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Clinical trials with PARP inhibitors (PARPi), particularly in Cisplatin\u2010treated UC, yielded limited response. Biomarker\u2010based patient selection (apart from BRCAness) or combination treatment may increase efficacy. To identify the most suitable PARPi for UC, we compared Olaparib with Talazoparib. RNA sequencing of PARPi\u2010treated UC lines revealed few common targets and a different impact on immune response. By analysis of experimental and public clinical data, we identified new UC\u2010specific PARPi response predictors SLFN5, SLFN11, and OAS1. We investigated a new combination treatment using PLX51107, an epigenetic BET protein inhibitor, to increase PARPi efficacy. The Talazoparib + PLX51107 combination had a strong synergistic impact on UC cells and organoids, including Cisplatin\u2010resistant cells, allowing dose reduction to spare benign cells. Mechanisms of synergism targeted homologous recombination repair, DNA replication, and apoptosis regulation. In conclusion, we suggest Talazoparib treatment of UC to be highly efficacious on all models examined when combined with PLX51107. 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