Cytoplasmic versus nuclear localization of androgen receptor splice variant 7 as a predictor of benefit from androgen receptor pathway inhibitors in metastatic castration-resistant prostate cancer (PROPHECY trial)

Background: Androgen receptor splice variant-7 (AR-V7), a constitutively active truncated protein, is linked to hormone therapy resistance. Nuclear AR-V7 in CTCs correlates with poor response and shorter progression-free survival (PFS) and overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) treated with ARPIs. The predictive value of cytoplasmic AR-V7 localization remains unclear. This exploratory study evaluated whether an AR-V7-agnostic CTC scoring criterion, including cytoplasmic detection, better predicts ARPI in this mCRPC setting. Methods: Baseline blood from 107/118 pre-ARPI mCRPC patients in the PROPHECY trial (NCT02269982) was analyzed for nuclear and cytoplasmic AR-V7 using Epic’s CTC platform. Associations with confirmed PSA50 response, OS, and PFS with abiraterone or enzalutamide treatment were examined. Correlations between AR overexpression, AR-V7 localization, and AR-V7 mRNA levels were assessed. Proportional hazards models adjusted for Halabi risk score and CellSearch CTC count (>5) evaluated cytoplasmic AR-V7 prognostic significance. Results: At baseline, 10% (11/107) had nuclear-localized AR-V7 and 14% (15/107) had cytoplasmic-only AR-V7, totaling 24% AR-V7-positive. All nuclear AR-V7 cases showed AR overexpression vs. 67% of cytoplasmic-only cases. PSA50 responses occurred in 0% nuclear, 13% cytoplasmic-only, and 30% AR-V7–negative patients. Cytoplasmic AR-V7+ patients had worse PFS and OS than AR-V7– patients, but similar PFS compared with nuclear AR-V7 +, despite numerically better PSA declines and OS. Conclusions: Cytoplasmic-only AR-V7 is more prevalent than nuclear AR-V7 in mCRPC and is associated with poor PFS and intermediate PSA and OS outcomes. Assessing both nuclear and cytoplasmic AR-V7 in CTCs may improve risk stratification before ARPI therapy. Clinical significance: This study clarifies the clinical relevance of cytoplasmic AR-V7 in circulating tumor cells from men with metastatic castration-resistant prostate cancer. While nuclear-localized AR-V7 predicts extremely poor response, PFS, and overall survival with AR pathway inhibitors, cytoplasmic AR-V7 expands the definition of AR-V7-positive status and identifies patients with equally poor PFS and intermediate response and overall survival outcomes. Assessing both nuclear and cytoplasmic AR-V7 fractions may thus improve risk stratification heterogeneity and could better guide poor-risk ARPI treatment decisions by avoiding ineffective ARPI treatment, helping personalize therapy, and improving outcomes in men with mCRPC.