Everolimus Enhances the Efficacy of Fulvestrant in ER⁺ Breast Cancer

Endocrine therapies, which include ER modulators, aromatase inhibitors, and selective ER downregulators (SERD), extend survival in patients with estrogen receptor (ER)–positive breast cancer. However, resistance can develop through aberrant activation of mTOR signaling, suggesting the potential for enhancing the efficacy of antiestrogen therapy by adding mTOR inhibitors. The mTOR inhibitor everolimus has been shown to improve the efficacy of aromatase inhibitors. Kornblum and colleagues sought to determine if everolimus could improve outcomes in patients treated with fulvestrant, a SERD that inhibits estrogen signaling more effectively than aromatase inhibitors. A total of 129 patients with ER-positive, aromatase inhibitor–resistant metastatic breast cancer were treated with fulvestrant plus everolimus (64 patients) or fulvestrant plus placebo (65 patients) in a randomized, double-blind, phase II trial. The primary endpoint was progression-free survival, and secondary endpoints included response rate, clinical benefit rate, and overall survival. Everolimus extended progression-free survival from 5.1 to 10.3 months, demonstrating clinical benefit of combined treatment with fulvestrant and everolimus. The addition of everolimus also resulted in a nonsignificant increase in objective response rate from 12.3% to 18.2% and a significant increase in the clinical benefit rate from 41.5% to 63.6%. There was no significant difference in overall survival between the everolimus and placebo arms. There was an increased incidence of adverse events in the everolimus arm compared with the placebo arm, but grade 3–4 adverse events were rare. Taken together, the results of this phase II trial suggest that mTOR inhibition with everolimus improves the efficacy of fulvestrant in patients with aromatase inhibitor–resistant ER-positive metastatic breast cancer.

Kornblum N, Zhao F, Manola J, Klein P, Ramaswamy B, Brufsky A, et al. Randomized phase II trial of fulvestrant plus everolimus or placebo in postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer resistant to aromatase inhibitor therapy: results of PrE0102. J Clin Oncol 2018 Apr 17 [Epub ahead of print].

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