Enzalutamide

rPFS was calculated as the time from the date of randomization to the first objective evidence of radiographic progression disease (rPD) at any time or death up to 24 weeks after study drug discontinuation without documented radiographic progression, whichever occurred first. rPD was defined as progressive disease by Response Evaluation Criteria in Solid Tumors version 1.1 for soft tissue disease or by appearance of 2 or more new lesions on bone scan compared to baseline or week 13 according to PCWG2 criteria, as assessed by ICR or death. In participants with no rPFS event, rPFS was censored on the date of last evaluable radiographic assessment prior to the data analysis cutoff date. In participants with no baseline radiographic assessment, participants with no postbaseline radiographic assessments and participants with all postbaseline radiographic assessments documented as "not evaluable (NE)," rPFS was censored on the date of randomization.

rPFS was calculated as the time from the date of randomization to the first objective evidence of radiographic progression disease (rPD) at any time or death up to 24 weeks after study drug discontinuation without documented radiographic progression, whichever occurred first. rPD was defined as progressive disease by Response Evaluation Criteria in Solid Tumors version 1.1 for soft tissue disease or by appearance of 2 or more new lesions on bone scan compared to baseline for week 13 or the best response on treatment for week 25 or later assessments, as assessed by ICR or death. In participants with no rPFS event, rPFS was censored on the date of last evaluable radiographic assessment prior to the data analysis cutoff date. In participants with no baseline radiographic assessment, participants with no postbaseline radiographic assessments and participants with all postbaseline radiographic assessments documented as "not evaluable (NE)," rPFS was censored on the date of randomization.

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.

MFS was defined as the duration of time in months between randomization and the earliest objective evidence of radiographic progression by central imaging or death without radiographic progression, whichever occurred first. Radiographic progression for soft tissue disease was defined by Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1). Radiographic progression for bone disease was defined as the appearance of 1 or more metastatic lesions on bone scan (a bone scan assesses 5 regions of the skeleton, including skull, thorax, spine, pelvis, and extremities). Confirmation with a second imaging modality (plain film, computed tomography \[CT\], or magnetic resonance imaging \[MRI\]) was to be required when bone lesions were found in a single region on the bone scan. Appearance of metastatic lesions in 2 or more of the 5 regions on a bone scan was not to require confirmation with a second imaging modality.

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.

Overall survival was defined as the time from randomization to death due to any cause. For patients who were alive at the time of the analysis data cutoff, overall survival was censored at the last date the patient was known to be alive or analysis data cutoff date, whichever was first. This included patients who were known to have died after the data analysis cutoff date. Patients with no post-baseline survival information were censored on the date of randomization.

Radiographic progression-free survival was defined as the time from randomization to the first objective evidence of radiographic disease progression assessed by independent central radiology review or death due to any cause within 168 days after treatment discontinuation, whichever was first. Radiographic disease progression was evaluated by CT scan or MRI and radionuclide bone scans at regularly scheduled visits. Radiographic disease progression in bone required a confirmatory scan. Radiographic disease progression in soft tissue did not require a confirmatory scan for purposes of analysis. Radiographic disease progression was evaluated by independent central radiology review using RECIST 1.1 for soft tissue disease and PCWG2 guidelines for bone disease. Patients who did not reach the endpoint were censored at their last assessment.

PFS is the time from randomization to the date of the first progression event detected. A progression event was defined as objective evidence of radiographic disease progression based on the assessments by the ICR, skeletal-related event, initiation of new antineoplastic therapy or death by any cause, whichever occurred first. Radiographic disease progression was defined as either a progression in soft tissue on computed tomography (CT)/magnetic resonance imaging (MRI) scan according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, and/or a progression in bone lesions on bone scan (≥ 2 new bone lesions) confirmed by the next bone scan. A skeletal-related event was any radiation therapy or surgery to bone, pathologic bone fracture, spinal cord compression or change in antineoplastic therapy to treat bone pain. The initiation of new antineoplastic therapy included any new therapy for the treatment of disease progression after the study drug administration started.

Time to cancer prostate progression (pathological or therapeutic): time (in months) from date of randomization until the date of cancer progression (pathological or therapeutic). Pathological progression: increase in primary or secondary Gleason pattern by greater than or equal (\>=) 1 or higher proportion of cancer positive cores (\>=15 percent \[%\] increase). Therapeutic progression: earliest occurrence of primary therapy for prostate cancer (prostatectomy/radiation/focal therapy/systemic therapy). Medians and 95% CIs were calculated with the Kaplan-Meier (KM) method. Participants with no cancer progression at the time of study completion, discontinuation or death were censored at the last assessment date. Participants switching therapy during the study were censored at the time of the initial therapy switch, and participants discontinuing therapy were censored at the time of study discontinuation.

OS was defined as the time from the date of randomization until the documented date of death from any cause. Participants who were still alive at the time of the data cut-off date was censored on the last date known to be alive or at the data cutoff date, whichever occurs first. Results based on Kaplan-Meier estimates.

A treatment-emergent adverse event (TEAE) was defined as an adverse event occurring or worsening between the start of study treatment date and the latest date of 30 days after the last dose date or the 30-day follow-up visit date, and not later than the data cut-off date or the date of death. AEs, including abnormal clinical laboratory values, were graded using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) guidelines (V4.03).

Clinical benefit rate was defined as the percentage of evaluable participants with best objective response of confirmed complete response or partial response per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, or prolonged stable disease (≥ 24 weeks). Complete response (CR) was defined as the disappearance of all target and non-target lesions and no new lesions, and lymph nodes all \< 10 mm in short axis. Partial response (PR) was defined as disappearance of target lesions or a ≥ 30% decrease in the size of target lesions, with persistence of non-target lesions and no new lesions. Stable disease (SD) was defined as \< 30% decrease and \< 20% increase in the size of target lesions, persistence of non-target lesions, and no new lesions. PR and CR required confirmation with equivalent or improved assessment no less than 4 weeks after the date that PR or CR was first observed. SD required confirmation with equivalent or improved assessment no less than 8 weeks after enrollment.

Bone lesion responded: if its change from baseline in SUVtotal is below limit of agreement (LOA, no specific value, based upon test/retest analysis using software). SUVtotal: total NaF uptake,indicated tumor burden across all bone lesions/in individual lesions reflecting bone-metastatic prostate cancer.NaF-3 performed on any of these: 1) prostate-specific antigen (PSA) progression(increase of \>=25% and absolute increase of \>=2.0 ng/mL above nadir); 2) bone progressive disease(PD)(appearance of \>=2 new lesions after screening assessed by technetium Tc 99m medronate \[99mTc-MDP\] bone scintigraphy); 3) soft tissue PD; 4) clinically relevant progression by investigator; 5) at 2 years without progression after treatment initiation. PD, RECIST1.1:\>=20% increase in sum of diameters of target lesions,(reference smallest sum on study, included baseline sum if that is smallest on study),relative increase of 20%,sum of diameters indicated absolute increase of \>=5mm, appearance of \>=1 new lesions.

PFS was defined as the time in months from randomization to the first documentation of progression of disease (PD) or death on study due to any cause, whichever occurred first. PD according to response evaluation criteria in solid tumors version 1.1 (RECIST 1.1) was defined as greater than or equal to (\>=) 20 percent (%) increase in the sum of diameters of the target lesions taking as a reference the smallest sum recorded since the start of treatment or unequivocal progression in non-target lesions or the appearance of 1 or more new lesions. The analysis of PFS was based on investigator assessment of disease progression. Participants who were not known to have had a PFS event at the analysis date were censored at last tumor assessment date prior to data cutoff or date of new treatment initiation, whichever occurred first.

PFS was defined as the time in months from randomization to the first documentation of PD or death on study due to any cause, whichever occurred first. PD according to RECIST 1.1, was defined as \>= 20% increase in the sum of diameters of the target lesions taking as a reference the smallest sum recorded since the start of treatment or unequivocal progression in non-target lesions or the appearance of 1 or more new lesions. The analysis of PFS was based on investigator assessment of disease progression. Participants who were not known to have had a PFS event at the analysis date were censored at last tumor assessment date prior to data cutoff or date of new treatment initiation, whichever occurred first.

Percentage of participants with a clinical benefit at Week 16 defined as percentage of participants with a best response of complete response (CR), partial response(PR), stable disease(SD) for \>=16 weeks on radiologic imaging based on Investigator assessment using Response Evaluation Criteria in Solid Tumors version 1.1(RECIST 1.1). An estimate of the percentage and its exact 2-sided 85% confidence interval(CI) were calculated using the Blaker method. As per RECIST 1.1, CR defined as disappearance of all target, non-target lesions and normalization of tumor marker level and all lymph nodes decreased to non-pathological in size \<10mm short axis. PR: At least 30% decrease in sum of longest diameter (LD) of target lesions taking as reference baseline sum of LD, without progression of non-target lesions, no appearance of new lesions. SD: Neither sufficient reduction to qualify as PR nor sufficient increase to qualify as PD, using the smallest sum diameters during the study as a reference.

Percentage of participants with a clinical benefit at Week 16 defined as percentage of participants with a best response of CR, PR, or SD for \>= 16 weeks on radiologic imaging based on Investigator assessment using RECIST 1.1. An estimate of the percentage and its exact 2-sided 85% CI were calculated using the Blaker method. As per RECIST 1.1, CR defined as disappearance of all target, non-target lesions and normalization of tumor marker level and all lymph nodes decreased to non-pathological in size \<10 mm short axis. PR: At least 30% decrease in sum of LD of target lesions taking as reference baseline sum of LD, without progression of non-target lesions, no appearance of new lesions. SD: Neither sufficient reduction to qualify as PR nor sufficient increase to qualify as PD, using the smallest sum diameters during the study as a reference.

Pathologic complete response rate was defined as percentage of participants with pathologic complete response. Pathologic complete response rate following triplet therapy (enzalutamide in combination with leuprolide and dutasteride) and enzalutamide alone when administered as neoadjuvant therapy for 180 days prior to prostatectomy in participants with localized prostate cancer. Pathologic complete response was defined as the absence of morphologically identifiable carcinoma in the prostatectomy specimen, as assessed by the local and central pathologist.

Bone marrow biopsies were performed at the Day 1 visit prior to initiation of enzalutamide administration. Repeat bone marrow biopsies were performed at the Week 9 visit. If a repeat bone marrow was not performed at the Week 9 visit or if a patient discontinued the study before the Week 9 visit, a bone marrow biopsy was obtained at the Safety Follow-up visit. Assessment of intratumoral testosterone was assessed by liquid chromatography mass spectrometry.

Bone marrow biopsies were performed at the Day 1 visit prior to initiation of enzalutamide administration. Repeat bone marrow biopsies were performed at the Week 9 visit. If a repeat bone marrow was not performed at the Week 9 visit or if a patient discontinued the study before the Week 9 visit, a bone marrow biopsy was obtained at the Safety Follow-up visit. Assessment of intratumoral dihydrotestosterone was assessed by liquid chromatography mass spectrometry.

Bone marrow biopsies were performed at the Day 1 visit prior to initiation of enzalutamide administration. Repeat bone marrow biopsies were performed at the Week 9 visit. If a repeat bone marrow was not performed at the Week 9 visit or if a patient discontinued the study before the Week 9 visit, a bone marrow biopsy was obtained at the Safety Follow-up visit. Assessment of intratumoral testosterone was assessed by liquid chromatography mass spectrometry. Serum samples for measurement of PSA levels were obtained at baseline prior to initiation of enzalutamide administration and at the Week 9 visit. The change from baseline in bone marrow testosterone levels at Week 9 was correlated with PSA response status at Week 9.

Bone marrow biopsies were performed at the Day 1 visit prior to initiation of enzalutamide administration. Repeat bone marrow biopsies were performed at the Week 9 visit. If a repeat bone marrow was not performed at the Week 9 visit or if a patient discontinued the study before the Week 9 visit, a bone marrow biopsy was obtained at the Safety Follow-up visit. Assessment of intratumoral dihydrotestosterone was assessed by liquid chromatography mass spectrometry. Serum samples for measurement of PSA levels were obtained at baseline prior to initiation of enzalutamide administration and at the Week 9 visit. The change from baseline in bone marrow dihydrotestosterone levels at Week 9 was correlated with PSA response status at Week 9.

This measure will be assessed on the dose escalation cohorts.

This measure will be assessed on the dose expansion cohort

Cmax will be recorded from the pharmacokinetic (PK) plasma samples collected.

AUClast will be recorded from the pharmacokinetic (PK) plasma samples collected.

AUCinf will be recorded from the pharmacokinetic (PK) plasma samples collected.

DLTs were defined as any of following events related to the study drug: Any adverse event (AE) consistent with a seizure of any grade; Grade greater than equal to (\>=) 3 fatigue, diarrhea, nausea, or vomiting that did not improve to Grade 1 within 14 days of initiating standard of care therapy; any Grade \>=3 hematologic toxicity with the following modifications: 1) Grade \>=3 platelet count associated with bleeding, 2) Grade \>=3 absolute neutrophil count that persists for 7 or more days or that was associated with fevers (febrile neutropenia); Grade \>=3 any other non-hematological toxicity that was determined to be related to study drug.

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. AE was assessed according to severity grading based on NCI CTCAE Version 4.03 and defined as Grade 3 AEs = severe or medically significant events but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated, disabling, limiting self-care activities of daily living; Grade 4 AEs = life-threatening, urgent intervention indicated; Grade 5 AEs = death related to adverse event.

An AE was any untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. 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 or incapacity, congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 30 days after last dose of study drug that were absent before treatment or that worsened relative to pretreatment state. AEs included both serious and non-serious adverse events.

An AE was any untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. 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 or incapacity, congenital anomaly.

An AE was any untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. 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 or incapacity, congenital anomaly.

Absolute systolic blood pressure (SBP) greater than (\>) 180 millimeter of mercury (mm Hg) and an increase of \>40 mm Hg from baseline; absolute SBP less than (\<) 90 mm Hg and an decrease of \>30 mm Hg from baseline. Absolute diastolic blood pressure (DBP) \>105 mm Hg and an increase of \>30 mm Hg from baseline; absolute DBP \<50 mm Hg and an increase of \>20 mm Hg from baseline. Absolute heart rate \>120 beats per minute (bpm) and an increase of \>30 bpm from baseline; absolute heart rate \<50 bpm and decrease of \>20 bpm from baseline. Participants with any of these abnormalities were reported for this outcome in each arm.

Carboxylic Acid (M1) and N-desmethyl (M2) are two metabolites of Enzalutamide.

Carboxylic Acid (M1) and N-desmethyl (M2) are two metabolites of Enzalutamide.

Carboxylic Acid (M1) and N-desmethyl (M2) are two metabolites of Enzalutamide.

AUCinf = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - inf).

Terminal elimination half-life is the time measured for the plasma concentration of Enzalutamide to decrease by one-half of its initial concentration.

Apparent oral clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. It was obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed.

Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed.

Carboxylic Acid (M1) and N-desmethyl (M2) are two metabolites of Enzalutamide.

Carboxylic Acid (M1) and N-desmethyl (M2) are two metabolites of Enzalutamide.

Area under the plasma concentration versus time-curve from time zero to end of dosing interval (AUCtau), where dosing interval was 24 hours. Carboxylic Acid (M1) and N-desmethyl (M2) are two metabolites of Enzalutamide.

Apparent oral clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. It was obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed.

Peak-to-trough ratio was calculated by dividing Cmax with Cmin of Enzalutamide and its Metabolites. Carboxylic Acid (M1) and N-desmethyl (M2) are two metabolites of Enzalutamide. Cmax was maximum plasma concentration during the dosing interval and Cmin was minimum observed plasma concentration during the dosing interval.

Accumulation Ratio was defined as the ratio of AUC24 of Day 50 to AUC24 of Day 1, where AUC24 was area under the plasma concentration-time curve from time zero to 24 hours post-dose. Carboxylic Acid (M1) and N-desmethyl (M2) are two metabolites of Enzalutamide.

Percentage of participants that required dose reductions of Docetaxel and Enzalutamide treatment were reported in this outcome measure. Dose modifications (interruptions or dose reductions) were permitted for participants who had adverse events that were intolerable or could not be improved by other means. Dose reductions or delays were determined according to the prescribing information and at the discretion of the investigator.

AE was any untoward medical occurrence in participant who received study drug without regard to possibility of causal relationship. Percentage of participants that discontinued study drug due to adverse events were reported in this outcome measure.

An adverse events (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An 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 was defined as an event that emerged during the treatment period that was absent before treatment, or worsened during the treatment period relative to the pretreatment state. AEs included both SAEs and non-SAEs.

DLT was defined as a national cancer institute's common toxicity criteria for adverse events (NCI-CTCAE) version 3.0 grade 3 or greater toxicity regardless of perceived causality that is not improved by the use of adequate/maximal medical intervention. Grade 3 alopecia, fever without neutropenia, nausea, vomiting, fatigue, and self-limited or medically controllable adverse events were not considered as DLTs.

Tolerability was defined as if less than (\<) 4/12 in participants with no prior exposure to MDV3100 (chemo-naive) and \< 4/12 prior chemotherapy participants experienced a DLT within the first 35 days of the multiple dose period. For doses higher than 360 mg/day, tolerability was defined if \<8/24 participants previously treated with chemotherapy experience a DLT within the first 35 days of the multiple dose period. MTD was defined as a dose below the intolerable dose.