Prospective multicenter validation of androgen receptor splice variant 7 and hormone therapy resistance in high-risk castration-resistant prostate cancer: The PROPHECY study

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. SomarelliSantosh Gupta, Simon G. Gregory, Howard I. Scher, Ryan Dittamore, Scott T. Tagawa, Emmanuel S. Antonarakis, Daniel J. George

Research output: Contribution to journalArticlepeer-review

246 Scopus citations

Abstract

PURPOSE Androgen receptor splice variant 7 (AR-V7) results in a truncated receptor, which leads to ligandindependent 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. PATIENTS AND METHODS PROPHECY (ClinicalTrials.gov identifier: NCT02269982) is a multicenter, prospectiveblinded 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. RESULTS 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%. CONCLUSION 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.

Original languageEnglish (US)
Pages (from-to)1120-1129
Number of pages10
JournalJournal of Clinical Oncology
Volume37
Issue number13
DOIs
StatePublished - 2019
Externally publishedYes

Bibliographical note

Funding Information:
Supported by a grant from the Prostate Cancer Foundation and Movember as well as infrastructure support from the Department of Defense Prostate Cancer Clinical Trials Consortium. A.J.A. was supported by a Prostate Cancer Foundation grant and Duke Cancer Institute (P30 CA014236) as well as by the Duke Cancer Institute–shared resources for biostatistics, flow cytometry, and sequencing and genomic technologies. This work was partially funded by Department of Defense grants W81XWH-13-PCRP-CCA, W81XWH-17-2-0021, and W81XWH-14-2-0179 (A.J.A., D.J.G., Duke University); W81XWH-14-2-0159 (D.M.N., Weill Cornell Medical College); W81XWH-15-2-0018 (R.Z.S., University of Chicago); W81XWH-15-2-0018 (H.I.S., Memorial Sloan Kettering Cancer Center); and W81XWH-16-PCRP-CCRSA (E.S.A., Johns Hopkins University). D.C.D. and H.I.S. were also supported in part by National Cancer Institute grant P30 CA008748 and the Memorial Sloan Kettering Cancer Center and Sidney Kimmel Center for Prostate and Urologic Cancers. This research was supported in part by National Cancer Institute grant T32 CA062948 and Clinical and Translational Science Center grants UL1 TR002384-01 and P30 CA014236.

Publisher Copyright:
© 2019 American Society of Clinical Oncology. All rights reserved.

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