Patients with nmCRPC experience prostate-specific antigen progression after definitive therapy despite the use of primary androgen deprivation therapy (ADT), without any evidence of metastases on conventional imaging. These individuals have no symptoms except for the ADT side effects, and the disease state is somewhat a reflection of our treatment. Until recently, there were no US Food and Drug Administration –approved therapies for these patients, who are often anxious about their rising prostate-specific antigen levels. Today, this is a very active area, with the addition of the following 3 newer AR antagonists to the treatment landscape: apalutamide, enzalutamide, and darolutamide. These next-generation AR-targeted therapies can offer clinically meaningful benefits to patients with M0 CRPC. For example, the clinical trials leading to US Food and Drug Administration approval showed that the development of bone metastases was delayed by approximately 2 years, and I think that most clinicians would agree that a 2-year delay in metastases is clinically meaningful. On the other hand, we are preventing a potential problem rather than treating an existing problem in these patients. And, since those with M0 CRPC are relatively asymptomatic, it is very important to examine the side effects of treatment reported in the respective phase 3 clinical trials (ie, PROSPER, SPARTAN, ARAMIS). I have sometimes referred to AR inhibition as “hormones squared” when talking to my patients. That is, patients already know what hormones feel like, as they have often been receiving ADT for many years, and now, with the addition of next-generation AR-targeted therapies, they are likely to experience more effects such as hot flashes, fatigue, and muscle weakness. The latter 2 side effects might contribute to an increased risk of falls and fractures, so that is a concern. Now, darolutamide is the newest agent in this group, and preclinical data with darolutamide suggested that it might not cross the blood-brain barrier to the same extent as the other 2 AR-targeted therapies. As a result, the hope has been that darolutamide may have fewer of the potentially centrally mediated toxicities such as fatigue, seizure disorder, or cognitive issues. There was some suggestion that this might be true in the ARAMIS trial, where the rates of falls and fractures were not increased with darolutamide compared with placebo, so physicians and patients are quite interested in learning more about these potential differences.