Safety and Efficacy Study of Enzalutamide Versus Bicalutamide in Men With Prostate Cancer

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety and efficacy of enzalutamide vs bicalutamide in asymptomatic or mildly symptomatic patients with prostate cancer who have disease progression despite primary androgen deprivation therapy.

Detailed Description
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This study is a multicenter phase 2, randomized, double-blind, efficacy and safety study of enzalutamide (160 mg/day) vs. bicalutamide (50 mg/day) in patients with recurrent prostate cancer who have serologic and/or radiographic disease progression despite primary androgen deprivation therapy. Throughout the study, safety and tolerability will be assessed by the recording of adverse events, monitoring of vital signs, physical examinations, and safety laboratory evaluations. Following study unblinding, study patients receiving enzalutamide or bicalutamide at the time of unblinding and qualifying patients randomized to bicalutamide who discontinued prior to unblinding will be offered the opportunity to receive open label enzalutamide treatment.

Official Title
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STRIVE: A MULTICENTER PHASE 2, RANDOMIZED, DOUBLE-BLIND, EFFICACY AND SAFETY STUDY OF ENZALUTAMIDE VS. BICALUTAMIDE IN MEN WITH PROSTATE CANCER WHO HAVE FAILED PRIMARY ANDROGEN DEPRIVATION THERAPY

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: Enzalutamide
* Drug: Bicalutamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males age 18 or older; Histologically or cytologically confirmed adenocarcinoma of the prostate; Ongoing androgen deprivation therapy; Serum testosterone level ≤ 50 ng/dL (1.73 nmol/L) at the Screening visit; Progressive disease at study entry defined by prostate-specific antigen (PSA) progression and/or radiographic progression that occurred while the patient was on primary androgen deprivation therapy; Asymptomatic or mildly symptomatic from prostate cancer; Eastern Cooperative Oncology Group (ECOG) performance status of 0-1; Estimated life expectancy of ≥ 12 months; Able to swallow the study drug and comply with study requirements. Exclusion Criteria: Severe concurrent disease, infection, or co-morbidity; Known or suspected brain metastasis or active leptomeningeal disease; History of another invasive malignancy within the previous 5 years other than treated non-melanomatous skin cancer and American Joint Committee on Cancer (AJCC) Stage 0 or Stage 1 cancers that have a remote probability of recurrence; Absolute neutrophil count < 1,500/µL, or platelet count < 100,000/µL, or hemoglobin < 9 g/dL at the Screening visit; Total bilirubin, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 times the upper limit of normal (ULN) at the Screening visit; Creatinine > 2 mg/dL at the Screening visit; Albumin < 3.0 g/dL at the Screening visit; History of seizure or any condition that may predispose to seizure; Clinically significant cardiovascular disease; Gastrointestinal disorder affecting absorption (e.g., gastrectomy, active peptic ulcer disease within last 3 months); Major surgery within 4 weeks of enrollment; Use of opiate analgesics for pain from prostate cancer within 4 weeks of enrollment; Radiation therapy for treatment of the primary tumor within 3 weeks of enrollment; Prior radiation or radionuclide therapy for treatment of distant metastases; Prior ketoconazole, abiraterone, or cytotoxic chemotherapy for prostate cancer; Treatment with hormonal therapy or biologic therapy for prostate cancer within 4 weeks of enrollment; Use of antiandrogens within 4 weeks prior to enrollment; Prior disease progression, as assessed by the Investigator, while receiving bicalutamide; Participation in a previous clinical trial of enzalutamide or an investigational agent that inhibits the androgen receptor or androgen synthesis (patients who received placebo are acceptable); Use of an investigational agent within 4 weeks of enrollment; Use of herbal products that may have hormonal anti-prostate cancer activity and/or are known to decrease PSA levels (e.g., saw palmetto) or systemic corticosteroids for prostate cancer within 4 weeks of enrollment; Any condition or reason that, in the opinion of the Investigator, interferes with the ability of the patient to participate in the trial, which places the patient at undue risk, or complicates the interpretation of safety data. Open-Label Treatment Period: Inclusion Criteria: Received randomized double blind treatment in MDV3100-09 as follows: Randomized to enzalutamide and receiving enzalutamide at the time of study unblinding; Randomized to bicalutamide and receiving bicalutamide at the time of study unblinding; Randomized to bicalutamide and discontinued bicalutamide before study unblinding; Willing to maintain androgen deprivation therapy with a gonadotropin releasing hormone (GnRH) agonist/antagonist or has had a bilateral orchiectomy. Exclusion Criteria: Is currently or has taken commercially available enzalutamide (Xtandi) prior to participation in this open-label extension; Discontinued enzalutamide during the double-blind portion of the study prior to unblinding; Has any clinically significant cardiovascular, dermatologic, endocrine, gastrointestinal, hematologic, hepatic, infectious, metabolic, neurologic, psychiatric, psychologic, pulmonary, or renal disorder or any other condition, including excessive alcohol or drug abuse, or secondary malignancy, that may interfere with study participation in the opinion of the investigator or medical monitor; Has a current or previously treated brain metastasis or leptomeningeal disease; Has a history of seizure or any condition that may predispose to seizure (eg, prior cortical stroke or significant brain trauma); Has a history of loss of consciousness or transient ischemic attack within 12 months of open label day 1; Has taken cytotoxic chemotherapy or investigational therapy within 4 weeks before enrollment (open label 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Enzalutamide<br>Enzalutamide 160 mg/day orally | Drug: Enzalutamide<br>* 160 mg, daily, by mouth.<br>* Other names: Xtandi;|
| Active Comparator: Bicalutamide<br>50 mg/day orally | Drug: Bicalutamide<br>* 50 mg, daily, by mouth<br>* Other names: Casodex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS was defined as time from randomization to earliest objective evidence of prostate specific-antigen (PSA) progression, radiographic progression, or death on study. PSA progression was defined as ≥ 25% increase in PSA with an absolute increase ≥ 2 ng/mL above the nadir and was to be confirmed by a second consecutive assessment. Radiographic progression in bone was based on The Prostate Cancer Clinical Trials Working Group (PCWG2) guidelines defined as at least 2 new lesions on bone scan. Radiographic progression in soft tissue on Computerized Tomography/Magnetic Resonance Imaging (CT/MRI) was based on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). CT/MRI and bone scans were read locally by the same radiologist (or nuclear medicine physician for interpretation of bone scans) whenever possible. Participants not known to have had a PFS event at the time of the analysis data cutoff were censored at the date of last assessment. | From randomization until the data cut-off date of 09 February 2015, median duration of treatment was 14.7 months in the enzalutamide arm and 8.4 months in the bicalutamide arm. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to PSA Progression | PSA progression was defined as ≥ 25% increase in PSA with an absolute increase ≥ 2 ng/mL above the nadir and was to be confirmed by a second consecutive assessment at least 3 weeks later. Participants not known to have had PSA progression were censored at the date of last PSA assessment. | From randomization until the data cut-off date of 09 February 2015, median duration of treatment was 14.7 months in the enzalutamide arm and 8.4 months in the bicalutamide arm. | 
| Percentage of Participants With a PSA Response ≥ 50% | PSA response was defined as a reduction in PSA of at least 50% from baseline at any post baseline assessment confirmed by a second PSA assessment at least 3 weeks later. | From randomization until the data cut-off date of 09 February 2015, median duration of treatment was 14.7 months in the enzalutamide arm and 8.4 months in the bicalutamide arm. | 
| Duration of Radiographic PFS | Duration of radiographic PFS was defined as the time from randomization to the earliest objective evidence of radiographic disease progression or death on study and was to be evaluated for participants with metastatic disease at study entry. Radiographic disease progression in bone was based on PCWG2 guidelines defined as at least 2 new lesions on bone scan. Radiographic disease progression in soft tissue on CT/MRI was based on RECIST 1.1. CT/MRI and bone scans were read locally by the same radiologist (or nuclear medicine physician for interpretation of bone scans) whenever possible. Participants not known to have had radiographic progression at the time of analysis data cutoff were censored at the date of last radiographic assessment. | From randomization until the data cut-off date of 09 February 2015, median duration of treatment was 14.7 months in the enzalutamide arm and 8.4 months in the bicalutamide arm. | 
| Quality of Life: Time to Degradation of Functional Assessment of Cancer Therapy - Prostate (FACT-P) | The FACT-P is a multidimensional, self-reported quality of life instrument consisting of 27 core items that assess patient function in 4 domains: physical, social/family, emotional, and functional well-being, and supplemented by 12 site-specific items to assess for prostate-related symptoms. Each item is rated on a 0 to 4 Likert-type scale, and then combined to produce subscale scores for each domain, as well as a global quality of life score (0 to 156) with higher scores representing better quality of life. Time to degradation of FACT-P was defined as the time from randomization to first assessment with at least a 10-point decrease from baseline in the global FACT-P score for each participant. Participants with no score degradation at the time of analysis data cutoff were censored at the date of last assessment showing no degradation. | From randomization until the data cut-off date of 09 February 2015, median duration of treatment was 14.7 months in the enzalutamide arm and 8.4 months in the bicalutamide arm. | 
| Best Overall Soft Tissue Response | Best overall soft tissue response is defined as partial response (PR) or complete response (CR) while on study treatment based on investigator assessment of target, nontarget, and new lesions using RECIST 1.1. Only participants in the metastatic population with measurable soft tissue disease (at least 1 target lesion identified per RECIST 1.1) at screening were included in the analysis. All percentages are based on number of participants with metastatic and measurable soft tissue disease at screening in each treatment group. | From randomization until the data cut-off date of 09 February 2015, median duration of treatment was 14.7 months in the enzalutamide arm and 8.4 months in the bicalutamide arm. | 
| Percentage of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE was any untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. An SAE was an AE resulting in any of 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. A treatment emergent AE defined as an event that emerged during treatment period (From first dose of study drug until end of open label phase [up to maximum duration of 65 months]) that was absent before treatment, or worsened during treatment period relative to pre-treatment state. AE included both serious and non- SAE. Treatment-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. An AE was considered related to study drug if event was assessed by investigator as probably or possibly related. | From first dose of study drug until the end of open label phase (up to maximum duration of 65 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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prostate cancer, enzalutamide, MDV3100