Clinical Summary: 

• Design/Population: The prospective ARACOG trial evaluated enzalutamide versus darolutamide in older adults with advanced prostate cancer, including nonmetastatic castration-resistant, metastatic castration-resistant, and metastatic hormone-sensitive prostate cancer, with cognitive function assessed through 24 weeks.
• Key Outcomes: The study met its primary end point, showing significantly greater cognitive decline with enzalutamide compared with darolutamide. More patients crossed over from enzalutamide to darolutamide, although financial considerations may have influenced treatment preference.
• Clinical Relevance: In clinical settings where enzalutamide and darolutamide are otherwise considered interchangeable for disease control, cognitive effects may be an important factor in shared decision-making, particularly for older adults or patients at risk for cognitive impairment.

Alicia Morgans, MD, Dana-Farber Cancer Institute, Boston, Massachusetts, discusses results from the randomized phase 3 ARACOG trial, comparing cognitive outcomes with enzalutamide and darolutamide in patients with advanced prostate cancer. The study was designed to evaluate whether differences in central nervous system penetration between the two agents translate into measurable differences in cognitive function. 

The study demonstrated that patients treated with enzalutamide experienced a significantly greater decline in cognitive performance over 24 weeks compared with those receiving darolutamide. These findings may help inform shared decision-making when selecting among androgen receptor pathway inhibitors, particularly for older patients or those concerned about cognitive side effects.

Dr Morgans presented these results at the 2026 ASCO Annual Meeting in Chicago, Illinois. 

Transcript: 

Hi, my name is Alicia Morgans and I'm a GU medical oncologist at Dana-Farber Cancer Institute in Boston, Massachusetts.

I presented at ASCO 2026, the ARACOG trial, which was a randomized prospective study of patients with advanced prostate cancer, either non-metastatic CRPC, metastatic CRPC, or metastatic hormone-sensitive prostate cancer, receiving treatment with either enzalutamide or darolutamide, 2 of our most commonly used androgen receptor pathway inhibitor medications. These medicines are considered equal in terms of cancer control generally and are used in multiple disease states interchangeably. We were able to randomize patients safely and effectively in this study.

The primary end point for the study was maximally changed cognitive domain because we were trying to understand if these drugs may have differential effects on cognitive function for our older adult cancer population, particularly because enzalutamide crosses the blood-brain barrier and is present in higher levels in preclinical models in the CNS than darolutamide is expected to be.

Patients were followed for a primary end point at 24 weeks in this study, though we did follow longitudinally and will eventually present data up through 48 weeks. If patients experienced a cognitive decline or had some reason to potentially cross from one treatment to another, they could at 12 or 24 weeks and we assessed cognitive function and patient reported outcome measures at baseline, 12, and 24 weeks for this presentation.

The primary end point was met in this study, and we did find that there was a significantly greater decline in patients treated with enzalutamide than with darolutamide during the study follow-up. There were also more patients who crossed from enzalutamide to darolutamide during study follow-up, though it's important to know that darolutamide was provided for free through the study and enzalutamide was something that patients had to receive through their standard of care insurance and so they may have a copayment associated with that. Of course, for eligibility for the trial, they had to have a copayment that was reasonable and acceptable for them, but anytime financial toxicity comes into play, this could affect a patient's preference in terms of crossover and should be stated.

Ultimately, we found that there was a statistically significantly difference in terms of the cognitive function decline being greater in treatment with enzalutamide than with darolutamide.

As a clinician in settings where both of these drugs might be used interchangeably, this is something that could be used in a shared decision to consider whether or not this may be a factor for a given patient in terms of choosing one treatment over another. I so appreciate your time. Thank you.

Source: 

Morgans AK, 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. Presented at the ASCO Annual Meeting. May 29 - June 2, 2026. Chicago, Illinois. Abstract 5005.