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 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.

Discordant and heterogeneous clinically relevant genomic alterations in circulating tumor cells vs plasma DNA from men with metastatic castration resistant prostate cancer

“…19 However, in matched cfDNA samples from the same patients, copy gain/ loss of these key genes were not observed despite the collection of samples at the same time points and using the same aCGH method of detection, and despite highTC of many cfDNA samples ( Figure S10B). For example, we identified copy gains for these seven osteoblast genes in patients, including ALPL (19%), CDH11 (16%), SPP1 (9%), and TNFSF11 (6%) and SPARC (9%), whereas, copy loss of RUNX2 was notable in 47% of CTCs.…”

“…We included two independent prospective cohorts of men with mCRPC, including men treated with radium-223 (NCT02204943) or abiraterone/enzalutamide (PROPHECY study, 19 …”

“…17,19,32 The JHU AR-V7 assay is an RT-PCR based assay to detect AR-V7 mRNA expression. A positive test for the Epic assay was defined as the presence of CTCs (CK+/−) expressing nuclear AR-V7 protein, as previously described.…”

“…19 The tumor content was determined in cfDNA from wholegenome sequencing data using the PRINCe method according to previously described methods. 19 The tumor content was determined in cfDNA from wholegenome sequencing data using the PRINCe method according to previously described methods.…”

“…6 While most men initially respond to novel hormonal therapies, such as abiraterone acetate or enzalutamide, nearly all men with mCRPC relapse and develop resistant progression over 1 to 3 years. [16][17][18][19] Yet, despite the importance of AR-V7 as a predictive biomarker, many men with AR-V7 negative disease have resistance to therapy or develop resistance over time that is currently unexplained by AR alterations. 15 Thus, optimal delivery of these agents in the second-line setting could be facilitated by the development of predictive biomarkers of treatment response and resistance.…”