Clinical efficacy and therapy response prediction of neoadjuvant dalpiciclib plus letrozole in postmenopausal patients with HR+/HER2- stage II-III breast cancer (DARLING 01): a single-arm, open-label, exploratory study.

Background: Hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer is the most common subtype of breast cancer, yet its response to traditional chemotherapy remains limited, posing a challenge in achieving optimal therapeutic outcomes. In this study, we aimed to evaluate the clinical efficacy and safety of dalpiciclib, a novel CDK4/6 inhibitor, combined with letrozole as neoadjuvant therapy (NAT) in postmenopausal patients with HR+/HER2- stage II-III breast cancer. Additionally, we explored potential predictive biomarkers for treatment response using gene analysis.

Methods: This single-arm, open-label, exploratory phase II trial involved 35 postmenopausal women with HR+/HER2- breast cancer (ClinicalTrials.gov identifier NCT05512780). Patients received four cycles of dalpiciclib (125 mg/day for 3 weeks, followed by 1 week off) plus continuous letrozole (2.5 mg/day). The primary endpoint was objective response rate (ORR), and secondary endpoints included changes in Ki-67 expression, complete cell cycle arrest (CCCA) rate, residual cancer burden (RCB), and safety profiles. Gene expression profiling and least absolute shrinkage and selection operator (LASSO) regression were conducted to identify biomarkers predictive of response to NAT.

Results: Among the 35 enrolled patients, 31 completed the full treatment course. Of the 29 patients with evaluable response data after 4 cycles, 16 achieved partial response (PR), resulting in an ORR of 55.2%. Following two weeks of treatment, the mean Ki-67 expression significantly decreased from a baseline of 17.5-1.8%, and CCCA was observed in 75% of patients. Grade ≥ 3 treatment-emergent adverse events (TEAEs) were mainly decreased neutrophil count (45.7%), with a median duration of 3 days. The NAT predictive model, developed using gene expression analysis and clinicopathological factors, achieved an area under the curve (AUC) of 0.928, indicating that TFRC, SCUBE2, and MMP11A could serve as novel predictive biomarkers for response to NAT.

Conclusions: Dalpiciclib combined with letrozole demonstrated promising antitumor activity and an acceptable safety profile in postmenopausal patients with HR+/HER2- breast cancer. The identification of TFRC, SCUBE2, and MMP11A as predictive biomarkers provides insights into the potential for personalized neoadjuvant treatment strategies.