Does cytoplasmic AR-V7 circulating tumor cell (CTC) detection add utility in predicting AR pathway inhibitor benefit in men with mCRPC? A retrospective analysis of the PROPHECY study.

Androgen receptor splice variant-7 (AR-V7) is a constitutively active truncated protein that emerges during hormone therapy resistance in prostate cancer. We have shown that circulating tumor cell (CTC) AR-V7 nuclear localization is strongly associated with worse responses, PFS, and overall survival with AR pathway inhibitors (ARPIs) such as abiraterone or enzalutamide in the metastatic castration-resistant prostate cancer (mCRPC) setting. The measurement of cytoplasmic AR-V7, however, has unclear predictive value and we thus sought to determine whether an AR-V7-agnostic CTC scoring criterion would identify more patients with ARPI resistance as compared to nuclear AR-V7 in the PROPHECY study (NCT02269982). Blood samples were available from 110 of 118pre-ARPI mCRPC patients and evaluated for both nuclear and cytoplasmic CTC only AR-V7 detection utilizing Epic’s CTC platform and associated with confirmed PSA50 response, overall survival (OS), and progression-free survival (PFS). We also assessed the correlation between AR overexpression and AR-V7 detection. The proportional hazards model was utilized to explore the prognostic significance of nuclear, cytoplasmic AR-V7 in predicting OS and PFS adjusting for Halabi clinical risk score and CellSearch CTCs≥5. At baseline, 11/107 (10%) mCRPC samples had AR-V7 nuclear expression, 15/107 (14%) had cytoplasmic only AR-V7 detection, and thus 26/107 (24%) cases were CTC AR-V7 positive. All of the nuclear AR-V7 positive cases had AR overexpression, while only 67% of cytoplasmic AR-V7 positive cases exhibited AR overexpression. We observed a confirmed PSA50 in 0%, 13%, and 29.6% of nuclear V7+, cytoplasmic V7+, and V7- patients. See the table for PFS and OS outcomes. Cytoplasmic AR-V7 detection in CTCs is more prevalent than nuclear only scoring. Cytoplasmic AR-V7 positive cases appear to have worse PFS, PSA50, and OS as compared to AR-v7 negative cases. However, men with cytoplasmic only CTC AR-V7 detection were more likely to have post-ARPI short term PSA declines and improved overall survival, despite a similar poor PFS as compared to nuclear AR-V7 positive patients with mCRPC. Knowledge of both CTC nuclear and cytoplasmic AR-V7 status could be helpful for improved risk stratification of patients with mCRPC prior to ARPI therapy. .

Duke Scholars

Author Andrew John Armstrong Medicine, Medical Oncology

Author Susan Halabi Biostatistics & Bioinformatics, Division of Biostatistics

Author Daniel James George Medicine, Medical Oncology