Efficacy and safety of treatments in HR+/HER2- advanced breast cancer after CDK4/6 inhibitor progression: a network meta-analysis and scoping review.

BACKGROUND: Considering limited therapeutic options and lack of consensus following cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) progression, we evaluated efficacy and safety of available treatments for hormone receptor-positive (HR+)/HER2- advanced breast cancer patients who progressed after CDK4/6i therapy. METHODS: PubMed, Embase, and the Cochrane Library were searched for relevant studies published between 2015 and 2024. Randomized controlled trials (RCTs) were included. Eligible treatments included endocrine therapy (ET) with targeted agents, CDK4/6i, oral selective estrogen receptor degraders (SERDs), and antibody–drug conjugates (ADCs), ET monotherapy, and chemotherapy. Bayesian hierarchical models were applied using a fixed-effects model. Descriptive statistical methods were used to summarize the effect of each treatment. The primary outcome was progression-free survival (PFS), while secondary outcomes were objective response rate (ORR) and adverse events (AEs). RESULTS: A total of 16 RCTs (n = 5,076) were included. Due to the absence of closed loops, two small networks formed based on ET monotherapy and chemotherapy. The camizestrant (HR = 0.49, 95% CI: 0.32–0.76), ribociclib plus ET (HR = 0.57, 95% CI: 0.39–0.84), capivasertib plus ET (HR = 0.59, 95% CI: 0.48–0.72), elacestrant (HR = 0.70, 95% CI: 0.55–0.89), and abemaciclib plus ET (HR = 0.73, 95% CI: 0.57–0.94) showed superior PFS compared to ET monotherapy. Camizestrant, ribociclib plus ET, and capivasertib plus ET demonstrated a significantly better PFS compared with amcenestrant or palbociclib plus ET. ADCs including trastuzumab deruxtecan (T-DXd) (PFS HR = 0.59, ORR OR = 3.53), sacituzumab govitecan (SG) (PFS HR = 0.63, ORR OR = 1.63), and datopotamab deruxtecan (Dato-DXd) (PFS HR = 0.63, ORR OR = 1.94) demonstrated better efficacy in both PFS and ORR compared with chemotherapy. Descriptive statistical analysis revealed that T-DXd showed superior efficacy in terms of PFS (11.56 months) and ORR(53–57%). The safety profile of each treatment demonstrated distinct AE incidence profiles, though differing monitoring intensities across regimens may affect AE detection rates. CONCLUSIONS: Multiple endocrine-based strategies, including oral SERDs, AKT inhibitors combined with ET, and continued CDK4/6 inhibition, demonstrated clinical activity for patients progressing after CDK4/6 inhibitors. ADCs are superior to chemotherapy, with T-DXd showed the highest efficacy regarding PFS and ORR. This analysis provides a structured, evidence-based overview of the current therapeutic landscape for this clinically challenging population, with some limitations in directly comparing endocrine therapies and ADCs within the present analysis framework.