An argument not to EMBARK on systemic therapy for biochemical recurrence of prostate cancer

Biochemical recurrence (BCR) of prostate cancer is recurrence after definitive local treatment that is detectable only by the presence of prostate-specific antigen (PSA) in circulation without evidence of cancer on computed tomography or technetium-99m bone scans. BCR does not cause symptoms, except perhaps for anxiety due to fear of true cancer progression. Physicians can typically alleviate this anxiety through patient education, as the majority of patients with BCR do not progress to metastatic or symptomatic disease (1-3). However, a minority of patients with BCR will progress and die from prostate cancer. Features of BCR that are associated with increased risk of death from prostate cancer include a Gleason sum of 9 or 10 and a PSA doubling time (PSADT) of less than 6 months (3). Findings on prostate-specific membrane antigen (PSMA) imaging have not been proven to be a feature of BCR associated with increased risk of death from prostate cancer to date (4,5). Though patients with high-risk BCR may eventually die from prostate cancer, they often can live with prostate cancer for more than a decade with preserved quality of life. A recent study estimated the median duration of overall survival from local therapy to death of patients with BCR and PSADT less than 6 months who were not treated systemically until metastatic disease to be 14 years (6). Therefore, BCR is typically an indolent disease state associated with long cancer-specific survival when monitored and not treated until metastases develop.

In contrast, metastatic prostate cancer is associated with significantly shorter survival than BCR. There is clear evidence that androgen deprivation therapy (ADT) provides palliative and survival benefits for patients with metastatic prostate cancer (7,8), which is increased further when ADT is combined with a second-generation androgen receptor pathway inhibitor (ARPI). For many years, there has been interest in determining whether it is beneficial to start ADT at the time of BCR for patients with high risk of developing metastases, rather than waiting until development of overt metastatic disease. The hypothesis was that ADT may be more effective when tumor burden is lower, providing a cancer-specific survival advantage, the benefit of which might offset toxicities of very prolonged ADT use in a population with indolent cancer. However, to our knowledge, there exists no preclinical nor clinical data to support this hypothesis. The TOAD trial suggested that early ADT does not prolong survival compared to delayed ADT among patients with BCR (9), and subsequent studies have failed to demonstrate a survival benefit of ADT for BCR (6,10-12). Alarmingly, there is reason to believe that ADT for BCR could actually shorten overall survival compared to surveillance until metastatic progression, not only due to toxicities such as increasing risk of cardiovascular events (13), but also due to earlier development of castration-resistance, which is associated with accelerated disease progression that can be more rapidly lethal (14). Therefore, our assessment of the current state of knowledge is that ADT is generally not beneficial for patients with BCR, and an alternative management strategy is monitoring, with prompt initiation of systemic therapy upon metastatic progression.

On this foundation of knowledge enters the EMBARK study. The primary objective of EMBARK was to evaluate the efficacy and safety of the ARPI enzalutamide plus ADT, as well as enzalutamide monotherapy, compared with ADT alone, in patients with BCR and a PSADT of less than 9 months (15). The investigators justified the use of ADT as the control arm in the protocol by citing “common use” when a decision is made to treat these patients. No data was cited to support this statement, which also begs the question of whether common use of a therapy without proven clinical benefit is sufficient to justify its use as a benchmark against which experimental therapies will be compared. Nonetheless, the trial proceeded to randomize 1068 patients to these three groups and reported that enzalutamide plus ADT, as well as enzalutamide monotherapy, was superior to ADT monotherapy with respect to the primary endpoint of metastasis-free survival (15). Enzalutamide plus ADT was also superior to ADT monotherapy with respect to the secondary endpoint of overall survival (16).

A plethora of data, including the phase III trials LATITUDE, STAMPEDE, ENZAMET, ARCHES, and TITAN, as well as real-world data, have demonstrated that the combination of ADT plus ARPI prolongs overall survival compared with sequential ADT then ARPI for patients with hormone-sensitive metastatic prostate cancer, at all levels of metastatic tumor burden (17-23). These agents clearly synergize to achieve greater antitumor efficacy in combination rather than in sequence. EMBARK also demonstrates this point, and the investigators can be commended for conducting a rigorous study to substantiate this concept at very low tumor burden. The major conclusion we can take away from EMBARK is that ADT plus ARPI is superior to ADT then ARPI when systemically treating patients with high risk BCR.

However, the key question is whether we should systemically treat high-risk BCR at all.

In our minds, this question is very much open to debate. Just as ADT for BCR may be inferior to surveillance, it is conceivable that ADT and ARPI may also be inferior to surveillance, both by survival and quality of life metrics. By providing ADT monotherapy to the control arm, EMBARK eliminated the opportunity for these patients to benefit from the synergy of ADT plus ARPI treatment at the time of metastatic disease, potentially building in a survival disadvantage to this control arm that would not be present for a surveillance control arm. Furthermore, a surveillance control arm would have the advantage of delaying castration-resistance and its associated accelerated disease progression, as well as reducing physical, time, and financial toxicities of treatment (24), all of which may improve duration and quality of life for this control group. Additionally, the ADT monotherapy control arm may have been further disadvantaged by mandated discontinuation of treatment only upon radiographic progression despite evidence that ARPI treatment prolongs overall survival in patients with non-metastatic castration-resistant prostate cancer (25).

Given these limitations of the control arm, we believe that the study investigators’ conclusion that the EMBARK findings “support enzalutamide plus ADT as the standard of care for patients with prostate cancer with high-risk BCR” (16) is not substantiated by the totality of data. In contrast, our conclusion is that the longitudinal goals of systemic treatment of prostate cancer are to delay the onset of the rapidly progressive castration-resistant state as much as possible and to utilize combined ADT and ARPI when a decision to treat is made. Therefore, at this time, we believe surveillance remains a very reasonable option for management of high-risk BCR, and we encourage future trials of systemic therapy for BCR to include a surveillance control arm. It is possible that future research will define subgroups of BCR who benefit from systemic treatment.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Andrology and Urology. The article has undergone external peer review.

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0438/prf

Funding: This work was supported by NCI grant K08CA273167 and the Prostate Cancer Foundation (to L.A.S.); and NCI grant P30 CA077598 and DOD grant W81XWH-22-2-0025 (to E.S.A.).

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0438/coif). L.A.S. reports grants, research support, or personal fees from Panbela Therapeutics, Abbott Lingo, and Delphia Therapeutics. E.S.A. reports grants and personal fees from Janssen, Johnson & Johnson, Sanofi, Bayer, Bristol Myers Squibb, Convergent Therapeutics, Curium, MacroGenics, Merck, Pfizer, and AstraZeneca; personal fees from Aadi Bioscience, Abbvie, Abeona Therapeutics, Aikido Pharma, Astellas, Amgen, BioNTech, Blue Earth, Boundless Bio, Corcept Therapeutics, Duality Bio, GlaxoSmithKline, Exact Sciences, Hookipa Pharma, Invitae, Eli Lilly, Foundation Medicine, Jazz Pharma, Menarini-Silicon Biosystems, Tango Therapeutics, Tempus, Tolmar Scientific, VIR Biotechnology, Delphia Therapeutics, and Z-alpha; and grants from Adcentrx, Acerand, Novartis, Celgene, and Orion. He has a patent for an AR-V7 biomarker technology that has been licensed to Qiagen. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are 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/.

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