Therapeutic advances in metastatic pancreatic cancer: a focus on targeted therapies

Mortality from pancreatic ductal adenocarcinoma (PDAC) is increasing worldwide and effective new treatments are urgently needed. The current treatment of metastatic PDAC in fit patients is based on two chemotherapy combinations (FOLFIRINOX and gemcitabine plus nab-paclitaxel) which were validated more than 8 years ago. Although almost all treatments targeting specific molecular alterations have failed so far when administered to unselected patients, encouraging results were observed in the small subpopulations of patients with germline BRCA 1/2 mutations, and somatic gene fusions (neurotrophic tyrosine receptor kinase, Neuregulin 1, which are enriched in KRAS wild-type PDAC), KRAS G12C mutations, or microsatellite instability. While targeted tumor metabolism therapies and immunotherapy have been disappointing, they are still under investigation in combination with other drugs. Optimizing pharmacokinetics and adapting available chemotherapies based on molecular signatures are other promising avenues of research. This review evaluates the current expectations and limits of available treatments and analyses the existing trials. A permanent search for actionable vulnerabilities in PDAC tumor cells and microenvironments will probably result in a more personalized therapeutic approach, keeping in mind that supportive care must also play a major role if real clinical efficacy is to be achieved in these patients.

Automated summary

Mortality from pancreatic ductal adenocarcinoma is increasing worldwide and there is an urgent need for effective new treatments. The current treatment for fit patients with metastatic PDAC is based on two chemotherapy combinations that were validated more than 8 years ago. Although treatments targeting specific molecular alterations have largely failed in unselected patients, encouraging results have been observed in subpopulations with certain mutations or gene fusions. Targeted tumor metabolism therapies and immunotherapy have been disappointing but are still being investigated in combination with other drugs. Optimizing pharmacokinetics and adapting available chemotherapies based on molecular signatures are promising avenues of research. Continuous search for actionable vulnerabilities in PDAC tumor cells and microenvironments may lead to more personalized therapeutic approaches.