Safety Study of Continued Enzalutamide Treatment In Prostate Cancer Patients

Study Overview
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Brief Summary
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The purpose of this study is to determine if continued treatment with Enzalutamide is effective in patients with metastatic prostate cancer.

Official Title
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A PHASE 4, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF CONTINUED ENZALUTAMIDE TREATMENT BEYOND PROGRESSION IN PATIENTS WITH CHEMOTHERAPY-NAÏVE METASTATIC CASTRATION-RESISTANT PROSTATE CANCER

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: Enzalutamide
* Drug: Abiraterone
* Drug: Placebo for Enzalutamide
* Drug: Prednisone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men with metastatic castration-resistant prostate cancer Progressive disease on androgen deprivation therapy Patients must agree to continue androgen deprivation therapy with a GnRH agonist/antagonist throughout the study or have had a prior bilateral orchiectomy ECOG performance score ≤ 1 Estimated life expectancy of ≥ 12 months Exclusion Criteria: Prior cytotoxic chemotherapy, aminoglutethimide, ketoconazole, abiraterone, or enzalutamide for the treatment of prostate cancer Prior participation in a clinical trial of an investigational agent that inhibits the androgen receptor or androgen synthesis (unless the treatment was placebo) History of brain metastasis, active leptomeningeal disease or seizure Severe cardiovascular or hepatic disease Pituitary or adrenal dysfunction

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 |
| --- | --- |
| Experimental: Enzalutamide & Abiraterone/prednisone<br>Enzalutamide (160 mg) administered as four 40-mg capsules by mouth once daily in combination with abiraterone (1000 mg) administered as four 250-mg tablets by mouth once daily and prednisone (10 mg) administered as one 5-mg tablet by mouth twice daily | Drug: Enzalutamide<br>* 160 mg by mouth once daily<br>* Other names: Xtandi;Drug: Abiraterone<br>* 1000 mg by mouth once daily<br>* Other names: Zytiga;Drug: Prednisone<br>* 5 mg by mouth twice daily<br>* Other names: prednisolone;|
| Active Comparator: Enzalutamide placebo & Abiraterone/prednisone<br>Enzalutamide placebo (placebo) capsules (identical in appearance to enzalutamide) administered as 4 capsules by mouth once daily in combination with abiraterone (1000 mg) administered as four 250-mg tablets by mouth once daily and prednisone (10 mg) administered as one 5-mg tablet by mouth twice daily. | Drug: Abiraterone<br>* 1000 mg by mouth once daily<br>* Other names: Zytiga;Drug: Placebo for Enzalutamide<br>* Sugar pill manufactured to mimic Enzalutamide 40 mg capsule<br>Drug: Prednisone<br>* 5 mg by mouth twice daily<br>* Other names: prednisolone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS = time from randomization to first documentation of radiographic progression (RP),unequivocal clinical progression or death due to any cause (death within 112 days of treatment discontinuation without objective evidence of RP),whichever occurred first as per investigator. Unequivocal disease progression was pain requiring chronic administration of analgesics, decline of prostate cancer of Eastern Cooperative Oncology Group (ECOG) performance status score to 3 or higher or initiation of new anticancer therapy/radiation therapy or surgical intervention due to tumor progression. ECOG score range= 0(no severity) to 5(maximum severity).RP for bone disease was evaluated by appearance of 2 or more new bone lesions as per Prostate Cancer Clinical Trials Working Group 2 (PCWG2) or for soft tissue disease according to Response Evaluation Criteria in Solid Tumor version 1.1. Participants with no PFS event at analysis date were censored at last tumor assessment date prior to data cutoff date. | From randomization until disease progression, last tumor assessment without disease progression or death due to any cause, whichever occurred first (maximum up to 20.3 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Prostate Specific Antigen (PSA) Progression | Time from date of randomization to the date of first confirmed PSA progression as per Prostate Cancer Clinical Trials Working Group 2 (PCWG2). For participant's whose PSA decreased at Week 13 after randomization, progression was defined as 25 percent (%) PSA increase relative to nadir or absolute increase of >=2 nanogram/milliliter (ng/mL) above nadir. Progression was confirmed if another assessment measured at least 3 weeks later met the criterion as well. For participant's whose PSA did not decrease at Week 13 after randomization, progression was defined as 25% PSA increase relative to baseline assessed 12 weeks after baseline. Participants who were not known to have had a PFS event at the analysis date were censored at last PSA assessment date prior to data cutoff date. | From randomization until disease progression, last tumor assessment without disease progression, whichever occurred first (maximum up to 11.1 months) | 
| Prostate Specific Antigen (PSA) Response Rate | PSA response rate was defined as percentage of participants with >=30% and >=50% decrease in PSA from baseline at randomization to the maximal PSA response with a threshold of 30% and 50% respectively. PSA response was confirmed if another assessment measured at least 3 weeks later met the criterion as well. | From randomization until disease progression, last tumor assessment without disease progression, whichever occurred first (maximum up to 11.1 months) | 
| Objective Response Rate (ORR) | Objective response rate as assessed by the investigator according to Response Evaluation Criteria in Solid Tumor version 1.1 (RECIST v1.1) was defined as 1) Percentage of participants with confirmed best overall complete response (CR) and partial response (PR); 2) Percentage of participants with CR, PR and stable disease (SD) for target lesions or non-progressive disease for non-target lesions. CR: Disappearance of all non-nodal target and non-target lesions, including target and non-target lymph nodes reduction to <10 millimeter (mm) in short axis. No new lesions and disappearance of all non-target lesions. PR: >= 30% decrease in sum of diameters of target lesions, compared to the sum at baseline. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. | From randomization until CR or PR, whichever occurred first (maximum up to 21.3 months) | 
| Rate of Pain Progression | Rate of pain progression was defined as percentage of participants with an increase of >=30% from baseline in the mean Brief Pain Inventory-Short Form (BPI-SF) pain intensity item scores of 4 items assessing average, worst, least, and intermediate pain severity. BPI-SF is an 11-item self-report questionnaire that is designed to assess the severity and impact of pain on daily functions of a participant. BPI-sf includes 4 questions that assess pain intensity (worst, least, average, right now) and 7 questions that assess impact of pain on daily functions (general activity, mood, walking ability, normal work, relations with other people, sleep, enjoyment of life). BPI-sf score range for each item was from 0=no pain to 10=worst possible pain. Total score was reported as average of individual questions ranges from 0 to 10, where lower scores indicated less pain or less pain interference. | Month 6 | 
| Time to First Use of New Antineoplastic Therapy for Prostate Cancer | It was defined as time from randomization to the date of first use of subsequent antineoplastic therapy for prostate cancer. For participants who had not started subsequent antineoplastic therapy as of data analysis cutoff date, the time to first use of subsequent antineoplastic therapy was censored at the date of last assessment. | From randomization until date of first use of any antineoplastic therapy (after last dose date of Period 2, maximum up to 22.3 months | 
| Change From Baseline in Quality of Life as Assessed by Functional Assessment of Cancer Therapy-Prostate (FACT-P) Global Score | The FACT-P is a multidimensional, self-reported quality of life instrument consisting of 27 core items that assess participant function in 4 domains: physical, social/family, emotional, 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 which is the sum of all 5 domain scores and ranges from 0 to 156 where higher scores represent better quality of life. | Baseline, Week 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89 | 
| Change From Baseline in Quality of Life as Assessed by Functional Assessment of Cancer Therapy-Prostate (FACT-P) Social/Family Well-Being Domain Scores | The FACT-P is a multidimensional, self-reported quality of life instrument consisting of 27 core items that assess participant function in 4 domains: physical, social/family, emotional, 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. Total subscale score range for social/family well-being domain is from 0 (worst response) to 32 (best response), where higher score indicate better quality of life. | Baseline, Week 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89 | 
| Change From Baseline in Quality of Life as Assessed by Functional Assessment of Cancer Therapy-Prostate (FACT-P) Emotional Well-Being Domain Scores | The FACT-P is a multidimensional, self-reported quality of life instrument consisting of 27 core items that assess participant function in 4 domains: physical, social/family, emotional, 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. Total subscale score range for emotional well-being domain is from 0 (worst response) to 24 (best response), where higher score indicate better quality of life. | Baseline, Week 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89 | 
| Change From Baseline in Quality of Life as Assessed by Functional Assessment of Cancer Therapy-Prostate (FACT-P) Functional Well-Being Domain Scores | The FACT-P is a multidimensional, self-reported quality of life instrument consisting of 27 core items that assess participant function in 4 domains: physical, social/family, emotional, 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. Total subscale score range for functional well-being domain is from 0 (worst response) to 28 (best response), where higher score indicate better quality of life. | Baseline, Week 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89 | 
| Change From Baseline in Quality of Life as Assessed by Functional Assessment of Cancer Therapy-Prostate (FACT-P) Prostate Cancer Domain Scores | The FACT-P is a multidimensional, self-reported quality of life instrument consisting of 27 core items that assess participant function in 4 domains: physical, social/family, emotional, 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. Total subscale score range for prostate cancer domain is from 0 (worst response) to 48 (best response), where higher score indicated better quality of life with fewer symptoms. | Baseline, Week 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89 | 
| Change From Baseline in Quality of Life as Assessed by Functional Assessment of Cancer Therapy-Prostate (FACT-P) Physical Well-Being Domain Scores | The FACT-P is a multidimensional, self-reported quality of life instrument consisting of 27 core items that assess participant function in 4 domains: physical, social/family, emotional, 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. Total subscale score range for physical well-being domain is from 0 (worst response) to 28 (best response), where higher score indicate better quality of life. | Baseline, Week 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89 | 
| Time to Degradation of the Functional Assessment of Cancer Therapy-Prostate (FACT-P) Global Score | 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. The FACT-P is a multidimensional, self-reported quality of life instrument consisting of 27 core items that assess participant 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 which is the sum of all 5 domain scores and ranges from 0 to 156 with higher scores representing better quality of life. 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 up to maximum of 18.4 months |