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DR MILLER: I think we’re left, still, with a wealth of preclinical data and very well-done science, using both genetic approaches and pharmacologic approaches. So it suggests, at least in patients with known BRCA mutations, they should have significant sensitivity to inhibition of PARP. But we have really little clinical data to know how well that preclinical science translates to the benefit for our patients.

The idea that inhibition of PARP would be helpful therapy has actually predated the identification of BRCA1 and was based on preclinical synergy between genetic approaches of inhibiting PARP in combination with DNA-damaging therapies, whether that was radiation or DNA-damaging chemotherapies. So it was on that basis of synergy that the very first PARP inhibitor was developed.

DR LOVE: So, Ana Maria, what happened? Is this a dead story, or is there any future for this?

DR GONZALEZ-ANGULO: No, I think this is not a dead story. What I think we need to do is to learn who are the patients that are going to benefit from it and, importantly, who are the patients that have BRCA — right now BRCA mutations — we just have to figure out who are the other patients that have tumors that may mirror that kind of DNA liability, if you will. So they already have DNA pathways that are broken, and that by using a PARP inhibitor, we can achieve that synthetic lethality that we achieve with patients that have germline mutations in BRCA.

There are some studies looking into that. There’s a group in the Netherlands that are looking to patients, for example, that underwent high-dose chemotherapy and used DNA-damaging agents, and basically showed that they could mimic, if you will, they came up with a genomic signature that could mimic their molecule profile of BRCA-mutant, if you will, tumor, and those were the patients that benefited from that type of chemotherapy. But I think a lot needs to be done still.

DR LOVE: Dan, you’re a philosopher: When you look back over the last couple of years, this whole PARP story, what are your thoughts about it? This whole idea of BRCAness that made so much sense or so much excitement. One trial gets presented and it seems like now we’ve lost interest.

DR HAYES: I don’t think our enthusiasm should be dampened by the larger, randomized iniparib study. To me, I mean, first of all, maybe that Phase II was a complete false positive, but the separation between the curves was huge. And even in the randomized Phase III the separation still exists. It’s just not as big as what they had hoped to see. To me, the Phase I and Phase II data are quite impressive. The biology is quite impressive. I think we just need to A) keep at it, and B) as Ana Maria just said, be smart about how we do it and try to define BRCAness above and beyond germline BRCA mutations.