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

Study Overview
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Brief Summary
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This is a randomized, double-blind, multicenter, phase 3 study evaluating orteronel (TAK-700) plus prednisone compared with placebo plus prednisone in the treatment of men with progressive, chemotherapy-naive, metastatic, castration-resistant prostate cancer (mCRPC)

Official Title
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A Phase 3, Randomized, Double-Blind, Multicenter Trial Comparing Orteronel Plus Prednisone With Placebo Plus Prednisone in Patients With Chemotherapy-Naive Metastatic Castration-Resistant Prostate Cancer

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: Orteronel
* Drug: Placebo
* Drug: Prednisone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Each patient must meet all of the following inclusion criteria: Voluntary written consent Male patients 18 years or older Histologically or cytologically confirmed diagnosis of prostate adenocarcinoma Radiograph-documented metastatic disease Progressive disease Prior surgical castration or concurrent use of an agent for medical castration Either absence of pain or pain not requiring use of any opioid or narcotic analgesia in the 2 weeks prior to study entry Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 Even if surgically sterilized, patients must practice effective barrier contraception during the entire study treatment and for 4 months after the last dose of study drug, OR abstain from heterosexual intercourse Meet screening laboratory values as specified in protocol Stable medical condition Exclusion Criteria: Patients meeting any of the following exclusion criteria are not to be enrolled in the study: Known hypersensitivity to orteronel, prednisone or gonadotropin-releasing hormone (GnRH) analogue Received prior therapy with orteronel, aminoglutethimide, ketoconazole or abiraterone Received antiandrogen therapy within 6 weeks for bicalutamide and 4 weeks for all others prior to first dose of study drug Continuous daily use of oral prednisone or oral dexamethasone for more than 14 days within 3 months prior to study Received prior chemotherapy for prostate cancer with exception of neoadjuvant/adjuvant therapy as part of initial primary treatment for local disease that was completed 2 or more years prior to screening Exposure to radioisotope therapy within 4 weeks of receiving first dose of study drug; exposure to external beam radiation within 2 weeks of start of screening until receiving the first dose of study drug Documented central nervous system metastases Treatment with any investigational compound within 30 days prior to first dose of study drug Current spinal cord compression, bilateral hydronephrosis or current bladder neck outlet obstruction Diagnosis or treatment of another malignancy within 2 years preceding first dose of study drug except nonmelanoma skin cancer or in situ malignancy completely resected Uncontrolled cardiovascular condition as specified in study protocol Known history of human immunodeficiency virus (HIV) infection, hepatitis B, or hepatitis C Unwilling or unable to comply with protocol Uncontrolled nausea, vomiting or diarrhea Known gastrointestinal disease or procedure that could interfere with oral absorption or tolerance of orteronel

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Orteronel + prednisone<br> | Drug: Orteronel<br>* Orteronel will be administered orally twice a day continuously throughout the study. Patients will also receive concomitant gonadotropin-releasing hormone (GnRH) analogue therapy unless they have previously undergone orchiectomy and have a testosterone concentration of <50 ng/dL.<br>Drug: Prednisone<br>* Prednisone will be administered orally twice a day continuously throughout the study. Patients will also receive concomitant gonadotropin-releasing hormone (GnRH) analogue therapy unless they have previously undergone orchiectomy and have a testosterone concentration of <50 ng/dL.<br>|
| Placebo Comparator: Placebo + prednisone<br> | Drug: Placebo<br>* Placebo will be administered orally twice a day continuously throughout the study. Additionally, all patients will receive concomitant gonadotropin-releasing hormone (GnRH) analogue therapy unless they have previously undergone orchiectomy and a testosterone concentration of <50 ng/dL.<br>Drug: Prednisone<br>* Prednisone will be administered orally twice a day continuously throughout the study. Patients will also receive concomitant gonadotropin-releasing hormone (GnRH) analogue therapy unless they have previously undergone orchiectomy and have a testosterone concentration of <50 ng/dL.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Radiographic Progression-free Survival (rPFS) | 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. | Baseline until radiographic disease progression or death, whichever occurred first (approximately up to 4.7 years) | 
| Overall Survival | 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. | Baseline until death (up to 4.7 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving 50 Percent Reduction From Baseline in Prostate Specific Antigen (PSA50) Response at Week 12 | The PSA50 is defined as a decline of at least 50 percent (%) from baseline. | Week 12 | 
| Percentage of Participants With Favorable Circulating Tumor Cell Count (CTC) Levels at Week 12 | 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. | Week 12 | 
| Time to Pain Progression | 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. | Baseline until End of treatment (EOT) (approximately up to 4.7 years) | 
| Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) |  | Baseline up to 30 days after last dose of study drug (Cycle 61 Day 58) | 
| Number of Participants With Treatment-emergent Adverse Events Greater Than or Equal to (>=) Grade 3 | 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. | Baseline up to 30 days after last dose of study drug (Cycle 61 Day 58) | 
| Number of Participants With TEAEs Related to Vital Signs |  | Baseline up to 30 days after last dose of study drug (Cycle 61 Day 58) | 
| Number of Participants With TEAEs Related to Weight |  | Baseline up to 30 days after last dose of study drug (Cycle 61 Day 58) | 
| Number of Participants With Worst Change From Baseline in Eastern Co-operative Oncology Group (ECOG) Performance Status | 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. | Baseline until EOT (approximately up to 4.7 years) | 
| Number of Participants With Abnormal Clinically Significant Electrocardiogram (ECG) Findings |  | Baseline up to EOT (Cycle 61 Day 58) | 
| Worst Change From Baseline Over Time in Cardiac Ejection Fraction | Worst change was defined as the worst overall change that occurred in cardiac ejection fraction at any measured time point. | Baseline up to 30 days or EOT whichever is later (approximately up to Cycle 61 Day 58) | 
| Number of Participants With TEAEs Categorized Into Investigations Related to Chemistry, Hematology or Coagulation |  | Baseline up to 30 days or EOT whichever is later (approximately up to Cycle 61 Day 58) | 
| Percentage of Participants With Skeletal Related Events (SRE) | 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. | Baseline up to EOT (approximately up to 4.7 years) | 
| Time to SRE | 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. | Baseline up to EOT (Cycle 61 Day 58) | 
| Percentage of Participants Achieving PSA50 Response at Any Time During the Study | The PSA50 is defined as a decline of PSA by 50 percent from baseline. | Cycle: 4, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34 and 37 | 
| Percentage of Participants Achieving 90 Percent Reduction From Baseline in Prostate Specific Antigen (PSA90 Response) at Week 12 | The PSA90 is defined as a decline of PSA by 90 percent from baseline. | Week 12 | 
| Percentage of Participants Achieving PSA90 Response at Any Time During the Study | The PSA90 is defined as a decline of PSA by 90 percent from baseline. | Cycle: 4, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34 and 37 | 
| Time to PSA Progression | 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. | 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) | 
| Time to Docetaxel Chemotherapy | 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. | Baseline until start of docetaxel chemotherapy (up to 4.7 years) | 
| Time to Subsequent Antineoplastic Therapy | 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. | Baseline until start of subsequent antineoplastic therapy (up to 4.7 years) | 
| Percentage of Participants With Objective Response | 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. | Baseline until disease progression or death, whichever occurred first (approximately up to 4.7 years) | 
| Time to Deterioration in Global Health Status | 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). | Baseline until EOT (approximately up to 4.7 years) |