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 evaluated maintenance pembrolizumab + olaparib after platinum chemotherapy in molecularly stratified metastatic pancreatic cancer. In the BRCA1/2- or PALB2-altered cohort (n=33), median progression-free survival was 8.3 months, median overall survival was 28 months, and estimated 3-year overall survival was 44%.
The trial did not meet its prespecified primary efficacy threshold. Its long-duration responses instead motivate the next question: which molecular and immune features identify the patients most likely to derive durable benefit from this chemotherapy-free maintenance approach?
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
POLAR integrated HRD status, ctDNA dynamics, tumor-infiltrating lymphocytes, genomic scars, DNA-repair alterations, and neoantigen profiles. Falling or clearing ctDNA, greater immune-cell infiltration, and frameshift-indel neoantigen enrichment were associated with durable clinical benefit.
The broad label “HRD-positive” is not interchangeable with BRCA1, BRCA2, or PALB2 biology. The canonical BRCA1/2/PALB2 cohort had stronger activity than the non-core HRD cohort, reinforcing the need to interpret individual DNA-repair alterations — including ATM — with molecular context.
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.