Prospective Multicenter Validation of Androgen Receptor Splice Variant 7 and Hormone Therapy Resistance in High-Risk Castration-Resistant Prostate Cancer: The PROPHECY Study.

Androgen receptor splice variant 7 (AR-V7) results in a truncated receptor, which leads to ligand-independent constitutive activation that is not inhibited by anti-androgen therapies, including abiraterone or enzalutamide. Given that previous reports suggested that circulating tumor cell (CTC) AR-V7 detection is a poor prognostic indicator for the clinical efficacy of secondary hormone therapies, we conducted a prospective multicenter validation study.

PROPHECY ( ClinicalTrials.gov identifier: NCT02269982) is a multicenter, prospective-blinded study of men with high-risk mCRPC starting abiraterone acetate or enzalutamide treatment. The primary objective was to validate the prognostic significance of baseline CTC AR-V7 on the basis of radiographic or clinical progression free-survival (PFS) by using the Johns Hopkins University modified-AdnaTest CTC AR-V7 mRNA assay and the Epic Sciences CTC nuclear-specific AR-V7 protein assay. Overall survival (OS) and prostate-specific antigen responses were secondary end points.

We enrolled 118 men with mCRPC who were starting abiraterone or enzalutamide treatment. AR-V7 detection by both the Johns Hopkins and Epic AR-V7 assays was independently associated with shorter PFS (hazard ratio, 1.9 [95% CI, 1.1 to 3.3; P = .032] and 2.4 [95% CI, 1.1 to 5.1; P = .020], respectively) and OS (hazard ratio, 4.2 [95% CI, 2.1 to 8.5] and 3.5 [95% CI, 1.6 to 8.1], respectively) after adjusting for CTC number and clinical prognostic factors. Men with AR-V7-positive mCRPC had fewer confirmed prostate-specific antigen responses (0% to 11%) or soft tissue responses (0% to 6%). The observed percentage agreement between the two AR-V7 assays was 82%.

Detection of AR-V7 in CTCs by two blood-based assays is independently associated with shorter PFS and OS with abiraterone or enzalutamide, and such men with mCRPC should be offered alternative treatments.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2019 Mar 13 [Epub ahead of print]

Andrew J Armstrong, Susan Halabi, Jun Luo, David M Nanus, Paraskevi Giannakakou, Russell Z Szmulewitz, Daniel C Danila, Patrick Healy, Monika Anand, Colin J Rothwell, Julia Rasmussen, Blair Thornburg, William R Berry, Rhonda S Wilder, Changxue Lu, Yan Chen, John L Silberstein, Gabor Kemeny, Giuseppe Galletti, Jason A Somarelli, Santosh Gupta, Simon G Gregory, Howard I Scher, Ryan Dittamore, Scott T Tagawa, Emmanuel S Antonarakis, Daniel J George

1 Duke University, Durham, NC., 2 Johns Hopkins University, Baltimore, MD., 3 Weill Cornell Medical College, New York, NY., 4 University of Chicago, Chicago, IL., 6 Epic Sciences, San Diego, CA.

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