A phase II trial of abiraterone combined with dutasteride for men with metastatic castration-resistant prostate cancer.

Publication Type:

Journal Article

Source:

Clinical cancer research : an official journal of the American Association for Cancer Research (2016)

Abstract:

PURPOSE: Despite the efficacy of abiraterone, a CYP17A1 inhibitor, in metastatic castration-resistant prostate cancer (CRPC), nearly all patients develop resistance. The purpose of this phase II study was to evaluate mechanisms of resistance to more complete androgen synthesis inhibition with abiraterone and dutasteride.

EXPERIMENTAL DESIGN: Eligible metastatic CRPC patients underwent a baseline metastasis biopsy. Patients received abiraterone and prednisone for two 4-week cycles. After this time, high-dose dutasteride (3.5mg daily) was added. Patients continued therapy until study withdrawal or radiographic progression. Repeat metastasis biopsy was obtained at progression. The primary endpoint was to assess mechanisms of resistance. Serum hormone and abiraterone levels were assessed. Tissue was assessed for androgen receptor (AR) and AR splice variant-7 (ARV7) expression.

RESULTS: Forty patients were enrolled. 60% (n=24) achieved a {greater than or equal to}50% reduction in PSA. The median time to radiographic progression was 11 months. Nearly all baseline (n=29/30) and post-treatment (n=16/16) tumors tested for AR nuclear expression were positive. Of those tested, ARV7 expression was present in 48% (n=10/21) of baseline and 42% (n=5/12) of treatment discontinuation specimens. Compared to patients with higher serum abiraterone levels at treatment discontinuation, patients with lower levels had higher circulating androgens.

CONCLUSIONS: Despite increased androgen synthesis inhibition, we demonstrate that tumor AR axis remains important in disease progression. We highlight that abiraterone metabolism and pharmacokinetics may play a role in resistance. The non-comparative design limits conclusions on the efficacy of dual therapy with abiraterone and dutasteride, but the results support development of further multifaceted approaches towards AR inhibition.