Discussion
PD, tumor, endocrine-resistant, endocrine-resistant disease
TUMOR
In this randomized phase 2 clinical trial, the clinical efficacy and safety of alisertib alone or combined with fulvestrant was evaluated in ERBB2These results confirm prior findings demonstrating the antitumor activity of alisertib in endocrine-resistant, ERWhile caution must be applied when conducting cross-trial comparisons, to our knowledge, there is a paucity of clinical data regarding the efficacy of approved or investigational therapies following CDK 4/6i progression. Evaluating the current study results in this context may help to understand the potential value of alisertib in the evolving landscape of endocrine-resistant and CDK 4/6i–resistant MBC. Notably, single-agent ET has limited efficacy in this setting, as evidenced by the phase 2 VERONICA trial (n = 101) in which mPFS to fulvestrant was 1.94 months (95% CI, 1.84-3.55).In the BYLieve trial, a single-arm study of alpelisib with fulvestrant in patients with CDK 4/6i–resistant, The phase 3 TROPICS-02 trial (n = 543) included patients with endocrine-resistant and CDK 4/6i–resistant MBC and reported an improvement in mPFS with the antibody drug conjugate sacituzumab govitecan (5.5 months; 95% CI, 4.2-7.0) compared with single-agent chemotherapy of the physician’s choice (4.0 months; 95% CI, 3.1-4.4).An increased rate of investigational therapy discontinuation for reasons other than PD was observed in this trial among those receiving combination fulvestrant and alisertib. This was unexpected given the lack of overlapping toxic effects and favorable safety profile observed in our prior phase 1 trial of combination therapy.Given the clinical efficacy and safety results observed in TBCRC 041, continued clinical development of alisertib is warranted and planned. Further supporting this is the observation of clinical activity among those who received prior everolimus. If the clinical outcomes observed in this study were confirmed in a subsequent registration trial, alisertib may provide a new treatment option for endocrine-resistant disease to a broader cohort of patients given that alpelisib is only available for The correlative studies indicated that high AURKA registration tumor expression was associated with poor clinical outcomes, which was consistent with prior studies.While alisertib did not restore sensitivity to fulvestrant as preclinical studies