Aditya Bardia, MD, MPH, FASCO, on Novel Therapies Targeting the Estrogen Receptor

As a brief background for patients with metastatic hormone receptor-positive breast cancer in the first-line setting, we'd recommend endocrine therapy fulvestrant or aromatase inhibitor in combi-nation with a CDK4/6 inhibitor. But patients have disease progression. In the second-line setting, one common mechanism of resistance, particularly to aromatase inhibitor, is the development of estrogen receptor mutations, or ESR1 mutations. These are mutations which make the tumor es-trogen-independent. It's still dependent on ER, but it's estrogen-independent, and thus, aromatase inhibitors don't work in this setting. But drugs that directly bind to ER would conceptually work in this setting, and that's led to interest in a number of novel ER therapies. One that was recently approved is elacestrant. Elacestrant is a novel oral selective estrogen recep-tor degrader. It was evaluated in the pivotal phase III EMERALD study where it was compared head-to-head against fulvestrant or aromatase inhibitor in the second-line plus setting in patients who had received prior CDK4/6 inhibitor. It showed evidence of clinical activity, particularly in patients who had detectable ESR1 mutations. If you look at the clinical trial, you see a subset of patients had disease progression in both arms, a drop in the Kaplan-Meier curves, as the best response, but then in other patients you could see separation of the curves. So a question in the field has been, can we identify patients who have endocrine-resistant versus sensitive disease with a simple clinical pathological feature? And one marker that appears to pre-dict patients who have more endocrine-sensitive disease is how they did on prior CDK4/6 inhibitor. So in patients who were on prior CDK4/6 inhibitor for at least 12 months, in this setting, elac-estrant, when used after a CDK4/6 inhibitor, showed a median progression-free survival of eight-and-a-half months versus about two months with standard endocrine therapy. So it appears to be a marker that can predict for more endocrine-sensitive disease and more benefit with single-agent elacestrant. Now, besides this, there are other drugs in clinical development, camizestrant, imlunestrant, gire-destrant, and in the future we might have multiple oral SERDs available. So the question would be, how would we select between these agents? How would we sequence these different agents? It's likely that the efficacy would not be that different between these agents, and we might be looking more at the toxicity profile to select these different selective estrogen receptor degraders or SERDs. And they do have a slightly different adverse event profile. Elacestrant tends to cause nausea. Usually you don't need anti-nausea medication, you should take the drug with food, but that is a known side effect. Giredestrant can cause decrease in the heart rate, bradycardia. Camizestrant can cause bradycardia as well as visual disturbance. And then im-lunestrant tends to cause more diarrhea as the major side effect. In terms of sequencing, we need to understand resistance to these agents as we have multiple drugs in the future that we have to select from. There's also interest in combining these drugs with other agents that target the PI3 kinase/AKT/mTOR pathway, so combining these oral SERDs with al-pelisib or other PI3 kinase inhibitors, combining them with capivasertib, the AKT inhibitor, as well as combining them with everolimus, the mTOR inhibitor. We also know that endocrine therapies work best in early breast cancer, and a number of trials are ongoing evaluating these oral selective estrogen receptor degraders in early breast cancer, either as upfront therapies just after surgery, such as the lidERA trial, comparing giredestrant to standard endocrine therapy, or in patients who've been on endocrine therapy for at least two to three years, and then after that switch to the same endocrine therapy or to one of these oral surges. So in the future, the landscape will likely change further as these drugs move into early breast can-cer, as these drugs are combined with other agents. But for now, the drug that is FDA approved is elacestrant. It's recommended in the second-line plus setting or patients with ESR1-mutant meta-static breast cancer. The main side effect is nausea. A subset of patients might have ESR1 and PIK3CA-mutant disease. In this setting, also elacestrant is likely the preferred agent. Subgroup anal-yses have shown that in patients with dual mutants, ESR1 and PIK3CA, the drug does work, is supe-rior to standard endocrine therapy. And then after elacestrant, one could use fulvestrant plus ei-ther a PI3 kinase inhibitor or AKT inhibitor. There's a lot of exciting developments and look forward to having additional discussions related to these agents in the future.