番茄社区

At the San Antonio Breast Cancer Symposium (SABCS), researchers presented findings from two phase III trials -- EMERALD and -- that may help oncologists identify which metastatic breast cancer patients will benefit most from treatment with selective estrogen receptor degraders (SERDs).

The EMERALD trial showed that the oral SERD elacestrant improved outcomes compared with standard of care in previously treated estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer, while the PADA-1 trial explored the effect of switching treatment to include a SERD -- fulvestrant (Faslodex) -- once an ESR1 mutation was detected in circulating tumor DNA (ctDNA).

番茄社区 has brought together three expert leaders in their field -- moderator , of UT Health San Antonio, , of the University of Rochester Medical Center in New York, and , of Northwestern University Feinberg School of Medicine in Chicago -- for a virtual roundtable discussion on these two studies and other practice-changing data from the meeting. This is the second of four exclusive episodes.

Following is a transcript of their remarks:

Kaklamani: Hello. My name is Virginia Kaklamani, professor of medicine at UT Health San Antonio, MD Anderson Cancer Center, and leader of the breast cancer program. Today I have with me two esteemed colleagues: Dr. Ruth O'Regan, who is chair of medicine at the University of Rochester; and Dr. William Gradishar, who is the chief of the division of medical oncology at the Northwestern University. We're going to be talking about the San Antonio Breast Cancer Symposium 2021 highlights and themes.

So let's move on to a couple of presentations on endocrine therapy and endocrine resistance. And that is the EMERALD trial that was presented at SABCS, but also the PADA-1 trial that was presented. Dr. O'Regan, would you like to give us your thoughts on these two clinical trials?

O'Regan: Sure thing. So the EMERALD trial, obviously we've been very excited waiting for some data with the oral SERDs, apart from the phase I data that we've had so far. The EMERALD study is the first randomized study looking at an oral SERD. It randomized patients with ESR1-positive metastatic breast cancer who had received prior treatments. So they were reasonably heavily pretreated, and they were randomized to the oral SERD elacestrant, or to single-agent endocrine therapy, which was investigator's choice. So either an aromatase inhibitor or fulvestrant.

And what it showed was that there was approximately a doubling in progression-free survival with the oral SERD compared to the single-agent endocrine therapy. I think it was like a month and a half up to 3 months -- and that was statistically significant; no survival data as yet. The oral SERD was associated with a little bit more GI toxicities than the other endocrine agents that they used.

I think my take on this is certainly ... and I actually should mention as well that if you compare to fulvestrant, the oral surge was better in terms of progression-free survival. So I think this is encouraging. It was a positive trial.

However, what it really brought home to me was how poorly these patients do, because the progression-free survival was 3 months in both arms. And I do think that these agents probably will move into their first-line setting pretty quickly with the CDK inhibitor, because the early phase data with these agents is better when you give them a combination of CDK inhibitor.

So I think maybe a little bit disappointing, but I think there certainly is utility of these agents because they are oral. And also unlike fulvestrant, they'll maintain the ER suppression much more continuously than we do with fulvestrant by giving it like once every 4 weeks.

So the PADA-1 study was actually really quite interesting. This was a study in which patients were receiving first-line aromatase inhibitor [AI] with CDK inhibitor treatment. And what they did was they monitored ctDNA looking specifically for ESR1 mutations at 1 month and then every 2 months.

And what they did, was in patients who developed ESR1 mutations on the ctDNA, they then scanned them. And if they did not have evidence of disease progression on the scan, they randomized to either continue the aromatase inhibitor with the CDK inhibitor, so standard of care, or to switch to fulvestrant with continuing the CDK inhibitor, which was palbociclib.

And what they found was that there was a doubling in progression-free survival [PFS] in the patients that they switched to fulvestrant. So it was 12 months or 6 months if you continued the aromatase inhibitor. And they also were able to compare that with patients that had disease progression and then switched to fulvestrant at that point with CDK inhibitor, and those patients had a shorter PFS in the patients that they changed based on ctDNA. So I actually thought that was quite interesting.

You know, I think the jury's a little bit out on whether the ESR1 mutations are just representative of resistance to all endocrine therapy versus just the aromatase inhibitors -- some conflicting data there.

And I should also mention that with the EMERALD study, the second primary endpoint was patients who had ESR1 mutations. And in that group, the benefit of the oral SERD actually appeared to be a little bit greater in terms of its benefit and progression-free survival than the group overall.

So I think very interesting data and obviously the question would be with the data from the EMERALD study, should we be checking ctDNA looking for ESR1 mutations and then if that drug does get approved, would you switch to that drug rather than fulvestrant? So I think very interesting studies.

Kaklamani: So we typically do genomic profiling because we're going to be looking for PIK3CA mutations. And I personally do it in my first-line settings. And when you do the genomic profile, you actually get ESR1 mutation status or not.

So, Dr. Gradishar, if you have a patient who in that first-line setting, you do that genomic profiling, they have an ESR1 mutation, do you tend to switch the patient from the AI [aromatase inhibitor] to fulvestrant or do you continue them with the AI?

Gradishar: No. You know, keep in mind that most of these patients are getting a CDK4/6 inhibitor in the first-line setting. And older data would suggest that if they had an ESR1 mutation, as long as a CDK4/6 inhibitor was on board, you basically offset the effect of that ESR1 mutation.

So if it was a monotherapy issue, perhaps I would do it, but since patients are getting a CDK4/6 inhibitor, I would not likely do it.

Kaklamani: And obviously the PADA-1 trial is potentially helping us in doing sequential ctDNA testing in these patients and maybe changing our therapy. Obviously, I don't think this is ready for prime time, but it might be something that we'll be eventually doing.

Gradishar: Yeah, and I think one other thing I wanted to say about that experience is that one of the big issues, of course, is do we change the big picture, the ultimate endpoint with these strategies?

So you're basically looking at a more granular level, are patients developing mutations, and should you switch, but does the switching ultimately end in better overall survival? And we don't know that yet. So I think we're all advocates of precision medicine, but do all these hoops we're jumping through actually improve the outcome of patients and that's yet to be determined.

Kaklamani: And to your point, I think these trials, if we move forward to larger trials, the primary endpoint should be overall survival, not just progression-free survival.

O'Regan: Yeah, I agree with that. I think that's very important point.

Watch Episode One of the roundtable: Latest on Immunotherapy in Triple-Negative Breast Cancer

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