Targeting ESR1 Mutations in Breast Cancer With Novel Therapies

Seth Wander, MD, PhD, a medical oncologist at the Massachusetts General Hospital and instructor in medicine at Harvard Medical School, discusses approved and upcoming targeted therapies for patients with ESR1-mutated breast cancer.

Current options for these patients include elacestrant (Orserdu), a selective estrogen receptor degrader (SERD), and fulvestrant, a chemotherapy. However, Wander says fulvestrant’s effectiveness varies among ESR1 mutations. Some, such as Y537S, may have resistance to this therapy.

Recent trials including the phase 3 EMBER-3 trial (NCT04975308) investigating imlunestrant with or without abemaciclib (Verzenios) have shown potential in subpopulations of patients with ESR1 mutations. Imlunestrant is also a SERD but Wander notes that therapies such as selective estrogen receptor modulators, proteolysis targeting chimeras, and covalent estrogen receptor antagonists are also being looked at as single agents and in combination for use in this patient population.

TRANSCRIPTION:

0:10 | Patients who demonstrate endocrine sensitivity and then they develop the ESR1 mutation, they're good candidates for using elacestrant. There are many other drugs that are being developed right now for patients with ESR1-mutant breast cancer. Fulvestrant can work, although I would argue that the preconceived notion that fulvestrant works across the board for ESR1-mutant patients is not entirely true. Not all ESR1 mutations are created equally. Some of them probably have distinct neomorphic activities and may be more resistant to a drug like fulvestrant, for example, the Y537S mutation. We're still learning a lot about what these mutations do at the cellular biochemical level. So fulvestrant can be helpful in some cases. Elacestrant is FDA approved for ESR1-mutant breast cancer that's progressed on prior endocrine therapy.

1:08 | Now we have a number of newer drugs that we have phase 3 data coming online. We just saw phase 3 data from the EMBER-3 trial, looking at imlunestrant either as a single agent or with abemaciclib...that showed very similar results where there was activity as a single agent in the ESR1-mutant subpopulation of that study. Then we have other newer drugs coming up. We have lots of other oral SERDS. We have SERMs, selective estrogen receptor modulators. We have PROTACs, proteolysis targeting chimeras. We have SERCAs, covalent estrogen receptor antagonists. So lots of new mechanisms, new anti-estrogen agents being developed as single agents and also as combinations with various targeted therapies.