TY - JOUR
T1 - Prospective multicenter validation of androgen receptor splice variant 7 and hormone therapy resistance in high-risk castration-resistant prostate cancer
T2 - The PROPHECY study
AU - Armstrong, Andrew J.
AU - Halabi, Susan
AU - Luo, Jun
AU - Nanus, David M.
AU - Giannakakou, Paraskevi
AU - Szmulewitz, Russell Z.
AU - Danila, Daniel C.
AU - Healy, Patrick
AU - Anand, Monika
AU - Rothwell, Colin J.
AU - Rasmussen, Julia
AU - Thornburg, Blair
AU - Berry, William R.
AU - Wilder, Rhonda S.
AU - Lu, Changxue
AU - Chen, Yan
AU - Silberstein, John L.
AU - Kemeny, Gabor
AU - Galletti, Giuseppe
AU - Somarelli, Jason A.
AU - Gupta, Santosh
AU - Gregory, Simon G.
AU - Scher, Howard I.
AU - Dittamore, Ryan
AU - Tagawa, Scott T.
AU - Antonarakis, Emmanuel S.
AU - George, Daniel J.
N1 - Publisher Copyright:
© 2019 American Society of Clinical Oncology. All rights reserved.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85065325919&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85065325919&partnerID=8YFLogxK
U2 - 10.1200/JCO.18.01731
DO - 10.1200/JCO.18.01731
M3 - Article
C2 - 30865549
AN - SCOPUS:85065325919
SN - 0732-183X
VL - 37
SP - 1120
EP - 1129
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 13
ER -