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Clin Cancer Res. 2014 Dec 15;20(24):6269-76. doi: 10.1158/1078-0432.CCR-14-1595. Epub 2014 Oct 21.

Sequential use of the androgen synthesis inhibitors ketoconazole and abiraterone acetate in castration-resistant prostate cancer and the predictive value of circulating androgens.

Author information

1
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California. won.kim@ucsf.edu.
2
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California.
3
Department of Medicine, PK/PD Core Resource, Roswell Park Cancer Institute, Buffalo, New York.
4
Department of Urology, Roswell Park Cancer Institute, Buffalo, New York.
5
Section of Hematology and Oncology, University of Chicago, Chicago, Illinois.
6
Janssen Research and Development, Menlo Park, California.

Abstract

PURPOSE:

Patients previously treated with ketoconazole were excluded from phase III trials of abiraterone acetate due to potential overlapping mechanism of action. The purpose of this study was to determine the clinical utility of abiraterone and its impact on circulating androgens following ketoconazole.

EXPERIMENTAL DESIGN:

Chemotherapy-naïve patients with progressive metastatic castration-resistant prostate cancer (mCRPC) and prior ketoconazole therapy ≥28 days received abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. The primary endpoint was the proportion of patients with PSA response, defined as ≥30% PSA decline at 12 weeks. H0 = 0.30 versus H1 = 0.50 (α = 0.05, power = 0.83). Circulating androgen levels were measured using liquid chromatography tandem mass spectrometry.

RESULTS:

Thirty-nine patients were included in the final analysis. Twenty (51%; 95% confidence interval, 36%-66%) patients had ≥30% PSA decline; the null hypothesis was rejected. Sixteen (41%) had ≥50% PSA decline. Median PFS (progression-free survival) was 16 weeks; median radiographic PFS (rPFS) was 36 weeks. Samples for measurement of baseline androgens were available in 37 patients. The PSA response proportion was 59% in 29 patients with DHEA ≥ limit of quantitation (LOQ), compared with 13% in 8 patients with DHEA < LOQ (P = 0.042). Median PFS was 6 and 16 weeks in DHEA < LOQ and DHEA ≥ LOQ patients, respectively (P = 0.017); median rPFS was 14 and 36 weeks in DHEA < LOQ and DHEA ≥ LOQ patients, respectively (P < 0.001).

CONCLUSIONS:

Abiraterone demonstrates modest clinical efficacy in mCRPC patients previously treated with ketoconazole. Patients with DHEA ≥ LOQ were more likely to demonstrate PSA responses and longer PFS. Analysis of circulating androgens merits further investigation as a biomarker for response to androgen synthesis inhibitor therapy.

PMID:
25336698
PMCID:
PMC4277885
DOI:
10.1158/1078-0432.CCR-14-1595
[Indexed for MEDLINE]
Free PMC Article

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