Hormonal Receptor (HR)-Positive HER2 Negative Breast Cancer Patients Treated With Preoperative ELacestrant and PULSAR Adaptive Radiotherapy: a Phase II Study (HELP Trial)

This is a proof-of-concept phase II trial to assess the safety (as primary endpoint) and clinical efficacy of neoadjuvant therapy with Elacestrant and PULSAR.
The study will enroll 21 postmenopausal patients with early HR+ HER2- node positive BC, clinically staged II-III. Patients will receive Elacestrant 345 mg orally once daily for 24 weeks and PULSAR on the MRI-based breast gross tumor volume (GTVt), consisting of 10 Gy "pulse" every 4 weeks for a maximum of 5 or less in case of radiologic complete response.
Surgery will be planned 24 weeks after Elacestrant initiation and at least 2 weeks from the last pulse and will be performed as per recommended clinical practice. Patients will then receive adjuvant systemic therapy as per standard of care and postoperative RT to the locoregional lymph nodes in case of nodal residual disease, if indicated.

Start Date01 Sep 2025

Sponsor / Collaborator

Azienda Ospedaliero-Universitaria Careggi

NCT06923527

/ Not yet recruitingPhase 2IIT

A Single Arm Phase II Trial of Circulating Tumor DNA-guided Adjuvant Therapy With Elacestrant in Hormone Receptor Positive HER2 Negative Breast Cancers at Risk for Late Recurrence (CATE)

This is a single-arm, phase II study examining elacestrant in the adjuvant treatment of patients with ER+ breast cancer who test positive for circulating tumor DNA (ctDNA) during the screening period of the trial.

Start Date01 Jun 2025

Sponsor / Collaborator

Yale University

[+2]

NCT06201234

/ RecruitingPhase 2

Phase II Study Evaluating the Addition of Elacestrant, an Oral Selective Estrogen Receptor Degrader (SERD), to Standard-of-care Olaparib in Patients with Hormone Receptor (HR)-positive, HER2-negative Locally Advanced or Metastatic Breast Cancer with GBRCA1/2 Mutations

Trial design:
Phase II, prospective, multi-center, randomized, open label, parallel group study in patients with HR-positive, HER2-negative locally advanced or metastatic breast cancer with gBRCA1/2 mutation, with 2:1 randomization into Arm A (olaparib + elacestrant) or arm B (olaparib). Treatment in either arm will be given until disease progression, unacceptable toxicity, withdrawal of patient´s consent to study participation, or end of study.
Trial population:
Patients with HR-positive, HER2-negative locally advanced or metastatic breast cancer with gBRCA1/2 mutation, with an indication for standard-of-care PARP inhibitor therapy and planned treatment with olaparib, an ECOG performance status of 0-2 and life expectancy of > 6 months, with normal bone marrow and kidney functions and no active or newly diagnosed central nervous system (CNS) metastases or symptomatic metastatic visceral disease at risk of life-threatening complications.
Interventions:
Patients randomized to Arm A will receive 600 mg olaparib daily and 400 mg elacestrant daily, while patients randomized to Arm B will receive 600 mg olaparib daily. Blood tests (hematology, biochemistry) will be performed at the beginning of every cycle, and imaging for tumor assessment (chest and abdominopelvic imaging) as well as QoL assessments will be performed every three months and in case of suspicion of progression/end of study.

Start Date13 Dec 2024

Sponsor / Collaborator

GBG Forschungs GmbH

[+1]

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 May 2025·Molecular Diagnosis & Therapy

Clinical Actionability of Molecular Targets in Multi-Ethnic Breast Cancer Patients: A Retrospective Single-Institutional Study

Article

Author: Naghi, Leah ; Mortimer, Joanne ; Yost, Susan E ; Kang, Irene

BACKGROUND:

Precision oncology is making remarkable advancements in optimizing patient care by personalizing treatments. To date, the US Food and Drug Administration (FDA) has approved poly(ADP-ribose) polymerase inhibitors (PARPi) olaparib (Lynparza, AstraZeneca and Merck) and talazoparib (Talzenna, Pfizer Oncology Together™) for germline or somatic BRCA1/2-mutated metastatic breast cancer (BC) patients, and PI3K inhibitor alpelisib (Piqray, Novartis) plus fulvestrant for patients with hormone receptor-positive human epidermal growth factor receptor 2-negative (HR+HER2-) PIK3CA-mutated advanced BC. In addition, the FDA approved capivasertib (Trucap, AstraZeneca) for HR+HER2- locally advanced or metastatic BC patients with one or more AKT1, PIK3CA, or PTEN alterations. Finally, the FDA recently approved elacestrant (Orserdu, Stemline Therapeutics, Inc.) for postmenopausal patients with ER+ HER2- ESR1-mutated advanced or metastatic BC with disease progression following at least one line of endocrine therapy.

METHODS:

This study presents a single institutional retrospective review of genomic reports of patients with BC. Analysis of genomic reports of 1361 BC sequencing reports was performed for 1010 patients with BC from 2013 to 2023 (23% of patients had multiple reports). Eligible patients had at least one primary or metastatic tumor. Multiple sequencing platforms were used for FFPE specimens including Tempus xT targeted next-generation sequencing (NGS), Foundation One Medicine, HopeSeq, Ashion Analytics GEM ExTra, and Exact Sciences Oncomap. Liquid biopsies were performed by Guardant, Tempus, and Foundation One Medicine. Chart reviews were performed to collect patient characteristics. BRCA1/2-mutated, metastatic BC patients who initiated treatment with olaparib or talazoparib, and PIK3CA-mutated, HR+ metastatic BC patients who initiated treatment with alpelisib were reported. In addition, patients with ESR1 or AKT1/PIK3CA/PTEN mutations were identified. Clinical outcomes, including progression-free survival (PFS) and overall survival (OS) were analyzed for BRCA1/2 and PIK3CA-mutated patients who received PARPi or alpelisib. Survival curves were generated using the Kaplan Meier method.

RESULTS:

A cohort of 1010 BC patients with 1361 genomic reports was identified. A total of 935/1361 (69%) specimens were formalin-fixed paraffin-embedded (FFPE) tumor biopsies and 426/1361 (31%) were liquid biopsies. Receptor status included 65% HR+HER2-, 8% HR+HER2+, 4% HR-HER2+, and 23% TNBC. Racial and ethnic distribution of these patients included 50% non-Hispanic White, 26% Hispanic, 17% Asian, 6% African American, 1% other (Native Hawaiian or Other Pacific Islander, American Indian or Alaska Native, or unknown). Sequencing platforms included 30% Tempus xT, 31% Foundation One, 10% HopeSeq, 20% GEM ExTra, and 9% Exact Sciences. Liquid biopsies included 79% Guardant, 20% Tempus, and 1% Foundation One. Of 1010 patients, the most common mutations were TP53 (44%), PIK3CA (38%), ESR1 (14%), PTEN (12%), CCND1 (11%), FGFR1 (10%), CDH1 (10%), ERBB2 (9%), MYC (9%), FGF3 (8%), GATA3 (8%), FGF19 (8%), FGF4 (7%), ARID1A (6%), RB1 (5%), BRCA2 (5%), MAP3K1 (4%), AKT1 (4%), NF1 (4%), MLL3 (4%), ZNF703 (4%), CDKN2A (4%), BRCA1 (4%), MCL1 (3%), ATM (3%), PALB2 (1%), and CHEK2 (1%). The majority of reports with tumor mutation burden (TMB) results (97%) had low or intermediate TMB. A total of 784 actionable mutations in 1010 patients were reported, including 381/1010 (38%) PIK3CA; 144/1010 (14%) ESR1; 122/1010 (12%) PTEN; 48/1010 (5%) BRCA2; 36/1010 (4%) BRCA1; 41/1010 (4%) AKT1; and 12/1010 (1%) PALB2. Of the 96/1010 (10%) patients with BRCA1, BRCA2, or PALB2 mutations not including variants of uncertain significance (VUS), 33/96 (34.4%) received olaparib and 3/96 (3%) received talazoparib in the metastatic setting, and 28 were eligible for response (one had toxicity, two were lost to follow-up, and two went to hospice). Median PFS was 9.0 months and median OS was 21.8 months for patients receiving PARPi. Of the 381/1010 (38%) patients with PIK3CA mutations, 84/381 (22%) received alpelisib and 41 were eligible for response (22 had toxicity, 13 were discontinued, six were lost to follow-up, and two went to hospice). Median PFS was 7.9 months and median OS was 31.2 months for patients receiving alpelisib. A total of 544/1010 (54%) patients had AKT1, PIK3CA, or PTEN mutations which are now FDA approved for capivasertib in HR+HER2- metastatic BC patients. In addition, 144/1010 (14%) patients had ESR1 mutations which are FDA approved for elacestrant in HR+HER2- metastatic BC patients.

CONCLUSIONS:

In this study, a total of 784 clinically actionable mutations were reported for 1010 patients with genomic sequencing. Of these, 96/1010 (10%) patients had at least one actionable mutation in homologous recombination repair genes (BRCA1, BRCA2, PALB2) and 36/96 (37.5%) patients received PARP inhibitors (33 olaparib and three talazoparib). In addition, 381/1010 (38%) patients had at least one clinically actionable PIK3CA mutation, and 84/381 (22%) received alpelisib. Additionally, 544/1010 (54%) of patients had either AKT1 (41/1010), PIK3CA (381/1010), or PTEN (122/1010) alterations that were FDA approved in November 2023 for capivasertib in the treatment of HR+HER2- metastatic BC (MBC) patients. Furthermore, 144/1010 (14%) patients in this study had at least one ESR1 mutation, a clinically actionable mutation that was FDA approved in January 2023 for elacestrant in the treatment of ER+HER2- MBC patients (44% detected by liquid biopsy). Future studies are needed to determine the efficacy of elacestrant and capivasertib for patients with these mutations, and to tailor strategies for optimal patient quality of life and cancer outcome.

01 Apr 2025·CANCER TREATMENT REVIEWS

Post-progression treatment options after CDK4/6 inhibitors in hormone receptor-positive, HER2-negative metastatic breast cancer

Review

Author: Sahin, Taha Koray ; Aksoy, Sercan ; Guven, Deniz Can ; Rizzo, Alessandro

The combination of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) and endocrine therapy (ET) is the standard first-line treatment for hormone receptor-positive (HR + ) and HER2-negative metastatic breast cancer (mBC). Despite their efficacy, resistance inevitably develops, necessitating alternative therapeutic strategies post-progression. This review explores current and emerging treatment options following progression on CDK4/6i, focusing on endocrine therapies, targeted therapies, combination approaches, and the continued use of CDK4/6i. Endocrine therapies, including fulvestrant and novel oral selective estrogen receptor degraders (SERDs) like elacestrant, show promise, especially in patients with ESR1 mutations. Targeted therapies such as PI3K/AKT/mTOR inhibitors, exemplified by alpelisib and capivasertib, offer potential by addressing downstream signaling pathways involved in resistance. Additionally, FGFR inhibitors like erdafitinib are under investigation for their role in overcoming specific resistance mechanisms. Combination strategies involving CDK4/6 inhibitors with immune checkpoint inhibitors or other targeted agents are also being explored, with early trials suggesting possible synergistic effects, although further validation is required. Continuation of CDK4/6 inhibitors beyond progression has shown potential benefits in selected patients, but the data are heterogeneous, and further studies are needed to clarify their role. While chemotherapy remains a standard option for patients who progress on these treatments, the goal is to delay its use through the effective utilization of endocrine and targeted therapies. Understanding resistance mechanisms and tailoring treatment to individual patient profiles is crucial for optimizing outcomes. Ongoing clinical trials are expected to provide deeper insights, guiding the development of more effective post-progression therapeutic strategies. This evolving landscape highlights the need for continuous research and individualized patient care to improve survival and quality of life in HR + mBC patients.

01 Apr 2025·CLINICAL CANCER RESEARCH

Elacestrant in Women with Estrogen Receptor–Positive and HER2-Negative Early Breast Cancer: Results from the Preoperative Window-of-Opportunity ELIPSE Trial

Article

Author: Bellet, Meritxell ; Cortadellas, Tomás ; Gonzalez-Farré, Xavier ; Falato, Claudette ; Muñoz-Mateu, Montserrat ; Siso, Christian ; Amillano, Kepa ; Pascual, Tomás ; Bergamino, Milana A. ; Luna, Miguel A. ; Espinosa Guerrero, Alejandra ; Salvador, Fernando ; Cebrecos, Isaac ; Galván, Patricia ; Ferrero-Cafiero, Juan M. ; Sanfeliu, Esther ; Prat, Aleix ; Margelí Vila, Mireia ; Vidal, Maria ; Sanchez-Bayona, Rodrigo ; Pare, Laia

Abstract:

Purpose::

Elacestrant has shown significantly prolonged progression-free survival compared with standard-of-care endocrine therapy in estrogen receptor–positive (ER-positive), HER2-negative metastatic breast cancer, whereas potential benefit in early-stage disease requires further exploration. The SOLTI-ELIPSE window-of-opportunity trial investigated the biological changes induced by a short course of preoperative elacestrant in postmenopausal women with early breast cancer.

Patients and Methods::

Eligible patients with untreated T1c (≥1.5 cm)-T3, N0, ER-positive/HER2-negative breast cancer with locally assessed Ki67 ≥10% received elacestrant at a daily dose of 345 mg for 4 weeks. The primary efficacy endpoint was complete cell cycle arrest, defined as Ki67 ≤2.7%, on day 28.

Results::

Overall, 22 patients were evaluable for the primary endpoint. Elacestrant was associated with a complete cell cycle arrest rate of 27.3% and a statistically significant Ki67 geometric mean change of −52.9% (P = 0.007; 95% confidence interval, −67.4 to −32.1). Notably, the treatment with elacestrant led to a shift toward a more endocrine-sensitive and less proliferative tumor phenotype based on PAM50-based gene signatures. Elacestrant increased the expression of immune-response genes (GZMB, CD4, and CD8A) and suppressed proliferation and estrogen-signaling genes (MKI67, ESR1, and AR). These biological changes were independent of the levels of Ki67 suppression on day 28. The most common adverse events were grade 1 anemia (21.7%), hot flushes (8.7%), constipation (8.7%), and abdominal pain (8.7%). One patient experienced a grade 3 cutaneous rash, leading to treatment discontinuation. No other serious adverse events were reported.

Conclusions::

Preoperative treatment with elacestrant in early breast cancer demonstrated relevant biological and molecular responses and exhibited a manageable safety profile. These findings support further investigation of elacestrant in the early setting.

119

News (Medical) associated with Elacestrant hydrochloride

31 May 2025

·pipelinereview.com

Arvinas and Pfizer's Vepdegestrant Significantly Improves Progression-Free Survival for Patients with ESR1-Mutant, ER+/HER2- Advanced Breast Cancer

NEW HAVEN, CT and NEW YORK, NY, USA I May 31, 2025 I Arvinas, Inc. (Nasdaq: ARVN) and Pfizer Inc. (NYSE: PFE) today announced detailed results from the Phase 3 VERITAC-2 clinical trial (NCT05654623) evaluating vepdegestrant monotherapy versus fulvestrant in adults with estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+/HER2-) advanced or metastatic breast cancer (MBC) whose disease progressed following prior treatment with cyclin-dependent kinase (CDK) 4/6 inhibitors and endocrine therapy. These data, which were highlighted in the American Society of Clinical Oncology (ASCO ® ) press briefing and selected for Best of ASCO, will be presented today in a late-breaking oral presentation (Abstract LBA1000) and have been simultaneously published in the New England Journal of Medicine . In the trial, vepdegestrant demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) among patients with an estrogen receptor 1 (ESR1) mutation, reducing the risk of disease progression or death by 43% compared to fulvestrant [Hazard Ratio (HR)=0.57 (95% CI 0.42–0.77); 2-sided P<0.001]. The median PFS, as assessed by blinded independent central review (BICR), was 5.0 months with vepdegestrant versus 2.1 months with fulvestrant. Investigator-assessed PFS was consistent with the BICR-assessed PFS. In patients with ESR1 mutations, vepdegestrant demonstrated a consistent PFS benefit over fulvestrant across all pre-specified subgroups. The trial did not reach statistical significance in improvement in PFS in the intent-to-treat (ITT) population, with a median PFS of 3.7 months for vepdegestrant versus 3.6 for fulvestrant [HR=0.83 (95% CI 0.68–1.02); 2-sided P=0.07]. “Many patients with ER+/HER2- metastatic breast cancer who progress on endocrine therapy have tumors with ESR1 mutations, which drive resistance to standard treatments,” said Erika P. Hamilton, M.D., Director, Breast Cancer Research, Sarah Cannon Research Institute, and a principal investigator of the VERITAC-2 trial. “The VERITAC-2 results are promising and suggest that vepdegestrant could offer a much-needed treatment option for these patients, with a low incidence of burdensome GI effects that can meaningfully affect daily life.” Vepdegestrant was generally well tolerated in the trial, with a safety profile consistent with what has been observed in previous studies, and mostly low-grade treatment-emergent adverse events (TEAEs). Rates and severity of gastrointestinal adverse events were low with vepdegestrant (nausea, 13.5%; vomiting, 6.4%; diarrhea, 6.4%). Grade 4 TEAEs were reported in 5 patients (1.6%) in the vepdegestrant arm versus 9 patients (2.9%) in the fulvestrant arm. The three most common TEAEs observed with vepdegestrant were fatigue (26.6%), increased alanine transaminase (ALT) (14.4%) and increased aspartate aminotransferase (AST) (14.4%). TEAEs leading to treatment discontinuation occurred in 2.9% of patients taking vepdegestrant versus 0.7% of patients taking fulvestrant. “Based on these strong data from VERITAC-2, we believe that vepdegestrant has the potential to be a best-in-class monotherapy treatment for patients in the second-line ESR1-mutant setting,” said John Houston, Ph.D., Chairperson, Chief Executive Officer and President at Arvinas. “We are excited to engage with regulatory authorities on next steps to potentially bring vepdegestrant to healthcare providers and their patients as swiftly as possible.” Overall survival (OS), the key secondary endpoint in VERITAC-2, was immature at the time of the analysis, with less than a quarter of the required number of events having occurred. Additional secondary endpoints include clinical benefit rate (CBR) and objective response rate (ORR) and duration of response by BICR. In patients with an ESR1 mutation, CBR was 42.1% with vepdegestrant versus 20.2% with fulvestrant [odds ratio 2.88 (95% CI: 1.57–5.39); nominal P<0.001] and ORR was 18.6% with vepdegestrant versus 4.0% with fulvestrant [odds ratio 5.45 (95% CI: 1.69–22.73); nominal P=0.001]. The median duration of response was not reached. “Patients whose tumors harbor ESR1 mutations can face a poor prognosis, often experiencing rapid disease progression on endocrine therapy,” said Johanna Bendell, M.D., Chief Oncology Development Officer, Pfizer. “These results highlight the important role vepdegestrant may play in combating ESR1 mutation treatment resistance for these patients.” Approximately 2.3 million new breast cancer diagnoses were reported globally in 2022, and it is estimated there will be nearly 320,000 new diagnoses in the United States in 2025. ER+/HER2- breast cancer accounts for approximately 70% of all cases. Nearly 30% of women initially diagnosed with early-stage breast cancer will ultimately develop metastatic disease, 1 with resistance to current standard-of-care treatments often emerging during first-line therapy, leading to disease progression. ESR1 mutations are a common cause of acquired resistance and are found in approximately 40% of patients in the second-line setting. 2,3,4 Vepdegestrant, an investigational oral PROTAC ER degrader for ER+/HER2- breast cancer being jointly developed by Arvinas and Pfizer, is designed to harness the body’s natural protein disposal system to specifically target and degrade the ER. These detailed results follow the March 2025 announcement of the topline results from VERITAC-2. The companies plan to submit a New Drug Application (NDA) for vepdegestrant to the U.S. Food & Drug Administration (FDA) in the second half of 2025. ASCO Presentation Details “Vepdegestrant, a PROTAC Estrogen Receptor Degrader, vs Fulvestrant in ER-Positive/Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Results of the Global, Randomized, Phase 3 VERITAC-2 Study” will be presented by Dr. Erika Hamilton, MD, Sarah Cannon Research Institute, in the Oral Abstract Session, Breast Cancer—Metastatic on Saturday, May 31, 1:15 – 4:15 p.m. CDT in Hall B1. Abstract LBA1000. Investor Call and Webcast Details Arvinas will host a conference call and webcast on June 2, 2025, at 8:00 a.m. ET to review these data. Participants are invited to listen by going to the Events and Presentation section under the Investors page on the Arvinas website at www.arvinas.com . A replay of the webcast will be available on the Arvinas website following the completion of the event and will be archived for up to 30 days. About the VERITAC-2 Clinical Trial The Phase 3 VERITAC-2 clinical trial ( NCT05654623 ) is a global randomized trial evaluating the efficacy and safety of vepdegestrant (ARV-471) as a monotherapy compared to fulvestrant in patients with ER+/HER2- advanced or metastatic breast cancer. The trial enrolled 624 patients at sites in 26 countries who had previously received treatment with a CDK4/6 inhibitor plus endocrine therapy. Patients were randomized 1:1 to receive either vepdegestrant once daily, orally on a 28-day continuous dosing schedule, or fulvestrant, administered intramuscularly on Days 1 and 15 of Cycle 1 and then on Day 1 of each 28-day cycle starting from Day 1 of Cycle 2. In the trial, 43% of patients (n=270) had ESR1 mutations detected. The primary endpoint was progression-free survival (PFS) in the ESR1-mutation and intent-to-treat populations as determined by blinded independent central review. Overall survival is the key secondary endpoint. About Vepdegestrant Vepdegestrant is an investigational, orally bioavailable PROteolysis TArgeting Chimera (PROTAC) protein degrader designed to specifically target and degrade the estrogen receptor (ER) for the treatment of patients with ER-positive (ER+)/human epidermal growth factor receptor 2 (HER2)-negative (ER+/HER2-) breast cancer. Vepdegestrant is being developed as a potential monotherapy for ER+/HER2- advanced or metastatic breast cancer with estrogen receptor 1 (ESR1) mutations in the second line-plus setting. In July 2021, Arvinas announced a global collaboration with Pfizer for the co-development and co-commercialization of vepdegestrant; Arvinas and Pfizer will share worldwide development costs, commercialization expenses, and profits. The U.S. Food and Drug Administration (FDA) has granted vepdegestrant Fast Track designation as a monotherapy in the treatment of adults with ER+/HER2- advanced or metastatic breast cancer previously treated with endocrine-based therapy. About Arvinas Arvinas (Nasdaq: ARVN) is a clinical-stage biotechnology company dedicated to improving the lives of patients suffering from debilitating and life-threatening diseases. Through its PROTAC protein degrader platform, Arvinas is pioneering the development of protein degradation therapies designed to harness the body’s natural protein disposal system to selectively and efficiently degrade and remove disease-causing proteins. Arvinas is currently progressing multiple investigational drugs through clinical development programs, including vepdegestrant, targeting the estrogen receptor for patients with locally advanced or metastatic ER+/HER2- breast cancer; ARV-393, targeting BCL6 for relapsed/refractory non-Hodgkin Lymphoma; and ARV-102, targeting LRRK2 for neurodegenerative disorders. Arvinas is headquartered in New Haven, Connecticut. For more information about Arvinas, visit www.arvinas.com and connect on LinkedIn and X . About Pfizer Oncology At Pfizer Oncology, we are at the forefront of a new era in cancer care. Our industry-leading portfolio and extensive pipeline includes three core mechanisms of action to attack cancer from multiple angles, including small molecules, antibody-drug conjugates (ADCs), and bispecific antibodies, including other immune-oncology biologics. We are focused on delivering transformative therapies in some of the world’s most common cancers, including breast cancer, genitourinary cancer, hematology-oncology, and thoracic cancers, which includes lung cancer. Driven by science, we are committed to accelerating breakthroughs to help people with cancer live better and longer lives. About Pfizer: Breakthroughs That Change Patients’ Lives At Pfizer, we apply science and our global resources to bring therapies to people that extend and significantly improve their lives. We strive to set the standard for quality, safety and value in the discovery, development and manufacture of health care products, including innovative medicines and vaccines. Every day, Pfizer colleagues work across developed and emerging markets to advance wellness, prevention, treatments and cures that challenge the most feared diseases of our time. Consistent with our responsibility as one of the world’s premier innovative biopharmaceutical companies, we collaborate with health care providers, governments and local communities to support and expand access to reliable, affordable health care around the world. For 175 years, we have worked to make a difference for all who rely on us. We routinely post information that may be important to investors on our website at www.pfizer.com . In addition, to learn more, please visit us on www.pfizer.com and follow us on X at @Pfizer and @Pfizer_News , LinkedIn , YouTube and like us on Facebook at Facebook.com/Pfizer . 1 Redig AJ, McAllister SS. Breast cancer as a systemic disease: a view of metastasis. J Intern Med . 2013;274(2):113-126. doi:10.1111/joim.12084. 2 Bidard F-C, et al. Elacestrant (oral selective estrogen receptor degrader) Versus Standard Endocrine Therapy for Estrogen Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer: Results From the Randomized Phase III EMERALD Trial. Journal of Clinical Oncology. 2022 May https://doi.org/10.1200/JCO.22.00338 . 3 Kalinsky, K. Abemaciclib Plus Fulvestrant in Advanced Breast Cancer After Progression on CDK4/6 Inhibition: Results From the Phase III postMONARCH Trial. Journal of Clinical Oncology. 2024 Dec. https://pubmed.ncbi.nlm.nih.gov/39693591/ . 4 Tolaney, S. et al. AMEERA-3: Randomized Phase II Study of Amcenestrant (Oral Selective Estrogen Receptor Degrader) Versus Standard Endocrine Monotherapy in Estrogen Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer. Journal of Clinical Oncology. https://ascopubs.org/doi/full/10.1200/JCO.22.02746 . SOURCE: Arvinas

Clinical ResultPhase 3ASCOPhase 2Fast Track

31 May 2025

·pipelinereview.com

HER3-DXd shows promising results in the phase II TUXEDO-3 study for patients with limited therapeutic options

CHICAGO, IL, USA I May 30, 2025 I Leading international medical research company, MEDSIR announced today the positive results of the TUXEDO-3 trial at the American Society of Clinical Oncology (ASCO) Annual Meeting 2025. This phase II study funded by Daiichi Sankyo and Merck, known as MSD outside of the United States and Canada, evaluates the efficacy and safety of patritumab deruxtecan (HER3-DXd) in patients with active brain metastases and leptomeningeal disease, serious complications associated with advanced stages of the cancer. The study was carried out to evaluate HER3-DXd in patients with metastatic breast cancer (mBC) and advanced non-small cell lung cancer (aNSCLC) with active brain metastases, and patients with leptomeningeal disease from solid tumors. This is an antibody-drug conjugate to target HER3, a protein receptor found on the surface of cancer cells in brain metastases. HER3-DXd is an investigational agent consisting of a fully human anti-HER3 IgG1 monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers. The DXd ADC Technology payload causes tumor DNA damage, killing cancer cells within and surrounding the tumor microenvironment The study showed promising results, which were presented today in an oral session. Results from the leptomeningeal cohort have been simultaneously published in the renowned journal Nature Medicine due to its potential benefit in patients with a high unmet medical need. In patients with breast cancer and brain metastases, intracranial responses were observed across all breast cancer subtypes, including luminal, HER2-positive, and triple-negative. Furthermore, some patients with breast cancer who had previously received antibody-drug conjugates also responded to HER3-DXd, highlighting the potential of HER3-DXd to overcome resistance and expand treatment options in refractory disease. Intracranial activity was also observed in patients with aNSCLC and brain metastases, intracranial responses were observed in patients whose tumors contained no activating driver mutations as well as patients whose tumors contained an EGFR or KRAS mutation. Overall, the data suggest that HER3-DXd may offer a novel treatment option for patients with secondary CNS involvement. KEY HIGHLIGHTS OF THE TUXEDO-3 STUDY The TUXEDO-3 study aimed to assess whether HER3-DXd could be an effective treatment option for patients with mBC and aNSCLC with active brain metastases, and leptomeningeal disease from solid tumors. The study met its primary objectives, with 23.8% and 30% patients achieving intracranial responses in active brain metastases from patients with mBC and aNSCLC, respectively, and 65% patients with leptomeningeal disease alive after 3 months. Side effects were consistent with previous studies using HER3-DXd. Tests evaluating quality of life and neurocognitive functions showed that patients remained stable or improved during the treatment follow-up. The primary objectives consisted of assessing the intracranial objective response rate in patients with active brain metastases from mBC and aNSCLC, and determining the number of patients with leptomeningeal disease alive after 3 months of starting the treatment. A NEW HOPE FOR DIFFICULT-TO-TREAT METASTASES “This study represents a significant advancement in our understanding of how to treat brain metastases and leptomeningeal disease, and we are hopeful that our findings will pave the way for new, effective therapies for these patients,” stated Dr. Matthias Preusser, MD, Medical Oncologist and Head of the Clinical Division of Oncology, Medical University of Vienna and Principal Investigator of TUXEDO-3. Dr. Rupert Bartsch, MD, PhD, Consultant Hematology and Medical Oncology, Medical University of Vienna, added: “Brain metastases and leptomeningeal disease represent severe complications in cancer, leading to increased morbidity and mortality, and HER3-DXd could be a promising therapeutic alternative for these patients.” ABOUT UMMET CANCER NEEDS Unmet cancer needs refer to gaps in resources, support, and treatment options that exist for cancer patients. Addressing unmet cancer needs is crucial to improving quality of life and outcomes for cancer patients. Through the collaborative work of healthcare providers, policymakers, and patient advocacy groups unmet cancer needs can be identified to help provide patients with comprehensive and quality care. SHOWCASING PROMISING COLLABORATIVE TRIALS AT ASCO In addition to the oral presentation of TUXEDO-3, MEDSIR will present both ADELA and WIN-B studies in poster format. The ADELA clinical trial is an ongoing international phase III study in collaboration with The Menarini Group, a leading international pharmaceutical and diagnostics company, and Stemline Therapeutics, Inc., a wholly-owned subsidiary of the Menarini Group focused on bringing transformational oncology treatments to cancer patients. The study is being conducted across multiple countries which combines elacestrant with everolimus to treat advanced ER+/HER2- breast cancer with ESR1 mutations, aiming to delay disease progression. Regarding WIN-B , is a phase Ib/II, multi-center investigator-initiated trial, evaluating the safety and preliminary efficacy of combining Debiopharm’s selective WEE1 inhibitor, Debio 0123 and Gilead’s antibodydrug conjugate Trodelvy ® (sacituzumab govitecan-hziy) in advanced HR+/HER2- and triple-negative breast cancers. MEDSIR active presence at the ASCO Annual Meeting 2025 reinforces its leadership in excellence-driven oncology research and highlights its focus on addressing unmet needs in cancer treatment, with the aim of not leaving any patient left behind. ABOUT MEDSIR Established in 2012, MEDSIR prides itself on working closely with its strategic partners to drive innovation in oncology research. Operating in Spain and the United States, the company provides end-to-end clinical trial management, from study design to publication, with an extensive global network of experts and integrated technology to streamline the process. The company offers proof-of-concept support and a strategic approach that enables research partners to benefit from the best of both worlds: industry clinical research and investigator-driven trials. With the aim of promoting independent research worldwide, MEDSIR has formed a strategic alliance with Oncoclínicas, the leading oncology group in Brazil, which offers outstanding research potential in South America. For further information: www.medsir.org SOURCE: MEDSIR

Clinical ResultPhase 2ASCOPhase 3Phase 1

31 May 2025

·www.biopharmadive.com

Full Arvinas, Pfizer data confirm potential, limits of ‘Protac’ drug in breast cancer

CHICAGO An experimental breast cancer drug from Arvinas and partner Pfizer modestly slowed disease progression in people whose tumors had changes to a specific gene, but did not provide a clear benefit to others who lacked that mutation.Full study results set to be presented Saturday at the American Society of Clinical Oncologys annual meeting provide a clearer picture of the drugs potential and its limitations than were available in March, when the companies shared an overview of trial outcomes.While the findings suggest the drug, an oral pill called vepdegestrant, may be a new option for a subset of breast cancer patients, they likely mean its use will remain narrow, should it win an approval.In their Phase 3 trial, Arvinas and Pfizer tested vepdegestrant against the injectable drug fulvestrant in 624 people who had the most common type of advanced breast cancer tumors positive for estrogen receptors but negative for a protein called HER2. Trial participants had been treated before with hormone therapy and another type of drug known as a CDK4/6 inhibitor. Two-hundred and seventy participants had mutations in the ESR1 gene, which is known to help tumors develop resistance to treatment.The detailed data unveiled Saturday show vepdegestrant extended progression-free survival in people with ESR1 mutations by a median of five months, compared to 2.1 months for those on fulvestrant.Among study participants overall, however, median progression-free survival was similar: 3.8 months on vepdegestrant versus 3.6 months on fulvestrant. PFS measures the time from a treatment response to when either disease progression or death.Speaking in a briefing with reporters ahead of ASCO, Jane Lowe Meisel, co-director of breast medical oncology at the Winship Cancer Institute of Emory University School of Medicine, described vepdegestrant as an exciting option.Yet she noted in a statement how on average, patients did not have prolonged responses on either agent, highlighting the need for combination therapies and continued development in this space.Fulvestrant, the drug Arvinas and Pfizer tested vepdegestrant against, is a common treatment for advanced breast cancers that are hormone receptor positive and HER2 negative. The drug, which has been on the market for over two decades, blocks growth signaling to tumors through those hormone receptors. But the therapy has drawbacks, such as monthly intramuscular injections and a range of side effects.Vepdegestrant works differently. The oral drug is whats known as a proteolysis-targeting chimera, or PROTAC. It is designed to break down estrogen receptors, thereby cutting off the signals that promote tumor growth. To date, vepdegestrant is the first PROTAC to advance through Phase 3 testing, and the first of its type to tested in people with advanced breast cancer.Study researchers also measured overall survival but data on that score remain immature. Essentially, too few people have died in the trial to draw conclusions about the statistical differences between the vepdegestrant and fulvestrant groups.Side effects for both treatments were common. Just over one-fifth of participants taking vepdegestrant experienced side effects that were rated severe or life-threatening, compared to 17.6% on fulvestrant. More participants on vepdegestrant 2.9% stopped treatment due to side effects at 2.9%, compared to 0.7% among those on fulvestrant.While vepdegestrant held no apparent benefit among the overall population, the drug could still hold promise for breast cancer patients with the ESR1 mutation.Such a role would be valuable as treating ESR1-mutated breast cancer remains challenging. Research led by Memorial Sloan Kettering Cancer Center researchers a decade ago found ESR1 mutations change the shape of the estrogen receptor in such a way that keeps pushing the cancer to grow, even in the absence of an estrogen signal. ESR1 mutations are estimated occur in approximately 40% to 50% of patients who undergo first-line therapy for metastatic breast cancer.Testing for the mutation is now done regularly, but typically occurs only after cancer has progressed or returned. Its become more prevalent since the approval of Orserdu, which is cleared for use in people with ER-positive, HER2-negative breast cancer that is positive for ESR1 mutations.Pfizer and Arvinas said in a statement Saturday they plan to submit an approval application for vepdegestrant to the Food and Drug Administration in the second half of this year. But the companies have also scaled back their development of vepdegestrant, removing plans for two other Phase 3 trials. In May, Arvinas cut one-third of its staffEditors note: This story has been updated to note Pfizer and Arvinas submission plans. '

Phase 3Clinical ResultASCO

100 Deals associated with Elacestrant hydrochloride

External Link

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
Node-positive breast cancer	Phase 3	United States	Stemline Therapeutics, Inc.	27 Sep 2024
Node-positive breast cancer	Phase 3	Australia	Stemline Therapeutics, Inc.	27 Sep 2024
Node-positive breast cancer	Phase 3	Austria	Stemline Therapeutics, Inc.	27 Sep 2024
Node-positive breast cancer	Phase 3	Belgium	Stemline Therapeutics, Inc.	27 Sep 2024
Node-positive breast cancer	Phase 3	Canada	Stemline Therapeutics, Inc.	27 Sep 2024
Node-positive breast cancer	Phase 3	Czechia	Stemline Therapeutics, Inc.	27 Sep 2024
Node-positive breast cancer	Phase 3	France	Stemline Therapeutics, Inc.	27 Sep 2024
Node-positive breast cancer	Phase 3	Germany	Stemline Therapeutics, Inc.	27 Sep 2024
Node-positive breast cancer	Phase 3	Hungary	Stemline Therapeutics, Inc.	27 Sep 2024

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT06492616 (ELEGANT, ASCO2025)	Phase 3	Node-positive breast cancer \| Estrogen receptor positive breast cancer Adjuvant Ki67	-	Elacestrant	szquhxlbee(bzqobbfask) = cssarmbuqm tzwarvkfcn (glslhmwmrt )	Positive	30 May 2025
				Standard Endocrine Therapy (AI or tamoxifen)	szquhxlbee(bzqobbfask) = ossjpijapu tzwarvkfcn (glslhmwmrt )
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	fqdpodmgyt(iifwtrohjo) = wnmdddftbj focffudvum (idckenqovt ) View more	Positive	30 May 2025
NCT05563220 (ELEVATE, ASCO2025)	Phase 1/2	ER-positive/HER2-negative Breast Cancer	-	Elacestrant + Ribociclib	jqkqsdbymf(pvxaoabzxk) = 43% (7% ≥Gr3) with Ela + Eve sdilfurfgf (upweeutqht ) View more	-	30 May 2025
				Elacestrant + Everolimus
NCT03778931 (EMERALD, ESMO_BC2025)	Phase 3	Metastatic breast cancer ESR1	966	elacestrant (ESR1 mutation testing by liquid biopsy using ddPCR)	eytvkmvhgn(ucvnowvdot) = lmjysmdsnk wtwepcgcfy (mtldngyhau, 33.2% - 39.4) View more	Positive	14 May 2025
NCT06492616 (ELEGANT, AACR2025)	Phase 3	Node-positive breast cancer \| Estrogen receptor positive breast cancer ESR1	-	Elacestrant	tngiqcocjq(wrxowwrlut): HR = 0.7 (95% CI, 0.55 - 0.88), P-Value = 0.0018	Positive	29 Apr 2025
				Standard Endocrine Therapy (AI or tamoxifen)
SABCS2024 Manual	Not Applicable	ER-positive/HER2-negative Breast Cancer HER2 Negative	212	Elacestrant	xjmxmmfhrc(xbfjsnkwws) = zncilvkedn wyfebpiqqx (zpeghdhgvk, 5.4 - NR)	Positive	10 Dec 2024
				Elacestrant (1-2 lines of prior ET)	xjmxmmfhrc(xbfjsnkwws) = swbpytoymz wyfebpiqqx (zpeghdhgvk, 4.9 - NR)
NCT05563220 \| NCT05386108 (ELEVATE, SABCS2024) Manual	Phase 1/2	ER-positive/HER2-negative Breast Cancer HER2 Negative	55	Elacestrant + Abemaciclib (all efficacy-evaluable)	ncpbtirdwk(wvsljpvjtt) = fgatynuebr zjlkttkwkp (mzypjdpqpj )	Positive	10 Dec 2024
				Elacestrant + Abemaciclib (ESR1-mut population)	ncpbtirdwk(wvsljpvjtt) = ezicmmixfi zjlkttkwkp (mzypjdpqpj )
NCT05563220 (ELEVATE, ESMO2024)	Phase 1/2	ER-positive/HER2-negative Breast Cancer ER+ \| HER2-negative \| ESR1-mut	-	Elacestrant + Everolimus	qxlkgpjhmb(skkeldjpih) = 10 (43) 2 (9) tiaxcnwxjj (mmsqmpvhzs ) View more	Positive	16 Sep 2024
				Elacestrant + Palbociclib
NCT05563220 (ELEVATE, ASCO2024) Manual	Phase 1/2	ER-positive/HER2-negative Breast Cancer HER2 Positive	20	Elacestrant + Ribociclibribociclib	gsfmjajqza(cudunmyaty) = Most common (≥30%) all-grade (Gr) AEs were decreased neutrophils/neutropenia (n=6, 50%; Gr3+ n=4, 33%) in the elacestrant (86-172 mg) + ribociclib (400 mg) cohorts szmcujtxbd (mgobgqarfw ) View more	Positive	24 May 2024
				elacestrantelacestrant (258-345 mg) + palbociclib (100 mg) cohorts
NCT05386108 (ELECTRA, ASCO2024) Manual	Phase 1/2	ER-positive/HER2-negative Breast Cancer Second line ER Positive \| HER2 Negative \| ESR1 Mutation	26	Elacestrant + Abemaciclib	zpyfflzild(sconknzqgo) = zolkcicwxe okoyvdqqum (vmriulrpyo ) View more	Positive	24 May 2024

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