Chapters Transcript Video 2026 ASCO Breast Cancer Highlights: persevERA Harold Burstein, MD, PhD, and Erica Mayer, MD, MPH, discuss the persevERA trial and oral SERDS in metastatic breast cancer. I'm Doctor Harold Burstein. Welcome back to our breast cancer breakthroughs. This is a series of programs we've been doing from Dana-Farber, where we've been featuring some of the exciting updates and new data from the ASCO 2026 presentations in breast cancer. Very pleased to be today with Doctor Erica Mayer, who has been involved in many clinical trials and looking at novel surs and other targeted drugs to give us an update on the Persavera study. Tell us about Persavera and what it means. So, thank you so much, Hal, for having me. And I'm excited to talk today about the Persevera study, um, which was presented for the first presentation at ASCO 2026. So, Persevera is a phase 3 clinical trial that evaluates one of the novel oral surges, Gridestrant, in the first line setting. Um, this is a trial that enrolled patients who had not had any prior therapy for metastatic hormone receptor positive HER2 negative breast cancer, and randomized the patients to one of two potential first line options, the oral ser giridestriant in combination with the CDK46 inhibitor palbociclib, or in the control arm, um, letrozole, aromatase inhibitor with palbociclib. This was a randomized double-blind placebo-controlled trial, so both arms of the study also had a placebo. Um, this is the first study that is evaluated in oral cert in the first line setting. All of the other data we have are in pre-treated settings. The primary endpoint of the study was progression-free survival. So in this first report, it was demonstrated that there actually was no significant difference between the arms in terms of the primary endpoint of progression-free survival. In the control arm, which is a standard regimen of AI, letrozole, and palbociclib, the PFS was 28 months. In the experimental arm with gerodestriant and palbociclib, the PFS was 33 months. This led to a hazard ratio of 0.89, which did not meet statistical significance. It's very interesting, however, to look at the data for the PFS curve. Um, as you look at the data, you will find that for the 1st 1 to 1.5 years, the curves from the two arms are completely overlapping, but then there seems to be a little separation between the arms. Some have proposed that this may reflect the development of resistance mutations, and ESR1 mutation, um, in the study population. It has been well demonstrated that oral serts may have their best activity in the setting of an ESR1 mutation. And so while these mutations are very rare, when patients are first diagnosed with metastatic breast cancer, they do emerge over time, and it's possible after a year or a year and a half of therapy, that might be what is being seen. So we await data from the study to learn more about the ESR1 mutation status, both at baseline and moving forward. But there's also been a lot of questions about why these drugs that have performed so well up to date did not perform well in Persavera. And I think another important possibility is that CDK46 inhibitors work really well. And we've actually seen this from an older study. Uh, the Parsifal study, which looked at first line patients randomized to aromatase inhibitor and CDK versus fulvestrant and CDK and saw no significant difference between the arms. And so it may be that the efficacy of the CDK 46 inhibitor in the first line setting overwhelms the difference between the two endocrine agents. Um, now, we await another study in the first line endocrine sensitive population. This is the Serena 4 study, which uses the oral ser camazestrin, and is a somewhat larger study than Persavera. And so we'll see what the results of that study are, um, particularly in the context of what we've just seen from Persavera. Now, further data from Persavera included a look at overall survival. Uh, this was not significant between the arms and also remains immature. Um, I also want to take a moment to think about the toxicity profile. Oral surs are extremely well tolerated therapies. They contribute very little toxicity to, to patients. When we use them in combination, most of the toxicity that we've seen is driven by the partner agent, and that is indeed what was seen in, uh, this trial. We can see the most common toxicities seen were hematologic, primarily neutropenia. This is a classic toxicity of pabociclib, and so this is being driven. By the palbociclib and not potentiated by the, the novel oral cert. One unique toxicity though, that did come out, which has been seen with some of the oral certs, including gerridestrian, is mild bradycardia. And there were some cases of uh uh mild asymptomatic bradycardia seen in the gerridestrian arm. However, this does not lead to any symptoms, it doesn't require any intervention. So overall, we would conclude that the regimen was very well tolerated for patients. Great. Thank you for that summary. So let me just ask you a few questions. First, just on the drug itself and the side effects you just mentioned. Uh, so 10% chance of bradycardia. That means that every, if you were to imagine patients on this, 1 in every 10, the clinic assistant is gonna come to you and say the heart rate is too low today, what's the workup for that? Well, um, the bradycardia with oral surgeons and gyridestri in particular has been known about for a while, and actually, um, there was a very interesting cardiology substudy in a uh prior phase one gyridestri trial where the cardiologist took a population of patients receiving gyridestri and put them through comprehensive exercise stress testing. And interestingly, even with that baseline bradycardia, patients are able to exercise, they can increase their heart rate, their blood pressure, they have no limitations. So it truly is an asymptomatic state. I do think that that we, uh, might get a little surprised by some of the, uh, heart rates in triage, but we're gonna get used to it. I don't think that for these patients with heart rates in the 40s who are asymptomatic on Gidestrin, they're gonna need a. I'm paging you when my patient comes in with a heart rate in the 40s. Bring it to me. Um, let me ask you again about Perseverra, which is that a lot of the interest in this study has been sort of trying to handicap how these drugs move into the early stage setting. And as you know, of course, the Ladera study used monotherapy with geridestrian to show a modest improvement compared to AIs in a high risk early stage population. Since those same patients would nowadays be expected to get a CDK 46 inhibitor, is that the great equalizer here, or is there something else that we need to know to think about how these are going to play out in an early stage? I think there's a lot of moving pieces here. We, we consider the presence or absence of an ESR-1 mutation. We consider the presence or absence of a partner drug. And uh the overall disease setting. Um, I do think though that seeing the results from Persavera does perhaps give us a little pause about this idea of combining with CDK 46 inhibitor in an endocrine sensitive population. Um, you know, I, I think I'm looking forward to hopefully having oral surges available in the early stage setting. But it, it does to me, uh, teach me that if I'm using them, I should use them in the manner in which they were studied in the trial that leads to approval and not expand out of that just because we have a number of drugs available. So Girodespan has been studied in a different population of more resistant tumors in the Avera study. Tell us about the results of the Avera study and what they mean for the drug development. Well, we've, so we already have, um, two oral SERDs approved as monotherapy. For pre-treated metastatic disease, we also have a Protac Veptogesran approved as monotherapy. The two oral surges would be, um, the LSSran and immunestrant, um, and these drugs do perform well in a specific subset of patients, but I think that what we've learned is that perhaps the best way to use oral surges is in combination fashion, and we've seen combination data from a number of trials, including MR3 with immunestrant and the. Vera study in which we had the combination of gerridestrin and the oral MTOR inhibitor Erolius. And in these trials, we consistently see progression-free survival benefits that break a six-month barrier that perhaps was hard to break when we were using monotherapy. So, I think moving forward, I'm looking forward to a future state where I have easy access to oral cert combinations, um, including the ones that have been studied in the most recent phase 3 trials. Well, it's an exciting time, as you mentioned. There are 3 essentially commercially available SERDs at the moment and likely more in the future, tons of data pouring in from all of these landmark studies, and I'm kind of with you. I think that the way this shapes up for the most part is you're going to have sort of column A, which is going to be your endocrine approach, whether it's tamoxifen or an AI or SERD, whether it's fulvestrant or an oral SERD, and then column B, which is going to be a targeted drug like a CDK 46 inhibitor or an MTOR PIC 3CA. This targeting drug and multiple lines you're gonna get a pair one from column A and one from column B. And I think the, the secret sauce here is doing our genomic testing so we can look for the presence of uh targetable mutations, the emergence of mutations, and use that to guide the selection from the two columns. OK, I'm being a little cute here, but I mean to be just to push on that, we now have data from Lidera that you don't need to pre-select for gerodestrant in the adjuvant setting based on mutation. We have data for geta tulisib that it's active in PICC 3CA wild type. You said gerodestriant and MTOR inhibition with everolimus, that's not a targetable mutation necessarily. So might a wise acre say something like, Well, I don't actually see why you need that testing anymore? I think it's a provocative perspective. Well, that's what we're all about here is provocative perspectives. Well, I, I think that the key thing is we've learned so much from the cancer biology lab about mechanisms of resistance, and we have these drugs that have really been designed to target the mechanisms of resistance. We see our best results with oral SERDs when used in an ESR1 positive population. And I think PICC 3CA, you know, in particular, is a mutation that's associated with a lot of resistance and sometimes a little bit more aggressive tumor biology. So I, I do think that we should not be completely agnostic with these selections, but we have to really understand the tumor biology to make the best choice. I'm Hal Burstein. This is Dr. Erica Mayer. We've been talking about new data on SERDS from ASCO 2026 as part of our breast cancer breakthroughs. Thanks for joining us today. Thank you. Published August 22, 2026 Created by Related Presenters Harold Burstein, MD, PhD Medical Oncology View Full Profile Erica Mayer, MD, MPH Medical Oncology View full profile