KRAS has long defined pancreatic ductal adenocarcinoma—and for decades, it was considered untouchable. Dr. Nicholas Hornstein discusses how new KRAS-targeted strategies emerging around ESMO 2025 are poised to change that narrative, with agents now capable of targeting multiple G12 mutations that cover the vast majority of patients. While single-agent responses are encouraging, the real opportunity lies in rational combination strategies to dramatically improve efficacy. Together, these advances signal a future where precision therapy could fundamentally alter outcomes and possibly even eliminate the need for surgery in select patients.