In terms of PARP inhibitors for treating metastatic breast cancer we’ve made great advances in the last few years. We have two phase III studies showing an almost doubling or more of response using a PARP inhibitor compared to chemotherapy of physician’s choice in patients who are germline carriers of BRCA1 and 2, leading to the approval of both olaparib and talazoparib. We know that progression free survival is longer, although not quite as long as we’d like to see it, and that quality of life is better maintained with the PARP inhibitors compared to chemotherapy.

We also know that these drugs are generally active only in patients who carry germline mutations but there are a number of different research studies now looking at both somatic acquired mutations in BRCA and also the effectiveness of PARP inhibitors in patients who carry alternative DNA damaging mutations that we see now much more frequently because we do these multigene panels to screen for genetic mutations.

We know that the toxicity includes bone marrow suppression, primarily anaemia and some nausea, but overall the drugs are pretty well tolerated and as we start using the drugs earlier in the course of therapy we hope to see less of the unmanageable toxicities. In general you can get around the toxicities and in community based compassionate use databases in Europe and in other places very few patients discontinued therapy and almost no patient discontinued therapy due to toxicity.

We’ve also seen survival data from the OlympiA trial that looked at olaparib and in that trial there was no survival difference in the overall population but there was a suggestion of a really clinically important survival difference in the first line setting compared to greater lines which goes along with what we know about the acquired mechanisms of resistance to PARP inhibitors. We’re awaiting results from the adjuvant OlympiA trial with olaparib and then we also saw a small study with neoadjuvant talazoparib showing a really remarkable pathological complete response rate from just six months of talazoparib in patients who were germline BRCA1 or 2 carriers.

So overall this suggests that PARP inhibitors have a very important role to play in patients who come in with a germline BRCA associated breast cancer. In metastatic breast cancer they clearly play an important role and we’ll learn more about their role in early stage breast cancer over the next few years. I think that it’s going to probably be an important treatment, my guess is, in patients who don’t have disease that melts away with chemotherapy. So that if you give neoadjuvant therapy in patients who have residual disease the PARP inhibitors may play an important role. Maybe we can select out a group of patients who are treated with PARP inhibitors alone but that remains to be seen.

Then the last avenue of exploration is combining low dose PARP inhibition in triple negative breast cancer with checkpoint inhibitors to try and enhance the immune response. That’s under active investigation both in the metastatic and early stage settings.