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.
OBJECTIVE
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.


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.


CONCLUSIONS
Abiraterone acetate was well tolerated and demonstrated activity in CRPC, including in patients previously treated with ketoconazole. Continued clinical study is warranted.
Ryan
Charles J
CJ
Urologic Oncology Program, University of California, San Francisco, San Francisco, CA 94115, USA. ryanc@medicine.ucsf.edu
Smith
Matthew R
MR
Fong
Lawrence
L
Rosenberg
Jonathan E
JE
Kantoff
Philip
P
Raynaud
Florence
F
Martins
Vanessa
V
Lee
Gloria
G
Kheoh
Thian
T
Kim
Jennifer
J
Molina
Arturo
A
Small
Eric J
EJ
D000368:Aged; D000369:Aged, 80 and over; D000726:Androgen Antagonists / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000728:Androgens / Q000378:metabolism; D000736:Androstenes; D000737:Androstenols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007654:Ketoconazole / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009919:Orchiectomy; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000601:surgery; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors; D016896:Treatment Outcome
D000726:Androgen Antagonists; D000728:Androgens; D000736:Androstenes; D000737:Androstenols; D000970:Antineoplastic Agents; D013254:Steroid 17-alpha-Hydroxylase; D017430:Prostate-Specific Antigen; C089740:abiraterone; D007654:Ketoconazole