We continue to make tremendous progress in the field of breast cancer research and developing more personalized strategies for systemic therapy. With expanded use of novel targeted and immune-oncology agents, the landscape of therapy for advanced breast cancer is changing. However, several questions remain unanswered as to which approach will be optimal for given patients.

In this OncLive® Peer Exchange discussion, I am joined by my panel of colleagues. Together, we will look at the newest data, including those from the San Antonio Breast Cancer Symposium 2019, the annual meeting, that will shed light on therapies for advanced breast cancer, how they are evolving, and the implications for clinical practice.

I am Dr Debu Tripathy, professor and chair of the department of breast medical oncology at The University of Texas MD Anderson Cancer Center in Houston, Texas.

Participating today on our distinguished panel are:

Dr Adam Brufsky, professor of medicine and associate chief of hematology/oncology at the University of Pittsburgh School of Medicine and co-director of the Comprehensive Breast Cancer Center in Pittsburgh, Pennsylvania;

Dr Ian Krop, associate chief of the division of breast oncology, at the Susan F. Smith Center for Women's Cancers and associate professor of medicine at Harvard Medical School in Boston, Massachusetts;

Dr Joyce A. O’Shaughnessy, chair of cancer research at Baylor Charles A. Sammons Cancer Center, Texas Oncology, and The US Oncology Network in Dallas, Texas;

And Dr Hope Rugo, professor of medicine and director of breast cancer oncology and clinical trials education at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center in San Francisco, California.

Thank you so much for joining us. Let’s begin.

I want to start off with a discussion on hormone receptor-positive breast cancer. The landscape for advanced disease has changed rapidly there with CDK [cyclin-dependent kinase] inhibitors now being commonly used in first-line and second-line therapy. We’ve recently seen data showing that there’s actually a survival benefit. The next generation of questions to ask include things like who will respond best. Another important question is, should there be patients who receive chemotherapy initially? We know that to receive a chemotherapy may influence outcomes to subsequent CDK based therapies, but it’s critical to look at if there are patients who should start off with cytotoxic treatment.

To that question, Hope, I would like you to discuss some of the key findings that emerged from San Antonio in December.

Hope S. Rugo, MD: One big question, as you mentioned, is regarding effective chemotherapy in metastatic disease and then your subsequent response to endocrine therapy. Certainly in some places in the world and some physicians have thought that starting with chemotherapy might be better because you would debulk the disease.

But with the advent of CDK4/6 inhibitors we have a relatively less toxic combination therapy with these dramatic survival benefits that we’ve seen in 2 different major meetings in 2019. One of the questions that came up, and actually these studies of course started before we knew anything about the survival benefit, was whether you would be better to be treated with an endocrine therapy plus a CDK4/6 inhibitor, or chemotherapy, in the metastatic setting.

At ASCO [the American Society of Clinical Oncology annual meeting] last year we saw data from Young-PEARL, which was a premenopausal investigator-initiated study in Korea, very well done. The study took patients who had a little bit of chemotherapy, tamoxifen before, and were premenopausal. They went on ovarian suppression and aromatase inhibitor and then palbociclib, so triplet therapy, versus getting capecitabine. What this relatively small study showed was that patients actually did better on the triplet therapy with palbociclib, the aromatase inhibitor, and ovarian suppression, and actually subsequently they showed that there was better quality of life in those patients as well.

These were encouraging data. Then we saw the much larger PEARL study through GEICAM in Spain, where they randomized patients who’d actually relapsed within a year of adjuvant aromatase inhibitor therapy, or within a month of receiving it last in the metastatic setting. They could have had prior chemotherapy. Actually, about three quarters of those patients had received chemotherapy and several lines of treatment. So, they’re very heavily pretreated. Then those patients were randomized to receive first exemestane and palbociclib versus capecitabine. About halfway through the trial, they got impressed with the ESR1 mutation data, and they randomized people to receive fulvestrant and palbociclib versus capecitabine.

What’s interesting in this group of patients is they showed absolutely no difference in terms of outcome between the 2 arms. Their hypothesis was that if you had hormone receptor-positive disease, you do better on the CDK4/6 inhibitor combination.

But in looking at those data it’s actually very interesting. The patients who received capecitabine had a median PFS [progression-free survival] of 10 months, which in pretreated metastatic disease doesn’t match any other trial. For some reason people did really well on capecitabine. The interesting thing is the patients treated with fulvestrant treated and patients treated with exemestane did about the same. It didn’t really matter whether they were ESR1 wild type or not. It’s an interesting analysis, doesn’t really fit into our pre-ideas. But it does fit somewhat nicely into PALOMA-3, where patients who had prior chemotherapy, which was about a third of those patients, had a much shorter progression-free survival on fulvestrant alone. In fact, in PEARL, the PFS in these heavily treated patients was better on fulvestrant than it was on PALOMA-3. But again, you’re getting into small numbers.

But it’s interesting. It’s half that as if you don’t get chemotherapy. My take-home from these is that CDK4/6 inhibitor and an aromatase inhibitor, or fulvestrant, is really good treatment. We should do it before chemotherapy, and there’s no clear benefit for doing chemotherapy first.

Joyce A. O’Shaughnessy, MD: Yes. I think we’ve had a couple of trials now that really have been quite convincing in that regard. Even in the preoperative setting head-to-head with chemotherapy and CDK4/6 inhibitor and endocrine therapy, no difference in clinical CR [complete response], path [pathologic] CRs are very low. It was looking if anything that the CDK4/6 inhibitors in Young-PEARL were superior, but at least as good. I think it’s very convincing data that we can really back away from chemotherapy in the frontline setting, unless somebody has true visceral crisis.

Transcript Edited for Clarity