Pembrolizumab and Olaparib (POLAR) Maintenance Therapy in Metastatic Pancreatic Cancer With or Without Homologous Repair Deficiency: A Biomarker Selected Phase II Trial

The phase 2 POLAR trial evaluated maintenance pembrolizumab plus olaparib in 63 participants with metastatic pancreatic cancer with disease control on platinum-based chemotherapy. Participants were prospectively stratified into three cohorts by type of HRD: Cohort A (homologous recombination deficient [HRD] by BRCA1/2 or PALB2 mutations, N=33), Cohort B (non-core HRD mutations, N=15), and Cohort C (platinum-sensitive without HRD mutations, N=15). Cohort A used a two-stage design with co-primary endpoints of objective response rate (ORR) ≥43% and 6-month progression-free survival ≥77% per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. For Cohort A, ORR was 35% (95% CI: 15-59) and 6-month-PFS rate was 64% (95% CI: 49-82), not meeting the primary endpoint. Among surviving participants (N=17), the median follow-up was 26.0 months (range: 1.4-52.5), and the 2-year overall survival rate was 56% (95% CI: 41-76). Median PFS for Cohort A was 8.3 months (95% CI: 5.3-not reached), 4.8 months (95% CI: 4-12) for Cohort B, and 3.3 months (95% CI: 1.9-4.8) for Cohort C. Pre-planned translational profiling demonstrated that molecular response by circulating cell-free DNA (cfDNA), high tumor-infiltrating lymphocyte (TIL) density, and increased abundance of frameshift indels and neoantigens were associated with durable benefit, particularly in HRD tumors. These findings support a precision immunotherapy approach for biomarker-defined subsets of pancreatic cancer. ClinicalTrials.gov identifier: NCT04666740