Homologous Recombination Repair in Biliary Tract Cancers: A Prime Target for PARP Inhibition?

Simple Summary Biliary tract cancers (BTCs) are a rare but deadly group of gastrointestinal tumors that are often diagnosed in the advanced stages of disease. Despite large studies investigating optimal systemic therapy options in BTCs, current chemotherapies provide only modest benefits in overall survival. The rapidly evolving study of homologous recombination repair (HRR) as part of the broader DNA damage repair (DDR) system makes it possible to exploit deficiencies in this pathway with targeted agents such as PARP inhibitors (PARPi). We will review the rationale for PARPi use, as well as considerations for further unlocking their potential in treating BTC. Biliary tract cancers (BTCs) are a heterogeneous group of malignancies that make up similar to 7% of all gastrointestinal tumors. It is notably aggressive and difficult to treat; in fact, >70% of patients with BTC are diagnosed at an advanced, unresectable stage and are not amenable to curative therapy. For these patients, chemotherapy has been the mainstay treatment, providing an inadequate overall survival of less than one year. Despite the boom in targeted therapies over the past decade, only a few targeted agents have been approved in BTCs (i.e., IDH1 and FGFR inhibitors), perhaps in part due to its relatively low incidence. This review will explore current data on PARP inhibitors (PARPi) used in homologous recombination deficiency (HRD), particularly with respect to BTCs. Greater than 28% of BTC cases harbor mutations in genes involved in homologous recombination repair (HRR). We will summarize the mechanisms for PARPi and its role in synthetic lethality and describe select genes in the HRR pathway contributing to HRD. We will provide our rationale for expanding patient eligibility for PARPi use based on literature and anecdotal evidence pertaining to mutations in HRR genes, such as RAD51C, and the potential use of reliable surrogate markers of HRD.