Phase I evaluation of abiraterone acetate (CB7630), a 17 alpha hydroxylase C17,20-Lyase inhibitor in androgen-independent prostate cancer (AiPC)

Abstract

5064 Background: Abiraterone acetate (Ab) is an oral inhibitor of 17 alpha hydroxylase and C17,20-Lyase, which are important in adrenal androgen synthesis. A phase I study was undertaken to define the maximum tolerated dose (MTD) of Ab in patients (pts) with AIPC, the need for corticosteroid replacement (CSR) and the effects of Ab on hormone levels. Methods: Eligible pts had progressive AIPC by consensus criteria and normal organ and adrenal function. Dose escalations both while fasting and with food range from 250 mg to a maximum planned dose of 2,000 mg per day. Single dose pharmacokinetic (pK) analysis was performed prior to the onset of continuous daily dosing. Results: Sixteen pts have been enrolled, 3 with non-metastatic AIPC and 13 with bone/soft tissue metastases. Median PSA and testosterone levels are 26.7 and 7.7 ng/dL, respectively. Fourteen of 16 received prior ketoconazole. CSR has been required during the first month in 1 pt at a dose level of 500 and in 1 pt in month 3. Two pts experienced syncopal events (grade 3) on Ab, one at 250 mg and one at 500 mg, both after starting CSR. Mineralocorticoid-induced hypertension (grade 2) developed in 4 pts and was treated with aldosterone antagonists. Grade 1 edema has occurred in 3 pts. Testosterone became undetectable in 4/9 pts with available data, the mineralocorticoid deoxycorticosterone rose by a median 6.7 fold on therapy (range 1.5–67 fold). PK suggest maximum concentrations of Ab are achieved within 2 hr post dose with a mean t 1/2 of 7.8 hr, and interpatient variability in AUC and Cmax of approximately 2.5 fold. A decline in PSA by >50% occurred in 7 of 14 patients (50%) completing the initial 28 days of treatment. Five of 9 pts with ketoconazole refractory disease experienced a >50% reduction in PSA. Conclusions: Abiraterone appears to have moderate activity in AIPC pts (including significant activity in pts treated previously with ketoconazole) and an acceptable toxicity profile. CSR has not been consistently required. No significant financial relationships to disclose.