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A correlative biomarker study and integrative prognostic model in chemotherapy-naive metastatic castration-resistant prostate cancer treated with enzalutamide

Fernandez-Perez, Maria P; Perez-Navarro, Enrique; Alonso-Gordoa, Teresa; Conteduca, Vicenza; Font, Albert; Vazquez-Estevez, Sergio; Gonzalez-del-Alba, Aranzazu; ... Gonzalez-Billalabeitia, Enrique; + view all (2023) A correlative biomarker study and integrative prognostic model in chemotherapy-naive metastatic castration-resistant prostate cancer treated with enzalutamide. Prostate , 83 (4) pp. 376-384. 10.1002/pros.24469. Green open access

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Abstract

Background: There is a considerable need to incorporate biomarkers of resistance to new antiandrogen agents in the management of castration-resistant prostate cancer (CRPC). Methods: We conducted a phase II trial of enzalutamide in first-line chemo-naïve asymptomatic or minimally symptomatic mCRPC and analyzed the prognostic value of TMPRSS2-ERG and other biomarkers, including circulating tumor cells (CTCs), androgen receptor splice variant (AR-V7) in CTCs and plasma Androgen Receptor copy number gain (AR-gain). These biomarkers were correlated with treatment response and survival outcomes and developed a clinical–molecular prognostic model using penalized cox-proportional hazard model. This model was validated in an independent cohort. Results: Ninety-eight patients were included. TMPRSS2-ERG fusion gene was detected in 32 patients with no differences observed in efficacy outcomes. CTC detection was associated with worse outcome and AR-V7 in CTCs was associated with increased rate of progression as best response. Plasma AR gain was strongly associated with an adverse outcome, with worse median prostate specific antigen (PSA)-PFS (4.2 vs. 14.7 m; p < 0.0001), rad-PFS (4.5 vs. 27.6 m; p < 0.0001), and OS (12.7 vs. 38.1 m; p < 0.0001). The clinical prognostic model developed in PREVAIL was validated (C-Index 0.70) and the addition of plasma AR (C-Index 0.79; p < 0.001) increased its prognostic ability. We generated a parsimonious model including alkaline phosphatase (ALP); PSA and AR gain (C-index 0.78) that was validated in an independent cohort. Conclusions: TMPRSS2-ERG detection did not correlate with differential activity of enzalutamide in first-line mCRPC. However, we observed that CTCs and plasma AR gain were the most relevant biomarkers.

Type: Article
Title: A correlative biomarker study and integrative prognostic model in chemotherapy-naive metastatic castration-resistant prostate cancer treated with enzalutamide
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1002/pros.24469
Publisher version: https://doi.org/10.1002/pros.24469
Language: English
Additional information: © 2022 The Authors. The Prostate published by Wiley Periodicals LLC. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Keywords: Science & Technology, Life Sciences & Biomedicine, Endocrinology & Metabolism, Urology & Nephrology, AR gain, AR-V7, CTCs, enzalutamide, prostate cancer, TMPRSS2-ERG, CIRCULATING TUMOR-CELLS, GENE STATUS, ANDROGEN RECEPTOR, CLINICAL-TRIALS, ABIRATERONE, SURVIVAL, SURROGATE, TMPRSS2, FUSION, MEN
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: https://discovery.ucl.ac.uk/id/eprint/10164231
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