Appropriate Identification of Candidates for and Practical Implementation of Oral Selective Estrogen Receptor Degraders (SERDs) for Progressive HR-Positive, HER2-Negative Metastatic Breast Cancer (mBC) — Aditya Bardia, MD, MPH

DR BARDIA: Hello, I’m Aditya Bardia, medical oncologist at UCLA, and I’m excited to talk about oral SERDs for patients with metastatic breast cancer. We’ll do a Year in Review. We’ll talk about practice-changing studies, different oral SERDs and how they fit in clinical practice.

So let’s first start with mutations in the estrogen receptor or what are called ESR1 mutations. So these are mutations in the ligand-binding domain of the estrogen receptor, so the site where estrogen binds to the estrogen receptor, the ligand, that’s where there’s a mutation, and with the mutation the tumor becomes independent of the ligand, or estrogen, so it becomes an estrogen-independent tumor, but it’s still dependent on the estrogen receptor. So drugs which lower estrogen, like aromatase inhibitors, would not work, but drugs that directly bind to the estrogen receptor, like selective estrogen receptor degraders, which we’ll review, would work in this setting. So this has led to tremendous interest in this area of targeting ESR1 mutations with these novel drugs.

How common are these ESR1 mutations? Well, these are acquired mutations. If you profile a primary tumor, it’s unlikely that you would find these mutations, but in the metastatic setting, under selective pressure from aromatase inhibitors, the tumors acquire this mutation, which makes them resistant to aromatase inhibitors and thus disease progression.

So there have been a number of studies, including a recent publication in 2026, which looked at the frequency of these mutations in matched primary versus metastatic samples, and not surprisingly the frequency is much, much higher in the metastatic setting, in the metastatic samples, as compared to the primary sample for the same patient. And that’s why often we recommend blood-based genotyping or plasma-based genotyping to pick up these mutations and doing serial testing with every disease progression because the fact that it’s not present in the first setting does not mean it will not be present in the second one or the third one, so serial testing can be very valuable.

Now, does this impact clinical practice? And the answer is yes. This started with the EMERALD study. EMERALD was a pivotal randomized Phase III clinical trial, which evaluated oral SERD elacestrant versus investigator choice of endocrine therapy, which would be fulvestrant or an aromatase inhibitor for patients with ER-positive metastatic breast cancer in the second-line and plus setting. And important point to note is in the first-line setting we tend to use CDK4/6 inhibitors, so this trial required all patients to have received prior CDK4/6 inhibitor, and then after that were randomized to elacestrant versus investigator choice of endocrine therapy.

The primary endpoint was progression-free survival in all comers, but importantly this was the first study that did this: the study had a primary endpoint of looking at progression-free survival in patients with detectable ESR1 mutations. The idea was in this setting if a patient has detectable ESR1 mutation the tumor is likely still dependent on ER, and if you use an oral SERD that would work in this setting.

This was different from some of the other studies at that time. AMEERA-3, as well as the acelERA study, asked similar questions in terms of looking at oral SERD, amcenestrant and giredestrant respectively, in the second-line-plus setting. But the differences were that they did not mandate prior CDK4/6 inhibitor, and also the primary endpoint was not looking at ESR1 mutations, it was the overall population. Both of those trials were negative, AMEERA and acelERA, but if you look at subgroup analyses from those studies and look at patients who had ESR1 mutations you could see that the study was positive in that subgroup, very similar to what was seen in EMERALD. So partly the reason for these negative studies could be because of study design and the endpoint.

In terms of looking at who does well on single-agent endocrine therapy, subgroup analyses from the EMERALD study looked at can we predict who can do well with single-agent elacestrant and a simple clinical biomarker of looking at the prior duration of CDK4/6 inhibitor of more than 12 months. If a patient is on first-line therapy, as long as they are on CDK4/6 inhibitor plus endocrine therapy for more than 12 months, in that setting the median progression-free survival with elacestrant was close to 9 months versus about 2 months with standard endocrine therapy. So some clinicians, some providers have used this in their clinical practice to see who could still receive single-agent endocrine therapy, such as elacestrant, is to look at the prior duration of CDK4/6 inhibitor, and as long as that’s more than 12 months that’s a setting one could consider single-agent endocrine therapy.

How about patients with double mutations? A subgroup of patients have both detectable ESR1 as well as PIK3CA mutation. These are not mutually exclusive, and the question becomes should I consider elacestrant or should I consider say fulvestrant plus capi or fulvestrant plus alpelisib. So subgroup analyses from EMERALD showed that as long as a patient was on prior CDK4/6 inhibitor for more than 12 months in that setting elacestrant monotherapy still has activity in patients who have double mutations, both ESR1 and PIK3CA, and maybe that’s because the tumor is still dependent on ER and may be more dependent on ER than the PI3 kinase pathway, so if you use an agent that targets ER, like elacestrant, that would work in this setting.

How about real-world data? We have now 2 prominent publications, 1 from Max Lloyd, the other from Hope Rugo, both published in CCR, demonstrating that the median progression-free survival or time to next therapy from real-world analyses is quite similar to what was seen in the EMERALD study in patients who have CDK4/6 inhibitor for at least 12 months. So the median progression-free survival or time to next therapy ranged from 6-8 months, something that is clinically meaningful, and we now have real-world data as well.

How about AEs? We talked about efficacy. We talked about the median PFS being in the range of 6-9 months with monotherapy in the right setting. What are the downsides of using elacestrant? The most common side effect is nausea. After nausea you can see endocrine side effects like hot flashes, but it’s nausea which is the predominant side effect. But you don’t need antinausea medications because the incidence of Grade 3 or higher nausea is very low. So most of this can be managed with taking the medication with food, but if a patient really has severe side effects you can consider antinausea medication. Now some patients also have upper GI upset, and if that’s the case you could consider a PPI and again taking the medication with food.

So that was elacestrant, which was the first oral SERD approved for patients with ESR1-mutant breast cancer, but now we have a second drug approved, and that’s imlunestrant. That was based on the EMBER-3 study, which looked at imlunestrant versus standard-of-care endocrine therapy in second-line-plus setting.

There are 3 differences to consider between EMBER-3 and EMERALD. The first is this trial also had a third arm of imlunestrant plus abema, and the way the study was designed was if imlunestrant is superior to endocrine therapy, either in all patients or patients with ESR1 mutation, then you could look at the third arm. The second difference was this trial did not mandate prior CDK4/6 inhibitor, but prior CDK4/6 inhibitor was allowed in this trial. And the third is looking at imlunestrant plus abema was allowed in this study, but it was based on what you would see with monotherapy, so as long as single-agent imlunestrant is superior to endocrine therapy then you could look at the combination.

So what did the results show? Somewhat similar to EMERALD in patients with ESR1 mutations that were detectable you could see that the median progression-free survival with imlunestrant was superior to standard endocrine therapy. In the ITT population, similar to acelERA, similar to the AMEERA study, the study was negative. There was no difference — or statistically significant difference between imlunestrant and standard-of-care endocrine therapy. But looking at this ESR1-mutant subgroup you could see benefit with imlunestrant versus standard-of-care endocrine therapy, again highlighting the point I mentioned previously, study design and the primary endpoint.

In terms of looking at imlunestrant plus abema versus imlunestrant, because the study was significant in the ESR1-mutant population the team could look at doublet versus single agent, and the doublet was better than single agent, not surprisingly, and you can see median PFS 10 months, 11 months, getting close to a year with combination therapy.

In terms of subgroups, all the subgroups derived benefit. Patients with visceral metastases, patients with dural ESR1 as well as PIK3CA mutation also derived benefit similar to what was seen in the EMERALD study. So there were no surprises seen here.

In terms of side effects, the side effect with imlunestrant is — number 1 side effect is diarrhea, and obviously with the combination of imlunestrant plus abemaciclib you have more diarrhea because both the drugs tend to cause diarrhea, and that’s an important differentiating factor between imlunestrant and elacestrant. Both of these drugs are now FDA approved, and the question becomes which one to consider, and often it’s the side effect profile. One tends to cause more nausea, upper GI upset, the other one tends to cause more diarrhea, and that’s a consideration in terms of discussing these options with the patient.

If we specifically look at patients who received prior CDK4/6 inhibitor you see the benefit was slightly less as compared to the CDK4/6 naïve but still the benefit was maintained, particularly with the combination imlunestrant plus abemaciclib, where the median PFS was 9.1 months versus 3.7 with imlunestrant as a single agent. And if we look in subgroups but just for patients who had received prior CDK4/6 inhibitor, again pretty much all the subgroups derived benefit. We look at type of prior CDK4/6.

If there was a signal, if the patient had received prior abema, then the benefit was less in terms of using imlunestrant plus abema, but wide confidence interval and also less relevant in clinical practice because we often use ribo as the preferred CDK4/6 in the first line, sometimes use palbo as well, and in both those subgroups you can see benefit with imlunestrant plus abema over imlunestrant alone.

How about the line of therapy? If you look at first line, second line, first line being patients who had disease recurrence on adjuvant therapy, not surprisingly the benefit is higher in terms of the absolute magnitude as compared to second line. We know with every line of therapy the median progression-free survival tends to decrease.

They also did efficacy in terms of looking at the combination of imlunestrant plus abema and again benefit larger in first line, where the median PFS was more than 12 months with imlunestrant plus abema, and in the second-line setting still pretty good, 9 months and again highlights that later on the median progression-free survival tends to decrease with subsequent line of therapy.

How about safety? As I mentioned previously, the main side effect with imlunestrant is diarrhea. Many patients needed dose reduction with combination therapy of imlunestrant plus abema. You could decrease from 150 to 100 mg and even 50 mg.

In terms of the actual onset of these AEs the median time to onset in the imlunestrant arm was 30 days, with imlunestrant plus abema was 5 days, predominantly secondary to diarrhea, which tends to occur in the first cycle. And at least in the adjuvant setting some providers have started using abema in terms of ramping the dose up, starting with 50 mg then 100 then 150, and so that is an important strategy to consider if you’re concerned about the AEs. Or if a patient has a history of diarrhea and other GI AEs in the past you could potentially consider starting low and then ramping up the dose of abemaciclib.

Obviously, in the adjuvant setting you have much more time. You’re getting 2 years of abema therapy. It’s less than the metastatic setting, so I would not recommend it for every patient, but for an individual patient if there’s a concern something to consider.

In terms of other AEs, bradycardia, photopsia was really not seen. Why is this relevant? This becomes relevant as we talk about other SERDs, particularly giredestrant and camizestrant, which tend to have these side effects, and again it’s the side effect profile which becomes a differentiating factor in terms of selecting these agents. But with elacestrant, as well as imlunestrant, we don’t see bradycardia or photopsia.

Okay. So we reviewed 2 drugs that are FDA approved. Now I’ll review 3 drugs which might get FDA approved in 2026. The first one is vepdeg, or ARV-471. This was also evaluated in the second-line-plus setting, very similar to EMERALD and the EMBER-3 study. Primary endpoint PFS ITT but also PFS in ESR1 mutation.

And pretty much identical results. All comers, no difference, but in patients with ESR1 mutations you could see vepdeg was superior to fulvestrant.

In terms of safety/tolerability, fatigue was the most common AE seen. Some increase in ALT/AST that was slightly higher than fulvestrant but overall very well tolerated. Some neutropenia also seen in this trial.

So here’s a summary of all these studies, EMERAL, AMEERA, acelERA, EMBER-3 and VERITAC. Most of these trials either required or allowed prior CDK4/6. All the trials which had ESR1 mutation as a coprimary endpoint were positive. The trials that just had ITT as the primary endpoint were negative. And in the EMERALD study elacestrant was superior to standard-of-care endocrine therapy in the ITT population, as well, so among all these studies that’s the only study that was positive in the ITT population also. And in terms of AEs, nausea with elacestrant, diarrhea with imlunestrant and then some degree of anemia and neutropenia with vepdeg.

Okay. So we talk about — we talked about these second-line options as monotherapy. Now I’ll talk about 2 additional drugs, first camizestrant in combination with a CDK4/6 inhibitor and then giredestrant in combination with everolimus.

So let’s start with camizestrant. Essentially, the background of the trial evaluating camizestrant, SERENA-6, was set by PADA-1. PADA-1 was an investigator-initiated study done in Europe, very interesting study, which asked the question in the first-line setting we use AI plus CDK4/6, and we know a subset of patients develop ESR1 mutation, which can be detected by blood-based test. So similar to tumor markers can we screen and detect ESR1 mutations during routine surveillance when the patient is on first-line therapy, and if a patient has detectable ESR1 mutation can we switch therapy in the absence of radiological progression, so at the time of molecular progression? So this was evaluated in the PADA-1 study and provided proof of principle that can be done.

The team also did additional analysis to see what are the factors that predict who would develop ESR1 mutation, and they found that elevated LDH, patients who have bone metastases, these were predictors of developing ESR1 mutation.

They also then looked at how patients do in terms of PFS1 and PFS2, and this becomes relevant with SERENA-6, and found that early switch also helps with PFS2. They have not demonstrated improvement in overall survival yet, but it does make the case that with an early switch patients tend to do better.

And this essentially set the stage for the registration study, SERENA-6, which was presented at ASCO in the Plenary Session in 2025. It was a large study. More than 3000 patients in the first-line setting were screened for ESR1 mutations, and about 10% of them had detectable ESR1 mutations in the absence of radiological progression and were randomized to continue the same therapy versus switch to camizestrant.

And the trial showed that if you switched to camizestrant you have a much better median progression-free survival, 16 months, so that’s a year and a half with an early switch versus about 9 months with continuing same therapy. So it’s not like patients had disease progression on the next scan. They still derived some benefit by continuing the same therapy before you could see progression on scans, but by early switch that was even better.

Now, some have raised the question does early switch necessarily improve overall survival. That’s not answered yet, but what we do have data is that PFS2 was prolonged, and also time to deterioration in quality of life was prolonged with the early switch as opposed to continuing the same therapy. So the sponsor has filed for approval of camizestrant in the public domain. It’s announced that there’s an ODAC that will happen sometime this year, and the FDA will make a decision about potential approval of camizestrant in this setting.

How about other combinations? I want to touch on another drug, which is giredestrant. Giredestrant was evaluated in the EVERA study in combination with everolimus versus endocrine therapy, which could be exemestane or fulvestrant, plus everolimus again in the second-line-plus setting.

The results, as presented by Dr Erica Mayer at ESMO last year, showed that the combination of giredestrant plus everolimus was superior to endocrine therapy plus everolimus in the overall population. And if you look at the ESR1-mutant subgroup that’s where you clearly see a separation in favor of the combination.

And conversely, if you look at the non-ESR1-mutant setting, the benefit is much less as compared to what was seen in the ESR1-mutant setting. So even with combination therapy with giredestrant plus everolimus we see very similar results to what was seen with the other oral SERDs, that the benefit is in the ESR1-mutant setting when we talk about using these agents either as single agent or combination in the metastatic setting.

In terms of AEs, with everolimus we tend to see stomatitis, diarrhea, some myelosuppression, so that was seen in both the arms. What was unique to giredestrant was bradycardia. That is a side effect that’s seen with giredestrant, also seen with camizestrant, and appears to be related to the impact on the estrogen receptor and the parasympathetic tone that these drugs can impact.

How about combination with elacestrant? The ELEVATE study looked at elacestrant in combination with other drugs, with alpelisib, with CDK4/6 inhibitor, with everolimus, and we’ve seen some data now. Now, this is not a randomized study. These are results from single arm combining elacestrant plus everolimus or elacestrant with CDK4/6 inhibitor such as ribociclib in second-line-plus setting, and you’re seeing results similar to what was seen in the other studies like EVERA. We have the caveat of cross-trial comparisons, but we’re seeing median progression-free survival close to 9 months with the combination therapy.

So this was all in the metastatic setting. We reviewed elacestrant, imlunestrant. We reviewed camizestrant, giredestrant, as well as vepdeg. But we know the mainstay of management of ER-positive breast cancer with endocrine therapy is in the localized setting. The majority of patients get diagnosed with localized disease, and the mainstay of management there is endocrine therapy.

The mainstay has been aromatase inhibitor or tamoxifen, but these oral SERDs are challenging that. There are 2 different study designs that different sponsors have taken. The first one is up-front strategy, which is after surgery randomization to oral SERD such as giredestrant versus endocrine monotherapy like AI/tamoxifen. This was evaluated in the lidERA study, which we’ll review, and is ongoing in CAMBRIA-2 study.

The other approach, which is being evaluated in EMBER-4, CAMBRIA-1, as well as ELEGANT, is the switch strategy. The idea being patients would do endocrine therapy alone with/without a CDK4/6 inhibitor for 2-3 years and then after that switch to an oral SERD versus continuing the same therapy in the adjuvant setting. That’s being evaluated with imlunestrant, elacestrant, as well as camizestrant.

So how about the up-front strategy, the lidERA study. We saw the results at SABCS 2025 that giredestrant after surgery in the up-front setting was superior to standard-of-care endocrine therapy, both tamoxifen, as well as aromatase inhibitor, with a hazard ratio of 0.70. That was pretty impressive because that’s similar to what we’re seeing with combination therapy with endocrine therapy plus CDK4/6 inhibitor in this setting and much better than what was seen with AI versus tamoxifen with BIG 1-98 and ATAC and other studies. So this provides clear proof of principle that giredestrant and next-generation oral SERD is superior to aromatase inhibitor and tamoxifen in this adjuvant setting.

The team looked at subgroups, as well, and in all subgroups there was benefit, including Stage II and Stage III disease. In Stage I disease, which was included in this trial, the confidence interval crossed 1, but the number of events were few, so we need more follow-up.

In terms of side effects, as I mentioned previously, giredestrant tends to cause bradycardia, so that is what was seen in this study as well, higher frequency as compared to standard-of-care endocrine therapy. What was lower with giredestrant was the rate of discontinuation because of musculoskeletal symptoms like arthralgias. We know that’s a common side effect from aromatase inhibitors and some patients have to discontinue the drug because of arthralgias and musculoskeletal AEs. And the discontinuation rate, not surprisingly, was higher in the standard-of-care endocrine therapy as compared to giredestrant.

So to summarize, endocrine therapy is the mainstay, and I predict will continue to remain the mainstay of management for ER-positive breast cancer. The strategies have changed but the principle remains the same. Currently we have elacestrant, as well as imlunestrant approved in the meta setting for patients with detectable ESR1 mutations. In the second-line-plus setting in the future there will be — there could be additional drugs, vepdeg, giredestrant, as well as camizestrant. In the localized setting giredestrant demonstrated superiority over standard endocrine therapy and could be a drug that becomes approved, the first oral SERD in the adjuvant setting, for patients with ER-positive breast cancer.

The landscape continues to evolve. In the future we’re likely going to see combination therapy with these oral SERDs with CDK4/6, PI3 kinase, maybe newer agents, as well, and that will further define the therapeutic landscape for patients with breast cancer.

So how do we put all of this in clinical practice? We have a number of drugs now. For patients with ER-positive metastatic breast cancer the first-line setting continues to be endocrine therapy such as an AI plus CDK4/6 inhibitor. When patients have disease progression genotyping is strongly recommended because that’s actionable. In patients who have ESR1 mutation elacestrant is an option to consider. One could also consider imlunestrant with/without abemaciclib. And in the future giredestrant, everolimus, vepdeg could be potential options and maybe camizestrant with a CDK4/6 inhibitor as well.

For patients who have PI3 kinase mutation fulvestrant/alpelisib, fulvestrant/capi are potential options. For patients with detectable PTEN/AKT alterations fulvestrant/capi is a potential option. For those with germline BRCA mutation PARP inhibitors, olaparib, talazoparib are potential options. And if there are no actionable alterations one could consider exemestane/everolimus, fulvestrant with abemaciclib, or consider other potential options as well. We always recommend clinical trials, and in any of these settings clinical trials could also be considered.

Thank you so much for your attention.

Future Directions in the Use of Oral SERDs for HR-Positive, HER2-Negative BC — Erica Mayer, MD, MPH, FASCO

DR MAYER: I’m Erica Mayer from the Dana-Farber Cancer Institute, I’m our Director of Breast Cancer Clinical Research, and I’m very excited to review for us future directions in the use of oral SERDs for HR-positive, HER2-negative breast cancer in our Year in Review.

So we’ve selected 9 different papers and abstracts that we wanted to cover, and these really span a whole range of different scenarios and different agents in the oral SERD space. We’re going to start out talking about camizestrant, then switch to giredestrant, then shift to elacestrant. We’re then going to cover a series of small but very provocative window-of-opportunity preoperative studies, and then finally we will close out with a large adjuvant trial, which is perhaps the blockbuster trial for 2025.

So let’s jump right in. And we’re going to start with the publication of the SERENA-1 trial. So this is a Phase I trial that was looking at different dose levels of the oral SERD camizestrant in combination with our commercially available CDK4/6 inhibitors as treatment for HR-positive, HER2-negative metastatic breast cancer. The 3 agents that we will be looking at include abemaciclib, palbociclib and ribociclib, and you can see the size of the cohorts listed here.

So first of all, the study was designed to look at efficacy at the different dose levels that were available for camizestrant, as well as different dose levels of the CDK4/6 inhibitors. I recognize there’s a lot of different pieces of data on this slide, but in summary I’d say that there was evidence of activity across the board with all of the 3 dose levels of camizestrant that were studied, including the lowest dose level of 75 mg. And this activity was observed in a variety of subgroups, including patients with prior exposure to the SERD fulvestrant, patients with prior exposure to CDK4/6 inhibitors, patients with and without ESR1 mutations and in patients with visceral disease.

Regarding toxicity, the safety profile that was observed with camizestrant was quite consistent with what has previously been seen when the agent has been studied as monotherapy. I will point out some specific toxicities that can be seen with camizestrant include something call photopsia, which is when patients may report flashing lights or halos around lights that are very brief and short-lasting and may happen at times of day when there’s low light, for example in the evening. This is not something that impacts visual acuity or patient functioning, but it is something that a patient might report.

Additionally, some of the oral SERDs can cause bradycardia, and there was some Grade 1 bradycardia seen in SERENA-1, but this is asymptomatic bradycardia and does not require any interventions. In combination with the CDK4/6 inhibitors there was no evidence of additive toxicity. The safety profile was consistent with the known safety profiles of the individual agents.

So in considering SERENA-1 I think this teaches us that camizestrant is well tolerated and active in combination with all 3 CDK4/6 inhibitors, and based on this data this helped establish the 75 mg dosing level of camizestrant as the dose to move forward in combination study. This was one of the earlier studies to note the photopsia as this unique toxicity that can be seen with oral SERDs, but as I said this is brief and doesn’t impact patient activities or visual acuity.

And importantly the data that was generated from SERENA-1 was very helpful in the design of subsequent studies that are either ongoing or have reported, including the SERENA-6 study, which we’re about to get to, and the ongoing SERENA-4 and CAMBRIA-2 trials, and so this is really the basis of what led to the much larger trials.

So speaking of SERENA-6, at San Antonio this year we saw updated results from this Phase III trial, as well as a very interesting exploratory analysis of ESR1 circulating tumor DNA dynamics. So let’s take a look.

So first, just as a review, SERENA-6 has a somewhat complex design, so it’s important to remember what that is. This is a study that has 2 steps to it. Step 1 was a screening step where patients who were receiving first-line aromatase inhibitor and CDK4/6 inhibitor for at least 6 months began a screening process of serial ctDNA, usually every 2-3 months, looking for the emergence of a resistance mutation, an ESR1 mutation. If that mutation was found in the absence of clinical progression, then those patients could move to step 2 of SERENA-6, which you see listed here, which was a more traditional randomized Phase III design.

Three hundred and fifteen patients moved to step 2. They were randomized to switch their endocrine therapy from aromatase inhibitor to the oral SERD camizestrant and continue CDK4/6 inhibitor, and they did have a placebo added, or remain on the same aromatase inhibitor and CDK4/6 inhibitor, and they got a placebo for camizestrant. Now, on the bottom you can see that there was a ctDNA schedule of checking ctDNA every 2 weeks for the first 8 weeks of treatment to look at the kinetics of ESR1 mutations.

So first this is updated data from SERENA-6. Now we already saw the primary report of the study at ASCO Plenary earlier in the year, and at San Antonio we saw updated data, which confirms the benefit in the primary endpoint of progression-free survival. We see a prolongation from 9.2 months in those who remained on the standard-of-care aromatase inhibitor arm prolonged to over 16 months in the patients who made the switch to the oral SERD at the time of emergence of the ESR1 mutation. There was also a prolongation in time to first subsequent therapy.

Additionally, there was updated PFS2, and so this would be from randomization to the second progression. And this data remains immature but has a favorable trajectory. We can see there’s about a 6-month improvement in PFS2 for the patients who make the switch to camizestrant versus those who had remained on aromatase inhibitor and also a favorable time to second subsequent therapy.

Another very interesting observation in this presentation was looking at these ctDNA dynamics. And so what this is looking at is the ESR1-mutant allele frequency. On the left column we can see that for the camizestrant arm, for the patients who switched to camizestrant, there was a profound reduction in the ESR1 mutation allele frequency, with a median change of 100%.

Now in contrast, in the column on the right, which is the aromatase inhibitor column, those who stayed on aromatase inhibitor, there was no decrease. In fact, there was a median increase of 66%, and actually a quarter of patients had a 500% increase from baseline. So I think this is really interesting because it’s showing us that the oral SERD is hitting the target. The target is the estrogen receptor and in particular the mutated estrogen receptor, so it’s really a very nice pharmacodynamic signal.

So in summary from these results, we can see that with greater maturity of SERENA-6 after the initial ASCO presentation this data continues to support this concept that changing to camizestrant at the time of emergence of an ESR1 mutation significantly prolongs progression-free survival, there’s a favorable trend for PFS2, and it’s prolonging time to second therapy. That reduction in the ESR1 mutation level with exposure to the oral SERD really supports this pharmacodynamic activity of camizestrant and the molecular benefit of making this switch.

We need more maturity of PFS2, we need more maturity of overall survival and also potentially a drug approval here, to understand if this SERENA-6 approach, the serial monitoring for emergence of a resistance mutation and then switching to a therapy when that’s found if that could become a new standard of care. So definitely something to keep our eyes on.

So let’s switch now and talk a little bit about another oral SERD, and this is giredestrant, and the major trial for 2025 with giredestrant was the Phase III evERA study.

So let’s take a look at the schema for this trial. So this was a global Phase III trial that enrolled patients who had already progressed on at least 1 prior line of endocrine therapy in the metastatic setting. Everybody in this trial had prior CDK4/6 inhibitor, nobody had prior chemotherapy, and patients needed to have been stable on their prior therapy for at least 6 months before progression, so not an entirely endocrine-resistant population.

These patients were randomized, 373, to 2 different combination arms. One combination arm was the oral SERD giredestrant in combination with the mTOR inhibitor everolimus, and the control arm was standard-of-care endocrine therapy, so it could be exemestane or fulvestrant, in combination with everolimus. And there were coprimary endpoints in this study, PFS in the ITT population and PFS in the population of patients whose tumors had an ESR1 mutation.

I think it’s important in just looking at this schema that what sets this trial apart from the other Phase III oral SERD studies is this is a combination versus a combination, and the control arm, the endocrine with everolimus, is a standard-of-care combination. This is something that many of us might be using in our clinics. So it’s in contrast to other studies, where we are often comparing a combination to a monotherapy.

So the primary results were presented at ESMO this past year and demonstrated that the study met both of the coprimary endpoints. Progression-free survival was substantially prolonged in both the ESR1 mutation population, from about 5 1/2 months, to about 10 months, hazard ratio 0.38, and also in the ITT population with similar favorable PFS. So this was a positive study.

There was a subgroup analysis subsequently presented at San Antonio looking at outcomes based on PI3 kinase mutation status or PIK3CA pathway status and thinking about the 3 groups, those with ESR1 mutation, those whose tumors did not have ESR1 mutation and in the ITT population. So we can see that just starting from the bottom the ITT patients, whether PIK3CA was present or absent, are all getting benefit from giredestrant. In the top category patients who have an ESR1 mutation, here we’re thinking about the idea of comutation, so having both ESR1 and PIK3CA, we see a sustained benefit from giredestrant. In those patients who do not have an ESR1 mutation the potential benefit of giredestrant, I would say, is less pronounced.

Additionally, there was an analysis looking at outcome based on duration of prior CDK4/6 inhibitor as that has been, in some ways, a marker of endocrine sensitivity or resistance, at least in the monotherapy studies of oral SERDs. And here we see in the ESR1-mutant population, whether the patient had less than 12 months of prior CDK or more than 12 months, we see very much a preserved benefit of giredestrant in both groups, and this was also observed in the ITT population as well.

So in summary, in the evERA trial the combination of giredestrant and everolimus prolongs progression-free survival in both the ITT and ESR1-mutant population, so it met both of the primary endpoints. And as I pointed out, this is the first Phase III trial that is comparing an oral SERD combination to a standard-of-care combination instead of comparing to a monotherapy arm, so for example in contrast to EMBER-3 that had the combination of imlunestrant and abemaciclib, but the comparison was imlunestrant monotherapy not a combination arm.

Importantly, the updated data has shown that the benefit of giredestrant and everolimus was observed in the prespecified subgroups, including PIK3CA-mutated, so that co-mutated group, regardless of duration of prior CDK4/6 inhibitor, but benefit is not as pronounced in the ESR1 no mutation detected or what we might think of as ESR1-wild-type group. And so we await to see if there will be regulatory approval for this particular combination.

And now let’s change over to a different oral SERD. This is elacestrant, and we have seen data coming out from the Phase II multiplatform ELEVATE study. So this is a study that has looked at different combinations of elacestrant with targeted partners in an umbrella fashion with different platforms. So this was a study for patients with metastatic hormone receptor-positive, HER2-negative breast cancer with 1-2 lines of prior endocrine therapy plus/minus CDK4/6 inhibitor. Patients were allowed to have prior fulvestrant. They could have primary endocrine resistance but no prior chemotherapy.

Now the 2 cohorts which we saw reported at San Antonio this year were elacestrant and everolimus, so with the mTOR inhibitor, and elacestrant with abemaciclib, a CDK4/6 inhibitor. Primary endpoint of the study is progression-free survival, and we can see the PFS curves listed here, so what we’re looking at is the single-arm PFS. So the combination of elacestrant and everolimus has median PFS 8.3 months; elacestrant and abemaciclib median PFS 14.3 months.

I think in both of these we can say that there is activity of these combinations, and in general we see very consistently the combination of an oral SERD with a targeted partner gives us a PFS beyond 6 months, which had been a kind of ceiling prior to initiation of these combination concepts.

But it’s important as we look at this that we recognize that this is not a randomized trial and there could be different patient populations in each of these cohorts. So for example, in the everolimus cohort, elacestrant and everolimus, 100% of patients had prior CDK4/6 inhibitor, but in the elacestrant and abemaciclib cohort that number was only 50% and the degree of pretreatment and prior exposures may influence the sensitivity of the disease to what is being offered as part of the trial. So it’s important that as we look at this that we don’t start to think of cross-trial comparisons in our mind because the patient population may be different trial to trial.

So I think we see from ELEVATE that these combinations with elacestrant are active and they are tolerable. We previously had actually seen the combination with ribociclib with a PFS of 7.8 months. A combination with capivasertib is currently ongoing. But, as I point out, this is not randomized so it does limit the interpretation due to the degree of patient pretreatment. But I think our big signal here is that oral SERD combinations are definitely the way forward as we are seeing this more than 6-month PFS and we see very little additional toxicity from the endocrine agent.

Okay, so now let’s switch gears, and we’re going to move from the metastatic setting to the very early preoperative setting and look at a series of window-of-opportunity studies. So these tend to be studies offering very short durations of novel agents prior to surgery looking at biologic endpoints, often cellular proliferation or cell cycle arrest. These are not preoperative trials where patients are getting 6 months of therapy and we’re looking at pCR; instead it’s really much more molecularly based.

And so the first study we’ll look at is called the SOLTI-ELIPSE trial, and this is using elacestrant. This trial enrolled a small number of patients, just 22 patients, postmenopausal, with hormone receptor-positive, HER2-negative breast cancer and a Ki-67 of 10% or more. These patients got a month of elacestrant and then they went to surgery, so they had tissue collection from the baseline biopsy and then at the time of surgery. And the primary endpoint of this study was looking at complete cell cycle arrest, so a profound suppression of cellular proliferation as measured by a very low Ki-67.

So what did we learn from this study? Well, in general exposure for the 1 month of elacestrant did lead to a decrease in Ki-67. The mean decrease was 8.4%. And there was a lot of effort put into looking at different tumor types and how they responded to the 1 month of elacestrant. In general, 27% of all of the patients achieved the primary endpoint of complete cell cycle arrest, so a quarter of patients had the cell cycle arrest, but this was much more prominent in Luminal A cancers. Forty two percent had cell cycle arrest. It was actually not seen in Luminal B. There was 0% with cell cycle arrest. Even though many of these patients did have a drop in Ki-67 it just did not suppress them to the very low level.

Similarly, the benefit appeared greater in those with low Ki-67 versus high Ki-67 at baseline.

Also very interestingly exposure to the 1 month of oral SERD led to some molecular changes that create perhaps a more favorable tumor biology. For example, there was an increased signature for Luminal A and something called chemo-endocrine score, which is favorable. There was decreases in ESR and PGR, there was a decrease in PAM50 proliferation signatures and increases in immune-related genes, so in general setting the stage for a more favorable tumor biology.

Let’s move to the second of the window studies, and this is the SERENA-3 trial. So trials that are called SERENA are trials that are using camizestrant. So this was a study looking at a very short exposure to camizestrant in 132 postmenopausal patients. They received different dose levels of camizestrant and for different durations, ranging from 5-7 days or 12-15 days, so very short exposures, looking at a primary endpoint of change in estrogen receptor.

I know there’s a lot of data present on this slide, but I would sum it up by saying that the reduction in the primary endpoint of estrogen receptor happened very quickly. Within about a week of treatment there was a profound drop in estrogen receptor, so a pharmacodynamic example of the drug hitting the target. A reduction in Ki-67 was maximal, about 2 weeks into treatment. And the interpretation of these results was that that lower dose, 75 mg, which we already just saw in the Phase I trial, was confirmed through this trial to be the dose for the larger adjuvant studies. And this was also confirmed by other data from the metastatic setting.

And our third preoperative trial is a trial called EMPRESS, which was presented at ESMO this year, and this is looking at giredestrant.

Now, a very important feature of the EMPRESS study, in contrast to the 2 that we just looked at, is that this study was for premenopausal patients only, and that is really important because we don’t have much data on how to use oral SERDs in patients who are premenopausal with functioning ovaries. So this trial enrolled an exclusively premenopausal patient population and randomized patients to receive 2 weeks of giredestrant or 2 weeks of tamoxifen. There was no use of LHRH agonist, so it was just pure drug in both arms of the study, with the primary endpoint of changes in Ki-67.

And what we learned from this is that patients who received the giredestrant had a substantial drop in Ki-67 levels. It was a greater drop with giredestrant than what was seen with tamoxifen, a greater reduction in proliferation. Now, we don’t know if ovarian function suppression was added to both arms if we would see a difference here, if that’s necessary to see a greater difference with giredestrant, so this is just pure drug versus tamoxifen. Additionally, we can see here a greater complete cell cycle arrest with the exposure to giredestrant, as well as a much greater drop in estrogen receptor levels, which again is consistent with the mechanism of action of the agent.

So in thinking about the discussion of all 3 of these window studies, just to quickly summarize, the SOLTI-ELIPSE study, that’s the elacestrant study, led to the 27% complete cell cycle arrest rate and created this more endocrine sensitive, less proliferative tumor phenotype. SERENA-3, which was a very short exposure to camizestrant, suppressed estrogen receptor, progesterone receptor, Ki-67 and helps identify the dose to move forward with in adjuvant trials. And finally EMPRESS with giredestrant in premenopausal patients shows activity of this drug without the GnRH agonist, although, again, this is in the absence of a comparison to using the GnRH agonist.

So that brings the question do we need this ovarian function suppression when we use oral SERDs in our younger patients. There are 2 trials that will ask and answer this question, including SOLTI-PREMIER, which uses elacestrant and pre-EMBER, which will use imlunestrant. I think it’s also important to note that the evidence of molecular response in the drops in estrogen receptor and Ki-67 helps to support moving these drugs into the early breast cancer setting. And in general window studies are really interesting and they help us evaluate activity, safety and dosing in a very careful way in a curative population preparing for what become very large adjuvant trials.

And on that note let’s move to our final abstract, which is a large adjuvant trial. So this is the Phase III lidERA trial, which is looking at the use of giredestrant versus standard-of-care endocrine therapy in early-stage disease. And this was probably the biggest presentation we saw at San Antonio this year.

Let’s take a look. So this is a global Phase III trial that enrolled patients with Stage I-III ER-positive, HER2-negative breast cancer. And in terms of the staging, they could be node positive or node negative with a tumor size more than a centimeter, and they needed an additional high-risk feature: Grade 3, high Ki-67 or high genomic score — a high Oncotype Score. Over 4,000 patients were randomized 1:1 to receive giredestrant monotherapy or standard-of-care endocrine treatment with either tamoxifen or an aromatase inhibitor.

Now, I think it’s worth noting that use of LHRH agonist was a little asymmetric. So premenopausal patients, and that was 40% of the enrolled patients, if they got giredestrant they took ovarian function suppression, if they were on aromatase inhibitor they took ovarian function suppression, but with tamoxifen it was optional, so there was a little asymmetry created there. Primary endpoint of the study is invasive disease-free survival.

And let’s take a look. So this is results from the first interim analysis, where the study became statistically significantly positive. Patients who received giredestrant had an improved invasive disease-free survival, with a hazard ratio of 0.70, corresponding to a 2.8% absolute difference between the arms. And this is at about two and three quarters year of follow-up.

We can see that the curves, in the blown up portion of the Kaplan-Meier, the curves begin to separate as early as 12 months into treatment, and there is a growing separation, which perhaps may deepen with time. In the little exploratory analysis we can see the benefit of giredestrant was consistent whether the comparison standard of care was aromatase inhibitor or tamoxifen.

In terms of toxicity, on the left is the tornado plot, and we can see this is incredibly symmetric. There is no signal of increased toxicity with the use of giredestrant compared to standard-of-care endocrine therapy. There is, however, a hint that giredestrant may be better tolerated, in particular, with less musculoskeletal disorder and arthralgia. We see there’s about 50% fewer discontinuations for musculoskeletal disorders with the use of giredestrant. As I mentioned before, oral SERDs can cause asymptomatic bradycardia, and about 10% of patients experience this as part of the trial.

There was a really beautiful discussion at San Antonio from Lisa Carey trying to put this data into context of other adjuvant advances. And this is a really nice slide that she showed demonstrating that our other very large, pivotal studies in the same population of higher-risk, hormone receptor-positive, HER2-negative breast cancer, that includes monarchE, which led to the approval of abemaciclib, NATALEE, which led to the approval of ribociclib, when they had their first report, which was at the same period of time, about 2 and a half years into treatment, had very similar findings, with an absolute benefit of about 2-2.5% and similar hazard ratio of 0.7 — so suggesting to us that given the similarity are these agents in some way interchangeable, oral SERD or CDK4/6 inhibitor.

So it sets up some very interesting questions, especially because when you look at the schema for lidERA there was no CDK4/6 inhibitor included in the treatment, it was just endocrine monotherapy.

It’s also important to try to put the eligibility side by side because you can see the different populations who are eligible for CDK4/6 inhibitors or for oral SERD. We can see on the right monarchE shows the eligibility for adjuvant abemaciclib is restricted to high-risk, node-positive patients. NATALEE eligibility includes high-risk, node-negative patients, particularly T2N0 patients who have additional high-risk features. If we move to the left, and we add lidERA, we can see now we have the higher-risk Stage I population covered, a group of patients who really are not candidates for adjuvant CDK4/6 inhibitor. But there is a lot of overlap between the lidERA population and the NATALEE population, particularly in that T2N0 higher-risk category.

And so there’s been so much discussion and chatter in the breast cancer world since we saw these data. Some of the topics and thoughts that have come out include that this is a very early readout in a population where the risk of recurrence goes on for years and years. Will these benefits that we see persist over time? These are very early recurrence events and perhaps reflect more of a Luminal B tumor biology, so is there going to be a time-dependent effect, and perhaps this is better for Luminal B versus Luminal A. I think we need more maturity to see that.

There were very few events in the Stage I patients or the patients who we might call medium risk, and that’s expected because they are lower-risk patients, so we need more maturity and more events to have confirmation in the lower-risk patients.

As I mentioned, there was no concurrent or sequential CDK4/6 inhibitor used in this trial, and that’s different than our current standard of care. We don’t know if combining SERD and CDK4/6 inhibitor is additive or not. It is not a strategy that one would recommend in the absence of seeing confirmatory data in this setting, so that is a big unknown question.

As I pointed out, the premenopausal patients may have had slightly heterogeneous treatment, and that was a pretty good percentage of the patients in the trial.

Another important point has to do with ESR1. This is a resistance mutation that develops over time when patients are receiving aromatase inhibitor. It would be anticipated that there would be a very low percentage of ESR1-mutant patients at baseline who are entering the lidERA study. And we do think of oral SERDs as medications which are particularly effective when that mutation is found.

So how do we explain the activity of the SERDs over AI monotherapy in the absence of the mutation and are there biomarkers that we could look to that might help predict benefit? And I think as many have pointed out, if this drug is approved for such a broad population of patients there will be some financial implications as well.

I’ve been trying to put the lidERA data together within my group trying to think about who might be good candidates should this drug get approved. And it’s hard to know right now, but I think here’s a little table that would just be my thoughts, in that our Stage I higher-risk patients, the ones who are lidERA and not for CDK4/6 inhibitors, this might be an option for some of the select high-risk cases.

Flipping to the Stage IIB or III patients, our multi-node-positive, high-risk patients, these are patients where we very much want to offer CDK4/6 inhibitors, where we have an overall survival advantage. And so I don’t think we’d be swapping out CDK4/6 for a novel oral SERD, but perhaps there is a way to sequence this, give a CDK4/6 inhibitor and give a SERD later. This was not at all part of the design of lidERA, but it is the design of some of the ongoing studies, including CAMBRIA-1, EMBER-4 and ELEGANT, and that may help answer that question.

I think the greatest debate will be in the Stage IIA patients, where we have that precise overlap between the NATALEE population and the lidERA population. And here we may end up with a choice to offer one agent or another, and that’s going to require a lot more thought and discussion with our patients and with each other.

And so we’ve reached the end of our Year in Review for oral SERDs. We have a lot of exciting data and certainly more to come in 2026.