Alisertib monotherapy has shown activity in postmenopausal patients with endocrine-resistant, HER2-negative, metastatic breast cancer, according to research published in JAMA Oncology.

However, alisertib was not able to restore sensitivity to fulvestrant in this patient population. There was no difference in response or survival outcomes between patients who received alisertib monotherapy and those who received fulvestrant and alisertib in combination. 

This phase 2 trial ( Identifier: NCT02860000) included 91 patients with endocrine-resistant, HER2-negative, metastatic breast cancer who had received prior endocrine therapy and CDK4/6 inhibitor therapy in the metastatic setting.

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The patients were randomly assigned to receive alisertib monotherapy (n=46) or alisertib plus fulvestrant (n=45). Prior chemotherapy for metastatic disease was more common in the combination arm (68.9%) than in the monotherapy arm (47.8%). Most patients had secondary endocrine resistance — 76.1% in the monotherapy arm and 82.2% in the combination arm.  

Patients received a median of 6 cycles of alisertib monotherapy (range, 1-34) and a median of 4 cycles of combination treatment (range, 1-44). Disease progression was the most common reason for treatment discontinuation in the monotherapy arm (82.6%) and the combination arm (68.9%).

The objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were similar between the treatment arms. 

“[W]hile alisertib did not restore fulvestrant sensitivity and increase ORRs, promising clinical activity was observed with alisertib monotherapy,” the researchers wrote.

The ORR was 19.6% with alisertib and 20.0% with the combination. The median duration of response was 15.1 months in the monotherapy arm and 8.5 months with the combination. 

The median PFS was 5.6 months in the monotherapy arm and 5.4 months in the combination arm. The median OS was 22.7 months and 19.8 months, respectively. 

There were 17 patients who crossed over from the monotherapy arm to the combination arm after disease progression. After crossover, 1 patient achieved a partial response, and the median PFS was 3.7 months.

The most common grade 3 or higher adverse events in the monotherapy arm were neutropenia (43.4%), leukopenia (17.4%), and anemia (19.6%). The most common grade 3 or higher adverse events in the combination arm were neutropenia (42.2%), leukopenia (31.1%), lymphopenia (15.6%), fatigue (11.1%), and anemia (8.9%).

The researchers concluded that alisertib “is among the first investigational targeted therapies demonstrating promising clinical activity and a tolerable safety profile” in patients with endocrine- and CDK4/6 inhibitor-resistant metastatic breast cancer.

Disclosures: This research was supported by Takeda Oncology. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


Haddad TC, Suman VJ, D’Assoro AB, et al. Evaluation of alisertib alone or combined with fulvestrant in patients with endocrine-resistant advanced breast cancer: The phase 2 TBCRC041 randomized clinical trial. JAMA Oncol. Published online March 9, 2023. doi:10.1001/jamaoncol.2022.7949

This article originally appeared on Cancer Therapy Advisor