Prostate cancer patients treated with enzalutamide plus leuprolide have a higher probability of remaining free of distant metastasis, castration resistance, symptomatic progression, and first symptomatic skeletal event (SSE) at 5 years than those treated with leuprolide alone, as shown by the results of the EMBARK study.
On the other hand, “[t]ime to confirmed clinically meaningful deterioration of hormonal treatment-related symptoms favoured leuprolide alone, although the median difference was small,” the investigators said.
Patients with prostate cancer were randomized to receive enzalutamide combination, leuprolide alone, or enzalutamide monotherapy. Non-key secondary endpoints were as follows: time to distant metastasis, resumption of any hormonal therapy, castration resistance, symptomatic progression, and first SSE.
The investigators assessed hormonal treatment-related symptoms using the Quality-of-Life Questionnaire-Prostate 25. They also summarized time-to-event endpoints using the Kaplan-Meier method, with nominal p-values.
Enzalutamide combination, compared with leuprolide alone, resulted in increased 5-year probabilities for remaining free of distant metastasis (91.0 percent vs 81.5 percent), resumption of any hormonal therapy after treatment suspension (14.9 percent vs 7.8 percent), castration resistance (96.6 percent vs 67.8 percent), symptomatic progression (70.9 percent vs 53.3 percent), and first SSE (97.8 percent vs 91.5 percent). [J Urol 2026;215:512-525]
In contrast, leuprolide alone performed better than enzalutamide combination regarding time to confirmed clinically meaningful deterioration of hormonal treatment-related symptoms, but the median difference was small (0.03 months).
“Overall, these results, combined with the primary analysis from EMBARK, support the role of enzalutamide combined with leuprolide as a new standard of care for patients with high-risk BCR,” the investigators said.
EMBARK
In the primary analysis of EMBARK, metastasis-free survival improved with enzalutamide combination compared with leuprolide alone in patients with high-risk biochemical recurrence (BCR) while delaying prostate-specific antigen progression and prolonging the time to first antineoplastic therapy. [New Engl J Med 2023;389:1453-1465]
“Expanding on these findings, the current analyses of non–key secondary endpoints support the longer-term favourable impact of enzalutamide combination on other potentially clinically relevant endpoints for patients with high-risk BCR,” the investigators said.
Furthermore, treatment with enzalutamide combination prolonged the time to resumption of any hormonal therapy after treatment suspension. This delay may have a beneficial impact on the adverse effects associated with long-term use of androgen receptor pathway inhibitors or androgen deprivation therapy. [Expert Rev Anticancer Ther 2018;18:193-198; J Urol 2017;197:1251-1257]
“The primary results of EMBARK along with the secondary endpoints presented herein are consistent with the clinical trial data from the oligometastatic and metastatic castration-sensitive prostate cancer populations,” the investigators said. [J Clin Oncol 2022;40:1616-1622; J Clin Oncol 2022;40(17_suppl l):LBA5004; J Clin Oncol 2019;37:2974-2986; Eur Urol 2023;84:229-241; N Engl J Med 2019;381:121-131]
“Together, they provide strong evidence for the additive benefits of enzalutamide plus leuprolide vs leuprolide alone for delaying metastatic progression and improving tumour response, while preserving global quality of life and potentially improving cancer-specific survival in the high-risk BCR setting,” they added.