Darolutamide Preserves Cognitive Function Better Than Enzalutamide in Prostate Cancer

Why is this important?

Androgen receptor pathway-targeted treatments such as abiraterone, enzalutamide, apalutamide and darolutamide are now used at many stages of prostate cancer. These drugs can significantly improve disease control; however, adverse effects that directly affect patients’ lives, such as fatigue, fall risk, neurological effects and problems with attention and memory, are becoming increasingly important during long-term use.

Especially in older patients with coexisting diabetes, hypertension, vascular disease, sleep disorders, depression or mild cognitive impairment at baseline, treatment selection cannot be based solely on the question “which drug is more powerful?” Among options in the same efficacy category, preserving the patient’s mental function and independence also becomes an important decision-making consideration.

Study design: what did ARACOG compare?

ARACOG (AFT-47) is a randomized phase 2 study directly comparing the cognitive effects of darolutamide and enzalutamide in men with advanced prostate cancer. Such studies are highly valuable in oncology because drugs are often assessed separately for efficacy, whereas toxicity and quality of life are not measured with the same rigor in head-to-head comparisons.

A total of 111 patients from the United States were enrolled. Patients were randomized to receive darolutamide or enzalutamide. There were 55 patients in the darolutamide arm and 56 in the enzalutamide arm. Median ages were similar: in the darolutamide arm, 70,7, and in the enzalutamide arm, 71,3.

Main result: greater cognitive decline with enzalutamide

At week 24, the decline in MCCD was significantly greater in the enzalutamide arm than with darolutamide. Median MCCD change was reported as -15,8in the darolutamide arm and -36,1 in the enzalutamide arm. The difference was statistically significant: p=0,009.

The researchers emphasized that some patients may show a “learning effect” with repeated testing. In other words, when the same test is repeated, scores may remain stable or improve because the patient is more familiar with it. This learning effect was more evident in the darolutamide arm, especially in executive function and working memory; no similar protective effect was observed in the enzalutamide arm.

Treatment switches: a signal that adds clinical weight to the results

The study allowed patients meeting certain criteria for cognitive or neurological deterioration to switch to the other treatment. These included a decline of at least %30 in any CANTAB module, a decline of at least 10 points on FACT-Cog, falls or increased fall risk, and grade 2 or higher neurological toxicity.

One of the most notable findings was the direction of treatment switches: 30 of the 36 eligible patients switched from enzalutamide to darolutamide. In contrast, there were no switches from darolutamide to enzalutamide. This can be interpreted as a clinical signal consistent with the cognitive test results of the study.

Possible mechanism: a difference in the blood–brain barrier

ARACOG was not designed to definitively explain the mechanism behind the cognitive difference between the two drugs. However, the researchers think that the difference in crossing the blood–brain barrier between darolutamide and enzalutamide may explain these results. Darolutamide is an androgen receptor inhibitor thought to enter the central nervous system to a more limited extent because of its structural properties.

This biological difference supports the hypothesis that darolutamide may cause fewer central nervous system adverse effects. However, this interpretation should be made cautiously; cognitive function is multifactorial. Age, previous duration of ADT, depression, sleep, pain, fatigue, coexisting vascular diseases, other medications and the disease itself can affect cognitive performance.

How do these data affect treatment selection?

ARACOG’s most important clinical message is not that enzalutamide should not be used. Enzalutamide is a powerful treatment with proven efficacy in many clinical settings of prostate cancer. However, if both darolutamide and enzalutamide are options for the same patient, darolutamide may become more attractive, particularly in patients with cognitive vulnerability.

Critical reading: how should these data be interpreted in a balanced way?

Message for clinical practice

Selection of an androgen receptor pathway inhibitor in prostate cancer should no longer depend solely on disease stage, PSA, metastatic burden and previous treatments. The patient’s age, mental reserve, fall risk, expectations for daily life, coexisting diseases and the quality of life expected from treatment should also be part of the decision.

ARACOG highlights an issue that directly affects patients’ lives: drugs considered to be in the same class may differ in cognitive tolerability. This difference may influence treatment selection, especially in older and vulnerable patients.

Conclusion

ARACOG (AFT-47) is an important randomized phase 2 study directly comparing the cognitive effects of darolutamide and enzalutamide in advanced prostate cancer. At week 24, the decline in MCCD was significantly greater in the enzalutamide arm than with darolutamide: -36,1 vs -15,8, p=0,009.

This suggests that darolutamide may preserve cognitive function better. Clinically, the most important application is when both treatments are suitable, but the patient is more vulnerable because of older age, fall risk, mild cognitive impairment or susceptibility to central nervous system adverse effects.

ARACOG’s strongest message is this: in prostate cancer, preserving the patient’s mental clarity, independence and everyday quality of life is part of true treatment success, alongside the goal of a longer life.