Abstract 2438: Discovery of predictive circulating proteomic biomarkers for therapy response in HRR-driven solid tumors

Abstract Background: The IMAGENE trial (jRCT2051210120) is a multicenter, tumor-agnostic, phase II basket study evaluating the combination of the PARP inhibitor niraparib and PD-1 inhibitors in patients with homologous recombination repair (HRR) gene mutations who have progressed following prior immune checkpoint inhibitor (ICI) therapy. In this tumor-agnostic setting, patients were enrolled with unresectable, locally advanced urothelial carcinoma (UC), renal cell carcinoma (RCC), gastric cancer (GC), esophageal cancer (EC), head and neck cancer (HNC), and melanoma (MC), all harboring HRR gene alterations. A total of 45 patients were enrolled in the primary cohort between April 2022 and April 2024. Existing biomarkers such as PD-L1 expression and tumor mutation burden (TMB) have shown limited predictive power in ICI-treated and HRR-driven tumors. To address this gap, we performed unbiased deep plasma proteomic profiling, complemented by a targeted inflammatory marker panel, on baseline and on-treatment samples from HNC participants enrolled in the IMAGENE trial. Methods: Citrate plasma samples were collected from patients at baseline and two post-dose time points after treatment with niraparib plus anti-PD-1 therapy. To study proteomic differences between responders and non-responders, and their temporal dynamics, we employed two complementary approaches: (i) unbiased plasma proteome profiling using the P2 enrichment system combined with mass spectrometry (DIA-MS), and (ii) targeted quantification of inflammatory proteins using a proximity ligation assay (NULISA) panel of ∼250 markers. Results: A total of 4,875 proteins and 67,311 peptides were quantified by P2-enriched LC-MS/MS across all samples. Comparative analysis of post-treatment samples identified 160 proteins differentially abundant between responders and non-responders, with enrichment in complement activation and immune-related pathways. Longitudinal analysis revealed 46 proteins significantly altered between pre- and post-treatment samples in responders, again highlighting immune and complement system activation as key features. Targeted NULISA profiling confirmed 20 markers differing between responders and non-responders and 11 markers dynamically regulated during response. Collectively, these findings suggest that complement activation, humoral immune response, and B-cell-mediated immunity are critical determinants of therapeutic response to niraparib plus anti-PD-1 combination therapy. Citation Format: Anamarija Pfeiffer, Wouter van Bergen, Martin Mehnert, Polina Shichkova, Vanessa Bühlmann, Amaury Lachaud, Yuehan Feng, Takayuki Yoshino, Norio Nonomura, Taigo Kato. Discovery of predictive circulating proteomic biomarkers for therapy response in HRR-driven solid tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2438.