 The only thing I’ll bring up about the new ADCs [antibody-drug conjugates] coming out is that there is also datopotamab deruxtecan, which is also a deruxtecan-based ADC, but targets Trop-2

 Similar to T-DXd [trastuzumab deruxtecan] targeting HER2, this is targeting Trop-2 with the same payload as T-DXd. This is similar to the idea of sacituzumab targeting Trop-2, but they’ve presented some early data in triple-negative disease, which looked very impressive, in pretreated disease with about a 30% response rate and 50% if you excluded patients who had had prior topoisomerase 1 inhibition. We haven’t seen the data yet from hormone receptor-positive patients; they had conducted an expansion cohort in their phase 1 setting. But there is an ongoing phase 3 trial, the TROPION-Breast01 study. This is randomizing patients to get datopotamab deruxtecan or to get treatment of physician’s choice who’ve had 1 to 2 prior lines of chemotherapy in the metastatic setting. If that study is positive, this whole thing is going to blow up in terms of our treatment paradigm, because what do we think about sacituzumab and T-DXd….

 It’s like many different options, that’s true. The last question is, do you think that these fantastic data with HER2 disease in general, and breast cancer in particular, that we’ve been seeing in the pretreated and advanced disease setting, will similar results also be seen in the early, first-line setting? The tumor is not the same, and there is more expression of different oncogenic antigens as the tumor progresses. The microenvironment is changing, vasculature is changing, and all of these things are important for an ADC, which is a complex extractor, to get to the right place. I don’t know its role in adjuvant treatment. There isn’t a microscopic tumor there, or in the first-line setting, or neoadjuvant. I’m not so sure that its efficacy in pretreated patients…would it have the same degree of efficacy in less pretreated patients or in the neoadjuvant setting? Do you have any opinion on that?

 It’s a very good question. Again, the ADC data in the metastatic setting are impressive and robust, but I think the question is going to be if it can replace chemotherapy in an early stage patient. We saw some hints of data at ASCO [American Society of Clinical Oncology annual meeting]. There were data presented for the preoperative sacituzumab study, the NeoSTAR trial, with just 4 cycles of preoperative sacituzumab in triple-negative disease. There was about a 30% pCR [pathologic complete response] rate. It was only 4 cycles, but to me it suggested that it is a robust agent, even in the preoperative setting. We need more data to understand duration and combination. Can it replace part of the chemotherapy, or all of the chemotherapy? I think we’re going to have to see, but given the data that we’ve seen with trastuzumab deruxtecan, it begs the question: can this agent help us in our early disease patients and help cure more patients? It’s clearly better than standard chemotherapy for metastatic disease, but is it going to be better than, for example, ACT [doxorubicin, cyclophosphamide, paclitaxel]?

 I think that’s a movement we need to go in, but your question is a good one. Is it going to have the same efficacy in an early stage patient or not? This is my very simplistic way of thinking, but if ADCs are just a mechanism to deliver chemotherapy into a cell with a target, if the target is there, and this chemotherapy is so potent and works, then hopefully it should help us replace chemotherapy. But again, we clearly don’t understand the biology and mechanism of action as clearly as I wish we did.

 I’m afraid it’s much more complicated than that.

 It’s so complicated to make decisions in clinics, but we are medical oncologists and we are trying to fight against death. We’re fighting against a very difficult situation, which is progressive cancers. We’ll manage with our algorithms, and we’ll keep helping patients as much as possible. Thank you for being here with me.

Videos

Breast medical oncologists close out the program on HR+ metastatic breast cancer by highlighting ongoing clinical trials with antibody-drug conjugate therapy. 

Ongoing Clinical Trials With ADC Therapy in HR+ Metastatic Breast Cancer

: Second question is the obvious one: how do we introduce sacituzumab govitecan [Trodelvy]? Yesterday, we discussed some data of sacituzumab govitecan and its efficacy irrespectively of HER2 status. It has been trying to help in the algorithm. When to use sacituzumab govitecan: before or after T-DXd [trastuzumab deruxtecan] in the HER2-low space? T-DXd works for HER2-zero and HER2-low. Maybe that is why this analysis was done and presented yesterday. In direct comparison between 2 trials, what would be your optimal sequence when sacituzumab govitecan is approved for this indication as well?

: First of all, I was very excited to see the data from TROPiCS-02 with regards to overall survival. We saw the initial data comparing sacituzumab to the treatment of physician’s choice at ASCO [American Society of Clinical Oncology] with regards to progression-free survival [PFS] showing modest benefit. The PFS Delta, just about 2 months, was not as large as I think we wanted to see it. Seeing that there’s over a 3-month Delta in terms of overall survival, favoring sacituzumab, makes me think that it should be a standard option for our patients, but it is for a population of patients though that were pretreated more than DESTINY-Breast04 with 2 to 4 prior lines of chemotherapy for their metastatic disease. I tend to think of sacituzumab as a later-line agent, as was used in TROPiCS-02, meaning that I would think about using T-DXd probably in a second-line chemotherapy setting. Then, post-T-DXd, if they’re HER2-low, they could get sacituzumab. But if they’re HER2-zero, and not a candidate for T-DXd—which is about a third of our hormone receptor-positive patients—then it could be used as a second- [or] third-line chemotherapy agent. I think it just depends on their HER2-low status to make that decision.

: Would you recommend retesting HER2 status when you have to make that decision? In our first-line patients, we didn’t used to biopsy and rebiopsy but it may be the next recommendation: to biopsy and rebiopsy to look for this dynamic X person on the targeted antigens. This may be a problem or an issue to be addressed when we plan to use particular ADCs [antibody-drug conjugates] because we’ll have many options. Maybe if it’s striving because of expression levels, we’ll have to biopsy, and rebiopsy. HER2 and HER3 is a very dynamic biomarker.

: I think this is a question I’m struggling with in clinic currently because HER2-low status is dynamic. We’ve seen some publications where if you go from a primary setting to a metastatic setting, you can see it go either way. You can see it go from HER2-low to HER2-zero, or HER2-zero to HER2-low. Even in the metastatic setting, we’re seeing the same dynamic trend. We don’t have as much data about how it trends through the metastatic setting, but just anecdotally in the clinic, I’ve seen this, and I have started biopsying more. The question I have is if I biopsy someone and they’re HER2-zero, but their biopsy in the prior metastatic setting it was HER2-low, what do I believe? Because 1. it’s dynamic, but 2. it’s probably also heterogeneous, so where I biopsied may also impact one, if another location is actually a HER2-low. In truth, I’ve been giving the patient the benefit of the doubt that if they’ve had 1 biopsy that was HER2-low, even if it’s not necessarily the most recent biopsy, I’ve been using T-DXd. But I think your point is super important. We need to understand this better because I don’t know. Does it matter, at the time that you start, if the biopsy is HER2-low, especially because our testing is not even so accurate? That is what worries me to make that decision.

: No, sure. Maybe activity won’t depend on that. Let’s wait for it.

: That’s true. What if ultra-low works too?

: Maybe this hasn’t been so much the “magic bullet” but has been the driver. In fact, maybe these drugs are so effective that for some reason, they can be administered on patients with a wider therapeutic window when compared to conventional chemotherapy, but maybe they are not so dependent on the antigen or antibody. Maybe the antibody has its own mechanism of action, but the level of antigen doesn’t mean anything. We have data from–

: This is the very earliest scenario, pre-surgery trial, and activity of patritumab, biologically speaking, through CelTIL [tumor cellularity and tumor-infiltrating lymphocyte] score that does not depend on IHC [immunohistochemistry ] expression, but mRNA expression, on this gene on HER3. I just know that I don’t know anything.

: I think the question is unknown. The DAISY data, I think, is what really threw that into the mix because if you’re seeing responses in HER2-zero, is it that it doesn’t matter what your HER2 IHC 4 is, or that you’ve captured some HER2-zeros that have HER2 expression that’s not enough to be 1+, but it’s that sort of 10% faint staining that’s getting them to be HER2-zero, yet still getting responses. I think we really need to understand if HER2 quantitation matters or not.

: Sure. And we need more translational approaches and projects. Are you performing biopsies at your clinics because you’re using a disease? I think that it’s relevant for clinicians to perform biopsies the most they can because we do need those samples, just to have that ready for new investigational projects or collaborations so we can see what’s happening when a patient progresses to a particular ADC. This will help to take decisions in the clinics.

: It’s so interesting that you bring that up because our institute started a biopsy protocol for pre- and post-ADC. Particularly with this idea, as you pointed out, we don’t know for what biomarkers or for who’s going to respond to ADCs, but the resistance mechanism is going to be critical to understand.

: We talked about maybe using sacituzumab post T-DXd, but clearly, we have no data what the efficacy is going to be when you’re using topA. What if the ADC mechanism of resistance to T-DXd was that the tumor developed resistance because it was resistant to the deruxtecan? Does that mean that you’re not going to respond to an SN38 payload with sacituzumab because you have a topA-I resistance? We have a very small case series. One of my colleagues, Aditya Bardia, MD, MPH, had published literature looking at sacituzumab resistance, where they saw it could either be the target, or the payload that led to the resistance. This clearly shows that we need to learn a lot more in order to think about ADC sequencing, especially as there are so many new ADCs that are coming out.

: Sure. That’s impressive. It’s like cooking. You combine different ingredients and you can make your own ADC. Please stop and let’s review what we have on how to move forward.

Centering discussion on antibody-drug conjugates in HR+ metastatic breast cancer, panelists consider the selection and use of these agents in practice.

HR+ Metastatic Breast Cancer: What is the Role of Antibody-Drug Conjugates? 

: Sara, now we are talking about HER2-low. Does HER2-low exist? I don’t know. The first question is how do you measure HER2 expression in histochemistry with quantitative analysis or not? It’s really difficult to capture HER2-zero, or very low, or ultra-low. I’m getting crazy with this.

: I wish I had a good answer. I think it’s obviously a very important question. Now that we have T-DXd [trastuzumab deruxtecan] for our HER2-low patients, figuring out how to select which patients are candidates for T-DXd is really important. In DB04 [DESTINY-Breast04], they selected patients who were 1+, or 2+, and not FISH [fluorescent in situ hybridization]-amplified. This sounds very straightforward, but the problem is that we’ve seen a lot of discordance in testing, particularly when looking at HER2-zero and HER2-one disease, where it’s such a critical distinction because it determines whether you get the drug or not. There is a very nice publication by David Rimm’s, MD, PhD, group at the Yale School of Medicine in New Haven, Connecticut, that shows there’s only about a 20% concordance amongst pathologists when given the same slides to read.

: That is actually pretty disturbing. We had a discussion with the pathologists at our institution about this because we wanted them to realize that these assays were originally developed just like patients for trastuzumab [Enhertu], but it didn’t matter if you were 1+ or a zero. It didn’t have any treatment implications.

: But now it matters. I think it’s really important to discuss these implications with your pathologist and hopefully be able to figure out what the correct result is. I think the challenge is that we need a quantitative assay because even HER2-zero disease has up to a 10% staining. Having a quantitative assay will be more important. We’ll have to see what the results are from DESTINY-Breast06 study which was including some ultra-low patients—meaning they could have any staining between zero and one. If that group has benefit, this is going to get even more confusing.

: Sure. I think that we have a pathologist problem here. In Spain, we are performing HER2 predictions at SOLTI, trying to guess what the 1+, 2+ HER2 expression means versus mRNA expression in the majority of patients who are participating in clinical trials with T-DXd. Maybe this is the way to move forward and try to have a quantitative study that could be robust, reproducible, and be proceeded as the companion diagnostic. Why not? If there’s a very effective track behind T-DXd, then we should work very hard on selecting patients. This is the first step. What are your feelings on HER2-negative? Do you think that we are ready to begin to use T-DXd? T-DXd has recently been approved by the FDA for this indication. Are you ready to treat your HER2-low patients with this drug right now? What is your sequencing to this treatment landscape for ER-positive disease?

: I don’t know. I mean, when those data came out at ASCO [American Society of Clinical Oncology] from the DESTINY-Breast04 study I got a standing ovation. I think it was deserving, not just because use of T-DXd is improving both progression-free survival [PFS] and overall survival [OS], but it’s also a paradigm shift in the way we think about treating breast cancer. We’re so used to thinking about subtypes, such as ER-positive, HER2-positive, and triple negative. I don’t think HER2-low is a new subtype of disease. I don’t think it’s biologically unique and associated with a different prognosis. I think it’s just trying to find a marker as a target for a drug to get drug delivery in. But it’s a completely different way of thinking because if you can find that marker on the cell to deliver your chemotherapy, it works irrespective of subtype. I think it’s really going to change the way we do drug development in general. Again, it was very deserving of the ovation that it got and, given how active the drug is, as soon as we got approval from the FDA, the USA started using it right away. In essence, T-DXd is doubling PFS and dramatically improving OS. I think the only challenge that we’ve had is the toxicity in trying to balance benefit with potential risk. We know that about 10% of people can get interstitial lung disease [ILD] from T-DXd, and there were 3 deaths in DESTINY-Breast04 from ILD. I don’t take that lightly. I think our group has made sure that we are getting routine high-resolution CT scans. I restage people a lot more often than I would normally if they’re getting T-DXd. Usually, I am reimaging patients every 6 to 9 weeks to make sure that I’m not seeing greater pneumonitis on imaging. I think it’s really important that we’re aware of that, and that we inform patients about that risk. But in terms of where I’m placing it, DESTINY-Breast04 was meant for someone who had had 1 or 2 prior lines of chemotherapy in the metastatic setting, post-endocrine therapy. Similar to your algorithm where you give your CDK4/6 and then endocrine therapy plus fulvestrant [Faslodex]—fulvestrant plus everolimus [Afinitor] or alpelisib [Piqray]—after that, I am usually moving to chemotherapy quickly because not much works at that point in time. Usually, as you pointed out, capecitabine [Xeloda] is a wonderful option there. But if the patient is post-capecitabine, and if they’re HER2-low, I’m thinking about T-DXd at that point in time. Then the question arises: Can you use it earlier than that? Certainly, we don’t have the data from DESTINY-Breast04 to support using T-DXd earlier, but DESTINY-Breast06 will address that question because it’s immediately post 2 lines of endocrine therapy prior to chemotherapy.

: We’ll have to wait to see and continue to watch the toxicity to balance that risk-benefit.

: But I think I’ve been mostly utilizing it after 1 line of chemotherapy.

: This is an important issue. As patients have been treated with oral drugs for many years, with a nice quality of life, their status was good until they suddenly needed an IV [intravenous] therapy that could potentially risk their lives because of ILD. This is a big change for them, especially if they come from hormonal treatments or capecitabine. This is not HER2-positive disease because many came up before in this higher-risk patient. This is an issue.

Centering their discussion on the HER2 low setting of HR+ metastatic breast cancer, medical oncologists review data behind trastuzumab deruxtecan therapy. 

HER2-Low Metastatic Breast Cancer and Use of Trastuzumab Deruxtecan

 We are talking about what to do with a patient who progresses after a CDK4/6 inhibitor. In a very select patient, you may be able to continue a CDK4/6 inhibitor, but what about other more standard strategies? For example, are you testing patients for acquiring 

 or PI3 kinase mutations? What do you think about utilization of alpelisib here?

Eva M. Ciruelos Gil, MD, PhD:Excellent question. I don’t think 

 has been recommended to be routinely tested by medical societies, but as soon as we have these new data inserts, we should be able to begin testing our patients routinely, especially in the post-CDK scenario when they’ve been pretreated with an aromatase inhibitor. They are gaining probability of having an 

mutation. This is not done routinely in the clinics, but maybe it should be, or we should start. 

 must be routinely screened for, if the patient is metastatic, maybe before or after the first line because the impact on the status of 

 won’t affect the decision nor the efficacy on CDK inhibitors but could affect decisions on the second line. So if a patient has a 

 mutation, she should be treated with alpelisib now plus a different hormonal combination; it could be fulvestrant per the SOLAR trial, or it could be letrozole per the BYLieve Cohort B trial. Thanks to BYLieve, we have many potential drugs, with some nice efficacy and toxicity data, to combine with alpelisib. BYLieve seemed to not be a positive trial, but at that time, we didn’t realize the difficulties in the post-CDK case scenario. If you have 5 months of progression-free survival [PFS] after CDKs, these are good data, so BYLieve is a positive trial. We’ve realized that after seeing SERDS [selective estrogen receptor downregulators], VERONICA, and other trials that specifically test second-line treatments after CDK4/6 inhibitors.

At least for me, I wouldn’t recommend treating unmutated patients with a hormonal therapy alone because median progression-free survival is around 2 to 3 months. This is very poor. I would need to offer some new combinations, preferably on a clinical trial. Going back to everolimus, everolimus has data from a phase 3 trial with exemestane, BOLERO-2, from phase 2 trials with fulvestrant in the…and MANTA trials, and also with tamoxifen in the TAMRAD trial. We have all of these possibilities to combine everolimus in this post-CDK scenario in unmutated patients. These would be my recommendations unless there are other clinical trials that would benefit these patients. The evERA trial will combine a new SERD with everolimus. This may be a very good option, for SERDS to be combined, after palbociclib or what you mentioned before.

 I agree with you. I generally like using combination therapy post-progression on CDK.

 This is because the PFS with endocrine monotherapy is so poor. I think your algorithm is really helpful, to think about testing for PI3 kinase mutations, using alpelisib there; if there isn’t a mutation, thinking about an everolimus combination.

 It’s been a pity to not have more possibilities for using these targeted drugs against the PIK3/Akt/mTOR or PTEN signaling pathway. It was a negative trial, after some positive results in patients in which this pathway is altered. There are still some pending trials on capivasertib. Maybe we should revisit how we selected patients in those trials, as in the triple-negative scenario, if you test the whole pathway, you are able to capture more patients and turn a negative trial into a positive trial, as seen at the last ASCO [American Society of Clinical Oncology] meeting. I don’t know if there’s still a role for some type of Akt inhibitors, as well as complementary drugs to be combined with our mono treatments in the second- and third-line scenario. That should be welcomed.

 No, I think it was quite impressive, when they were able to capture all of the pathway alterations, the benefit in terms of PFS and OS [overall survival] was quite striking. We’ll wait to see the phase 3 data to see if there will be a role for Akt inhibition in this space.

 It is nice to think about these different scenarios.

Shared insight on appropriate treatment options for patients with HR+ metastatic breast cancer following progression on CDK4/6 inhibitors. 

Treatment for HR+ Metastatic Breast Cancer After Progression on CDK4/6 Inhibitors

 Now that we have these agents to use in the first-line setting, what do you think about continuing CDK4/6 inhibition beyond progressive disease? Do you do it? What did you think of the MAINTAIN data?

 Yes, the PADA and MAINTAIN trials are small, but really intelligent trials. This is emergent. I think this is similar to the ADAPT trial in terms of when somebody has an important question, you don’t need a big phase 3 trial for this question to be discussed at least, or to be followed. MAINTAIN is a trial that was presented earlier this year, and we know that maintaining ribociclib after progression on palbociclib, or even ribociclib, is good and is better than discontinuing CDK inhibition. So, this could be a new standard. I wouldn’t recommend this practice because we need phase 3 data on that. There’s an abemaciclib trial in which patients who have been pretreated with palbociclib or ribociclib, when they progress, they are randomly assigned to stay on abemaciclib versus hormonal treatment. This trial may have the final answer to that question. But I think maintaining the inhibition of CDK; I don’t know if different CDKs, such as 4/6 or many others that play an important role in the acquired resistances, will be relevant, but they are in urgent clinical need by these second-line patients because of the post-CDK scenarios.

Let’s also put an eye on biology. PATA has tested 

 mutations. HARMONIA is testing the only direct comparison between palbociclib and ribociclib in a specific subset of patients. Selected by intrinsic subtype, there are around 20% of patients who are HER2 enriched, or even more if you test the metastatic samples, metastatic disease. Maybe these patients need a more potent CDK inhibitor. Maybe palbociclib is not enough in that case; maybe this is the best niche for ribociclib. We don’t know. We are doing this direct comparison in the HARMONIA trial. There are many remaining questions.

 It’s amazing how much data continue to come out about these.

 I think your point about MAINTAIN is excellent. I honestly thoughtit was very impressive data for a randomized phase 2 investigator-initiated trial. I will say, occasionally I use CDK4/6 inhibition beyond progression in a very select patient population, where I think maybe continuation would be of benefit. But I think the question will be, as you pointed out, does it matter which agent you use? Do you need to switch the CDK4/6 inhibitor?

 Yes. A small proportion of patients in MAINTAIN started with and maintained ribociclib and benefited in the same way as patients who were pretreated with palbociclib, so we never know. It opens the possibility of retreating with a CDK inhibitor when patients relapse after having adjuvant abemaciclib because more patients are receiving this drug in the earlier scenario as well.

 That’s an excellent point. We don’t have any data about how to appropriately treat someone who relapses after having abemaciclib.

We’ll see more data come out. As you point out, the PACE study may get presented at San Antonio Breast Cancer Symposium 2022, which is predominantly looking at post-palbociclib. Those data will be interesting to see if it matters.

Expert panelists consider when it is appropriate to continue the use of CDK4/6 inhibitors beyond progression in HR+ metastatic breast cancer. 

HR+ Metastatic Breast Cancer: Continuing CDK4/6 Inhibition Beyond Progression

 We’ve seen a lot of other exciting data come out in the metastatic hormone receptor-positive setting. I was very eager to see the data of 1 trial in particular; it was from MONARCH 3 [NCT02246621], post ASCO [American Society of Clinical Oncology Annual Meeting 2022], where we’d seen survival data from PALOMA-2 [NCT01740427]. I was curious to hear what you thought of the MONARCH 3 data and how it impacts your vision of the 3 CDK4/6 inhibitors. Does it have an impact on what you’re going to select for patients?

: That’s a fantastic question because it is really relevant for making decisions in the clinic. Fortunately, the majority of clinicians have the opportunity to choose between palbociclib [Ibrance], ribociclib [Kisqali] , and abemaciclib [Verzenio]. Which is our preferred first option? Even when overall survival [OS] hasn’t been the primary objective in any of these trials, suddenly it has converted into a very important thing. So we used to work with progression-free survival results until the first of these 7 randomized trials with CDK4/6 inhibitors achieved a significant impact on overall survival. From then, we’ve been comparing overall survival for the rest of them. This is a curious thing, yet funny thing for me. It’s relevant because we have the choice to choose between drugs despite comorbidities, toxicity profiles, and experience. I think that is the most important in overall survival results because that is the general gold standard in oncology. I have to say, ribociclib is the only drug that has robust data on progression-free survival and overall survival in pre- and postmenopausal patients. At least for me, I think that ribociclib should be the first option, even though it has not been used the most frequently because all of us have been using palbociclib for the past 10 years. Experience is great, and real-world data are great, but overall survival results are not statistically significant.

PALOMA-2 had bad luck in being the first trial in the first-line scenario. Maybe that is why many trials censor patients because they discontinued the double-blind treatment, and they went into palbociclib because of the patients’ and investigators’ decision. This has been an issue: to achieve statistically significant results favoring overall survival. Data are difficult to change. Overall, I would say that maybe ribociclib is the preferred option. Palbociclib is still up there with much more experience in real world as well. Lastly, we suddenly have abemaciclib. Abemaciclib was the third, maybe the most potent, clinically speaking. From MONARCH 2 [NCT02107703] and MONARCH 3 trials, we have data that this drug has impressive efficacy in visceral metastases in patients who relapse very early after the adjuvant treatment, and in tumors that seems to have a higher great or low PR [progesterone receptor] expression. This is some type of more biologically aggressive disease. I’ve been using abemaciclib for those patients who relapse very early on during adjuvant treatment and have visceral metastases. We don’t have final analysis on overall survival. MONARCH 3 has shown results that are not statistically significant, but it could be clinically meaningful in favoring abemaciclib for first-line patients. In a few months, we’ll have the final results, or maybe the end of next year. This is what we have today: robust data favoring ribociclib, which shows the high probability to achieving positive results in overall survival as well as in the next follow-up because 20% of patients are still alive in the sixth year. This is impressive. I think that the longer the follow-up, the more we’ll achieve statistical results. So this could be my second and third option for comorbidities or because of experience….I think that palbociclib is still there¾ especially in combination with new agents. SERDs [selective estrogen receptor degraders] and many other new compounds are being tested in combination with palbociclib because of that excellent toxicity profile. We shouldn’t forget that. This could be the companion CDK inhibitor when we’re trying to use new drugs in this landscape.

: Excellent overview. It’s really nice to see that we have choice. It is definitely exciting to see the overall survival from MONARCH 3. Again, it’s not statistically significant, but definitely has almost more than a 13-month OS difference, which is very clinically meaningful.

In the context of recent clinical trials, experts share their perspective on the selection and use of CKD4/6 inhibitor therapy in patients with HR+ metastatic breast cancer. 

Interpreting Data With CDK4/6 Inhibitors in HR+ Metastatic Breast Cancer 

 Lasofoxifene is not a SERD [selective estrogen receptor degraders], it’s a SERM [selective estrogen receptor modulator]. Based on any differences you’ve seen in the different drug pools, or your conclusions for SERDs and lasofoxifene data, do you see any different roles for this drug?

 I think it’s being developed in a similar way. It seems as though the data that we saw yesterday were comparing lasofoxifene [Fablyn] with fulvestrant [Faslodex] in the 

-mutant population and showing pretty similar data. This may be a trend toward a benefit. But again, I think it’s an active agent that is well tolerated. I thought the data we saw at ASCO [

American Society of Clinical Oncology Annual Meeting 2022

] were quite impressive. This was the agent in combination with abemaciclib [Verzenio]. It is moving forward into registrational studies. As you point out, it is different. It’s a SERM, as opposed to a SERD, so I think it has a lot of potential because the abemaciclib combination data looked outstanding. We’ll have to see what happens.

Closing out their review of endocrine therapy in HR+ metastatic breast cancer, panelists consider clinical trial data with selective estrogen receptor modulators [SERMs].

Brief Review of SERM Therapy Data in HR+ Metastatic Breast Cancer

: I was going to give an overview of SERDs [selective estrogen receptor degraders], Sara, because they have been promising drugs and so pharmacologists, patients, and clinicians have high expectations for them. However, we’ve had some disappointing data from European Society for Medical Oncology Congress 2022; ESMO on SERDs. Could we have your general view on these drugs and particular view on some of them?

: There has been so much hope placed in these agents. We’ve been looking for better endocrine therapies for patients, and the opportunity to have an oral agent instead of the intermuscular fulvestrant [Faslodex] has been attractive to both patients and physicians. We’ve been eagerly awaiting these data. We initially saw data came out from the EMERALD trial [NCT03778931], which had compared the oral agent elacestrant with endocrine therapy, a physician’s choice. That study was a positive study, but we all felt the benefit was fairly modest. For the intent-to-treat population, there was only a delta of approximately 1 month. What we saw was that the 

-mutant patients were seeing larger benefits. 

-mutant patient population intent delta increased from just under 2 months to almost 4 months. This seemed like a promising group of patients. This agent is currently under FDA [United States Food and Drug Administration] review, so we’ll see if it leads to an approval soon. It would be nice to have an oral agent.

As you point out, post CDK4/6 inhibition, there is a 2-month PFS [progression-free survival] that we’re seeing with standard endocrine therapy, which is a bit disappointing. I think combination therapy is probably where we need to go. There are multiple oral SERDs in development, not just elacestrant. We saw data at ESMO. One study was AMEERA-3 [NCT04059484], which compared an oral SERD, amcenestrant, with treatment, the physician’s choice. This was in a patient population where 80% of patients had had a prior CDK4/6 inhibitor. This is different than the EMERALD study where 100% of patients were post CDK. SERDs were also compared with endocrine therapy, but here about 90% of patients got fulvestrant, which was more than in EMERALD where it was more like 70%. So there were some differences in patient populations. It was a smaller, randomized, phase 2 trial with 290 patients. It showed that there isn’t a difference with amcenestrant compared with endocrine therapy of choice. Both therapies had almost identical progression-free survivals at 3.6 and 3.7 months. The trend was seen in the 

-mutant patients. Similar to what we saw in EMERALD, there seems to be this benefit in that group of 

-mutant patients. It went from approximately 2 months to 3.7 months. That trend, in that group, although present, is not statistically significant. I think the data were a bit disappointing. We kept hoping for more. Sanofi decided to discontinue development of amcenestrant based on the data from AMEERA-3, but they also had a readout from their interim analysis of their phase 3 study, which was in the first-line metastatic setting, combining amcenestrant with palbociclib (Ibrance), and comparing it with letrozole with palbociclib. That interim did not meet prespecified criteria to continue. That was also disappointing. Given the combined data, they’ve decided to not develop that agent further. We also saw data on giredestrant, an oral SERD. Those data were somewhat similar to what we saw in AMEERA-3. It was a different patient population. All of these trials have slightly different populations. In this one, only 40% of patients had a prior-CDK4/6 inhibitor. They didn’t show a real difference between giredestrant and treatment of choice endocrine therapy, but in the 

: I think there were modest benefits, but really only in the ESR-mutant patient population. It’s interesting because despite the limited data that we have here, these agents have already moved to the adjuvant setting in development. We have an adjuvant giredestrant study that’s currently enrolling. There are other agents moving into the adjuvant setting very quickly as well, so we’ll have to see what happens with the SERDs. There was some thought that maybe they could be used in the first-line setting with CDK4, but then we saw the press release for the readout of AMEERA-5. I truthfully wasn’t expecting those studies to be positive given what we’ve seen from PARSIFAL [NCT02491983]. When you compared fulvestrant with palbociclib vs letrozole with palbociclib, there wasn’t really a difference. It makes you think that maybe the endocrine backbone doesn’t matter here so much. I think we need to figure out the correct patient population. My hope is that these agents will have benefit post CDK on the 

-mutant population, but I do think more combination therapy studies are needed.

: Combination therapies and better selection of patients are needed, including patients with 

 mutations and maybe others. This is a reflection to not go to adjuvant trials with more than 3000 to 4000 participants until we have robust data biomarkers. For advanced disease, the adjuvant scenario is the best one to explore about biomarkers selection of patients. That is what’s happening with different new drugs and SERDs. You think that these drugs have nearly the same mechanism of action as PROTACs [proteolysis-targeting chimeric molecules] or Seran’s agent? Could we improve in the efficacy results? Do you have expectations of them?

: That’s an excellent question because you’re right, there are so many other agents in development that also work to degrade the estrogen receptor. Maybe a different mechanism of action could be different or better. We’ve seen some data come out with Arvinas’ PROTAC agent ARV-471. I think that agent looks very promising. They’ve had some data from phase 1 that showed responses in patients who have progressed on fulvestrant and in oral investigational SERDs, and then went on to ARV-471, which is really interesting.

: It is generally well tolerated, but we only have data in heterogenous patients. There’s the Olema agent, and the Seran agent, which we also think looks really interesting. There are lots of drugs in development, but we just need more data.

: My final question is: Would you still recruit your patients into the ongoing adjuvant trials with different SERDs? Or do you prefer to wait until you see what happens?

: It’s interesting. I think our group has struggled with this decision quite a bit. Obviously, these are curable patients, and we have drugs that do work. Aromatase inhibitors and tamoxifen are standard and definitely prevent recurrence, but at least we’re seeing that they’re probably equivalent to endocrine of choice. It’s different to compare in a treatment-naïve population where they’re not the same resistance mechanisms. I think it’s reasonable to consider, and I don’t think it’s going to do harm. I think there’s a chance it could be better. I think the challenge is, as you’re pointing out, the patient selection. I wonder, in an adjuvant setting, if therapy should be up front or more sequential when resistance mechanisms have built up? Should it be in particular adjuvant patients? Is there just clinical pathologic risk or does it need to be biomarker driven, even in the early-stage setting? We just don’t have enough information. I would enroll patients to an adjuvant trial. I feel comfortable with it, and generally, they’re pretty well tolerated.

: They’re not worse. They’re not harmful. That should be the main thing to focus on.

Comprehensive insight to the development and use of selective estrogen receptor degraders [SERDs] in HR+ metastatic breast cancer treatment.

What is the Role of Oral SERD Therapy in HR+ Metastatic Breast Cancer?

 Hi. Welcome to our post–ESMO [European Society for Medical Oncology Congress 2022] conference perspective. Today we’re going to be discussing metastatic hormone receptor–positive breast cancer. My name is Sara Tolaney and I’m from the Dana-Farber Cancer Institute in Boston, Massachusetts. I’m joined by my colleague, Eva Ciruelos Gil of University Hospital 12 de Octubre and SOLTI Group in Madrid, Spain. Today we’re discussing all the impressive data that have come out over the past few days. Could you tell us a little about how you’re treating your patients who have metastatic hormone receptor–positive disease? What are you thinking about when integrating therapies?

 This is the most important question, in terms of clinical guidelines and experience, for a majority of patients with advanced breast cancer. Seventy percent of them will have a luminal-type disease. They will live longer, longer, and longer, fortunately. However, there are many questions that arise. As soon as we have new data, we have new questions as well. I think that the first-line treatment with any type of hormonal therapy plus CDK4/6 inhibitors is standard. A small percentage of patients who are not candidates, or shouldn’t be, should be treated with these approaches, because there isn’t an exception for that in the subgroup analysis of the 7 different phase 3 trials. All patients will benefit from these combinations. Pre- and postmenopausal patients, as soon as possible, should be treated with abema [abemaciclib (Verzenio)], palbo [palbociclib (Ibrance)], or ribociclib [Kisqali] plus aromatase inhibitors or fulvestrant [Faslodex]. When a patient progresses, we should have the information on 

 status so we have the best second-line therapy for them. In case 

 is mutated, we should combine alpelisib [Piqray], which is currently approved and reimbursed in majority of countries, with fulvestrant or letrozole—supported by the BYLieve [NCT03056755] trial. We have some nice data on different hormonal combinations in the post-CDK scenario. In non–

 mutated patients, I think it’s a risky to maintain a hormonal therapy alone because results have not been nice. I think that type of therapy is still there. We learned to monitor everolimus many years ago since the BOLERO-2 trial [NCT00863655] results led to approval of this drug in combination. This was the first targeted combination with a hormonal treatment. We have revisited everolimus for non–

 mutated patients avoiding monotherapy with 1 single hormonal therapy in the post-CDK scenario because median progression-free survival in those patients is so poor. SERDs [selective estrogen receptor degraders] may be a new option. We’ll talk about them. With progressive disease, we have few opportunities]to try to reuse hormonal treatments. Maybe now is the time to start chemotherapies in the first line. Maybe capecitabine [Xeloda] would be a good option in patients who don’t need, or don’t want to go into, IV [intravenous] chemotherapies. Capecitabine and oral vinorelbine [Navelbine] are good options. IV therapies include taxanes or anthracyclines that have been already approved in this setting. The main message is to give the best therapy as soon as possible. I think that the best therapies are the new combinations of CDK inhibitors with hormonal treatment. This is the first-line impact on overall survival and progression-free survival. Afterward, we try to explore all the possible combinations with hormonal treatment before chemotherapy, but we try to avoid monotherapies with hormonal therapies because in the post-CDK scenario we have an urgent clinical need.

Opening their discussion on the HR+ metastatic breast cancer treatment landscape, expert oncologists share a broad overview of treatment modalities in this setting.

Eva M. Ciruelos Gil, MD, PhD

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