A Safety and Efficacy Study of Oral MDV3100 in Chemotherapy-Naive Patients With Progressive Metastatic Prostate Cancer (PREVAIL)

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ClinicalTrials.gov Identifier: NCT01212991

Recruitment Status : Completed

First Posted : October 1, 2010

Results First Posted : October 16, 2014

Last Update Posted : March 17, 2020

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Sponsor:

Collaborators:

Astellas Pharma Inc

Medivation LLC, a wholly owned subsidiary of Pfizer Inc.

Information provided by (Responsible Party):

Pfizer

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition	Prostate Cancer
Interventions	Drug: Enzalutamide Drug: Placebo
Enrollment	1717

Participant Flow

Recruitment Details
Pre-assignment Details	Following the independent data monitoring committee's recommendation, a protocol amendment was implemented for double-blind phase to be proceeded to open-label phase, which allowed previously placebo treated participants who had not received commercial enzalutamide the opportunity, to receive open-label access to enzalutamide.


Arm/Group Title	Enzalutamide	Placebo	Placebo Participants Crossover to Enzalutamide
Arm/Group Description	Participants received enzalutamide ...	Participants received placebo, admi...	Participants who received placebo i...
Arm/Group Description	Participants received enzalutamide 160 mg, administered as four 40-mg capsules, once per day by mouth.	Participants received placebo, administered as four capsules, once per day by mouth.	Participants who received placebo in double-blind period and who agreed to proceed to open-label phase period, received enzalutamide 160 mg, administered as four 40-mg capsules, once per day by mouth.
Period Title: Double-blind
Started	872	845	0
Safety Population	871	844	0
Completed	0	234	0
Not Completed	872	611	0
Reason Not Completed
Lost to Follow-up	8	4	0
Death	699	550	0
Withdrawal by Subject	16	19	0
Other	7	0	0
Sponsor decision	142	38	0
Period Title: Open-label
Started	0	0 ^[1]	234 ^[2]
Completed	0	0	0
Not Completed	0	0	234
Reason Not Completed
Death	0	0	166
Lost to Follow-up	0	0	5
Withdrawal by Subject	0	0	7
Sponsor decision	0	0	53
Other	0	0	3
[1] participants were given the opportunity to receive open-label access to enzalutamide [2] previous placebo treated participants were given the opportunity to receive enzalutamide

Baseline Characteristics

Arm/Group Title		Enzalutamide	Placebo	Total
Arm/Group Description		Participants received enzalutamide ...	Participants received placebo, admi...	Total of all reporting groups
Arm/Group Description		Participants received enzalutamide 160 mg, administered as four 40-mg capsules, once per day by mouth.	Participants received placebo, administered as four capsules, once per day by mouth.	Total of all reporting groups
Overall Number of Baseline Participants		872	845	1717
Baseline Analysis Population Description		[Not Specified]
Baseline Analysis Population Description		[Not Specified]
Age, Categorical Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	872 participants	845 participants	1717 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	179 20.5%	179 21.2%	358 20.9%
	>=65 years	693 79.5%	666 78.8%	1359 79.1%
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	872 participants	845 participants	1717 participants
		71.3 (8.51)	71.2 (8.42)	71.3 (8.47)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	872 participants	845 participants	1717 participants
	Female	0 0.0%	0 0.0%	0 0.0%
	Male	872 100.0%	845 100.0%	1717 100.0%
Region of Enrollment Measure Type: Number Unit of measure: Count of participants	Number Analyzed	872 participants	845 participants	1717 participants
United States		127	120	247
Slovakia		13	14	27
Finland		18	15	33
Spain		44	37	81
Lithuania		8	6	14
Austria		9	9	18
Russian Federation		12	10	22
Israel		14	11	25
United Kingdom		78	75	153
Italy		15	15	30
France		85	90	175
Canada		91	88	179
Poland		21	18	39
Belgium		28	29	57
Singapore		5	4	9
Australia		116	116	232
Denmark		43	44	87
Netherlands		15	13	28
Germany		41	42	83
Japan		28	33	61
Sweden		21	18	39
Korea, Republic of		40	38	78

Outcome Measures

1.Primary Outcome


Title	Overall Survival
Description	Overall survival was defined as the time from randomization to death d...
Description	Overall survival was defined as the time from randomization to death due to any cause. For patients who were alive at the time of the analysis data cutoff, overall survival was censored at the last date the patient was known to be alive or analysis data cutoff date, whichever was first. This included patients who were known to have died after the data analysis cutoff date. Patients with no post-baseline survival information were censored on the date of randomization.
Time Frame	During study period (up to 3 years)

Outcome Measure Data

Analysis Population Description

Intent to Treat (ITT) - All patients randomly assigned to treatment.


Arm/Group Title	Enzalutamide	Placebo
Arm/Group Description:	Participants received enzalutamide ...	Participants received placebo, admi...
Arm/Group Description:	Participants received enzalutamide 160 mg, administered as four 40-mg capsules, once per day by mouth.	Participants received placebo, administered as four capsules, once per day by mouth.
Overall Number of Participants Analyzed	872	845
Median (95% Confidence Interval) Unit of Measure: months
	32.4 ^[1] (30.1 to NA)	30.2 ^[1] (28.0 to NA)

[1]

The upper limit of the 95% confidence interval was not calculable because an insufficient number of participants reached the event at the final time point for assessment.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enzalutamide, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	A 2-stage group sequential method (Lan DeMets OBF) assigned the level of significance for the pre-specified interim overall survival analysis (p<0.015) based on overall 2-sided type I error rate of 0.049. Final results based upon interim analysis.
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.706
	Confidence Interval	(2-Sided) 95% 0.596 to 0.837
	Estimation Comments	The hazard ratio is based on an unstratified Cox regression model (with treatment as the only covariate) and is relative to placebo with <1 favoring enzalutamide.

2.Primary Outcome


Title	Radiographic Progression-free Survival (rPFS)
Description	Radiographic progression-free survival was defined as the time from ra...
Description	Radiographic progression-free survival was defined as the time from randomization to the first objective evidence of radiographic disease progression assessed by independent central radiology review or death due to any cause within 168 days after treatment discontinuation, whichever was first. Radiographic disease progression was evaluated by CT scan or MRI and radionuclide bone scans at regularly scheduled visits. Radiographic disease progression in bone required a confirmatory scan. Radiographic disease progression in soft tissue did not require a confirmatory scan for purposes of analysis. Radiographic disease progression was evaluated by independent central radiology review using RECIST 1.1 for soft tissue disease and PCWG2 guidelines for bone disease. Patients who did not reach the endpoint were censored at their last assessment.
Time Frame	During study period (up to 20 months)

Outcome Measure Data

Analysis Population Description

Intent to Treat (ITT) - All patients randomly assigned to treatment excluding 84 patients who were not randomized before the radiographic Progression-free Survival data cutoff date of 06 May 2012.


Arm/Group Title	Enzalutamide	Placebo
Arm/Group Description:	Participants received enzalutamide ...	Participants received placebo, admi...
Arm/Group Description:	Participants received enzalutamide 160 mg, administered as four 40-mg capsules, once per day by mouth.	Participants received placebo, administered as four capsules, once per day by mouth.
Overall Number of Participants Analyzed	832	801
Median (95% Confidence Interval) Unit of Measure: months
	NA ^[1] (13.8 to NA)	3.9 (3.7 to 5.4)

[1]

The median time to radiographic progression-free survival and its upper 95% confidence limit were not yet reached in the enzalutamide group because an insufficient number of patients had an event at the time of analysis.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enzalutamide, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	The assigned 2-sided type I error rate was 0.001 for the analysis of radiographic progression-free survival.
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.186
	Confidence Interval	(2-Sided) 95% 0.149 to 0.231
	Estimation Comments	The hazard ratio is based on an unstratified Cox regression model (with treatment as the only covariate) and is relative to placebo with < 1 favoring enzalutamide.

3.Secondary Outcome


Title	Time to First Skeletal-related Event
Description	Time to first skeletal-related event was defined as the time from rand...
Description	Time to first skeletal-related event was defined as the time from randomization to the date of the first occurrence of a skeletal-related event for each patient. A skeletal-related event was defined as radiation therapy or surgery to bone for prostate cancer, pathological bone fracture, spinal cord compression, or initiation/change in antineoplastic therapy to treat bone pain from prostate cancer. Skeletal-related events were recorded at each scheduled and unscheduled study visit and during long-term follow-up if a skeletal-related event was not documented previously. Patients who did not have a skeletal-related event at the time of the analysis data cutoff were censored at the date of last assessment indicating no evidence of skeletal-related event. Patients with no postbaseline assessments were censored on the date of randomization.
Time Frame	During study period (up to 3 years)

Outcome Measure Data

Analysis Population Description

Intent to Treat (ITT) - All patients randomly assigned to treatment.


Arm/Group Title	Enzalutamide	Placebo
Arm/Group Description:	Participants received enzalutamide ...	Participants received placebo, admi...
Arm/Group Description:	Participants received enzalutamide 160 mg, administered as four 40-mg capsules, once per day by mouth.	Participants received placebo, administered as four capsules, once per day by mouth.
Overall Number of Participants Analyzed	872	845
Median (95% Confidence Interval) Unit of Measure: months
	31.1 ^[1] (29.5 to NA)	31.3 ^[1] (23.9 to NA)

[1]

The upper limit of the 95% confidence interval was not calculable because an insufficient number of participants reached the event at the final time point for assessment.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enzalutamide, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	The Holm step down method of multiple comparisons was used to maintain a study wide type I error of 5% for prespecified secondary efficacy analyses. The 2-sided type I error rate was 0.01 for this analysis.
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.718
	Confidence Interval	95% 0.610 to 0.844
	Estimation Comments	The hazard ratio is based on an unstratified Cox regression model (with treatment as the only covariate) and is relative to placebo with < 1 favoring enzalutamide.

4.Secondary Outcome


Title	Time to Initiation of Cytotoxic Chemotherapy
Description	The time to initiation of cytotoxic chemotherapy is defined as the tim...
Description	The time to initiation of cytotoxic chemotherapy is defined as the time from randomization to the date of initiation of cytotoxic chemotherapy for the treatment of prostate cancer for each patient. For patients who did not start cytotoxic chemotherapy at the time of the analysis data cutoff, time to initiation of cytotoxic chemotherapy was censored at the date of last assessment where no cytotoxic chemotherapy was indicated or at the analysis data cutoff date, whichever was first. Time to initiation of cytotoxic chemotherapy for patients with no postbaseline assessments was censored on the date of randomization.
Time Frame	During study period (up to 3 years)

Outcome Measure Data

Analysis Population Description

Intent to Treat (ITT) - All patients randomly assigned to treatment.


Arm/Group Title	Enzalutamide	Placebo
Arm/Group Description:	Participants received enzalutamide ...	Participants received placebo, admi...
Arm/Group Description:	Participants received enzalutamide 160 mg, administered as four 40-mg capsules, once per day by mouth.	Participants received placebo, administered as four capsules, once per day by mouth.
Overall Number of Participants Analyzed	872	845
Median (95% Confidence Interval) Unit of Measure: months
	28.0 ^[1] (25.8 to NA)	10.8 (9.7 to 12.2)

[1]

The upper limit of the 95% confidence interval was not calculable because an insufficient number of participants reached the event at the final time point for assessment.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enzalutamide, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	The Holm step down method of multiple comparisons was used to maintain a study wide type I error of 5% for prespecified secondary efficacy analyses. The 2-sided type I error rate was 0.0125 for this analysis.
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.349
	Confidence Interval	95% 0.303 to 0.403
	Estimation Comments	The hazard ratio is based on an unstratified Cox regression model (with treatment as the only covariate) and is relative to placebo with < 1 favoring enzalutamide.

5.Secondary Outcome


Title	Time to Prostate-specific Antigen (PSA) Progression
Description	Time to PSA progression was defined as the time from randomization to ...
Description	Time to PSA progression was defined as the time from randomization to date of first confirmed observation of PSA progression for each patient. For patients with PSA declines at week 13, the PSA progression date was defined as the date that a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL above the nadir was documented, and confirmed 3 or more weeks later. For patients with no PSA decline at week 13, the PSA progression date was defined as the date that a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL above baseline was documented, and confirmed 3 or more weeks later. For patients who did not have confirmed PSA progression at the time of the analysis data cutoff, time to PSA progression was censored at the date of the last PSA assessment showing no evidence of confirmed PSA progression or the analysis data cutoff date, whichever was first. Time to PSA progression for patients with no postbaseline assessments was censored on the date of randomization.
Time Frame	During study period (up to 3 years)

Outcome Measure Data

Analysis Population Description

Intent to Treat (ITT) - All patients randomized.


Arm/Group Title	Enzalutamide	Placebo
Arm/Group Description:	Participants received enzalutamide ...	Participants received placebo, admi...
Arm/Group Description:	Participants received enzalutamide 160 mg, administered as four 40-mg capsules, once per day by mouth.	Participants received placebo, administered as four capsules, once per day by mouth.
Overall Number of Participants Analyzed	872	845
Median (95% Confidence Interval) Unit of Measure: months
	11.2 (11.1 to 13.7)	2.8 (2.8 to 2.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enzalutamide, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	The Holm step down method of multiple comparisons was used to maintain a study wide type I error of 5% for prespecified secondary efficacy analyses. The 2-sided type I error rate was 0.0167 for this analysis.
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.169
	Confidence Interval	95% 0.147 to 0.195
	Estimation Comments	The hazard ratio is based on an unstratified Cox regression model (with treatment as the only covariate) and is relative to placebo with < 1 favoring enzalutamide.

6.Secondary Outcome


Title	Percentage of Patients With Prostate Specific Antigen (PSA) Response ≥ 50%
Description	PSA response was defined as a ≥ 50% reduction in PSA from baseli...
Description	PSA response was defined as a ≥ 50% reduction in PSA from baseline to the lowest postbaseline PSA value and required confirmation by a consecutive assessment at least 3 weeks later. Patients were evaluable for PSA response rate if a patient had a PSA level measured at baseline and at least one postbaseline assessment.
Time Frame	During study period (up to 3 years)

Outcome Measure Data

Analysis Population Description

Evaluable intent to treat (ITT) population - All patients randomly assigned to treatment with PSA values at baseline and at least one postbaseline assessment.


Arm/Group Title	Enzalutamide	Placebo
Arm/Group Description:	Participants received enzalutamide ...	Participants received placebo, admi...
Arm/Group Description:	Participants received enzalutamide 160 mg, administered as four 40-mg capsules, once per day by mouth.	Participants received placebo, administered as four capsules, once per day by mouth.
Overall Number of Participants Analyzed	854	777
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: Percentage of Participants
	78 (75.1 to 80.7)	3.5 (2.3 to 5.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enzalutamide, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	The Holm step down method of multiple comparisons was used to maintain a study wide type I error of 5% for prespecified secondary efficacy analyses. The 2-sided type I error rate was 0.025 for this analysis.
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Difference in response rates
	Estimated Value	74.51
	Confidence Interval	95% 71.45 to 77.57
	Estimation Comments	[Not Specified]

7.Secondary Outcome


Title	Best Overall Soft Tissue Response
Description	The best overall soft tissue objective response is defined as partial ...
Description	The best overall soft tissue objective response is defined as partial response [PR] or complete response [CR] while on study treatment based on investigator assessments of target, nontarget, and new lesions using RECIST 1.1. Soft tissue was assessed by CT or MRI at regularly scheduled visits. Only patients with measurable soft tissue disease (ie, at least 1 target lesion identified per RECIST 1.1) at screening are included in this analysis. All percentages are based on number of participants with measurable soft tissue disease at screening in each treatment group.
Time Frame	During study period (up to 3 years)

Outcome Measure Data

Analysis Population Description

Intent to treat (ITT) population With Measurable Disease - All participants who were randomly assigned to treatment and had at least one target lesion at screening.


Arm/Group Title	Enzalutamide	Placebo
Arm/Group Description:	Participants received enzalutamide ...	Participants received placebo, admi...
Arm/Group Description:	Participants received enzalutamide 160 mg, administered as four 40-mg capsules, once per day by mouth.	Participants received placebo, administered as four capsules, once per day by mouth.
Overall Number of Participants Analyzed	396	381
Measure Type: Number Unit of Measure: Percentage of participants
	58.8	5.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Enzalutamide, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	The Holm step down method of multiple comparisons was used to maintain a study wide type I error of 5% for prespecified secondary efficacy analyses. The 2-sided type I error rate was 0.05 for this analysis.
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Difference in objective response rate
	Estimated Value	53.85
	Confidence Interval	95% 48.53 to 59.17
	Estimation Comments	[Not Specified]

8.Other Pre-specified Outcome


Title	Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description	An AE was any untoward medical occurrence in a participant who receive...
Description	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug and up to a maximum of 6.5 years that were absent before treatment or that worsened relative to pretreatment state. AEs included both serious and non-serious AEs.
Time Frame	Baseline to discontinuation from the study or death, whichever occurred first (maximum duration of 6.5 years)

Outcome Measure Data

Analysis Population Description

The safety analysis set included all randomized participants who received at least 1 dose or partial dose of study drug.


Arm/Group Title	Enzalutamide	Placebo	Placebo Participants Crossover to Enzalutamide
Arm/Group Description:	Participants received enzalutamide ...	Participants received placebo, admi...	Participants who received placebo i...
Arm/Group Description:	Participants received enzalutamide 160 mg, administered as four 40-mg capsules, once per day by mouth.	Participants received placebo, administered as four capsules, once per day by mouth.	Participants who received placebo in double-blind period and who agreed to proceed to open-label phase period, received enzalutamide 160 mg, administered as four 40-mg capsules, once per day by mouth.
Overall Number of Participants Analyzed	871	844	234
Measure Type: Count of Participants Unit of Measure: Participants
AEs	857 98.4%	791 93.7%	212 90.6%
SAEs	384 44.1%	229 27.1%	104 44.4%

9.Other Pre-specified Outcome


Title	Number of Participants With Treatment-Emergent Adverse Events (AEs) Greater Than or Equal to (>=) Grade 3, Based on National Cancer Institute Common Terminology Criteria for AEs (CTCAE), Version 4.0
Description	An AE is any untoward medical occurrence in participant who received s...
Description	An AE is any untoward medical occurrence in participant who received study drug without regard to possibility of causal relationship. As per NCI CTCAE, Grade 3 events =medically significant but not immediately life-threatening, unacceptable or intolerable events, significantly interrupting usual daily activity, require systemic drug therapy/other treatment, Grade 4 events =participant to be in imminent danger of death. Grade 5 events =death. A treatment-emergent AE (TEAE) was defined as an AE that occurred from the date and time of the first dose of study drug up to a maximum duration of 6.5 years. Number of participants with AEs of any of the Grade 3 or above (Grade 4, 5) were reported.
Time Frame	Baseline to discontinuation from the study or death, whichever occurred first (maximum duration of 6.5 years)

Outcome Measure Data

Analysis Population Description

The safety analysis set included all randomized participants who received at least 1 dose or partial dose of study drug.


Arm/Group Title	Enzalutamide	Placebo	Placebo Participants Crossover to Enzalutamide
Arm/Group Description:	Participants received enzalutamide ...	Participants received placebo, admi...	Participants who received placebo i...
Arm/Group Description:	Participants received enzalutamide 160 mg, administered as four 40-mg capsules, once per day by mouth.	Participants received placebo, administered as four capsules, once per day by mouth.	Participants who received placebo in double-blind period and who agreed to proceed to open-label phase period, received enzalutamide 160 mg, administered as four 40-mg capsules, once per day by mouth.
Overall Number of Participants Analyzed	871	844	234
Measure Type: Count of Participants Unit of Measure: Participants
	465 53.4%	318 37.7%	129 55.1%

10.Other Pre-specified Outcome


Title	Number of Participants With Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description	Treatment-related AE was any untoward medical occurrence attributed to...
Description	Treatment-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug and up to a maximum duration of 6.5 years that were absent before treatment or that worsened relative to pre-treatment state. Relatedness to study drug was assessed by the investigator.
Time Frame	Baseline to discontinuation from the study or death, whichever occurred first (maximum duration of 6.5 years)

Outcome Measure Data

Analysis Population Description

The safety analysis set included all randomized participants who received at least 1 dose or partial dose of study drug.


Arm/Group Title	Enzalutamide	Placebo	Placebo Participants Crossover to Enzalutamide
Arm/Group Description:	Participants received enzalutamide ...	Participants received placebo, admi...	Participants who received placebo i...
Arm/Group Description:	Participants received enzalutamide 160 mg, administered as four 40-mg capsules, once per day by mouth.	Participants received placebo, administered as four capsules, once per day by mouth.	Participants who received placebo in double-blind period and who agreed to proceed to open-label phase period, received enzalutamide 160 mg, administered as four 40-mg capsules, once per day by mouth.
Overall Number of Participants Analyzed	871	844	234
Measure Type: Count of Participants Unit of Measure: Participants
AEs	579 66.5%	423 50.1%	119 50.9%
SAEs	38 4.4%	22 2.6%	14 6.0%

Adverse Events

Time Frame	Baseline to discontinuation from the study or death, whichever occurred first (maximum duration of 6.5 years)
Adverse Event Reporting Description	Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Analysis was performed on safety set.

Arm/Group Title	Enzalutamide	Placebo	Placebo Participants Crossover to Enzalutamide
Arm/Group Description	Participants received enzalutamide ...	Participants received placebo, admi...	Participants who received placebo i...
Arm/Group Description	Participants received enzalutamide 160 mg, administered as four 40-mg capsules, once per day by mouth.	Participants received placebo, administered as four capsules, once per day by mouth.	Participants who received placebo in double-blind period and who agreed to proceed to open-label phase period, received enzalutamide 160 mg, administered as four 40-mg capsules, once per day by mouth.
All-Cause Mortality
	Enzalutamide	Placebo	Placebo Participants Crossover to Enzalutamide
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	699/871 (80.25%)	550/844 (65.17%)	166/234 (70.94%)
Serious Adverse Events Serious Adverse Events
	Enzalutamide	Placebo	Placebo Participants Crossover to Enzalutamide
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	384/871 (44.09%)	229/844 (27.13%)	104/234 (44.44%)
Blood and lymphatic system disorders
Anaemia ^* 1	18/871 (2.07%)	9/844 (1.07%)	6/234 (2.56%)
Disseminated intravascular coagulation ^* 1	1/871 (0.11%)	1/844 (0.12%)	1/234 (0.43%)
Iron deficiency anaemia ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Neutropenia ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Pancytopenia ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Haemolytic Uraemic Syndrome ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Idiopathic Thrombocytopenic Purpura ^* 1	2/871 (0.23%)	0/844 (0.00%)	0/234 (0.00%)
Lymphadenopathy ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Platelet Dysfunction ^* 1	0/871 (0.00%)	0/844 (0.00%)	1/234 (0.43%)
Cardiac disorders
Atrial fibrillation ^* 1	10/871 (1.15%)	6/844 (0.71%)	0/234 (0.00%)
Acute myocardial infarction ^* 1	11/871 (1.26%)	0/844 (0.00%)	1/234 (0.43%)
Arteriosclerosis coronary artery ^* 1	1/871 (0.11%)	1/844 (0.12%)	1/234 (0.43%)
Atrioventricular block ^* 1	1/871 (0.11%)	1/844 (0.12%)	0/234 (0.00%)
Acute coronary syndrome ^* 1	5/871 (0.57%)	0/844 (0.00%)	0/234 (0.00%)
Angina pectoris ^* 1	3/871 (0.34%)	0/844 (0.00%)	1/234 (0.43%)
Angina unstable ^* 1	0/871 (0.00%)	1/844 (0.12%)	1/234 (0.43%)
Cardiac failure acute ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Congestive cardiomyopathy ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Hypertensive heart disease ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Sick sinus syndrome ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Sinus tachycardia ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Ventricular tachycardia ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Ventricular extrasystoles ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Atrial Flutter ^* 1	0/871 (0.00%)	0/844 (0.00%)	2/234 (0.85%)
Atrial Tachycardia ^* 1	0/871 (0.00%)	0/844 (0.00%)	1/234 (0.43%)
Atrioventricular Block Complete ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Bradycardia ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Cardiac Arrest ^* 1	3/871 (0.34%)	2/844 (0.24%)	0/234 (0.00%)
Cardiac Failure ^* 1	5/871 (0.57%)	2/844 (0.24%)	3/234 (1.28%)
Cardiac Failure Congestive ^* 1	2/871 (0.23%)	1/844 (0.12%)	1/234 (0.43%)
Cardiopulmonary Failure ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Cardiovascular Insufficiency ^* 1	0/871 (0.00%)	0/844 (0.00%)	1/234 (0.43%)
Coronary Artery Disease ^* 1	6/871 (0.69%)	0/844 (0.00%)	0/234 (0.00%)
Coronary Artery Stenosis ^* 1	0/871 (0.00%)	0/844 (0.00%)	1/234 (0.43%)
Ischaemic Cardiomyopathy ^* 1	0/871 (0.00%)	0/844 (0.00%)	1/234 (0.43%)
Left Ventricular Failure ^* 1	2/871 (0.23%)	0/844 (0.00%)	0/234 (0.00%)
Mitral Valve Disease ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Mitral Valve Incompetence ^* 1	0/871 (0.00%)	0/844 (0.00%)	1/234 (0.43%)
Myocardial Infarction ^* 1	6/871 (0.69%)	1/844 (0.12%)	1/234 (0.43%)
Supraventricular Tachycardia ^* 1	2/871 (0.23%)	0/844 (0.00%)	1/234 (0.43%)
Tricuspid Valve Incompetence ^* 1	0/871 (0.00%)	0/844 (0.00%)	1/234 (0.43%)
Ventricular Fibrillation ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Wolff-Parkinson-White Syndrome ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Ear and labyrinth disorders
Vertigo ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Endocrine disorders
Adrenal insufficiency ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Goitre ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Inappropriate antidiuretic hormone secretion ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Eye disorders
Amaurosis ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Cataract ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Retinal artery occlusion ^* 1	2/871 (0.23%)	0/844 (0.00%)	0/234 (0.00%)
Eyelid Ptosis ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Retinal Vein Occlusion ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Gastrointestinal disorders
Constipation ^* 1	5/871 (0.57%)	5/844 (0.59%)	2/234 (0.85%)
Vomiting ^* 1	2/871 (0.23%)	2/844 (0.24%)	0/234 (0.00%)
Diarrhoea ^* 1	3/871 (0.34%)	1/844 (0.12%)	1/234 (0.43%)
Nausea ^* 1	3/871 (0.34%)	0/844 (0.00%)	2/234 (0.85%)
Upper gastrointestinal haemorrhage ^* 1	4/871 (0.46%)	0/844 (0.00%)	0/234 (0.00%)
Abdominal pain ^* 1	1/871 (0.11%)	1/844 (0.12%)	0/234 (0.00%)
Gastrointestinal haemorrhage ^* 1	1/871 (0.11%)	1/844 (0.12%)	1/234 (0.43%)
Inguinal hernia ^* 1	1/871 (0.11%)	1/844 (0.12%)	0/234 (0.00%)
Intestinal obstruction ^* 1	0/871 (0.00%)	2/844 (0.24%)	0/234 (0.00%)
Melaena ^* 1	1/871 (0.11%)	1/844 (0.12%)	0/234 (0.00%)
Small intestinal obstruction ^* 1	2/871 (0.23%)	1/844 (0.12%)	1/234 (0.43%)
Duodenal ulcer haemorrhage ^* 1	2/871 (0.23%)	0/844 (0.00%)	0/234 (0.00%)
Abdominal pain lower ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Diverticulum intestinal haemorrhagic ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Dysphagia ^* 1	1/871 (0.11%)	1/844 (0.12%)	0/234 (0.00%)
Gastric ulcer haemorrhage ^* 1	2/871 (0.23%)	0/844 (0.00%)	0/234 (0.00%)
Large intestinal haemorrhage ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Large intestine polyp ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Lower gastrointestinal haemorrhage ^* 1	2/871 (0.23%)	0/844 (0.00%)	0/234 (0.00%)
Pancreatitis acute ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Peritoneal haemorrhage ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Rectal stenosis ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Subileus ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Duodenal ulcer ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Gastritis ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Anal Stenosis ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Gastrointestinal Ulcer ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Ileus ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Oesophageal Spasm ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Peptic Ulcer ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Rectal Haemorrhage ^* 1	0/871 (0.00%)	0/844 (0.00%)	2/234 (0.85%)
General disorders
General physical health deterioration ^* 1	15/871 (1.72%)	10/844 (1.18%)	6/234 (2.56%)
Disease progression ^* 1	10/871 (1.15%)	7/844 (0.83%)	11/234 (4.70%)
Death ^* 1	5/871 (0.57%)	1/844 (0.12%)	0/234 (0.00%)
Oedema peripheral ^* 1	2/871 (0.23%)	3/844 (0.36%)	0/234 (0.00%)
Fatigue ^* 1	5/871 (0.57%)	0/844 (0.00%)	2/234 (0.85%)
Gait disturbance ^* 1	2/871 (0.23%)	1/844 (0.12%)	0/234 (0.00%)
Pain ^* 1	3/871 (0.34%)	0/844 (0.00%)	0/234 (0.00%)
Performance status decreased ^* 1	0/871 (0.00%)	2/844 (0.24%)	0/234 (0.00%)
Pyrexia ^* 1	2/871 (0.23%)	1/844 (0.12%)	3/234 (1.28%)
Asthenia ^* 1	0/871 (0.00%)	1/844 (0.12%)	5/234 (2.14%)
Chest pain ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Device dislocation ^* 1	1/871 (0.11%)	1/844 (0.12%)	1/234 (0.43%)
Drowning ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Generalized oedema ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Medical device complication ^* 1	0/871 (0.00%)	1/844 (0.12%)	1/234 (0.43%)
Non-cardiac chest pain ^* 1	2/871 (0.23%)	0/844 (0.00%)	0/234 (0.00%)
Oedema ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Sudden death ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Suprapubic pain ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Adverse drug reaction ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Device occlusion ^* 1	2/871 (0.23%)	1/844 (0.12%)	0/234 (0.00%)
Local swelling ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Device Malfunction ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Medical Device Pain ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Multi-Organ Failure ^* 1	3/871 (0.34%)	0/844 (0.00%)	0/234 (0.00%)
Hepatobiliary disorders
Bile duct obstruction ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Cholecystitis ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Cholecystitis chronic ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Hepatic failure ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Hepatic function abnormal ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Jaundice ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Jaundice cholestatic ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Bile Duct Stone ^* 1	1/871 (0.11%)	0/844 (0.00%)	1/234 (0.43%)
Cholangitis ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Hepatic Cyst ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Immune system disorders
Anaphylactic shock ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Drug hypersensitivity ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Infections and infestations
Pneumonia ^* 1	14/871 (1.61%)	7/844 (0.83%)	8/234 (3.42%)
Urinary tract infection ^* 1	8/871 (0.92%)	5/844 (0.59%)	10/234 (4.27%)
Urosepsis ^* 1	5/871 (0.57%)	3/844 (0.36%)	4/234 (1.71%)
Sepsis ^* 1	3/871 (0.34%)	4/844 (0.47%)	1/234 (0.43%)
Gastroenteritis ^* 1	4/871 (0.46%)	1/844 (0.12%)	0/234 (0.00%)
Device related infection ^* 1	2/871 (0.23%)	1/844 (0.12%)	0/234 (0.00%)
Bronchitis ^* 1	1/871 (0.11%)	1/844 (0.12%)	0/234 (0.00%)
Cellulitis ^* 1	2/871 (0.23%)	1/844 (0.12%)	0/234 (0.00%)
Herpes zoster ^* 1	1/871 (0.11%)	1/844 (0.12%)	0/234 (0.00%)
Appendicitis ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Appendicitis perforated ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Bacteraemia ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Diverticulitis ^* 1	2/871 (0.23%)	0/844 (0.00%)	0/234 (0.00%)
Gallbladder abscess ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Gastroenteritis staphylococcal ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Lower respiratory tract infection ^* 1	2/871 (0.23%)	0/844 (0.00%)	0/234 (0.00%)
Osteomyelitis ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Peritonitis ^* 1	1/871 (0.11%)	0/844 (0.00%)	1/234 (0.43%)
Respiratory tract infection ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Septic shock ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Urinary tract infection fungal ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Viral infection ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Wound infection ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Chronic sinusitis ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Acute Sinusitis ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Arthritis Bacterial ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Cholecystitis Infective ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Clostridium Difficile Colitis ^* 1	0/871 (0.00%)	0/844 (0.00%)	1/234 (0.43%)
Clostridium Difficile Sepsis ^* 1	0/871 (0.00%)	0/844 (0.00%)	1/234 (0.43%)
Erysipelas ^* 1	0/871 (0.00%)	0/844 (0.00%)	1/234 (0.43%)
Escherichia Urinary Tract Infection ^* 1	0/871 (0.00%)	0/844 (0.00%)	1/234 (0.43%)
Infected Dermal Cyst ^* 1	0/871 (0.00%)	0/844 (0.00%)	1/234 (0.43%)
Infection ^* 1	2/871 (0.23%)	0/844 (0.00%)	3/234 (1.28%)
Meningitis Pneumococcal ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Postoperative Wound Infection ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Pulmonary Sepsis ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Pyelonephritis Acute ^* 1	0/871 (0.00%)	0/844 (0.00%)	1/234 (0.43%)
Upper Respiratory Tract Infection ^* 1	0/871 (0.00%)	0/844 (0.00%)	2/234 (0.85%)
Injury, poisoning and procedural complications
Fall ^* 1	12/871 (1.38%)	3/844 (0.36%)	2/234 (0.85%)
Femoral neck fracture ^* 1	7/871 (0.80%)	0/844 (0.00%)	0/234 (0.00%)
Femur fracture ^* 1	3/871 (0.34%)	2/844 (0.24%)	1/234 (0.43%)
Spinal compression fracture ^* 1	4/871 (0.46%)	1/844 (0.12%)	0/234 (0.00%)
Road traffic accident ^* 1	2/871 (0.23%)	1/844 (0.12%)	0/234 (0.00%)
Humerus fracture ^* 1	4/871 (0.46%)	0/844 (0.00%)	1/234 (0.43%)
Wrist fracture ^* 1	3/871 (0.34%)	0/844 (0.00%)	0/234 (0.00%)
Hip fracture ^* 1	3/871 (0.34%)	2/844 (0.24%)	1/234 (0.43%)
Subdural haematoma ^* 1	0/871 (0.00%)	2/844 (0.24%)	2/234 (0.85%)
Toxicity to various agents ^* 1	2/871 (0.23%)	0/844 (0.00%)	0/234 (0.00%)
Cystitis radiation ^* 1	2/871 (0.23%)	0/844 (0.00%)	0/234 (0.00%)
Ankle fracture ^* 1	1/871 (0.11%)	1/844 (0.12%)	0/234 (0.00%)
Chest injury ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Clavicle fracture ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Extradural haematoma ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Facial bones fracture ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Foreign body ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Gastroenteritis radiation ^* 1	2/871 (0.23%)	0/844 (0.00%)	0/234 (0.00%)
Hand fracture ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Head injury ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Lumbar vertebral fracture ^* 1	1/871 (0.11%)	1/844 (0.12%)	0/234 (0.00%)
Post procedural haemorrhage ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Radiation oesophagitis ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Radius fracture ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Skeletal injury ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Subdural haemorrhage ^* 1	1/871 (0.11%)	1/844 (0.12%)	0/234 (0.00%)
Tibia fracture ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Traumatic fracture ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Traumatic intracranial haemorrhage ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Upper limb fracture ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Contrast media reaction ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Contusion ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Lower limb fracture ^* 1	2/871 (0.23%)	0/844 (0.00%)	0/234 (0.00%)
Post procedural haematuria ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Procedural pain ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Pubis fracture ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Vascular pseudoaneurysm ^* 1	2/871 (0.23%)	0/844 (0.00%)	0/234 (0.00%)
Back Injury ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Cervical Vertebral Fracture ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Joint Injury ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Post Procedural Bile Leak ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Renal Haematoma ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Rib Fracture ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Spinal Fracture ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Sternal Fracture ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Thoracic Vertebral Fracture ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Investigations
Electrocardiogram QT prolonged ^* 1	1/871 (0.11%)	1/844 (0.12%)	0/234 (0.00%)
Haemoglobin decreased ^* 1	2/871 (0.23%)	0/844 (0.00%)	0/234 (0.00%)
Platelet count decreased ^* 1	1/871 (0.11%)	1/844 (0.12%)	1/234 (0.43%)
Hepatic enzyme increased ^* 1	0/871 (0.00%)	2/844 (0.24%)	0/234 (0.00%)
Arteriogram coronary ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Blood creatinine increased ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Coagulation time prolonged ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Eastern cooperative oncology group performance status worsened ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
International normalized ratio increased ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Electrocardiogram repolarisation abnormality ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Weight decreased ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Biopsy ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Ejection Fraction Decreased ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Electrocardiogram Abnormal ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Metabolism and nutrition disorders
Dehydration ^* 1	2/871 (0.23%)	3/844 (0.36%)	1/234 (0.43%)
Decreased appetite ^* 1	2/871 (0.23%)	2/844 (0.24%)	1/234 (0.43%)
Hypercalcaemia ^* 1	3/871 (0.34%)	0/844 (0.00%)	0/234 (0.00%)
Hypoglycaemia ^* 1	1/871 (0.11%)	1/844 (0.12%)	0/234 (0.00%)
Cachexia ^* 1	1/871 (0.11%)	1/844 (0.12%)	0/234 (0.00%)
Fluid retention ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Hyperkalaemia ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Hypokalaemia ^* 1	2/871 (0.23%)	0/844 (0.00%)	0/234 (0.00%)
Hyponatraemia ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Type 2 diabetes mellitus ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Metabolic acidosis ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Hypophagia ^* 1	0/871 (0.00%)	0/844 (0.00%)	1/234 (0.43%)
Malnutrition ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Musculoskeletal and connective tissue disorders
Pathological Fracture ^* 1	15/871 (1.72%)	6/844 (0.71%)	3/234 (1.28%)
Back pain ^* 1	4/871 (0.46%)	5/844 (0.59%)	0/234 (0.00%)
Bone pain ^* 1	3/871 (0.34%)	5/844 (0.59%)	0/234 (0.00%)
Osteoarthritis ^* 1	8/871 (0.92%)	2/844 (0.24%)	2/234 (0.85%)
Intervertebral disc protrusion ^* 1	4/871 (0.46%)	1/844 (0.12%)	0/234 (0.00%)
Muscular weakness ^* 1	1/871 (0.11%)	2/844 (0.24%)	1/234 (0.43%)
Musculoskeletal chest pain ^* 1	0/871 (0.00%)	3/844 (0.36%)	0/234 (0.00%)
Arthralgia ^* 1	2/871 (0.23%)	0/844 (0.00%)	1/234 (0.43%)
Neck pain ^* 1	0/871 (0.00%)	2/844 (0.24%)	0/234 (0.00%)
Osteolysis ^* 1	0/871 (0.00%)	2/844 (0.24%)	0/234 (0.00%)
Spinal column stenosis ^* 1	2/871 (0.23%)	0/844 (0.00%)	0/234 (0.00%)
Lumbar spinal stenosis ^* 1	1/871 (0.11%)	1/844 (0.12%)	1/234 (0.43%)
Musculoskeletal pain ^* 1	1/871 (0.11%)	0/844 (0.00%)	1/234 (0.43%)
Myalgia ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Myopathy ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Periostitis ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Rhabdomyolysis ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Spinal osteoarthritis ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Arthritis ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Groin pain ^* 1	1/871 (0.11%)	1/844 (0.12%)	0/234 (0.00%)
Pain in extremity ^* 1	1/871 (0.11%)	1/844 (0.12%)	0/234 (0.00%)
Bursitis ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Cervical Spinal Stenosis ^* 1	0/871 (0.00%)	0/844 (0.00%)	1/234 (0.43%)
Synovial Cyst ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastatic pain ^* 1	18/871 (2.07%)	17/844 (2.01%)	4/234 (1.71%)
Cancer pain ^* 1	3/871 (0.34%)	3/844 (0.36%)	2/234 (0.85%)
Gastric cancer ^* 1	2/871 (0.23%)	1/844 (0.12%)	0/234 (0.00%)
Transitional cell carcinoma ^* 1	4/871 (0.46%)	0/844 (0.00%)	2/234 (0.85%)
Adenocarcinoma of colon ^* 1	2/871 (0.23%)	1/844 (0.12%)	0/234 (0.00%)
Lung adenocarcinoma ^* 1	1/871 (0.11%)	1/844 (0.12%)	0/234 (0.00%)
Malignant pleural effusion ^* 1	1/871 (0.11%)	1/844 (0.12%)	0/234 (0.00%)
Metastases to central nervous system ^* 1	2/871 (0.23%)	1/844 (0.12%)	0/234 (0.00%)
Metastases to liver ^* 1	0/871 (0.00%)	2/844 (0.24%)	0/234 (0.00%)
Metastases to meninges ^* 1	1/871 (0.11%)	1/844 (0.12%)	1/234 (0.43%)
Metastases to soft tissue ^* 1	1/871 (0.11%)	1/844 (0.12%)	0/234 (0.00%)
Metastases to spine ^* 1	2/871 (0.23%)	0/844 (0.00%)	0/234 (0.00%)
Prostate cancer metastatic ^* 1	0/871 (0.00%)	2/844 (0.24%)	1/234 (0.43%)
Rectal cancer ^* 1	2/871 (0.23%)	0/844 (0.00%)	0/234 (0.00%)
Malignant melanoma ^* 1	2/871 (0.23%)	0/844 (0.00%)	0/234 (0.00%)
Prostate cancer ^* 1	1/871 (0.11%)	1/844 (0.12%)	1/234 (0.43%)
Tonsil cancer ^* 1	2/871 (0.23%)	0/844 (0.00%)	0/234 (0.00%)
Adenocarcinoma gastric ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Anal cancer ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Bladder cancer ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Bladder transitional cell carcinoma ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Colon cancer ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Colorectal cancer ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Hepatocellular carcinoma ^* 1	3/871 (0.34%)	0/844 (0.00%)	0/234 (0.00%)
Intestinal adenocarcinoma ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Lung neoplasm malignant ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Metastases to bladder ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Metastases to bone ^* 1	2/871 (0.23%)	0/844 (0.00%)	0/234 (0.00%)
Metastases to bone marrow ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Metastases to breast ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Metastases to lung ^* 1	0/871 (0.00%)	1/844 (0.12%)	2/234 (0.85%)
Metastases to peritoneum ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Neuroendocrine carcinoma of the skin ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Osteosarcoma ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Renal cell carcinoma ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Small cell lung cancer limited stage ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Thyroid adenoma ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Tumour associated fever ^* 1	0/871 (0.00%)	1/844 (0.12%)	1/234 (0.43%)
Tumour embolism ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Tumour pain ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
B-cell lymphoma ^* 1	3/871 (0.34%)	0/844 (0.00%)	0/234 (0.00%)
Gastrointestinal stromal tumour ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Myelodysplastic syndrome ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Acute Myeloid Leukaemia ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Basal Cell Carcinoma ^* 1	2/871 (0.23%)	0/844 (0.00%)	0/234 (0.00%)
Brain Neoplasm ^* 1	0/871 (0.00%)	0/844 (0.00%)	1/234 (0.43%)
Colorectal Adenocarcinoma ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Colorectal Cancer Metastatic ^* 1	0/871 (0.00%)	0/844 (0.00%)	1/234 (0.43%)
Diffuse Large B-Cell Lymphoma ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Gastric Cancer Recurrent ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Gastrointestinal Cancer Metastatic ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Glioblastoma Multiforme ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Metastases To Chest Wall ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Metastases To Penis ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Metastatic Neoplasm ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Myxofibrosarcoma ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Non-Hodgkin's Lymphoma ^* 1	1/871 (0.11%)	0/844 (0.00%)	1/234 (0.43%)
Plasma Cell Myeloma ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Small Cell Lung Cancer ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Squamous Cell Carcinoma Of Skin ^* 1	0/871 (0.00%)	0/844 (0.00%)	1/234 (0.43%)
Nervous system disorders
Spinal cord compression ^* 1	35/871 (4.02%)	25/844 (2.96%)	10/234 (4.27%)
Syncope ^* 1	8/871 (0.92%)	0/844 (0.00%)	3/234 (1.28%)
Cerebrovascular accident ^* 1	7/871 (0.80%)	1/844 (0.12%)	0/234 (0.00%)
Cauda equina syndrome ^* 1	4/871 (0.46%)	0/844 (0.00%)	0/234 (0.00%)
Nerve root compression ^* 1	2/871 (0.23%)	2/844 (0.24%)	0/234 (0.00%)
Transient ischaemic attack ^* 1	6/871 (0.69%)	3/844 (0.36%)	0/234 (0.00%)
Presyncope ^* 1	3/871 (0.34%)	0/844 (0.00%)	0/234 (0.00%)
Paraesthesia ^* 1	0/871 (0.00%)	2/844 (0.24%)	0/234 (0.00%)
Paraparesis ^* 1	1/871 (0.11%)	1/844 (0.12%)	0/234 (0.00%)
Ataxia ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Brain injury ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Cerebral haemorrhage ^* 1	1/871 (0.11%)	1/844 (0.12%)	0/234 (0.00%)
Cerebral infarction ^* 1	2/871 (0.23%)	0/844 (0.00%)	0/234 (0.00%)
Cervicobrachial syndrome ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Coma hepatic ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Dementia ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Memory impairment ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Meningorrhagia ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Metabolic encephalopathy ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Reversible ischaemic neurological deficit ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Spinal cord ischaemia ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Subarachnoid haemorrhage ^* 1	2/871 (0.23%)	0/844 (0.00%)	0/234 (0.00%)
Vith nerve disorder ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Complex partial seizures ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Neuralgia ^* 1	1/871 (0.11%)	0/844 (0.00%)	1/234 (0.43%)
Sciatica ^* 1	0/871 (0.00%)	2/844 (0.24%)	0/234 (0.00%)
Cervical Cord Compression ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Convulsion ^* 1	1/871 (0.11%)	0/844 (0.00%)	1/234 (0.43%)
Cranial Nerve Paralysis ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Grand Mal Convulsion ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Haemorrhage Intracranial ^* 1	2/871 (0.23%)	0/844 (0.00%)	0/234 (0.00%)
Headache ^* 1	1/871 (0.11%)	0/844 (0.00%)	1/234 (0.43%)
Hypoxic-Ischaemic Encephalopathy ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Lethargy ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Loss Of Consciousness ^* 1	1/871 (0.11%)	0/844 (0.00%)	1/234 (0.43%)
Neurological Symptom ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Sensory Loss ^* 1	0/871 (0.00%)	0/844 (0.00%)	1/234 (0.43%)
Vith Nerve Paralysis ^* 1	0/871 (0.00%)	0/844 (0.00%)	1/234 (0.43%)
Dizziness ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Epiduritis ^* 1	0/871 (0.00%)	0/844 (0.00%)	1/234 (0.43%)
Monoplegia ^* 1	0/871 (0.00%)	0/844 (0.00%)	1/234 (0.43%)
Status Epilepticus ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Psychiatric disorders
Confusional state ^* 1	1/871 (0.11%)	4/844 (0.47%)	2/234 (0.85%)
Suicide attempt ^* 1	1/871 (0.11%)	1/844 (0.12%)	1/234 (0.43%)
Depression ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Major depression ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Delirium ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Renal and urinary disorders
Urinary retention ^* 1	10/871 (1.15%)	13/844 (1.54%)	3/234 (1.28%)
Haematuria ^* 1	11/871 (1.26%)	12/844 (1.42%)	3/234 (1.28%)
Urinary tract obstruction ^* 1	8/871 (0.92%)	9/844 (1.07%)	1/234 (0.43%)
Hydronephrosis ^* 1	2/871 (0.23%)	11/844 (1.30%)	1/234 (0.43%)
Renal failure acute ^* 1	6/871 (0.69%)	5/844 (0.59%)	2/234 (0.85%)
Ureteric obstruction ^* 1	4/871 (0.46%)	4/844 (0.47%)	1/234 (0.43%)
Obstructive uropathy ^* 1	5/871 (0.57%)	6/844 (0.71%)	3/234 (1.28%)
Bladder outlet obstruction ^* 1	2/871 (0.23%)	3/844 (0.36%)	0/234 (0.00%)
Postrenal failure ^* 1	2/871 (0.23%)	3/844 (0.36%)	0/234 (0.00%)
Urinary bladder haemorrhage ^* 1	3/871 (0.34%)	0/844 (0.00%)	0/234 (0.00%)
Calculus bladder ^* 1	1/871 (0.11%)	1/844 (0.12%)	1/234 (0.43%)
Prerenal failure ^* 1	1/871 (0.11%)	1/844 (0.12%)	0/234 (0.00%)
Renal failure ^* 1	3/871 (0.34%)	1/844 (0.12%)	0/234 (0.00%)
Acute prerenal failure ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Bladder obstruction ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Renal failure chronic ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Urethral meatus stenosis ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Urethral obstruction ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Urine flow decreased ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Bladder neck obstruction ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Micturition urgency ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Calculus Ureteric ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Nephrolithiasis ^* 1	2/871 (0.23%)	0/844 (0.00%)	0/234 (0.00%)
Renal Colic ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Urethral Stenosis ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Urinary Incontinence ^* 1	0/871 (0.00%)	0/844 (0.00%)	1/234 (0.43%)
Nephrotic Syndrome ^* 1	0/871 (0.00%)	0/844 (0.00%)	1/234 (0.43%)
Calculus Urinary ^* 1	2/871 (0.23%)	0/844 (0.00%)	0/234 (0.00%)
Reproductive system and breast disorders
Benign prostatic hyperplasia ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Pelvic pain ^* 1	1/871 (0.11%)	0/844 (0.00%)	1/234 (0.43%)
Prostatic obstruction ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Prostatitis ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Testicular pain ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Epididymitis ^* 1	0/871 (0.00%)	0/844 (0.00%)	1/234 (0.43%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism ^* 1	6/871 (0.69%)	7/844 (0.83%)	0/234 (0.00%)
Chronic obstructive pulmonary disease ^* 1	5/871 (0.57%)	3/844 (0.36%)	0/234 (0.00%)
Dyspnoea ^* 1	3/871 (0.34%)	2/844 (0.24%)	0/234 (0.00%)
Pleural effusion ^* 1	2/871 (0.23%)	1/844 (0.12%)	0/234 (0.00%)
Epistaxis ^* 1	1/871 (0.11%)	1/844 (0.12%)	0/234 (0.00%)
Acute pulmonary oedema ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Aspiration ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Asthma ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Haemothorax ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Hydrothorax ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Hypoxia ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Nasal polyps ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Organising pneumonia ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Pneumonia aspiration ^* 1	3/871 (0.34%)	0/844 (0.00%)	1/234 (0.43%)
Pneumonitis ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Pulmonary haemorrhage ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Restrictive pulmonary disease ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Tracheal obstruction extrinsic ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Bronchiectasis ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Pneumothorax ^* 1	2/871 (0.23%)	1/844 (0.12%)	1/234 (0.43%)
Skin and subcutaneous tissue disorders
Toxic skin eruption ^* 1	2/871 (0.23%)	0/844 (0.00%)	0/234 (0.00%)
Rash ^* 1	1/871 (0.11%)	0/844 (0.00%)	1/234 (0.43%)
Swelling face ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Rash Maculo-Papular ^* 1	0/871 (0.00%)	0/844 (0.00%)	1/234 (0.43%)
Surgical and medical procedures
Cancer hormonal therapy ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Pain management ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Knee Arthroplasty ^* 1	0/871 (0.00%)	0/844 (0.00%)	1/234 (0.43%)
Radical Cystectomy ^* 1	0/871 (0.00%)	0/844 (0.00%)	1/234 (0.43%)
Umbilical Hernia Repair ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Vascular disorders
Deep vein thrombosis ^* 1	4/871 (0.46%)	2/844 (0.24%)	0/234 (0.00%)
Hypertension ^* 1	4/871 (0.46%)	0/844 (0.00%)	1/234 (0.43%)
Hypotension ^* 1	1/871 (0.11%)	1/844 (0.12%)	0/234 (0.00%)
Orthostatic hypotension ^* 1	1/871 (0.11%)	1/844 (0.12%)	0/234 (0.00%)
Aortic aneurysm ^* 1	1/871 (0.11%)	1/844 (0.12%)	0/234 (0.00%)
Aortic aneurysm rupture ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Circulatory collapse ^* 1	2/871 (0.23%)	0/844 (0.00%)	0/234 (0.00%)
Hypovolaemic shock ^* 1	1/871 (0.11%)	0/844 (0.00%)	1/234 (0.43%)
Lymphoedema ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Vena cava thrombosis ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Aortic stenosis ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Phlebitis ^* 1	0/871 (0.00%)	1/844 (0.12%)	0/234 (0.00%)
Subclavian artery stenosis ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Aneurysm ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
Peripheral Artery Stenosis ^* 1	1/871 (0.11%)	0/844 (0.00%)	0/234 (0.00%)
1 Term from vocabulary, MedDRA 16.1 * Indicates events were collected by non-systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Enzalutamide	Placebo	Placebo Participants Crossover to Enzalutamide
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	814/871 (93.46%)	723/844 (85.66%)	180/234 (76.92%)
Blood and lymphatic system disorders
Anaemia ^* 1	76/871 (8.73%)	68/844 (8.06%)	23/234 (9.83%)
Gastrointestinal disorders
Nausea ^* 1	211/871 (24.23%)	192/844 (22.75%)	34/234 (14.53%)
Constipation ^* 1	220/871 (25.26%)	145/844 (17.18%)	38/234 (16.24%)
Diarrhoea ^* 1	160/871 (18.37%)	121/844 (14.34%)	20/234 (8.55%)
Vomiting ^* 1	64/871 (7.35%)	70/844 (8.29%)	9/234 (3.85%)
Abdominal pain ^* 1	56/871 (6.43%)	31/844 (3.67%)	4/234 (1.71%)
General disorders
Fatigue ^* 1	332/871 (38.12%)	220/844 (26.07%)	63/234 (26.92%)
Asthenia ^* 1	122/871 (14.01%)	69/844 (8.18%)	15/234 (6.41%)
Oedema peripheral ^* 1	115/871 (13.20%)	70/844 (8.29%)	20/234 (8.55%)
Infections and infestations
Urinary tract infection ^* 1	70/871 (8.04%)	56/844 (6.64%)	11/234 (4.70%)
Nasopharyngitis ^* 1	74/871 (8.50%)	44/844 (5.21%)	6/234 (2.56%)
Upper respiratory tract infection ^* 1	61/871 (7.00%)	30/844 (3.55%)	7/234 (2.99%)
Injury, poisoning and procedural complications
Fall ^* 1	136/871 (15.61%)	42/844 (4.98%)	15/234 (6.41%)
Investigations
Weight decreased ^* 1	122/871 (14.01%)	72/844 (8.53%)	26/234 (11.11%)
Metabolism and nutrition disorders
Decreased appetite ^* 1	182/871 (20.90%)	139/844 (16.47%)	36/234 (15.38%)
Musculoskeletal and connective tissue disorders
Back pain ^* 1	280/871 (32.15%)	188/844 (22.27%)	32/234 (13.68%)
Arthralgia ^* 1	206/871 (23.65%)	137/844 (16.23%)	22/234 (9.40%)
Pain in extremity ^* 1	124/871 (14.24%)	97/844 (11.49%)	13/234 (5.56%)
Bone pain ^* 1	100/871 (11.48%)	116/844 (13.74%)	18/234 (7.69%)
Musculoskeletal pain ^* 1	112/871 (12.86%)	74/844 (8.77%)	28/234 (11.97%)
Musculoskeletal chest pain ^* 1	73/871 (8.38%)	40/844 (4.74%)	5/234 (2.14%)
Myalgia ^* 1	59/871 (6.77%)	49/844 (5.81%)	8/234 (3.42%)
Muscular Weakness ^* 1	45/871 (5.17%)	27/844 (3.20%)	8/234 (3.42%)
Nervous system disorders
Headache ^* 1	102/871 (11.71%)	59/844 (6.99%)	15/234 (6.41%)
Dizziness ^* 1	85/871 (9.76%)	54/844 (6.40%)	13/234 (5.56%)
Dysgeusia ^* 1	67/871 (7.69%)	31/844 (3.67%)	5/234 (2.14%)
Psychiatric disorders
Insomnia ^* 1	78/871 (8.96%)	48/844 (5.69%)	10/234 (4.27%)
Renal and urinary disorders
Haematuria ^* 1	93/871 (10.68%)	43/844 (5.09%)	11/234 (4.70%)
Pollakiuria ^* 1	62/871 (7.12%)	37/844 (4.38%)	6/234 (2.56%)
Respiratory, thoracic and mediastinal disorders
Cough ^* 1	95/871 (10.91%)	58/844 (6.87%)	2/234 (0.85%)
Dyspnoea ^* 1	88/871 (10.10%)	60/844 (7.11%)	14/234 (5.98%)
Skin and subcutaneous tissue disorders
Rash ^* 1	31/871 (3.56%)	21/844 (2.49%)	14/234 (5.98%)
Vascular disorders
Hot flush ^* 1	159/871 (18.25%)	66/844 (7.82%)	11/234 (4.70%)
Hypertension ^* 1	148/871 (16.99%)	36/844 (4.27%)	28/234 (11.97%)
1 Term from vocabulary, MedDRA 16.1 * Indicates events were collected by non-systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

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

PI agrees not to independently publish the results before the publication of the multi-center PI paper. Sponsor shall review and comment 30 days prior to submission or disclosure. If publication or disclosure contains Sponsor Confidential Information, other than study data, PI agrees to remove Confidential Information from publication or disclosure. Sponsor may request that PI delay such publication for an additional 60 days to protect the patentability of any invention described.

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	Pfizer ClinicalTrials.gov Call Center
Organization:	Pfizer Inc.
Phone:	8007181021
EMail:	ClinicalTrials.gov_Inquiries@pfizer.com

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.

Joshua AM, Armstrong A, Crumbaker M, Scher HI, de Bono J, Tombal B, Hussain M, Sternberg CN, Gillessen S, Carles J, Fizazi K, Lin P, Duggan W, Sugg J, Russell D, Beer TM. Statin and metformin use and outcomes in patients with castration-resistant prostate cancer treated with enzalutamide: A meta-analysis of AFFIRM, PREVAIL and PROSPER. Eur J Cancer. 2022 Jul;170:285-295. doi: 10.1016/j.ejca.2022.04.005. Epub 2022 May 26.

Tombal BF, Freedland SJ, Armstrong AJ, Beer TM, Stenzl A, Sternberg CN, Hussain M, Ganguli A, Ramaswamy K, Bhadauria H, Ivanescu C, Turnbull J, Holmstrom S, Saad F. Impact of enzalutamide on patient-reported fatigue in patients with prostate cancer: data from the pivotal clinical trials. Prostate Cancer Prostatic Dis. 2022 Feb;25(2):288-295. doi: 10.1038/s41391-021-00447-9. Epub 2021 Sep 13.

Armstrong AJ, Lin P, Tombal B, Saad F, Higano CS, Joshua AM, Parli T, Rosbrook B, van Os S, Beer TM. Five-year Survival Prediction and Safety Outcomes with Enzalutamide in Men with Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer from the PREVAIL Trial. Eur Urol. 2020 Sep;78(3):347-357. doi: 10.1016/j.eururo.2020.04.061. Epub 2020 Jun 9.

Armstrong AJ, Al-Adhami M, Lin P, Parli T, Sugg J, Steinberg J, Tombal B, Sternberg CN, de Bono J, Scher HI, Beer TM. Association Between New Unconfirmed Bone Lesions and Outcomes in Men With Metastatic Castration-Resistant Prostate Cancer Treated With Enzalutamide: Secondary Analysis of the PREVAIL and AFFIRM Randomized Clinical Trials. JAMA Oncol. 2020 Feb 1;6(2):217-225. doi: 10.1001/jamaoncol.2019.4636.

Armstrong AJ, Lin P, Higano CS, Iversen P, Sternberg CN, Tombal B, Phung D, Parli T, Krivoshik A, Beer TM. Prognostic Association of Prostate-specific Antigen Decline with Clinical Outcomes in Men with Metastatic Castration-resistant Prostate Cancer Treated with Enzalutamide in a Randomized Clinical Trial. Eur Urol Oncol. 2019 Nov;2(6):677-684. doi: 10.1016/j.euo.2018.11.005. Epub 2018 Dec 3.

Armstrong AJ, Lin P, Higano CS, Sternberg CN, Sonpavde G, Tombal B, Templeton AJ, Fizazi K, Phung D, Wong EK, Krivoshik A, Beer TM. Development and validation of a prognostic model for overall survival in chemotherapy-naive men with metastatic castration-resistant prostate cancer. Ann Oncol. 2018 Nov 1;29(11):2200-2207. doi: 10.1093/annonc/mdy406.

Rathkopf DE, Beer TM, Loriot Y, Higano CS, Armstrong AJ, Sternberg CN, de Bono JS, Tombal B, Parli T, Bhattacharya S, Phung D, Krivoshik A, Scher HI, Morris MJ. Radiographic Progression-Free Survival as a Clinically Meaningful End Point in Metastatic Castration-Resistant Prostate Cancer: The PREVAIL Randomized Clinical Trial. JAMA Oncol. 2018 May 1;4(5):694-701. doi: 10.1001/jamaoncol.2017.5808.

Kim CS, Choi YD, Lee SE, Lee HM, Ueda T, Yonese J, Fukagai T, Chiong E, Lau W, Abhyankar S, Theeuwes A, Tombal B, Beer TM, Kimura G. Post hoc analyses of East Asian patients from the randomized placebo-controlled PREVAIL trial of enzalutamide in patients with chemotherapy-naive, metastatic castration-resistant prostate cancer. Medicine (Baltimore). 2017 Jul;96(27):e7223. doi: 10.1097/MD.0000000000007223.

Devlin N, Herdman M, Pavesi M, Phung D, Naidoo S, Beer TM, Tombal B, Loriot Y, Ivanescu C, Parli T, Balk M, Holmstrom S. Health-related quality of life effects of enzalutamide in patients with metastatic castration-resistant prostate cancer: an in-depth post hoc analysis of EQ-5D data from the PREVAIL trial. Health Qual Life Outcomes. 2017 Jun 23;15(1):130. doi: 10.1186/s12955-017-0704-y.

Bryce AH, Alumkal JJ, Armstrong A, Higano CS, Iversen P, Sternberg CN, Rathkopf D, Loriot Y, de Bono J, Tombal B, Abhyankar S, Lin P, Krivoshik A, Phung D, Beer TM. Radiographic progression with nonrising PSA in metastatic castration-resistant prostate cancer: post hoc analysis of PREVAIL. Prostate Cancer Prostatic Dis. 2017 Jun;20(2):221-227. doi: 10.1038/pcan.2016.71. Epub 2017 Jan 24.

Beer TM, Armstrong AJ, Rathkopf D, Loriot Y, Sternberg CN, Higano CS, Iversen P, Evans CP, Kim CS, Kimura G, Miller K, Saad F, Bjartell AS, Borre M, Mulders P, Tammela TL, Parli T, Sari S, van Os S, Theeuwes A, Tombal B. Enzalutamide in Men with Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer: Extended Analysis of the Phase 3 PREVAIL Study. Eur Urol. 2017 Feb;71(2):151-154. doi: 10.1016/j.eururo.2016.07.032. Epub 2016 Jul 28.

Kim CS, Theeuwes A, Kwon DD, Choi YD, Chung BH, Lee HM, Lee KH, Lee SE. The PREVAIL trial of enzalutamide in men with chemotherapy-naive, metastatic castration-resistant prostate cancer: Post hoc analysis of Korean patients. Investig Clin Urol. 2016 May;57(3):174-83. doi: 10.4111/icu.2016.57.3.174. Epub 2016 May 10.

Graff JN, Baciarello G, Armstrong AJ, Higano CS, Iversen P, Flaig TW, Forer D, Parli T, Phung D, Tombal B, Beer TM, Sternberg CN. Efficacy and safety of enzalutamide in patients 75 years or older with chemotherapy-naive metastatic castration-resistant prostate cancer: results from PREVAIL. Ann Oncol. 2016 Feb;27(2):286-94. doi: 10.1093/annonc/mdv542. Epub 2015 Nov 16.

Loriot Y, Miller K, Sternberg CN, Fizazi K, De Bono JS, Chowdhury S, Higano CS, Noonberg S, Holmstrom S, Mansbach H, Perabo FG, Phung D, Ivanescu C, Skaltsa K, Beer TM, Tombal B. Effect of enzalutamide on health-related quality of life, pain, and skeletal-related events in asymptomatic and minimally symptomatic, chemotherapy-naive patients with metastatic castration-resistant prostate cancer (PREVAIL): results from a randomised, phase 3 trial. Lancet Oncol. 2015 May;16(5):509-21. doi: 10.1016/S1470-2045(15)70113-0. Epub 2015 Apr 14.

Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, Iversen P, Bhattacharya S, Carles J, Chowdhury S, Davis ID, de Bono JS, Evans CP, Fizazi K, Joshua AM, Kim CS, Kimura G, Mainwaring P, Mansbach H, Miller K, Noonberg SB, Perabo F, Phung D, Saad F, Scher HI, Taplin ME, Venner PM, Tombal B; PREVAIL Investigators. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014 Jul 31;371(5):424-33. doi: 10.1056/NEJMoa1405095. Epub 2014 Jun 1.

Layout table for additonal information

Responsible Party:	Pfizer
ClinicalTrials.gov Identifier:	NCT01212991
Other Study ID Numbers:	MDV3100-03 2010-020821-41 ( EudraCT Number ) C3431003 ( Other Identifier: Alias Study Number )
First Submitted:	September 29, 2010
First Posted:	October 1, 2010
Results First Submitted:	October 8, 2014
Results First Posted:	October 16, 2014
Last Update Posted:	March 17, 2020

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