Abstract A029: PARP-targeted alpha therapy for the treatment of PARP inhibitor resistant ovarian cancer

Abstract Background: While epithelial ovarian cancer (EOC) generally responds to frontline therapy, most tumors develop resistance to current treatments, prompting the need for innovative therapies. Homologous recombination deficient EOC with PARP inhibitor (PARPi) resistance are particularly difficult to treat. Here, we evaluate a novel theranostic approach for the treatment of drug-resistant EOC that leverages overexpression of PARP1 in EOC (even when PARPi resistant). Our platform is based on a small molecule similar to rucaparib labeled with 211At for alpha therapy (211AtParaThanatrace, PTT) and 18F for PET/CT (18FFluorThanatrace, FTT). Materials and Methods: PTT was synthesized and evaluated for cytotoxicity and binding properties in 16 human and 2 murine EOC cell lines with varying sensitivity to PARPi and chemotherapy. Maximum specific binding (Bmax), equilibrium dissociation constant (Kd), and half minimal effective concentration (EC50) were calculated. PTT efficacy was evaluated in a syngeneic mouse model of mouse oviduct secretory epithelial derived cells (MOSEC) engineered to include loss of Trp53 and Pten. Results: PTT had a 30-fold greater in vitro cytotoxicity than untargeted 211At. Comparing EOC OVCAR8 cells with endogenous PARP1 expression versus OVCAR8-PARP1KO cells, PTT activity was dependent on PARP1 expression (EC50 0. 0079 vs. 0. 027 MBq/mL, respectively). Human ovarian cancer cell lines had variable sensitivity with a range of EC50’s from 0. 0021-0. 80 MBq/mL (mean=0. 011, median=0. 007), concentrations that are safely achievable in vivo. Cytotoxicity was similar between PARPi-sensitive and -resistant cells (P=0. 86). The number of PTT binding sites per cell (Bmax) ranged from 6. 31x105-2. 14x106 and the binding affinity was 2. 0-11. 4 nM. EC50 values significantly correlated to binding affinity (r=0. 69, P=0. 009), whereas no correlation was observed with Bmax, PARP1 expression, or tumor cell doubling time. To evaluate the anti-tumor efficacy in ovarian cancer in vivo, homologous proficient MOSECs were inoculated intraperitoneally into immunocompetent C57BL/6 mice. Four days following tumor inoculation; mice were treated intravenously with four fractionated doses of PTT at the MTD (48 MB/kg/fraction) or ½ MTD (24 MB/kg/fraction) over two weeks. PTT treatment was tolerable and significantly prolonged survival compared to untreated control mice (P=0. 0027). In vitro cytotoxicity determined an IC50 of 0. 97 mCi/mL in MOSEC, which is considerably higher than most of the evaluated human EOC cell lines, further supporting the efficacy of PTT in vivo. Conclusions: PTT cytotoxicity is largely independent of PARPi-sensitivity but reliant on PARPi binding affinity and line-specific radiation sensitivity. In vivo data supports the safety and efficacy of PTT. Overall, this study highlights a novel role for theranostic radiopharmaceutical therapy in drug-resistant EOC. Citation Format: Sarah B. Gitto, Aladdin Riad, Alastair McArthur, Fiona Simpkins, Daniel A. Pryma, Micheal D. Farwell. PARP-targeted alpha therapy for the treatment of PARP inhibitor resistant ovarian cancer 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 (18Suppl): Abstract nr A029.