NSAAs

Nonsteroidal antiandrogens (NSAAs) are a class of drugs that inhibit androgen receptor signaling by binding to the receptor and blocking activation by androgens such as testosterone and dihydrotestosterone. Unlike steroidal antiandrogens, NSAAs do not share a steroid backbone. They are used primarily in the treatment of androgen-driven conditions, most notably prostate cancer, where they are employed in combination with androgen deprivation therapy or as part of treatment for metastatic castration-resistant disease.

Mechanistically, NSAAs act as competitive antagonists of the androgen receptor, preventing AR translocation to the nucleus and transcription of AR target genes in many cases. Some first-generation agents can exhibit weak partial agonist activity under certain circumstances, which has influenced their clinical use and resistance mechanisms. Generations beyond the first—such as enzalutamide and apalutamide—offer higher affinity AR blockade and fewer agonist effects, but carry distinct adverse-effect profiles, including seizures or CNS effects with enzalutamide and fatigue, hypertension, and rash with others.

Representative NSAAs include flutamide, nilutamide, and bicalutamide (early-generation agents) and enzalutamide and apalutamide (later-generation agents). They are approved for various prostate cancer indications and are being studied for other androgen-dependent conditions. Safety monitoring focuses on liver function tests due to hepatotoxicity concerns with some agents and on neurological symptoms for CNS-active drugs.

Related topics include androgen receptor antagonists and steroidal antiandrogens.