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The phase 2 ARACOG (AFT-47) trial reports the first prospective randomized comparison of cognitive outcomes between darolutamide and enzalutamide in patients with advanced prostate cancer. Alicia Morgans, MD, MPH, of Dana-Farber Cancer Institute, presents the data today at the 2026 ASCO Annual Meeting (Abstract 5005). The Alliance Foundation Trials study enrolled 111 patients with metastatic hormone-sensitive prostate cancer, metastatic castration-resistant prostate cancer, or nonmetastatic castration-resistant prostate cancer, randomizing to either an oral androgen receptor pathway inhibitor.
Investigators used the validated CANTAB computerized platform to test memory recall, spatial working memory, executive function, and rapid visual processing at baseline, week 12, and week 24. At 24 weeks, patients receiving enzalutamide showed significantly greater decline in the maximally changed cognitive domain compared with those receiving darolutamide. Among 95 evaluable participants, 48 received darolutamide and 47 received enzalutamide. Prespecified crossover at weeks 12 or 24 was permitted for participants who met clinical or cognitive thresholds. Thirty crossovers from enzalutamide to darolutamide were observed; no patients crossed in the opposite direction despite similar numbers meeting crossover criteria.
For managed care leaders, the trial enters a market where both agents are widely prescribed across the prostate cancer continuum and carry substantial monthly costs. The investigators noted that enzalutamide is known to cross the blood-brain barrier at higher levels than darolutamide, providing a pharmacologic basis for the observed signal. Prior real-world comparisons have linked enzalutamide with higher rates of fatigue, falls, fractures, and arthralgias. ASCO President Eric J. Small, MD, FASCO, urged caution in translating CANTAB domain scores directly into clinical practice without a broader quality-of-life context. The investigators also noted that darolutamide in the trial was provided without a copay, whereas enzalutamide patients incurred out-of-pocket costs, a factor that may have influenced crossover behavior. Dr. Morgans stated the cognitive differences may inform clinician selection when both treatment options are available. Frontline Care Team awareness of differential cognitive risk could be relevant in older patients and those with baseline impairment.
