Abstract A043: Preclinical evaluation of PTT, an At-211-Labeled rucaparib analogue, as a theranostic agent for cancer therapy

Abstract Epithelial ovarian cancer (EOC) is generally sensitive to radiation. However, the widespread peritoneal dissemination of advanced EOC renders external beam radiotherapy limited as the required dose has substantial off-target toxicities. Targeted radionuclide therapy can deliver ionizing radiation directly to tumor cells while sparing healthy tissues, offering an alternative strategy to safely exploit the radiosensitivity of these tumors. Our platform is based on the FDA-approved small molecule PARP inhibitor, rucaparib, labeled with 211At for targeted alpha therapy ([211At]Parthanatrace, [211At]PTT). Our prior and ongoing studies support significant anti-tumor efficacy in preclinical neuroblastoma and ovarian cancer models. Here, in vivo studies were performed to evaluate the tolerability of [211At]PTT. C57BL/6 mice (n = 10) were treated intravenously with four fractionated doses of [211At]PTT at the MTD (48 MBq/kg/fraction) over 2 weeks. Generally, mice tolerated the treatment well, with statistically similar weight compared to untreated control mice (n = 6) up to 30 days following treatment, supporting a favorable safety profile. Peripheral blood was collected 5, 13, and 20 days following the last treatment and a subset of mice were euthanized after 30 days for full pathological assessment and additional blood analysis. The data indicated a significant decline in red blood cells (RBCs), white blood cells (WBCs), and hemoglobin in the peripheral blood following treatment. Levels were fully restored by 20 days post treatment. Lymphocyte and platelet counts were similar to untreated mice after 30 days. Additional blood analyses showed statistically similar levels for aspartate aminotransferase (AST), alanine transferase (ALT), bilirubin (BUN), and creatine in mice treated with [211At]PTT compared to untreated controls. Full histological and pathological assessment is ongoing. Subsequent biodistribution studies demonstrated selective tissue uptake of [211At]PTT following a single infusion of 48 MBq/kg, with limited off-target accumulation and rapid clearance from non-target organs. Overall, these findings support the safety of [211At]PTT as a promising candidate for targeted alpha therapy in oncology. Citation Format: Aladdin Riad, Alastair McArthur, Hasan Babazda, David Mankoff, Robert H. Mach, Michael D. Farwell, Sarah B. Gitto. Preclinical evaluation of PTT, an At-211-Labeled rucaparib analogue, as a theranostic agent for cancer therapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr A043.