Prognostic Value of Androgen Receptor Splice Variant 7 in the Treatment of Castration-resistant Prostate Cancer with Next generation Androgen Receptor Signal Inhibition: A Systematic Review and Meta-analysis

Abstract

Context: Androgen receptor splice variant 7 (AR-V7) may be associated with resistance to next-generation androgen receptor signaling (ARS) inhibitors in castration-resistant prostate cancer (CRPC) sensitive to chemotherapy.

Objective: To evaluate the prognostic value of AR-V7 for prostate specific antigen (PSA) response, progression-free survival (PFS), and overall survival (OS) among CRPC patients treated with ARS inhibitors or chemotherapy.

Evidence acquisition: A search of PubMed, Embase, and Web of Science databases was performed using the keywords "prostate cancer", "prostate tumor", "prostate neoplasm", "prostate carcinoma"; "AR-V7", "AR3", "androgen receptor splicing variant-7" and "androgen receptor-3". Fourteen trials published up to August 2016 were selected.

Evidence synthesis: A significantly greater proportion of CRPCs than newly diagnosed prostate cancers were AR-V7-positive (odds ratio [OR] 8.29, 95% confidence interval [CI] 5.06-13.57; p<0.001). AR-V7-positive patients treated with ARS inhibitors had a significantly lower PSA response than those who were AR-V7-negative (OR 0.05, 95% CI 0.02-0.16; p<0.001).The difference was not significant in chemotherapy-treated patients (OR 0.64, 95% CI 0.3-1.33; p=0.23). Both PFS (hazard ratio [HR] 4.05, 95% CI 1.91-8.59; p=0.0003) and OS (HR 4.79, 95% CI 2.14-10.72; p<0.001) were better in AR-V7-negative than AR-V7-positive CRPC patients treated with ARS inhibitors. In chemotherapy patients, AR-V7 status had no significant effect on PFS (HR 1.26, 95% CI 0.80-2.00; p=0.32).However, AR-V7-negative patients had significantly better OS (HR 2.82, 95% CI 1.72-4.62; p<0.001). The limitations of our meta-analysis were differences in study sample size and design, AR-V7 assay, and disease characteristics.

Conclusions: AR-V7 positivity was associated with poorer PSA response and PFS prognosis in CRPC patients treated with ARS inhibitors, but did not affect outcomes except OS for those treated with chemotherapy. Additional studies are warranted to confirm these findings.

Patient summary: We concluded from several studies that androgen receptor splice variant 7 (AR-V7) could predict the outcomes of prostate cancer. AR-V7-positive patients have poorer outcomes when treated with abiraterone or enzalutamide, but relatively better outcomes when treated by chemotherapy.

Keywords: Androgen receptor signaling inhibition therapy; Androgen receptor splice variant 7; Castration-resistant prostate cancer; Chemotherapy; Predictor; Survival.