Nonmetastatic hormone-sensitive biochemical recurrence (BCR) after radical prostatectomy or radiation has a very high prevalence of prostate cancer (PC) patients given it occurs in upwards of 70,000 US patients per year.¹ Prior studies have clearly established that patients with a PSA doubling time (PSADT) ≤ 9 months are at high risk of progression to metastatic disease² and death from PC.³ Until the EMBARK trial results, we had limited options for high-risk BCR patients beyond a surveillance approach or androgen deprivation therapy (ADT). Despite a paucity of evidence-based publications, intermittent or continuous early ADT alone (prior to metastases) and/or first-generation androgen receptor blockers (eg, bicalutamide) were the commonly chosen therapeutic strategies.⁴

Given this gray zone of evidence-based trials, the EMBARK trial was completed after 8 years of global site participation with over 1000 subjects. EMBARK was a global phase 3 trial assessing whether intensified ADT (adding enzalutamide or enzalutamide monotherapy) could improve outcomes for high-risk BCR vs ADT alone. Patients with nonmetastatic BCR (by conventional imaging) with a PSADT ≤ 9 months and PSA ≥ 1 ng/mL post prostatectomy or PSA ≥ 2 ng/mL above the nadir for those without prostatectomy were randomized to enzalutamide + ADT, ADT alone, or enzalutamide alone. As previously reported,⁵ enzalutamide with or without ADT delayed metastasis-free survival with trends toward improved overall survival, though results for overall survival are immature; however, these patients are being followed and we’ll hopefully report in the near future. Furthermore, global quality of life (QoL) was preserved as assessed by patient-reported outcomes (PROs) completed every 12 weeks.⁶ This led the Food and Drug Administration to approve enzalutamide for high-risk BCR in November 2023, its inclusion into the National Comprehensive Cancer Network guidelines in April 2024, the European Medicines Agency’s approval in April 2024, and inclusion into European Association of Urology guidelines in the same month.

Notably, a unique aspect of EMBARK is that if the PSA was < 0.2 at week 36, then at week 37 treatment for all 3 arms could be suspended. The rationale was to balance oncological benefits (more therapy) with improved QoL (less therapy). As previously presented,⁵ the treatment suspension occurred more often in the enzalutamide arms (> 90% in enzalutamide + ADT and > 85% in enzalutamide monotherapy) vs ADT alone (67%). At the ASCO (American Society of Clinical Oncology) 2024 annual meeting, the question we assessed was the impact of stopping treatment on QoL. We analyzed data from the PROs every 12 weeks for those who received the treatment suspension and for as long as they remained on treatment suspension. Using the last time point before suspension (week 36) as the new baseline, we assessed what happens to QoL when treatment is suspended through week 109 (ie, over 2 years in the study). After week 109, the majority of patients in all 3 arms had gone back on treatment and thus the number of patients left was small, thereby leading to wide confidence intervals and unreliable estimates.

Remarkably, for global QoL as well as for nearly every subdomain of QoL analyzed, we found no statistically significant nor clinically meaningful benefit to stopping treatment. This was even true in the enzalutamide monotherapy arm, wherein testosterone levels are elevated during treatment, and thus our results do not reflect any possible lingering effects of ADT to suppress testosterone. While perhaps counterintuitive, intriguingly, when looking back at the impact of initially starting treatment, we also saw no impact of treatment on global QoL. As such, if the initial treatment does not negatively impact QoL, it makes sense that stopping treatment does not improve QoL. Said in another way, enzalutamide for high-risk BCR does not negatively affect QoL and thus stopping it does not improve QoL.

One exception to the above general rule was in hormonal symptoms, which rapidly improved (at the next PRO measurement 12 weeks later) in all 3 treatment arms. As these are the some of the most bothersome symptoms patients get from enzalutamide, it is reassuring that with enzalutamide the likelihood of receiving treatment suspension is very high and patients can be reassured that those symptoms rapidly resolve when stopping therapy.

In summary, our recent ASCO 2024 presentation adds to the narrative that enzalutamide with or without ADT for high-risk BCR improves oncological outcomes without negatively affecting QoL. Given these data, it further supports the conclusion that enzalutamide is the new standard of care for high-risk nonmetastatic BCR.