Abstract C096: Improving patient management in mCRPC: Combined <i>in vitro</i> alpha particle and x-ray radiotherapies with Enzalutamide

Abstract Prostate cancer is the most common cancer in men, with an estimated 300,000 new cases in the United States in 2024, and a leading cause of cancer mortality. The lethal form of the disease, metastatic castrate resistant prostate cancer (mCRPC), is incurable. Radiation is a pillar of cancer care, as cancer cells are sensitive to ionizing radiation; however conventional external beam therapy can only be used sparingly in the metastatic context. The rise of theranostics has seen the systemic administration of radionuclides that target cancer sites to locally provide radiation doses through alpha and beta particle emissions. The first and only approved alpha particle emitter is Radium-223 dichloride, which targets the bone tumor microenvironment, but there is great academic and clinical interest in novel targeted alpha emitters in various stages of development and trial, many of which target the prostate-specific membrane antigen (PSMA). PSMA is a type II transmembrane protein possessing a large extracellular domain that can be targeted by a variety of ligands making it a promising component in treating prostate cancer. In healthy prostate tissue, salivary glands, kidneys, and small intestine, PSMA expression is low, however, its overexpression is a consequence in both primary and metastatic prostate cancer cells. High energy α-emitting radionuclides appended to short peptides or monoclonal antibodies establish the backbone of targeted alpha therapies—recent methods include 225Ac-PSMA-617, 213Bi-PSMA-617, 211At-PSMA-pentanedioic acid, and 227Th-PSMA-IgG1. Despite their potential, we have a limited understanding of the molecular and radiological effects of this novel class of therapies. This is in part due to the inherent complexities of alpha particle (high linear energy transfer and short path length of ∼50µm). We have established a bench-top α-particle irradiator to investigate the destructive potential of alpha particle irradiation, compare this to conventional x-ray radiotherapy, and evaluate its immediate and lasting effects with combined administration of androgen receptor (AR) antagonist, enzalutamide. The androgen receptor is the primary molecular driver of prostate cancer, even in the castrate setting. AR inhibitors disrupt the DNA-repair function, and are under investigation for combined use with targeted radiotherapies. Our aim is to improve the therapeutic potential of alpha particle and combination radiotherapies in improving mCRPC patient management. Citation Format: John M. Van Wazer, Wen Jiang, Nathaniel Brennen, Shenjian Ai, Daniel LJ. Thorek. Improving patient management in mCRPC: Combined in vitro alpha particle and x-ray radiotherapies with Enzalutamide [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C096.