Safety and Efficacy Study of Enzalutamide in Patients With Nonmetastatic Castration-Resistant Prostate Cancer

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety and efficacy of enzalutamide in patients with non metastatic prostate cancer.

Official Title
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PROSPER: A MULTINATIONAL, PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, EFFICACY AND SAFETY STUDY OF ENZALUTAMIDE IN PATIENTS WITH NONMETASTATIC CASTRATION-RESISTANT PROSTATE CANCER

Conditions
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Nonmetastatic Castration-Resistant Prostate Cancer, Prostate Cancer, Cancer of the Prostate

Intervention / Treatment
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* Drug: Enzalutamide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation, signet cell, or small cell features; Ongoing androgen deprivation therapy with a gonadotropin-releasing hormone (GnRH) agonist/antagonist or prior bilateral orchiectomy (medical or surgical castration); Testosterone ≤ 50 ng/dL (≤ 1.73 nmol/L) at screening; Progressive disease on androgen deprivation therapy at enrollment; PSA and the screening PSA assessed by the central laboratory (central PSA) should be ≥ 2 µg/L (2 ng/mL: PSA doubling time ≤ 10 months; No prior or present evidence of metastatic disease; Asymptomatic prostate cancer; Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; Estimated life expectancy ≥ 12 months. Exclusion Criteria: Prior cytotoxic chemotherapy; Use of hormonal therapy or biologic therapy for prostate cancer (other than approved bone targeting agents and GnRH agonist/antagonist therapy) or use of an investigational agent within 4 weeks of randomization; Known or suspected brain metastasis or active leptomeningeal disease; History of another invasive cancer within 3 years of randomization; Absolute neutrophil count < 1000/μL, platelet count < 100,000/μL, or hemoglobin < 10 g/dL (6.2 mmol/L) at screening; Total bilirubin ≥ 1.5 times the upper limit of normal; Creatinine > 2 mg/dL (177 µmol/L) at screening; Albumin < 3.0 g/dL (30 g/L) at screening; History of seizure or any condition that may predispose to seizure; Clinically significant cardiovascular disease; Gastrointestinal disorder affecting absorption; Major surgery within 4 weeks of randomization; Hypersensitivity reaction to the active pharmaceutical ingredient or any of the capsule components, including Labrasol, butylated hydroxyanisole, and butylated hydroxytoluene; Any concurrent disease, infection, or comorbid condition that interferes with the ability of the patient to participate in the trial, which places the patient at undue risk, or complicates the interpretation of data, in the opinion of the investigator or medical monitor.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Sham Comparator: Placebo<br>Sugar pill manufactured to mimic enzalutamide 40 mg capsule | Drug: Placebo<br>* Sugar pill to mimic enzalutamide<br>|
| Experimental: Enzalutamide<br>160 mg by mouth once daily | Drug: Enzalutamide<br>* 160 mg by mouth once daily<br>* Other names: Xtandi;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Metastasis Free Survival (MFS) | MFS:time from randomization to first date of radiographic progression (RP) (by Blinded independent central radiology review [BICR]) at any time or death within 112 days of treatment discontinuation without evidence of RP.RP for bone disease:appearance of 1 or more metastatic lesions on bone scan.RP for soft tissue disease:per Response Evaluation Criteria in Solid Tumors,[RECIST 1.1])-at least a 20 percent (%) increase in the sum of diameters of target lesions,taking as reference the smallest sum on study (includes the baseline sum if smallest on study).Participants who did not have MFS event at the time of analysis data cut-off (28 June 2017) were censored at date of last assessment showing no objective evidence of RP prior to skeletal-related event or two or more consecutive missed tumor assessments. Participants who were randomized but later confirmed to have metastatic disease before randomization were censored on date of randomization. Analysis was based on Kaplan-Meier estimates. | From randomization until radiographic progression at any time, or death within 112 days of treatment discontinuation, whichever occurred first (until the data cut-off date of 28 June 2017, maximum duration of treatment: 42.8 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Prostate-Specific Antigen (PSA) Progression | Time to PSA progression was defined as the time from randomization to the date of first PSA value demonstrating progression, which was subsequently confirmed. For participants with PSA decline at Week 17, PSA progression was defined according to Prostate Cancer Working Group 2 (PCWG2) guidelines as the date that a 25% or greater increase and an absolute increase of 2 nanograms per milliliter (ng/mL) above the nadir (or baseline for participants with no PSA decline by Week 17) was documented, which was confirmed by a second consecutive value obtained at least 3 weeks or later. Participants without confirmed PSA progression at the time of analysis were right censored at the date of last PSA assessment before the analysis data cut-off date for the purposes of analysis. Analysis was based on Kaplan-Meier estimates. | From randomization until first PSA progression (until the data cut-off date of 28 June 2017, maximum duration of treatment: 42.8 months) | 
| Time to First Use of New Antineoplastic Therapy | Time to first use of new antineoplastic therapy was defined as the time from randomization to first use of new antineoplastic for prostate cancer. Participants not starting treatment with a new antineoplastic therapy at the time of analysis were right censored at the date of last assessment before the analysis data cutoff date for the purposes of analysis. Analysis was based on Kaplan-Meier estimates. | From randomization until first use of new antineoplastic therapy(until the data cut-off date of 28 June 2017, maximum duration of treatment: 42.8 months) | 
| Overall Survival | Overall survival (OS) was defined as the time (in months) from randomization to death from any cause. For participants who were alive at the time of the analysis data cutoff, OS time was censored at the last date the participant was known to be alive or analysis data cutoff date, whichever was earlier. Participants with no post baseline survival information were censored on the date of randomization. Analysis was based on Kaplan-Meier estimates. | From randomization until death (up to a maximum of 68.8 months) | 
| Time to Pain Progression | Pain was assessed using the score from the Brief Pain Inventory-Short Form (BPI-SF) question 3: Please rate your pain by marking the box beside the number that best describes your pain at its worst in the last 24 hours. Time to this event was defined as the time from randomization to onset of pain progression, where pain progression was defined as a 2-point or more increase from baseline in the question 3 score. Participants without observed pain progression at the time of analysis were right censored at the date of last pain assessment for the purposes of analysis. Analysis was based on Kaplan-Meier estimates. | From randomization until onset of pain progression (until the data cut-off date of 28 June 2017, maximum duration of treatment: 42.8 months) | 
| Time to First Use of Cytotoxic Chemotherapy | Time to first use of cytotoxic chemotherapy was defined as the time from randomization to the first use of cytotoxic chemotherapy for prostate cancer. Participants not starting treatment with a cytotoxic chemotherapy for prostate cancer at the time of analysis were right censored at the date of last assessment before the analysis data cutoff date for the purposes of analysis. Analysis was based on Kaplan-Meier estimates. | From randomization up to the first use of cytotoxic chemotherapy (until the data cut-off date of 28 June 2017, maximum duration of treatment: 42.8 months) | 
| Chemotherapy-Free Disease Specific Survival | Chemotherapy-free disease-specific survival was defined as the time from randomization to first use of cytotoxic chemotherapy for prostate cancer or death due to prostate cancer as assessed by the investigator. Participants not starting treatment with a cytotoxic chemotherapy or not known to have died due to prostate cancer at the time of analysis were right censored at the date of last assessment before the analysis data cutoff date for the purposes of analysis. Analysis was based on Kaplan-Meier estimates. | From randomization up to first use of cytotoxic chemotherapy for prostate cancer or death due to prostate cancer (until the data cut-off date of 28 June 2017, maximum duration of treatment: 42.8 months) | 
| Chemotherapy-Free Survival | Chemotherapy-free survival was defined as the time from randomization to first use of cytotoxic chemotherapy for prostate cancer or death due to any cause. Participants not starting treatment with a cytotoxic chemotherapy or not known to have died at the time of analysis were censored at the date of last assessment before the analysis data cutoff date for the purposes of analysis. Analysis was based on Kaplan-Meier estimates. | From randomization up to first use of cytotoxic chemotherapy for prostate cancer or death due to any cause (until the data cut-off date of 28 June 2017, maximum duration of treatment: 42.8 months) | 
| Percentage of Participants With Prostate Specific Antigen (PSA) Response | PSA response was calculated at each visit as a decline from baseline in PSA (ng/mL) to the maximal PSA response with thresholds at 50% and 90%. Additionally, PSA response was assessed as a decline to undetectable levels, where undetectable level was defined as below the limit of quantification of the centrally assessed PSA results (the lower limit of quantification was 0.02 ng/mL). PSA response was confirmed by a second consecutive value at least 3 weeks later. | From randomization until first PSA progression (until the data cut-off date of 28 June 2017, maximum duration of treatment: 42.8 months) | 
| Change From Baseline in Quality of Life as Assessed by Functional Assessment of Cancer Therapy-Prostate (FACT-P) Global Score | The FACT-P questionnaire is a multidimensional, self-reported quality of life instrument consisting of 27 core items that assess participant function in 4 domains: physical, social/family, emotional, functional well-being, and supplemented by 12 site-specific items to assess prostate-related symptoms. Each item was rated on a 0 to 4 Likert-type scale, and then combined to produce subscale scores for each domain, as well as a global quality of life score which ranged from 0 to 156 where higher scores represented better quality of life. | Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177 | 
| Number of Participants With European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Mobility Domain Score | EQ-5D-5L is a standardized instrument that measures health-related quality of life for men with prostate cancer. EQ-5D consists of EQ-5D descriptive system and EQ visual analogue scale (VAS). EQ-5D descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: 1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems, and 5=extreme problems. Number of participants with various responses to the mobility questionnaire are reported. | Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177 | 
| Number of Participants With European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Self-Care Domain Score | EQ-5D-5L is a standardized instrument that measures health-related quality of life for men with prostate cancer. EQ-5D consists of EQ-5D descriptive system and EQ VAS. EQ-5D descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: 1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems, and 5=extreme problems. Number of participants with various responses to the self-care questionnaire are reported. | Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177 | 
| Number of Participants With European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Usual Activities Domain Score | EQ-5D-5L is a standardized instrument that measures health-related quality of life for men with prostate cancer. EQ-5D consists of EQ-5D descriptive system and EQ visual analogue scale (VAS). EQ-5D descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: 1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems, and 5=extreme problems. Number of participants with various responses to the usual activities questionnaire are reported. | Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177 | 
| Number of Participants With European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Pain/Discomfort Domain Score | EQ-5D-5L is a standardized instrument that measures health-related quality of life for men with prostate cancer. EQ-5D consists of EQ-5D descriptive system and EQ visual analogue scale (VAS). EQ-5D descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: 1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems, and 5=extreme problems. Number of participants with various responses to the pain/discomfort questionnaire are reported. | Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177 | 
| Number of Participants With European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Anxiety/ Depression Domain Score | EQ-5D-5L is a standardized instrument that measures health-related quality of life for men with prostate cancer. EQ-5D consists of EQ-5D descriptive system and EQ visual analogue scale (VAS). EQ-5D descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: 1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems, and 5=extreme problems. Number of participants with various responses to the anxiety/depression questionnaire are reported. | Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177 | 
| European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Overall Health Status Visual Analog Score (VAS) | EQ-5D-5L is a standardized instrument that measures health-related quality of life for men with prostate cancer. EQ-5D consists of EQ-5D descriptive system and EQ VAS. EQ-5D-5L-VAS records participant's self-rated health on a vertical VAS that allows them to indicate their health state that can range from 0 (worst imaginable) to 100 (best imaginable), higher scores indicating a better health state. | Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177 | 
| Number of Participants With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 31 | The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Participants answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of participants with various responses to the question 31 are reported. Question 31 was following: Have you had to urinate frequently during the day? | Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177 | 
| Number of Participants With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 32 | The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Participants answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of participants with various responses to the question 32 are reported. Question 32 was following: Have you had to urinate frequently at night? | Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177 | 
| Number of Participants With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 33 | The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Participants answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of participants with various responses to the question 33 are reported. Question 33 was following: When you felt the urge to pass urine, did you have to hurry to get to the toilet? | Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177 | 
| Number of Participants With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 34 | The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Participants answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of participants with various responses to the question 34 are reported. Question 34 was following: Was it difficult for you to get enough sleep, because you needed to get up frequently at night to urinate? | Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177 | 
| Number of Participants With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 35 | The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Participants answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of participants with various responses to the question 35 are reported. Question 35 was following: Have you had difficulty going out of the house because you needed to be close to a toilet? | Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177 | 
| Number of Participants With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 36 | The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Participants answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of participants with various responses to the question 36 are reported. Question 36 was following: Have you had any unintentional release (leakage) of urine? | Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177 | 
| Number of Participants With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 37 | The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Participants answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of participants with various responses to the question 37 are reported. Question 37 was following: Did you have pain when you urinated? | Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177 | 
| Number of Participants With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 38 | The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Participants answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of participants with various responses to the question 38 are reported. Question 38 was following: Has wearing an incontinence aid been a problem for you?. This question was answered by only those participants who wore incontinence aid. | Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177 | 
| Number of Participants With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 39 | The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Participants answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of participants with various responses to the question 39 are reported. Question 39 was following: Have your daily activities been limited by your urinary problems? | Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177 | 
| Number of Participants With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 40 | The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Participants answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of participants with various responses to the question 40 are reported. Question 40 was following: Have your daily activities been limited by your bowel problems? | Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177 | 
| Number of Participants With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 41 | The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Participants answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of participants with various responses to the question 41 are reported. Question 41 was following: Have you had any unintentional release (leakage) of stools? | Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177 | 
| Number of Participants With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 42 | The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Participants answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of participants with various responses to the question 42 are reported. Question 42 was following: Have you had blood in your stools? | Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177 | 
| Number of Participants With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 43 | The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Participants answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of participants with various responses to the question 43 are reported. Question 43 was following: Did you have a bloated feeling in your abdomen? | Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177 | 
| Number of Participants With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 44 | The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Participants answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of participants with various responses to the question 44 are reported. Question 44 was following: Did you have hot flushes? | Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177 | 
| Number of Participants With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 45 | The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Participants answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of participants with various responses to the question 45 are reported. Question 45 was following: Have you had sore or enlarged nipples or breasts? | Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177 | 
| Number of Participants With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 46 | The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Participants answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of participants with various responses to the question 46 are reported. Question 46 was following: Have you had swelling in your legs or ankles? | Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177 | 
| Number of Participants With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 47 | The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Participants answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of participants with various responses to the question 47 are reported. Question 47 was following: Has weight loss been a problem for you? | Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177 | 
| Number of Participants With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 48 | The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Participants answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of participants with various responses to the question 48 are reported. Question 48 was following: Has weight gain been a problem for you? | Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177 | 
| Number of Participants With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 49 | The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Participants answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of participants with various responses to the question 49 are reported. Question 49 was following: Have you felt less masculine as a result of your illness or treatment? | Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177 | 
| Number of Participants With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 50 | The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Participants answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of participants with various responses to the question 50 are reported. Question 50 was following: To what extent were you interested in sex? | Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177 | 
| Number of Participants With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 51 | The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Participants answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of participants with various responses to the question 51 are reported. Question 51 was following: To what extent were you sexually active (with or without intercourse)? | Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177 | 
| Number of Participants With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 52 | The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Participants answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of participants with various responses to the question 52 are reported. Question 52 was following: To what extent was sex enjoyable for you? | Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177 | 
| Number of Participants With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 53 | The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Participants answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of participants with various responses to the question 53 are reported. Question 53 was following: Did you have difficulty getting or maintaining an erection? | Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177 | 
| Number of Participants With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 54 | The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Participants answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of participants with various responses to the question 54 are reported. Question 54 was following: Did you have ejaculation problems (e.g, dry ejaculation)? | Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177 | 
| Number of Participants With European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) Module Score for Question 55 | The EORTC QLQ-PR25, a module of the EORTC QLQ-30 questionnaire was used to assess the quality of life. It consisted of 25 questions (Question 31 to 55) distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Participants answered each of these questions using 4 point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Number of participants with various responses to the question 55 are reported. Question 55 was following: Have you felt uncomfortable about being sexually intimate? | Baseline, Weeks 17, 33, 49, 65, 81, 97, 113, 129, 145,161 and 177 | 
| Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. A treatment-emergent AE (TEAE) was defined as an AE that occurred from the date and time of the first dose of study drug through the date of last dose +30 days (or the day before initiation of a new antineoplastic treatment, whichever occurred first). AEs included both non-serious adverse events (AEs) and SAEs. | From first dose of study drug to the last dose + 30 days (or the day before initiation of a new antineoplastic treatment, whichever occurred first) (until the data cut-off date of 28 June 2017, maximum duration of treatment: 42.8 months) | 
| Number of Participants With Treatment-Emergent Adverse Events Greater Than or Equal to Grade 3, Based on National Cancer Institute (NCI) Common Terminology Criteria (CTC) for AEs (CTCAE), Version 4.0 | An AE is any untoward medical occurrence in participant who received study drug without regard to possibility of causal relationship. As per NCI CTCAE, Grade 3 events =medically significant but not immediately life-threatening, unacceptable or intolerable events, significantly interrupting usual daily activity, require systemic drug therapy/other treatment, Grade 4 events =participant to be in imminent danger of death. Grade 5 events =death. A treatment-emergent AE (TEAE) was defined as an AE that occurred from the date and time of the first dose of study drug through the date of last dose +30 days (or the day before initiation of a new antineoplastic treatment, whichever occurred first).Number of participants with AEs of any of the Grade 3 or above (Grade 4, 5) were reported. | From first dose of study drug to the last dose + 30 days (or the day before initiation of a new antineoplastic treatment, whichever occurred first) (until the data cut-off date of 28 June 2017, maximum duration of treatment: 42.8 months) | 
| Number of Participants With Discontinuations From Study Treatment Due to Adverse Events (AEs) | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs included both non-serious adverse events (AEs) and SAEs. | From first dose of study drug to the last dose + 30 days (or the day before initiation of a new antineoplastic treatment, whichever occurred first) (until the data cut-off date of 28 June 2017, maximum duration of treatment: 42.8 months) | 
| Number of Participants With Increase of 2 or More National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE) (Version 4.0) Toxicity Grades Above Baseline - Hematology | Hematology parameters: Haemoglobin (grams per liter [g/L]); leukocytes (log 10 raised to power 9 per liter [10*9/L]); lymphocytes (log 10 raised to power 6 per liter [10*6/L]); neutrophils (log 10 raised to power 6 per liter [10*6/L]); platelets (log 10 raised to power 9 per litre [10*9/L]). | From first dose of study drug to the last dose + 30 days (or the day before initiation of a new antineoplastic treatment, whichever occurred first) (until the data cut-off date of 28 June 2017, maximum duration of treatment: 42.8 months) | 
| Number of Participants With Increase of 2 or More National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE) (Version 4.0) Toxicity Grades Above Baseline - Chemistry | Chemistry parameters: Alanine aminotransferase (units per liter [U/L]); albumin (g/L); alkaline phosphatase (U/L); bilirubin (micromoles per liter [umol/L]); calcium (millimoles per liter [mmol/L]); creatine kinase (U/L); creatinine (umol/L); glucose, magnesium, phosphate, potassium, sodium (mmol/L). | From first dose of study drug to the last dose + 30 days (or the day before initiation of a new antineoplastic treatment, whichever occurred first) (until the data cut-off date of 28 June 2017, maximum duration of treatment: 42.8 months) | 
| Number of Participants With Clinically Significant Vital Signs | Vital signs included Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and heart rate. | From first dose of study drug to the last dose + 30 days (or the day before initiation of a new antineoplastic treatment, whichever occurred first) (until the data cut-off date of 28 June 2017, maximum duration of treatment: 42.8 months) |