ABSTRACT Metastatic castration-resistant prostate cancer (mCRPC) is a lethal, incurable disease that will kill ~33,500 patients in the US in 2020. Responding to the urgent need for novel treatments that are safe and efficacious, and leveraging the high expression of prostate specific membrane antigen (PSMA) in mCRPC lesions, several small-molecule-based targeted radionuclide therapies (TRTs) have been developed. Among them, targeted alpha therapy agent (TAT) with [225Ac]-PSMA-617 in particular has demonstrated striking responses in the treatment of refractory patients — even achieving complete and durable responses in a subset of patients. However, many responding patients have discontinued treatment due to non-target toxicity. Salivary gland toxicity (irreversible xerostomia) and potential renal toxicity place hard limits on patient eligibility, maximum dose and maximum number of doses, severely restricting the use of [225Ac]-PSMA-617. As such, there is an urgent and unmet need to develop strategies that can reduce the unwanted side effects of these treatments without compromising treatment efficacy. We in turn are proposing a simple method to reduce salivary gland and kidney toxicity by reducing the effective specific activity (ESA) of [225Ac]-PSMA-617 by addition of PSMA-11. In our preliminary studies, reducing the ESA of [68Ga]-PSMA-11 and [177Lu]-PSMA-617 with PSMA-11 led to significantly reduced salivary gland and kidney uptake without compromising tumor uptake in mouse models of prostate cancer. We have assembled a highly qualified and collaborative team of researchers — including radiochemists, medical physicists, nuclear medicine physicians, genitourinary oncologists, veterinary pathologists and toxicologists — to unequivocally demonstrate the efficacy of our methodology for reducing the salivary gland and renal radiation dose of [225Ac]-PSMA-617 or other PSMA-TRT agents in clinically relevant mouse and rat models. As part of our proposal, we will determine the range of ESAs that will reduce salivary gland and kidney dose of [225Ac]-PSMA-617 by > 75% without compromising tumor radiation dose in mice and rats; demonstrate that salivary gland and renal function are maintained long-term(~2 years post-treatment) while eliminating tumor burden; demonstrate the methodology’s applicability to other PSMA-TRT agents; conduct a GLP toxicology study of PSMA-11 at required doses (5–10 mgs/patient) to establish its safety; and make the data available to all researchers in order to facilitate clinical trials. The experiments are being conducted as IND- enabling studies for near-term clinical translation. Once established, our simple but innovative approach will refine treatment with [225Ac]-PSMA-617 and other PSMA-TRT agents by reducing toxicity to salivary glands and kidneys without compromising treatment efficacy and help to extend the lives of mCRPC patients while maintaining their quality of life.