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

Abstract

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.

Fig. 1. Efficacy of enzalutamide plus fulvestrant in advanced ER+/HER2− breast cancer patients.

a Clinical benefit rate at 12 weeks (CBR12) and 24 weeks (CBR24). b Kaplan–Meier of progression-free survival (PFS) in all patients treated with enzalutamide plus fulvestrant. Censored times are marked with vertical dashes, and the median time to progression (8 weeks) is noted. c Violin plots of steroid hormone receptor IHC quantification ER, AR, PR, GR, as well as Ki67 and Cleaved Caspase 3 (CC3) IHC, are stratified by baseline (BL) and week 5 (W5) of treatment. Plots show the distribution of the observed values with the time-specific minimum and maximums as the lowest and highest gray horizontal lines, respectively. Corresponding p-values and black points indicate observed values as assessed with the Wald two-sided test. d Kaplan–Meier curve of overall survival probability in patients treated with enzalutamide plus fulvestrant stratified by AR and ER protein expression as determined by immunohistochemistry. e Swimmer plot representing each patient’s progression-free survival time in weeks. Censored end times are marked with open circles, and participants who experienced an event are marked with black squares. PIK3CA and PTEN are represented by color, and prior treatments and biomarkers are indicated with symbols.

Fig. 2. RPPA analysis of frozen core biopsies from tumors at baseline and following enzalutamide plus fulvestrant.

a Volcano plot of differences in baseline detection across the Long and Short PFS groups. b Differentially expressed phospho-proteins in the mTOR signaling pathway in Long PFS versus Short PFS at baseline. The lower and upper bounds of the boxes represent the first (Q1) and third (Q3) quartiles, respectively, which cover the interquartile range (IQR). The horizontal line within each box represents the median. The whiskers extending vertically out from the boxes are computed as Q1 − 1.5*IQR and Q3 + 1.5*IQR. Outliers are data points outside of this range and are indicated with dots. c Volcano plot of differences in fold change detection across Long and Short PFS groups. All statistical analyses were performed with the Bayes log2 two-sided moderated t-test.

Fig. 3. Analysis of plasma metabolomics performed via UHPLC-MS at baseline and after treatment.

Metabolites with significant differences between Long and Short PFS are presented in heatmaps a at baseline and b after treatment. c The mean fold changes with treatment are presented for metabolites with significant differences between the Long and Short PFS groups.