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BACKGROUND: Enfortumab vedotin (EV) and Sacituzumab govitecan (SG) are antibody-drug conjugates (ADCs) with demonstrated activity in advanced bladder cancer. A subset of bladder tumors harbors a DNA repair deficiency in either the homologous recombination (HR) or nucleotide excision repair (NER) pathway that has the potential to impact sensitivity to specific classes of therapeutics.OBJECTIVE: Define the impact of HR or NER deficiency on sensitivity to ADC payloads alone or in combination with DNA repair targeted agents in bladder cancer.METHODS: Isogenic cell pairs with versus without HR or NER deficiency were profiled using DNA repair and drug sensitivity assays. Sensitivity to the ADC payloads monomethyl auristatin E (MMAE) and SN-38 alone or in combination with small molecule inhibitors of poly(ADP-ribose) polymerase (PARP), ATR, or USP1 were measured using cell viability assays.RESULTS: BRCA2 loss was sufficient to confer an HR deficient phenotype and increase sensitivity to cisplatin and PARP inhibition in bladder cancer cell lines. HR deficiency, but not NER deficiency, increased sensitivity to MMAE and SN-38 in bladder cancer cells. The combination of SN-38 and PARP inhibition displayed synergistic cell killing independent of HR or NER status.CONCLUSION: HR and NER deficiency have distinct impacts on sensitivity to cisplatin and ADC payloads in bladder cancer preclinical models.