Abstract A088: Genomic Scar to Immune Signals: Translational Insights from the POLAR Trial Reveal POLQ-Driven Immunogenicity in HRD Pancreatic Cancer

Abstract BACKGROUND: Pancreatic cancer (PC) remains largely unresponsive to immunotherapy, underscoring the need for biomarker-guided approaches. In the Phase II POLAR trial, 63 participants with metastatic PC and disease control after platinum-based chemotherapy received maintenance pembrolizumab and olaparib. Participants were prospectively stratified into three molecular cohorts: Cohort A (BRCA1/2 or PALB2-mutated homologous recombination–deficient [HRD], N=33), Cohort B (non-core HRD, 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) and 6-month progression-free survival (PFS). Cohort A demonstrated promising activity, with an ORR of 35% (95% CI: 15–59), a 6-month PFS of 64% (95% CI: 49–82), and a 2-year overall survival of 56% (95% CI: 41–76), where responses in Cohorts B and C were infrequent. These results prompted investigation into molecular features underlying immunogenicity and resistance. METHODS: We performed integrated genomic and immune profiling of POLAR trial samples (WES N=40, cfDNA, mIF), along with an independent multi-omic iPC cohort (WES N=71; snRNA-seq N=23, 59,771 nuclei). A POLQ Deletion Footprint (PDF) score was developed based on the frequency and length of short deletions to infer theta-mediated end joining (TMEJ) activity. Associations between PDF, neoantigen burden and quality, immune infiltration, tumor cell DNA repair evolution were assessed. RESULTS: Tumors with high PDF exhibited were marked by enriched short deletions, increased high-quality neoantigens (R=0.75, p=0.0013), and infiltration by cytolytic CD8+T cells (PRF1hiGZMBhiGNLYhi), suggesting immune engagement. In contrast, PDF-low tumors displayed ongoing replication stress leading to R-loop accumulation (p=4.8e–14) and a trend toward whole-genome doubling (p=0.072). Along a neoantigen pseudotime trajectory, POLQ-dependent TMEJ activity peaked during early HRD tumor evolution and waned over time, giving rise to STING activation and subsequent type I interferon signaling, which in turn fostered immune diversification and ultimately drove neoepitope editing. In the POLAR trial, patients lacking PDF-derived neoantigens had significantly worse progression-free and overall survival (log-rank p=0.0007 and 0.018, respectively). These findings highlight PDF reflects accumulation of past POLQ activity and informs functional quality of the tumor neoantigens and promotes T cell–mediated tumor recognition. CONCLUSIONS: The POLQ Deletion Footprint (PDF) score identifies a distinct subset of HRD pancreatic tumors shaped by prior POLQ-mediated repair. PDF encodes scars, enriched for immunogenic neoantigens and immune infiltration. Absence of PDF in HRD PC is associated with poor outcomes and unresolved replication stress. These findings establish PDF as a mechanistic biomarker that links replication dynamics, DNA repair and immune recognition, and may guide future precision strategies. Citation Format: Wungki Park, Catherine O'Connor, Marc Hilmi, Shigeaki Umeda, Roshan Sharma, Kevin Soares, Joshua Schoenfeld, Nuray Tezcan, Anupriya Singhal, Kenneth Yu, Joanne Chou, Olca Basturk, Nadeem Riaz, Walid Chatila, Chaitanya Bandlamudi, Vinod Balachandran, Dana Pe'er, Benjamin Greenbaum, Christine Iacobuzio-Donahue, Eileen M. O'Reilly. Genomic Scar to Immune Signals: Translational Insights from the POLAR Trial Reveal POLQ-Driven Immunogenicity in HRD Pancreatic Cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr A088.