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    Clinical Trial Results:
    A Phase 2, Open-label, Single-arm, Efficacy and Safety Study of Enzalutamide (MDV3100) in Patients with Hormone-naïve Prostate Cancer

    Summary
    EudraCT number
    		 2010-021287-16
    Trial protocol
    		 BE   CZ   DE   DK  
    Global end of trial date
    27 Apr 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Apr 2018
    First version publication date
    22 Apr 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    9785-CL-0321
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Astellas Pharma BV
    Sponsor organisation address
    Sylviusweg 62, Leiden, Netherlands, 2333
    Public contact
    Clinical Trial Disclosure, Astellas Pharma BV, astellas.resultsdisclosure@astellas.com
    Scientific contact
    Clinical Trial Disclosure, Astellas Pharma BV, 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
    27 Apr 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Apr 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to evaluate the effect of enzalutamide on prostate-specific antigen (PSA) and to evaluate the safety and tolerability of enzalutamide in participants who have not previously received hormone treatment for prostate cancer.
    Protection of trial subjects
    This clinical study was written, conducted and reported in accordance with the protocol, International Council for Harmonisation 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
    06 May 2011
    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: 25
    Country: Number of subjects enrolled
    Czech Republic: 9
    Country: Number of subjects enrolled
    Denmark: 26
    Country: Number of subjects enrolled
    Germany: 7
    Worldwide total number of subjects
    67
    EEA total number of subjects
    67
    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)
    11
    From 65 to 84 years
    55
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was a multinational, phase 2, open-label, single-arm, efficacy and safety study of oral enzalutamide in participants with prostate cancer who had noncastrate levels of testosterone at study entry.

    Pre-assignment
    Screening details
    		 Eighty-two participants were assessed for participation in the study, 15 were excluded and 67 were enrolled. Participants who continued to receive clinical benefit as assessed by the investigator and did not meet any treatment discontinuation criteria were eligible to transition to an open-label extension study 9785-CL-0123 (2016-001694-32).

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Enzalutamide
    Arm description
    		 Participants received oral enzalutamide at 160 mg once daily for 24 weeks. Participants who had clinical benefit at week 25 could continue to receive enzalutamide until disease progression, objective or clinical, or occurrence of an unacceptable toxicity, at the discretion of the investigator.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Enzalutamide
    Investigational medicinal product code
    MDV3100
    Other name
    Xtandi
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 160 mg of enzalutamide orally once a day, at the same time of day.

    Number of subjects in period 1
    		Enzalutamide
    Started
    67
    Treatment Received
    67
    Completed
    27
    Not completed
    40
         Adverse event, serious fatal
    5
         Consent withdrawn by subject
    4
         Other-Transitioned to 9785-CL-0123
    29
         Other-Miscellaneous Reason
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Enzalutamide
    Reporting group description
    		 Participants received oral enzalutamide at 160 mg once daily for 24 weeks. Participants who had clinical benefit at week 25 could continue to receive enzalutamide until disease progression, objective or clinical, or occurrence of an unacceptable toxicity, at the discretion of the investigator.

    Reporting group values
    		 Enzalutamide Total
    Number of subjects
    		 67
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        median (full range (min-max))
    		 73.0 (48 to 86) -
    Gender categorical
    Units: Subjects
        Female
    		 0 0
        Male
    		 67 67
    Total Gleason Score at Initial Diagnosis
    A system of grading prostate cancer tissue based on how it looks under a microscope. Gleason scores range from 2 to 10 and indicate how likely it is that a tumor will spread. A low Gleason score means the cancer tissue is similar to normal prostate tissue and the tumor is less likely to spread; a high Gleason score means the cancer tissue is very different from normal and the tumor is more likely to spread.
    Units: Subjects
        Score=4
    		 1 1
        Score=5
    		 5 5
        Score=6
    		 10 10
        Score=7
    		 34 34
        Score=8
    		 7 7
        Score=9
    		 6 6
        Score=10
    		 3 3
        Unknown
    		 1 1
    Clinical Tumor Stage (T) at Initial Diagnosis
    Units: Subjects
        TX: Primary tumor cannot be assessed
    		 1 1
        T0: No evidence of primary tumor
    		 1 1
        T1: Tumor neither palpable or visible by imaging
    		 9 9
        T2: Tumor confined within the prostate
    		 31 31
        T3: Tumor extends through the prostatic capsule
    		 18 18
        T4: Tumor is fixed or invades adjacent structures
    		 1 1
        Unknown
    		 6 6
    Clinical Lymph Node Stage (N) at Initial Diagnosis
    Units: Subjects
        NX: Regional lymph nodes were not assessed
    		 24 24
        N0: No regional lymph node metastasis
    		 22 22
        N1: Metastasis in regional lymph node(s)
    		 6 6
        Unknown
    		 15 15
    Distant Metastasis (M) at Initial Diagnosis
    Units: Subjects
        MX: Distant metastasis could not be assessed
    		 11 11
        M0: No distant metastasis
    		 35 35
        M1: Distant metastasis
    		 10 10
        Unknown
    		 11 11
    Participants With Metastases at Study Entry
    Units: Subjects
        Yes
    		 26 26
        No
    		 41 41
    Body Mass Index (BMI)
    Units: kg/m²
        median (full range (min-max))
    		 26.17 (20.8 to 39.7) -
    Prostate Specific Antigen (PSA)
    Units: ng/mL
        median (inter-quartile range (Q1-Q3))
    		 18.2 (6.4 to 45.0) -
    Duration of Prostate Cancer
    Units: Years
        median (full range (min-max))
    		 1.0 (0 to 16) -
    Number of Metastatic Lesions by Bone Scan
    Units: Lesions
        median (full range (min-max))
    		 1 (1 to 8) -

    End points

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    End points reporting groups
    Reporting group title
    Enzalutamide
    Reporting group description
    		 Participants received oral enzalutamide at 160 mg once daily for 24 weeks. Participants who had clinical benefit at week 25 could continue to receive enzalutamide until disease progression, objective or clinical, or occurrence of an unacceptable toxicity, at the discretion of the investigator.

    Primary: Percentage of Participants With a Prostate-Specific Antigen (PSA) Response at Week 25

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    End point title
    		 Percentage of Participants With a Prostate-Specific Antigen (PSA) Response at Week 25 [1]
    End point description
    A PSA response was defined as a decline from baseline in PSA level of 80% or greater, where blood samples for PSA were collected and analyzed at a central laboratory. Participants with an unknown or missing response or who discontinued prior to week 25 for any reason were treated as non-responders. No statistical comparisons were performed since this was a single-arm study. The analysis population was safety analysis set (SAF), which consisted of participants who received at least one dose of study drug.
    End point type
    Primary
    End point timeframe
    Baseline and Week 25
    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: No statistical comparisons were performed since this was a single-arm study.
    End point values
    		 Enzalutamide
    Number of subjects analysed
    67
    Units: Percentage of Participants
    number (confidence interval 95%)
        Percentage of Participants
    92.5 (83.44 to 97.53)
    No statistical analyses for this end point

    Secondary: Number of Participants With Adverse Events

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    End point title
    		 Number of Participants With Adverse Events
    End point description
    Each adverse event (AE) was assessed by the investigator for causal relationship to the study drug; those deemed possibly or probably related to study drug are reported as drug regimen related AEs (DRRAEs). A serious adverse event (SAE) was defined as any untoward medical occurrence that at any dose: - Resulted in death - Was life-threatening - Resulted in persistent or significant disability/incapacity - Resulted in congenital anomaly or birth defect - Required inpatient hospitalization or led to prolongation of hospitalization - Other medically important events. The analysis population was safety analysis set (SAF).
    End point type
    Secondary
    End point timeframe
    From first dose of study drug up to 30 days after last dose of study drug (up to week 169)
    End point values
    		 Enzalutamide
    Number of subjects analysed
    67
    Units: Participants
        Any Adverse Events
    67
        Drug Regimen Related Adverse Events
    65
        Deaths
    5
        Serious Adverse Events
    24
        Drug Regimen Related Serious Adverse Events
    5
        AEs Leading to Discontinuation of Study Drug
    14
        DRRAEs Leading to Discontinuation of Study Drug
    7
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in PSA

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    End point title
    		 Percent Change From Baseline in PSA
    End point description
    The analysis population was safety analysis set (SAF). N is the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 25, 49, 97, 169 and End of Study [EoS])
    End point values
    		 Enzalutamide
    Number of subjects analysed
    67
    Units: Percent Change
    arithmetic mean (standard deviation)
        Week 25 (N=63)
    -97.82 ( 5.744 )
        Week 49 (N=54)
    -98.96 ( 2.767 )
        Week 97 (N=45)
    -99.44 ( 1.114 )
        Week 169 (N=42)
    -91.74 ( 27.808 )
        End of Study (N=27)
    -0.70 ( 368.253 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Sex Hormone-Binding Globulin (SHBG)

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    End point title
    		 Percent Change From Baseline in Sex Hormone-Binding Globulin (SHBG)
    End point description
    The analysis population was safety analysis set (SAF). N is the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 25 and 49
    End point values
    		 Enzalutamide
    Number of subjects analysed
    67
    Units: Percent Change
    arithmetic mean (standard deviation)
        Week 25 (N=59)
    100.60 ( 49.362 )
        Week 49 (N=53)
    88.45 ( 41.911 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Androstenedione

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    End point title
    		 Percent Change From Baseline in Androstenedione
    End point description
    The analysis population was safety analysis set (SAF). N is the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 25 and 49
    End point values
    		 Enzalutamide
    Number of subjects analysed
    67
    Units: Percent Change
    arithmetic mean (standard deviation)
        Week 25 (N=61)
    51.06 ( 59.367 )
        Week 49 (N=51)
    49.94 ( 55.449 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Dehydroepiandrosterone (DHEA)

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    End point title
    		 Percent Change From Baseline in Dehydroepiandrosterone (DHEA)
    End point description
    The analysis population was safety analysis set (SAF). N is the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 25 and 49
    End point values
    		 Enzalutamide
    Number of subjects analysed
    67
    Units: Percent Change
    arithmetic mean (standard deviation)
        Week 25 (N=62)
    9.59 ( 58.247 )
        Week 49 (N=51)
    10.54 ( 54.864 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Dihydrotestosterone (DHT)

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    End point title
    		 Percent Change From Baseline in Dihydrotestosterone (DHT)
    End point description
    The analysis population was safety analysis set (SAF). N is the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 25 and 49
    End point values
    		 Enzalutamide
    Number of subjects analysed
    67
    Units: Percent Change
    arithmetic mean (standard deviation)
        Week 25 (N=61)
    51.72 ( 57.511 )
        Week 49 (N=45)
    74.35 ( 101.451 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Estradiol

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    End point title
    		 Percent Change From Baseline in Estradiol
    End point description
    The analysis population was safety analysis set (SAF). N is the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 25 and 49
    End point values
    		 Enzalutamide
    Number of subjects analysed
    67
    Units: Percent Change
    arithmetic mean (standard deviation)
        Week 25 (N=59)
    71.69 ( 73.150 )
        Week 49 (N=52)
    81.00 ( 82.811 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Follicle-Stimulating Hormone (FSH)

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    End point title
    		 Percent Change From Baseline in Follicle-Stimulating Hormone (FSH)
    End point description
    The analysis population was safety analysis set (SAF). N is the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 25 and 49
    End point values
    		 Enzalutamide
    Number of subjects analysed
    67
    Units: Percent Change
    arithmetic mean (standard deviation)
        Week 25 (N=58)
    46.99 ( 46.389 )
        Week 49 (N=52)
    62.18 ( 78.371 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Luteinizing Hormone (LH)

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    End point title
    		 Percent Change From Baseline in Luteinizing Hormone (LH)
    End point description
    The analysis population was safety analysis set (SAF). N is the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 25 and 49
    End point values
    		 Enzalutamide
    Number of subjects analysed
    67
    Units: Percent Change
    arithmetic mean (standard deviation)
        Week 25 (N=58)
    184.66 ( 120.683 )
        Week 49 (N=52)
    215.18 ( 163.732 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Prolactin

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    End point title
    		 Percent Change From Baseline in Prolactin
    End point description
    The analysis population was safety analysis set (SAF). N is the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 25 and 49
    End point values
    		 Enzalutamide
    Number of subjects analysed
    67
    Units: Percent Change
    arithmetic mean (standard deviation)
        Week 25 (N=60)
    16.79 ( 45.497 )
        Week 49 (N=53)
    9.64 ( 30.003 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Total Testosterone

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    End point title
    		 Percent Change From Baseline in Total Testosterone
    End point description
    The analysis population was safety analysis set (SAF). N is the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 25 and 49
    End point values
    		 Enzalutamide
    Number of subjects analysed
    67
    Units: Percent Change
    arithmetic mean (standard deviation)
        Week 25 (N=63)
    114.29 ( 73.692 )
        Week 49 (N=51)
    101.73 ( 76.070 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Free Testosterone

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    End point title
    		 Percent Change From Baseline in Free Testosterone
    End point description
    The analysis population was safety analysis set (SAF). N is the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 25 and 49
    End point values
    		 Enzalutamide
    Number of subjects analysed
    67
    Units: Percent Change
    arithmetic mean (standard deviation)
        Week 25 (N=60)
    46.39 ( 59.551 )
        Week 49 (N=51)
    43.74 ( 55.721 )
    No statistical analyses for this end point

    Secondary: Plasma Concentration of Enzalutamide at Pre-dose (Ctrough)

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    End point title
    		 Plasma Concentration of Enzalutamide at Pre-dose (Ctrough)
    End point description
    The analysis population was pharmacokinetic analysis set (PKAS), which consisted of participants who received at least one dose of study drug and had at least one pharmacokinetic concentration value. N is the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Pre-dose at Weeks 2, 3, 4, 5, 9, 13, 21 and 25
    End point values
    		 Enzalutamide
    Number of subjects analysed
    67
    Units: μg/mL
    arithmetic mean (standard deviation)
        Week 2 (N=61)
    7.225 ( 1.8050 )
        Week 3 (N=66)
    10.559 ( 2.1967 )
        Week 4 (N=62)
    11.838 ( 2.4605 )
        Week 5 (N=65)
    12.161 ( 2.8496 )
        Week 9 (N=63)
    11.606 ( 3.0084 )
        Week 13 (N=63)
    11.868 ( 2.9760 )
        Week 21 (N=62)
    11.224 ( 2.8899 )
        Week 25 (N=63)
    11.668 ( 2.7624 )
    No statistical analyses for this end point

    Secondary: Plasma Concentration of Enzalutamide Metabolite M2 at Pre-dose (Ctrough)

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    End point title
    		 Plasma Concentration of Enzalutamide Metabolite M2 at Pre-dose (Ctrough)
    End point description
    The analysis population was pharmacokinetic analysis set (PKAS). N is the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Pre-dose at Weeks 2, 3, 4, 5, 9, 13, 21 and 25
    End point values
    		 Enzalutamide
    Number of subjects analysed
    67
    Units: μg/mL
    arithmetic mean (standard deviation)
        Week 2 (N=61)
    2.527 ( 1.0440 )
        Week 3 (N=66)
    5.344 ( 1.7079 )
        Week 4 (N=62)
    8.182 ( 2.4366 )
        Week 5 (N=65)
    9.962 ( 2.7584 )
        Week 9 (N=63)
    12.128 ( 3.1262 )
        Week 13 (N=63)
    12.780 ( 3.2564 )
        Week 21 (N=62)
    11.717 ( 2.9502 )
        Week 25 (N=63)
    12.146 ( 2.5845 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants With a PSA Response at Weeks 49, 97 and 169

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    End point title
    		 Percentage of Participants With a PSA Response at Weeks 49, 97 and 169
    End point description
    A PSA response was defined as a decline from baseline in PSA level of 80% or greater. Blood samples for PSA were collected and analyzed at a central laboratory. Participants with an unknown or missing response or who discontinued prior to week 49, week 97 or week 169 for any reason were treated as non-responders. The analysis population was safety analysis set (SAF).
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 49, 97 and 169
    End point values
    		 Enzalutamide
    Number of subjects analysed
    67
    Units: Percentage of Participants
    number (confidence interval 95%)
        Week 49
    80.6 (69.11 to 89.24)
        Week 97
    67.2 (54.60 to 78.15)
        Week 169
    56.7 (44.04 to 68.78)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With a 90% or Greater Reduction From Baseline in PSA Level

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    End point title
    		 Percentage of Participants With a 90% or Greater Reduction From Baseline in PSA Level
    End point description
    Participants with unknown or missing PSA results at week 25 or who discontinued prior to week 25 were considered non-responders at week 25. Participants with unknown or missing PSA results at week 49, week 97 or week 169 were considered non-responders. The analysis population was safety analysis set (SAF). Week 49, 97 and 169 analyses include participants who were on study at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 25, 49, 97 and 169
    End point values
    		 Enzalutamide
    Number of subjects analysed
    67
    Units: Percentage of Participants
    number (not applicable)
        Week 25 (N=67)
    91.0
        Week 49 (N=54)
    98.1
        Week 97 (N=45)
    100.0
        Week 169 (N=42)
    88.1
    No statistical analyses for this end point

    Secondary: Percentage of Participants with PSA ≤ 4 ng/ml

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    End point title
    		 Percentage of Participants with PSA ≤ 4 ng/ml
    End point description
    Participants with unknown or missing PSA results at week 25 or who discontinued prior to Week 25 were considered non-responders at Week 25. Participants with unknown or missing PSA results at week 49, 97 or 169 were considered non-responders. The analysis population was safety analysis set (SAF). Week 49, 97 and 169 analyses include participants who were on study at each time point.
    End point type
    Secondary
    End point timeframe
    Weeks 25, 49, 97 and 169
    End point values
    		 Enzalutamide
    Number of subjects analysed
    67
    Units: Percentage of Participants
    number (not applicable)
        Week 25 (N=67)
    92.5
        Week 49 (N=54)
    94.4
        Week 97 (N=45)
    100.0
        Week 169 (N=42)
    95.2
    No statistical analyses for this end point

    Secondary: Percentage of Participants with PSA ≤ 0.1 ng/ml

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    End point title
    		 Percentage of Participants with PSA ≤ 0.1 ng/ml
    End point description
    Participants with unknown or missing PSA results at week 25 or who discontinued prior to week 25 were considered non-responders at week 25. Participants with unknown or missing PSA results at week 49, 97 or 169 were considered non-responders. The analysis population was safety analysis set (SAF). N is the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Weeks 25, 49, 97 and 169
    End point values
    		 Enzalutamide
    Number of subjects analysed
    67
    Units: Percentage of Participants
    number (not applicable)
        Week 25 (N=67)
    44.8
        Week 49 (N=54)
    63.0
        Week 97 (N=45)
    73.3
        Week 169 (N=42)
    61.9
    No statistical analyses for this end point

    Secondary: Maximum Decline From Baseline in PSA

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    End point title
    		 Maximum Decline From Baseline in PSA
    End point description
    The maximum decline from Baseline in PSA was calculated as the largest reduction from Baseline in PSA level that occurred at any point after treatment start up to week 25 and up to and including the assessment made at the safety follow-up visit, divided by the PSA Baseline value and multiplied by 100, i.e., the maximum percent change from baseline. The analysis population was safety analysis set (SAF).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 25 and from Baseline up to the EOS date of 27 Apr 2017; median duration of treatment of 1666.0 days (range of 52-2052)
    End point values
    		 Enzalutamide
    Number of subjects analysed
    67
    Units: Percent Change
    arithmetic mean (standard deviation)
        Maximum Decline by Week 25
    -98.32 ( 2.880 )
        Maximum Decline by EOS
    -99.10 ( 2.659 )
    No statistical analyses for this end point

    Secondary: Time to PSA Response

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    End point title
    		 Time to PSA Response
    End point description
    Time to PSA response (PSA decline ≥ 80% from Baseline) is defined as the time interval from the first study drug dose to the first date a decline from Baseline in PSA level of 80% or greater was recorded. Time to response was estimated using the Kaplan-Meier method. The analysis population was safety analysis set (SAF).
    End point type
    Secondary
    End point timeframe
    From first dose until the EOS date of 27-Apr-2017; median duration of treatment of 1666.0 days (range of 52-2052)
    End point values
    		 Enzalutamide
    Number of subjects analysed
    67
    Units: Days
    median (inter-quartile range (Q1-Q3))
        Days
    29 (28 to 31)
    No statistical analyses for this end point

    Secondary: Time to PSA Decline ≥ 90%

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    End point title
    		 Time to PSA Decline ≥ 90%
    End point description
    Time to PSA decline ≥ 90% is defined as the time interval from the first study drug dose to the first date a decline from Baseline in PSA level of 90% or greater was recorded. Time to PSA decline ≥ 90% was estimated using the Kaplan-Meier method. The analysis population was safety analysis set (SAF).
    End point type
    Secondary
    End point timeframe
    From first dose until the EOS date of 27-Apr-2017; median duration of treatment of 1666.0 days (range of 52-2052)
    End point values
    		 Enzalutamide
    Number of subjects analysed
    67
    Units: Days
    median (inter-quartile range (Q1-Q3))
        Days
    55 (29 to 57)
    No statistical analyses for this end point

    Secondary: Time to PSA ≤ 4 ng/ml

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    End point title
    		 Time to PSA ≤ 4 ng/ml
    End point description
    Time to PSA ≤ 4 ng/ml is defined as the time interval from the first study drug dose to the first date a decline in PSA to a result of 4 ng/ml or below was recorded. Time to PSA ≤ 4 ng/ml was estimated using the Kaplan-Meier method. The analysis population was safety analysis set (SAF).
    End point type
    Secondary
    End point timeframe
    From first dose until the EOS date of 27-Apr-2017; median duration of treatment of 1666.0 days (range of 52-2052)
    End point values
    		 Enzalutamide
    Number of subjects analysed
    67
    Units: Days
    median (inter-quartile range (Q1-Q3))
        Days
    29 (9 to 57)
    No statistical analyses for this end point

    Secondary: Time to PSA ≤ 0.1 ng/ml

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    End point title
    		 Time to PSA ≤ 0.1 ng/ml
    End point description
    Time to PSA ≤ 0.1 ng/ml is defined as the time interval from the first study drug dose to the first date a decline in PSA to a result of 0.1 ng/ml or below was recorded. Time to PSA ≤ 0.1 ng/ml was estimated using the Kaplan-Meier method. The analysis population was safety analysis set (SAF).
    End point type
    Secondary
    End point timeframe
    From first dose until the EOS date of 27-Apr-2017; median duration of treatment of 1666.0 days (range of 52-2052)
    End point values
    		 Enzalutamide
    Number of subjects analysed
    67
    Units: Days
    median (inter-quartile range (Q1-Q3))
        Days
    168 (58 to 581)
    No statistical analyses for this end point

    Secondary: Time to PSA Progression

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    End point title
    		 Time to PSA Progression
    End point description
    Time to PSA progression is defined as the time interval from the first study drug dose to the first date of PSA progression. PSA progression is defined as a ≥ 25% increase in PSA with an absolute increase of ≥ 2 ng/mL above the nadir unless the PSA next measurement(s), if available, does not confirm the PSA progression. "99999" indicates data that could not be estimated due to the low number of events. The analysis population was safety analysis set (SAF).
    End point type
    Secondary
    End point timeframe
    From first dose until the EOS date of 27-Apr-2017; median duration of treatment of 1666.0 days (range of 52-2052)
    End point values
    		 Enzalutamide
    Number of subjects analysed
    67
    Units: Days
    median (inter-quartile range (Q1-Q3))
        Days
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: PSA Doubling Time

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    End point title
    		 PSA Doubling Time
    End point description
    PSA doubling time was to be calculated from the slope estimated from a linear regression of the natural log of PSA fitted on time, if the slope was positive. Since the slope was negative for all participants, PSA doubling time could not be calculated. The analysis population was safety analysis set (SAF) with a positive PSA versus time slope.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 25
    End point values
    		 Enzalutamide
    Number of subjects analysed
    0 [2]
    Units: Months
    arithmetic mean (standard deviation)
        Months
    ( )
    Notes
    [2] - No participants had a positive PSA versus time slope
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug up to 30 days after last dose of study drug; median duration of treatment of 1666.0 days (range of 52-2052)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    12.0
    Reporting groups
    Reporting group title
    Enzalutamide
    Reporting group description
    		 Participants received oral enzalutamide at 160 mg once daily for 24 weeks. Participants who had clinical benefit at week 25 could continue to receive enzalutamide until disease progression, objective or clinical, or occurrence of an unacceptable toxicity, at the discretion of the investigator.

    Serious adverse events
    		 Enzalutamide
    Total subjects affected by serious adverse events
         subjects affected / exposed
    24 / 67 (35.82%)
         number of deaths (all causes)
    5
         number of deaths resulting from adverse events
    5
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Benign neoplasm
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bladder transitional cell carcinoma
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Colon cancer metastatic
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Malignant neoplasm progression
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Metastases to abdominal cavity
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metastases to bladder
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metastases to liver
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metastases to lung
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oesophageal carcinoma
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal cancer
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Schwannoma
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin cancer
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Chronic fatigue syndrome
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Device dislocation
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Prostatic calcification
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Clavicle fracture
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Concussion
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Angina pectoris
         subjects affected / exposed
    2 / 67 (2.99%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Arrhythmia
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    4 / 67 (5.97%)
         occurrences causally related to treatment / all
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Sick sinus syndrome
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Normal pressure hydrocephalus
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Seizure anoxic
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 67 (2.99%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Dyspepsia
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary retention
         subjects affected / exposed
    2 / 67 (2.99%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal column stenosis
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    2 / 67 (2.99%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Hypoglycaemia
         subjects affected / exposed
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Enzalutamide
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    66 / 67 (98.51%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    4 / 67 (5.97%)
         occurrences all number
    5
    Vascular disorders
    Hot flush
         subjects affected / exposed
    15 / 67 (22.39%)
         occurrences all number
    18
    Hypertension
         subjects affected / exposed
    17 / 67 (25.37%)
         occurrences all number
    18
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    5 / 67 (7.46%)
         occurrences all number
    5
    Headache
         subjects affected / exposed
    4 / 67 (5.97%)
         occurrences all number
    8
    Memory impairment
         subjects affected / exposed
    6 / 67 (8.96%)
         occurrences all number
    7
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    28 / 67 (41.79%)
         occurrences all number
    40
    Oedema peripheral
         subjects affected / exposed
    8 / 67 (11.94%)
         occurrences all number
    10
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    4 / 67 (5.97%)
         occurrences all number
    5
    Constipation
         subjects affected / exposed
    9 / 67 (13.43%)
         occurrences all number
    11
    Diarrhoea
         subjects affected / exposed
    11 / 67 (16.42%)
         occurrences all number
    14
    Dry mouth
         subjects affected / exposed
    5 / 67 (7.46%)
         occurrences all number
    5
    Nausea
         subjects affected / exposed
    11 / 67 (16.42%)
         occurrences all number
    14
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    6 / 67 (8.96%)
         occurrences all number
    7
    Gynaecomastia
         subjects affected / exposed
    36 / 67 (53.73%)
         occurrences all number
    43
    Nipple pain
         subjects affected / exposed
    13 / 67 (19.40%)
         occurrences all number
    13
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 67 (7.46%)
         occurrences all number
    5
    Dyspnoea
         subjects affected / exposed
    6 / 67 (8.96%)
         occurrences all number
    6
    Dysphonia
         subjects affected / exposed
    4 / 67 (5.97%)
         occurrences all number
    4
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    7 / 67 (10.45%)
         occurrences all number
    7
    Rash
         subjects affected / exposed
    4 / 67 (5.97%)
         occurrences all number
    4
    Psychiatric disorders
    Depression
         subjects affected / exposed
    5 / 67 (7.46%)
         occurrences all number
    5
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    10 / 67 (14.93%)
         occurrences all number
    12
    Musculoskeletal pain
         subjects affected / exposed
    4 / 67 (5.97%)
         occurrences all number
    4
    Myalgia
         subjects affected / exposed
    4 / 67 (5.97%)
         occurrences all number
    5
    Osteoporosis
         subjects affected / exposed
    7 / 67 (10.45%)
         occurrences all number
    9
    Pain in extremity
         subjects affected / exposed
    8 / 67 (11.94%)
         occurrences all number
    9
    Infections and infestations
    Cystitis
         subjects affected / exposed
    4 / 67 (5.97%)
         occurrences all number
    4
    Nasopharyngitis
         subjects affected / exposed
    6 / 67 (8.96%)
         occurrences all number
    9
    Pneumonia
         subjects affected / exposed
    5 / 67 (7.46%)
         occurrences all number
    6
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    4 / 67 (5.97%)
         occurrences all number
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Jun 2011
    The changes include: Change to study contact details; clarification of requirements for assessment of metastases; change in timing of first dual-energy x-ray absorptiometry scan; change in serious adverse event reporting responsibility; change in dose for an excluded medication; corrections in laboratory parameters; addition of instructions for participants withdrawn before week 25; removed reference to treatment number.
    17 Oct 2012
    The changes include: Change to study contact details; change in Schedule of Assessments and adverse event collection; clarification of pharmacokinetic sampling; change to statistical definition and interim analysis; change to administrative procedures and drug storage; clarification of central laboratory testing; update of participant information sheet; changes to protocol authors; update to drug-induced liver injury requirements; update to drug-drug interaction information; update to reporting of serious adverse events.
    21 Jul 2014
    The changes include: Schedule of Assessments updated to include additional assessments performed at week 169; Schedule of Assessments table, related footnotes, and description of those assessments in different sections of the protocol were updated, along with the study period to reflect an overall extension in study duration to 4Q 2016; dosing instructions modified for participants who experienced a grade 3 or greater toxicity attributed to the study drug and when the study drug was coadministered with a strong cytochrome P450 (CYP) 2C8 inhibitor; Section 1.3 Summary of Key Safety Information for MDV3100 updated to reflect current information; protocol updated regarding reporting and management of protocol deviations, and contact details for Astellas Pharma Europe BV, 24 hour serious adverse event reporting and the Medical Monitor were updated; Appendix 4 “Events Always Considered to be Serious” was deleted and a new Appendix 3 “Common Serious Adverse Events” was added; new information concerning “always serious adverse event” was added to Section 5.5.3; study drug storage conditions updated; for current efficacy and safety information on enzalutamide, the investigator is referred to the current edition of the Investigator’s Brochure; Appendix 3 (Subject Insurance) and Appendix 5 (Elements of Informed Consent) deleted; cover page, sponsor’s signature and investigator’s signatures updated; minor administrative type corrections, e.g., typos, spelling, format, renumbering of tables and appendices throughout the protocol updated as required.
    24 Jun 2016
    The changes include: The study design was revised so that participants who continue to derive clinical benefit from treatment with enzalutamide, based on the investigator’s medical opinion, and who had not met any of the discontinuation criteria were eligible to continue treatment in Study 9785-CL-0123 upon approval of the protocol and activation of the study at participating institutions. Minor administrative revisions were also made to 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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