Abstract Several treatments (tx) are available for HR+/HER2- mBC; however, choosing subsequent tx after progression on first-line CDK4/6 inhibitor + endocrine therapy (ET) remains challenging. Assessing the safety profiles of these options is crucial for guiding tx selection. We performed a network meta-analysis (NMA) to compare the safety of systemic tx approved for this setting. Tx strategies were retrieved through a systematic review of randomized phase II-III trials published from January 2014 to October 2025 (PROSPERO CRD420251234039) and only FDA- and/or EMA-approved tx were included. Each tx was compared with standard ET or chemotherapy (CT). A frequentist random-effects NMA was performed using the netmeta package in R. Risk ratios (RRs) for safety outcomes (gradeG ≥3 adverse events AEs, any grade AEs, and AEs leading to discontinuation) were calculated from each trial using pairwise comparisons and pooled using a random-effects model estimated by restricted maximum likelihood. Results were shown as forest plots with 95% confidence intervals (CI), and tx ranked based on P-scores. The NMA included 16 trials. Among ET-based strategies, the lowest RRs were observed for: imlunestrant alone (0.98, 95% CI 0.92-1.05) for any G AEs; camizestrant 75 mg (0.81, 0.36-1.83) for G≥3 AEs; elacestrant (1.45, 0.66-3.16) for AEs leading to discontinuation. While among antibody-drug conjugates (ADCs) the lowest RRs were observed for: sacituzumab govitecan (SG) for any G AEs (1.00, 0.99-1.01); datopotamab deruxtecan (Dato-DXd) (0.47, 0.37-0.59) for G≥3 AEs; SG (0.83, 0.26-2.66) for AEs leading to discontinuation. The estimated RRs and P-scores are shown in table. Among ET-based options, novel mono-ETs (oral SERDs and PROTACs) showed the lowest risk of discontinuation and G≥3 AEs. Among ADCs, TROP2-directed agents had fewer discontinuations, while ADCs with DXd as a payload showed higher rates of any G AEs but (except for DESTINY-Breast06) lower G≥3 AEs risk than other tx strategies. Citation Format: Martina Pagliuca, Roberto Buonaiuto, Michelino De Laurentiis, Carmine De Angelis. Safety profile of post-CDK4/6 treatments in HR+/HER2− metastatic breast cancer (mBC): A network meta-analysis abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6441.
Pagliuca et al. (2026) studied this question.