Addition of Fulvestrant to Alisertib in Endocrine-Resistant Metastatic Breast Cancer

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In the phase II TBCRC041 trial reported in JAMA Oncology, Haddad et al found that the addition of fulvestrant to alisertib did not improve objective response rate in postmenopausal patients with HER2-negative, endocrine-resistant metastatic breast cancer.

Study Details

The multicenter trial, conducted through the Translational Breast Cancer Research Consortium, enrolled patients between July 2017 and November 2019. A total of 91 evaluable patients were randomly assigned to receive the Aurora A kinase inhibitor alisertib alone at 50 mg twice daily on days 1 to 3, 8 to 10, and 15 to 17 of 28-day cycles (n = 46) or alisertib plus fulvestrant at 500 mg on days 1 and 15 of cycle 1 and day 1 of all subsequent cycles. All patients had received prior treatment with cyclin-dependent kinase (CDK) 4/6 inhibitors. All patients but one had received prior fulvestrant. The primary outcome measure was objective response rate, with the hypothesis that the rate in the alisertib/fulvestrant group would be at least 20% greater than the expected rate of 20% in the alisertib group.


Objective responses (all partial) were achieved in 9 of 46 patients (19.6%, 90% confidence interval [CI] = 10.6%–31.7%) in the alisertib group vs 9 of 45 patients (20.0%, 90% CI = 10.9%–32.3%) in the alisertib/fulvestrant group, including a complete response in 1.


  • The addition of fulvestrant to alisertib did not improve objective response rate.
  • Alisertib monotherapy showed promising activity in this setting.

For the alisertib vs alisertib/fulvestrant groups, median duration of response was 15.1 months vs 8.5 months, and the 24-week clinical benefit rate was 41.3% vs 28.9%. Estimated median progression-free survival was 5.6 months (95% CI = 3.9–10.0 months) in the alisertib group vs 5.4 months (95% CI = 3.9–7.8 months) in the alisertib/fulvestrant group. Estimated 1-year overall survival was 75.1% vs 62.7%, with estimated median overall survival of 22.7 months (95% CI = 18.4 months to not estimable) in patients receiving alisertib vs 19.8 months (95% CI = 11.5 months to not estimable) in those receiving alisertib/fulvestrant. A total of 17 of 37 patients whose disease progressed during alisertib treatment crossed over to receive the combination.

Adverse Events

The most common grade ≥ 3 adverse events in the alisertib group were neutropenia (43.4%), anemia (19.6%), and leukopenia (17.4%). The most common grade ≥ 3 adverse events in the alisertib/fulvestrant group were neutropenia (42.2%), leukopenia (31.1%), lymphopenia (15.6%), fatigue (11.1%), and anemia (8.9%). Treatment was discontinued because of toxicity or patient refusal in 10.9% vs 26.7% of patients. One death considered possibly related to treatment occurred in the alisertib/fulvestrant group (from respiratory failure).

The investigators concluded: “The trial results found that while alisertib did not restore fulvestrant sensitivity and increase [objective response rates], promising clinical activity was observed with alisertib monotherapy among patients with endocrine-resistant and [CDK]4/6 inhibitor–resistant metastatic breast cancer.”

Tufia Haddad, MD, of the Department of Oncology, Mayo Clinic, Rochester, is the corresponding author of the JAMA Oncology article.

Disclosure: The study was supported by Takeda Oncology, Breast Cancer Research Foundation, Susan G. Komen, and others. For full disclosures of the study authors, visit

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