Introduction: How Selective Estrogen Receptor Degraders (SERDs) Work

DR LOVE: Good afternoon, everyone. I’m Neil Love from Research To Practice, and welcome back to Year in Review, as today we focus on the use of oral SERDs in the management of breast cancer. We have a great faculty today: Dr Aditya Bardia from UCLA Health Jonsson Comprehensive Cancer Center in Los Angeles and Dr Erica Mayer from the Dana-Farber Cancer Institute in Boston.

Today we’re going to dive into oral SERDs with breast cancer. And as always, we will be talking about the use of unapproved agents and regimens so check out package inserts for more information.

As with all of our Year in Review programs I met individually separately with our faculty to record a presentation reviewing key papers and also giving me a chance to kind of talk to the faculty and get their take on what are some of the things we might talk about here in this webinar. So in the chat room you can click if you want to see them now. Otherwise, we’ll be distributing it when we send this webinar out. They’re both really great presentations.

There are a lot of datasets to go through. Here are the ones that they went through. We’re not going to go through presenting all the details of all these programs — all these papers. We will be referring to them. We have some slides in the webinar, but as always with our Year in Review programs we’re really here to pick the brains of our faculty and see what these data mean in terms of patient care and where we’re heading in terms of clinical research.

Here’s our agenda for today. I want to start out with kind of an introduction before we get into a lot of specifics about these papers, really focusing also on the issue of how these agents work and what are some of the biopharmacologic issues that have come up with these. Then we’ll talk about the initial use of selective estrogen receptor degraders in practice in second-line treatment of metastatic disease, typically a patient getting first-line CDK and endocrine therapy. Then we’ll talk about the minimal information that’s available, but some interesting coming out, on first-line therapy, and then of course we’ll delve deeply into adjuvant treatment and particularly Aditya’s presentation at the December San Antonio meeting of the lidERA study. Then we’ll talk about toxicity and how that ties into some of these agents and papers that we’re going to talk about, and we’ll finish with some views in terms of where things are heading.

But I know it’s supposedly a simple question of how these work, but I continue to have questions. I asked both of them — both of our faculty a lot about that, but before we get into that I just want to reflect back on this presentation of lidERA at San Antonio. I’m just kind of curious. I mentioned actually — we actually are doing a program — a CME program when lidERA was presented, actually Erica was part of that, and we’re reflecting back a little bit on the history. Here’s the program at San Antonio we were doing. And one of the things I showed, Aditya, was video from Sir Richard Peto in the 1985 Consensus Conference presenting the first results of the meta-analysis of tamoxifen, and that led to actually the approval in the mid 1980s of tamoxifen.

But I was reflecting back on a lot of the other important moments at San Antonio, Aditya: dose-dense chemotherapy presented around 2005, the ATAC trial, tamoxifen versus anastrozole versus the combination, that unfortunately wasn’t positive. The first presentation of the Oncotype data was actually also at San Antonio by Dr Paik, and also the big non-anthracycline adjuvant trastuzumab trial presented by Dr Slamon, your colleague at UCLA, Aditya. And then, again, from my point of view the paper of the year in oncology, period, not just breast cancer, the lidERA study.

I’m just kind of curious, Aditya, what your thoughts were when you first saw the data. Were you surprised? Were you expecting it? Were you disappointed? What were you thinking?

DR BARDIA: How can I not be disappointed? To be honest, we were a bit surprised by the results. We were expecting this to be a positive study given that in preclinical models in the neoadjuvant window-of-opportunity setting giredestrant demonstrated superiority over AI and tamoxifen. But we were not expecting this degree of magnitude of benefit, with the hazard ratio of 0.70, which is similar to what was seen with cross-trial comparisons, but similar to what was seen with ribociclib and abemaciclib.

You were mentioning ATAC. In ATAC the hazard ratio with AI versus tamoxifen was around 0.80. So again, cross-trial comparison caveats, but the results were better than what we had expected.

DR LOVE: So Erica, I call this how SERDs work because initially, I don’t know whether other people have had the same experience, but I was associating, particularly because of the second-line trials, for example, with the EMERALD study with elacestrant, that the benefits from SERDs were related to ESR1, and then Aditya comes along and presents the lidERA study, where these patients don’t have ESR1, and yet it’s really positive. So I kind of found it a little confusing. And I was kind of reflecting back, and the general oncologists on the program today will be familiar with EGFR-mutant lung cancer.

I was mentioning we’re doing a program just on that. But initially osimertinib was actually used with patients who progressed on the first generation of EGFR-mutant disease, and then osimertinib was able to treat the patients who relapsed who had this T790M mutation. I’m not saying it’s exactly the same as ESR1. And then osimertinib was moved up because it actually was better than them. And now we have adjuvant osimertinib. But I do think it’s still maybe a little bit confusing and maybe is going to get more confusing when we talk about this new press release.

But how do you put together the fact that in the second-line endocrine setting, Erica, it seems that you’re seeing most of the benefit in this endocrine-resistant situation in patients with ESR1, and yet with lidERA you see the benefit without ESR1?

DR MAYER: Yeah. So I think it’s a great analogy and really highlights that oral SERDs are highly effective endocrine medications. There’s a twofold mechanism of action by binding the estrogen receptor both preventing transcription of estrogen responsive genes, as well as leading to degradation of the receptor. And it's a more profound way of inhibiting estrogen-related cancer cell stimulation than the type of medicine like an aromatase inhibitor, which removes the ligand but isn’t actually impacting the estrogen receptor itself.

As you point out, we’ve seen now repetitively in the pretreated setting in metastatic disease that these agents have substantial activity in the setting of an ESR1 mutation beyond what we see with something like fulvestrant and certainly more than aromatase inhibitor. And so our current approvals for oral SERDs are for ESR1-mutant populations, and there’s interesting data from combination studies suggesting maybe we can overcome the requirement for an ESR1 mutation when we combine with a targeted partner.

But that’s where lidERA is so interesting because as we’ve said, I mean we don’t — we haven’t seen the ESR1-mutant population yet called out from that study, but our assumption is that the majority of people will not have cancers with ESR1 mutations as these are acquired mutations, they occur over time when patients are getting aromatase inhibitors, and in a treatment-naïve early stage setting we would anticipate the prevalence of ESR1 mutation to be very low.

I think what we learned from the lidERA data, at least at this early look at the study, is that the oral SERD is a better drug than an aromatase inhibitor. I think that’s one of my takeaways. It’s more effective and from my perspective better tolerated than aromatase inhibitors, and that appears to be beyond the restriction on ESR1 mutation. So I think we can see activity in both different settings perhaps for different reasons, but I do think in the metastatic setting there is a primary efficacy signal associated with the development of an ESR1 mutation.

DR LOVE: So Aditya, in Erica’s presentation she went through a number of “window-of-opportunity” studies. I always love those studies, where you look at the tumor preoperatively so you can see what happens inside; when the patient goes to surgery repeat it. And this has been looked at with imlunestrant, as well as also with elacestrant, also windows-of-opportunities in terms of camizestrant, SERENA-3, and then giredestrant as well. And the giredestrant one was in premenopausal woman.

Now, I know in lidERA premenopausal got giredestrant, as well as AI, of course, had LHRH, but as we move forward do you think we are going to need LHRH with these SERDs? It looked like in the window-of-opportunity it does seem to have activity without LHRH agonist.

And also, those studies demonstrated — of course Ki-67 dropped, which we saw that before with endocrine therapy. But also reduction in ER and PR, which kind of makes sense when you think about the mechanism.

Any thoughts about what we’ve learned about these mechanisms, Aditya? And do you foresee a future where maybe we’ll be able to use these SERDs without LHRH? Big difference in quality of life.

DR BARDIA: Yeah, absolutely. I think that would be great from a quality-of-life perspective for patients. Mechanistically the SERDs block ER, and the reason that we use LHRH is from historical data with fulvestrant, but if you have a very good agent that blocks ER potentially we would not need LHRH agonist, and those studies are ongoing at this time looking at that question.

With these newer agents I think we will see more and more of these window-of-opportunity studies, which are fantastic not just from a pharmacodynamic perspective, but then it can also give you a readout with Ki-67, which is a good surrogate marker for invasive disease-free survival.

Erica, I thought I was understanding all of this, particularly after I talked to the 2 of you, in terms of why lidERA was positive even though there wasn’t ESR1, and then my world got upside down here with this press release from the persevERA study. I like the name of the study. But you would think you’ve got adjuvant over here, you’ve got second line over here, you would think if it’s a better — you said it’s a better endocrine agent — that you would see it in the first-line setting. Of course, we haven’t seen this. As typically happens we have a press release. Hopefully we’ll see it soon. Maybe at ASCO. Who knows?

But a first-line study looking at giredestrant with palbo, which was not positive. Any thoughts about why? You were saying the Twitter universe hasn’t figured it out. What are you hearing, Erica?

DR MAYER: Yeah. So the persevERA study is one of the first-line studies looking at oral SERDs. The other studies that we’ve previously seen and reviewed have all been in pretreated patients; post CDK for the most part.

So this is trying to move oral SERDs up to the first-line setting. These are patients newly diagnosed with metastatic hormone receptor-positive, HER2-negative disease who were randomized to receive the oral SERD giredestrant with the CDK4/6 inhibitor palbociclib versus a standard of care regimen, letrozole with palbociclib. And what we saw just within the past few weeks is a fairly terse press release suggesting to us it did not meet the primary endpoint, which was looking at progression-free survival in the ITT population. That’s all we know about the trial right now. And as you said, maybe later this year we’re going to see the data.

First-line patients are — we know from looking at several other first-line studies the rate of ESR1 mutation in this population is very low, single digit, 4 or 5%, so we would anticipate that this is a, for the most part, ESR no mutation detected population. Based on the data we have from previous oral SERD studies in the metastatic setting, where we’ve seen the stronger signal with the ESR1-mutant cancers, perhaps this makes sense if the population doesn’t have ESR1 mutations. But this is flies in the face of lidERA, where we’ve also just said the majority of patients likely did not have ESR1 mutations.

And so how is this population different from the lidERA population? One important difference is this is a combination study of oral SERD with CDK4/6 inhibitor. Remember, lidERA was oral SERD monotherapy versus endocrine monotherapy. And it’s possible that when we combine endocrine therapy with a CDK4/6 inhibitor, and we have the synergy of those 2 agents together, that that is so powerful that it overcomes any difference that we might see between the arms if we were just looking at endocrine monotherapy.

So I think there’s a few different potential possibilities that have been floated. Ultimately, of course, we need to see the data and in particular look at the statistical plan of this study versus what we actually see in practice. But I agree with you that this is continuing to create kind of a mental pretzel for us to try to figure out who are the best candidates for oral SERDs and what is the role of ESR1 mutation as we’re selecting patients.

DR LOVE: So I was chatting with Aditya about this and would like him to kind of verbalize what he was telling me. But when I showed that picture of Richard Peto, the thing that he really brought to the table for oncology in general was the issue of events, that you need enough events if you’re going to see a benefit and really change all of oncology research, not just breast cancer. Aditya, you brought up the possibility of maybe the study just needed to be bigger. Maybe there is an effect there. Maybe it’s getting dampened by the impact of CDK. Do you want to elaborate on that?

DR BARDIA: Yeah, absolutely. I fully agree with what Erica was saying, that in this setting it’s a combination study, so it’s not fair from that perspective to compare lidERA and persevERA because lidERA was monotherapy and persevERA was combination therapy. The best comparison would be if there was a study comparing AI versus giredestrant in the first-line metastatic setting as monotherapy. We’ve had studies like these in the past comparing fulvestrant with AI, and so a study like that would essentially answer that question. But given that we’re in the CDK4/6 era at this time ethnically it’s not feasible to do such a study, but then you blunt the effect, the CDK4/6 inhibitor dominates, and you can blunt the effect between a superior endocrine agent versus not.

Second-Line Treatment for Metastatic Breast Cancer

DR LOVE: So we’re going to move on now and talk about what most of the news about SERDs was until this past San Antonio, which was in the second-line setting, patients with prior first-line treatment, usually with a CDK inhibitor. And 1 issue that came out as a result of these studies that I thought was very interesting, again getting back to you, Erica, was the impact on how — of how long the patient was on prior CDK therapy. Aditya had presented a lot of this data trying to kind of tease out was it an endocrine-sensitive or endocrine-resistant situation, and we kind of came up with this concept of at least a year on a CDK inhibitor with endocrine therapy in the first line to maybe see the benefit, and maybe the longer time.

How do you decide whether you’re even going to use hormonal therapy, Erica, if you have a patient who relapses 6 months later? Will you go to chemotherapy or an ADC? And how do you factor in what you perceive to be the endocrine sensitivity of a patient?

DR MAYER: Yeah. Well, I think it’s very interesting how we try to use these kind of peripheral markers about the patient’s experience and their treatment history to get a sense of what the tumor biology is and use that to try to predict how they’re going to do, and I think the EMERALD study is a great example of that. EMERALD, which is a monotherapy study with elacestrant versus standard of care in the pretreated setting, was a positive study, but the difference between the arms in the ITT and the ESR1 populations was shall we say modest, and when you look at the Kaplan-Meier curves at time of first restaging half of the patients are exhibiting progressive disease.

And so I really loved the subgroup analysis that Aditya led looking at the time on prior CDK4/6 inhibitor and showing, perhaps it’s a little arbitrary, 12 months on prior CDK4/6 as a marker of a person whose cancer remains sensitive to endocrine treatment. And when you look at just that population then you can see a very different result, an improvement from about 2 months to 8 months with use of the oral SERD, and the Kaplan-Meier curve is looking much more favorable. So I think that was a really lovely way to use a very obvious piece of clinical information to learn about tumor biology.

Now, interestingly when we apply that same kind of 12 months on prior therapy to combination oral SERD studies, for example evERA, as well as EMBER-3, we can see that that time on therapy doesn’t actually matter so much. We see preserved benefits whether the time on therapy was shorter versus longer, and that suggests that when we combine the oral SERD with a targeted partner that may be helping to overcome endocrine resistance, and we can see this in the Kaplan-Meier curves. If you look at the evERA Kaplan-Meier curves the curves separate very early and continue to separate. They do not show that very steep dropoff at time of first restaging. So I’m really of the belief that ultimately we want to use oral SERDs as combination regimens with a targeted partner.

That being said, there are definitely patients for whom oral SERD monotherapy is a very nice choice, and I tend to think of this as perhaps an older patient, bone-only disease, more slow growing, that long duration of time on prior therapy. Those are the patients where I really feel like they’ve gotten great benefits from oral SERD monotherapy.

DR LOVE: So as I do, Aditya, for all of our Year in Review programs, after I meet with the faculty I jot down a bunch of questions I want to bring up, and I only have 25, as usual, for you all. I don’t know if we’re going to get through them all, but we’ll just try to — we’ll at least do a little bit of a tasting menu of just this part of breast cancer.

So one thing now we have in terms of if you’re going to use SERD monotherapy, we have a choice. We have 2 approved agents, elacestrant and then more recently imlunestrant. Just curious — we’ll talk later about relative toxicity, but I’m curious how you decide which one you would use, and then also the issue that’s been out there since the beginning of this, which is the patient with a double mutation, not only ESR1 but also AKT/PIK3/PTEN, where they may be eligible, for example, for capivasertib or another AKT inhibition.

We have seen some data, both from the EMERALD and evERA studies, and maybe there’s other data out there, on these double-mutant patients that seem to respond the same as with just ESR1. I don’t know if we’ve seen the reverse like from CAPItello, whether they have that. I haven’t seen that. But how do you decide which monotherapy you’re going to use, Aditya, and how do you approach a patient with double mutations?

DR BARDIA: Yeah. So we have 2 options now; one is elacestrant, the other is imlunestrant. Generally, the drug that is first approved has an advantage because providers are more familiar with the drug, and that tends to continue. We saw this initially with olaparib, talazoparib. We’ve seen this with other agents as well. Having said that, it’s a discussion with patients. Elacestrant tends to cause more upper GI side effects and imlunestrant more lower GI side effects, like diarrhea, so it’s a discussion of the side effect profile as well.

In terms of how to select these drugs in a patient who has both ESR1 and PIK3CA mutation the options would be elacestrant, imlunestrant, imlunestrant plus abema, as well as fulvestrant in combination with alpelisib or in combination with capivasertib. We use these drugs in sequence. It’s not wrong to use one over the other. I generally try to use the agent that has lower toxicity, so I would use oral monotherapy first but do a scan at 8 weeks or maximum 12 weeks because if a patient has disease progression, I want to catch that early. And if a patient does not have PD and doing well I’ll continue with the monotherapy and then at the time of disease progression consider combination therapy.

DR LOVE: Yeah. I was just flashing on the fact we just did a program at the GU ASCO Meeting on AKT inhibition in prostate cancer, so they’re just starting to get into the AKT scene. I’m curious how the urologists are going to think about this.

Erica, another thing I was curious about. I always love the real-world studies, and I’ve seen — the data looks with SERDs like what we’re seeing in practice reflects what we saw in terms of the trials, particularly in terms of PFS. Any comment on what we’ve seen in the real world? And then your thoughts about SERENA-6 of course using the SERD camizestrant in patients without clinical progression but with the development of ESR1 on first-line therapy with an AI and CDK. Switching, where we saw PFS advantage. There’s some really cool data looking at allele fraction, where — from SERENA-6 at San Antonio, where you see the ESR1 go away when they treat the patient with camizestrant.

So any thoughts about whether these data from the trials are getting reflected in the real world? And any thoughts about the SERENA-6 strategy? We’re waiting to see, I guess, whether the FDA is going to approve it or not. Is that a strategy, Erica, you think you’d want to use in your practice?

DR MAYER: Yeah. So regarding real-world data there have been some datasets looking at elacestrant, real-world data suggesting median PFS that’s not dissimilar from what we see in the EMERALD study in the endocrine-sensitive population. I find that very reassuring, of course, to know that in patients who are beyond the kind of rigid clinical trial population that these drugs have activity and that they’re well tolerated but also that we as providers are picking the right patients for the study and that the patients who are receiving elacestrant are the ones who should be receiving. So that data I find very reassuring, and it helps me encourage use.

Regarding SERENA-6, I love the SERENA-6 study. I think it’s just the coolest study, and let’s just review it. So it’s a 2-step study. The first step is the screening step. This is the step that enrolled patients who had been stable on CDK4/6 and aromatase inhibitor in the first-line setting for at least 6 months, and they entered into a screening process where ctDNA was drawn around the time of restaging. So essentially 4 times a year they had ctDNA drawn looking for emergence of an ESR1 mutation. The idea is that while on aromatase inhibitor the tumor might mutate and become resistant, as demonstrated by an ESR1 mutation in the absence of clinical progression. So trying to catch a window when something’s happened with the cancer, but it has not led to the patient progressing.

The trial screened over 2000 patients and was able to identify 315 who moved on to step 2, which was a more traditional Phase III randomization. The patients who were in step 2 were randomized to switch from aromatase inhibitor to the oral SERD camizestrant with CDK4/6 inhibitor and with a placebo versus stay on aromatase inhibitor, CDK4/6 inhibitor and add a placebo.

The data was first presented at the plenary at ASCO last year and updated at San Antonio and showed a substantial prolongation in progression-free survival from about 9 months by staying on AI to almost 17 months by switching to the camizestrant. Other endpoints, including PFS2, is trending favorably with a 6-month difference, although it remains immature. Overall survival remains immature.

A couple other features that you point out. First of all, there’s a very compelling difference in deterioration in quality of life. It’s a year and a half difference. So the patients who switched to camizestrant had a full year and a half longer before they experienced deterioration in quality of life compared to the patients who stayed on aromatase inhibitor.

And there was some discussion about maybe it has to do with drug side effects or differences like that, but when you break it down into the different components of quality of life the components that are deteriorating in the AI patients are things like pain, shortness of breath, fatigue, all the symptoms of subclinical cancer progression. So I look at that data and say that we’re really showing that switching to camizestrant is preventing clinical progression and meaningful progression in patients. So we’re making a difference by putting them on the more effective drug.

The other part that you brought, which is really cool, is looking at that allele fraction of ESR1, which is like a marker, is the drug hitting the target. And in the group who switched to camizestrant the median change in ESR1 allele fraction is 100% decrease, so it’s getting rid of ESR1. In contrast, on the aromatase inhibitor arm the median increase was in the 60% range, but about a quarter of patients had a 500% increase in ESR1, so completely the opposite. So I really think that’s a great example of how the oral SERD is hitting the target.

We know it’s helping in terms of benefitting progression-free survival, benefiting quality of life, and on a molecular level showing benefit as well. So we’ll see what happens in terms of drug approvals, but I think the data’s really interesting and really compelling.

DR LOVE: So Aditya, Erica referred to the future in terms of combinations with SERDs, and the first time we that I think was the EMBER-3 study also at San Antonio. And I remember when Hal Burstein did the discussion, he said I’m not supposed to put up these indirect comparisons, but here they are, and he showed that with abemaciclib and imlunestrant, instead of the 6 months — or 5 or 6 months we were seeing with SERD monotherapy it was more like 9 months.

I’m curious. I know it’s maybe not — imlunestrant is approved, but I think you probably can access abemaciclib, but what do you think about that combination, the combination of SERD and CDK? How much of an issue is diarrhea, incidentally? And do you use the abemaciclib ramp up in this combination, and are you using it in general?

DR BARDIA: Yeah. I can answer this 3 ways. First, from a mechanistic perspective there is strong synergy between ER and CDK4/6. I think that’s great that these drugs were combined. Second, from a clinical perspective we saw median progression-free survival of 9, 10 months, and that’s great for an individual patient if they can remain on the drug and have the disease under control.

The side effect is diarrhea, and that’s an overlapping side effect with both imlunestrant and abemaciclib. Generally we tend to see diarrhea in the first 2 cycles. Erica led a very nice study, which showed that if you start with a lower dose of abema, 50 BID, and then increase to 100 and 150, and much more relevant in the adjuvant setting, that’s a strategy to manage diarrhea. So as long as you can control and manage the diarrhea in the first couple cycles it’s much easier for the patient to then continue.

A third component is the clinical trial component, and I guess that was the FDA perspective as well. One arm that was missing in the trial was fulvestrant/abema, so you can not necessarily say that imlunestrant plus abema was superior to fulvestrant versus abema. You can not sort the contribution of these components, which maybe led the FDA to only approve imlunestrant rather than imlunestrant plus abema. But from a clinical perspective, again, it’s a good combination.

DR LOVE: So and then Erica, speaking of combinations, you presented the evERA study with giredestrant and everolimus at the ESMO meeting. Again we saw bumping through the 6-month PFS, going beyond that. Can you talk about that study, what was observed, what your thoughts are in terms of tolerability, what kind of issues you see, I assume it’s mainly related to the everolimus, and whether you think it’s worth considering as opposed to just SERD monotherapy?

DR MAYER: Yeah. So evERA is one of the other combination SERD studies that enrolled patients who had all received prior endocrine therapy, all received prior CDK4/6 inhibitor, and they were randomized to either receive a combination of giredestrant with the mTOR inhibitor everolimus or standard of care endocrine therapy with everolimus, so that could be fulvestrant or an aromatase inhibitor.

The study was enriched for ESR1 mutation, 55% of patients had ESR1 mutation, and the study — what I think is really interesting and important about the trial is that, and as Aditya alluded to, the comparison is between a combination of oral SERD and everolimus versus a standard of care combination, so it wasn’t a combination versus monotherapy as we’ve seen in many of the other trials. So this is the only trial that’s looking at combination versus combination.

The primary endpoint of the study was progression-free survival in both the ITT and the ESR1 populations, and the study met both primary endpoints, showing an improvement up to 10 months in PFS, particularly in the ESR1-mutant population.

In terms of tolerability, I think the theme we see from the combination studies is that the oral SERDs in general are really well-tolerated drugs. It’s the combination partner that might be contributing some of the side effects. The tornado plot, which is that plot we look at for toxicity, in evERA is remarkably symmetric. We really don’t see any major differences between the 2 arm, suggesting that the toxicity contribution is primarily due to the mTOR inhibitor everolimus.

And the major side effects seen include the traditional things with everolimus, mucositis, rash, diarrhea. I will add that steroid mouthwash was strongly encouraged in evERA. It wasn’t mandated, but many of the patients in evERA did use steroid mouthwash. So I think as we consider using the combinations the challenge is really more about toxicity management for the partner drug and not so much for the oral SERD, which is great that we’re using novel endocrine agents that are extremely well tolerated.

DR LOVE: So I was flipping through the slides in the deck for those of you who are watching as opposed to listening. You can check it out later. Also, we’re seeing combinations with the other SERDs. Here’s a study looking at elacestrant in combination. Actually, there was more data from the evERA study presented at San Antonio, as well as this ELEVATE study looking at combinations with elacestrant.

First-Line Therapy for Metastatic Disease

DR LOVE: So we’ll see where this all leads. We already talked a little bit about first-line therapy. One thing I was just curious about, Aditya, have we seen any data in the first-line setting? I was thinking about the fact that EMBER-3 had people who’d never received CDK inhibitors, but I don’t know whether we have any in the first line. I know there are — a study. There’s this SERENA-4 study that also is going to look at SERD, camizestrant, with palbo, just like the trial we just talked about.

Any thoughts — as well as this pionERA, a Phase III study comparing giredestrant plus CDK and fulvestrant plus CDK. Any thoughts about where things are heading in the first-line setting, Aditya? I know we need to see the data from the giredestrant first-line setting, but any thoughts about where we might land in the next few years? Do you think we’ll end up giving a SERD plus CDK first line in the future?

DR BARDIA: Yeah. So persevERA, as we discussed, was a negative study, and it’s unlikely that the drug would get approved in the first-line setting. SERENA-4 is asking a similar question but with camizestrant. And there’s some difference in study design, so over time we’ll know whether that’s a positive study versus not. If it is a positive study, then we will have an oral SERD in the first-line setting.

The pionERA is more like a second-line study. It’s for patients who have disease progression on adjuvant endocrine therapy, so more like PALOMA-3 in that setting or MONARCH 2, which were for patients who had disease progression on adjuvant endocrine therapy. So unless these drugs are approved we can always use them off label in the first-line setting, but AIs are also very well tolerated in the first-line setting. So unless we see a positive study I don’t foresee these oral SERDs, which might be more expensive than AIs, in the first-line setting with a CDK4/6 inhibitor.

Adjuvant Therapy

DR LOVE: So let’s talk about adjuvant therapy and the lidERA study. I guess 1 thing I’m just kind of curious about, I don’t know how much data we have, actually I’m going to come back to you, Aditya, since you presented it, which is the idea of how much of the benefit that we saw with giredestrant over an AI was just because they were able to get more drug because it’s better tolerated and how much was it because of inherent antitumor effect. Any thoughts, Aditya?

DR BARDIA: I think it’s more the latter for a couple reasons. First, in the trial the rate of discontinuation in both the arms were single digits. It was not like 20, 30% of patients discontinued AI and say 5% discontinued giredestrant, so it’s because of drug exposure. In both the arms the rate of discontinuation was low. And the second reason is, again, in the preclinical and window studies, where you had short exposure, you saw giredestrant was superior to AI, so I truly believe it’s a better endocrine agent, which led to the benefit we saw in lidERA.

DR LOVE: So just a few hours after Aditya presented this, we were in this CME program, Erica, that you were at. I went down all 5 faculty, asked each one what they thought lidERA meant, and I will say there was a variety of immediate reaction. I’m not sure how it’s changed since then. But can you talk a little bit about how, right now, a few months later, you’re thinking this through, Erica, in terms of what are the situations that you might consider it.

One of the things I’ve noticed recently is in the past I was talking about the overview and all. We just figured out what’s the hazard rate, and then we just took the hazard rate and applied it to whatever the risk was and calculated the absolute benefit because it seemed you could do that, and yet more recently, like with the adjuvant CDK inhibitors, people are using the entry criteria of higher-risk patients.

But would you expect, theoretically, that this adjuvant strategy of a SERD you would see benefits? Maybe the absolute benefit wouldn’t be as much, but you would see benefits kind of regardless of risk. And how are you — if you had giredestrant available how would you decide who to use it on up front, Erica?

DR MAYER: Yeah. So there’s been so much for us to consider with lidERA since Aditya’s great presentation at San Antonio, and I would point out that immediately following the presentation our colleague Lisa Carey discussed the abstract and really, I thought, did a great job putting it into context, both celebrating this amazing data but also pointing out some questions and kind of how we — how we would accept this data into our current treatment paradigms.

An important thing for us to remember as we consider lidERA is that CDK4/6 inhibitor was not part of the regimen. This was endocrine monotherapy, and in our general practice for higher-risk Stage II and III patients we’re offering — we often are offering a CDK4/6 inhibitor, either abemaciclib or ribociclib.

Lisa put up a really beautiful slide looking at the past decade of advances in the early stage hormone receptor-positive setting and demonstrated that both our CDK4/6 inhibitor trials, NATALEE with ribociclib and monarchE with abemaciclib, they had their first reports at a very similar median time of follow up, with fairly similar populations, with fairly similar hazard ratios and absolute benefits between the arms.

So it’s really striking how in the 2 studies that are adding the CDK4/6 inhibitor to endocrine therapy we’re getting a very similar benefit to lidERA, where we are switching the endocrine backbone. And it raises this question do we need to be adding CDK or do we need to be offering different endocrine, and who are the right patients for all of this.

I think also in this context we’ve seen recent updates from the adjuvant CDK studies at ESMO last year, including a monarchE presentation showing an overall survival benefit to adjuvant abemaciclib and follow up from NATALEE showing significant benefits in high-risk node-negative populations. So we can’t combine giredestrant with CDK4/6 inhibitor. That data does not exist in lidERA. That would not be appropriate to do.

But we have to think about should giredestrant be approved how would it fit into our current paradigms. I think we’ve all been talking about this a lot. I would just say in our conversations for our high-risk patients who are let’s say high-risk node-positive patients, where we are very routinely and broadly using adjuvant CDK4/6 inhibitors with overall survival benefits, I don’t think we’re going to pull away from that. People have suggested perhaps we could offer oral SERD after the CDK4/6. That isn’t at all what was studied in lidERA. That is the way that some of the other adjuvant SERD trials are structured, but that is something that’s been proposed.

I think it’s really interesting to think about the high-risk Stage I patients. They were not included in either of the adjuvant CDK trials, and they were included in lidERA. Now granted there are very few events in that population because those are overall good-risk patients, but that might be a good group of people where it’d be interesting to be able to offer giredestrant.

And then there’s the group of the kind of Stage IIA (T2N0) patients who we’re often offering ribociclib, and there’s a lot of overlap with lidERA in offering giredestrant. And so that’s the group where I think we’re going to have to figure out how to move forward and who’s going to be the best candidate for either agent.

Over the next few years, we’re going to see more data from adjuvant SERD studies in different study structures and in different settings, and that may also help clarify where oral SERDs will fit in the early stage setting and how we’re going to best use them.

DR LOVE: And actually here’s the slide that — from Lisa Carey’s presentation. I really recommend you go back and watch that again. I did also, and there’s so much in there.

DR MAYER: Yeah.

DR LOVE: I was just thinking I’d love to try to put together an algorithm summarizing what you just said, Erica. It would be a little complicated.

But anyhow, Aditya, anything you want to add to what Erica said? And also, your comments on another issue that I think is also very important. You reported a lot less musculoskeletal issues that you see a lot with AIs, and we talked about the fact not much that much discontinuation, but you wonder whether people cut back on it or they hold off on it when they’re having a lot of arthralgias. Everyone is familiar with the challenge of adjuvant AI therapy.

Theoretically, if you could, in addition to going through what your algorithm is, Aditya, what would be your bar to switch somebody from an AI to, for example, giredestrant? Would they have to be miserable on the AI? Would they have to have any symptoms? If they requested it would you give it? If you had a medical oncologist as a patient who said oh, I’ve seen what happens with an AI, I don’t even want to start it, would you use giredestrant if you could? What about these patients who have tolerability issues? Is your expectation that they’re going to do better on giredestrant?

DR BARDIA: Potentially, yes. I’ll answer the second question first. And if you look at the lidERA study the rate of discontinuation because of musculoskeletal symptoms was lower with giredestrant as compared to AI, so it does appear to provide that benefit. So I would have a very low threshold of switching from AI to giredestrant when it’s approved if a patient is having side effects, or even potentially start up front with giredestrant. Which brings me to the algorithm that Erica outlined, which I very much agree with. For patients with Stage I disease who were included in lidERA they were not included in NATALEE or monarchE, so this is a potential option.

And then for patients with very high-risk disease, like monarchE, who had multiple positive nodes, you potentially could use AI plus CDK4/6 and then after that consider giredestrant, as was mentioned by Lisa Carey as well. It’s not as per the trial, but at the end of the day we want to use the best agent to reduce risk of recurrence in the adjuvant setting, so that’s a reasonable strategy to consider.

And then for patients who have 1 positive lymph node or patients with lymph node-negative disease, who were included in NATALEE but not monarchE, that does overlap with lidERA, and the question would be AI/CDK4/6 versus giredestrant monotherapy. And the advantage with monotherapy, obviously, is you have lower side effects. You don’t have the LFT problems that can be seen with the ribo. But then the downside is we don’t have the follow up we’ve seen with NATALEE and lidERA. So over time, once we get the 4-year and the 5-year iDFS results I think that’ll give more confidence related to giredestrant monotherapy versus CDK4/6 inhibitor plus AI.

DR LOVE: So actually, this is not exactly an algorithm slide, but it is a summary of your thoughts. This is from your presentation that you did for this program here, Erica. You have Stage I higher-risk, what about anybody who’s getting an AI adjuvantly, including lower-risk Stage I? I know there’s a financial cost issue that has to be — if you put that aside and just look at the pure risk/benefit do you think you can justify using it in even lower-risk Stage I?

DR MAYER: Well, I’d want to be very careful with Stage I. Although Stage I was included in lidERA it was a very specific high-risk Stage I population, for example having Grade 3 disease, high Oncotype, micromet in a lymph node. So if I’m imagining my Stage I giredestrant candidate I’m going to say it’s a young patient, high grade, Oncotype 30, got chemo, has a micromet. Someone you’re worried about, and you want to give them CDK4/6, but maybe they don’t meet criteria for CDK4/6. So that to me would be a perfect adjuvant giredestrant patient.

I think that ultimately we may be looking at a future where oral SERDs replace aromatase inhibitors and potentially replace tamoxifen and become the endocrine backbone of choice across the spectrum for management of hormone receptor-positive disease. We don’t have the data for all of that yet, but that might be where we’re heading. However, I think right now if we have availability in the adjuvant setting, I think we need to really go by the design of lidERA, the population of lidERA and just keep in mind that financially it will be a burden on our system if we are offering the drug too broadly and certainly outside of the clinical trial guidance.

DR LOVE: So Aditya, we see also listed here on this slide some of the ongoing adjuvant trials, CAMBRIA 1/2, EMBER-4 and ELEGANT. One of the strategies that some of these other studies are looking at is using 2 years of AI and then switching to a SERD. Any thoughts about the advantage of disadvantage of that compared to starting with a SERD up front, Aditya?

DR BARDIA: It is a potential strategy, and it’s also a practical strategy. Out of the different adjuvant studies lidERA was the first one to be launched, and it was towards the end of lidERA completion that CDK4/6 inhibitors were approved. So at that time endocrine monotherapy was the standard of care, but that’s not the standard of care now with the approval of ribo/abema.

So if you were to design an up-front study technically you cannot do just a single-agent endocrine agent. But this is a very practical design with EMBER-4, with ELEGANT, where patients once they complete the CDK4/6 inhibitor you can either continue the same therapy or switch to the oral SERD. The other advantage of this design is if the mechanism is to reduce the emergence of ESR1 mutations then using these drugs a bit later on, once patients have been on AIs for 2 or 3 years, you have more chance of reducing the ESR1-mutant clone with an oral SERD.

DR LOVE: Interesting.

Toxicity, Quality of Life

DR LOVE: Alright. I want to talk a little bit about toxicity with SERDs. We don’t talk about that too much because they’re so well tolerated, fortunately, but there are issues. And I thought it might be interesting, rather than kind of going through the trial data, Erica, I’m just kind of curious, right now you have a patient let’s say you’re about to start on elacestrant monotherapy. There’s kind of a limit to how much you can talk to a patient at one time, but they’re about to start it. What are some of the things you bring up to a patient that you’re going to be looking for, you want them to look for as they start therapy?

And how does this discussion vary when you use other SERDs, including camizestrant, giredestrant, as well as imlunestrant?

DR MAYER: Yeah. So I think, as you point out, an important thing to keep in mind is that oral SERDs are incredibly well-tolerated endocrine agents, and for the most part any toxicities we’re speaking about are quite mild in contrast to some of the other novel targeted agents that are entering space, including antibody-drug conjugates. So it’s very fortunate that these are very well-tolerated drugs.

As Aditya pointed out before, there can be some mild GI toxicity associated with elacestrant or imlunestrant. I like that you said that Aditya, upper GI for elacestrant, lower GI for imlunestrant. I definitely have seen some of that in practice, although it’s usually very easily managed with supportive care medications, and patients just generally get used to it over time. In comparison to the type of GI toxicity we see with other types of medications we offer for breast cancer I’d say it’s really quite mild.

There are these other interesting side effects that have come up with some of the agents, including bradycardia, which has been seen with giredestrant and camizestrant. This is typically Grade 1 bradycardia, meaning completely asymptomatic. Patient will come to clinic, their heart rate in triage might be in the 40s, but they are not feeling anything. It doesn’t affect them. They can exercise. They can do all their usual activities. It’s just something that we might find when the patient comes to see us.

I suspect over time if this is something that we begin to encounter clinically when we’re using these agents, we’re just going to get used to it. It’s not an emergency, it doesn’t mean that the patient is having a worrisome cardiac toxicity, and generally these just can be monitored.

The other unique toxicity is something called photopsia, which is an ocular toxicity where patients will mention they might see flashing lights or afterimages or halos around lights in the periphery of their vision, particularly in low-light conditions. This is something that has been seen with camizestrant. And I would say that there’s been a real deep dive into understanding this better, and what we’ve learned is this is a very short-lived toxicity. It just occurs for a few seconds. It in no way affects vision acuity. It does not impact patient’s function. For example, they can drive at night. They can do all their activities. It’s just a little something that a patient might notice.

I think also if we begin to use drugs commercially that cause photopsia we’ll just have to learn how to ask the questions to see if the patient’s experiencing it, but it’s not something that would require urgent ophthalmologic consultation or stroke evaluation or anything like that. It’s just something that we’ll note and carry on with our treatment.

DR LOVE: Anything you want to add to that, Aditya? Any thoughts about the — I don’t remember. I can’t actually remember anything that has a side effect of bradycardia. I’m sure there must be some drugs, but any thoughts about why you would see bradycardia with SERDs? And how does it manifest? Do people have normal responses to exercise with increasing heart rate? Do you ever see any symptoms from this? How low? Erica was saying maybe as low as 40. How low does it go?

DR BARDIA: Absolutely. There was a very nice publication 3 or 4 months ago, I think it was in JCI, where they talk about the mechanism of bradycardia from oral SERDs. It was from David … and his group. And it appears that because these endocrine agents are better than what we’ve seen previously ER is expressed in the heart, it’s expressed in the parasympathetic system as well, so it’s modulation of the parasympathetic system and the ER receptors in the heart that lead to bradycardia.

But it does not impair the ability of someone’s heart rate to increase with exercise, and they’ve done studies with these drugs where patients were put under stress test and under exercise treadmill test, and in all of those they ability to increase the heart rate was maintained.

So it does not have any physiological consequence from that perspective, it’s something that’s seen on EKG or other monitors, and as Erica mentioned a majority of the patients are asymptomatic, so does not have clinical consequence.

DR LOVE: Yeah. So amazing being in oncology nowadays. I noticed there was actually a poster at ESMO on the ophthalmic effects of SERDs, a poster just on the ophthalmic effect. We did an entire webinar on ophthalmic issues in oncology, which — particularly the ADCs of course.

So another question back to you, Erica. We didn’t talk about vepdegestrant, which kind of looks to me it’s very similar to the story we’ve already heard. Can you kind of summarize what we know about this SERD and whether you think it’ll get approved and what role, if any, do you think it’s going to have? And for that matter how you differentiate other than looking at what kind of trials are being done between these 4 agents. They seem more similar than different, even more similar than CDK I think.

DR MAYER: Yeah. So vepdegestrant is a novel endocrine agent. It’s a PROTAC, so it is a medication that’s really meant to be a profound antagonist of estrogen receptor. And it was studied in the VERITAC trial, in which pretreated patients were randomized to receive vepdegestrant monotherapy or standard of care endocrine monotherapy, and the results were actually quite similar to what we’ve seen with the EMERALD study and the EMBER-3 study in that the real benefit of the vepdegestrant was in patients with ESR1 mutations. So the data, even the numbers, were really quite symmetric with those 2 other studies.

This was a registration study. The data could lead to an approval of the drug as monotherapy. It would then be the third monotherapy endocrine agent for ESR1 population, and how that might play in practice we’d have to see. So I’m not sure it moves the needle that much compared to the data we already have, but it’s a drug that I think there’s been a lot of interest and excitement about.

DR LOVE: Yeah. I kind of wonder if it’s going to be able to squeeze in there with all the other things that are going on.

So my crack chat room is reminding me that lenalidomide and ondansetron can cause bradycardia. A question from Charles: do you see QTc prolongation. Aditya, do you see that with SERDs?

DR BARDIA: No, not to my knowledge, we’ve not seen any QTc prolongation with camizestrant or giredestrant.

New Directions

DR LOVE: So finally, I’m just kind of curious where you think things are heading. Maybe you can make some predictions on if we do Year in Review next year at this time on SERDs what we’re going to be talking about. We just brought up the issue of PROTACs, whether you think that’s ever going to be part of the menus here so to speak, and any trials that you think might be maturing, Erica, over the next year that could help shape this whole increasingly complex topic?

DR MAYER: Well, there are other novel endocrine agents that we’re keeping our eye on. There is palazestrant, which is an oral CERAN that is entering Phase III trials right now and has shown a lot of nice activity in heavily pretreated patients. There’s also lasofoxifene, which is a novel oral SERM that is in the Elaine-3 Phase III trial that we’re also keeping an eye on. So I think those are 2 agents that may also be entering the space for us.

But I think in 2026 what we may be faced with is a number of new drug approvals because we have a lot of this data currently at the FDA. And it’s been really exciting to see the data come out and to think about it and talk about it, but I think the real kind of rubber hits the road is going to be if these drugs are approved how do we actually begin using them, where do they fit in our algorithm, and how are we going to sequence medicines.

For example, do we sequence SERD after SERD if we have multiple SERDs available? We have no idea. So I think the next challenge for us is going to be with commercial availability of more of these drugs and more of these combinations how do we actually fit this into practice.

DR LOVE: So Erica and Aditya, thank you so much for working with us today and also for recording your great presentations that I really recommend to the audience.

Audience, thank you for attending. Be safe, stay well and have a great night.

Thanks so much, Erica. Aditya, thank you so much.