ARACOG Trial Links Enzalutamide to Greater Cognitive Decline Compared With Darolutamide: Alicia Morgans, MD, MPH

Darolutamide is associated with significantly less cognitive decline than enzalutamide at 24 weeks, explains Alicia Morgans, MD, MPH, genitourinary medical oncologist and the director of the survivorship program at Dana-Farber Cancer Institute. The darolutamide group had a 15.8% decline vs the enzalutamide group that had a 36.1% decline on one of the tests, according to results from the phase 2 ARACOG trial (NCT06312670), the first head-to-head comparison of 2 androgen receptor pathway inhibitors (ARPIs) with a rigorous cognitive primary end point in patients with advanced prostate cancer.

These data were presented today at the American Society of Clinical Oncology (ASCO) annual meeting.

What the ARACOG Data Revealed

The trial enrolled over 100 males across nonmetastatic castration-resistant, metastatic castration-resistant, and metastatic hormone-sensitive prostate cancer settings. Participants completed 5 computer-based assessments from the Cambridge Neuropsychological Test Automated Battery at baseline and at 12 and 24 weeks. Final results were drawn from 95 evaluable participants, with 48 on darolutamide and 47 on enzalutamide. The cognitive advantage with darolutamide was consistent across multiple domains and statistically significant. Notably, darolutamide-treated patients appeared to demonstrate a learning effect over time, while enzalutamide patients did not. No participants were clinically diagnosed with dementia or mild cognitive impairment during the trial.

The switch-eligibility findings were striking: although a similar proportion in each arm qualified to switch treatments (roughly 32-33 per arm), all 23 patients who actually switched were in the enzalutamide arm, most commonly due to worsening cognitive impairment by testing or self-report.

Why This Matters for Treatment Decisions

When 2 ARPIs offer comparable oncologic efficacy, quality-of-life factors increasingly drive shared decision-making. Patients consistently rank maintaining cognitive independence near the top of their priorities. ARACOG now quantifies that difference prospectively in a controlled trial.

What This Means for Managed Care

From a payer and adherence standpoint, cognitive preservation may support long-term medication compliance. Co-pay burden, drug interactions, and organ tolerability also factor into adherence, but cognitive function is now one dimension that clinicians and payers can reference with direct trial-level evidence. Planned analyses include 48-week follow-up and a polygenic hazard score analysis examining genetic predisposition to cognitive decline.