Next-Generation Endocrine Therapies Reshape Treatment of ER-Positive, HER2-Negative Metastatic Breast Cancer

Clinical Summary: 

• Seth Wander, MD, PhD, examines the evolving treatment landscape for ER-positive, HER2-negative metastatic breast cancer, including next-generation endocrine therapies, ESR1 mutation testing, and emerging targeted combinations. 
• Recent developments have expanded treatment options with oral SERDs, novel estrogen receptor-targeting agents, and CKD4/6 inhibitor combinations. Findings from SERENA-6 support ctDNA-guided endocrine therapy modification before clinical progression. 
• These advances highlight the growing importance of molecular monitoring and individualized treatment sequencing to address endocrine resistance, optimize therapeutic selection, and improve outcomes for patients with ER-positive, HER2-negative metastatic breast cancer.

Seth Wander, MD, PhD, Mass General Brigham Cancer Institute, Boston, Massachusetts, discusses the rapidly evolving treatment landscape for ER-positive, HER2-negative metastatic breast cancer, including next-generation endocrine therapies, recent regulatory developments, and biomarker-guided treatment strategies. 

Dr Wander reviews emerging treatment options targeting ESR1 mutations, including elacestrant, imlunestrant, vepdegestrant, and camizestrant, as well as combinations with CDK4/6 inhibitors. He also discusses findings from EMBER-3 and SERENA-6, highlighting the potential for ctDNA-guided treatment modification before clinical progression and the integration of novel targeted agents such as gedatolisib to personalize treatment across metastatic disease settings. 

Transcript: 

My name is Seth Wander, and I'm joining you from the Mass General Brigham Cancer Institute in Boston. It's been my pleasure to join the Great Debates Conference here in New York City. 

We had a lively discussion this morning about the emerging landscape of next-generation anti-estrogen therapies for ER-positive HER2-negative metastatic breast cancer. We've had unprecedented activity in recent weeks with several new FDA approvals, including new doublet regimens such as camizestrant with a CDK inhibitor and imlunestrant with a CDK inhibitor. 

This morning, we talked about the nature of mutations in ESR1, the gene that encodes the estrogen receptor, and how these mutations develop on aromatase inhibitor therapy, and how we now have multiple options to address this. 

We could think about next-generation anti-estrogen monotherapy with FDA approvals for elacestrant, imlunestrant, and the proteolysis targeting chimera, vepdegestrant, all as a single-agent. We also now have an FDA approval for imlunestrant with abemaciclib from the EMBER-3 study, also in the second-line setting.

Finally, we talked about data related to the SERENA-6 study, where patients who were on front-line, therapy with an aromatase inhibitor and a CDK inhibitor, who had emerging ESR1 mutations based on ctDNA, without clinical or radiographic progression, were treated with an adjustment from the aromatase inhibitor to the oral SERD camizestrant while continuing the CDK4/6 inhibitor.

We have all of those new options with these emerging anti-estrogen agents. They have slightly different toxicity profiles, we discussed some of the things we would educate patients about in that setting. We also discussed other factors in the landscape for treatment for ER-positive disease, including new drugs like gedatolisib, the first PI3K/AKT/mTOR pathway inhibitor. 

All of this is presenting new challenges for oncologists, but importantly, new opportunities for patients to think about better personalization and better deployment of precision therapeutic approaches in the first- and second-line metastatic setting.