TY - JOUR
T1 - Sequential use of the androgen synthesis inhibitors ketoconazole and abiraterone acetate in castration-resistant prostate cancer and the predictive value of circulating androgens
AU - Kim, Won
AU - Zhang, Li
AU - Wilton, John H.
AU - Fetterly, Gerald
AU - Mohler, James L.
AU - Weinberg, Vivian
AU - Morse, Allison
AU - Szmulewitz, Russell Z.
AU - Friedler, Terence W.
AU - Fong, Lawrence
AU - Lin, Amy M.
AU - Harzstark, Andrea L.
AU - Molina, Arturo
AU - Small, Eric J.
AU - Ryan, Charles J.
N1 - Publisher Copyright:
© 2014 American Association for Cancer Research.
PY - 2014/12/15
Y1 - 2014/12/15
N2 - 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-naäve 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 (αa = 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 PFS 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.
AB - 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-naäve 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 (αa = 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 PFS 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.
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U2 - 10.1158/1078-0432.CCR-14-1595
DO - 10.1158/1078-0432.CCR-14-1595
M3 - Article
C2 - 25336698
AN - SCOPUS:84919652846
SN - 1078-0432
VL - 20
SP - 6269
EP - 6276
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 24
ER -
