Impacting approximately 260,000 patients each year, breast cancer remains one of the most prevalent cancers diagnosed in women. With an estimated 40,000 deaths, it also is the leading cause of death among women.
More than 70% of diagnosed cancers can be classified as hormone receptor-positive breast cancer [2]
Hormone therapy remains the primary treatment option to delay the need for chemotherapy in patients diagnosed with estrogen receptor-positive (ER+) metastatic breast cancer, [3] with the current standard-of-care a combination of hormone therapy and cyclin-dependent kinase 4/6 inhibitors (CDK 4/6) inhibitors. [4] However, the fact that a majority of patients eventually develop resistance to available standards of care prompted the development of oral selective estrogen receptor degraders (SERDs). These novel agents have demonstrated improved bioavailability and effectiveness and could potentially meet an important unmet medical need: improving treatment outcomes and patients’ health related Quality of Life (hrQoL).
Several SERDs are currently in clinical development, including oral options being studied in both the metastatic and adjuvant settings for ER-positive breast cancer. Observing the efficacy of these novel agents in the treatment of advanced disease prompted researchers to investigate their use in earlier disease setting to reduce breast cancer recurrence.
For example, researchers are studying camizestrant (AZD9833; AstraZeneca) versus Standard of Care (SoC) endocrine therapy in patients with ER-positive/HER2-negative early breast cancer, who are at intermediate or high risk of disease recurrence. Other SERDs in development include giredestrant (GDC-9545; Genentech/Roche), palazestrant (OP-1250; Olema Pharmaceuticals) and imlunestrant (LY3484356; Eli Lilly and Company).
In January 2023, elacestrant (Orserdu®; Stemline Therapeutics, a Menarini Group Company) which has shown promise in early-phase clinical trials as well shows positive preliminary outcomes in ongoing studies,*[5][6] became the first oral SERD to be approved by the US Food and Drug Administration (FDA) for the treatment of postmenopausal women or adult men with ER+/HER2-, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least one line of Endocrine Therapy.
The approval of elacestrant was largely based on the outcome of the results of the international, multicenter, randomized, open-label, phase 3 EMERALD-study in postmenopausal women and in men with ER+/HER2-advanced or metastatic breast cancer to evaluate the efficacy and safety of elacestrant compared to the standard of care (SoC) options.
Efficacy and Safety
Updated preliminary efficacy and safety results from the Phase 1b/2 ELEVATE study in patients with estrogen receptor-positive (ER+), HER2-negative (HER2-) locally advanced or metastatic breast cancer (mBC) demonstrates favorable preliminary progression-free survival (PFS) when elacestrant is combined with ribociclib (Kisqali®; Novartis) and everolimus (Afinitor®; Novartis) reinforces the tolerability of elacestrant in combination with ribociclib, everolimus, alpelisib (Piqray®; Novartis), and capivasertib (Truqap®; AstraZeneca), and support elacestrant’s potential of elacestrant as an endocrine therapy backbone.
These preliminary conclusions from the ELEVATE study, which was designed to evaluate the safety and efficacy of oral-oral combination treatment options to overcome different resistance mechanisms observed in ER+/HER2- mBC and improve patient outcomes, will be presented during the annual meeting of the annual meeting of the American Society of Clinical Oncology, held May 30 through June 3, 2025 in Chicago, Illinois.
In addition, various other trial-in-progress updates from studies investigating elacestrant’s potential to become an endocrine therapy (ET) backbone across the spectrum of breast cancer will be presented.
Elevate study
The ELEVATE study is comprised of six treatment regimens evaluating elacestrant in combination with CDK4/6 inhibitors (palbociclib, abemaciclib and ribociclib) and with inhibitors of the PI3K/AKT/mTOR pathway (everolimus, alpelisib and capivasertib).
The study outcomes reported this year include updated efficacy data which demonstrate favorable preliminary progression-free survival (PFS) from the elacestrant plus ribociclib and the elacestrant plus everolimus cohorts (abstract 1070/49). These study results recommended phase 2 dose (RP2D) was determined to be elacestrant 345 mg plus ribociclib 400 mg. The RP2D of elacestrant 345 mg plus everolimus 7.5 mg was previously reported.
“It is encouraging to see the positive preliminary efficacy and safety results when everolimus and ribocilib, respectively, are combined with elacestrant. These findings are consistent with the promising elacestrant plus abemaciclib cohort data from the same study that was presented last December, which also demonstrated favorable preliminary efficacy and safety in this setting,” noted Hope S. Rugo, MD, Director, Women’s Cancers Program and Division Chief, Breast Medical Oncology, City of Hope Comprehensive Cancer Center.
Endocrine therapy backbone
“As the progression-free survival data and safety data continue to mature across the various cohorts of the ELEVATE study, we are encouraged by elacestrant’s potential to become an endocrine therapy backbone in combination regimens for the treatment of metastatic breast cancer,” Rugo added.
Additional data reported separately provided updated Phase 1b/2 safety results from four cohorts of the ELEVATE study, including elacestrant plus ribociclib, everolimus, alpelisib, and capivasertib. These updated preliminary results show that the combinations are consistent with the known safety profiles of each targeted therapy plus standard of care endocrine therapy (abstract 1079/58).
“These data continue to underscore the potential value of elacestrant as a combination partner in the ER+/HER2- metastatic breast cancer treatment landscape,” noted Elcin Barker Ergun, CEO of the Menarini Group.
“We are also exploring the potential of elacestrant in other patient populations, including our currently enrolling ELEGANT study, which is designed to assess its potential benefit in early breast cancer patients with high risk of recurrence,” Ergun concluded.
Presentations
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Note: * In the United States, elacestrant, 345 mg tablets, has been approved and is indicated for the treatment of postmenopausal women or adult men with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy.
Clinical Trials
Open-Label Umbrella Study To Evaluate Safety And Efficacy Of Elacestrant In Various Combination In Patients With Metastatic Breast Cancer (ELEVATE) – ClinicalTrials.gov ID NCT05563220
Study of Abemaciclib and Elacestrant in Patients With Brain Metastasis Due to ER+/HER-2- Breast Cancer (ELECTRA) – ClinicalTrials.gov ID NCT05386108
ELACESTRANT in Women and Men With CDK4/6 Inhibitor-Naive Estrogen Receptor Positive, HER-2 Negative Metastatic Breast Cancer Study (ELCIN) – ClinicalTrials.gov ID NCT05596409
Elacestrant + Everolimus in Patients ER+/HER2-, ESR1mut, Advanced Breast Cancer Progressing to ET and CDK4/6i. (ADELA) – ClinicalTrials.gov ID NCT06382948
Phase 3 Trial of Elacestrant vs. Standard of Care for the Treatment of Patients With ER+/HER2- Advanced Breast Cancer (EMERALD) – ClinicalTrials.gov ID NCT03778931
An Adjuvant Endocrine-based Therapy Study of Camizestrant (AZD9833) in ER+/HER2- Early Breast Cancer (CAMBRIA-2) (CAMBRIA-2) – ClinicalTrials.gov ID NCT05952557
A Study of Camizestrant in ER+/HER2- Early Breast Cancer After at Least 2 Years of Standard Adjuvant Endocrine Therapy (CAMBRIA-1) – ClinicalTrials.gov ID NCT05774951
Highlights of prescribing information
Elacestrant (Orserdu®; Stemline Therapeutics, Inc., a Menarini Group Company)[Prescribing Information]
Ribociclib (Kisqali®; Novartis)[Prescribing Information]
Everolimus (Afinitor®; Novartis)[Prescribing Information]
Alpelisib (Piqray®; Novartis)[Prescribing Information]
Capivasertib (Truqap®; AstraZeneca)[Prescribing Information]
References
[1] Shah N, Mohammad AS, Saralkar P, Sprowls SA, Vickers SD, John D, Tallman RM, Lucke-Wold BP, Jarrell KE, Pinti M, Nolan RL, Lockman PR. Investigational chemotherapy and novel pharmacokinetic mechanisms for the treatment of breast cancer brain metastases. Pharmacol Res. 2018 Jun;132:47-68. doi: 10.1016/j.phrs.2018.03.021. Epub 2018 Mar 28. PMID: 29604436; PMCID: PMC5997530.
[2] Lim E, Metzger-Filho O, Winer EP. The natural history of hormone receptor-positive breast cancer. Oncology (Williston Park). 2012 Aug;26(8):688-94, 696. PMID: 22957400.
[3] Elayoubi J, Chi J, Mahmoud AA, Alloghbi A, Assad H, Shekhar M, Simon MS. A Review of Endocrine Therapy in Early-stage Breast Cancer: The Journey From Crudeness to Precision. Am J Clin Oncol. 2023 May 1;46(5):225-230. doi: 10.1097/COC.0000000000000993. Epub 2023 Mar 1. PMID: 36856249.
[4] Al-Qasem AJ, Alves CL, Ditzel HJ. Resistance Mechanisms to Combined CDK4/6 Inhibitors and Endocrine Therapy in ER+/HER2- Advanced Breast Cancer: Biomarkers and Potential Novel Treatment Strategies. Cancers (Basel). 2021 Oct 27;13(21):5397. doi: 10.3390/cancers13215397. PMID: 34771560; PMCID: PMC8582464.
[5] Sanchez KG, Nangia JR, Schiff R, Rimawi MF. Elacestrant and the Promise of Oral SERDs. J Clin Oncol. 2022 Oct 1;40(28):3227-3229. doi: 10.1200/JCO.22.00841. Epub 2022 Jun 23. PMID: 35737918.
[6] Sarfraz A, Sarfraz M, Javad F, Khalid M, Shah B, Gul A, Ganiyani MA, Ismail A, Cheema K. Elacestrant in hormone receptor-positive metastatic breast cancer: a post-hoc analysis. Explor Target Antitumor Ther. 2025 Feb 20;6:1002293. doi: 10.37349/etat.2025.1002293. PMID: 39991467; PMCID: PMC11847623.
Featured image: Encouraging mother with breast cancer. Photo courtesy: © 2018-2020 Fotolia/Adobe. used with permission.
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