Study on Enzalutamide and Flutamide in Patients With Castration Resistant Prostate Cancer

Sponsor
Astellas Pharma Inc (Industry)
Overall Status
Completed
CT.gov ID
NCT02918968
Collaborator
Pfizer (Industry)
206
47
2
40.8
4.4
0.1

Study Details

Study Description

Brief Summary

The objective of this study was to compare the efficacy and safety of the combination therapy with enzalutamide + androgen deprivation therapy (ADT) and the combination therapy with flutamide + ADT in patients with castration resistant prostate cancer who had relapsed during combined androgen blockade (CAB) therapy with bicalutamide and ADT. This study also investigated the order of alternative antiandrogen therapy (AAT) by changing the 1st line medication after relapse of prostate-specific antigen (PSA).

Condition or Disease Intervention/Treatment Phase
Phase 4

Study Design

Study Type:
Interventional
Actual Enrollment :
206 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Randomized Phase IV Study Comparing Enzalutamide Versus Flutamide in Castration-resistant Prostate Cancer (CRPC) Patients Who Have Failed Combined Androgen Blockade Therapy With Bicalutamide Plus Androgen Deprivation Therapy (ADT)
Actual Study Start Date :
Nov 2, 2016
Actual Primary Completion Date :
Mar 27, 2020
Actual Study Completion Date :
Mar 27, 2020

Arms and Interventions

Arm Intervention/Treatment
Experimental: Enzalutamide 160 mg 1st line AAT/Flutamide 375 mg 2nd line AAT

Participants received enzalutamide 160 mg capsules, orally once daily as 1st line of alternative antiandrogen therapy (AAT) until confirmed prostate-specific antigen (PSA) progression, other disease progression, or an intolerable adverse event. After confirmation of PSA progression, other disease progression, or an intolerable adverse event, participants received flutamide 125 mg tablets orally thrice daily after each meal as 2nd line of AAT. Treatment with each drug was continued until the participant met any of the discontinuation criteria or until 2 years from the enrollment of the last participant (approximately 38 months).

Drug: Enzalutamide
Oral Capsule
Other Names:
  • Xtandi
  • MDV3100
  • Drug: Flutamide
    Oral tablet

    Other: Androgen deprivation therapy
    All subjects must undergo continuous Androgen deprivation therapy with GnRH agonist/antagonist or bilateral orchiectomy during the study period.

    Experimental: Flutamide 375 mg 1st line AAT/Enzaltumide 160 mg 2nd line AAT

    Participants received flutamide 125 mg tablets orally thrice daily after each meal as 1st line of AAT until confirmed PSA progression, other disease progression, or an intolerable adverse event. After confirmed PSA progression, other disease progression, or an intolerable adverse event. participants received enzalutamide 160 mg capsules orally once daily as 2nd line of AAT. Treatment with each drug was continued until the participant met any of the discontinuation criteria or until 2 years from the enrollment of the last participant (approximately 38 months).

    Drug: Enzalutamide
    Oral Capsule
    Other Names:
  • Xtandi
  • MDV3100
  • Drug: Flutamide
    Oral tablet

    Other: Androgen deprivation therapy
    All subjects must undergo continuous Androgen deprivation therapy with GnRH agonist/antagonist or bilateral orchiectomy during the study period.

    Outcome Measures

    Primary Outcome Measures

    1. Time to PSA Progression With 1st Line AAT (TTPP1) [From date of randomization to the date of PSA progression in the 1st line AAT period (Up to 38 months)]

      TTPP1 was defined as the period from the date of randomization to the date of PSA progression in the 1st line AAT period. PSA progression was defined according to the consensus guidelines of prostate cancer clinical trials working group 2 (PCWG2). For participants with PSA declines at week 13, the PSA progression date was defined as the date that a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL above the nadir were documented, which was confirmed by a second consecutive value obtained 3 or more weeks later. For participants with no PSA decline at week 13, the PSA progression date was defined as the date that a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL above the baseline were documented. Time to event analysis was performed using kaplan-meier (KM) estimates.

    Secondary Outcome Measures

    1. Time to PSA Progression With 2nd Line AAT (TTPP2) [From date of randomization to the date of PSA progression in 2nd line AAT (Up to 38 months)]

      TTPP2 was defined as the period from day 1 of the 2nd line AAT to the date of PSA progression with the 2nd line AAT. PSA progression was defined according to the consensus guidelines of PCWG2. For participants with PSA declines at week 13, the PSA progression date was defined as the date that a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL above the nadir were documented, which was confirmed by a second consecutive value obtained 3 or more weeks later. For participants with no PSA decline at week 13, the PSA progression date was defined as the date that a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL above the baseline were documented. Time to event analysis was performed using kaplan-meier estimates.

    2. Percentage of Participants Achieving at Least 50 or 90 Percent (%) Reduction From Baseline and Up To Week 38 in Prostate Specific Antigen (PSA) Response at 1st Line AAT [Baseline and at least 3 weeks after, the lowest PSA decreased by at least 50% or 90% from baseline (Up to 38 months)]

      PSA response was defined as PSA decreased by at least 50% or 90% from baseline when at least 3 weeks passed after the lowest PSA decreased by at least 50% or 90% from baseline in the 1st line AAT period after baseline. Data was reported per each disease stage (M0/N0, M0/N1, M1). 1) M0/N0: No distant metastasis and no lymph node metastasis. 2) M0/N1: Without distant metastasis, but with metastasis in lymph nodes distal to the aortic bifurcation. 3) M1: With distant metastasis (including metastasis in lymph nodes proximal to the aortic bifurcation).

    3. Percentage of Participants Achieving at Least 50 or 90 Percent (%) Reduction From Baseline to Week 13 in Prostate Specific Antigen (PSA) Response at 1st Line AAT [Baseline and week 13]

      PSA response was defined as the lowest PSA at week 13 decreased by at least 50% or 90% from baseline in the 1st line AAT period. Data was reported per each disease stage (M0/N0, M0/N1, M1). 1) M0/N0: No distant metastasis and no lymph node metastasis. 2) M0/N1: Without distant metastasis, but with metastasis in lymph nodes distal to the aortic bifurcation. 3) M1: With distant metastasis (including metastasis in lymph nodes proximal to the aortic bifurcation).

    4. Time to PSA Decrease by 50% From Baseline With 1st Line AAT [From date of randomization to the day when the decrease of PSA from baseline by 50% is first identified (Up to 38 months)]

      Time to PSA decrease by 50% with 1st line AAT was defined as the period from the date of randomization to the day when the decrease of PSA from baseline by 50% is first identified. Time to event analysis was performed using kaplan-meier estimates. Data was reported per each disease stage (M0/N0, M0/N1, M1). 1) M0/N0: No distant metastasis and no lymph node metastasis. 2) M0/N1: Without distant metastasis, but with metastasis in lymph nodes distal to the aortic bifurcation. 3) M1: With distant metastasis (including metastasis in lymph nodes proximal to the aortic bifurcation).

    5. Time to Treatment Failure of 1st Line AAT (TTF1) [From date of randomization to discontinuation of 1st line AAT (Up to 38 months)]

      TTF1 was defined as the period from randomization to study drug discontinuation of 1st line AAT for any reason that includes disease progression, onset of adverse events (AEs), participants request, or death. Time to event analysis was performed using kaplan-meier estimates. Data was reported per each disease stage (M0/N0, M0/N1, M1). 1) M0/N0: No distant metastasis and no lymph node metastasis. 2) M0/N1: Without distant metastasis, but with metastasis in lymph nodes distal to the aortic bifurcation. 3) M1: With distant metastasis (including metastasis in lymph nodes proximal to the aortic bifurcation).

    6. Time to Treatment Failure of 2nd Line AAT (TTF2) [From date of randomization to discontinuation of 2nd line AAT (Up to 38 months)]

      TTF2 was defined as the period from randomization to study drug discontinuation of 2nd line AAT for any reason that includes disease progression, onset of AEs, participants request, or death. Time to event analysis was performed using kaplan-meier estimates.

    7. Radiographic Progression-free Survival (rPFS) [From date of randomization to the time when radiographic disease progression is observed or death of any cause (up to 38 months)]

      rPFS was defined as the period from randomization to the time when radiographic disease progression is observed or death of any cause during the study period, whichever occurs earlier. Time to event analysis was performed using kaplan-meier estimates. Data was reported per each disease stage (M0/N0, M0/N1, M1). 1) M0/N0: No distant metastasis and no lymph node metastasis. 2) M0/N1: Without distant metastasis, but with metastasis in lymph nodes distal to the aortic bifurcation. 3) M1: With distant metastasis (including metastasis in lymph nodes proximal to the aortic bifurcation).

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    20 Years and Older
    Sexes Eligible for Study:
    Male
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Subject is diagnosed with histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small-cell histology.

    • Subject on continuous ADT with Gonadotropin Releasing Hormone (GnRH) agonist/antagonist or bilateral orchiectomy.

    • Serum testosterone level below the target level at screening visit.

    • Subject with asymptomatic or mildly symptomatic prostate cancer.

    • Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

    • Subject has progression of the disease as defined by rising PSA levels or progressive soft tissue or bony disease during CAB therapy in combination of bicalutamide and ADT.

    • A sexually active male subject and the subject's female partner who is of childbearing potential must use 2 acceptable birth control methods from screening to 3 months after the last dose of the study drug.

    • Subject must agree not to donate sperm from screening to 3 months after the last dose of the study drug.

    Exclusion Criteria:
    • Subject with severe concurrent diseases, infections, or complications.

    • Subject with confirmed or suspected brain metastasis or active leptomeningeal metastasis.

    • Subject with a history of malignant tumor other than prostate cancer in the past 5 years.

    • Subject hypersensitive to the ingredients of enzalutamide capsules or flutamide tablets.

    • Subject with a history of convulsive attack, or prone to convulsive attack.

    • Subject with liver disorder such as viral hepatitis and hepatic cirrhosis, or subject with Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) at screening visit higher than the upper limit of normal.

    • Subject received treatment for prostate cancer with cytocidal chemotherapy that includes anti androgenic agents other than bicalutamide, abiraterone, or estramustine.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Site JP00024 Nagoya Aichi Japan
    2 Site JP00025 Nagoya Aichi Japan
    3 Site JP00038 Matsuyama Ehime Japan
    4 Site JP00051 Iizuka Fukuoka Japan
    5 Site JP00045 Isesaki Gunma Japan
    6 Site JP00005 Maebashi Gunma Japan
    7 Site JP00043 Ota Gunma Japan
    8 Site JP00054 Hakodate Hokkaido Japan
    9 Site JP00001 Sapporo Hokkaido Japan
    10 Site JP00002 Sapporo Hokkaido Japan
    11 Site JP00048 Sapporo Hokkaido Japan
    12 Site JP00055 Mito Ibaraki Japan
    13 Site JP00019 Sagamihara Kanagawa Japan
    14 Site JP00020 Yokohama Kanagawa Japan
    15 Site JP00021 Yokohama Kanagawa Japan
    16 Site JP00044 Yokosuka Kanagawa Japan
    17 Site JP00046 Kashihara Nara Japan
    18 Site JP00033 Kurashiki Okayama Japan
    19 Site JP00028 Hirakata Osaka Japan
    20 Site JP00030 Osakasayama Osaka Japan
    21 Site JP00027 Suita Osaka Japan
    22 Site JP00009 Kitaadachi-gun Saitama Japan
    23 Site JP00022 Hamamatsu Shizuoka Japan
    24 Site JP00049 Utsunomiya Tochigi Japan
    25 Site JP00011 Bunkyo-ku Tokyo Japan
    26 Site JP00017 Bunkyo-ku Tokyo Japan
    27 Site JP00013 Koto-ku Tokyo Japan
    28 Site JP00014 Nakano-ku Tokyo Japan
    29 Site JP00016 Shinagawa-ku Tokyo Japan
    30 Site JP00018 Shinjuku-ku Tokyo Japan
    31 Site JP00034 Ube Yamaguchi Japan
    32 Site JP00010 Chiba Japan
    33 Site JP00053 Chiba Japan
    34 Site JP00039 Fukuoka Japan
    35 Site JP00040 Fukuoka Japan
    36 Site JP00050 Fukuoka Japan
    37 Site JP00035 Hiroshima Japan
    38 Site JP00026 Kyoto Japan
    39 Site JP00006 Nagano Japan
    40 Site JP00008 Nagano Japan
    41 Site JP00041 Nagasaki Japan
    42 Site JP00029 Osaka Japan
    43 Site JP00031 Osaka Japan
    44 Site JP00032 Osaka Japan
    45 Site JP00042 Saga Japan
    46 Site JP00037 Tokushima Japan
    47 Site JP00052 Toyama Japan

    Sponsors and Collaborators

    • Astellas Pharma Inc
    • Pfizer

    Investigators

    • Study Director: Medical Director, Astellas Pharma Inc

    Study Documents (Full-Text)

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    Astellas Pharma Inc
    ClinicalTrials.gov Identifier:
    NCT02918968
    Other Study ID Numbers:
    • 9785-MA-3051
    First Posted:
    Sep 29, 2016
    Last Update Posted:
    May 21, 2021
    Last Verified:
    May 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Product Manufactured in and Exported from the U.S.:
    Yes
    Keywords provided by Astellas Pharma Inc
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details Participants with M0 or M1 castration-resistant prostatic neoplasm that relapsed during Combined Androgen Blockade (CAB) therapy with bicalutamide were enrolled in this study.
    Pre-assignment Detail Randomization was stratified by disease stages (M0/N0, M0/N1 or M1).
    Arm/Group Title Enzalutamide 160 mg 1st Line AAT/Flutamide 375 mg 2nd Line AAT Flutamide 375 mg 1st Line AAT/Enzaltumide 160 mg 2nd Line AAT
    Arm/Group Description Participants received enzalutamide 160 mg capsules, orally once daily as 1st line of alternative antiandrogen therapy (AAT) until confirmed prostate-specific antigen (PSA) progression, other disease progression, or an intolerable adverse event. After confirmed PSA progression, other disease progression, or an intolerable adverse event, participants received flutamide 125 mg tablets orally thrice daily after each meal as 2nd line of AAT. Treatment with each drug was continued until the participant met any of the discontinuation criteria or until 2 years from the enrollment of the last participant (approximately 38 months). Participants received flutamide 125 mg tablets orally thrice daily after each meal as 1st line of AAT until confirmed PSA progression, other disease progression, or an intolerable adverse event. After confirmed PSA progression, other disease progression, or an intolerable adverse event, participants received enzalutamide 160 mg capsules orally once daily as 2nd line of AAT. Treatment with each drug was continued until the participant met any of the discontinuation criteria or until 2 years from the enrollment of the last participant (approximately 38 months).
    Period Title: 1st Line AAT
    STARTED 102 104
    Maintained 1st Line AAT Without Progression 25 8
    COMPLETED 73 93
    NOT COMPLETED 29 11
    Period Title: 1st Line AAT
    STARTED 48 85
    COMPLETED 23 73
    NOT COMPLETED 25 12

    Baseline Characteristics

    Arm/Group Title Enzalutamide 160 mg 1st Line AAT/Flutamide 375 mg 2nd Line AAT Flutamide 375 mg 1st Line AAT/Enzaltumide 160 mg 2nd Line AAT Total
    Arm/Group Description Participants received enzalutamide 160 mg capsules, orally once daily as 1st line of AAT until confirmed PSA progression, other disease progression, or an intolerable adverse event. After confirmed PSA progression, other disease progression, or an intolerable adverse event, participants received flutamide 125 mg tablets orally thrice daily after each meal as 2nd line of AAT. Treatment with each drug was continued until the participant met any of the discontinuation criteria or until 2 years from the enrollment of the last participant (approximately 38 months). Participants received flutamide 125 mg tablets orally thrice daily after each meal as 1st line of AAT until confirmed PSA progression, other disease progression, or an intolerable adverse event. After confirmed PSA progression, other disease progression, or an intolerable adverse event, participants received enzalutamide 160 mg capsules orally once daily as 2nd line of AAT. Treatment with each drug was continued until the participant met any of the discontinuation criteria or until 2 years from the enrollment of the last participant (approximately 38 months). Total of all reporting groups
    Overall Participants 102 104 206
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    74.4
    (7.6)
    74.1
    (7.6)
    74.2
    (7.6)
    Sex: Female, Male (Count of Participants)
    Female
    0
    0%
    0
    0%
    0
    0%
    Male
    102
    100%
    104
    100%
    206
    100%
    Race and Ethnicity Not Collected (Count of Participants)
    Count of Participants [Participants]
    0
    0%
    Disease Stages at Randomization (Number) [Number]
    M0/N0
    24
    23.5%
    25
    24%
    49
    23.8%
    M0/N1
    3
    2.9%
    4
    3.8%
    7
    3.4%
    M1
    75
    73.5%
    75
    72.1%
    150
    72.8%

    Outcome Measures

    1. Primary Outcome
    Title Time to PSA Progression With 1st Line AAT (TTPP1)
    Description TTPP1 was defined as the period from the date of randomization to the date of PSA progression in the 1st line AAT period. PSA progression was defined according to the consensus guidelines of prostate cancer clinical trials working group 2 (PCWG2). For participants with PSA declines at week 13, the PSA progression date was defined as the date that a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL above the nadir were documented, which was confirmed by a second consecutive value obtained 3 or more weeks later. For participants with no PSA decline at week 13, the PSA progression date was defined as the date that a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL above the baseline were documented. Time to event analysis was performed using kaplan-meier (KM) estimates.
    Time Frame From date of randomization to the date of PSA progression in the 1st line AAT period (Up to 38 months)

    Outcome Measure Data

    Analysis Population Description
    ITT Population
    Arm/Group Title Enzalutamide 160 mg 1st Line AAT/Flutamide 375 mg 2nd Line AAT Flutamide 375 mg 1st Line AAT/Enzaltumide 160 mg 2nd Line AAT
    Arm/Group Description Participants received enzalutamide 160 mg capsules, orally once daily as 1st line of AAT until confirmed PSA progression, other disease progression, or an intolerable adverse event. After confirmed PSA progression, other disease progression, or an intolerable adverse event, participants received flutamide 125 mg tablets orally thrice daily after each meal as 2nd line of AAT. Treatment with each drug was continued until the participant met any of the discontinuation criteria or until 2 years from the enrollment of the last participant (approximately 38 months). Participants received flutamide 125 mg tablets orally thrice daily after each meal as 1st line of AAT until confirmed PSA progression, other disease progression, or an intolerable adverse event. After confirmed PSA progression, other disease progression, or an intolerable adverse event, participants received enzalutamide 160 mg capsules orally once daily as 2nd line of AAT. Treatment with each drug was continued until the participant met any of the discontinuation criteria or until 2 years from the enrollment of the last participant (approximately 38 months).
    Measure Participants 102 104
    Median (95% Confidence Interval) [Months]
    21.39
    5.78
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Enzalutamide 160 mg 1st Line AAT/Flutamide 375 mg 2nd Line AAT, Flutamide 375 mg 1st Line AAT/Enzaltumide 160 mg 2nd Line AAT
    Comments
    Type of Statistical Test Superiority
    Comments The significance level was 0.05 (two-sided).
    Statistical Test of Hypothesis p-Value <0.001
    Comments P-value is based on a log-rank test stratified disease stages (M0/N0, M0/N1, or M1).
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.42
    Confidence Interval (2-Sided) 95%
    0.29 to 0.61
    Parameter Dispersion Type:
    Value:
    Estimation Comments Hazard ratio and P-value calculated using unstratified Cox proportional hazards model with treatment and disease stages (M0/N0, M0/N1, or M1) as covariate.
    2. Secondary Outcome
    Title Time to PSA Progression With 2nd Line AAT (TTPP2)
    Description TTPP2 was defined as the period from day 1 of the 2nd line AAT to the date of PSA progression with the 2nd line AAT. PSA progression was defined according to the consensus guidelines of PCWG2. For participants with PSA declines at week 13, the PSA progression date was defined as the date that a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL above the nadir were documented, which was confirmed by a second consecutive value obtained 3 or more weeks later. For participants with no PSA decline at week 13, the PSA progression date was defined as the date that a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL above the baseline were documented. Time to event analysis was performed using kaplan-meier estimates.
    Time Frame From date of randomization to the date of PSA progression in 2nd line AAT (Up to 38 months)

    Outcome Measure Data

    Analysis Population Description
    ITT population
    Arm/Group Title Enzalutamide 160 mg 1st Line AAT/Flutamide 375 mg 2nd Line AAT Flutamide 375 mg 1st Line AAT/Enzaltumide 160 mg 2nd Line AAT
    Arm/Group Description Participants received enzalutamide 160 mg capsules, orally once daily as 1st line of AAT until confirmed PSA progression, other disease progression, or an intolerable adverse event. After confirmed PSA progression, other disease progression, or an intolerable adverse event, participants received flutamide 125 mg tablets orally thrice daily after each meal as 2nd line of AAT. Treatment with each drug was continued until the participant met any of the discontinuation criteria or until 2 years from the enrollment of the last participant (approximately 38 months). Participants received flutamide 125 mg tablets orally thrice daily after each meal as 1st line of AAT until confirmed PSA progression, other disease progression, or an intolerable adverse event. After confirmed PSA progression, other disease progression, or an intolerable adverse event, participants received enzalutamide 160 mg capsules orally once daily as 2nd line of AAT. Treatment with each drug was continued until the participant met any of the discontinuation criteria or until 2 years from the enrollment of the last participant (approximately 38 months).
    Measure Participants 102 104
    Median (95% Confidence Interval) [Months]
    NA
    21.22
    3. Secondary Outcome
    Title Percentage of Participants Achieving at Least 50 or 90 Percent (%) Reduction From Baseline and Up To Week 38 in Prostate Specific Antigen (PSA) Response at 1st Line AAT
    Description PSA response was defined as PSA decreased by at least 50% or 90% from baseline when at least 3 weeks passed after the lowest PSA decreased by at least 50% or 90% from baseline in the 1st line AAT period after baseline. Data was reported per each disease stage (M0/N0, M0/N1, M1). 1) M0/N0: No distant metastasis and no lymph node metastasis. 2) M0/N1: Without distant metastasis, but with metastasis in lymph nodes distal to the aortic bifurcation. 3) M1: With distant metastasis (including metastasis in lymph nodes proximal to the aortic bifurcation).
    Time Frame Baseline and at least 3 weeks after, the lowest PSA decreased by at least 50% or 90% from baseline (Up to 38 months)

    Outcome Measure Data

    Analysis Population Description
    ITT population with participants in each disease stage.
    Arm/Group Title Enzalutamide 160 mg 1st Line AAT/Flutamide 375 mg 2nd Line AAT Flutamide 375 mg 1st Line AAT/Enzaltumide 160 mg 2nd Line AAT
    Arm/Group Description Participants received enzalutamide 160 mg capsules, orally once daily as 1st line of AAT until confirmed PSA progression, other disease progression, or an intolerable adverse event. After confirmed PSA progression, other disease progression, or an intolerable adverse event, participants received flutamide 125 mg tablets orally thrice daily after each meal as 2nd line of AAT. Treatment with each drug was continued until the participant met any of the discontinuation criteria or until 2 years from the enrollment of the last participant (approximately 38 months). Participants received flutamide 125 mg tablets orally thrice daily after each meal as 1st line of AAT until confirmed PSA progression, other disease progression, or an intolerable adverse event. After confirmed PSA progression, other disease progression, or an intolerable adverse event, participants received enzalutamide 160 mg capsules orally once daily as 2nd line of AAT. Treatment with each drug was continued until the participant met any of the discontinuation criteria or until 2 years from the enrollment of the last participant (approximately 38 months).
    Measure Participants 102 104
    M0/N0: (≥ 50% reduction)
    75.0
    73.5%
    48.0
    46.2%
    M0/N1: (≥ 50% reduction)
    66.7
    65.4%
    0.0
    0%
    M1: (≥ 50% reduction)
    72.0
    70.6%
    32.0
    30.8%
    All participants: (≥ 50% reduction)
    72.5
    71.1%
    34.6
    33.3%
    M0/N0: (≥ 90% reduction)
    62.5
    61.3%
    8.0
    7.7%
    M0/N1: (≥ 90% reduction)
    33.3
    32.6%
    0.0
    0%
    M1: (≥ 90% reduction)
    53.3
    52.3%
    20.0
    19.2%
    All participants: (≥ 90% reduction)
    54.9
    53.8%
    16.3
    15.7%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Enzalutamide 160 mg 1st Line AAT/Flutamide 375 mg 2nd Line AAT, Flutamide 375 mg 1st Line AAT/Enzaltumide 160 mg 2nd Line AAT
    Comments >=50% reduction
    Type of Statistical Test Superiority
    Comments The significance level was 0.05 (two-sided).
    Statistical Test of Hypothesis p-Value <0.001
    Comments P-value is based on Cochran-Mantel-Haenszel mean score test stratified disease stages (M0/N0, M0/N1, or M1).
    Method Mantel Haenszel
    Comments Mantel Haenszel common risk difference
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 37.8
    Confidence Interval (2-Sided) 95%
    25.2 to 50.4
    Parameter Dispersion Type:
    Value:
    Estimation Comments Difference of response rate.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Enzalutamide 160 mg 1st Line AAT/Flutamide 375 mg 2nd Line AAT, Flutamide 375 mg 1st Line AAT/Enzaltumide 160 mg 2nd Line AAT
    Comments ≥ 90% reduction
    Type of Statistical Test Superiority
    Comments The significance level was 0.05 (two-sided).
    Statistical Test of Hypothesis p-Value <0.001
    Comments P-value is based on Cochran-Mantel-Haenszel mean score test stratified disease stages (M0/N0, M0/N1, or M1).
    Method Mantel Haenszel
    Comments Mantel Haenszel common risk difference
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 38.4
    Confidence Interval (2-Sided) 95%
    26.3 to 50.4
    Parameter Dispersion Type:
    Value:
    Estimation Comments Difference of response rate
    4. Secondary Outcome
    Title Percentage of Participants Achieving at Least 50 or 90 Percent (%) Reduction From Baseline to Week 13 in Prostate Specific Antigen (PSA) Response at 1st Line AAT
    Description PSA response was defined as the lowest PSA at week 13 decreased by at least 50% or 90% from baseline in the 1st line AAT period. Data was reported per each disease stage (M0/N0, M0/N1, M1). 1) M0/N0: No distant metastasis and no lymph node metastasis. 2) M0/N1: Without distant metastasis, but with metastasis in lymph nodes distal to the aortic bifurcation. 3) M1: With distant metastasis (including metastasis in lymph nodes proximal to the aortic bifurcation).
    Time Frame Baseline and week 13

    Outcome Measure Data

    Analysis Population Description
    ITT population with participants in each disease stage.
    Arm/Group Title Enzalutamide 160 mg 1st Line AAT/Flutamide 375 mg 2nd Line AAT Flutamide 375 mg 1st Line AAT/Enzaltumide 160 mg 2nd Line AAT
    Arm/Group Description Participants received enzalutamide 160 mg capsules, orally once daily as 1st line of AAT until confirmed PSA progression, other disease progression, or an intolerable adverse event. After confirmed PSA progression, other disease progression, or an intolerable adverse event, participants received flutamide 125 mg tablets orally thrice daily after each meal as 2nd line of AAT. Treatment with each drug was continued until the participant met any of the discontinuation criteria or until 2 years from the enrollment of the last participant (approximately 38 months). Participants received flutamide 125 mg tablets orally thrice daily after each meal as 1st line of AAT until confirmed PSA progression, other disease progression, or an intolerable adverse event. After confirmed PSA progression, other disease progression, or an intolerable adverse event, participants received enzalutamide 160 mg capsules orally once daily as 2nd line of AAT. Treatment with each drug was continued until the participant met any of the discontinuation criteria or until 2 years from the enrollment of the last participant (approximately 38 months).
    Measure Participants 102 104
    M0/N0: (≥ 50% reduction)
    83.3
    81.7%
    40.0
    38.5%
    M0/N1: (≥ 50% reduction)
    66.7
    65.4%
    0.0
    0%
    M1: (≥ 50% reduction)
    72.0
    70.6%
    33.3
    32%
    All participants: (≥ 50% reduction)
    74.5
    73%
    33.7
    32.4%
    M0/N0: (≥ 90% reduction)
    50.0
    49%
    8.0
    7.7%
    M0/N1: (≥ 90% reduction)
    33.3
    32.6%
    0.0
    0%
    M1: (≥ 90% reduction)
    49.3
    48.3%
    18.7
    18%
    All participants: (≥ 90% reduction)
    49.0
    48%
    15.4
    14.8%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Enzalutamide 160 mg 1st Line AAT/Flutamide 375 mg 2nd Line AAT, Flutamide 375 mg 1st Line AAT/Enzaltumide 160 mg 2nd Line AAT
    Comments ≥ 50% reduction
    Type of Statistical Test Superiority
    Comments The significance level was 0.05 (two-sided).
    Statistical Test of Hypothesis p-Value <0.001
    Comments P-value is based on Cochran-Mantel-Haenszel mean score test stratified disease stages (M0/N0, M0/N1, or M1).
    Method Mantel Haenszel
    Comments Mantel Haenszel common risk difference
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 40.7
    Confidence Interval (2-Sided) 95%
    28.3 to 53.1
    Parameter Dispersion Type:
    Value:
    Estimation Comments Difference of response rate.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Enzalutamide 160 mg 1st Line AAT/Flutamide 375 mg 2nd Line AAT, Flutamide 375 mg 1st Line AAT/Enzaltumide 160 mg 2nd Line AAT
    Comments ≥90% reduction
    Type of Statistical Test Superiority
    Comments The significance level was 0.05 (two-sided).
    Statistical Test of Hypothesis p-Value <0.001
    Comments P-value is based on Cochran-Mantel-Haenszel mean score test stratified disease stages (M0/N0, M0/N1, or M1).
    Method Mantel Haenszel
    Comments Mantel Haenszel common risk difference
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 33.5
    Confidence Interval (2-Sided) 95%
    21.5 to 45.4
    Parameter Dispersion Type:
    Value:
    Estimation Comments Difference of response rate
    5. Secondary Outcome
    Title Time to PSA Decrease by 50% From Baseline With 1st Line AAT
    Description Time to PSA decrease by 50% with 1st line AAT was defined as the period from the date of randomization to the day when the decrease of PSA from baseline by 50% is first identified. Time to event analysis was performed using kaplan-meier estimates. Data was reported per each disease stage (M0/N0, M0/N1, M1). 1) M0/N0: No distant metastasis and no lymph node metastasis. 2) M0/N1: Without distant metastasis, but with metastasis in lymph nodes distal to the aortic bifurcation. 3) M1: With distant metastasis (including metastasis in lymph nodes proximal to the aortic bifurcation).
    Time Frame From date of randomization to the day when the decrease of PSA from baseline by 50% is first identified (Up to 38 months)

    Outcome Measure Data

    Analysis Population Description
    ITT population with participants in each disease stage.
    Arm/Group Title Enzalutamide 160 mg 1st Line AAT/Flutamide 375 mg 2nd Line AAT Flutamide 375 mg 1st Line AAT/Enzaltumide 160 mg 2nd Line AAT
    Arm/Group Description Participants received enzalutamide 160 mg capsules, orally once daily as 1st line of AAT until confirmed PSA progression, other disease progression, or an intolerable adverse event. After confirmed PSA progression, other disease progression, or an intolerable adverse event, participants received flutamide 125 mg tablets orally thrice daily after each meal as 2nd line of AAT. Treatment with each drug was continued until the participant met any of the discontinuation criteria or until 2 years from the enrollment of the last participant (approximately 38 months). Participants received flutamide 125 mg tablets orally thrice daily after each meal as 1st line of AAT until confirmed PSA progression, other disease progression, or an intolerable adverse event. After confirmed PSA progression, other disease progression, or an intolerable adverse event, participants received enzalutamide 160 mg capsules orally once daily as 2nd line of AAT. Treatment with each drug was continued until the participant met any of the discontinuation criteria or until 2 years from the enrollment of the last participant (approximately 38 months).
    Measure Participants 102 104
    M0/N0
    2.79
    3.94
    M0/N1
    2.79
    NA
    M1
    2.79
    7.49
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Enzalutamide 160 mg 1st Line AAT/Flutamide 375 mg 2nd Line AAT, Flutamide 375 mg 1st Line AAT/Enzaltumide 160 mg 2nd Line AAT
    Comments
    Type of Statistical Test Superiority
    Comments The significance level was 0.05 (two-sided).
    Statistical Test of Hypothesis p-Value <0.001
    Comments P-value is based on a log-rank test stratified disease stages (M0/N0, M0/N1, or M1).
    Method Log Rank
    Comments
    6. Secondary Outcome
    Title Time to Treatment Failure of 1st Line AAT (TTF1)
    Description TTF1 was defined as the period from randomization to study drug discontinuation of 1st line AAT for any reason that includes disease progression, onset of adverse events (AEs), participants request, or death. Time to event analysis was performed using kaplan-meier estimates. Data was reported per each disease stage (M0/N0, M0/N1, M1). 1) M0/N0: No distant metastasis and no lymph node metastasis. 2) M0/N1: Without distant metastasis, but with metastasis in lymph nodes distal to the aortic bifurcation. 3) M1: With distant metastasis (including metastasis in lymph nodes proximal to the aortic bifurcation).
    Time Frame From date of randomization to discontinuation of 1st line AAT (Up to 38 months)

    Outcome Measure Data

    Analysis Population Description
    ITT population with participants in each disease stage.
    Arm/Group Title Enzalutamide 160 mg 1st Line AAT/Flutamide 375 mg 2nd Line AAT Flutamide 375 mg 1st Line AAT/Enzaltumide 160 mg 2nd Line AAT
    Arm/Group Description Participants received enzalutamide 160 mg capsules, orally once daily as 1st line of AAT until confirmed PSA progression, other disease progression, or an intolerable adverse event. After confirmed PSA progression, other disease progression, or an intolerable adverse event, participants received flutamide 125 mg tablets orally thrice daily after each meal as 2nd line of AAT. Treatment with each drug was continued until the participant met any of the discontinuation criteria or until 2 years from the enrollment of the last participant (approximately 38 months). Participants received flutamide 125 mg tablets orally thrice daily after each meal as 1st line of AAT until confirmed PSA progression, other disease progression, or an intolerable adverse event. After confirmed PSA progression, other disease progression, or an intolerable adverse event, participants received enzalutamide 160 mg capsules orally once daily as 2nd line of AAT. Treatment with each drug was continued until the participant met any of the discontinuation criteria or until 2 years from the enrollment of the last participant (approximately 38 months).
    Measure Participants 102 104
    M0/N0
    17.58
    7.72
    M0/N1
    5.55
    4.73
    M1
    12.02
    3.94
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Enzalutamide 160 mg 1st Line AAT/Flutamide 375 mg 2nd Line AAT, Flutamide 375 mg 1st Line AAT/Enzaltumide 160 mg 2nd Line AAT
    Comments
    Type of Statistical Test Superiority
    Comments The significance level was 0.05 (two-sided).
    Statistical Test of Hypothesis p-Value <0.001
    Comments P-value is based on a log-rank test stratified disease stages (M0/N0, M0/N1, or M1).
    Method Log Rank
    Comments
    7. Secondary Outcome
    Title Time to Treatment Failure of 2nd Line AAT (TTF2)
    Description TTF2 was defined as the period from randomization to study drug discontinuation of 2nd line AAT for any reason that includes disease progression, onset of AEs, participants request, or death. Time to event analysis was performed using kaplan-meier estimates.
    Time Frame From date of randomization to discontinuation of 2nd line AAT (Up to 38 months)

    Outcome Measure Data

    Analysis Population Description
    ITT population
    Arm/Group Title Enzalutamide 160 mg 1st Line AAT/Flutamide 375 mg 2nd Line AAT Flutamide 375 mg 1st Line AAT/Enzaltumide 160 mg 2nd Line AAT
    Arm/Group Description Participants received enzalutamide 160 mg capsules, orally once daily as 1st line of AAT until confirmed PSA progression, other disease progression, or an intolerable adverse event. After confirmed PSA progression, other disease progression, or an intolerable adverse event, participants received flutamide 125 mg tablets orally thrice daily after each meal as 2nd line of AAT. Treatment with each drug was continued until the participant met any of the discontinuation criteria or until 2 years from the enrollment of the last participant (approximately 38 months). Participants received flutamide 125 mg tablets orally thrice daily after each meal as 1st line of AAT until confirmed PSA progression, other disease progression, or an intolerable adverse event. After confirmed PSA progression, other disease progression, or an intolerable adverse event, participants received enzalutamide 160 mg capsules orally once daily as 2nd line of AAT. Treatment with each drug was continued until the participant met any of the discontinuation criteria or until 2 years from the enrollment of the last participant (approximately 38 months).
    Measure Participants 102 104
    Median (95% Confidence Interval) [Months]
    23.03
    16.59
    8. Secondary Outcome
    Title Radiographic Progression-free Survival (rPFS)
    Description rPFS was defined as the period from randomization to the time when radiographic disease progression is observed or death of any cause during the study period, whichever occurs earlier. Time to event analysis was performed using kaplan-meier estimates. Data was reported per each disease stage (M0/N0, M0/N1, M1). 1) M0/N0: No distant metastasis and no lymph node metastasis. 2) M0/N1: Without distant metastasis, but with metastasis in lymph nodes distal to the aortic bifurcation. 3) M1: With distant metastasis (including metastasis in lymph nodes proximal to the aortic bifurcation).
    Time Frame From date of randomization to the time when radiographic disease progression is observed or death of any cause (up to 38 months)

    Outcome Measure Data

    Analysis Population Description
    ITT population with M1 diseases stage participants. No data reported for M0/N0 and M0/N1 as there are zero participants with event.
    Arm/Group Title Enzalutamide 160 mg 1st Line AAT/Flutamide 375 mg 2nd Line AAT Flutamide 375 mg 1st Line AAT/Enzaltumide 160 mg 2nd Line AAT
    Arm/Group Description Participants received enzalutamide 160 mg capsules, orally once daily as 1st line of AAT until confirmed PSA progression, other disease progression, or an intolerable adverse event. After confirmed PSA progression, other disease progression, or an intolerable adverse event, participants received flutamide 125 mg tablets orally thrice daily after each meal as 2nd line of AAT. Treatment with each drug was continued until the participant met any of the discontinuation criteria or until 2 years from the enrollment of the last participant (approximately 38 months). Participants received flutamide 125 mg tablets orally thrice daily after each meal as 1st line of AAT until confirmed PSA progression, other disease progression, or an intolerable adverse event. After confirmed PSA progression, other disease progression, or an intolerable adverse event, participants received enzalutamide 160 mg capsules orally once daily as 2nd line of AAT. Treatment with each drug was continued until the participant met any of the discontinuation criteria or until 2 years from the enrollment of the last participant (approximately 38 months).
    Measure Participants 75 104
    M1
    NA
    NA
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Enzalutamide 160 mg 1st Line AAT/Flutamide 375 mg 2nd Line AAT, Flutamide 375 mg 1st Line AAT/Enzaltumide 160 mg 2nd Line AAT
    Comments
    Type of Statistical Test Superiority
    Comments The significance level was 0.05 (two-sided).
    Statistical Test of Hypothesis p-Value 0.669
    Comments P-value is based on a log-rank test stratified disease stages (M0/N0, M0/N1, or M1)
    Method Log Rank
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.87
    Confidence Interval (2-Sided) 95%
    0.45 to 1.67
    Parameter Dispersion Type:
    Value:
    Estimation Comments Hazard ratio and P-value calculated using unstratified Cox proportional hazards model with treatment and disease stages (M0/N0, M0/N1, or M1) as covariate.

    Adverse Events

    Time Frame From of date of randomization to end of study (up to 38 months)
    Adverse Event Reporting Description
    Arm/Group Title Enzalutamide 160mg 1st Line AAT Enzalutamide 160mg 2nd Line AAT Flutamide 375mg 1st Line AAT Flutamide 375mg 2nd Line AAT
    Arm/Group Description Participants received enzalutamide 160mg capsules orally once daily as 1st line of AAT until confirmed PSA progression, other disease progression, or an intolerable adverse event (approximately 38 months). Participants received enzalutamide 160mg capsules orally once daily as 2nd line of AAT after confirmed PSA progression, other disease progression, or an intolerable adverse event (approximately 38 months). Participants received flutamide 125mg tablets orally thrice daily after each meal as 1st line of AAT until confirmed PSA progression, other disease progression, or an intolerable adverse event (approximately 38 months). Participants received flutamide 125mg tablets orally thrice daily as 2nd line of AAT after confirmed PSA progression, other disease progression, or an intolerable adverse event (approximately 38 months).
    All Cause Mortality
    Enzalutamide 160mg 1st Line AAT Enzalutamide 160mg 2nd Line AAT Flutamide 375mg 1st Line AAT Flutamide 375mg 2nd Line AAT
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 1/102 (1%) 1/85 (1.2%) 0/104 (0%) 0/48 (0%)
    Serious Adverse Events
    Enzalutamide 160mg 1st Line AAT Enzalutamide 160mg 2nd Line AAT Flutamide 375mg 1st Line AAT Flutamide 375mg 2nd Line AAT
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 29/102 (28.4%) 18/85 (21.2%) 15/104 (14.4%) 4/48 (8.3%)
    Blood and lymphatic system disorders
    Anaemia 1/102 (1%) 1 0/85 (0%) 0 0/104 (0%) 0 0/48 (0%) 0
    Pancytopenia 1/102 (1%) 1 0/85 (0%) 0 0/104 (0%) 0 0/48 (0%) 0
    Cardiac disorders
    Acute myocardial infarction 1/102 (1%) 1 1/85 (1.2%) 1 0/104 (0%) 0 0/48 (0%) 0
    Angina pectoris 1/102 (1%) 1 1/85 (1.2%) 1 1/104 (1%) 1 0/48 (0%) 0
    Atrial fibrillation 0/102 (0%) 0 0/85 (0%) 0 1/104 (1%) 1 0/48 (0%) 0
    Cardiac failure 0/102 (0%) 0 0/85 (0%) 0 0/104 (0%) 0 1/48 (2.1%) 1
    Cardiac failure acute 1/102 (1%) 1 0/85 (0%) 0 0/104 (0%) 0 0/48 (0%) 0
    Coronary artery stenosis 1/102 (1%) 1 0/85 (0%) 0 0/104 (0%) 0 0/48 (0%) 0
    Eye disorders
    Cataract 1/102 (1%) 2 1/85 (1.2%) 1 0/104 (0%) 0 0/48 (0%) 0
    Gastrointestinal disorders
    Abdominal discomfort 0/102 (0%) 0 0/85 (0%) 0 1/104 (1%) 1 0/48 (0%) 0
    Diverticulum intestinal 0/102 (0%) 0 0/85 (0%) 0 1/104 (1%) 1 0/48 (0%) 0
    Gastric ulcer haemorrhage 0/102 (0%) 0 0/85 (0%) 0 1/104 (1%) 1 0/48 (0%) 0
    Ileus paralytic 0/102 (0%) 0 0/85 (0%) 0 0/104 (0%) 0 1/48 (2.1%) 1
    Inguinal hernia 1/102 (1%) 1 0/85 (0%) 0 0/104 (0%) 0 0/48 (0%) 0
    Large intestine polyp 0/102 (0%) 0 2/85 (2.4%) 2 0/104 (0%) 0 0/48 (0%) 0
    General disorders
    Pyrexia 1/102 (1%) 1 0/85 (0%) 0 0/104 (0%) 0 0/48 (0%) 0
    Hepatobiliary disorders
    Hepatic function abnormal 1/102 (1%) 1 2/85 (2.4%) 2 1/104 (1%) 1 0/48 (0%) 0
    Liver disorder 1/102 (1%) 1 0/85 (0%) 0 0/104 (0%) 0 0/48 (0%) 0
    Infections and infestations
    Appendicitis 0/102 (0%) 0 1/85 (1.2%) 1 0/104 (0%) 0 0/48 (0%) 0
    Enterocolitis bacterial 0/102 (0%) 0 0/85 (0%) 0 1/104 (1%) 1 0/48 (0%) 0
    Periodontitis 1/102 (1%) 1 0/85 (0%) 0 1/104 (1%) 2 0/48 (0%) 0
    Pneumonia 0/102 (0%) 0 0/85 (0%) 0 2/104 (1.9%) 2 0/48 (0%) 0
    Pneumonia bacterial 0/102 (0%) 0 0/85 (0%) 0 1/104 (1%) 1 0/48 (0%) 0
    Pneumonia pneumococcal 1/102 (1%) 1 0/85 (0%) 0 0/104 (0%) 0 0/48 (0%) 0
    Urinary tract infection 0/102 (0%) 0 0/85 (0%) 0 1/104 (1%) 1 0/48 (0%) 0
    Injury, poisoning and procedural complications
    Brain contusion 1/102 (1%) 1 0/85 (0%) 0 0/104 (0%) 0 0/48 (0%) 0
    Compression fracture 1/102 (1%) 1 0/85 (0%) 0 0/104 (0%) 0 0/48 (0%) 0
    Fall 1/102 (1%) 3 0/85 (0%) 0 1/104 (1%) 1 0/48 (0%) 0
    Femur fracture 1/102 (1%) 1 0/85 (0%) 0 0/104 (0%) 0 0/48 (0%) 0
    Fracture 0/102 (0%) 0 1/85 (1.2%) 1 0/104 (0%) 0 0/48 (0%) 0
    Gastroenteritis radiation 0/102 (0%) 0 1/85 (1.2%) 1 0/104 (0%) 0 0/48 (0%) 0
    Heat illness 1/102 (1%) 1 0/85 (0%) 0 0/104 (0%) 0 0/48 (0%) 0
    Radius fracture 1/102 (1%) 2 0/85 (0%) 0 1/104 (1%) 1 0/48 (0%) 0
    Spinal compression fracture 2/102 (2%) 2 1/85 (1.2%) 1 0/104 (0%) 0 0/48 (0%) 0
    Subdural haematoma 1/102 (1%) 1 0/85 (0%) 0 0/104 (0%) 0 0/48 (0%) 0
    Tibia fracture 1/102 (1%) 1 0/85 (0%) 0 0/104 (0%) 0 0/48 (0%) 0
    Investigations
    Alanine aminotransferase increased 1/102 (1%) 1 0/85 (0%) 0 0/104 (0%) 0 0/48 (0%) 0
    Aspartate aminotransferase increased 1/102 (1%) 1 0/85 (0%) 0 0/104 (0%) 0 0/48 (0%) 0
    Eastern Cooperative Oncology Group performance status worsened 0/102 (0%) 0 1/85 (1.2%) 1 0/104 (0%) 0 0/48 (0%) 0
    Platelet count decreased 0/102 (0%) 0 1/85 (1.2%) 1 0/104 (0%) 0 0/48 (0%) 0
    Musculoskeletal and connective tissue disorders
    Muscular weakness 1/102 (1%) 1 0/85 (0%) 0 0/104 (0%) 0 0/48 (0%) 0
    Neck pain 0/102 (0%) 0 0/85 (0%) 0 1/104 (1%) 1 0/48 (0%) 0
    Osteoarthritis 1/102 (1%) 1 0/85 (0%) 0 0/104 (0%) 0 0/48 (0%) 0
    Rhabdomyolysis 1/102 (1%) 1 0/85 (0%) 0 0/104 (0%) 0 0/48 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenoma benign 0/102 (0%) 0 1/85 (1.2%) 1 0/104 (0%) 0 0/48 (0%) 0
    Benign duodenal neoplasm 0/102 (0%) 0 1/85 (1.2%) 1 0/104 (0%) 0 0/48 (0%) 0
    Cancer pain 1/102 (1%) 1 2/85 (2.4%) 2 0/104 (0%) 0 0/48 (0%) 0
    Colon cancer 1/102 (1%) 1 1/85 (1.2%) 1 0/104 (0%) 0 0/48 (0%) 0
    Gastric cancer 0/102 (0%) 0 0/85 (0%) 0 1/104 (1%) 1 0/48 (0%) 0
    Lung neoplasm malignant 0/102 (0%) 0 2/85 (2.4%) 2 0/104 (0%) 0 0/48 (0%) 0
    Malignant neoplasm papilla of Vater 1/102 (1%) 1 0/85 (0%) 0 0/104 (0%) 0 0/48 (0%) 0
    Pancreatic carcinoma 1/102 (1%) 1 0/85 (0%) 0 0/104 (0%) 0 0/48 (0%) 0
    Prostate cancer 1/102 (1%) 1 0/85 (0%) 0 0/104 (0%) 0 0/48 (0%) 0
    Nervous system disorders
    Altered state of consciousness 1/102 (1%) 1 0/85 (0%) 0 0/104 (0%) 0 0/48 (0%) 0
    Carotid artery stenosis 1/102 (1%) 1 0/85 (0%) 0 0/104 (0%) 0 0/48 (0%) 0
    Cerebellar haemorrhage 0/102 (0%) 0 1/85 (1.2%) 1 0/104 (0%) 0 0/48 (0%) 0
    Cerebral haematoma 1/102 (1%) 1 0/85 (0%) 0 0/104 (0%) 0 0/48 (0%) 0
    Cerebral infarction 3/102 (2.9%) 3 0/85 (0%) 0 1/104 (1%) 1 0/48 (0%) 0
    Embolic stroke 1/102 (1%) 1 0/85 (0%) 0 1/104 (1%) 1 0/48 (0%) 0
    Loss of consciousness 1/102 (1%) 1 0/85 (0%) 0 0/104 (0%) 0 1/48 (2.1%) 1
    Monoplegia 0/102 (0%) 0 0/85 (0%) 0 1/104 (1%) 1 0/48 (0%) 0
    Nervous system disorder 1/102 (1%) 1 0/85 (0%) 0 0/104 (0%) 0 0/48 (0%) 0
    Subarachnoid haemorrhage 1/102 (1%) 1 0/85 (0%) 0 1/104 (1%) 1 0/48 (0%) 0
    Psychiatric disorders
    Delirium 0/102 (0%) 0 1/85 (1.2%) 1 0/104 (0%) 0 1/48 (2.1%) 1
    Mental fatigue 0/102 (0%) 0 0/85 (0%) 0 1/104 (1%) 1 0/48 (0%) 0
    Renal and urinary disorders
    Acute kidney injury 1/102 (1%) 1 0/85 (0%) 0 0/104 (0%) 0 1/48 (2.1%) 1
    Chronic kidney disease 1/102 (1%) 1 0/85 (0%) 0 0/104 (0%) 0 0/48 (0%) 0
    Nephrolithiasis 1/102 (1%) 1 0/85 (0%) 0 0/104 (0%) 0 0/48 (0%) 0
    Postrenal failure 1/102 (1%) 1 0/85 (0%) 0 0/104 (0%) 0 0/48 (0%) 0
    Urinary bladder haemorrhage 0/102 (0%) 0 1/85 (1.2%) 1 0/104 (0%) 0 0/48 (0%) 0
    Urinary retention 0/102 (0%) 0 1/85 (1.2%) 1 0/104 (0%) 0 1/48 (2.1%) 1
    Respiratory, thoracic and mediastinal disorders
    Hypoxia 0/102 (0%) 0 1/85 (1.2%) 1 0/104 (0%) 0 0/48 (0%) 0
    Pneumonia aspiration 1/102 (1%) 1 0/85 (0%) 0 0/104 (0%) 0 0/48 (0%) 0
    Respiratory failure 0/102 (0%) 0 0/85 (0%) 0 0/104 (0%) 0 1/48 (2.1%) 1
    Surgical and medical procedures
    Aortic stent insertion 1/102 (1%) 1 0/85 (0%) 0 0/104 (0%) 0 0/48 (0%) 0
    Cataract operation 0/102 (0%) 0 1/85 (1.2%) 1 1/104 (1%) 1 0/48 (0%) 0
    Inguinal hernia repair 1/102 (1%) 1 0/85 (0%) 0 0/104 (0%) 0 0/48 (0%) 0
    Large intestinal polypectomy 0/102 (0%) 0 0/85 (0%) 0 1/104 (1%) 1 0/48 (0%) 0
    Ureteric calculus removal 0/102 (0%) 0 0/85 (0%) 0 0/104 (0%) 0 1/48 (2.1%) 2
    Vascular disorders
    Aortic aneurysm 0/102 (0%) 0 1/85 (1.2%) 1 0/104 (0%) 0 0/48 (0%) 0
    Aortic dissection 0/102 (0%) 0 1/85 (1.2%) 1 0/104 (0%) 0 0/48 (0%) 0
    Other (Not Including Serious) Adverse Events
    Enzalutamide 160mg 1st Line AAT Enzalutamide 160mg 2nd Line AAT Flutamide 375mg 1st Line AAT Flutamide 375mg 2nd Line AAT
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 79/102 (77.5%) 56/85 (65.9%) 65/104 (62.5%) 22/48 (45.8%)
    Blood and lymphatic system disorders
    Anaemia 3/102 (2.9%) 3 1/85 (1.2%) 1 2/104 (1.9%) 2 4/48 (8.3%) 4
    Gastrointestinal disorders
    Constipation 14/102 (13.7%) 16 2/85 (2.4%) 2 3/104 (2.9%) 3 0/48 (0%) 0
    Dental caries 1/102 (1%) 1 5/85 (5.9%) 5 7/104 (6.7%) 7 1/48 (2.1%) 1
    Diarrhoea 7/102 (6.9%) 7 2/85 (2.4%) 3 12/104 (11.5%) 14 6/48 (12.5%) 6
    Nausea 7/102 (6.9%) 8 6/85 (7.1%) 7 5/104 (4.8%) 5 2/48 (4.2%) 2
    General disorders
    Fatigue 15/102 (14.7%) 17 8/85 (9.4%) 10 3/104 (2.9%) 3 0/48 (0%) 0
    Malaise 15/102 (14.7%) 16 17/85 (20%) 19 4/104 (3.8%) 4 2/48 (4.2%) 2
    Hepatobiliary disorders
    Hepatic function abnormal 2/102 (2%) 2 2/85 (2.4%) 2 9/104 (8.7%) 10 2/48 (4.2%) 2
    Infections and infestations
    Influenza 7/102 (6.9%) 7 1/85 (1.2%) 1 2/104 (1.9%) 2 0/48 (0%) 0
    Nasopharyngitis 23/102 (22.5%) 36 12/85 (14.1%) 17 17/104 (16.3%) 33 2/48 (4.2%) 2
    Injury, poisoning and procedural complications
    Fall 18/102 (17.6%) 21 10/85 (11.8%) 10 4/104 (3.8%) 4 1/48 (2.1%) 1
    Spinal compression fracture 6/102 (5.9%) 6 1/85 (1.2%) 1 0/104 (0%) 0 1/48 (2.1%) 1
    Investigations
    Alanine aminotransferase increased 1/102 (1%) 1 0/85 (0%) 0 7/104 (6.7%) 8 1/48 (2.1%) 1
    Aspartate aminotransferase increased 1/102 (1%) 1 0/85 (0%) 0 6/104 (5.8%) 7 2/48 (4.2%) 2
    Metabolism and nutrition disorders
    Decreased appetite 11/102 (10.8%) 11 8/85 (9.4%) 9 4/104 (3.8%) 5 2/48 (4.2%) 2
    Musculoskeletal and connective tissue disorders
    Back pain 15/102 (14.7%) 16 4/85 (4.7%) 4 6/104 (5.8%) 6 1/48 (2.1%) 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain 5/102 (4.9%) 5 4/85 (4.7%) 4 4/104 (3.8%) 4 4/48 (8.3%) 4
    Nervous system disorders
    Dizziness 6/102 (5.9%) 6 5/85 (5.9%) 5 3/104 (2.9%) 3 0/48 (0%) 0
    Renal and urinary disorders
    Haematuria 6/102 (5.9%) 6 2/85 (2.4%) 2 2/104 (1.9%) 2 0/48 (0%) 0
    Vascular disorders
    Hot flush 4/102 (3.9%) 4 1/85 (1.2%) 1 6/104 (5.8%) 6 0/48 (0%) 0
    Hypertension 13/102 (12.7%) 15 5/85 (5.9%) 6 2/104 (1.9%) 2 0/48 (0%) 0

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

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

    Institute and/or Principal Investigator may publish trial data generated at their specific study site after Sponsor publication of the multi-center data. Sponsor must receive a site's manuscript prior to publication for review and comment as specified in the Investigator Agreement.

    Results Point of Contact

    Name/Title Clinical Trial Disclosure
    Organization Astellas Pharma Inc.
    Phone +81 3-3244-6500 Japanese only
    Email astellas.resultsdisclosure@astellas.com
    Responsible Party:
    Astellas Pharma Inc
    ClinicalTrials.gov Identifier:
    NCT02918968
    Other Study ID Numbers:
    • 9785-MA-3051
    First Posted:
    Sep 29, 2016
    Last Update Posted:
    May 21, 2021
    Last Verified:
    May 1, 2021