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

Author:

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

Abstract

AbstractThis 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.

Funder

U.S. Department of Defense

Publisher

Springer Science and Business Media LLC

Subject

Pharmacology (medical),Radiology, Nuclear Medicine and imaging,Oncology

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