Abstract PS1-10-11: Safety of CDK 4/6 inhibitors Combined with Radiotherapy in HR+/HER2- Metastatic Breast Cancer: A Meta-Analysis

Abstract Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are crucial in the treatment of hormone-positive, HER2-negative (HR+/HER2-) metastatic breast cancer (MBC), with radiotherapy (RT) remaining an important modality for symptom control. With increasing clinical use of CDK4/6i in combination with RT, questions have emerged regarding its safety. Although formal prospective guidelines are lacking, increasing retrospective data and expert consensus has begun to inform practice, particularly around timing and toxicity management. This meta-analysis evaluates its safety and feasibility. Methods: We systematically searched PubMed, Embase, Scopus and Cochrane CENTRAL (as of June 2025) to identify studies evaluating the safety of CDK4/6i + RT in HR+/HER2- MBC patients (pts). Eligible studies included those reporting safety outcomes such as grade ≥3 adverse events (AEs), dose reduction, or treatment discontinuations. Data were pooled using a random-effects model. We calculated pooled proportions (PP) and odds ratios (ORs) with 95% CIs. Statistical significance was set at p 0.05. Heterogeneity was assessed using the I2 statistic (low: 0-25%, moderate: 26-50%, high: 50%). The protocol was registered with PROSPERO (CRD420251080439). Results: Nineteen studies comprising 843 HR+/HER2- MBC pts treated with CDK4/6i and RT were included. The median follow-up was 18 months (IQR: 14.7-19.0), and median age was 58.8 years (IQR: 57.15-60.13). The PP of all hematological toxicity was 27.8% (95% CI: 15.6-44.5, I2=85.7%, p 0.0001), with neutropenia in 24.3% of pts (95% CI: 14.9-37.0, I2=79.8%, p 0.0001). Non-hematological toxicities were infrequent, with a PP of 5.4% (95% CI: 3.8-7.7, I2=0.0%, p=0.986). Severe AEs (grade ≥3) occurred in 29.9% (95% CI: 19.8-42.5; I2=79.3%; p0.0001). Dose reduction due to toxicity occurred in 26.7% of pts (95% CI: 17.8-38.1, I2=77.7%, p 0.0001), while treatment discontinuation occurred in 6.3% (95% CI: 4.4-8.9, I2=0.0%, p=0.69). When compared to CDK4/6i therapy alone, the addition of RT was not associated with significantly increased odds of neutropenia (1.13; 95% CI: 0.35-3.68; I2=64.8%; p=0.85), dose reduction (1.06; 95% CI: 0.81-1.40; I2=0%; p=0.58), or treatment discontinuation (0.75; 95% CI: 0.07-8.26; I2=19.5%; p=0.66). Conclusion: CDK4/6i + RT appear to be safe and generally well tolerated in HR+/HER2- MBC, with no significant increase in severe toxicities, dose reductions, or treatment discontinuation vs CDK4/6i alone, supporting feasibility in clinical practice. However, the evidence is limited to retrospective studies with heterogeneous designs, small cohorts, and short follow up, which may underestimate late or site-specific toxicities. Prospective studies with standardized toxicity reporting and stratification by radiation site, dose, and sequencing are needed to better assess long-term safety. Citation Format: K. A. Qidwai, V. Andion Camargo, F. Akkoc Mustafayev, M. Jaramillo, Z. Sarfraz, L. S. Spiegelman, M. A. Ganiyani, M. S. Ahluwalia, R. L. Mahtani. Safety of CDK 4/6 inhibitors Combined with Radiotherapy in HR+/HER2- Metastatic Breast Cancer: A Meta-Analysis abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-10-11.