Darolutamide is a nonsteroidal androgen receptor (AR) antagonist with a unique molecular structure, distinct from other AR antagonists such as enzalutamide and apalutamide. Here, we report the first results with darolutamide monotherapy. Darolutamide was associated with a significant prostate-specific antigen response in nearly all men with hormone-naïve prostate cancer. Testosterone-level changes and most common adverse events (gynecomastia, fatigue, hypertension, and hot flush) were consistent with potent AR inhibition.