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    Clinical Trial Results:
    A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Efficacy and Safety of Enzalutamide in Combination With Exemestane in Patients With Advanced Breast Cancer That is Estrogen or Progesterone Receptor-Positive and HER2-Normal

    Summary
    EudraCT number
    		 2013-002717-35
    Trial protocol
    		 IE   BE   GB   IT   ES  
    Global end of trial date
    23 Aug 2024

    Results information
    Results version number
    		 v4(current)
    This version publication date
    05 Sep 2025
    First version publication date
    14 Oct 2017
    Other versions
    		 v1 , v2 , v3
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    C3431008
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02007512
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Other study ID: MDV3100-12
    Sponsors
    Sponsor organisation name
    Pfizer Inc.
    Sponsor organisation address
    66 Hudson Boulevard East, New York, United States, NY 10001-2192
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    13 Jan 2025
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Aug 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the benefit of exemestane plus enzalutamide versus exemestane plus placebo as assessed by progression free survival (PFS) in participants with advanced breast cancer.
    Protection of trial subjects
    This study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Council for Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. In addition, all local regulatory requirements were followed, in particular, those affording greater protection to the safety of participants.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Dec 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 119
    Country: Number of subjects enrolled
    Belgium: 18
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    Ireland: 16
    Country: Number of subjects enrolled
    Italy: 44
    Country: Number of subjects enrolled
    Spain: 31
    Country: Number of subjects enrolled
    United Kingdom: 15
    Worldwide total number of subjects
    247
    EEA total number of subjects
    109
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    151
    From 65 to 84 years
    92
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 247 participants were enrolled.

    Pre-assignment
    Screening details
    		 This was a Phase 2, randomized, double blind, placebo-controlled study.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Subject
    Blinding implementation details
    Subject and investigator were blinded.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Double blind Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg
    Arm description
    		 Participants with no previous hormonal treatment for advanced breast cancer, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Enzalutamide
    Investigational medicinal product code
    MDV3100
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Enzalutamide 160 mg was received once daily as 4 capsules (40 mg each).

    Investigational medicinal product name
    Exemestane
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Exemestane 50 mg was received orally.

    Arm title
    		 Double blind Cohort 1: Placebo + Exemestane 25 mg
    Arm description
    		 Participants with no previous hormonal treatment for advanced breast cancer received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo capsule matched to enzalutamide was received orally, once daily.

    Investigational medicinal product name
    Exemestane
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Exemestane 25 mg was received orally, once daily.

    Arm title
    		 Double blind Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg
    Arm description
    		 Participants with previous disease progression following hormonal treatment for advanced breast cancer, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Enzalutamide
    Investigational medicinal product code
    MDV3100
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Enzalutamide 160 mg was received once daily as 4 capsules (40 mg each).

    Investigational medicinal product name
    Exemestane
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Exemestane 50 mg was received orally.

    Arm title
    		 Double blind Cohort 2: Placebo + Exemestane 25 mg
    Arm description
    		 Participants with previous disease progression following hormonal treatment for advanced breast cancer, received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo capsule matched to enzalutamide was received orally, once daily.

    Investigational medicinal product name
    Exemestane
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Exemestane 25 mg was received orally, once daily.

    Arm title
    		 Open label Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg
    Arm description
    		 Participants with no previous hormonal treatment for advanced breast cancer, received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Enzalutamide
    Investigational medicinal product code
    MDV3100
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Enzalutamide 160 mg was received once daily as 4 capsules (40 mg each).

    Investigational medicinal product name
    Exemestane
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Exemestane 50 mg was received orally.

    Arm title
    		 Open label Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg
    Arm description
    		 Participants with previous disease progression following hormonal treatment for advanced breast cancer received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Exemestane
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Exemestane 50 mg was received orally.

    Investigational medicinal product name
    Enzalutamide
    Investigational medicinal product code
    MDV3100
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Enzalutamide 160 mg was received once daily as 4 capsules (40 mg each).

    Number of subjects in period 1
    		Double blind Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg Double blind Cohort 1: Placebo + Exemestane 25 mg Double blind Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg Double blind Cohort 2: Placebo + Exemestane 25 mg Open label Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg Open label Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg
    Started
    63
    64
    60
    60
    25
    12
    Treated
    62
    63
    60
    60
    24
    11
    Completed
    0
    0
    0
    0
    0
    0
    Not completed
    63
    64
    60
    60
    25
    12
         Adverse event, serious fatal
    1
    -
    -
    -
    -
    -
         Consent withdrawn by subject
    3
    3
    3
    3
    -
    -
         Disease progression
    51
    57
    50
    52
    23
    11
         Adverse event, non-fatal
    4
    2
    6
    2
    1
    -
         Randomised but not treated
    1
    1
    -
    -
    -
    -
         Unspecified
    2
    1
    1
    2
    1
    1
         Protocol deviation
    1
    -
    -
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Double blind Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg
    Reporting group description
    		 Participants with no previous hormonal treatment for advanced breast cancer, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.

    Reporting group title
    Double blind Cohort 1: Placebo + Exemestane 25 mg
    Reporting group description
    		 Participants with no previous hormonal treatment for advanced breast cancer received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.

    Reporting group title
    Double blind Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg
    Reporting group description
    		 Participants with previous disease progression following hormonal treatment for advanced breast cancer, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.

    Reporting group title
    Double blind Cohort 2: Placebo + Exemestane 25 mg
    Reporting group description
    		 Participants with previous disease progression following hormonal treatment for advanced breast cancer, received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.

    Reporting group title
    Open label Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg
    Reporting group description
    		 Participants with no previous hormonal treatment for advanced breast cancer, received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.

    Reporting group title
    Open label Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg
    Reporting group description
    		 Participants with previous disease progression following hormonal treatment for advanced breast cancer received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.

    Reporting group values
    		 Double blind Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg Double blind Cohort 1: Placebo + Exemestane 25 mg Double blind Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg Double blind Cohort 2: Placebo + Exemestane 25 mg Open label Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg Open label Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg Total
    Number of subjects
    		 63 64 60 60 25 12 284
    Age Categorical
    Units: Subjects
        <=18 years
    		 0 0 0 0 0 0 0
        Between 18 and 65 years
    		 42 32 37 40 12 9 172
        >=65 years
    		 21 32 23 20 13 3 112
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 59.0 ( 10.82 ) 63.5 ( 11.56 ) 60.1 ( 11.27 ) 60.6 ( 13.47 ) 63.5 ( 10.22 ) 61.8 ( 11.68 ) -
    Gender categorical
    Units: Subjects
        Male
    		 0 0 0 0 0 0 0
        Female
    		 63 64 60 60 25 12 284
    Subject analysis sets

    Subject analysis set title
    Enzalutamide 160 mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received enzalutamide 160 mg dose orally, once daily, either in double blind treatment period or in open label treatment period until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after the last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.

    Subject analysis set title
    Exemestane 25 mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received exemestane 25 mg dose orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after the last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.

    Subject analysis set title
    Exemestane 50 mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received exemestane 50 mg dose orally, once daily until disease progression or permanent treatment discontinuation, either in double blind treatment period or in open label treatment period. Participants were followed-up until 30 days after the last dose of study drug, the date of death, or before initiation of a new antitumor treatment, whichever occurred first.

    Subject analysis sets values
    		 Enzalutamide 160 mg Exemestane 25 mg Exemestane 50 mg
    Number of subjects
    114
    114
    115
    Age Categorical
    Units: Subjects
        <=18 years
        Between 18 and 65 years
        >=65 years
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    0 ( 0 )
    0 ( 0 )
    0 ( 0 )
    Gender categorical
    Units: Subjects
        Male
    0
    0
    0
        Female
    0
    0
    0

    End points

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    End points reporting groups
    Reporting group title
    Double blind Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg
    Reporting group description
    		 Participants with no previous hormonal treatment for advanced breast cancer, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.

    Reporting group title
    Double blind Cohort 1: Placebo + Exemestane 25 mg
    Reporting group description
    		 Participants with no previous hormonal treatment for advanced breast cancer received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.

    Reporting group title
    Double blind Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg
    Reporting group description
    		 Participants with previous disease progression following hormonal treatment for advanced breast cancer, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.

    Reporting group title
    Double blind Cohort 2: Placebo + Exemestane 25 mg
    Reporting group description
    		 Participants with previous disease progression following hormonal treatment for advanced breast cancer, received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.

    Reporting group title
    Open label Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg
    Reporting group description
    		 Participants with no previous hormonal treatment for advanced breast cancer, received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.

    Reporting group title
    Open label Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg
    Reporting group description
    		 Participants with previous disease progression following hormonal treatment for advanced breast cancer received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.

    Subject analysis set title
    Enzalutamide 160 mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received enzalutamide 160 mg dose orally, once daily, either in double blind treatment period or in open label treatment period until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after the last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.

    Subject analysis set title
    Exemestane 25 mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received exemestane 25 mg dose orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after the last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.

    Subject analysis set title
    Exemestane 50 mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received exemestane 50 mg dose orally, once daily until disease progression or permanent treatment discontinuation, either in double blind treatment period or in open label treatment period. Participants were followed-up until 30 days after the last dose of study drug, the date of death, or before initiation of a new antitumor treatment, whichever occurred first.

    Primary: Progression Free Survival (PFS): Intent-to-Treat (ITT) Population Stratified Analyses By Interactive Web Recognition System (IWRS)

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    End point title
    		 Progression Free Survival (PFS): Intent-to-Treat (ITT) Population Stratified Analyses By Interactive Web Recognition System (IWRS) [1]
    End point description
    PFS was defined as the time in months from randomisation to the first documentation of progression of disease (PD) or death on study due to any cause, whichever occurred first. PD according to response evaluation criteria in solid tumors version 1.1 (RECIST 1.1) was defined as greater than or equal to (>=) 20 percent (%) increase in the sum of diameters of the target lesions taking as a reference the smallest sum recorded since the start of treatment or unequivocal progression in non-target lesions or the appearance of 1 or more new lesions. The analysis of PFS was based on investigator assessment of disease progression. Participants who were not known to have had a PFS event at the analysis date were censored at last tumor assessment date prior to data cutoff or date of new treatment initiation, whichever occurred first. ITT population included all the participants randomly assigned to double-blind study treatment.
    End point type
    Primary
    End point timeframe
    From randomisation until PD, last tumor assessment without PD before new antitumor treatment initiation or death due to any cause, whichever occurred first (up to 3 years)
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Reporting groups specific to this endpoint are included.
    End point values
    		 Double blind Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg Double blind Cohort 1: Placebo + Exemestane 25 mg Double blind Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg Double blind Cohort 2: Placebo + Exemestane 25 mg
    Number of subjects analysed
    63
    64
    60
    60
    Units: Months
        median (confidence interval 95%)
    11.8 (7.3 to 15.9)
    5.8 (3.5 to 10.9)
    3.6 (1.9 to 5.5)
    3.9 (2.6 to 5.4)
    Statistical analysis title
    		 Progression Free Survival: ITT Population By IWRS
    Statistical analysis description
    Progression Free Survival (PFS): Intent-to-Treat (ITT) Population By Interactive Web Recognition System (IWRS)
    Comparison groups
    Double blind Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg v Double blind Cohort 2: Placebo + Exemestane 25 mg
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.9212
    Method
    		 Stratified log-rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.022
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.659
         upper limit
    		 1.586
    Notes
    [2] - Hazard ratio was based on stratified Cox regression model.
    Statistical analysis title
    		 PFS: Intent-to-Treat Population By IWRS
    Statistical analysis description
    Progression Free Survival (PFS): Intent-to-Treat (ITT) Population By Interactive Web Recognition System (IWRS)
    Comparison groups
    Double blind Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg v Double blind Cohort 1: Placebo + Exemestane 25 mg
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.3631
    Method
    		 Stratified log-rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.535
         upper limit
    		 1.257
    Notes
    [3] - Hazard ratio was based on stratified Cox regression model.

    Primary: Progression Free Survival (PFS): Diagnostic Positive (DX+) Population Stratified Analyses By Interactive Web Recognition System (IWRS)

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    End point title
    		 Progression Free Survival (PFS): Diagnostic Positive (DX+) Population Stratified Analyses By Interactive Web Recognition System (IWRS) [4]
    End point description
    PFS: time from randomisation to first documentation of PD or death on study due to any cause, whichever occurred first. PD per RECIST 1.1: >= 20% increase in sum of diameters of target lesions taking as reference smallest sum recorded since start of treatment or unequivocal progression in non-target lesions or appearance of 1 or more new lesions. Analysis of PFS was based on investigator assessment of disease progression. Participants who were not known to have had PFS event at analysis date were censored at last tumor assessment date prior to data cutoff or date of new treatment initiation, whichever occurred first. Dx+ population: Subset of ITT population, defined prior to first unblinded analysis as meeting threshold for diagnostic score based on ribonucleic acid (RNA) sequencing data from tumor tissue. "Subjects Analyzed"= participants evaluable for this endpoint.99999 =Upper limit (UL)of 95% CI not reached due to insufficient number of participants with events.
    End point type
    Primary
    End point timeframe
    From randomisation until PD, last tumor assessment without PD before new antitumor treatment initiation or death due to any cause, whichever occurred first (up to 3 years)
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Reporting groups specific to this endpoint are included.
    End point values
    		 Double blind Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg Double blind Cohort 1: Placebo + Exemestane 25 mg Double blind Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg Double blind Cohort 2: Placebo + Exemestane 25 mg
    Number of subjects analysed
    24
    26
    15
    20
    Units: Months
        median (confidence interval 95%)
    16.5 (11.0 to 99999)
    4.3 (1.9 to 10.9)
    6.0 (2.3 to 26.7)
    5.3 (1.8 to 6.7)
    Statistical analysis title
    		 Diagnostic Positive Population By IWRS
    Comparison groups
    Double blind Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg v Double blind Cohort 2: Placebo + Exemestane 25 mg
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.1936
    Method
    		 Stratified log-rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.554
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.225
         upper limit
    		 1.363
    Notes
    [5] - Hazard ratio was based on stratified Cox regression model.
    Statistical analysis title
    		 Diagnostic Positive Population By IWRS
    Comparison groups
    Double blind Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg v Double blind Cohort 1: Placebo + Exemestane 25 mg
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 0.0335
    Method
    		 Stratified log-rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.442
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.205
         upper limit
    		 0.955
    Notes
    [6] - Hazard ratio was based on stratified Cox regression model.

    Secondary: Clinical Benefit Rate-24 (CBR-24)

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    End point title
    		 Clinical Benefit Rate-24 (CBR-24) [7]
    End point description
    CBR-24: Percentage of participants with best response of complete response (CR), partial response (PR), or stable disease (SD) sustained for at least 24 weeks, determined by investigator using RECIST 1.1. CR: Disappearance of all (target, non-target) lesions, normalization of non-target lesion's tumor marker level. Non-pathological size (< 10-millimeter [mm] short axis) lymph nodes (target, non-target [NT]) included. PR:>=30% decreased target lesion diameter's sum, by baseline sum diameters as reference. SD: Insufficient reduction to qualify as PR, insufficient increase to qualify as PD, by smallest sum diameters during study as reference.PD:>=20% increase (absolute increase of >=5 mm) in sum of target lesion's diameters, by smallest sum during study as reference (including baseline sum),or unequivocal progression of existing NT lesions, or appearance of at least 1 new target or NT lesions. ITT population included all participants randomly assigned to double-blind study treatment.
    End point type
    Secondary
    End point timeframe
    From randomisation up to 3 years
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Reporting groups specific to this endpoint are included.
    End point values
    		 Double blind Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg Double blind Cohort 1: Placebo + Exemestane 25 mg Double blind Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg Double blind Cohort 2: Placebo + Exemestane 25 mg
    Number of subjects analysed
    63
    64
    60
    60
    Units: Percentage of participants
        number (confidence interval 95%)
    61.9 (48.8 to 73.9)
    45.3 (32.8 to 58.3)
    20.0 (10.8 to 32.3)
    31.7 (20.3 to 45.0)
    No statistical analyses for this end point

    Secondary: Time to Response

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    End point title
    		 Time to Response [8]
    End point description
    Time to response: Time from randomisation to first documentation of CR/PR. CR:Disappearance of all(target and NT)lesions, normalized tumor marker level for NT lesions. All lymph nodes must be non-pathological in size.PR:>=30% decreased target lesion's sum of diameters, with baseline sum of diameters as reference.PD:>=20% increased (>=5mm)target lesion's sum of diameters,with smallest sum as reference,or progression of existing non-target lesions,or appearance of atleast 1 new target or NT lesions.Participants not known to have had CR/PR were censored at last tumor assessment date prior to data cutoff or date of new treatment initiation,whichever occurred first.ITT population used."Subjects analyzed"=participants evaluable for endpoint.99999=UL of 95% CI not reached due to insufficient events during data cutoff.88888=Median and UL of 95% CI not reached due to insufficient events during data cutoff.77777=Median and 95% CI not reached due to insufficient events during data cutoff.
    End point type
    Secondary
    End point timeframe
    From randomisation until first documentation of CR or PR, or last tumor assessment without PD or death prior to new antitumor treatment initiation, whichever occurred first (up to 3 years)
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Reporting groups specific to this endpoint are included.
    End point values
    		 Double blind Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg Double blind Cohort 1: Placebo + Exemestane 25 mg Double blind Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg Double blind Cohort 2: Placebo + Exemestane 25 mg
    Number of subjects analysed
    39
    42
    42
    42
    Units: Months
        median (confidence interval 95%)
    12.9 (7.3 to 99999)
    14.0 (7.4 to 99999)
    88888 (3.9 to 88888)
    77777 (77777 to 77777)
    No statistical analyses for this end point

    Secondary: Duration of Objective Response (DOR)

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    End point title
    		 Duration of Objective Response (DOR) [9]
    End point description
    DOR: Time from first documentation of CR/PR to first documentation of PD/death by any cause, whichever occurred first,determined using RECIST 1.1.CR: Disappearance of all (target and NT)lesions, normalisation of tumor marker level for NT lesions. All lymph nodes must be non-pathological in size. PR: >=30% decrease in sum of diameters of target lesions, by baseline sum diameters as reference. PD: >=20% increase (absolute increase of >=5mm) in target lesions sum of diameters, with smallest sum as reference (including baseline sum), or unequivocal progression of existing non-target lesions, or appearance of atleast 1 new target or NT lesions. Participants with no PD or death (after initial CR or PR) at analysis date were censored at last tumor assessment date prior to date of new antitumor treatment or data cutoff. ITT population used."Subjects analyzed"=participants evaluable for this endpoint.99999=UL of 95% CI not reached due to insufficient number of events during data cutoff.
    End point type
    Secondary
    End point timeframe
    From first documentation of CR or PR until PD, or last tumor assessment without PD before new antitumor treatment initiation or death due to any cause, whichever occurred first (up to 3 years)
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Reporting groups specific to this endpoint are included.
    End point values
    		 Double blind Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg Double blind Cohort 1: Placebo + Exemestane 25 mg Double blind Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg Double blind Cohort 2: Placebo + Exemestane 25 mg
    Number of subjects analysed
    39
    42
    42
    42
    Units: Months
        median (confidence interval 95%)
    14.0 (5.6 to 99999)
    9.1 (3.2 to 10.2)
    18.3 (3.3 to 23.1)
    4.6 (1.9 to 7.4)
    No statistical analyses for this end point

    Secondary: Best Objective Response Rate

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    End point title
    		 Best Objective Response Rate [10]
    End point description
    Best objective response rate: Percentage of participants with measurable disease and with a best response of CR or PR according to RECIST 1.1. CR: Disappearance of all (target and non-target) lesions and normalisation of tumor marker level for non-target lesions. All lymph nodes (target and non-target) must be non-pathological in size (<10 mm short axis). PR: Atleast 30% decrease in sum of diameters of target lesions, using baseline sum diameters as reference. Response evaluation was based on investigators' judgment. ITT population included all the participants randomly assigned to double-blind study treatment. Here "subjects analysed" signifies participants with measurable response.
    End point type
    Secondary
    End point timeframe
    From randomisation until CR or PR, whichever occurred first (up to 3 years)
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Reporting groups specific to this endpoint are included.
    End point values
    		 Double blind Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg Double blind Cohort 1: Placebo + Exemestane 25 mg Double blind Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg Double blind Cohort 2: Placebo + Exemestane 25 mg
    Number of subjects analysed
    39
    42
    42
    42
    Units: Percentage of participants
        number (confidence interval 95%)
    30.8 (17.0 to 47.6)
    19.0 (8.6 to 34.1)
    9.5 (2.7 to 22.6)
    4.8 (0.6 to 16.2)
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS) at 6 Months

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    End point title
    		 Progression Free Survival (PFS) at 6 Months [11]
    End point description
    PFS at 6 months was defined as the percentage of participants with no event of disease progression at Month 6 landmark, estimated by Kaplan-Meier methods. PFS was defined as the time in months from randomisation to the first documentation of PD or death on study due to any cause, whichever occurred first. PD: >=20% increase (an absolute increase of >=5 mm) in sum of diameters of target lesions, using the smallest sum during the study as a reference (including baseline sum), or unequivocal progression of existing non-target lesions, or appearance of at least 1 new target or non-target lesions. The analysis of PFS was based on investigator assessment of disease progression. ITT population included all the participants randomly assigned to double-blind study treatment.
    End point type
    Secondary
    End point timeframe
    Month 6
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Reporting groups specific to this endpoint are included.
    End point values
    		 Double blind Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg Double blind Cohort 1: Placebo + Exemestane 25 mg Double blind Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg Double blind Cohort 2: Placebo + Exemestane 25 mg
    Number of subjects analysed
    63
    64
    60
    60
    Units: Percentage of participants
        number (confidence interval 95%)
    66.7 (53.2 to 77.0)
    50.0 (37.1 to 61.6)
    31.5 (19.7 to 43.9)
    33.3 (21.6 to 45.5)
    No statistical analyses for this end point

    Secondary: Concentration Versus Time Summary of Enzalutamide

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    End point title
    		 Concentration Versus Time Summary of Enzalutamide
    End point description
    Concentration versus time summary was calculated by setting concentration values below limit of quantitation to zero. Pharmacokinetic (PK) population for enzalutamide included all participants in safety population who received any amount of enzalutamide and had at least 1 reportable concentration value for enzalutamide or its active metabolite (N-desmethyl enzalutamide). Here, "Subjects Analysed" signifies subjects evaluable for this endpoint and "n" signifies participants evaluable for the specified rows.
    End point type
    Secondary
    End point timeframe
    Predose on Day 29, 57 and 113
    End point values
    		 Enzalutamide 160 mg
    Number of subjects analysed
    114
    Units: Microgram per milliliter
    arithmetic mean (standard deviation)
        Day 29 (n=109)
    14.2 ( 2.97 )
        Day 57 (n=92)
    14.2 ( 3.21 )
        Day 113 (n=67)
    13.2 ( 4.51 )
    No statistical analyses for this end point

    Secondary: Time to Progression

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    End point title
    		 Time to Progression [12]
    End point description
    Time to progression was defined as the time from the date of randomisation to PD defined by the investigator using RECIST 1.1. PD: >=20% increase (an absolute increase of >=5 mm) in sum of diameters of target lesions, using the smallest sum during the study as a reference (including baseline sum), or unequivocal progression of existing nontarget lesions, or appearance of at least 1 new target or non-target lesions. Participants who did not experience disease progression, time to progression was right censored at the date of the last tumor assessment prior to data cutoff or date of new antitumor treatment, whichever occurred first. ITT population included all the participants randomly assigned to double-blind study treatment.
    End point type
    Secondary
    End point timeframe
    From randomisation until PD or last tumor assessment without PD before new antitumor treatment initiation, whichever occurred first (up to 3 years)
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Reporting groups specific to this endpoint are included.
    End point values
    		 Double blind Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg Double blind Cohort 1: Placebo + Exemestane 25 mg Double blind Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg Double blind Cohort 2: Placebo + Exemestane 25 mg
    Number of subjects analysed
    63
    64
    60
    60
    Units: Months
        median (confidence interval 95%)
    11.8 (7.3 to 15.9)
    7.4 (3.5 to 13.5)
    3.6 (1.9 to 5.6)
    3.9 (2.6 to 5.4)
    No statistical analyses for this end point

    Secondary: Concentration Versus Time Summary of Exemestane

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    End point title
    		 Concentration Versus Time Summary of Exemestane
    End point description
    Concentration versus time summary was calculated by setting concentration values below limit of quantitation to zero. PK population for exemestane was defined as all participants in the safety population who received any amount of exemestane and had at least 1 reportable plasma concentration value for exemestane. 99999= Standard deviation could not be estimated since only 1 participant was analysed. 88888= Arithmetic mean and standard deviation could not be estimated since 0 participants were analysed. Here, "n" signifies participants evaluable for the specified rows.
    End point type
    Secondary
    End point timeframe
    Predose, 1 and 6 hour post dose on Day 29, 57, 113 and 169
    End point values
    		 Exemestane 25 mg Exemestane 50 mg
    Number of subjects analysed
    114
    115
    Units: Picogram per milliliter
    arithmetic mean (standard deviation)
        Day 29: Predose (n=108, 108)
    1010 ( 1600 )
    943 ( 939 )
        Day 29: 1 hour Postdose (n=99, 102)
    17000 ( 16400 )
    19200 ( 17800 )
        Day 29: 6 hour Postdose (n=57, 55)
    5590 ( 4750 )
    6850 ( 9090 )
        Day 57: Predose (n=89, 92)
    1160 ( 2590 )
    1100 ( 2650 )
        Day 57: 1 hour Postdose (n=76, 83)
    19900 ( 18600 )
    15300 ( 14500 )
        Day 57: 6 hour Postdose (n=26, 23)
    5890 ( 4880 )
    5650 ( 6200 )
        Day 113: Predose (n=65, 68)
    1160 ( 2870 )
    1330 ( 3380 )
        Day 113: 1 hour Postdose (n=58, 58)
    20800 ( 18100 )
    19400 ( 18500 )
        Day 113: 6 hour Postdose (n=12, 14)
    3510 ( 3850 )
    5600 ( 5290 )
        Day 169: Predose (n=0, 0)
    88888 ( 88888 )
    88888 ( 88888 )
        Day 169: 1 hour Postdose (n=0, 1)
    88888 ( 88888 )
    22800 ( 99999 )
        Day 169: 6 hour Postdose (n=0, 1)
    88888 ( 88888 )
    6020 ( 99999 )
    No statistical analyses for this end point

    Secondary: Concentration Versus Time Summary of N-desmethyl Enzalutamide

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    End point title
    		 Concentration Versus Time Summary of N-desmethyl Enzalutamide
    End point description
    N-desmethyl enzalutamide was the active metabolite of enzalutamide. Concentration versus time summary was calculated by setting concentration values below limit of quantitation to zero. PK population for N-desmethyl enzalutamide included all the participants in safety population who received any amount of enzalutamide and had at least 1 reportable concentration value for N-desmethyl enzalutamide. Here, "n" signifies participants evaluable for the specified rows.
    End point type
    Secondary
    End point timeframe
    Predose on Day 29, 57 and 113
    End point values
    		 Enzalutamide 160 mg
    Number of subjects analysed
    114
    Units: Microgram per milliliter
    arithmetic mean (standard deviation)
        Day 29 (n=109)
    11.6 ( 4.10 )
        Day 57 (n=92)
    15.2 ( 4.76 )
        Day 113 (n=67)
    15.2 ( 5.81 )
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life Core Questionnaire (QLQ-C30) at Weeks 5, 9, 17, 25, 33, 41, 49, 61, 73, 85, 97, 109, 121 and 133: Global Health/Quality of Life

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    End point title
    		 Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life Core Questionnaire (QLQ-C30) at Weeks 5, 9, 17, 25, 33, 41, 49, 61, 73, 85, 97, 109, 121 and 133: Global Health/Quality of Life [13]
    End point description
    EORTC QLQ-C30 questionnaire: standardized instrument to assess quality of life of cancer participants. Participants self-rated their self-care, activity level, pain/discomfort, and mental health during the past week by choosing 1 of 4 possible responses that recorded level of intensity (not at all, a little, quite a bit, and very much) within each dimension, where higher score=more level of intensity. Questionnaire also asked participants to rate their overall health or quality of life within past week on scale of 1: very poor to 7: excellent. Higher global health/quality scores of life indicated better overall health or quality of life. ITT population evaluated. Here, “Subjects Analyzed” contributed data to table but may not have evaluable data for every row and "n"=participants evaluable for specified rows. 88888=standard deviation (SD) not estimated as 1 participant analysed.99999=arithmetic mean and SD not estimated as 0 participants were analysed.
    End point type
    Other pre-specified
    End point timeframe
    Baseline; Weeks 5, 9, 17, 25, 33, 41, 49, 61, 73, 85, 97, 109, 121 and 133
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Reporting groups specific to this endpoint are included.
    End point values
    		 Double blind Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg Double blind Cohort 1: Placebo + Exemestane 25 mg Double blind Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg Double blind Cohort 2: Placebo + Exemestane 25 mg
    Number of subjects analysed
    62
    63
    60
    60
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 5 (n=55, 56, 53, 55)
    1.2 ( 19.14 )
    1.3 ( 21.19 )
    -4.6 ( 16.55 )
    0.3 ( 15.87 )
        Week 9 (n=54, 50, 43, 44)
    -1.9 ( 21.21 )
    1.3 ( 18.77 )
    -5.6 ( 19.13 )
    -1.3 ( 14.37 )
        Week 17 (n=42, 38, 25, 30)
    -3.0 ( 19.46 )
    -1.8 ( 19.29 )
    -7.3 ( 24.45 )
    -0.8 ( 15.98 )
        Week 25 (n=37, 34, 15, 21)
    3.6 ( 18.17 )
    -3.4 ( 21.03 )
    0.6 ( 18.76 )
    -4.8 ( 16.79 )
        Week 33 (n=34, 29, 9, 15)
    2.2 ( 19.60 )
    -0.9 ( 19.59 )
    -8.3 ( 17.68 )
    -5.0 ( 15.04 )
        Week 41 (n=29, 22, 9, 12)
    -0.9 ( 16.11 )
    -1.5 ( 16.99 )
    -9.3 ( 17.40 )
    -1.4 ( 9.95 )
        Week 49 (n=25, 21, 7, 8)
    -0.7 ( 19.53 )
    0.8 ( 13.67 )
    -8.3 ( 12.73 )
    -4.2 ( 16.06 )
        Week 61 (n=22, 19, 7, 4)
    3.8 ( 18.32 )
    -5.7 ( 19.26 )
    -1.2 ( 20.65 )
    6.3 ( 18.48 )
        Week 73 (n=15, 13, 7, 4)
    -1.1 ( 19.64 )
    0.0 ( 14.03 )
    -6.0 ( 15.00 )
    2.1 ( 21.92 )
        Week 85 (n=9, 8, 5, 1)
    0.9 ( 27.78 )
    -5.2 ( 7.63 )
    -3.3 ( 18.26 )
    0.0 ( 88888 )
        Week 97 (n=4, 6, 2, 0)
    -8.3 ( 6.80 )
    -2.8 ( 6.80 )
    0.0 ( 0.00 )
    99999 ( 99999 )
        Week 109 (n=3, 1, 2, 0)
    -13.9 ( 17.35 )
    0.0 ( 88888 )
    12.5 ( 5.89 )
    99999 ( 99999 )
        Week 121 (n=0, 1, 0, 0)
    99999 ( 99999 )
    -8.3 ( 88888 )
    99999 ( 99999 )
    99999 ( 99999 )
        Week 133 (n=0, 1, 0, 0)
    99999 ( 99999 )
    0.0 ( 88888 )
    99999 ( 99999 )
    99999 ( 99999 )
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Breast Cancer Module (QLQ-BR23) at Weeks 5, 9, 17, 25, 33, 41, 49, 61, 73, 85, 97, 109, 121 and 133

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    End point title
    		 Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Breast Cancer Module (QLQ-BR23) at Weeks 5, 9, 17, 25, 33, 41, 49, 61, 73, 85, 97, 109, 121 and 133 [14]
    End point description
    EORTC QLQ-BR23=disease-specific module for breast cancer developed as supplement for EORTC QLQ-C30 that assessed quality of life of breast cancer participants. Participants self-rated on frequent symptoms or problems reported, e.g., pain/discomfort, body satisfaction, self-esteem during past week by choosing 1 of 4 possible responses that recorded level of intensity (not at all, a little, quite a bit, very much) within each dimension. They also self-rated on sexual health/interest during last 4 weeks using same scale. In this endpoint body image functioning, sexual functioning, systemic therapy side effects (SE), upset by hair loss were assessed.ITT population used.Here,“Subjects Analyzed”contributed data to table but may not have evaluable data for every row and "n"=participants evaluable for specified rows. 99999=standard deviation could not be estimated as 1 participant was analysed.88888=arithmetic mean and standard deviation could not be estimated as 0 participants were analysed.
    End point type
    Other pre-specified
    End point timeframe
    Baseline; Weeks 5, 9, 17, 25, 33, 41, 49, 61, 73, 85, 97, 109, 121 and 133
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Reporting groups specific to this endpoint are included.
    End point values
    		 Double blind Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg Double blind Cohort 1: Placebo + Exemestane 25 mg Double blind Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg Double blind Cohort 2: Placebo + Exemestane 25 mg
    Number of subjects analysed
    62
    63
    60
    60
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Body Image Functioning: Week 5(n=55,57,52,54)
    1.8 ( 16.01 )
    1.9 ( 19.10 )
    -6.1 ( 13.92 )
    2.2 ( 15.74 )
        Body Image Functioning: Week 9(n=53,50,40,44)
    -3.5 ( 12.91 )
    -0.2 ( 17.91 )
    -3.7 ( 12.51 )
    2.1 ( 15.58 )
        Body Image Functioning: Week 17(n=43,38,24,31)
    -2.9 ( 20.16 )
    -3.5 ( 19.24 )
    -9.0 ( 19.34 )
    1.3 ( 13.98 )
        Body Image Functioning: Week 25(n=36,33,15,21)
    2.8 ( 16.55 )
    -7.4 ( 24.24 )
    -9.4 ( 16.33 )
    -0.8 ( 7.86 )
        Body Image Functioning: Week 33(n=34,29,9,14)
    -2.9 ( 22.08 )
    -5.7 ( 17.55 )
    -1.9 ( 9.11 )
    -1.8 ( 8.12 )
        Body Image Functioning: Week 41(n=29,22,9,12)
    -2.5 ( 18.76 )
    -1.3 ( 13.36 )
    0.0 ( 4.17 )
    4.2 ( 14.43 )
        Body Image Functioning: Week 49(n=27,21,7,8)
    -2.4 ( 19.79 )
    -5.2 ( 17.57 )
    -1.2 ( 3.15 )
    1.0 ( 8.26 )
        Body Image Functioning: Week 61(n=20,19,7,4)
    3.3 ( 19.94 )
    -5.7 ( 15.23 )
    -4.8 ( 6.56 )
    0.0 ( 13.61 )
        Body Image Functioning: Week 73(n=14,13,7,4)
    -3.2 ( 29.70 )
    -3.2 ( 12.05 )
    1.2 ( 5.75 )
    4.2 ( 10.76 )
        Body Image Functioning: Week 85(n=10,8,5,1)
    8.3 ( 28.05 )
    -13.5 ( 24.78 )
    1.7 ( 3.73 )
    -16.7 ( 99999 )
        Body Image Functioning: Week 97(n=3,6,2,0)
    -5.6 ( 17.35 )
    -1.4 ( 3.40 )
    -4.2 ( 5.89 )
    88888 ( 88888 )
        Body Image Functioning: Week 109(n=4,1,2,0)
    0.0 ( 35.36 )
    0.0 ( 99999 )
    -8.3 ( 11.79 )
    88888 ( 88888 )
        Body Image Functioning: Week 121(n=0,1,0,0)
    88888 ( 88888 )
    0.0 ( 99999 )
    88888 ( 88888 )
    88888 ( 88888 )
        Body Image Functioning: Week 133(n=0,1,0,0)
    88888 ( 88888 )
    0.0 ( 99999 )
    88888 ( 88888 )
    88888 ( 88888 )
        Sexual Functioning: Week 5(n=53, 52, 50, 53)
    1.9 ( 12.08 )
    -0.3 ( 13.40 )
    0.3 ( 17.00 )
    1.9 ( 10.16 )
        Sexual Functioning: Week 9(n=50, 48, 38, 41)
    2.3 ( 16.15 )
    -1.4 ( 16.78 )
    1.3 ( 15.68 )
    2.8 ( 11.73 )
        Sexual Functioning: Week 17(n=40, 35, 23, 29)
    3.3 ( 15.65 )
    0.0 ( 20.21 )
    7.2 ( 23.48 )
    0.6 ( 12.18 )
        Sexual Functioning: Week 25(n=35, 32, 15, 19)
    1.4 ( 17.33 )
    0.5 ( 19.16 )
    0.0 ( 25.20 )
    1.8 ( 10.96 )
        Sexual Functioning: Week 33(n=33, 28, 9, 12)
    4.0 ( 20.43 )
    3.0 ( 12.05 )
    7.4 ( 22.22 )
    4.2 ( 12.56 )
        Sexual Functioning: Week 41(n=28, 21, 9, 10)
    2.4 ( 23.00 )
    0.8 ( 15.34 )
    9.3 ( 22.22 )
    1.7 ( 9.46 )
        Sexual Functioning: Week 49(n=26, 20, 7, 8)
    7.1 ( 21.69 )
    5.8 ( 11.18 )
    9.5 ( 26.97 )
    0.0 ( 0.0 )
        Sexual Functioning: Week 61(n=18, 18, 7, 4)
    7.4 ( 21.56 )
    1.9 ( 20.52 )
    7.1 ( 25.20 )
    0.0 ( 13.61 )
        Sexual Functioning: Week 73(n=14, 12, 7, 4)
    8.3 ( 16.98 )
    2.8 ( 13.91 )
    9.5 ( 31.71 )
    4.2 ( 8.33 )
        Sexual Functioning: Week 85(n=9, 7, 5, 1)
    7.4 ( 22.22 )
    4.8 ( 15.85 )
    -6.7 ( 27.89 )
    0.0 ( 99999 )
        Sexual Functioning: Week 97(n=3, 5, 2, 0)
    -5.6 ( 25.46 )
    6.7 ( 9.13 )
    16.7 ( 23.57 )
    88888 ( 88888 )
        Sexual Functioning: Week 109(n=3, 1, 2, 0)
    0.0 ( 16.67 )
    0.0 ( 99999 )
    33.3 ( 0.00 )
    88888 ( 88888 )
        Sexual Functioning: Week 121(n=0, 1, 0, 0)
    88888 ( 88888 )
    0.0 ( 99999 )
    88888 ( 88888 )
    88888 ( 88888 )
        Sexual Functioning: Week 133(n=0, 1, 0, 0)
    88888 ( 88888 )
    0.0 ( 99999 )
    88888 ( 88888 )
    88888 ( 88888 )
        Systemic Therapy SE: Week 5(n=55, 57, 54, 54)
    4.5 ( 10.59 )
    3.7 ( 10.06 )
    7.1 ( 11.49 )
    3.3 ( 10.82 )
        Systemic Therapy SE: Week 9(n=53, 51, 42, 45)
    7.5 ( 15.24 )
    2.7 ( 10.24 )
    6.5 ( 11.32 )
    3.9 ( 10.77 )
        Systemic Therapy SE: Week 17(n=43, 38, 25, 31)
    7.5 ( 10.81 )
    2.0 ( 8.79 )
    7.6 ( 16.61 )
    6.0 ( 12.51 )
        Systemic Therapy SE: Week 25(n=37, 34, 15, 21)
    8.3 ( 13.90 )
    2.3 ( 7.35 )
    5.6 ( 10.86 )
    5.7 ( 16.05 )
        Systemic Therapy SE: Week 33(n=35, 29, 9, 14)
    6.5 ( 13.54 )
    -0.2 ( 9.74 )
    8.5 ( 7.05 )
    5.3 ( 13.10 )
        Systemic Therapy SE: Week 41(n=30, 22, 9, 12)
    8.4 ( 10.03 )
    1.3 ( 9.20 )
    10.6 ( 4.63 )
    2.0 ( 10.04 )
        Systemic Therapy SE: Week 49(n=27, 21, 7, 8)
    7.8 ( 10.18 )
    2.5 ( 11.03 )
    9.7 ( 12.78 )
    7.7 ( 9.84 )
        Systemic Therapy SE: Week 61(n=20, 19, 7, 4)
    7.6 ( 11.07 )
    2.5 ( 10.45 )
    14.7 ( 10.11 )
    4.8 ( 6.73 )
        Systemic Therapy SE: Week 73(n=14, 13, 7, 4)
    4.9 ( 11.90 )
    4.4 ( 6.29 )
    11.6 ( 10.95 )
    -1.2 ( 5.99 )
        Systemic Therapy SE: Week 85(n=10, 8, 5, 1)
    10.7 ( 12.58 )
    2.4 ( 8.82 )
    9.5 ( 6.73 )
    4.8 ( 99999 )
        Systemic Therapy SE: Week 97(n=3, 6, 2, 0)
    8.2 ( 13.52 )
    3.2 ( 10.29 )
    7.1 ( 10.10 )
    88888 ( 88888 )
        Systemic Therapy SE: Week 109(n=4, 1, 2, 0)
    14.1 ( 9.71 )
    4.8 ( 99999 )
    9.5 ( 6.73 )
    88888 ( 88888 )
        Systemic Therapy SE: Week 121(n=0, 1, 0, 0)
    88888 ( 88888 )
    9.5 ( 99999 )
    88888 ( 88888 )
    88888 ( 88888 )
        Systemic Therapy SE: Week 133(n=0, 1, 0, 0)
    88888 ( 88888 )
    4.8 ( 99999 )
    88888 ( 88888 )
    88888 ( 88888 )
        Upset by Hair Loss: Week 5(n=12, 11, 18, 12)
    -5.6 ( 19.25 )
    18.2 ( 31.14 )
    0.0 ( 28.01 )
    0.0 ( 24.62 )
        Upset by Hair Loss: Week 9(n=6, 10, 15, 10)
    0.0 ( 36.51 )
    23.3 ( 31.62 )
    -6.7 ( 18.69 )
    3.3 ( 24.60 )
        Upset by Hair Loss: Week 17(n=6, 7, 9, 6)
    0.0 ( 21.08 )
    9.5 ( 16.27 )
    3.7 ( 20.03 )
    0.0 ( 36.51 )
        Upset by Hair Loss: Week 25(n=5, 7, 5, 4)
    -6.7 ( 14.91 )
    28.6 ( 35.63 )
    26.7 ( 27.89 )
    -8.3 ( 16.67 )
        Upset by Hair Loss: Week 33(n=5, 5, 5, 2)
    0.0 ( 23.57 )
    -6.7 ( 14.91 )
    20.0 ( 29.81 )
    0.0 ( 0.00 )
        Upset by Hair Loss: Week 41(n=4, 3, 5, 2)
    -16.7 ( 33.33 )
    0.00 ( 0.00 )
    13.3 ( 18.26 )
    16.7 ( 23.57 )
        Upset by Hair Loss: Week 49(n=5, 2, 3, 2)
    6.7 ( 36.51 )
    0.00 ( 0.00 )
    11.1 ( 19.25 )
    0.00 ( 0.00 )
        Upset by Hair Loss: Week 61(n=3, 2, 4, 0)
    11.1 ( 19.25 )
    16.7 ( 23.57 )
    25.0 ( 31.91 )
    88888 ( 88888 )
        Upset by Hair Loss: Week 73(n=2, 1, 5, 0)
    0.0 ( 0.0 )
    0.0 ( 99999 )
    40.0 ( 43.46 )
    88888 ( 88888 )
        Upset by Hair Loss: Week 85(n=1, 0, 3, 0)
    33.3 ( 99999 )
    88888 ( 88888 )
    0.0 ( 0.0 )
    88888 ( 88888 )
        Upset by Hair Loss: Week 97(n=0, 0, 1, 0)
    88888 ( 88888 )
    88888 ( 88888 )
    0.0 ( 99999 )
    88888 ( 88888 )
        Upset by Hair Loss: Week 109(n=0, 0, 2, 0)
    88888 ( 88888 )
    88888 ( 88888 )
    0.0 ( 0.0 )
    88888 ( 88888 )
        Upset by Hair Loss: Week 121(n=0, 0, 0, 0)
    88888 ( 88888 )
    88888 ( 88888 )
    88888 ( 88888 )
    88888 ( 88888 )
    No statistical analyses for this end point

    Other pre-specified: Number of Participants With Positive Androgen Receptor (AR) Expression by Immunohistochemistry (IHC)

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    End point title
    		 Number of Participants With Positive Androgen Receptor (AR) Expression by Immunohistochemistry (IHC) [15]
    End point description
    Protocol of this study was amended and data for this endpoint was not analysed as per planned analysis.
    End point type
    Other pre-specified
    End point timeframe
    Day 1, 29, 57, 113 and 169
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Reporting groups specific to this endpoint are included.
    End point values
    		 Double blind Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg Double blind Cohort 1: Placebo + Exemestane 25 mg Double blind Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg Double blind Cohort 2: Placebo + Exemestane 25 mg
    Number of subjects analysed
    0 [16]
    0 [17]
    0 [18]
    0 [19]
    Units: Participants
    Notes
    [16] - Protocol was amended and data for this endpoint was not analysed as per planned analysis.
    [17] - Protocol was amended and data for this endpoint was not analysed as per planned analysis.
    [18] - Protocol was amended and data for this endpoint was not analysed as per planned analysis.
    [19] - Protocol was amended and data for this endpoint was not analysed as per planned analysis.
    No statistical analyses for this end point

    Other pre-specified: Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [20]
    End point 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 endpoints 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. A treatment emergent AE was defined as an event that emerged during the treatment period that was absent before treatment or worsened during the treatment period relative to the pretreatment state. AEs included both serious and non-serious AEs. Safety population included all the participants who received study drug either in double blind or in open label treatment period.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to 30 days after the last dose of study drug or before initiation of a new antitumor treatment, whichever occurred first (approximately up to 10.13 years)
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Reporting groups specific to this endpoint are included.
    End point values
    		 Double blind Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg Double blind Cohort 1: Placebo + Exemestane 25 mg Double blind Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg Double blind Cohort 2: Placebo + Exemestane 25 mg
    Number of subjects analysed
    62
    63
    60
    60
    Units: Participants
        AEs
    59
    58
    58
    53
        SAEs
    14
    13
    10
    8
    No statistical analyses for this end point

    Other pre-specified: Number of Participants With Clinically Significant Vital Sign Abnormalities

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    End point title
    		 Number of Participants With Clinically Significant Vital Sign Abnormalities [21]
    End point description
    Criteria for clinically significant vital sign abnormalities: Systolic blood pressure (SBP): absolute SBP <90 millimeters of mercury (mmHg) and decrease from baseline (DFB) >30 mmHg, absolute SBP>180 mmHg and increase from baseline (IFB) >40 mmHg, final visit or 2 consecutive visits SBP >=20 mmHg change from baseline (CFB), most extreme post-baseline SBP >=140 mmHg, most extreme post-baseline SBP >=180 mmHg, most extreme SBP >=140 mmHg and >=20 mmHg CFB, most extreme SBP >=180 mmHg and >=20 mmHg CFB; diastolic blood pressure (DBP): absolute DBP > 105 mmHg and IFB >30 mmHg, absolute DBP <50 mmHg and DFB >20 mmHg, final visit or 2 consecutive visits DBP >=15 mmHg CFB, most extreme post-baseline DBP >=90 mmHg, most extreme post-baseline DBP >=105 mmHg, most extreme DBP >=90 mmHg and >=15 mmHg CFB, most extreme DBP >=105 mmHg and >=15 mmHg CFB; heart rate <50 beats per minute (BPM) and DFB >20 BPM or heart rate >120 BPM and IFB >30 BPM. Safety population was analysed in this endpoint.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to 30 days after the last dose of study drug or before initiation of a new antitumor treatment, whichever occurred first (approximately up to 10.13 years)
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Reporting groups specific to this endpoint are included.
    End point values
    		 Double blind Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg Double blind Cohort 1: Placebo + Exemestane 25 mg Double blind Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg Double blind Cohort 2: Placebo + Exemestane 25 mg
    Number of subjects analysed
    62
    63
    60
    60
    Units: Participants
        Blood pressure
    38
    39
    43
    25
        Heart rate
    0
    2
    0
    0
    No statistical analyses for this end point

    Other pre-specified: Number of Participants With Treatment-Emergent Adverse Events of Grade 3 or Higher Severity

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    End point title
    		 Number of Participants With Treatment-Emergent Adverse Events of Grade 3 or Higher Severity [22]
    End point description
    An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Severity of the AEs was graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Only the participants with treatment-emergent AEs of grade 3 (severe) or higher grade were reported in this endpoint. Safety population included all the participants who received study drug either in double blind or in open label treatment period.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to 30 days after the last dose of study drug or before initiation of a new antitumor treatment, whichever occurred first (approximately up to 10.13 years)
    Notes
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Reporting groups specific to this endpoint are included.
    End point values
    		 Double blind Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg Double blind Cohort 1: Placebo + Exemestane 25 mg Double blind Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg Double blind Cohort 2: Placebo + Exemestane 25 mg
    Number of subjects analysed
    62
    63
    60
    60
    Units: Participants
    21
    16
    22
    12
    No statistical analyses for this end point

    Other pre-specified: Progression Free Survival (PFS): Stratified Analyses By Electronic Data Capture (EDC)

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    End point title
    		 Progression Free Survival (PFS): Stratified Analyses By Electronic Data Capture (EDC) [23]
    End point description
    PFS =time in months from randomization to first documentation of PD or death on study due to any cause, whichever occurred first. PD according to RECIST 1.1= >=20 % increase in sum of diameters of target lesions taking as reference smallest sum recorded since start of treatment/unequivocal progression in non-target lesions or appearance >=1 lesion. PFS was analysed based on investigator assessment of disease progression. Participants who were not known to have had PFS event at analysis date were censored at last tumor assessment date prior to data cutoff/start date of new therapy, whichever occurred first. Analysis was performed on all randomized participants. Randomization to cohort was based on participant’s exposure to advance setting hormonal therapy. Initial randomization was done by IWRS. Later, upon detailed data entry in EDC, it was determined 1 participant was incorrectly assigned to Cht1:Enz+Exe by IWRS, hence counted in Cht2:Enz+Exe by EDC.
    End point type
    Other pre-specified
    End point timeframe
    From randomization until PD, last tumor assessment without PD before new antitumor treatment initiation or death due to any cause, whichever occurred first (up to 3 years)
    Notes
    [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Reporting groups specific to this endpoint are included.
    End point values
    		 Double blind Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg Double blind Cohort 1: Placebo + Exemestane 25 mg Double blind Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg Double blind Cohort 2: Placebo + Exemestane 25 mg
    Number of subjects analysed
    62
    64
    60
    60
    Units: months
        median (confidence interval 95%)
    11.8 (7.3 to 14.6)
    5.8 (3.5 to 10.9)
    3.6 (1.9 to 5.6)
    3.9 (2.6 to 5.4)
    Statistical analysis title
    		 PFS: By Electronic Data Capture (EDC)
    Comparison groups
    Double blind Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg v Double blind Cohort 2: Placebo + Exemestane 25 mg
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 other [24]
    P-value
    		 = 0.8817
    Method
    		 Stratified log-rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.968
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.632
         upper limit
    		 1.483
    Notes
    [24] - Hazard ratio was based on stratified Cox regression model.
    Statistical analysis title
    		 PFS: By Electronic Data Capture (EDC)
    Comparison groups
    Double blind Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg v Double blind Cohort 1: Placebo + Exemestane 25 mg
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.7378
    Method
    		 Stratified log-rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.928
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.599
         upper limit
    		 1.438

    Other pre-specified: Number of Participants With Clinically Significant Laboratory Abnormalities

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    End point title
    		 Number of Participants With Clinically Significant Laboratory Abnormalities [25]
    End point description
    Laboratory tests included hematology (hematocrit, hemoglobin, platelet count, red blood cell count, total neutrophils [absolute] and white blood cell count with differential) and serum chemistry (albumin, alkaline phosphatase, alanine aminotransferase [ALT], aspartate transaminase [AST], blood urea nitrogen and creatinine, calcium, sodium, potassium, chloride, glucose (non-fasting), lactate dehydrogenase, magnesium, phosphorus/phosphate, total bilirubin, total bicarbonate, total protein and uric acid). Clinically significant abnormality evaluation was based on clinical investigator’s judgment. Safety population included all the participants who received study drug either in double blind or in open label treatment period.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to 30 days after the last dose of study drug or before initiation of a new antitumor treatment, whichever occurred first (up to 3 years)
    Notes
    [25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Reporting groups specific to this endpoint are included.
    End point values
    		 Double blind Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg Double blind Cohort 1: Placebo + Exemestane 25 mg Double blind Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg Double blind Cohort 2: Placebo + Exemestane 25 mg
    Number of subjects analysed
    62
    63
    60
    60
    Units: Participants
    0
    0
    0
    0
    No statistical analyses for this end point

    Other pre-specified: Progression Free Survival (PFS): Diagnostic Positive (DX+) Population Stratified Analyses By Electronic Data Capture (EDC)

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    End point title
    		 Progression Free Survival (PFS): Diagnostic Positive (DX+) Population Stratified Analyses By Electronic Data Capture (EDC) [26]
    End point description
    PFS: time from randomization to first documentation of PD or death on study due to any cause, whichever occurred first. PD per RECIST 1.1: >= 20% increase in sum of diameters of target lesions taking as reference smallest sum recorded since start of treatment or unequivocal progression in non-target lesions or appearance of 1 or more new lesions. The analysis of PFS was based on investigator assessment of disease progression. Participants who were not known to have had a PFS event at analysis date were censored at last tumor assessment date prior to data cutoff or date of new treatment initiation, whichever occurred first. Dx+ population: Subset of ITT population, defined prior to the first unblinded analysis as meeting the threshold for diagnostic score based on ribonucleic acid (RNA) sequencing data from tumor tissue. “Subjects Analyzed” =participants evaluable for this endpoint. Here, 99999=Upper limit of 95% CI not reached due to insufficient number of participants with events.
    End point type
    Other pre-specified
    End point timeframe
    From randomization until PD, last tumor assessment without PD before new antitumor treatment initiation or death due to any cause, whichever occurred first (up to 3 years)
    Notes
    [26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Reporting groups specific to this endpoint are included.
    End point values
    		 Double blind Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg Double blind Cohort 1: Placebo + Exemestane 25 mg Double blind Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg Double blind Cohort 2: Placebo + Exemestane 25 mg
    Number of subjects analysed
    23
    26
    16
    20
    Units: Months
        median (confidence interval 95%)
    16.9 (11.0 to 99999)
    4.3 (1.9 to 10.9)
    6.0 (3.5 to 16.6)
    5.3 (1.8 to 6.7)
    Statistical analysis title
    		 DX+ Population By Electronic Data Capture (EDC)
    Comparison groups
    Double blind Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg v Double blind Cohort 1: Placebo + Exemestane 25 mg
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.127
    Method
    		 Stratified log-rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.522
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.224
         upper limit
    		 1.217
    Statistical analysis title
    		 DX+ Population By Electronic Data Capture (EDC)
    Comparison groups
    Double blind Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg v Double blind Cohort 2: Placebo + Exemestane 25 mg
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other [27]
    P-value
    		 = 0.0359
    Method
    		 Stratified log-rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.143
         upper limit
    		 0.961
    Notes
    [27] - Hazard ratio was based on stratified Cox regression model.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to 30 days after the last dose of study drug or before initiation of a new antitumor treatment, whichever occurred first (up to 10.13 years)
    Adverse event reporting additional description
    Same event may appear as both an adverse event (AE) and a serious AE, but they are distinct events. Event may be categorized as serious in one participant and as non-serious in another, or one may have experienced both serious and non-serious event during study. AEs and all-cause mortality were collected and evaluated for safety population.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg
    Reporting group description
    		 Participants with no previous hormonal treatment for advanced breast cancer, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.

    Reporting group title
    Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg
    Reporting group description
    		 Participants with previous disease progression following hormonal treatment for advanced breast cancer, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.

    Reporting group title
    Cohort 2: Placebo + Exemestane 25 mg
    Reporting group description
    		 Participants with previous disease progression following hormonal treatment for advanced breast cancer, received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.

    Reporting group title
    Cohort 1: Placebo + Exemestane 25 mg
    Reporting group description
    		 Participants with no previous hormonal treatment for advanced breast cancer received placebo matched to enzalutamide along with exemestane 25 mg, orally, once daily in double blind treatment period until disease progression or permanent treatment discontinuation. Eligible participants with disease progression in double blind period, on their discretion, received enzalutamide 160 mg along with exemestane 50 mg, orally, once daily up to disease progression in open label treatment period. Participants were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.

    Serious adverse events
    		 Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg Cohort 2: Placebo + Exemestane 25 mg Cohort 1: Placebo + Exemestane 25 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    14 / 62 (22.58%)
    10 / 60 (16.67%)
    8 / 60 (13.33%)
    13 / 63 (20.63%)
         number of deaths (all causes)
    2
    3
    2
    8
         number of deaths resulting from adverse events
    2
    2
    0
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    ADENOCARCINOMA PANCREAS
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BREAST CANCER METASTATIC
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    BREAST CANCER
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    METASTATIC PAIN
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 60 (1.67%)
    0 / 60 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CONTRALATERAL BREAST CANCER
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LYMPHANGIOSIS CARCINOMATOSA
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MALIGNANT PLEURAL EFFUSION
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    PLASMA CELL MYELOMA
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    METASTASES TO CENTRAL NERVOUS SYSTEM
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MALIGNANT ASCITES
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 60 (1.67%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    PAIN
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    NON-CARDIAC CHEST PAIN
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INFLUENZA LIKE ILLNESS
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DISEASE PROGRESSION
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 60 (1.67%)
    0 / 60 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    ASTHENIA
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CHILLS
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GENERAL PHYSICAL HEALTH DETERIORATION
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 60 (1.67%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    FATIGUE
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 60 (1.67%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    FACIAL PAIN
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 60 (1.67%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    DRUG HYPERSENSITIVITY
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ANAPHYLACTIC REACTION
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 60 (1.67%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    DYSPNOEA
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 60 (0.00%)
    1 / 60 (1.67%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DYSPNOEA EXERTIONAL
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PLEURAL EFFUSION
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 60 (0.00%)
    1 / 60 (1.67%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PULMONARY EMBOLISM
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    SUICIDAL IDEATION
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 60 (0.00%)
    1 / 60 (1.67%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DELIRIUM
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 60 (1.67%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    FALL
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HUMERUS FRACTURE
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 60 (0.00%)
    1 / 60 (1.67%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LACERATION
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RADIATION PNEUMONITIS
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    TRAUMATIC HAEMORRHAGE
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OPTIC NERVE INJURY
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 60 (1.67%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SPINAL COMPRESSION FRACTURE
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 60 (1.67%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    CARDIAC FAILURE CONGESTIVE
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 60 (0.00%)
    1 / 60 (1.67%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CEREBROVASCULAR ACCIDENT
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    BRACHIAL PLEXOPATHY
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HAEMORRHAGE INTRACRANIAL
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    SPINAL CORD COMPRESSION
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SYNCOPE
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    EMBOLIC STROKE
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 60 (0.00%)
    1 / 60 (1.67%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GRAND MAL CONVULSION
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 60 (1.67%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    STATUS EPILEPTICUS
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 60 (1.67%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INTRACRANIAL HAEMATOMA
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 60 (0.00%)
    1 / 60 (1.67%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SPEECH DISORDER
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 60 (1.67%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    THROMBOCYTOPENIA
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    ANAEMIA
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 60 (1.67%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    FAECES DISCOLOURED
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    OESOPHAGEAL STENOSIS
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    VOMITING
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INTESTINAL OBSTRUCTION
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 60 (1.67%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 60 (1.67%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    HEPATIC HAEMORRHAGE
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 60 (0.00%)
    1 / 60 (1.67%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    CHOLECYSTITIS
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 60 (1.67%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 60 (0.00%)
    1 / 60 (1.67%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    BACK PAIN
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 60 (0.00%)
    1 / 60 (1.67%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PAIN IN EXTREMITY
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PATHOLOGICAL FRACTURE
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 60 (1.67%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    NECK PAIN
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 60 (1.67%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MASTICATION DISORDER
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 60 (1.67%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    BREAST CELLULITIS
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    WOUND INFECTION
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PYELONEPHRITIS
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 60 (0.00%)
    1 / 60 (1.67%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    URINARY TRACT INFECTION
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 60 (0.00%)
    1 / 60 (1.67%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    POSTOPERATIVE WOUND INFECTION
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 60 (1.67%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INFECTIVE EXACERBATION OF CHRONIC OBSTRUCTIVE AIRWAYS DISEASE
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 60 (1.67%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    HYPERCALCAEMIA
         subjects affected / exposed
    2 / 62 (3.23%)
    2 / 60 (3.33%)
    1 / 60 (1.67%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPOPHOSPHATAEMIA
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPONATRAEMIA
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 60 (1.67%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg Cohort 2: Placebo + Exemestane 25 mg Cohort 1: Placebo + Exemestane 25 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    59 / 62 (95.16%)
    57 / 60 (95.00%)
    52 / 60 (86.67%)
    57 / 63 (90.48%)
    Investigations
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    0 / 62 (0.00%)
    2 / 60 (3.33%)
    3 / 60 (5.00%)
    4 / 63 (6.35%)
         occurrences all number
    0
    3
    3
    4
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    0 / 62 (0.00%)
    2 / 60 (3.33%)
    4 / 60 (6.67%)
    3 / 63 (4.76%)
         occurrences all number
    0
    3
    5
    3
    Vascular disorders
    HOT FLUSH
         subjects affected / exposed
    19 / 62 (30.65%)
    14 / 60 (23.33%)
    9 / 60 (15.00%)
    14 / 63 (22.22%)
         occurrences all number
    21
    19
    10
    16
    HYPERTENSION
         subjects affected / exposed
    8 / 62 (12.90%)
    2 / 60 (3.33%)
    1 / 60 (1.67%)
    3 / 63 (4.76%)
         occurrences all number
    9
    2
    1
    3
    Nervous system disorders
    AMNESIA
         subjects affected / exposed
    4 / 62 (6.45%)
    1 / 60 (1.67%)
    1 / 60 (1.67%)
    0 / 63 (0.00%)
         occurrences all number
    4
    1
    1
    0
    DIZZINESS
         subjects affected / exposed
    7 / 62 (11.29%)
    5 / 60 (8.33%)
    2 / 60 (3.33%)
    4 / 63 (6.35%)
         occurrences all number
    8
    5
    2
    4
    HEADACHE
         subjects affected / exposed
    9 / 62 (14.52%)
    9 / 60 (15.00%)
    10 / 60 (16.67%)
    6 / 63 (9.52%)
         occurrences all number
    10
    12
    18
    6
    NEUROPATHY PERIPHERAL
         subjects affected / exposed
    4 / 62 (6.45%)
    0 / 60 (0.00%)
    1 / 60 (1.67%)
    3 / 63 (4.76%)
         occurrences all number
    4
    0
    1
    3
    PARAESTHESIA
         subjects affected / exposed
    4 / 62 (6.45%)
    2 / 60 (3.33%)
    2 / 60 (3.33%)
    2 / 63 (3.17%)
         occurrences all number
    5
    2
    2
    2
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    9 / 62 (14.52%)
    6 / 60 (10.00%)
    4 / 60 (6.67%)
    7 / 63 (11.11%)
         occurrences all number
    9
    9
    8
    7
    FATIGUE
         subjects affected / exposed
    24 / 62 (38.71%)
    21 / 60 (35.00%)
    13 / 60 (21.67%)
    23 / 63 (36.51%)
         occurrences all number
    31
    24
    17
    26
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    4 / 62 (6.45%)
    6 / 60 (10.00%)
    3 / 60 (5.00%)
    1 / 63 (1.59%)
         occurrences all number
    11
    8
    9
    1
    Gastrointestinal disorders
    VOMITING
         subjects affected / exposed
    11 / 62 (17.74%)
    6 / 60 (10.00%)
    3 / 60 (5.00%)
    7 / 63 (11.11%)
         occurrences all number
    17
    8
    4
    12
    CONSTIPATION
         subjects affected / exposed
    11 / 62 (17.74%)
    8 / 60 (13.33%)
    8 / 60 (13.33%)
    7 / 63 (11.11%)
         occurrences all number
    11
    10
    9
    7
    DYSPEPSIA
         subjects affected / exposed
    1 / 62 (1.61%)
    5 / 60 (8.33%)
    4 / 60 (6.67%)
    6 / 63 (9.52%)
         occurrences all number
    1
    5
    4
    6
    NAUSEA
         subjects affected / exposed
    24 / 62 (38.71%)
    18 / 60 (30.00%)
    11 / 60 (18.33%)
    10 / 63 (15.87%)
         occurrences all number
    33
    23
    17
    11
    DIARRHOEA
         subjects affected / exposed
    14 / 62 (22.58%)
    7 / 60 (11.67%)
    11 / 60 (18.33%)
    10 / 63 (15.87%)
         occurrences all number
    18
    9
    16
    10
    ABDOMINAL PAIN
         subjects affected / exposed
    1 / 62 (1.61%)
    2 / 60 (3.33%)
    4 / 60 (6.67%)
    2 / 63 (3.17%)
         occurrences all number
    1
    2
    5
    2
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    3 / 62 (4.84%)
    4 / 60 (6.67%)
    2 / 60 (3.33%)
    2 / 63 (3.17%)
         occurrences all number
    4
    4
    3
    2
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    10 / 62 (16.13%)
    2 / 60 (3.33%)
    4 / 60 (6.67%)
    8 / 63 (12.70%)
         occurrences all number
    11
    2
    5
    10
    DYSPNOEA
         subjects affected / exposed
    9 / 62 (14.52%)
    5 / 60 (8.33%)
    4 / 60 (6.67%)
    8 / 63 (12.70%)
         occurrences all number
    10
    7
    5
    9
    OROPHARYNGEAL PAIN
         subjects affected / exposed
    4 / 62 (6.45%)
    1 / 60 (1.67%)
    0 / 60 (0.00%)
    2 / 63 (3.17%)
         occurrences all number
    4
    1
    0
    3
    Skin and subcutaneous tissue disorders
    ALOPECIA
         subjects affected / exposed
    8 / 62 (12.90%)
    5 / 60 (8.33%)
    2 / 60 (3.33%)
    4 / 63 (6.35%)
         occurrences all number
    9
    5
    2
    4
    Psychiatric disorders
    INSOMNIA
         subjects affected / exposed
    5 / 62 (8.06%)
    5 / 60 (8.33%)
    4 / 60 (6.67%)
    4 / 63 (6.35%)
         occurrences all number
    5
    5
    4
    4
    ANXIETY
         subjects affected / exposed
    6 / 62 (9.68%)
    2 / 60 (3.33%)
    1 / 60 (1.67%)
    4 / 63 (6.35%)
         occurrences all number
    7
    2
    1
    4
    DEPRESSED MOOD
         subjects affected / exposed
    1 / 62 (1.61%)
    4 / 60 (6.67%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    3
    4
    0
    0
    Musculoskeletal and connective tissue disorders
    MUSCULOSKELETAL CHEST PAIN
         subjects affected / exposed
    7 / 62 (11.29%)
    3 / 60 (5.00%)
    3 / 60 (5.00%)
    4 / 63 (6.35%)
         occurrences all number
    9
    4
    3
    4
    BONE PAIN
         subjects affected / exposed
    3 / 62 (4.84%)
    5 / 60 (8.33%)
    2 / 60 (3.33%)
    4 / 63 (6.35%)
         occurrences all number
    3
    6
    4
    4
    BACK PAIN
         subjects affected / exposed
    11 / 62 (17.74%)
    4 / 60 (6.67%)
    11 / 60 (18.33%)
    6 / 63 (9.52%)
         occurrences all number
    12
    5
    13
    7
    ARTHRALGIA
         subjects affected / exposed
    15 / 62 (24.19%)
    10 / 60 (16.67%)
    7 / 60 (11.67%)
    11 / 63 (17.46%)
         occurrences all number
    18
    11
    9
    16
    MYALGIA
         subjects affected / exposed
    4 / 62 (6.45%)
    0 / 60 (0.00%)
    4 / 60 (6.67%)
    4 / 63 (6.35%)
         occurrences all number
    4
    0
    6
    5
    MUSCULOSKELETAL PAIN
         subjects affected / exposed
    7 / 62 (11.29%)
    2 / 60 (3.33%)
    2 / 60 (3.33%)
    1 / 63 (1.59%)
         occurrences all number
    8
    3
    4
    2
    PAIN IN EXTREMITY
         subjects affected / exposed
    4 / 62 (6.45%)
    3 / 60 (5.00%)
    5 / 60 (8.33%)
    8 / 63 (12.70%)
         occurrences all number
    6
    5
    6
    13
    Infections and infestations
    INFLUENZA
         subjects affected / exposed
    3 / 62 (4.84%)
    1 / 60 (1.67%)
    2 / 60 (3.33%)
    4 / 63 (6.35%)
         occurrences all number
    4
    1
    2
    7
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    4 / 62 (6.45%)
    1 / 60 (1.67%)
    3 / 60 (5.00%)
    1 / 63 (1.59%)
         occurrences all number
    4
    1
    5
    1
    URINARY TRACT INFECTION
         subjects affected / exposed
    2 / 62 (3.23%)
    1 / 60 (1.67%)
    4 / 60 (6.67%)
    3 / 63 (4.76%)
         occurrences all number
    3
    1
    9
    5
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    6 / 62 (9.68%)
    6 / 60 (10.00%)
    2 / 60 (3.33%)
    6 / 63 (9.52%)
         occurrences all number
    9
    7
    2
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Feb 2024
    A secondary immunogenicity objective in response to a regulatory (CBER) request was added.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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