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

Why It Matters

Because ARPIs have similar survival outcomes, preserving cognitive function becomes a key differentiator that can influence patient preference, adherence, and overall healthcare costs.

Key Takeaways

• Darolutamide reduced cognitive decline by 20.3% versus enzalutamide.
• Trial enrolled 95 evaluable patients across three prostate cancer stages.
• All 23 treatment switches occurred in the enzalutamide arm due to cognition.
• Cognitive preservation may improve long‑term adherence and payer outcomes.

Pulse Analysis

Androgen‑receptor pathway inhibitors (ARPIs) have become a cornerstone of therapy for both castration‑resistant and hormone‑sensitive prostate cancer. While agents such as enzalutamide and darolutamide deliver comparable oncologic control, emerging evidence suggests they differ markedly in neurocognitive side‑effects. Cognitive health is increasingly recognized as a critical component of survivorship, influencing everything from daily functioning to the ability to manage complex medication regimens. As the population of long‑term prostate cancer survivors grows, clinicians are seeking data that go beyond tumor response to address quality‑of‑life outcomes.

The ARACOG trial, a phase‑2, head‑to‑head study enrolling 95 evaluable men across three disease stages, used the Cambridge Neuropsychological Test Automated Battery to assess five cognitive domains at baseline, 12 weeks, and 24 weeks. Darolutamide patients showed a modest 15.8% decline, while enzalutamide patients declined 36.1%, a statistically significant gap that held across memory, attention, and executive function. Notably, the darolutamide cohort exhibited a learning effect over time, whereas the enzalutamide group did not, underscoring a potential protective benefit. All 23 participants who elected to switch therapy did so from the enzalutamide arm, citing worsening cognition as the primary driver.

For managed‑care organizations and payers, these findings translate into actionable insights. Cognitive preservation can boost medication adherence, reduce the need for supportive services, and ultimately lower total cost of care. Incorporating cognitive outcomes into formulary decisions may differentiate value‑based contracts, especially as longer‑term data—such as the planned 48‑week follow‑up and polygenic hazard analyses—become available. By quantifying a quality‑of‑life advantage, the ARACOG trial equips clinicians and insurers with evidence to support shared decision‑making that aligns therapeutic efficacy with patient‑centered priorities.