Abstract A011: Activity of antibody-drug conjugates with radiation in preclinical bladder cancer models

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Abstract Antibody-drug conjugates (ADCs) are transforming the treatment landscape in metastatic bladder cancer, but the role of ADCs in localized disease is uncertain. Radiation is a central component of trimodality therapy (TMT), a curative-intent treatment approach for muscle-invasive bladder cancer (MIBC) that includes concurrent radiation and cytotoxic chemotherapy. We investigated the safety and efficacy of combining novel ADCs with radiation in preclinical bladder cancer models. We observed additive cytotoxicity in vitro, and the combination of ADCs with conformal fractionated radiation was well-tolerated and resulted in improved tumor control compared to either agent alone in vivo. We also assessed the impact of DNA repair pathway alterations commonly observed in bladder tumors on sensitivity to ADCs alone and in combination with radiation and DNA repair targeted agents. Homologous recombination (HR) deficiency modestly sensitized bladder cancer cells to MMAE, the payload of the ADC enfortumab vedotin (EV), and potently sensitized cells to govitecan, the payload of the ADC sacitumuzab govitecan (SG). Conversely, nucleotide excision repair (NER) deficiency did not sensitize cells to either MMAE or govitecan. The combination of govitecan and PARP inhibition resulted in synergistic cell killing independent of HR or NER status. Together these data provide preclincal support for clinical efforts to combine ADCs with radiation in MIBC and identify rationale combination therapy approaches. Citation Format: Yuzhen Zhou, Surish Shanmugam, Vincent D'Andrea, Isabella Stelter, Dag Stormoen, Rea Chroneos, Timothy Hanlon, Ilana Epstein, Raie Bekele, William Anderson, Zoltan Szallasi, Joaquim Bellmunt, Kent Mouw. Activity of antibody-drug conjugates with radiation in preclinical bladder cancer models. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr A011.