Prospective multicenter study of circulating tumor cell AR-V7 and taxane versus hormonal treatment outcomes in metastatic castration-Resistant prostate cancer

Andrew J. Armstrong, Jun Luo, David M. Nanus, Paraskevi Giannakakou, Russell Z. Szmulewitz, Daniel C. Danila, Patrick Healy, Monika Anand, William R. Berry, Tian Zhang, Michael R. Harrison, Changxue Lu, Yan Chen, Giuseppe Galletti, Joseph D. Schonhoft, Howard I. Scher, Richard Wenstrup, Scott T. Tagawa, Emmanuel S. Antonarakis, Daniel J. GeorgeSusan Halabi

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Abstract

PURPOSE Androgen receptor splice variant 7 (AR-V7) detection in circulating tumor cells (CTCs) is associated with a low probability of response and short progression-free (PFS) and overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC) treated with enzalutamide or abiraterone. However, it is unclear whether such men benefit from taxane chemotherapy. PATIENTS AND METHODS PROPHECY is a multicenter prospective blinded study of patients with poor-risk mCRPC starting abiraterone or enzalutamide and observed through subsequent progression and taxane chemotherapy. We assessed AR-V7 status using the Johns Hopkins modified AdnaTest CTC AR-V7 messenger RNA assay and the Epic Sciences CTC nuclear-localized AR-V7 protein assay before treatment. The primary objective was to validate the independent prognostic value of CTC AR-V7 status based on radiographic/clinical PFS. OS, confirmed prostate-specific antigen (PSA), and objective radiologic responses were secondary end points. RESULTS We enrolled 118 men with mCRPC treated with abiraterone or enzalutamide, 51 of whom received subsequent docetaxel or cabazitaxel. Pretreatment CTC AR-V7 status by the Johns Hopkins and Epic Sciences assays was independently associated with worse PFS (hazard ratio [HR], 1.7; 95% CI, 1.0 to 2.9 and HR, 2.1; 95% CI, 1.0 to 4.4, respectively) and OS (HR, 3.3; 95% CI, 1.7 to 6.3 and HR, 3.0; 95% CI, 1.4 to 6.3, respectively) and a low probability of confirmed PSA responses, ranging from 0% to 11%, during treatment with abiraterone or enzalutamide. At progression, subsequent CTC AR-V7 detection was not associated with an inferior PSA or radiographic response or worse PFS or OS with subsequent taxane chemotherapy after adjusting for CellSearch CTC enumeration and clinical prognostic factors. CONCLUSION Detection of AR-V7 in CTCs by two different blood-based assays is independently associated with shorter PFS and OS with abiraterone or enzalutamide, but such men with AR-V7–positive disease still experience clinical benefits from taxane chemotherapy.

Original languageEnglish (US)
Pages (from-to)1285-1301
Number of pages17
JournalJCO Precision Oncology
Volume4
DOIs
StatePublished - 2020
Externally publishedYes

Bibliographical note

Funding Information:
Supported by a grant from the Prostate Cancer Foundation and Movember; by the Department of Defense Prostate Cancer Clinical Trials Consortium, which provided infrastructural support; by the National Institutes of Health and Grant 1R01CA233585-01, Duke Cancer Institute (DCI) Grant No. P30 CA014236, and DCI shared resources for biostatistics, flow cytometry, and sequencing and genomic technologies (A.J.A.); in part by Department of Defense Grants No. W81XWH-13-PCRP-CCA, W81XWH-17-2-0021, and W81XWH-14-2-0179 (D.J.G., A.J.A.; Duke University), W81XWH-14-2-0159 (D.M.N.; Weill Cornell), W81XWH-15-2-0018 (R.Z.S.; University of Chicago), W81XWH-15-2-0018 (H.I.S.; Memorial Sloan Kettering Cancer Center [MSKCC]), and W81XWH-16-PCRP-CCRSA (E.S.A., Johns Hopkins); in part by National Cancer Institute (NCI) Grant No. P30CA008748 and the MSKCC Sidney Kimmel Center for Prostate and Urologic Cancers (D.C.D., H.I.S.); NCI Grant No. P30CA006973 (E.S.A.); in part by NCI Grant No. T32CA062948; and in part by Clinical and Translational Science Center Grants No. UL1 TR002384-01 and P30 CA014236.

Publisher Copyright:
© 2020 by American Society of Clinical Oncology.

PubMed: MeSH publication types

  • Journal Article

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