Novel Hormone Receptor–Driven Therapies Tackling Endocrine Resistance in Breast Cancer

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In hormone receptor–positive metastatic breast cancer, tumors eventually become resistant not only to endocrine blockade but to inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6). This obstacle to successful treatment is being tackled with novel hormone receptor–directed therapies, with the aim of effectively treating the growing number of patients whose disease progresses after treatment with CDK4/6 inhibitors, said Erica Stringer-Reasor, MD, Associate Professor of Medicine and Director of the Breast Cancer Program at the University of Alabama at Birmingham and O’Neal Comprehensive Cancer Center.

Stringer-Reasor, MD

Stringer-Reasor, MD

In a presentation about novel endocrine therapy approaches at the 2023 Miami Breast Cancer Conference, Dr. Stringer-Reasor focused her discussion on the 25% or so of patients who develop ESR1 mutations after exposure to aromatase inhibitors, which confers resistance.1 This is a subset of patients for whom new endocrine-directed therapeutics are particularly needed.

The novel agents that are addressing the escape pathways that become important after endocrine resistance occurs primarily include the orally delivered selective estrogen receptor degraders (SERDs) and selective estrogen receptor modulators (SERMs), with several other classes in the early development phase.

Updates on SERMs

The ELAINE-1 study compared the orally delivered SERM lasofoxifene with standard therapy with the intramuscularly administered SERD fulvestrant in 201 patients with metastatic disease and ESR1 mutations whose disease progressed on aromatase inhibitors and CDK4/6 inhibitors.2 Among these patients, 40% had the “aggressive and hard-to-treat” Y537S type.

Treatment with lasofoxifene led to numerical though not statistically significant improvements over fulvestrant. Median progression-free survival was 6 months with lasofoxifene vs 4 months with fulvestrant (hazard ratio [HR] = 0.699; P = .138), and at 1 year, 31% vs 14% of patients, respectively, were progression-free. Other efficacy outcomes were numerically higher with lasofoxifene, including clinical benefit rate (36.5% vs 21.6%) and objective response rate (13.2% vs 2.9%). Most adverse events (most commonly nausea, fatigue, arthralgias, and hot flushes) were grade 1 or 2, and no thrombotic events occurred.

An exploratory analysis based on circulating tumor DNA (ctDNA) at 8 weeks showed the median relative reduction in the ESR1-mutant allele fraction to be 87% with lasofoxifene vs 15% with fulvestrant. In patients with the more challenging Y537S mutations, the reduction was 89% with lasofoxifene, whereas fulvestrant resulted in an 82% increase in the mutant allele fraction. “The oral therapy lasofoxifene seems to be hitting the target well. We saw more degradation of the estrogen receptor,” she noted.

“Moving forward, we also want to know whether combination therapy is better than monotherapy,” she said. The combination of lasofoxifene plus abemaciclib was evaluated in the open-label phase II ELAINE-2 trial of 29 women with ESR1 mutations after disease progression on prior endocrine agents and CDK4/6 inhibitors.3 Median progression-free survival was 13.9 months, the objective response rate was 50%, the clinical benefit rate was 69%, median time to next treatment was 169 days, and most toxicities were grades 1 and 2. Based on the efficacy and safety observed in ELAINE-1 and ELAINE-2, the phase III ELAINE-3 combination study of lasofoxifene and abemaciclib has been planned.

Updates on SERDs

SERDs treat estrogen receptor–positive breast cancer by binding to the receptor and causing its degradation and subsequent downregulation. Until January 2023, intramuscularly delivered fulvestrant was the only U.S. Food and Drug Administration (FDA)-approved SERD, but elacestrant is now approved, based on the results of the phase III EMERALD trial.4 The FDA also approved the Guardant360 CDx assay as a companion diagnostic to identify patients who can be treated with elacestrant. Several other oral SERDs are in development.

EMERALD showed the efficacy of elacestrant. In a post hoc analysis, longer duration of prior CDK4/6 inhibitor exposure was positively associated with longer progression-free survival on elacestrant but not standard therapy. For example, for patients exposed to CDK4/6 inhibitors for at least 18 months, median progression-free survival was 5.5 months with elacestrant vs 3.3 months with standard therapy—a 30% reduction in risk. Among the population with ESR1 mutations, findings were even more marked. For those with at least 18 months of prior exposure to CDK4/6 inhibitors, median progression-free survival was 8.6 months on elacestrant vs 2.1 months on standard therapy—a 53% reduction in risk.

Another SERD, camizestrant, proved superior to fulvestrant in the phase II SERENA-2 trial of 240 previously treated patients, approximately one-third of whom had ESR1 mutations.5 Patients receiving higher-dose camizestrant had a median progression-free survival, by investigator assessment, that was more than doubled that achieved with fulvestrant. Although median progression-free survival was 3.7 months with fulvestrant, it was 7.2 months with camizestrant at 75 mg (HR = 0.58; P = .0124) and 7.7 months with camizestrant at 150 mg (HR = 0.67; P = .0161). Treatment with camizestrant at both doses reduced the level of ESR1 mutation to undetectable or near-undetectable levels.

In the subpopulations of patients previously treated with CDK4/6 inhibitors and those with ESR1 mutations, camizestrant at both doses produced clinically meaningful improvements over fulvestrant. Dose reductions and interruptions were infrequent. “It seems there was better progression-free survival with the oral SERD, no matter the dose level. The dose level that will move forward is the lower dose of 75 mg,” she said.

These two SERDs, elacestrant and camizestrant, cannot be compared for efficacy because the study populations and comparators were different. In EMERALD, 100% of patients had prior treatment with both endocrine therapy and CDK4/6 inhibitors, whereas in SERENA-2, only 51% received a CDK4/6 inhibitor. The endocrine partner was fulvestrant in 69% of the EMERALD population but in 100% of the SERENA population.

Summing up the current state of SERD therapeutics, Dr. -Stringer-Reasor noted that monotherapy with elacestrant and camizestrant demonstrated clinical activity in the second- and third-line settings, with moderate progression-free survival benefit; overall survival data are pending. Side effects were manageable, and about 3% of patients discontinued treatment. Prolonged duration of CDK4/6 inhibitor therapy (≥ 12 months) and the presence of ESR1 mutations have been associated with the most benefit.

Regardless of benefit, however, about one-third of patients experience primary disease progression with SERD monotherapy, indicating that endocrine resistance has not been overcome. “We still have to figure out that escape pathway, but it’s very encouraging that patients who tend to have some endocrine sensitivity (as indicated by a prolonged duration of prior CDK4/6 inhibitors) and those with ESR1 mutations had great clinical benefit with these SERDs,” she commented.

Several other oral SERDs are in phase II and III development. Giredestrant is being evaluated in combination with exemestane in the phase III evERA BC trial; as monotherapy, it demonstrated no benefit in the negative phase II aceIERA BC trial. Imlunestrant with or without abemaciclib is being studied in the ongoing phase III EMBER-3 trial. The AMEERA-3 study of amcenestrant was halted because of futility.

Updates on PROTAC Inhibitors, Other Agents

The PROTAC [PROteolysis-TArgeting Chimera] inhibitors may be the next addition to the treatment landscape for endocrine-resistant patients. At the 2022 San Antonio Breast Cancer Symposium, investigators presented early data for ARV-471,6 which is a selective, orally administered PROTAC protein degrader that targets wild-type and mutant estrogen receptors. ARV-471 has been shown to exert substantially greater estrogen receptor degradation and tumor growth inhibition than fulvestrant in breast cancer xenograft models.

The phase II VERITAC study included 71 heavily pretreated patients, essentially all of whom had received prior endocrine therapy (79% prior fulvestrant, 90% prior aromatase inhibitor) and CDK4/6 inhibition; 55% had visceral metastases. Clinical benefit, the primary endpoint, was achieved by 38% of patients, increasing to 51% among patients with ESR1 mutations. Median progression-free survival was 3.6 months for all patients and 5.6 months for those with ESR1 mutations. Mean estrogen receptor degradation was 71%. One patient discontinued treatment because of QT prolongation, but this was present at baseline; one patient died of causes unrelated to ARV-471. All other adverse events were low-grade. “These findings are encouraging, and phase III trials are planned or underway,” Dr. Stringer-Reasor said.

Complete estrogen receptor antagonists, selective estrogen receptor covalent antagonists SERM/SERD hybrids, and chimeric estrogen receptor degraders are also in phase I/II studies in this setting. 

DISCLOSURE: Dr. Stringer-Reasor has served as a consultant to Eli Lilly, Mylan, Novartis, Immunomedics, AstraZeneca, Seagen, and Merck.


1. Stringer-Reasor E: Newer hormone receptor-directed therapies. 2023 Miami Breast Cancer Conference. Presented March 3, 2023.

2. Goetz MP, Plourde P, Stover DG, et al: Open-label, randomized study of lasofoxifene vs fulvestrant for women with locally advanced/metastatic ER+/HER2– breast cancer, an estrogen receptor 1 mutation, and disease progression on aromatase and cyclin-dependent kinase 4/6 inhibitors. ESMO Congress 2022. Abstract LBA20. Presented September 10, 2022.

3. Damodaran S, Plourde PV, Moore HCF, et al: Open-label, phase 2, multicenter study of lasofoxifene combined with abemaciclib for treating pre- and postmenopausal women with locally advanced or metastatic ER+/HER2− breast cancer and an ESR1 mutation after progression on prior therapies. 2022 ASCO Annual Meeting. Abstract 1022.

4. Kaklamani V, 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. 2022 San Antonio Breast Cancer Symposium. Abstract GS3-01. Presented December 8, 2022.

5. 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. Abstract GS3-02. Presented December 8, 2022.

6. Hurvitz SA, Schott AF, Ma C, et al: ARV-471, a PROTAC estrogen receptor 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. 2022 San Antonio Breast Cancer Symposium. Abstract GS3-03. Presented December 8, 2022.