There has been a recent shift in the management of advanced prostate cancer toward earlier initiation of treatment. One result of this change is that patients who are relatively asymptomatic are being treated for longer periods. The benefit of this approach is that patients are living longer with fewer metastases, but they are also facing greater challenges in terms of maintaining quality of life. Although it is reassuring that some of the patient-reported quality-of-life data that have been presented do not show a difference between treatment and placebo, it has been my experience that some patients may experience an increase in fatigue and weakness with drugs such as enzalutamide and apalutamide. Most men do well with these treatments, but there is a small subset of men who does poorly, and weakness is a significant concern owing to the risk of falls and fractures. In some of these individuals, I may lower the dose, interrupt treatment, or consider switching them to an alternative therapy. Our greatest experience is with enzalutamide because this drug has been around the longest. In the asymptomatic CRPC setting, enzalutamide is generally well tolerated, but approximately 5% to 10% of patients experience profound fatigue and/or muscle weakness. In those settings, I will often stop the drug and see whether their symptoms improve or resolve. If they do, I may re-challenge them, either with a lower dose of enzalutamide or I might consider switching to a drug such as abiraterone in the M1 CRPC setting or to apalutamide or darolutamide in the M0 CRPC setting, the latter of which is the newest of the 3 agents. 

A benefit of having different options in the same drug class is that there may be slight differences in their tolerability and side-effect profiles. One of the original ideas with darolutamide was that it might not cross the blood-brain barrier and therefore might not potentiate centrally mediated adverse events such as fatigue. There was an intriguing suggestion that this might be true in ARAMIS (eg, no increase vs placebo in falls, fractures, or seizures). However, we do not know whether apalutamide, enzalutamide, and darolutamide are equivalent in terms of side effects because they have not yet been directly compared. As clinicians, we now have the opportunity to switch between drugs if we think that a patient may tolerate a particular agent better than another.