FOLFIRINOX vs. Gemcitabine/Nab‐Paclitaxel for Pancreatic Cancer by BRCA2 and TMB Status: A Japanese C‐ CAT Database Study

ABSTRACT The clinical impact of BRCA2 variants and tumor mutational burden (TMB) on first‐line regimen selection—FOLFIRINOX (FFX) versus gemcitabine plus nab‐paclitaxel (GnP)—for pancreatic ductal adenocarcinoma (PDAC) remains unclear. Using the Center for Cancer Genomics and Advanced Therapeutics (C‐CAT) database, we analyzed patients with unresectable or recurrent PDAC treated with first‐line FFX or GnP. Overall survival (OS) and time to treatment failure (TTF) were compared, stratified by BRCA2 pathogenic variants (PVs) and TMB status. A total of 4356 patients were included. In the overall population, GnP was associated with superior adjusted OS compared with FFX (adjusted hazard ratio HR 0.90, p = 0.015), while TTF was comparable. In patients with BRCA2 PVs (3.3%), FFX demonstrated a significantly higher objective response rate (66.7% vs. 33.3%) and longer TTF compared with GnP. However, OS in patients with BRCA2 PVs was comparable between the two regimens (HR 1.11, p = 0.665). Among patients with BRCA2 PVs treated with GnP, OS was numerically longer with second‐line FFX than with nal‐IRI/5‐FU/leucovorin (HR 0.51; p = 0.119). In patients without BRCA2 PVs, OS was longer with GnP. TMB‐high status (2.9%) predicted significantly longer OS regardless of the first‐line regimen (HR 0.64, p < 0.001). In conclusion, GnP was associated with superior adjusted OS in the overall population. In BRCA2 PV tumors, greater tumor shrinkage with first‐line FFX did not translate into longer OS, underscoring the importance of sequencing strategies that ensure timely exposure to platinum‐based therapy. TMB‐high tumors may benefit from timely access to immunotherapy.