Androgen Receptor Inhibitors in Patients With Nonmetastatic Castration-Resistant Prostate Cancer

Importance Novel androgen receptor inhibitors (ARIs; darolutamide, enzalutamide, and apalutamide) are standard-of-care treatments for nonmetastatic castration-resistant prostate cancer (nmCRPC). However, there are sparse data comparing their clinical use and tolerability. Objective To compare clinical use and outcomes for darolutamide, enzalutamide, and apalutamide in patients with nmCRPC. Design, Setting, and Participants This retrospective cohort study reviewed electronic medical records from the Precision Point Specialty network of US urology practices. Eligible patients had nmCRPC and no prior novel hormonal therapy and initiated novel ARI treatment between August 1, 2019, and March 31, 2022. Data were analyzed from February 1, 2019, to December 31, 2022. Exposures Patients were prescribed darolutamide, enzalutamide, or apalutamide as their first novel ARI for nmCRPC. Main Outcomes and Measures The main outcome was a composite of 2 end points, treatment discontinuation and progression to metastatic CRPC (mCRPC), whichever occurred first. Both end points were also assessed separately. Results All 870 patients meeting eligibility criteria were included (362 receiving darolutamide 41.6%; 382, enzalutamide 43.9%; 126, apalutamide 14.5%); mean (SD) age was 78.8 (8.7) years. Self-reported race was Black or African American in 187 patients (21.5%), White in 585 (67.2%), and other or unknown in 98 (11.3%). The darolutamide cohort had lower proportions of patients with a composite end point event (134 37.0% vs 201 52.6% for enzalutamide and 66 52.4% for apalutamide), discontinuation (110 30.4% for darolutamide vs 156 40.8% for enzalutamide and 58 46.0% for apalutamide), and progression to mCRPC (64 17.7% for darolutamide vs 108 28.3% for enzalutamide and 35 27.8% for apalutamide) during the study period. After adjusting for baseline covariates, patients receiving darolutamide had a lower risk of a composite end point event compared with enzalutamide (risk reduction, 33.8%; hazard ratio HR, 0.66 95% CI, 0.53-0.84) and apalutamide (risk reduction, 35.1%; HR, 0.65 95% CI, 0.48-0.88). Similarly, patients receiving darolutamide had a lower risk of discontinuation compared with enzalutamide (risk reduction, 27.4%; HR, 0.73 95% CI, 0.56-0.94) and apalutamide (risk reduction, 39.1%; HR, 0.61 95% CI, 0.44-0.85) and a lower risk of progression to mCRPC compared with enzalutamide (risk reduction, 40.6%; HR, 0.59 95% CI, 0.43-0.82) and apalutamide (risk reduction, 35.3%; HR, 0.65 95% CI, 0.42-0.99). There was no difference between enzalutamide and apalutamide treatment across outcomes. Conclusions and Relevance In this large cohort study of patients with nmCRPC treated with novel ARIs, results suggest better tolerability for darolutamide compared with enzalutamide and apalutamide, which may be associated with a clinical effectiveness advantage. Comparative clinical studies are needed to guide treatment decisions in the absence of head-to-head clinical trials.