SAN ANTONIO — The addition of enzalutamide to exemestane significantly prolonged PFS and appeared well tolerated among patients with hormone receptor-positive metastatic breast cancer who had not received prior endocrine therapy and who expressed an androgen receptor gene signature, according to results of a placebo-controlled randomized phase 2 trial presented at the San Antonio Breast Cancer Symposium.
Androgen receptor signaling — expressed in more than 75% of hormone receptor-positive tumors — has been associated with resistance to endocrine therapy.
Enzalutamide (Xtandi; Astellas, Medivation) — an inhibitor of androgen receptor signaling — is approved to treat men with metastatic castration-resistant prostate cancer, and has demonstrated clinical activity among patients with androgen receptor-positive triple-negative breast cancer.
“Aromatase inhibitors divert estrogen precursors to androgens,” Denise Yardley, MD, medical oncologist at Tennessee Oncology, said during her presentation. “In preclinical models, enzalutamide blocked both estrogen- and androgen-mediated growth of hormone receptor-positive breast cancer cells.”
Yardley and colleagues randomly assigned 247 patients with hormone receptor-positive advanced/metastatic breast cancer to receive 25 mg exemestane plus placebo, or 50 mg exemestane plus 160 mg enzalutamide daily. The analysis included two parallel cohorts who had no prior endocrine therapy (cohort 1; n = 127) or who had received one prior endocrine therapy for metastatic breast cancer (cohort 2; n = 120).
PFS in the intention-to-treat population, as well as in a gene-signature based biomarker cohort indicating androgen receptor signaling predictive of response to enzalutamide, served as the study’s primary endpoint. Secondary endpoints included clinical benefit at 24 weeks, best overall response and safety.
In total, 50 patients (39.4%) in cohort 1 and 35 (29.2%) in cohort 2 expressed the biomarker signature.
Enzalutamide did not significantly prolong PFS in the intention-to-treat population of cohort 1 (11.8 months vs. 5.8 months; HR = 0.82; 95% CI, 0.54-1.25) or cohort 2 (3.6 months vs. 3.9 months; HR = 1.02; 95% CI, 0.66-1.59).
Only patients who had not received prior endocrine therapy and who expressed the biomarker signature demonstrated significant improvements in PFS (median, 16.5 months vs. 4.3 months; HR = 0.44; 95% CI, 0.21-0.96) and 24-week clinical benefit (83% vs. 38%; P = .0012).
The most common adverse events that occurred in the enzalutamide and exemestane arm included nausea (39%) in cohort 1 and fatigue (37%) in cohort 2.
In cohort 1, 15% of patients assigned the combination and 16% assigned exemestane alone discontinued treatment due to toxicity. In cohort 2, 18% of patients assigned the combination and 8% assigned exemestane alone discontinued treatment.
“The role of the androgen receptor in hormone receptor-positive breast cancer and the predictive value of the identified biomarker are still unclear and will require further studies,” Yardley said. – by Alexandra Todak
Krop I, et al. Abstract GS4-07. Presented at: San Antonio Breast Cancer Symposium; Dec. 5-9, 2017; San Antonio.
Disclosures: The authors report no relevant financial disclosures.