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. Somarelli & 7 others Santosh Gupta, Simon G. Gregory, Howard I. Scher, Ryan Dittamore, Scott T. Tagawa, Emmanuel Antonarakis, Daniel J. George

Research output: Contribution to journalArticle

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 - Jan 1 2019

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Castration
Androgen Receptors
Prostatic Neoplasms
Hormones
Circulating Neoplastic Cells
Disease-Free Survival
Therapeutics
Prostate-Specific Antigen
Multicenter Studies
Survival
Validation Studies
Androgens
Protein Isoforms
Cell Count
Messenger RNA
MDV 3100

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Prospective multicenter validation of androgen receptor splice variant 7 and hormone therapy resistance in high-risk castration-resistant prostate cancer : The PROPHECY study. / Armstrong, Andrew J.; Halabi, Susan; Luo, Jun; Nanus, David M.; Giannakakou, Paraskevi; Szmulewitz, Russell Z.; Danila, Daniel C.; Healy, Patrick; Anand, Monika; Rothwell, Colin J.; Rasmussen, Julia; Thornburg, Blair; Berry, William R.; Wilder, Rhonda S.; Lu, Changxue; Chen, Yan; Silberstein, John L.; Kemeny, Gabor; Galletti, Giuseppe; Somarelli, Jason A.; Gupta, Santosh; Gregory, Simon G.; Scher, Howard I.; Dittamore, Ryan; Tagawa, Scott T.; Antonarakis, Emmanuel; George, Daniel J.

In: Journal of Clinical Oncology, Vol. 37, No. 13, 01.01.2019, p. 1120-1129.

Research output: Contribution to journalArticle

Armstrong, AJ, Halabi, S, Luo, J, Nanus, DM, Giannakakou, P, Szmulewitz, RZ, Danila, DC, Healy, P, Anand, M, Rothwell, CJ, Rasmussen, J, Thornburg, B, Berry, WR, Wilder, RS, Lu, C, Chen, Y, Silberstein, JL, Kemeny, G, Galletti, G, Somarelli, JA, Gupta, S, Gregory, SG, Scher, HI, Dittamore, R, Tagawa, ST, Antonarakis, E & George, DJ 2019, 'Prospective multicenter validation of androgen receptor splice variant 7 and hormone therapy resistance in high-risk castration-resistant prostate cancer: The PROPHECY study', Journal of Clinical Oncology, vol. 37, no. 13, pp. 1120-1129. https://doi.org/10.1200/JCO.18.01731
Armstrong, Andrew J. ; Halabi, Susan ; Luo, Jun ; Nanus, David M. ; Giannakakou, Paraskevi ; Szmulewitz, Russell Z. ; Danila, Daniel C. ; Healy, Patrick ; Anand, Monika ; Rothwell, Colin J. ; Rasmussen, Julia ; Thornburg, Blair ; Berry, William R. ; Wilder, Rhonda S. ; Lu, Changxue ; Chen, Yan ; Silberstein, John L. ; Kemeny, Gabor ; Galletti, Giuseppe ; Somarelli, Jason A. ; Gupta, Santosh ; Gregory, Simon G. ; Scher, Howard I. ; Dittamore, Ryan ; Tagawa, Scott T. ; Antonarakis, Emmanuel ; George, Daniel J. / Prospective multicenter validation of androgen receptor splice variant 7 and hormone therapy resistance in high-risk castration-resistant prostate cancer : The PROPHECY study. In: Journal of Clinical Oncology. 2019 ; Vol. 37, No. 13. pp. 1120-1129.
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title = "Prospective multicenter validation of androgen receptor splice variant 7 and hormone therapy resistance in high-risk castration-resistant prostate cancer: The PROPHECY study",
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.",
author = "Armstrong, {Andrew J.} and Susan Halabi and Jun Luo and Nanus, {David M.} and Paraskevi Giannakakou and Szmulewitz, {Russell Z.} and Danila, {Daniel C.} and Patrick Healy and Monika Anand and Rothwell, {Colin J.} and Julia Rasmussen and Blair Thornburg and Berry, {William R.} and Wilder, {Rhonda S.} and Changxue Lu and Yan Chen and Silberstein, {John L.} and Gabor Kemeny and Giuseppe Galletti and Somarelli, {Jason A.} and Santosh Gupta and Gregory, {Simon G.} and Scher, {Howard I.} and Ryan Dittamore and Tagawa, {Scott T.} and Emmanuel Antonarakis and George, {Daniel J.}",
year = "2019",
month = "1",
day = "1",
doi = "10.1200/JCO.18.01731",
language = "English (US)",
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pages = "1120--1129",
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publisher = "American Society of Clinical Oncology",
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}

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

AU - George, Daniel J.

PY - 2019/1/1

Y1 - 2019/1/1

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.

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U2 - 10.1200/JCO.18.01731

DO - 10.1200/JCO.18.01731

M3 - Article

VL - 37

SP - 1120

EP - 1129

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 0732-183X

IS - 13

ER -