Abstract Background: Dalpiciclib, a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, has shown significant efficacy and a favorable safety profile when combined with endocrine therapy for advanced hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer. Building on this evidence, the present study evaluated the efficacy and safety of neoadjuvant dalpiciclib plus letrozole compared with standard chemotherapy in patients with high-risk HR+/HER2- early breast cancer. Methods: DARLING-02 was a multicenter, randomized, phase II non-inferiority trial (NCT06107673). Key eligibility criteria included women aged ≥18 years; Eastern Cooperative Oncology Group performance status 0-1; clinical stage T1c-2N1-2 or T3-4N0-2; estrogen receptor (ER) expression ≥50%; HER2- status; and Ki-67 level ≤30%. Patients were randomized 1:1 to receive 24-week treatment. The experimental arm received dalpiciclib 150 mg orally once daily (3 weeks on, 1 week off) plus letrozole 2.5 mg orally once daily. The control arm received epirubicin 100 mg/m2 plus cyclophosphamide 500 mg/m2 intravenously on day 1 every 3 weeks for 4 cycles, followed by docetaxel 100 mg/m2 intravenously on day 1 every 3 weeks for 4 cycles. The primary endpoint was objective response rate (ORR), assessed per Response Evaluation Criteria in Solid Tumors, version 1.1. Results: Between August 2023 and April 2025, 170 patients were screened; 158 met the eligibility criteria and were randomized to the dalpiciclib-letrozole (n = 80) or chemotherapy (n = 78) group. At the data cut-off date (September 17, 2025), 9 patients in the experimental arm and 10 in the control arm were still on neoadjuvant therapy. Among patients with completed short-term efficacy assessment, the ORR was 69.0% (49/71) with dalpiciclib-letrozole and 70.5% (48/68) with chemotherapy; total pathological complete response (tpCR) rate was 5.6% (4/71) and 1.5% (1/68), respectively. The proportion of patients with Preoperative Endocrine Prognostic Index (PEPI) score ≥4 was higher in the chemotherapy group (74.6% 44/59) than in the dalpiciclib-letrozole group (53.3% 32/60). Grade ≥3 adverse events were predominantly hematological toxicities and occurred less frequently with dalpiciclib-letrozole than with chemotherapy (decreased white blood cell count: 36.4% 28/77 vs 64.0% 39/61; decreased neutrophil count: 74.0% 57/77 vs 86.9% 53/61). Conclusions: These findings support dalpiciclib plus letrozole as a promising neoadjuvant option for patients with high-risk HR+/HER2- early breast cancer and warrant confirmation in phase III trials. Citation Format: C. Geng, L. Zhang, C. Yang, T. Zhou, L. Ma, R. Luo, Z. Song, Y. Qi, J. Yang, X. Wang, J. Han, J. Ma, Z. Zhang, Y. Li, C. Gao, L. Yang, J. Yu. Neoadjuvant Dalpiciclib Plus Letrozole Versus Standard Chemotherapy in High-Risk HR+/HER2- Negative Breast Cancer (DARLING-02): A Randomized Phase II Trial 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 PS2-13-08.
Geng et al. (2026) studied this question.