Pancreatic Cancer: BRCA Targeted Therapy and Beyond

SIMPLE SUMMARY: Pancreatic cancer is associated with poor outcomes for several reasons, including diagnosis at an advanced stage, the absence of effective screening for the diagnosis, and resistance to treatments. Pancreatic cancers associated with BRCA1/2 mutations have emerged as a distinct subgroup with sensitivity to other treatments and, in some cases, durable responses. Furthermore, beyond BRCA1/2 mutations, there is increasing recognition that other gene mutations may behave in a similar manner. The focus of this review is to discuss recent developments in the management of BRCA-associated pancreatic cancer, emerging therapeutic strategies, and future directions for this subgroup of patients. ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer-related death in the US by 2030, despite accounting for only 5% of all cancer diagnoses. Germline gBRCA1/2-mutated PDAC represents a key subgroup with a favorable prognosis, due at least in part to additional approved and guideline-endorsed therapeutic options compared with an unselected PDAC cohort. The relatively recent incorporation of PARP inhibition into the treatment paradigm for such patients has resulted in renewed optimism for a biomarker-based approach to the management of this disease. However, gBRCA1/2 represents a small subgroup of patients with PDAC, and efforts to extend the indication for PARPi beyond BRCA1/2 mutations to patients with PDAC and other genomic alterations associated with deficient DNA damage repair (DDR) are ongoing, with several clinical trials underway. In addition, despite an array of approved therapeutic options for patients with BRCA1/2-associated PDAC, both primary and acquired resistance to platinum-based chemotherapies and PARPi presents a significant challenge in improving long-term outcomes. Herein, we review the current treatment landscape of PDAC for patients with BRCA1/2 and other DDR gene mutations, experimental approaches under investigation or in development, and future directions.