Biomarker studies of circulating tumor cells (CTCs) have clinical utility in castration-resistant prostate cancer (CRPC) and constitutively active androgen receptor (AR) splice variants, especially the most common AR variant 7 (AR-V7), are undoubtedly associated with decreased sensitivity to endocrine therapy. In this issue of JAMA Oncology, Scher et al1 present a correlative study of CTC nuclear AR-V7 protein expression as a biomarker for treatment selection in CRPC. They claim that assay positivity supports choosing taxane chemotherapy rather than administering abiraterone after enzalutamide, or enzalutamide after abiraterone, in keeping with previous reports.2 Multiple studies have described AR-V7 messenger RNA (mRNA) positivity by binary assays, in CTCs or whole blood, associating AR-V7 positivity with decreased response rates to endocrine therapy and sensitivity to taxanes.3 Scher et al1 describe CTC nuclear AR-V7 protein, correctly pointing out the advantages of protein measurements, although CTC mRNA can be collected by methods providing years of stability. Overall, if confirmed by prospective randomized studies generating level 1 evidence, data on AR-V7 could affect survival and quality of life and substantially decrease the high costs of therapy. A test that truly demonstrates futility of a specific treatment could be important, since treatment efficacy currently requires following prostate-specific antigen response for at least 4 weeks of abiraterone after enzalutamide, or enzalutamide after abiraterone.4 Neither of these treatment switches have, however, been proven to impart survival benefit with modest antitumor activity, and are not widely reimbursed. Nonetheless, such validation of predictive biomarkers and clinical qualification would have major implications, especially in earlier treatment settings, although many challenges need to be met.