A PARP/I-O Strategy in Breast Cancer: The MEDIOLA Trial

Transcript: Joyce A. O’Shaughnessy, MD: PARP inhibitors inhibit a very important enzyme called PARP that is involved in the repair of single-strand DNA breaks. And if those are not repaired upon cell proliferation, cell division, they turn into double-strand breaks. And then those double-strand breaks have to be repaired by the homologous recombination pathway. And if that’s already gone because a cancer has inherited a germline BRCA 1 or 2 mutation, then homologous recombination cannot proceed. And now that cell has lost 2 legs of the DNA repair tool and will die. It’s called synthetic lethality.

The MEDIOLA trial is a very important first step in combining the PARP inhibitor olaparib with the checkpoint inhibitor durvalumab. The idea of putting these 2 classes of agents together in patients with germline BRCA-mutant metastatic breast cancer makes a great deal of sense because there’s a fair amount of preclinical information suggesting that PARP inhibitors could make the tumor cells more immunogenic. Potentially we could even change cancers that are poorly immunogenic, immunogenically cold, to hot. So the PARP inhibitor stops DNA repair in germline BRCA breast cancers and increases the neoantigen presentation and may activate the STING pathway, and then that would, presumably, make the checkpoint inhibitor therapy more effective. So there’s very, very compelling rationale to combine these two.

So the MEDIOLA trial is doing that in patients with metastatic breast cancer, in women with germline BRCA mutations. And the first thing to say is, the safety appears to be good. There are no unexpected toxicities. Basically, the toxicities are present from both agents, but nothing unexpected. The response rate appears to be excellent. In fact, in women who are first-line or second-line receiving the combination early, the response rate was over 70%, and that compares favorably to single-agent olaparib in the OlympiAD trial, where the response rate was around 60%.

More importantly it appears that the duration of response is greater. Now this is just a single-arm trial, and we’re doing cross-trial comparisons, and these are small numbers. But the duration of response was only around 6 to 7 months in the OlympiAD trial. We really need to get responses much longer than that to have durable control of this disease. And that’s where the hope for checkpoint inhibitors and immunologic stimulation against the cancer comes into play. It was over 9 months with the combination, and this was in the patients receiving treatment in the first or second line.

So for the PARP inhibitors and the checkpoint inhibitors, as you get into later lines of therapy in metastatic breast cancer, the effectiveness really falls off. So we’re clearly going to want to use them in early-line, hopefully in first-line, therapy. That would be the hope, once we have more data, that olaparib plus a checkpoint inhibitor will be used in the first line for germline BRCA metastatic breast cancer patients. So the MEDIOLA trial is the first step in showing safety and the promise of greater activity with the combination than with either one alone.

Transcript Edited for Clarity