SAN ANTONIO (FRONTLINE MEDICAL NEWS) – Enzalutamide added to exemestane improved progression-free survival (PFS) in patients with hormone receptor (HR)-positive advanced breast cancer, investigators reported.

Specifically, it improved outcomes in patients who had not received any prior endocrine therapy and who were positive for a gene signature-based biomarker indicating androgen receptor (AR) signaling.

Patients in this subset who were treated with combination enzalutamide and exemestane achieved a median PFS of 16.5 months, which was significantly higher than the 4 months observed with placebo and exemestane.

However, the addition of enzalutamide had no effect on PFS in the overall cohort or among patients who were biomarker positive but who had received prior endocrine therapy.

“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,” Denise A. Yardley, MD, of Tennessee Oncology, Nashville, said at the San Antonio Breast Cancer Symposium.

“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,” said Dr. Yardley.

Targeting AR is an active area of breast cancer research, as a majority of HR-positive tumors express the AR, as do a moderate number of HER2-positive tumors and almost a third of triple-negative breast cancers. AR signaling has also been associated with resistance to endocrine therapy. Aromatase inhibitors divert estrogen precursors to androgens and data from preclinical models have shown that enzalutamide blocked both estrogen- and androgen-mediated growth of HR+ cells.

Enzalutamide is an inhibitor of AR signaling that is currently used to treat patients with castration-resistant prostate cancer, and has demonstrated clinical activity and was well tolerated in patients with AR-positive advanced triple negative breast cancer, explained Dr. Yardley.

In this study, Dr. Yardley and her colleagues conducted a placebo-controlled phase 2 randomized trial that included 247 patients with HR+/HER2-normal advanced/metastatic breast cancer who were assigned to either 25 mg exemestane plus placebo or 50 mg exemestane and 160 mg enzalutamide daily.

The patients were divided into two parallel cohorts: those with no prior endocrine therapy (C1; n = 127) or those who had received one prior endocrine therapy for metastatic disease (C2; n = 120).

The primary endpoint was PFS in the intent-to-treat population and in the biomarker subgroup of each cohort. Secondary endpoints included the clinical benefit rate at 24 weeks, best overall response, and safety.

The authors found that the PFS in the intent-to-treat population did not significantly differ between those 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 (hazard ratio, 0.82; P = .3631), and in cohort 2, 3.6 months and 3.9 months, respectively (HR, 1.02; P = .9212).

However, statistically significant improvements in median PFS and clinical benefit rate at 24 weeks were observed only in the group with a positive biomarker who had not received any prior endocrine therapy. In cohort 1, the median PFS was 16.5 months in the enzalutamide arm vs. 4.3 months in the placebo arm (HR, 0.44, P = .0335). In cohort 2, median PFS did not significantly differ between groups (6.0 vs. 5.3 months; HR, 0.55; P = .1936).

The clinical response rate in cohort 1 of the biomarker positive group was 83% in the enzalutamide arm versus 38% in the placebo arm (P = .0012).

Adverse events with enzalutamide was similar to those previously reported, and the most common were nausea (39%) in cohort 1 and fatigue (37%) in cohort 2. Dose interruptions due to adverse events occurred in 21.0% and 25.0% of patients randomized to enzalutamide in cohorts 1 and 2 vs. 20.6% and 15.0% in the placebo group.

Dr. Yardley explained that the biomarker used in the study was identified on PAM50. “It was exploratory and proprietary,” she noted, adding that she is unable to share any further information about it at this time.

SOURCE: Yardley et al. SABCS Abstract GS4-07