Systemic Therapy of Metastatic Pancreatic Adenocarcinoma: Current Status, Challenges, and Opportunities

SIMPLE SUMMARY: Pancreatic ductal adenocarcinoma (PDAC) is a common type of cancer originating from the pancreatic glands and is characterized by a rapidly progressive course and a dismal prognosis. Currently, chemotherapy is the cornerstone of treatment that has modest efficacy. Targeted treatment options are rapidly evolving with the growing understanding of pathobiological underpinnings of tumorigenesis, progression, and treatment resistance mechanisms. Combination strategies targeting multiple signaling pathways supporting tumor growth and propagation are active areas of contemporary research that will likely transform the treatment paradigm of pancreatic cancer. ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by nonspecific presenting symptoms, lack of a screening test, rapidly progressive clinical course, and presentation with an advanced-stage disease in the majority of patients. PDAC is essentially a systemic disease irrespective of the initial stage, as most patients with non-metastatic PDAC undergoing curative-intent treatment eventually experience metastatic relapse. Currently, cytotoxic chemotherapy remains the cornerstone of treatment in patients with advanced disease. However, the current standard treatment with multiagent chemotherapy has modest efficacy and results in median overall survival (OS) of less than a year and a 5-year OS of about 10%. The pathobiology of PDAC poses many challenges, including a unique tumor microenvironment interfering with drug delivery, intratumoral heterogeneity, and a strongly immunosuppressive microenvironment that supports cancer growth. Recent research is exploring a wide range of novel therapeutic targets, including genomic alterations, tumor microenvironment, and tumor metabolism. The rapid evolution of tumor genome sequencing technologies paves the way for personalized, targeted therapies. The present review summarizes the current chemotherapeutic treatment paradigm of advanced PDAC and discusses the evolving novel targets that are being investigated in a myriad of clinical trials.