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

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 ESR1-mutant tumors and among patients with prolonged prior CDK4/6i exposure. Ipatasertib and alpelisib showed the greatest benefits in patients with PI3K/PTEN/AKT alterations. Antibody–drug conjugates (ADCs), such as trastuzumab deruxtecan and sacituzumab govitecan, outperformed standard chemotherapy, albeit with higher toxicity. 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).