Safety profile of post-CDK4/6 treatments in HR+/HER2− metastatic breast cancer (mBC): A network meta-analysis

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 (grade[G] ≥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. Trial Treatment strategy Control arm RR (95% CI) any grade AEs P-score any grade AEs RR (95% CI) G≥3 AEs P-score G≥3 AEs RR (95% CI) AEs leading to discontinuation P-score AEs leading to discontinuation SERENA-2 Camizestrant 75mg ET 1.12 (0.92-1.37) 0.44 0.81 (0.36-1.83) 0.86 4.93 (0.24-101.00) 0.47 SERENA-2 Camizestrant 150mg ET 1.32 (1.11-1.57) 0.09 1.55 (0.78-3.07) 0.58 NA NA EMBER-3 Imlunestrant ET 0.98 (0.92-1.05) 0.90 0.83 (0.60-1.14) 0.90 3.47 (1.15-10.42) 0.57 EMBER-3 Imlunestrant+abemaciclib ET 1.16 (1.11-1.22) 0.29 2.35 (1.82-3.03) 0.38 5.06 (1.67-15.32) 0.44 EMERALD Elacestrant ET 1.07 (1.00-1.14) 0.60 1.32 (0.95-1.83) 0.66 1.45 (0.66-3.16) 0.82 VERITAC-2 Vepdegestrant ET 1.07 (1.00-1.14) 0.61 1.71 (1.25-2.36) 0.65 4.47 (0.97-20.53) 0.48 SOLAR-1 Alpelisib+ET ET 1.07 (1.03-1.10) 0.61 2.13 (1.75-2.58) 0.44 5.98 (3.32-10.78) 0.36 CAPItello-291 Capivasertib+ET ET 1.17 (1.11-1.24) 0.26 3.11 (2.30-4.23) 0.22 5.67 (2.72-11.84) 0.39 postMONARCH Abemaciclib+ET ET 1.19 (1.11-1.28) 0.22 2.76 (2.01-3.79) 0.28 23.51 (1.40-395.96) 0.17 PALMIRA Palbociclib+ET ET 1.07 (0.96-1.19) 0.61 4.00 (1.82-8.78) 0.18 NA NA PACE Palbociclib+ET ET NA NA 22.16 (3.14-156.38) 0.05 NA NA BOLERO-2 Everolimus+ET ET NA NA NA NA 5.04 (2.59-9.81) 0.44 MAINTAIN Ribociclib+ET ET NA NA NA NA 4.92 (0.59-40.83) 0.46 TROPION-Breast01 Datopotamab deruxtecan CT 1.08 (1.03-1.14) 0.02 0.47 (0.37-0.59) 1.00 1.01 (0.44-2.29) 0.67 DESTINY-Breast04 Trastuzumab deruxtecan CT 1.04 (1.01-1.08) 0.56 0.81 (0.70-0.93) 0.80 2.05 (1.18-3.56) 0.12 DESTINY-Breast06 Trastuzumab deruxtecan CT 1.04 (1.01-1.06) 0.25 1.19 (1.03-1.37) 0.22 1.53 (1.05-2.23) 0.32 EVER-132-002 Sacituzumab govitecan CT 1.00 (0.99-1.01) 0.83 1.18 (1.04-1.33) 0.25 0.83 (0.26-2.66) 0.75 TROPiCS-02 Sacituzumab govitecan CT NA NA 1.23 (1.08-1.39) 0.14 1.44 (0.69-3.01) 0.40