Pancreatic cancer remains one of the most lethal malignancies, with five-year survival rates below 10 percent. Finding effective first-line treatments that balance efficacy with tolerability could extend survival while preserving quality of life for thousands of patients annually. A phase II clinical trial involving 129 patients with advanced pancreatic ductal adenocarcinoma tested whether SLOG—a combination of S-1, leucovorin, oxaliplatin, and gemcitabine—could outperform the established modified FOLFIRINOX regimen. Both treatment arms demonstrated nearly identical efficacy metrics: median progression-free survival of 7.5 months for SLOG versus 6.5 months for modified FOLFIRINOX, with overall survival reaching 12.9 and 12.1 months respectively. Objective response rates also proved comparable at 38.5 percent versus 26.6 percent. The safety profiles diverged significantly, with SLOG causing substantially less severe neutropenia—a dangerous drop in infection-fighting white blood cells affecting only 15.4 percent of patients compared to 53.1 percent with the standard regimen. However, SLOG produced more non-blood-related severe toxicities. An important secondary finding emerged regarding patients carrying homologous recombination deficiency mutations, present in 12.9 percent of the cohort. These individuals experienced markedly longer survival with either treatment—nearly 12 months progression-free versus 7 months for those without the mutations. While SLOG failed to demonstrate superiority in the primary endpoint, its reduced hematologic toxicity profile suggests potential value for patients at high risk for neutropenia complications. The biomarker findings reinforce growing evidence that genetic profiling could guide personalized treatment selection in pancreatic cancer, though larger studies are needed to validate these observations.