ARACOG, a phase II randomized trial, reports a significantly greater decline in objectively assessed cognitive function for advanced prostate cancer patients treated with enzalutamide vs darolutamide over 24 weeks, according to data presented at ASCO 2026.
“Previous data describing the effects of hormonal therapy on cognitive function [in patients with advanced prostate cancer] have been limited, with many studies of poor quality and rigor,” stated Dr Alicia Morgans of Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, US. “We specifically chose [enzalutamide and darolutamide], because there are structural differences suggesting that, at least in preclinical models, blood–brain barrier penetration and central nervous system [CNS] levels are greater with enzalutamide than darolutamide.” [J Clin Oncol 2018;36:345]
A total of 111 patients with metastatic castration-resistant, non-metastatic castration-resistant, or metastatic hormone-sensitive prostate cancer were randomized to receive either darolutamide (n=55) or enzalutamide (n=56). Cognitive and patient-reported assessments were performed at baseline and at 12, 24, and 48 weeks using Cambridge Neuropsychological Test Automated Battery (CANTAB) cognitive modules and Patient-Reported Outcomes Measurement Information System (PROMIS)/Timed Up and Go (TUG) evaluations. [ASCO 2026, abstract 5005]
The primary endpoint was the CANTAB Maximally Changed Cognitive Domain (MCCD), which compared the percent change between baseline and 24 weeks in what was identified as the MCCD in each treatment arm. “We wanted to understand the worst effect in the worst module for each treatment … and not miss any impaired behaviour for these patients,” explained Morgans.
In the darolutamide arm, the MCCD was visual memory/executive function assessed through the Paired Associates Learning First Attempt Memory (PALFAM) CANTAB module, with a median change of -15.8. In contrast, patients receiving enzalutamide experienced a decline in working memory/executive function measured through the Spatial Working Memory (SWM) module, with a median change of -36.1. Although the MCCDs were different for the two treatment arms, overall, treatment with enzalutamide was associated with significantly greater deterioration in cognitive function compared with darolutamide (p=0.009).
Morgans also highlighted the “learning effect”, which was observed in the study. With repeated testing over time, observed scores should increase in patients with stable cognitive function, while stable test scores in the setting of repeated testing represent cognitive decline. Patients treated with darolutamide had increased median test scores between baseline and 24 weeks, while enzalutamide-treated patients had stable to decreased median test scores within this timeframe.
The study had a secondary endpoint of crossover, which was offered at 12 or 24 weeks for patients who met one of four criteria (≥30 percent decline in any CANTAB module; ≥10 point decline in Functional Assessment of Cancer Therapy-Cognitive Function [FACT-Cog]; fall or increased risk of fall per investigator assessment; grade ≥2 neurologic toxicity event) and preferred to cross to the other treatment.
“Although there were relatively similar number of patients eligible for crossover [darolutamide group: n=34; enzalutamide group: n=36], only patients treated with enzalutamide decided to cross over, which, by 24 weeks, was 30 patients,” reported Morgans. She stressed that an important limitation of the study was that darolutamide was provided per the trial and enzalutamide was provided through standard of care, which may have affected the crossover rates.