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

## TL;DR

This study compares the effectiveness and safety of various treatments for advanced breast cancer patients who stopped responding to CDK4/6 inhibitors.

## Contribution

The study provides a network meta-analysis and scoping review of treatment options after CDK4/6 inhibitor progression in HR+/HER2- advanced breast cancer.

## Key findings

- Camizestrant, ribociclib plus ET, and capivasertib plus ET showed superior progression-free survival (PFS) compared to ET monotherapy.
- Trastuzumab deruxtecan (T-DXd) demonstrated the highest efficacy in PFS and ORR compared to chemotherapy.
- ADCs showed better efficacy than chemotherapy in both PFS and ORR.

## Abstract

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.

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).

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.

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.

The online version contains supplementary material available at 10.1186/s12885-026-15632-z.