Trial Outcomes & Findings for Study Comparing Orteronel Plus Prednisone in Participants With Chemotherapy-Naive Metastatic Castration-Resistant Prostate Cancer (NCT NCT01193244)

NCT ID: NCT01193244

Last Updated: 2017-05-17

Results Overview

rPFS 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, whichever occurred first. Radiographic disease progression was evaluated by computerized tomography (CT) scan or magnetic resonance imaging (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 Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 for soft tissue disease and Prostate Cancer Working Group (PCWG2) guidelines for bone disease. Participants who did not reach the endpoint were censored at their last assessment.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1560 participants

Primary outcome timeframe

Baseline until radiographic disease progression or death, whichever occurred first (approximately up to 4.7 years)

Results posted on

2017-05-17

Participant Flow

Participants took part in the study at 324 investigative sites in North America, Europe, Australia, Brazil, Chile, Colombia, Hong Kong, Peru, Puerto Rico, Israel, Japan, Mexico, New Zealand, Singapore, South Africa, and Taiwan from 19 October 2010 to 7 April 2016.

Male participants who were chemotherapy-naive and had metastatic castration-resistant prostate cancer (mCRPC) with documented progressive metastatic disease were enrolled in 1 of 2 treatment groups to receive Orteronel 400 milligram (mg) + Prednisone 5 mg or Placebo + Prednisone 5 mg.

Participant milestones

Participant milestones
Measure	Placebo + Prednisone 5 mg Orteronel placebo-matching tablets, orally, twice daily (BID) and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.	Orteronel 400 mg + Prednisone 5 mg Orteronel 400 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study. In Japan, participants were administered with Orteronel 300 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.
Overall Study STARTED	779	781
Overall Study Treated	770	784
Overall Study COMPLETED	391	391
Overall Study NOT COMPLETED	388	390

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo + Prednisone 5 mg Orteronel placebo-matching tablets, orally, twice daily (BID) and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.	Orteronel 400 mg + Prednisone 5 mg Orteronel 400 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study. In Japan, participants were administered with Orteronel 300 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.
Overall Study Withdrawal by Subject	79	97
Overall Study Other	303	278
Overall Study Lost to Follow-up	6	15

Baseline Characteristics

Study Comparing Orteronel Plus Prednisone in Participants With Chemotherapy-Naive Metastatic Castration-Resistant Prostate Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo + Prednisone 5 mg n=779 Participants Orteronel placebo-matching tablets, orally, twice daily (BID) and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.	Orteronel 400 mg + Prednisone 5 mg n=781 Participants Orteronel 400 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study. In Japan, participants were administered with Orteronel 300 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.	Total n=1560 Participants Total of all reporting groups
Age, Continuous	71.1 years STANDARD_DEVIATION 8.19 • n=5 Participants	70.9 years STANDARD_DEVIATION 8.26 • n=7 Participants	71.0 years STANDARD_DEVIATION 8.22 • n=5 Participants
Sex: Female, Male Female	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Sex: Female, Male Male	779 Participants n=5 Participants	781 Participants n=7 Participants	1560 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	90 Participants n=5 Participants	107 Participants n=7 Participants	197 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	672 Participants n=5 Participants	669 Participants n=7 Participants	1341 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	17 Participants n=5 Participants	5 Participants n=7 Participants	22 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	10 participants n=5 Participants	12 participants n=7 Participants	22 participants n=5 Participants
Race/Ethnicity, Customized Asian	51 participants n=5 Participants	38 participants n=7 Participants	89 participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	2 participants n=5 Participants	1 participants n=7 Participants	3 participants n=5 Participants
Race/Ethnicity, Customized Black or African American	19 participants n=5 Participants	25 participants n=7 Participants	44 participants n=5 Participants
Race/Ethnicity, Customized White	670 participants n=5 Participants	685 participants n=7 Participants	1355 participants n=5 Participants
Race/Ethnicity, Customized Unknown or Not Reported	12 participants n=5 Participants	3 participants n=7 Participants	15 participants n=5 Participants
Race/Ethnicity, Customized Other	15 participants n=5 Participants	17 participants n=7 Participants	32 participants n=5 Participants
Region of Enrollment Canada	22 participants n=5 Participants	22 participants n=7 Participants	44 participants n=5 Participants
Region of Enrollment United States	147 participants n=5 Participants	148 participants n=7 Participants	295 participants n=5 Participants
Region of Enrollment Austria	12 participants n=5 Participants	12 participants n=7 Participants	24 participants n=5 Participants
Region of Enrollment Belarus	6 participants n=5 Participants	10 participants n=7 Participants	16 participants n=5 Participants
Region of Enrollment Belgium	18 participants n=5 Participants	21 participants n=7 Participants	39 participants n=5 Participants
Region of Enrollment Bulgaria	6 participants n=5 Participants	6 participants n=7 Participants	12 participants n=5 Participants
Region of Enrollment Croatia	5 participants n=5 Participants	1 participants n=7 Participants	6 participants n=5 Participants
Region of Enrollment Czech Republic	13 participants n=5 Participants	18 participants n=7 Participants	31 participants n=5 Participants
Region of Enrollment Estonia	2 participants n=5 Participants	4 participants n=7 Participants	6 participants n=5 Participants
Region of Enrollment Finland	9 participants n=5 Participants	4 participants n=7 Participants	13 participants n=5 Participants
Region of Enrollment France	66 participants n=5 Participants	55 participants n=7 Participants	121 participants n=5 Participants
Region of Enrollment Germany	29 participants n=5 Participants	40 participants n=7 Participants	69 participants n=5 Participants
Region of Enrollment Greece	23 participants n=5 Participants	16 participants n=7 Participants	39 participants n=5 Participants
Region of Enrollment Hungary	3 participants n=5 Participants	4 participants n=7 Participants	7 participants n=5 Participants
Region of Enrollment Ireland	11 participants n=5 Participants	13 participants n=7 Participants	24 participants n=5 Participants
Region of Enrollment Italy	10 participants n=5 Participants	8 participants n=7 Participants	18 participants n=5 Participants
Region of Enrollment Latvia	12 participants n=5 Participants	14 participants n=7 Participants	26 participants n=5 Participants
Region of Enrollment Lithuania	19 participants n=5 Participants	18 participants n=7 Participants	37 participants n=5 Participants
Region of Enrollment Netherlands	35 participants n=5 Participants	38 participants n=7 Participants	73 participants n=5 Participants
Region of Enrollment Poland	0 participants n=5 Participants	4 participants n=7 Participants	4 participants n=5 Participants
Region of Enrollment Portugal	4 participants n=5 Participants	4 participants n=7 Participants	8 participants n=5 Participants
Region of Enrollment Romania	20 participants n=5 Participants	13 participants n=7 Participants	33 participants n=5 Participants
Region of Enrollment Slovakia	9 participants n=5 Participants	11 participants n=7 Participants	20 participants n=5 Participants
Region of Enrollment Spain	14 participants n=5 Participants	12 participants n=7 Participants	26 participants n=5 Participants
Region of Enrollment Sweden	11 participants n=5 Participants	6 participants n=7 Participants	17 participants n=5 Participants
Region of Enrollment Switzerland	10 participants n=5 Participants	8 participants n=7 Participants	18 participants n=5 Participants
Region of Enrollment Ukraine	25 participants n=5 Participants	23 participants n=7 Participants	48 participants n=5 Participants
Region of Enrollment United Kingdom	42 participants n=5 Participants	53 participants n=7 Participants	95 participants n=5 Participants
Region of Enrollment Australia	27 participants n=5 Participants	27 participants n=7 Participants	54 participants n=5 Participants
Region of Enrollment Brazil	41 participants n=5 Participants	50 participants n=7 Participants	91 participants n=5 Participants
Region of Enrollment Chile	20 participants n=5 Participants	20 participants n=7 Participants	40 participants n=5 Participants
Region of Enrollment Colombia	3 participants n=5 Participants	6 participants n=7 Participants	9 participants n=5 Participants
Region of Enrollment Hong Kong	1 participants n=5 Participants	3 participants n=7 Participants	4 participants n=5 Participants
Region of Enrollment Israel	14 participants n=5 Participants	4 participants n=7 Participants	18 participants n=5 Participants
Region of Enrollment Japan	22 participants n=5 Participants	18 participants n=7 Participants	40 participants n=5 Participants
Region of Enrollment Mexico	7 participants n=5 Participants	9 participants n=7 Participants	16 participants n=5 Participants
Region of Enrollment New Zealand	25 participants n=5 Participants	26 participants n=7 Participants	51 participants n=5 Participants
Region of Enrollment Peru	6 participants n=5 Participants	10 participants n=7 Participants	16 participants n=5 Participants
Region of Enrollment Puerto Rico	1 participants n=5 Participants	1 participants n=7 Participants	2 participants n=5 Participants
Region of Enrollment Singapore	5 participants n=5 Participants	2 participants n=7 Participants	7 participants n=5 Participants
Region of Enrollment South Africa	6 participants n=5 Participants	4 participants n=7 Participants	10 participants n=5 Participants
Region of Enrollment Taiwan, Province Of China	12 participants n=5 Participants	10 participants n=7 Participants	22 participants n=5 Participants
Region of Enrollment Russia	6 participants n=5 Participants	5 participants n=7 Participants	11 participants n=5 Participants
Height	172.77 centimeter STANDARD_DEVIATION 7.485 • n=5 Participants	173.26 centimeter STANDARD_DEVIATION 7.858 • n=7 Participants	173.02 centimeter STANDARD_DEVIATION 7.675 • n=5 Participants
Weight	84.04 kilogram STANDARD_DEVIATION 15.846 • n=5 Participants	85.09 kilogram STANDARD_DEVIATION 16.286 • n=7 Participants	84.57 kilogram STANDARD_DEVIATION 16.071 • n=5 Participants
Body Mass Index (BMI)	28.09 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 4.651 • n=5 Participants	28.28 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 4.730 • n=7 Participants	28.19 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 4.690 • n=5 Participants

PRIMARY outcome

Timeframe: Baseline until radiographic disease progression or death, whichever occurred first (approximately up to 4.7 years)

Population: ITT population included all participants who were randomized.

Outcome measures

Outcome measures
Measure	Placebo + Prednisone 5 mg n=779 Participants Orteronel placebo-matching tablets, orally, twice daily (BID) and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.	Orteronel 400 mg + Prednisone 5 mg n=781 Participants Orteronel 400 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study. In Japan, participants were administered with Orteronel 300 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.
Radiographic Progression-free Survival (rPFS)	8.7 months Interval 8.32 to 10.91	13.8 months Interval 13.05 to 14.92

PRIMARY outcome

Timeframe: Baseline until death (up to 4.7 years)

Population: ITT population included all participants who were randomized.

Overall survival was calculated from the date of participant randomization to the date of participant death due to any cause. Participants without documentation of death at time of the analysis were censored as of the date the participant was last known to be alive, or the data cutoff date, whichever was earlier.

Outcome measures

Outcome measures
Measure	Placebo + Prednisone 5 mg n=779 Participants Orteronel placebo-matching tablets, orally, twice daily (BID) and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.	Orteronel 400 mg + Prednisone 5 mg n=781 Participants Orteronel 400 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study. In Japan, participants were administered with Orteronel 300 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.
Overall Survival	29.5 months Interval 27.28 to 32.38	29.9 months Interval 27.88 to 33.04

SECONDARY outcome

Timeframe: Week 12

Population: ITT population included all participants who were randomized.

The PSA50 is defined as a decline of at least 50 percent (%) from baseline.

Outcome measures

Outcome measures
Measure	Placebo + Prednisone 5 mg n=779 Participants Orteronel placebo-matching tablets, orally, twice daily (BID) and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.	Orteronel 400 mg + Prednisone 5 mg n=781 Participants Orteronel 400 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study. In Japan, participants were administered with Orteronel 300 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.
Percentage of Participants Achieving 50 Percent Reduction From Baseline in Prostate Specific Antigen (PSA50) Response at Week 12	24.6 percentage of participants Interval 21.7 to 27.8	42.6 percentage of participants Interval 39.1 to 46.2

SECONDARY outcome

Timeframe: Week 12

Population: ITT population included all participants who were randomized.

A favorable CTC count was defined as less than \<5 counts per 7.5 milliliter (mL) in whole blood. An unfavorable CTC count was defined as greater than or equal to (\>=) 5 counts/7.5 mL in whole blood.

Outcome measures

Outcome measures
Measure	Placebo + Prednisone 5 mg n=779 Participants Orteronel placebo-matching tablets, orally, twice daily (BID) and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.	Orteronel 400 mg + Prednisone 5 mg n=781 Participants Orteronel 400 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study. In Japan, participants were administered with Orteronel 300 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.
Percentage of Participants With Favorable Circulating Tumor Cell Count (CTC) Levels at Week 12	9.1 percentage of participants Interval 7.2 to 11.4	15.4 percentage of participants Interval 12.9 to 18.1

SECONDARY outcome

Timeframe: Baseline until End of treatment (EOT) (approximately up to 4.7 years)

Population: ITT population included all participants who were randomized.

Time to pain progression was defined as the time from participant randomization to the first assessment date of pain progression. Pain progression was defined as the occurrence of 1 of the following and confirmed by an additional assessment, at least 3 weeks but not more than 5 weeks later: The brief pain inventory-short form (BPI-SF) worst pain score was \>=4 with a \>=2 point increase over baseline in BPI-SF worst pain score with stable or increased analgesic use; The BPI-SF worst pain score was \>=4 but not less than baseline with new or increased (relative to baseline) Step II or Step III analgesic use; The BPI-SF worst pain score was \<=3 but not less than baseline with new or increased (relative to baseline) Step III analgesic use. BPI-SF was an 11-item questionnaire, designed to assess severity and impact of pain on daily functions. Total score ranged from 0 to 100 with lower scores being indicative of less pain or pain interference.

Outcome measures

Outcome measures
Measure	Placebo + Prednisone 5 mg n=779 Participants Orteronel placebo-matching tablets, orally, twice daily (BID) and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.	Orteronel 400 mg + Prednisone 5 mg n=781 Participants Orteronel 400 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study. In Japan, participants were administered with Orteronel 300 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.
Time to Pain Progression	NA months Median was not estimable due to low number of events in the arm.	NA months Interval 28.57 to Median was not estimable due to low number of events in the arm.

SECONDARY outcome

Timeframe: Baseline up to 30 days after last dose of study drug (Cycle 61 Day 58)

Population: Safety population included all participants who received at least 1 dose of any study drug.

Outcome measures

Outcome measures
Measure	Placebo + Prednisone 5 mg n=770 Participants Orteronel placebo-matching tablets, orally, twice daily (BID) and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.	Orteronel 400 mg + Prednisone 5 mg n=784 Participants Orteronel 400 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study. In Japan, participants were administered with Orteronel 300 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.
Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) TEAE	733 participants	769 participants
Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) Serious Adverse Events (SAE)	321 participants	380 participants

SECONDARY outcome

Timeframe: Baseline up to 30 days after last dose of study drug (Cycle 61 Day 58)

Population: Safety population included all participants who received at least 1 dose of any study drug.

Grade 3 (Severe) events=unacceptable or intolerable events, significantly interrupting usual daily activity, require systemic drug therapy/other treatment. Grade 4 (Life-threatening) events caused participant to be in imminent danger of death. Grade 5 (Death) events=death related to an AE.

Outcome measures

Outcome measures
Measure	Placebo + Prednisone 5 mg n=770 Participants Orteronel placebo-matching tablets, orally, twice daily (BID) and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.	Orteronel 400 mg + Prednisone 5 mg n=784 Participants Orteronel 400 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study. In Japan, participants were administered with Orteronel 300 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.
Number of Participants With Treatment-emergent Adverse Events Greater Than or Equal to (>=) Grade 3 Grade 3 or higher TEAE	405 participants	537 participants
Number of Participants With Treatment-emergent Adverse Events Greater Than or Equal to (>=) Grade 3 Grade 5 (Death)	78 participants	77 participants

SECONDARY outcome

Timeframe: Baseline up to 30 days after last dose of study drug (Cycle 61 Day 58)

Population: Safety population included all participants who received at least 1 dose of any study drug.

Outcome measures

Outcome measures
Measure	Placebo + Prednisone 5 mg n=770 Participants Orteronel placebo-matching tablets, orally, twice daily (BID) and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.	Orteronel 400 mg + Prednisone 5 mg n=784 Participants Orteronel 400 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study. In Japan, participants were administered with Orteronel 300 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.
Number of Participants With TEAEs Related to Vital Signs Hypertension	76 participants	98 participants
Number of Participants With TEAEs Related to Vital Signs Pyrexia	26 participants	41 participants
Number of Participants With TEAEs Related to Vital Signs Hypotension	12 participants	26 participants

SECONDARY outcome

Timeframe: Baseline up to 30 days after last dose of study drug (Cycle 61 Day 58)

Population: Safety population included all participants who received at least 1 dose of any study drug.

Outcome measures

Outcome measures
Measure	Placebo + Prednisone 5 mg n=770 Participants Orteronel placebo-matching tablets, orally, twice daily (BID) and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.	Orteronel 400 mg + Prednisone 5 mg n=784 Participants Orteronel 400 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study. In Japan, participants were administered with Orteronel 300 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.
Number of Participants With TEAEs Related to Weight Weight decreased	47 participants	119 participants
Number of Participants With TEAEs Related to Weight Weight increased	36 participants	10 participants

SECONDARY outcome

Timeframe: Baseline until EOT (approximately up to 4.7 years)

Population: Safety population where baseline and post-baseline assessments were available. Safety population included all participants who received at least 1 dose of any study drug.

ECOG assessed participant's performance status on 5 point scale: 0=Fully active/able to carry on all pre-disease activities without restriction; 1=restricted in physically strenuous activity, ambulatory/able to carry out light or sedentary work; 2=ambulatory (\>50 percent of waking hours \[hrs\]), capable of all self care, unable to carry out any work activities; 3=capable of only limited self care, confined to bed/chair \>50 percent of waking hrs; 4=completely disabled, cannot carry on any self care, totally confined to bed/chair; 5=dead. Worst change was defined as the worst overall change that occurred in ECOG status at any measured time point during the treatment period.

Outcome measures

Outcome measures
Measure	Placebo + Prednisone 5 mg n=760 Participants Orteronel placebo-matching tablets, orally, twice daily (BID) and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.	Orteronel 400 mg + Prednisone 5 mg n=771 Participants Orteronel 400 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study. In Japan, participants were administered with Orteronel 300 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.
Number of Participants With Worst Change From Baseline in Eastern Co-operative Oncology Group (ECOG) Performance Status Baseline: 2; Overall: 2	1 participants	1 participants
Number of Participants With Worst Change From Baseline in Eastern Co-operative Oncology Group (ECOG) Performance Status Baseline: 0; Overall: 0	251 participants	200 participants
Number of Participants With Worst Change From Baseline in Eastern Co-operative Oncology Group (ECOG) Performance Status Baseline: 0; Overall: 1	177 participants	237 participants
Number of Participants With Worst Change From Baseline in Eastern Co-operative Oncology Group (ECOG) Performance Status Baseline: 0; Overall: 2	47 participants	66 participants
Number of Participants With Worst Change From Baseline in Eastern Co-operative Oncology Group (ECOG) Performance Status Baseline: 0; Overall: 3	22 participants	15 participants
Number of Participants With Worst Change From Baseline in Eastern Co-operative Oncology Group (ECOG) Performance Status Baseline: 0; Overall: 4	7 participants	7 participants
Number of Participants With Worst Change From Baseline in Eastern Co-operative Oncology Group (ECOG) Performance Status Baseline: 1; Overall: 0	6 participants	6 participants
Number of Participants With Worst Change From Baseline in Eastern Co-operative Oncology Group (ECOG) Performance Status Baseline: 1; Overall: 1	162 participants	147 participants
Number of Participants With Worst Change From Baseline in Eastern Co-operative Oncology Group (ECOG) Performance Status Baseline: 1; Overall: 2	57 participants	60 participants
Number of Participants With Worst Change From Baseline in Eastern Co-operative Oncology Group (ECOG) Performance Status Baseline: 1; Overall: 3	28 participants	26 participants
Number of Participants With Worst Change From Baseline in Eastern Co-operative Oncology Group (ECOG) Performance Status Baseline: 1; Overall: 4	2 participants	6 participants

SECONDARY outcome

Timeframe: Baseline up to EOT (Cycle 61 Day 58)

Population: Safety population included all participants who received at least 1 dose of any study drug.

Outcome measures

Outcome measures
Measure	Placebo + Prednisone 5 mg n=770 Participants Orteronel placebo-matching tablets, orally, twice daily (BID) and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.	Orteronel 400 mg + Prednisone 5 mg n=784 Participants Orteronel 400 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study. In Japan, participants were administered with Orteronel 300 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.
Number of Participants With Abnormal Clinically Significant Electrocardiogram (ECG) Findings	130 participants	163 participants

SECONDARY outcome

Timeframe: Baseline up to 30 days or EOT whichever is later (approximately up to Cycle 61 Day 58)

Population: Safety population where baseline and post-baseline assessments were available. Safety population included all participants who received at least 1 dose of any study drug.

Worst change was defined as the worst overall change that occurred in cardiac ejection fraction at any measured time point.

Outcome measures

Outcome measures
Measure	Placebo + Prednisone 5 mg n=676 Participants Orteronel placebo-matching tablets, orally, twice daily (BID) and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.	Orteronel 400 mg + Prednisone 5 mg n=670 Participants Orteronel 400 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study. In Japan, participants were administered with Orteronel 300 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.
Worst Change From Baseline Over Time in Cardiac Ejection Fraction	-3.8 percent ejection fraction Standard Deviation 6.93	-4.8 percent ejection fraction Standard Deviation 7.00

SECONDARY outcome

Timeframe: Baseline up to 30 days or EOT whichever is later (approximately up to Cycle 61 Day 58)

Population: Safety population included all participants who received at least 1 dose of any study drug.

Outcome measures

Outcome measures
Measure	Placebo + Prednisone 5 mg n=770 Participants Orteronel placebo-matching tablets, orally, twice daily (BID) and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.	Orteronel 400 mg + Prednisone 5 mg n=784 Participants Orteronel 400 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study. In Japan, participants were administered with Orteronel 300 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.
Number of Participants With TEAEs Categorized Into Investigations Related to Chemistry, Hematology or Coagulation Blood and lymphatic system disorders	114 participants	107 participants
Number of Participants With TEAEs Categorized Into Investigations Related to Chemistry, Hematology or Coagulation Investigations	215 participants	399 participants
Number of Participants With TEAEs Categorized Into Investigations Related to Chemistry, Hematology or Coagulation Metabolism and nutrition disorders	204 participants	336 participants

SECONDARY outcome

Timeframe: Baseline up to EOT (approximately up to 4.7 years)

Population: The ITT population included all participants who were randomized.

Skeletal related (SRE) event is defined as a fracture or spinal cord compression or the need for radiation or surgery at the site of a prostate cancer metastatic lesion that is substantiated by radiographic or pathologic evidence.

Outcome measures

Outcome measures
Measure	Placebo + Prednisone 5 mg n=779 Participants Orteronel placebo-matching tablets, orally, twice daily (BID) and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.	Orteronel 400 mg + Prednisone 5 mg n=781 Participants Orteronel 400 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study. In Japan, participants were administered with Orteronel 300 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.
Percentage of Participants With Skeletal Related Events (SRE)	10.9 percentage of participants Interval 8.8 to 13.3	8.6 percentage of participants Interval 6.7 to 10.8

SECONDARY outcome

Timeframe: Baseline up to EOT (Cycle 61 Day 58)

Population: The ITT population included all participants who were randomized.

Time to SRE is defined as the time from randomization to SRE, or death due to any cause, whichever comes first. SRE is defined as a fracture or spinal cord compression or the need for radiation or surgery at the site of a prostate cancer metastatic lesion that is substantiated by radiographic or pathologic evidence.

Outcome measures

Outcome measures
Measure	Placebo + Prednisone 5 mg n=779 Participants Orteronel placebo-matching tablets, orally, twice daily (BID) and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.	Orteronel 400 mg + Prednisone 5 mg n=781 Participants Orteronel 400 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study. In Japan, participants were administered with Orteronel 300 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.
Time to SRE	9.0 months Interval 8.32 to 10.98	13.9 months Interval 13.68 to 16.57

SECONDARY outcome

Timeframe: Cycle: 4, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34 and 37

Population: ITT population where baseline and post-baseline assessments were available. The ITT population included all participants who were randomized.

The PSA50 is defined as a decline of PSA by 50 percent from baseline.

Outcome measures

Outcome measures
Measure	Placebo + Prednisone 5 mg n=779 Participants Orteronel placebo-matching tablets, orally, twice daily (BID) and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.	Orteronel 400 mg + Prednisone 5 mg n=781 Participants Orteronel 400 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study. In Japan, participants were administered with Orteronel 300 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.
Percentage of Participants Achieving PSA50 Response at Any Time During the Study Cycle 4 (n= 687, 672)	28.09 percentage of participants Interval 24.76 to 31.62	49.70 percentage of participants Interval 45.86 to 53.55
Percentage of Participants Achieving PSA50 Response at Any Time During the Study Cycle 7 (n= 541, 540)	34.94 percentage of participants Interval 30.92 to 39.12	54.81 percentage of participants Interval 50.51 to 59.07
Percentage of Participants Achieving PSA50 Response at Any Time During the Study Cycle 10 (n= 438, 450)	36.99 percentage of participants Interval 32.45 to 41.7	56.00 percentage of participants Interval 51.28 to 60.64
Percentage of Participants Achieving PSA50 Response at Any Time During the Study Cycle 13 (n= 344, 382)	37.21 percentage of participants Interval 32.09 to 42.56	53.14 percentage of participants Interval 48.0 to 58.24
Percentage of Participants Achieving PSA50 Response at Any Time During the Study Cycle 16 (n= 286, 303)	34.27 percentage of participants Interval 28.78 to 40.08	54.13 percentage of participants Interval 48.33 to 59.84
Percentage of Participants Achieving PSA50 Response at Any Time During the Study Cycle 19 (n= 228, 272)	37.72 percentage of participants Interval 31.41 to 44.36	52.94 percentage of participants Interval 46.82 to 59.0
Percentage of Participants Achieving PSA50 Response at Any Time During the Study Cycle 22 (n= 184, 211)	33.15 percentage of participants Interval 26.4 to 40.46	54.03 percentage of participants Interval 47.05 to 60.89
Percentage of Participants Achieving PSA50 Response at Any Time During the Study Cycle 25 (n= 109, 119)	35.78 percentage of participants Interval 26.83 to 45.53	46.22 percentage of participants Interval 37.04 to 55.59
Percentage of Participants Achieving PSA50 Response at Any Time During the Study Cycle 28 (n= 67, 77)	44.78 percentage of participants Interval 32.6 to 57.42	48.05 percentage of participants Interval 36.52 to 59.74
Percentage of Participants Achieving PSA50 Response at Any Time During the Study Cycle 31 (n= 35, 39)	34.29 percentage of participants Interval 19.13 to 52.21	48.72 percentage of participants Interval 32.42 to 65.22
Percentage of Participants Achieving PSA50 Response at Any Time During the Study Cycle 34 (n= 22, 18)	36.36 percentage of participants Interval 17.2 to 59.34	38.89 percentage of participants Interval 17.3 to 64.25
Percentage of Participants Achieving PSA50 Response at Any Time During the Study Cycle 37 (n= 7, 5)	71.43 percentage of participants Interval 29.04 to 96.33	40.00 percentage of participants Interval 5.27 to 85.34

SECONDARY outcome

Timeframe: Week 12

Population: ITT population included all participants who were randomized.

The PSA90 is defined as a decline of PSA by 90 percent from baseline.

Outcome measures

Outcome measures
Measure	Placebo + Prednisone 5 mg n=779 Participants Orteronel placebo-matching tablets, orally, twice daily (BID) and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.	Orteronel 400 mg + Prednisone 5 mg n=781 Participants Orteronel 400 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study. In Japan, participants were administered with Orteronel 300 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.
Percentage of Participants Achieving 90 Percent Reduction From Baseline in Prostate Specific Antigen (PSA90 Response) at Week 12	5.4 percentage of participants	16.7 percentage of participants

SECONDARY outcome

Timeframe: Cycle: 4, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34 and 37

Population: ITT population where baseline and post-baseline assessments were available. The ITT population included all participants who were randomized.

The PSA90 is defined as a decline of PSA by 90 percent from baseline.

Outcome measures

Outcome measures
Measure	Placebo + Prednisone 5 mg n=779 Participants Orteronel placebo-matching tablets, orally, twice daily (BID) and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.	Orteronel 400 mg + Prednisone 5 mg n=781 Participants Orteronel 400 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study. In Japan, participants were administered with Orteronel 300 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.
Percentage of Participants Achieving PSA90 Response at Any Time During the Study Cycle 25 (n= 109, 119)	11.01 percentage of participants Interval 5.82 to 18.44	21.01 percentage of participants Interval 14.08 to 29.43
Percentage of Participants Achieving PSA90 Response at Any Time During the Study Cycle 4 (n= 687, 672)	5.39 percentage of participants Interval 3.82 to 7.35	16.67 percentage of participants Interval 13.93 to 19.7
Percentage of Participants Achieving PSA90 Response at Any Time During the Study Cycle 7 (n= 541, 540)	8.69 percentage of participants Interval 6.45 to 11.39	22.22 percentage of participants Interval 18.78 to 25.97
Percentage of Participants Achieving PSA90 Response at Any Time During the Study Cycle 10 (n= 438, 450)	11.64 percentage of participants Interval 8.79 to 15.02	26.44 percentage of participants Interval 22.42 to 30.78
Percentage of Participants Achieving PSA90 Response at Any Time During the Study Cycle 13 (n= 344, 382)	12.79 percentage of participants Interval 9.45 to 16.79	26.18 percentage of participants Interval 21.84 to 30.89
Percentage of Participants Achieving PSA90 Response at Any Time During the Study Cycle 16 (n= 286, 303)	12.24 percentage of participants Interval 8.67 to 16.61	25.74 percentage of participants Interval 20.91 to 31.05
Percentage of Participants Achieving PSA90 Response at Any Time During the Study Cycle 19 (n= 228, 272)	12.72 percentage of participants Interval 8.69 to 17.75	26.10 percentage of participants Interval 20.99 to 31.75
Percentage of Participants Achieving PSA90 Response at Any Time During the Study Cycle 22 (n= 184, 211)	10.87 percentage of participants Interval 6.77 to 16.29	28.44 percentage of participants Interval 22.45 to 35.03
Percentage of Participants Achieving PSA90 Response at Any Time During the Study Cycle 28 (n= 67, 77)	16.42 percentage of participants Interval 8.49 to 27.48	27.27 percentage of participants Interval 17.74 to 38.62
Percentage of Participants Achieving PSA90 Response at Any Time During the Study Cycle 31 (n= 35, 39)	8.57 percentage of participants Interval 1.8 to 23.06	12.82 percentage of participants Interval 4.3 to 27.43
Percentage of Participants Achieving PSA90 Response at Any Time During the Study Cycle 34 (n= 22, 18)	4.55 percentage of participants Interval 0.12 to 22.84	22.22 percentage of participants Interval 6.41 to 47.64
Percentage of Participants Achieving PSA90 Response at Any Time During the Study Cycle 37 (n= 7, 5)	14.29 percentage of participants Interval 0.36 to 57.87	20.00 percentage of participants Interval 0.51 to 71.64

SECONDARY outcome

Timeframe: Baseline until the final on treatment assessment or until end of short term follow-up following discontinuation of treatment, whichever occurred later (approximately up to 4.7 years)

Population: ITT population included all participants who were randomized.

Time to PSA progression was defined as time from randomization to a PSA increase of 25 percent and PSA rise of at least 2 nanogram per milliliter (ng/mL) above the lowest value observed post baseline or, if no PSA decline occurred post baseline, compared to baseline PSA.

Outcome measures

Outcome measures
Measure	Placebo + Prednisone 5 mg n=779 Participants Orteronel placebo-matching tablets, orally, twice daily (BID) and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.	Orteronel 400 mg + Prednisone 5 mg n=781 Participants Orteronel 400 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study. In Japan, participants were administered with Orteronel 300 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.
Time to PSA Progression	5.59 months Interval 5.56 to 5.59	8.3 months Interval 8.28 to 8.35

SECONDARY outcome

Timeframe: Baseline until start of docetaxel chemotherapy (up to 4.7 years)

Population: ITT population included all participants who were randomized.

Time to docetaxel based chemotherapy is defined as the time from randomization to the start of docetaxel based chemotherapy for prostate cancer, regardless of whether the participant received concurrent orteronel or not. Deaths due to disease progression prior to Docetaxel based chemotherapy were considered as events.

Outcome measures

Outcome measures
Measure	Placebo + Prednisone 5 mg n=779 Participants Orteronel placebo-matching tablets, orally, twice daily (BID) and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.	Orteronel 400 mg + Prednisone 5 mg n=781 Participants Orteronel 400 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study. In Japan, participants were administered with Orteronel 300 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.
Time to Docetaxel Chemotherapy	19.0 months Interval 16.44 to 21.43	23.0 months Interval 20.71 to 24.65

SECONDARY outcome

Timeframe: Baseline until start of subsequent antineoplastic therapy (up to 4.7 years)

Population: The ITT population included all participants who were randomized.

Time to subsequent antineoplastic therapy is defined as the time from randomization to the start of any alternate antineoplastic therapy for prostate cancer. Deaths due to disease progression prior to antineoplastic therapy for prostate cancer are considered as events. Otherwise, time to next therapy is censored at the date of death or the last date the participant was known to be alive or the data cutoff date, whichever is earlier.

Outcome measures

Outcome measures
Measure	Placebo + Prednisone 5 mg n=779 Participants Orteronel placebo-matching tablets, orally, twice daily (BID) and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.	Orteronel 400 mg + Prednisone 5 mg n=781 Participants Orteronel 400 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study. In Japan, participants were administered with Orteronel 300 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.
Time to Subsequent Antineoplastic Therapy	13.9 months Interval 12.16 to 14.86	17.2 months Interval 15.09 to 18.97

SECONDARY outcome

Timeframe: Baseline until disease progression or death, whichever occurred first (approximately up to 4.7 years)

Population: The Response Evaluation Criteria in Solid Tumors (RECIST) evaluable population included all participants who had measurable disease by RECIST 1.1 at the baseline assessment.

Percentage of participants with objective response based assessment of confirmed complete response (CR) or confirmed partial response (PR) according to RECIST 1.1. A CR was defined as the disappearance of all target lesions determined by computerized tomography (CT) or MRI. Any pathological lymph nodes (whether target or non-target) must have had reduction in short axis to \<10 millimetre (mm). A PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of longest diameters of non-lymph node lesions and of the short diameter or short axis of lymph nodes.

Outcome measures

Outcome measures
Measure	Placebo + Prednisone 5 mg n=243 Participants Orteronel placebo-matching tablets, orally, twice daily (BID) and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.	Orteronel 400 mg + Prednisone 5 mg n=236 Participants Orteronel 400 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study. In Japan, participants were administered with Orteronel 300 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.
Percentage of Participants With Objective Response	15.2 percentage of participants Interval 11.0 to 20.4	34.7 percentage of participants Interval 28.7 to 41.2

SECONDARY outcome

Timeframe: Baseline until EOT (approximately up to 4.7 years)

Population: The ITT population included all participants who were randomized.

Global health status deterioration is defined as a drop greater than 16 points from the baseline assessment, confirmed at least 3 weeks later, on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core Module 30 (EORTC QLQ-C30) index after the score has been linearly transformed to a 0 to 100 scale. EORTC QLQ-C30 consists of 30 questions, where question 1 to 28 can be answered with 1: Not at all, 2: A little, 3: Quite a bit, 4: Very much and question 29 to 30 with 1: Very poor to 7: Excellent. For subscales a high score from 0-100 indicates: high global quality of life, high level of functioning (physical, role, emotional, cognitive, social) or a high level of symptoms (fatigue, nausea, pain, dyspnea, insomnia, appetite loss, constipation, diarrhoea, financial difficulties).

Outcome measures

Outcome measures
Measure	Placebo + Prednisone 5 mg n=779 Participants Orteronel placebo-matching tablets, orally, twice daily (BID) and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.	Orteronel 400 mg + Prednisone 5 mg n=781 Participants Orteronel 400 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study. In Japan, participants were administered with Orteronel 300 mg, tablets, orally, BID and Prednisone 5 mg, tablets, orally, BID for up to Day 28 of each treatment cycle throughout the study.
Time to Deterioration in Global Health Status	10.7 months Interval 8.97 to 11.11	8.3 months Interval 7.36 to 10.16

Adverse Events

Placebo + Prednisone 5 mg

Serious events: 321 serious events

Other events: 721 other events

Deaths: 0 deaths

Orteronel 400 mg + Prednisone 5 mg

Serious events: 380 serious events

Other events: 757 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Director

Takeda

Phone: +1-877-825-3327

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee In general, Investigators may publish clinical data after the earlier of (i) publication by the Sponsor or (ii) 12 months following the abandonment, early termination or database lock; provided a copy of the publication provided to Sponsor at least 30 days ahead of publication, the Sponsor's confidential information is removed as may be requested by Sponsor and Investigator defers publication for up to 60 days in the event Sponsor provides notice that it intends to file a patent application.
Publication restrictions are in place

Restriction type: OTHER