Prostate cancer and prostatic diseases · 2026
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).
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Gupta Santosh, Guo Siyuan, Halabi Susan, Yu Chenxi, Kim Hyotae, McKenzie Jane, George Daniel J, Nanus David M, Szmulewicz Russell Z, Danila Daniel C, Luo Jun, Antonarakis Emmanuel S, Armstrong Andrew J
Аннотация
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.
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.