Phase 2 ARASEC data add US population evidence for darolutamide in mHSPC

The phase 2 ARASEC trial (NCT05059236) adds US-based, contemporary data supporting darolutamide (Nubeqa) plus androgen deprivation therapy in metastatic hormone-sensitive prostate cancer¹—but its most important contribution may be methodologic rather than clinical, according to Michael S. Cookson, MD, MMHC, FACS, who, speaking at the 2026 American Urological Association (AUA) Annual Meeting in Washington, DC, offered context on how the findings fit into a treatment landscape that has shifted substantially since darolutamide's foundational trial was conducted.

Darolutamide already carries FDA approval for metastatic hormone-sensitive prostate cancer based on the global phase 3 ARANOTE trial (NCT04736199), which demonstrated significant improvement in radiological progression-free survival. ARASEC was designed to address 2 gaps that remained after ARANOTE: the absence of US population data and the absence of overall survival end points.

"My guess is that this was an attempt to bridge 2 gaps—the desire to use a US population for metastatic disease, and to get some overall survival points on the board in that space," said Cookson, a professor of urology and the Donald D. Albers Endowed Chair in Urology at the University of Oklahoma Health Sciences Center in Oklahoma City.

The trial's design reflects the ethical constraints of the current treatment environment. By the time investigators sought to enroll a US cohort, doublet therapy had become standard of care, making a contemporaneous ADT-alone control arm untenable.

"It really isn't ethical to tell people…that you should just go on ADT alone," Cookson noted. The solution was to compare a prospectively enrolled darolutamide-plus-ADT arm against the ADT arm from the historical phase 3 CHAARTED trial (NCT00309985), using propensity score matching on six baseline variables to balance the groups.

The clinical results were consistent with what the existing evidence base would predict. Darolutamide plus ADT significantly improved PFS versus ADT alone (HR 0.29; 95% CI 0.20–0.40; P < .001), OS (HR 0.50; 95% CI 0.30–0.82; P = .003), time to metastatic castration-resistant disease (HR 0.26), and prostate-specific antigen response rates at all time points. The 24-month OS rates were 89% in the combination arm and 80% in the ADT arm—a benefit achieved despite proportionately more patients in the ADT arm receiving subsequent life-prolonging therapies. Cookson cited a 71% risk reduction in death from prostate cancer as among the most striking findings.

He was direct, however, about the study's interpretive limitations.

"It's not what we normally think of when we think about randomized controlled studies," he said, noting that the external historical control introduces inherent confounding that propensity score matching can mitigate but not eliminate. In that context, the results are best understood as affirming rather than generating new evidence.

"It is affirming what we thought would happen in that environment," Cookson said. "It just adds to their database—a little more US-based population, a little more contemporary data."

For practicing urologists, the practical takeaway aligns with existing guideline direction. Both the AUA and the Society of Urologic Oncology have emphasized combination therapy in the metastatic hormone-sensitive setting, and ARASEC reinforces that framework with a domestic population.

"It emphasizes that we've moved the needle when it comes to treating patients if we give them combination treatment when they're diagnosed with metastatic disease," Cookson said.

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