Adjuvant Dalpiciclib Plus Endocrine Therapy Improves iDFS in HR+/HER2– Early Breast Cancer

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The addition of dalpiciclib (SHR6390) to adjuvant endocrine therapy (ET) led to a statistically significant improvement in invasive disease-free survival (iDFS) compared with placebo plus ET in patients with hormone receptor–positive, HER2-negative early breast cancer, meeting the primary end point of the phase 3 DAWNA-A trial (NCT04842617).

Findings presented at the 2025 ASCO Annual Meeting showed that at the time of the trial’s first interim analysis, the dalpiciclib regimen reduced the risk of invasive recurrence or death by 44% compared with the placebo regimen (HR, 0.56; 95% CI, 0.43-0.71; P < .0001). In the dalpiciclib arm (n = 2640), patients achieved 24- and 36-month iDFS rates of 94.7% and 89.1%, respectively. These respective rates were 90.2% and 86.2% in the placebo arm (n = 2634).

“Our data support dalpiciclib plus ET as a new adjuvant treatment option for [patients with] hormone receptor–positive/HER2-negative early breast cancer,” lead study author Zhi-Ming Shao, MD, of Fudan University Shanghai Cancer Center in China, said in a presentation of the data.

DAWNA-A Background

Although adjuvant ET—with or without chemotherapy/radiation as indicated—serves as a standard of care (SOC) for patients with hormone receptor–positive early breast cancer, Shao explained that recurrence remains a risk for this population. After dalpiciclib, a novel CDK4/6 inhibitor, displayed improvements in progression-free survival when combined with ET in advanced disease settings, investigators sought to evaluate the regimen as adjuvant therapy.

The study included patients with pathologically confirmed stage II or II hormone receptor–positive, HER2-negative breast cancer. Patients needed to have at least 4 positive axillary lymph nodes, or 1 to 3 positive nodes with at least 1 high-risk factor, including a tumor size of at least 5 cm; histologic grade 3 disease; residual invasive breast cancer after neoadjuvant therapy; or a Ki-67 level of at least 30%.

Patients were randomly assigned 1:1 to receive dalpiciclib at 125 mg once per day on days 1 to 21 of each 28-day cycle for up to 2 years in combination with SOC ET for at least 5 years; or placebo plus ET. In both arms, premenopausal patients were required to receive LHRH agonists; these could be given at the investigator’s discretion for perimenopausal patients.

Key stratification factors included menopausal status (postmenopausal vs pre/perimenopausal), clinical disease stage (II vs III), positive lymph nodes (≥4 vs <4), and adjuvant chemotherapy (yes vs no).

Along with the primary end point of iDFS, secondary end points comprised DFS, distant DFS (DDFS), overall survival, and safety.

Patient Disposition and Baseline Characteristics

The dalpiciclib arm included 2640 patients in the intention-to-treat (ITT) population and 2629 patients in the safety set. At data cutoff, 49.8% of patients had discontinued the CD4/6 inhibitor due completing 2 years of treatment (37.8%), patient withdrawal (6.0%), progressive disease (2.7%), adverse effects (AEs; 2.7%), and other reasons (0.8%). ET was discontinued in 10.9% of patients due to patient withdrawal (5.8%), progressive disease (3.3%), AEs (1.2%), and other reasons (0.7%). Treatment with any agent was ongoing in 88.6% of patients.

In the placebo group, 2634 and 2629 patients comprised the ITT and safety populations, respectively. Placebo was discontinued in 37.3% of patients due to completion of 2 years of treatment (37.3%), patient withdrawal (6.9%), progressive disease (5.2%), AEs (1.6%), and other reasons (0.6%). ET was discontinued in 14.6% of patients due to patient withdrawal (7.1%), progressive disease (5.2%), AEs (1.1%), and other reasons (0.7%). Treatment with any agent was ongoing in 85.2% of patients.

At baseline, the median age was 50 years (interquartile range [IQR], 43-56) in the dalpiciclib arm vs 49 years (IQR, 43-56) in the placebo arm. Most patients were under 65 years of age (dalpiciclib arm, 93.3%; placebo arm, 92.8%), had an ECOG performance status of 0 (74.0%; 74.0%), were premenopausal (46.9%; 47.9%), had estrogen receptor–positive disease (99.7%; 99.6%), had progesterone receptor–positive disease (79.6%; 78.9%), had AJCC stage III disease (71.5%; 71.4%), had histologic grade 2 disease (67.2%; 64.8%), and had at least 4 positive axillary lymph nodes (77.3%; 77.4%).

Prior therapies included neoadjuvant chemotherapy (dalpiciclib arm, 33.9%; placebo arm, 34.4%), adjuvant chemotherapy (70.5%; 70.5%), ET (67.3%; 67.3%), and radiotherapy (98.3%; 98.1%). Ki-67 expression levels included less than 20% (40.0%; 39.0%), at least 20% (59.6%; 61.0%), less than 30% (56.8%; 54.6%), and at least 30% (42.8%; 45.4%).

Additional Efficacy and Safety Data

Findings also showed statistically significant improvements in DFS (HR, 0.53; 95% CI, 0.42-0.67; P < .0001) and DDFS (HR, 0.60; 95% CI, 0.46-0.78; P < .0001).

The median duration of treatment was 19.1 months (IQR, 10.2-24.2) in the dalpiciclib arm vs 18.6 months (IQR, 10.0-24.0) in the placebo arm. Any-grade AEs occurred in 99.5% and 93.6% of patients, respectively. The respective rates of grade 3 or higher AES were 84.4% and 17.3%. Serious AEs occurred in 8.9% and 7.6% of patients, respectively; the respective rates of serious treatment-related AEs were 3.7% and 1.5%. AEs led to death in 1 patient (<0.1%) in the experimental arm vs 2 patients (0.1%) in the control arm.

AEs led to dose interruptions, dose reductions, and treatment discontinuation of dalpiciclib in 75.6%, 12.7%, and 2.6% of patients in the experimental arm, respectively. In the control arm, these respective rates were 29.5%, 0.5%, and 1.4% for placebo. AEs led to dose interruptions of ET in 16.0% of patients in the experimental arm vs 12.4% of patients in the control arm. AEs led to the discontinuation of ET in 1.7% of patients in both arms.

The most common any-grade AEs reported in at least 15% of patients in either arm comprised decreased neutrophil count (dalpiciclib arm, 97.5%; placebo arm, 22.7%), decreased white blood cell count (97.3%; 30.4%), anemia (54.2%; 7.9%), decreased platelet count (41.3%; 6.2%), hypertriglyceridemia (33.2%; 35.8%), increased alanine aminotransferase levels (24.2%; 26.4%), decreased lymphocyte count (24.2%; 7.4%), increased aspartate aminotransferase levels (23.5%; 23.1%), COVID-19 (21.6%; 18.0%), arthralgia (17.7%; 22.5%), urinary tract infection (16.2%; 18.1%), and upper respiratory tract infection (15.8%; 14.1%).

Reference

Shao Z-M, Hao J, Wang S, et al. Dalpiciclib (Dalp) plus endocrine therapy (ET) as adjuvant treatment for HR+/HER2– early breast cancer (BC): The randomized, phase 3, DAWNA-A trial. J Clin Oncol. 2025;43(suppl 16):515. doi:10.1200/JCO.2025.43.16_suppl.515