Abiraterone acetate, exemestane or the combination in postmenopausal patients with estrogen receptor-positive metastatic breast cancer

Abstract

Background: Androgen receptor (AR) signaling and incomplete inhibition of estrogen signaling may contribute to metastatic breast cancer (MBC) resistance to a nonsteroidal aromatase inhibitor (NSAI; letrozole or anastrozole). We assessed whether combined inhibition of androgen biosynthesis with abiraterone acetate plus prednisone and estradiol synthesis with exemestane (E) may be of clinical benefit to postmenopausal patients with NSAI-pretreated estrogen receptor-positive (ER+) MBC.

Patients and methods: Patients (N = 297) were stratified by the number of prior therapies for metastatic disease (0-1 versus 2) and by prior NSAI use (adjuvant versus metastatic), and randomized (1 : 1 : 1) to receive oral once daily 1000 mg abiraterone acetate plus 5 mg prednisone (AA) versus AA with 25 mg E (AAE) versus 25 mg E alone (E). Each treatment arm was well balanced with regard to the proportion of patients with AR-positive breast cancer. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, clinical benefit rate, duration of response, and overall response rate.

Results: There was no significant difference in PFS with AA versus E (3.7 versus 3.7 months; hazard ratio [HR] = 1.1; 95% confidence interval [CI] 0.82-1.60; P = 0.437) or AAE versus E (4.5 versus 3.7 months; HR = 0.96; 95% CI 0.70-1.32; P = 0.794). Increased serum progesterone concentrations were observed in both arms receiving AA, but not with E. Grade 3 or 4 treatment-emergent adverse events associated with AA, including hypokalemia and hypertension, were less common in patients in the E (2.0% and 2.9%, respectively) and AA arms (3.4% and 1.1%, respectively) than in the AAE arm (5.8% for both).

Conclusions: Adding AA to E in NSAI-pretreated ER+ MBC patients did not improve PFS compared with treatment with E. An AA-induced progesterone increase may have contributed to this lack of clinical activity.

Clinicaltrialsgov: NCT01381874.

Keywords: abiraterone acetate; androgen receptor; estrogen receptor-positive breast cancer; metastatic breast cancer; postmenopausal breast cancer.

© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

Figures

Figure 1.

Patient enrollment and disposition CONSORT diagram. Percentages are calculated with the number of treated patients in each treatment arm as the denominator. AA, abiraterone acetate; AAE, abiraterone acetate plus exemestane; CBR, clinical benefit rate; E, exemestane; ORR, overall response rate; OS, overall survival; PFS, progression-free survival.

Figure 2.

Progression-free survival of the intent-to-treat population. AA, abiraterone acetate; AAE, abiraterone acetate plus exemestane; CI, confidence interval; E, exemestane; ECOG, Eastern Cooperative Oncology Group; EE, Eastern Europe; HR, hazard ratio; MBC, metastatic breast cancer; NA, North America; OTH, other; WE, Western Europe.

Figure 3.

Box plot of serum endocrine analysis by visit: (A) testosterone, (B) estradiol, (C) estrone and (D) progesterone. The lower limit of quantification was 2 ng/dl (0.07 nmol/l) for testosterone, 0.5 pg/ml (1.8 pmol/l) for estradiol and estrone, and 0.5 ng/ml (1.6 nmol/l) for progesterone. Dashed lines at base of the box plots represent undetectable levels. Dots represent outliers. AA, abiraterone acetate; AAE, abiraterone acetate plus exemestane; C, cycle; D, day; E, exemestane; EOT, end of treatment.