Patients with advanced prostate cancer treated with darolutamide experienced significantly less objectively assessed cognitive decline over 24 weeks than those receiving enzalutamide, according to results from the prospective, randomized open-label phase II ARACOG (AFT-47) trial to be presented at the 2026 ASCO Annual Meeting (Abstract 5005). Of note, although a similar number of patients receiving either androgen receptor pathway inhibitor met eligibility criteria for crossover, only those treated with enzalutamide switched to the alternate therapy.
Previous studies have shown that androgen receptor pathway inhibitors—including darolutamide and enzalutamide, two of the most prescribed agents in this class—may differ in central nervous system penetration and have differential effects on cognition and quality of life, but the drugs had not been directly compared using rigorous cognitive testing in U.S. populations.
“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,” presenting author Alicia K. Morgans, MD, MPH, FASCO, Medical Director of the Survivorship Program at Dana-Farber Cancer Institute and Associate Professor of Medicine at Harvard Medical School, commented in an ASCO press release.
Study Details
In this U.S.-based study, 111 men with nonmetastatic castration-resistant, metastatic castration-resistant, or metastatic hormone-sensitive prostate cancer were randomly assigned in a 1:1 ratio to receive darolutamide or enzalutamide. The median age of the population was approximately 71 years, 83% of patients were White, and baseline characteristics were described as generally well balanced between the treatment arms, although a greater proportion of Black patients were assigned to receive enzalutamide than darolutamide (12.5% vs 1.8%).
The primary endpoint was the percent change in the maximally changed cognitive domain (MCCD) from baseline to 24 weeks, assessed using five computer-based tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB) administered at baseline and 12, 24, and 48 weeks: PALFAM, SWM, SSP, RVP, and OTSMCC, with comparisons between treatment groups performed using the Wilcoxon rank-sum test. Executive function, visual memory, attention, and working memory were objectively evaluated, according to Dr. Morgans, who noted during a premeeting press briefing that there was overlap among these cognitive domains of interest across the tests, “making MCCD a critical method to assess the complexity of cognitive change.”
Patients crossing over before 24 weeks were analyzed with the score at the time of crossover and within their randomized treatment arm.
Additional assessments included patient-reported outcome measures (FACT-Cog, FACT-P, PHQ-9, and Sleep Scale); functional status via the Timed Up and Go test; and adverse events, including those of special interest (eg, falls, severe neurologic toxicity [including fatigue], posterior reversible encephalopathy syndrome, seizure).
Crossover was a secondary endpoint. Patients were permitted to cross over to the alternate therapy at 12 or 24 weeks if they elected to do so after experiencing a decline of at least 30% in any CANTAB module, a decline of at least 10 points in FACT-Cog score, falls or increased fall risk, or grade 2 or higher neurologic toxicity.
Less Cognitive Decline With Darolutamide
Among 95 evaluable patients, baseline CANTAB scores appeared to be similar between the treatment arms. By 24 weeks, treatment with enzalutamide was found to be associated with a significantly greater decline in MCCD compared with darolutamide; median change from baseline was –15.8% in PALFAM for darolutamide-treated patients and –36.1% in SWM for those who received enzalutamide (P = .009).
The cognitive domains contributing most to the MCCD differed between the arms, with visual memory and executive function driving changes in the darolutamide arm and working memory and executive function driving changes in the enzalutamide arm, according to Dr. Morgans.
Individual cognitive domains suggested a possible learning effect among darolutamide-treated patients, reflected by increased scores over time, whereas scores among enzalutamide-treated patients remained stable or showed mild decline at 24 weeks.
One-Way Crossover Pattern
Thirty crossovers from enzalutamide to darolutamide were observed, whereas no patients crossed over from darolutamide to enzalutamide, despite similar numbers in each treatment arm meeting eligibility criteria for crossover, according to Dr. Morgans.
In the press release, the investigators suggested several possible explanations for preferential switches to darolutamide, including that patients receiving darolutamide may have been less bothered by symptoms. In addition, darolutamide was provided through the study without a copay, whereas patients receiving enzalutamide may have incurred out-of-pocket costs.
Understanding the Cognitive Findings
“While it is important to acknowledge the quantitative differences observed…, it can be easy to lose the real-life context of these CANTAB domains,” Eric J. Small, MD, FASCO, President of ASCO for the 2025–2026 term, stated during the press briefing, describing cognitive loss as “devastating.”
Dr. Small continued, “Most people would agree that [the observed differences in cognitive outcomes] may be explained by darolutamide’s limited ability to enter the brain.”
Echoing this in the press release, Samuel U. Takvorian, MD, MSHP, Deputy Director of the Penn Center for Cancer Care Innovation at Abramson Cancer Center, Philadelphia, and an ASCO expert in genitourinary cancers, added that the trial “potentially offers a favorable option for preserving cognitive health in men with advanced prostate cancer.”
Dr. Morgans acknowledged several study limitations, including that enzalutamide was obtained through standard-of-care insurance approval rather than supplied through the study, which may have influenced crossover decisions. In addition, the trial was conducted only at U.S. academic medical centers and enrolled a predominantly White population; most Black patients and those reporting other or unknown race were randomly assigned to the enzalutamide arm.
Longer-term follow-up evaluating cognitive changes and patient-reported outcomes through 48 weeks is ongoing. The investigators are also exploring whether genetic factors may contribute to susceptibility to cognitive changes associated with androgen receptor pathway inhibitors.
DISCLOSURE: The study was funded by a Prostate Cancer Foundation Challenge Award, an Alliance Scholar Award, and Bayer. For full disclosures of the study authors, visit coi.asco.org.
