Session 1: Estrogen Receptor Biomarker Testing, Targeting Mechanisms, and Treatment Decisions in Breast Cancer Care

Seth Wander, MD, PhD, provides a focused review of estrogen receptor 1 (ESR1) mutations in estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer.

Good afternoon, and welcome. Thank you for joining us, and thanks to the team at Oncology Learning Network for the invitation today. We are going to be pursuing this Community Connect webinar series focused on estrogen receptor biomarker testing, targeting mechanisms, and treatment decisions in breast cancer care. My name is Seth Wander, and I'm joining you from Boston, Massachusetts, where I'm one of the breast oncologists at the Mass General Cancer Institute. And today's objectives are to explain the clinical relevance of ESR1 mutations and distinguish testing-at-progression guidance from the label requirements for an FDA-authorized plasma test. We'll differentiate selective estrogen receptor degrader (SERD) from proteolysis targeting chimera (PROTAC)-mediated ER degradation and other ER-targeted approaches and interpret use cases for each of these. And we'll apply label-based patient selection, dosing, adverse event monitoring, dose modification and counseling and practice. And the goal is—it's a relatively short slide presentation; we're not going to cover everything in this space. We're going to try to leave some time at the end to refer to any of your questions, which I think you can add in the chat.

So let's talk for a second about ESR1. ESR1 is the gene that encodes the estrogen receptor. And if you look at primary breast cancers or breast cancers in the metastatic setting that have not received prior therapy, mutations in ESR1 are exceedingly rare, well under 5%, sometimes even under 2 to 3%. But if you repeat testing in the metastatic setting after the patient has had treatment, typically on an aromatase inhibitor, you start to see enrichment in these acquired mutations in ESR1 upwards of about 30 to 40%, depending on the patient cohort that you're exploring. As you can see in the schematic here, which is from a review that we published a few years ago, most of these mutations cluster in the ligand-binding domain of the protein, and they allow the estrogen receptor to be constitutively active regardless of whether or not there's any estrogen ligand present.

So this is an evolutionary mechanism of adaptation to estrogen deprivation, typically with an aromatase inhibitor. ASCO expert guideline recommendations suggest routine testing for the emergence of ESR1 mutations at recurrence or progression because of this data. As you can see, the testing should be pursued with a CLIA-certified assay at the time of progression. Blood-based circulating tumor DNA is preferred due to greater sensitivity. We can get some false negatives with tissue-only testing here. And then, testing should be repeated even if the prior tests were negative or if the ESR1 was wild type because, again, these mutations are most often acquired after progression on endocrine therapy over time.

Now there are many different ways to target estrogen signaling in the estrogen receptor, and these are some of them though not all of them. We've had the aromatase inhibitors around now since the early 1990s. This is letrozole, anastrozole, exemestane. These drugs block the peripheral conversion of androgens to estradiol in adipose tissue. So they are only useful in postmenopausal patients or in premenopausal patients that have either had oophorectomy or have had treatment with ovarian suppression. We have the selective estrogen-receptor modulators. The most commonly utilized one in the early-stage setting is tamoxifen. These drugs have been around also for quite a long time, since the 1970s. So, these bind to the estrogen receptor and, in some context, antagonize activity (for example, in the breast tissue) and in other areas, agonize activity, meaning they activate the receptor (for example, in the bone or in the uterus).

And then we have the selective estrogen receptor degraders, the SERDs. The first of these was the injectable fulvestrant in the early 2000s, but we've now had multiple new oral agents that have been developed or are under active clinical development, including as of last week, 3 of these that have had FDA approval. So the selective estrogen receptor degraders bind to the estrogen receptor, and they promote conformational changes that eventually impact estrogen-receptor stability and lead to degradation. And then we have the newest agent in terms of mechanism. This is the PROTAC. This is a proteolysis targeting chimera. So, like the SERMs or the SERDs, the PROTAC binds to the ER, but this is actually a different type of molecule. So one part of the drug binds to the ER. The other part of the drug actually recruits the E3 ubiquitin ligase, and this is the machinery that the cells use to target proteins for degradation.

So by bringing the ubiquitin ligase machinery into proximity of the estrogen receptor, that tags the estrogen receptor and leads to degradation. So both the SERD and the PROTAC lead to degradation through different mechanisms. If you look at preclinical studies in laboratory models, the PROTAC actually has the highest degree of degradation based upon its distinctive mechanism.

And so here we have a number of different FDA-approved ER-targeted options for patients with ESR1- mutant disease. You can see here for patients that have had progression on endocrine therapy with a CDK4/6 inhibitor, which is by far the most common frontline therapy used in the metastatic setting. Now in the second line, we have a number of different options. We try to avoid use of antibody drug conjugates or cytotoxic chemotherapy unless the patient is in visceral crisis or is felt to be endocrine completely refractory. If the patients have PIK3CA, AKT or PTEN alterations, we have a number of different therapeutic options in the second-line setting. In the first-line setting, we have the inavolisib triplet regimens, but those are only for patients with a PIK3CA mutation who are endocrine refractory, meaning they progress on or shortly after adjuvant endocrine therapy. In the second-line setting, we have fulvestrant alpelisib and fulvestrant capivasertib, PI3-kinase and AKT inhibitor combinations, again, for patients who have one of these mutations.

If the patients have ESR1 mutations, we have 3 FDA-approved single agents in the second-line setting. We have the first oral SERD elacestrant, based on the EMERALD study. We have the second oral SERD, imlunestrant, based on the EMBER-3 study, and we have the new proteolysis-targeting chimera PROTAC vepdegestrant, based on the VERITAC-2 study, and we'll review some of that data in a moment. If the patients don't have PI3K pathway or ESR1 mutations, this has been an area of significant unmet clinical need. Those patients could go onto fulvestrant monotherapy. They could get fulvestrant with, for example, everolimus or another endocrine agent like exemestane with everolimus, mTOR inhibitor. They could get CDK switch and re-challenge. This would be something like the postMONARCH regimen, fulvestrant-abemaciclib. And as of a couple of weeks ago, we had an FDA approval in that population, PIK3CA wild type, second-line metastatic for gedatolisib, which is an IV PI3K/AKT/mTOR pathway inhibitor with fulvestrant plus or minus palbociclib.

But we're going to spend just the next 15 minutes or so focusing in a little bit on the ESR1 mutant population in the second-line setting. Just the other day we had an FDA approval in the first-line setting for potential use of camizestrant with a CDK inhibitor based upon emerging ESR1 mutation. This is from the SERENA-6 study. But again, that's not really a second-line post-clinical radiographic progression. So that's what we're going to focus on here and we're going to focus on the single agents.

Now we have the EMBER-3 study. I just want to mention we have older data from the EMERALD study, which for the interest of time, I don't think we're going to review the exact curves today, but I'm happy to talk about them during the Q&A. The EMERALD study led to the first FDA approval, elacestrant. That study was more heavily pretreated population, 1 to 2  prior lines of endocrine therapy, up to 1 prior line of chemotherapy, and a 100% prior CDK4/6 inhibitor progression. We saw that elacestrant, the oral SERD, was superior to conventional endocrine therapy AI or fulvestrant in that treatment-refractory population, and that the benefit was larger in the ESR1 mutant subpopulation. So that was actually the first data where we saw the benefit being enriched in ESR1 alteration, and that led to the first FDA approval of elacestrant in ESR1-mutant patients who had had progression on prior endocrine therapy, typically with a CDK4/6 inhibitor. 

The second drug approved was this one. This is the EMBER-3 study. So this study has less prior therapy. So these patients were only allowed to have had 1 prior line of endocrine therapy; 40% of them had never had a CDK inhibitor. There was no prior use of cytotoxic chemotherapy. So, in this kind of second-line population, there was a randomization over 650 patients between standard endocrine treatment, clinician's choice of fulvestrant or exemestane versus the oral SERD imlunestrant. There was a third arm that was added later, imlunestrant plus abemaciclib, but there was no doublet control arm in this trial. The primary endpoint was progression-free survival via investigator assessment. 

And here you can see the baseline characteristics from the EMBER-3 study. As I said, these are less heavily pretreated patients, only about 60 to 70% previously had a prior CDK4/6 inhibitor, 60-ish percent visceral metastatic disease, and about 10 to 15% pre- or perimenopausal. And here are the curves looking at the single agent. So this is single-agent standard endocrine therapy versus imlunestrant in the subgroup with ESR1 mutation. There was no benefit in the ITT population. Similar to what we saw in the EMERALD study, the benefit was larger in terms of magnitude in the subgroup who had ESR1 mutation. Here you can see an improvement from just under 4 months to over 5½ months with a hazard ratio around 0.6. You can see the clinical benefit rate about 36% improving to 46+ %. You can see the overall response rate improving from about 6 to 12%.

And this data led to a similar FDA approval for imlunestrant in ESR1-mutant patients who had had prior progression in the metastatic setting on endocrine therapy with or without a CDK inhibitor. Here's the safety data from EMBER-3. Now with elacestrant in the EMERALD study, we saw mostly low-grade GI toxicity. So perhaps we had less menopausal symptoms, less arthralgia, the trade-off being maybe a little bit more nausea, reflux or change in bowel function. We see a similar pattern here with imlunestrant. It's almost all low-grade toxicity. Arthralgia, mostly low grade, fatigue and some GI-related nausea, diarrhea, constipation, or abdominal discomfort. But you can see the high-grade toxicity rate typically very low on the order of 1% or less, maybe slightly higher for the myalgia arthralgia. 

And here in terms of laboratory studies, again, mostly low grade, a little bit of changes in transaminases or lipid profile, slight changes in CBC, mostly low grade here. The discontinuation rate was only 5%, similar with elacestrant, mostly low single digits. Now here's the VERITAC-2 study. So this is the first novel antiestrogen in terms of mechanism that we've had. The SERDs, remember they're oral and that's a new formulation, but fulvestrant's been around for quite some time. So this is the VERITAC-2 study. Again, these patients were allowed to have had, I think, 1 to 2 prior lines of endocrine therapy. They were all previously treated with CDK4/6-inhibitor therapy. They were not allowed to have had prior fulvestrant or PAM pathway, no prior chemotherapy. So these patients are a bit more heavily pretreated than EMBER-3, but less heavily pretreated than EMERALD. Almost 300 patients randomized to fulvestrant, so there was no AI option in the control arm. This was a stronger control arm, all fulvestrant-naive and fulvestrant monotherapy in the control arm versus the PROTAC vepdegestrant as a single agent. Primary endpoint to progression-free survival by RECIST via blinded central review.

And here are the baseline characteristics. Pre- and perimenopausal, about 20% good performance status. You can see the race─ethnic breakdown there. Prior CDK treatment, 100%. There was more visceral disease here than in EMBER-3, about 70%, and about 20% of these patients that had 2 prior lines of endocrine therapy in the metastatic setting. And here are the curves. So just like in EMERALD and in EMBER-3, we do see a drop-off anywhere from 20 to 40% of patients on both arms, kind of endocrine refractory. Then the curves begin to separate, and we do see a tail here. Again, we're looking at the ESR1 mutant subpopulation. In the overall population, again, no major change in the ITT, but there was separation for patients who had ESR1 mutations, and we saw an improvement here from about 2 months to 5 months with a hazard ratio just below 0.6. I would point out, even though you have that steep drop, you actually have the tail here, which we have seen on some of the other next-gen oral antiestrogen studies as well.  

About 30% of patients receiving vepdegestrant actually have durable disease control in this trial extending out to about a year and a half, and that curve is still staying pretty flat. Overall survival, which was a secondary endpoint, is immature at the time of this analysis. We can see the clinical benefit rate increasing from about 20 to 40%. We can see the overall response rate increasing from less than 5% to almost 20%. So, clear signs of additional clinical benefit and radiographic response with the vepdegestrant.

And just like the oral SERDs, this drug is generally very well tolerated. Remember, this is endocrine monotherapy in the second-line setting. So here you can see, again, mostly low-grade toxicity, the grade 3+ toxicity rate on the order of less than 1% or low single digits. Again, we see some myalgia, arthralgia, mostly low grade, mostly low-grade fatigue, a little bit of GI, nausea, constipation, almost all low grade, as you can see, and very rare QT prolongation. Again, almost all low grade, just about a 1 to 2% grade 3. In terms of some laboratory abnormalities, again, almost all low-grade minor changes in blood counts on the order of 10 to 30% in terms of cytopenias, low-grade ALT/AST elevation, or slight changes in potassium or bilirubin. The high-grade toxicity rate here, again, low, 1 to 2% or less. The discontinuation rate with vepdegestrant, similar to what we've seen with the other next-generation antiestrogens, low single digits, only about 3%.

So let's think about a patient case in the context of some of these newer drugs—65-year-old patient, hypertension, hyperlipidemia. She was diagnosed with de novo metastatic ER-positive HER2-negative breast cancer. She had bone disease and 2 liver lesions, but normal LFTs and no significant symptom burden. At baseline, circulating tumor DNA was negative for any actionable mutations. She received standard therapy with an aromatase inhibitor and ribociclib and did well for 3 years, but she now has some new bony lesions and a couple of areas of progression in the liver measuring up to 2 to 3 centimeters. She remains asymptomatic. Her laboratory studies are normal, so no evidence of any visceral crisis. When they repeat the circulating tumor DNA, now they see after 3 years on an AI and a CDK, acquisition of an ESR1 D538G mutation. This is the most common mutation that we see with ESR1. 

So in terms of treatment decision-making in the setting of ESR1 mutation, we want to confirm in this case that there's progression of disease, although now we also have SERENA-6 data that we could talk about during the chat if there's questions where you could theoretically test for ESR1 acquisition before there's clinical or radiographic progression. But if we're doing this the traditional way as of before last week, there would be confirmation of clinical radiographic progression. We would confirm the presence or absence of ESR1 via CLIA-approved, preferably circulating tumor DNA assay. We would review prior therapies. What did the patient have in the frontline setting? Did they have prior CDK4/6 inhibitor exposure? We would confirm eligibility for ESR1-directed therapy, no other major baseline, hugely significant laboratory abnormalities, et cetera. Evaluate comorbidities and other medications that the patient is on, for example, other QTC prolonging things, et cetera, and then think about putting all that together to decide whether this patient might be a good candidate for 1 of the 3 single-agent next-generation antiestrogens that are available, the 2 SERDs, elacestrant, imlunestrant, and the new PROTAC, vepdegestrant.

So some of the key takeaways, and then we'll switch for the second half of our time together to chatting about some of your questions. The clinical impact of ESR1 mutations has driven the development of these new next-generation ER-targeted therapies designed to address this continued ER addiction and dependence and resistance to, for example, AI. Routine testing for ESR1 mutations at recurrence or progression is important to identify patients who may be eligible for these 3 new agents, and now the fourth being camizestrant with a CDK inhibitor. Differentiates SERD-mediated ER antagonism. So these are the kind of indirect promotion of ER degradation versus PROTAC-mediated targeted degradation, where we're actually utilizing the cellular machinery, the ubiquitin ligase, to tag the ER and more completely degrade it.

Okay, with that, let me say thank you. I think we did about 20 minutes of content review here, and we will be happy to take your questions in the chat. And I think if you send them in, the team at Oncology Learning Network is able to pass those over to me. So the first question that's coming in here is, "In your practice, what is the most important trigger for repeating ESR1 testing and how do you operationalize retesting at progression?"

And this is a moving target. I think this is an important question. Up until last week, the standard approach would've been to wait for signs of clinical or radiographic progression and then repeat next-generation sequencing. My practice has been to test tissue at the time of metastatic diagnosis because we always have a biopsy, typically to identify metastatic disease. So we'll use that tissue, we'll send next-generation sequencing at the time of metastatic diagnosis. I will also send a circulating tumor DNA assay at that time. Concordance rates between solid and liquid biopsies for next-generation sequencing are generally high, but they're not 100%. In some studies, it can be as high as 20+ %, where there may be positive on one and negative on another.

So I'll do both solid and liquid at the time of metastatic diagnosis to look at concordance and baseline alterations. And then with clinical or radiographic progression, I'll repeat liquid testing only. I would only do another solid biopsy if I thought it would really change patient management, meaning one area of the tumor is behaving differently than the others. I'm worried about receptor switching or down the road I'm thinking about using something like trastuzumab deruxtecan, but I previously had a HER2 zero result, so I'm thinking about retesting there. Otherwise, I'm almost always doing liquid biopsy because that has higher sensitivity, particularly for ESR1.

And then I would think about whether the patient might be a candidate for one of these novel targeted agents, an endocrine agent or a PI3K pathway inhibitor. I do just want to make one comment about this. We had just last week the FDA approval for camizestrant with a CDK inhibitor, based on the SERENA-6 study. Now, this could change things in the sense that the way they did that study, patients were tested after at least 6 months of treatment every 2 to 3 months for acquisition of a new ESR1 mutation based on ctDNA. If they lacked clinical or radiographic progression, they were randomized to continue AI CDK or make an early switch to camizestrant and continue the same CDK, and that showed clinical benefit in terms of PFS and PFS2 and time to chemotherapy, et cetera.

Now, when the FDA approved camizestrant last week, they were quite vague in the label. They did not indicate that the patient had to be without clinical or radiographic progression. They just said you could consider camizestrant with a CDK inhibitor in the presence of a new ESR1 mutation that would allow you to test without clinical progression or with clinical progression. I think it remains to be seen how most people are going to actually use that, whether it would fit into the traditional paradigm at clinical radiographic progression or whether people would be testing on treatment without clinical or radiographic progression. Either way, the 3 other approved single-agent drugs are available in the second line if the patient has ESR1 at the time of clinical or radiographic progression.

Okay, the next question is, "When considering an ESR1 mutant situation tumor, which clinical or disease features most influence your choice among available ER directed therapies?" So I think this is an interesting and complex question. When you look at the top-line clinical data, the patterns are very similar across elacestrant, imlunestrant, vepdegestrant. They all had a sort of negative or negligible benefit in the ITT, but more notable clinical benefit in the ESR1 mutant subpopulation. I think we're still working on figuring out exactly which clinical parameters we might want to choose to help decide among these 3 agents. We've had elacestrant around longer; we have more real-world data with elacestrant, yet at the same time, vepdegestrant is the newest mechanism and does have some distinct activity in preclinical or laboratory models. The other thing I'll say about the VERITAC-2 study is that it, in many ways, sort of had the strongest control arm.

There was no prior fulvestrant therapy, no prior SERD or PAM inhibitor-based treatment, and everybody got a SERD on the control arm, which is in contrast to EMBER-3 and EMERALD, where many of the patients got an AI after having prior progression, for example, on AI and/or SERD therapy. And so in that sense, maybe it was a little bit of a harder bar to cross. I think it's hard to look at the absolute numbers in terms of PFS magnitude, because again, the EMERALD study was much more heavily pretreated with 20+ % prior chemotherapy, and also a lot more prior use of fulvestrant and more prior endocrine treatment. So, I think I would discuss it with the patient. I would want to understand how much endocrine therapy they'd had previously, whether they'd ever been exposed to a SERD previously, and I think it comes down to clinician preference.

From a toxicity profile, all of these 3 drugs are very well tolerated. There may be some slight differences between them in terms of the rate of GI toxicity being higher or lower, or in terms of some of the minor laboratory grade-1 abnormalities, or the QT, low-grade QT issue. None of those, in my opinion, are majorly dose-limiting, with the exception of patients who maybe have significant GI-related issues at baseline or patients who are on other medications that already prolong the QT or might limit the ability to combine with a QT-prolonging medication.

Okay, the next question. "How do visceral disease burden, pace of progression, symptoms, and the absence or presence of visceral crisis affect your treatment decision?" Okay, there's a lot to unpack in that question, and we could do kind of an hour talk on all of the different second-line regimens. We were just really zeroing in on the newer single-agent antiestrogens here. Let me take this backwards. So if the patient had visceral crisis, I would be not very enthusiastic about using endocrine-based therapy either as a single or a doublet potentially. If the patient is truly in visceral crisis, which is rapidly rising laboratory abnormality, end-organ dysfunction, hugely significant symptom burden, I would be thinking about debulking with cytotoxic chemotherapy or probably more likely an ADC. If the patient had HER2-low disease, I would give them trastuzumab deruxtecan. One of the, I think, misconceptions in this field right now is that visceral disease does not equal visceral crisis.

The vast majority of patients with visceral disease do not have visceral crisis. True visceral crisis is relatively rare in this population because we're monitoring these patients pretty closely. So the presence or absence of liver disease, like in the patient we just discussed with normal transaminases and no symptoms would not deter me or would not stop me from using an antiestrogen-based approach. But if the patient really had end-organ dysfunction and huge symptom burden, then I would think about cytotoxic therapy, ADC, or chemo for debulking. Now, otherwise, I think it depends a lot on who's the patient, what's their functional status, what are their medical comorbidities, what treatments did they have previously, how long were they on them, and what is their molecular genomic profile? For example, if the patient has no ESR1 or PIK3CA, now we're looking at fulvestrant-based therapies, maybe fulvestrant everolimus, postMONARCH, or the new gedatolisib doublet or triplet regimen once it becomes routinely available in clinic.  

These are for your kind of biomarker-negative patients. If the patient has a PI3K pathway alteration, most of us are using capivasertib with fulvestrant in that situation. Again, gedatolisib has some positive data there, but no FDA approval at the moment for patients with PIK3CA mutations. If the patient has ESR1, we're back to the conversation we were just having. I would be more enthusiastic about endocrine monotherapy, oral SERD, or PROTAC if the patient had at least a year to a year and a half on their frontline CDK4/6 inhibitor therapy. I think one of the hardest situations right now is what about a patient who has dual-mutant disease, so a patient who's got both PIK3CA and ESR1. It's relatively rare, but it's probably 20-ish, 20 to 25% of the overall population. Here, we need more data. Our team and others are working on this. We have some presentations coming up at San Antonio, looking at what's happening with those patients in the real-world setting.  

I think you could go both ways there. If the patient had a shorter duration on their frontline CDK therapy, a higher burden of disease, you're worried about endocrine monotherapy, you might want to prioritize the PI3K/AKT pathway inhibitor. If the patient had a longer duration on their frontline therapy, no huge amount of visceral rapidly increasing disease burden and you feel okay with a single agent, then I would try to prioritize the endocrine monotherapy. And if there's any way for me to give them endocrine monotherapy, I'd like to do it because it's a lot less toxic than chemo or than a PI3K pathway blockade. You don't need as much laboratory monitoring, clinical visits, et cetera. And of course, if the patient were to have diabetes or other medical comorbidities, that might limit your ability to give, for example, a PI3K pathway inhibitor in that situation. 

Okay, next question. "If plasma ctDNA testing is negative for ESR1, despite clear disease progression, how do you interpret that result and what would you consider next?" So if the ctDNA testing is negative for ESR1, we have to understand a couple of things, and we're learning more and more about this, and we're getting a little bit into the weeds of next-generation sequencing and molecular testing. What is the tumor fraction of the test? So, for example, if you have ctDNA testing and there's no tumor fraction or the tumor fraction is extremely low, a fraction of a percent, it just means there's not a lot of tumor DNA in the blood. So you could have a false negative there for ESR1. This is why it's important to retest in the future. If the tumor fraction is reasonably high and you have detectable circulating tumor DNA and there's no ESR1, it probably means that the patient falls into the 40 or 50% of patients, 50+, 50 to 60% of patients who don't have ESR1.

It means they're developing resistance to their frontline AI and CDK therapy in some ESR1-independent way. And there's lots of other things that we and others have identified that can provoke resistance. Could be PI3K/AKT pathway, could be Ras/MAP kinase pathway, could be CDK2, could be aurora kinase, could be RB loss. And there are a lot of other therapeutic efforts being made to target those pathways, the non─ESR1-dependent pathways. We have drugs making their way from phase 1 through phase 2 and 3 trials at this moment. So if the patient's negative for ESR1, we go back to our prior algorithm, we look at the presence or absence of PI3K/AKT. If all of that is negative, then I think I'm choosing obviously a clinical trial if one's available, fulvestrant everolimus-based combos, postMONARCH-type fulvestrant CDK, or in the near future the gedatolisib doublet or triplet.

Okay, the next question. "Without making cross-trial comparisons, what aspects of the available phase 3 data are most useful when evaluating different ER-directed options for an individual patient?" So I think this question is really focusing on the 3 single agent next-gen antiestrogens, elacestrant, imlunestrant, vepdegestrant. So when you're looking at those trials, doing the thing we tell our fellows never to do, comparing across clinical trials, what are the things that jump out from one to the other? To me, as I was alluding to, it's the degree of prior therapy. So the EMERALD study was much more heavily pretreated than either of the other two, whereas the VERITAC-2 study was somewhere in between, and the EMBER-3 study had the least degree of prior therapy, with only 1 line of endocrine treatment, no prior chemotherapy, and 40% were CDK4/6 inhibitor naive. Second aspect that I think we need to think hard about is what was being used on the control arm.

So in both EMERALD and in EMBER-3, the control arm allowed either an aromatase inhibitor or fulvestrant, and many of these patients had already had progression on one or both of those agents, particularly in the EMERALD study. So when you have a patient who, for example, has already progressed on an AI and you give them an AI, it's almost like having a placebo comparator arm. When you contrast that with VERITAC-2, there was no prior SERD use in that study, and everybody got fulvestrant. So to me, the control arm was sort of best designed in VERITAC-2. You actually had the hardest control arm. Many of us don't really love the use of single-agent fulvestrant anymore in this population, but at the time that the study was designed, this kind of is what it is. With all those caveats in place, when you look at the shape of the curves, when you look at the hazard ratios and the magnitude of the benefit in the median PFS, I think they look more similar than they are different.

And then the other factor that we're looking at is clinical benefit rate, response rates, et cetera. We looked at the data from VERITAC-2 looking maybe a bit more promising there in terms of the difference when you compare the fulvestrant control arm to the intervention arm. And of course, the tox profile that we've already discussed, we do see some minor differences in toxicity, but almost all of the toxicity across all 3 drugs is low grade, and I think pretty manageable.

Okay. Any other questions? Those are all great questions. I mean, I have a couple of questions that I don't have answers to, so I'll leave you with them as sort of food for future thought. I don't know with these most recent FDA approvals, so we have a recent FDA approval for vepdegestrant with the drug moving into clinic soon. For camizestrant based on SERENA-6, again, drug moving into clinic soon, and for gedatolisib. I don't know what the uptake is going to be and how that's going to reshape the resistance landscape. So, for example, if a patient were to go on camizestrant in the one-and-a-half-line setting based on SERENA-6 and then has clinical radiographic progression, we really don't know much about what the genomics look like. We know they had an ESR1 initially. Do they still have the ESR1 progression? Have they developed other secondary mutations? Can you use, for example, a different type of antiestrogen, like a PROTAC, in that situation? Do you need doublets there?

And if so, which doublet should you be using? What are the resistance mechanisms to gedatolisib, if that's being used in a kind of biomarker-agnostic way? I think these are all complicated questions that we're going to have to start to answer over the next 6 to 12 to 18 months. It's going to take cooperation on the academic and community side to develop some of these large real-world data sets. I think having more options is always good for patients, but it poses a lot of challenges for clinicians because a lot of these trials will run in parallel without any kind of cross-exposure to these drugs. So we may be talking about using drugs in sequence, where in the clinical trial setting, we don't have any data for that. So we'll be trying to generate real-world data for that as the months go on.

Other questions. The team at Oncology Learning Network is saying no additional questions so far. While we're waiting to wrap up, I think we're either on time or 5 minutes ahead of schedule. I want to thank everybody for coming during their lunch break. I know people are busy in clinic, and for me, I'm on the inpatient service, so this is a nice break, but all of us are probably going to be going back to writing notes pretty soon. For the OLN team, any other housekeeping or questions that are coming up? I'm getting a message in the chat that I think we're all good. All right. Well, with that, again, thanks to everybody. We appreciate the opportunity to connect with you, and I hope to see you all again on either a virtual seminar or in person at San Antonio or ASCO. And I think we'll have a lot of exciting new data and new therapeutic options to talk about in the coming months. I hope you all have a good afternoon. Thank you.