A new phase 3 randomized clinical trial has found that enzalutamide, either in combination with leuprolide or as monotherapy, significantly improved metastasis-free survival in men with high-risk biochemically recurrent prostate cancer compared to leuprolide alone. The international EMBARK trial, funded by Pfizer and Astellas Pharma, was published in The New England Journal of Medicine on October 19, 2023.
The study aimed to evaluate the efficacy and safety of enzalutamide plus androgen-deprivation therapy (ADT) and enzalutamide monotherapy compared to ADT alone in patients with prostate cancer who had high-risk biochemical recurrence after primary therapy. Biochemical recurrence is characterized by rising prostate-specific antigen (PSA) levels after definitive treatment and can indicate the presence of micrometastatic disease. Patients with a PSA doubling time of less than 9 months are considered at high risk for rapid disease progression and increased mortality.
The trial enrolled 1068 patients across 244 sites in 17 countries between January 2015 and August 2018. Eligible patients had histologically confirmed prostate adenocarcinoma with high-risk biochemical recurrence, defined as a PSA doubling time of 9 months or less and PSA levels of 2 ng/mL or higher above nadir after radiation therapy or 1 ng/mL or higher after radical prostatectomy. Key exclusion criteria included previous cytotoxic chemotherapy, history of seizure, evidence of distant metastases on conventional imaging, and candidacy for salvage radiation therapy after radical prostatectomy.
Patients were randomized 1:1:1 to receive enzalutamide (160 mg daily) plus leuprolide (22.5 mg every 12 weeks), placebo plus leuprolide, or enzalutamide monotherapy. The primary endpoint was metastasis-free survival in the combination therapy group compared to the leuprolide-alone group. Key secondary endpoints included metastasis-free survival with enzalutamide monotherapy vs leuprolide alone, time to PSA progression, time to first use of new antineoplastic therapy, and overall survival.
Baseline characteristics were well-balanced between groups. The median age was 69 years, median PSA doubling time was 4.9 months, and median PSA level was 5.2 ng/mL. The majority of patients (83.2%) were White. After a median follow-up of 60.7 months, the study found significant improvements in metastasis-free survival with both enzalutamide-containing regimens compared to leuprolide alone.
The 5-year metastasis-free survival rate was 87.3% in the enzalutamide plus leuprolide group, compared to 71.4% in the leuprolide-alone group. This translated to a 57.6% reduction in the risk of metastasis or death (hazard ratio 0.42, 95% CI 0.30-0.61, p<0.001). Enzalutamide monotherapy also demonstrated superiority over leuprolide alone, with a 5-year metastasis-free survival rate of 80.0% and a 36.9% risk reduction (hazard ratio 0.63, 95% CI 0.46-0.87, p=0.005).
Both enzalutamide-containing regimens showed significant benefits across other key secondary endpoints. The risk of PSA progression was reduced by 93% with combination therapy (hazard ratio 0.07, 95% CI 0.03-0.14, p<0.001) and by 67% with monotherapy (hazard ratio 0.33, 95% CI 0.23-0.49, p<0.001) compared to leuprolide alone. Time to first use of new antineoplastic therapy was also significantly prolonged in both enzalutamide groups.
The safety profile of enzalutamide was consistent with previous studies, with no new safety signals observed. Over 97% of patients in all groups experienced adverse events, with the most common in the combination and leuprolide-alone groups being hot flashes and fatigue. In the monotherapy group, gynecomastia, hot flashes, and fatigue were most frequent. Adverse events leading to treatment discontinuation occurred in 20.7% of patients on combination therapy, 10.2% on leuprolide alone, and 17.8% on enzalutamide monotherapy.
An important aspect of the trial design was the prespecified treatment suspension at week 37 if PSA levels became undetectable (<0.2 ng/mL). This strategy allowed for intermittent therapy, potentially reducing treatment-related adverse effects. A higher proportion of patients in the enzalutamide groups had treatment suspended compared to the leuprolide-alone group (90.9% and 85.9% vs 67.8%, respectively). The median duration of treatment suspension was longer in the combination group (20.2 months) compared to the monotherapy (11.1 months) and leuprolide-alone (16.8 months) groups.
The study had several limitations. Overall survival data were immature at the time of analysis. The trial population was predominantly White (>80%), limiting the generalizability of results to other racial groups. Long-term consequences of prolonged enzalutamide exposure on tolerance of subsequent treatments remain unknown. Additionally, the open-label design of the monotherapy arm may have introduced some bias.
The authors concluded that in patients with prostate cancer and high-risk biochemical recurrence, both enzalutamide plus leuprolide and enzalutamide monotherapy were superior to leuprolide alone in prolonging metastasis-free survival. The safety profile was consistent with previous enzalutamide studies, and there was no apparent detrimental effect on quality of life.
These findings have potentially significant clinical implications for the management of high-risk biochemically recurrent prostate cancer. The study provides level 1 evidence supporting the use of enzalutamide, either in combination with ADT or as monotherapy, in this patient population. The substantial improvements in metastasis-free survival and other key endpoints suggest that earlier intensification of treatment with enzalutamide may delay disease progression and potentially improve long-term outcomes.
The demonstration of efficacy with enzalutamide monotherapy is particularly noteworthy, as it offers a potential alternative to ADT that may avoid some of the adverse effects associated with testosterone suppression. This could be especially relevant for younger patients or those concerned about the impact of ADT on quality of life. However, the shorter duration of treatment suspension with monotherapy suggests that the benefits may not be as durable as with combination therapy.
The prespecified treatment suspension strategy used in this trial also provides valuable insights into the potential for intermittent therapy in this setting. The ability to suspend treatment in a high proportion of patients, particularly in the enzalutamide groups, suggests that this approach may be feasible and could help mitigate long-term treatment-related toxicities.
While the results are promising, several questions remain. Longer follow-up will be necessary to determine if the improvements in metastasis-free survival translate to overall survival benefits. The optimal duration of therapy and the long-term impact of treatment intensification on subsequent lines of therapy are also important areas for future research.
In conclusion, the EMBARK trial provides compelling evidence for the use of enzalutamide in high-risk biochemically recurrent prostate cancer. The significant improvements in metastasis-free survival and other clinically relevant endpoints, coupled with a manageable safety profile, suggest that enzalutamide-based regimens could become a new standard of care in this setting. However, as with any new treatment strategy, careful patient selection and consideration of individual risk-benefit profiles will be crucial in implementing these findings into clinical practice.
References
Freedland SJ, de Almeida Luz M, De Giorgi U, et al. Improved Outcomes with Enzalutamide in Biochemically Recurrent Prostate Cancer. N Engl J Med. 2023;389(16):1453-1465. doi:10.1056/NEJMoa2303974
