A phase III trial presented at ESMO 2025 shows that combining enzalutamide with hormone therapy (ADT) cuts the risk of death by over 40% in men with advanced prostate cancer that returns after surgery or radiation. The EMBARK trial, involving 1,068 men, tested enzalutamide plus leuprolide, leuprolide alone, or enzalutamide monotherapy in high-risk, biochemically recurrent prostate cancer. The combination improved 8-year survival to 78.9% versus 69.5% for leuprolide alone, delayed metastasis, and reduced the need for new therapies. Side effects like fatigue and fractures were manageable, and enzalutamide monotherapy preserved sexual health better. Unlike the ENZARAD trial, which showed no benefit in localized disease, this sets a new standard for recurrent prostate cancer, with FDA approval and NCCN support. Future research will optimize dosing and explore PSMA-PET imaging for personalized care, improving men’s health outcomes.
Long Version
Breakthrough in Prostate Cancer Treatment: Enzalutamide Plus Hormone Therapy Reduces Mortality Risk in Recurrent Disease
In the field of oncology, advancements in cancer treatment continue to reshape outcomes for men’s health, particularly in prostate cancer, the second most common cancer among men worldwide. A recent phase III trial presented at ESMO 2025 has demonstrated that a drug combination of enzalutamide, an androgen receptor inhibitor, and androgen deprivation therapy (ADT) significantly lowers the risk of death in men with advanced prostate cancer that recurs after initial interventions like surgery or radiation. This finding marks a pivotal step forward in managing biochemical recurrence, a stage where rising prostate-specific antigen (PSA) levels signal potential progression to metastasis, even in non-metastatic prostate cancer.
Understanding Prostate Cancer and Its Recurrence
Prostate cancer often begins as localized disease, treated effectively with radical prostatectomy or radiotherapy. However, in up to 40% of cases, the cancer returns, manifesting as biochemical recurrence characterized by elevated PSA without detectable metastases on conventional imaging. This recurrence poses a high risk for developing castration-resistant prostate cancer, where the disease progresses despite low testosterone levels. Factors like a PSA doubling time of 9 months or less identify high-risk patients prone to poorer survival rates and eventual metastatic spread.
Hormone therapy, or ADT, has long been a cornerstone for suppressing androgen-driven growth in prostate cancer. Yet, traditional ADT alone has not consistently improved overall survival in recurrent settings, leaving a gap for more effective strategies. Salvage therapy options, including additional radiation or systemic treatments, aim to delay progression, but optimizing combinations remains crucial for enhancing metastasis-free survival and quality of life.
The Role of Enzalutamide in Prostate Cancer Management
Enzalutamide, a potent androgen receptor inhibitor, blocks testosterone’s effects on cancer cells, offering benefits across various stages of prostate cancer, from non-metastatic to metastatic hormone-sensitive disease. Approved for use in castration-resistant prostate cancer, it has shown promise in delaying metastasis and improving survival when added to ADT. This drug’s mechanism addresses resistance pathways, making it a key player in combination regimens for advanced prostate cancer.
The EMBARK Trial: A Landmark Phase III Study
The EMBARK trial, a randomized controlled trial involving 1,068 men from 244 sites across 17 countries, evaluated enzalutamide’s efficacy in high-risk, biochemically recurrent prostate cancer negative on conventional imaging. Patients were stratified by prior treatments—such as radical prostatectomy with or without radiotherapy, or primary radiotherapy alone—and randomized 1:1:1 to three arms: enzalutamide (160 mg daily) plus leuprolide (a form of ADT administered every 12 weeks), leuprolide plus placebo, or enzalutamide monotherapy.
Inclusion criteria targeted high-risk profiles: PSA doubling time ≤9 months, with PSA ≥1 ng/mL post-prostatectomy or ≥2 ng/mL above nadir post-radiotherapy. Treatment was intermittent—suspended if PSA dropped below 0.2 ng/mL and resumed upon rise—allowing assessment of long-term effects over a median follow-up of 94 months.
The primary endpoint was metastasis-free survival comparing the combination to leuprolide alone, with overall survival as a key secondary endpoint. Other secondary measures included time to new antineoplastic therapy, time to first symptomatic skeletal event, and second progression-free survival.
Key Findings: Substantial Survival Benefits
Final results, presented at ESMO 2025 and published in The New England Journal of Medicine, revealed a 40.3% reduction in the risk of death with enzalutamide plus leuprolide versus leuprolide alone (hazard ratio [HR] 0.597; 95% CI 0.444–0.804; P=0.0006). Eight-year overall survival rates were 78.9% (95% CI 73.9%–83.1%) for the combination, compared to 69.5% (95% CI 64.0%–74.3%) for leuprolide monotherapy.
Enzalutamide monotherapy yielded an 8-year survival rate of 73.1% (HR 0.830; 95% CI 0.630–1.095; P=0.1867), a 17% risk reduction that did not achieve statistical significance. Both enzalutamide-containing arms significantly delayed time to new therapy (combination HR 0.374; P
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