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, Journal Year: 2022, Volume and Issue: 40(28), P. 3246 - 3256

Published: May 18, 2022

Patients with pretreated estrogen receptor (ER)-positive/human epidermal growth factor 2 (HER2)-negative advanced breast cancer have poor prognosis. Elacestrant is a novel, oral selective ER degrader that demonstrated activity in early studies.

Language: Английский

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Overall Survival with Palbociclib and Fulvestrant in Women with HR+/HER2− ABC: Updated Exploratory Analyses of PALOMA-3, a Double-blind, Phase III Randomized Study

Clinical Cancer Research, Journal Year: 2022, Volume and Issue: 28(16), P. 3433 - 3442

Published: May 12, 2022

Abstract Purpose: To conduct an updated exploratory analysis of overall survival (OS) with a longer median follow-up 73.3 months and evaluate the prognostic value molecular by circulating tumor DNA (ctDNA). Patients Methods: hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2−) advanced breast cancer (ABC) were randomized 2:1 to receive palbociclib (125 mg orally/day; 3/1 week schedule) fulvestrant (500 intramuscularly) or placebo fulvestrant. This OS was performed when 75% enrolled patients died (393 events in 521 patients). ctDNA among who provided consent. Results: At data cutoff (August 17, 2020), 258 135 deaths occurred groups, respectively. The [95% confidence interval (CI)] 34.8 (28.8–39.9) group 28.0 (23.5–33.8) (stratified hazard ratio, 0.81; 95% CI, 0.65–0.99). 6-year rate (95% CI) 19.1% (14.9–23.7) 12.9% (8.0–19.1) Favorable plus compared observed most subgroups, particularly endocrine-sensitive disease, no prior chemotherapy for ABC low fraction regardless ESR1, PIK3CA, TP53 mutation status. No new safety signals identified. Conclusions: clinically meaningful improvement associated maintained >6 years HR+/HER2− ABC, supporting as standard care these patients.

Language: Английский

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An emerging generation of endocrine therapies in breast cancer: a clinical perspective

npj Breast Cancer, Journal Year: 2023, Volume and Issue: 9(1)

Published: April 5, 2023

Abstract Anti-estrogen therapy is a key component of the treatment both early and advanced-stage hormone receptor (HR)-positive breast cancer. This review discusses recent emergence several anti-estrogen therapies, some which were designed to overcome common mechanisms endocrine resistance. The new generation drugs includes selective estrogen modulators (SERMs), orally administered degraders (SERDs), as well more unique agents such complete antagonists (CERANs), proteolysis targeting chimeric (PROTACs), covalent (SERCAs). These are at various stages development being evaluated in metastatic settings. We discuss efficacy, toxicity profile, completed ongoing clinical trials for each drug highlight differences their activity study population that have ultimately influenced advancement.

Language: Английский

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Datopotamab Deruxtecan in Advanced or Metastatic HR+/HER2– and Triple-Negative Breast Cancer: Results From the Phase I TROPION-PanTumor01 Study

Journal of Clinical Oncology, Journal Year: 2024, Volume and Issue: 42(19), P. 2281 - 2294

Published: April 23, 2024

Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate consisting of a humanized antitrophoblast cell-surface antigen 2 (TROP2) monoclonal antibody linked to potent, exatecan-derived topoisomerase I inhibitor payload via plasma-stable, selectively cleavable linker.

Language: Английский

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Recent progress of CDK4/6 inhibitors’ current practice in breast cancer

Cancer Gene Therapy, Journal Year: 2024, Volume and Issue: 31(9), P. 1283 - 1291

Published: Feb. 26, 2024

Dysregulated cellular proliferation represents a hallmark feature across all cancers. Aberrant activation of the cyclin-dependent kinase 4 and 6 (CDK4/6) pathway, independent mitogenic signaling, engenders uncontrolled breast cancer cell proliferation. Consequently, advent CDK4/6 inhibition has constituted pivotal milestone in realm targeted therapy. The combination inhibitors (CDK4/6i) with endocrine therapy (ET) emerged as foremost therapeutic modality for patients afflicted hormone receptor-positive (HR + )/HER2-negative (HER2-) advanced cancer. At present, Food Drug Administration (FDA) sanctioned various CDK4/6i employment primary treatment regimen HR /HER2- This approach demonstrated substantial extension progression-free survival (PFS), often amounting to several months, when administered alongside Within this comprehensive review, we systematically evaluate utilization strategies subpopulations explore potential avenues following disease progression during application

Language: Английский

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Giredestrant for Estrogen Receptor–Positive, HER2-Negative, Previously Treated Advanced Breast Cancer: Results From the Randomized, Phase II acelERA Breast Cancer Study

Journal of Clinical Oncology, Journal Year: 2024, Volume and Issue: 42(18), P. 2149 - 2160

Published: March 27, 2024

PURPOSE To compare giredestrant and physician's choice of endocrine monotherapy (PCET) for estrogen receptor–positive, HER2-negative, advanced breast cancer (BC) in the phase II acelERA BC study (ClinicalTrials.gov identifier: NCT04576455 ). METHODS Post-/pre-/perimenopausal women, or men, age 18 years older with measurable disease/evaluable bone lesions, whose disease progressed after 1-2 lines systemic therapy (≤1 targeted, ≤1 chemotherapy regimen, prior fulvestrant allowed) were randomly assigned 1:1 to (30 mg oral once daily) fulvestrant/aromatase inhibitor per local guidelines (+luteinizing hormone–releasing hormone agonist pre-/perimenopausal men) until progression/unacceptable toxicity. Stratification was by visceral versus nonvisceral disease, cyclin-dependent kinase 4/6 inhibitor, fulvestrant. The primary end point investigator-assessed progression-free survival (INV-PFS). RESULTS At clinical cutoff (February 18, 2022; median follow-up: 7.9 months; N = 303), INV-PFS hazard ratio (HR) 0.81 (95% CI, 0.60 1.10; P .1757). In prespecified secondary analysis ESR1 mutation (m) status circulating tumor DNA–evaluable patients (n 232), HR a detectable ESR1m 90) 0.35 1.03) 0.88 0.54 1.42) no detected 142). Related grade 3-4 adverse events (AEs), serious AEs, discontinuations due AEs balanced across arms. CONCLUSION Although did not reach statistical significance its point, there consistent treatment effect most key subgroups trend toward favorable benefit among ESR1-mutated tumors. Giredestrant well tolerated, safety profile comparable PCET known risks. Overall, these data support continued investigation other studies.

Language: Английский

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VERITAC-2: a Phase III study of vepdegestrant, a PROTAC ER degrader, versus fulvestrant in ER+/HER2- advanced breast cancer

Future Oncology, Journal Year: 2024, Volume and Issue: 20(32), P. 2447 - 2455

Published: July 29, 2024

Vepdegestrant (ARV-471) is an oral PROTAC ER degrader that binds E3 ubiquitin ligase and to directly trigger ubiquitination of its subsequent proteasomal degradation. In a first-in-human Phase I/II study, vepdegestrant monotherapy was well tolerated with clinical activity in pretreated patients ER+/HER2- advanced breast cancer. The global, randomized III VERITAC-2 study compares efficacy safety versus fulvestrant adults cancer after treatment CDK4/6 inhibitor plus endocrine therapy. Progression-free survival by blinded independent central review (primary end point) will be assessed the intention-to-treat population ESR1 mutation-positive subpopulation. Secondary points include overall survival, tumor response, safety, pharmacokinetics, patient-reported outcomes, circulating DNA biomarkers.

Language: Английский

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Elacestrant in ER+, HER2– MBC with ESR1-mutated tumors: Subgroup Analyses from the Phase III EMERALD Trial by Prior Duration of Endocrine Therapy Plus CDK4/6 Inhibitor and in Clinical Subgroups

Clinical Cancer Research, Journal Year: 2024, Volume and Issue: 30(19), P. 4299 - 4309

Published: Aug. 1, 2024

Abstract Purpose: Elacestrant significantly prolonged progression-free survival (PFS) with manageable safety versus standard-of-care (SOC) endocrine therapy (ET) in patients estrogen receptor–positive (ER+), HER2− metastatic breast cancer and tumors harboring receptor 1 (ESR1) mutation following ET plus a cyclin-dependent kinase 4/6 inhibitor (ET+CDK4/6i). In ESR1-mutated tumors, we evaluated the efficacy of elacestrant SOC based on prior ET+CDK4/6i duration clinical subgroups ≥12 months. Patients Methods: EMERALD, an open-label phase III trial, randomly assigned ER+, who had received 1–2 lines ET, mandatory CDK4/6i, ≤1 chemotherapy to (345 mg daily) or (aromatase fulvestrant). PFS was assessed across post hoc exploratory analyses without adjustment for multiple testing. Results: months, median 8.6 1.9 months (HR, 0.41; 95% confidence interval, 0.26–0.63). this population, (in months) 9.1 (bone metastases), 7.3 (liver and/or lung 9.0 (<3 sites), 10.8 1.8 (≥3 5.5 (PIK3 catalytic subunit α mutation), (tumor protein p53 gene (HER2-low), (ESR1D538G-mutated tumors), (ESR1Y537S/N-mutated tumors). Subgroup consistent overall population. Conclusions: The associated clinically meaningful improvement compared all HER2−, tumors.

Language: Английский

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Circulating tumor DNA validity and potential uses in metastatic breast cancer

npj Breast Cancer, Journal Year: 2024, Volume and Issue: 10(1)

Published: March 12, 2024

Abstract Following the first characterization of circulating tumor DNA (ctDNA) in 1990s, recent advances led to its introduction clinics. At present, European Society Of Medical Oncology (ESMO) recommendations endorse ctDNA testing routine clinical practice for genotyping direct molecularly targeted therapies patients with metastatic cancer. In studies on breast cancer, has been utilized treatment tailoring, tracking mechanisms drug resistance, and predicting disease response before imaging. We review available evidence regarding applications

Language: Английский

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Current Molecular Combination Therapies Used for the Treatment of Breast Cancer

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(19), P. 11046 - 11046

Published: Sept. 20, 2022

Breast cancer is the second leading cause of death for women worldwide. While monotherapy (single agent) treatments have been used many years, they are not always effective, and patients relapse after initial treatment. Moreover, in some response to therapy becomes weaker, or resistance develops over time. This especially problematic metastatic breast triple-negative cancer. Recently, combination therapies (in which two more drugs target pathways) emerged as promising new treatment options. Combination often effective than monotherapies demonstrate lower levels toxicity during long-term In this review, we provide a comprehensive overview current therapies, including molecular-targeted therapy, hormone immunotherapy, chemotherapy. We also describe molecular basis various options different subtypes. promising, discuss challenges. Despite these challenges, use innovative holds great promise compared with traditional monotherapies. addition, multidisciplinary technologies (such nanotechnology computer technology) has potential optimize even further.

Language: Английский

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