Denise Yardley, MD
In patients with hormone receptor (HR)-positive advanced breast cancer and no prior endocrine therapy who were positive for a gene signature-based biomarker indicating androgen receptor (AR)-signaling, the addition of enzalutamide (Xtandi) to exemestane was found to significantly improve progression-free survival (PFS) from 4 months to 16.5 months.1
Moreover, the phase II trial showed no effect of enzalutamide on PFS in the overall cohort of patients nor in the biomarker-positive population who received prior endocrine therapy, said Denise Yardley, MD, at the 2017 San Antonio Breast Cancer Symposium.
“The study met its primary endpoint in improving PFS in the enzalutamide- plus exemestane-treated patients who were biomarker-positive and HR-positive with no prior endocrine therapy for advanced disease as compared [with] exemestane alone,” said Yardley. “The role of the AR in HR-positive breast cancer and the predictive value of the identified biomarker are still unclear and will require further studies and validation.”
Enzalutamide is an inhibitor of AR signaling that is approved by the FDA for the treatment of patients with castration-resistant prostate cancer. “It inhibits binding of androgens to the AR, it inhibits the AR nuclear translocation, and it inhibits AR-mediated DNA binding,” said Yardley. “In HR-positive breast cancer patients, AR expression is higherupwards of about 90%—and is associated with resistance to endocrine therapy. Enzalutamide in preclinical models demonstrated a blockage of both estrogen- and androgen-mediated growth of HR-positive breast cancer cells.”2,3
Data in the AR-negative population with triple-negative breast cancer showed clinical activity and good tolerability of enzalutamide.
A total of 247 postmenopausal women with metastatic or locally advanced HR-positive breast cancer who were treated with up to 1 prior line of chemotherapy for advanced disease and up to 1 prior endocrine therapy for advanced disease were enrolled in 1 of 2 cohorts. In cohort 1, 127 patients who received no prior endocrine therapy for advanced disease were enrolled. In cohort 2, 120 patients with 1 prior endocrine therapy for advanced breast cancer were enrolled. In both cohorts, patients were randomized in a 1:1 ratio to receive enzalutamide at 160 mg/day or placebo.
Enzalutamide is a potent CYP3A4 inducer and thereby decreases exemestane exposure by two-fold, said Yardley. To maintain the same exposure of exemestane to the control arm in the study (25 mg), a 50-mg dose of exemestane was chosen in the patients randomized to enzalutamide.
There were co-primary endpoints of PFS in the intent-to-treat population and PFS in a subset of patients who had a positive gene signature-based biomarker. The median patient age was 60 years. About two-thirds of patients had a disease-free interval >12 months, 25% were de novo stage IV at study entry, visceral disease was present in slightly more than half, about one-fourth had bone-only disease, and about 70% had ≥3 metastatic disease sites. All patients were required to be estrogen receptor-positive. Approximately 50% had received chemotherapy for early-stage disease and about 20% for advanced-stage disease. Hormone resistance to adjuvant therapy was present in about 10%.
PFS in the intent-to-treat (ITT) population was not significantly different between the patients randomized to enzalutamide or placebo in either cohort. In cohort 1, the median PFS was 11.8 months in the enzalutamide arm and 5.8 months in the placebo arm (HR, 0.82;P= .3631). In cohort 2, median PFS was 3.6 months and 3.9 months in the 2 arms, respectively (HR, 1.02;P= .9212).
In an attempt to establish a diagnostic tool to aid and assist in predicting response to enzalutamide, the investigators employed AR testing in the first 112 patients enrolled. The subset that had positive nuclear AR staining was found to be similar to the ITT population, and further AR testing was halted. In a prespecified analysis, tumor samples were evaluated in an attempt to develop a gene signature-based biomarker indicating AR signaling predictive of response.
A training set of RNA sequenced data from two-thirds of the randomized patients was used to develop the biomarker. Data from the remaining one-third of patients were used as validation of the biomarker. Patients with biomarker-positive breast cancer in the training set and validation populations had improvement of PFS with enzalutamide. About 40% of patients in cohort 1 and about 29.2% in cohort 2 were biomarker-positive.
In the biomarker-positive population, median PFS in cohort 1 was 16.5 months in the enzalutamide arm compared with 4.3 months in the placebo arm, corresponding to an HR of 0.44 (P= .0335). In cohort 2, median PFS was not significantly different between the enzalutamide and placebo arms (6.0 vs 5.3 months; HR 0.55;P= .1936). In the biomarker-negative population, there was no benefit to adding enzalutamide to exemestane in either cohort of patients. In the biomarker-positive population, the clinical benefit rate at 24 weeks was approximately 80% in the enzalutamide arm versus approximately 40% in the placebo arm (P= .0012) while the overall response rate showed a trend in favor of enzalutamide that did not achieve significance (P= .0877). There was no benefit to enzalutamide in cohort 2 of the biomarker-positive subset. There was no significant difference in achievement of these endpoints between treatment groups in the ITT population. In the biomarker-negative population, a significantly higher percentage of the placebo arm achieved complete benefit compared with the enzalutamide arm (P= .0082).
The adverse event (AE) profile with enzalutamide was similar to those in previous clinical trials. AEs led to dose interruptions in 21.0% and 25.0% of patients randomized to enzalutamide in cohorts 1 and 2, respectively, compared with 20.6% and 15.0%, respectively, randomized to placebo. AEs leading to treatment discontinuation occurred at a rate of 14.5% and 18.3% in cohorts 1 and 2 of the enzalutamide arm, compared with 15.9% and 8.3%, respectively, in the placebo arm. The most common AEs reported in the enzalutamide arms were nausea (39%) in cohort 1 and fatigue (37%) in cohort 2.