Safety and Efficacy Study of Enzalutamide Plus Leuprolide in Patients With Nonmetastatic Prostate Cancer (EMBARK)

Study Overview
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Brief Summary
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The purpose of this study is to assess enzalutamide plus leuprolide in patients with high-risk nonmetastatic prostate cancer progressing after radical prostatectomy or radiotherapy or both. The randomized / blinded portion of the study is now completed following primary endpoint analyses. The study remains ongoing in open label format.

Official Title
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A Phase 3, Randomized, Efficacy and Safety Study of Enzalutamide Plus Leuprolide, Enzalutamide Monotherapy, and Placebo Plus Leuprolide in Men With High-Risk Nonmetastatic Prostate Cancer Progressing After Definitive Therapy

Conditions
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Hormone Sensitive Prostate Cancer, Prostate Cancer, Cancer of the Prostate

Intervention / Treatment
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* Drug: Enzalutamide
* Drug: Placebo (No longer applicable in Open Label study period)
* Drug: Leuprolide Open Label


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed adenocarcinoma of the prostate at initial biopsy, without neuroendocrine differentiation, signet cell, or small cell features; Prostate cancer initially treated by radical prostatectomy or radiotherapy (including brachytherapy) or both, with curative intent; PSA doubling time ≤ 9 months; Screening PSA by the central laboratory ≥ 1 ng/mL for patients who had radical prostatectomy (with or without radiotherapy) as primary treatment for prostate cancer and at least 2 ng/mL above the nadir for patients who had radiotherapy only as primary treatment for prostate cancer; Serum testosterone ≥ 150 ng/dL (5.2 nmol/L). Exclusion Criteria: Prior or present evidence of distant metastatic disease as assessed by radiographic imaging; Prior hormonal therapy. Neoadjuvant/adjuvant therapy to treat prostate cancer ≤ 36 months in duration and ≥ 9 months before randomization, or a single dose or a short course (≤ 6 months) of hormonal therapy given for rising PSA ≥ 9 months before randomization is allowed.; Prior cytotoxic chemotherapy, aminoglutethimide, ketoconazole, abiraterone acetate, or enzalutamide for prostate cancer; Prior systemic biologic therapy, including immunotherapy, for prostate cancer; Major surgery within 4 weeks before randomization; Treatment with 5-α reductase inhibitors (finasteride, dutasteride) within 4 weeks of randomization; Known or suspected brain metastasis or active leptomeningeal disease; History of another invasive cancer within 3 years before screening, with the exception of fully treated cancers with a remote probability of recurrence

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 plus leuprolide<br>Enzalutamide (160 mg) administered as four 40-mg capsules by mouth once daily in combination with leuprolide administered as as a single intramuscular or subcutaneous injection once every 12 weeks | Drug: Enzalutamide<br> <br> * Other names: Xtandi;Drug: Leuprolide Open Label<br> <br> * Other names: Lupron;|
| Experimental: Enzalutamide monotherapy<br>Enzalutamide (160 mg) administered as four 40-mg capsules by mouth once daily | Drug: Enzalutamide<br> <br> * Other names: Xtandi;|
| Active Comparator: Leuprolide plus placebo<br>Enzalutamide placebo (placebo) capsules (identical in appearance to enzalutamide) administered as 4 capsules by mouth once daily in combination with leuprolide administered as a single intramuscular or subcutaneous injection once every 12 weeks. The randomized blinded portion of the study has concluded following primary endpoint analyses. In the Open Label Period the placebo is no longer applicable in this study arm, and patients continue to receive leuprolide alone. | Drug: Placebo (No longer applicable in Open Label study period)<br>* Sugar pill to mimic enzalutamide<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Metastasis-free survival (MFS) | Compared between enzalutamide plus leuprolide and placebo plus leuprolide. | Up to approximately 90 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival |  | Up to approximately 132 months | 
| Time to castration resistance |  | Up to approximately 90 months | 
| Composite of safety | Safety will be evaluated by the incidence of serious adverse events, incidence and severity of adverse events, incidence of permanent treatment discontinuation due to adverse events, and incidence of new clinically significant changes in clinical laboratory values and vital signs. | Up to approximately 90 months | 
| Metastasis-free survival (MFS) | Compared between enzalutamide monotherapy versus placebo plus leuprolide. | Up to approximately 90 months | 
| Time to prostate specific antigen (PSA) progression; |  | Up to approximately 90 months | 
| Time to first use of new antineoplastic therapy |  | Up to approximately 90 months | 
| Time to distant metastasis |  | Up to approximately 90 months | 
| Proportion of patients per group who remain treatment free 2 years after suspension of study drug treatment at week 37 due to undetectable PSA |  | From baseline (week 37) up to 90 months | 
| Proportion of patients per group with undetectable PSA 2 years after suspension of study drug treatment at week 37 due to undetectable PSA |  | From baseline (week 37) up to 90 months | 
| Proportion of patients per group with undetectable PSA at 36 weeks on study drug |  | At week 36 | 
| Time to resumption of any hormonal therapy following suspension at week 37 due to undetectable PSA |  | From baseline (week 37) up to 90 months | 
| Time to symptomatic progression |  | Up to approximately 90 months | 
| Time to first symptomatic skeletal event |  | Up to approximately 90 months | 
| Time to clinically relevant pain |  | Up to approximately 90 months | 
| Quality of life via the Functional Assessment of Cancer Therapy Prostate (FACT P) questionnaire, |  | Up to approximately 90 months | 
| Quality of life via the European Quality of Life 5 Dimensions 5 Levels Health Questionnaire (EQ 5D 5L), |  | Up to approximately 90 months | 
| Quality of life via the Quality of Life Questionnaire Prostate 25 (QLQ PR25) module |  | Up to approximately 90 months |