The issue of resistance to anti-androgens has been quite intriguing, with work ongoing at many levels. A large repertoire of AR aberrations has been associated with castration-resistant prostate cancer, including AR amplifications, mutations, and constitutively active AR splice variants. We have known for more than 25 years that sometimes the resistance can be related to mutations in the AR, with certain mutations in the AR linked to disease progression and resistance to ADT in rather well-defined ways. There are 2 mutations, a mutation at position 875 (H875Y) and another at position 878 (T878A), that result in a promiscuous AR, such that, in addition to binding testosterone and dihydrotestosterone, these abnormal ARs can bind to nonandrogen steroids (eg, estrogens, megestrol acetate) in an agonistic fashion. The result is that your abnormal AR becomes responsive to compounds that are not ordinarily stimulating. A separate mutation at position 702 seems to promote growth in response to corticosteroids, including prednisone, and has been linked to enzalutamide and abiraterone resistance. Thus, one of the mechanisms of resistance appears to be the development of a mutated AR that is no longer antagonized by AR-targeted therapy. There are some preliminary data suggesting that several AR mutations may be antagonized by darolutamide, the most recent US Food and Drug Administration–approved next-generation anti-androgen, but we need more definitive data before we can say whether the newer AR antagonists differ from one another in terms of their effects (ie, the various AR mutation sensitivities). Constitutively active AR splice variants such as the AR splice variant-7 are particularly challenging in that the receptor remains active in a ligand-independent fashion, promoting growth, resistance, and disease progression. Ultimately, you need to move on to chemotherapy and precision medicine (eg, PARP inhibitors in patients with BRCA1/BRCA2 mutations, immunotherapy with agents such as pembrolizumab for patients with mutations such as MSH2/MSH6). Something that is generating a lot of excitement right now is prostate-specific membrane antigen (PSMA)–targeted therapy. PSMA is overexpressed in prostate cancer cells, and several PSMA blockers are in late-stage clinical development. One of these, lutetium-177 (¹⁷⁷Lu)-PSMA-617, is a radiolabeled small molecule that selectively binds to PSMA, allowing beta radiation to be delivered directly to tumors. Precision medicine is currently evolving rapidly, and it is truly fascinating to be an investigator in the field at this time.