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

Abstract

Purpose: 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.

Patients and methods: 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.

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.

Figures

FIG 1.
FIG 1.
Kaplan-Meier plots of (A) progression-free survival (PFS) and (B) overall survival (OS) by Johns Hopkins University circulating tumor cell androgen receptor splice variant 7 (AR-V7) detection criteria and of (C) PFS and (D) OS by Epic Sciences circulating tumor cell AR-V7 detection criteria.
FIG 2.
FIG 2.
Swimmer plot of patient status according to androgen receptor splice variant 7 (AR-V7) status. Each lane is color coded according to whether the patient tested positive for each AR-V7 test, one test, or neither test or was not evaluable for either test. Epic, Epic Sciences circulating tumor cell AR-V7 protein assay; JHU, Johns Hopkins University circulating tumor cell AR-V7 mRNA assay; PROPHECY, Prospective Circulating Prostate Cancer Predictors in Higher Risk mCRPC [metastatic castration-resistant prostate cancer] Study; PSA50, 50% or greater prostate-specific antigen.
FIG 3.
FIG 3.
Prostate-specific antigen (PSA) waterfall plots of the best overall confirmed PSA decline from baseline with abiraterone or enzalutamide according to (A) Johns Hopkins University circulating tumor cell androgen receptor splice variant 7 (AR-V7) status and (B) Epic Sciences circulating tumor cell AR-V7 status.
FIG 4.
FIG 4.
Plot of the proportion of circulating tumor cells (CTCs) that tested positive for androgen receptor splice variant 7 (AR-V7) nuclear protein (red) at (A) baseline and at (B) progression on abiraterone acetate or enzalutamide as a function of the total number of CTCs, including AR-V7–negative CTCs (blue).

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Source: PubMed

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