DAROLUTAMIDE showed less cognitive decline than enzalutamide in ARACOG results presented at ASCO 2026 for prostate cancer.
The prospective, randomized, open label phase 2 ARACOG trial, also known as AFT 47, compared cognitive and quality of life outcomes in patients with metastatic hormone sensitive prostate cancer, metastatic castration resistant prostate cancer, or non metastatic castration resistant prostate cancer receiving darolutamide or enzalutamide.
Androgen receptor pathway inhibitors may differ in central nervous system penetration, raising clinically relevant questions about cognitive effects, patient reported outcomes, and quality of life. ARACOG directly examined these concerns using objective cognitive testing and patient reported measures over time.
Cognitive Testing Favored Darolutamide
Between August 17, 2021, and March 11, 2025, 111 patients were enrolled and randomized 1:1 to darolutamide or enzalutamide. Median age was 71 years, and 83% of patients were White. Overall, 95 patients were evaluable for the primary endpoint, including 48 receiving darolutamide and 47 receiving enzalutamide.
Cognitive performance was assessed using CANTAB, a validated computer based platform evaluating memory recall, spatial working memory, short term visual memory, rapid visual processing, and executive function. Testing was performed at baseline and at 12, 24, and 48 weeks.
The primary endpoint was percent change from baseline to 24 weeks in the maximally changed cognitive domain. Median cognitive change was minus 15.8% with darolutamide compared with minus 36.1% with enzalutamide, a statistically significant difference favoring darolutamide.
Crossover Patterns Reinforce Cognitive Signal
Crossover was allowed at 12 or 24 weeks for prespecified cognitive decline, patient reported outcome decline, or central nervous system associated adverse events, including falls. By 24 weeks, 32 patients receiving darolutamide and 33 receiving enzalutamide were eligible for crossover.
Among 23 patients who crossed over by 24 weeks, all had been randomized to enzalutamide and crossed to darolutamide. The most common reasons were decline in objective cognitive testing and subjective cognitive testing.
Individual cognitive domains suggested a possible learning effect with darolutamide, while scores with enzalutamide were stable or showed mild decline at 24 weeks. Longer term cognitive follow up and patient reported outcome analyses are ongoing.
Reference
Morgans A et al. Cognitive effects of darolutamide vs enzalutamide: Results of ARACOG (AFT-47), a randomized clinical trial from the Alliance for Clinical Trials in Oncology. Abstract 5005. ASCO Annual Meeting, May 29-June 2, 2026.
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