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William J. Gradishar, MD, FACP, FASCO
William J. Gradishar, MD, FACP, FASCO
Posted: Wednesday, May 10, 2023
Reports have shown that the use of the aurora A kinase (AURKA) inhibitor alisertib may restore endocrine sensitivity and induce upregulation of estrogen receptor α expression; however, its effects on CDK4/6 inhibitor–resistant metastatic breast cancer are unknown. Matthew P. Goetz, MD, of the Mayo Clinic, Rochester, Minnesota, and colleagues found that adding fulvestrant to alisertib did not improve objective response rates or progression-free survival in endocrine-resistant advanced breast cancer. However, alisertib monotherapy did demonstrate clinical activity among those with endocrine-resistant and CDK4/6 inhibitor–resistant disease. The detailed results of the phase II TBCRC041 trial were published in JAMA Oncology.
“AURKA activation, related in part to AURKA amplification and variants, is associated with downregulation of estrogen receptor α expression, endocrine resistance, and implicated in [CDK 4/6 inhibitor] resistance…. Effective approaches to overcome endocrine therapy resistance remain a major challenge in estrogen receptor–positive breast cancer management,” stated Dr. Goetz and colleagues.
A total of 91 postmenopausal women with endocrine-resistant, ERBB2-negative metastatic breast cancer were included in this randomized clinical trial. Patients were randomly assigned on a 1:1 basis to arm 1 (alisertib alone) or arm 2 (alisertib plus fulvestrant). The primary endpoint was the objective tumor response rate; the secondary endpoints included the 24-week clinical benefit rate, duration of response, progression-free survival, and overall survival.
There were no statistical differences in objective tumor response rate for arm 1 (19.6%; 90% confidence interval [CI] = 10.6%–31.7%) and arm 2 (20.0%; 90% CI = 10.9%–32.3%). There were also no differences reported in median progression-free survival between arm 1 (5.6 months; 95% CI = 3.9 months–10.0 months) and arm 2 (5.4 months; 95% CI = 3.9 months–7.8 months). Additional findings revealed that progression-free survival increased for those with AURKA-negative versus -positive tumors (hazard ratio = 0.25; 95% CI = 0.10–0.62). Neutropenia (41.8%) and anemia (13.2%) were the most common grade 3 or higher adverse events attributed to alisertib.
Disclosure: For full disclosures of the study authors, visit jamanetwork.com.
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