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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

    Results information
    Results version number
    		 v3(current)
    This version publication date
    23 Dec 2018
    First version publication date
    14 Oct 2017
    Other versions
    		 v1 , v2
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    MDV3100-12
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02007512
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer, Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    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
    Interim
    Date of interim/final analysis
    07 Mar 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Sep 2016
    Global end of trial reached?
    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 subjects with advanced breast cancer that was estrogen or progesterone receptor-positive or both (ER+/PgR+), human epidermal growth factor receptor 2 (HER2) - normal and the subset that was also diagnostic-positive (Dx+) as followed: • Cohort 1: Subjects who had not previously received hormone treatment for advanced breast cancer • Cohort 2: Subjects who previously progressed following 1 (one) hormone treatment for advanced breast cancer
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trials subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 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
    124
    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
    		 -

    Pre-assignment
    Screening details
    		 This was a phase 2, randomized, double blind, placebo-controlled study. The results disclosed in this draft were based on the data collected till 23 Sep 2016.

    Period 1
    Period 1 title
    Double Blind Treatment Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg
    Arm description
    		 Subjects with no previous hormonal treatment for advanced breast cancer, received enzalutamide 160 milligram (mg) along with exemestane 50 mg, orally, once daily until disease progression or permanent treatment discontinuation. Subjects 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
    Other name
    MDV3100
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Enzalutamide 160 mg was administered 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 50 mg was administered orally, once daily.

    Arm title
    		 Cohort 1: Placebo + Exemestane 25 mg
    Arm description
    		 Subjects 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 subjects 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. Subjects 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 matched to enzalutamide was administered 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 administered orally, once daily.

    Arm title
    		 Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg
    Arm description
    		 Subjects 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. Subjects 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 administered orally, once daily.

    Investigational medicinal product name
    Enzalutamide
    Investigational medicinal product code
    Other name
    MDV3100
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Enzalutamide 160 mg was administered orally, once daily.

    Arm title
    		 Cohort 2: Placebo + Exemestane 25 mg
    Arm description
    		 Subjects 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 subjects 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. Subjects 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
    Exemestane
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Exemestane 25 mg was administered orally, once daily.

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

    Number of subjects in period 1
    		Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg Cohort 1: Placebo + Exemestane 25 mg Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg Cohort 2: Placebo + Exemestane 25 mg
    Started
    63
    64
    60
    60
    Completed
    45
    49
    45
    51
    Not completed
    18
    15
    15
    9
         Consent withdrawn by subject
    4
    2
    3
    3
         Ongoing as of the data cutoff date (23 Sep 2016)
    10
    11
    5
    1
         Adverse event
    4
    2
    6
    2
         Unspecified
    -
    -
    1
    2
         Protocol deviation
    -
    -
    -
    1
    Period 2
    Period 2 title
    Open Label Treatment Period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1: Placebo + Exemestane 25 mg
    Arm description
    		 Subjects 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 subjects 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. Subjects 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
    Enzalutamide
    Investigational medicinal product code
    MDV3100
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Enzalutamide 160 mg was administered 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 50 mg was administered orally, once daily.

    Arm title
    		 Cohort 2: Placebo + Exemestane 25 mg
    Arm description
    		 Subjects 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 subjects 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. Subjects 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
    Exemestane
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Exemestane 50 mg was administered orally, once daily.

    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 administered orally, once daily

    Number of subjects in period 2 [1]
    		Cohort 1: Placebo + Exemestane 25 mg Cohort 2: Placebo + Exemestane 25 mg
    Started
    21
    12
    Treated
    21
    12
    Completed
    17
    11
    Not completed
    4
    1
         Ongoing as of the data cutoff date (23 Sep 2016)
    3
    -
         Adverse event
    1
    -
         Unspecified
    -
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: From ''double blind'' period, only eligible participants of ''Placebo + Exemestane 25 mg'' reporting arm entered into the ''open label'' period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg
    Reporting group description
    		 Subjects with no previous hormonal treatment for advanced breast cancer, received enzalutamide 160 milligram (mg) along with exemestane 50 mg, orally, once daily until disease progression or permanent treatment discontinuation. Subjects 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
    		 Subjects 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 subjects 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. Subjects 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
    		 Subjects 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. Subjects 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
    		 Subjects 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 subjects 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. Subjects 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
    		 Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg Cohort 1: Placebo + Exemestane 25 mg Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg Cohort 2: Placebo + Exemestane 25 mg Total
    Number of subjects
    		 63 64 60 60 247
    Age Categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 42 32 37 40 151
        From 65-84 years
    		 20 31 23 18 92
        85 years and over
    		 1 1 0 2 4
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 59.0 ( 10.82 ) 63.5 ( 11.56 ) 60.1 ( 11.27 ) 60.6 ( 13.47 ) -
    Gender, Male/Female
    Units: Subjects
        Female
    		 63 64 60 60 247
        Male
    		 0 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg
    Reporting group description
    		 Subjects with no previous hormonal treatment for advanced breast cancer, received enzalutamide 160 milligram (mg) along with exemestane 50 mg, orally, once daily until disease progression or permanent treatment discontinuation. Subjects 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
    		 Subjects 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 subjects 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. Subjects 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
    		 Subjects 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. Subjects 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
    		 Subjects 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 subjects 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. Subjects 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
    		 Subjects 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 subjects 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. Subjects 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
    		 Subjects 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 subjects 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. Subjects 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
    Subjects 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. Subjects 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
    Subjects received exemestane 25 mg dose orally, once daily, in double blind treatment period until disease progression or permanent treatment discontinuation. Subjects 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
    Subjects 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. Subjects 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 set title
    Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg (EDC)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects 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. Subjects 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
    Cohort 1: Placebo + Exemestane 25 mg (EDC)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects 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 subjects 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. Subjects 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
    Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg (EDC)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects 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. Subjects 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
    Cohort 2: Placebo + Exemestane 25 mg (EDC)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects 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 subjects 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. Subjects were followed-up until 30 days after last dose of study drug, death, or before initiation of a new antitumor treatment, whichever occurred first.

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

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    End point title
    		 Progression Free Survival (PFS): Intent-to-Treat (ITT) Population By Interactive Web Recognition System (IWRS)
    End point description
    PFS was defined as the time in months from randomization 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. Subjects 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. Intent-to-treat (ITT) population included all the subjects randomly assigned to double-blind study treatment.
    End point type
    Primary
    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 the data cutoff date [23 Sep 2016])
    End point values
    		 Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg Cohort 1: Placebo + Exemestane 25 mg Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg 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
    		 Cohort 1 (Experimental versus Placebo)
    Statistical analysis description
    Hazard ratio was based on stratified Cox regression model.
    Comparison groups
    Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg v Cohort 1: Placebo + Exemestane 25 mg
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    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
    Statistical analysis title
    		 Cohort 2 (Experimental versus Placebo)
    Statistical analysis description
    Hazard ratio was based on stratified Cox regression model.
    Comparison groups
    Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg v Cohort 2: Placebo + Exemestane 25 mg
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    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

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

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    End point title
    		 Progression Free Survival (PFS): Diagnostic Positive (DX+) Population By Interactive Web Recognition System (IWRS)
    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 (as per RECIST 1.1): >= 20% increase in sum of diameters of target lesions taking as a 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. Subjects 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 sequencing data from tumor tissue. '99999'= data not available as upper limit of 95% CI was not reached due to insufficient number of events. “Number of Subjects Analysed” = subjects evaluable for endpoint.
    End point type
    Primary
    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 the data cutoff date [23 Sep 2016])
    End point values
    		 Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg Cohort 1: Placebo + Exemestane 25 mg Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg 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
    		 Cohort 1 (Experimental versus Placebo)
    Statistical analysis description
    Hazard ratio was based on stratified Cox regression model.
    Comparison groups
    Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg v Cohort 1: Placebo + Exemestane 25 mg
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    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
    		 0.995
    Statistical analysis title
    		 Cohort 2 (Experimental versus Placebo)
    Statistical analysis description
    Hazard ratio was based on stratified Cox regression model.
    Comparison groups
    Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg v Cohort 2: Placebo + Exemestane 25 mg
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    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

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

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    End point title
    		 Clinical Benefit Rate-24 (CBR-24)
    End point description
    CBR-24:Subjects (%) with best response of complete response (CR), partial response (PR) or stable disease (SD) sustained >=24 weeks, determined by investigator using RECIST 1.1. CR:Disappearance of all lesions and normalization of tumor marker level for non-target lesions, also, lymph nodes must be non-pathological in size (less than [<] 10 millimeter [mm] short axis). PR:>=30% decrease in sum of diameters of target lesions, using baseline sum diameters as reference. SD: Neither sufficient reduction to qualify as PR nor sufficient increase to qualify as PD, using the smallest sum diameters as reference. PD:>=20% increase in sum of diameters of target lesions, using smallest sum as reference (including baseline), also, the sum must demonstrate an absolute increase of at least 5 mm, or unequivocal progression of existing non-target lesions or appearance of 1 or more new target or non-target lesions. ITT population included all subjects randomly assigned to double-blind study treatment.
    End point type
    Secondary
    End point timeframe
    From randomization up to the data cutoff date (23 Sep 2016)
    End point values
    		 Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg Cohort 1: Placebo + Exemestane 25 mg Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg Cohort 2: Placebo + Exemestane 25 mg
    Number of subjects analysed
    63
    64
    60
    60
    Units: percentage of subjects
        number (confidence interval 95%)
    61.9 (48.8 to 73.9)
    45.3 (38.2 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: Best Objective Response Rate (BORR)

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    End point title
    		 Best Objective Response Rate (BORR)
    End point description
    BORR: Subjects (%) with measurable disease and best response of CR or PR using RECIST 1.1. CR:Disappearance of all lesions and normalization of tumor marker level for non-target lesions, also, lymph nodes must be non-pathological in size (<10 mm short axis). PR:>=30% decrease in sum of diameters of target lesions, using baseline sum diameters as reference. SD: Neither sufficient reduction to qualify as PR nor sufficient increase to qualify as PD, using smallest sum diameters as reference. PD:>=20% increase (absolute increase of >=5 mm) in sum of diameters of target lesions, using smallest sum as reference (including baseline), or unequivocal progression of existing non-target lesions, or appearance of 1 or more new lesions. ITT population included all subjects randomly assigned to double-blind study treatment. Here 'Number of subjects analyzed' signifies subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    From randomization until CR or PR, whichever occurred first (up to the data cutoff date [23 Sep 2016])
    End point values
    		 Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg Cohort 1: Placebo + Exemestane 25 mg Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg Cohort 2: Placebo + Exemestane 25 mg
    Number of subjects analysed
    39
    42
    42
    42
    Units: percentage of subjects
        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: Duration of Objective Response (DOR)

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    End point title
    		 Duration of Objective Response (DOR)
    End point description
    DOR: Time from first documentation of CR or PR, to first documentation of PD or death due to any cause, whichever occurred first, using RECIST 1.1. CR: Disappearance of all lesions and normalization of tumor marker level for non-target lesions, also, lymph nodes must be non-pathological in size (<10 mm short axis). PR: >=30% decrease in sum of diameters of target lesions, using baseline sum diameters as reference. SD: Neither sufficient reduction to qualify as PR nor sufficient increase to qualify as PD, using smallest sum diameters as reference. PD: >=20% increase (absolute increase of >=5 mm) in sum of diameters of target lesions, compared to smallest sum, or unequivocal progression of existing non-target lesions, or appearance of 1 or more new lesions. ITT population. 'Number of subjects analyzed' signifies subjects evaluable for this endpoint. '99999' signifies data not available as upper limit of 95% confidence interval was not reached due to insufficient number of events.
    End point type
    Secondary
    End point timeframe
    From first documentation of CR or PR until PD, last tumor assessment without PD before new antitumor treatment initiation or death due to any cause, whichever occurred first (up to the data cutoff date [23 Sep 2016])
    End point values
    		 Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg Cohort 1: Placebo + Exemestane 25 mg Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg 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: Time to Response

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    End point title
    		 Time to Response
    End point description
    Time to response: Time from randomization to first documentation of CR or PR. CR: Disappearance of all (target and non-target) lesions and normalization 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: >=30% decrease in the sum of diameters of target lesions, using baseline sum diameters as a reference. Subjects with no CR or PR were censored at last tumor assessment date prior to data cutoff or date of new treatment initiation, whichever occurred first. ITT population. 'Number of subjects analyzed' signifies subjects evaluable for this endpoint. '99999' signifies data not available as either, median and/ or upper limit of 95% confidence interval, or median and 95% confidence interval were not reached due to insufficient number of events at the time of data cutoff.
    End point type
    Secondary
    End point timeframe
    From randomization until first documentation of CR, PR, last tumor assessment without PD before new antitumor treatment initiation or death due to any cause, whichever occurred first (up to the data cutoff date [23 Sep 2016])
    End point values
    		 Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg Cohort 1: Placebo + Exemestane 25 mg Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg 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)
    99999 (3.9 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Time to Progression

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    End point title
    		 Time to Progression
    End point description
    Time to progression was defined as the time from the date of randomization to PD defined by the investigator using RECIST 1.1. PD: >=20% increase in the sum of diameters of target lesions, using the smallest sum during the study as a reference (including baseline sum if it is the smallest), also, the sum must demonstrate an absolute increase of at least 5 mm, unequivocal progression of existing non-target lesions or appearance of 1 or more new lesions (target or non-target). Subjects 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 subjects randomly assigned to double-blind study treatment.
    End point type
    Secondary
    End point timeframe
    From randomization until PD or last tumor assessment without PD before new antitumor treatment initiation, whichever occurred first (up to the data cutoff date [23 Sep 2016])
    End point values
    		 Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg Cohort 1: Placebo + Exemestane 25 mg Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg 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: Progression Free Survival (PFS) at 6 Months

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    End point title
    		 Progression Free Survival (PFS) at 6 Months
    End point description
    PFS at 6 months was defined as the percentage of subjects with no event of disease progression at Month 6 landmark, estimated by Kaplan-Meier methods. PFS was defined as the time in months from randomization to the first documentation of PD or death on study due to any cause, whichever occurred first. PD: >=20% increase in the sum of diameters of target lesions, using the smallest sum during the study as a reference (including baseline sum if it is the smallest), also, the sum must demonstrate an absolute increase of at least 5 mm, unequivocal progression of existing non-target lesions or appearance of 1 or more new lesions (target or non-target). The analysis of PFS was based on investigator assessment of disease progression. ITT population included all the subjects randomly assigned to double-blind study treatment.
    End point type
    Secondary
    End point timeframe
    Month 6
    End point values
    		 Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg Cohort 1: Placebo + Exemestane 25 mg Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg Cohort 2: Placebo + Exemestane 25 mg
    Number of subjects analysed
    63
    64
    60
    60
    Units: percentage of subjects
        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 subjects 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, ‘’n’’ signifies number of subjects evaluable at each specified time-point.
    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: 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 subjects in the safety population who received any amount of exemestane and had at least 1 reportable plasma concentration value for exemestane. Here, ‘’n’’ signifies number of subjects evaluable at each specified time-point. Here '99999' signifies data not available as either no subjects were evaluable, or only one subject was evaluable at specified time points.
    End point type
    Secondary
    End point timeframe
    Predose, 1 and 6 hour postdose 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)
    99999 ( 99999 )
    99999 ( 99999 )
        Day 169: 1 hour Postdose (n=0, 1)
    99999 ( 99999 )
    22800 ( 99999 )
        Day 169: 6 hour Postdose (n=0, 1)
    99999 ( 99999 )
    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 subjects in safety population who received any amount of enzalutamide and had at least 1 reportable concentration value for N-desmethyl enzalutamide. Here, ‘’n’’ signifies number of subjects evaluable at each specified time-point.
    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: European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life Core Questionnaire (QLQ-C30)

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    End point title
    		 European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life Core Questionnaire (QLQ-C30)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Month 24
    End point values
    		 Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg Cohort 1: Placebo + Exemestane 25 mg Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg Cohort 2: Placebo + Exemestane 25 mg
    Number of subjects analysed
    0 [1]
    0 [2]
    0 [3]
    0 [4]
    Units: units on a scale
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    Notes
    [1] - Data was not analyzed at this time point and will be reported at the time of final analysis.
    [2] - Data was not analyzed at this time point and will be reported at the time of final analysis.
    [3] - Data was not analyzed at this time point and will be reported at the time of final analysis.
    [4] - Data was not analyzed at this time point and will be reported at the time of final analysis.
    No statistical analyses for this end point

    Other pre-specified: European Organization for Research and Treatment of Cancer (EORTC) Breast Cancer Module (QLQ-BR23)

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    End point title
    		 European Organization for Research and Treatment of Cancer (EORTC) Breast Cancer Module (QLQ-BR23)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Month 24
    End point values
    		 Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg Cohort 1: Placebo + Exemestane 25 mg Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg Cohort 2: Placebo + Exemestane 25 mg
    Number of subjects analysed
    0 [5]
    0 [6]
    0 [7]
    0 [8]
    Units: units on a scale
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    Notes
    [5] - Data was not analyzed at this time point and will be reported at the time of final analysis.
    [6] - Data was not analyzed at this time point and will be reported at the time of final analysis.
    [7] - Data was not analyzed at this time point and will be reported at the time of final analysis.
    [8] - Data was not analyzed at this time point and will be reported at the time of final analysis.
    No statistical analyses for this end point

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

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    End point title
    		 Number of Subjects With Positive Androgen Receptor (AR) Expression by Immunohistochemistry (IHC)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Day 1, 29, 57, 113 and 169
    End point values
    		 Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg Cohort 1: Placebo + Exemestane 25 mg Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg Cohort 2: Placebo + Exemestane 25 mg
    Number of subjects analysed
    0 [9]
    0 [10]
    0 [11]
    0 [12]
    Units: subjects
    Notes
    [9] - Protocol was amended and data not analyzed as per planned analysis.
    [10] - Protocol was amended and data not analyzed as per planned analysis.
    [11] - Protocol was amended and data not analyzed as per planned analysis.
    [12] - Protocol was amended and data not analyzed as per planned analysis.
    No statistical analyses for this end point

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

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    End point title
    		 Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. 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 subjects 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 data cutoff date [23 Sep 2016])
    End point values
    		 Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg Cohort 1: Placebo + Exemestane 25 mg Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg Cohort 2: Placebo + Exemestane 25 mg
    Number of subjects analysed
    62
    63
    60
    60
    Units: subjects
        AEs
    59
    58
    58
    53
        SAEs
    15
    12
    10
    8
    No statistical analyses for this end point

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

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    End point title
    		 Number of Subjects With Treatment-Emergent Adverse Events of Grade 3 or Higher Severity
    End point description
    An AE was any untoward medical occurrence in a subject 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 subjects with treatment-emergent AEs of grade 3 (severe) or higher grade were reported in this endpoint. Safety population included all the subjects 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 data cutoff date [23 Sep 2016])
    End point values
    		 Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg Cohort 1: Placebo + Exemestane 25 mg Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg Cohort 2: Placebo + Exemestane 25 mg
    Number of subjects analysed
    62
    63
    60
    60
    Units: subjects
    20
    15
    22
    12
    No statistical analyses for this end point

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

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    End point title
    		 Number of Subjects With Clinically Significant Vital Sign Abnormalities
    End point description
    Clinically significant vital sign abnormality criteria: 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 (MEPB) SBP >=140 mmHg, MEPB 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, MEPB DBP >=90 mmHg, MEPB DBP >=105 mmHg, most extreme DBP >=90 mmHg and >=15 mmHg CFB, most extreme DBP >=105 mmHg and >=15 mmHg CFB; heart rate (HR) <50 beats per minute (BPM) and DFB >20 BPM or HR >120 BPM and IFB >30 BPM. Safety population included all subjects who received study drug 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 data cutoff date [23 Sep 2016])
    End point values
    		 Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg Cohort 1: Placebo + Exemestane 25 mg Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg Cohort 2: Placebo + Exemestane 25 mg
    Number of subjects analysed
    62
    63
    60
    60
    Units: subjects
        Blood pressure
    36
    39
    43
    24
        Heart rate
    0
    2
    0
    0
    No statistical analyses for this end point

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

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    End point title
    		 Number of Subjects With Clinically Significant Laboratory Abnormalities
    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 subjects 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 data cutoff date [23 Sep 2016])
    End point values
    		 Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg Cohort 1: Placebo + Exemestane 25 mg Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg Cohort 2: Placebo + Exemestane 25 mg
    Number of subjects analysed
    62
    63
    60
    60
    Units: subjects
    0
    0
    0
    0
    No statistical analyses for this end point

    Other pre-specified: Progression Free Survival (PFS): by Electronic Data Capture (EDC)

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    End point title
    		 Progression Free Survival (PFS): by Electronic Data Capture (EDC)
    End point description
    PFS=time in months from randomization to first (1st) documentation of PD or death on study due to any cause, whichever occurred 1st. PD by RECIST 1.1: >=20% increase in sum of diameters of target lesions (TLs) taking as a reference the smallest sum recorded since start of treatment or unequivocal progression in non-TLs or appearance of 1 or more new lesions. Analysis of PFS was based on investigator assessment of PD. Subjects 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 1st. Analysis performed on all randomized subjects. Randomization to cohort based on subject’s exposure to advance setting hormonal therapy. Initial randomization done by IWRS. Later,upon detailed data entry in EDC, it was determined 1 subject incorrectly assigned to Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg by IWRS, so counted in Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg 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 the data cutoff date [23 Sep 2016])
    End point values
    		 Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg (EDC) Cohort 1: Placebo + Exemestane 25 mg (EDC) Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg (EDC) Cohort 2: Placebo + Exemestane 25 mg (EDC)
    Number of subjects analysed
    62
    64
    61
    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
    		 Cohort 1 (Experimental versus Placebo)
    Statistical analysis description
    Hazard ratio was based on stratified Cox regression model.
    Comparison groups
    Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg (EDC) v Cohort 1: Placebo + Exemestane 25 mg (EDC)
    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
    Statistical analysis title
    		 Cohort 2 (Experimental versus Placebo)
    Statistical analysis description
    Hazard ratio was based on stratified Cox regression model.
    Comparison groups
    Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg (EDC) v Cohort 2: Placebo + Exemestane 25 mg (EDC)
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    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

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

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    End point title
    		 Progression Free Survival (PFS): Diagnostic Positive (DX+) Population By Electronic Data Capture (EDC)
    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 (as per RECIST 1.1): >= 20% increase in sum of diameters of target lesions taking as a 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. Subjects 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 sequencing data from tumor tissue. '99999'= data not available as upper limit of 95% CI was not reached due to insufficient number of events. “Number of Subjects Analysed” = subjects evaluable for endpoint.
    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)
    End point values
    		 Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg (EDC) Cohort 1: Placebo + Exemestane 25 mg (EDC) Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg (EDC) Cohort 2: Placebo + Exemestane 25 mg (EDC)
    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
    		 Cohort 1 (Experimental versus Placebo)
    Statistical analysis description
    Hazard ratio was based on stratified Cox regression model.
    Comparison groups
    Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg (EDC) v Cohort 1: Placebo + Exemestane 25 mg (EDC)
    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
    		 Cohort 2 (Experimental versus Placebo)
    Statistical analysis description
    Hazard ratio was based on stratified Cox regression model.
    Comparison groups
    Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg (EDC) v Cohort 2: Placebo + Exemestane 25 mg (EDC)
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    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

    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 data cutoff date [23 Sep 2016])
    Adverse event reporting additional description
    Same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as non-serious in another subject, or one subject may have experienced both a serious and non-serious event during the study. AEs and SAEs were collected 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
    		 Subjects 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. Subjects 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
    		 Subjects 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 subjects 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. Subjects 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
    		 Subjects 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. Subjects 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
    		 Subjects 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 subjects 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. Subjects 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 1: Placebo + Exemestane 25 mg Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg Cohort 2: Placebo + Exemestane 25 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 62 (24.19%)
    12 / 63 (19.05%)
    10 / 60 (16.67%)
    8 / 60 (13.33%)
         number of deaths (all causes)
    2
    8
    3
    2
         number of deaths resulting from adverse events
    2
    2
    2
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    ADENOCARCINOMA PANCREAS
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 63 (0.00%)
    0 / 60 (0.00%)
    0 / 60 (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
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 63 (1.59%)
    0 / 60 (0.00%)
    0 / 60 (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
    BREAST CANCER METASTATIC
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 63 (1.59%)
    0 / 60 (0.00%)
    0 / 60 (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
    CONTRALATERAL BREAST CANCER
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 63 (0.00%)
    0 / 60 (0.00%)
    0 / 60 (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%)
    1 / 63 (1.59%)
    0 / 60 (0.00%)
    0 / 60 (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
    MALIGNANT ASCITES
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    1 / 60 (1.67%)
    0 / 60 (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
    MALIGNANT PLEURAL EFFUSION
         subjects affected / exposed
    2 / 62 (3.23%)
    0 / 63 (0.00%)
    0 / 60 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    METASTASES TO CENTRAL NERVOUS SYSTEM
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 63 (0.00%)
    0 / 60 (0.00%)
    0 / 60 (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
    METASTATIC PAIN
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 63 (1.59%)
    1 / 60 (1.67%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PLASMA CELL MYELOMA
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 63 (1.59%)
    0 / 60 (0.00%)
    0 / 60 (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
    ASTHENIA
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 63 (0.00%)
    0 / 60 (0.00%)
    0 / 60 (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 / 63 (0.00%)
    0 / 60 (0.00%)
    0 / 60 (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
    DISEASE PROGRESSION
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 63 (1.59%)
    1 / 60 (1.67%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    FACIAL PAIN
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    1 / 60 (1.67%)
    0 / 60 (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
    FATIGUE
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    1 / 60 (1.67%)
    0 / 60 (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
    GENERAL PHYSICAL HEALTH DETERIORATION
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    1 / 60 (1.67%)
    0 / 60 (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
    1 / 1
    0 / 0
    INFLUENZA LIKE ILLNESS
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 63 (0.00%)
    0 / 60 (0.00%)
    0 / 60 (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
    NON-CARDIAC CHEST PAIN
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 63 (0.00%)
    0 / 60 (0.00%)
    0 / 60 (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
    PAIN
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 63 (0.00%)
    0 / 60 (0.00%)
    0 / 60 (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
    Immune system disorders
    ANAPHYLACTIC REACTION
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    1 / 60 (1.67%)
    0 / 60 (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
    DRUG HYPERSENSITIVITY
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 63 (0.00%)
    0 / 60 (0.00%)
    0 / 60 (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
    Respiratory, thoracic and mediastinal disorders
    DYSPNOEA
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 63 (1.59%)
    0 / 60 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    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%)
    1 / 63 (1.59%)
    0 / 60 (0.00%)
    0 / 60 (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
    PLEURAL EFFUSION
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 63 (1.59%)
    0 / 60 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PULMONARY EMBOLISM
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 63 (0.00%)
    0 / 60 (0.00%)
    0 / 60 (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
    DELIRIUM
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    1 / 60 (1.67%)
    0 / 60 (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
    SUICIDAL IDEATION
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    0 / 60 (0.00%)
    1 / 60 (1.67%)
         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
    Injury, poisoning and procedural complications
    FALL
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 63 (1.59%)
    0 / 60 (0.00%)
    0 / 60 (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
    HUMERUS FRACTURE
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 63 (1.59%)
    0 / 60 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    LACERATION
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 63 (1.59%)
    0 / 60 (0.00%)
    0 / 60 (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
    OPTIC NERVE INJURY
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    1 / 60 (1.67%)
    0 / 60 (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
    RADIATION PNEUMONITIS
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 63 (1.59%)
    0 / 60 (0.00%)
    0 / 60 (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%)
    0 / 63 (0.00%)
    1 / 60 (1.67%)
    0 / 60 (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
    TRAUMATIC HAEMORRHAGE
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 63 (1.59%)
    0 / 60 (0.00%)
    0 / 60 (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 / 63 (0.00%)
    0 / 60 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    BRACHIAL PLEXOPATHY
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    0 / 60 (0.00%)
    1 / 60 (1.67%)
         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
    CEREBROVASCULAR ACCIDENT
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 63 (0.00%)
    0 / 60 (0.00%)
    0 / 60 (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
    DIZZINESS
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 63 (0.00%)
    0 / 60 (0.00%)
    0 / 60 (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 / 63 (0.00%)
    0 / 60 (0.00%)
    1 / 60 (1.67%)
         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
    GRAND MAL CONVULSION
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    1 / 60 (1.67%)
    0 / 60 (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
    HAEMORRHAGE INTRACRANIAL
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 63 (1.59%)
    0 / 60 (0.00%)
    0 / 60 (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
    INTRACRANIAL HAEMATOMA
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    0 / 60 (0.00%)
    1 / 60 (1.67%)
         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
    SPEECH DISORDER
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    1 / 60 (1.67%)
    0 / 60 (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
    SPINAL CORD COMPRESSION
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 63 (1.59%)
    0 / 60 (0.00%)
    0 / 60 (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%)
    0 / 63 (0.00%)
    1 / 60 (1.67%)
    0 / 60 (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
    SYNCOPE
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 63 (0.00%)
    0 / 60 (0.00%)
    0 / 60 (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
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    1 / 60 (1.67%)
    0 / 60 (0.00%)
         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
    THROMBOCYTOPENIA
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 63 (0.00%)
    0 / 60 (0.00%)
    0 / 60 (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
    Gastrointestinal disorders
    FAECES DISCOLOURED
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 63 (1.59%)
    0 / 60 (0.00%)
    0 / 60 (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%)
    0 / 63 (0.00%)
    1 / 60 (1.67%)
    0 / 60 (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
    INTESTINAL OBSTRUCTION
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    1 / 60 (1.67%)
    0 / 60 (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
    OESOPHAGEAL STENOSIS
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 63 (1.59%)
    0 / 60 (0.00%)
    0 / 60 (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
    VOMITING
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 63 (0.00%)
    0 / 60 (0.00%)
    0 / 60 (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
    Hepatobiliary disorders
    CHOLECYSTITIS
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    1 / 60 (1.67%)
    0 / 60 (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
    HEPATIC HAEMORRHAGE
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    0 / 60 (0.00%)
    1 / 60 (1.67%)
         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
    Renal and urinary disorders
    RENAL FAILURE
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    0 / 60 (0.00%)
    1 / 60 (1.67%)
         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
    Musculoskeletal and connective tissue disorders
    BACK PAIN
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 63 (0.00%)
    0 / 60 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MASTICATION DISORDER
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    1 / 60 (1.67%)
    0 / 60 (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
    NECK PAIN
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    1 / 60 (1.67%)
    0 / 60 (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
    PAIN IN EXTREMITY
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 63 (0.00%)
    0 / 60 (0.00%)
    0 / 60 (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
    PATHOLOGICAL FRACTURE
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    1 / 60 (1.67%)
    0 / 60 (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
    Infections and infestations
    BREAST CELLULITIS
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 63 (0.00%)
    0 / 60 (0.00%)
    0 / 60 (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
    INFECTIVE EXACERBATION OF CHRONIC OBSTRUCTIVE AIRWAYS DISEASE
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    1 / 60 (1.67%)
    0 / 60 (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
    PNEUMONIA
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 63 (0.00%)
    0 / 60 (0.00%)
    0 / 60 (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
    POSTOPERATIVE WOUND INFECTION
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    1 / 60 (1.67%)
    0 / 60 (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
    PYELONEPHRITIS
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    0 / 60 (0.00%)
    1 / 60 (1.67%)
         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
    URINARY TRACT INFECTION
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    0 / 60 (0.00%)
    1 / 60 (1.67%)
         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
    WOUND INFECTION
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 63 (1.59%)
    0 / 60 (0.00%)
    0 / 60 (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%)
    0 / 63 (0.00%)
    2 / 60 (3.33%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HYPONATRAEMIA
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    1 / 60 (1.67%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 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 / 63 (0.00%)
    0 / 60 (0.00%)
    0 / 60 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort 1: Enzalutamide 160 mg + Exemestane 50 mg Cohort 1: Placebo + Exemestane 25 mg Cohort 2: Enzalutamide 160 mg + Exemestane 50 mg Cohort 2: Placebo + Exemestane 25 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    59 / 62 (95.16%)
    58 / 63 (92.06%)
    58 / 60 (96.67%)
    53 / 60 (88.33%)
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    2 / 60 (3.33%)
    4 / 60 (6.67%)
         occurrences all number
    0
    0
    3
    5
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    0 / 62 (0.00%)
    4 / 63 (6.35%)
    2 / 60 (3.33%)
    3 / 60 (5.00%)
         occurrences all number
    0
    4
    3
    3
    WHITE BLOOD CELL COUNT DECREASED
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    3 / 60 (5.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    3
    1
    Vascular disorders
    HOT FLUSH
         subjects affected / exposed
    19 / 62 (30.65%)
    14 / 63 (22.22%)
    14 / 60 (23.33%)
    9 / 60 (15.00%)
         occurrences all number
    21
    16
    19
    10
    HYPERTENSION
         subjects affected / exposed
    6 / 62 (9.68%)
    4 / 63 (6.35%)
    0 / 60 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    7
    4
    0
    0
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    8 / 62 (12.90%)
    4 / 63 (6.35%)
    5 / 60 (8.33%)
    2 / 60 (3.33%)
         occurrences all number
    8
    4
    5
    2
    HEADACHE
         subjects affected / exposed
    9 / 62 (14.52%)
    6 / 63 (9.52%)
    9 / 60 (15.00%)
    10 / 60 (16.67%)
         occurrences all number
    10
    6
    12
    17
    AMNESIA
         subjects affected / exposed
    4 / 62 (6.45%)
    0 / 63 (0.00%)
    0 / 60 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    4
    0
    0
    0
    COGNITIVE DISORDER
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    3 / 60 (5.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    3
    1
    DISTURBANCE IN ATTENTION
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    3 / 60 (5.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    4
    0
    NEUROPATHY PERIPHERAL
         subjects affected / exposed
    4 / 62 (6.45%)
    3 / 63 (4.76%)
    0 / 60 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    4
    3
    0
    0
    PARAESTHESIA
         subjects affected / exposed
    4 / 62 (6.45%)
    2 / 63 (3.17%)
    0 / 60 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    5
    2
    0
    0
    SOMNOLENCE
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    3 / 60 (5.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    4 / 62 (6.45%)
    1 / 63 (1.59%)
    6 / 60 (10.00%)
    3 / 60 (5.00%)
         occurrences all number
    11
    1
    8
    9
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    10 / 62 (16.13%)
    7 / 63 (11.11%)
    6 / 60 (10.00%)
    4 / 60 (6.67%)
         occurrences all number
    9
    7
    8
    8
    FATIGUE
         subjects affected / exposed
    23 / 62 (37.10%)
    21 / 63 (33.33%)
    22 / 60 (36.67%)
    13 / 60 (21.67%)
         occurrences all number
    29
    24
    24
    16
    OEDEMA PERIPHERAL
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    2 / 60 (3.33%)
    3 / 60 (5.00%)
         occurrences all number
    0
    0
    2
    4
    PAIN
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    0 / 60 (0.00%)
    3 / 60 (5.00%)
         occurrences all number
    0
    0
    0
    4
    PYREXIA
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    0 / 60 (0.00%)
    3 / 60 (5.00%)
         occurrences all number
    0
    0
    0
    3
    Gastrointestinal disorders
    CONSTIPATION
         subjects affected / exposed
    10 / 62 (16.13%)
    7 / 63 (11.11%)
    8 / 60 (13.33%)
    8 / 60 (13.33%)
         occurrences all number
    10
    7
    10
    9
    DIARRHOEA
         subjects affected / exposed
    12 / 62 (19.35%)
    10 / 63 (15.87%)
    6 / 60 (10.00%)
    10 / 60 (16.67%)
         occurrences all number
    16
    10
    8
    15
    DYSPEPSIA
         subjects affected / exposed
    1 / 62 (1.61%)
    6 / 63 (9.52%)
    5 / 60 (8.33%)
    4 / 60 (6.67%)
         occurrences all number
    1
    6
    5
    4
    NAUSEA
         subjects affected / exposed
    24 / 62 (38.71%)
    10 / 63 (15.87%)
    18 / 60 (30.00%)
    11 / 60 (18.33%)
         occurrences all number
    33
    11
    23
    17
    VOMITING
         subjects affected / exposed
    11 / 62 (17.74%)
    7 / 63 (11.11%)
    6 / 60 (10.00%)
    3 / 60 (5.00%)
         occurrences all number
    17
    12
    8
    4
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    4 / 60 (6.67%)
    2 / 60 (3.33%)
         occurrences all number
    0
    0
    4
    3
    ABDOMINAL PAIN
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    2 / 60 (3.33%)
    4 / 60 (6.67%)
         occurrences all number
    0
    0
    2
    5
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    9 / 62 (14.52%)
    6 / 63 (9.52%)
    2 / 60 (3.33%)
    4 / 60 (6.67%)
         occurrences all number
    10
    7
    2
    5
    DYSPNOEA
         subjects affected / exposed
    9 / 62 (14.52%)
    7 / 63 (11.11%)
    5 / 60 (8.33%)
    5 / 60 (8.33%)
         occurrences all number
    10
    8
    7
    5
    OROPHARYNGEAL PAIN
         subjects affected / exposed
    4 / 62 (6.45%)
    2 / 63 (3.17%)
    0 / 60 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    4
    2
    0
    0
    Skin and subcutaneous tissue disorders
    ALOPECIA
         subjects affected / exposed
    8 / 62 (12.90%)
    3 / 63 (4.76%)
    5 / 60 (8.33%)
    2 / 60 (3.33%)
         occurrences all number
    9
    3
    5
    2
    RASH
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    3 / 60 (5.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Psychiatric disorders
    ANXIETY
         subjects affected / exposed
    7 / 62 (11.29%)
    4 / 63 (6.35%)
    0 / 60 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    8
    4
    0
    0
    INSOMNIA
         subjects affected / exposed
    5 / 62 (8.06%)
    4 / 63 (6.35%)
    5 / 60 (8.33%)
    4 / 60 (6.67%)
         occurrences all number
    5
    4
    5
    4
    DEPRESSED MOOD
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    4 / 60 (6.67%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    4
    0
    DEPRESSION
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    3 / 60 (5.00%)
    3 / 60 (5.00%)
         occurrences all number
    0
    0
    3
    5
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    14 / 62 (22.58%)
    11 / 63 (17.46%)
    10 / 60 (16.67%)
    7 / 60 (11.67%)
         occurrences all number
    16
    14
    11
    9
    BACK PAIN
         subjects affected / exposed
    11 / 62 (17.74%)
    5 / 63 (7.94%)
    4 / 60 (6.67%)
    12 / 60 (20.00%)
         occurrences all number
    11
    6
    5
    13
    BONE PAIN
         subjects affected / exposed
    2 / 62 (3.23%)
    4 / 63 (6.35%)
    5 / 60 (8.33%)
    2 / 60 (3.33%)
         occurrences all number
    2
    4
    6
    4
    MUSCULOSKELETAL CHEST PAIN
         subjects affected / exposed
    7 / 62 (11.29%)
    4 / 63 (6.35%)
    2 / 60 (3.33%)
    3 / 60 (5.00%)
         occurrences all number
    9
    4
    3
    3
    MUSCULOSKELETAL PAIN
         subjects affected / exposed
    7 / 62 (11.29%)
    1 / 63 (1.59%)
    0 / 60 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    8
    2
    0
    0
    MYALGIA
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    0 / 60 (0.00%)
    4 / 60 (6.67%)
         occurrences all number
    0
    0
    0
    6
    PAIN IN EXTREMITY
         subjects affected / exposed
    8 / 62 (12.90%)
    8 / 63 (12.70%)
    3 / 60 (5.00%)
    5 / 60 (8.33%)
         occurrences all number
    6
    13
    5
    6
    MUSCULOSKELETAL STIFFNESS
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    3 / 60 (5.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    3
    2
    Infections and infestations
    URINARY TRACT INFECTION
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    1 / 60 (1.67%)
    4 / 60 (6.67%)
         occurrences all number
    0
    0
    1
    9
    Influenza
         subjects affected / exposed
    2 / 62 (3.23%)
    4 / 63 (6.35%)
    0 / 60 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    2
    5
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 62 (0.00%)
    0 / 63 (0.00%)
    3 / 60 (5.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    3
    1
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    6 / 62 (9.68%)
    6 / 63 (9.52%)
    6 / 60 (10.00%)
    2 / 60 (3.33%)
         occurrences all number
    9
    6
    7
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Oct 2016
    To add an open-label period if the study met its primary endpoint.
    01 Feb 2017
    To define and analyze subject cohorts by gene expression status rather than Immunohistochemistry analysis of breast tumor tissue for nuclear androgen receptor staining.

    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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