Evaluation of Alisertib Alone or Combined With Fulvestrant in Patients With Endocrine-Resistant Advanced Breast Cancer: The Phase 2 TBCRC041 Randomized Clinical Trial

Authors

Tufia C Haddad
Vera J Suman
Antonino B D'Assoro
Jodi M Carter
Karthik V Giridhar
Brendan P McMenomy
Katelyn Santo
Erica L Mayer
Meghan S Karuturi
Aki Morikawa
P Kelly Marcom
Claudine J Isaacs
Sun Young Oh
Amy S Clark
Ingrid A Mayer
Khandan Keyomarsi
Timothy J Hobday
Prema P Peethambaram
Ciara C O'Sullivan
Roberto A Leon-Ferre
Minetta C Liu
James N Ingle
Matthew P Goetz

Publication Date

6-1-2023

Journal

JAMA Oncology

Abstract

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 (

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.

Keywords

Humans, Female, Middle Aged, Fulvestrant, Breast Neoplasms, Estrogen Receptor alpha, Aurora Kinase A, Receptor, ErbB-2, Receptors, Estrogen, Antineoplastic Combined Chemotherapy Protocols

Comments

Trial registration: ClinicalTrials.gov Identifier: NCT02860000.

Supplementary Materials

PMID: 36892847