Darolutamide Linked to Cognitive Benefit Over Enzalutamide in Prostate Cancer

Darolutamide (Nubeqa) caused significantly less cognitive decline than enzalutamide (Xtandi) over 24 weeks in men with advanced prostate cancer, according to results from the phase 2 ARACOG trial, which are scheduled to be presented at the 2026 ASCO Annual Meeting.

The findings represent the first randomized, prospective head-to-head comparison of the cognitive effects of two androgen receptor pathway inhibitors in a US population. That makes the study especially important in a disease setting where quality of life is a major treatment consideration.

ARACOG trial enrolled 111 patients with metastatic castration-resistant prostate cancer, nonmetastatic castration-resistant prostate cancer, or metastatic hormone-sensitive prostate cancer at US academic medical centers and affiliated satellite sites between August 2021 and March 2025. Patients were randomized equally to receive either darolutamide or enzalutamide, with groups balanced by age.

The primary end point was change in objective cognitive performance from baseline to 24 weeks, measured with five remotely administered Cambridge Neuropsychological Test Automated Battery modules assessing executive function, visual memory, attention, and working memory. Secondary assessments included patient-reported cognitive function, quality of life, mood, sleep, physical function, and adverse events such as falls and neurologic toxicity.

Of the 111 enrolled patients, 95 were evaluable for the primary analysis. Baseline characteristics were generally similar between groups, including age, disease state, and prior treatment history. However, the investigators noted that the study population was predominantly White, which they identified as a limitation.

At 24 weeks, enzalutamide was associated with a greater decline in cognitive performance than darolutamide. The median change in the study’s main cognitive measure showed a significantly worse outcome for enzalutamide, indicating a clinically meaningful difference between the two treatments.

The pattern over time also differed between groups. Patients receiving darolutamide appeared to improve on repeated testing, which may reflect a learning effect, while patients receiving enzalutamide did not show the same benefit. Investigators suggested that treatment-related cognitive impairment may have offset the expected practice-related gains in the enzalutamide group.

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