Abiraterone Acetate plus Enzalutamide in Modulation of Androgen Signaling

Chicago—Previous studies have observed a high degree of heterogeneity in cytoreduction in localized high-risk prostate cancer (LHRPC) after treatment with abiraterone acetate (AA) plus enzalutamide (AA + E) and leuprolide acetate (LHRHa) and AA plus LHRHa. According to Eleni Efstathiou, MD, PhD, and colleagues, a rationale exists for the AA + E combination therapy and promising efficacy has been reported in patients with metastatic castration-resistant prostate cancer.

The researchers conducted a single-institution, preoperative study designed to assess the effects of AA + E versus AA and modulation of androgen signaling in LHRPC. They reported the study’s results during a poster session at the ASCO 2015 Annual Meeting in a poster titled Effects of Preoperative Abiraterone Acetate (AA) plus Enzalutamide (E) and Leuprolide Acetate (LHRHa) versus AA and LHRHA in Localized High-Risk Prostate Cancer (LHRPC).

LHRPC patients with clinical stage T1c/T2, biopsy Gleason score ≥8, or ≥T2b with Gleason score ≥7 and prostate-specific antigen (PSA) >10 ng/mL were randomized 2:1 to receive either 24 weeks of 1 g AA + 160 mg E + 5 mg prednisone daily + LHRHa (arm A) or AA + prednisone + LHRHa (arm B).

Assessments were conducted on safety and treatment effect on pathology stage, androgen metabolites, cellular density (percent epithelial component of tumor volume), and the link between molecular markers (by immunohistochemistry) with clinical, pathology, and cellular response was addressed.

A total of 66 patients were eligible for the study, of whom 39 completed 24 weeks of therapy and had robot-assisted laparoscopic prostatectomy. Among patients with evaluable data, there were no perioperative grade 3 or higher adverse events (AEs). On-treatment Grade 3 AEs included liver function test elevation (seven patients in arm A and two patients in arm B); hypertension (five in arm A and one in arm B); hypokalemia (one in arm A); cognitive disturbance (one in arm A); pulmonary embolism (one in arm A); and fatigue (one in arm A). Fatigue Grade 1/2 was reported in 38 of 55 evaluable patients (29 of 38 in arm A and nine of 17 in arm B).

Preoperative PSA was ≤0.1 ng/mL in 89% of patients in arm A (23 of 26) versus 91% in arm B (10 of 11)—a nonsignificant difference. Pathologic downstaging, to date, (≤ypT2NO) occurred in 41% of patients in arm A (n=11 of 27) versus 58% in arm B (n=7 of 12)—also nonsignificant.

Tumors were segregated by low (≤30%) versus high (≥45%) cellular density; low density tumors were found in 63% of patients in arm A and 77% in arm B. Preoperative testosterone was undetectable in 33 of 39 patients; when detectable, the range was 1 pg/mL to 10 pg/mL. Tumors with pathology stage ≤ypT2NO had higher AR-N terminal expression (85% vs 58% and AR-C/AR-N ratio; P=.008).

“Tumor cytoreduction is dichotomized despite universal serum PSA decline at 6 months preoperative treatment. Planned comprehensive molecular characterization of androgen biosynthesis will inform marker-driven LHRPC treatment strategy,” the researchers concluded.

Source: Efstathiou E, Troncoso P, Ning Tapia EL, et al. Effects of preoperative abiraterone acetate (AA) plus enzalutamide (E) and leuprolide acetate (LHRHa) versus AA and LHRHa in localized high-risk prostate cancer (LHRPC). Abstract of poster presentation at the American Society of Clinical Oncology 2015 Annual Meeting, Chicago, Illinois, May 30, 2105.