Oral Toxicities of PSMA-Targeted Therapies: Mitigation Strategies and Translational Opportunities

Prostate-specific membrane antigen (PSMA) has gained prominence as a key target in the treatment of metastatic castration-resistant prostate cancer (mCRPC) therapy. Integrating radionuclide therapies such as Lutetium-177 [¹⁷⁷Lu]-PSMA-617 has significantly advanced treatment outcomes while posing unique challenges related to off-tumor toxicities in other tissues that express PSMA, particularly in salivary glands. Furthermore, there are novel cancer therapeutics in development including PSMA-targeted immunotherapies and antibody drug conjugates which hold promise for the treatment of prostate cancer and may contribute to the burden of oral toxicity. The oral toxicity of PSMA-targeted radioligand therapy arises from PSMA-mediated salivary gland uptake and radionuclide retention, differing fundamentally from the nonspecific tissue damage mechanisms of traditional external beam radiotherapy. In parallel, targeted therapies, including small molecules and monoclonal antibodies, exert direct effects by binding to PSMA and delivering anti-tumor metabolites and/or amplifying the immune response. The resultant off-tumor on-target tissue damage can lead to distinct oral complications such as xerostomia, dysgeusia and mucositis. Although PSMA-targeted therapies are primarily used for the management of prostate cancer, they are also being explored in treatment of salivary gland malignancies including adenoid cystic carcinoma. This review explores the mechanisms and clinical manifestations of PSMA-related oral toxicities in the context of prostate cancer, diagnosis, possible mitigation strategies, the need for preclinical models to study regulation of PSMA expression leading to oral toxicities, current challenges and future directions.