The study examines the capture of pancreatic ductal adenocarcinoma (PDAC) by KRAS inhibitors in preclinical models. The KRAS G12D inhibitor INCB161734 achieved disease control in nearly 80% of patients with advanced or metastatic PDAC with a KRAS G12D mutation after intensive prior therapy[1][4]. In 80% of patients with a detectable KRAS G12D mutation in plasma DNA, two-thirds treated with the 1200 mg dose achieved an early molecular response (a 90% reduction in variant allele frequency)[1]. The drug showed a manageable safety profile in patients with advanced solid tumors with the KRAS G12D mutation[1]. Combination with chemotherapy (mFOLFIRINOX or gemcitabine/nab-paclitaxel) showed deep molecular responses and supports the initiation of a phase III study in first-line metastatic PDAC[1][4]. KRAS G12D mutations are frequent oncogenic drivers of PDAC, and inhibition of KRAS leads to rapid cell death or cell cycle arrest[3]. Preclinical models confirm that inhibition of mutant KRAS eliminates PanIN precursor lesions and prevents tumorigenesis[2].