Redefining the standard of care for high-risk biochemical recurrence of prostate cancer after definitive therapy: insights from the EMBARK final analysis

The 2022 GLOBOCAN report highlights that prostate cancer (PCa) is the second most common cancer and the fifth most fatal malignancy among men, accounting for approximately 1.46 million new cases and over 396,000 deaths globally (1). Although patients with localized PCa receive definitive interventions such as radical prostatectomy (RP) or radiotherapy (RT), approximately half of these patients develop biochemical recurrence (BCR) within a decade. BCR is characterized by a subsequent increase in prostate-specific antigen (PSA) levels in the absence of detectable lesions via conventional imaging modalities, including bone scintigraphy, computed tomography, or magnetic resonance imaging (2,3). A systematic review evaluating the prognostic value of BCR following curative intent for localized PCa revealed that BCR influenced patient survival but the prognostic impact seemed to be restricted to specific high-risk subgroups. Key determinants included (I) a short PSA doubling time (PSADT) combined with a high final Gleason score after RP, and (II) a high biopsy Gleason score coupled with a brief interval to biochemical failure after RT (4). High-risk BCR was correlates with elevated risks of distant metastasis, cancer-specific death, and all-cause mortality (4,5). Despite this poor prognosis, optimal management for high-risk BCR remains inconsistent across clinical guidelines. While PSA observation is recommended by some guidelines, others advocate for continuous androgen deprivation therapy (ADT). Alternatively, intermittent ADT is utilized to mitigate adverse events such as hot flashes, obesity, sexual impairment, depression, cognitive decline, and overall reduction in quality of life, which are caused by testosterone suppression (6,7). Thus, there is a need for efficient and well-tolerated therapy that can be used long-term in this population (3).

As a second-generation non-steroidal androgen receptor pathway inhibitor (ARPI), enzalutamide exerts its antineoplastic effects by competitively targeting the ligand-binding domain of the androgen receptor. This binding effectively blocks multiple signaling events, specifically preventing androgen receptor translocation into the nucleus, obstructing the recruitment of androgen receptor cofactors, and disrupting androgen receptor binding to DNA (8). Enzalutamide has a 10-fold higher affinity for the androgen receptor compared with the first-generation non-steroidal antiandrogen bicalutamide and distinguishes itself from bicalutamide by completely lacking the partial agonist activity at the androgen receptor level (5). Enzalutamide is currently approved for use in a variety of clinical settings. The PREVAIL trial revealed that enzalutamide (160 mg per day) improved radiological progression [hazard ratio (HR), 0.19; 95% confidence interval (CI): 0.15–0.23; P<0.001] compared with placebo at 12 months after treatment in metastatic castration-resistant PCa (CRPC) before chemotherapy. Enzalutamide also prolonged overall survival (OS) (HR, 0.71; 95% CI: 0.60–0.84; P<0.001) and time to the use of cytotoxic chemotherapy (HR, 0.35; 95% CI: 0.30–0.40; P<0.001) (8). The PROSPER trial revealed that enzalutamide (160 mg per day) plus ADT extended metastasis-free survival (MFS) (HR, 0.29; 95% CI: 0.24–0.35; P<0.001) and improved OS (HR, 0.73; 95% CI: 0.61–0.89; P=0.001) compared with placebo in nonmetastatic CRPC (PSADT ≤10 months) (9). The AFFIRM trial revealed that enzalutamide (160 mg per day) prolonged OS (HR, 0.63; 95% CI: 0.53–0.75; P<0.001), radiological progression-free survival (PFS) (HR, 0.40; 95% CI: 0.35–0.47; P<0.001), and Functional Assessment of Cancer Therapy-Prostate (FACT-P) quality of life response compared with placebo in docetaxel-treated metastatic CRPC (10). The TERRAIN trial revealed that enzalutamide (160 mg per day) increased PFS compared with bicalutamide (50 mg per day) (HR, 0.44; 95% CI: 0.34–0.57; P<0.0001) in treatment-naïve metastatic CRPC (11). The ARCHES trial revealed that enzalutamide (160 mg per day) plus ADT improved radiographic PFS (HR, 0.39; 95% CI: 0.30–0.50; P<0.001) compared with placebo plus ADT in metastatic castration-sensitive PCa. Subgroup analyses demonstrated a comparable treatment benefit for the enzalutamide and ADT combination, which was unaltered by baseline disease volume or previous docetaxel therapy (12). The ENZAMET trial revealed that enzalutamide (160 mg per day) plus ADT resulted in longer OS compared with first-generation antiandrogens (e.g., bicalutamide, nilutamide, flutamide) plus ADT (HR, 0.67; 95% CI: 0.52–0.86; P=0.002) in metastatic castration-sensitive PCa. In addition, enzalutamide plus ADT improved PSA PFS (HR, 0.39; 95% CI: 0.33–0.47; P<0.001) and clinical PFS (HR, 0.40; 95% CI: 0.33–0.49; P<0.001) (13).

The phase 3 EMBARK trial evaluated the efficacy and safety of enzalutamide (160 mg per day) plus leuprolide (enzalutamide combination) and enzalutamide monotherapy, both compared with leuprolide plus placebo (leuprolide alone), in patients with high-risk BCR (PSADT ≤9 months and no apparent distant metastasis on conventional radiological assessments). The results are shown in Table 1. Eligible patients were randomized 1:1:1 fashion to receive enzalutamide combination, leuprolide alone, or enzalutamide monotherapy. The primary endpoint was MFS. The 5-year MFS rates were documented at 87.3% (95% CI: 83.0–90.6%) for the combination cohort, 71.4% (95% CI: 65.7–76.3%) for the leuprolide monotherapy cohort, and 80.0% (95% CI: 75.0–84.1%) for those receiving enzalutamide alone. At primary analysis, the enzalutamide combination demonstrated a clear MFS advantage over leuprolide monotherapy (HR, 0.42; 95% CI: 0.3–0.61; P<0.001). A key secondary endpoint, enzalutamide monotherapy also demonstrated superior MFS compared to leuprolide alone (HR, 0.63; 95% CI: 0.46–0.87; P=0.005) (14). These robust findings prompted both the U.S. Food and Drug Administration and the European Medicines Agency to approve enzalutamide as the inaugural ARPI indicated for high-risk BCR, applicable either in combination with or without ADT (5). However, as of 2023, data on OS were immature (14).

The 2025 update to the phase 3 EMBARK trial included the final analysis of OS. The 8-year OS was 78.9% (95% CI: 73.9–83.1%) in the enzalutamide combination group and 69.5% (95% CI: 64.0–74.3%) in the leuprolide-alone group, and the risk of death was reduced by 40% (HR, 0.6; 95% CI: 0.44–0.80; P<0.001). This final analysis revealed that enzalutamide combination therapy significantly prolonged OS relative to leuprolide alone, despite mandatory treatment holidays for patients with undetectable PSA at week 36. Conversely, enzalutamide monotherapy failed to demonstrate a significant survival benefit over leuprolide alone, with an 8-year OS rate of 73.1% (95% CI: 67.6–77.9%) (15). Consequently, while enzalutamide monotherapy was not superior to leuprolide alone, these findings establish that enzalutamide combination therapy significantly extends OS compared with leuprolide monotherapy, thereby supporting its implementation for patients with high-risk BCR following definitive therapy. The 2026 European Urological Association guidelines endorse the administration of enzalutamide in conjunction with ADT for individuals meeting the EMBARK criteria, specifically those with M0 disease on conventional imaging and a PSADT of 9 months or less (strength rating: strong) (16). Hot flashes and fatigue were the most common adverse events in both the enzalutamide combination group (69.7% and 43.6%, respectively) and the leuprolide-alone group (58.2% and 33.6%, respectively), while fatigue (48.0%) and gynecomastia (46.0%) were the most common in the enzalutamide monotherapy group. Breast-related adverse events such as gynecomastia, nipple pain, and breast tenderness were the most common adverse events in the enzalutamide monotherapy group (15). Although the EMBARK trial did not use prostate-specific membrane antigen (PSMA) positron emission tomography (PET) for metastasis detection, combination enzalutamide and leuprolide regimen should be considered as a standard of care for patients with high-risk BCR (15,17).

Apalutamide and darolutamide are two other second-generation non-steroidal ARPIs. The phase 3 PRESTO study enrolled patients with high BCR (PSADT ≤9 months and no evidence of metastases on conventional imaging after RP), and metastases detected on PSMA or Axumin PET were allowed. Participants underwent 1:1:1 randomization to be allocated to one of three fixed 52-week treatment regimens: ADT alone, ADT plus apalutamide (240 mg per day), or ADT plus apalutamide (240 mg per day) plus abiraterone (1,000 mg per day) acetate plus prednisone (5 mg per day). The primary endpoint was PSA PFS. After a median follow-up of 21.5 months, the risk of PSA progression was significantly reduced by the addition of apalutamide to ADT (median, 24.9 vs. 20.3 months for ADT alone; HR, 0.52; 95% CI: 0.35–0.77; P=0.005). A comparable clinical benefit was observed with the intensive regimen adding apalutamide, abiraterone acetate, and prednisone to ADT, yielding a median PSA PFS of 26.0 vs. 20.0 months in the ADT-alone arm (HR, 0.48; 95% CI: 0.32–0.71; P<0.001) (18). However, the U.S. Food and Drug Administration has not yet approved apalutamide plus ADT for the treatment of high-risk BCR after RP.

The ongoing phase 3 ARASTEP trial enrolled patients with high-risk BCR [PSADT <12 months and ≥1 PSMA PET/computed tomography (CT)-positive PCa lesion with no visible lesions on conventional imaging after RP or RT]. The trial design required a 1:1 allocation of patients to receive ADT plus either darolutamide (1,200 mg per day) or a placebo for a predefined 24-month duration. The primary endpoint is radiological PFS by PSMA PET/CT (3).

Patients with high-risk BCR after definitive therapy have a higher risk of distant metastasis, PCa-specific mortality, and overall mortality. Based on the results of the final analysis of the EMBARK trial, physicians should consider enzalutamide plus leuprolide regimen as a standard of care for patients with high-risk BCR (PSADT ≤9 months) in order to improve OS.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Andrology and Urology. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0437/coif). The author has no conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2024;74:229-63. [Crossref] [PubMed]
2. Morgans AK, Touya M, El-Chaar N, et al. Does Physician Documentation of Patients' Prostate-Specific Antigen Doubling Time Affect Treatment Decisions in High-Risk Biochemically Recurrent Prostate Cancer? Clin Genitourin Cancer 2026;24:102496. [Crossref] [PubMed]
3. Morgans AK, Chehrazi-Raffle A, Niazi T, et al. Darolutamide plus androgen-deprivation therapy in high-risk biochemical recurrence of prostate cancer (ARASTEP). Future Oncol 2025;21:3491-8. [Crossref] [PubMed]
4. Van den Broeck T, van den Bergh RCN, Arfi N, et al. Prognostic Value of Biochemical Recurrence Following Treatment with Curative Intent for Prostate Cancer: A Systematic Review. Eur Urol 2019;75:967-87. [Crossref] [PubMed]
5. Shore ND, De Giorgi U, Tutrone RF, et al. Enzalutamide Monotherapy for the Treatment of Prostate Cancer With High-Risk Biochemical Recurrence: EMBARK Secondary End Points. J Urol 2026;215:396-407. [Crossref] [PubMed]
6. Aprikian A, Chilelli A, McLean T, et al. Comparing the safety and efficacy of systemic therapies for high-risk biochemically recurrent hormone-sensitive prostate cancer: a network meta-analysis. Front Oncol 2025;15:1638405. [Crossref] [PubMed]
7. Laccetti AL, Smith MR, Scher HI, et al. ARAMON, a phase 2 open-label trial of darolutamide monotherapy in patients with biochemical recurrence or oligometastatic castration-sensitive prostate cancer after radical prostatectomy or primary radiotherapy. Eur Urol Focus 2026;S2405-4569(26)00034-9.
8. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014;371:424-33. [Crossref] [PubMed]
9. Sternberg CN, Fizazi K, Saad F, et al. Enzalutamide and Survival in Nonmetastatic, Castration-Resistant Prostate Cancer. N Engl J Med 2020;382:2197-206. [Crossref] [PubMed]
10. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012;367:1187-97. [Crossref] [PubMed]
11. Shore ND, Chowdhury S, Villers A, et al. Efficacy and safety of enzalutamide versus bicalutamide for patients with metastatic prostate cancer (TERRAIN): a randomised, double-blind, phase 2 study. Lancet Oncol 2016;17:153-63. [Crossref] [PubMed]
12. Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. ARCHES: A Randomized, Phase III Study of Androgen Deprivation Therapy With Enzalutamide or Placebo in Men With Metastatic Hormone-Sensitive Prostate Cancer. J Clin Oncol 2019;37:2974-86. [Crossref] [PubMed]
13. Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. N Engl J Med 2019;381:121-31. [Crossref] [PubMed]
14. 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;389:1453-65. [Crossref] [PubMed]
15. Shore ND, Luz MA, De Giorgi U, et al. Improved Survival with Enzalutamide in Biochemically Recurrent Prostate Cancer. N Engl J Med 2026;394:563-75. [Crossref] [PubMed]
16. Prostate Cancer. Accessible online: https://d56bochluxqnz.cloudfront.net/documents/full-guideline/EAU-EANM-ESTRO-ESUR-ISUP-SIOG-Guidelines-on-Prostate-Cancer-2026_2026-03-14-104356_ixav
17. Shore ND, Gleave M, De Giorgi U, et al. Treatment of High-Risk Biochemically Recurrent Prostate Cancer With Enzalutamide in Combination With Leuprolide: Secondary End Points From the EMBARK Trial. J Urol 2026;215:512-25. [Crossref] [PubMed]
18. Aggarwal R, Heller G, Hillman DW, et al. PRESTO: A Phase III, Open-Label Study of Intensification of Androgen Blockade in Patients With High-Risk Biochemically Relapsed Castration-Sensitive Prostate Cancer (AFT-19). J Clin Oncol 2024;42:1114-23. [Crossref] [PubMed]