Developing Story: Beyond Camizestrant — The Evolving Landscape of ER+/HER2- MBC with Dr. Sarah Premji

The field of hormone receptor-positive, HER2-negative metastatic breast cancer is moving faster than ever, and in this episode, we go beyond SERENA-6 to map the full picture of what's changing.

Joining hosts Victoria Goldberg and Abigail Johnston is Dr. Sarah Premji, Assistant Director of Breast Cancer Research at Sarah Cannon in Nashville, for a comprehensive deep dive into the new wave of endocrine therapies reshaping treatment for the most common subtype of breast cancer.

Together, they cover the evolution from CDK4/6 inhibitors to the era of oral SERDs, FDA approvals of elacestrant, imlunestrant, and vepdegestrant and what makes each unique, the emerging mechanisms of PROTACs and CERANs, and how ESR1 mutations drive treatment decisions at progression. Dr. Premji also shares her real-world approach to sequencing therapy, weighing tumor profiling, prior treatment history, sites of disease, and each patient's individual lifestyle and priorities. The conversation closes with a look at the growing role of AI in oncology, from clinical trial matching to pathology and imaging.

Whether you are a community oncologist navigating an increasingly complex algorithm or a patient advocate trying to stay current, this episode is your guide to where ER+ breast cancer treatment stands today and where it is headed.

Thanks for listening. If you enjoyed the episode, subscribe and leave a review — it really helps. Follow us on social media @livefromstage4 and visit our website at www.livefromstage4.org for show notes and links.

 Your support helps us continue to share important stories and advocate for those living with metastatic breast cancer.

Until next time, take care and keep pushing for progress.

Transcript

SPEAKER_02 0:09

Could cure for cancer be closer than you think? Welcome to Life from Stage 4, where MBC takes center stage as we talk to experts, share inspiring stories, break down signs, and shine the spotlight on what matters most. Because when it comes down to it, the spot, for us and by us, is all about us. Welcome back to Life from Stage 4. I'm Victoria Goldberg. In the last month, if you've been following along, you know we spent a lot of time, and rightfully so. Deep in the weeds of Serena 6 and Cam Zastri. Between our patient panel episode, our conversation with Dr. Sarah Sammons and Dr. Neil Vassan, and everything in between. We have really given the story the attention it deserved. And it deserved it. Using a block test to detect resistance before a scan even shows progression is a genuine paradigm shift, even if the regulatory path is still being sorted out. But to understand why all of this matters, it helps to zoom out. Dr. Erica Hamilton, in her recent interview with Oncology Brothers, put it well. For over a decade, our advances in ER-positive HER2-negative breast cancer have come from targeted agents. CDK46 inhibitors, PI3, PI3K and AKT inhibitors, but we haven't had a truly novel endocrine backbone since Volvestra. This is what has changed. We are now in the era of oral CERDs, and the field is moving fast. In the past year alone, the docastron, a first in-class product degradator, a different mechanism of action from a CERD, one that flags the estrogen receptor for destruction and recycles itself. To do it again, received FDA approval for ESR1 mutated metastatic breast cancer based on the Very TAC2 trial. Immunestrin. Another oral CERP received FDA approval as a single agent and updated amber 3 data from SCO2026 showed it improved overall survival in ESR1 mutated patients to 35.4 months versus 23.1 months with standard therapy. And when combined with IBRANDS, progression-free survival nearly doubled. The field is now seriously asking whether CERT targeted agent combination should become the new standard of care for most PSR1 mutated patients. And that is exactly the question. There are now multiple oral CERDs, pro-TAC, new CERMS, new serums, combinations being explored across lines of therapy, trials in the first-line setting, adjuvant trials. The landscape has become rich and frankly very complex. We have spent our last few episodes focused on Serena 6 and Kamisestrin. Today it is time to talk about everything else. Joining me, my co-host and friend Abigail Johnston and Dr. Sarah Pramji, a medical oncologist from Sarah Canon in Nashville. And so, without further ado, let's get started. Abigail Johnston is with me. I so love having her with us. And now we have a new friend that we just met. Her name is Dr. Sarah Premji. And we're here to talk about the fast and furious development in the space of metastatic breast cancer for HR-positive HER2 negative population. And Sarah, please introduce yourself and tell us about yourself.

SPEAKER_00 4:26

Absolutely. Thanks so much for having me. So, just as Victoria mentioned, my name is Sarah Premje. I serve as the assistant director of breast cancer research at Sarah Canon in Nashville, Tennessee. I graduated from Mayo Clinic in Rochester, Minnesota, where I discovered my love of breast cancer and got a chance to work on some really cool projects over there that I'm continuing on here, along with my role in serving as the principal investigator on several different trials, looking at early phase development of novel therapeutics in breast cancer and also in the phase three space. So happy to be here, happy to provide any insights, and thanks again for having me.

SPEAKER_02 5:08

Absolutely. We honored to have you with us. And Dr. Erica Hamilton has introduced us, and we love Dr. Erica Hamilton. So thank you for being here.

SPEAKER_00 5:20

She is a wonderful mentor. I'm so lucky to learn and get to work with her.

SPEAKER_02 5:24

Yes, yes, we feel the same way. So let's start. It will be important for us to start from the beginning and actually talk a little bit about the landscape and what is currently happening with this space.

SPEAKER_00 5:47

Yeah, absolutely. So I feel like hormone-positive breast cancer, it's evolved rapidly and really over the past decade or so has revolutionized. So we do know that in early 2015, I think it was February of 2015, palbocyclib, our first CDK4-6 inhibitor, was approved for hormone positive metastatic breast cancer. And we've come such a long way since then. There are additional CDK4-6 inhibitors that have been approved. There's various additional endocrine therapies. And really in the last five years or so, there's been a revolution of different targetable mutations that we've been able to find and now target. So an example of this would be a PIG3CA mutation that we found that we now have drugs that we can use to target. Alpaliciv was the first one of these drugs. It was approved in May of 2019. And then after that, we had development of AKT inhibitors, CERDs for ESR1 mutations, and there's a lot of work being done to find additional mutations that we can target and we can hone in on for what is driving tumor growth, and then really try to get to the source of the growth that's driving that tumor via various mutations.

SPEAKER_03 7:02

Sarah, I just want to break in here and just for our listeners that may not realize that pelviclib is ibrants and alpellisib is pickree. Just if we could use those names also for our listeners to know what you're talking about. Also, SERDs are selective estrogen receptor degraders.

SPEAKER_00 7:22

Absolutely. You got it. I'll use some of the trade names too moving forward. I think that'll be helpful for the listeners. And I also think that in the last several years, and this is really important, there's been a push to try to mitigate the toxicities of the targeted agents so that we can help improve quality of life for our patients. So an example of that, we know that AlpaliCib or PICRE has high rates of hyperglycemia. So about two-thirds of patients on the trial that approved that were found to have high glucose or hyperglycemia. And about a third of the patients were found to have a rash. And those things really compromise patients' quality of life. So the newest generation of these types of drugs, PI3K inhibitors that are in development, that are actively being developed and being studied in trials, are really aimed at isolating the target and then trying to reduce these other side effects of what we call off-target effects. So there's been a big push, and I think just so critical that we try to find drugs that patients can stay on and try to preserve their quality of life. And that's another big evolution here. We've come a long way. We still have such a long way to go, but it's always nice sometimes to take a step back and look at where we've come from. And then we also learn a lot from that. So as a field, we identify this is an active drug, this is something we can use, but wait, we need to think about it really critically. What does this do for our patients truly in the long run? And how can we optimize our therapies? How can we sequence them? How can we try to reconcile all of the different side effects that a patient could be experiencing and what their life would look like on this drug so that we can really find the right sequence, the right means for each and every patient. And that might be different for every single patient, depending on a variety of factors, what other conditions they're facing, where they live, what kind of financial implications for different types of drugs that are out there. And so I just think as we learn so much from where we've come, this hopefully helps us shape where we're going.

SPEAKER_03 9:29

So one thing that we've started to see in a lot of the phase three trials is combining therapies in a different way. And I do like to tell everyone that I combined Pick Ray, Kiscali, and Fastletx back before it was cool. But what is it that you're finding that patients are concerned about when you're talking about combining therapies?

SPEAKER_00 9:50

A hundred percent. You hit the nail on the head. We believe that if we combine therapies, this could be more efficacious because if you're hitting various targets, especially after CDK 4.6 inhibitors, what happens? What causes these tumors to develop resistance to the drugs that they're on? And this can happen early. This can happen later. We know in the trials that led to the approval of CDK 4.6 inhibitors, patients on average time before their next progression on scans was about two years. So for each of these patients, their tumors are all very different. A patient whose tumors progressed within less than two years, it's a very different disease than a patient who was on a CDK4-6 inhibitor for five plus years. And we have those patients. And so all of this helps us inform what we do next. And so to your point, Abigail, there's been a lot of push that, okay, if we combine therapies, if we hit various targets. And I can talk about a trial that was recently presented that looked at a triplet therapy that combined three very active agents together, but that came with efficacy, but it also came with toxicity. And so that's really where we have to think about okay, it's great to combine things, but where are we gonna get the biggest bang for our buck? Where are we gonna be able to truly add value to prolonging progression-free survival? But actually realistically having our patients be able to stay on these drugs and have some sort of quality of life and try to work towards better quality of life for our patients. So combinations are great, but I think that we have to look at each one very critically.

SPEAKER_02 11:30

So were you referring to the innovalisb trial that was presented last year at San Antonio as breaking news and again this year? And this is a very interesting first line treatment. Maybe we should talk a little bit about that.

SPEAKER_00 11:46

Yeah, absolutely, Victoria. So yeah, you're absolutely right. It was the Inovo 120 trial, and that actually was really exciting. Basically, there was a press release for positive results for the trial, and we were all in San Antonio, and everyone on the planning committee had worked together in a very speedy fashion to be able to present that while everybody was gathered at the San Antonio conference, and then there's been updated results since then, which has been awesome. And then there also was a trial called the Victoria One trial that also looked at a triplet. But for Inavo, that was looking at our patients who we believe are the patients that have the highest risk tumors. I don't ever really like to say highest risk patients. It's their tumors, it's their tumors that have the highest risk. But really, these are patients who were on endocrine therapy or had recently completed endocrine therapy and they developed metastatic disease.

SPEAKER_02 12:39

In the adjuvant setting, we're talking about the adjuvant setting early stage breast scans.

SPEAKER_00 12:44

You got it, exactly. And so these patients were getting their endocrine therapy, and either while they were on it or within 12 months of having finished it, they unfortunately developed metastatic disease or stage four disease. So you would know right there, that's pretty aggressive. That means that these patients were getting treatment that was theoretically going around their whole body to try to prevent cancer from coming back, and despite that, cancer still came back. So there's something about that tumor biology that's very aggressive, unfortunately. So what they did is they looked at patients who have the PIC3CA mutations. I alluded to that earlier. So that's one of the mutations that a patient can have that can drive tumor growth. And this can happen after treatment, but more commonly when tumors develop first, they have this mutation. It's what we call a truncal mutation. And really what that means is at the genesis of the tumor, when the tumor was born, this is more common for patients to either have this mutation or not. I believe it's about 40% of patients that can have this mutation. And so what they did is they identified these patients that have this mutation and they gave them three agents. And the new agent was in evolution. So it's a PI3K alpha isoform inhibitor. So it's very specific against this mutation. And then when combined with the Ibrands and with fulvestrant, it actually improved the amount of time the patients had before the next treatment that they needed. And then actually, we got some updated results this past year that it resulted in patients living longer. And so that's overall survival. In general, we end up needing to wait a long time with all of these new trials to get overall survival. So the fact that we have overall survival data on this group of patients already tells you right there that this is a very aggressive tumor group that we're treating. And so at this point, this is very much something that we're adopting in practice. And we really encourage every provider that is seeing patients to try to do profiling or mutational analysis up front so that we can see if this is a treatment option for those patients. But I will caveat that it's approved in a very specific fashion and it should be given the way the label is evaluating it. So, not for patients, for example, who developed de novo disease and they never had gotten endocrine therapy to begin with. It wasn't looked at in that fashion. There are trials that are looking at inovolisive in other ways. But really, this is how the trial was studied and this is how the drug was approved, just as you said, Victoria, as patients were getting endocrine therapy in the early stage setting.

SPEAKER_03 15:33

That's the medication, though, that there was a pretty high incidence of stomatitis, right? So controlled the hyperglycemia, not so much of the rash, but the stomatitis, I think, was pretty significant, a grade three.

SPEAKER_00 15:46

Yes, you're right. And hyperglycemia as well. And there's a lot more data that's coming out and anecdotal experience from folks that are using these drugs, and especially in the community. Because if you think about it, these patients who are on trial, they're fit enough to be able to go on trial. They're able to get to a center where there is a trial offered, and there's a number of factors that plays into a patient group that's on clinical trial. So then when you institute that into the community and widespread use, you can see slight differences there. Because there's a lot of different things. We have lots of patients who are faced with diabetes, especially in the United States, and it's important to think about that if that's a side effect that we're experiencing. Now, in the trial, they did have cutoffs for hemoglobin A1C, and that is important here. But really, to your point, Abigail, stomatitis, so mouth ulcers, being on top of that, and then hyperglycemia, and then also there was some rash there too.

SPEAKER_02 16:47

This regimen is tough, but at the same time, sometimes people think that this is the first line. So these people who come into the first line treatment are still pretty healthy overall for the most part. So if there were time to go aggressive, this would be it. So let's talk a little bit about Victoria, shall we? And you know. It warms my heart to talk about Victoria.

SPEAKER_00 17:20

I will say, I feel like in the field of breast cancer, we do come up with some pretty cool names and ones that are easier to remember. I think my colleagues who are practicing in other tumor groups will comment on that that we're quite creative with our names. So definitely love the Victoria trial. And I'll briefly step back to this is what we were talking about earlier with triplet therapies, right? So if we feel strongly that a triplet's going to work, and not only does it allow patients to have more time before they progress again, but it actually allows them to live longer. This is where we do our risk-benefit analysis and there's a trade-off there. But it's also so important to make sure that both our patients and all providers who are using these drugs feel empowered and educated on how to act ahead, how to try to prevent toxicities, how to counsel their patients on it, and how to think about these things, right? And then not just incorporating uh pharmaceutical type interventions, so lifestyle interventions that we should be able to talk about with our patients and other strategies that they can use at home because I think everybody is motivated to. We just have to be able to talk about it. And that's where we have to weigh things out. But Victoria, so this was a really exciting trial. It was presented first, as I mentioned, in Europe this past year, 2025. So this was evaluating a drug that we call getatolisin.

SPEAKER_03 18:47

Can we just say that the way that they develop names? These names are so hard to pronounce. I realize that it'll be the same. So alpella sib, sib, getolisib, right? We know that it's in that PI3 kinase pathway class, but they're still so hard to say.

SPEAKER_00 19:06

You're absolutely right. And there's so many more that are coming out. I think when Vab Degastret was first published, for example, that's another one.

SPEAKER_02 19:14

The mouthful.

SPEAKER_00 19:15

Everyone was like, how do we say this drug name? We definitely appreciate an easier way to be able to identify these drugs. But yeah, so Victoria was evaluating a novel drug called get a tolecid, and this is a PAM pathway inhibitor. So, what does that mean? So we do know that as I mentioned before, there's the PI3K pathway, and that's one pathway that tumors can utilize to enhance their tumor growth along with the mTOR pathway and AKT. So these things all work in sync. And so this drug is a PAM pathway inhibitor. So it hits the full pathway. Although I'll caution, it's an IV drug. So this is a trial that's looking at combining the getatolis of the IV drug with Ibrands and fulvestrant. So here you have an intra drug, you have an oral drug, and you have an IV drug. All right, so that's what's going on here, right? But actually, it's a very smartly designed study. They have two different studies. One was looking at a group of patients that do not have a PIC3CA mutation, and then those that did have a PIC3C mutation. And the results that were presented so far were the patients that do not have a PIC3CA mutation. And so within that, there were three cohorts of patients. There was one group of patients who received all three drugs, the getta tollacib, the Ibrands, and the fulvestrant. The second group received the getta tolacib and the fulvestrant. And then the last group received fulvestrant alone. And there's a lot of questions here because really there was a group of patients who received only one drug. And back then, that was standard of care. That's what we were doing for our patients. That's what we had available. And this is a problem that we're running into as we're getting readouts for clinical trials, is that what we were doing back then is not necessarily what we're doing now. This is something that, you know, as the paradigm of hormone-positive breast cancer and really all areas of breast cancer, as we're shifting our standard of care, the control arm or the arm that's getting one specific type of treatment, which at the time was the standard, ends up changing. What's nice about this trial is that they did allow for patients who progressed to then cross over or switch to the other arms. So that's a positive thing. The other thing to mention is that this trial, along with all the other trials that we've talked about, these are global trials. So they're looking across the world and they're looking at patients in various countries. And that's also really important because the standard is different in all of these countries. What's approved. What's not approved, what investigators and clinicians are able to get for their patients versus not be able to give. And all of these things impact the results of a clinical trial and how we think about it. But nonetheless, the triplet combination resulted in an improvement in the progression-free survival for these patients without a PIG 3CA mutation. The updated results from the San Antonio Breast Conference this year, I believe, showed, if I remember correctly, it was about 12.4 months compared to 1.9 months with the fulvestrin. And what does this tell us here? One, we know that single agent endocrine therapy, like fulvestrin alone, is not sufficient. We can't do this anymore. Our single agent endocrine therapies that are approved, which we touched on before, the CERDs, that's for a specific patient population. But beyond that, we know combinations work better. And what we need to do is find the right combination. The great data, a lot of questions on the IV use, how practical that is. Maybe it is practical for some patients, maybe it's not. And so that really has to be considered when we take all of this into account. But again, very exciting data. I think we're moving forward.

SPEAKER_02 23:23

Before we continue, here is some quick context on why the updated Victoria One results from ASCO 2026 are such a big deal. Get a Tolus works by shutting down the entire growth signaling pathway that PIC3CA mutant tumors rely on. Not just one part of it, but the whole chain. In the Victoria One trial, it was tested in patients whose cancer had already grown through a CDK4-6 inhibitor and who had a PIC3CA mutation driving their tumor. The numbers were impressive. Patients on the getadolisp triplet went nearly 11 months before their cancer progression. The doublet hit just over 11 months. Compare that to five and a half months with alpelicip plus fulvestrin, the current standard. Both combinations basically doubled the time patients had before needing their next treatment. And here is the other big win. Alpelicip has always been tough on blood sugar. Get a tellycip caused far fewer severe blood sugar spikes, which means patients may actually be able to stay on it longer, better results, and easier to tolerate. That's what has oncologists paying attention.

SPEAKER_00 24:47

I can just very briefly touch on there is an ongoing trial called the Elevate trial that's actually looking at several different combinations of medications and it's constantly reading out. So at San Antonio, there were two combinations that were shared with us that also looked promising. And so while that's a little bit earlier, it's a phase two trial, it also is giving us a lot of data on combinations. And as we go along, we're looking at safety and tolerability along with efficacy.

SPEAKER_02 25:17

So why don't we do that? Why don't we dive into this new exciting world of SERDs? Gamasestrin, alocestrin, gerodestrin. What else? Which one? Imlunestrin.

SPEAKER_00 25:32

You're so right. Pick your favorite one. There's so many. They're out there, many others that are under development. And Abigail touched on this before. What are CERDs? So, as she mentioned, just perfectly mentioned, these are selective estrogen receptor graders. And these are a novel form of endocrine therapy. So, unlike the previous generation of endocrine therapies, which either blocked the production of estrogen, or they, for example, competitively inhibited receptor activation, these SERDs directly degrade the receptor. And this type of mechanism, it allows SERDS to overcome one of the key resistance mechanisms that can develop to, for example, aromatase inhibitors. And that is what I briefly touched on before, which is an ESR1 mutation, in which the receptor is constituently activated. So it's constantly on, it's constantly running. And so if you can degrade that receptor effectively, that's one way to target this. We do know that these SERDs are still active in patients who don't necessarily have an ESR1 mutation, or that ESR1 mutations are driving the cancer or leading to the growth of tumors, but on their own, they're not sufficient. And this is again where the combination therapy comes in. But nonetheless, the SERDs are very exciting, and we have two that are out there in the metastatic setting that have been approved for those patients that have ESR1 mutations and multiple other SERDs that are being studied in combination with other targeted therapies like CDK4-6 inhibitors, which are all very exciting. There also was presented this year the use of cambasestrin, Victoria, you mentioned this, which was studied in the Serena 6 trial presented at ASCO this past year, 2025. This was a really novel type of clinical trial. So these are patients who were already on their first line of treatment, the aromatase inhibitor and CDK4-6 inhibitors, and they looked at what we call circulating tumor DNA, so fragments of DNA that was shed by tumors into the bloodstream to evaluate for ESR-1 mutations showing up in the blood. And they were looking to see, this trial was looking to see that if you switch the aromatase inhibitor to the CERD and keep the CDK4-6 inhibitor going, versus if you continue the aromatase inhibitor as those patients were receiving with the CDK4-6 inhibitor until the scans picked up progression, which is the way that we treat our patients most commonly right now, doesn't make a difference in how long patients have until their next progression. What we did find is that medium progression-free survival, it was prolonged. It certainly was. However, there's a lot of caveats here. We didn't really quite identify, at least not yet, that if we switch treatments, are patients really living longer? Or are we just moving our treatments earlier and using up some of our good treatments earlier than they need to be used up? And that still remains to be seen. I think CT DNA or circulating tumor DNA is very cool technology. I think we're getting there. I don't know that we're quite there, but we're getting there. I really believe in the next three to five years, we hopefully will be there in really detecting at a low level these mutations in the blood and then trying to figure out how exactly we act on them. And then really, it gets more complicated than that. Of all patients who have ESR1 mutations picked up in their blood, do all of them need to switch? Maybe only some of them need to switch. We have to try to hone in on really personalizing this type of strategy. It's a great strategy. It's really unique, it's really novel, but it may only be important for us to do this for some patients, maybe not all patients. And that's really where we need to go, and that's where I believe that we're headed.

SPEAKER_03 29:34

Sarah, you are at a wonderful institution who is very much looking at those biomarker testing, looking at CT DNA. And that's great for people who are in an academic setting or treated at one of these wonderful comprehensive cancer centers. But we know a large majority of people living with cancer are treated in a community setting, in a rural setting, often with an oncologist who may not specialize in breast cancer. And so we're talking about these great tests. You talked about biomarker testing early on. You talked about CT DNA testing. What is the language that patients can be using to ask their doctors for the testing that will give them these targets or give them more options for treatment for those people whose doctors may not be up on all the tests for all the different kinds of cancer? Because not everybody can do that.

SPEAKER_00 30:27

You're exactly right, they can't. So a lot of these providers in the community, they're seeing every type of cancer. And I'm so lucky that I get to specialize really in breast cancer, and then I also treat patients with gynecologic cancer. But a lot of providers they don't have that luxury. They're keeping up to date, as you mentioned, on so many different types of cancers. And they're, for example, walking down a hallway and they're seeing a patient that has a blood cancer, and then they're seeing a patient that has lung cancer, and they're seeing a patient that has a GI cancer and breast cancer. And while the field of breast cancer is moving fast, so are all these other tumors. And so, how do they truly keep track of all of this? Now at Sarah Canon, we are predominantly academic in the sense that we have investigators here who get the chance to do research and also see patients. The network is fully integrated within the community, which has been so awesome. So we've got sites that are all over the community and we work with local community doctors to try to enroll patients onto clinical trials. And through that, it's been great because we get to work with clinicians who treat all types of cancers. And if these providers are able to work with their patients who want to go on clinical trials and educate their patients on clinical trials, they get to use these drugs earlier than sometimes they're approved. And so then they feel more comfortable with using it. They're able to really teach their other colleagues who they work with on how to mitigate side effects or how to act ahead or how things were instituted. But for any patient who's interested in learning about clinical trials, there's so many patient advocacy groups that are out there that really partner with a lot of these institutions in trying to teach what's out there, what's available. If there's any message I could give to any patient about this, it's ask questions. Ask your doctors. You can always ask, what were the latest clinical trials that were presented? Could we look at it together? Could we explore what's out there? Or would you be willing to connect with any scientist that you know that maybe is a little bit more up to date on the breast cancer trials and maybe see if any of them would be options for me. But also, there's so many amazing resources that are geared to patient education because I just think our breast cancer patients, they're so savvy. They do their research, they know their stuff. Not everyone can. Some people don't have the chance to, some people don't have the means to, some people don't have the time to. And that's where really the partnership between a patient and a provider is so sacred. And I think that anyone I'm hoping is feeling encouraged and empowered to just ask their doctor questions. If they don't know exactly why they're getting what they're getting, what else they could be getting, don't be afraid to ask your doctor. That's why we're here, and that's ultimately what we're here to do. And so definitely encourage that.

SPEAKER_02 33:21

So we touched upon SERDs, and I think it's important to mention that even though CERDs are novel, we already have one CERD that we've been using for a very long time. It's pulvestrin or Fazilodex. So these are new novel oral SERDs, but they are not novel classic drugs. And speaking of gyrodestrin, or gerodestrin, you pick. We just got major news from ESCOTA 2026 that is worth a quick pause. Gerodestrin is a next generation oral hormone therapy. The idea being it could replace letrozole as the estrogen blocking partner alongside a CDK4-6 inhibitor, like polbocyclip, or Ibrands in the first-line setting. The phase three persevered trial put that to the test. Giridestrin plus polvocyclip versus the current standard of letrozole plus polvocyclip. Here is the honest read on the results. Patients on juridestrin went about 33 months before their cancer progressed, compared to 28 months on the standard arm. That's a five-month difference. And it's real, but it didn't cross the threshold for statistical significance. In clinical trial terms, that means we can definitely call it superior. Not a practice changer today. But here is the takeaway that often gets buried. Patients on both arms are now averaging nearly three years before needing to switch treatments. That's a remarkable benchmark for first-line metastatic breast cancer. And it tells us just how far this disease has come. Jodesterin isn't done. Longer follow-up and overall survival data are still to come. Okay, so let's talk about things other than CERDs. And there are many of those, right? There are CRANs and Protax, and what else is there?

SPEAKER_00 35:23

You got it. There are CRANs, there's Protax.

SPEAKER_02 35:26

CERMS. There's even a novel CERM. I've been on tamoxifen for 20 years. So this is interesting to see a new tamoxifen-like agent coming to market.

SPEAKER_00 35:37

Yep. This is what we call at this point our word salad. We have so many different types of novel endocrine therapies. Just as you said, we have a new generation of the selective estrogen receptor modulators.

SPEAKER_02 35:56

Before Sarah gives her own explanation, here is a quick breakdown of what a protuc actually is. Think of a protock like a seek and destroy mechanism for the estrogen receptor. Instead of just blocking it, the drug marks it for destruction using the cell's own internal disposal system. Once the receptor is tagged, it gets broken down, and then the drug gets recycled to do it again. That's what makes a dagostone different from a standard estrogen receptor blocker. On May 1st, 2025, the FDA approved a pedestrian for this exact indication, making it the third oral endocrine agent approved for ESR1 mutated metastatic breast cancer, joining LS estrant and immunestrin. And the tolerability profile is notably cleaned, low rates of nausea, minimal diarrhea, and a small, non-clinically significant QTC signals. A baseline EKG is recommended, but ongoing cardiac monitoring is not required.

SPEAKER_00 37:02

The protex, what are those? Those are proteolysis targeting chimera.

SPEAKER_02 37:06

Say it five times.

SPEAKER_00 37:08

Yep, yep, the protex. That's the BEP dagastriant that we talked about. That's one of the drugs that tries to more potently degrade the ER receptor. There's the CERANs, those are complete estrogen receptor antagonists. So what they do is they block multiple domains of the receptor to degrade it. So there's just so many exciting new drugs out there. But what we need to figure out is what we were chatting about earlier, which ones are the most effective for which patients and in what combination. And so that's really what's being studied now.

SPEAKER_02 37:39

All right. We have taken up a lot of your time. Well, we say goodbye. A difficult question for you. Yeah. So do you have an algorithm now? So what happens? Okay, you know what to do on the first line. Not quite, actually. There are options there. A lot of these drugs have not been approved yet. They're not FDA approved, they're only available in the clinical trial setting. But assuming they are going to be approved, what's the new algorithm for treating HR positive HER2 negative MBC population?

SPEAKER_00 38:13

In my mind, this is constantly evolving and it's evolving on a monthly, if not sometimes weekly basis. But just as you said, I really try to think about each patient in front of me individually. So there's a number of factors. Number one is doing what we mentioned, which is profiling their tumors, identifying which mutations do they have. Because even if they don't necessarily have a ESR1 mutation or a PIG3CA mutation, or we didn't touch on this, but a BRCA mutation, or the very rare mutations like NTREC fusions, for example, that opens up another treatment line. If they don't have one of those, it's still really important to know what mutations do they have, because that can tell you a little bit about their tumor. So doing that, also trying to look at how long was a patient on their first treatment, because that can give you a little bit of an idea. If they were on the first treatment for a long time, maybe they have endocrine sensitive disease, or the estrogen receptor is still playing an active role in the growth of a tumor versus a patient's tumor who's endocrine resistant, meaning their tumor found lots of other ways to grow around the estrogen receptor. So I think that's important. I think how a patient did on their first line treatment is important. What side effects did they experience? What are things to think about as we pick our next line of treatment? Also trying to think about what is the best thing for our patient. Do they live really far away? And trying to think about an oral regimen versus an IV regimen. And then what quality of life factors are important to our patient? If it's really important for that patient to be able to travel, then I wouldn't necessarily jump to an IV drug unless I felt like it was really needed for that patient. And then I would talk through that with that patient versus picking an oral drug, intramuscular drug, the fulvestrant, like you mentioned, depending on what they received in the first line. So there's just so many factors that go into it. But I think that the first thing is look at the patient in front of you. What did they receive? How long do they receive it for? What other conditions are they facing? What are their lifestyle factors? What is a priority for that patient at that time? Because that can change as well over a patient's lifespan. What certain life factors and what things are happening in their life outside of their cancer can certainly help you decide what you're doing next. And then of course, where are the sites of disease? Is this disease that's only in the bone? Is this disease that's spread to the liver? Is this involving the lungs, the bone, the liver involving all of these? Is the brain involved? These are all things that are really important to consider. I think also the subtype of breast cancer is important. We know our two most common is ductal and lobular. We didn't really go into the nuances there, but these are two different types of breast cancer, especially in the hormone-positive space. And so these are all things that play a role. If somebody has a lot of gastric disease, I would be hesitant to use something oral, for example. So there's just so many different factors that play into it. But starting first with overall survival data, we know that patients live longer with aromatase inhibitors and CDK4-6 inhibitors in the first line. Then after that, profiling our patients' tumors, understanding what mutations they have, and then taking into account all of the other factors to decide what is next, and then what is after that is really my approach.

SPEAKER_02 41:40

So basically, this is hard for you guys who specialize in breast cancer. What about the community general oncologists? How are they going to decide all of this? What is the role of AI, in your opinion, given this landscape right now?

SPEAKER_00 42:01

It's a great question. I think AI is being used in a lot of different ways. I think that providers are learning how to leverage AI, either to learn what the latest data is that's out there. We use AI for clinical trial matching sometimes. AI is being integrated more in pathologies when we look under the microscope and try to identify what type of cancer is there or what subtype of cancer is there. We can try to use AI for imaging, for modeling, and determining what could be there, and then also trying to integrate it with CT DNA monitoring. So I think AI is making its way into this. And the hope is that AI will help providers be more efficient at their jobs, and it will help because that relationship that I have with my patients is just so sacred. It's so special that I hope that never goes away. That's my favorite thing about my job, working with my patients. So I hope that is there to stay. But the other hope is that AI can be used to make our jobs easier. And this busy, evolving world that we're in, as there's so many competing efforts on our time and our attention, if we can use AI in the smartest way possible and responsibly, of course, making sure that AI is correct. That's what we're honing in on, is that it actually can help us enable us to do an even better job.

SPEAKER_02 43:22

To sum it all up, you're feeling optimistic about the future for this subtype. I certainly the most common subtype in breast cancer.

SPEAKER_00 43:32

The most common subtype, 70% of our patients having hormone-positive breast cancer. Feeling optimistic about all subtypes, but also in hormone-positive breast cancer, I think we've come a long way. I think we have a long way to go. I think we're trying to ask the right questions and we're actively trying to address them, whether that's in the lab, whether that's in clinical trials, and we all learn from each other. I learn from other investigators, we learn from our patients, learn from us. We're all one big community. And I really believe, I feel that together, the hope and prayer is that one day we will be rid of this. We will eradicate this and this will not be a problem for us anymore. I think we're moving closer there. I think we still humbly have a way to go, but at least if we're moving in the right direction, it gives us a lot of hope.

SPEAKER_02 44:20

That is such a wonderful way to end. Thank you so very much for being here. It was such a pleasure to have you with us. And I have learned something about you that you also treat gynecological cancer. So we need to have you back and talk about sex.

SPEAKER_00 44:42

I would be happy to join you again. Absolutely.

SPEAKER_02 44:45

Thank you so much. And we'll see you soon when we do the part two, when we talk about HERTU positive MBC. Take care.

SPEAKER_00 44:56

You got it. Thanks again for having me.

SPEAKER_02 45:08

That wraps up our discussion. Here's what we covered. The treatment landscape has evolved dramatically with oral SERDs now leading the charge. We discussed how CK46 inhibitors remain the first-line backbone and why ESR-1 mutations are a critical biomarker to track progression. We explored the new wave of endocrine agents, LSE and luminestrin, and lepiduchestrand, as well as next generation mechanisms like Protex and CERMS, and what distinguishes them from traditional estrogen receptor blockers. We heard from Dr. Sarah Pramgee about how she approaches treatment decisions in the real world, weighing tumor profiling, priotherapy sites of disease, and each patient's individual lifestyle and priorities. And we touched on the emerging role of AI in oncology, from clinical trial matching to pathology and imaging with the hope that technology can support and not replace the sacred patient-physician relationship. The bottom line we're in the period of rapid and meaningful progress for the most common subtype of breast cancer. The right questions are being asked, the trials are underway, and there is a real reason for optimism and a disclaimer. This podcast is intended for educational purposes only and does not constitute medical advice. The opinions expressed are those of the speakers and do not represent any institution or organization. Treatment decisions should always be made in consultation with a qualified healthcare provider. Thank you for being here, and we'll see you next time at Live from Stage Four. Goodbye.