Safety and Efficacy Study of MDV3100 in Patients With Castration-Resistant Prostate Cancer Who Have Been Previously Treated With Docetaxel-based Chemotherapy

Survival was defined as time from randomization to death due to any cause. The duration of overall survival was right-censored for participants who were lost to follow-up since randomization or not known to have died at the data analysis cut-off date (this included participants who were known to have died after the data analysis cut-off date).

Time frame: During study period (up to 101 months)

Population: ITT included all participants who were randomized into the study.

EQ-5D: participant rated questionnaire to assess health-related quality of life in terms of a single utility or index score. Five parameters (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) were assessed on 3-point categorical scale (1= no problems, 2= some/moderate problems and 3= severe problem). Score were transformed and resulted in a total EQ-5D score range of 0 (worst imaginable health state) to 100 (best imaginable health state), with higher scores indicating better health and quality of life.

Time frame: Week 13

Population: Evaluable ITT included participants who were part of the ITT Population and who were evaluable for EQ-5D.

The FACT-P was a 39-item participant questionnaire which assessed physical well-being (7 items), social/family well-being (7 items), emotional well-being (6 items), functional well-being (7 items), and additional prostate cancer specific concerns (12 items). All items were scored from 0 (not at all) to 4 (very much). The sum of scores on all 5 domains constitutes the global FACT-P. The global/total FACT-P score ranged from 0 (worst) to 156 (best), higher scores indicate better health status. Responders were those participants who had a 10-point improvement in their total FACT-P score, as compared with baseline, on two consecutive measurements obtained at least 3 weeks apart.

Time frame: Baseline up to 24 months

Population: Evaluable intent to treat (ITT) - all participants who were part of the ITT population and had a global FACT-P score at baseline and at least 1 post-baseline assessment.

CTC conversion was assessed for participants with baseline CTC counts of greater than or equal to (\>=) 5 cells per 7.5 milliliter (mL) of blood. A CTC conversion was defined as a decline in the CTC count to less than (\<) 5 cells per 7.5 mL of blood. In this outcome measure percentage of participants with CTC conversion was reported.

Time frame: Baseline up to 24 months

Population: CTC evaluable population included participants with a baseline and at least 1 post baseline CTC assessment.

The proportion of participants with pain palliation was assessed for participants with a stable and sufficient pain burden at study entry. Pain burden was measured by question #3 of the Brief Pain Inventory (Short Form). This scale measures pain on a 0 to 10 scale with 0 indicating no pain and 10 indicating pain as bad as you can imagine. Pain palliation at Week 13 was determined for the proportion of men with baseline bone metastasis(es) who had baseline pain attributable to the metastasis(es). Palliation was defined as \>=30% reduction in average pain score at Week 13 compared to baseline without a \>=30% increase in analgesic use.

Time frame: Baseline up to 24 months

Population: Evaluable ITT Population included participants with metastatic bone disease at baseline; provided answers to Question #3 of the Brief Pain Inventory - Short Form for a minimum of 4 out of 7 days in the baseline run-in period; stable baseline pain; stable analgesic use; and had an average pain score during the baseline run-in period of \>= 4.

Participants were evaluable for PSA response rate if they had a PSA level measured at baseline and at least 1 post-baseline assessment. Both PSA responses of \> 50% and \> 90% were determined. PSA responses required confirmation with a subsequent assessment that was conducted at least 3 weeks later.

Time frame: During DB phase (up to 24 months)

Population: Evaluable ITT population included participants who were part of the ITT Population and had a PSA level measured at baseline and at least 1 post-baseline assessment.

The best overall soft tissue response as assessed using RECIST v1.1 during the study was summarized using the investigators' response assessments and also the derived response assessments by treatment group. Only participants with measurable soft tissue disease at screening were included in this analysis. Participants with measurable disease at screening are participants who had at least 1 target lesion identified per RECIST v1.1 at screening. Percentage of participants summarizes the number of participants with complete or partial objective response (%). Soft Tissue assessment based on Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45:228-247.

Time frame: During DB phase (up to 24 months)

Population: ITT with measurable disease population included participants who were part of the ITT Population and had measurable soft tissue disease at screening, defined by at least 1 target lesion according to RECIST v1.1.

Radiographic progression-free survival was defined as time from randomization to the earliest objective evidence of radiographic progression or death due to any cause. Participants were assessed for objective disease progression at regularly scheduled visits. The consensus guidelines of the Prostate Cancer Clinical Trials Working Group 2 were taken into consideration for the determination of disease progression. Radiographic disease progression was defined by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 for soft tissue disease, or the appearance of two or more new bone lesions on bone scan. Progression at the first scheduled reassessment at Week 13 required a confirmatory scan 6 or more weeks later. Participants who did not reach the endpoint were right censored at their last assessment.

Time frame: During DB phase (up to 24 months)

Population: ITT included all participants who were randomized into the study.

The time to first skeletal-related event was defined as time from randomization to the occurrence of the first skeletal-related event. Participants were assessed for skeletal-related events at regularly scheduled visits. A skeletal-related event was defined as radiation therapy or surgery to bone, pathologic bone fracture, spinal cord compression, or change of antineoplastic therapy to treat bone pain. Participants who did not reach the endpoint were right censored at their last assessment.

Time frame: During DB Phase (up to 24 months)

Population: ITT included all participants who were randomized into the study.

Time to PSA progression was defined as time from randomization to PSA progression. Participants who did not reach the endpoint were right censored at their last assessment or for participants with no post-baseline PSA assessment, date of randomization. For participants with PSA declines at Week 13, the PSA progression date was defined as the date that a \>=25% increase and an absolute increase of \>=2 nanogram per milliliter (ng/mL) above the nadir was documented, which was confirmed by a second consecutive value obtained 3 or more weeks later (required only if PSA progression did not occur at last PSA assessment). For participants with no PSA declines at Week 13, PSA progression date was defined as the date that a \>=25% increase and an absolute increase of \>=2 ng/mL above the baseline was documented, which was confirmed by a second consecutive value 3 or more weeks later (required only if PSA progression did not occur at last PSA assessment).

Time frame: Baseline and at every study visit from Week 13 while on study drug (up to 24 months)

Population: ITT included all participants who were randomized into the study.

Any new post baseline abnormality was defined as any abnormal ECG finding that appeared after baseline assessment which was not seen at the screening or baseline ECG assessment. Where, criteria of abnormality was QTcF interval \> 470 millisecond (msec). Participants were counted once only for a specific abnormality. This outcome measure was planned to be analysed in double blind phase only. Unscheduled visit was performed at any time during the study whenever necessary to assess for or follow-up on AEs, at the participant's request or if deemed necessary by the investigator.

Time frame: Baseline, up to the end of DB phase or unscheduled visit (up to 24 months)

Population: Safety population was defined as all randomized participants who received at least 1 dose of study drug.

Criteria for abnormalities in vital signs included: sitting/supine systolic blood pressure (SBP) values: absolute result greater than (\>) 180 millimeter of mercury (mmHg) and \>40 mmHg increase from baseline (BL) and less than (\<) 90 mmHg and \>30 mmHg decrease from BL; diastolic blood pressure (DBP) values: absolute result \>105 mmHg and \>30 mmHg increase from BL and absolute result \< 50 mmHg and \>20 mmHg decrease from BL; any abnormalities in SBP or DBP; heart rate values: absolute result \> 120 beats per minute (bpm) and \>30 bpm increase from BL and absolute result \< 50 bpm and \>20 bpm decrease from BL or any abnormalities in heart rate. Unscheduled visit was performed at any time during the study whenever necessary to assess for or follow-up on AEs, at the participant's request or if deemed necessary by the investigator.

Time frame: Baseline, up to the safety follow-up visit or unscheduled visit or the initiation of another anti-neoplastic therapy whichever occurred first (up to 101 months)

Population: Safety population was defined as all randomized participants who received at least 1 dose of study drug.

Laboratory parameters included hematological and chemistry parameters. Chemistry parameters included alanine aminotransferase, albumin, alkaline phosphatase, aspartate aminotransferase, bilirubin, calcium, creatine kinase, creatinine, glucose, magnesium, phosphate, potassium and sodium. Hematology parameters included haemoglobin, leukocytes, lymphocytes, neutrophils and platelet. Test abnormalities were graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03 as Grade 3= severe and Grade 4= life-threatening or disabling. Only categories with at least 1 participant with abnormality are reported in this outcome measure. Unscheduled visit was performed at any time during the study whenever necessary to assess for or follow-up on AEs, at the participant's request or if deemed necessary by the investigator.

Time frame: Baseline, up to the safety follow-up visit or unscheduled visit or the initiation of another anti-neoplastic therapy whichever occurred first (up to 101 months)

Population: Safety population was defined as all randomized participants who received at least 1 dose of study drug.

AE: any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAE: AE resulting in any of following outcomes or deemed significant and jeopardized participants or required treatment to prevent other AE outcomes for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. TEAEs were events which occurred between first dose of study drug and up to the safety follow-up visit or the initiation of another anti-neoplastic therapy, whichever occurred first (up to 101 months). AEs included both serious and non-serious AEs. Clinically significant physical examination abnormalities were reported as AEs. Unscheduled visit was performed at any time during the study whenever necessary to assess for or follow-up on AEs, at the participant's request or if deemed necessary by the investigator.

Time frame: Baseline, up to the safety follow-up visit or unscheduled visit or the initiation of another anti-neoplastic therapy whichever occurred first (up to 101 months)

Population: Safety population was defined as all randomized participants who received at least 1 dose of study drug.