Rana R. McKay, MD, FASCO, details ARASEC findings in mHSPC

In this video, Rana R. McKay, MD, FASCO, discusses findings from the phase 2 ARASEC trial (NCT05059236), which evaluated darolutamide (Nubeqa) plus androgen deprivation therapy (ADT) in patients with metastatic hormone-sensitive prostate cancer (mHSPC) using a novel external control-arm design.¹ These results were presented at the 2026 American Urological Association Annual Meeting in Washington, DC.

McKay is a genitourinary medical oncologist at the University of California, San Diego.

McKay explained that ARASEC was developed in response to the rapidly evolving mHSPC treatment landscape, where combination therapy had become the standard of care, making a traditional US trial with a prospective ADT-alone control arm impractical. To address this challenge, investigators designed a prospective, open-label phase 2 study comparing darolutamide plus ADT with a matched external ADT control cohort derived from the phase 3 CHAARTED trial. The study mirrored CHAARTED’s inclusion criteria, end point definitions, and assessment schedule, while propensity score matching was used to balance key baseline characteristics including age, ECOG performance status, disease burden, prior local therapy, Gleason score, and prostate-specific antigen (PSA) level.

ARASEC met its primary end point, demonstrating a significant progression-free survival benefit with darolutamide plus ADT compared with ADT alone (HR, 0.29; 95% CI, 0.20 to 0.40; P < .001). The combination also significantly improved overall survival (HR, 0.50; 95% CI, 0.30 to 0.82; P = .003), despite more patients in the ADT-alone cohort subsequently receiving life-prolonging therapies. Additional secondary end points favored the darolutamide regimen, including improvements in time to metastatic castration-resistant prostate cancer (HR, 0.26; 95% CI, 0.18 to 0.38; P < .001) and radiographic progression-free survival (HR, 0.30; 95% CI, 0.19 to 0.48; P < .001). PSA response rates were also notably higher with the combination, with 68% of patients achieving a PSA level below 0.2 ng/mL at any point during the study compared with 33% in the ADT arm (P < .001).

Multiple sensitivity analyses were conducted to strengthen confidence in the findings and address limitations associated with the external control design. These analyses included comparisons with the contemporary ADT arm from the phase 3 ARANOTE study as well as evaluations of the broader unmatched study population, both of which supported the primary efficacy results. Safety findings from the darolutamide arm were also consistent with the favorable tolerability profile previously reported in ARANOTE, without evidence of increased toxicity compared with ADT alone.

McKay concluded that ARASEC reinforces prior evidence supporting darolutamide plus ADT in mHSPC while also demonstrating the potential utility of pragmatic, externally controlled trial designs to accelerate clinical research in rapidly changing treatment settings.

REFERENCE

1. McKay R, et al. ARASEC: A novel pragmatic trial design comparing darolutamide plus ADT versus ADT in US patients with metastatic hormone-sensitive prostate cancer using propensity score matching with an external phase 3 trial control arm. J Urol. 2025;213(5S). doi:10.1097/01.JU.0001109788.ARASEC