Results from the phase 2 ARACOG study, the first direct comparison of the cognitive effects of androgen receptor pathway inhibitors (ARPIs), show that darolutamide impairs memory and thinking less than enzalutamide in people with advanced prostate cancer.

Because the drugs are often used for a prolonged time, this quality-of-life effect is particularly important, especially if patients already have an increased risk of cognitive impairment.

The research will be presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting, taking place May 29 to June 2 in Chicago. 

“This is the first randomized comparison of American patients receiving enzalutamide or darolutamide for advanced prostate cancer that compares cognitive effects as the primary endpoint. Enzalutamide and darolutamide appear to work similarly in terms of prostate cancer control. But knowing that there can be differences in cognitive effects between these drugs may affect a clinician’s choice for treating prostate cancer if both options are available,” said lead study author Alicia Morgans, MD, MPH, Dana-Farber Cancer Institute, Boston, Massachusetts.

Both darolutamide and enzalutamide reduce tumor progression and improve survival in people with prostate cancer.

However, studies have suggested that those who take enzalutamide have a higher risk of neurological symptoms, such as seizures and falls, than those who take darolutamide.

This is likely because enzalutamide crosses the blood-brain barrier at higher levels than darolutamide.

Researchers conducted the ARACOG trial to compare the cognitive effects of the two drugs directly.

The study included 111 males in the United States with nonmetastatic castration-resistant (nmCRPC), metastatic castration-resistant (mCRPC), or metastatic hormone-sensitive (mHSPC) prostate cancer.

The median age of participants was 71, and the majority were White. 

Participants were divided into 2 groups: About half received darolutamide, and half received enzalutamide.

All participants took 5 computer-based tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB) that measured various aspects of their memory and thinking abilities. (These are not clinical tests, and they do not diagnose dementia.)

Participants took the tests before treatment and 12 and 24 weeks after starting the drugs.

Researchers compared how each participant performed on the tests after 24 weeks to how they had done before treatment.

Key Findings

• Results were available for 95 participants: 48 who were getting darolutamide and 47 who were getting enzalutamide.
• Darolutamide was associated with less cognitive impairment than enzalutamide. Researchers compared the results of whichever test showed the greatest change after 24 weeks. The darolutamide group had a 15.8% decline in one test, compared to a 36.1% decline in one test for the enzalutamide group.
• The results suggested that participants in the darolutamide group got better at testing over time (a learning effect), but participants in the enzalutamide group did not. 
• If the cognitive impairments or neurologic side effects were bad enough, participants could choose to take the other medicine. While nearly the same number of people in each group met the requirements to switch—32 to 33—only participants taking enzalutamide chose to change drugs; 23 of them switched to darolutamide during the trial. The most common reason was worsening cognitive impairment, either shown by testing or reported by the participant.
  • The authors suggest a couple of possible reasons for the preferential switch: Participants in the darolutamide group may have been less bothered by the symptoms. In addition, darolutamide was provided without a copay, while enzalutamide may have required a copay.

“Darolutamide and enzalutamide are widely used and highly effective treatments for advanced prostate cancer, but they may differ in their impact on cognitive function. In a new randomized phase 2 study, men treated with darolutamide experienced less cognitive decline than those receiving enzalutamide. This difference may be explained by darolutamide’s limited ability to enter the brain, potentially offering a favorable option for preserving cognitive health in men with advanced prostate cancer,” said Samuel U. Takvorian, MD, MSHP, Deputy Director of the Penn Center for Cancer Care Innovation at Abramson Cancer Center and an ASCO Expert in genitourinary cancers.

Researchers are continuing to follow participants to see the drugs’ effects on thinking and memory over 48 weeks.

They are also looking into whether there may be genetic factors contributing to an increased likelihood of cognitive change.  

This study was funded by a Prostate Cancer Foundation Challenge Award, an Alliance Scholar Award, and Bayer.

Source: ASCO