# Sequential platinum and PARP Inhibition enhances PD1 immunotherapy efficacy in murine Brca2 mutated pancreatic cancer

## TL;DR

A new mouse model of BRCA2-mutated pancreatic cancer shows that combining platinum chemotherapy, PARP inhibitors, and immunotherapy improves treatment outcomes.

## Contribution

A novel syngeneic mouse model of Brca2-mutated PDAC was developed and used to demonstrate a more effective treatment sequence involving platinum, PARPi, and anti-PD1 immunotherapy.

## Key findings

- The Brca2-mutated PDAC mouse model showed sensitivity to cisplatin plus gemcitabine but limited response to PARPi alone.
- Platinum-based chemotherapy followed by PARPi maintenance therapy created a T cell-inflamed tumor microenvironment but led to resistance linked to CDX2 expression.
- Adding anti-PD1 immunotherapy to PARPi maintenance significantly enhanced tumor regression and survival in the mouse model.

## Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a challenging malignancy to treat, but emerging evidence suggests that specific subtypes may respond more favorably to certain therapies. BRCA-mutated PDAC represents a distinct subtype that is particularly sensitive to DNA-damaging therapies. The current standard of care for advanced BRCA-mutated PDAC involves induction platinum-based chemotherapy followed by maintenance therapy with a poly (ADP-ribose) polymerase inhibitor (PARPi). However, the randomized phase III POLO trial, upon which this standard is based, did not demonstrate an improved overall survival in patients who received olaparib compared to those who received placebo, highlighting the need for new therapeutic approaches. Additionally, there is a lack of robust models that recapitulate the tumor microenvironment of BRCA mutated PDAC, limiting the development of next-generation maintenance treatment options. In this study, we developed a syngeneic and immunocompetent mouse model of Brca2-mutated PDAC. The model demonstrated high sensitivity to cisplatin plus gemcitabine, but limited efficacy of PARPi monotherapy. Induction with platinum-based chemotherapy sensitized tumors to PARPi maintenance therapy and promoted an exhausted, T cell-inflamed tumor microenvironment. However, resistance emerged which was associated with CDX2 expression and tumor differentiation. The addition of anti-PD1 treatment to PARPi maintenance enhanced tumor regression and prolonged overall survival. These findings provide preclinical support for ongoing clinical trials investigating immunotherapy with PARPi as a maintenance strategy in homologous recombination-deficient PDAC.

The online version contains supplementary material available at 10.1038/s41598-026-35423-7.