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

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Journal: Nature medicine

Phase 2 POLAR Trial Overview

Phase 2 POLAR was a biomarker-stratified maintenance trial of pembrolizumab plus olaparib in metastatic pancreatic cancer after platinum-based chemotherapy.

Design

  • 63 patients divided into:
    • Cohort A: BRCA1/BRCA2/PALB2-mutated HRD (n=33)
    • Cohort B: non-core HRD (other DNA repair alterations; n=15)
    • Cohort C: HRD–wild type but platinum-sensitive (n=15)
  • In Cohort A, co-primary endpoints:
    • ≥43% RECIST ORR
    • ≥77% 6‑month PFS

Efficacy

  • Cohort A (core HRD)
    • ORR: 35% (95% CI 15–59; n=20 RECIST-evaluable) – below the prespecified 43% threshold.
    • 6‑month PFS: 64% (95% CI 49–82; n=33) – below the 77% target.
    • Median PFS: 8.3 months (95% CI 5.3–NR).
    • Median OS: 28 months (95% CI 12–NR).
    • 2‑year OS: 56% (95% CI 41–76); 3‑year OS: 44% (95% CI 28–69).
  • Cohort B (non-core HRD)
    • ORR: 8% (95% CI 0–38).
    • Median PFS: 4.8 months (95% CI 4.0–12).
    • Median OS: 18 months (95% CI 13–NR).
  • Cohort C (HRD–wild type, platinum-sensitive)
    • ORR: 14% (95% CI 2–43).
    • Median PFS: 3.3 months (95% CI 1.9–4.8).
    • Median OS: 10 months (95% CI 8.9–24).

Translational findings

  • Durable benefit was associated with:
    • Circulating tumor DNA (ctDNA) response.
    • Increased tumor-infiltrating lymphocytes.
    • Enrichment of frameshift indel–derived neoantigens.

Interpretation

  • The primary efficacy thresholds in the core HRD cohort were not met.
  • Nonetheless, a subset of BRCA1/BRCA2/PALB2-mutated HRD pancreatic cancers experienced prolonged PFS and OS on pembrolizumab plus olaparib maintenance.
  • Responses were uncommon and less durable in non-core HRD and HRD–wild-type, platinum-sensitive cohorts.
  • Data support further exploration of biomarker-driven PARP–ICI maintenance strategies in HRD-enriched pancreatic cancer.

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