ADT and the second-generation AR inhibitors enzalutamide and apalutamide are some of the androgen axis–targeted treatments that can have significant CNS side effects. The reported effects have been wide ranging and include, fatigue, weakness, diminished cognition or mentation, and—very rarely for selected agents—seizures.

The issue of CNS side effects is of acute interest to men with prostate cancer. For example, if you consider the case of a patient with some baseline cognitive impairment (eg, from vascular disease) and add a therapy that has even nominal CNS effects, that may determine whether that individual is functional and/or able to live independently. On the other end of the age spectrum, CNS side effects may affect a younger patient’s ability to continue to work and engage in activities that they enjoy. Selecting the appropriate treatment for a patient based on the CNS side-effect profile and the impact that it may have on a patient’s quality of life is part of the art of medicine.

Some agents, such as darolutamide, have been developed with an eye toward minimizing these CNS effects, based on a putative reduction in the agent’s ability to cross the blood-brain barrier. Promisingly, in the ARAMIS trial, ADT and darolutamide were compared with ADT and placebo in men with high-risk nonmetastatic castration-resistant prostate cancer. In that study, metastasis-free survival was improved with the addition of darolutamide (hazard ratio, 0.41 [95% CI, 0.34-0.50]), without an apparent increase in CNS effects relative to the placebo-controlled arm. For instance, there were no apparent significant differences in fatigue, falls, seizures, dizziness, cognitive disorders, and impairments in memory or mental status.

Despite the favorable side-effect profile that darolutamide had compared with placebo in ARAMIS, it is important to note that ARAMIS did not demonstrate that darolutamide has a superior side-effect profile relative to other agents, such as enzalutamide or apalutamide. How favorable a drug appears in a study depends not only on the drug’s toxicity profile but also on the performance of the control arm.

As a result, comparing the side-effect profiles of these agents will require direct head-to-head comparisons. Such trials are planned or are underway. For instance, a phase 2b study is currently underway to determine the effects of darolutamide and enzalutamide on physical function, including balance and daily activity, in patients with castration-resistant prostate cancer. In the upcoming ARACOG trial (NCT04335682), enzalutamide and darolutamide will be compared with regard to cognitive functionality in a randomized, phase 2, crossover design.

These studies highlight how the field is now generating data to allow for more informed decision making in selecting an AR-targeted agent for a given patient. There is increasing recognition that these drugs can produce similar results from a cancer outcomes perspective, thereby raising the importance of the potential CNS effects when selecting one drug over another. Such data will allow patients and their doctors to make more informed decisions, not only in terms of treating their disease but also with regard to preserving quality of life and functionality.