Investigational PARP inhibitors for the treatment of biliary tract cancer: spotlight on preclinical and clinical studies

ABSTRACT

Introduction: Alterations in DNA damage repair (DDR) genes are observed in up to 60% of biliary tract cancer (BTC) patients. Patients with advanced/metastatic BTC have few therapeutic options, so there is a demand for the development of new and innovative treatment approaches. The use of poly-adenosine diphosphate-ribose polymerase (PARP) inhibitors (PARPis), either as a monotherapy or in combination, is being extensively studied in clinical trials.

Areas Covered: This review examines the targeting of the DDR pathway with PARPis as a potential novel treatment option for the management of BTCs. The rationale behind the use of PARPis and current clinical experience is discussed. Moreover, further insights into potential future directions concerning the applicability of PARPis in the treatment of BTCs are proposed.

Expert Opinion: Prospective clinical data with PARPis in the treatment of BTCs are limited. The potential combination of PARPis and IDH1 inhibitors or immune checkpoint inhibitors in clinical trials is interesting because of the potential synergistic preclinical data. There are other possible combinations including those drugs that target the angiogenesis or STAT3 pathways. An enhanced understanding of acquired resistance to PARPis is necessary to progress the use of these agents in clinical trials.

KEYWORDS:

• Cholangiocarcinoma
• biliary tract tumors
• DDR alterations
• PARP inhibitors

Declaration of interest

R Kim has received honorarium from Lilly, BMS, and Incyte, and research funding from Bayer, BMS, and Eisai outside of the submitted work. R Mehta has received honorarium from Lilly, BMS and NCCN. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Article highlights

• The increased use of next generation sequencing has helped us identify several new potential targets in biliary tract cancers

• DNA damage repair pathway alterations can be found in up to 60% of biliary tract tumors and offers several therapeutic advantages with PARP inhibitors.

• Currently, clinical data for use of PARP inhibitors is limited in biliary tract cancers, but several trials are ongoing.

• In this review, we provide a comprehensive overview of available pre clinical and clinical evidence of PARP inhibitors for the treatment of biliary tract cancer

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This paper was not funded.