Phase I clinical trial of the CYP17 inhibitor abiraterone acetate demonstrating clinical activity in patients with castration-resistant prostate cancer who received prior ketoconazole therapy

Abstract

Purpose: Abiraterone acetate is a prodrug of abiraterone, a selective inhibitor of CYP17, the enzyme catalyst for two essential steps in androgen biosynthesis. In castration-resistant prostate cancers (CRPCs), extragonadal androgen sources may sustain tumor growth despite a castrate environment. This phase I dose-escalation study of abiraterone acetate evaluated safety, pharmacokinetics, and effects on steroidogenesis and prostate-specific antigen (PSA) levels in men with CPRC with or without prior ketoconazole therapy.

Patients and methods: Thirty-three men with chemotherapy-naïve progressive CRPC were enrolled. Nineteen patients (58%) had previously received ketoconazole for CRPC. Bone metastases were present in 70% of patients, and visceral involvement was present in 18%. Three patients (9%) had locally advanced disease without distant metastases. Fasted or fed cohorts received abiraterone acetate doses of 250, 500, 750, or 1,000 mg daily. Single-dose pharmacokinetic analyses were performed before continuous daily dosing.

Results: Adverse events were predominantly grade 1 or 2. No dose-limiting toxicities were observed. Hypertension (grade 3, 12%) and hypokalemia (grade 3, 6%; grade 4, 3%) were the most frequent serious toxicities and responded to medical management. Confirmed > or = 50% PSA declines at week 12 were seen in 18 (55%) of 33 patients, including nine (47%) of 19 patients with prior ketoconazole therapy and nine (64%) of 14 patients without prior ketoconazole therapy. Substantial declines in circulating androgens and increases in mineralocorticoids were seen with all doses.

Conclusion: Abiraterone acetate was well tolerated and demonstrated activity in CRPC, including in patients previously treated with ketoconazole. Continued clinical study is warranted.

Fig 1.

Changes in mean levels of endocrine steroids from baseline to day 28 of therapy, by dose (A-C), in men with castration-resistant prostate cancer receiving abiraterone acetate. DHEA-S, dehydroepiandrosterone sulfate.

Fig 2.

Relative levels of (A) dehydroepiandrosterone sulfate and (B) testosterone (commercial assay) at baseline, at day 28, and at the time of disease progression in patients treated with abiraterone acetate, by dose.

Fig 3.

Relative change in prostate-specific antigen (PSA) levels at week 12 of therapy in men with castration-resistant prostate cancer treated with abiraterone acetate. Patients who had received prior ketoconazole therapy appear on the left; those who had not received prior ketoconazole appear on the right.

Fig A1.

Effects of abiraterone acetate on adrenal steroid biosynthesis. Inhibition of 17α-hydroxylase and and C_17,20-lyase resulted in substantial decreases in circulating androgen levels (dehydroepiandrosterone sulfate [DHEA-S] and testosterone), with increases in upstream mineralocorticoids (deoxycorticosterone and corticosterone). Adrenocorticotropic hormone (ACTH) levels increased in response to decreases in circulating cortisol levels. LLQ, lower limit of quantitation.

Fig A2.

Abiraterone (A) maximum concentrations (C_max) and (B) area under the curve (AUC) by dose level in fed and fasting patients.

Fig A3.

Abiraterone concentration-time profiles at the 1,000-mg dose level in fed and fasting patients.

Fig A4.

Kaplan-Meier plot of the probability of prostate-specific antigen (PSA) progression over time in all patients (N = 33) and subgroups of patients with prior ketoconazole therapy (n = 19) and without prior ketoconazole therapy (n = 14).