Elacestrant-Based Combinations Show Efficacy, Safety in ER+, HER2-Negative Breast Cancer

Elacestrant (Orserdu) plus everolimus (Afinitor) or abemaciclib (Verzenio) continued to show tolerability and yielded a clinically meaningful progression-free survival (PFS) benefit in patients with estrogen receptor (ER)–positive, HER2-negative metastatic breast cancer, particularly those who received prior treatment with a CDK4/6 inhibitor and endocrine therapy, according to data from the phase 1b/2 ELEVATE trial (NCT05563220).1

Findings from the phase 2 portion of the study, which were presented during the 2025 San Antonio Breast Cancer Symposium, showed that, at a median follow-up of 4.1 months (95% CI, 3.6-8.3), patients treated with elacestrant plus everolimus (n = 50) achieved a median PFS of 8.3 months (95% CI, 4.0-10.2). The disease control rate (DCR) was 89.2%, the overall response rate (ORR) was 19.5%, and the median duration of response (DOR) was 8.54 months.

At a median follow-up of 8.6 months (95% CI, 6.5-12.6), patients who received elacestrant plus abemaciclib (n = 60) had a median PFS of 14.3 months (95% CI, 7.3-16.6). The DCR was 91.2%, the ORR was 24.6%, and the median DOR was 14.75 months. This PFS benefit was consistent across all patient subgroups in both treatment arms.

“There were low rates of drug withdrawal or dose reduction and no new safety signals based on this analysis,” presenting author Hope S. Rugo, MD, the principal investigator of ASCENT-07, as well as chief of the Division of Breast Oncology and director of Women’s Cancer Program at City of Hope in Duarte, California, stated during the presentation. “[Based on these data], elacestrant has the potential to become one of the endocrine backbones for a combination strategy with the abemaciclib or everolimus [in ER-positive, HER2-negative disease], supporting an all-oral approach.”

What was the rationale for evaluating elacestrant in combination with other targeted agents for pretreated ER-positive/HER2-negative breast cancer?

In January 2023, the FDA approved elacestrant for the treatment of postmenopausal women or adult men with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least 1 line of endocrine therapy.2

“Resistance mechanisms in patients with hormone receptor–positive metastatic disease who have been treated with first-line endocrine therapy and CDK 4/6 inhibitors clearly impact the efficacy of subsequent therapy,” Rugo explained.1 “Elacestrant is the only oral selective estrogen receptor degrader that significantly improved PFS vs standard-of-care endocrine therapy in all patients with metastatic breast cancer.”

Accordingly, Rugo and colleagues designed the ELEVATE trial to evaluate the safety and efficacy of elacestrant in combination with multiple targeted agents to potentially improve outcomes with subsequent CDK 4/6 and PI3K inhibitors in patients experiencing treatment resistance.

What was the design of ELEVATE?

ELEVATE was an open-label, umbrella study enrolling pre- peri- or post-menopausal women or men with ER-positive, HER2-negative, advanced or metastatic breast cancer. Patients were required to have received 1 to 2 prior lines of endocrine therapy with or without CDK 4/6 inhibition; no prior exposure to chemotherapy in the advanced/metastatic setting; and 1 or more measurable lesion per RECIST 1.1 criteria or a mainly lytic bone lesion. Prior fulvestrant (Faslodex) and primary endocrine resistance were permitted. In phase 1b, eligible patients (n = 90) received 86 mg to 345 mg of elacestrant in combination with either: 150 mg to 250 mg of alpelisib (Piqray), 5 mg to 10 mg of everolimus, 100 mg to 125 mg of palbociclib (Ibrance), 400 to 600 mg of ribociclib (Kisqali), or 320 mg to 400 mg of capivasertib (Truqap). In the phase 1b ELECTRA portion, 258 mg to 345 mg of elacestrant was administered alongside 100 mg to 150 mg of abemaciclib.

After identification of the recommended phase 2 dose, patients proceeed to phase 2, where they received 345 mg of elacestrant daily in combination with: 7.5 mg of everolimus (n = 50), 150 mg of abemaciclib (n = 60), 400 mg of ribociclib (n = 30), or 320 mg of capivasertib (n = 60).

The primary end point in phase 2 was PFS per RECIST 1.1 criteria. Secondary end points included ORR, DOR, clinical benefit rate, PFS, overall survival, and safety.

What were the baseline characteristics of patients in the elacestrant/everolimus and elacestrant/abemaciclib arms?

The median age was 58 years (range, 30-83) in the elacestrant plus everolimus arm, and 61 years (range, 29-84) in the elacestrant plus abemaciclib arm. The majority of patients in both arms were assigned female at birth (100%; 95%), had an ECOG performance status of 0 (52%; 77%), and had visceral metastasis (72%; 92%), ESR1 mutations were present in 42% and 33% of patients in these respective arms; 50% and 27%, respectively, harbored PI3KCA mutations.

In the elacestrant plus everolimus arm, patients had received a median of 1 (range, 1-4) prior line of therapy, with most patients receiving 1 prior line of endocrine therapy (70%), followed by 2 lines (28%), and 3 or more lines (2%). All patients previously received a CDK 4/6 inhibitor, including ribociclib (50%), palbociclib (44%), or abemaciclib (22%). Half of patients had previously received fulvestrant.

In the elacestrant plus abemaciclib arm, patients had received a median of 1 (range, 0-3) prior line of therapy, with most patients receiving 1 prior line of endocrine therapy (78%), followed by 2 lines (17%), 0 lines (3%), and 3 or more lines (2%). Half of patients previously received a CDK 4/6 inhibitor, including palbociclib (32%), or ribociclib (20%). Thirty percent of patients had previously received fulvestrant.

What were the efficacy outcomes with each combination according to patient subgroup?

In the elacestrant plus everolimus arm, the median PFS was 7.7 months (95% CI, 3.7-9.4) in patients with visceral disease (n = 36),8.3 months (95% CI, 4.2-12.9) in those with no prior exposure to fulvestrant (n = 25), 8.3 months (95% CI, 4.0-12.9) for those with no primary endocrine resistance (n = 40). In patients with ESR1-mutant (n = 21) vs ESR1 wild-type disease (n = 27), the median PFS was 8.3 months (95% CI, 3.5-12.9) and 9.0 months (95% CI, 4.2-12.7), respectively. For patients with PIK3CA-mutant (n = 25) vs PIK3CA wild-type disease (n = 23), the median PFS was 8.3 months (95% CI, 3.6-10.2) vs 9.4 months (95% CI, 4.0-not reached [NR]).

In the elacestrant plus everolimus arm, the median PFS was 14.3 months (95% CI, 7.4-16.6) for patients with visceral disease (n = 55), 14.8 months (95% CI, 8.7-NR) for those with no prior fulvestrant exposure (n = 42), and 14.3 (95% CI, 7.3-16.6) in those with no primary endocrine resistance (n = 51).

What were the safety profiles of each elacestrant-based regimen?

Both elacestrant-based combinations displayed safety profiles consistent with that of either the inhibitor plus standard endocrinte therapy or elacestrant monotherapy. No bradycardia or photopsia were reported, and no new safety signals were observed across both arms.

In the elacestrant plus everolimus arm, any-grade treatment-emergent adverse effects (TEAEs) led to treatment withdrawal and reduction in 6% and 2% of patients. Any-grade TEAEs led to treatment reduction in 5% of patients treated with elacestrant plus abemaciclib; no patients in this arm withdrew from treatment.

The most common any-grade TEAEs in at least 20% of patients in either arm were diarrhea (elacestrant/everolimus, n = 23; elacestrant/abemaciclib, n = 50), nausea (n = 29; n = 41), fatigue (n = 22; n = 29), vomiting (n = 21; n = 28), stomatitis (n = 20; n = 0), hypercholesterolemia (n = 16; n = 0), anemia (n = 13; n = 23), neutropenia (n = 0; n = 21), abdominal pain (n = 15; n = 20), dysgeusia (n = 12; n = 0), decreased appetite (n = 0; n = 18), mucosal inflammation (n = 12; n = 0), increased aspartate aminotransferase levels (n = 10; n = 0), weight decrease (n = 0; n = 17), constipation (n = 0; n = 16), rash (n = 14; n = 16), dizziness (n = 0; n = 13), headache (n = 10; n = 12), thrombocytopenia (n = 10; n = 12), leukopenia (n = 0; n = 12), and hyperglycemia (n = 10; n = 0).
Disclosures: Rugo reported consulting or advisory roles for Napo, Bristol Myers Squibb, Helsinn and BioNTech; receiving institutional or research funding to her prior institution (UCSF) from Astra Zeneca, Ambryx, Daiichi Sankyo, Gilead Sciences, F. Hoffman-La Roche/AG/Genentech,Lilly, Merck, Novartis, Pfizer, and Stemline Therapeutics; and has received institutional research funding at her current institution from Bicycle Therapeutics,F. Hoffman-La Roche/AG/Genentech, and Stemline Therapeutics.

References

1. Rugo H, Tolaney S, Chan N, et al. Elacestrant in combination with everolimus or abemaciclib in patients with ER+/HER2- locally advanced or metastatic breast cancer (mBC): phase 2 results from ELEVATE, an open-label, umbrella study. Presented at: 2025 San Antonio Breast Conference Symposium; December 9-12, 2024; San Antonio, TX. Abstract RF7-01.
2. FDA approves elacestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. News release. FDA. January 27, 2023. Accessed December 11, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-elacestrant-er-positive-her2-negative-esr1-mutated-advanced-or-metastatic-breast-cancer