Phase II trial of fulvestrant plus enzalutamide in ER+/HER2− advanced breast cancer

Anthony D. Elias*, Nicole S. Spoelstra, Alyse W. Staley, Sharon Sams, Lyndsey S. Crump, Gregory A. Vidal, Virginia F. Borges, Peter Kabos, Jennifer R. Diamond, Elena Shagisultanova, Anosheh Afghahi, Jose Mayordomo, Tessa McSpadden, Gloria Crawford, Angelo D’Alessandro, Kathryn L. Zolman, Adrie van Bokhoven, Yonghua Zhuang, Rosa I. Gallagher, Julia D. WulfkuhleEmanuel F. Petricoin, Dexiang Gao, Jennifer K. Richer

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


This clinical trial combined fulvestrant with the anti-androgen enzalutamide in women with metastatic ER+/HER2− breast cancer (BC). Eligible patients were women with ECOG 0–2, ER+/HER2− measurable or evaluable metastatic BC. Prior fulvestrant was allowed. Fulvestrant was administered at 500 mg IM on days 1, 15, 29, and every 4 weeks thereafter. Enzalutamide was given at 160 mg po daily. Fresh tumor biopsies were required at study entry and after 4 weeks of treatment. The primary efficacy endpoint of the trial was the clinical benefit rate at 24 weeks (CBR24). The median age was 61 years (46–87); PS 1 (0–1); median of 4 prior non-hormonal and 3 prior hormonal therapies for metastatic disease. Twelve had prior fulvestrant, and 91% had visceral disease. CBR24 was 25% (7/28 evaluable). Median progression-free survival (PFS) was 8 weeks (95% CI: 2–52). Adverse events were as expected for hormonal therapy. Significant (p < 0.1) univariate relationships existed between PFS and ER%, AR%, and PIK3CA and/or PTEN mutations. Baseline levels of phospho-proteins in the mTOR pathway were more highly expressed in biopsies of patients with shorter PFS. Fulvestrant plus enzalutamide had manageable side effects. The primary endpoint of CBR24 was 25% in heavily pretreated metastatic ER+/HER2− BC. Short PFS was associated with activation of the mTOR pathway, and PIK3CA and/or PTEN mutations were associated with an increased hazard of progression. Thus, a combination of fulvestrant or other SERD plus AKT/PI3K/mTOR inhibitor with or without AR inhibition warrants investigation in second-line endocrine therapy of metastatic ER+ BC.

Original languageEnglish
Article number41
Journalnpj Breast Cancer
Issue number1
StatePublished - Dec 2023
Externally publishedYes


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