The predictive value of ARv7 expression in localized prostate caner treated with abiraterone, degarelix, and bicalutamide (original) (raw)

Journal of Clinical Oncology, 2015

Abstract

71 Background: Androgen receptor splice variants (ARvs) are upregulated in response to castration, and can activate transcription in the absence of ligand. Recent evidence indicates that CTC ARv7 expression is an accurate predictor of absence of response to abiraterone and enzalutamide, providing strong clinical support for ARv7 upregulation as potential overarching mechanism of castration resistance. There is however limited data regarding the expression of ARv7 in clinically localized prostate cancer (CaP), and it is unknown if expression in the primary tumor is similarly predictive. We were therefore interested to determine the expression of ARv7 in high-risk disease, and correlate this with response to an abiraterone-containing castrating regimen. Methods: We performed an open label non-randomized Phase II neoadjuvant study of ‘supercastration’ in men with high-risk clinically localized CaP using an optimal 2-stage design (ACTRN12612000772842). Treatment consisted of degarelix 240/80mg q 1/12, abiraterone 1000mg OD, bicalutamide 50mg OD and prednisolone 5mg OD for 24 weeks. The primary endpoints were safety/tolerability and pT0 response rate. ARv7 expression was determined by immunohistochemistry and qRT-PCR in both pre- and post treatment tumor specimens, and correlated with pathological response. Fresh specimens from resistant tumors are currently being profiled by RNA-seq. Results: 17 patients were recruited to the study. The combination treatment was well tolerated, with hot flushes and fatigue being the most commonly reported side effects, and all patients completed six months of treatment. Six patients with asymptomatic elevation of liver transaminases required Abiraterone dose reductions, and there were no unexpected toxicities. 16 patients proceeded to prostatectomy, and a pT0 response observed in one patient, with minimal residual disease present in a further three patients. ARv7 expression was uniformly present in all pre-treatment specimens, and neither level nor localization of expression predicted tumor response. Conclusions: ARv7 expression in primary CaP does not predict response to abiraterone-based castration. Clinical trial information: ACTRN12612000772842.

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