Novel Estrogen Receptor-Targeted Agents for Breast Cancer

Opinion statement It has become clear that patients whose cancers have progressed post-CDK4/6 inhibitor therapy (CDK4/6i) are not deriving the same magnitude of benefit to subsequent standard endocrine therapy as historical studies would suggest. For example, anticipated duration of benefit to fulvestrant prior to CDK4/6i historically was ~ 5–6 months, and data from the VERONICA and EMERALD trials report less than 2 months. This has magnified our need for novel endocrine agents. Some have argued that patients post-CDK4/6i may just have more endocrine-resistant tumors and perhaps should just receive chemotherapy. While this may be appropriate for some, we do not currently have an assay that reliably predicts whose cancers remain endocrine sensitive and whose are endocrine resistant. ESR1 mutations can enrich for patients whose tumors are more likely to be heavily dependent on estrogen, but this is certainly not the whole answer and many patients without ESR1 mutations continue to derive benefit from subsequent endocrine agents. Most patients would strongly prefer the side effect profile of endocrine agents compared to chemotherapy, and thus, premature use of cytotoxic agents when subsequent ER targeting can control disease is not preferred. These novel ER targeting agents (PROTAC, SERD, SERCA, CERAN) hold great promise to not only outperform standard agents like fulvestrant, but also offer the promise of agents with a different side effect profile that may be more advantageous when compared to menopausal symptoms, hot flashes, arthralgias, and sexual side effects so commonly seen with AIs. We also are likely to see these novel agents move to earlier lines, whether that be 1st line in combination with CDK4/6i or even adjuvant disease.