The ongoing first-line treatment race for metastatic pancreatic ductal adenocarcinomas: will a tough disease lose its horror?

Pancreatic ductal adenocarcinomas (PDACs) are found to account for more than 5% of all cancer-related deaths worldwide. The 5-year survival rates are still low (<5% for in the metastatic setting). In patients with metastatic disease, combination chemotherapy regimens are currently standard of care. PDACs are K-RAS addicted (incidence >90%), however, RAS oncogenes have been regarded to be "undruggable." Several highly specific inhibitors have been developed with atebimetinib (MEK inhibitor), daraxonrasib (tri-complex pan-K-RAS inhibitor), zoldonrasib (tri-complex K-RAS G12D inhibitor), INCB161734 (non-covalent ON/OFF inhibitor specific for K-RAS G12D), HRS-4642 (liposomal G12D inhibitor), and setidegrasib (G12D degrader) currently undergoing phase III evaluation in first-line PDACs. Five trials (RASolute-305 [zoldonrasib], DAWN-303 [INCB161734], MAPKeeper-301 [atebimetinib]), HRS-4642, and setidegrasib are comparing chemotherapy plus inhibitor with chemotherapy alone. In contrast, RASolute-303 (daraxonrasib) is a three-arms randomized trial with an additional arm being daraxonrasib monotherapy. Since the benefits provided by chemotherapy regimens are limited, it is conceivable that the novel targeted approaches may have the potential to overcome these limitations. Of note, outcomes for some of these compounds numerically exceeded the historical benchmarks with standard chemotherapy suggesting that a chemotherapy backbone might no longer be needed in the future.