Metastatic HR+ Breast Cancer SABCS 2025 Highlights: Dr. Hope Rugo

Updates on CDK4-6 Inhibitors in Frontline HR+ Breast Cancer Hello, and welcome back to the Oncology Brothers Podcast. I'm Rohed Gosain and as always, I'm joined by my brother and Co host, Rahul Gosain. Today, we're excited to bring you the conference highlights from SABCS 2025 focusing on key abstracts from metastatic hormone receptor positive breast cancer space. Speaker 2 Rohed after ASCO and then ESMO Here at SABCS 2025, we saw quite a few updates. We have 67 studies to touch on, but let's put them in three broad buckets. Role of CDK 46 inhibitors in frontline and for this we have Ambra and Mona Lisa updates. Then what to do in second line. And for this we want to touch on updates from Victoria one ever trial, Amber 3 and Serena 6. And to close off to a negative study ascent O7, let's talk through the role of ADC in endocrine resistant disease. To walk us through all this, we're thrilled to have Doctor Hope Rugo, a world renowned best medical oncologist from City of Hope. Hope thank you so much for joining us. Speaker 3 Thanks so much for having me. Speaker 1 Hopefully, let's dive right in. We got quite a bit to cover here. So for the first two studies, the focus is CDK 46 inhibitor. First is ombre study looking at Abama Cyclip plus endocrine therapy in high tumor burden disease. And next is Mona Lisa where we are seeing few updates where Ribocyclip plus endocrine therapy in frontline settings. What can we learn from these studies and importantly, your preferred CDK 46 inhibitor upfront? How are you deciding amongst the two available? Speaker 3 Well, maybe before I talk about what I decided in terms of giving the CDK 46 inhibitor, the OMBRE study is really important to highlight for a minute, because we now have a bunch of trials comparing endocrine therapy with CDK 46 inhibitor compared to chemotherapy. You know, that first trial the right choice compared to combination chemo, which, you know, we're really don't like to use combination chemo. But you know, they really, you know, this was a study done in Asia, our countries in Africa, Egypt and the Eastern Europe where a lot of times chemo is given 1st and they pre menopausal women and they, you know, a lot of very symptomatic disease. But you know, big surprise ribosiclib and then aromatase neighbors better, you know, longer PFS and equal to rate time to response. People think, oh, I can get a better response if I give chemo first or a faster response. That wasn't the case. So then we saw Padma, which is sort of a more real world. You choose what you think you want to give. And again, same thing with Halbo and an aromatase inhibitor. We even had a chemo induction called Abigail with paclitaxel not better And at 12 weeks of paclitaxel versus AI and CDK 46 inhibitor, the endocrine arm was better. So the ombre now is the icing on a cake. This study defined high tumor burden really nicely in the population exactly what we would be worried about more visceral sites, high LDH etcetera and you know gave a nice the capes cedamine or paclitaxel as the common the comparator exactly what we would use in that setting. Abemaciclib and the aromatase inhibitor resulted in a markedly longer progression free survival no difference in response or time to response. This was really cool. And it in my, your mind really closes that question about what we should do. How do we decide, you know, what endocrine therapy. So we had, you know, we're always thinking like, is there a subtype of breast cancer where you'd get more mileage out of one drug versus another? And there's enormous interest right now in looking at lobular cancer, which we know is biologically quite different, more often to be invisible where we can't see the sites of disease and also is a cancer, cancer which is often diagnosed as de Novo metastatic. So in this classic globular cancer, you know, that would have been enrolled in Mona Lisa three, you can see that they really saw a marked improvement with RIBO, CICLIB and fulvestrant, Bosus, fulvestrant and placebo. Most of our patients are treated with AI's in the first line setting, but this would be really important for patients who are recurring on an aromatase inhibitor within a year or who didn't get the drug in the first line setting, which sometimes isn't appropriate for an older patient. It's really quite remarkable in the first line setting. Early relapse patients also saw a benefit. So what do we use first line In the first line setting, we have the survival data from the phase three trial with ribociclib in both the first and second line and early relapse populations as well as in premenopausal populations, which has really changed the thinking in premenopausal patients. AI, full Western CDK 46 inhibitor trials. I think that for most people they will give RIBO first in patients who are older, have cardiac issues, don't tolerate RIBO, have bone marrow suppression, we might choose a different CDK 46 inhibitor. So Palbo for the older patients, the patients with cardiac issues, QT prolongation, things like that. Palbo is really a gentler drug for those patients and very well tolerated and it also plays in the sandbox well with other agents when we use triplets. So that's another place where we're really using palbociclib. And for Bama Ciclib, I think the issue has really been the diarrhea in patients and how to manage that. There are patients, for example, who get liver enzyme elevations and Ribo Ciclib where we'll use Abama Ciclib where blood count suppression is a really big issue, where ABAMA is better. And we have the data from trade, which tells us that we can dose escalate. I usually start at 100 BID. The trade started at 50 BID. There's blister packs you can get for free starting patients. So I think in that situation when I do use them acyclib, I start at 100 the ID to try and maximize the tolerance of drug and minimize discontinuation. Speaker 2 Oh, thank you so much for walking us through this so thoroughly. Again, CDK 46 inhibitors with endocrine therapy still remain the preferred option and majority of our patients in frontline settings via with high tumor Burton or otherwise. Exploring New Second-Line Options for HR+ Breast Cancer OK. Now on to second line, which is starting to get very crowded with our pick 3 inhibitors, though IV and Victoria one trial, we're seeing benefit in all comers. We're also seeing combination trials with oral surge, particularly with Juridestrin, with everolimus. And at SOBCS you saw updates from Serena 6, an Amber three study. Well, can you broadly touch these four studies and what can we learn from this? There's a lot to cover here, but importantly, if this all was to become available out in the clinic, what are we going to do? Speaker 3 It's such an incredibly important topic and so fascinating, but really tough in the clinic right now. We're thinking what are we going to do and in what setting? If you go backwards to Serena 6, which we'll talk about first because this is the first line study, essentially it's really a second line study, but it's first line in that you change treatment before there's there's disease progression. At San Antonio, we saw the updated PFS, there's a benefit about 7.4 months. But importantly, the patients who developed an ESR one mutation without evidence of disease progression stayed on their AI and CDK for six inhibitors for 9 more months. So the question is do you change earlier or do you wait for disease progression? The second question was PFS 2, which as you can see is much longer, but with the switch, but even now you've gone on to your next treatment, but you start counting at the initial randomization. What's the combined PFS one and PFS 2 is what PFS 2 represents. If that's clear, I think the question there that's arisen is that no one who stayed on their IAI and CDK 46 inhibitor could get the combination of an oral cert and ACDK 46 inhibitor next. And very few patients could have received the only approved oral CERT LS estrin in that trial which started before LS estrin was even really available to most people who would participate in the trial. So it does bring up the question we saw in Serena 6 at ESMO that, you know, we had seen in the primary data that the quality of life seemed to be preserved and have a longer time to deterioration if you switch. And at ESMO we saw that difference was really primarily pain and fatigue. So what I've taken from that with the data we have now given that we can't give this treatment yet and are waiting for the FDA, is that this might be considered for a patient who you think is progressing. Their markers are going up, they have pain, they're symptomatic, but their scans don't show it. We see this all the time with ER positive disease. They're on liver Mets that are growing in these patients. This might be something we would pursue. Another question is should you change the CDK 46 inhibitor? Would it be even better? This question will be addressed in a trial run by Unit Cancer, which we will open in the US called Taylor Switch. So now let's think about what we do in patients who get their first line treatment. They're doing really well and then they pop up with their liver Med or new pleural effusion or some symptomatic bone Med. It's a treatment approach. If we go to Victoria, this is an IV drug. They're calling it a Pam inhibitor. So it doesn't inhibit AKT except for downstream from PI3 kinase. So it's an inhibitor, PI3 kinase and mtor. I did some of the Phase 1B work with this drug in phase one and it was very effective, but this was before we had all these other treatments also. But the triplet and doublet efficacy here surprised people. It's an IV drug given three weeks on, one week off. The triplet therapy was remarkably better than fulvestrant alone, as was the doublet therapy. We'll see data from the optional crossover to ARM A or BA progression in the future, which I think is important. The important part of this data is this is patients who are wild type for PIC 3 CA, and yet we're seeing a big benefit. What we need to know is get A totally with an oral cord now that's going to be really important and the next step in the trials that will be going on. And they're also seeing doesn't make a difference in the early relapsers and late relapsers in the first line setting. So we'll learn a lot more. One of the concerning factors was stomatitis, 19% grade 3 in the triplet and 12% of the doublet. Although they told everybody to use the steroid mouthwash and gave it to people, we don't really know whether people used it and how easy it will be to control this. And I think that's going to be the IV and the side effects of the stomatitis will be the key issues in using this treatment, which is really remarkably beneficial whether we can combine it easily with an oral cert. So that's one. We'll wait and see what the pick three CA mutated subgroup shows and that will be next year, you know, which is coming up in a few days, but sometime in the middle of next year. And then when we think about like Ember 3 and Avera, these are really interesting trials. So Vera is the only trial so far that compared apples to apples. Both arms got everolimus. So there's no crossover issue or access or whatever. What did you get after the study? It's really everolimus in both arms and very clean. Everybody had a prior CDK 46 inhibitor. They either got gerodeastrant and oral cert or standard of care endocrine therapy. I will say that center of endocrine therapy was exomesting in the majority of patients because it was only part way through the trial that we switched and allowed patients to also get fulvestrant or tamoxifen based on the phase two data and the overall guidelines. And also patients had to be on their first line treatment for at least six months. This was limited to patients who have endocrine sensitive disease. That wasn't true in the Victoria One trial. So we don't know yet about the very short rapid relapsers in that population. Most people had one line of prior therapy and they predetermined the population. So 55% would have an ESR 1 mutation. The you know the progression free survival was longer with jardestrant in the intent to treat an ESR one mutant population. When we looked at the wild type, we didn't see that difference, but overall response was better, which is perplexing and if you think about it's because they didn't really power for the ESR one wild type population to look at PFS, they did see an improvement in response which is unique to this trial design and results at San Antonio. We looked at the patients who had that 6 to 12 month progression on ACDK 46 inhibitor or greater than 12 months, big benefit in both groups, although you can see the less than 12 months have a shorter PFS in both groups as we would expect. We also looked at the presence or absence of pick three CA mutations or pathway mutations and we saw the benefit was maintained. So that was great. And how do we compare that to the imulinestrins and abemaciclib trial? Well, with ebrolimus you get stomatitis, with imulinestrin, abemaciclib you get diarrhea. How do we assess this? We know imulinestrin is now approved for the ESR one mute population. So we have two oral cerids here, Imulinestrins and abemaciclib was better than imulinestrin, but we would expect that when we looked at the patients without ESR one mutations, it also looked better, which goes along with the idea that when you combine oral cords with the targeted agent, you don't need the ESR one mutation to see the benefit. The problem is we don't know what this would look like. When you looked at the imlunestrin tabema versus fulvestrin tabema, they also had a more heterogeneous population. Some had received CDK 46 inhibitors and some had not. But when they looked at the subset analysis, it looked like it worked better even if you'd had a prior CDK 46 inhibitor. It's a heterogeneous population. But I think what we're going to be doing moving forward is if the FDA decides to approve this combination with the caveat that it wasn't an apples to apples comparison, which I think is a stumbling block, and also the Avera and Victoria, right, what do we do? I think we're going to have to individualize it to the patient whether they prefer an all oral regimen, what the toxicity is of the regimen and the unique characteristics of their cancer in terms of response. I still think we're going to be using single agent oral cords in the 80 year olds who are progressing and have an ESR one mutation who have limited disease. I've seen responses in liver in these kinds of patients with single agent LS Estrin. We're going to really be tasked with more individualization based on more factors than we've had before. Choice is always better. Will oral surds work after oral surds? We need to have real world data to figure out. Speaker 1 Indeed, quite a bit to unpack here. Thanks so much for summarizing that. So let's start off with the first thing that you mentioned about Victoria trial it one has to realize this is weekly regimen that's a big ask for patients and that to IV and you stated stomatitis 19% something for us to keep in mind and also when he wants here is the comparator arm. We'll have to see how that all plays out for a long term data. But again for Victoria one that fulvestrant again that's not a clinical practice. With regards to chemisestrin from Serena sex, it's interesting how often we do not check CTDNA that often. So how's that going to translate into our clinical practice And now enlunestrin with abemaciclib, though it is singly approved for ESR, one mutated disease. With regards to Immolestrin, Camisestrin, Gerdestrin, they're generally better tolerated if you could just sum it up from important clinical pearls around these. Speaker 3 I think that in general we like to give combination therapy. We want to minimize the toxicity and issues with our patients. I think that they're tolerated, these oral surds. They, as I said before, play well in the sandbox. We don't seem to escalate any of the unique toxicities of the oral surds by mixing them with targeted agents. We've seen that across the board. We know that some of the drugs like camisestrin can cause photopsia. They cause bradycardia occasionally, but it seems to be all Grade 1 to rare grade 2 with some of them. There's a little bit of nausea with just taking pills for most of these. I would say that overall it's been hard to differentiate, although we saw it a little bit in phase one. In these phase three trials, it's been a little bit hard to differentiate toxicities. My guess is in the real world we're going to see differences and we're going to be switching around to try and optimize the tolerability for individual patients. Even though we've got those percentages, you don't get photopsy on bradycardia with LS Ester for example, but you get some nausea. How do we differentiate? It's going to be on the individual patient basis. You know the idea of apples to apples is important and that there was data at San Antonio from the ELEVATE trial looking at shingle arm combination of alisestrant with everolimus and with abemaciclib showing very similar PFS as these randomized trials. Speaker 2 You know, on our end all this data is overwhelming, but appreciating these nuances is going to be important. The Role of ADCs in Endocrine-Resistant Breast Cancer OK. Now to close our last study Ascent O7 looking at Sassitismab Gova Tican versus chemotherapy in earlier lines for endocrine resistant disease accessitism that is already approved. And later Ryan from your work hope can you touch on what can we learn from Ascent O 7 And today in your practice, how do you sequence AD CS for hormone receptor positive disease? Speaker 3 So yeah, this is of course near and near to my heart because I helped design the trial and and the Co Pi with Amal Javeri who presented the data for us at San Antonio, We were very disappointed with the results. I've spent a lot of time looking at this giving SG versus K paclitoxyl or napaclitoxyl was identical in terms of PFS in this 2 to 1 randomized trial. And I will say that compared to Destin breast O 6 which looked at TDXD versus chemotherapy regimens, most of the patients got Cape here it was 40%. But it did appear that the PFS in the Cape treated arms is relatively similar to in subset analysis, the PFS very similar to the control arm in DBO 6. And because of the need for a measurable disease and just who we give Adcs to, most of the patients had visceral disease with only three percent or so in both trials having bone only disease. I will say that there are some marked differences. This was by blinded independent central review and you can't really see it on this slide, but there were a lot of censoring in that first few months. And when we looked at the censoring overall, there's like all those little dots are censored patients and you can't see like the enormous number of dots early on because they're all melded together. And it was due primarily to new lesions. The blinded folks were like, we're not really sure this is a new lesion, whereas the docs were sure. And if you looked at the PFS in the investigator assessment, there was a difference. That's not the end point. It's a negative trial in terms of showing identical results. It is interesting that censoring played a big role here where VICAR did not think patients were progressing, but we did as their doctors sitting with them. And I think that's important and it may have some impact on the overall survival, which we saw at the primary analysis that the overall survival favored. It's not statistically significant for what you would need and it was a hierarchical design, so OS this was only significant if PFS was. But this is really important to us because we saw this hint of an overall survival analysis. At primary analysis, 2/3 of the patients in the treatment of physician choice group received an ATC as their next treatment. So that suggests to me and we know these AD CS have an immune effect. Could they be changing the microenvironment a little bit where we are really seeing some difference by giving the drugs in different sequencing? We don't know. And it also teaches us a few things. One is that it appears that in the largely her too low, ultra low population that are HR positive, TDXT was better than standard chemotherapy, 60% received capecitabine, but we didn't see differences based on drugs in a sento 7. So what do we do with IHC zero patients and how do we treat those the true zeros And that's an investigation that we'll be doing as a subset analysis in a sento 7, but also a future investigation. Does it mean that SG doesn't work? No, SG works as well as the chemotherapy where 60% of patients received a taxane. The tolerance was pretty similar between chemo and SG because you get neutropenia with taxanes. Tropics O2 showed that SG was better than standard chemotherapy in patients who'd received a median of three prior lines of chemotherapy for metastatic disease. What we don't understand is a sequencing for HR positive disease with bone, maybe bone dominant disease, long response to endocrine therapy, you know, good organ function. I still use Kapa as my first treatment. I think giving an ADC next for her to low, ultra low, I think we would give TDXD. But sequencing is an important option. We don't yet know which patients benefit from sequencing. We have a lot of data that's confusing, but it suggests that the resistance is primarily to the payload. Having more Adcs in the future will help us, but I've had a patient who responded better to the second than the first. We all have. So I think understanding those biomarkers will make a difference in patients IHC zero who might not qualify for TDXD and where I've seen very poor responses to TDXDI, think SG might be a good option for those patients in the second or greater line. In that situation, I would consider SG. And that's really the take home from this right now in HR positive disease, we want to improve survival. We want patients to tolerate their treatment in the best way possible and this has given us additional information to guide our treatment well, we know. Recap of SABCS 2025 HR+ Breast Cancer Highlights Sasatusumab is an active drug as we've seen that from Tropics O2. But as always, these negative trials continue to teach us so much more and from all this work that you and others are doing in this field continue to bring novel treatment options in front of us. So thank you. Well, there's a lot happening in this space and we would love to see these intervention result into seeing our patients live longer and better. Hope we have covered quite a bit in a short period of time. Thank you so much for sharing your thoughts around these key studies from metastatic hormone receptor positive breast cancer space from SABCS 2025. For those who tuned in, let's go over a quick recap from today's discussion in this. Speaker 2 Episode with Doctor Ho Prugo, we focused on metastatic hormone receptor positive breast cancer. Highlights from SABCS 2025. We started off with frontline therapy where HOMBRE and Mona Lisa study continues to support the use of CDK 46 inhibitors with endocrine therapy in majority of our patients. We have the strongest data with Ribocyclid and D settings. Rohit space and later lines is starting to get crowded and we touched on quite a few updates here. What can we walk away with? Yes, Rahul, we. Speaker 1 Covered quite a bit here. In later lines we talked about Victoria one study suggesting that IV get a tolisib in combination with palbociclib and foliscerin could provide benefit in all Comer patient population. But this is an IV treatment which is a big ask and that too for three consecutive weeks and then followed by one week off. We also touched on Evra trial, EMBER 3 and Serena 6 updates where we have data from oral surge. Finally, we covered Ascent O7. Despite being a negative trial, Adcs still remain an active treatment option in hormone receptor positive disease space. Thanks for tuning in. Be sure to check out our other episodes on treatment algorithm, recent approvals and more conference highlights. We are the oncology brothers.