In a multicenter, phase III, randomised DAWNA-1 study, the combination of dalpiciclib, a new cyclin-dependent kinase (CDK) 4 and 6 inhibitor, with fulvestrant improved progression-free survival (PFS) with manageable safety in patients with hormone receptor (HR)-positive, HER2-negative advanced breast cancer who progressed or relapsed on endocrine therapy. The researchers from the DAWNA-1 Study Consortium led by doctors from the Department of Medical Oncology and Clinical Trial Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College in Beijing, China, who reported the interim results on 4 November 2021 in the Nature Medicine wrote that their findings support the application of dalpiciclib plus fulvestrant as a new treatment option for patients with HR-positive, HER2-negative advanced breast cancer who relapse or progress on previous endocrine therapy.
Dalpiciclib (SHR6390) is a new, orally administered, selective CDK4/6 inhibitor. In preclinical studies, dalpiciclib was shown to exert potent antitumour activity via retinoblastoma protein-dependent cytostasis. Dalpiciclib as monotherapy has demonstrated tolerability and preliminary clinical activity in patients with heavily pretreated HR-positive, HER2-negative advanced breast cancer. In a phase Ib study, the researchers established the synergic effects of dalpiciclib with fulvestrant in the treatment of advanced breast cancer.
The DAWNA-1 investigators conducted a randomised, double-blind, placebo-controlled phase III study to further assess the efficacy and safety of dalpiciclib plus fulvestrant in patients with HR-positive, HER2-negative advanced breast cancer who relapsed or progressed on previous endocrine therapy.
In total, 361 patients were randomised 2:1 to receive dalpiciclib plus fulvestrant or placebo plus fulvestrant. The study met the primary endpoint, showing significantly prolonged PFS assessed by investigators with dalpiciclib plus fulvestrant (15.7 months, 95% confidence interval (CI) 11.1–not reached) versus placebo plus fulvestrant (7.2 months, 95% CI 5.6–9.2) with hazard ratio 0.42 (95% CI 0.31–0.58; one-sided p < 0.0001).
The most common grade 3 or 4 adverse events with dalpiciclib plus fulvestrant were neutropenia (84.2%) and leukopenia (62.1%). The incidence of serious adverse events was 5.8% with dalpiciclib plus fulvestrant versus 6.7% with placebo plus fulvestrant.
The study team resported some limitations. Only patients with HR-positive, HER2-negative advanced breast cancer and secondary endocrine resistance were enroled. The role of dalpiciclib combination therapy in the treatment of patients with primary endocrine resistance requires further investigation. The study was conducted in Chinese patients and the efficacy and tolerability of dalpiciclib plus fulvestrant in other populations is to be established. The overall survival data are not mature yet. The long-term survival benefits of adding dalpiciclib to fulvestrant will be further elucidated in final analysis of the study.
The authors concluded that their findings support the application of dalpiciclib plus fulvestrant as a new treatment option for patients with HR-positive, HER2-negative advanced breast cancer who relapse or progress on previous endocrine therapy.
The study was funded by Jiangsu Hengrui Pharmaceuticals (formerly Jiangsu Hengrui Medicine).
Xu B, Zhang Q, Zhang P, et al. Dalpiciclib or placebo plus fulvestrant in hormone receptor-positive and HER2-negative advanced breast cancer: a randomized, phase 3 trial. Nature Medicine 2021;27:1904-1909.