Evaluation of Alisertib Alone or Combined With Fulvestrant in Patients With Endocrine-Resistant Advanced Breast Cancer

Abstract

ImportanceAurora 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.ObjectiveTo assess the effect of adding fulvestrant to alisertib on objective tumor response rates (ORRs) in endocrine-resistant MBC.Design, Setting, and ParticipantsThis 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.InterventionsAlisertib, 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 MeasuresImprovement in ORR in arm 2 of at least 20% greater than arm 1 when the expected ORR for arm 1 was 20%.ResultsAll 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 RelevanceThis 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 RegistrationClinicalTrials.gov Identifier: NCT02860000

Community cohesion looseness in gene networks reveals individualized drug targets and resistance

“…Interestingly, anti-cancer drugs targeting AURKA (e.g. Alisertib) are recently considered as potential therapeutic options [ 39 ].…”

Seize the engine: Emerging cell cycle targets in breast cancer

“…In the phase 2 study by Haddad et al., 162 91 patients who had previously received ET and CDK4/6i were treated with alisertib alone or in combination with fulvestrant. For alisertib monotherapy, ORR was 20%, 24‐week CBR was 41%, and median PFS was 5.6 months; all similar to the combination where ORR was 20%, CBR was 29% and median PFS was 5.4 months 162 . The correlative analyses published with this study are based solely on ER and AURKA expression in pre‐treatment biopsies, where a positive AURKA expression was significantly associated with a shorter PFS in the monotherapy arm but not in the combination arm, and with additional studies underway 162 .…”

“… 159 , 160 In the first phase 2 study, alisertib monotherapy demonstrated a manageable safety profile in a cohort of 53 BC patients, with an ORR of 18% in HR + or HER2 + BC patients resistant to ET, but minimal activity in TNBC. 161 In the phase 2 study by Haddad et al., 162 91 patients who had previously received ET and CDK4/6i were treated with alisertib alone or in combination with fulvestrant. For alisertib monotherapy, ORR was 20%, 24‐week CBR was 41%, and median PFS was 5.6 months; all similar to the combination where ORR was 20%, CBR was 29% and median PFS was 5.4 months.…”

The golden key to open mystery boxes of SMARCA4-deficient undifferentiated thoracic tumor: focusing immunotherapy, tumor microenvironment and epigenetic regulation

“…In SMARCA4-deficient tumor cells, the activity of AURKA is necessary for mitotic spindle assembly and cell survival, and it has been demonstrated that the AURKA inhibitor (VX-680) induces tumror cells death in vitro and in mouse vivo assays [ 51 ]. Shi [ 52 ] found that AURKA was a potential lung cancer marker by KEGG and GO enrichment analysis, and Alisertib has shown promising clinical activity in solid tumors [ 53 ].…”