Efficacy and Safety of Next-Generation Oral SERDs for HR+/HER2– mBC

Combination Therapy Development and Oral SERD Pipeline

The Elevate study represents a comprehensive phase 1b/2 umbrella trial investigating elacestrant combinations with various targeted therapies, including CDK4/6 inhibitors and PI3K pathway inhibitors. Recent 2025 American Society of Clinical Oncology Annual Meeting updates demonstrated promising early efficacy with elacestrant plus ribociclib and elacestrant plus everolimus combinations, showing median progression-free survival in the range of 7 to 8 months. The safety profiles remained consistent with individual agent toxicities, with increased neutropenia from ribociclib and stomatitis from everolimus as expected.

The oral SERD landscape is expanding rapidly, with multiple agents in clinical development, including capivasertib, imlunestrant, and giredestrant, all demonstrating superior efficacy compared with fulvestrant, specifically in populations with ESR1-mutant disease. These agents share common characteristics of being well-tolerated oral medications that provide modest but clinically meaningful improvements over standard fulvestrant therapy. The consistency of efficacy across different oral SERDs suggests a class effect in hormone-sensitive, ESR1-mutant disease.

Proteolysis-targeting chimera technology adds another dimension to the oral SERD pipeline, with agents showing benefit across all patients with hormone receptor–positive disease while maintaining superior efficacy in populations with ESR1-mutant disease. The abundance of effective oral SERD options will likely provide clinicians with multiple therapeutic choices, allowing selection based on individual patient factors, combination potential, and specific toxicity profiles rather than efficacy differences alone.