期刊
JOURNAL OF CLINICAL ONCOLOGY
卷 26, 期 28, 页码 4563-4571出版社
AMER SOC CLINICAL ONCOLOGY
DOI: 10.1200/JCO.2007.15.9749
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资金
- Cougar Biotechnology
- Cancer Research UK
- Medical Reserach Council
- Prostate Cancer Research Foundation
- Royal Marsden Hospital Research Fund
- Experimental Cancer Medicine Centre
- Bob Champion Cancer Trust
- Medical Research Council [G0501019] Funding Source: researchfish
- MRC [G0501019] Funding Source: UKRI
Purpose Studies indicate that castration-resistant prostate cancer (CRPC) remains driven by ligand-dependent androgen receptor (AR) signaling. To evaluate this, a trial of abiraterone acetate-a potent, selective, small-molecule inhibitor of cytochrome P (CYP) 17, a key enzyme in androgen synthesis-was pursued. Patients and Methods Chemotherapy-naive men (n = 21) who had prostate cancer that was resistant to multiple hormonal therapies were treated in this phase I study of once-daily, continuous abiraterone acetate, which escalated through five doses (250 to 2,000 mg) in three-patient cohorts. Results Abiraterone acetate was well tolerated. The anticipated toxicities attributable to a syndrome of secondary mineralocorticoid excess-namely hypertension, hypokalemia, and lower-limb edema-were successfully managed with a mineralocorticoid receptor antagonist. Antitumor activity was observed at all doses; however, because of a plateau in pharmacodynamic effect, 1,000 mg was selected for cohort expansion (n = 9). Abiraterone acetate administration was associated with increased levels of adrenocorticotropic hormone and steroids upstream of CYP17 and with suppression of serum testosterone, downstream androgenic steroids, and estradiol in all patients. Declines in prostate-specific antigen >= 30%, 50%, and 90% were observed in 14 (66%), 12 (57%), and 6 (29%) patients, respectively, and lasted between 69 to >= 578 days. Radiologic regression, normalization of lactate dehydrogenase, and improved symptoms with a reduction in analgesic use were documented. Conclusion CYP17 blockade by abiraterone acetate is safe and has significant antitumor activity in CRPC. These data confirm that CRPC commonly remains dependent on ligand-activated AR signaling.
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