The Evolution of Selective Estrogen Receptor Degraders (SERDs) in Breast Cancer Treatment

Selective estrogen receptor degraders (SERDs) are just one of the many mechanisms that can be utilized in the treatment of breast cancer. Rinath Jeselsohn, MD, presented an educational session at the 2024 San Antonio Breast Cancer Symposium focusing on the latest information regarding SERDs.

Dr Jeselsohn first began by giving a brief history and overview of SERDs. While recently in the limelight due to new approvals and data disclosures for drugs such as imlunestrant or camizestrant, research into SERDs has been ongoing since 1987. The concept of utilizing SERDs for the treatment of breast cancer results from role of the estrogen receptor (ER) in ER-positive breast cancer transcription. When estradiol binds to the estrogen receptor, the receptor is dimerized and phosphorylated, allowing it to translocate to the nucleus. The binding of this receptor along with co-activators and co-receptors to the ERE region allows for modulated control of transcription. SERDs act in 2 primary ways; first by preventing co-activator recruitment, and second by increasing surface hydrophobicity of the ligand binding domain, which is associated with decreased stability of ER and increased ER degradation.

However, Dr Jeselsohn also noted that there are limitations with current generation SERDs, namely the monthly injection schedule, poor bioavailability and pharmacokinetic parameters, and the ability of ESR1 mutations to confer resistance to fulvestrant specifically. Particularly regarding ESR1 mutations, these mutations have been shown to have a decreased effect on both ER degradation and transcription activity, leading to decreased patient outcomes. Dr Jeselsohn emphasized this point by showing retrospective data from the PALOMA-3 trial, in which patients with an ESR1 mutation had decreased progression-free survival compared with those without the mutation.

Dr Jeselsohn then discussed 2 more novel SERDs, elacestrant and imlunestrant, as well as data surrounding them. Elacestrant was approved in January 2023 for treatment of ER-positive, HER2-negative, ESR1-mutated advanced breast cancer with disease progression following at least 1 line of endocrine therapy. Preclinical studies showed both superior activity to fulvestrant as well as a unique pharmacology at different concentrations. Elacestrant was studied through the phase 3 EMERALD trial, which enrolled ER-positive, HER2-negative patients who had progressed or relapsed on or after 1-2 lines of endocrine therapy for advanced disease, 1 of which had to be given in combination with a CDK4/6 inhibitor. Patients were randomized to either receive elacestrant monotherapy or investigator’s choice of treatment (fulvestrant, anastrozole, letrozole, or exemastane). The trial had shown particular PFS benefit in patients with ESR1 mutation (median PFS, elacestrant vs SOC: 3.8 vs 1.9 months), though it was noted that early in the treatment of both the elacestrant and control groups, approximately 30% of patients had a rapid progression, highlighting the need for to explore subgroups and identify those patients who would benefit most from SERD monotherapy. A follow-up analysis did just this and saw that a longer duration on prior CDK4/6 inhibitor treatment was associated with improved benefit from elacestrant in patients with ESR1 mutation (median PFS, elacestrant vs SOC: 8.61 vs 1.91 months; hazard ratio, 95% CI: 0.41, 0.26-0.63).

Imlunestrant has been evaluated in the EMBER-3 trial, but also has had its ability to affect transcription studied in the laboratory. Researchers found that in hormone-deprived wild-type ER cells, at both 6 and 12 hours, there were no transcriptional changes. However, transcriptional changes were seen in ER-mutated cells under the same conditions. Imlunestrant was also shown to have greater levels of ER degradation than fulvestrant under laboratory conditions in ER-mutated cells. PDX models have further shown that imlunestrant has enhanced tumor growth suppression activity when compared with vehicle control or fulvestrant.

While SERDs such as fulvestrant have been utilized in the past, a new wave of SERDs that have better bioavailability and pharmacokinetics have gained approval recently. Furthermore, these agents are chemically different from fulvestrant, allowing them to have distinct interactions in the ligand binding site that fulvestrant may not have. Both elacestrant and imlunestrant represent more optimized treatment options for patients with breast cancer, all while overcoming some of the pitfalls of older agents.

Source

Jeselsohn R. Latest on selective estrogen receptor degraders (SERDs). Presented at: San Antonio Breast Cancer Symposium. December 11, 2024; San Antonio, TX.