An Asian Study to Evaluate Efficacy and Safety of Oral Enzalutamide in Progressive Metastatic Prostate Cancer Participants

Study Overview
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Brief Summary
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Purpose of the study was to assess the effect of enzalutamide on time to Prostate Specific Antigen (PSA) progression as compared to placebo in chemotherapy naïve participants with progressive metastatic prostate cancer who have failed androgen deprivation therapy.

Detailed Description
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The study was a multinational Phase 3, randomized, double-blind, placebo-controlled efficacy and safety study of oral enzalutamide (formerly MDV3100) in asymptomatic or mildly symptomatic participants with progressive metastatic prostate cancer who have disease progression despite androgen deprivation therapy. In order to join the study, participants could not have been previously treated with cytotoxic chemotherapy. Approximately 30 Chinese participants were allocated to the pharmacokinetic (PK) cohort. Participants in the PK cohort were required to be hospitalized from Day 1 before the randomization date to at least the completion of all the assessments planned on Day 3. All participants in the PK cohort underwent blood sampling for the PK analysis. Data reported in the results section was based on data cutoff dates of 20 Sept 2015 for efficacy and safety data and 20 Jan 2016 for PK outcome measures. The study completed double-blind period and is now in the open-label period.

Official Title
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Asian Multinational Phase 3, Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study of Oral Enzalutamide in Chemotherapy Naïve Subjects With Progressive Metastatic Prostate Cancer Who Have Failed Androgen Deprivation Therapy

Conditions
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Progressive Metastatic Prostate Cancer

Intervention / Treatment
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* Drug: Enzalutamide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features Ongoing androgen deprivation therapy with a GnRH analogue or bilateral orchiectomy Progressive disease despite androgen deprivation therapy as defined by rising PSA levels or progressive soft tissue or bone disease No prior treatment with cytotoxic chemotherapy Asymptomatic or mildly symptomatic from prostate cancer Exclusion Criteria: Severe concurrent disease, infection, or co-morbidity that, in the judgment of the Investigator, would make the patient inappropriate for enrollment Known or suspected brain metastasis or active leptomeningeal disease History of another malignancy within the previous 5 years other than curatively treated non-melanomatous skin cancer History of seizure including febrile seizure or any condition that may predispose to seizure (e.g., prior stroke, brain arteriovenous malformation, head trauma with loss of consciousness requiring hospitalization).

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<br>Participants received 160 mg of enzalutamide orally once a day during double blind period until Prostate-Specific Antigen (PSA) progression and radiographic disease progression were centrally confirmed and 1 of the following 2 events became applicable to the participants: (1) initiation of cytotoxic chemotherapy or (2) initiation of an investigational agent for treatment of prostate cancer. Eligible participants who received enzalutamide during double blind and who provided consent to take part in open-label period continued to receive 160 mg of enzalutamide in open-label period orally once a day until PSA progression and radiographic disease progression were centrally confirmed and 1 of the following 2 events became applicable to the participants: (1) initiation of cytotoxic chemotherapy or (2) initiation of an investigational agent for treatment of prostate cancer. | Drug: Enzalutamide<br>* Oral<br>* Other names: MDV3100;|
| Experimental: Placebo<br>Participants received enzalutamide matching placebo orally once a day during double-blind period until PSA progression and radiographic disease progression were centrally confirmed and 1 of the following 2 events became applicable to the participants: (1) initiation of cytotoxic chemotherapy or (2) initiation of an investigational agent for treatment of prostate cancer. | Drug: Placebo<br>* Oral<br>|
| Experimental: Placebo followed by Enzalutamide<br>Eligible participants who received enzalutamide matching placebo during double-blind period and who provided consent to take part in open-label period, received 160 mg of enzalutamide orally once a day during open-label period until PSA progression and radiographic disease progression were centrally confirmed and 1 of the following 2 events became applicable to the participants: (1) initiation of cytotoxic chemotherapy or (2) initiation of an investigational agent for treatment of prostate cancer. | Drug: Enzalutamide<br>* Oral<br>* Other names: MDV3100;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Prostate-specific Antigen (PSA) Progression | The time to Prostate Specific Antigen (PSA) progression was defined as the time from randomization to the PSA progression. The PSA progression was defined according to the consensus guidelines of Prostate Cancer Clinical Trials Working Group 2 (PCWG2).For participants with PSA decline at Week 13, the PSA progression date was defined as a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL above the nadir, which would be confirmed by a second consecutive value obtained 3 or more weeks later. For participants with no PSA decline at Week 13, the PSA progression date was defined as the date when a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL above the baseline was documented, which was confirmed by a second consecutive value 3 or more weeks later. PSA progression at the time of the data analysis cutoff date could only be declared on or after week 13. Time to PSA progression was estimated using the Kaplan-Meier method. Participants without confirmed PSA progression were censored. | From randomization up to data cut off date of 20 Sept 2015; median follow-up time is 7.33 months for enzalutamide and 3.02 months for placebo | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Overall Survival | Duration of overall survival was defined as the time from the randomization to deaths from any cause. For participants who were alive at the time of the data analysis, overall survival time was censored to the last know date the participants were known to be alive or data analysis cutoff date, whichever occurred first. | From randomization up to data cutoff date of 04 Nov 2020; median follow-up time is 21.9 months for enzalutamide and 7.29 months for placebo | 
| Duration of Radiographic Progression-free Survival (rPFS) Based on Independent Central Review Facility Assessment | Duration of Radiographic Progression-free Survival (rPFS) was defined as the time from randomization to the rPFS event (deaths from any cause and radiographic disease progression). Radiographic disease progression is defined by RECIST 1.1 for soft tissue disease, or PCWG2 for bone lesions. If a participant met the criteria for more than 1 censoring rule, they were censored with the earliest censoring date. The radiographic progression date was the first date when progression definition was met, not confirmed. | From randomization up to data cutoff date of 20 Sept 2015; median follow-up time is 5.55 months for enzalutamide and 3.71 months for placebo | 
| Time to First Skeletal-Related Event | Time to first skeletal-related event (SRE) was defined as the time from randomization to the first skeletal-related event, defined as radiation therapy or surgery to bone, pathologic bone fracture, spinal cord compression, or change of anti-neoplastic therapy to treat bone pain. Participants who have not had a SRE at the time of the analysis were censored at their last assessment indicating no evidence of SRE. | From randomization up to data cutoff date of 20 Sept 2015; median follow-up time is 7.39 months for enzalutamide and 5.29 months for placebo | 
| Time to Initiation of Cytotoxic Chemotherapy | Time to initiation of cytotoxic chemotherapy was defined as the time from randomization to initiation of cytotoxic chemotherapy. It included only therapies for prostate cancer. When multiple cytotoxic chemotherapies were initiated, the first chemotherapy was used to determine the time to event. Participants who did not start cytotoxic chemotherapy at the time of analysis data cutoff were censored at the date of their last assessment indicating no evidence of cytotoxic chemotherapy usage. | From randomization up to data cutoff date of 20 Sept 2015; median follow-up time is 7.39 months for enzalutamide and 4.93 months for placebo | 
| Number of Participants With Confirmed Best PSA Response (≥50% Decrease From Baseline) | Best PSA response was defined as as ≥50% reductions in PSA level from baseline to the lowest post-baseline PSA result as determined by the central laboratory, with a consecutive assessment conducted at least 3 weeks later to confirm the PSA response. Only participants who had both baseline and post-baseline assessments were included in the analysis. | Baseline up to data cut off date of 20 Sept 2015; median treatment duration is 6.60 months for enzalutamide and 3.70 months for placebo | 
| Best Overall Soft Tissue Response | Participants with measurable soft tissue disease at screening visit (i.e., at least one target lesion per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) who have an objective response (complete response (CR) or partial response (PR)) during the study were included in the best overall soft tissue response assessment. The best overall soft tissue response was based on the investigator assessment using RECIST 1.1. | From randomization up to data cut off date of 20 Sept 2015; median treatment duration is 6.60 months for enzalutamide and 3.70 months for placebo | 
| Time to Maximum Concentration (Tmax) of Enzalutamide, M1,M2 and Enzalutamide Plus M2 |  | From randomization up to data cutoff date of 20 Jan 2016; Single Dosing Day 1 and Multiple Dosing Day 85 | 
| Maximum Observed Plasma Concentration During the First 24 Hours After Dosing (Cmax) Enzalutamide, M1,M2 and Enzalutamide Plus M2 |  | From randomization up to data cutoff date of 20 Jan 2016; Single Dosing Day 1 and Multiple Dosing Day 85 | 
| AUC From the Time of Dosing to 24 h After Dosing (AUC24h) Enzalutamide, M1,M2 and Enzalutamide Plus M2 |  | From randomization up to data cutoff date of 20 Jan 2016; Single Dosing Day 1 | 
| Concentration 24 h After Dosing (C24h) Enzalutamide, M1,M2 and Enzalutamide Plus M2 | N is the number of participants with available data at this time point. | From randomization up to data cutoff date of 20 Jan 2016; Single Dosing Day 1 and Multiple Dosing Day 85 | 
| Observed Plasma Concentration in Predose Samples Obtained During Multiple-dose Administration of Minimum Concentration (Plasma Concentration at Pre Dose) (Cmin) Enzalutamide, M1,M2 and Enzalutamide Plus M2 | N is the number of participants with available data at this time point. | From randomization up to data cutoff date of 20 Jan 2016; Day 2, 3, 8, 22, 29, 43, 57, 85, 86, 113, 141 and 169 | 
| Apparent Total Systemic Clearance After Multiple Dosing (CL/F) Enzalutamide, M1,M2 and Enzalutamide Plus M2 (For Unchanged Enzalutamide Only) |  | From randomization up to data cutoff date of 20 Jan 2016; Multiple Dosing Day 85 | 
| Peak-Trough Ratio (PTR) Enzalutamide, M1,M2 and Enzalutamide Plus M2 |  | From randomization up to data cutoff date of 20 Jan 2016; Multiple Dosing Day 85 | 
| AUC From the Time of Dosing to the Start of the Next Dosing Interval (AUCtau) Enzalutamide, M1,M2 and Enzalutamide Plus M2 |  | From randomization up to data cutoff date of 20 Jan 2016; Multiple Dosing Day 85 | 
| Number of Participants With Adverse Events (AE) | The Treatment-Emergent Adverse Events are defined as AEs with a possible or probable relationship to study drug. If participant was still on study drug at the analysis data cutoff date, then the length of the treatment-emergent period was calculated through the cutoff date. | From first dose of study drug up to data cut off date of 04 Nov. 2020(up to 18.6 months for 'Placebo'; up to 4 weeks after last dose of enzalutamide-up to 84.7 months for 'Enzalutamide' and up to 54.8 months for 'Placebo followed by Enzalutamide') | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Enzalutamide, Androgen receptor, Prostate cancer, Xtandi