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

Metastasis-free Survival (MFS) Compared Between Enzalutamide Plus Leuprolide and Placebo Plus Leuprolide

Time frame · 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.

Metastasis-free Survival (MFS) Compared Between Enzalutamide Monotherapy and Placebo Plus Leuprolide

Time frame · 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.

Time to Prostate-specific Antigen (PSA) Progression

Time frame · 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

Time frame · 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)

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)

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

Time to Distant Metastasis

Time frame · 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 With Undetectable Prostate-specific Antigen (PSA) at 36 Weeks on Study Drug

Time frame · 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.

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

Time frame · 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.

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

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

Time frame · 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.

Time to Castration Resistance

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 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).