Influence of menopausal status on the efficacy of adjuvant CDK4/6 inhibitors in hormone receptor–positive early breast cancer: A pooled meta-analysis of phase III clinical trials.

e12506 Background: Adjuvant cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) improve outcomes in hormone receptor–positive (HR+), HER2-negative early breast cancer, though trial results have been heterogeneous. MONARCH-E and NATALEE demonstrated significant invasive disease-free survival (iDFS) benefit, while PALLAS and PENELOPE-B did not. Menopausal status and endocrine therapy backbone represent potential sources of variability; however, there is a paucity of data exploring the influence of menopausal status on CDK4/6i efficacy. Methods: Phase III randomized trials evaluating adjuvant CDK4/6i in HR+/HER2− early breast cancer (PALLAS, PENELOPE-B, MONARCH-E, NATALEE) were identified. Trial-level hazard ratios (HRs) and 95% confidence intervals (CIs) for iDFS and overall survival (OS) were extracted separately for subgroups of pre/perimenopausal and postmenopausal participants. HRs were pooled using inverse variance and random-effects modeling (DerSimonian–Laird). Heterogeneity was assessed using I², and Cochran Q statistics. Subgroups were compared using the Deeks method. A sensitivity analysis was performed limiting the analysis to approved CDK4/6i (Ribociclib and Abemaciclib). Results: Among 4 trials comprising 17, 749 participants, 45% were pre/perimenopausal and 55% were postmenopausal. OS analyses excluded NATALEE as OS data were not reported based on menopause status. Results of the analysis are shown in the Table. Pooled iDFS HR was 0. 80 (I²=64%) in pre/perimenopausal patients and 0. 79 (I²=0%) in postmenopausal patients. Pooled OS HRs were 1. 02 (I²=80%) in pre/perimenopausal and 0. 89 (I²=0%) in postmenopausal patients. These differences were not statistically significant for either iDFS or OS (subgroup difference p = 0. 87 and 0. 57). Compared to post-menopausal participants, those who were premenopausal had 2. 9% fewer absolute IDFS events at 5-6 years. Conclusions: Randomized trials do not suggest any influence of menopausal status on the efficacy of adjuvant CDK4/6 inhibition. Higher heterogeneity among pre/perimenopausal patients suggests variability related to endocrine therapy backbone and patient risk, warranting further investigation. Meta-analysis of iDFS and OS with adjuvant CDK4/6i by menopausal status. Pre/Peri-menopausal Post-menopausal Subgroup difference p n HR (95% CI) Absolute difference at 5-6 years HR (95% CI) Absolute difference at 5-6 years Full cohort IDFS 4 0. 80 (0. 67-0. 97) 3. 3% (n=3) ^ 0. 79 (0. 72-0. 86) 4. 2% (n=3) ^ 0. 87 OS 3 1. 02 (0. 67-1. 54) 0. 2% (n=2) * 0. 89 (0. 78-1. 03) 1. 2% (n=2) * 0. 57 Sensitivity analysis limited to approved CDK4/6i IDFS 2 0. 69 (0. 60-0. 79) 4. 9% 0. 73 (0. 68-0. 85) 4. 9% n/a OS 1 0. 72 (0. 55-0. 94) 2. 5% 0. 91 (0. 75-1. 09) 1. 6% n/a PENELOPE-B excluded due to absence of IDFS subgroup data. *NATALEE/PENELOPE-B excluded due to absence of OS subgroup data.