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

ABSTRACT: 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.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 (? = 0.05, power = 0.83). Circulating androgen levels were measured using liquid chromatography tandem mass spectrometry.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).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.

SUBMITTER: Kim W

PROVIDER: S-EPMC4277885 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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

Kim Won W Zhang Li L Wilton John H JH Fetterly Gerald G Mohler James L JL Weinberg Vivian V Morse Allison A Szmulewitz Russell Z RZ Friedlander Terence W TW Fong Lawrence L Lin Amy M AM Harzstark Andrea L AL Molina Arturo A Small Eric J EJ Ryan Charles J CJ

Clinical cancer research : an official journal of the American Association for Cancer Research 20141021 24

<h4>Purpose</h4>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.<h4>Experimental design</h4>Chemotherapy-naïve patients with progressive metastatic castration-resistant prostate cancer (mCRPC) and prior ketoconazole therapy ≥28 days received abiratero ...[more]

PMID: 25336698

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Project description:IntroductionCastration-resistant prostate cancer (CRPC) remains dependent on androgen receptor (AR) signalling, which is largely driven by conversion of adrenal androgen precursors lasting after castration. Abiraterone, an inhibitor of the steroidogenic enzyme CYP17A1, has been demonstrated to reduce adrenal androgen synthesis and prolong CRPC patient survival. To study mechanisms of resistance to castration and abiraterone, we created coculture models using human prostate and adrenal tumours.Materials and methodsCastration-naïve and CRPC clones of VCaP were incubated with steroid substrates or cocultured with human adrenal cells (H295R) and treated with abiraterone or the antiandrogen enzalutamide. Male mice bearing VCaP xenografts with and without concurrent H295R xenografts were castrated and treated with placebo or abiraterone. Response was assessed by tumour growth and PSA release. Plasma and tumour steroid levels were assessed by LC/MS-MS. Quantitative polymerase chain reaction determined steroidogenic enzyme, nuclear receptor and AR target gene expression.ResultsIn vitro, adrenal androgens induced castration-naïve and CRPC cell growth, while precursors steroids for de novo synthesis did not. In a coculture system, abiraterone blocked H295R-induced growth of VCaP cells. In vivo, H295R promoted castration-resistant VCaP growth. Abiraterone only inhibited VCaP growth or PSA production in the presence of H295R. Plasma steroid levels demonstrated CYP17A1 inhibition by abiraterone, whilst CRPC tumour tissue steroid levels showed no evidence of de novo intratumoural androgen production. Castration-resistant and abiraterone-resistant VCaP tumours had increased levels of AR, AR variants and glucocorticoid receptor (GR) resulting in equal AR target gene expression levels compared to noncastrate tumours.ConclusionsIn our model, ligand-dependent AR-regulated regrowth of CRPC was predominantly supported via adrenal androgen precursor production while there was no evidence for intratumoural androgen synthesis. Abiraterone-resistant tumours relied on AR overexpression, expression of ligand-independent AR variants and GR signalling.

Project description:Abiraterone acetate (AA) is an androgen biosynthesis inhibitor shown to prolong life in patients with castration-resistant prostate cancer (CRPC) already treated with chemotherapy. AA treatment results in dramatic declines in prostate-specific antigen (PSA) in some patients and no declines in others, suggesting the presence of molecular determinants of sensitivity in tumors.To study the role of transmembrane protease, serine 2 (TMPRSS2)-v-ets erythroblastosis virus E26 oncogene homolog (ERG) fusion, an androgen-dependent growth factor, in circulating tumor cells (CTCs) as a biomarker of sensitivity to AA.The predictive value of TMPRSS2-ERG status was studied in 41 of 48 men with postchemotherapy-treated CRPC enrolled in sequential phase 2 AA trials.Patients received AA 1000 mg daily and continuously.TMPRSS2-ERG status was characterized by a sensitive, analytically valid reverse transcription polymerase chain reaction assay in CTCs enriched from ethylene-diaminetetraacetic acid anticoagulated blood obtained prior to AA treatment. Outcomes were measured by PSA Working Group 1 criteria.Standard procedures for specimen acquisition, processing, and testing using the validated TMPRSS2-ERG assay on a multiplex platform gave intra-assay and interassay coefficients of variation <7%. TMPRSS2-ERG fusion was present in 15 of 41 patients (37%), who had a median baseline CTC count of 17 (interquartile range: 7-103 cells per 7.5 ml). A PSA decline ?50% was observed in 7 of 15 patients (47%) with the fusion and in 10 of 26 patients (38%) without the fusion. Although limited by the low number of patients, a posttherapy CTC count of less than five per 7.5 ml was prognostic for longer survival relative to a CTC count five or more. TMPRSS2-ERG status did not predict a decline in PSA or other clinical outcomes.Molecular profiles of CTCs with an analytically valid assay identified the presence of the prostate cancer-specific TMPRSS2-ERG fusion but did not predict for response to AA treatment. This finding demonstrates the role of CTCs as surrogate tissue that can be obtained in a routine practice setting.ClinicalTrials.gov: NCT00474383 (COU-AA-003), NCT00485303 (COU-AA-004).

Project description:Chronic supraphysiological glucocorticoid therapy controls the androgen excess of 21-hydroxylase deficiency (21OHD) but contributes to the high prevalence of obesity, glucose intolerance, and reduced bone mass in these patients. Abiraterone acetate (AA) is a prodrug for abiraterone, a potent CYP17A1 inhibitor used to suppress androgens in the treatment of prostate cancer.The objective of the study was to test the hypothesis that AA added to physiological hydrocortisone and 9?-fludrocortisone acetate corrects androgen excess in women with 21OHD without causing hypertension or hypokalemia.This was a phase 1 dose-escalation study.The study was conducted at university clinical research centers.We screened 14 women with classic 21OHD taking hydrocortisone 12.5-20 mg/d to enroll six participants with serum androstenedione greater than 345 ng/dL (>12 nmol/L).AA was administered for 6 days at 100 or 250 mg every morning with 20 mg/d hydrocortisone and 9?-fludrocortisone acetate.The primary endpoint was normalization of mean predose androstenedione on days 6 and 7 (< 230 ng/dL [<8 nmol/L)] in greater than 80% of participants. Secondary end points included serum 17-hydroxyprogesterone and testosterone (T), electrolytes, plasma renin activity, and urine androsterone and etiocholanolone glucuronides.With 100 mg/d AA, mean predose androstenedione fell from 764 to 254 ng/dL (26.7-8.9 nmol/L). At 250 mg/d AA, mean androstenedione normalized in five participants (83%) and decreased from 664 to 126 ng/dL (23.2-4.4 nmol/L), meeting the primary end point. Mean androstenedione declined further during day 6 to 66 and 38 ng/dL (2.3 and 1.3 nmol/L) at 100 and 250 mg/d, respectively. Serum T and urinary metabolites declined similarly. Abiraterone exposure was strongly negatively correlated with mean androstenedione. Hypertension and hypokalemia were not observed.AA 100-250 mg/d added to replacement hydrocortisone normalized several measures of androgen excess in women with classic 21OHD and elevated serum androstenedione.

Dataset Information

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

Publications

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

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