ASCO 2026
Darolutamide shows cognitive advantage over enzalutamide in prostate cancer trial
Clinical Takeaway: Darolutamide was associated with less cognitive decline than enzalutamide in men with advanced prostate cancer across multiple cognitive domains. These findings may help inform androgen receptor pathway inhibitor selection in patients at higher risk for cognitive impairment, falls, or central nervous system adverse effects.
Cognitive adverse effects remain an important concern with androgen receptor pathway inhibitors (ARPIs), particularly in older patients with advanced prostate cancer. Randomized phase 2 data presented at the 2026 American Society of Clinical Oncology annual meeting suggest darolutamide may have a more favorable cognitive profile than enzalutamide.
The ARACOG (AFT-47) trial enrolled 111 patients with metastatic hormone-sensitive prostate cancer, metastatic castration-resistant prostate cancer, or nonmetastatic castration-resistant prostate cancer and randomized them to darolutamide or enzalutamide. Investigators used a validated computerized cognitive testing platform to assess multiple domains including memory recall, spatial working memory, executive function, and rapid visual processing.
At 24 weeks, patients receiving enzalutamide experienced significantly greater decline in the maximally changed cognitive domain compared with those receiving darolutamide. Median cognitive change was -36.1% with enzalutamide versus -15.8% with darolutamide (P=.009).
Investigators also observed evidence of a possible learning effect with darolutamide, while cognitive scores in the enzalutamide group remained stable or declined slightly across domains.
Crossover was permitted for significant cognitive decline, patient-reported deterioration, or central nervous system–associated adverse events such as falls. By 24 weeks, all treatment crossovers occurred in patients originally randomized to enzalutamide, most commonly because of worsening objective or subjective cognitive measures.
The findings may be clinically important because many patients receiving ARPIs are older adults who may already be vulnerable to cognitive impairment, fatigue, falls, or reduced quality of life. Longer-term cognitive and patient-reported outcome analyses are ongoing.
Source: Morgans AK. ASCO 2026 Annual Meeting Abstract 5005. Cognitive effects of darolutamide vs enzalutamide: Results of ARACOG (AFT-47), a randomized clinical trial from the Alliance for Clinical Trials in Oncology