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PRESIDE: A Study to Assess the Benefit of Treatment Beyond Progression With Enzalutamide in Men Who Are Starting Treatment With Docetaxel After Worsening of Their Prostate Cancer When Taking Enzalutamide Alone

Sponsor
Astellas Pharma Europe Ltd. (Industry)
Overall Status
Active, not recruiting
CT.gov ID
NCT02288247
Collaborator
Medivation LLC, a wholly owned subsidiary of Pfizer Inc. (Industry)
688
Enrollment
89
Locations
2
Arms
94
Anticipated Duration (Months)
7.7
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of the study was to understand if there was benefit in continued treatment with a medicine called enzalutamide, when starting treatment with docetaxel and prednisolone (a standard chemotherapy for prostate cancer), after the prostate cancer had gotten worse when treated with enzalutamide alone.

Condition or Disease Intervention/Treatment Phase
Phase 3

Detailed Description

The study was conducted in consecutive periods of open label treatment with enzalutamide followed by randomized double-blind treatment with continued enzalutamide or placebo, in combination with docetaxel and prednisolone.

Open Label (Period 1)

Participants received open label treatment (OL) with enzalutamide. At week 13, all participants were assessed by prostate-specific antigen (PSA) and imaging. Participants with no confirmed PSA response or evidence of radiographic progression were ineligible for participation in Period 2 and typically had safety follow up; however, Period 1 treatment continued for some participants as long as the investigator considered it to be of clinical benefit (stopping on initiation of any new antineoplastic therapy). Participants with confirmed PSA response continued Period 1 until disease progression.

Enrollment to Period 2 ceased after approximately 274 participants had been enrolled or 182 primary endpoint events had been reached, whichever occurred first. Participants who were not randomized into period 2 at this time continued to receive open label treatment in an extension period.

Randomization (Double Blind [DB]) (Period 2)

Participants with confirmed disease progression on enzalutamide alone who continued to meet all eligibility criteria proceeded to randomization. Treatment allocation was in a 1:1 ratio, stratified by disease progression in Period 1 to the following treatments:

  • Enzalutamide with docetaxel and prednisolone

  • Placebo with docetaxel and prednisolone

Any ongoing participants in Period 2 at the point of unblinding in the enzalutamide+docetaxel arm that were still receiving and benefitting from enzalutamide treatment, had the option to continue treatment via an extension period.

Study Design

Study Type:
Interventional
Actual Enrollment :
688 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
A Randomized, Double Blind, Placebo-Controlled, Phase IIIb Study of the Efficacy and Safety of Continuing Enzalutamide in Chemotherapy Naïve Metastatic Castration Resistant Prostate Cancer Patients Treated With Docetaxel Plus Prednisolone Who Have Progressed on Enzalutamide Alone
Actual Study Start Date :
Dec 1, 2014
Actual Primary Completion Date :
Apr 30, 2020
Anticipated Study Completion Date :
Sep 30, 2022

Arms and Interventions

Arm Intervention/Treatment
Experimental: Enzalutamide

Participants received an OL treatment with enzalutamide 160 milligrams (mg) capsules, orally once daily from day 1 in period 1 until randomization to period 2, confirmation of ineligibility for period 2, intolerable toxicity, withdrawal, or death. Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received enzalutamide 160 mg capsules, orally once daily in combination with docetaxel 75 milligrams per square meter (mg/m^2) in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, DB period 2. Docetaxel and prednisolone were administered up to 10 cycles (3 weeks/cycle) or more as assessed by the investigator. Enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death. Participants could continue the extension period, until investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death.

Drug: Enzalutamide
Oral
Other Names:
  • Xtandi
  • ASP9785

    • Drug: Docetaxel
    intravenous infusion

    Drug: Prednisolone
    Oral
    Placebo Comparator: Placebo

    Participants received an OL treatment with enzalutamide 160 mg capsules, orally once daily from day 1 in period 1 until randomization to period 2, confirmation of ineligibility for period 2, intolerable toxicity, withdrawal, or death. Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received placebo matched to enzalutamide, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, in period 2. Docetaxel and prednisolone were administered up to 10 cycles (3 weeks/cyle) or more as assessed by the investigator. Enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death. Participants could continue the extension period, until investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death.

    Drug: Docetaxel
    intravenous infusion

    Drug: Prednisolone
    Oral

    Drug: Placebo
    Oral

    Outcome Measures

    Primary Outcome Measures

    1. Progression Free Survival (PFS) [From date of randomization to the earliest of either documented disease progression (median duration: 35 weeks)]

      PFS: time from randomization (Period 2 Week 1) to earliest progression event. Progression is defined as radiographic progression, unequivocal clinical progression, or death on study. Radiographic progression is defined for bone disease by appearance of ≥ 2 new lesions on whole-body radionuclide bone scan per Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria (i.e., unconfirmed progressive disease) that needs to be confirmed in the next assessment (i.e., progressive disease in the next assessment) or for soft tissue disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Unequivocal clinical progression is defined as new onset cancer pain requiring chronic administration of opiate analgesia or deterioration from prostate cancer of Eastern Cooperative Oncology Group (ECOG) performance status score to ≥ 3, or initiation of subsequent lines of cytotoxic chemotherapy or radiation therapy or surgical intervention due to complications of tumor progression.

    Secondary Outcome Measures

    1. Time to Prostate-specific Antigen (PSA) Progression [From date of randomization to the first PSA value (median duration: 35 weeks)]

      Time to PSA progression, defined as the time from randomization (Period 2 Week 1) to the date of the first PSA value in Period 2 demonstrating progression (Period 2). The PSA progression date is defined as the date that a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL above the nadir recorded in Period 2 is documented, which must be confirmed by a second consecutive value obtained at least 3 weeks later.

    2. Prostate-specific Antigen (PSA) Response [Randomization, Week 13, any time after randomization in Period 2 (median of 35 weeks)]

      PSA response, defined as a decrease in percentage change from randomization (Period 2 Week 1) of 50% or more. PSA response was derived at Week 13 and at any time after randomization in Period 2. PSA response at any time is defined as a decrease in percentage change from randomization (Period 2 Week 1) at any time after randomization of 50% or more. Percentage of participants with PSA response was reported.

    3. Objective Response Rate (ORR) [From date of randomization up to median duration of 35 weeks]

      ORR, defined as the best overall radiographic response after randomization (Period 2 Week 1) as per Investigator assessments of response for soft tissue disease per RECIST 1.1, in participants who had a measurable tumor. ORR was reported as the percentage of participants with complete response (CR) or partial response (PR). CR was defined as disappearance of all target and nontarget lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to < 10 mm from baseline measurement. PR was defined as at least a 30% decrease in the sum of diameters (longest for nonnodal lesions, short axis for nodal lesions) of target lesions taking as reference to the baseline sum of diameters.

    4. Time to Pain Progression [From date of randomization up to median duration of 35 weeks]

      The time to an increase of >=30% from randomization (Period 2 Week 1) in average BPI-SF item scores (items 3, 4, 5, 6) at two consecutive evaluations >=3 weeks apart without decrease in analgesic score according to the World health Organization (WHO). Only participants with an average pain intensity item score >=4 were considered. The BPI-SF was an instrument to document pain-related functional impairment and contains 7 questions which included pain intensity [(items 3, 4, 5 and 6): worst pain, least pain, average pain and current pain, with scales from 0 (no pain) to 10 (pain as bad as you can imagine)] and pain interference ](items 9A to 9G): general activity, mood, walking ability, normal work, relations with other people, sleep and enjoyment of life, with scales from 0 (does not interfere) to 10 (completely interferes)]. The BPI-SF total score for pain intensity was calculated as the mean of the 4 scores for the 4 items of pain intensity.

    5. Time to Opiate Use for Cancer-related Pain [From date of randomization up to median duration of 35 weeks]

      Time to opiate use for cancer-related pain, defined as the time from randomization (Period 2 Week 1) to initiation of chronic administration of opiate analgesia [parenteral opiate use for ≥7 days or use of WHO Analgesic Ladder Level 3 oral opiates for ≥3 weeks].

    6. Time to First Skeletal-related Event (SRE) [From date of randomization up to median duration of 35 weeks]

      Time to first SRE, defined as the time from randomization (Period 2 Week 1) to radiation therapy or surgery to bone, pathologic bone fracture, spinal cord compression, or change of antineoplastic therapy to treat bone pain.

    7. Change From Baseline in Functional Assessment of Cancer Therapy - Prostate (FACT-P) [Period 2: Baseline, weeks 1, 13, 25, 37, 49, 61, 73, 85, 97, 109, 121, 133, 145, 157, 169, 181]

      FACT-P quality of life questionnaire is a multi-dimensional, self-reported quality of life instrument specifically designed for use with prostate cancer participants. It consists of 27 core items which assess participant function in four domains rated on 0 to 4 Likert-type scale: physical well-being (PWB) (7 items; 0 [worst] to 4 [better], score range 0-28), social/family well-being (SWB) (7 items; 0 [worst] to 4 [better], score range 0-28), emotional well-being (EWB) (6 items; 0 [worst] to 4 [better], score range 0-24), and functional well-being (FWB) (7 items; 0 [worst] to 4 [better], score range 0-28), which is further supplemented by 12 site-specific items to assess for prostate-related symptoms (Prostate Cancer Subscale [PCS] 12 items rated on Likert-type scale 0 [worst] to 4 [better], score range 0-48). The total domain scores and PCS subscale score are then combined to a global quality of life score ranging between 0 to 156; higher scores representing better quality of life.

    8. Change From Baseline in EuroQOL 5-dimension 5-level Questionnaire [EQ-5D-5L] Visual Analog Scale (VAS) [Period 2: Baseline, weeks 1, 13, 25, 37, 49, 61, 73, 85, 97, 109, 121, 133, 145, 157, 169, 181]

      The EQ-5D-5L VAS records the participant's self-rated health on a vertical visual analogue scale, where the endpoints are labelled from 0 (worst health imaginable) to 100 (best health imaginable).

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    Male
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Histologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features;

    • Ongoing androgen deprivation therapy (ADT) with a luteinizing hormone-releasing hormone (LHRH) agonist or antagonist at a stable dose and schedule within 4 weeks of initiation of investigational medicinal product (IMP), or bilateral orchiectomy (i.e., surgical or medical castration);

    • Metastatic disease documented by at least 2 bone lesions on bone scan, or soft tissue disease documented by computed tomography (CT)/magnetic resonance imaging (MRI);

    • Progressive disease at study entry defined as the following occurring in the setting of castrate levels of testosterone: Prostate specific antigen (PSA) progression defined by a minimum of three rising PSA levels with an interval of ≥ 1 week between each determination.

    • Asymptomatic or minimally symptomatic prostate cancer (Brief Pain Inventory - Short Form (BPI-SF) question 3 score of < 4);

    • Eastern Cooperative Oncology Group (ECOG) performance score of 0-1;

    • Estimated life expectancy of ≥ 12 months;

    • Be suitable and willing to receive chemotherapy as part of the trial;

    • Able to swallow the IMP and comply with study requirements;

    • Subject agreed not to participate in another interventional study while on treatment.

    Exclusion Criteria:

    • Prior treatment with the following agents for the treatment of prostate cancer: Aminoglutethimide; Ketoconazole; Abiraterone; Enzalutamide or participation in a clinical trial of enzalutamide; 223Ra, 89Sr, 153Sm, 186Re/188Re; Immunomodulatory therapies; Cytotoxic chemotherapy; Participation in a clinical trial of an investigational agent that inhibits the AR or androgen synthesis unless the treatment was placebo;

    • Current or prior treatment within 4 weeks prior to initiation of investigational medicinal product (IMP) with the following agents for the treatment of prostate cancer: Antiandrogens; 5-α reductase inhibitors; Estrogens; Anabolic steroids; Drugs with antiandrogenic properties; Progestational agents;

    • Subject had received investigational therapy within 28 days or 5 half-lives whichever was longer, prior to initiation of IMP;

    • Use of opiate analgesia for pain from prostate cancer within 4 weeks prior to initiation of IMP;

    • Radiation therapy to bone lesions or prostatic bed within 4 weeks prior to initiation of IMP;

    • Major surgery within 4 weeks prior to initiation of IMP;

    • History of seizure or any condition that may predispose to seizures at any time in the past. History of loss of consciousness or transient ischemic attack within 12 months prior to Screening;

    • Known or suspected brain metastasis or active leptomeningeal disease;

    • History of another malignancy within the previous 5 years other than non-melanoma skin cancer;

    • Clinically significant cardiovascular disease;

    • Gastrointestinal disorders affecting absorption;

    • Medical contraindications to the use of prednisolone or docetaxel;

    • Allergies to any of the active ingredients or excipients in the study drugs

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Site AT43004 Linz Austria 4010
    2 Site AT43001 Vienna Austria 1090
    3 Site BE32003 Bonheiden Belgium 2820
    4 Site BE32002 Liege Belgium 4000
    5 Site BE32004 Ottignies Belgium 1340
    6 Site CZ42004 Brno Czechia 656 91
    7 Site CZ42003 Olomouc Czechia 77520
    8 Site CZ42002 Plzeň -Lochotín Czechia 30460
    9 Site CZ42001 Praha 2 Czechia 12808
    10 Site FR33012 Albi France 81000
    11 Site FR33003 Montpellier France 34298 cedex 5
    12 Site FR33002 Nîmes France 30907 cedex 2
    13 Site FR33008 Paris France 75014
    14 Site FR33014 Paris France 75014
    15 Site FR33004 Plerin France 22190
    16 Site FR33013 Quimper France 29000
    17 Site FR33011 Reims France 51056
    18 Site FR33005 Suresnes France 92151
    19 Site DE49018 Nürtingen Baden-Württemberg Germany 72622
    20 Site DE49008 Aachen Germany 52074
    21 Site DE49010 Bergisch Gladbach Germany 51465
    22 Site DE49001 Hannover Germany 30625
    23 Site DE49006 Heidelberg Germany 69120
    24 Site DE49003 Mannheim Germany 68167
    25 Site DE49002 Munster Germany 48149
    26 Site DE49015 Tübingen Germany 72076
    27 Site DE49017 Ulm Germany 89075
    28 Site DE49004 Wuppertal Germany 42103
    29 Site GR30001 Heraklion Crete Greece 70013
    30 Site GR30004 Heraklion Crete Greece 71403
    31 Site GR30003 Athens Greece 14564
    32 Site GR30006 Athens Greece 155 62
    33 Site GR30005 Thessaloniki Greece 54007
    34 Site IT39001 Arezzo Italy 52100
    35 Site IT39012 Brescia Italy 25126
    36 Site IT39003 Milano Italy 20100
    37 Site IT39008 Naples Italy 80131
    38 Site IT39010 Pavia Italy 27100
    39 Site IT39005 Roma Italy 00128
    40 Site IT39004 Rome Italy 161
    41 Site IT39002 Terni Italy 05100
    42 Site NL31002 Amsterdam Netherlands 1066 CX
    43 Site NL31007 Blaricum Netherlands 1261 AN
    44 Site NL31004 Hoofddorp Netherlands 2134 TM
    45 Site NL31010 Nieuwegein Netherlands 3435 CM
    46 Site NL31003 Rotterdam Netherlands 3045 PM
    47 Site NO47005 Drammen Norway 3004
    48 Site NO47001 Kristiansand Norway 4615
    49 Site NO47004 Stavanger Norway 4011
    50 Site PL48004 Gdańsk Poland 80-952
    51 Site PL48003 Krakow Poland 31-501
    52 Site PL48002 Lodz Poland 93-513
    53 Site PL48006 Warszawa Poland 02-507
    54 Site PL48005 Warszawa Poland 04-141
    55 Site RU70004 Obninsk Kaluga Russian Federation 24903
    56 Site RU70002 Moscow Russian Federation 105077
    57 Site RU70001 Moscow Russian Federation 115478
    58 Site RU70003 Moscow Russian Federation 125284
    59 Site RU70005 St. Petersburg Russian Federation 197022
    60 Site RU70006 St. Petersburg Russian Federation 197758
    61 Site ES34005 Lugo Spain 27003
    62 Site ES34003 Madrid Spain 28007
    63 Site ES34001 Madrid Spain 28040
    64 Site ES34002 Madrid Spain 28041
    65 Site ES34010 Madrid Spain
    66 Site ES34007 Malaga Spain 29010
    67 Site ES34009 Murcia Spain 30008
    68 Site ES34008 Santander Spain 39008
    69 Site ES34004 Sevilla Spain 41013
    70 Site ES34006 Valencia Spain 46009
    71 Site SE46002 Göteborg Sweden 413 45
    72 Site SE46005 Kalmar Sweden 39185
    73 Site SE46003 Solna Sweden 171 76
    74 Site SE46004 Uppsala Sweden 751 85
    75 Site CH41005 Locarno Tessin Switzerland 6600
    76 Site CH41009 Zurich Switzerland CH-8038
    77 Site TR90001 Ankara Turkey 06500
    78 Site TR90003 Istanbul Turkey 34722
    79 Site TR90002 Izmir Turkey 35340
    80 Site GB44010 Aberdeen United Kingdom AB25 2ZN
    81 Site GB44004 Cambridge United Kingdom CB2 0QQ
    82 Site GB44018 Cardiff United Kingdom CF4 7XL
    83 Site GB44014 Exeter United Kingdom
    84 Site GB44003 London United Kingdom SE1 9RT
    85 Site GB44020 Northwood United Kingdom HA62RN
    86 Site GB44015 Norwich United Kingdom NR4 7UY
    87 Site GB44002 Nottingham United Kingdom NG5 1PB
    88 Site GB44017 Swansea United Kingdom SA2 8QA
    89 Site GB44007 Wirral United Kingdom CH63 4JY

    Sponsors and Collaborators

    • Astellas Pharma Europe Ltd.
    • Medivation LLC, a wholly owned subsidiary of Pfizer Inc.

    Investigators

    • Study Director: Medical Director, Astellas Pharma Europe Ltd.

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Astellas Pharma Europe Ltd.
    ClinicalTrials.gov Identifier:
    NCT02288247
    Other Study ID Numbers:
    • 9785-MA-1001
    • 2013-004711-50
    First Posted:
    Nov 11, 2014
    Last Update Posted:
    Jul 12, 2022
    Last Verified:
    Jul 1, 2022
    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 Europe Ltd.
    Metastatic
    Castration-resistant
    Docetaxel
    Chemotherapy- Naïve
    Enzalutamide
    Prostate Cancer
    Chemotherapy Naïve Metastatic Castration Resistant Prostate Cancer
    Prednisolone
    Xtandi
    Metastatic Castration Resistant Prostate Cancer
    Additional relevant MeSH terms:
    Prostatic Neoplasms
    Prednisolone
    Docetaxel

    Study Results

    Participant Flow

    Recruitment Details Male participants with metastatic Castration-Resistant Prostate Cancer (mCRPC) who had progressed while on luteinizing hormone-releasing hormone (LHRH) agonist/antagonist or after receiving a bilateral orchiectomy and had not yet received chemotherapy were enrolled in the study.
    Pre-assignment Detail Following Screening, participants received open-label (OL) treatment with enzalutamide in period 1 followed by period 2 randomized double-blind (DB) treatment with continued enzalutamide or placebo, adding with docetaxel and prednisolone. Participants were stratified by disease progression in Period 1 (evidence of radiographic progression or not).
    Arm/Group Title Enzalutamide Placebo
    Arm/Group Description Participants received an OL treatment with enzalutamide 160 milligrams (mg) capsules, orally once daily from day 1 in period 1 until randomization to period 2 treatment, confirmation of ineligibility for period 2 treatment, intolerable toxicity, withdrawal, or death, whichever occurred first. Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received enzalutamide 160 mg capsules, orally once daily in combination with docetaxel 75 milligrams per square meter (mg/m^2) in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, DB treatment in period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants received an OL treatment with enzalutamide 160 mg capsules, orally once daily from day 1 in period 1 until randomization to period 2 treatment, confirmation of ineligibility for period 2 treatment, intolerable toxicity, withdrawal, or death, whichever occurred first. Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received placebo matched to enzalutamide, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, DB in period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first.
    Period Title: Period 1: OL Treatment (Max: 315 Weeks)
    STARTED 688 0
    Treated 687 0
    COMPLETED 41 0
    NOT COMPLETED 647 0
    Period Title: Period 1: OL Treatment (Max: 315 Weeks)
    STARTED 137 136
    Treated 136 135
    COMPLETED 1 1
    NOT COMPLETED 136 135

    Baseline Characteristics

    Arm/Group Title Enzalutamide
    Arm/Group Description Participants received an OL treatment with enzalutamide 160 mg capsules, orally once daily from day 1 in period 1 until randomization to period 2 treatment, confirmation of ineligibility for period 2 treatment, intolerable toxicity, withdrawal, or death, whichever occurred first. Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received enzalutamide 160 mg capsules/placebo matched to enzalutamide, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, DB treatment in period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first.
    Overall Participants 687
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    71.0
    (7.8)
    Sex: Female, Male (Count of Participants)
    Female
    0
    0%
    Male
    687
    100%
    Race/Ethnicity, Customized (Count of Participants)
    White
    681
    99.1%
    Black Or African American
    5
    0.7%
    Other
    1
    0.1%

    Outcome Measures

    1. Primary Outcome
    Title Progression Free Survival (PFS)
    Description PFS: time from randomization (Period 2 Week 1) to earliest progression event. Progression is defined as radiographic progression, unequivocal clinical progression, or death on study. Radiographic progression is defined for bone disease by appearance of ≥ 2 new lesions on whole-body radionuclide bone scan per Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria (i.e., unconfirmed progressive disease) that needs to be confirmed in the next assessment (i.e., progressive disease in the next assessment) or for soft tissue disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Unequivocal clinical progression is defined as new onset cancer pain requiring chronic administration of opiate analgesia or deterioration from prostate cancer of Eastern Cooperative Oncology Group (ECOG) performance status score to ≥ 3, or initiation of subsequent lines of cytotoxic chemotherapy or radiation therapy or surgical intervention due to complications of tumor progression.
    Time Frame From date of randomization to the earliest of either documented disease progression (median duration: 35 weeks)

    Outcome Measure Data

    Analysis Population Description
    The Full Analysis Set (FAS) consisted of all participants who were randomized and received at least one dose of IMP.
    Arm/Group Title Enzalutamide Placebo
    Arm/Group Description Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received enzalutamide 160 mg capsules, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, in DB treatment period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received placebo matched to enzalutamide, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, in DB treatment period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first.
    Measure Participants 136 135
    Median (95% Confidence Interval) [months]
    9.53
    8.28
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Enzalutamide, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.027
    Comments From the Cox proportional hazards model with covariates for treatment and disease progression in Period 1 (radiographic, nonradiographic).
    Method Cox proportional hazards model
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.72
    Confidence Interval (2-Sided) 95%
    0.53 to 0.96
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Secondary Outcome
    Title Time to Prostate-specific Antigen (PSA) Progression
    Description Time to PSA progression, defined as the time from randomization (Period 2 Week 1) to the date of the first PSA value in Period 2 demonstrating progression (Period 2). The PSA progression date is defined as the date that a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL above the nadir recorded in Period 2 is documented, which must be confirmed by a second consecutive value obtained at least 3 weeks later.
    Time Frame From date of randomization to the first PSA value (median duration: 35 weeks)

    Outcome Measure Data

    Analysis Population Description
    FAS
    Arm/Group Title Enzalutamide Placebo
    Arm/Group Description Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received enzalutamide 160 mg capsules, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, in DB treatment period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received placebo matched to enzalutamide, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, in DB treatment period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first.
    Measure Participants 136 135
    Median (95% Confidence Interval) [months]
    8.44
    6.24
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Enzalutamide, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.002
    Comments From the Cox proportional hazards model with covariates for treatment and disease progression in Period 1 (radiographic, nonradiographic).
    Method Cox proportional hazards model
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.58
    Confidence Interval (2-Sided) 95%
    0.41 to 0.82
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    3. Secondary Outcome
    Title Prostate-specific Antigen (PSA) Response
    Description PSA response, defined as a decrease in percentage change from randomization (Period 2 Week 1) of 50% or more. PSA response was derived at Week 13 and at any time after randomization in Period 2. PSA response at any time is defined as a decrease in percentage change from randomization (Period 2 Week 1) at any time after randomization of 50% or more. Percentage of participants with PSA response was reported.
    Time Frame Randomization, Week 13, any time after randomization in Period 2 (median of 35 weeks)

    Outcome Measure Data

    Analysis Population Description
    FAS
    Arm/Group Title Enzalutamide Placebo
    Arm/Group Description Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received enzalutamide 160 mg capsules, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, in DB treatment period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received placebo matched to enzalutamide, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, in DB treatment period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first.
    Measure Participants 136 135
    Week 13
    44.9
    6.5%
    25.2
    NaN
    Any time after randomization (median of 35 weeks)
    55.9
    8.1%
    37.0
    NaN
    4. Secondary Outcome
    Title Objective Response Rate (ORR)
    Description ORR, defined as the best overall radiographic response after randomization (Period 2 Week 1) as per Investigator assessments of response for soft tissue disease per RECIST 1.1, in participants who had a measurable tumor. ORR was reported as the percentage of participants with complete response (CR) or partial response (PR). CR was defined as disappearance of all target and nontarget lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to < 10 mm from baseline measurement. PR was defined as at least a 30% decrease in the sum of diameters (longest for nonnodal lesions, short axis for nodal lesions) of target lesions taking as reference to the baseline sum of diameters.
    Time Frame From date of randomization up to median duration of 35 weeks

    Outcome Measure Data

    Analysis Population Description
    FAS
    Arm/Group Title Enzalutamide Placebo
    Arm/Group Description Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received enzalutamide 160 mg capsules, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, in DB treatment period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received placebo matched to enzalutamide, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, in DB treatment period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first.
    Measure Participants 136 135
    Number [percentage of participants]
    31.6
    4.6%
    25.9
    NaN
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Enzalutamide, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.142
    Comments From the Cochran-Mantel-Haenszel test stratified by disease progression (radiographic, non-radiographic) in Period 1.
    Method Cochran-Mantel-Haenszel
    Comments
    5. Secondary Outcome
    Title Time to Pain Progression
    Description The time to an increase of >=30% from randomization (Period 2 Week 1) in average BPI-SF item scores (items 3, 4, 5, 6) at two consecutive evaluations >=3 weeks apart without decrease in analgesic score according to the World health Organization (WHO). Only participants with an average pain intensity item score >=4 were considered. The BPI-SF was an instrument to document pain-related functional impairment and contains 7 questions which included pain intensity [(items 3, 4, 5 and 6): worst pain, least pain, average pain and current pain, with scales from 0 (no pain) to 10 (pain as bad as you can imagine)] and pain interference ](items 9A to 9G): general activity, mood, walking ability, normal work, relations with other people, sleep and enjoyment of life, with scales from 0 (does not interfere) to 10 (completely interferes)]. The BPI-SF total score for pain intensity was calculated as the mean of the 4 scores for the 4 items of pain intensity.
    Time Frame From date of randomization up to median duration of 35 weeks

    Outcome Measure Data

    Analysis Population Description
    Data was not estimable as none of the participants met the criteria for pain progression
    Arm/Group Title Enzalutamide Placebo
    Arm/Group Description Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received enzalutamide 160 mg capsules, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, in DB treatment period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received placebo matched to enzalutamide, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, in DB treatment period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first.
    Measure Participants 0 0
    6. Secondary Outcome
    Title Time to Opiate Use for Cancer-related Pain
    Description Time to opiate use for cancer-related pain, defined as the time from randomization (Period 2 Week 1) to initiation of chronic administration of opiate analgesia [parenteral opiate use for ≥7 days or use of WHO Analgesic Ladder Level 3 oral opiates for ≥3 weeks].
    Time Frame From date of randomization up to median duration of 35 weeks

    Outcome Measure Data

    Analysis Population Description
    Data was not estimable as none of the participants had cancer-related pain.
    Arm/Group Title Enzalutamide Placebo
    Arm/Group Description Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received enzalutamide 160 mg capsules, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, in DB treatment period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received placebo matched to enzalutamide, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, in DB treatment period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first.
    Measure Participants 0 0
    7. Secondary Outcome
    Title Time to First Skeletal-related Event (SRE)
    Description Time to first SRE, defined as the time from randomization (Period 2 Week 1) to radiation therapy or surgery to bone, pathologic bone fracture, spinal cord compression, or change of antineoplastic therapy to treat bone pain.
    Time Frame From date of randomization up to median duration of 35 weeks

    Outcome Measure Data

    Analysis Population Description
    FAS
    Arm/Group Title Enzalutamide Placebo
    Arm/Group Description Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received enzalutamide 160 mg capsules, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, in DB treatment period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received placebo matched to enzalutamide, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, in DB treatment period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first
    Measure Participants 136 135
    Median (95% Confidence Interval) [months]
    21.98
    17.35
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Enzalutamide, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.994
    Comments From the Cox proportional hazards model with covariates for treatment and disease progression in Period 1 (radiographic, nonradiographic).
    Method Cox proportional hazards model
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.00
    Confidence Interval (2-Sided) 95%
    0.47 to 2.13
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    8. Secondary Outcome
    Title Change From Baseline in Functional Assessment of Cancer Therapy - Prostate (FACT-P)
    Description FACT-P quality of life questionnaire is a multi-dimensional, self-reported quality of life instrument specifically designed for use with prostate cancer participants. It consists of 27 core items which assess participant function in four domains rated on 0 to 4 Likert-type scale: physical well-being (PWB) (7 items; 0 [worst] to 4 [better], score range 0-28), social/family well-being (SWB) (7 items; 0 [worst] to 4 [better], score range 0-28), emotional well-being (EWB) (6 items; 0 [worst] to 4 [better], score range 0-24), and functional well-being (FWB) (7 items; 0 [worst] to 4 [better], score range 0-28), which is further supplemented by 12 site-specific items to assess for prostate-related symptoms (Prostate Cancer Subscale [PCS] 12 items rated on Likert-type scale 0 [worst] to 4 [better], score range 0-48). The total domain scores and PCS subscale score are then combined to a global quality of life score ranging between 0 to 156; higher scores representing better quality of life.
    Time Frame Period 2: Baseline, weeks 1, 13, 25, 37, 49, 61, 73, 85, 97, 109, 121, 133, 145, 157, 169, 181

    Outcome Measure Data

    Analysis Population Description
    Participants in the FAS population with available data were analyzed.
    Arm/Group Title Enzalutamide Placebo
    Arm/Group Description Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received enzalutamide 160 mg capsules, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, in DB treatment period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received placebo matched to enzalutamide, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, in DB treatment period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first.
    Measure Participants 124 133
    EWB: Baseline
    0.00
    (0.00)
    0.00
    (0.00)
    EWB: Change at Week 1
    0.00
    (0.00)
    0.00
    (0.00)
    EWB: Change at Week 13
    1.15
    (4.15)
    1.36
    (3.63)
    EWB: Change at Week 25
    0.69
    (3.85)
    1.03
    (3.58)
    EWB: Change at Week 37
    1.91
    (3.85)
    1.43
    (3.73)
    EWB: Change at Week 49
    1.22
    (3.62)
    0.73
    (4.24)
    EWB: Change at Week 61
    0.59
    (4.52)
    2.00
    (3.58)
    EWB: Change at Week 73
    1.69
    (3.13)
    -1.00
    EWB: Change at Week 85
    1.00
    (4.06)
    -5.00
    EWB: Change at Week 97
    3.90
    (4.75)
    EWB: Change at Week 109
    2.93
    (3.49)
    EWB: Change at Week 121
    4.00
    (2.83)
    EWB: Change at Week 133
    2.00
    (0.00)
    EWB: Change at Week 145
    2.00
    EWB: Change at Week 157
    2.00
    EWB: Change at Week 169
    1.00
    EWB: Change at Week 181
    2.00
    FWB: Baseline
    0.0000
    (0.0000)
    0.0000
    (0.0000)
    FWB: Change at Week 1
    0.0000
    (0.0000)
    0.0000
    (0.0000)
    FWB: Change at Week 13
    -1.8144
    (5.0586)
    -0.3121
    (4.7437)
    FWB: Change at Week 25
    -2.4472
    (5.2508)
    -0.8229
    (5.2563)
    FWB: Change at Week 37
    -1.5697
    (6.3251)
    -0.1459
    (3.2857)
    FWB: Change at Week 49
    -1.1579
    (6.7284)
    -1.3818
    (4.5238)
    FWB: Change at Week 61
    0.0000
    (4.7651)
    -2.3333
    (2.8048)
    FWB: Change at Week 73
    -1.8182
    (3.5726)
    -2.0000
    FWB: Change at Week 85
    1.2000
    (4.8166)
    0.0000
    FWB: Change at Week 97
    -0.5000
    (1.7321)
    FWB: Change at Week 109
    -1.3333
    (3.2146)
    FWB: Change at Week 121
    -1.5000
    (0.7071)
    FWB: Change at Week 133
    -0.5000
    (2.1213)
    FWB: Change at Week 145
    -2.0000
    FWB: Change at Week 157
    0.0000
    FWB: Change at Week 169
    -1.0000
    FWB: Change at Week 181
    0.0000
    Global Score: Baseline
    0.0000
    (0.0000)
    0.0000
    (0.0000)
    Global Score: Change at Week 1
    0.0000
    (0.0000)
    0.0000
    (0.0000)
    Global Score: Change at Week 13
    -0.7836
    (17.7356)
    1.7986
    (16.3294)
    Global Score: Change at Week 25
    -5.9204
    (18.2107)
    1.0762
    (17.0168)
    Global Score: Change at Week 37
    -1.5351
    (20.3721)
    0.1649
    (15.8335)
    Global Score: Change at Week 49
    -4.4880
    (24.6865)
    -4.6202
    (17.9530)
    Global Score: Change at Week 61
    -0.2957
    (17.6915)
    6.0939
    (8.8208)
    Global Score: Change at Week 73
    -0.3917
    (18.3346)
    Global Score: Change at Week 85
    1.7636
    (11.7476)
    Global Score: Change at Week 97
    6.2864
    (9.8128)
    Global Score: Change at Week 109
    -2.7333
    (17.6299)
    Global Score: Change at Week 121
    4.0000
    Global Score: Change at Week 133
    -7.0000
    (4.2426)
    Global Score: Change at Week 145
    -11.0000
    Global Score: Change at Week 157
    -1.0000
    Global Score: Change at Week 169
    -10.0000
    Global Score: Change at Week 181
    -4.0000
    PWB: Baseline
    0.0000
    (0.0000)
    0.0000
    (0.0000)
    PWB: Change at Week 1
    0.0000
    (0.0000)
    0.0000
    (0.0000)
    PWB: Change at Week 13
    -1.3322
    (6.0823)
    -0.6347
    (4.4643)
    PWB: Change at Week 25
    -3.1317
    (6.5208)
    -0.4590
    (4.2887)
    PWB: Change at Week 37
    -2.1786
    (5.5611)
    -0.9556
    (4.3691)
    PWB: Change at Week 49
    -2.5316
    (8.0882)
    -1.3913
    (6.1625)
    PWB: Change at Week 61
    -1.3889
    (6.9886)
    1.3333
    (3.8297)
    PWB: Change at Week 73
    -0.3636
    (8.0408)
    3.0000
    PWB: Change at Week 85
    1.0000
    (10.3682)
    3.0000
    PWB: Change at Week 97
    1.7500
    (10.4363)
    PWB: Change at Week 109
    -0.6667
    (13.6504)
    PWB: Change at Week 121
    -4.0000
    (1.4142)
    PWB: Change at Week 133
    -4.5000
    (0.7071)
    PWB: Change at Week 145
    -4.0000
    PWB: Change at Week 157
    0.0000
    PWB: Change at Week 169
    -4.0000
    PWB: Change at Week 181
    -2.0000
    PCS: Baseline
    0.0000
    (0.0000)
    0.0000
    (0.0000)
    PCS: Change at Week 1
    0.0000
    (0.0000)
    0.0000
    (0.0000)
    PCS: Change at Week 13
    1.1842
    (6.1843)
    1.6011
    (6.0731)
    PCS: Change at Week 25
    -0.4775
    (6.2665)
    1.8632
    (6.3433)
    PCS: Change at Week 37
    -1.1433
    (7.3006)
    0.6988
    (7.1353)
    PCS: Change at Week 49
    -1.8465
    (8.6083)
    -0.7223
    (7.8442)
    PCS: Change at Week 61
    0.3690
    (6.0031)
    4.2606
    (3.1148)
    PCS: Change at Week 73
    0.9174
    (7.8001)
    PCS: Change at Week 85
    2.1636
    (5.6123)
    PCS: Change at Week 97
    3.8864
    (3.3380)
    PCS: Change at Week 109
    -1.6667
    (5.8595)
    PCS: Change at Week 121
    2.0000
    PCS: Change at Week 133
    -3.0000
    (4.2426)
    PCS: Change at Week 145
    -5.0000
    PCS: Change at Week 157
    0.0000
    PCS: Change at Week 169
    -3.0000
    PCS: Change at Week 181
    -2.0000
    SWB: Baseline
    0.0000
    (0.0000)
    0.0000
    (0.0000)
    SWB: Change at Week 1
    0.0000
    (0.0000)
    0.0000
    (0.0000)
    SWB: Change at Week 13
    -0.1581
    (4.1893)
    -0.2953
    (5.0738)
    SWB: Change at Week 25
    -0.3634
    (5.6959)
    -0.0462
    (3.7933)
    SWB: Change at Week 37
    0.8798
    (4.6897)
    -0.3963
    (3.3279)
    SWB: Change at Week 49
    -0.0719
    (6.2561)
    -0.7536
    (4.3164)
    SWB: Change at Week 61
    -0.8167
    (3.3323)
    0.8333
    (5.7067)
    SWB: Change at Week 73
    -0.8182
    (2.7863)
    -24.0000
    SWB: Change at Week 85
    -3.6000
    (3.7815)
    -24.0000
    SWB: Change at Week 97
    -2.7500
    (5.8523)
    SWB: Change at Week 109
    -2.0000
    (4.3589)
    SWB: Change at Week 121
    0.5000
    (0.7071)
    SWB: Change at Week 133
    -1.0000
    (1.4142)
    SWB: Change at Week 145
    -2.0000
    SWB: Change at Week 157
    -3.0000
    SWB: Change at Week 169
    -3.0000
    SWB: Change at Week 181
    -2.0000
    9. Secondary Outcome
    Title Change From Baseline in EuroQOL 5-dimension 5-level Questionnaire [EQ-5D-5L] Visual Analog Scale (VAS)
    Description The EQ-5D-5L VAS records the participant's self-rated health on a vertical visual analogue scale, where the endpoints are labelled from 0 (worst health imaginable) to 100 (best health imaginable).
    Time Frame Period 2: Baseline, weeks 1, 13, 25, 37, 49, 61, 73, 85, 97, 109, 121, 133, 145, 157, 169, 181

    Outcome Measure Data

    Analysis Population Description
    Participants in the FAS population with available data were analyzed.
    Arm/Group Title Enzalutamide Placebo
    Arm/Group Description Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received enzalutamide 160 mg capsules, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, in DB treatment period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received placebo matched to enzalutamide, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, in DB treatment period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants could continue the extension period if they were still receiving study drug in Period 1 when enrollment to Period 2 closed or when the data cut-off for analysis was reached in Period 2, until the investigator or participant decided to stop or disease progression, intolerable toxicity, withdrawal or death, whichever occurred first.
    Measure Participants 121 130
    Baseline
    0.0
    (0.0)
    0.0
    (0.0)
    Change at Week 1
    0.0
    (0.0)
    0.0
    (0.0)
    Change at Week 13
    2.3
    (19.7)
    -0.8
    (17.8)
    Change at Week 25
    -3.0
    (18.6)
    -0.2
    (17.7)
    Change at Week 37
    -1.3
    (21.7)
    0.4
    (15.8)
    Change at Week 49
    -2.5
    (25.7)
    -8.3
    (23.3)
    Change at Week 61
    1.3
    (22.6)
    2.5
    (25.2)
    Change at Week 73
    -3.5
    (30.8)
    -20.0
    Change at Week 85
    7.2
    (20.7)
    -10.0
    Change at Week 97
    17.8
    (27.0)
    Change at Week 109
    17.7
    (23.6)
    Change at Week 121
    -7.0
    (4.2)
    Change at Week 133
    0.5
    (13.4)
    Change at Week 145
    1.0
    Change at Week 157
    -4.0
    Change at Week 169
    2.0
    Change at Week 181
    -4.0

    Adverse Events

    Time Frame From first dose up to 30 days after last dose (median duration: 35 weeks)
    Adverse Event Reporting Description
    Arm/Group Title Period 1: Enzalutamide Period 2: Enzalutamide Period 2: Placebo
    Arm/Group Description Participants received an OL treatment with enzalutamide 160 mg capsules, orally once daily from day 1 in period 1 until randomization to period 2 treatment, confirmation of ineligibility for period 2 treatment, intolerable toxicity, withdrawal, or death, whichever occurred first. Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received enzalutamide 160 mg capsules, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, DB treatment in period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first. Participants with confirmed disease progression on enzalutamide in period 1 and who continued to meet all eligibility criteria received placebo matched to enzalutamide, orally once daily in combination with docetaxel 75 mg/m^2 in a one-hour infusion every 3 weeks and prednisolone 5 mg orally twice daily, DB in period 2. Docetaxel and prednisolone were administered up to 10 cycles (1 cycle= 3 weeks) or additional cycles as assessed by the investigator and enzalutamide was administered until disease progression, intolerable toxicity, withdrawal or death, whichever occurred first.
    All Cause Mortality
    Period 1: Enzalutamide Period 2: Enzalutamide Period 2: Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 50/687 (7.3%) 18/136 (13.2%) 14/135 (10.4%)
    Serious Adverse Events
    Period 1: Enzalutamide Period 2: Enzalutamide Period 2: Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 235/687 (34.2%) 67/136 (49.3%) 52/135 (38.5%)
    Blood and lymphatic system disorders
    Anaemia 9/687 (1.3%) 17 3/136 (2.2%) 3 2/135 (1.5%) 2
    Disseminated intravascular coagulation 0/687 (0%) 0 0/136 (0%) 0 1/135 (0.7%) 1
    Febrile neutropenia 1/687 (0.1%) 1 10/136 (7.4%) 10 15/135 (11.1%) 17
    Leukopenia 0/687 (0%) 0 2/136 (1.5%) 3 1/135 (0.7%) 1
    Neutropenia 0/687 (0%) 0 11/136 (8.1%) 21 5/135 (3.7%) 12
    Pancytopenia 1/687 (0.1%) 2 0/136 (0%) 0 1/135 (0.7%) 1
    Thrombocytopenia 0/687 (0%) 0 0/136 (0%) 0 1/135 (0.7%) 1
    Cardiac disorders
    Acute coronary syndrome 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Acute myocardial infarction 2/687 (0.3%) 2 0/136 (0%) 0 0/135 (0%) 0
    Angina pectoris 3/687 (0.4%) 3 0/136 (0%) 0 0/135 (0%) 0
    Arrhythmia 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Atrial fibrillation 12/687 (1.7%) 14 3/136 (2.2%) 3 2/135 (1.5%) 2
    Atrial flutter 0/687 (0%) 0 1/136 (0.7%) 1 1/135 (0.7%) 1
    Atrioventricular block 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Cardiac arrest 3/687 (0.4%) 3 1/136 (0.7%) 1 0/135 (0%) 0
    Cardiac failure 6/687 (0.9%) 6 0/136 (0%) 0 1/135 (0.7%) 1
    Cardiac failure acute 0/687 (0%) 0 0/136 (0%) 0 1/135 (0.7%) 1
    Cardiac failure congestive 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Cardiogenic shock 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Cardiopulmonary failure 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Congestive cardiomyopathy 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Coronary artery disease 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Dressler's syndrome 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Ischaemic cardiomyopathy 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Left ventricular failure 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Myocardial infarction 8/687 (1.2%) 9 2/136 (1.5%) 2 0/135 (0%) 0
    Palpitations 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Stress cardiomyopathy 1/687 (0.1%) 2 0/136 (0%) 0 0/135 (0%) 0
    Ear and labyrinth disorders
    Vertigo 0/687 (0%) 0 1/136 (0.7%) 1 0/135 (0%) 0
    Endocrine disorders
    Goitre 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Eye disorders
    Blindness 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Exfoliation glaucoma 0/687 (0%) 0 0/136 (0%) 0 1/135 (0.7%) 1
    Retinal detachment 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Vision blurred 2/687 (0.3%) 2 0/136 (0%) 0 0/135 (0%) 0
    Gastrointestinal disorders
    Abdominal pain 2/687 (0.3%) 2 0/136 (0%) 0 1/135 (0.7%) 2
    Abdominal pain upper 1/687 (0.1%) 1 0/136 (0%) 0 1/135 (0.7%) 1
    Ascites 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Constipation 2/687 (0.3%) 2 0/136 (0%) 0 2/135 (1.5%) 2
    Diarrhoea 1/687 (0.1%) 1 1/136 (0.7%) 1 3/135 (2.2%) 3
    Duodenal ulcer perforation 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Gastric haemorrhage 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Gastrointestinal haemorrhage 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Ileus 5/687 (0.7%) 7 0/136 (0%) 0 1/135 (0.7%) 1
    Ileus paralytic 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Incarcerated inguinal hernia 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Inguinal hernia 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Intestinal ischaemia 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Intestinal obstruction 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Large intestine perforation 0/687 (0%) 0 0/136 (0%) 0 1/135 (0.7%) 1
    Mechanical ileus 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Nausea 1/687 (0.1%) 1 1/136 (0.7%) 1 2/135 (1.5%) 2
    Pancreatitis 1/687 (0.1%) 1 0/136 (0%) 0 1/135 (0.7%) 1
    Pancreatitis acute 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Rectal haemorrhage 3/687 (0.4%) 3 1/136 (0.7%) 3 0/135 (0%) 0
    Small intestinal haemorrhage 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Vomiting 2/687 (0.3%) 2 2/136 (1.5%) 2 1/135 (0.7%) 1
    General disorders
    Asthenia 2/687 (0.3%) 2 2/136 (1.5%) 2 0/135 (0%) 0
    Chest pain 4/687 (0.6%) 5 0/136 (0%) 0 1/135 (0.7%) 1
    Chills 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Death 4/687 (0.6%) 4 1/136 (0.7%) 1 0/135 (0%) 0
    Fatigue 1/687 (0.1%) 1 1/136 (0.7%) 1 0/135 (0%) 0
    Gait disturbance 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    General physical health deterioration 5/687 (0.7%) 6 1/136 (0.7%) 1 3/135 (2.2%) 4
    Generalised oedema 0/687 (0%) 0 1/136 (0.7%) 2 1/135 (0.7%) 1
    Hypothermia 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Malaise 1/687 (0.1%) 1 1/136 (0.7%) 1 0/135 (0%) 0
    Pain 5/687 (0.7%) 6 0/136 (0%) 0 0/135 (0%) 0
    Pyrexia 2/687 (0.3%) 2 6/136 (4.4%) 7 2/135 (1.5%) 2
    Sudden death 2/687 (0.3%) 2 1/136 (0.7%) 1 0/135 (0%) 0
    Hepatobiliary disorders
    Cholelithiasis 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Hepatic function abnormal 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Immune system disorders
    Drug hypersensitivity 0/687 (0%) 0 1/136 (0.7%) 1 1/135 (0.7%) 1
    Infections and infestations
    Bronchitis bacterial 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Catheter bacteraemia 0/687 (0%) 0 0/136 (0%) 0 1/135 (0.7%) 1
    Cellulitis 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Dacryocystitis 0/687 (0%) 0 1/136 (0.7%) 1 0/135 (0%) 0
    Device related infection 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Diverticulitis 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Erysipelas 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Infection 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Infective aneurysm 0/687 (0%) 0 1/136 (0.7%) 1 0/135 (0%) 0
    Influenza 0/687 (0%) 0 1/136 (0.7%) 1 0/135 (0%) 0
    Klebsiella sepsis 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Lower respiratory tract infection 1/687 (0.1%) 1 2/136 (1.5%) 3 0/135 (0%) 0
    Lyme disease 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Meningitis bacterial 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Neutropenic sepsis 1/687 (0.1%) 1 5/136 (3.7%) 6 3/135 (2.2%) 3
    Peritonitis 4/687 (0.6%) 4 0/136 (0%) 0 0/135 (0%) 0
    Pneumonia 4/687 (0.6%) 4 4/136 (2.9%) 4 3/135 (2.2%) 3
    Pulmonary tuberculosis 0/687 (0%) 0 1/136 (0.7%) 1 0/135 (0%) 0
    Respiratory tract infection 0/687 (0%) 0 0/136 (0%) 0 1/135 (0.7%) 1
    Respiratory tract infection fungal 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Sepsis 5/687 (0.7%) 5 2/136 (1.5%) 2 0/135 (0%) 0
    Septic shock 0/687 (0%) 0 3/136 (2.2%) 3 0/135 (0%) 0
    Streptococcal urinary tract infection 0/687 (0%) 0 0/136 (0%) 0 1/135 (0.7%) 1
    Upper respiratory tract infection 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Urinary tract infection 2/687 (0.3%) 2 1/136 (0.7%) 1 1/135 (0.7%) 1
    Urinary tract infection bacterial 1/687 (0.1%) 1 0/136 (0%) 0 1/135 (0.7%) 1
    Urinary tract infection pseudomonal 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Urosepsis 6/687 (0.9%) 7 0/136 (0%) 0 0/135 (0%) 0
    Injury, poisoning and procedural complications
    Ankle fracture 3/687 (0.4%) 3 0/136 (0%) 0 0/135 (0%) 0
    Clavicle fracture 0/687 (0%) 0 1/136 (0.7%) 1 0/135 (0%) 0
    Contusion 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Fall 8/687 (1.2%) 9 0/136 (0%) 0 0/135 (0%) 0
    Femoral neck fracture 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Femur fracture 6/687 (0.9%) 7 0/136 (0%) 0 0/135 (0%) 0
    Hand fracture 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Hip fracture 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Infusion related reaction 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Injury 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Lower limb fracture 2/687 (0.3%) 2 1/136 (0.7%) 1 0/135 (0%) 0
    Lumbar vertebral fracture 2/687 (0.3%) 2 0/136 (0%) 0 0/135 (0%) 0
    Medication error 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Overdose 0/687 (0%) 0 1/136 (0.7%) 1 0/135 (0%) 0
    Patella fracture 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Procedural pain 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Product dispensing error 0/687 (0%) 0 1/136 (0.7%) 1 0/135 (0%) 0
    Radius fracture 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Rib fracture 2/687 (0.3%) 2 0/136 (0%) 0 0/135 (0%) 0
    Spinal compression fracture 2/687 (0.3%) 2 0/136 (0%) 0 0/135 (0%) 0
    Spinal fracture 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Tibia fracture 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Urostomy complication 0/687 (0%) 0 1/136 (0.7%) 1 0/135 (0%) 0
    Investigations
    Alanine aminotransferase increased 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Aspartate aminotransferase increased 1/687 (0.1%) 1 0/136 (0%) 0 1/135 (0.7%) 1
    Blood bilirubin increased 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Eastern Cooperative Oncology Group performance status worsened 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    General physical condition abnormal 5/687 (0.7%) 8 1/136 (0.7%) 1 0/135 (0%) 0
    Haemoglobin decreased 1/687 (0.1%) 1 0/136 (0%) 0 1/135 (0.7%) 1
    Liver function test increased 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Neutrophil count decreased 0/687 (0%) 0 2/136 (1.5%) 3 1/135 (0.7%) 1
    Platelet count decreased 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Troponin I increased 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Metabolism and nutrition disorders
    Cachexia 2/687 (0.3%) 2 0/136 (0%) 0 0/135 (0%) 0
    Dehydration 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Diabetes mellitus 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Hypercalcaemia 2/687 (0.3%) 2 0/136 (0%) 0 0/135 (0%) 0
    Hyperglycaemia 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Hypocalcaemia 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Hypoglycaemia 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Hypokalaemia 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Hyponatraemia 1/687 (0.1%) 3 1/136 (0.7%) 1 0/135 (0%) 0
    Hypophagia 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Musculoskeletal and connective tissue disorders
    Arthritis 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Back pain 12/687 (1.7%) 14 2/136 (1.5%) 2 3/135 (2.2%) 4
    Bone pain 2/687 (0.3%) 2 1/136 (0.7%) 1 1/135 (0.7%) 1
    Cervical spinal stenosis 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Flank pain 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Intervertebral disc disorder 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Lumbar spinal stenosis 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Mobility decreased 2/687 (0.3%) 2 0/136 (0%) 0 0/135 (0%) 0
    Muscular weakness 2/687 (0.3%) 2 0/136 (0%) 0 0/135 (0%) 0
    Musculoskeletal chest pain 2/687 (0.3%) 2 0/136 (0%) 0 0/135 (0%) 0
    Musculoskeletal pain 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Myalgia 1/687 (0.1%) 1 0/136 (0%) 0 1/135 (0.7%) 1
    Osteoarthritis 1/687 (0.1%) 2 1/136 (0.7%) 1 0/135 (0%) 0
    Osteonecrosis of jaw 2/687 (0.3%) 2 1/136 (0.7%) 2 1/135 (0.7%) 1
    Pain in extremity 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Pathological fracture 5/687 (0.7%) 5 0/136 (0%) 0 0/135 (0%) 0
    Spinal pain 2/687 (0.3%) 2 0/136 (0%) 0 0/135 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    B-cell lymphoma 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Basal cell carcinoma 2/687 (0.3%) 3 0/136 (0%) 0 0/135 (0%) 0
    Bladder cancer 1/687 (0.1%) 2 0/136 (0%) 0 0/135 (0%) 0
    Bladder transitional cell carcinoma 3/687 (0.4%) 5 0/136 (0%) 0 0/135 (0%) 0
    Bladder transitional cell carcinoma recurrent 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Bowen's disease 1/687 (0.1%) 1 0/136 (0%) 0 1/135 (0.7%) 1
    Cancer pain 4/687 (0.6%) 4 2/136 (1.5%) 2 1/135 (0.7%) 1
    Colon cancer 2/687 (0.3%) 2 0/136 (0%) 0 0/135 (0%) 0
    Gastric cancer 1/687 (0.1%) 2 0/136 (0%) 0 0/135 (0%) 0
    Intestinal adenocarcinoma 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Lip neoplasm malignant stage unspecified 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Liposarcoma 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Lung adenocarcinoma 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Lung neoplasm malignant 1/687 (0.1%) 1 1/136 (0.7%) 1 0/135 (0%) 0
    Lymphoma 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Malignant neoplasm of pleura 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Malignant neoplasm progression 23/687 (3.3%) 25 6/136 (4.4%) 6 6/135 (4.4%) 6
    Malignant peritoneal neoplasm 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Myeloproliferative neoplasm 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Non-small cell lung cancer 1/687 (0.1%) 2 0/136 (0%) 0 0/135 (0%) 0
    Pancreatic carcinoma 3/687 (0.4%) 3 0/136 (0%) 0 0/135 (0%) 0
    Plasma cell myeloma 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Small cell lung cancer 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Soft tissue sarcoma 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Squamous cell carcinoma of lung 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Transitional cell carcinoma 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Nervous system disorders
    Amnesia 0/687 (0%) 0 1/136 (0.7%) 1 0/135 (0%) 0
    Amyotrophic lateral sclerosis 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Aphasia 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Ataxia 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Brain compression 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Cerebral haemorrhage 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Cerebral ischaemia 2/687 (0.3%) 2 0/136 (0%) 0 0/135 (0%) 0
    Cerebrovascular accident 4/687 (0.6%) 4 1/136 (0.7%) 1 0/135 (0%) 0
    Dementia Alzheimer's type 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Dizziness 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Epilepsy 3/687 (0.4%) 3 0/136 (0%) 0 0/135 (0%) 0
    Haemorrhage intracranial 0/687 (0%) 0 1/136 (0.7%) 1 0/135 (0%) 0
    Headache 3/687 (0.4%) 4 0/136 (0%) 0 0/135 (0%) 0
    Hemiplegia 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Hypertensive encephalopathy 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Ischaemic stroke 3/687 (0.4%) 3 0/136 (0%) 0 0/135 (0%) 0
    Motor dysfunction 0/687 (0%) 0 1/136 (0.7%) 1 0/135 (0%) 0
    Paraesthesia 2/687 (0.3%) 2 0/136 (0%) 0 0/135 (0%) 0
    Paraplegia 2/687 (0.3%) 2 1/136 (0.7%) 1 0/135 (0%) 0
    Parkinson's disease 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Polyneuropathy 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Presyncope 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Sciatica 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Seizure 2/687 (0.3%) 2 0/136 (0%) 0 0/135 (0%) 0
    Spinal cord compression 6/687 (0.9%) 6 5/136 (3.7%) 5 1/135 (0.7%) 1
    Syncope 5/687 (0.7%) 5 0/136 (0%) 0 0/135 (0%) 0
    Transient ischaemic attack 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Vascular dementia 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Product Issues
    Device dislocation 3/687 (0.4%) 3 0/136 (0%) 0 0/135 (0%) 0
    Thrombosis in device 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Psychiatric disorders
    Confusional state 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Hallucination 0/687 (0%) 0 0/136 (0%) 0 1/135 (0.7%) 1
    Renal and urinary disorders
    Acute kidney injury 7/687 (1%) 8 2/136 (1.5%) 2 2/135 (1.5%) 2
    Bladder outlet obstruction 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Bladder tamponade 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Haematuria 12/687 (1.7%) 17 1/136 (0.7%) 1 1/135 (0.7%) 1
    Hydronephrosis 6/687 (0.9%) 7 0/136 (0%) 0 1/135 (0.7%) 1
    Nephrolithiasis 2/687 (0.3%) 2 0/136 (0%) 0 0/135 (0%) 0
    Urethral obstruction 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Urethral stenosis 1/687 (0.1%) 2 0/136 (0%) 0 1/135 (0.7%) 1
    Urinary bladder polyp 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Urinary retention 7/687 (1%) 7 0/136 (0%) 0 1/135 (0.7%) 1
    Urinary tract disorder 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Urinary tract obstruction 3/687 (0.4%) 3 0/136 (0%) 0 0/135 (0%) 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Prostatitis 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Scrotal pain 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Cough 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Dyspnoea 8/687 (1.2%) 9 2/136 (1.5%) 2 1/135 (0.7%) 1
    Hydrothorax 0/687 (0%) 0 1/136 (0.7%) 1 0/135 (0%) 0
    Interstitial lung disease 0/687 (0%) 0 1/136 (0.7%) 1 0/135 (0%) 0
    Lung disorder 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Pleural effusion 2/687 (0.3%) 2 1/136 (0.7%) 1 0/135 (0%) 0
    Pneumonitis 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Pneumothorax 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Pulmonary embolism 3/687 (0.4%) 3 2/136 (1.5%) 2 0/135 (0%) 0
    Pulmonary oedema 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Pulmonary thrombosis 0/687 (0%) 0 1/136 (0.7%) 1 0/135 (0%) 0
    Respiratory failure 0/687 (0%) 0 0/136 (0%) 0 1/135 (0.7%) 1
    Skin and subcutaneous tissue disorders
    Stevens-Johnson syndrome 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Surgical and medical procedures
    Bone operation 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Cardiac pacemaker removal 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Carpal tunnel decompression 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Catheterisation venous 0/687 (0%) 0 0/136 (0%) 0 1/135 (0.7%) 1
    Vascular disorders
    Arterial insufficiency 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Circulatory collapse 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Deep vein thrombosis 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Haematoma 0/687 (0%) 0 0/136 (0%) 0 1/135 (0.7%) 1
    Hypertension 3/687 (0.4%) 3 0/136 (0%) 0 0/135 (0%) 0
    Hypertensive crisis 2/687 (0.3%) 2 0/136 (0%) 0 0/135 (0%) 0
    Hypotension 1/687 (0.1%) 1 1/136 (0.7%) 1 0/135 (0%) 0
    Malignant hypertension 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Orthostatic hypotension 0/687 (0%) 0 0/136 (0%) 0 1/135 (0.7%) 1
    Shock haemorrhagic 0/687 (0%) 0 1/136 (0.7%) 1 0/135 (0%) 0
    Thrombosis 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Venous thrombosis limb 1/687 (0.1%) 1 0/136 (0%) 0 0/135 (0%) 0
    Other (Not Including Serious) Adverse Events
    Period 1: Enzalutamide Period 2: Enzalutamide Period 2: Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 521/687 (75.8%) 125/136 (91.9%) 123/135 (91.1%)
    Blood and lymphatic system disorders
    Anaemia 49/687 (7.1%) 63 27/136 (19.9%) 47 15/135 (11.1%) 32
    Leukopenia 1/687 (0.1%) 1 11/136 (8.1%) 37 16/135 (11.9%) 48
    Neutropenia 5/687 (0.7%) 5 41/136 (30.1%) 124 43/135 (31.9%) 129
    Eye disorders
    Lacrimation increased 2/687 (0.3%) 3 25/136 (18.4%) 28 6/135 (4.4%) 7
    Gastrointestinal disorders
    Constipation 60/687 (8.7%) 64 12/136 (8.8%) 21 15/135 (11.1%) 17
    Diarrhoea 63/687 (9.2%) 76 37/136 (27.2%) 51 42/135 (31.1%) 67
    Nausea 69/687 (10%) 79 26/136 (19.1%) 33 25/135 (18.5%) 31
    Stomatitis 2/687 (0.3%) 2 5/136 (3.7%) 5 8/135 (5.9%) 9
    Vomiting 22/687 (3.2%) 25 8/136 (5.9%) 8 6/135 (4.4%) 6
    General disorders
    Asthenia 109/687 (15.9%) 175 46/136 (33.8%) 92 35/135 (25.9%) 64
    Fatigue 158/687 (23%) 193 40/136 (29.4%) 65 28/135 (20.7%) 41
    Mucosal inflammation 3/687 (0.4%) 3 10/136 (7.4%) 14 17/135 (12.6%) 19
    Oedema peripheral 26/687 (3.8%) 31 16/136 (11.8%) 18 20/135 (14.8%) 23
    Pyrexia 17/687 (2.5%) 18 9/136 (6.6%) 11 7/135 (5.2%) 9
    Infections and infestations
    Nasopharyngitis 28/687 (4.1%) 33 4/136 (2.9%) 5 8/135 (5.9%) 8
    Injury, poisoning and procedural complications
    Fall 45/687 (6.6%) 61 6/136 (4.4%) 7 4/135 (3%) 4
    Investigations
    Haemoglobin decreased 15/687 (2.2%) 17 2/136 (1.5%) 3 7/135 (5.2%) 7
    Neutrophil count decreased 3/687 (0.4%) 4 7/136 (5.1%) 14 7/135 (5.2%) 27
    Weight decreased 30/687 (4.4%) 36 11/136 (8.1%) 11 2/135 (1.5%) 2
    White blood cell count decreased 9/687 (1.3%) 12 5/136 (3.7%) 17 7/135 (5.2%) 24
    Metabolism and nutrition disorders
    Decreased appetite 69/687 (10%) 86 23/136 (16.9%) 28 17/135 (12.6%) 18
    Musculoskeletal and connective tissue disorders
    Arthralgia 70/687 (10.2%) 85 25/136 (18.4%) 27 10/135 (7.4%) 10
    Back pain 116/687 (16.9%) 152 13/136 (9.6%) 15 14/135 (10.4%) 15
    Bone pain 64/687 (9.3%) 79 12/136 (8.8%) 14 14/135 (10.4%) 16
    Musculoskeletal pain 32/687 (4.7%) 37 5/136 (3.7%) 7 7/135 (5.2%) 12
    Myalgia 22/687 (3.2%) 23 9/136 (6.6%) 9 7/135 (5.2%) 9
    Pain in extremity 43/687 (6.3%) 54 7/136 (5.1%) 10 7/135 (5.2%) 7
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain 22/687 (3.2%) 25 8/136 (5.9%) 12 11/135 (8.1%) 14
    Nervous system disorders
    Dizziness 45/687 (6.6%) 49 5/136 (3.7%) 5 6/135 (4.4%) 6
    Dysgeusia 10/687 (1.5%) 12 18/136 (13.2%) 22 9/135 (6.7%) 9
    Headache 44/687 (6.4%) 56 5/136 (3.7%) 6 8/135 (5.9%) 10
    Neuropathy peripheral 2/687 (0.3%) 2 22/136 (16.2%) 29 12/135 (8.9%) 21
    Paraesthesia 22/687 (3.2%) 24 8/136 (5.9%) 10 10/135 (7.4%) 21
    Peripheral sensory neuropathy 1/687 (0.1%) 1 12/136 (8.8%) 16 14/135 (10.4%) 25
    Taste disorder 7/687 (1%) 7 6/136 (4.4%) 6 9/135 (6.7%) 11
    Renal and urinary disorders
    Haematuria 39/687 (5.7%) 48 4/136 (2.9%) 5 7/135 (5.2%) 8
    Respiratory, thoracic and mediastinal disorders
    Cough 26/687 (3.8%) 30 11/136 (8.1%) 15 10/135 (7.4%) 11
    Dyspnoea 28/687 (4.1%) 31 11/136 (8.1%) 13 4/135 (3%) 4
    Epistaxis 10/687 (1.5%) 11 13/136 (9.6%) 16 7/135 (5.2%) 9
    Skin and subcutaneous tissue disorders
    Alopecia 2/687 (0.3%) 2 44/136 (32.4%) 56 37/135 (27.4%) 48
    Dry skin 14/687 (2%) 14 12/136 (8.8%) 12 5/135 (3.7%) 5
    Nail disorder 0/687 (0%) 0 13/136 (9.6%) 13 7/135 (5.2%) 8
    Nail dystrophy 0/687 (0%) 0 7/136 (5.1%) 9 2/135 (1.5%) 3
    Nail toxicity 0/687 (0%) 0 11/136 (8.1%) 16 5/135 (3.7%) 7
    Onycholysis 0/687 (0%) 0 13/136 (9.6%) 14 12/135 (8.9%) 16
    Palmar-plantar erythrodysaesthesia syndrome 0/687 (0%) 0 10/136 (7.4%) 15 1/135 (0.7%) 1
    Vascular disorders
    Hot flush 73/687 (10.6%) 89 1/136 (0.7%) 1 1/135 (0.7%) 1
    Hypertension 90/687 (13.1%) 102 3/136 (2.2%) 5 2/135 (1.5%) 2

    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 Europe Ltd. (APEL)
    Phone +31 (0) 71 5455 050
    Email astellas.resultsdisclosure@astellas.com
    Responsible Party:
    Astellas Pharma Europe Ltd.
    ClinicalTrials.gov Identifier:
    NCT02288247
    Other Study ID Numbers:
    • 9785-MA-1001
    • 2013-004711-50
    First Posted:
    Nov 11, 2014
    Last Update Posted:
    Jul 12, 2022
    Last Verified:
    Jul 1, 2022