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Murthy et al. Cancer Drug Resist 2019;2:665-79 Cancer
DOI: 10.20517/cdr.2019.002 Drug Resistance

Review Open Access

PARP inhibitors: clinical development, emerging
differences, and the current therapeutic issues

Pooja Murthy , Franco Muggia 2
1
1 Department of Medicine, Maimonides Cancer Center, Brooklyn, NY 11220, USA.
2 New York University School of Medicine, New York, NY 10016, USA.
Correspondence to: Dr. Pooja Murthy, Department of Medicine, Maimonides Cancer Center, 6300 8th Avenue, Brooklyn, NY
11220, USA. E-mail: murthypj@gmail.com

How to cite this article: Murthy P, Muggia F. PARP inhibitors: clinical development, emerging differences, and the current
therapeutic issues. Cancer Drug Resistance 2019;2:665-79. http://dx.doi.org/10.20517/cdr.2019.002

Received: 7 Jan 2019 First Decision: 25 Mar 2019 Revised: 9 May 2019 Accepted: 26 Jun 2019 Published: 19 Sep 2019

Science Editor: Enrico Mini Copy Editor: Cai-Hong Wang Production Editor: Jing Yu

Abstract

Following years in development, poly-adenosyl-ribose polymerase (PARP) inhibitors continue to advance the
treatment of ovarian and breast cancers, particularly in patients with pathogenic BRCA mutations. Differences in
clinical trial design have contributed to distinct indications for each of the PARP inhibitors. Toxicity patterns are
also emerging that suggest agents differ in their normal tissue tolerance - beyond what might be expected by
dose variations and/or exposure to prior treatment. PARP inhibitor resistance is an increasingly relevant issue as
the drugs move to the forefront of advanced ovarian/breast cancer treatment, and is an active area of ongoing
research. This review examines the PARP inhibitor clinical trials that have led to approved indications in ovarian
and breast cancers, PARP inhibitor targets and pharmacological differences between the PARP inhibitors, emerging
mechanisms of resistance, and key clinical questions for future development.

Keywords: poly-adenosyl-ribose polymerase inhibitors, poly-adenosyl-ribose polymerase inhibition, breast cancer,
ovarian cancer, BRCA, homologous recombination deficiency, poly-adenosyl-ribose polymerase inhibitor resistance

INTRODUCTION
The poly-adenosyl-ribose polymerase 1 (PARP1) and PARP2 enzymes are involved in base-excision repair
[1]
of DNA single-strand breaks, and PARP1 also plays a role in nucleotide excision repair and the regulation
[4,5]
of both nonhomologous end-joining repair [2,3] and microhomology mediated end-joining repair of

© The Author(s) 2019. Open Access This article is licensed under a Creative Commons Attribution 4.0
International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
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