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    Clinical Trial Results:
    A Phase 2, Multicenter, Open-label Study to Assess the Efficacy and Safety of Enzalutamide with Trastuzumab in Subjects with HER2+ AR+ Metastatic or Locally Advanced Breast Cancer

    Summary
    EudraCT number
    2013-000093-29
    Trial protocol
    BE   GB   ES   IT  
    Global end of trial date
    30 Jan 2024

    Results information
    Results version number
    v1(current)
    This version publication date
    22 Dec 2024
    First version publication date
    22 Dec 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    9785-CL-1121
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02091960
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Astellas Pharma Global Development, Inc
    Sponsor organisation address
    1 Astellas Way, Northbrook, IL, United States, 60062
    Public contact
    Clinical transparency, Astellas Pharma Global Development, Inc, astellas.resultsdisclosure@astellas.com
    Scientific contact
    Clinical transparency, Astellas Pharma Global Development, Inc, astellas.resultsdisclosure@astellas.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Jan 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jan 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the efficacy of enzalutamide with trastuzumab in evaluable participants with human epidermal growth factor receptor 2 positive (HER2+) and androgen receptor positive (AR+) metastatic or locally advanced breast cancer, as measured by Clinical Benefit Rate (CBR).
    Protection of trial subjects
    This clinical study was written, conducted and reported in accordance with the protocol, International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines, and applicable local regulations, including the European Directive 2001/20/EC, on the protection of human rights, and with the ethical principles that have their origin in the Declaration of Helsinki. Astellas ensures that the use and disclosure of protected health information (PHI) obtained during a research study complies with the federal, national and/or regional legislation related to the privacy and protection of personal information.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    05 Sep 2014
    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
    Belgium: 14
    Country: Number of subjects enrolled
    Canada: 9
    Country: Number of subjects enrolled
    Italy: 11
    Country: Number of subjects enrolled
    Spain: 7
    Country: Number of subjects enrolled
    United Kingdom: 18
    Country: Number of subjects enrolled
    United States: 44
    Worldwide total number of subjects
    103
    EEA total number of subjects
    32
    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)
    75
    From 65 to 84 years
    28
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 35 clinical sites in Belgium, Canada, Italy, Spain, the United Kingdom and the United States.

    Pre-assignment
    Screening details
    This study enrolled women with HER2+ and AR+ metastatic or locally advanced breast cancer who progressed on anti-HER2 therapy in the metastatic or advanced setting.

    Period 1
    Period 1 title
    Overall Period
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Enzalutamide + Trastuzumab
    Arm description
    Participants received 160 (milligrams) mg enzalutamide orally once daily and 6 mg/kg trastuzumab administered by intravenous infusion or subcutaneous injection every 21 days. Participants continued on treatment until disease progression, unacceptable toxicity or any other discontinuation criteria were met.
    Arm type
    Experimental

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion, Solution for injection
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    Participants received 6 mg/kg trastuzumab intravenously/subcutaneously once every 21 days.

    Investigational medicinal product name
    Enzalutamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 160 mg enzalutamide orally once daily.

    Number of subjects in period 1
    Enzalutamide + Trastuzumab
    Started
    103
    Completed
    58
    Not completed
    45
         Adverse event, serious fatal
    7
         Consent withdrawn by subject
    1
         Miscelleneous
    37

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Enzalutamide + Trastuzumab
    Reporting group description
    Participants received 160 (milligrams) mg enzalutamide orally once daily and 6 mg/kg trastuzumab administered by intravenous infusion or subcutaneous injection every 21 days. Participants continued on treatment until disease progression, unacceptable toxicity or any other discontinuation criteria were met.

    Reporting group values
    Enzalutamide + Trastuzumab Total
    Number of subjects
    103 103
    Age Categorical
    Units: Participants
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    75 75
        From 65-84 years
    28 28
        85 years and over
    0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    59.3 ( 10.0 ) -
    Gender Categorical
    Units: Participants
        Female
    103 103
        Male
    0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    5 5
        Not Hispanic or Latino
    98 98
    Race/Ethnicity, Customized
    Units: Subjects
        White
    90 90
        Black or African American
    8 8
        Asian
    3 3
        American Indian or Alaskan Native
    0 0
        Native Hawaiian or other Pacific Islander
    1 1
        Other
    1 1
    Eastern Cooperative Oncology Group (ECOG) Performance Status
    A scale to assess a patient's disease status. 0 = Fully active, able to carry out all pre-disease performance without restriction; 1 = Restricted in physically strenuous activity, ambulatory and able to carry out work of a light nature; 2 = Ambulatory and capable of all self care, unable to carry out any work activities. Up and about > 50% of waking hours; 3 = Capable of only limited self-care, confined to bed or chair > 50% of waking hours; 4 = Completely disabled, confined to bed or chair; 5 = Dead.
    Units: Subjects
        Grade 0
    51 51
        Grade 1
    51 51
        Missing
    1 1
    Histopathology at Diagnosis
    Units: Subjects
        Ductal
    73 73
        Inflammatory
    5 5
        Intraductal
    6 6
        Lobular
    6 6
        Mixed
    1 1
        Not otherwise specified
    1 1
        Other
    5 5
        Unknown
    6 6
    Anatomic Stage
    Breast cancer staging is based on size of the tumor, whether cancer cells have spread to lymph nodes or to other parts of the body, how aggressive the cells appear when viewed under a microscope, whether the cancer cells have receptors for estrogen and progesterone or have a gene mutation that causes them to make excess HER2 protein, and the results of gene expression profiling tests. The stages of breast cancer range from 0 to IV, where Stage 0 is noninvasive or contained within the milk ducts and Stage IV breast cancer, also called metastatic, has spread to other areas of the body.
    Units: Subjects
        Stage 0
    3 3
        Stage IA
    6 6
        Stage IB
    1 1
        Stage IIA
    14 14
        Stage IIB
    12 12
        Stage IIIA
    5 5
        Stage IIIB
    7 7
        Stage IIIC
    7 7
        Stage IV
    28 28
        Unknown
    20 20
    Time from Initial Diagnosis of Primary Cancer to Enrollment
    Number of participants analyzed = 95
    Units: days
        median (full range (min-max))
    1199 (30 to 4713) -

    End points

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    End points reporting groups
    Reporting group title
    Enzalutamide + Trastuzumab
    Reporting group description
    Participants received 160 (milligrams) mg enzalutamide orally once daily and 6 mg/kg trastuzumab administered by intravenous infusion or subcutaneous injection every 21 days. Participants continued on treatment until disease progression, unacceptable toxicity or any other discontinuation criteria were met.

    Subject analysis set title
    Efficacy Evaluable Set (EES)
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The EES was a subset of the FAS (Full analysis set) defined as all enrolled participants who had centrally assessed AR+ breast cancer (defined as >10% of tumor cells with nuclear expression), received at least one dose of study drug, and had at least one available post baseline tumor assessment.

    Subject analysis set title
    Safety Analysis Set (SAF)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The SAF consisted of all participants who had received at least 1 or partial dose of study drug.

    Primary: Clinical Benefit Rate (CBR)

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    End point title
    Clinical Benefit Rate (CBR) [1]
    End point description
    CBR was defined as percentage of evaluable participants with best objective response of confirmed complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, or prolonged stable disease (≥ 24 weeks). CR was defined as the disappearance of all target and non-target lesions and no new lesions, and lymph nodes all < 10 mm in short axis. PR was defined as disappearance of target lesions or a ≥ 30% decrease in the size of target lesions, with persistence of non-target lesions and no new lesions. Stable disease (SD) was defined as < 30% decrease and < 20% increase in size of target lesions, persistence of non-target lesions, and no new lesions. PR and CR required confirmation with equivalent or improved assessment no less than 4 weeks after date that PR or CR was first observed. SD required confirmation with equivalent or improved assessment no less than 8 weeks after enrollment. Participants in EES with available data were analyzed.
    End point type
    Primary
    End point timeframe
    Tumor assessments were performed every 8 weeks through week 49, and then every 12 weeks thereafter until disease progression or death; the median duration of treatment was 70 days, and the maximum was 660 days.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Per protocol, statistical analysis was not planned for this endpoint.
    End point values
    Enzalutamide + Trastuzumab
    Number of subjects analysed
    89
    Units: Percentage of participants
        number (confidence interval 95%)
    23.6 (15.2 to 33.8)
    No statistical analyses for this end point

    Secondary: Best Overall Response Rate

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    End point title
    Best Overall Response Rate
    End point description
    Best overall response was the best response across all time points, based on investigator assessments. Best overall response rate was defined as the percentage of evaluable participants with a best objective response of confirmed complete response (CR) or partial response (PR) at any time during the study per RECIST 1.1. Complete response was defined as the disappearance of all target and non-target lesions and no new lesions, and lymph nodes all < 10 mm in short axis. Partial response was defined as disappearance of target lesions or a ≥ 30% decrease in the size of target lesions with persistence of non-target lesions and no new lesions. PR and CR required confirmation with equivalent or improved assessment no less than 4 weeks after the date of scan that PR or CR was first observed. Participants in the EES population with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Tumor assessments were performed every 8 weeks through week 49, and then every 12 weeks thereafter until disease progression or death; the median duration of treatment was 70 days, and the maximum was 660 days.
    End point values
    Enzalutamide + Trastuzumab
    Number of subjects analysed
    89
    Units: percentage of participants
        number (confidence interval 95%)
    4.5 (1.2 to 11.1)
    No statistical analyses for this end point

    Secondary: Overall Response Rate at Week 24

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    End point title
    Overall Response Rate at Week 24
    End point description
    Overall response rate was defined as the percentage of evaluable participants with a best objective response of confirmed complete response (CR) or partial response (PR) per RECIST 1.1. Complete response was defined as the disappearance of all target and non-target lesions and no new lesions, and lymph nodes all < 10 mm in short axis. Partial response was defined as disappearance of target lesions or a ≥ 30% decrease in the size of target lesions with persistence of non-target lesions and no new lesions. PR and CR required confirmation with equivalent or improved assessment no less than 4 weeks after the date of scan that PR or CR was first observed. Participants in the EES population with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    Enzalutamide + Trastuzumab
    Number of subjects analysed
    89
    Units: percentage of participants
        number (confidence interval 95%)
    3.4 (0.7 to 9.5)
    No statistical analyses for this end point

    Secondary: Progression-free Survival

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    End point title
    Progression-free Survival
    End point description
    Progression-free survival was defined as the time from the date of first dose of enzalutamide until the date of disease progression per RECIST 1.1, or death from any cause on study, whichever occurred first. Participants who initiated another antitumor therapy before documented progressive disease (PD) or death, or who progressed or died after missing 2 or more consecutive radiological assessments were censored at the date of the last radiological assessment showing no progression. Progressive disease was defined as a ≥ 20% increase in the size of target lesions and at least a 5 mm increase in size of target lesions from smallest size on study, or unequivocal progression of non-target lesions, or any new lesions. Participants in the EES population with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    From the date of first dose of study drug until disease progression or death; the median duration of treatment was 70 days, and the maximum was 660 days.
    End point values
    Enzalutamide + Trastuzumab
    Number of subjects analysed
    89
    Units: days
        median (confidence interval 95%)
    105.0 (61 to 116)
    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 first date of enzalutamide treatment until the date of disease progression per RECIST 1.1. Participants who initiated another anti-tumor therapy before documented PD, who progressed after missing two or more consecutive radiological assessments or who died before disease progression were censored at the date of the last radiological assessment showing no progression. Participants in the EES population with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    From the date of first dose of study drug until disease progression or death; the median duration of treatment was 70 days, and the maximum was 660 days.
    End point values
    Enzalutamide + Trastuzumab
    Number of subjects analysed
    89
    Units: days
        median (full range (min-max))
    108.0 (61 to 116)
    No statistical analyses for this end point

    Secondary: Duration of Response

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    End point title
    Duration of Response
    End point description
    Duration of response was defined as the time from the date of first documentation of response (CR or PR) until the date of disease progression per RECIST 1.1. Participants who initiated another anti-tumor therapy before documented PD, progressed after missing two or more consecutive radiological assessments or who died before disease progression were censored at the date of the last radiological assessment showing no progression. Participants in the EES population with best overall response of CR or PR were analyzed. 99999 = the data could not be analyzed due to low number of events.
    End point type
    Secondary
    End point timeframe
    Tumor assessments were performed every 8 weeks through week 49, and then every 12 weeks thereafter until disease progression or death; the median duration of treatment was 70 days, and the maximum was 660 days.
    End point values
    Enzalutamide + Trastuzumab
    Number of subjects analysed
    4
    Units: days
        median (confidence interval 95%)
    99999 (99999 to 99999)
    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 was defined as the time from the first date of enzalutamide treatment to initial CR or PR and was calculated for participants with a CR or PR. Participants in the EES population with best overall response of CR or PR were analyzed.
    End point type
    Secondary
    End point timeframe
    From the date of first dose of study drug until disease progression or death; the median duration of treatment was 70 days, and the maximum was 660 days.
    End point values
    Enzalutamide + Trastuzumab
    Number of subjects analysed
    4
    Units: days
        median (confidence interval 95%)
    57 (57 to 222)
    No statistical analyses for this end point

    Secondary: Number of Participants with Treatment Emergent Adverse Events (TEAEs)

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    End point title
    Number of Participants with Treatment Emergent Adverse Events (TEAEs)
    End point description
    An AE was defined as any untoward medical occurrence in a participant administered study drug/who underwent study procedures and did not necessarily have a causal relationship with treatment. Abnormalities identified during medical tests were defined as an AE if they induced clinical signs/symptoms, required active intervention, interruption or discontinuation of study medication, or were clinically significant to investigator. An AE was defined as serious if any of the following resulted: Death, was life-threatening, persistent or significant disability/incapacity or substantial disruption of ability to conduct normal life functions, congenital anomaly/ birth defect, inpatient hospitalization/prolongation of hospitalization or other medically important event. TEAE was defined as an AE observed during the treatment emergent period, which is from first dose date of study drug to 30 days after last dose date or start of subsequent treatment or date of death, whichever is first. SAF.
    End point type
    Secondary
    End point timeframe
    From the first dose date of study drug to 30 days after the last dose date of study drug or the start of subsequent treatment or date of death, whichever is first (Up to 3031 days)
    End point values
    Enzalutamide + Trastuzumab
    Number of subjects analysed
    103
    Units: Participants
        Any treatment emergent adverse events (TEAE)
    97
        Enzalutamide Related TEAE
    75
        Trastuzumab Related TEAE
    40
        Any Drug Related TEAE
    78
        Deaths
    4
        Serious TEAE
    24
        Enzalutamide Related Serious TEAE
    3
        Trastuzumab Related Serious TEAE
    0
        Any Drug Related Serious TEAE
    3
        TEAE leading to discontinuation of enzalutamide
    23
        TEAE leading to discontinuation of trastuzumab
    21
        TEAE leading to discontinuation of any study drug
    24
        Discontinuation due to enzalutamide Related TEAE
    5
        Discontinuation due to trastuzumab Related TEAE
    5
        Discontinuation due to Any Drug Related TEAE
    9
        TEAE Leading to Dose Reduction
    7
        TEAE Leading to Dose Interruption
    23
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose date of study drug to 30 days after the last dose date of study drug or the start of subsequent treatment or date of death, whichever is first (Up to 3031 days).
    Adverse event reporting additional description
    The Safety Analysis Set (SAF) consisted of all participants who had received at least 1 or partial dose of study drug.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    v23.0
    Reporting groups
    Reporting group title
    Enzalutamide + Trastuzumab
    Reporting group description
    Participants received 160 mg enzalutamide orally once daily and 6 mg/kg trastuzumab administered by intravenous infusion or subcutaneous injection every 21 days. Participants continued on treatment until disease progression, unacceptable toxicity or any other discontinuation criteria were met.

    Serious adverse events
    Enzalutamide + Trastuzumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    24 / 103 (23.30%)
         number of deaths (all causes)
    7
         number of deaths resulting from adverse events
    4
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin neoplasm bleeding
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin cancer
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Myxoid liposarcoma
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metastases to skin
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    5 / 103 (4.85%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 2
    Brain neoplasm malignant
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Accidental overdose
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Embolism
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Asthenia
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Dyspepsia
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Abdominal pain
         subjects affected / exposed
    2 / 103 (1.94%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    3 / 103 (2.91%)
         occurrences causally related to treatment / all
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 103 (2.91%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    2 / 103 (1.94%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    3 / 103 (2.91%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    2 / 103 (1.94%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infection
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Enzalutamide + Trastuzumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    89 / 103 (86.41%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    17 / 103 (16.50%)
         occurrences all number
    18
    Hypertension
         subjects affected / exposed
    7 / 103 (6.80%)
         occurrences all number
    9
    Nervous system disorders
    Restless legs syndrome
         subjects affected / exposed
    7 / 103 (6.80%)
         occurrences all number
    7
    Headache
         subjects affected / exposed
    17 / 103 (16.50%)
         occurrences all number
    19
    Dizziness
         subjects affected / exposed
    14 / 103 (13.59%)
         occurrences all number
    16
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    9 / 103 (8.74%)
         occurrences all number
    10
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    37 / 103 (35.92%)
         occurrences all number
    60
    Asthenia
         subjects affected / exposed
    6 / 103 (5.83%)
         occurrences all number
    6
    Gastrointestinal disorders
    Dyspepsia
         subjects affected / exposed
    10 / 103 (9.71%)
         occurrences all number
    10
    Diarrhoea
         subjects affected / exposed
    14 / 103 (13.59%)
         occurrences all number
    16
    Constipation
         subjects affected / exposed
    15 / 103 (14.56%)
         occurrences all number
    16
    Nausea
         subjects affected / exposed
    28 / 103 (27.18%)
         occurrences all number
    33
    Vomiting
         subjects affected / exposed
    10 / 103 (9.71%)
         occurrences all number
    10
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    15 / 103 (14.56%)
         occurrences all number
    16
    Epistaxis
         subjects affected / exposed
    9 / 103 (8.74%)
         occurrences all number
    13
    Cough
         subjects affected / exposed
    10 / 103 (9.71%)
         occurrences all number
    10
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    6 / 103 (5.83%)
         occurrences all number
    6
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    9 / 103 (8.74%)
         occurrences all number
    12
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    13 / 103 (12.62%)
         occurrences all number
    19
    Pain in extremity
         subjects affected / exposed
    13 / 103 (12.62%)
         occurrences all number
    14
    Neck pain
         subjects affected / exposed
    6 / 103 (5.83%)
         occurrences all number
    7
    Muscle spasms
         subjects affected / exposed
    7 / 103 (6.80%)
         occurrences all number
    8
    Back pain
         subjects affected / exposed
    15 / 103 (14.56%)
         occurrences all number
    16
    Musculoskeletal pain
         subjects affected / exposed
    6 / 103 (5.83%)
         occurrences all number
    7
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    15 / 103 (14.56%)
         occurrences all number
    16

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Oct 2014
    Changes included: • Updated the primary objective to clarify that CBR is evaluable participants with CR, PR at any point or stable disease ≥ 24 weeks. • Removed OS (long-term follow-up post study drug termination). • Updated timeline for prestudy radiographic bone assessment requirement at 6 mo prior to enrollment (day 1). • Updated prior line requirements to provide clarity regarding prior lines of therapy, the definition of disease progression, and the use of trastuzumab in the adjuvant setting in Inclusion Criterion 7. • Aligned protocol visits with trastuzumab infusion visits. All protocol-required visits are now in increments of 3 weeks (i.e., 6, 9, 12) in order to line-up with the trastuzumab infusion visits conducted every 3 weeks. • Clarified language allowing fresh tissue biopsy to be done only in cases of known local AR+ status per local report but insufficient tissue sample available to send for central confirmation. • Updated pregnancy language to remove hormonal contraceptive agents (oral, injected or implanted hormones) as a possible form of contraception. The pregnancy language was updated per the Astellas standard protocol template. • Updated the duration requirement for contraception and breastfeeding. Inclusion Criterion 12 extended the contraceptive use and breastfeeding restriction requirement from 3 to 6 months after study drug discontinuation.
    06 Oct 2014
    Changes also included: • Updated exclusion language to prevent enrollment of patients with potential renal insufficiency. Exclusion Criterion 4 includes creatinine clearance in addition to the creatinine level to restrict entry of patients with renal insufficiency. • Updated trastuzumab dose noted per locally available formulation. Subcutaneous added as available route of administration. • Clarified allowed estrogen use. Vaginal estrogen creams were allowed while on study. • Updated scope of efficacy endpoint. Removed initiation of new antitumor therapy from efficacy endpoint. • Updated pharmacokinetic data in Introduction section. • Updated statistical sections to reflect clarifications made to primary efficacy definition, clarification in various analyses sets and removal of OS. • Added myocardial perfusion scintigraphy (MPS) as allowable procedure for screening and subsequent visits in lieu of an echocardiogram (ECHO) or multigated acquisition (MUGA) scan. • Updated physical examination and added a 7-day window within screening visit for the physical examination to be done prior to signing of the informed consent form. • Removed vital sign requirement that temperature should be measured orally. • Removed the pharmacodynamic blood draw for circulating hormones and protein marker collection at the screening visit.
    10 Jun 2015
    Changes included: • Removed requirement for participants to have HER2 positive breast cancer that is ER negative and PgR negative. • Updated Inclusion Criterion 7 to remove the cap on the required number of prior lines of therapy the participants can receive, to clarify the definition of a prior line of therapy, to allow discontinuation of the most recent regimen for any toxicity except cardiotoxicity and to allow nonapproved anti-HER2 agents in the most recent regimen. • Updated Inclusion Criterion 6 to allow participants with non-measurable, evaluable disease per RECIST 1.1 to be eligible for enrollment in the study. In addition, the Schedule of Assessments was modified to clarify when patients with non-measurable, evaluable disease must have efficacy assessments completed. • Updated Inclusion Criterion 7 and Exclusion Criterion 16 to allow patients that had received pertuzumab as the most recent line of therapy. • Updated the protocol text and Inclusion Criterion 10 to change the preferred source of archival tissue from a primary tumor to the most recent biopsy available. • Updated Exclusion Criterion 16 to exclude participants who, in the investigator’s opinion, may benefit from hormonal therapy during the study.
    09 Aug 2018
    Changes included: • Removed assessment of circulating endocrine and other protein markers and pharmacokinetic samples. • Updated to include the definition of urgent safety measures and procedures for reporting them.
    30 Nov 2020
    Changes included: • The instruction that participants who discontinued study drug for a reason other than disease progression will continue to have tumor assessments performed was removed from the protocol.

    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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