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

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.