Enzalutamide is an orally administered potent androgen-receptor signaling inhibitor that targets multiple steps in the androgen signaling pathway including ligand-receptor binding, nuclear translocation, DNA binding, and coactivator recruitment.¹ Enzalutamide was initially approved in 2012 for the treatment of castrate-resistant prostate cancer (CRPC) in patients who previously received docetaxel based on the AFFIRM trial, which demonstrated both a statistically significant radiographic progression-free survival and overall survival for patients receiving enzalutamide.¹ Its therapeutic approvals have subsequently migrated earlier in the treatment paradigm for patients with prostate cancer including metastatic CRPC without prior docetaxel (TERRAIN, PREVAIL), nonmetastatic CRPC (STRIVE, PROSPER), and metastatic hormone-sensitive prostate cancer (ARCHES, ENZAMET).^2-7 These successful trial results are reflected in our current guidelines for advanced prostate cancer treatment, which includes enzalutamide in combination with androgen deprivation therapy (ADT) as a standard of care for these men (see Figure).⁸

Figure. Utilization of enzalutamide in prostate cancer treatment. Blue shading indicates guidelines-approved areas for use of enzalutamide. Orange shading indicates trials evidence to suggest potential future utilization of enzalutamide in this space. CRPC indicates castrate-resistant prostate cancer; HSPC, hormone-sensitive prostate cancer.

Recent trials are now investigating the current standards of care for men with earlier stage disease including patients with high-risk localized prostate cancer, on active surveillance (AS), or those with biochemical recurrence (BCR; see Figure). First, while AS delays the side effects and morbidity of local treatment, about 40% of men will discontinue AS within 5 years of diagnosis.⁹ There may be an opportunity for earlier introduction of systemic therapy in men diagnosed with localized prostate cancer who desire to prolong time on AS and delay prostate cancer progression. The phase 2 ENACT trial compared men on AS alone (113 men) to 1 year of enzalutamide monotherapy plus AS (114 men) with up to 2 years of follow-up.¹⁰ Importantly, enzalutamide reduced the risk of prostate cancer histopathological progression by 46% compared to AS alone (HR 0.54, 95% CI 0.33-0.89, P = .02). Secondary end points included time to PSA progression, odds of negative biopsy at 1 and 2 years, and volume of disease (cancer positive cores) at 1 and 2 years. Enzalutamide was well tolerated with most common adverse events being fatigue (62 [55.4%]) and gynecomastia (41 [36.6%]).¹⁰ While there are limitations to the ENACT trial such as PSA rebound after enzalutamide cessation, side effects, and cost associated with treatment, it is hypothesis generating as we try to elucidate ways to delay prostate cancer progression in men with earlier stage, low-grade disease and encourage greater adoption of AS protocols.

Following definitive primary therapy (eg, surgery or radiotherapy) and prior to the development of detectable metastatic disease on conventional imaging, nearly one-third of men with prostate cancer will experience a PSA-only rise, termed BCR. Patients with BCR at highest risk for progression are those with PSA doubling time ≤9-12 months, PSA ≥1 ng/mL following radical prostatectomy, PSA ≥2 ng/mL above nadir postradiotherapy, Gleason 8 or more, adverse pathological features at time of radical prostatectomy, and/or shorter interval to biochemical failure. While their current options include observation, intermittent ADT, or salvage radiation, the soon-to-be published EMBARK trial, which was recently presented at AUA2023, explores enzalutamide as a novel option for men with BCR. Conducted over an 8-year period, EMBARK is a phase 3 global, multicenter study of 1,068 high-risk men with BCR who were randomized 1:1:1 to enzalutamide+ADT, placebo+ADT, or enzalutamide monotherapy. Compared to ADT+placebo, enzalutamide monotherapy and enzalutamide+ADT significantly reduced risk of metastasis and death by 36.9% (HR 0.63, 95% CI 0.46-0.87, P = .005) and 57.6% (HR 0.42, 95% CI 0.31-0.61, P < .001), respectively. This clinically meaningful treatment effect was consistent across their prespecified subgroups and remained significant regardless of prior hormonal therapy, prior prostatectomy, baseline PSA, PSA doubling time, and age. With regard to secondary end points, (1) time to first new neoplastic agent and (2) time to PSA progression, enzalutamide+ADT combination was superior in efficacy compared to ADT alone (new neoplastic agent: HR 0.36, 95% CI 0.26-0.49, P < .001; PSA progression: HR 0.07, 95% CI 0.03-0.14, P < .001). The side-effect profile of combination enzalutamide+ADT was consistent with the established safety profile for enzalutamide in other prostate cancer treatment settings.

While enzalutamide is currently 1 standard of care option for advanced prostate cancer treatment, the recent ENACT and EMBARK trials offer compelling data for understanding the role of enzalutamide earlier within the prostate cancer treatment paradigm. Additional questions remain to better understand which prostate cancer patients can optimally benefit from earlier utilization of enzalutamide.