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  • Review Article
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An update on PARP inhibitors—moving to the adjuvant setting

Nature Reviews Clinical Oncology volume 12, pages 27–41 (2015)Cite this article

Subjects

Key Points

  • The poly(ADP-ribose) polymerases (PARPs) are a large family of multifunctional enzymes that have a role in the repair of single-strand breaks in DNA

  • BRCA1 or BRCA2 mutation, resulting in a lack of homologous recombination, sensitizes cells to inhibition of PARP activity, which in turn leads to chromosomal instability, cell-cycle arrest, and subsequent apoptosis

  • The most-compelling evidence of the efficacy of PARP inhibitors in the treatment of cancer comes from studies that involved patients with BRCA1 or BRCA2 mutations

  • Approximately 70% of BRCA1-mutant and 20% of BRCA2-mutant breast tumours present as triple-negative breast cancer, a disease with poor prognosis; no targeted treatments have been approved specifically in this setting

  • In the adjuvant setting, a positive therapeutic effect of PARP inhibitors is anticipated in the well-defined population of patients with high-risk BRCA-mutated primary breast cancer

Abstract

Inhibition of poly(ADP-ribose) polymerase (PARP) enzymes is a potential synthetic lethal therapeutic strategy in cancers harbouring specific DNA-repair defects, including those arising in carriers of BRCA1 or BRCA2 mutations. Since the development of first-generation PARP inhibitors more than a decade ago, numerous clinical trials have been performed to validate their safety and efficacy, bringing us to the stage at which adjuvant therapy with PARP inhibitors is now being considered as a viable treatment option for patients with breast cancer. Nevertheless, the available data do not provide clear proof that these drugs are efficacious in the setting of metastatic disease. Advancement of a therapy to the neoadjuvant and adjuvant settings without such evidence is exceptional, but seems reasonable in the case of PARP inhibitors because the target population that might benefit from this class of drugs is small and well defined. This Review describes the evolution of PARP inhibitors from bench to bedside, and provides an up-to-date description of the key published or otherwise reported clinical trials of these agents. The specific considerations and challenges that might be encountered when implementing these compounds in the adjuvant treatment of breast cancer in the clinic are also highlighted.

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Figure 1: The role of PARP inhibitors in synthetic lethality.
Figure 2: The different biological PARP functions relevant to cancer.
Figure 3: Mechanisms of resistance to PARP inhibitor therapy.

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  1. Department of Medicine, BrEAST Data Centre, Institut Jules Bordet, Université Libre de Bruxelles, Boulevard de Waterloo 125, Brussels, B-1000, Belgium

    Amir Sonnenblick, Evandro de Azambuja, Hatem A. Azim Jr & Martine Piccart

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A.S. researched the data for the article, and all authors contributed substantially to discussion of content, writing, and review/editing of the manuscript before submission.

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Correspondence to Martine Piccart.

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E.d.A. holds an advisory role for and has received research funding from GlaxoSmithKline. H.A.A. is a consultant for Celgene, Nanostring and Novartis, and has received honouraria from Celgene, GlaxoSmithKline, Nanostring and Novartis. M.P. is a consultant to, and has received honouraria and grant support from, Amgen, Bayer, Boehringer, Bristol-Myers Squibb, Roche and Sanofi; M.P. has also received grant support from Pfizer and honouraria from AstraZeneca. A.S. declares no competing interests.

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Sonnenblick, A., de Azambuja, E., Azim, H. et al. An update on PARP inhibitors—moving to the adjuvant setting. Nat Rev Clin Oncol 12, 27–41 (2015). https://doi.org/10.1038/nrclinonc.2014.163

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