Randomized Phase III Study of Enzalutamide Compared With Enzalutamide Plus Abiraterone for Metastatic Castration-Resistant Prostate Cancer (Alliance A031201 Trial)

Abstract

Purpose: Enzalutamide and abiraterone both target androgen receptor signaling but via different mechanisms. The mechanism of action of one drug may counteract the resistance pathways of the other. We sought to determine whether the addition of abiraterone acetate and prednisone (AAP) to enzalutamide prolongs overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) in the first-line setting.

Patients and methods: Men with untreated mCRPC were randomly assigned (1:1) to receive first-line enzalutamide with or without AAP. The primary end point was OS. Toxicity, prostate-specific antigen declines, pharmacokinetics, and radiographic progression-free survival (rPFS) were also examined. Data were analyzed using an intent-to-treat approach. The Kaplan-Meier estimate and the stratified log-rank statistic were used to compare OS between treatments.

Results: In total, 1,311 patients were randomly assigned: 657 to enzalutamide and 654 to enzalutamide plus AAP. OS was not statistically different between the two arms (median, 32.7 [95% CI, 30.5 to 35.4] months for enzalutamide v 34.2 [95% CI, 31.4 to 37.3] months for enzalutamide and AAP; hazard ratio [HR], 0.89; one-sided P = .03; boundary nominal significance level = .02). rPFS was longer in the combination arm (median rPFS, 21.3 [95% CI, 19.4 to 22.9] months for enzalutamide v 24.3 [95% CI, 22.3 to 26.7] months for enzalutamide and AAP; HR, 0.86; two-sided P = .02). However, pharmacokinetic clearance of abiraterone was 2.2- to 2.9-fold higher when administered with enzalutamide, compared with clearance values for abiraterone alone.

Conclusion: The addition of AAP to enzalutamide for first-line treatment of mCRPC was not associated with a statistically significant benefit in OS. Drug-drug interactions between the two agents resulting in increased abiraterone clearance may partly account for this result, although these interactions did not prevent the combination regimen from having more nonhematologic toxicity.

Trial registration: ClinicalTrials.gov NCT01949337.

FIG 1.

CONSORT diagram for A031201. AAP, abiraterone acetate and prednisone; AE, adverse event.

FIG 2.

Kaplan-Meier curves of (A) OS and (B) rPFS according to the standard definition of progression (PCWG), (C) the PCWG definition with the addition of clinical progression, and (D) the PCWG definition with the addition of post-treatment radiographic progression of disease. AAP, abiraterone acetate and prednisone; enza, enzalutamide; HR, hazard ratio; OS, overall survival; PCWG, Prostate Cancer Clinical Trials Working Group; rPFS, radiographic progression-free survival; RUCP, radiographic and unequivocal clinical progression.

FIG 3.

Forest plot for OS in A031201. The cutoffs for BPI, PSA, LDH, and ALP were the median values. AAP, abiraterone acetate and prednisone; ALP, alkaline phosphatase; BPI, Brief Pain Inventory; BSL, baseline; ECOG, Eastern Cooperative Oncology Group; enza, enzalutamide; HR, hazard ratio; LDH, lactate dehydrogenase; OS, overall survival; PS, performance score; PSA, prostate-specific antigen.