DR LOVE: So another case that was presented got into a different issue that you actually spoke about at the meeting. This is a 72-year-old lady with diffuse metastatic disease, has received multiple treatment therapies for an ER-positive, HER2-negative disease. And the patient has a BRCA2 germline mutation. And the question that the doc had as she’s starting to run out of options for this woman in the metastatic disease is, what about a PARP inhibitor? So far there’s one available, obviously, olaparib in ovarian cancer. But what about a PARP inhibitor, particularly in patients with BRCA germline mutations with breast cancer?

And when we asked the audience in general, do they entertain that possibility or actually do it, actually about half of the audience said that they either have or would for the right patient. The other half wouldn’t. What’s your take on where we are right now with PARP inhibitors? And for practical purposes, have you utilized, for example, olaparib in a patient with breast cancer?

DR O’SHAUGHNESSY: Yes, I have. I do try to get it. And I look at prior platinum treatment, Neil, exposure or potentially refractoriness, not so much an issue in the ER-positive, HER2-negative metastatic patient. Chances are reasonable that she hasn’t had carboplatin, for example. And if she hadn’t, and even though she was heavily pretreated, if she still had a good performance status, good end organ function, et cetera, I would try to get olaparib approved by her insurance company for her. If I couldn’t, I would reach out to AstraZeneca and see if they might provide it through a single-patient IND for the patient, et cetera.

So I do think it’s quite reasonable based on the data. All of the single-agent PARP inhibitor trials in BRCA germline — 1 or 2 germline mutations all show a robust level of response that really support it going forward into the Phase III trials that are either finished accrual or very close to finishing accrual. All of the PARP inhibitors are into randomized trials of PARP inhibitor versus chemotherapy of physician’s choice. So all of the level of activity was good enough to support those Phase III. So yes, I think for these patients, I think it’s a very reasonable option. It’s going to be great, of course, once we have 1 or 2 of them approved for breast cancer.

DR LOVE: Just to clarify, though, have you yourself observed clinically useful objective responses to, say, olaparib in breast cancer?

DR O’SHAUGHNESSY: I have not myself had anyone respond yet. Truthfully, in my practice, though, Neil, I’ve only utilized it in triple-negative BRCA1. And they’ve all had platinum. It was later line. That’s been my experience so far. But I think if you look at the totality of the data, however, and in talking to other folks, I have heard some of my colleagues talk about some very nice responses in that setting. So I feel that it’s just been a matter of my limited experience so far with it and the fact that it’s just been the patient selection.

DR LOVE: We were talking at the meeting that this paper had just been presented at the ESMO meeting looking at a different PARP inhibitor in ovarian cancer, niraparib.

But the amazing thing about that — I’m curious what your thoughts are with your background in this area. The thing that was amazing to me about that was they used it in this postchemo maintenance setting. But they saw benefit not just in BRCA germline patients, but — not just in patients with increased HR, based on the — that’s homologous recombinant deficiency. But then the wild type in the non-HR, they saw, like, a hazard rate of, like, 50%. We were talking at the meeting about the biology of ovarian cancer as opposed to breast cancer. Any kind of comments about that?

DR O’SHAUGHNESSY: Yes. In the TCGA, Cancer Genome Atlas, complete genomic evaluation of ovarian cancer and triple-negative breast cancer, there was a lot of similarity in terms of the buckets of these mutations that are found somatically in these cancers, in triple-negative and ovarian cancer. And in the niraparib trial in ovarian cancer, Neil, the patients received carboplatin/paclitaxel and, once they had benefited, the chemotherapy was stopped and then they were randomized.

And so as you said, it was a maintenance trial versus not, essentially. Now, we’ve seen that as well, Neil, in breast cancer, that if you continue therapy, for example, chemotherapy, we have the recent Korean trial. That was a paclitaxel/gemcitabine. You got an induction therapy, 6 cycles. Then the patients were randomized to continue the chemotherapy versus not. There was a big progression-free survival and even a survival advantage in that trial. So the PARP inhibitors put the same kind of stress, a similar type of stress, Neil, on DNA repair, as does platinum. They’re not dissimilar.

One of the themes that I think is coming up as a hypothesis is that could the PARP inhibitor agents at the end of the day be a kinder, gentler platinum and something that would be more amenable to maintenance therapy, which the platinum-based agents are not over time because of cumulative toxicity? And so I actually think of the PARP inhibitors in that regard.

So just as we’ve seen in metastatic breast cancer, maintenance therapy can really substantially improve progression-free and sometimes even, to some extent, overall survival. I guess I’m not too surprised at the ovarian cancer results and not even in the wild type, Neil, as you point out, even those without homologous recombination deficiency. Our assays still for that, Neil, still are not perfect. There may be more DNA repair problems going on there that are necessarily manifest in the HRD assays we have so far. They’re good, but they may not be complete yet. So the benefit from platinum can probably come through numerous DNA repair pathway deficiencies.

DR LOVE: And it’s so fascinating. I’ve already interviewed a bunch of ovarian cancer investigators. And nobody brought up what you just said, which I think is fascinating. So you’re saying that maybe it was the platinum chemo that preceded the PARP inhibitor that set the cells up for it?

DR O'SHAUGHNESSY: No. No, no. It’s just that in those patients who did well with the platinum, and then they’re getting randomized to stop it or not, gee, why stop it? Why not give them a PARP inhibitor that has similar effectiveness to platinum-based agents in terms of leading to inability — the platinums cause single-strand breaks. And those are converted on cell division to double-strand breaks. And many ovarian cancers and triple-negative breast cancers have intrinsic inability to repair well those double-strand breaks.

And the PARP inhibitors basically stop that DNA repair, single-strand break repair. But the PARP inhibitors as well can interfere with homologous recombination itself. But they basically inhibit a leg of the DNA repair mechanisms. And these cancers, they can’t be cancers unless they have DNA repair deficiency. So they already have a problem. And when you come in with platinum, you are putting a lot of stress on the base excision repair pathway, and you overwhelm it. You overwhelm it with platinum. And with the PARP inhibitors, you inhibit base excision repair and homologous recombination, to some extent, and other pathways as well.

And so it’s just knocking out another leg of the stool on your DNA repair is kind of how I simply look at it, Neil. And platinum stresses it to the point where it can’t do it anymore. So they’re not exactly the same, but they’re similar in terms of the functional output, I think. That is the way I look at it. And so it’s just a question of keeping that pressure on the cancer versus stopping. And the hope might be that some of those might go into just permanent senescence, if you can keep that kind of pressure on them indefinitely. Some of them will go into permanent senescence. And we’ve certainly seen that, Neil, with platinum agents in triple-negative breast cancer. There’s a group that will not come back in the first line in particular. They will not come back after platinum-based therapy. So that’s the hope.

Adjuvant and neoadjuvant therapy for HER2-positive breast cancer (BC)

Management of HER2-positive metastatic BC (mBC)

Clinical decision-making for patients with ER-positive early BC

Management of ER-positive, HER2-negative mBC

Indications for BRCA testing in BC and ongoing investigation of PARP inhibition

Treatment of triple-negative BC (TNBC)