Endocrine-based strategies after CDK4/6 inhibitors in biomarker-selected subgroup of hormone receptor positive advanced breast cancer: A systematic review and network meta-analysis

Abstract

Background: Several endocrine-based strategies have been evaluated following CDK4/6 inhibition (CDK4/6i) in hormone receptor-positive advanced breast cancer. However, the absence of head-to-head comparisons leave uncertainty regarding the optimal treatment selection. Methods: A systematic literature search was performed to identify randomized controlled trials (RCTs) evaluating endocrine-based strategies after CDK4/6i for hormone receptor-positive advanced breast cancer. A network meta-analysis was used to compare overall treatment strategies, rather than individual treatments. In addition, an extracted individual patient data meta-analysis was conducted. The primary endpoint was progression-free survival (PFS) evaluated independently in tumors with PI3K-AKT-PTEN alterations, ESR1-mutated and wild-type tumors. Results: A total of 20 RCTs including 4,716 patients were included. In ESR1-mutated tumors, oral SERD/SERM/PROTAC showed numerically better PFS compared with switching CDK4/6i plus fulvestrant (HR = 0.67, 95 % CI 0.45-1.00). In this population, the addition of i) CDK4/6i or ii) mTORi to oral SERDs improved PFS compared with oral SERD/SERM/PROTAC alone (HR = 0.44, 95 % CI 0.27-0.72 and HR = 0.45, 95 % CI 0.23-0.89, respectively). In PI3K-AKT-PTEN altered tumors, the greatest benefit was observed with PI3K/AKT/mTORi plus fulvestrant and oral SERDs plus CDK4/6i (P-scores > 0.75). In ESR1 and PI3K/AKT/PTEN wild-type tumors, several treatment combinations outperformed fulvestrant. The use of PI3K/AKT/mTORi plus fulvestrant was associated with the highest incidence of grade ≥ 3 adverse events (66.0 %). Conclusion: This meta-analysis reinforces the importance of molecular stratification in treatment decisions after CDK4/6i progression, highlighting the need for efficacy and safety assessments across biomarker-selected subgroups.