Defining the Role of ER-Directed Therapies in HR-Positive MBC

There are several trials with oral SERDs in clinical development for hormone-receptor-positive metastatic breast cancer as both monotherapies and in combination therapy.

Endocrine therapy is the backbone of treatment management for patients with hormone receptor (HR)–positive mutant breast cancer (mBC), but resistance to treatment continues to pose a clinical challenge. In general, ESR1 mutations, or other genomic alterations, may inhibit estrogen-independent and estrogen-receptor mediated signaling, so investigators continue to search for effective treatments.

Aditya Bardia, MD, MPH, FASCO, said a treatment option to consider was the use of selective estrogen receptor downgraders (SERDs) or combination therapy in patients with estrogen receptor (ER)-positive mBC during his presentation at the 21st Annual International Congress on the Future of Breast Cancer® East in New York, New York.1

One emerging oral SERD that has shown promising activity is elacestrant, said Bardia, associate professor, Harvard Medical School, director, Breast Cancer Research, and attending physician, Mass General Cancer Center. The phase 1 RAD1901 study (NCT02650817) found higher antitumor activity in patients who received elacestrant over fulvestrant (Faslodex). The trial included patients treated with prior fulvestrant. Elecestrant was particularly effective in patients harboring ESR1-mutant tumors, with investigators reporting a clinical benefit rate (CBR) of 42.6% at 24 weeks.2 Given in 400 mg doses, elacestrant showed an overall response rate (ORR) of 19.4% and a median progression-free survival (PFS) of 4.5 months in this trial.

Other effective oral SERDs included giredestrant, amcenestrant, camizestrant, rintodesstrant, and imlunestrant. Bardia noted, however, that he “would caution…doing cross trial comparisons because if you look at prior [cyclin-dependent kinase 4/6 inhibitors] or prior fulvestrant use, that was very different between these trials. It's really not fair to compare the CBR in 1 study to another.”

The phase 3 EMERALD study (NCT03778931), which met its primary end point, evaluated 400 mg of oral elacestrant vs investigator’s choice in patients with ER+/HER2-breast cancer. Elacestrant showed favorable PFS at 6 and 12 months in all patients, and was especially effective among patients harboring ESR1 tumors. The PFS rate at 6 and 12 months for this patient population was 40.8% (95% CI, 30.1%-51.4%) and 26.8% (95% CI, 16.2%-37.4%), respectively vs investigators choice of 19.1% (95% CI, 14.1%-26.7%) and 8.2% (95% CI, 1.3%-15.1%), respectively.3

Bardia is awaiting more news from 2 studies, AMEERA-03 (NCT04059484) and acelERA (NCT04576455),4,5 which evaluated amcenestrant and giredestrant, respectively, but have not met their respective end points. Bardia commented, “The efficacy with the oral SERD was higher in patients with higher dependence of estrogen receptor activities. This does suggest that in the right setting, where the tumor is dependent on the ER pathway, you're likely going to see a signal.”

Bardia elaborated on why the EMERALD study had positive results compared to the other 2 studies, AMEERA-03 and acelERA, which did not. “One hypothesis is that the tumor is dependent on the ER pathway. The other hypothesis is that the disease progression is because the tumor is independent of the ER pathway to be driven by other [receptor tyrosine kinases]. And in that setting, a single agent endocrine therapy is unlikely going to work.”

Turning to combination therapy, Bardia explained the effects that combination therapy has had in this indication. Briefly, both the SOLAR-1 study (NCT02437318) and the FAKTION study (NCT01992952) revealed improved PFS when pairing fulvestrant with a PI3K inhibitor and an AKT inhibitor, respectively.6,7

In the first line, the MONALEESA-3 (NCT02422615) and MONALEESA-2 (NCT01958021) studies demonstrated overall survival (OS) improvement with endocrine therapy plus CDK4/6i.8,9 Median OS was not reached with ribociclib plus fulvestrant vs 45.1 months with placebo plus fulvestrant in the MONALEESA-3 study.

Bardia asked, “What about other endocrine therapies outside of SERDs?” He highlighted selective estrogen receptor covalent antagonists or SERCAs, including H3B-6545. H3B-6545 displayed an ORR of 16.4% and a CBR of 39.7% in patients with HR-postive/HER2– mBC.10 ARV-471 also showed promising efficacy in this same patient population with an ORR of 5.2% and a CBR of 40%.11

There are several trials with oral SERDs in clinical development for HR+ metastatic breast cancer as both monotherapies and in combination therapy. Some of the trials listed included the SERENA-1 (NCT03616587), SERENA-2 (NCT04214288), SERENA-4 (NCT04711252), ENZENO (NCT04669587), and EMBER (NCT04188548) studies. Investigators await further data in these settings that have the potential to change future management of HR+ mBC.


1. Bardia, A. Biology of ESR1 mutations and oral SERDs. Presented at the 21st Annual International Congress on the Future of Breast Cancer® East; July 15-16, 2022; New York, NY.

2. Jager A, de Vries EGE, der Houven van Oordt CWM, et al. A phase 1b study evaluating the effect of elacestrant treatment on estrogen receptor availability and estradiol binding to the estrogen receptor in metastatic breast cancer lesions using 18F-FES PET/CT imaging. Breast Cancer Res. 2020;22(1):97. Published 2020 Sep 11. doi:10.1186/s13058-020-01333-31370

3. Bardia A, Aftimos P, Bihani T, et al. EMERALD: Phase III trial of elacestrant (RAD1901) vs endocrine therapy for previously treated ER+ advanced breast cancer. Future Oncol. 2019;15(28):3209-3218. doi:10.2217/fon-2019-0370

4. Tolaney SM, Cicin I, Betancourt R, et al. Phase II trial of SAR439859 vs endocrine monotherapy in pre- and post-menopausal, estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-), locally advanced or metastatic breast cancer (BC) with prior exposure to hormonal therapies. J Clin Oncol. 2020; Doi: 10.1200/JCO.2020.38.15_suppl.TPS1107

5. Martin M, Lim E, Mac Gregor EM,et al. acelERA Breast Cancer (BC): Phase II study evaluating efficacy and safety of giredestrant (GDC-9545) versus physician’s choice of endocrine monotherapy in patients (pts) with estrogen receptor-positive, HER2-negative (ER+/HER2-) locally advanced or metastatic breast cancer (LA/mBC). J Clin Oncol. 2021; doi: 10.1200/JCO.2021.39.15_suppl.TPS1100

6. André F, Ciruelos E, Rubovszky G, et al. Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2019;380(20):1929-1940. doi:10.1056/NEJMoa1813904

7. Jones RH, Casbard A, Carucci M, et al. Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive breast cancer (FAKTION): a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 2020;21(3):345-357. doi:10.1016/S1470-2045(19)30817-4

8. Slamon DJ, Neven P, Chia S, et al. Phase III Randomized Study of Ribociclib and Fulvestrant in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: MONALEESA-3. J Clin Oncol. 2018;36(24):2465-2472. doi:10.1200/JCO.2018.78.9909HortobagyiG et al ESMO 2021

9. Hortobagyi GN, Stemmer SM, Burris HA, et al. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann Oncol. 2019 Nov 1;30(11):1842]. Ann Oncol. 2018;29(7):1541-1547. doi:10.1093/annonc/mdy155

10. Furman C, Puyang X, Zhang Z, et al. Covalent ERα Antagonist H3B-6545 Demonstrates Encouraging Preclinical Activity in Therapy-Resistant Breast Cancer. Mol Cancer Ther. 2022;21(6):890-902. doi:10.1158/1535-7163.MCT-21-0378

11. Hamilton EP, Schott AF, Nanda R, et al. ARV-471, an estrogen receptor (ER) PROTAC degrader, combined with palbociclib in advanced ER+/human epidermal growth factor receptor 2–negative (HER2-) breast cancer: Phase 1b cohort (part C) of a phase 1/2 study. J Clin Oncol. 2022; doi: 10.1200/JCO.2022.40.16_suppl.TPS1120