Chapters Transcript Video ESMO25 Breast Cancer Highlights: evERA and SERENA6 Harold Burstein, MD, PhD, and Erica Mayer, MD, MPH, discuss the evERA and SERENA6 trials investigating oral selective estrogen receptor degraders (SERDs). One of the highlights at ESO 2025 in breast cancer were updates on oral surs, a class of drugs that we're seeing more and more clinical trials and FDA approvals for, uh, so speaking with Erica Mayer, our director of research in the breast cancer program who. was a leader of a couple of these trials that we'll be speaking about. Erica, let's talk about the Avera trial first, this was a study of girogeant, a new oral surge in combination with Evaolimus. Tell me a little bit about the development of that trial. Yeah, so the, for the vast majority of our patients with metastatic HR positive, HER2 negative breast cancer, we are typically offering endocrine therapy with a CDK46 inhibitor, which, you know, I think we're very grateful it's very effective for people for, for quite some time. However, eventually cancer will progress and increasingly we understand the mechanisms of resistance that underlie that progression. And so, uh, oral serts are a new category of endocrine therapies designed to in particular help overcome some of those aspects of resistance. So, uh the Avera study was designed to think about the post CDK46 phase in a very contemporary way because we often are using a combination regimen such as endocrine therapy and aymus in post CDK46 patients. And so wanted to study whether improving the endocrine backbone would be effective in the setting. So it's a Modern drug with an old drug, right? Eolimus, a drug that predated all the molecular testing. We don't really know its activities in PIC 3CA selected or not or other subtypes of breast cancer. Is that actually a drug you use regularly? I, I do use it and you know, in this era, we have our PF 3 kinase inhibitors or AKT inhibitors for that actual mutation, and we have oral er monotherapy for ESR1 mutation, but MLMus is approved for all patients, and it is quite effective in combination. With endocrine therapy, the tricky thing with Eymus is that it's very important to use prophylactic steroid mouthwash to help prevent stomatitis. So what's the regimen you use to do that? So we use a dexamethasone mouthwash, as was studied in the Swish study, which was published several years ago by our colleague Hoperugo, and a patient uses it 4 times a day, usually for the first couple of months of treatment and then tapers as needed. Now the original study with Everol is actually never showed an overall survival benefit. Was that something that you guys were concerned about in developing this trial? I think Erolimus-based regimens are very much a standard of care in our practice and are used around the world. And so we wanted to use a modern regimen that we're all comfortable using. So here's the schema for the trial. It's irostrin with Evarolimus versus the standard of care, either an aromatase inhibitor or fulvestrid. Almost all the patients that essentially had an AI before. Is that correct in this trial? So the patients could have up to 2 prior lines of endocrine therapy, but importantly, 100% of patients had prior CDK46 inhibitor, which is a little. Different than some of the other oral search studies, and none of the patients had had prior chemotherapy in the metastatic setting. So many of them would have had, probably all of them would have had an AI. Half, I think, would have previously had full vetrine if I looked at the 47%, 47%, we'll call that half, and the randomization was 1 to 1. So what we learned from this trial? What's the top line takeaway here? So the trial was designed with two primary endpoints progression free survival in the ITT population and progression free survival in the ESR-1. mutated population. Importantly, the trial was designed to enrich for ESR1 mutant disease. So 55% of patients had cancers that had an ESR-1 mutation at baseline. The trial met both of the primary endpoints, in particular, in the ESR1 mutant population, patients who received geridesttrin and everolimus had a substantial and statistically significant prolongation and progression-free survival to almost 10 months compared to about 5.5 months in the control arm. Um, this was a 64% improvement in progression free survival. The ITT population was also positive with a significant improvement in PFS. It was about 8.7 months versus the 5.5 in the standard of care arm, so overall a positive trial. And did it work in the ESR Wild type group? It's a great question. Um, the subpopulation of ESR-1, what we would say no mutation detected, was looked at in an exploratory analysis, so the trial wasn't powered to look at that smaller group. There was no, no difference between the arms in progression free survival, although the hazard ratio at 0.8 was trending in the right direction. Importantly though, um, for some of the key secondary endpoints including response rate, duration of response. And overall survival, which does remain immature, um, the patients in that no mutation directed detected group had an improved response rate, duration of response, and a favorable separation of the curves for overall survival. Interesting. I want to switch gears and talk about a previous study you've been involved with Serena 6. So Serena 6 had a novel design here which was taking patients who were on a CDK46 inhibitor and an aromatase inhibitor and taking them for. Serial testing if they acquired an ESR1 mutation but did not have clinical progression at that time, they were randomized to switch to Cambaran to different oral cert or simply continue the ongoing AI and CDK 46 inhibitor. So the top line results from that study, which had previously been shown, suggested there was an improvement in the near term progression free survival by switching to Camusesttri. You gave an update that looked at quality of life in that study. What did you find? Yeah, so, um, Serena 6 has this very interesting design, not only the kind of step 2, which has the oral ser, but importantly the step 1, which is the serial CTDNA testing. Um, when the Serena 6 trial was originally presented, which was, um, ASCO 2025 plenary, in addition to the positive result for progression free survival, there was a substantial delay in deterioration of global health status and quality of life. So, uh, a linkage between patients um who made that switch, having a prolonged progression free survival and also a protection from deterioration in quality of life. So what we presented was really digging into the quality of life data to understand it more deeply. Now, the quality of life um type of data that was collected included patient symptoms, as well as what's called functioning. So how the patient is functioning and how they're kind of feeling about everything. And what was very interesting was that for the, both the patients symptoms and for the functioning, there was similarly a delay and deterioration. And this was for some very clinically relevant symptoms, including pain, fatigue, and shortness of breath. And the curves separate very early and Stay separated, which one could interpret as saying that making that early switch at the time of this detection of the resistance mutation may be preventing symptoms related to subclinical progression of disease. Obviously an important thing for patients. So I put together this chart here. There are by my count at least 5 urs that have reached phase 2 or phase 3 randomized trials, and if you look at them all, they've been compared in various contexts. Most have been in the setting of prior CDK46 inhibition. In broad strokes, the benefit is almost exclusively seen as compared to standard of care in tumors with ESR1 mutations as opposed to mutations not detected or wild type groups. Looking at that, do you think this is a class of drugs where there's going to be substantial differences between these products? How are clinicians and patients going to be thinking about these drugs in the months to come? Yeah, isn't this a lucky time that we live in to have so many exciting new medicines? So, um, yeah, there's been quite a consistent signal in the oral er monotherapy studies that the greatest benefit seems to be seen in cancers that have developed an ESR-1 mutation, and that really lies the guidance for clinicians that we need to check for these mutations not only at the time of detection of metastatic disease, when honestly the rate of detection is low, but more importantly, at times of future progression because the chance of catching the mutation goes up and up with longer exposure to endocrine therapy. Um, but I think what we're seeing from the combination studies is not only, uh, substantially improved progression-free survival when we use a novel oral cert with a, um, combination partner, as we've seen in Avera, as we've seen in MBE 3, and perhaps one could include Serena 6 in that. Um, but also, uh, we might be seeing that when we add these two drugs together, this may overcome a little bit of this, um, uh, exclusion to the ESR-1 mutant population. And we did see data from MBRR 3 earlier this year, um, in which the combination of mlunstrin and Abemacycllib compared to imlunestric monotherapy was significantly more active in both the ESR1 mutant. And the no mutation detected populations. So I think we need more data and study, you know, and granted, none of these combinations are currently FDA approved, but the data is very strong and very interesting. We also are awaiting data from first line studies that are using the oral certs as the first line agent in combination with CDK46 inhibitor. Well, it's, uh, I guess it is a lucky time in the sense there's a lot of these drugs. I, I, I worry that It's gonna be very hard to ever figure out you know how they compare against one another and simply to do an endless series of comparisons between sort of, you know, one phase 3 trial and another phase 3 trial is probably not the most productive academic exercise. So thanks so much. This is exciting. These drugs are coming forward and I think your point about thinking about the monotherapy versus combination therapy differently is going to be a really important one. Thanks for having me. Published November 21, 2025 Created by Related Presenters Erica Mayer, MD, MPH Institute PhysicianAssistant Professor of Medicine, Harvard Medical School Dr. Mayer is a medical oncologist and clinical investigator in the Breast Oncology Center. View full profile
