Overview
Roughly one in six pancreatic cancers harbour defects in DNA damage repair. We exploit those defects therapeutically by combining PARP inhibition with immune checkpoint blockade in biomarker-selected patients.
The POLAR trial
Our investigator-initiated phase 2 POLAR trial demonstrated that maintenance pembrolizumab + olaparib yields a median overall survival of 28 months and a 3-year OS rate of 44% in BRCA/PALB2-mutated metastatic pancreatic cancer.
These results, published in Nature Medicine (2026), establish a chemotherapy-free maintenance strategy for a genetically defined subgroup and link ctDNA dynamics and neoantigen landscape to durable benefit.
Mechanistic rationale
Homologous-recombination deficiency leaves tumors dependent on error-prone repair, so PARP inhibition drives a synthetic-lethal accumulation of DNA damage.
That damage also increases genomic instability and neoantigen load, which can render tumors more visible to the immune system — providing the biological rationale for pairing PARP inhibition with checkpoint blockade.
Biomarkers
We use HRD status, mutational signatures (COSMIC signature 3, LST, LOH, TAI), and ctDNA response to identify the patients most likely to benefit and to monitor response in real time.
What's next
We are working to extend chemotherapy-free maintenance to broader DDR-altered populations beyond BRCA/PALB2, and to define who benefits from the addition of immunotherapy versus PARP inhibition alone.
Serial ctDNA and neoantigen profiling are being developed into adaptive readouts that could guide escalation or de-escalation during maintenance.