Related Experiment Video
Updated: Aug 7, 2025
Endobronchial Ultrasound-guided Intratumoral Injection of Cisplatin for the Treatment of Isolated Mediastinal Recurrence of Lung Cancer
Published on: February 12, 2017
Evaluation of Alisertib Alone or Combined With Fulvestrant in Patients With Endocrine-Resistant Advanced Breast
Tufia C Haddad1, Vera J Suman2, Antonino B D'Assoro1
1Department of Oncology, Mayo Clinic, Rochester, Minnesota.
Importance:
Aurora A kinase (AURKA) activation, related in part to AURKA amplification and variants, is associated with downregulation of estrogen receptor (ER) α expression, endocrine resistance, and implicated in cyclin-dependent kinase 4/6 inhibitor (CDK 4/6i) resistance. Alisertib, a selective AURKA inhibitor, upregulates ERα and restores endocrine sensitivity in preclinical metastatic breast cancer (MBC) models. The safety and preliminary efficacy of alisertib was demonstrated in early-phase trials; however, its activity in CDK 4/6i-resistant MBC is unknown.
Objective:
To assess the effect of adding fulvestrant to alisertib on objective tumor response rates (ORRs) in endocrine-resistant MBC.
Design, Setting, And Participants:
This phase 2 randomized clinical trial was conducted through the Translational Breast Cancer Research Consortium, which enrolled participants from July 2017 to November 2019. Postmenopausal women with endocrine-resistant, ERBB2 (formerly HER2)-negative MBC who were previously treated with fulvestrant were eligible. Stratification factors included prior treatment with CDK 4/6i, baseline metastatic tumor ERα level measurement (<10%, ≥10%), and primary or secondary endocrine resistance. Among 114 preregistered patients, 96 (84.2%) registered and 91 (79.8%) were evaluable for the primary end point. Data analysis began after January 10, 2022.
Interventions:
Alisertib, 50 mg, oral, daily on days 1 to 3, 8 to 10, and 15 to 17 of a 28-day cycle (arm 1) or alisertib same dose/schedule with standard-dose fulvestrant (arm 2).
Main Outcomes And Measures:
Improvement in ORR in arm 2 of at least 20% greater than arm 1 when the expected ORR for arm 1 was 20%.
Results:
All 91 evaluable patients (mean [SD] age, 58.5 [11.3] years; 1 American Indian/Alaskan Native [1.1%], 2 Asian [2.2%], 6 Black/African American [6.6%], 5 Hispanic [5.5%], and 79 [86.8%] White individuals; arm 1, 46 [50.5%]; arm 2, 45 [49.5%]) had received prior treatment with CDK 4/6i. The ORR was 19.6%; (90% CI, 10.6%-31.7%) for arm 1 and 20.0% (90% CI, 10.9%-32.3%) for arm 2. In arm 1, the 24-week clinical benefit rate and median progression-free survival time were 41.3% (90% CI, 29.0%-54.5%) and 5.6 months (95% CI, 3.9-10.0), respectively, and in arm 2 they were 28.9% (90% CI, 18.0%-42.0%) and 5.4 months (95% CI, 3.9-7.8), respectively. The most common grade 3 or higher adverse events attributed to alisertib were neutropenia (41.8%) and anemia (13.2%). Reasons for discontinuing treatment were disease progression (arm 1, 38 [82.6%]; arm 2, 31 [68.9%]) and toxic effects or refusal (arm 1, 5 [10.9%]; arm 2, 12 [26.7%]).
Conclusions And Relevance:
This randomized clinical trial found that adding fulvestrant to treatment with alisertib did not increase ORR or PFS; however, promising clinical activity was observed with alisertib monotherapy among patients with endocrine-resistant and CDK 4/6i-resistant MBC. The overall safety profile was tolerable.
Trial Registration:
ClinicalTrials.gov Identifier: NCT02860000.
Insights
Alisertib monotherapy showed promising clinical activity in patients with endocrine-resistant metastatic breast cancer (MBC) previously treated with CDK 4/6 inhibitors. Adding fulvestrant to alisertib did not improve objective tumor response rates or progression-free survival.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Aurora A kinase (AURKA) activation is linked to estrogen receptor (ER) downregulation, endocrine resistance, and cyclin-dependent kinase 4/6 inhibitor (CDK 4/6i) resistance in metastatic breast cancer (MBC).
- Alisertib, an AURKA inhibitor, has shown potential in preclinical models to restore ERα expression and endocrine sensitivity.
- The efficacy of alisertib in CDK 4/6i-resistant MBC requires further investigation.
Purpose of the Study:
- To evaluate the impact of combining alisertib with fulvestrant on objective tumor response rates (ORRs) in patients with endocrine-resistant MBC.
- To assess the clinical activity and safety of alisertib, both as monotherapy and in combination with fulvestrant, in a heavily pre-treated MBC population.
Main Methods:
- A phase 2 randomized clinical trial (NCT02860000) enrolled postmenopausal women with ERBB2-negative, endocrine-resistant MBC previously treated with fulvestrant.
- Participants were randomized to receive either alisertib monotherapy (arm 1) or alisertib plus fulvestrant (arm 2).
- Stratification included prior CDK 4/6i treatment, baseline ERα levels, and type of endocrine resistance. ORR was the primary endpoint.
Main Results:
- A total of 91 patients were evaluable. The ORR was 19.6% for alisertib monotherapy and 20.0% for alisertib plus fulvestrant, showing no significant difference.
- Median progression-free survival was 5.6 months for alisertib monotherapy and 5.4 months for the combination arm.
- Common grade 3 or higher adverse events included neutropenia (41.8%) and anemia (13.2%). Treatment discontinuation due to toxic effects was higher in the combination arm.
Conclusions:
- Adding fulvestrant to alisertib did not improve ORR or progression-free survival in endocrine-resistant MBC.
- Alisertib monotherapy demonstrated promising clinical activity in patients with endocrine-resistant and CDK 4/6i-resistant MBC.
- The overall safety profile of alisertib was tolerable, suggesting potential for its use as a monotherapy in this patient population.
More Related Videos
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:56Treatment Resistant Cancers