PARP inhibitors
Poly(ADP-ribose) polymerase (PARP) inhibitors
This is a relatively new class of highly specialised anti-cancer drugs. They cause DNA damage that in normal cells, would be repaired by alternative DNA damage repair processes, such as BRCA-mediated homologous recombination 1. However, in certain cancers that carry genetic defects in these alternate pathways, the additive damage becomes lethal. This mechanism of promoting cell death by adding pharmacologically-induced DNA damage on top of the inbuilt BRCA deficiency in DNA repair is a manipulation of the concept of ‘synthetic lethality' 2. The original use of PARP inhibitors was based on their efficacy in cancers with germline loss-of-function mutations in either BRCA1 or BRCA2.
The first PARP inhibitor, olaparib, was approved by the US FDA and EU EMA in 2014. It was originally indicated to treat advanced ovarian cancer in patients with BRCA gene mutations.
Since 2014 a number of additional PARP inhibitors have been granted clinical use authorisations:
Rucaparib (2016 FDA). In 2020, rucaparib’s approval was expanded to include treatment of certain cases of BRCA mutation +ve metastatic castration-resistant prostate cancer.
Niraparib (2017 FDA and EMA)
Talazoparib (2018 FDA) was the first PARP inhibitor to be approved to treat locally advanced or metastatic HER2 negative breast cancers with deleterious germline BRCA mutations.
Pamiparib (2021 China)
The currently used drugs are non-selective with respect to PARP isozymes. Inhibition of PARP1 appears to mediate the majority of the DNA-damaging effect of the drugs. Whereas, disrupting PARP2 activity is thought to be associated with their haematological toxicity (they are generally myelosuppressive). In the future, PARP1-selective inhibitors my offer an improved therapeutic index.
Initially, PARP inhibitors were used to treat selected advanced and recurrent cancers with BRCA mutations, particularly when other therapeutic options had been exhausted 3. More recently they have been authorised for both relapsed and newly diagnosed disease, with BRCA mutations or mutations in other DNA repair proteins (such as ATM serine/threonine kinase) 4.
References:
1 Helleday (2011) The underlying mechanism for the PARP and BRCA synthetic lethality: clearing up the misunderstandings PMID: 21821475
2 Setton et al. (2021) Synthetic Lethality in Cancer Therapeutics: The Next Generation PMID: 33795234
3 Virtanen et al. (2019) PARP Inhibitors in Prostate Cancer–the Preclinical Rationale and Current Clinical Development PMID: 31357527
4 Groelly et al. (2023) Targeting DNA damage response pathways in cancer PMID: 36471053
What’s next for PARP inhibitors? (Nature 2021)
This Outlook article written by Simon Makin was published in Nature in 2021. It is an excellent introduction to PARP inhibitors, their use and limitations in cancer therapy.
This page is maintained by Drugs.com, and provides an up to date list of the PARP inhibitor drugs that are approved by the US FDA. It provides useful links to more details about the individual drugs.