New oral SERD plus CDK4/6 inhibitors in recurrent or metastatic ER+/HER2- breast cancer: A systematic review and single-arm meta-analysis.

Abstract

e13072 Background: Hormone-positive breast cancer is prone to late recurrence and is biologically heterogeneous. The advent of selective estrogen receptor degraders (SERDs), such as fulvestrant, has improved treatment for metastatic disease. However, resistance to hormones and ESR1 mutations continues to impede disease control. Emerging drug combinations aim to address these obstacles while avoiding more systemic chemotherapy. We analyzed the efficacy of novel oral SERDs combined with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in recurrent or metastatic hormone-positive breast cancer. Methods: We searched for randomized clinical trials that reported the use of new oral SERDs combined with CDK4/6 inhibitors in patients with recurrent or stage IV breast cancer, using the PubMed, Cochrane, and Embase databases up to December 2025. The primary efficacy endpoints were Objective Response Rate (ORR), Clinical Benefit Rate (CBR), and Progression-Free Survival (PFS) in both intention-to-treat and ESR1 mutation-positive patients. Considering safety, we assessed treatment-related adverse events (TRAEs) by any grade and grade 3. Statistical analysis was performed using R software. We analysed heterogeneity with I² statistics and pooled proportions using a random-effects model. Results: We included six prospective studies with 1178 patients that met eligibility criteria. The pooled median PFS was 10.09 months (95% CI 6.79 - 15, I² = 88.7%), while subgroup analysis of patients in second-line endocrine therapy has a similar PFS of 10.26 months (95% CI 5.80 - 18.17, i² = 91,1%). The ORR was 21.90% (95% CI 13.37- 33.77, I² = 84.5%) and CBR 68.97% (95% CI 53.33-81.22, I² = 92.3%). Patients harboring ESR1 mutations present a median PFS of 11.61 months (95% CI 7.81-17.21, I² 83.5%). TRAEs by any grade were 89.17% (95% CI 66.67- 97.13, I2 = 95.1%), while grade 3 were 49.42% (95% CI 31.88-67.10, I2 = 88.6%). Conclusions: The combination of new oral SERDs and CDK 4/6 inhibitors in hormone-positive breast cancer constitutes a promising and effective strategy for metastatic disease control with manageable toxicity. Addressing the ESR1 mutational profile is crucial to optimizing the impact of this therapeutic approach.