The MEDIOLA study is a phase II trial investigating the use of olaparib, which is a PARP inhibitor, in combination with durvalumab, a PD-L1 inhibitor, in BRCA1 and 2 mutation carriers with metastatic breast cancer. The rationale behind this is that we know that there are high response rates to olaparib in BRCA1 and 2 breast cancer, the OlympiAD trial showed a 60% response rate. The hope is that the addition of an immune checkpoint inhibitor would potentially expand those durations of response and lead to improved progression free or overall survival.
This was an initial phase II trial to just see about the safety and potential efficacy of the combination. It’s a relatively small trial with 34 patients. The response rate was 63% but there were some encouraging signals in terms of duration of response, that is once you have a response that it’s possible that it could be prolonged in combination with durvalumab. The study is really too small to give any exact clues about this but we saw that response rates, for instance, were higher in patients who had had either no or just one first line therapy with a response rate of 70%. Similarly, there was an improvement in duration of response and progression free survival in earlier lines of therapy as well.
The hope is that we can obtain more data and start to narrow this down. Again, this was a heterogeneous population, it allowed for more lines of therapy. We also don’t know the best biomarkers. So an initial analysis wasn’t clear that there was a particular biomarker that would predict response to the combination but, again, a small study so we still have work to do.
The nice part about breast cancer is that we have two PARP inhibitors, both olaparib and talazoparib that are active in metastatic BRCA1 and 2 breast cancer. There’s a lot of work in this field, first of all to see whether you can expand the group of breast cancer patients for whom these drugs would be indicated , whether or not that’s mutations of other homologous recombination repair pathway genes or whether or not there’s HRD analogues in breast cancer like there are in ovarian cancer. By the way, it’s not clear that they’re completely interchangeable so we really have work to do there. So that’s one clear area.
There’s a lot of interest, also, then in BRCA1 and 2 mutation breast cancers. Although these drugs are terrific and in both studies showed improvement in quality of life compared to standard chemotherapy, the progression free survival is not as long as we’d like, resistance mechanisms developed. So we have to understand the resistance mechanisms and try to overcome them. There’s a lot of work with combinations, so this is one example – a combination of a PARP inhibitor with immunotherapy – but there are a lot of other combinations that are being studied to see whether we can do better with what we’ve got right now.