SERDs, PROTAC, and CERANs Offer Hope Following ET/CDK4/6 Inhibitor Resistance in Breast Cancer

Several promising new agents are currently in development across various mechanisms of action to address the unmet need resulting from resistance to the combination of endocrine therapy (ET) and CDK4/6 inhibition for patients with hormone receptor–positive breast cancer, according to a session by Hope S. Rugo, MD, at the 42nd Annual Miami Breast Cancer Conference.1

“We stand here at the brink of a precipice. There’s going to be a whole lot of these drugs approved in the future. We’re going to need to understand how to use them alone or in combination. They’re oral agents, and that’s huge for our patients,” said Rugo, professor of medicine and Winterhof Professor of Breast Oncology, director, Breast Oncology and Clinical Trials Education, University of California San Francisco Comprehensive Cancer Center. “I think that this is a really exciting advance. We’ve seen some great data in the past couple of years.”

The first agents to kick off this sea change in managing resistant HR-positive breast cancer were the oral selective estrogen receptor degraders (SERDs), which work best in those with the ESR1 resistance mutation. In 2023, the FDA approved the first of these agents, elacestrant (Orserdu), for patients with estrogen receptor (ER)–positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer following progression on at least 1 prior line of ET. This approval was based on data from the phase 3 EMERALD trial (NCT03778931).

In the phase 3 EMERALD trial,2 which enrolled patients with or without ESR1 mutations, the progression-free survival (PFS) was significantly prolonged with elacestrant compared with standard of care ET (HR, 0.70; 95% CI, 0.55-0.88; P = .002). In those with ESR1 mutations, the benefit in PFS was even more pronounced with elacestrant compared with standard of care (HR, 0.55; 95% CI, 0.39-0.77; P = .0005).

A follow up analysis further found that response to prior therapy could be used to help select which tumors would be more sensitive to treatment with elacestrant.3 For those who received ET plus CDK4/6 inhibition for 12 months or greater, the median PFS was 8.61 months (95% CI, 4.14-10.84) with elacestrant compared with 1.91 months (95% CI, 1.87-3.68) with standard of care (HR, 0.41; 95% CI, 0.26-0.63).

The ability to predict sensitivity led to the next question of whether combinations could be effective, Rugo noted. The ELECTRA (NCT05386108) and ELEVATE (NCT05563220) trials sought to examine this question by combining elacestrant with the CDK4/6 inhibitor abemaciclib (Verzenio). Data from a pooled analysis from the studies for patients pretreated with ET and CDK4/6 inhibitors were presented at the 2024 San Antonio Breast Cancer Symposium showing an intriguing efficacy.

In the analysis,4 the objective response rate (ORR) with the combination was 18%, which included 5% who had a complete response. There were 66% of patients beyond this who also had stable disease, for a clinical benefit rate (CBR) of 84%. In all patients, the median PFS with elacestrant plus abemaciclib was 8.7 months. In those who received prior ET/CDK4/6 treatment for 12 months or longer, the median PFS was 16.6 months with elacestrant plus abemaciclib.

“We saw an encouraging clinical benefit rate,” said Rugo. “Then we also looked at our response and many of these patients are staying on treatment for a long period of time, which is really encouraging.”

Other SERDs on the Horizon

Other investigational SERDs are also currently being explored as treatments for patients with ET and CDK4/6 resistance, potentially offering an abundance of choices soon. The phase 2 SERENA-2 trial (NCT04214288) was recently published showing efficacy for the SERD camizestrant vs fulvestrant (Faslodex) for patients with ER-positive, HER2-negative advanced breast cancer.5 The median PFS with fulvestrant was 3.7 months (90% CI, 2.0-6.0) compared with 7.2 months (90% CI, 3.7-10.9) with a 75-mg dose of camizestrant (HR, 0.59 vs fulvestrant) and 7.7 months (90% CI, 5.5-12.9) with a 150-mg dose (HR, 0.64 vs fulvestrant).

Recent data from the phase 3 SERENA-6 trial (NCT04964934) also showed utility for camizestrant in the first-line setting in combination with a CDK4/6 inhibitor.6 The data from the study have not yet been released but a statement said that the study met its primary end point of improved PFS with the combination compared with standard of care aromatase inhibition plus CDK4/6 inhibition. AstraZeneca, the company developing camizestrant, said the data would be presented at an upcoming medical meeting and shared with global regulatory authorities.

Another SERD, imlunestrant, has also demonstrated promise with or without the addition of abemaciclib for patients with ER-positive, HER2-negative advanced breast cancer in the phase 3 EMBER-3 trial (NCT04975308).7 In data from the study, the median PFS was 5.6 months (95% CI, 5.3-7.3) with imlunestrant and 5.5 months (95% CI, 4.6-5.6) with standard therapy (HR, 0.87; 95% CI, 0.72-1.04; P = .12); however, in those with ESR1 mutations, the median PFS was 5.5 months (95% CI, 3.9-7.4) with imlunestrant compared with 3.8 months (95% CI, 3.7-5.5) for standard therapy.

The combination of imlunestrant plus abemaciclib was also compared with imlunestrant monotherapy in the study. The median PFS with the combination was 9.4 months compared with 5.5 months with imlunestrant monotherapy (HR, 0.57; 95% CI, 0.44-0.73; P <.001). In those with ESR1 mutations, the median PFS with the combination was 11.1 months (95% CI, 7.4-13.7) compared with 5.5 months (95% CI, 3.8-7.2) with monotherapy (HR, 0.53; 95% CI, 0.35-0.80).

“The only downside here is that there’s no comparison of imlunestrant/abemaciclib vs standard of care ET,” said Rugo. “It is difficult to assess the impact of the ESR1 mutations in the combination group.”

Another SERD, giredestrant, is also being examined in combination with palbociclib (Ibrance) plus letrozole in a phase 3 study labeled persevERA (NCT04546009).1 This trial is currently active but not recruiting, with an estimated primary completion date in October 2025.

Novel Agents for ER Targeting Under Investigation

The novel agent vepdegestrant (ARV-471) offers another method for approaching ET resistance. The agent is a proteolysis-targeting chimera (PROTAC), which act as protein degraders targeted to ER proteins. A phase 1b study (NCT04072952) assessed vepdegestrant in combination with palbociclib for patients with ER-positive, HER2-negative breast cancer following exposure to ET with or without CDK4/6.8 The CBR with the combination was 63% (95% CI, 47.6%-76.8%) in the overall population enrolled. For those with the ESR1 mutation, the CBR was 72.4% (95% CI, 52.8%-87.3%). The median PFS was 11.2 months (95% CI, 8.2-16.5) in the overall population and 13.7 months (95% CI, 8.2-not reached) in the ESR1 group.

In February 2024, vepdegestrant received a fast track designation from the FDA, a distinction that is meant to speed up the development of new medications. The phase 3 VERITAC-3 study (NCT05909397) is also assessing the agent with palbociclib compared with palbociclib and letrozole. The phase 3 VERITAC-2 trial (NCT05654623) is currently assessing vepdegestrant vs fulvestrant for patients with ER-positive, HER2-negative advanced breast cancer. The study indicates that it has fully recruited with results expected soon.

“These are very exciting drugs and many of them [are] still in development,” said Rugo. “The trial is fully accrued so we’re going to see the results relatively sooner.”

Another approach to ET resistance comes through the complete ER antagonist (CERAN) palazestrant (OP-1250). This agent was examined in combination with ribociclib (Kisqali) in a phase 1b/2 study (NCT05508906). In findings from the study,9 the median PFS was not reached. The 6-month PFS rate was 72% across all patients and 81% in those with ESR1 mutations.

Based on these findings, Olema Oncology, the company developing palazestrant, is launching the phase 3 OPERA-02 study to further assess the combination for patients with breast cancer. The FDA granted palazestrant a fast track designation in 2022.

Disclosures: Rugo received institutional research support from AstraZeneca, Daiichi Sankyo, Inc., F. Hoffmann-La Roche AG/Genentech, Inc., Gilead Sciences, Inc., Lilly, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Pfizer, Stemline Therapeutics, OBI Pharma, and Ambryx; and served in a consulting/advisory role for Chugai, Sanofi, Napo, and Mylan.

References

1. Rugo HS. Emerging therapies: updates on oral SERDs for metastatic HR+ breast cancer. Presented at: 42nd Annual Miami Breast Cancer Conference. March 6-9, 2025; Miami, Florida.
2. Bidard FC, Kaklamani VG, Neven P, et al. Elacestrant (oral selective estrogen receptor degrader) versus standard endocrine therapy for estrogen receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer: results from the randomized phase III EMERALD trial. J Clin Oncol. 2022;40(28):3246-3256. doi:10.1200/JCO.22.00338
3. Bardia A, Cortés J, Bidard FC, et al. Elacestrant in ER+, HER2- metastatic breast cancer with ESR1-mutated tumors: subgroup analyses from the phase III EMERALD trial by prior duration of endocrine therapy plus CDK4/6 inhibitor and in clinical subgroups. Clin Cancer Res. 2024;30(19):4299-4309. doi:10.1158/1078-0432.CCR-24-1073
4. Rugo HS, Tolaney SM, Chan N, et al. Elacestrant plus abemaciclib (abema) combination in patients (pts) with estrogen receptor-positive (ER+), HER2-negative (HER2-) advanced or metastatic breast cancer (mBC). Presented at: 2024 San Antonio Breast Cancer Symposium; December 10-13, 2024; San Antonio, TX. Poster PS7-07.
5. Oliveira M, Pominchuk D, Nowecki Z, et al. Camizestrant, a next-generation oral SERD, versus fulvestrant in post-menopausal women with oestrogen receptor-positive, HER2-negative advanced breast cancer (SERENA-2): a multi-dose, open-label, randomised, phase 2 trial. Lancet Oncol. 2024;25(11):1424-1439. doi:10.1016/S1470-2045(24)00387-5
6. Camizestrant demonstrated highly statistically significant and clinically meaningful improvement in progression-free survival in 1st-line advanced HR-positive breast cancer with an emergent ESR1 tumour mutation in SERENA-6 phase III trial. News release. AstraZeneca. February 26, 2025. Accessed February 26, 2025. https://www.astrazeneca.com/media-centre/press-releases/2025/camizestrant-improved-pfs-in-1l-hr-breast-cancer.html
7. Jhaveri KL, Neven P, Casalnuovo ML, et al. Imlunestrant with or without abemaciclib in advanced breast cancer. N Engl J Med. Published online December 11, 2024. doi:10.1056/NEJMoa2410858
8. Hamilton EP, Hurvitz SA, McAndrew NP, et al. Vepdegestrant, a proteolysis targeting chimera (PROTAC) estrogen receptor (ER) degrader, plus palbociclib (palbo) in ER+/human epidermal growth factor receptor 2 (HER2)- advanced breast cancer: updated phase Ib cohort results. ESMO Open. 2024;9(suppl 4):103240. doi:10.1016/j.esmoop.2024.103240
9. Borges V, Mouabbi JA, Chien J, et al. A phase 1b/2 study of palazestrant (OP-1250) in combination with ribociclib, in patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+/HER2-), advanced or metastatic breast cancer. Presented at: 2024 San Antonio Breast Cancer Symposium; December 10-13, 2024; San Antonio, TX. Abstract P2-09-16.