants received enzalutamide 160 mg capsules, orally QD during double blind treatment period until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Median treatment duration was 64 days.
Progression Free Survival (PFS)	1.87 months Interval 1.84 to 3.45	2.23 months Interval 1.87 to 3.52

Adverse Events

Placebo

Serious events: 22 serious events

Other events: 46 other events

Deaths: 45 deaths

Enzalutamide

Serious events: 47 serious events

Other events: 96 other events

Deaths: 82 deaths

Serious adverse events

Other adverse events

Additional Information

Clinical Trial Disclosure

Astellas Pharma Global Development, Inc.

Phone: 800-888-7704

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER

Measure	Placebo n=55 participants at risk Participants received enzalutamide matching placebo orally, QD during double blind treatment period until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Median treatment duration was 64 days.	Enzalutamide n=107 participants at risk Participants received enzalutamide 160 mg capsules, orally, QD during double blind treatment period until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Eligible participants received enzalutamide 160 mg capsules, orally QD during open label period until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Median treatment duration was 64 days.
General disorders Oedema peripheral	5.5% 3/55 • Number of events 3 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo	5.6% 6/107 • Number of events 7 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo
Blood and lymphatic system disorders Anaemia	12.7% 7/55 • Number of events 8 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo	11.2% 12/107 • Number of events 17 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo
Cardiac disorders Tachycardia	5.5% 3/55 • Number of events 3 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo	0.00% 0/107 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo
Gastrointestinal disorders Abdominal discomfort	5.5% 3/55 • Number of events 3 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo	1.9% 2/107 • Number of events 2 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo
Gastrointestinal disorders Abdominal distension	5.5% 3/55 • Number of events 6 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo	5.6% 6/107 • Number of events 6 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo
Gastrointestinal disorders Abdominal pain	14.5% 8/55 • Number of events 9 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo	14.0% 15/107 • Number of events 24 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo
Gastrointestinal disorders Abdominal pain upper	16.4% 9/55 • Number of events 9 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo	6.5% 7/107 • Number of events 10 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo
Gastrointestinal disorders Ascites	3.6% 2/55 • Number of events 2 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo	10.3% 11/107 • Number of events 16 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo
Gastrointestinal disorders Constipation	9.1% 5/55 • Number of events 5 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo	14.0% 15/107 • Number of events 18 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo
Gastrointestinal disorders Diarrhoea	23.6% 13/55 • Number of events 22 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo	12.1% 13/107 • Number of events 17 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo
Gastrointestinal disorders Dyspepsia	10.9% 6/55 • Number of events 6 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo	8.4% 9/107 • Number of events 13 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo
Gastrointestinal disorders Nausea	10.9% 6/55 • Number of events 6 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo	27.1% 29/107 • Number of events 33 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo
Gastrointestinal disorders Vomiting	9.1% 5/55 • Number of events 5 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo	10.3% 11/107 • Number of events 13 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo
General disorders Asthenia	20.0% 11/55 • Number of events 12 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo	10.3% 11/107 • Number of events 26 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo
General disorders Fatigue	18.2% 10/55 • Number of events 11 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo	35.5% 38/107 • Number of events 49 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo
General disorders Pyrexia	9.1% 5/55 • Number of events 5 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo	7.5% 8/107 • Number of events 9 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo
Investigations Alanine aminotransferase increased	12.7% 7/55 • Number of events 10 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo	7.5% 8/107 • Number of events 8 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo
Investigations Aspartate aminotransferase increased	16.4% 9/55 • Number of events 10 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo	15.0% 16/107 • Number of events 23 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo
Investigations Blood alkaline phosphatase increased	7.3% 4/55 • Number of events 4 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo	4.7% 5/107 • Number of events 5 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo
Investigations Blood bilirubin increased	3.6% 2/55 • Number of events 2 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo	5.6% 6/107 • Number of events 9 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo
Investigations Weight decreased	9.1% 5/55 • Number of events 6 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo	14.0% 15/107 • Number of events 17 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo
Metabolism and nutrition disorders Decreased appetite	21.8% 12/55 • Number of events 13 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo	30.8% 33/107 • Number of events 40 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo
Metabolism and nutrition disorders Hyperkalaemia	9.1% 5/55 • Number of events 5 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo	1.9% 2/107 • Number of events 3 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo
Musculoskeletal and connective tissue disorders Arthralgia	5.5% 3/55 • Number of events 3 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo	3.7% 4/107 • Number of events 5 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo
Musculoskeletal and connective tissue disorders Back pain	5.5% 3/55 • Number of events 3 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo	9.3% 10/107 • Number of events 13 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo
Musculoskeletal and connective tissue disorders Bone pain	5.5% 3/55 • Number of events 3 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo	1.9% 2/107 • Number of events 2 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo
Musculoskeletal and connective tissue disorders Musculoskeletal pain	7.3% 4/55 • Number of events 8 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo	5.6% 6/107 • Number of events 6 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo
Musculoskeletal and connective tissue disorders Pain in extremity	5.5% 3/55 • Number of events 4 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo	2.8% 3/107 • Number of events 3 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo
Nervous system disorders Dizziness	9.1% 5/55 • Number of events 7 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo	3.7% 4/107 • Number of events 7 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo
Nervous system disorders Dysgeusia	7.3% 4/55 • Number of events 5 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo	1.9% 2/107 • Number of events 2 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo
Nervous system disorders Headache	7.3% 4/55 • Number of events 4 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo	6.5% 7/107 • Number of events 9 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo
Psychiatric disorders Insomnia	12.7% 7/55 • Number of events 7 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo	12.1% 13/107 • Number of events 14 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo
Reproductive system and breast disorders Gynaecomastia	0.00% 0/55 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo	11.2% 12/107 • Number of events 14 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo
Respiratory, thoracic and mediastinal disorders Cough	10.9% 6/55 • Number of events 6 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo	11.2% 12/107 • Number of events 14 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo
Respiratory, thoracic and mediastinal disorders Dyspnoea	10.9% 6/55 • Number of events 6 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo	7.5% 8/107 • Number of events 11 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo
Skin and subcutaneous tissue disorders Pruritus	7.3% 4/55 • Number of events 4 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo	12.1% 13/107 • Number of events 14 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo
Vascular disorders Hypertension	0.00% 0/55 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo	5.6% 6/107 • Number of events 14 • From first dose of study drug up to 30days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo