Perspectives on PARP inhibitors as pharmacotherapeutic strategies for breast cancer

ABSTRACT

Introduction Approximately 10% of all breast cancer cases occur in individuals who have germline pathogenic variants of the BRCA 1, BRCA 2, and other genes associated with impaired DNA damage repair that is associated with an increased risk of breast, ovarian, and other cancers. Inhibitors of poly-ADP ribose polymerase (PARP) induce synthetic lethality in cancer cells harboring such pathogenic variants.

Area covered In this review, the authors review the mechanisms of action, antitumor activity, and adverse events associated with PARP inhibitors for the treatment of advanced breast cancer. The authors then summarize the area and provide their expert perspectives on the area.

Expert opinion Two PARP inhibitors are approved in metastatic breast cancer, including olaparib and talozaparib. Both agents were approved based on phase III trials demonstrating that they were associated with improved progression-free survival compared with treatment of physician’s choice in patients receiving second-third line therapy for locally advanced, inoperable, or metastatic breast cancer in patients with germline pathogenic BRCA 1 or BRCA2 variants.

KEYWORDS:

• PARP inhibitor
• breast cancer
• BRCA 1 or 2 mutation
• DNA repair defect

Article highlights

• Poly-ADP-ribose polymerase (PARP) comprises a group of nuclear proteins that are activated upon binding to damaged DNA and involved in DNA repair.

• Individuals harboring germline pathogenic variants of the BRCA1 or BRCA2 gene exhibit defective DNA repair due to deficient homologous recombination.

• PARP inhibitors induce synthetic lethality in breast cancers occurring in individuals with germline BRCA 1 or BRCA 2 genes.

• PARP inhibitors exert their effects via inhibition of the catalytic enzyme activity and trapping of PARP on damaged DNA.

• Two PARP inhibitors, including olaparib and talazoparib, are currently approved for the metastatic breast cancer treatment in individuals with gBRCA+ based on phase III trials indicating improved progression-free survival compared with standard chemotherapy.

• Multiple studies of PARP inhibitors are ongoing in combination with other targeted therapies.

This box summarizes key points contained in the article.

Acknowledgments

Supported in part by United States Department of Health and Human Service grant P30-CA113330.

Declaration of interest

S Rahman is a fellow at Montefiore Medical Center with a Hematology/Oncology Fellowship. J Sparano received financial compensation as a consultant for AstraZeneca, Pfizer, GlaxoSmithKline, Eli Lilly and Company, Celgene, Roche, Novartis, Daiichi Sankyo, CStone Pharmaceuticals and Epic Sciences. 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 apart from those disclosed.

Reviewer Disclosures

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

Additional information

Funding

The authors are supported by the U.S. Department of Health and Human Services via grant P30-CA113330