The BROCADE-3 study is a phase III study. It’s looking at the combination of veliparib, which is a PARP inhibitor, in combination with carboplatin and paclitaxel versus placebo and the chemotherapy in patients with germline BRCA mutation positive breast cancers in the advanced setting. So this was a phase III trial and the idea was that patients were to receive the combination until progression but in patients in the veliparib arm they could receive veliparib monotherapy after they couldn’t tolerate the chemotherapy anymore. So they could stop the chemo and continue on with the veliparib, which is the PAPR inhibitor, as a single agent. That’s different to the control arm because they continued on placebo.

The population was largely an untreated first line population. When we think about BRCA carriers we want to know how much prior platinum exposure they’ve had. These patients had less than 10% prior platinum exposure so that’s very different to some of the studies with PARP inhibitors.

The trial was positive, it met its primary endpoint in that the progression free survival was improved with the addition of veliparib. Interestingly, both arms received on average around eleven cycles of carboplatin and paclitaxel so the veliparib didn’t seem to add any excessive toxicity to the combination. But when you look at the survival curves it does look like the curves are roughly overlapping for those eleven cycles with equivalent response rates for both arms. The effect does seem to be after when the chemo stops. So the separation at two and three years is very much in favour of the veliparib monotherapy for the patients that just continued that compared to patients who were on placebo.
So it’s unclear to me if the effect of this treatment is due to the veliparib combination in chemotherapy up front and/or the continuation of the veliparib monotherapy. Certainly the data in ovarian suggests that the maintenance PARP inhibitor is important and certainly you’re selecting out the patients that are still responding to treatment and continuing them on active treatment therapy which was unlike the placebo control arm.

So there are a lot of adverse events, obviously, with the chemotherapy combination which is important for patients who are in the incurable setting. There has not been any formal patient reported outcomes presented so that will be important for understanding the data because, obviously, the current ESMO guidelines suggest that we should be treating patients sequentially for better quality of life. If you look at the other data with the PARP inhibitors, so olaparib and talazoparib are approved as monotherapy, it certainly seems that their response rates are quite high as single agents and they do have less toxicity as compared with chemotherapy. But it’s unclear how we should sequence chemotherapy and PARP inhibitors – which you should do first or second.

So it looks very good, the combination. The overall survival as yet is not yet significant but there are obviously issues with giving patients an intensive chemotherapy regimen up front. So we need to wait for overall survival data, that’s my impression. I think the most important trial for these patients is looking at perhaps the BROCADE arm, maybe a PARP inhibitor up front or/and perhaps looking at an ovarian strategy which is CarboTaxol followed by maintenance PARP. So just to try and understand what’s best for these patients.