EMBARK Phase III: Enzalutamide Plus ADT Improves Survival in High-Risk Biochemically Recurrent Prostate Cancer

High-risk biochemically recurrent (hrBCR) prostate cancer represents a clinically challenging disease state, characterized by rising prostate-specific antigen (PSA) levels despite prior definitive local therapy and the absence of radiographic metastases on conventional imaging. Historically, androgen deprivation therapy (ADT) alone has been the standard approach, though outcomes have remained suboptimal. Results from the phase III EMBARK trial now demonstrate that treatment intensification with enzalutamide plus ADT produces a clinically meaningful and statistically significant overall survival (OS) benefit, redefining the standard of care for patients with hrBCR prostate cancer.

Clinical Takeaway

Enzalutamide combined with ADT significantly improves OS, metastasis-free survival, and multiple clinically relevant secondary endpoints in patients with hrBCR prostate cancer compared with ADT alone.

Drug Profile & Mechanism

• Agent: enzalutamide (Xtandi) plus leuprolide (Lupron, Eligard)
• Class:
  • enzalutamide: androgen receptor inhibitor
  • leuprolide: gonadotropin-releasing hormone (GnRH) agonist
• Mechanism of action:
  • enzalutamide: inhibits androgen receptor signaling by preventing androgen binding, nuclear translocation, and DNA binding
  • leuprolide: suppresses pituitary secretion of luteinizing hormone and follicular-stimulating hormone, thereby suppressing gonadal sex steroid production
• Route of administration:
  • enzalutamide: oral
  • leuprolide: intramuscular (IM) or subcutaneous (SubQ) injection
• Dosing Schedule:
  • enzalutamide:
    • 160 mg once daily (administered as four 40-mg capsules)
  • leuprolide:
    • single IM or SubQ injection administered once every 12 weeks

Target Population

• Adult males with high-risk biochemically recurrent, nonmetastatic, castration-sensitive prostate cancer, defined by elevated PSA following radical prostatectomy or radiation therapy, rapid PSA doubling time, and no evidence of metastases on conventional imaging.

Phase III EMBARK Trial Study Design (NCT02319837)

• Study Type: Randomized, international, phase III trial
• Population: 1,068 male patients
• Comparator: placebo plus leuprolide (ADT alone)
• Treatment Regimen:
  • enzalutamide: 160 mg orally once daily
  • leuprolide: 22.5 mg IM or SubQ once every 12 weeks
• Follow-Up Duration:
  • Median follow-up for OS analysis: ~8 years
• Estimated study completion: September 2026

Endpoints

• Primary Endpoint:
  • Metastasis-free survival (MFS) assessed by blinded independent central review
• Key Secondary Endpoints:
  • OS
  • Time to PSA progression
  • Time to first use of new antineoplastic therapy
  • Time to first symptomatic skeletal event
  • Progression-free survival (PFS) on first subsequent therapy

Efficacy Outcomes

• Primary Endpoint Results:
  • enzalutamide plus leuprolide significantly improved MFS compared with leuprolide alone
• Secondary Endpoint Results:
  • Significant improvements observed in time to PSA progression, time to first new antineoplastic therapy, symptomatic skeletal events, and PFS on first subsequent therapy
• Overall Survival:
  • OS (Final Analysis):
    • 8-year OS rate of 78.9% with enzalutamide plus leuprolide
    • 8-year OS rate of 69.5% with leuprolide alone
  • Median OS: Not reached
  • Hazard ratio for death: 0.597, representing a 40.3% reduction in risk of death with combination therapy

Subgroup analysis demonstrated consistent OS benefit across all predefined patient subsets, with no subgroup failing to derive benefit from the addition of enzalutamide.

Regulatory Milestones

• Approval Status: Approved (enzalutamide) for prostate cancer; EMBARK data support expanded use in hrBCR
• Regulatory Pathway: Label expansion supported by phase III survival data
• Regulatory Review: Ongoing post-trial analyses and long-term follow-up

Safety

• Overall Safety Profile: Comparable to previously reported enzalutamide and ADT safety profiles
• Grade ≥3 Events:
  • enzalutamide: <10% treatment-related serious adverse events
  • leuprolide: <10% treatment-related serious adverse events
• Treatment-related deaths: Rare across all treatment arms
• Notable toxicity patterns:
  • No new safety signals identified with extended follow-up
  • Safety profile remained consistent over more than 2.5 years of additional observation

Key Clinical Implications

✔ Establishes enzalutamide plus leuprolide as the standard of care for high-risk biochemically recurrent prostate cancer

✔ Demonstrates one of the largest overall survival hazard ratio reductions reported in a global phase III prostate cancer trial

✔ Supports early systemic intensification prior to radiographic metastases

✔ Confirms consistent benefit across all predefined patient subgroups

✔ Reinforces durability of benefit with favorable long-term safety

Bottom Line

The EMBARK trial confirms that adding enzalutamide to ADT significantly improves survival outcomes in patients with hrBCR prostate cancer, establishing combination therapy as the new treatment benchmark in this disease setting.

Sources:

• European Journal of Cancer. (2026). Enzalutamide with or without leuprolide in patients with high-risk biochemically recurrent prostate cancer: EMBARK post hoc analysis by age. European Journal of Cancer, 232. https://doi.org/10.1016/j.ejca.2025.116110
• Saylor, B. P. (2025, October 19). EMBARK data indicate large OS benefit with enzalutamide/ADT in prostate cancer. Urology Times. https://www.urologytimes.com/view/embark-data-indicate-large-os-benefit-with-enzalutamide-adt-in-prostate-cancer
• U.S. National Library of Medicine. (n.d.). Safety and efficacy study of enzalutamide with or without leuprolide and leuprolide alone in high-risk nonmetastatic prostate cancer (EMBARK) (NCT02319837). ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT02319837