Elacestrant and Exemestane for Patients With Pretreated HR+/HER2- Metastatic Breast Cancer and [18F] FES-avid Lesions (COMBINE): a Proof-of-concept Phase 2 Clinical Trial

Single agent endocrine therapy (ET), with selective estrogen receptor degraders (SERDs; i.e. fulvestrant or elacestrant), is an option for patients with pre-treated hormone receptor-positive (HR+) breast cancer (BC) with indolent behaviour beyond the first line therapy with CDK4/6 inhibitors (CDK4/6i) + ET, in order to spare the adverse events related to chemotherapy.
Anyway, the efficacy of endocrine monotherapy in patients progressing on first line therapy is low, because of the occurrence of endocrine resistance mechanisms, like the HR loss and the switch to HR-negative subtype, caused by the selective pressure of first line therapy; furthermore, biomarkers for patient selection are missing.
Recently, the 16a-[18F]fluoro-17b-estradiol positron emission tomography ([18F]FES-PET) demonstrated a sensitivity and specificity of 86% in estrogen receptor expression prediction; therefore it is a promising tool to select patients progressing on CDK4/6i + ET without HR loss.
Single agent endocrine therapy (ET), with selective estrogen receptor degraders (SERDs; i.e. fulvestrant or elacestrant), is an option for patients with pre-treated hormone receptor-positive (HR+) breast cancer (BC) with indolent behaviour beyond the first line therapy with target cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i) + ET, in order to spare the adverse events related to chemotherapy.
Anyway, the efficacy of endocrine monotherapy in patients progressing on first line therapy is low, because of the occurrence of endocrine resistance mechanisms, like the Hormon Receptor (HR) loss and the switch to HR-negative subtype, caused by the selective pressure of first line therapy; furthermore, biomarkers for patient selection are missing.
Recently, the 16a-[18F] fluoro-17b-estradiol positron emission tomography ([18F] FES-PET) demonstrated a sensitivity and specificity of 86% in estrogen receptor expression prediction; therefore it is a promising tool to select patients progressing on CDK4/6i + ET without HR loss.
The combination of endocrine agent, namely fulvestrant 250 mg plus anastrozole 1 mg (an aromatase inhibitor), demonstrated to provide an overall survival benefit in patients with Hormon Receptor positive Breast Cancer only in first line setting but not in patients progressing to ET. However, meanwhile, fulvestrant 500 mg was demonstrated to be superior to fulvestrant 250 mg in 2nd line setting, and oral SERDs (e.g. Elacestrant, Camizestrant) were demonstrated to be superior in terms of Progression Free Survival to fulvestrant 500 mg in patients progressing on ET, in the subgroup of patients with estrogen receptor 1 gene (ESR1) mutations.
Hypothesis: there is a strong rationale to assess the safety and the activity of Elacestrant plus exemestane in patients with pre-treated HR+ and Human Epidermal Growth Factor Receptor 2 negative (HER2-) metastatic breast cancer and at least 50% of [18F]FES-avid measurable lesions, using [18F]FES PET/CT to evaluate the early response to treatment.

Start Date01 Apr 2026

Sponsor / Collaborator

Istituto Europeo di Oncologia Srl

NCT07198724

/ Not yet recruitingPhase 1/2IIT

ERADICATE: A Phase Ib/II Study of Elacestrant Plus Trastuzumab Deruxtecan in Patients With CDK4/6 Inhibitor and Endocrine-resistant HR+/HER2-low or HER2-ultralow Metastatic Breast Cancer

The goal of this study is to evaluate the safety and efficacy of elacestrant in combination with trastuzumab deruxtecan (T-DXd) in participants with hormone receptor-positive (HR+), HER2-low or HER2-ultralow, metastatic breast cancer that is resistant to prior CDK4/6 inhibitor and endocrine therapy.
The names of the study drugs involved in this study are:
* Elacestrant (a type of selective estrogen receptor degrader)
* Trastuzumab deruxtecan (a type of standard of care antibody drug conjugate)

Start Date01 Mar 2026

Sponsor / Collaborator

Dana-Farber Cancer Institute, Inc.

[+1]

NCT07242352

/ Not yet recruitingPhase 3IIT

Dynamic Marker - Adjusted Therapy Comparing Adjuvant Elacestrant With Standard Endocrine Treatment in Genomically and/or Clinically High-risk ER+/HER2- Early Breast Cancer (ADAPTela)

In this clinical trial, the Sponsor plans to investigate whether patients with HR+/HER2- eBC identified during routine clinical assessments and treatments as having intermediate to high-risk (based on Oncotype DX® or similar tests and on response assessment to 2-6 weeks of preoperative ET) achieve a survival benefit from an initial 5-years use of elacestrant (with or without a CDK 4/6 inhibitor) followed by SoC ET for further 0-2.5 years in comparison to at least 5 up to 7.5 years SoC ET therapy (+/- CDK4/6 inhibitor).
Based on several studies in the metastatic setting, it is reasonable to assume that the adjuvant use of elacestrant with or without CDK 4/6 inhibitors will prevent or delay the activation of mechanisms conferring resistance to ET (e.g., ESR1 mutations).

Start Date31 Jan 2026

Sponsor / Collaborator

Berlin-Chemie/Menarini Pharma GmbH

100 Clinical Results associated with Elacestrant hydrochloride

100 Translational Medicine associated with Elacestrant hydrochloride

100 Patents (Medical) associated with Elacestrant hydrochloride

104

Literatures (Medical) associated with Elacestrant hydrochloride

01 Mar 2026·BIOMEDICAL CHROMATOGRAPHY

Characterization of In Vitro Metabolic Profiles of Elacestrant in Rat and Human Liver Microsomes Using HPLC–MS/MS and HPLC–Q‐Orbitrap–HRMS

Article

Author: Chen, Yonggang ; Wang, Fang ; Liu, Wenxia ; Hu, Min ; Chen, Shangxiu

ABSTRACT:

Elacestrant is an orally administered selective estrogen receptor degrader designed for the treatment of ER‐positive, HER2‐negative breast cancer. In this study, a simple and sensitive HPLC–MS/MS method was developed and validated for the quantification of elacestrant in liver microsomes. Chromatographic separation was achieved on a Waters ACQUITY BEH C 18 column using a gradient of 0.1% formic acid in water and acetonitrile. Elacestrant and the internal standard (elacestrant‐d 6 ) were detected in multiple reaction monitoring mode via the transitions of m/z 459.2 → 298.3 and m/z 465.3 → 304.4, respectively. The method exhibited excellent linearity over the range of 1.0–2000 nM ( r > 0.995). Elacestrant was rapidly metabolized, showing half‐lives of 22.45 ± 0.66 min in rat liver microsomes and 43.36 ± 2.48 min in human liver microsomes. Using HPLC–Q‐Orbitrap–HRMS, seven metabolites were identified, with M5 ( N ‐deethylation) being the most abundant. Key metabolic pathways involved O ‐demethylation, N ‐deethylation, N ‐dealkylation, and oxidative deamination, primarily mediated by cytochrome P450 3A4. This study establishes the first HPLC–MS/MS and HPLC–Q‐Orbitrap–HRMS–based analytical strategy for in vitro metabolic profiling of elacestrant, supporting its future application in clinical pharmacokinetic and metabolism investigations.

02 Feb 2026·CANCER RESEARCH

ESR1 -Activating Mutations Confer Metabolic Vulnerabilities in ER+ Breast Cancer

Article

Author: Tani, Gabriele ; Gangarossa, Giulia ; Bonechi, Francesca ; Duatti, Assia ; Segatto, Ilenia ; Bacci, Marina ; Marangoni, Elisabetta ; Subbiani, Angela ; Sourd, Laura ; El Botty, Rania ; Lorito, Nicla ; Meattini, Icro ; Belletti, Barbara ; Comito, Giuseppina ; Smiriglia, Alfredo ; Romano, Elisabetta ; Cerbelli, Bruna ; Livi, Lorenzo ; Morandi, Andrea ; Fiorillo, Marco ; Botticelli, Andrea ; Pagliantini, Edoardo

Abstract:

Endocrine therapy (ET) is the standard of care for estrogen receptor (ER)–positive breast cancer. Point mutations in the ligand-binding domain of the gene encoding the estrogen receptor (ESR1) are rare in naïve ER+ breast cancer while becoming common in the ET-resistant setting. In this study, we found that ESR1 mutations expose breast cancers to critical vulnerabilities related to lipid metabolism. Particularly, ESR1 mutations that induce constitutive ER activation drove aberrant lipid biogenesis and lipid upload in parallel with increased expression of acyl-CoA synthetase long-chain family member 4 (ACSL4), which plays a crucial role in fatty acid activation and has been shown to correlate with increased ferroptosis susceptibility. Although ER+ breast cancer cells displayed ferroptosis resistance, the presence of ESR1 mutations rendered tumor cells sensitive to ferroptosis induction. Importantly, ferroptosis inducers potentiated the effects of the selective ER degraders fulvestrant and elacestrant, which are the standard of care for breast cancers carrying ESR1 mutations. These findings, validated both in preclinical models and in patient-derived material, identify a combinatory therapeutic approach in the setting of ET resistance and establish ACSL4 as an important biomarker to recognize ER+ breast cancers susceptible to ferroptosis induction.

Significance::

ESR1 mutations in breast cancer induce metabolic changes that trigger ferroptosis sensitivity, enabling ferroptosis inducers to enhance selective ER degraders' efficacy and positioning ACSL4 as a biomarker for guiding therapy in endocrine-resistant disease.

01 Feb 2026·GENES & DEVELOPMENT

Mutant p53 binds and controls estrogen receptor activity to drive endocrine resistance in ovarian cancer

Article

Author: Bitler, Benjamin G. ; Indeglia, Alexandra ; Modarai, Shirin R. ; Zhang, Nan ; Duong, Bryant ; Leung, Jessica ; Mes-Masson, Anne-Marie ; Foster, Maya ; Murphy, Maureen E. ; Casey, Kaitlyn ; Drapkin, Ronny ; Auslander, Noam ; Sims-Mourtada, Jennifer ; Shao, Chunlei ; Leu, Julia I-Ju

High-grade serous ovarian cancer (HGSOC) is a highly lethal gynecologic malignancy in women. Women diagnosed with HGSOC initially respond to chemotherapy, but there is a >80% rate of relapse. There is thus a significant unmet need for new therapeutic targets for HGSOC. Estrogen receptor α (ERα) is a particularly attractive candidate, as ∼70% of HGSOC tumors stain positively for ERα and there are approved inhibitors that show limited toxicity. However, unlike the case for breast cancer, endocrine therapy for HGSOC has not shown consistently promising results. In this work, we show that missense mutant forms of p53, which occur in >60% of HGSOC, bind and inhibit ERα function and confer resistance to fulvestrant and elacestrant. Mechanistically, we show that mutant p53 predominantly inhibits one arm of the ERα pathway—the transactivation of jointly regulated ERα–SP1 target genes such as the mTOR regulator DEPTOR . We show that silencing mutant p53 restores the ability of ERα to transactivate ERα–SP1 target genes and renders HGSOC markedly more sensitive to endocrine therapy. Consistent with this premise, we show that the p53 mutant Y220C refolding compound rezatapopt enhances fulvestrant response in a Y220C mutant cell line.

134

News (Medical) associated with Elacestrant hydrochloride

12 Dec 2025

·www.fiercepharma.com

Lilly shifts ambition for broader oral SERD label to largest oncology trial in company history

With target enrollment of 8,000 patients, the Ember-4 trial of Inluriyo in early-stage breast cancer will be Eli Lilly’s largest oncology trial in the company’s history, according to Jake Van Naarden, president of Lilly Oncology. Eli Lilly will not seek a broad FDA approval for a combination of the company’s oral SERD med Inluriyo and CDK4/6 inhibitor Verzenio despite seemingly promising phase 3 results.Instead, the Indianapolis pharma will only pursue a label for the combo covering patients with ER-positive, HER2-negative advanced breast cancer who carry ESR1 gene mutations, the same limited indication that Inluriyo monotherapy recently obtained from the FDA, Jake Van Naarden, president of Lilly Oncology, told Fierce Pharma.“I don’t think there’s a path to an [intent-to-treat] indication. It’s just not been where the conversation has been,” Van Naarden said in an interview with Fierce about Lilly’s interactions with the FDA, later adding that “we’re not going to fight with them on that.” The intent-to-treat description refers to all participants randomized in a clinical trial, rather than specific subgroups. The revelation comes as a disappointment, because, while Inluriyo itself previously failed to show a progression-free survival benefit against endocrine therapy in patients without ESR1 mutations in the company’s phase 3 Ember-3 trial, the Inluriyo-Verzenio combo yielded better results in that patient subgroup. For the Inluriyo-Verzenio combo, the trial assessed outcomes against Inluriyo monotherapy.When Inluriyo was initially cleared by the FDA in September, Lilly said it would share a more mature analysis of the combo with the FDA. The 2nd-line fightAn updated analysis from the Ember-3 trial shows the two-drug combo reduced the risk of progression or death by 41% compared with Inluriyo alone in a group of previously treated patients regardless of their ESR1 status, according to results presented at the 2025 San Antonio Breast Cancer Symposium (SABCS).Patients with and those without ESR1 mutations appeared to have benefited from the combo. The ESR1-mutant group logged a progression-free survival improvement of 51%, while the effect size was smaller, at 36%, in patients without the biomarker. None of those numbers bear statistical significance because the study had already met the statistical bar during the primary analysis, which recorded a 43% PFS benefit for the combo in all patients. But, while the combo’s performance in the ESR1 subgroup improved from 47% at the primary analysis, its results deteriorated from 41% in the nonmutant population. At the current second interim analysis with 14 months of additional follow-up from the first, the trial didn’t achieve a high prespecified threshold for significance on overall survival. At 33% data maturity, Inluriyo and Verzenio showed a favorable trend toward an 18% OS improvement in the overall population, with the duo’s advantage over single-agent Inluriyo starting to show after two years. No breakdown of OS data by patients' ESR1 status was offered.But, as Van Naarden hinted when commenting about common FDA practice, “when the effect size is enriched in a subpopulation that’s identifiable, that’s where the agency wants to go.” Lilly’s acknowledgement of defeat in an all-comers second-line population could hand rival Roche a win. But Van Naarden doesn’t think so.Similar to Ember-3’s combo arm, Roche’s evERA trial recently found that the Swiss pharma’s oral SERD candidate giredestrant, used alongside everolimus (Novartis’ Afinitor), significantly lowered the risk of progression or death by 44% versus everolimus alone in patients with second-line ER-positive, HER2-negative breast cancer. Based on the results, Roche is pushing for an all-comers label.But the regimen’s benefit similarly appeared to be mostly driven by the ESR1-mutant group, which logged a 62% PFS improvement. The ESR1 wild-type patients who received the Roche combo only saw a minor 16% difference on PFS, according to an exploratory analysis. An immature OS analysis produced a 21% trend in favor of the combo in the wild-type group, which Roche argued was clinically meaningful.“We’ve seen this exact movie before. It’s not going to end differently,” Van Naarden said, suggesting that Roche will end up with an ESR1-mutant label, too. He was referring to how Menarini’s first-in-class oral SERD, Orserdu, also only secured an ESR1-mutant label even though its pivotal study, Emerald, showed a benefit in an all-comers population. An exploratory analysis found a weak 14% advantage on PFS in patients without ESR1 mutations. The fight beyond 2nd lineWith these data, Van Naarden argued that the second-line setting is “done and dusted” for oral SERDs to be simply ESR1-mutant drugs.Meanwhile, Roche has a first-line trial, pionERA, which is pitting giredestrant against AstraZeneca’s injectable SERD Faslodex, both combined with a CDK4/6 inhibitor, in patients who developed resistance to prior endocrine therapy as adjuvant treatment for early-stage breast cancer.Van Naarden, calling the future outcome of that first-line study “a big unknown,” instead highlighted efforts in the adjuvant setting, which he said the entire oral SERD class was really meant for.There, Roche is currently one step ahead. At SABCS, the Swiss drugmaker reported that, in the phase 3 lidERA trial, giredestrant led to a 30% reduction in the risk of invasive disease recurrence or death versus endocrine therapy when used as an adjuvant therapy after surgery for early-stage breast cancer. RELATEDRoche links oral SERD to 30% breast cancer risk reduction in phase 3 adjuvant trialTo counter Roche’s offering, Lilly is running the Ember-4 trial, which is different from lidERA in that it’s being conducted in patients who have previously received two to five years of adjuvant endocrine therapy. More importantly, participants are allowed to have received a CDK4/6 inhibitor. With that design, Ember-4 is effectively testing Inluriyo in a post-CDK4/6 setting, as adjuvant Verzenio is given for up to two years alongside endocrine therapy, and Novartis’ Kisqali is dosed for three years.In lidERA, only a short course of up to 12 weeks of CDK4/6 inhibitor therapy prior to randomization is allowed.With target enrollment of 8,000 patients, Ember-4 will be Lilly’s largest oncology trial in the company’s history, according to Van Naarden. Following all the positive oral SERD readouts, Van Naarden said he now has increased confidence that the study will be successful.“I think that study will work, and I think it will be a lot more relevant clinically than the Roche study that is reading out now,” Van Naarden said. “In second line, I think the medicine can help people. But I think we can all agree that, if you have the opportunity to increase the cure fraction of an early-stage disease setting, that is more important than prolonging survival in a late-stage setting.”

Phase 3Clinical ResultASCO

11 Dec 2025

·www.prnewswire.com

The PHERGuide study demonstrates the utility of circulating tumor DNA for the early detection and real-time monitoring of localized HER2+ breast cancer

The results of the PHERGuide study, presented during the 2025 San Antonio Breast Cancer Symposium (SABCS), demonstrate that the presence of circulating tumor DNA (ctDNA) is associated with disease stage. This research paves the way for the use of blood-based ctDNA as a non-invasive tool to determine disease status in real-time and achieve greater treatment personalization. During the congress, the design of the PONTIAC study was also presented, which evaluates trastuzumab deruxtecan (T-DXd) as a possible new first-line treatment in HR+ and HER2-low/ultralow breast cancer with a non-luminal subtype. SAN ANTONIO, Dec. 11, 2025 /PRNewswire/ -- MEDSIR, a leading international company in oncology research, has announced the results of the PHERGuide study during the 2025 San Antonio Breast Cancer Symposium (SABCS). This research, presented as an oral session during the congress, corresponds to a translational analysis of the PHERGain study and evaluates the correlation between the presence of circulating tumor DNA (ctDNA) in the blood of the patients, with the response to treatment and the risk of recurrence in patients with HER2+ early breast cancer. Continue Reading Dr. Antonio Llombart-Cussac during the PHERGuide presentation at SABCS 2025 With more than 250 samples analyzed, the results show a direct association between the levels of ctDNA in blood at the start of the study and the stage of the disease. Furthermore, this study also reveals a significant correlation between ctDNA and the response to treatment. After two cycles of therapy, an elimination of ctDNA was observed in 75% of the patients; before surgery, these values reached a negativization of 83%. Consistently, the patients who presented elimination of ctDNA showed a higher probability of responding to the treatment. Notably, patients without ctDNA at the start of the study or who achieved its elimination before surgery, showed a notably more favorable prognosis, with a probability of developing invasive disease between four and five times lower during a follow-up period of three years. "This finding opens the way for us to the utilization of liquid biopsy as a non-invasive tool to know the status of the patients' disease," highlighted Dr. Antonio Llombart-Cussac, principal investigator of the study and Head of the Oncology Service at the Hospital Arnau de Villanova in Valencia, Spain. "In this way, by being able to know the status and response of the disease in real time, we could make more personalized and efficient treatment decisions for the patients," he added. Advances in breast cancer: PONTIAC and CEBBRAH MEDSIR's activity at SABCS 2025 has also included the presentation of the PONTIAC and CEBBRAH studies. PONTIAC is a Phase II trial evaluating the efficacy and safety of the use of trastuzumab deruxtecan (T-DXd) as a first-line treatment for patients with HR+/HER2-low/ultralow breast cancer and a non-luminal genomic subtype. This type of cancer is characterized by having lower sensitivity to hormonal therapy, which is the current standard of treatment for this subgroup of patients; therefore, their therapeutic options are limited. T-DXd is a next-generation therapy that combines two components into a single drug: trastuzumab, an antibody that specifically identifies the HER2 protein present on cancer cells, and deruxtecan, a potent chemotherapeutic drug. This design allows for a selective delivery of the chemotherapy payload into cancer cells, maximizing the anti-tumor effect and minimizing damage to healthy cells and, consequently, reducing side effects. "The design of the PONTIAC study is innovative and highly promising, as it offers a new targeted treatment option for patients with HR+ and HER2- breast cancer with a non-luminal subtype. The objective is to demonstrate whether this represents a more effective and less harmful treatment alternative", highlighted Dr. Javier Cortés, principal investigator of the study, Head of the International Breast Cancer Center in Madrid and Barcelona, Spain. During the congress, MEDSIR also presented the results of the CEBBRAH translational analysis, which evaluates for the first time the presence of ctDNA in both plasma and cerebrospinal fluid of patients with HER2+ breast cancer and leptomeningeal disease treated with T-DXd. The patients who, after receiving T-DXd, showed a reduction of ctDNA in the cerebrospinal fluid presented better control of the leptomeningeal disease, which supports its possible role as a biomarker of the disease. MEDiscussion: ctDNA and other new trends in breast cancer research Within the framework of the congress, MEDSIR held a meeting to debate and analyze the new trends in oncological research. The event featured presentations by three international leaders in oncology: Dr. Antonio Llombart-Cussac, Head of Service at Hospital Arnau de Villanova in Valencia; Dr. Javier Cortés, Director of the International Breast Cancer Center-Pangaea Oncology in Barcelona; and Dr. Naoto Ueno, Director of the University of Hawaii Cancer Center. The session was moderated by Dr. Giampaolo Bianchini, a leading specialist in breast oncology at the Clinical Oncology Department of the Ospedale San Raffaele in Milan, and included the participation of an expanded panel of prominent international oncologists in an open debate together with a specialized audience. Specifically, the debate addressed the relevance of implementing new molecular tools in the clinic, such as ctDNA, for the management of luminal HER2+ breast tumors, as well as the growing role of translational research in the advancement towards precision oncology that improves the patients' quality of life. The Phase III ADELA and TUXEDO-3 studies, also present at SABCS 2025 The company has also presented a poster in a highlighted session regarding a sub-analysis of its TUXEDO-3 study, a multicenter and international Phase II trial that has demonstrated the potential of the antibody-drug conjugate patritumab deruxtecan (HER3-DXd) in patients with brain metastases derived from HER2+ breast cancer [and] advanced non-small cell lung cancer, as well as in patients with leptomeningeal disease of any solid tumor. Now, this sub-analysis examines the efficacy of this drug in those patients with metastatic HER2-positive breast cancer who had already received another type of antibody-drug conjugate in previous lines of treatment. The results point towards a potential strategy of sequential antibody-drug conjugate treatment, by demonstrating the benefit of the use of HER3-DXd in these patients with a median overall survival of 8.1 months, as well as a median progression-free survival of 6.3 months evaluated for intracranial lesions, 11.3 months evaluated for extracranial lesions, and 6.3 months evaluated for combined lesions. Furthermore, the ADELA study, an international Phase III clinical trial, was also present at the SABCS 2025 congress. This study is evaluating a new treatment approach that combines elacestrant with everolimus in a broad group of patients with advanced ER+/HER2- breast cancer and mutations in the ESR1 gene. About MEDSIR Established in 2012, MEDSIR distinguishes itself by its close collaboration with strategic partners to drive innovation in oncological research. With headquarters in Spain and the United States, the company manages the comprehensive management of clinical trials, covering from the study design to its subsequent publication, counting on an extensive global network of experts and integrated technology to streamline the process. The company offers support for proof of concept and a strategic approach that allows research partners to benefit from the best of both worlds: industry clinical research and investigator-driven trials. With the objective of promoting independent research at a global level, MEDSIR has established a strategic alliance with Oncoclínicas, the leading oncological group in Brazil with outstanding research potential in South America. For more information: SOURCE MEDSIR 21% more press release views with Request a Demo

Clinical ResultPhase 2Phase 3ASCO

08 Dec 2025

·www.globenewswire.com

Menarini Group Presents Elacestrant (ORSERDU®) Phase 2 Combination Data in Patients with ER+, HER2- Metastatic Breast Cancer (mBC) at the 2025 San Antonio Breast Cancer Symposium

In addition, the expansive elacestrant clinical development program updates reinforce its potential as a backbone endocrine therapy in combination settings, as well as in both metastatic and early stage breast cancer. FLORENCE, Italy and NEW YORK, Dec. 08, 2025 (GLOBE NEWSWIRE) -- The Menarini Group (“Menarini”), a leading international pharmaceutical and diagnostics company, and Stemline Therapeutics, Inc. (“Stemline”), a wholly-owned subsidiary of the Menarini Group, focused on bringing transformational oncology treatments to cancer patients, will present updated meaningful median progression-free survival (mPFS) efficacy results from two combination regimens of the Phase 2 ELEVATE study in patients with estrogen receptor-positive (ER+), HER2-negative (HER2-) locally advanced or metastatic breast cancer (mBC). The ELEVATE study was designed to evaluate the safety and efficacy of oral-oral combination treatment options to overcome different resistance mechanisms observed in ER+/HER2- mBC with the goal of improving patient outcomes. These data will be presented at the 2025 San Antonio Breast Cancer Symposium (SABCS), December 9-12. “The encouraging progression-free survival data increase our confidence in the role elacestrant could play as an endocrine therapy backbone in the combination setting,” said Virginia Kaklamani, MD, DSc, Professor of Medicine in the Division of Hematology/Oncology at UT Health San Antonio, and Leader of the Breast Cancer Program at UT Health San Antonio MD Anderson Cancer Center. “The safety profile of elacestrant in combination with everolimus or abemaciclib is consistent with the known safety profiles of each drug. No new safety signals have been observed.” The ELEVATE data to be presented at SABCS demonstrate that elacestrant in combination with everolimus or with abemaciclib shows a consistent PFS benefit, irrespective of ESR1 mutation status in patients with ER+/HER2- mBC, who experience disease progression on endocrine therapy (ET), with or without prior exposure to CDK4/6 inhibitors. These updated results also show that the safety of the combinations are consistent with the known safety profiles of each targeted therapy plus standard of care endocrine therapy. Phase 2 mPFS in months (95% CI) in all patients and subgroups Patient Population Elacestrant 345 mg QD+ Everolimus 7.5mg QD(n=50)Elacestrant 345 mg QD+ Abemaciclib 150 mg BID(n=60)All patients 8.3 [4.0 – 10.2]14.3 [7.3-16.6]Visceral disease 7.7 [3.8 – 9.4]14.3 [7.4-16.6]No prior fulvestrant 8.3 [4.2 – 12.9]14.8 [8.7-NR]No primary endocrine resistance 8.3 [4.0-12.9]14.3 [7.3-16.6]ESR1mut 8.7 [3.5 – 12.9]*ESR1wt 9.0 [4.2 – 12.7]*PIK3CAmut 8.3 [3.6 - 10.2]*PIK3CAwt 9.6 [5.6 - NR]* *Maturity not reached for PFS (95% CI) for genomic subgroups (ESR1 / PIK3CA) in the elacestrant + abemaciclib cohort. “The extensive evidence for elacestrant spans the monotherapy setting in our pivotal EMERALD study, now backed by two recent real-world data publications1, 2, and in its growing potential in combination regimens, as highlighted by the data presented at SABCS,” said Elcin Barker Ergun, CEO of the Menarini Group. “We remain deeply committed to fully exploring elacestrant’s potential benefit across multiple ongoing trials in both early stage and metastatic breast cancer.” Additionally, other elacestrant updates will be presented at SABCS, investigating its potential across the spectrum of breast cancer: Presentation Title: 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 studyAbstract Number: 1255Presentation Date & Time: Thursday, December 11, 2025, 1:00 – 2:00 PM Location: Hemisfair1-2Presenting Author: Hope S. Rugo Presentation Title: Elacestrant alone or in combination with triptorelin in premenopausal women with ER+/HER2-early breast cancer: primary analysis from the phase 2 SOLTI-2104-PremiÈRe trialAbstract Number: 1123Presentation Date & Time: Friday, December 12, 2025, 7:30 – 7:33 AMLocation: 301 ABCPresenting Author: Mertixell Bellet Presentation Title: ELEGANT: Elacestrant Versus Standard Endocrine Therapy (ET) in Women and Men With Node-positive, Estrogen Receptor-positive (ER+), HER2-negative (HER2-), Early Breast Cancer (eBC) With High Risk of Recurrence in a Global, Multicenter, Randomized, Open-label Phase 3 Study.Abstract Number: 1276Presentation Date & Time: Thursday, December 11, 2025, 12:30 – 2:00 PMLocation: Henry B. Convention CenterPresenting Author: Aditya Bardia Presentation Title: The ADELA study: A Double-blind, Placebo-controlled, Randomized Phase 3 Trial of Elacestrant (ELA)+ Everolimus (EVE) Versus ELA + Placebo (PBO) in ER+/HER2-Advanced Breast Cancer (aBC) Patients with ESR1-mutated Tumors Progressing on Endocrine Therapy (ET) + CDK4/6iAbstract Number: 1141Presentation Date & Time: Wednesday, December 10, 2025, 12:30 – 2:00 PMLocation: Henry B. Convention CenterPresenting Author: Antonio Llombart-Cussac Presentation Title: ERADICATE: A phase Ib/II study of elacestrant plus trastuzumab deruxtecan in patients with CDK4/6 inhibitor and endocrine-resistant HR+/HER2-low or HER2-ultralow metastatic breast cancerAbstract Number: 2119Presentation Date & Time: Friday, December 12, 2025, 12:30 – 2:00 PMLocation: Henry B. Convention CenterPresenting Author: Sara L. Sammons Presentation Title: Hormonal receptor (HR)-positive HER2 negative breast cancer patients treated with preoperative Elacestrant and PULSAR adaptive radiotherapy: a phase II study (HELP Trial)Abstract Number: 1071Presentation Date & Time: Friday, December 12, 2025, 12:30 – 2:00 PMLocation: Henry B. Convention CenterPresenting Author: Luca Visani About The Elacestrant Clinical Development ProgramElacestrant is also being investigated in several company-sponsored clinical trials in metastatic breast cancer disease, alone or in combination with other therapies. ELEVATE (NCT05563220) is a phase 1b/2 clinical trial evaluating the safety and efficacy of elacestrant combined with alpelisib, everolimus, capivasertib, palbociclib, ribociclib or abemaciclib. ELECTRA (NCT05386108) is an open-label phase 1b/2, multicenter study evaluating elacestrant in combination with abemaciclib in patients with ER+, HER2- breast cancer. The phase 2 portion evaluates this treatment regimen in patients with brain metastases. ELCIN (NCT05596409) is a phase 2 trial evaluating the efficacy of elacestrant in patients with ER+, HER2- advanced/metastatic breast cancer who received one or two prior hormonal therapies and no prior CDK4/6 inhibitors in the metastatic setting. ADELA (NCT06382948) is a phase 3 randomized, double-blinded trial evaluating elacestrant in combination with everolimus in patients with ER+, HER2- mBC with ESR1-mut tumors. Elacestrant is also being evaluated in additional investigator-led trials, in trials conducted in collaboration with other companies, in metastatic breast cancer as well as in early disease. About ORSERDU (elacestrant)U.S. Indication: ORSERDU (elacestrant), 345 mg tablets, 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. Full prescribing information for the U.S. can be found at www.orserdu.com. Important Safety InformationWarning and Precautions Dyslipidemia: Hypercholesterolemia and hypertriglyceridemia occurred in patients taking ORSERDU at an incidence of 30% and 27%, respectively. The incidence of Grade 3 and 4 hypercholesterolemia and hypertriglyceridemia were 0.9% and 2.2%, respectively. Monitor lipid profile prior to starting and periodically while taking ORSERDU.Embryo-Fetal Toxicity: Based on findings in animals and its mechanism of action, ORSERDU can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ORSERDU and for 1 week after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ORSERDU and for 1 week after the final dose. Adverse Reactions Serious adverse reactions occurred in 12% of patients who received ORSERDU. Serious adverse reactions in >1% of patients who received ORSERDU were musculoskeletal pain (1.7%) and nausea (1.3%). Fatal adverse reactions occurred in 1.7% of patients who received ORSERDU, including cardiac arrest, septic shock, diverticulitis, and unknown cause (one patient each).The most common adverse reactions (>10%), including laboratory abnormalities, of ORSERDU were musculoskeletal pain (41%), nausea (35%), increased cholesterol (30%), increased AST (29%), increased triglycerides (27%), fatigue (26%), decreased hemoglobin (26%), vomiting (19%), increased ALT (17%), decreased sodium (16%), increased creatinine (16%), decreased appetite(15%), diarrhea(13%), headache (12%), constipation (12%), abdominal pain (11%), hot flush (11%), and dyspepsia (10%). Drug interactions Concomitant use with CYP3A4 Inducers and/or inhibitors: Avoid concomitant use of strong or moderate CYP3A4 inhibitors with ORSERDU. Avoid concomitant use of strong or moderate CYP3A4 inducers with ORSERDU. Use in specific populations Lactation: Advise lactating women to not breastfeed during treatment with ORSERDU and for 1 week after the last dose.Hepatic Impairment: Avoid use of ORSERDU in patients with severe hepatic impairment (Child-Pugh C). Reduce the dose of ORSERDU in patients with moderate hepatic impairment (Child-Pugh B).The safety and effectiveness of ORSERDU in pediatric patients have not been established. To report SUSPECTED ADVERSE REACTIONS, contact Stemline Therapeutics, Inc. at 1-877-332-7961 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. About The Menarini GroupThe Menarini Group is a leading international pharmaceutical and diagnostics company, with a turnover of $5 billion and over 17,000 employees. Menarini is focused on therapeutic areas with high unmet needs with products for cardiology, oncology, pneumology, gastroenterology, infectious diseases, diabetology, inflammation, and analgesia. With 18 production sites and 9 Research and Development centers, Menarini’s products are available in 140 countries worldwide. For further information, please visit www.menarini.com. About Stemline Therapeutics Inc.Stemline Therapeutics, Inc. (“Stemline”), a wholly-owned subsidiary of the Menarini Group, is a commercial-stage biopharmaceutical company focused on bringing transformational oncology treatments to patients. Stemline commercializes elacestrant, an oral endocrine therapy 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, in the U.S., Europe, and other global regions. Stemline also commercializes tagraxofusp-erzs, a novel targeted therapy directed to CD123, for patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive hematologic cancer, in the United States, Europe, and other global regions. In addition, Stemline commercializes selinexor, an XPO1 inhibitor for multiple myeloma, in Europe. The company is also conducting multiple label-expansion studies with elacestrant and tagraxofusp in breast and hematologic cancer indications, respectively, and has an extensive clinical pipeline of additional drug candidates in various stages of development for a host of solid and hematologic cancers. Media ContactsThe Menarini GroupValeria Speroni CardiEmail: pressoffice@menarini.com Stemline Therapeutics, Inc.Cheya PopeEmail: media@menarinistemline.com 1 Lloyd et al. Clinical and genomic factors associated with elacestrant outcomes in ESR1-mutant metastatic breast cancer. Clin Cancer Res (2025). https://aacrjournals-org.libproxy1.nus.edu.sg/clincancerres/article/doi/10.1158/1078-0432.CCR-25-3033/768341/Clinical-and-Genomic-Factors-Associated-with 2 Rugo et al. Real-World Outcomes of Elacestrant in ER+, HER2-, ESR1-mutant Metastatic Breast Cancer. Clin Cancer Res, 2025. CCR-25-3040R1. https://aacrjournals-org.libproxy1.nus.edu.sg/clincancerres/article/doi/10.1158/1078-0432.CCR-25-3040/768340/Real-World-Outcomes-of-Elacestrant-in-ER-HER2-ESR1

Phase 2Phase 3Clinical Result

100 Deals associated with Elacestrant hydrochloride

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KEGG	Wiki	ATC	Drug Bank
D11671	Elacestrant hydrochloride	-	DB06374

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Advanced breast cancer	United Kingdom	Stemline Therapeutics, Inc.	05 Jan 2024
Metastatic breast cancer	United Kingdom	Stemline Therapeutics, Inc.	05 Jan 2024
ER-positive/HER2-negative/ ESR1-mutated breast cancer	United States	Stemline Therapeutics, Inc.	27 Jan 2023

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Breast Cancer	NDA/BLA	United States	Radius Pharmaceuticals, Inc.	22 Jun 2022
Hormone receptor positive HER2 negative breast cancer	Phase 3	United States	Stemline Therapeutics, Inc.	24 Mar 2025
Hormone receptor positive HER2 negative breast cancer	Phase 3	Argentina	Stemline Therapeutics, Inc.	24 Mar 2025
Hormone receptor positive HER2 negative breast cancer	Phase 3	Australia	Stemline Therapeutics, Inc.	24 Mar 2025
Hormone receptor positive HER2 negative breast cancer	Phase 3	Austria	Stemline Therapeutics, Inc.	24 Mar 2025
Hormone receptor positive HER2 negative breast cancer	Phase 3	Belgium	Stemline Therapeutics, Inc.	24 Mar 2025
Hormone receptor positive HER2 negative breast cancer	Phase 3	Brazil	Stemline Therapeutics, Inc.	24 Mar 2025
Hormone receptor positive HER2 negative breast cancer	Phase 3	Canada	Stemline Therapeutics, Inc.	24 Mar 2025
Hormone receptor positive HER2 negative breast cancer	Phase 3	Czechia	Stemline Therapeutics, Inc.	24 Mar 2025
Hormone receptor positive HER2 negative breast cancer	Phase 3	Denmark	Stemline Therapeutics, Inc.	24 Mar 2025

Clinical Result

Indication

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Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT06492616 (ELEGANT, SABCS2025)	Phase 3	ER-positive/HER2-negative Breast Cancer ESR1-mut \| ER+ \| HER2-	4,220	Elacestrant	lcwbhzchfy(barepkkime) = igcthvirsv dbywrggxoa (lxxdgbjcia )	Positive	11 Dec 2025
NCT06382948 (ADELA, SABCS2025)	Phase 3	ESR1-mutated \| ER+/HER2-	240	Elacestrant + Everolimus	szdpzhysoj(wwmwhgtdwa) = wbisrmsktf hsmjufodle (iejqokbnxk )	Positive	10 Dec 2025
				Elacestrant + Placebo	irlfxrtdna(fvpamcmkyt) = efjjakvmpq jabmkadckr (kjgxnfvtjk )
SABCS2025	Not Applicable	Hormone receptor positive breast cancer PIK3CA \| ESR1	107	alpelisib+fulvestrant	dtgshawdgg(xrztvgcbqi) = One patient with alpelisib experienced treatment interruption and dose reduction due to skin toxicity, while Elacestrant was well-tolerated without major adverse effects. cgyzqbovmg (kakwfwqgtr )	Positive	10 Dec 2025
				capivasertib+fulvestrant
ESMO2025	Not Applicable	Advanced breast cancer HR+ \| HER2-	16	Camizestrant	-	Positive	17 Oct 2025
				Ribociclib plus ET
NCT05563220 (ELEVATE, ASCO2025)	Phase 1/2	ER-positive/HER2-negative Breast Cancer	-	Elacestrant + Ribociclib	quavbslnyy(qtrzceleqt) = 43% (7% ≥Gr3) with Ela + Eve xcqkazlkxq (gslmazxurx ) View more	-	30 May 2025
				Elacestrant + Everolimus
NCT06382948 (ADELA, ASCO2025)	Phase 3	ER-positive/HER2-negative/ ESR1-mutated breast cancer \| HER2-negative breast cancer \| Estrogen receptor positive breast cancer ... ESR1-mutated tumors View more	240	Elacestrant 345 mg + Everolimus 7.5 mg	zbdmthsrnd(hjqokhzxkv) = rtwccemaui qateypenco (zhxxfloalz ) View more	Positive	30 May 2025
NCT06492616 (ELEGANT, ASCO2025)	Phase 3	Node-positive breast cancer \| Estrogen receptor positive breast cancer Adjuvant Ki67	-	Elacestrant	vcnoywoabf(sqxaalcxbp) = kegwkkdhug oyblgwwrln (histthnyin )	Positive	30 May 2025
				Standard Endocrine Therapy (AI or tamoxifen)	vcnoywoabf(sqxaalcxbp) = mqrlrqyhwr oyblgwwrln (histthnyin )
NCT03778931 (EMERALD, ESMO_BC2025)	Phase 3	Metastatic breast cancer ESR1	966	elacestrant (ESR1 mutation testing by liquid biopsy using ddPCR)	vubertbjrd(kkpmwnaujg) = elrhagsrec vtzlhrysyc (hmuzvmgrql, 33.2% - 39.4) View more	Positive	14 May 2025
NCT05563220 \| NCT05386108 (ELEVATE, SABCS2024) Manual	Phase 1/2	ER-positive/HER2-negative Breast Cancer HER2 Negative	55	Elacestrant + Abemaciclib (all efficacy-evaluable)	vsiankwhju(utpgpodoob) = hhrnyvneoj tvilaqkbsc (rcrivfykbd )	Positive	10 Dec 2024
				Elacestrant + Abemaciclib (ESR1-mut population)	vsiankwhju(utpgpodoob) = axqxnadviq tvilaqkbsc (rcrivfykbd )
SABCS2024 Manual	Not Applicable	ER-positive/HER2-negative Breast Cancer HER2 Negative	212	Elacestrant	pfjwbkopwc(orshidvsgx) = pzrldlucuo jzabapguoh (mwyktqsyqv, 5.4 - NR)	Positive	10 Dec 2024
				Elacestrant (1-2 lines of prior ET)	pfjwbkopwc(orshidvsgx) = ubirydqcgb jzabapguoh (mwyktqsyqv, 4.9 - NR)

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