# Improving PARP inhibitor efficacy in bladder cancer without genetic BRCAness by combination with PLX51107

## TL;DR

This study finds a new combination of drugs that improves bladder cancer treatment effectiveness, even in patients without specific genetic traits.

## Contribution

Identified new biomarkers and a synergistic drug combination for PARP inhibitor efficacy in bladder cancer.

## Key findings

- SLFN5, SLFN11, and OAS1 are new UC-specific predictors of PARP inhibitor response.
- Talazoparib combined with PLX51107 shows strong synergy in UC cells and organoids, including Cisplatin-resistant models.
- The combination targets homologous recombination repair, DNA replication, and apoptosis regulation.

## Abstract

Advanced urothelial carcinoma (UC) requires new therapeutics beyond chemo‐ and immunotherapies. Clinical trials with PARP inhibitors (PARPi), particularly in Cisplatin‐treated UC, yielded limited response. Biomarker‐based 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‐treated 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‐specific 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‐resistant 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. This new combination treatment allows efficient application of PARPi Talazoparib to all UC patients, independent of Cisplatin pretreatment and genetic BRCAness.

Clinical trials on PARP inhibitors in urothelial carcinoma (UC) showed limited efficacy and a lack of predictive biomarkers. We propose SLFN5, SLFN11, and OAS1 as UC‐specific response predictors. We suggest Talazoparib as the better PARP inhibitor for UC than Olaparib. Its combination with the BET inhibitor PLX51107 overcame resistance, acted synergistically, suggesting a promising, broadly applicable UC treatment strategy. Mechanisms were identified.