Background
Aurora kinase A (AURKA) plays an integral role in the mitotic cell cycle, regulating spindle assembly, centrosome function, chromosome alignment, and mitotic entry. In addition to its mitotic role, activated AURKA has been shown to induce epithelial-mesenchymal transition reprogramming and contribute to endocrine resistance in estrogen receptor–positive (ER+) breast cancer models. Amplification/overexpression of AURKA is linked to poor prognosis across multiple tumor types, including ER+/HER2-negative (HER2–) breast cancer. Alisertib is a selective, reversible, ATP-competitive AURKA inhibitor that has been shown to disrupt spindle formation, leading to mitotic defects and cell death. In xenografts, the potent inhibition of AURKA by alisertib led to antitumor activity across a variety of tumor types. Preliminary clinical data with alisertib have shown significant antitumor activity and a manageable safety profile in patients with various cancers, including ER+/HER2– breast cancer. This study aims to better characterize the role of alisertib in patients with breast cancer to provide a rationale for future clinical studies.
Methods
Three studies evaluating alisertib in patients with ER+/HER2– metastatic breast cancer have been completed, including a phase 1 study of alisertib plus fulvestrant, a phase 2 alisertib monotherapy study, and a phase 2 study of alisertib with or without fulvestrant. Descriptive summary statistics were utilized for patient characteristics, as well as clinical safety and efficacy data.
Results
A total of 126 patients were enrolled and evaluable in the 3 clinical studies, as per Table. All patients had metastatic breast cancer and received prior endocrine therapy and chemotherapy. All patients in TBCRC 041 also received a prior CDK4/6 inhibitor (CDK 4/6i). In these heavily pretreated patients, tumor objective response rates (ORR) were approximately 20%, and 6-month clinical benefit rates (CBRs) were 29% to 78%. The most common grade 3/4 adverse events (AEs) across studies were hematologic AEs (neutropenia, leukopenia, and anemia), and fatigue. In TBCRC 041, ctDNA- and tumor-derived RNA-Seq–based biomarker assessments are ongoing to investigate associations with clinical benefit from alisertib alone or combined with fulvestrant.
Conclusions
Alisertib has shown efficacy and safety across multiple clinical studies in patients with ER+/HER2– metastatic breast cancer and could provide a novel option for treating those who have progressed on endocrine therapy and a CDK4/6i. These findings provide a strong rationale for further development of alisertib in this patient population. The ongoing phase 2 ALISCA-Breast1 study (NCT06369285) is investigating the optimal dose of alisertib in combination with standard endocrine therapies in this setting.
