Pembrolizumab and olaparib in homologous-recombination-deficient metastatic pancreatic cancer: the phase 2 POLAR trial.

Homologous recombination deficiency (HRD) arising from BRCA1or BRCA2 or PALB2 mutations confers sensitivity to platinum chemotherapy and PARP inhibition in pancreatic cancer (PC) and may enable prolonged disease control with immune checkpoint blockade (ICB). The phase 2 POLAR trial evaluated maintenance pembrolizumab plus olaparib following platinum-based chemotherapy in biomarker-stratified metastatic PC. Sixty-three participants were enrolled into three cohorts: cohort A (BRCA1/BRCA2-mutated or PALB2-mutated HRD, n = 33), cohort B (non-core HRD, n = 15) and cohort C (platinum sensitive, HRD-wild type, n = 15). Cohort A used a two-stage design with co-primary endpoints of at least 43% Response Evaluation Criteria in Solid Tumors (RECIST) objective response rate (ORR) and at least 77% 6-month progression-free survival (PFS) rate. Among RECIST-evaluable participants in cohort A (n = 20), ORR was 35% (95% confidence interval (CI): 15-59%), whereas 6-month PFS rate in the full cohort (n = 33) was 64% (95% CI: 49-82%), not meeting the primary endpoint. At a median follow-up of 37 months (95% CI: 27-47), median PFS and overall survival (OS) for cohort A were 8.3 (95% CI: 5.3-not reached (NR)) and 28 (95% CI: 12-NR) months, with 2-year and 3-year OS rates of 56% (95% CI: 41-76%) and 44% (95% CI: 28-69%), respectively. In cohorts B and C, ORR was 8% (95% CI: 0-38%) and 14% (95% CI: 2%-43%); median PFS was 4.8 (95% CI: 4.0-12) and 3.3 (95% CI: 1.9-4.8) months; and median OS was 18 (95% CI: 13-NR) and 10 (95% CI: 8.9-24) months, respectively. Preplanned translational analyses showed that circulating tumor DNA response, increased tumor-infiltrating lymphocytes and enrichment of frameshift indel neoantigens were associated with durable clinical benefit. These data suggest that a subset of HRD PC may derive prolonged benefit from PARP-ICB maintenance and support further development of biomarker-guided precision immunotherapy strategies in PC. ClinicalTrials.gov identifier: NCT04666740 .