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

Time to Prostate-specific Antigen (PSA) Progression

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 frame: From randomization until first PSA progression (up to Month 98)

Time to First Use of New Antineoplastic Therapy

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.

Time frame: From randomization until first use of new antineoplastic therapy (up to Month 98)

Overall Survival (OS)

Overall survival was defined as the time in months between randomization and death due to any cause.

Time frame: From randomization until death due to any cause (up to Month 98 when at least 197 MFS events occurred among the 3 treatment groups)

Time to Distant Metastasis

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).

Time frame: From randomization until the earliest objective evidence of distant soft tissue metastases or metastatic bone disease (up to Month 98)

Percentage of Participants With Undetectable Prostate-specific Antigen (PSA) at 36 Weeks on Study Drug

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 frame: At Week 36

Percentage of Participants Who Remained Treatment-free 2 Years After Suspension of Study Treatment at Week 37 Due to Undetectable Prostate-specific Antigen (PSA)

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 frame: From randomization until 2 years after Week 37 (up to Month 34)

Percentage of Participants With Undetectable Prostate-specific Antigen (PSA) 2 Years After Suspension of Treatment at Week 37 Due to Undetectable PSA

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 frame: From randomization until 2 years after Week 37 (up to Month 34)

Time to Resumption of Any Hormonal Therapy Following Suspension at Week 37 Due to Undetectable Prostate-specific Antigen (PSA)

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.

Time frame: From treatment suspension at Week 37 until resumption of any hormonal therapy (up to Month 98)

Time to Castration Resistance

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 frame: 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 Symptomatic Progression

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.

Time frame: From randomization until the first development of events defined as symptomatic progression (up to Month 98)

Time to First Symptomatic Skeletal Event (SSE)

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 frame: From randomization until the first development of events defined as SSE (up to Month 98)

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

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 frame: From randomization until a 2-point or greater increase from baseline in the BPI-SF question 3 score (up to Month 98)

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

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.

Time frame: From randomization to first assessment with at least a 10-point decrease from baseline in the FACT-P total score (up to Month 98)

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

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.

Time frame: 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)

Number of Participants With Grade 3 or Higher Treatment-emergent Adverse Events (TEAEs) (All-causality) - at PCD Cut-off Date of 31 January 2023

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).

Time frame: 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)

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

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).

Time frame: 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)

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

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.

Time frame: 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)

Number of Participants With Treatment-emergent Adverse Events (TEAEs) Leading to Enzalutamide or Placebo Discontinuation - at PCD Cut-off Date of 31 January 2023

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.

Time frame: 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)

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

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.

Time frame: 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)

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

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 frame: 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)

Number of Participants With Potentially Clinically Significant Vital Signs - at PCD Cut-off Date of 31 January 2023

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.

Time frame: 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)