The most widely accepted definition of nonmetastatic castration-resistant prostate cancer is prostate-specific antigen (PSA) progression after primary androgen deprivation therapy, confirmed by a serum testosterone level of less than 50 ng/dL and no evidence of any lesion with conventional imaging, such as radionuclide bone scan, computed tomography scan, or magnetic resonance imaging. In the past, many urologists faced the challenge of having few treatment options available for men in the setting of nmCRPC. However, with the recent approval of 3 second-generation androgen receptor antagonists for nmCRPC (ie, apalutamide, enzalutamide, darolutamide), there are now multiple options for these patients. 

Factors to consider when determining which patients would potentially benefit from treatment include the aggressiveness of their disease, PSA levels, and, especially, PSA doubling time. Patient-specific factors and the adverse-event profile for each of these agents further guide treatment selection. The men included in the clinical trials that led to the approval of these agents had a rapid PSA doubling time of 10 months or less, which has been shown to be a strong predictor for the development of metastasis in this population. In the SPARTAN trial, the median MFS with apalutamide was 40.5 months, compared with 16.2 months for placebo. In the PROSPER trial, enzalutamide significantly prolonged median MFS relative to placebo (36.6 months vs 14.7 months, respectively). The median MFS with darolutamide in the ARAMIS trial was 40.4 months, compared with 18.4 months with placebo. However, these agents differed in their adverse-event profiles relative to placebo; with darolutamide, no clinically relevant difference was seen in the incidence of adverse events that occurred during the treatment period, including falls, fractures, seizures, cognitive disorders, and hypertension.

Not every individual with nmCRPC needs treatment escalation, and it is up to the clinician to assess the overall health of the patient, but the availability of these novel anti-androgens is a significant step forward, as we can now use them to prolong MFS. For those patients who would likely benefit from treatment, the safety and tolerability profiles of these agents may be important considerations. The adverse-event profiles appeared to be somewhat different, at least based on the noncomparative data available thus far. That is, darolutamide appears to have less central nervous system toxicity and less of an incidence of fractures, falls, and seizures. We have more experience with enzalutamide at this point, and we do understand that some patients, particularly older patients, may be more likely to develop cognitive issues with enzalutamide. So, these may be important considerations.

What is remarkable about these 3 studies is the consistency of the data in terms of MFS. You really can virtually superimpose these MFS curves on each other, and they basically become aligned.. More follow-up is needed to determine how MFS relates to overall survival, but right now we are seeing a trend toward improved overall survival. With similar efficacy, then, these agents should be considered from the perspective of their toxicities. Darolutamide may have an advantage from the standpoint that there is less penetration into the central nervous system, and this may lead to less fatigue in patients; but, again, there has not yet been a head-to-head comparison of these novel anti-androgens to generate the comparative data on patient quality-of-life issues. So, we are extrapolating from these phase 3 studies.

It is also important to note that nmCRPC was defined before the era of next-generation imaging (NGI), in which we can now detect micrometastatic disease in a proportion of patients who would not be identified as metastatic by conventional imaging. This generates questions about what constitutes appropriate use of these agents by stage, as determined by NGI. This also relates to the question of optimal treatment of oligometastatic disease, as we have ongoing investigations into irradiation of individual oligometastatic sites. We are going to have to think about how we incorporate NGI into this particular definition of nmCRPC.