Enzalutamide monotherapy improves outcomes in prostate cancer with hrBCR

Treatment with enzalutamide monotherapy demonstrates numerically higher overall survival (OS) in prostate cancer patients with high-risk biochemical recurrence (hrBCR) when compared with leuprolide alone, but the difference is not statistically significant, as shown by the results of the EMBARK study.

Enzalutamide monotherapy also shows better metastasis-free survival (MFS), as well as clinically meaningful delays in time to distant metastasis, symptomatic progression, and first symptomatic skeletal event, relative to leuprolide alone.

“The EMBARK trial demonstrates that enzalutamide monotherapy now represents an important therapeutic option to be considered between clinicians and their patients with hrBCR during shared decision-making,” the investigators said. 

“Clinicians should consider potential benefits and risks for each patient, including potential financial costs, when evaluating enzalutamide monotherapy as a therapeutic option,” they added.

In EMBARK, patients were randomly assigned 1:1:1 to receive enzalutamide plus leuprolide, leuprolide alone, or enzalutamide monotherapy. The investigators assessed sexual health using the Quality of Life (QoL) Questionnaire–Prostate 25 (QLQ-PR25) and summarized time-to-event endpoints using Kaplan-Meier methods.

At 5 years, OS was 89.5 percent (95 percent confidence interval [CI], 85.6–92.4) with enzalutamide monotherapy vs 87.2 percent (95 percent CI, 83.0–90.4) with leuprolide alone. [J Urol 2026;215:396-407]

Enzalutamide monotherapy also demonstrated better 5-year probability rates than leuprolide alone in time to remaining free from distant metastasis (86.8 percent vs 81.5 percent), symptomatic progression (66.6 percent vs 53.3 percent), and first symptomatic skeletal event (95.8 percent vs 91.5 percent).

Following treatment suspension, the probability rate of remaining free from resumption of any hormonal therapy at 5 years was 5.6 percent with enzalutamide monotherapy vs 7.8 percent with leuprolide alone.

Patients treated with enzalutamide monotherapy had better preserved sexual health than those who received leuprolide alone (hazard ratio [HR], 0.76, 95 percent confidence interval [CI], 0.62–0.94; p=0.008). After discontinuation, most patients were treated with hormonal therapies.

Sexual function

“Patients considering enzalutamide monotherapy should be aware of factors affecting adverse events, sexual function, and QoL,” the investigators said. 

“These data should be considered alongside analyses of QLQ-PR25 in the domains of sexual activity and sexual functioning and item-level analyses of sexual activity-related health-related QoL,” they added. [NEJM Evid 2023;2:EVIDoa2300251; Eur Urol 2025;87:507-511]

Many patients express concern about their loss of sexual function, which is why modest improvements can still affect treatment decision-making, according to the investigators.

Furthermore, nearly 15 percent of patients treated with enzalutamide monotherapy reported having nipple pain and breast tenderness, almost half (45 percent) experienced gynecomastia, which was greater than those who received leuprolide alone. [New Engl J Med 2023;389:1453-1465]

“Prophylactic radiation to the breast tissue, aromatase inhibitors, serum estrogen receptor modulators (eg, tamoxifen), and subareolar removal of breast tissue may be appropriate treatments to prevent and/or address these adverse events reported by patients treated with enzalutamide monotherapy,” the investigators said. [Strahlenther Onkol 2020;196:589-597] 

“Prophylactic treatments were not routinely administered to patients enrolled in EMBARK but may have been effective in reducing reports of these breast-related adverse events, although these treatment options require further study,” they added.