ArticleEClinicalMedicine2025
Efficacy and safety of systemic therapies following progression on CDK4/6 inhibitors in patients with HR+/HER2- metastatic breast cancer: a systematic review and network meta-analysis.
Article in EClinicalMedicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
5 citing papers in PubMed.
- Review
- Article
- Article
- Cell-cycle targeted cancer therapy: clinical advances, biological gaps, and the emergence of selective CDK4 inhibitors.Journal of hematology & oncology · 2026Review
- Precision Endocrine-Based Combinations After CDK4/6 Inhibitor Progression in HR-Positive Metastatic Breast Cancer.Drug design, development and therapy · 2026Review
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Authors and funding
22 authors.
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Abstract
Background: In the absence of head-to-head trials, optimal treatment sequencing following disease progression on a CDK4/6 inhibitor (CDK4/6i) combined with endocrine therapy (ET) in hormone receptor-positive, HER2-negative (HR+/HER2-) metastatic breast cancer (mBC) remains challenging. To address this gap, we conducted a systematic review and network meta-analysis (NMA) to provide evidence-based guidance for treatment selection in this setting. Methods: We identified randomized phase II-III trials involving HR+/HER2- mBC patients whose tumors progressed on CDK4/6i-based therapy, published between January 1, 2014 and June 6, 2025 (PROSPERO n° CRD42024604417). Hazard ratios (HRs) for progression-free survival (PFS) were extracted from published data and analyzed using a frequentist random-effects model. Subgroup analyses were performed based on the duration of CDK4/6i treatment and the presence of ESR1 or PI3K/PTEN/AKT pathway alterations. Treatments were compared with conventional ET or chemotherapy and ranked using the P-score metric. Confidence in network estimates was evaluated using the CINeMA framework. Safety data, including grade ≥3 adverse events (AEs) and treatment discontinuation, were descriptively analyzed. Findings: Twenty-eight randomized trials (n = 6544) were included in the NMA. Sapanisertib plus fulvestrant provided the greatest PFS benefit (HR 0.34, 95% CI 0.14-0.82) but had a high discontinuation rate (>15%). Among the approved therapies, ribociclib plus ET (HR 0.57, 95% CI 0.39-0.84), capivasertib plus fulvestrant (HR 0.62, 95% CI 0.51-0.75), and elacestrant (HR 0.70, 95% CI 0.55-0.89) demonstrated superior efficacy. Elacestrant was most effective in patients with Interpretation: Combinations of targeted agents with ET or novel endocrine agents such as oral selective estrogen receptor degraders (SERDs) demonstrated favorable efficacy and safety profiles in biomarker-selected populations, supporting a shift toward biomarker-driven treatment algorithms. In endocrine-resistant diseases that require chemotherapy, ADCs are the most effective therapeutic option. Funding: We acknowledge financial support under the National Recovery and Resilience Plan (NRRP), Mission 4, Component 2, Investment 1.1, Call for tender No. 1409 published on 14.9.2022 by the Italian Ministry of University and Research (MUR), funded by the European Union - NextGenerationEU - Project Title: Identifying predictive/prognostic biomarkers and mechanisms underlying resistance to CDK4/6 inhibition beyond progression in hormone receptor-positive/HER2-negative metastatic breast cancer - CUP E53D23020460001 (Project code: P2022FK2J8, ERC panel: LS7, Principal Investigator: Carmine De Angelis). Grant Assignment Decree No. 1369 adopted on 01.09.2023 by the Italian Ministry of University and Research (MUR).
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.