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

Phase 3

Active, not recruiting

Conditions: Hormone Sensitive Prostate Cancer
Prostate Cancer
Cancer of the Prostate

Interventions: Drug: Enzalutamide
Drug: Placebo (No longer applicable in Open Label study period)
Drug: Leuprolide Open Label

Registration Number: NCT02319837

Lead Sponsor: Pfizer

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: Male

Target Recruitment: 1068

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Enzalutamide plus leuprolide	Enzalutamide	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
Enzalutamide plus leuprolide	Leuprolide Open Label	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
Enzalutamide monotherapy	Enzalutamide	Enzalutamide (160 mg) administered as four 40-mg capsules by mouth once daily
Leuprolide plus placebo	Placebo (No longer applicable in Open Label study period)	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.

Primary Outcome Measures

Name	Time	Method
Metastasis-free Survival (MFS) Compared Between Enzalutamide Plus Leuprolide and Placebo Plus Leuprolide	From randomization until radiographic progression or death without radiographic progression, whichever occurred first (up to Month 98 when at least 197 MFS events occurred among the 3 treatment groups)	MFS was defined as the duration of time in months between randomization and the earliest objective evidence of radiographic progression by central imaging or death without radiographic progression, whichever occurred first. Radiographic progression for soft tissue disease was defined by Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1). Radiographic progression for bone disease was defined as the appearance of 1 or more metastatic lesions on bone scan (a bone scan assesses 5 regions of the skeleton, including skull, thorax, spine, pelvis, and extremities). Confirmation with a second imaging modality (plain film, computed tomography \[CT\], or magnetic resonance imaging \[MRI\]) was to be required when bone lesions were found in a single region on the bone scan. Appearance of metastatic lesions in 2 or more of the 5 regions on a bone scan was not to require confirmation with a second imaging modality.

Secondary Outcome Measures

Name	Time	Method
Metastasis-free Survival (MFS) Compared Between Enzalutamide Monotherapy and Placebo Plus Leuprolide	From randomization until radiographic progression or death without radiographic progression, whichever occurred first (up to Month 98 when at least 197 MFS events occurred among the 3 treatment groups)	MFS was defined as the duration of time in months between randomization and the earliest objective evidence of radiographic progression by central imaging or death without radiographic progression, whichever occurred first. Radiographic progression for soft tissue disease was defined by RECIST 1.1. Radiographic progression for bone disease was defined as the appearance of 1 or more metastatic lesions on bone scan (a bone scan assesses 5 regions of the skeleton, including skull, thorax, spine, pelvis, and extremities). Confirmation with a second imaging modality (plain film, CT, or MRI) was to be required when bone lesions were found in a single region on the bone scan. Appearance of metastatic lesions in 2 or more of the 5 regions on a bone scan was not to require confirmation with a second imaging modality.
Percentage of Participants With Undetectable Prostate-specific Antigen (PSA) at 36 Weeks on Study Drug	At Week 36	Undetectable PSA at 36 weeks was serum PSA levels \<0.2 ng/mL at Week 36. Percentage of participants with undetectable PSA at 36 weeks on study drug was calculated as the number of participants with undetectable PSA at Week 36 divided by the number of participants with PSA values at Week 36, and multiplied by 100.
Time to Prostate-specific Antigen (PSA) Progression	From randomization until first PSA progression (up to Month 98)	Time to PSA progression was defined as the time in months from randomization to the date of the first PSA value demonstrating progression, while participants were on study treatment, which was subsequently confirmed at least 3 weeks later. PSA progression date was defined as the date that a ≥25% increase and an absolute increase of ≥2 micrograms per liter (μg/L) (2 nanograms per milliliter \[ng/mL\]) above the nadir (or baseline for participants with no PSA decline by Week 25) that was confirmed by a second consecutive value at least 3 weeks later. For participants who had suspended treatment at Week 37 and later reinitiated treatment, baseline was reset as the last PSA assessment prior to or on the date of reinitiation of treatment.
Time to First Use of New Antineoplastic Therapy	From randomization until first use of new antineoplastic therapy (up to Month 98)	Time to first use of new antineoplastic therapy was defined as the time in months from randomization to first use of new antineoplastic therapy for prostate cancer.
Overall Survival (OS)	From randomization until death due to any cause (up to Month 98 when at least 197 MFS events occurred among the 3 treatment groups)	Overall survival was defined as the time in months between randomization and death due to any cause.
Time to Distant Metastasis	From randomization until the earliest objective evidence of distant soft tissue metastases or metastatic bone disease (up to Month 98)	The time to distant metastasis was defined as the time in months from randomization to the earliest objective evidence of distant soft tissue metastases or metastatic bone disease by blinded independent central review (BICR).
Percentage of Participants Who Remained Treatment-free 2 Years After Suspension of Study Treatment at Week 37 Due to Undetectable Prostate-specific Antigen (PSA)	From randomization until 2 years after Week 37 (up to Month 34)	Undetectable PSA at 36 weeks was serum PSA levels \<0.2 ng/mL at Week 36. At Week 37, study treatment was suspended for participants whose PSA values were undetectable (\<0.2 ng/mL) at Week 36 as determined by the central laboratory. Study treatment may have been suspended only once (at Week 37) due to undetectable PSA and was reinitiated if subsequent central laboratory PSA values increased to ≥2.0 ng/mL for participants with prior prostatectomy or ≥5.0 ng/mL for participants without prostatectomy. Percentage of participants who remained treatment-free 2 years after suspension of study treatment at Week 37 was calculated as the number of participants who remained treatment-free 2 years after suspension of study treatment at Week 37 divided by the number of participants with treatment suspension and multiplied by 100.
Time to Resumption of Any Hormonal Therapy Following Suspension at Week 37 Due to Undetectable Prostate-specific Antigen (PSA)	From treatment suspension at Week 37 until resumption of any hormonal therapy (up to Month 98)	Undetectable PSA at 36 weeks was serum PSA levels \<0.2 ng/mL at Week 36. At Week 37, study treatment was suspended for participants whose PSA values were undetectable (\<0.2 ng/mL) at Week 36 as determined by the central laboratory. Study treatment may have been suspended only once (at Week 37) due to undetectable PSA and was reinitiated if subsequent central laboratory PSA values increased to ≥2.0 ng/mL for participants with prior prostatectomy or ≥5.0 ng/mL for participants without prostatectomy. The time to resumption of any hormonal therapy following suspension at Week 37 due to undetectable PSA was defined as the time in months between the date of treatment suspension at Week 37 due to undetectable PSA and the date that hormonal therapy was restarted.
Percentage of Participants With Undetectable Prostate-specific Antigen (PSA) 2 Years After Suspension of Treatment at Week 37 Due to Undetectable PSA	From randomization until 2 years after Week 37 (up to Month 34)	Undetectable PSA at 36 weeks was serum PSA levels \<0.2 ng/mL at Week 36. At Week 37, study treatment was suspended for participants whose PSA values were undetectable (\<0.2 ng/mL) at Week 36 as determined by the central laboratory. Study treatment may have been suspended only once (at Week 37) due to undetectable PSA and was reinitiated if subsequent central laboratory PSA values increased to ≥2.0 ng/mL for participants with prior prostatectomy or ≥5.0 ng/mL for participants without prostatectomy. Percentage of participants with undetectable PSA 2 years after suspension of treatment at Week 37 due to undetectable PSA was calculated as the number of participants with undetectable PSA 2 years after suspension of treatment at Week 37 due to undetectable PSA divided by the number of participants with treatment suspension and multiplied by 100.
Time to Symptomatic Progression	From randomization until the first development of events defined as symptomatic progression (up to Month 98)	Time to symptomatic progression was defined as the time in months from randomization to development of a skeletal-related event, worsening of disease-related symptoms requiring initiation of a new antineoplastic therapy, or development of adverse events (AEs) and clinically significant signs and/or symptoms due to loco-regional tumor progression requiring opiate use, surgical intervention or radiation therapy, whichever occurred first.
Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or Grade 4 Post-baseline in Chemistry Laboratory Test Values - at PCD Cut-off Date of 31 January 2023	From first dose of study drug to the last dose + 30 days, or the day before initiation of a new antineoplastic treatment (up to Month 98)	Participants who experienced chemistry laboratory test abnormalities were summarized according to worst toxicity grade observed for each chemistry laboratory test. Chemistry laboratory abnormalities were graded according to CTCAE version 4.03 (Grade 1: mild; Grade 2: moderate; Grade 3: severe; Grade 4: life-threatening consequences, urgent intervention indicated; Grade 5: death). This outcome measure calculated the number of participants with chemistry laboratory abnormalities that were shifted from ≤Grade 2 at baseline to Grade 3 and Grade 4 post-baseline for the following parameters: alanine aminotransferase, albumin, alkaline phosphatase, aspartate aminotransferase, calcium, creatine kinase, glucose, magnesium, phosphate, potassium, sodium.
Time to Castration Resistance	From randomization to the first occurrence of radiographic disease progression, PSA progression or SSE, whichever occurred first with castrate levels of testosterone (up to Month 98)	Time to castration resistance applied only to participants receiving leuprolide treatment and was defined as the time in months from randomization to the first occurrence of radiographic disease progression by BICR, PSA progression or symptomatic skeletal event (SSE) whichever occurred first with castrate levels of testosterone (\<50 ng/dL).
Time to First Symptomatic Skeletal Event (SSE)	From randomization until the first development of events defined as SSE (up to Month 98)	Time to first symptomatic skeletal event was defined as the time in months from randomization to use of radiation therapy (external beam radiation therapy or radionuclides) or surgery to bone for prostate cancer, findings of clinically apparent pathologic bone fracture or of spinal cord compression, or new use of opiate and/or systemic antineoplastic therapy due to bone pain collected in the SSE case report form (CRF), whichever occurred first.
Time From Randomization to Onset of Clinically Relevant Pain Progression, Defined as a 2-point or Greater Increase From Baseline in the Brief Pain Inventory-Short Form (BPI-SF) Question 3 Score	From randomization until a 2-point or greater increase from baseline in the BPI-SF question 3 score (up to Month 98)	Time to clinically relevant pain progression was defined as the time from randomization to onset of pain progression, where clinically relevant pain progression was defined as a 2-point or greater increase from baseline in the BPI-SF question 3 score. BPI-SF is a self-administered questionnaire containing 9 main questions related to pain and analgesic medication use, where question 3 (paraphrased) is "On a scale of 0 \[no pain\] to 10 \[pain as bad as you can imagine\], please rate your pain at its worst in the last 24 hours" with higher score indicating worse pain.
Time From Randomization to First Assessment With at Least a 10-point Decline (Deterioration) From Baseline in Functional Assessment of Cancer Therapy-Prostate (FACT-P) Total Score	From randomization to first assessment with at least a 10-point decrease from baseline in the FACT-P total score (up to Month 98)	Time to first deterioration of the FACT-P total score was defined as the time from randomization to first assessment with at least a 10-point decrease from baseline in the FACT-P total score. FACT-P total score is based on subscale scores of physical, social/family, emotional, and functional well-being, as well as 12 site-specific items to assess prostate-related symptoms, ranging 0-156, with higher score representing better quality of life.
Number of Participants With Treatment-emergent Adverse Events (TEAEs) (All-causality) During On-treatment Period, Modified Treatment Period, and Treatment Reinitiation Period - at PCD Cut-off Date of 31 January 2023	From first dose of study drug to the last dose + 30 days, or the day before initiation of a new antineoplastic treatment (up to Month 98)	An AE was any untoward medical occurrence (eg, sign, symptom, illness, disease or injury) in a participant administered study drug or other protocol-imposed intervention, regardless of attribution. TEAEs were those events with onset dates occurring during the on-treatment period for the first time. On-treatment period was the time from the date of first dose of study treatment through a minimum of 30 days after last dose of study treatment, or the start day of new antineoplastic drug therapy minus 1 day. Modified TEAEs (mTEAEs) were AEs that occurred during the modified treatment period (events occurring or worsening during the treatment suspension period after 30 days of last dose prior to treatment suspension were excluded). Reinitiated TEAEs (rTEAEs) were AEs that occurred with a start date during the dosing period after suspension and reinitiation of study treatment as defined by the reinitiation treatment period.
Number of Participants With Grade 3 or Higher Treatment-emergent Adverse Events (TEAEs) (All-causality) - at PCD Cut-off Date of 31 January 2023	From first dose of study drug to the last dose + 30 days, or the day before initiation of a new antineoplastic treatment (up to Month 98)	An AE was any untoward medical occurrence (e.g., sign, symptom, illness, disease or injury) in a participant administered study drug or other protocol-imposed intervention, regardless of attribution. TEAEs were those events with onset dates occurring during the on-treatment period for the first time. On-treatment period was defined as the time from the date of first dose of study treatment through a minimum of 30 days after last dose of study treatment, or the start day of new antineoplastic drug therapy minus 1 day. The severity of all TEAEs was evaluated by the investigator based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03: grade 1 (mild), grade 2 (moderate), grade 3 (severe), grade 4 (potentially life-threatening) and grade 5 (death related to AE).
Number of Participants With Treatment-emergent Adverse Events (TEAEs) (Treatment-related) During On-treatment Period, Modified Treatment Period, and Treatment Reinitiation Period - at PCD Cut-off Date of 31 January 2023	From first dose of study drug to the last dose + 30 days, or the day before initiation of a new antineoplastic treatment (up to Month 98)	An AE was any untoward medical occurrence (eg, sign, symptom, illness, disease or injury) in a participant administered study drug or other protocol-imposed intervention, regardless of attribution. TEAEs were those with onset dates occurring during the on-treatment period for the first time. On-treatment period was the time from date of first dose of study treatment through at least 30 days after last dose of study treatment or start day of new antineoplastic drug therapy minus 1 day. Treatment-related TEAEs were TEAEs attributed to study drug (enzalutamide, placebo or leuprolide). mTEAEs were AEs that occurred during the modified treatment period (events occurring or worsening during the treatment suspension period after 30 days of last dose prior to treatment suspension were excluded). rTEAEs were AEs that occurred with a start date during the dosing period after suspension and reinitiation of study treatment (reinitiation treatment period).
Number of Participants With SAEs (All-causality) During On-treatment Period, Modified Treatment Period and Treatment Reinitiation Period and SAEs (Treatment-related) During On-treatment period-at PCD Cut-off 31 Jan 2023	From first dose of study drug to the last dose + 30 days, or the day before initiation of a new antineoplastic treatment (up to Month 98)	An AE was any untoward medical occurrence in a participant administered study drug/other protocol-imposed intervention regardless of attribution. SAEs were AEs resulting in any of the following outcomes/deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent/significant disability/incapacity; congenital anomaly. On-treatment period was time from first dose date of study treatment through ≥30 days after last dose of study treatment or start day of new antineoplastic drug therapy -1 day. mSAEs were SAEs occurring during modified treatment period (events occurring/worsening during treatment suspension period after 30 days of last dose prior to treatment suspension were excluded). rSAEs were SAEs occurring with a start date during the dosing period after suspension and reinitiation of study treatment. Treatment-related SAEs were attributed to any study drug.
Number of Participants With Treatment-emergent Adverse Events (TEAEs) Leading to Enzalutamide or Placebo Discontinuation - at PCD Cut-off Date of 31 January 2023	From first dose of study drug to the last dose + 30 days, or the day before initiation of a new antineoplastic treatment (up to Month 98)	An AE was any untoward medical occurrence (eg, sign, symptom, illness, disease or injury) in a participant administered study drug or other protocol-imposed intervention, regardless of attribution. TEAEs were those events with onset dates occurring during the on-treatment period for the first time. On-treatment period was the time from the date of first dose of study treatment through a minimum of 30 days after last dose of study treatment, or the start day of new antineoplastic drug therapy minus 1 day.
Number of Participants With Shifts From Grade ≤2 at Baseline to Grade 3 or Grade 4 Post-baseline in Hematology Laboratory Test Values - at PCD Cut-off Date of 31 January 2023	From first dose of study drug to the last dose + 30 days, or the day before initiation of a new antineoplastic treatment (up to Month 98)	Participants who experienced hematology laboratory test abnormalities were summarized according to worst toxicity grade observed for each hematology laboratory test. Hematology laboratory abnormalities were graded according to CTCAE version 4.03 (Grade 1: mild; Grade 2: moderate; Grade 3: severe; Grade 4: life-threatening consequences, urgent intervention indicated; Grade 5: death). This outcome measure calculated the number of participants with hematology laboratory abnormalities that were shifted from ≤Grade 2 at baseline to Grade 3 and Grade 4 post-baseline for the following parameters: hemoglobin, leukocytes, lymphocytes, neutrophils, platelets.
Number of Participants With Potentially Clinically Significant Vital Signs - at PCD Cut-off Date of 31 January 2023	From first dose of study drug to the last dose + 30 days, or the day before initiation of a new antineoplastic treatment (up to Month 98)	Participants with potentially clinically significant abnormalities in vital signs were summarized for the following parameters: systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR). Potentially clinically significant abnormalities were defined as (1) SBP (mmHg): \>180 and increase from baseline \>40; \<90 and decrease from baseline \>30; final visit or 2 consecutive visits change from baseline (CFB) ≥10, ≥15, ≥20; final visit or most extreme result ≥140, ≥180, ≥140 and ≥20 CFB, ≥180 and ≥20 CFB; (2) DBP (mmHg): \>105 and increase from baseline \>30; \<50 and decrease from baseline \>20; final visit or 2 consecutive visits CFB ≥5, ≥10, ≥15; final visit or most extreme result ≥90, ≥105, ≥90 and ≥15 CFB, ≥105 and ≥15 CFB; (3) HR (bpm): \>120 and increase from baseline \>30; \<50 and decrease from baseline \>20.

Trial Locations

Locations (243): University of Alabama at Birmingham
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Birmingham, Alabama, United States
University of Alabama at Birmingham, IDS Pharmacy
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Birmingham, Alabama, United States
Alaska Urological Institute dba Alaska Clinical Research Center
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Anchorage, Alaska, United States
Urological Associates of Southern Arizona, PC
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Tucson, Arizona, United States
Tower Hematology Oncology Medical Group
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Beverly Hills, California, United States
Cedars-Senai OCC Pharmacy
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Los Angeles, California, United States
Cedars-Sinai Medical Center, Samuel Oschin Comprehensive Cancer Institute
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Los Angeles, California, United States
University of California, Irvine Medical Center
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Orange, California, United States
Sutter Medical Group, Vascular & Varicose Vein Center
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Roseville, California, United States
Sutter Medical Group
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Roseville, California, United States
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University of Alabama at Birmingham
🇺🇸Birmingham, Alabama, United States