Developing Story: The Camizestrant Vote, Doctors Weigh In with Dr. Sarah Sammons & Dr. Neil Vasan

Two weeks ago, we broke down the ODAC vote on camizestrant and SERENA-6 with seven patient advocates. This week, we go deeper — bringing in the clinical and regulatory perspectives from two of the most qualified voices in the field.

We're joined by Dr. Sarah Sammons, newly appointed Co-Leader of Breast Oncology at the University of Maryland Greenebaum Comprehensive Cancer Center and former faculty at Dana-Farber Cancer Institute and Harvard Medical School, and Dr. Neil Vasan, Director of Translational Research in Breast Cancer at NYU Langone Health — and the Acting Chair of the FDA's Oncologic Drugs Advisory Committee who sat in that room and cast a vote.

Plus, patient advocates Janice Cowden and Abigail Johnston are back to ask the questions the rest of us are thinking.

We cover:

• What SERENA-6 actually proved — and what it didn't
• Why the ODAC voted 6–3 against the ctDNA-guided switching strategy
• The four FDA critiques that drove the vote
• What the quality of life data showed — and why regulators couldn't act on it
• The persevERA trial and where oral SERDs actually fit right now
• What the vote means for the future of biomarker-driven trials
• The HERizon-Breast trial and ctDNA-guided scanning on the horizon

Breaking news: The FDA has extended the camizestrant review deadline to August 14, 2026, after AstraZeneca submitted a Major Amendment with additional SERENA-6 data. This story isn't over.

Show notes and resources at livefromstage4.org

This episode is for informational purposes only and does not constitute medical advice. Please consult your oncologist about your individual situation

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

Transcript

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With your footstands because of anything, we'll come to life from stage four, where NBC takes center stage as we talk to experts to their inspiring stories, break down signs, and find the spotlight on what matters most. Because when it comes down to it, the spot for us and by us is all about us. We're back for round two. This time, going even deeper. This is live from stage four, MBC News for Us by Us. I'm Victoria Goldberg. Before we dive in, I want to share a breaking update from this morning. The FDA has extended the review deadline for Kamisestrin by three months, moving the new decision date to August 14th, 2026. The reason? AstraZeneca submitted what the FDA calls a major amendment to their application. Additional data and analysis from the Serena 6 trial focused on three key areas. Further progression free survival analysis, reinforcing the trial's primary endpoint, updated safety data, and how camsestrian clear is circulating tumor DNA more effectively than continuing on an aromatase inhibitor. Despite the negative ODAC vote we've been talking about, AstraZeneca remains confident. Their executive vice president of oncology and the RD, Susan Galbraith, stated that they're working closely with the FDA to bring what they call a potential new standard of care to patients who currently have limited options once they develop ESR1 mutations. So the story is not over. And today's conversation is more timely than ever. On April 30th, Odak voted 6-3 against a strategy that would have used a blood test to guide when to switch therapies rather than waiting for a scan to show tumor growth. Last week, we broke down what happened and heard from seven patient advocates about what that vote could mean for us. This week, we're going deeper. We're bringing in the clinical perspective. I'm joined by two extraordinary clinician scientists and by two of my dear friends and fellow patient advocates. Dr. Sarah Sammons is a nationally recognized breast medical oncologist and clinical investigator, newly appointed as co-leader of breast oncology at the University of Maryland, Greenbaum Comprehensive Cancer Center, previously at Dana Farber Cancer Institute and Harvard Medical School. She specializes in targeted therapies, metastatic disease, and breast cancer brain metastasis. She is also one of the most influential voices in oncology at the intersection of clinical research and patient advocacy. Dr. Neil Vassan is a breast oncologist, physician scientist, and director of translational research in breast cancer at NYU Langone Health. His research identified double PIC3CA mutations as an oncogenic biomarker, a discovery that has moved directly from lab to clinical practice. He serves as acting chair and standing member of the oncologic drug advisory committee, ODAC, putting him at the absolute forefront of how next generation cancer therapies are evaluated, including this one. And joining us, my friends and fellow patient advocates, Janice Gowden and Abigail Johnston, two women who bring lived experience, sharp minds, and exactly the questions the rest of us are thinking but do not always know how to ask. All right, well, let us get into it. If they were on therapy with stable or responding disease for at least six months without progression, they could start getting blood tests to detect a mutation in the estrogen gene called an ESR1 mutation. And if the patients developed an ESR1 mutation and their scans showed that they did not have progressive disease on scans, then they could be randomized to either continue their current therapy, which is what we would do in clinical practice until they progressed on scans, or they could switch to chamisestrant, which is an oral selective estrogen degrader, so an oral SERD. And the rationale behind this is that we know that ESR1 mutations are really the major resistance mechanism in terms of why disease becomes resistant or progresses on scans to aromatase inhibitors. So we know that patients that have an ESR1 mutation don't respond as long to aromatase inhibitors and they do better with these oral SURDs or even the old SERD, rulvestrant. And so this was really the first trial to try to be proactive and say, let's not wait until patients progress on scans. Let's use the new science, the new tools that we have, try to detect these resistance mutations, and if we can detect them, intervene before a patient has progression on scans. And what the trial essentially showed was that in patients who switched to camisestrant while continuing their same CDK46 inhibitor versus staying on their AI and CDK46 inhibitor, if they switched to camisestrant, they had a median progression-free survival of 16 months versus 9.2 months if they stayed on the aromatase inhibitor. And they also showed some quality of life data that was quite compelling. Patients that switched had better quality of life, a longer time until they were feeling worse in terms of pain, in terms of shortness of breath. And there was also an improvement in progression free survival, too, which is you take the first progression and then the second progression and then you add them together. So that's the trial. Dr. Sammons just told us what the trial showed. But Dr. Neil Vassan, who served as chair of this ODAC, wants to draw a sharper line around what the trial actually proved and what it did not. What question did the trial answer? The trial answered the question that switching based on molecular progression is better than radiographic progression, but what it didn't test is early versus late. What the trial really showed is getting chamosesterin at some time point might be, I should say qualify all of this as conditional, be better than not getting it at all. And I say that because this is very hard. This trial started in 2021, five years ago. At that time, no oral CERD was FDA approved. Camisesterant is not FDA approved even now, but no oral CERG was approved. So the idea of in 2021, could you have designed a trial where you mandated that every woman in the second line, not in the first line, in the second line, cross over to a therapy in a class of drug that is not even approved yet? I don't think that would be feasible. I would argue it may not even be ethical. And I just say may because it's something worth speaking about. I mean, Abigail, right now, if there was some trial like this and that's second-line therapy, we didn't necessarily have a good track record. Is that something that you or you think other patients would sign up for or not? It's so dependent on particular circumstances. Trying to take two steps back as a patient. When we think of crossover, we think about people who are putting their lives on the line. They get randomized to the control arm, which is potentially a standard of care that they would have gotten anyway. And is the option of them then being able to still get the experimental treatment because that's what they signed up for. That's what they said they were willing to do. If you think about it in those terms, anybody who signs up for a clinical trial is signing up for something that's experimental, is taking that risk in some fashion. And so when we think about recruitment, when we think about retention, when we think about the people who are already saying, I'm willing to do the experimental thing, should we then still give them that option if they are randomized to the control arm? If we think about it in those terms, my answer is always going to be yes, because it puts the decision making in the hands of the patients who are actually taking the risk. From the clinical side and from the practitioner side, I get that this is more of a are patients really able to understand what they are signing up for? Can they understand the risks versus the benefits? And I think that this is an ongoing question that needs to happen between both parties. But generally, I fall on the side of supporting people being able to make those decisions for themselves and trials allowing to cross over into the experimental arm because they could still decide not to cross over, right? Yeah. I want to do something else at this point. The risks outweigh the benefits. So, anyway, I guess I always default to put that decision in the hands of the people who are taking the risk. And one thing I'll say as well for this trial, this trial was based on older trial called Pada 1, which was a similar idea but with full vestrant rather than an oral surge. That trial did allow for crossover, but only 30% of patients crossed over. So the tricky thing there is that it acknowledges everything you just said, Abigail, and invokes that. But from a design point of view and from a sort of a scientific experiment point of view, 30%, and it's still very hard to interpret what that really means. And so I think that that makes a trial like this very challenging. So, Dr. Vassan, could you tell us about what ODAC is? I know the acronym and I know what it does, but it would be really nice to actually understand how it comes together and what powers it has. So it's the Oncologic Drugs Advisory Committee. And so the FDA has 33 different advisory committees across all different branches of medicine. And I think that the advisory committees, in some ways, they're a little bit in the background. I do think that obviously during COVID, when the vaccine advisory committees, those are overseen by the CDC, not the FDA. But that advisory committee, of course, came into the national limelight and there was a lot of debate, et cetera, about that. And so this is one of those committees. And the Oncologic Drugs Advisory Committee is exactly what that is. It's an advisory committee. So we do not make the ultimate decision. I think that's very important to note. But we give advice as experts, both as oncologists in breast cancer, as oncologists in other diseases, as well as even patient advocates. So one of the members of every ODAC is a patient advocate, which is a really critical voice. The way that these ODACs work, they're very government. It's in a room at the FDA in Silver Spring, Maryland, imposing gigantic room with big video screens. And there are two sides in a way. There's the FDA, and then there's the sponsor, the company that has a drug that is in this gray area. And I think it's important to say also for the public that most decisions that the FDA makes are either yes or no and don't involve the advisory committee. It's only when there's this question of equipoise that the advisory committee convenes. That's very important to note. We just saw this past week TDXD get FDA approved for neoadjuvant and adjuvant. And that didn't involve the ODAC. Those were data that the FDA felt yes, we say yes. And there are times when the FDA also says, no, we say no. We don't need advisors to help us. It's when these questions of equipoise happen. And I've been part of the ODAC for about four years, and I've participated. This was my 21st and 22nd ODAC, the one that we had a month ago. And it's an incredible experience. I've learned a lot. And the regulatory thinking is very different than the way we think when we see individual patients. And I stress the word individual because these are decisions that are made for large groups of patients, large groups of women. It's also changed the way I think about cancer because I'm a breast oncologist, but this was our first ODAC since I've been on that was on breast cancer. So all the 21 ODACs we've had have been on other cancer types, myeloma, prostate cancer, et cetera. So totally different fields. And it's really enriched the way that I think about science, the way that I think about new drugs, the way that I think about papers that get published. We think in the field that just because it gets published in the New England Journal, it's like the gospel truth, right? And that's not the case. The FDA has a higher bar than what publications have for obvious reasons. I think it's good for the public to have these advisory committees because they get to hear what oncologists are thinking in real time when we're seeing patients and how we're thinking about these new drugs or new concepts that come into the clinic. But again, the quickest metaphor, it's an imperfect metaphor, is that we're like the Supreme Court of drug approvals, except we don't make the decisions. We're the advisors. So that's where the rub is. And yeah, so that's what ODAC is, that's what ODAC is not. And this is the first breast ODAC that we've had in a while. So in your experience, and you've been doing this for quite a while, how often does the FDA go along with the ODAC decision? That's a great question. But there's actually papers that have been published on this. I believe the number is north of 90%. There is a lot of concordance. That being said, it's not like the Supreme Court in the sense where in the Supreme Court, if there's like a 5-4 vote, it goes with the majority. That's not what this is. There have been some split votes that I've been part of, even where it was maybe a negative vote, but it was so close. And then the FDA ended up later, after more time, approving the drug. So it goes both ways. And again, it just really shows that it's an advisory committee. And I think I don't want to speak for the FDA, but there have been some examples. So it's important that people know that it's really more the directionality than I think the individual vote. So how does it actually work? The sponsor comes in and presents the trial, and then the FDA talks about why they oppose it or what questions they have, and then you guys vote. Is that how it works? So a little of both. So there's a lot of work that's done on the back end where we get these briefing documents. These briefing documents are available for the public a couple days before the ODAC meets, and I'm sure you all saw these documents. We get them many weeks and months in advance. And we go through the documents individually. We do not talk to each other before this vote. These are individual votes that we make in in the context of a group, but we're not conferring with each other. These are our individual thoughts. You know, in advance, who is going to be part of the committee, right? We actually find out just a couple days before, just like the public does, including myself, even as chair. And that's purposeful, obviously. So we read these briefing documents. They're very dense, they're very data-driven. Oftentimes there's data in the briefing documents that are not even available to the public at the time, which was also true for this ODAC. There were pieces of data, I see Abigail nodding, but there's some pieces of data that would have been new to the public reading that for the first time. So we're really working with the latest data around the topic. Just as you said, there's a little bit of Lincoln Douglas debate going on in the sense that the FDA presents their interpretation of the data, and then the sponsor presents their interpretation. And then there's what are called clarifying questions, which are really specific questions that the group on the advisory committee has about the data. And those questions are generally specific questions that we need clarification for. Or you showed this, but do you have data showing that? Those types of questions. And that lasts for maybe an hour. And then the discussion questions, which is really the group talking. And we try to really keep that discussion pretty intact with the group. Sometimes we ask the sponsor or the FDA to weigh in or to clarify something, but it really is a more group discussion. And that's where sometimes the discussions can change. Change isn't the right word, but they can take on different tones, where sometimes you're not necessarily sure what the directionality of where it's going. And sometimes the discussion synthesizes it altogether. And there's another very important part of the day, which is the public testimony. And so depending on the vote, there are anywhere from usually five to ten people who speak. Abigail, you know about that? I did, yes. Yes, you did. So how does one get to speak on behalf of the patients, I guess, in this case? You register on the website? On the website. And generally, there's many patients as individuals will speak. Sometimes caretakers speak, sometimes patient advocacy group directors speak, sometimes oncologists speak. It's a mixture of in-person and virtual. I will say that there are a lot of themes, I think, with ODACs now that are different from 10 years ago. One theme, which I think is very pertinent for this discussion, is that this is really about a strategy, not just about a drug. And I think actually we've seen many ODACs that are about a strategy or a new way of thinking or a new way of interpreting the data. That's very important. I think that's different from 10 years ago where they were just about individual drugs. And that makes the discussion more complex, but also more real. The second theme that we've seen is that patient advocacy groups have had a lot more parts of the discussion, which I think is very important. I think that the public discussion part is so much more real and alive when you see real people and real caretakers talking about their experiences with drugs. This gives a different gloss, I think, of the discussion. We've had one ODAC where some of the discussion points had to do with the need for blood transfusions for a certain type of leukemia. And there was this really interesting part of the discussion that had to do around people in rural areas where they have to drive two hours to get a blood transfusion. And it's not just the transfusion, it's actually the travel involved in those machinations of real life, how they bleed into the whole experience and change the whole experience. There are times when those testimonials really change the directionality of the vote, especially in that discussion. So I think that these are really important themes now that weren't necessarily part of the discussion 10 years ago. The last ODAC we had, they actually moved it up in the meeting to right after the two sides make their thing. I remember distinctly this one young woman who spoke at the end. She was very young in her 30s with metastatic, ER-positive breast cancer. And she talked about data and she wants her oncologists to understand all this data. And she really had this passionate plea about trying to extract all the data that we're gathering and do these studies, do these long-term studies. That was something that I found very moving. There were some testimonials, of course, about the fact that this is a very new endpoint and that we really need to be clear about how we're thinking about this. And that there could, of course, obviously this is all in public record, but there was some discussion both with the FDA and other patient advocates around does this create a precedent either in breast cancer or in other cancer types where we start to take apart these endpoints? And that was a concern that people brought up. But I do think that the public testimony piece is really a good, it's a very positive force in the whole day because it really personifies what we're doing. And I think that's also very positive for the public. Just getting back into the format, over the ODAC. After all of this is done, there's a voting question. We talk about the wording of the question and then we vote. I think this is very important for the public to know. We put our nickel down. It's easy for everyone to be an armchair quarterback. It's easy for us to talk about all these things, but we really put our nickel down and it's on the public record. And after the vote, we have the opportunity to say why we voted the way we did. What we call the justification. My justification was long and really went into some of the details around the second line therapy or the crossover issue. When a woman comes into my clinic or another clinic with metastatic breast cancer in the first line setting, we don't know what her second line therapy is going to be. It is not preordained. That is different in other cancer types. Breast cancer has made so much therapeutic innovation over the last 20 years that we're lucky that we have all these different therapies to offer in the second lines. And they differ in so many ways, in all the ways that we know. They differ in the biomarker, they differ in the IV or oral, they differ in the toxicity tremendously. They differ in the way it's administered. There's so many factors that go into that. And Abigail has lived this. Every time that she's on a new treatment, it's a different discussion. And you're going over the same variables, but there are just so many therapies. There's this plurality. And it's not even a majority. It's truly a plurality, meaning that it's not like 90% get one and 10%. Get a bunch of others. It's really across the board. And so I say this because in other cancer types, actually, that level of equipoise is less because there are fewer therapies in some, not all, of course, but some cancer types. I just give that as an example of how designing these types of clinical trials is actually very hard to do. And I bring that up because PFS2 in this trial was positive. The FDA, I think, really took it off the table as this is really not something we're going to discuss. And it really wasn't discussed at the ODAC for those reasons. Dr. Fasson, if you could talk more about this endpoint, what was novel about it? And maybe if you could just define an endpoint in a clinical trial for people who might not be familiar with that terminology. Yeah, so an endpoint is really what you're measuring in the first place. We know that there are studies that people can do where you're just looking for aggregate data, like how long do patients live, what percentage of patients don't have a particular side effect, et cetera. You have to statistically show that something is true prospectively. And so what the endpoint is, what you're measuring. And you could imagine that we have things that we call hard endpoints, overall survival, how long a patient actually lives, certain toxicities, which can be very hard endpoints. Did you get the side effect or not? And then we have different endpoints, what are called surrogate, endpoints that have some correlation with overall survival, but they're not overall survival, progression-free survival, which of course, when that was first conceived, was very controversial decades ago. And that actually was an ODAC to some of the discussion, Victoria, from earlier. That in and of itself was an ODAC decades ago. And that was actually very controversial. Mikhail Seckeris has written very eloquently about this in his book. It was a vote around bevisism abivastin in breast cancer, which had a progression-free survival benefit, but did not have an overall survival benefit. So very historically important in the field. I just say that because there's a historical precedent of these novel endpoints coming to ODAC and being larger discussions and being controversial. Sometimes overall response rate is an endpoint that we're thinking about. We live in a genomic era where we have a lot of rare diseases where there's just no way to enroll a randomized clinical trial, either due to low numbers or that it's really just not ethical because there's so few therapies available. They're specified in the trial as these are the endpoints we're really going to hang our hat to. And these are endpoints that are more exploratory. But obviously, if they agree with the primary endpoints, that's a good thing. If they disagree with the primary endpoints, we have to think about what that means, that sort of thing. So let's then talk specifics. The Serena Sixth Strat, the primary endpoint was the primary endpoint was progression-free survival as defined by the time from randomization, meaning the time of molecular detection of the mutation. So it is important to note that is not the traditional progression-free survival definition. You could argue right from the get-go, maybe we need to think of this as PSS with a little subscript molecular, something like that, to just take that into account. And the endpoint was met, but the question is really, what does that mean? There were other endpoints as well, the PFS2. The big picture here is that there's PFS and there's OS, and then there's a lot in between. And it's theoretically all measurable, but you could imagine that there could be changes in how we think about what's in between because patients are not necessarily on the trial. They're not being monitored in the same way. We're not offering and randomizing therapies in the same way. There might be some patients who you think about a subsequent treatment who look very different. They're less sick, they're more sick, they live in a different country where certain therapies are available and others are not. There's obviously a lot of biases that go into that, but it is an endpoint in a way. I will say it's interesting. PFS2, it's very controversial in general. Interestingly, in Europe, the EMA, which is their version of the FDA, uses PFS2 as a regulatory endpoint. The US does not. So that is actually an area of regulatory equipoise, even amongst the different nations in the world. And the FDA wrote a paper in the JCO that got published maybe six weeks ago around PFS2 and the challenges of PFS2 and the rationale for why they don't consider it a legitimate endpoint for these types of studies. Now, it's true that if PFS2 were treated very rigorously, where everyone had 100% crossover and everything was regulated, that PFS2 would become more legitimate. And that's hinted at in that article. But the way that PFS2 is currently deployed or measured, it's really that subsequent therapy. I think another meaningful endpoint is time to chemotherapy. It's something that's very hard to measure very rigorously. It's easy to measure, but it's hard to know between the different arms. There could be a lot of biases as well. And of course, sicker patients, we think about chemo, patients with more disease or disease in lungs and lung and liver, et cetera, we would offer chemo. So there's some differences. But I do think that fundamentally, time to chemotherapy is a meaningful idea. It's a meaningful endpoint. It's just very hard to balance and measure very rigorously. And I think with ER-positive breast cancer, there is that shared idea that oral medications, you have this phase of your life that you're on oral medications, and toxicities are not necessarily less for different drugs, but certainly different. And life is different. You're at home, you're not necessarily scheduling your IV infusion. Abigail, of course, can talk very eloquently about this, but I know that obviously from my patients, I know sometimes there's a lot of stress about, oh, it's not this day of the week. I have some recital to go to, I have something travel to go to. Could we switch it three days? Is that going to compromise? That whole world is just different when women are getting oral therapies. And so I wish there was a way that we could measure that endpoint because I do think it's meaningful. We need more rigorous ways to do that. It's interesting that people with the same type of cancer but different subtypes have different mindset about chemotherapy. People like me, or people with triple negative breast cancer, they start on chemotherapy and the hope is to get off chemotherapy. So it's time to when the chemotherapy ends, I guess, is an endpoint. But in the ER-positive category, this idea of chemotherapy, there are people who begin and say, I will never accept a line of chemotherapy. And so they have that bias from the beginning. And then you have the people who are de novo metastatic who maybe haven't had the experience with chemotherapy, like somebody who had an early stage diagnosis. And so people come in with very preconceived notions about this. But this idea of PFS2 is something that I think is really fascinating because it goes to the idea of sequencing. Which drug do you take first? Which do you take second, and then on down? And so, what was that something that was discussed as part of the justification for PFS2? Yes. And this was part of also why it's very challenging. I think that there were a lot of variables and a lot of pieces of data, but the strongest piece of data, in my opinion, of the imbalance in the arms and PFS2 is that something like 40% women who had molecular progression and stayed on the control arm, when they progressed, their next line of therapy was chemotherapy or ADC versus in the women who switched to the oral SERD. It was something like 40% versus 20%. That's a real difference. And there could be multiple reasons for that. I don't think it was the type of disease they have. I think it was the perception that in the camestrian arm, that was already this targeted therapy, that was already a second line therapy. And so maybe that's why there was an imbalance. So that's just my opinion. But there are a lot of reasons you could hypothesize why that's the case. It could have been shaped by the availability of next-line therapies in the country that they were in. There could be a lot of explanations, but I think that there is something about ER positive breast cancer, third line therapy. Most women are on an ADC in the third line setting. Some are not, but it's more the exception than the rule in my practice. I don't think those data were presented, those real-world data. But again, that's where these types of data are very helpful to just frame. And to Abigail's point, the PFS2, it's interesting because it's almost a bit like what's going to happen in the future. It's a little bit like being a fortune teller and saying, on this therapy is my next line, it's going to actually be better. I'm going to get more mileage out of that next line of therapy, or God forbid, less mileage. So I think that it is a very interesting concept. And it's different from some cancer types like lung cancer with EGFR mutations, where patients on those initial trials had been through multiple lines of therapy and then they had these miraculous Lazarus-like effects on eighth-line tarsiba back in the day. You heard stories like that. That is not what you need an ER-positive breast cancer. It's very rare that someone has this complete response, like you might see with TDXD and Hertz-positive breast cancer. That's not what ER positive breast cancer is. And this is where, again, the endpoint becomes really tricky because a lot of women will have stable disease for a while. And that's a win. That's a good thing. They're tolerating the therapy well. Not much is going on the scans. We think that's a good thing. Let's talk about the vote. You know, there were a couple big buckets of issues. I'll just really quickly summarize. There were really, I think, four major critiques. The first was we've spoken about this sort of unclear clinical meaning of molecular progression as the trigger for treatment change. The second, we've also spoken about PFS2 was really considered uninterpretable and not fit for regulatory decision making. The third, we also spoke about this lack of crossover to really answer that timing question cleanly. And then the fourth was that the overall survival was immature and likely underpowered. Something like 60% of it's called the information fraction, basically the patient data, was available at the time of review. And the overall survival was a little improved, not statistically significant. But the FDA had said, just based on their projections, that it wouldn't really be powered, even if they had 100% of the information. There were some other issues as well. There were some questions about safety and toxicity. There were some questions about, of course, the testing of patients, serial testing and what that means and what that is for our system. And I think those two issues were issues that were discussed. But those were the four main issues. And the vote was three to six. So three voted yes. The question was is the benefit clinically significant or clinically meaningful? And paraphrasing here, it's a clinically meaningful in this particular setting, and they spelled that out in the setting of molecular detection before radiographic progression. So three voted yes, I voted yes, along with Tony Chuerry at Dana Farber and Bill Gratishar at Northwestern, who's a breast oncologist. And then six voted no. And so that was the vote, including the patient advocate, which was unusual, actually. The vast majority of ODAX that have been part of the patient advocates have voted yes, even sometimes that's the sole yes vote. So that was different. That was the vote, and everyone talked about their justification. And I think everyone's point was very valid. This is the reason we have these votes, so that there can be this sort of open forum for what people really think about this trial and what people think about the endpoints. Why did you vote yes? We can all agree this tested molecular progression versus radiographic progression. It did not test early versus delayed. So I voted yes because I thought that the endpoints in their totality, PTFS2 and OS, were all consistent. We can debate about if it's clinically meaningful, but to me, it's not clinically meaningless. That's what I said. The first one is does PFS measured from the time of molecular progression have the same clinical meaning as PFS measured from radiographic progression? The short answer is this is the first phase three trial to ever do it. We don't know. But presumably AstraZeneca talked to the FDA about this endpoint before they decided to spend a lot of money doing the trial. I was not part of those conversations. So they raise that question is what does PFS even mean if the patient has not progressed, if it's just this molecular progression? That's sort of just a hypothetical. But then they also raised the question of PFS2. First of all, the FDA says we can't use really PFS2 to make regulatory decisions. But is the PFS2 that was measured in this trial really fair? Because you're measuring two regimens versus three regimens in some ways. And so they raise the question as to whether the PFS2 was really fair. And this was also raised by the discussant at ASCO when this trial was originally presented. With this trial, you really have two camps. And are we trying to use the novel scientific tools that we have to move along innovation? We know we have a biomarker that tells us patients are going to become resistant to AIs. We know from dozens of studies that SERDs work better than AIs for ESR1 mutations. And so we also know that if we wait until progression after CDK46 inhibitor to give a CERD, the efficacy is really limited. And if you can't tell, I stand in the camp that's a little bit disappointed by the ODAC decision. Yeah, we kind of see that. However, anytime we're doing novel trial design, we need to raise questions about whether or not we're really benefiting patients. And I think that's what we're hearing from the FDA and from the ODAC. Janice, do you have anything you wanted to ask? We've already talked about this previously, but I just think there are some questions. We don't have overall survival data. Do patients live longer when we switch due to molecular progression? What does that mean for treatments down the road? Because we have a finite number of treatments in the metastatic setting for all subtypes. And does that mean if we're switching earlier based upon molecular progression, does that then mean that we are burning through treatments faster and possibly not getting an overall survival benefit in the length of that person's life? What does that look like? And what does that mean? I'm disappointed because I am all pro CT DNA and biomarkers and all of that as a way to get closer to precision medicine for patients. So, in that respect, I felt disappointment too. But I just think there are questions that weren't answered, and that has me kind of straddling the fence in that camp of being disappointed versus I really think it wasn't a vote against camisastrin as much as it was a request for more clarity. That's how I look at it. Dennis, I wanted to piggyback on what you're saying. So, what does it actually mean for patients? Does it mean that camisastrin, when FDA votes on the drug, they will likely listen to the opinion of the committee? Does that mean that a chamasastrin will not be approved by the FDA? So I was looking into this and I actually read a Gemma article just to see what the outcome of ODACs have been over the last 20 years and how FDA approval has gone. And if the ODAC votes yes, there's something like a 97 to 98% chance of FDA approval. If the ODAC votes no, there's about a 60 to 70% chance that it won't get approved. And so we don't know. But camisesterin is also in a first-line study, camisesterin is also in adjuvant studies. There are a lot of other oral SERDs out there that are being studied. And so it's certainly not the end of the world for our patients. But I think the global question for me is when do patients benefit the most from adding an oral SERD? We're seeing studies look at them in first-line MBC versus AI. There was a press release of Persevera. That was a negative study. Before we continue, I want to take a quick detour. A little sign sidebar, so to speak. Because Dr. Sammons just mentioned something that deserves a bit more context. She referenced the Persevera trial. And if you're not familiar with it, here's why it matters to this conversation. For years, one of the big goals in ER-positive metastatic breast cancer research has been developing an oral CERT, a selective estrogen receptor degrader powerful enough to replace or improve on our current standard hormone therapies. Giridesterant was one of the drugs in this race. Persevera was the phase three trial that put it head-to-head against letrazole, both paired with Paulo Cyclip, essentially asking, should this be our new first line standard? In March 2026, we got the answer, and it was a no. The trial didn't meet its primary goal. Giridestrian was safe, showed some benefit, but wasn't better enough to clear the bar. I bring this up because it's an important backdrop for everything Dr. Sammons is describing. The field is really wrestling right now with where these drugs fit. Are they for everyone, or are they most powerful for patients with specific mutations like ESR1? There are no easy answers yet. Keep that in mind as we head back into the conversation. We know that after progression on CDK46 inhibitor, they only work in ESR1 mutant patients. And to be quite frank, they have very limited efficacy. And so we can use them in that place. I think we are moving towards using oral SERGs more in combinations post-CDK because we get a little bit more efficacy. I treat a lot of metastatic breast cancer patients. My view of patients with hormone receptor positive HERCU-negative breast cancer has been that really their best time of quality of life are on their first-line CDK-4-6 inhibitor with endocrine therapy. And so I was all for extending that period for our patients as long as possible to improve their quality of life on oral therapies that have less toxicity than moving to a Pic3CA inhibitor or an AKT inhibitor or ever limus or things like that. And so there's value in that. And it's not an endpoint that we looked at in the study or that we can really think about. But for me, it seems to be valuable to patients, and I'd love to hear more about the patient voice there as well. Right. I think in the trial they did follow the quality of life reported outcomes, and it showed that people who switched early had a better quality of life than those who stayed on AI. Now I want to pause for a second one more time. In clinical trials, patient-reported outcomes or PROs are how researchers capture the patient's actual experience. Not just what the scans show, but how patients actually feel. Are they in pain? Can they function day to day? That's what PROs are trying to measure. And in Serena 6, those numbers were striking. Patients on chamas estrent had a median time to quality of life decline of 23 months compared to just over six months for patients who stayed on the aromatase inhibitor. So here's what makes this so frustrating. The patients in the trial said they felt better, significantly better, for significantly longer. And yet the ODOC vote still went against the proposed strategy. Because in a regulatory setting, patient-reported outcomes are notoriously hard to interpret. The FDA wants to see survival data. The patients in the trial experienced something real, and it didn't move the needle the way we might have hoped. That tension between what patients experience and what regulators need to see is something that comes up again and again in this space. Keep it in mind as we head back to the conversation. Right. And it was mostly pain, it was shortness of breath, there were actually some mental health benefits. A lot of us in the field feel like what we were probably seeing there is, you know, before we see progression on scans, there's what we call subclinical progression going on, progression that we can't fully see on scans, but that's going on. For a tumor to form, we need billions of cells to come together to see something on scans. And when you're on a trial, we don't call progression unless there's 30% growth of an existing lesion or a new lesion. So there's a lot that goes on between that time. And so what I think we were probably seeing is actually treatment of subclinical progression. And they can see that by seeing the ct DNA ESR1 levels come down in the patients that were switched to camisestrin. I'd love to see us move to a more elegant place using the scientific tools that we have. But the technology is just moving a lot faster than we are. Able to do the trials and lots of questions will come up as we try to use these new tools. So, do you actually think that we're ready for the trial design that uses adaptive ct DNA switching? Again, I'll say two things. Number one is that, as I said right from the beginning, I think everyone agrees this is an important question for the field. I'll even go a step further. The only reason that breast cancer is able to even contemplate this question is because of the incredible innovation that's happened therapeutically and diagnostically. It's not just that we can detect these resistance mutations. We actually have drugs to overcome that. That is not necessarily true in many other cancer types, unfortunately. So it's because of this innovation. The second point is that I suspect that because the footprint of this trial was so infrastructure heavy, serial testing of patients every two to three months with CTDNA, they were looking for ESR one, but of course they would have seen other changes as well. What does that mean for patients, right? How is that communicated? What does that burden look like that was not actually looked at on the trial? I think that industry is going to be less enthusiastic about designing these types of studies. That's where the puck is going here. And I don't know what that means for the field. I do worry that this may stifle innovation to some extent. And I think there are a couple solutions to this. One might be that all the important groups, all the patient advocacy groups and breast cancer funding organizations decide this is a really important question. We want to figure out a way to answer this that is an answerable question for patients and oncologists and for regulatory bodies. But I think that's a challenge that we're all going to have to talk about as a field. When I think about how you would design this trial, I'm still at a loss for how one would have designed this in the perfect way. I think there are a lot of inconsistencies. And I would go a step further to saying, even if you designed this perfect scientific experiment in 2021, we would look back on this now and actually say, you only gave an oral CERT in the second line. We have so many other options, many of which have higher PFSs in the second line setting, if you have a PIC3CA mutation, for example. And so can we compare those data to our patients now? I think there are just a lot of challenges in designing this cleanly, at least for this trial at this time point in 2021. We'll be talking to Dr. Razavi from MSK, actually tomorrow. And he's starting a curative intent trial called Horizon Breast, where they will be using CT DNA to direct switching from one line of treatment to the next. Do you think this trial and that trial is a little ahead of its time and we're not ready yet for that? CT DNA is a very effective way to measure tumor burden and resistance. So it is time for us to test these principles, just like Serena 6 did. But I think what Serena 6 is a cautionary tale to the rest of the field, that we need to be very careful about trial design. I really truly don't feel like crossover is going to be possible in all trials. We probably need to try to power for overall survival, which is going to make trials a lot more expensive unless companies want to put money into it. It's tough, but I do think we're ready, Victoria, and I do think we need to try. Otherwise, we're just going to be stuck with the same way that we've always been doing things, with waiting for patients to progress until we try something new. And if we really want to be out of the box and move the needle forward and even start thinking about curative intent for some patients, I think it's time for us to try some of these novel principles. Janice, I would agree with you. One of my biggest concerns with the ODAC decision was whether or not this decision will slow the progress of utilizing biomarker tools in drug development. And the fact of the matter is that with us being engaged with the patient community so heavily, we hear that patients are already getting CT DNA testing. They're already making treatment decisions based upon their Cigna Terra testing or this or that. I know of a few patients who are newly diagnosed, because I facilitate a newly diagnosed MBC support group, whose oncologists have switched them based upon rising CT DNA from Cygna Terra testing without following up with the imaging, which that makes me very nervous. Makes you very nervous too. Oh, yes, that to me is not a good way to practice, but I'm not a physician. But at the same time, I do see that we're going in that direction. And patients are already, they're informed, they're asking for CT DNA testing. And then they're asking to switch treatment when their CT DNA is rising. Hopefully, this decision doesn't really cause too much of a delay in biomarker-driven trials, in addition to having access to a new treatment just because of this decision, is also of concern, I think, because of the fact that the quality of life was improved. Granted, it might have been from symptoms of disease when they were having subclinical progression already. But it did seem to be, and I haven't dug into the PROs that much, and don't know the specifics on the adverse events with camisestrin, but it appeared to be fairly well tolerated. That's a little bit low grade. And there is also some low-grade bradycardia. In a patient that was given chemizerin concurrently with ribo, but also had a lot of other medical things going on. There was an incidence of prolonged QT. So that would have to be something that was thought out just in terms of monitoring, as we monitor patients on ribocyclib in the beginning for QT. But overall, I would say the oral SERDs are very well tolerated. All right. What would be your parting thought about all of this? Is this a cautionary tale or a hopeful first trial that will get us to the paradigm shift in trial designs and treatments? It's a hopeful first step. When we are innovating, when we are changing the paradigm about how we do things, which is historically forever has been waiting until scan progression to change therapy, there's going to be some bumps in the road. But CT DNA technology is here to stay. I will not say that we are ready to change therapy based on what we find on CT DNA. And that's why we need to do trials to really understand how to effectively use these tools to improve the outcomes for patients. But we are moving in that direction and we need industry behind us to do these trials. One trial that you might talk to Dr. Rizavi about that one way CT DNA could help MBC in the short term. He's planning a trial that I'm sure he'll talk to you about that I have been weighing in on a little bit with him doing scans based on CT DNA. So maybe waiting a year if your CT DNA is down and not doing scans and only doing scans when we start to see a rise. Now we're gonna have to do studies to prove that we can do that. But how nice would that be? But that is an immediate way that I see us studying and using it, not having to have those patients go through scanxiety, get all that dye, that radiation. If their ct DNA levels are fine, we could spare a lot of headache. And that's where I first see it moving. And then hopefully we'll continue to see interventional trials, both in metastatic breast cancer and early stage breast cancer. I think it's moving in that direction. Just speaking from a personal standpoint, it's something I have literally begged for the last three years. I would stop getting scans. And I might stop getting scanned at this point, having no evidence of disease and being off treatment for over nine years. I haven't found anybody to agree to do that for me yet. You know, from a patient perspective, that is something that I've argued that I don't get scan xiety anymore. So that's not an issue. However, if I could use those as companion diagnostic tools as far as alternating, maybe I get CT DNA done, maybe get a scan every two years. There are just so many possibilities, I think, out there where this could work in select patients. And that really is where we're moving towards more precision medicine, more patient-centered medicine, where we're not all throwing everybody in the same box and saying this is what we do for everyone. And I just think that's so important. I was so glad to hear you say that, Dr. Sammons. This is a good place to stop. Thank you so much. So thank you so much for being here and take care. Bye. Bye bye. Bye, everyone. That's it for today's episode. Thank you so much to Dr. Sarah Sammons, Dr. Neil Lassen, Janice Cowden, and Abigail Johnston for such a rich and honest conversation. Today we covered the Serena 6 trial and what it actually proved and didn't prove about switching therapies based on ct DNA and molecular progression before scan confirms tumor growth. We heard from Dr. Vasson, who said in that room as ODAC chair and voted yes about why the 623 result came down the way it did. We heard from Dr. Simmons about what the data, what the data mean for patients right now, and from Janice and Abigail about what this moment feels like from the inside. And we shared this morning's breaking news. The FDA has extended the review deadline for chimaztering to August 14th, while AstraZeneca submits additional data. This story is not over. If this episode was helpful, please subscribe wherever you listen, share it with someone in the MBC community who needs to hear it, and head to livefromstage4.org for show notes, links, and resources from today's conversation. A quick note everything you heard today is for informational purposes only. It's not medical advice. Please talk to your own oncologist about what's right for your individual situation. I'm Victoria Goldberg. Thank you for being here. We'll see you next time.