Chapters Transcript Video SABCS Highlights: Advances in Oral SERD's for Breast Cancer Harold Burstein, MD, PhD, and Rinath M. Jeselsohn, MD, discuss the lidERA, evERA, and EMBER-3 trials researching oral selective estrogen receptor degraders (SERDs). One of the most exciting things happening in the most frequent type of breast cancer, estrogen receptor positive, HER2 negative breast cancer, has been the development of oral SEDs initially for metastatic disease and now for the first time some data in early stage breast cancer. Here to lead us through that discussion is Rath Jesselson, who's been a leader in this. Field of the molecular biology of ER positive disease in the clinical trials. Rath, tell us what's new with oral SEDS. Yeah, so this year has been a very exciting year for oral SEDS, and I'll go through some of the data that was presented at San Antonio and also data that was presented over the past year. So I'm going to talk about 3 studies. Uh, one is the Ladera, which was one of the exciting studies presented this year at San Antonio. Um, Amber 3 was presented last year at San Antonio, but there was an update this year, um, on this study, and then Avera was presented, um, at ESMO earlier this year, and updated data were presented at San Antonio. So starting with Ladera, that was one of the more exciting or most exciting studies at San Antonio this year. This is really the first phase 3 trial for adjuvant surge. So this is the first readout of one of the trials looking at an oral surge in the adjuvant setting. Um, the, uh, this study really included a relatively broad patient population, including patients stage 1 to Stage 3, with stage 1 being tumors that are more than 1 cm, um, had to have grade, disease or T67 above 20% or high molecular risk based on a genomic assay. T4 were included and basically any node positive disease. So pretty broad patient population. Um, and patients were randomized to either Gideran or standard of care endocrine therapy, and standard of care endocrine therapy was either tamoxifen or an aromatase inhibitor. Pre-menopausal women who received erodestrant or an aromatase inhibitor had to get, um, ovarian suppression. Um, and the primary endpoint was invasive disease free survival or IDFS. So, very excitingly, we saw early results from Ladera. This was a pre-specified interim analysis of at, um, close to 3 years, and As you can see here, um, the curves separated pretty, pretty early on. We're already seeing it at 12 months, there's a slight separation. And overall, at this time, at three years, the hazard ratio was 0.7, which means that gerardin reduced the risk of either invasive disease or death by 30%. So very impressive for an oral surge and also particularly since this is a very early readout. In an exploratory analysis, they looked at aromatase inhibitors and tamoxifen, as you can see here in this small forest plot on the side, and you can see that really the benefit was seen both when comparing to patients who received an aromatase inhibitor as well as patients who received tamoxifen. And then when we look at the different, uh, patient populations over the subgroups of patients, you can see that overall, um, for all patients, um, there was a benefit for Gerotri compared to standard of care endocrine therapy. But it is important to note that for some subgroups, the confidence intervals did cross one, particularly for the relatively lower risk patients, including the stage one or what they considered medium risk or patients who did not receive chemotherapy, i.e., these are patients that were relatively lower risk. As far as side effects, it was a little bit surprising that overall the side effects of Gridetrin were fairly comparable to aromatase inhibitors, as you can see here in this tornado plot. Arthralz was the most common side effect, and that was followed by hot flashes, and you can see here by the numbers that overall it was fairly similar compared to the standard of care endocrine therapy. Although the rate of, um, of patients who discontinued endocrine therapy was lower with Geroestrant. Um, it was 5% versus 8% with standard of care endocrine therapy. So, it was lower, albeit you can see the numbers are not very, um, large. And then when looking specifically at musculoskeletal, um, Effects. There were, there was a lower rate of discontinuation with Durant, and it was 1.8% versus 4.4%, um, with, um, with standard of care endocrine therapy. It's also important to note one of the side effects that's been seen with, um, dridetrin is bradycardia, and we, this was seen here in the study too. But these were all grade 1, so in around 10% of patients there were grade 1, which really is not symptomatic and doesn't require an intervention. So overall, very well tolerated drug and also very exciting results to see a positive study in the adjuvant setting. Um, 11 of the limitations of this study is really that, um, nowadays for high risk patients, we do give CDK 46 inhibitors, either, um, ribociclib or, um, abemiiclib, and, um, and in this study, patients went straight on to endocrine therapy, um, even though many of these patients would have been candidates for a CDK46 inhibitor. And as you can see here in this table, and this is a table from uh Lisa Carey's presentation at San Antonio where she showed that really the absolute benefit of Ladera really is highly comparable to the absolute benefit that was seen at Monarch E, um, and that's the adjuvant study for Abemaiclib at around the same time point, um, as well as Natalie. So one thing to learn from this is really that, um, in Monarch E and. We know that the curves even beyond 3 years are still separating, so this is very encouraging because it is highly likely that Ladero will continue to have a benefit beyond 3 years. But also now this raises the question really patients who have high risk disease and meet criteria for either monarchy or Natalie or Ladera, really what should we be giving? Should we be giving them endocrine therapy with a novelsERD, or should they be getting a combination? So I think we will have answers to this as some of the other studies are coming out. So there are studies, there are multiple adjuvant studies for relatively higher intermediate or high risk patients looking at novel SEDs, and the designs are slightly different. So Cambria 2 is looking at high risk ER positive breast cancers, and this is for initial adjuvant therapy similar to Ladara, but in this study, patients are allowed to receive a CDK 46 inhibitor, and the study will stratify based on yes or no CDK46 inhibitors. So this will be helpful for us to understand the benefit of CDK 46 inhibitors in addition to an oralERD. Um, I just, uh, showed this, the early data from Ladara. Um, one thing to note about Ladara is that it also included a a subgroup of patients, 100 patients who received a combination of Griran with a CDK46 inhibitor. Um, those results, uh, the results from those patients were not presented. Um, so we will hear more about this combination, which will be mostly a readout of safety. Um, and then there's, um, Elegant and AR4. Both are for patients who have received, um, who start on, basically who switch or don't switch endocrine therapy to a novel cert, um, after two years. So, patients are allowed to have a CDK46 inhibitor prior to participation in this study. So, it's for late endocrine, later, Endocrine therapy after completion of the first two years of endocrine therapy with or without a CDK46 inhibitor. And likewise, Cambria 1, has a similar design. And then there's another study which is the Treat CTDNA, which has a different design, and this is for, um, patients who are monitored for CTDNA and based on, um, evidence, Of, um, MRD patients are randomized, yes or no to receive, um, uh, uh, a, a switch to assert. Um, so, I think we'll, we'll have a lot more data as these, uh, studies read out and, um, hopefully these will, uh, enable us to better, um, understand what's the best adjuvant treatment in relatively higher risk patients. Um, the other study that, um, was, uh, presented at San Antonio was the EMRR3 trial. So, the initial, um, results of ERR3 were presented, uh, last year, and then there was an update, um, this year. EmBRR3 is a study looking at patients with advanced, um, ER positive breast cancer. Um, so, this study included patients who either recurred on, Endocrine therapy with or without a CDK46 inhibitor or progressed on first line endocrine therapy with or without a CDK46 inhibitor. Patients were randomized to imunneri. Um, so this is another oral steroid, uh, to standard of endocrine therapy, um, either fulvestrant or exemestane, and then, or, or to imunnerine plus ami. And the primary endpoint, there were three primary endpoints here. The first primary endpoint was immunnerant versus standard of care endocrine therapy in patients with an ESR 1 mutation, and then the same comparison in all patients. And then the third, um, primary endpoint was, uh, PFS in patients who received either imunneran versus imunnerant plus abemiiclib. So, the results, um, were very, uh, were, were shown already last year and updated this year. Um, and results were very comparable with the updated, um, data. And what we saw was that in patients who have an ESR-1 mutation, there was an, Improvement in PFS from 3.8 months in standard of care endocrine therapy versus 5.5 months, um, with immunes with a hazard ratio of 0.6, um, and this was statistically significant. However, when we looked at all, all patients, which was a, a second endpoint, um, there was no significant difference between, uh, between them. Um, this is an overall survival analysis that was presented, um, this year at San Antonio, um, and there was no, the, uh, this overall survival did not, uh, meet, um, the pre-specified threshold, so. Uh, there was no overall survival with immunnerine compared to standard of care endocrine therapy in the patients with an ESR1 mutation. However, it's important to note that really the study was not powered for overall survival, so this result is not very surprising. Um, and then, um, looking at the primary endpoint of immunnerit plus abeaciclib versus imunneri, um, in all patients, um, this was a positive endpoint and there was a significant improvement, um, with a hazard ratio of 0.6. Um, PFS improved, uh, to 10.9 months in the combination arm versus 5.5 months in mlurine alone. And it's important to also note, look at this is a subgroup analysis looking at patients with either an ESR-1 mutation or patients without an ESR-1 mutation, and in both subgroups there was a significant benefit to the combination compared to ne. There were additional, um, subgroup analyses, um, presented at, at San Antonio this year looking at patients with the PICC3CA mutation, and we saw that in these patients, there was still a benefit to the combination versus um versus the single. And then in patients who have an ESR1 mutation and a PICC3CA mutation, there was even enhanced benefit to the combination, albeit that that was a very small patient population overall. So we have to take that into consideration. And then the third trial, um, that was, uh, presented at, uh, at San Antonio is the updated data from Avera, which was a subgroup analysis of Vera of Avera. Avera, um, was initially presented at ESO by my colleague, uh, Doctor Erica Meyer. Um, and this is also a study looking at metastatic disease, uh, but looking at a different, um, at, at a different surge. This is errant, which is the same surge, uh, shown as As in Ladera. Um, and in this, um, study, patients who have advanced breast cancer, uh, ER positive, hormone receptor positive breast cancer, who had at least one line of endocrine therapy and, um, with a CDK46 inhibitor, but up to two prior lines of endocrine therapy, no prior chemotherapy. And also in this study, patients had to show disease stability of, uh, for at least 6 months while on endocrine therapy and a CDK46 inhibitor. meaning a relatively endocrine sensitive patient population. Um, patients were randomized to Gerotri plus everolimus versus standard of care endocrine therapy, which was exemestane, fulvesrant or tamoxifen, plus everolimus. And there were two primary endpoints in the study. One was, um, PFS in patients whose tumors had an ESR-1 mutation and then PFS in the intention to treat population. And as you can see here in this graph, this was also a positive study. Patients who received Geroestran plus everolimus did better than patients, um, on the standard of care, um, plus Everolimus with a hazard ratio of 0.4 and an increase in PFS from 5.4 months to close to 10 months. When looking at the intention to treat patient population, which was the second, um, primary endpoint, again, this was a positive study with a hazard ratio of 0.56 and improvement in PFS from 5.5 months to close to 9 months. Um, looking specifically at exemestane and fulvestrant, the subgroups, um, both, uh, there was a benefit when comparing, um, to exemestane or fulvestrant. So this benefit was irrespective of the, uh, standard of care endocrine therapy. Um, however, it's important to note also, um, although this was not a primary endpoint, But when looking at patients who did not have an ESR-1 mutation, there was no benefit to the combination with gerode compared to standard of care, suggesting that really the, the added benefit of gerotri versus standard of care is highly driven by the presence of an ESR-1 mutation. Um, so, these are, um, and these are the updated data that were presented this year, um, looking specifically at patients who have a mutation in the PA3 kinase pathway versus patients who did not. And we see here in these, um, Kaplan Meyer curves that there was, uh, an added benefit to Giderant plus everolimus versus standard of care in both patients who, Have a PICC-3CA or PI3 kinase pathway mutation, as well as patients who do not have one of these mutations, um, which is not very surprising since, um, everolimus is an mTOR inhibitor, which really, um, is a, is a, um, really inhibits many pathways that funnel into the mTOR, um, into MTOR and then downstream and not just, um, PICC3CA, that's, Also upstream to MTOR. Um, so, I think that was, um, those were all my, uh, slides. It's great. It's incredible to see all these data come forward. Um, let me just ask you a few questions here. So, um, the first is that why do you have to be postmenopausal for these SEDs to work? I would have thought they would work irrespective of menopausal status since you're degrading the receptor. So, this is still a um a little bit of a question that I, that um there are going to be studies looking at this, um, but Um, what happens is that when you degrade ER, um, you have a feedback, uh, mechanism where you have low, low ER leads to upregulation of, um, LH and FSH, which leads to upregulation of estrogen. So, basically, in the presence of surges, you have high levels of estrogen, and that could activate the estrogen receptor. And the question really is, is if you have a SED that really works so well and keeps estrogen receptor down consistently, um, could they still be effective when you have high levels of estrogen? So, in animal studies, we do see that if you have high levels of estrogen, um, asserted, at least fulvestrant is not effective. Um, so, when we give Fulvisin, for instance, in mice, we have to make sure that the estrogen levels are not very high. Got it. So, clinical point being, if you have a premenopausal woman thinking about these drugs, they need to be postmenopausal to facilitate treatment. Um, let's talk about the Ladera study. Obviously a really provocative study given the scale of early stage breast cancer and the early benefits that are emerging there. I will confess. I had not anticipated the study would be positive because much of the data, as you showed, has suggested that the real big difference in terms of metastatic disease for the SEDS versus other approaches like Fulvestri, the oral SERDS, was in that group that had the ESR-1 mutation. You had shown me some of the beautiful science work you've done, and it really looked like that was a population that might be most likely to benefit, whereas if the tumor was still otherwise endocrine sensitive, the other drugs would be OK. So I would have guessed in the early stage setting when you haven't selected for ESR-1 mutations that it would be a lot harder to show a benefit, and yet here we are, so. Not that I couldn't be wrong, but where, where was that analysis? Where did it go off the rails there? Yeah, I agree that these results were a little bit surprising, but a few things to consider. So SEDs really they overcome resistance that is due to ligand independent activity. And there are other mechanisms that lead to ligand independent activity. In addition to the ESR-1b mutations, we know that receptor tyrosine kinases can activate the estrogen receptor in a ligand independent manner. So, the surges may be overcoming some of that resistance. Um, and then, you know, although the ESR-1 mutations are relatively rare in, in, if you take all, Primary ER positive breast cancers, but we are learning that there are, um, there are specific patients who, when we look at, at, um, at the metastases, at a metastatic biopsy at the time of recurrence, patients who have earlier, um, recurrences or are considered either primary or secondary endocrine resistant. We're seeing that the percentage of the ESR-1 mutations is in the range of about 15%, so it's not such a small patient population. So there may be patients that are upfront very high risk with risk of early recurrences that actually have a higher rate of ESR-1 mutation. So you made a point about the durability of the adjuvant CDK46 effect. Do you think because we're talking about a subset effect here that we will see the persistent separation of the curves in Ladera, or do you think it's going to kind of flatten out? Um, I think that there are going, you know, there are other mechanisms of resistance that are more acquired over time, and we still might be overcoming there, but that's really a guess. Fair enough. One final question, it's conceivable in the next few months that we will have up to 5 SERD type drugs commercially available Eliestrant, imlinestri, Camizestrit, gyridestritt, and the related protag veptostrient. Is there a laboratory science reason to think that one, that these are all the same or that they're all different, or obviously there's empiric data here, but are these going to be interchangeable products or how are we going to think about this? Yeah, I mean, their chemistry is different, um, obviously. Um, but in the lab, we're seeing they're, uh, you know, overall, they're doing the same thing. They do. I mean, they, they, you know, they degrade ER. They antagonize ER. I think one of the big differences is their side effect profiles and one might be better tolerated than the other. Um, so it will be nice that we will have several of them, um, and that way, you know, certain side effects, uh, are, you know, won't be tolerated by, uh, specific patients, but other patients and patients will have more options. Great. Well, we've been talking about this exciting class of drugs, oral sEDs, which are taking the estrogen receptor positive breast cancer world by storm, and it sounds like we'll have a lot more to learn in the next few months. Thanks, Rath, for being with us. Thank you. Published March 17, 2026 Created by Related Presenters Harold Burstein, MD, PhD Medical Oncology View Full Profile Rinath Jeselsohn, MD View full profile