Darolutamide Shows Less Cognitive Decline Vs Enzalutamide in Advanced Prostate Cancer

Darolutamide (Nubeqa) was associated with significantly less objectively assessed cognitive decline compared with enzalutamide (Xtandi) over 24 weeks, according to results from the prospective, randomized open-label phase 2 ARACOG trial (AFT-47; NCT04335682) to be presented at the 2026 ASCO Annual Meeting.

Notably, while similar proportions of patients in each arm met criteria to cross over to the alternate therapy, all 30 crossovers observed moved from enzalutamide to darolutamide—none went the other direction.

For oncology nurses caring for patients with advanced prostate cancer on androgen receptor pathway inhibitors (ARPIs), the findings carry direct implications for patient monitoring, education, and care coordination. Cognitive impairment—including memory loss, slowed executive function, and increased fall risk—is a recognized and often underreported consequence of ARPI therapy that nurses are frequently first to detect through ongoing patient contact. These data may help nurses and the broader care team weigh cognitive health as a meaningful factor when supporting treatment decisions.

What should oncology nurses should know about the efficacy of darolutamide?

Among 95 evaluable patients, baseline cognitive scores were similar between the 2 treatment arms. By week 24, patients treated with enzalutamide experienced a significantly greater decline in the maximally changed cognitive domain (MCCD) compared with those receiving darolutamide (P = .009). The median change from baseline was –15.8% in the paired associates learning and forgetting and memory (PALFAM) domain for darolutamide-treated patients, versus –36.1% in the spatial working memory (SWM) domain for those who received enzalutamide.

The cognitive domains driving decline differed between the arms: visual memory and executive function were most affected in the darolutamide arm, while working memory and executive function drove changes in the enzalutamide arm. Importantly for oncology nurses monitoring patients across clinic visits, individual domain scores suggested a possible learning effect among darolutamide-treated patients — reflected by improving scores over time — while scores among enzalutamide-treated patients remained stable or showed mild decline through 24 weeks.

For nurses involved in patient education, these findings may help guide conversations about what patients can realistically expect on each therapy and reinforce the importance of reporting cognitive changes early, rather than normalizing them as an expected part of treatment.

What was the trial design of the ARACOG trial and its relevance to nursing practice?

The ARACOG trial enrolled 111 men across U.S. academic medical centers and randomly assigned them 1:1 to receive either darolutamide or enzalutamide. Eligible patients had nonmetastatic castration-resistant, metastatic castration-resistant, or metastatic hormone-sensitive prostate cancer. The median age was approximately 71 years; 83% of participants were White, and baseline characteristics were generally well balanced between arms—though a higher proportion of Black patients were assigned to the enzalutamide arm (12.5% vs 1.8% in the darolutamide arm).

The primary end point was the percent change in MCCD from baseline to 24 weeks, assessed using 5 computer-based tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB): PALFAM, SWM, spatial span (SSP), rapid visual processing (RVP), and one touch stockings of Cambridge (OTSMCC). These domains collectively evaluate executive function, visual memory, attention, and working memory. Assessments were conducted at baseline and at weeks 12, 24, and 48. Additional assessments included patient-reported outcomes via FACT-Cog, FACT-P, PHQ-9, and the Sleep Scale; functional status via the Timed Up and Go test; and adverse events of special interest such as falls, severe neurologic toxicity, posterior reversible encephalopathy syndrome, and seizure.

Crossover was permitted at weeks 12 or 24 for patients who experienced a decline of at least 30% in any CANTAB module, a drop of at least 10 points in FACT-Cog score, falls or increased fall risk, or grade 2 or higher neurologic toxicity. For oncology nursing teams coordinating follow-up, this crossover framework underscores the importance of documenting objective cognitive changes at each visit—not only as clinical data, but as a mechanism for ensuring patients can access a treatment change if their cognitive health is deteriorating.

What should nurses know about the crossover pattern from the ARACOG trial?

Thirty patients (54%) in the enzalutamide arm crossed over to darolutamide before or at week 24. No patients crossed over in the opposite direction, despite a similar number in the darolutamide arm meeting eligibility criteria for the switch. This one-way crossover pattern may reinforce the real-world cognitive burden that nurses may observe in patients receiving enzalutamide.

Investigators noted several possible explanations for the preferential crossover to darolutamide. Patients receiving darolutamide may have been less bothered by cognitive symptoms, making them less likely to pursue a switch. Additionally, darolutamide was provided through the study without a copay, whereas patients on enzalutamide may have encountered out-of-pocket costs that could have influenced their willingness to switch—a social determinant of health that nurses and navigators are well positioned to identify and address.

The mechanistic explanation most widely cited is darolutamide's limited ability to cross the blood-brain barrier, in contrast to enzalutamide, which does penetrate the central nervous system. Oncology nurses should be aware that this pharmacologic difference may be the likely driver of the cognitive outcomes observed.

What safety risks should oncology nurses be prepared to manage following treatment with ARPIs?

Both ARPIs carry known risks that oncology nurses must monitor proactively, and the ARACOG trial assessed several adverse events of special interest beyond cognitive decline—including falls, severe neurologic toxicity (including fatigue), posterior reversible encephalopathy syndrome, and seizure. Patients crossing over from enzalutamide often did so due to cognitive or neurologic concerns, reinforcing the importance of routine fall-risk screening and neurologic symptom assessment in this patient population.

Nurses caring for older men on ARPIs—with a median age of 71 years in ARACOG—should also remain attentive to the compounding effects of age-related cognitive vulnerability and androgen deprivation therapy on cognitive function and daily functioning. Symptoms patients may minimize or attribute to aging—forgetting appointments, difficulty concentrating, slower processing—may represent clinically meaningful cognitive changes that warrant documentation and escalation.

The ongoing 48-week follow-up in ARACOG will continue to characterize the longer-term cognitive and safety trajectory of both agents. Investigators are also exploring whether genetic factors may contribute to susceptibility to cognitive changes associated with ARPI therapy—a finding that, if validated, could one day inform personalized monitoring protocols for nursing teams.

Reference

1. Morgans AK, et al. ARACOG (AFT-47): A randomized phase II study of androgen receptor directed therapy on cognitive function in patients treated with darolutamide or enzalutamide. J Clin Oncol 44, 2026 (suppl 16; abstr 5005).

2. American Society of Clinical Oncology. Less cognitive decline with darolutamide treatment than enzalutamide in people with advanced prostate cancer. ASCO press release. May 21, 2026. Embargoed for release May 21, 2026, at 5 PM ET.