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

Astellas Pharma Inc395 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

395

Conditions

Progressive Metastatic Prostate Cancer

Interventions

EnzalutamideDRUG

Oral

PlaceboDRUG

Oral

Eligibility

Sex: MALEMin age: 18 Years

Medical Language ↔ Plain English

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).

Locations (47)

Outcomes

Primary Outcomes

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. Time to PSA progression was estimated using the Kaplan-Meier method. Participants without confirmed PSA progression were censored.

Time frame: From the date of randomization to PSA progression median follow-up time is 6.47 months for enzalutamide and 2.99 months for placebo

Secondary Outcomes

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.

Time frame: From the date of randomization to deaths from any cause median follow-up time is 42.32 months for enzalutamide and 26.81 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.

Data from ClinicalTrials.gov

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CN00103

Beijing, China

CN00104

Beijing, China

CN00106

Beijing, China

CN00111

Beijing, China

CN00112

Beijing, China

CN00114

Beijing, China

CN00115

Beijing, China

CN00127

Beijing, China

CN00121

Changsha, China

CN00107

Hangzhou, China

...and 37 more locations

Time frame: From the date of randomization to the rPFS event (deaths from any cause and radiographic disease progression) 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.

Time frame: From the date of randomization to the first skeletal-related event 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.

Time frame: From the date of randomization to initiation of cytotoxic chemotherapy median follow-up time is 7.39 months for enzalutamide and 5.19 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.

Time frame: From baseline to the lowest post-baseline PSA result 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. CR was defined as complete resolution of all attributable clinical symptoms and physical findings. PR was defined as partial resolution of at Least some of the clinical symptoms and physical findings.

Time frame: From the date of randomization 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

Time frame: From the date of randomization, 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

Time frame: From the date of randomization, 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

Time frame: From the date of randomization, Single Dosing Day 1 and Multiple Dosing Day 85

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.

Time frame: From the date of randomization, 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.

Time frame: From the date of randomization up to Days 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)

Time frame: From the date of randomization up to Multiple Dosing Day 85

Peak-Trough Ratio (PTR) Enzalutamide, M1,M2 and Enzalutamide Plus M2

Time frame: From the date of randomization up to 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

Time frame: From the date of randomization up to Multiple Dosing Day 85

Number of Participants With Adverse Events (AE)

An AE was defined as any untoward medical occurrence, temporally associated with use of medicinal product, whether considered related to medicinal product. AE could therefore be any unfavorable \& unintended sign, symptom, or disease temporally associated with use of a medicinal product. An AE was considered serious if, results in death; is life-threatening; results in persistent disability; results in congenital anomaly; requires inpatient hospitalization; or leads to prolongation of hospitalization; other medically important events. TEAE was defined as AE occurring from time of study drug administration on Day 1 until follow-up visit (28 days after last dose, or one day before date of initiation of cytotoxic chemotherapy or an investigational agent, whichever comes first). AEs were graded using National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03, where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Life-threatening; Grade 5 = Fatal.

Time frame: From first dose on Day 1 until 28 days after the last dose of study drug, or one day before the date of initiation of cytotoxic chemotherapy or an investigational agent for treatment of prostate cancer, whichever comes first, up to 123 months and 24 days