Androgen Receptor Splice Variant 7 and Hormone Therapy Resistance in High-Risk Castration-Resistant Prostate Cancer

[Balsam01]

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•The authors report the results from a multicenter, prospective, blinded study of 118 men with high-risk mCRPC starting abiraterone acetate or enzalutamide treatment, in which they evaluated circulating androgen receptor splice variant 7 (AR-V7) mRNA as a prognostic indicator. AR-V7 detection was significantly associated with shorter progression-free survival and overall survival.

•The detection of AR-V7 in circulating tumor cells is associated with shorter progression-free and overall survival in patients treated with abiraterone or enzalutamide.

– Jeffrey M. Wiisanen, MD

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.

Journal of Clinical Oncology

Prospective Multicenter Validation of Androgen Receptor Splice Variant 7 and Hormone Therapy Resistance in High-Risk Castration-Resistant Prostate Cancer: The PROPHECY Study

J. Clin. Oncol 2019 Mar 13;[EPub Ahead of Print], AJ Armstrong, S Halabi, J Luo, DM Nanus, P Giannakakou, RZ Szmulewitz, DC Danila, P Healy, M Anand, CJ Rothwell, J Rasmussen, B Thornburg, WR Berry, RS Wilder, C Lu, Y Chen, JL Silberstein, G Kemeny, G Galletti, JA Somarelli, S Gupta, SG Gregory, HI Scher, R Dittamore, ST Tagawa, ES Antonarakis, DJ George

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

[mdiaz76]

When I asked our MO about this testing he doesn’t think it has a role yet in determining next line of treatment. My concern is if we don’t do this and he is positive for ARV7, will Abiraterone or Xtandi make it more aggressive?