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

There is a considerable need to incorporate biomarkers of resistance to new antiandrogen agents in the management of castration-resistant prostate cancer (CRPC). We conducted a phase II trial of enzalutamide in first-line chemo-naïve asymptomatic or minimally symptomatic mCRPC and analyzed the progn...

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Detalles Bibliográficos
Autores: Fernandez-Perez, María P., Perez-Navarro, Enrique|||0000-0003-1091-8926, Alonso-Gordoa, Teresa|||0000-0002-8966-7236, Conteduca, Vincenza|||0000-0002-6921-714X, Font, Albert|||0000-0003-3908-1111, Vázquez-Estévez, Sergio, González-del-Alba, Aránzazu|||0000-0001-6570-009X, Wetterskog, Daniel, Antonarakis, Emmanuel S., Mellado, Begoña|||0000-0002-8088-5966, Fernández Calvo, Ovidio|||0000-0001-5283-9754, Mendez Vidal, María José|||0000-0002-7460-1859, Climent, Miguel Ángel|||0000-0001-7523-0212, Durán, Ignacio|||0000-0001-8571-7163, Gallardo Díaz, Enrique|||0000-0002-1375-3488, Rodríguez Sánchez, Ángel, Santander, Carmen, Sáez, Maria I., Puente, J.|||0000-0002-6910-1331, Tudela, Julian, Martínez, Alberto, López-Andreo, María José|||0000-0002-7015-8132, Padilla, José, Lozano, Rebeca, Hervas, David|||0000-0003-0635-4961, Luo, Jun, De Giorgi, Ugo|||0000-0001-7520-2908, Castellano, Daniel|||0000-0002-9106-0687, Attard, Gerhardt, Grande, Enrique|||0000-0002-0134-4732, Gonzalez-Billalabeitia, Enrique|||0000-0003-3143-3143
Tipo de recurso: artículo
Fecha de publicación:2022
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:281329
Acceso en línea:https://ddd.uab.cat/record/281329
https://dx.doi.org/urn:doi:10.1002/pros.24469
Access Level:acceso abierto
Palabra clave:AR gain
AR-V7
CTCs
Enzalutamide
Prostate cancer
TMPRSS2-ERG
Descripción
Sumario:There is a considerable need to incorporate biomarkers of resistance to new antiandrogen agents in the management of castration-resistant prostate cancer (CRPC). 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. 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. 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.

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