Elacestrant Regimens Show Activity in Pretreated ER+/HER2– Breast Cancer

“Elacestrant has the potential to become an endocrine therapy backbone for multiple targeted agents in patients with ER-positive/HER2-negative metastatic breast cancer due to its ability to extend PFS, provide an all-oral treatment option, and delay chemotherapy or antibody-drug conjugate–based regimens,” according to the study authors.

Efficacy and safety were reported in patients with estrogen receptor (ER)–positive, HER2-negative breast cancer previously managed with CDK4/6 inhibition plus endocrine therapy following treatment with elacestrant (Orserdu) plus everolimus (Afinitor) or ribociclib (Kisqali), according to findings from the phase 1b/2 ELEVATE trial (NCT05563220) presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.¹

Findings from the phase 1b portion of the study presented at the 2025 ASCO Annual Meeting showed that at a median follow-up of 5.5 months, patients treated with elacestrant plus everolimus (n = 23) experienced a median progression-free survival (PFS) of 8.3 months (95% CI, 3.9-not reached [NR]). At a median follow-up of 4.8 months, those administered elacestrant plus ribociclib (n = 33) experienced a median PFS of 7.8 months (95% CI, 5.6-NR).

Safety data for elacestrant were consistent with the known toxicity profiles of everolimus and ribociclib combined with endocrine therapy; no new safety signals were reported. Phase 1b investigations of the combination of elacestrant plus alpelisib (Piqray) and elacestrant plus capivasertib (Truqap) are ongoing.

“Elacestrant has the potential to become an endocrine therapy backbone for multiple targeted agents in patients with ER-positive/HER2-negative metastatic breast cancer due to its ability to extend PFS, provide an all-oral treatment option, and delay chemotherapy or antibody-drug conjugate–based regimens,” lead study author Hope S. Rugo, MD, and colleagues, wrote in a poster presentation of the data.

Rugo is a professor in the Department of Medical Oncology & Therapeutics Research, division chief of Breast Medical Oncology, and director of the Women's Cancers Program at City of Hope in Duarte, California.

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

ELEVATE Background

The ongoing study is enrolling patients at least 18 years of age with histopathologically or cytologically confirmed ER-positive/HER2-negative advanced breast cancer.¹ Female patients are allowed to enroll irrespective of menopausal status. At least 1 measurable lesion per RECIST 1.1 criteria or a mainly lytic bone lesion is required for enrollment, as is an ECOG performance status of 0 to 1.

One to 2 prior lines of endocrine therapy were required, including 1 with a CDK4/6 inhibitor such as palbociclib (Ibrance), ribociclib, or abemaciclib (Verzenio). Notably, patients enrolling to receive elacestrant plus alpelisib need to harbor PIK3CA mutations per local testing; and those receiving elacestrant plus capivasertib need to have a PIK3CA, AKT1, or PTEN alteration per local testing. For the latter group, 1 to 2 prior hormonal therapies in the advanced setting, or radiological evidence of breast cancer recurrence or progression within 12 months of the completion of adjuvant endocrine therapy, were required. In phase 1b, patients in the capivasertib arm are allowed to have prior exposure to a CDK4/6 inhibitor; however, in phase 2, no prior CDK4/6 inhibition will be permitted.

Investigators are excluding patients with active or newly diagnosed central nervous system metastases, including meningeal carcinomatosis; advanced, symptomatic visceral spread with risk of life-threatening complications in the short term; prior chemotherapy in the advanced or metastatic setting; or prior treatment with elacestrant or other investigational compounds in the advanced or metastatic setting. Notably, prior fulvestrant (Faslodex) is permitted.

Arm-specific exclusion criteria comprise type 1 diabetes or uncontrolled type 2 diabetes (alpelisib arm); a QTcF of at least 450 msec, significant risk of developing QTc prolongation, and treatment with drugs known to prolong QT interval within 14 days or 5 half-lives of first study treatment (ribociclib arm); and clinically significant abnormalities of glucose metabolism (capivasertib arm).

Phase 1b is evaluating 258 mg or 345 mg of elacestrant in combination with various doses of alpelisib, everolimus, palbociclib, ribociclib, and capivasertib. The recommended phase 2 dose (RP2D) of each combination will be evaluated in the next portion of the trial. Notably, the RP2Ds for the 2 combinations presented at ASCO are 345 mg of elacestrant plus 7.5 mg of everolimus once per day; and 345 mg of elacestrant plus 400 mg of ribociclib once per day.

Determining the RP2D of the combinations is the primary end point of phase 1b. PFS will be the primary end point in phase 2, along with other secondary efficacy and safety end points.

Among patients treated in phase 1b, the median age was 64 years (range, 38-76) in the everolimus arm and 66 years (range, 45-85) in the ribociclib arm. All patients in both arms were female; the majority had an ECOG performance status of 0 (everolimus arm, 65%; ribociclib arm, 73%), had visceral metastases (61%; 67%), did not harbor ESR1 mutations (57%; 61%), and did not have PIK3CA mutations (74%; 70%).

All patients received a prior CDK4/6 inhibitor. Primary endocrine resistance was reported in 17% of patients in the everolimus arm vs 9% of those in the ribociclib arm. The median number of prior lines of therapy was 2 (range, 1-3) and 1 (range, 1-2), respectively. In the everolimus arm, 4% of patients received no prior lines of therapy in the advanced setting, 61% received 1 prior line, and 35% had 2 prior lines. These respective rates were 0%, 79%, and 21% in the ribociclib arm. Forty-eight percent and 55% of patients received prior fulvestrant in the everolimus and ribociclib arms, respectively.

Efficacy and Safety Further Defined

The overall response rate was 25% for the everolimus arm (n = 16) and 10% for the ribociclib arm (n = 31). In the everolimus arm, the partial response, stable disease, and progressive disease rates were 25%, 44%, and 31%, respectively. These respective rates were 10%, 71%, and 19% in the ribociclib arm. The clinical benefit rates were 69% for elacestrant plus everolimus and 81% for elacestrant plus ribociclib.

In patients treated at the RP2D of elacestrant plus everolimus (n = 7), the most common any-grade treatment-emergent adverse effects (TEAEs) included fatigue (57%), diarrhea (43%), nausea (43%), vomiting (43%), dysgeusia (43%), decreased appetite (43%), stomatitis (29%), neutropenia (29%), insomnia (29%), and extremity pain (29%). Grade 3/4 stomatitis and neutropenia each occurred at rates of 14%. At the RP2D of elacestrant plus ribociclib (n = 8), the most common any-grade TEAEs included neutropenia (38%), nausea (25%), fatigue (25%), upper respiratory tract infection (25%), and decreased white blood cell count (25%). Grade 3/4 neutropenia was reported in 25% of patients, and 13% had grade 3/4 decreased white blood cell count.

The ongoing phase 2 portion of the study is currently evaluating elacestrant at 345 mg per day in combination with everolimus at 7.5 mg per day (arm B); in combination with ribociclib at 400 mg per day (arm C); and in combination with abemaciclib at 150 mg twice per day (arms C and D).

“Phase 1b combinations for alpelisib and capivasertib are ongoing,” the authors wrote.

References

1. Rugo HS, Tolaney S, Chan N, et al. Elacestrant (Ela) combinations with ribociclib (Ribo) and everolimus (Eve) in patients (pts) with ER+/HER2- locally advanced or metastatic breast cancer (mBC): Update from ELEVATE, a phase (Ph) 1b/2, open-label, umbrella study. J Clin Oncol. 2025;43(suppl 16):1070. doi:10.1200/JCO.2025.43.16_suppl.1070
2. FDA approves elacestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. News release. FDA. January 27, 2023. Accessed June 6, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-elacestrant-er-positive-her2-negative-esr1-mutated-advanced-or-metastatic-breast-cancer