Alicia Morgans, MD, discusses cognitive effects of darolutamide vs enzalutamide in prostate cancer

Enzalutamide (Xtandi) demonstrated significantly greater cognitive score decline compared with darolutamide (Nubeqa) at 24 weeks following treatment initiation for prostate cancer, according to results from the phase 2 ARACOG trial presented at the 2026 American Society of Clinical Oncology Annual Meeting in Chicago, Illinois. In the following video, the presenting author, Alicia K. Morgans, MD, MPH, discusses the study's design and key findings.

Morgans is a genitourinary medical oncologist at Dana-Farber Cancer Institute and an associate professor of medicine at Harvard Medical School in Boston, Massachusetts.

ARACOG (AFT-47) was a prospective, randomized phase 2 study designed to evaluate whether cognitive outcomes differ between the androgen receptor pathway inhibitors darolutamide and enzalutamide in patients with metastatic hormone-sensitive prostate cancer, metastatic castration-resistant prostate cancer, or nonmetastatic castration-resistant prostate cancer. Morgans explained that the trial was specifically powered to assess cognition as its primary end point, using a validated computer-based cognitive testing platform alongside patient-reported outcomes and other assessments. Participants were randomly assigned to receive either darolutamide or enzalutamide and underwent serial cognitive testing over time to capture treatment-related changes from baseline.

Among the 111 patients enrolled, 95 were evaluable for the primary analysis at 24 weeks. The study’s primary end point was the percent change in the maximally changed cognitive domain (MCCD), a prespecified measure designed to identify the cognitive test domain most affected within each treatment group. Morgans noted that cognition encompasses multiple overlapping domains, including executive function, attention, working memory, and visual memory, making it important to evaluate the greatest observed decline rather than focusing on a single predefined test. At 24 weeks, patients treated with enzalutamide experienced significantly greater cognitive score decline than those treated with darolutamide, with median changes in MCCD of –36.1% and –15.8%, respectively (P = .009). Although the specific cognitive domain demonstrating the greatest decline differed across treatment arms, the analysis suggested an overall advantage for darolutamide in preserving cognitive function.

Individual cognitive domain analyses suggested a potential learning effect among patients receiving darolutamide, reflected by improved scores over time. In contrast, cognitive performance among patients receiving enzalutamide remained stable or showed mild decline. Notably, crossover was permitted in the trial. By 24 weeks, 23 patients had crossed over, all from the enzalutamide arm to the darolutamide arm. Morgans emphasized that financial factors may have influenced these rates.

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