Abstract PS12-14: Phase II trial of fulvestrant plus enzalutamide in ER+/Her2- advanced breast cancer
Authors: Elias Anthony D , Spoelsta Nicole , Vidal Gregory A , Sams Sharon , Kabos Peter , Diamond Jennifer R , Shagisultanova Elena , Afghahi Anosheh , Mayordomo Jose , McSpadden Tessa , Crawford Gloria , Carter Lisa , Zolman Kathryn , Armstead Stephanie , Winchester Alyse , Borges Virginia , Wulfkuhle Julia , Petricoin Emanuel , Gao Dexiang , Richer Jennifer 
Published: February 2021

Abstract
Up to 91% of ER+ breast cancers express androgen receptor (AR), but its function is uncertain. Although AR expression is associated with more indolent tumors, high AR expression relative to ER is associated with endocrine resistance, and in the absence of estradiol or if ER function is blocked, preclinical studies suggest that AR can take over to signal cell survival and proliferation. Following extensive preclinical studies and a brief phase I to demonstrate a lack of significant PK interaction, this phase II trial of fulvestrant plus enzalutamide in ER+/Her2- metastatic breast cancer was conducted. Methods: Eligible patients were women with ECOG 0-2, ER+/Her2- measurable or evaluable metastatic breast cancer without CNS disease. Prior fulvestrant was allowed, if clinically indicated as per treating physician. Fulvestrant was administered in standard dosing at 500 mg IM days 1, 15, 29 and every 4 weeks thereafter. Enzalutamide was given at 160 mg po daily on a continual basis. Fresh tumor biopsies were required at study entry and at about 4 weeks on therapy. The primary efficacy endpoint of the trial was clinical benefit rate at 24 weeks (CBR24). Assuming the undesirable rate of 10% and desirable rate of 30%, a sample size of 24 provided 89% power to detect this 25% rate difference using an exact binomial test with a one-sided alpha of 0.085. Due to the exploratory nature of biomarker analysis, the type I error rate was not adjusted for exploring multiple biomarkers. Results: A total of 38 patients were consented, of whom 32 were eligible. Median age was 61 years (46-87); PS 1 (0-1); a median of 2 prior chemotherapy and 2 prior hormonal therapies for metastatic disease. Twelve patients had prior fulvestrant, and 90% had visceral disease. TEAEs &gt;20% included fatigue, nausea/vomiting, constipation, headache, anorexia, although most were low grade. There were no G4 or G5 toxicities. Median PFS was 2.0 months (0.5-12). CBR24 was 25% (7/28 evaluable).Conclusions: In a heavily pretreated population of women with metastatic ER+/Her2- BC, the combination of fulvestrant plus enzalutamide had manageable side effects, and modest activity. About 25% reached the primary endpoint of clinical benefit of more than 6 months on therapy. Extensive molecular studies of paired fresh biopsies from pretreatment and at 4 weeks are underway. These analyses and correlations with clinical outcome will be described.
Citation Format: Anthony D Elias, Nicole Spoelsta, Gregory A Vidal, Sharon Sams, Peter Kabos, Jennifer R Diamond, Elena Shagisultanova, Anosheh Afghahi, Jose Mayordomo, Tessa McSpadden, Gloria Crawford, Lisa Carter, Kathryn Zolman, Stephanie Armstead, Alyse Winchester, Virginia Borges, Julia Wulfkuhle, Emanuel Petricoin, Dexiang Gao, Jennifer Richer. Phase II trial of fulvestrant plus enzalutamide in ER+/Her2- advanced breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS12-14.