DR CAREY: In spite of the pendulum swinging around PARP inhibition — which, in truth, was driven by the iniparib negative Phase III and the finding that, in fact, it was not a true PARP inhibitor. It set everyone back because it was clearly the dominant drug for a long time. I think we’re back in a sort of reasonable phase of discovery here.
There have been several trials that suggest that in known mutation carriers — BRCA1 or BRCA2 — that true PARP inhibitors actually do have an effect and they have activity as single agents. The question of combinations has been out there for a long time and is being looked at, and that’s the subject of the randomized Phase II that was presented as a trial in progress.
This built on a couple of trials. One was a Phase I combining veliparib, which is a PARP inhibitor, with temozolomide, a DNA-damaging agent. Preclinical synergy. A metastatic breast cancer trial in unselected breast cancer was presented a couple of years ago, where all of the activity that they saw was in those patients that had BRCA mutations. Similarly, there was a Phase I study combining veliparib with carboplatin and paclitaxel. Again, with the platinum drugs, there’s preclinical synergy. That was also moving down the pike, so we’re seeing some activity in the early Phase I and expansion-phase trials.
This is now basically the proof of principle of a combination strategy with veliparib and chemo, a randomized Phase II. There’s 3 arms to it. It’s the temozolomide combination. There’s the carboplatin/paclitaxel combination. And then there’s a placebo arm with carboplatin/paclitaxel. It’s actually a reasonably large study in a narrow population — it’s first/second line, BRCA1 and 2 mutation carriers only. For that reason, it’s multinational. It takes a village to accrue to a study like this.
DR LOVE: Edith, where is the clinical research community right now in terms of PARP inhibitors — enthusiasm, caution?
DR PEREZ: The enthusiasm has diminished over the last few years, even with the understanding that iniparib is not truly a PARP inhibitor. It is amazing what’s happening. One of the reasons for that might be that these agents are being looked at not only in the BRCA1/BRCA2 mutation population, but they’re being looked at in all subtypes of breast cancer, trying to search for a particular population that may benefit. I think there’s interest, and we are really very supportive of the ongoing trials.