Abiraterone Acetate in Asymptomatic or Mildly Symptomatic Patients With Metastatic Castration-Resistant Prostate Cancer

Study Overview
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Brief Summary
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This is a phase 3 study to compare the clinical benefit of abiraterone acetate plus prednisone with placebo plus prednisone in asymptomatic or mildly symptomatic patients with metastatic castration-resistant prostate cancer (CRPC).

Detailed Description
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This is a randomized (individuals will be assigned by chance to study treatments), double-blind (individuals and study personnel will not know the identity of study treatments), placebo (an inactive substance that is compared with a drug to test whether the drug has a real effect in a clinical trial)-controlled study in approximately 1,000 medically or surgically castrated male patients with metastatic CRPC who have shown tumor progression and are asymptomatic or mildly symptomatic. The study period will consist of screening, treatment, and follow-up phases. Patients will receive study treatment (abiraterone acetate or placebo) plus prednisone until radiographic progression of disease and/or unequivocal clinical progression. Efficacy evaluations will be performed throughout the treatment period and safety will be assessed until 30 days after the last dose of abiraterone acetate. throughout the study. Follow-up will continue for up to 60 months (5 years) or until the patient dies, is lost to follow-up, or withdraws informed consent. At the interim analysis of overall survival (OS; 43% of death events), the independent data monitoring committee (IDMC) reviewed the efficacy and safety data and concluded that all of the data pointed to a significant advantage for patients in one arm of the study compared with the other arm thereby unanimously recommending unblinding the study and allowing crossover from the placebo arm to active therapy. Patients currently receiving placebo will be offered crossover therapy to abiraterone acetate. Treatment for patients who were originally randomized to the abiraterone acetate treatment group will not change. Patients will be discontinued from long term follow-up at the time of the Clinical Cut-Off Date for Final Analysis (CCO-FA); however, patients still receiving treatment with abiraterone acetate at the CCO-FA will be offered to receive continued treatment for an additional period of up to 3 years or until disease progression or unacceptable toxicity. For these patients, safety assessment will be performed while continuing treatment, and for 30 days after the last dose of abiraterone acetate.

Official Title
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A Phase 3, Randomized, Double-blind, Placebo-Controlled Study of Abiraterone Acetate (CB7630) Plus Prednisone in Asymptomatic or Mildly Symptomatic Patients With Metastatic Castration-Resistant Prostate Cancer

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: Abiraterone acetate
* Drug: Placebo
* Drug: Prednisone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Metastatic castration-resistant prostate cancer (CRPC) Previous anti-androgen therapy and progression after withdrawal ECOG performance status of either 0 or 1 Medical or surgical castration with testosterone less than 50 ng/dL Life expectancy of at least 6 months Exclusion Criteria: Prior cytotoxic chemotherapy or biologic therapy for CRPC Prior ketoconazole for prostate cancer Known brain metastasis or visceral organ metastasis Use of opiate analgesics for cancer-related pain, including codeine and dextropropoxyphene, currently or anytime within 4 weeks of Cycle 1 Day 1

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo + prednisone<br>Placebo plus prednisone | Drug: Placebo<br>* 4 placebo tablets per day taken orally.<br>Drug: Prednisone<br>* 5 mg tablet orally twice daily.<br>|
| Experimental: Abiraterone + prednisone<br>Abiraterone acetate plus prednisone | Drug: Abiraterone acetate<br>* 1000 mg per day (4 x 250-mg tablets) taken orally.<br>Drug: Prednisone<br>* 5 mg tablet orally twice daily.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival is defined as the time from randomization to date of death from any cause. | From randomization (Day 1) up to end of study (Month 60) | 
| Radiographic Progression-free Survival (rPFS) | The rPFS was defined as the time from randomization to the occurrence of one of the following: 1) a participant was considered to have progressed by bone scan if - a) the first bone scan with greater than or equal to (>=) 2 new lesions compared to baseline was observed in less than (<) 12 weeks from randomization and was confirmed by a second bone scan taken >=6 weeks later showing >=2 additional new lesions (a total of >=4 new lesions compared to baseline), b) the first bone scan with >=2 new lesions compared to baseline was observed in >=12 weeks from randomization and the new lesions were verified on the next bone scan >=6 weeks later (a total of >=2 new lesions compared to baseline); 2) progression of soft tissue lesions measured by computerized tomography (CT) or magnetic resonance imaging (MRI); 3) death from any cause. | From randomization (Day 1) up to first radiographic progression or cutoff date (Month 18) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Opiate Use for Prostate Cancer Pain | The time interval from the date of randomization to the date of opiate use for cancer pain. Participants who have no opiate use at the time of analysis were censored at the last known date of no opiate use for cancer pain. Participants with no assessment were censored at the date of randomization. | From randomization (Day 1) up to first opiate use or end of study (Month 60) | 
| Time to Initiation of Cytotoxic Chemotherapy | The time interval from the date of randomization to the date of initiation of cytotoxic chemotherapy for prostate cancer. Participants who had no cytotoxic chemotherapy administration at the time of analysis were censored at the last known date when no cytotoxic chemotherapy was administered. Participants with no assessment were censored at the date of randomization. | From randomization (Day 1) up to initiation of cytotoxic chemotherapy or cutoff date (Month 18) | 
| Time to Deterioration in Eastern Cooperative Oncology Group (ECOG) Performance Score by >=1 Point | The time interval from the date of randomization to the first date at which there was at least a 1 grade change (worsening) in the ECOG performance status grade. Participants who had no deterioration in ECOG performance status grade at the time of the analysis were censored at the last known date of no deterioration. ECOG is a 5-point scale, where 0=Fully active, 1=Ambulatory, carry out work of sedentary nature, 2=Ambulatory, capable of all self-care, 3=Capable of limited self-care, confined to bed or chair more than 50% of waking hours, 4=Completely disabled, no self-care, totally confined to bed or chair, 5=Dead. Participants with no assessment were censored at the date of randomization. | From randomization (Day 1) up to first radiographic progression or cutoff date (Month 18) | 
| Time to Prostate-specific Antigen (PSA) Progression | The time interval from the date of randomization to the date of PSA progression as defined in the protocol-specific prostate cancer Working Group 2 (PCWG2) criteria. A participant was considered to have a PSA progression if the PSA level had a 25 percent (%) or greater increase from nadir and an absolute increase of 2 nanogram/milliliter ((ng/mL) or more, which is confirmed by a second value obtained in 3 or more weeks. Participants who had no PSA progression at the time of the analysis were censored at the last known date of no PSA progression. Participants with no on-study PSA assessment or no baseline PSA assessment were censored at the date of randomization. | From randomization (Day 1) up to date of PSA progerssion or cutoff date (Month 18) | 
| Number of Participants With Treatment Emergent Adverse Events | An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between administration of study drug and up to 30 days after last dose of study drug that were absent before treatment or that worsened relative to pre-treatment state. | From first dose of study drug up to 30 days after the last dose of study drug | 
| Mean Plasma Concentrations of Abiraterone |  | Up to Cycle 5, Day 1 | 
| Maximum Plasma Concentrations of Abiraterone |  | Up to Cycle 5, Day 1 | 
| Area Under the Plasma Concentration-time Curve From Time 0 to Time the Last Quantifiable Concentration of Abiraterone (AUC[0-infinity]) | The AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time, calculated as the sum of AUC(last) and C(last)/lambda(z); wherein AUC(last) is area under the plasma concentration-time curve from time zero to last quantifiable time, C(last) is the last observed quantifiable concentration, and lambda(z) is elimination rate constant. | Up to Cycle 5, Day 1 | 
| Elimination Half-Life (t1/2) | The elimination half-life (t1/2) is the time measured for the plasma concentration to decrease by 1 half to its original concentration. It is associated with the terminal slope of the semi logarithmic drug concentration-time curve, and is calculated as 0.693/lambda(z). | Up to Cycle 5, Day 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prostate cancer, Abiraterone acetate, CB7630, CRPC, Metastatic castration-resistant prostate cancer, hormone refractory prostate cancer