Joyce A. O’Shaughnessy, MD: What are you doing with elacestrant in your practice? Where do you tend to use it? Actually, we just heard Komal [tell] us, basically she thinks it’s a very reasonable option post CDK4/6 [inhibitor] for the ESR mutant population. How about you, Pedram, where do you tend to use it?

Pedram Razavi, MD, PhD: So I have not much to add to what Komal suggested. I completely agree we should look into the trends and the type of response and the extent of disease at the time of progression, the patient who had progression on the first scan on AI [aromatase inhibitor] plus CDK4/6 inhibitors or fulvestrant plus CDK4/6 inhibitors. That patient probably has intrinsic resistance to both endocrine therapy and CDK4/6 inhibitors, putting the patient on a single-agent SERD [selective estrogen receptor degrader] probably [is] not the best idea, especially if this patient also has extensive amount of disease, visceral involvement, so on and so forth…. I would like to highlight that at the end of the day, the improvement [of] the hazard ratio that we see—that 0.5—is not because there is a significant difference in the median progression-free survival, but in the long tail the patients went about 6 months, went for 12 months. And there is a group of patients, as we know, [who] are very endocrine resistant. They had the ESR1 mutation as the sole mechanism of resistance to endocrine therapy. Now we’re giving them SERDs that [are] much more effective than that ESR1 for the blockage of those ESR1 mutations, but this is inherently still an endocrine-sensitive tumor. Those are the tumors that respond very nicely. So these are the patients who often passed the 2 years median time point in the first-line setting. They had a good response, bone-only disease, so on and so forth. Now after a while being on CDK4/6 inhibitors plus AI, they developed the ESR1 mutation—those are fantastic cases for elacestrant. So I hope soon we’re going to have combination data also with these oral SERDs and CDK4/6 inhibitors or other combinations. And then we’ll be using them more often for patients who [have] more aggressive disease. But at this point, I look [for] evidence of endocrine resistance in the tumor. Also going back to the discussion that we had in the very beginning of this and looking at beyond the ESR1 mutations, there are certain mutations and certain genomic alterations that result in resistance to all forms of endocrine therapy that we have. And if I find one of those in the tumor in instead of free DNA, I’m actually less likely to offer this patient an oral SERD, I’m more likely to give the patient combinations. For example, the patient has alterations in the Ras/Raf pathway, something that results in endocrine resistance, some other alterations that result [from] that. So I think we can take into account more complex points in our decision. But overall, the best indication in my mind is the duration of response in the first-line setting.

Joyce A. O’Shaughnessy, MD: Komal, anything to add about the sweet spot there for elacestrant assessment in your practice?

Komal Jhaveri, MD, FACP: I think we discussed the analysis that we discussed about anti-CDK4/6 duration. Is that a brilliant biomarker, really? No, it’s not. We all know [that] we kind of did that predating CDK4/6 inhibitors. We know that if a patient is doing well for a long time, even with [a] monotherapy single-agent aromatase inhibitor, we know that that is a sensitive tumor. And I think that’s the point we’re trying to drive [home]. ESR1 mutation, as we said, is a surrogate of PR [progesterone receptor] dependency. This is one way of identifying a tumor in the post CDK4/6 space where we think that is still ER [estrogen receptor]-dependent. It’s where targeting ER is still going to be effective. And so ESR1 mutation is one such way, and clinical characteristic-wise durability on first-line therapy then logically makes sense. And then when you combine both of them, it seemed like you have this nice agent that’s going to work really well and [is] super well tolerated, eat some food and there’s no nausea. I think financial toxicity is a different ballgame completely. That’s true with every new therapy that comes to market. But leaving that aside, I think offering this to our patients over standard-of-care therapy…or combination therapy, is where cost is an issue…[plus] toxicity concerns are still there. [It] seems like the right thing to do until we know better. I think the complexity of tumor biology and the genomic evolution of [hormone receptor–positive] disease is something we still need to understand better [and] identify better [to] understand the implications of various therapies based on that information.

Joyce A. O’Shaughnessy, MD: [What is] your general experience with fulvestrant versus elacestrant? You know, there have been docs, like you said. We got an endocrine therapy–sensitive breast cancer. There’s a good chance the patient might benefit. You know, that’s what the historical algorithm has been—to give the patient a chance at single-agent fulvestrant. It’s a smaller group of patients post CDK4/6. But, biologically, [with] the Y537S, fulvestrant, I think as you both said early on, fulvestrant really isn’t that effective there. But, the 538S, for example, there we have some activity of fulvestrant. But do you think that the elacestrant is really that much better against these ESR1 mutations than fulvestrant? Do you think we should just not be using fulvestrant for the ESR1 mutations? What do you think there, Pedram?

Pedram Razavi, MD, PhD: So the preclinical data suggests exactly what you just mentioned, that in a lot of these ESR1 mutations, [it] seems like fulvestrant is as effective as oral SERD and elacestrant. But going back to the fact that often these mutations are not alone, there [is] polyclonal resistance, one side of the disease has 538, another side of the disease could have 537, or there is a subclone that has 537 or other alterations that might be benefiting from oral SERD better than fulvestrant. So I think given that heterogeneity, spatial heterogeneity, and the complexity of endocrine resistance, when there is an option for and there is a good candidate for single-agent SERD or CDK4/6 [inhibitors], I think it’s reasonable just to put the patient on oral SERDs. Obviously, oral medication…for some patients is easier than injections. But again, if one decides to go for fulvestrant alone, that’s also not a bad idea. Going back to the fact that what we are seeing and the type of median progression-free survival that we see for single-agent SERDs post-CDK4/6 [inhibitors], these are in pancreatic cancer ranges. These are not the type of things that people see in breast cancer. One-point-something-months median survival, 2-point-something was median progression-free survival. So, for [the] majority of patients, probably that’s not the best choice. But at this point, I think [it’s about] finding that group of patients who would benefit from oral SERDs, put them on single-agent oral SERDs, give them the chance to be off targeted agents like everolimus, alpelisib, so on and so forth, that potentially have more [adverse] effects, and not as well tolerated as elacestrant post-CDK4/6 [inhibitors]. So I think that would be a good option for the patients. And again…with all of this analysis of clinical trial data, the real-world data that we are analyzing, we might be able to find the subgroup of patients and provide clinicians with some guidance.… I think that’s a lot of work for those of us who do translational work, basic science work, to figure out [who are] those groups of patients…. Until then, I think the best chance we have is exactly what we discussed.

Transcript is AI-generated and edited for clarity and readability.