New clinical data for AstraZeneca's first-in-class poly(ADP-ribose) polymerase (PARP) inhibitor olaparib has raised the bar for a bevy of would-be competitors.

The FDA granted accelerated approval to olaparib in 2014 for fourth-line treatment of BRCA-mutated ovarian cancer, but the drug came under pressure last year when Tesaro released phase III results that suggested that its as yet unapproved PARP inhibitor niraparib might offer better efficacy.

AstraZeneca has now reclaimed centre stage, reporting that its drug provided a median progression-free survival (PFS) of 19.1 months in BRCA-mutated platinum-sensitive, relapsed ovarian cancer, versus 5.5 months for placebo, in a phase III trial. This is in line with Tesaro's reported 21-month median PFS in BRCA-mutated ovarian cancer patients treated with niraparib, compared with 5.5 months in the control arm.

These drugs act by blocking DNA damage repair, which leads to the accumulation of toxic insults in highly mutated cancer cells. Mutations in BRCA1 and BRCA2 also compromise DNA damage repair, and so patients with such mutations are more likely to respond to PARP inhibition.

The field almost went off track in 2011 with the late-stage failure of Sanofi's iniparib, but made a roaring comeback with the realization that the failed candidate was not a bona fide PARP inhibitor (Nat. Rev. Drug Discov. 12, 725–727; 2013). The FDA approved a second PARP inhibitor, Clovis Oncology's rucaparib, late last year. Tesaro has filed its drug for approval, and is expecting a regulatory decision by the end of June. Other PARP inhibitors in phase III development include Pfizer's talazoparib and AbbVie's veliparib.

Although AstraZeneca secured the first approval in ovarian cancer, all of these companies are still chasing a first approval in other cancers. Next up is likely to be breast cancer, and so a recent study into the potential utility in this indication could be good news for the entire class. A large team of academic researchers developed an assay to detect BRCA1- and BRCA2-mutant tumours that might respond best to PARP inhibition. Whereas previous analyses estimated that ~1–5% of breast cancer patients carried these tumours, their analysis using a broader mutational signature approach estimated that up to 22% of breast cancer patients might be good candidates for treatment (Nat. Med., published online March 2017).

A recent review of the field also highlighted other opportunities to expand the scope of this class (Science 355, 1152–1158; 2017). Key priorities include the need to improve the understanding of who to treat, by further dissecting the mechanism by which PARP inhibition kills cancer cells, and to optimize combination therapy. “With the number of ongoing clinical trials, there is optimism that in the short term there will be additional regulatory approvals for [PARP inhibitors] in multiple cancers,” the authors write.