SERMS, SERDS, and PROTEC Are Poised to Shake Up Treatments for ER+ Breast Cancer

Novel selective estrogen receptor modulators, selective estrogen receptor degraders, and proteolysis-targeting chimera inhibitors have demonstrated early efficacy for patients with breast cancer who experience disease progression following CDK4/6 inhibitor treatment.

Erica Stringer-Reasor, MD

Erica Stringer-Reasor, MD

Treatment options developed to target the estrogen receptor (ER) have afforded patients with breast cancer many years of sustained on-treatment benefit. However, patients are prone to develop primary and secondary resistance to hormone therapies, with up to 25% of hormone receptor–positive patients experiencing acquired resistance with the development of ESR1 mutations following exposure to an aromatase inhibitor.

“Approximately 70% of our patients will have this hormone receptor–positive breast cancer and the main driver is estrogen, which causes a manipulation of these tumors,” said Erica Stringer-Reasor, MD, in a presentation during the 40th Annual Miami Breast Cancer Conference®.1 Stronger-Reasor is an assistant professor of medicine in the Division of Hematology and Oncology at the University of Alabama at Birmingham.

Novel selective estrogen receptor modulators (SERMs), selective estrogen receptor degraders (SERDs), and proteolysis-targeting chimera (PROTAC) inhibitors have demonstrated early efficacy for patients who experience disease progression following CDK4/6 inhibitor treatment. Additionally, improvements in response and progression-free survival (PFS) have been noted for those with ESR1-mutant disease, making these agents the next wave of treatments to increase the clinical benefit for this patient population.

“We are definitely seeing clinical benefit with SERMs, particularly as monotherapy as well in combination therapy with CDK4/6 inhibitors, [and we are] really excited to see phase 3 trials [in that space]. Additionally, in the [phase 3] EMERALD study [NCT03778931], we see that elacestrant [Orserdu] showed efficacy among [all patients] and those with ESR1-mutant tumors, and it’s very exciting to have the ER-directed therapy approved, the first approval since 2002. But we need more ER-directed therapies approved,” Stringer-Reasor said.


Available SERMs for the treatment of metastatic, advanced hormone receptor–positive breast cancer include tamoxifen and toremifene.2 However, targeted endocrine agents such as lasofoxifene (Fablyn) are under investigation for patients with ESR1-mutant disease after progression on CDK4/6 inhibitors. The open-label, phase 2 ELAINE-1 study (NCT03781063) randomly assigned patients with ER-positive, HER2-negative disease to lasofoxifene (n = 52) or fulvestrant (Faslodex; n = 51). The median PFS with lasofoxifene was 6.04 months (95% CI, 2.82-8.04) vs 4.04 months (95% CI, 2.93-6.04) with fulvestrant (HR, 0.699; 95% CI, 0.445-1.125; P = .138).3 The 6-month and 12-month PFS rates with lasofoxifene and fulvestrant were 53.4% vs 37.9% and 30.7% vs 14.1%, respectively.3

Most adverse effects were grade 1/2, and investigators noted that no thrombotic events occurred. In an exploratory circulating tumor DNA analysis, investigators noted that among 61 evaluable patients, the median relative change for all variants in the ESR1-mutant allele fraction was 87.1% among those treated with lasofoxifene compared with 14.7% among those who received fulvestrant.

“There’s definitely clinical activity with [SERMs], such as lasofoxifene, we can also see that clinical benefit and enhanced activity with ESR1-mutated tumors,” Stronger-Reasor said. She added that activity was seen in combination with CDK4/6 inhibitors in the phase 2 ELAINE-2 study (NCT04432454), which is combining lasofoxifene with abemaciclib (Verzenio) for the treatment of postmenopausal and premenopausal women on ovarian suppression with locally advanced or metastatic hormone receptor–positive/HER2-negative breast cancer who have an acquired ESR1 mutation.

Outcomes from the single-arm study showed that among 29 treated patients, the overall response rate (ORR) was 50% (95% CI, 29.0%-71.0%) with a clinical benefit rate (CBR) of 69%, a median time to response of 169 days, and a median duration of response of 164 days. The median PFS was 13.9 months, or 55.7 weeks (95% CI, 32.0–not estimable).4

A randomized phase 3 trial, to be called ELAINE-3, is planned for 2023/2024, based on the outcomes of the prior 2 studies. According to the sponsor Sermonix Pharmaceuticals, the study will compare lasofoxifene plus abemaciclib with fulvestrant and abemaciclib.5


The FDA approved elacestrant in January 2023 for the treatment of patients with ER-positive, HER2-negative, metastatic breast cancer who had prior treatment with a CDK4/6 inhibitor and whose tumors harbor and ESR1 mutation.6

Patients in the phase 3 EMERALD trial were randomly assigned to elacestrant, an oral SERD, or standard-of-care treatment, which for most clinicians would be an intramuscular SERD, according to Stringer-Reasor. At the 2022 San Antonio Breast Cancer Symposium, investigators presented data on the efficacy of both therapies based on length of prior CDK4/6 inhibition. Among patients with ESR1-mutant tumors who had received at least 12 months of treatment with a CDK4/6 inhibitor, the median PFS was 8.61 months with elacestrant (n = 78) vs 1.91 months with SOC (n = 81; HR, 0.410; 95% CI, 0.262-0.634).7

For those who had prior treatment lasting at least 6 months with a CDK4/6 inhibitor the median PFS was 4.14 months vs 1.87 months among patients who received elacestrant (n = 103) and SOC (n = 102), respectively (HR, 0.517; 95% CI, 0.361-0.738).7 Among those with at least 18 months of treatment, the median PFS was 8.61 months vs 2.10 months for those who received elacestrant (n = 55) vs SOC (n = 56; HR, 0.466; 95% CI, 0.270-0.791).7

Stringer-Reasor noted that all patients in EMERALD had prior CDK4/6 inhibition, which differs from another ongoing trial of an investigational oral SERD, camizestrant (AZD9833), in the phase 2 SERENA-2 trial (NCT04214288). At baseline only 50% of the population had prior treatment with a CDK4/6 inhibitor. The study is evaluating camizestrant at 2 dose levels (75 mg [n = 74] and 150 mg [n = 73]) vs fulvestrant (n = 73). The median PFS for the 3 cohorts was 7.2 months (95% CI, 3.7-10.9; HR vs fulvestrant, 0.58; 95% CI, 0.41-0.81; P = .0124), 7.7 months (95% CI, 5.5-12.9; HR vs fulvestrant, 0.67; 95% CI, 0.48-0.92; P = .0161), and 3.7 months (95% CI, 2.0-6.0), respectively.8

Camizestrant and elacestrant both demonstrated a PFS benefit as single agents; however giredestrant (GDC-9545) and amcenestrant (SAR439859) both resulted in negative trials. Ongoing investigations are underway for giredestrant in combination with everolimus (evERA Breast Cancer; NCT05306340), camizestrant plus a CDK4/6 inhibitor (SERENA-6; NCT04964934); and imlunestrant plus abemaciclib (EMBER-3; NCT04975308).1


Novel orally administered PROTAC protein degraders are also entering the scene for ER-positive breast cancer. ARV-471 is engineered to target wild-type and mutant ER by directly binding to the E3 ubiquitin ligase and ER. Unlike SERDs with indirectly recruit ubiquitin proteasome system, ARV-471 is designed to directly trigger ubiquitination of ER and its subsequent proteasomal degradation.9

In the phase 2 expansion VERITAC study (NCT04072952), ARV-471 monotherapy elicited a significant CBR in patients with ER-positive/HER2-negative locally advanced or metastatic breast cancer whose tumors had an ESR1 mutation. In this population, all patients received prior CDK4/6 inhibition.

Two doses were evaluated: 200 mg and 500 mg. Among patients with an ESR1 mutation, the CBR in the 200-mg arm (n = 19) was 47.4% (95% CI, 24.4%-71.1%) vs 54.5% (95% CI, 32.2%-75.6%) in the 500-mg arm (n = 22). The CBR among all patients with an ESR1 mutation (n = 41) was 51.2% (95% CI, 35.1%-67.1%).9 The median PFS for all patients with an ESR1-mutation regardless of dose level was 5.6 months. Most treatment-related adverse effects were grade 1/2 with 1 patient discontinuing due to QT prolongation, which was reported at baseline. One patient died on treatment due to acute respiratory failure and was noted as being unrelated to ARV-471.9

“This was a heavily pretreated group pretreated with a median of 3 prior lines of therapy [range, 0-7], and approximately half of patients had prior chemotherapy [45%],” Stringer-Reasor noted about the VERITAC study population. She added that the findings are encouraging and support the planned phase 3 trials that are forthcoming.


  1. Stringer-Reasor E. Newer hormone receptor-directed therapies. Presented at: 40th Annual Miami Breast Cancer Conference®; March 2-5, 2023; Miami Beach, FL.
  2. Hormone therapy for breast cancer. National Cancer Institute. Updated July 12, 2022. Accessed March 4, 2023.
  3. Goetz MP, Plourde P, Stover DG, et al. Open-label, randomized study of lasofoxifene (LAS) vs fulvestrant (Fulv) for women with locally advanced/metastatic ER+/HER2- breast cancer (mBC), an estrogen receptor 1 (ESR1) mutation, and disease progression on aromatase (AI) and cyclin-dependent kinase 4/6 (CDK4/6i) inhibitors. Ann Oncol. 2022;33(suppl 7):S808-S869. doi:10.1016/annonc/annonc1089
  4. Damodaran S, Plourde PV, Moore HCF, et al. Open-label, phase 2, multicenter study of lasofoxifene (LAS) combined with abemaciclib (Abema) for treating pre- and postmenopausal women with locally advanced or metastatic ER+/HER2− breast cancer and an ESR1 mutation after progression on prior therapies. J Clin Oncol. 2022;40(suppl 16):1022. doi:10.1200/JCO.2022.40.16_suppl.1022
  5. What are the ELAINE studies? Sermonix Pharmaceuticals. Accessed March 4, 2023.
  6. FDA approves elacestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. FDA. January 27, 2023. Accessed March 3, 2023.
  7. Bardia A, Bidard FC, Neven P, et al. EMERALD phase 3 trial of elacestrant versus standard of care endocrine therapy in patients with ER+/HER2- metastatic breast cancer: updated results by duration of prior CDK4/6i in metastatic setting. Presented at 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX.
  8. Oliveira M, Pominchuk D, Nowecki Z, et al. Camizestrant, a next generation oral SERD vs fulvestrant in post-menopausal women with advanced ER-positive HER2-negative breast cancer: Results of the randomized, multi-dose Phase 2 SERENA-2 trial. 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX.
  9. Hurvitz S, Ma C, Hamilton E, et al. GS3-03 ARV-471, a PROTAC® estrogen receptor (ER) degrader in advanced ER-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer: phase 2 expansion (VERITAC) of a phase 1/2 study. Presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX.

Editor’s Note: Dr Stringer-Reasor has the following disclosures consultant for Lilly, Mylan, Novartis, Immunomedics, AstraZeneca, SeaGen, and Merck; research supported by Susan G. Komen, Vfoundation, Breast Cancer Research Foundation of Alabama, and National Institutes of Health; clinical research for Pfizer, SeaGen, Tesaro, Lilly, Genetech, Calithera, and Corcept.

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