Breakthrough Clinical Results
Menarini Group presented updated data from the Phase 1b/2 ELEVATE study at ASCO 2025, showcasing the efficacy and safety of elacestrant (ORSERDU®) in combination with various targeted therapies for ER+, HER2- metastatic breast cancer (mBC). Preliminary results from cohorts combining elacestrant with ribociclib and everolimus demonstrated favorable progression-free survival (PFS). The data supports elacestrant's potential as an endocrine therapy backbone in combination regimens for mBC. Additional safety data from other combination arms were also presented, showing consistent safety profiles. Menarini is also exploring elacestrant's potential in other breast cancer settings, including early-stage disease.
Key Highlights
- Favorable preliminary PFS results from elacestrant plus ribociclib and everolimus cohorts in the ELEVATE study.
- Updated safety data from multiple elacestrant combination arms showing consistent safety profiles.
- Elacestrant's potential as an endocrine therapy backbone in combination regimens for ER+, HER2- mBC.
- Ongoing exploration of elacestrant in early-stage breast cancer and other patient populations.
Incidence and Prevalence
Global Incidence and Prevalence of Metastatic Breast Cancer
Metastatic breast cancer, also referred to as stage IV breast cancer, represents one of the most advanced forms of breast cancer with significant mortality rates. Based on available information, metastatic breast cancer has only about a 28% five-year survival rate, highlighting its severity.
Metastasis is identified as one of the most leading causes of death in breast cancer patients. When breast cancer becomes metastatic, it spreads to other parts of the body beyond the primary tumor site. The major sites of metastasis for breast cancer include the lymph nodes, bone, brain and lung. Notably, bone metastases occur in approximately 70% of patients with advanced breast cancer, making it the most common site of distant spread.
Research efforts continue to investigate the genomic landscape of metastatic breast cancer. One significant study examined somatic alterations in 617 metastatic breast cancers. This research revealed that metastatic triple-negative breast cancers showed an increase in the frequency of somatic biallelic loss-of-function mutations in genes related to homologous recombination DNA repair compared to early triple-negative breast cancers (7% versus 2%).
Regional epidemiological data from North Carolina has been collected, with researchers evaluating "the odds of localized, regional, or distant metastatic breast cancer" using cancer registry data from 2009-2014.
The understanding of metastatic breast cancer continues to evolve through ongoing research, with efforts focused on identifying genetic markers and developing targeted treatments for this advanced stage of disease.
Emerging Mechanism of Action
Emerging Mechanisms of Action for Metastatic Breast Cancer
Based on PubMed publications over the past 3 years, several key mechanisms of action (MoA) are emerging for metastatic breast cancer:
Growth Factor Receptor Inhibition
- Trastuzumab emtansine (T-DM1), an antibody drug conjugate, has shown improved outcomes in both early and advanced breast cancer
- Second generation growth factor inhibitors are showing promising results in clinical studies
Signal Transduction Pathway Targeting
- Actein (a cycloartane triterpenoid) down-regulates EGFR, AKT and NF-κB signaling proteins
- Actein exhibits anti-proliferative, anti-adhesion and anti-migration activities
- Tyrosine kinase inhibitors show hopeful results in patients with advanced breast cancer
Anti-angiogenesis Approaches
- Different anti-angiogenetic therapies are under preclinical and clinical phase-II trials
- Actein has demonstrated anti-angiogenic activities
Apoptosis Modulation
- Pro-apoptotic agents show synergistic effects with docetaxel in clinical phase-I trials
- Compounds targeting HSP 90, histone deacetylase and HMG-CoA reductase target atypical apoptotic pathways that are lethal to tumor cells but not normal tissue
Inhibition of Invasion and Metastasis
- Matrix metalloproteinase (MMP) inhibitors show promising results in patients with refractory malignant pleural effusion in phase-I trials
- Actein suppresses the protein expression of matrix metalloproteinases in breast cancer cells
Novel Therapeutic Approaches
- Cancer vaccination strategies with progress in defining immunogenic epitopes of tumor antigens
- Therapies like hyperbaric oxygen therapy, RNA interference and CRISPR/Cas9 are being explored
- Biologic agent combinations to overcome drug resistance
Study Design Parameters
Study Design Parameters and Endpoints in Key Trials for Metastatic Breast Cancer
Network Meta-analysis of Endocrine Monotherapies
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Design Parameters:
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Analyzed 6 first-line endocrine monotherapies for HR+ HER2- metastatic or locally advanced breast cancer
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Included 27 articles from 8 randomized controlled trials with 3492 patients
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Endpoints:
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Main outcomes: objective response rate (ORR), time to progression (TTP), and progression-free survival (PFS)
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Secondary outcomes: adverse events
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Found fulvestrant 500mg and letrozole to be optimal first-line choices
DETECT Trial for Circulating Tumor Cells (CTCs)
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Design Parameters:
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Prospective multicenter trial with 254 metastatic breast cancer patients
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Directly compared two CTC detection methods: AdnaTest Breast Cancer and CellSearch system
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Collection of whole-blood specimens at serial time points
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Endpoints:
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Overall survival (OS): CellSearch-positive patients had median OS of 18.1 months vs. 27 months for CTC-negative patients
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CellSearch system was superior to AdnaTest in predicting clinical outcome
Surgical Management Trials
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Design Parameters:
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Study of stage IV breast cancer with liver metastases examining impact of hepatic metastasectomy
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Analysis of 2,895 patients, with 90 (3.1%) undergoing hepatic resection
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Another study compared 54 surgery patients to 236 matched non-surgery patients with stage IV breast cancer
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Endpoints:
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Hepatic metastasectomy was associated with 37% reduction in risk of death
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Similar survival of 3.5 years (surgery) vs. 3.4 years (non-surgery)
Radiation Therapy with T-DM1 Study
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Design Parameters:
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Systematic review and meta-analysis included 9 articles
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Evaluated safety of combining trastuzumab emtansine (T-DM1) with radiation therapy
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Endpoints:
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Incidence of grade 3+ radionecrosis (17%)
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Rates of pneumonitis (<1%) and skin toxicity (1%)
Other Key Trials
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Design Parameters:
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Phase I dose-escalation study of capecitabine (7/7 schedule) with 21 patients
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Standard three-patients-per-cohort dose-escalation scheme for capecitabine
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Flat-dose capecitabine beginning at 1,500 mg orally twice daily on a 7/7 schedule
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Two-stage phase II trial evaluating megestrol acetate in 48 postmenopausal women with hormone-sensitive advanced breast cancer
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Single daily oral dose of 160 mg megestrol acetate
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Endpoints:
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Maximum tolerated dose (MTD)
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Toxicity assessment
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Clinical benefit rate (CBR) - reported as 40% [95% CI 25% to 55%] in the megestrol acetate trial
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Progression-free survival (PFS) - median 3.9 months [95% CI 3.0-4.8] in megestrol acetate trial
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Duration of clinical benefit - median 10.0 months [95% CI 8.0-14.2] in megestrol acetate trial
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Quality-adjusted life-year (QALY)
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Quality-adjusted progression-free survival (QPFS)
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Breast cancer-specific survival (BCSS)
Drug used in other indications
Elacestrant Clinical Trials Beyond Metastatic Breast Cancer
Elacestrant, a novel oral selective estrogen receptor degrader, is currently being investigated for several indications beyond its established use in metastatic breast cancer. These additional therapeutic applications include:
- Early breast cancer setting
- Treatment for CDK 4/6 inhibitor naïve patients
- As a component of combination therapy for first-line use
Intervention Models
The clinical trials exploring these additional indications employ various intervention models tailored to specific patient populations and treatment goals:
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Elacestrant in the early setting - These trials focus specifically on patients with early breast cancer, representing a significant expansion from the metastatic setting
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Elacestrant in combination with other targeted agents for metastatic breast cancer treatment - This approach explores potential synergistic effects when combining Elacestrant with other therapies
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Elacestrant as monotherapy in CDK 4/6 inhibitor naïve patients - This model evaluates the efficacy of Elacestrant alone in patients who have not previously received CDK 4/6 inhibitor treatment
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Elacestrant as a component of combination therapy for first-line treatment - This strategy positions Elacestrant as part of initial treatment protocols rather than after progression on other therapies
These diverse intervention models reflect the ongoing efforts to maximize the therapeutic potential of Elacestrant across different stages of breast cancer and in various treatment combinations, potentially expanding treatment options for patients beyond the current indications.