A Phase II Trial of Abiraterone Combined with Dutasteride for Men with Metastatic Castration-Resistant Prostate Cancer

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 patients with metastatic CRPC underwent a baseline metastasis biopsy. Patients received abiraterone and prednisone for two 4-week cycles. After this time, high-dose dutasteride (3.5 mg 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. Sixty percent (n = 24) achieved a ≥50% reduction in prostate-specific antigen (PSA). The median time to radiographic progression was 11 months. Nearly all baseline (n = 29 of 31) and posttreatment (n = 16 of 16) tumors tested for AR nuclear expression were positive. Of those tested, ARV7 expression was present in 48% (n = 10 of 21) of baseline and 42% (n = 5 of 12) of treatment discontinuation specimens. Compared with 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 noncomparative design limits conclusions on the efficacy of dual therapy with abiraterone and dutasteride, but the results support development of further multifaceted approaches toward AR inhibition. Clin Cancer Res; 23(4); 935-45. ©2016 AACR.

©2016 American Association for Cancer Research.

Figures

Figure 1

Waterfall plot of best PSA response to therapy with abiraterone and dutasteride. Red bars indicate prior ketoconazole. Purple bars indicate prior chemotherapy. Gray bars indicate prior enzalutamide. Yellow bars indicate prior ketoconazole and chemotherapy. Green bar indicates prior ketoconazole and enzalutamide.

Figure 2

Example of bone scan flare in a patient receiving abiraterone and dutasteride. A) Baseline bone scan PSA=45.96 ng/mL. B) 3-month bone scan PSA=10.19 ng/mL demonstrating increased and new areas of uptake in the ribs and spine. C) 6-month bone scan PSA=6.72 ng/mL demonstrating resolution of increased and new areas of uptake in the ribs and spine on 3-month scan.

Figure 3

A) Representative hematoxylin and eosin (HE) staining, and immunohistochemistry staining for cytokeratin (CK), the androgen receptor (AR) and AR variant 7 (ARV7) from the baseline and progression lymph node metastasis biopsy obtained from patient 36 (40X). The HE morphology of the baseline and progression biopsies was similar. ARV7 was weakly staining (+1,

Figure 3

A) Representative hematoxylin and eosin (HE) staining, and immunohistochemistry staining for cytokeratin (CK), the androgen receptor (AR) and AR variant 7 (ARV7) from the baseline and progression lymph node metastasis biopsy obtained from patient 36 (40X). The HE morphology of the baseline and progression biopsies was similar. ARV7 was weakly staining (+1,

Figure 4

Hormone levels at treatment-end and the prior cycle for patients with stable/increased (n=21) or decreased (n=19) abiraterone levels at treatment-end: A) Pregnenolone for patients with stable/increased abiraterone levels, B) Pregnenolone for patients with decreased abiraterone levels, C) Progesterone for patients with stable/increased abiraterone levels, D) Progesterone for patients with decreased abiraterone levels, E) Dehydroepiandrosterone sulfate (DHEAS) for patients with stable/increased abiraterone levels, F) DHEAS for patients with decreased abiraterone levels, G) Dehydroepiandrosterone (DHEA) for patients with stable/increased abiraterone levels, H) DHEA for patients with decreased abiraterone levels.

Figure 4

Hormone levels at treatment-end and the prior cycle for patients with stable/increased (n=21) or decreased (n=19) abiraterone levels at treatment-end: A) Pregnenolone for patients with stable/increased abiraterone levels, B) Pregnenolone for patients with decreased abiraterone levels, C) Progesterone for patients with stable/increased abiraterone levels, D) Progesterone for patients with decreased abiraterone levels, E) Dehydroepiandrosterone sulfate (DHEAS) for patients with stable/increased abiraterone levels, F) DHEAS for patients with decreased abiraterone levels, G) Dehydroepiandrosterone (DHEA) for patients with stable/increased abiraterone levels, H) DHEA for patients with decreased abiraterone levels.

Figure 4

Hormone levels at treatment-end and the prior cycle for patients with stable/increased (n=21) or decreased (n=19) abiraterone levels at treatment-end: A) Pregnenolone for patients with stable/increased abiraterone levels, B) Pregnenolone for patients with decreased abiraterone levels, C) Progesterone for patients with stable/increased abiraterone levels, D) Progesterone for patients with decreased abiraterone levels, E) Dehydroepiandrosterone sulfate (DHEAS) for patients with stable/increased abiraterone levels, F) DHEAS for patients with decreased abiraterone levels, G) Dehydroepiandrosterone (DHEA) for patients with stable/increased abiraterone levels, H) DHEA for patients with decreased abiraterone levels.

Figure 4

Hormone levels at treatment-end and the prior cycle for patients with stable/increased (n=21) or decreased (n=19) abiraterone levels at treatment-end: A) Pregnenolone for patients with stable/increased abiraterone levels, B) Pregnenolone for patients with decreased abiraterone levels, C) Progesterone for patients with stable/increased abiraterone levels, D) Progesterone for patients with decreased abiraterone levels, E) Dehydroepiandrosterone sulfate (DHEAS) for patients with stable/increased abiraterone levels, F) DHEAS for patients with decreased abiraterone levels, G) Dehydroepiandrosterone (DHEA) for patients with stable/increased abiraterone levels, H) DHEA for patients with decreased abiraterone levels.