Harold Burstein, MD, PhD, and Sarah Sammons, MD, discuss the monarchE and NATALEE trials, investigating CDK4/6 inhibitors for high-risk, early stage, HR+ breast cancer.
We're continuing our discussion of breast cancer highlights from ESO 2025 in Berlin, and now we're going to be switching gears. We've been talking about largely metastatic disease trials looking at antibody drug conjugates and selective estrogen receptor degraders and other newer approaches to metastatic disease, but now we're going to talk about high risk. Early stage hormone receptor positive breast cancer. Joining me, Doctor Sarah Salmonds, who's a wonderful clinician and a lead investigator for many trials in this space. Sarah, one of the highlights of the meeting was the updated data for the Monarch E and the Natalie trial. Remind us who are the patients who went on to those studies. Absolutely. So we now have two options for treating our high-risk hormone receptor positive, HER2 negative patients with CDK46 inhibitors. The trial populations for each drug were different though. Monarch E was a very high risk population. All patients had to be node positive and they could either have 4 or more positive. Lymph nodes, or they could have 1 to 3 positive lymph nodes with higher risk features, large tumors or high grade. So very, very high risk population for Monarch E. Natalie, which used 3 years of ribocyclib, included a lower risk population. They did include node negative patients. Node negative patients had to have high genomic risk or high grade, um, or they included any node positive patient. So just to be clear, these are stage 2 or 3 breast cancer patients who had some other adverse factor in their tumor biology or stage. This is not your average 64-year-old woman who had a 1.6 centimeter node negative breast cancer or even a somewhat larger tumor with otherwise favorable recurrence score or other biological features. Wouldn't include node negative grade 1 or 2 low oncotype patients. At all. So, um, here's the schema for the monarch E trial. Uh, the patients got standard of care, which could have meant chemotherapy for like 90% of them, and then they also got standard endocrine therapy and then there was a 1 to 1 randomization to a Bemacyclli for 2 years, as you said, 5600 patients. What did we learn at the updated uh ESO? Yes. So we've already known over Last 7 years really, that adding 2 years of abemacycllib reduces the risk of recurrence uh in these high-risk patients. Uh, we saw the 7-year recurrence data at this uh conference and we saw that at 7 years, the addition of Abemacycllib continues to reduce the risk of recurrence by about 6 6.5%. And so it's good to see that once they stop the drug after 2 years, 5 years later, we're still seeing that benefit continue. Now, what we also saw for the first time was that not only is it reducing the risk of recurrence, but it is also improving uh survival, meaning that patients that got a Bemacycllip for 2 years were more likely to live slightly longer than patients who did not. So that's obviously an important benchmark. For early stage treatment, I've been showing the forest plots here. I was struck by a couple of subsets, and again, the caveats about subset analysis, you'll always find something that catches your interest, but it struck me that there was greater benefit in premenopausal women than in postmenopausal, and there was greater benefit in women who had tamoxifen as their primary endocrine treatment as opposed to an aromatase inhibitor. Do you think that's gonna affect your practice and how you're thinking about which patients might get this drug? You know, I think about who I should escalate therapy to and give an extra 2 years of a drug that does have side effects based on overall risk. We've already known that premenopausal patients have, you know, higher risk of recurrence compared to post-menopausal patients. So that's just an added risk. Factor and it's nice to see here that the addition of a CDK46 inhibitor really helps that population. So I've already been worried about that subset of patients. This helps me understand that adding a CDK46, particularly a demicycllib, um, improves their outcomes, and we actually saw the same thing in a subset analysis with ribocyclli. Regarding the tamoxifen versus aromatase inhibitor, there was benefits whether or not they received either. And uh really, we're not giving much of Bamicyclli with tamoxifen in the clinic because of the rather high uh blood clot risk. Almost 1 in 25 patients who get the combination will have a blood clot. And so I would say I'm not so much uh concerned about that subset analysis, but I would uh I would give it to a higher-risk patient who is getting an aromatase inhibitor and, and certainly, um really premenopausal or post, but the premenopausal analysis was nice to see. Good point about the tamoxifen and the Abemacyclop thrombosis risk. I think that's something underappreciated by a lot of folks. So let's switch gears. Just quickly and talk about the Natalie trial. Fundamentally a similar study, the schema here standard of care again 90% got chemotherapy, standard of care, endocrine therapy that they all had to be postmenopausal in this trial and then randomized to receive 3 years of ribocyclib or not. Any critical differences in the design between Natalie and Monarchy? I would just say the critical differences in design are that they allowed node negative patients, whereas, which are historically thought of as being lower risk than node positive patients. Um, and the other critical factor and difference between abemacycllib and ribocycliv in the adjuvant setting is that the ribocycliv is given for 3 years. Now, it is given at a lower dose than we give it in the metastatic setting. It's given at 400 mg versus 600, but it is 3 years versus 2 years of Abemacyclli. And the other caveat to this trial was that all patients had a non-steroidal aromatase inhibitor, so nobody got tamoxifen, um, and premenopausal patients were mandated to get an ovarian suppression. All excellent points. So what did we learned from the longer follow up now with Natalie? Yeah, so we saw the 5-year follow-up data, um, and essentially we continue to see a reduction in the risk of recurrence with 3 years of ribocycllib added to endocrine therapy. The absolute benefit is around 5% reduction in the risk of recurrence. So, um, no real surprises there. Again, durable benefits persisting now through 5 to 7 years of follow up with these respective drugs. So let me just ask you, um, you're a busy clinician. I know you're seeing patients every day who are potential candidates for these drugs. First, tell us why are these updates important? What are you really, when you're talking to a patient, what are the takeaways from these updates? And then secondly, how do you go about selecting a particular agent? It's a really good question, Hal. Um, so, first of all, when I'm seeing in a patient, when I'm seeing a patient in the clinic, the first thing I'm thinking about is, are they a candidate for uh a Bemayli? We have longer follow-up data, we have, you know, 7 years of data now. We have an overall survival benefit. It's 2 years of drug versus 3. Um, and so if they met the monarchy criteria, I do have to say that I am usually starting them out on a Bemacyclli. Um, now, we had a nice trial presentation, um, by our colleague, Doctor Mayer this year, who showed that if you started themicycllib at a lower dose and then you slowly escalate it, you can head off some of that early diarrhea, early toxicity, and make the regimen a little bit more tolerable for patients because as we know, diarrhea in the clinic is a challenge. Um, so, you know, I'm at least usually starting for a Bemecyclli for the patients that qualify. Um, now, if they did not qualify or if they do not tolerate abemicycllib, then it is nice to have a second CDK46 inhibitor as an option. Um, ribocycllib is certainly more tolerable, um, but it is for 3 years instead of 2. and the, the approval is kind of more general, you know, that no negative high-risk patients were included. Um. I still think that it's a risk benefit discussion with our patients. I think that, you know, the benefits in reduction of recurrence at 5 to 7 years are somewhere between 5 and 7%. That's meaningful to some patients. It's not meaningful to other patients, and there are side effects and there are prices and co-pays to consider. Yeah, I think that's an excellent description. You know, when I speak to patients, these are not easy drugs to take for 2 to 3 years in my experience, and I seem to have a high frequency of patients who either have substantial GI side effects from a bemacycliv or liver function test problems with rivacycliv and I try to. Expectations by saying that all things considered, I think these are good options, but you know, if they cannot get through the whole course of therapy or if there are difficulties, you know, these are ultimately significant but modest steps forward, and most people are doing well even in these high risk cancers, even without these treatments. So, uh, important long-term follow-up, the durability of benefit from adjuvant CDK46 inhibitors in the Monarch E and Natalie trial, one of the highlights in breast cancer at ESO 2025. Thanks, Sarah. Thank you.
