Selective inhibition of CYP17 with abiraterone acetate is highly active in the treatment of castration-resistant prostate cancer

Abstract

Purpose: It has been postulated that castration-resistant prostate cancer (CRPC) commonly remains hormone dependent. Abiraterone acetate is a potent, selective, and orally available inhibitor of CYP17, the key enzyme in androgen and estrogen biosynthesis.

Patients and methods: This was a phase I/II study of abiraterone acetate in castrate, chemotherapy-naive CRPC patients (n = 54) with phase II expansion at 1,000 mg (n = 42) using a two-stage design to reject the null hypothesis if more than seven patients had a prostate-specific antigen (PSA) decline of > or = 50% (null hypothesis = 0.1; alternative hypothesis = 0.3; alpha = .05; beta = .14). Computed tomography scans every 12 weeks and circulating tumor cell (CTC) enumeration were performed. Prospective reversal of resistance at progression by adding dexamethasone 0.5 mg/d to suppress adrenocorticotropic hormone and upstream steroids was pursued.

Results: A decline in PSA of > or = 50% was observed in 28 (67%) of 42 phase II patients, and declines of > or = 90% were observed in eight (19%) of 42 patients. Independent radiologic evaluation reported partial responses (Response Evaluation Criteria in Solid Tumors) in nine (37.5%) of 24 phase II patients with measurable disease. Decreases in CTC counts were also documented. The median time to PSA progression (TTPP) on abiraterone acetate alone for all phase II patients was 225 days (95% CI, 162 to 287 days). Exploratory analyses were performed on all 54 phase I/II patients; the addition of dexamethasone at disease progression reversed resistance in 33% of patients regardless of prior treatment with dexamethasone, and pretreatment serum androgen and estradiol levels were associated with a probability of > or = 50% PSA decline and TTPP on abiraterone acetate and dexamethasone.

Conclusion: CYP17 blockade by abiraterone acetate results in declines in PSA and CTC counts and radiologic responses, confirming that CRPC commonly remains hormone driven.

Fig 1

Changes in prostate-specific antigen (PSA) with abiraterone acetate. Waterfall plot showing maximal percentage change in PSA from baseline with single-agent abiraterone acetate 1,000 mg at (A) 12 weeks and (B) any time point after 12 weeks. The dashed lines indicate PSA declines of 30%, 50%, and 90%.

Fig 2

Radiologic responses to abiraterone acetate. (A) Patient 203 had previously experienced progression on luteinizing hormone–releasing hormone (LHRH) agonists, bicalutamide, diethylstilboestrol, and the histone deacetylase inhibitor FK228. Before starting treatment with abiraterone acetate, he had a prostate-specific antigen (PSA) level of 200 ng/mL and multiple liver metastases but no bone metastasis on bone scan. The largest lesion in the liver was 102 mm. (B) After 12 months of treatment, his PSA had declined to 11.2 ng/mL, and his index lesion measured 46 mm. (C) Patient 214 had previously experienced progression on LHRH agonists and bicalutamide. Before starting treatment, he had a PSA of 129 ng/mL, mediastinal lymphadenopathy measuring 21 mm, and bone metastasis on bone scan. He also had bilateral pleural effusions indicated by the red arrows. (D) After 12 months of treatment, his PSA was 7.4 ng/mL, and his mediastinal lymphadenopathy measured 11 mm. His bone disease remained stable on bone scan, and the pleural effusions had resolved. (E) Patient 227 had previously experienced progression on LHRH agonists and bicalutamide. Before treatment, he had a PSA of 870 ng/mL and retroperitoneal lymphadenopathy measuring 15 mm. (F) After 9 months of treatment, his retroperitoneal lymphadenopathy measured 6 mm. His PSA had declined to 471 ng/mL but then increased to 1,334 ng/mL, necessitating addition of dexamethasone 0.5 mg daily. This resulted in a secondary decline in PSA to 820 ng/mL, and he continues on treatment after 12 months.

Fig 3

Time on treatment with abiraterone acetate. (A) Kaplan-Meier (KM) plot showing time to prostate-specific antigen progression (TTPP) on abiraterone acetate alone for 42 patients treated at 1,000 mg. (B) KM plot for TTPP for all patients (N = 54) after progression on addition of dexamethasone (or abiraterone acetate alone if dexamethasone was not added).