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Darolutamide impairs cognitive function less than enzalutamide in men with advanced prostate cancer, according to a randomized trial with 111 patients.

Patients completed five computerized tests from the Cambridge Neuropsychological Test Automated Battery to measure memory and thinking ability at baseline, 12 weeks, and 24 weeks. Researchers compared the results of the test with the greatest decline in each group at 24 weeks.

Patients taking darolutamide had a 15.8% decline on the visual memory and executive function test, whereas the enzalutamide group had a 36.1% decline on the related working memory and executive function test (P = .009).

“There was a significantly greater decline in objectively assessed cognitive function for patients treated with enzalutamide when compared with darolutamide over 24 weeks,” said lead investigator Alicia Morgans, MD, at an early press conference for the American Society of Clinical Oncology (ASCO) 2026.

Androgen receptor pathway inhibitors are widely used for advanced disease but are known to affect mental acuity in some instances. Until now, however, two haven’t been directly compared to see which one carries a greater risk.

Men in the open-label trial, dubbed ARACOG, were a median of 71 years old and had metastatic castration-resistant, nonmetastatic castration-resistant, or metastatic hormone-sensitive prostate cancer. Overall, 55 were randomly assigned to darolutamide and 56 to enzalutamide.

Darolutamide patients in the study also seemed to get better at testing over time, whereas learning scores stayed flat or declined slightly in the enzalutamide arm.

Thirty patients (54%) crossed over from enzalutamide to darolutamide, mostly due to cognitive issues; no one switched to enzalutamide.

Complicating the switch issue, however, was the fact that darolutamide was provided free to patients in the trial, whereas enzalutamide might have had a copay.

The better cognitive outcomes with darolutamide are probably because it doesn’t cross the blood-brain barrier as readily as enzalutamide, explained Morgans, who is a genitourinary medical oncologist at the Dana-Farber Cancer Institute in Boston.

The point of the study isn’t to draw a hard line in favor of darolutamide, Morgans said. For one, it has narrower indications than enzalutamide. Also, many men take enzalutamide without any brain fog.

But for older people and others who are at higher risk for cognitive issues, starting with darolutamide or switching to it if problems emerge are reasonable options, Morgans said.

Study discussant Eric Small, MD, agreed.

Cognitive decline can be devastating. There can be job loss, inability to plan, forgetting familiar surroundings, and more. “When it’s severe, it’s substantial,” said Small, urologic medical oncologist at the University of California, San Francisco.

The trial “makes us aware” that there’s an option that could help not only older men but also younger men who need to stay sharp for work and other obligations, he said.

The study was funded by Bayer, the maker of darolutamide, and others. Morgans disclosed having extensive industry ties, including serving as an advisor and researcher for Bayer and receiving honoraria, research funding, and travel expenses from the company. Small disclosed having no ties to Bayer but reported receiving support from Janssen, Johnson & Johnson, and other companies.

M. Alexander Otto is a physician assistant and award-wining journalist. He is also an MIT science journalism fellow. Email: aotto@medscape.net