A Multinational, Phase 3, Randomized, Double-blind, Placebo-controlled Efficacy and Safety Study of Enzalutamide Plus Androgen Deprivation Therapy (ADT) Versus Placebo Plus ADT in Patients With Metastatic Hormone Sensitive Prostate Cancer (mHSPC)
Overview
- Phase
- Phase 3
- Intervention
- Enzalutamide
- Conditions
- Metastatic Hormone Sensitive Prostate Cancer
- Sponsor
- Astellas Pharma Global Development, Inc.
- Enrollment
- 1150
- Locations
- 203
- Primary Endpoint
- Radiographic Progression-Free Survival (rPFS) Based on Independent Central Review (ICR) of Bone Scan According to Prostate Cancer Clinical Trials Working Group 2 (PCWG2) Criteria
- Status
- Completed
- Last Updated
- 6 months ago
Overview
Brief Summary
The purpose of this study was to evaluate the efficacy of enzalutamide plus androgen deprivation therapy (ADT) as measured by radiographic progression-free survival (rPFS) based on central review. The study also evaluated the safety of enzalutamide plus ADT in mHSPC.
Detailed Description
Following unblinding at the end of the double-blind period and demonstration of a statistically significant advantage of enzalutamide over placebo when added to ADT as assessed by the primary endpoint of rPFS, subjects were eligible to transition to an open-label portion of the study.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Subject is considered an adult according to local regulation at the time of signing informed consent.
- •Subject is diagnosed with histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation, signet cell or small cell histology.
- •Subject has metastatic prostate cancer documented by positive bone scan (for bone disease) or metastatic lesions on computed tomography (CT) or magnetic resonance imaging (MRI) scan (for soft tissue). Subjects whose disease spread is limited to regional pelvic lymph nodes are not eligible.
- •Once randomized at day 1, subject must maintain ADT with an LHRH agonist or antagonist during study treatment or have a history of bilateral orchiectomy (i.e., medical or surgical castration).
- •Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or
- •Inclusion Criteria for Open-Label Extension:
- •Subject received randomized double-blind treatment in ARCHES
- •Subject has not met any of the discontinuation criteria in the main ARCHES protocol
- •Subject is willing to maintain ADT with LHRH agonist or antagonist or has had a bilateral orchiectomy.
- •Subject is able to swallow enzalutamide capsules whole and to comply with study requirements throughout the study
Exclusion Criteria
- •Subject has received any prior pharmacotherapy, radiation therapy or surgery for metastatic prostate cancer (the following exceptions are permitted):
- •Up to 3 months of ADT with LHRH agonists or antagonists or orchiectomy with or without concurrent antiandrogens prior to day 1, with no radiographic evidence of disease progression or rising PSA levels prior to day 1;
- •Subject may have 1 course of palliative radiation or surgical therapy to treat symptoms resulting from metastatic disease if it was administered at least 4 weeks prior to day 1;
- •Up to 6 cycles of docetaxel therapy with final treatment administration completed within 2 months of day 1 and no evidence of disease progression during or after the completion of docetaxel therapy;
- •Up to 6 months of ADT with LHRH agonists or antagonists or orchiectomy with or without concurrent antiandrogens prior to day 1 if subject was treated with docetaxel, with no radiographic evidence of disease progression or rising PSA levels prior to day 1;
- •Prior ADT given for \< 39 months in duration and \> 9 months before randomization as neoadjuvant/adjuvant therapy.
- •Subject had a major surgery within 4 weeks prior to day
- •Subject received treatment with 5-α reductase inhibitors (finasteride, dutasteride) within 4 weeks prior to day
- •Subject received treatment with estrogens, cyprotoerone acetate or androgens within 4 weeks prior to day
- •Subject received treatment with systemic glucocorticoids greater than the equivalent of 10 mg per day of prednisone within 4 weeks prior to day 1, intended for the treatment of prostate cancer.
Arms & Interventions
Enzalutamide + Androgen Deprivation Therapy (ADT)
Participants received 160 mg enzalutamide orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. Eligible participants who received enzalutamide during double-blind treatment period and provided informed consent to take part in open-label period continued to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or Luteinizing hormone-releasing hormone (LHRH) agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.
Intervention: Enzalutamide
Placebo + Androgen Deprivation Therapy (ADT)
Participants received matching placebo orally once daily during double-blind treatment period until radiographic progression was documented or until the participants started an investigational agent or new therapy for treatment of prostate cancer or until any other discontinuation criterion was met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.
Intervention: Placebo
Placebo followed by Enzalutamide
Eligible participants who received enzalutamide matching placebo during double-blind treatment period and provided informed consent to take part in open-label period switched to receive 160 mg enzalutamide orally once daily in open-label period until disease progression, unacceptable toxicity or any other discontinuation criteria were met. ADT (either bilateral orchiectomy or LHRH agonist/antagonist) was maintained during study treatment as per standard of care and provided by the site's pharmacy stock.
Intervention: Enzalutamide
Outcomes
Primary Outcomes
Radiographic Progression-Free Survival (rPFS) Based on Independent Central Review (ICR) of Bone Scan According to Prostate Cancer Clinical Trials Working Group 2 (PCWG2) Criteria
Time Frame: From the date of randomization to the first objective evidence of rPD at any time or death (maximum duration was 26.6 months)
rPFS was calculated as the time from the date of randomization to the first objective evidence of radiographic progression disease (rPD) at any time or death up to 24 weeks after study drug discontinuation without documented radiographic progression, whichever occurred first. rPD was defined as progressive disease by Response Evaluation Criteria in Solid Tumors version 1.1 for soft tissue disease or by appearance of 2 or more new lesions on bone scan compared to baseline or week 13 according to PCWG2 criteria, as assessed by ICR or death. In participants with no rPFS event, rPFS was censored on the date of last evaluable radiographic assessment prior to the data analysis cutoff date. In participants with no baseline radiographic assessment, participants with no postbaseline radiographic assessments and participants with all postbaseline radiographic assessments documented as "not evaluable (NE)," rPFS was censored on the date of randomization.
rPFS Based on ICR of Bone Scan According to Protocol Assessment Criteria
Time Frame: From the date of randomization to the first objective evidence of rPD at any time or death (maximum duration was 26.6 months)
rPFS was calculated as the time from the date of randomization to the first objective evidence of radiographic progression disease (rPD) at any time or death up to 24 weeks after study drug discontinuation without documented radiographic progression, whichever occurred first. rPD was defined as progressive disease by Response Evaluation Criteria in Solid Tumors version 1.1 for soft tissue disease or by appearance of 2 or more new lesions on bone scan compared to baseline for week 13 or the best response on treatment for week 25 or later assessments, as assessed by ICR or death. In participants with no rPFS event, rPFS was censored on the date of last evaluable radiographic assessment prior to the data analysis cutoff date. In participants with no baseline radiographic assessment, participants with no postbaseline radiographic assessments and participants with all postbaseline radiographic assessments documented as "not evaluable (NE)," rPFS was censored on the date of randomization.
Secondary Outcomes
- Overall Survival (OS)(From randomization to death due to any cause (maximum duration was 58.6 months))
- Time to Prostate Specific Antigen (PSA) Progression(From the date of randomization to the first observation of PSA progression (maximum duration was 26.6 months))
- Time to Start of New Antineoplastic Therapy(From randomization to the date of the first dose administration of the first antineoplastic therapy (maximum duration was 58.6 months))
- PSA Undetectable Rate(From baseline to detectable PSA values (maximum duration was 26.6 months))
- Objective Response Rate (ORR)(From date of randomization up to 26.6 months)
- Time to Deterioration in Urinary Symptoms(From date of randomization to the first deterioration in urinary symptoms at any postbaseline visit (maximum duration was 26.6 months))
- Time to First Symptomatic Skeletal Event (SSE)(From randomization to the occurrence of the first SSE (maximum duration was 26.6 months))
- Time to Castration Resistance(From randomization to the first castration-resistant event (maximum duration was 26.6 months))
- Time to Deterioration of Quality of Life (QoL) in Functional Assessment of Cancer Therapy-Prostate (FACT-P)(From the date of randomization to the first date a decline from baseline of 10 points or more in the FACT-P total score (maximum duration was 26.6 months))
- Time to Pain Progression Based on Brief Pain Inventory-Short Form (BPI-SF)(From randomization to the first pain progression event (maximum duration was 26.6 months))