DR HERZOG: Well, it’s really our first foray into personalized precision medicine in ovarian cancer, in that we’re really going after an actionable mutation that we’re able to identify. What we’re really leveraging is the inability of a cell to repair its DNA in a very efficient and accurate way. So there’s a loss of fidelity in terms of that repair process once you move beyond homologous repair.

BRCA is a mechanism for repairing double-strand DNA breaks. And when that is present, that then gives us a leverage point to introduce these PARP inhibitors that knock out another pathway, a redundant pathway for DNA repair, such that the cancer cell can then no longer repair its DNA, causing it to die. And so it’s an exciting mechanism of action. It goes to this whole point of synthetic lethality and all the things that go with that. But what’s really exciting is that we’re seeing some off-target effects, as well, it appears, with these PARP inhibitors.

The other thing is that we have been able to expand the eligibility for these PARP inhibitors based on mutations beyond just BRCA. So not only would a patient with BRCA1 or BRCA2 mutation likely respond to a PARP inhibitor, but we’re finding a number of other pathways and genes are responsible for DNA repair as well. And so we’re trying to find those patients that would also benefit from this type of therapy. And so I think it’s been really exciting to see the science really drive the experiments and the trials, if you will. And so it’s been really a breakthrough, I’d have to say.

Treatment strategies in the management of ovarian cancer (OC)

Mechanism of action of PARP inhibitors and importance of BRCA testing

PARP inhibitors as primary treatment after multiple lines of therapy

PARP inhibitors as maintenance therapy

Tolerability of olaparib

Treatment options after olaparib failure

Differences among PARP inhibitors

Future directions in OC research