Alicia Morgans, MD, discusses cognitive outcomes with darolutamide vs enzalutamide

In this video, Alicia K. Morgans, MD, MPH, discusses updated findings from the phase 2 ARACOG trial (AFT-47; NCT04335682), which compared cognitive outcomes among patients with advanced prostate cancer treated with darolutamide (Nubeqa) or enzalutamide (Xtandi). She highlights the trial's 48-week results and findings exploring whether genetic predisposition to dementia may influence treatment-associated cognitive changes.

Morgans is a a GU medical oncologist at Dana-Farber Cancer Institute and associate professor of medicine at Harvard Medical School in Boston, Massachusetts.

Morgans explains that ARACOG was developed in response to clinical observations of cognitive changes among some patients receiving androgen receptor pathway inhibitors. The trial was designed to investigate whether differences in central nervous system penetration between enzalutamide and darolutamide could translate into differences in cognitive function. Earlier findings presented at the 2026 American Society of Clinical Oncology Annual Meeting showed significantly less change from baseline in the maximally changed cognitive domain (MCCD) among patients receiving darolutamide compared with enzalutamide at 24 weeks.¹

At the 2026 European Society for Medical Oncology Congress, investigators presented updated findings demonstrating that the differences in objective cognitive outcomes persisted through 48 weeks.² The median change in MCCD was −20.0% with darolutamide vs −33.3% with enzalutamide (P = .043), despite crossover between treatment arms during follow-up. Patient-reported cognitive outcomes, assessed using the Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog), also favored darolutamide. At 48 weeks, the between-group difference was 10.5 points, meeting the threshold for a clinically meaningful difference, although it did not reach statistical significance (95% CI, -0.8 to 21.7; P = .07).

A separate analysis evaluated whether a polygenic hazard score associated with Alzheimer's disease risk was linked to cognitive changes observed during treatment. Investigators found no significant association between the genetic risk score and objective cognitive changes at 24 weeks, while the differences between treatment groups remained apparent across genetic risk quartiles. According to Morgans, these findings suggest that treatment-associated cognitive changes may be more closely related to the drug used than to patients' underlying genetic predisposition to dementia.

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REFERENCES
1. Morgans A, Bobek O, Kwon DH, et al. Cognitive effects of darolutamide vs enzalutamide: results of ARACOG (AFT-47), a randomized clinical trial from the Alliance for Clinical Trials in Oncology. J Clin Oncol. 2026 (suppl 16; abstr 5005). doi:10.1200/JCO.2026.44.16_suppl.5005

2. Kwon D, Bobek O, Berg S, et al. Long-term patient-reported and objective cognitive effects of darolutamide vs enzalutamide in ARACOG (AFT-47). Presented at: European Society for Medical Oncology Congress 2026; October 23-27, 2026, Madrid, Spain. Abstract 2280P

3. Ryan CJ, Kwon D, Bobek O, et al. Genetic dementia risk and androgen receptor (AR) therapy-associated cognitive effects (ARTACE) results from AFT-47, a randomized comparison of darolutamide (DAR) and enzalutamide (ENZ). Presented at: European Society for Medical Oncology Congress 2026; October 23-27, 2026, Madrid, Spain. Abstract 2244P