Treating gBRCA1/2-Mutated HR+ Breast Cancer


Joyce A. O’Shaughnessy, MD: We talk about hormone receptor—positive, triple-negative, and HER2-amplified disease. Maybe we have a fourth subset of breast cancer now—the BRCA1/2 mutation, germline mutation carriers. Let’s talk about them in terms of the metastatic setting. We’re talking about the ER—positive patients with a germline BRCA mutation. How do you think about their therapy, Debu?

Debu Tripathy, MD: Well, we tend to think of BRCA mutation carriers as having triple-negative breast cancer. But if you look at all of the BRCA1 and BRCA2 patients who present with and have been enrolled on the 2 trials that have been reported with PARP inhibitors—the OlympiAD trial with olaparib and the talazoparib trial)—45% of the patients had HR-positive breast cancer. They did benefit from the addition of a PARP inhibitor. It was not as dramatic, but there was a benefit. They were required to have had at least 1 endocrine therapy to be eligible. So, I do think it is a viable option. It may even be a reasonable option before you use chemotherapy in these patients. Unfortunately, there may be many mechanisms of resistance to PARP inhibitors, and they tend to emerge more quickly than what we’re seeing with the CDK inhibitors. But nevertheless, I think it is an important part of our armamentarium. It does speak to the need for us to genotype our patients more frequently than we used to, because now it has implications on therapy.

Sara A. Hurvitz, MD: It’s interesting. In the OlympiAD study, the objective response rate was quite high. It was very similar for HR-positive versus negative disease. But, as you said, the hazard ratio didn’t look as good for HR-positive disease. On the other hand, in the EMBRACA study, which was a very similarly designed study with very similar outcomes, the hormone receptor status didn’t appear to impact benefit from the use of a PARP inhibitor versus chemotherapy. So, the data have been kind of inconsistent, and I’m wondering if it has to do with whether or not the patient is carrying a BRCA1 or BRCA2 mutation, which goes back to Hope’s point of, is it more of a luminal-behaving cancer—which many BRCA2 mutation carriers have—or basal? We’ve all seen very, very basal-like ER-positive breast cancers in our BRCA1 mutation carriers. An analysis incorporating the BRCA subtype or the intrinsic subtype of the tumor hasn’t been done yet, and I think this would be very interesting. If a patient has an ER-positive breast cancer in the frontline setting and they carry a BRCA2 mutation, I’m going to be inclined to use frontline endocrine therapy with a CDK4/6 inhibitor, as opposed to going straight to the PARP inhibitor.

Debu Tripathy, MD: Yes, absolutely.

Hope S. Rugo, MD: It’s an interesting question, because people tend to use the PARP inhibitors much earlier on, and there are some emerging data that suggest that the earlier you get the treatment, the longer it may take to develop resistance. I think our frustration with PARP inhibitors is that the response rates are more than doubled. It looks great, but it doesn’t last long. So, the progression-free survival, although longer, is not as long as we’d like it to be in those patients with such rapid responses. It may be that giving the treatment earlier, which we’ll presumably find out based on the OlympiA study, will be better off. A lot of people have been thinking that if you have metastatic ER-positive disease that is associated with a BRCA mutation, you could use endocrine therapy plus a PARP inhibitor—without any data in the first-line setting—and give your CDK4/6 inhibitor in the second-line setting. You’re giving something that’s more targeted to the biology of the tumor.

Komal Jhaveri, MD, FACP: I would actually think about using CDK4/6 inhibitors the way that we do. We think about chemotherapy and perhaps utilize this benefit of the rapid response rate that we see and use them before we use the chemotherapy. The overall survival data were updated at AACR…

Joyce A. O’Shaughnessy, MD: Right.

Komal Jhaveri, MD, FACP: From the OlympiA trial with 64% maturity, and there was no overall survival benefit for the overall population. But interestingly, the patients who had used a first-line PARP inhibitor had a longer overall survival benefit, as compared with those treated with the physician-choice chemotherapy.

Joyce A. O’Shaughnessy, MD: That was great, yes.

Hope S. Rugo, MD: So far, we don’t have survival data on CDK4/6 inhibitors. We know they work great in the second-line setting, so why not give the PARP first? I have to admit that I have a couple of patients on first-line…

Joyce A. O’Shaughnessy, MD: First-line, ER-positive…

Debu Tripathy, MD: There are probably mechanisms of resistance that overlap with chemotherapy and the PARP inhibitors. Talazoparib is a different drug. The PARP trapping is much stronger. It has more side effects, as well. I certainly would agree with everything that’s been said here—for endocrine therapy, we should initially be using the CDK inhibitors. You get the biggest bang for your buck—the longest extension in progression-free survival.

Joyce A. O’Shaughnessy, MD: Well, thank you. I think we all think very alike on all of the things that we’ve talked about, as a matter of fact. Thank you very much for a really great, great discussion. I think we really hit the high points from this year’s ASCO Annual Meeting.

Transcript Edited for Clarity

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