1. A correlative biomarker study and integrative prognostic model in chemotherapy-naïve metastatic castration-resistant prostate cancer treated with enzalutamide
- Author
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Astellas Pharma, Instituto de Salud Carlos III, Ministerio de Sanidad, Servicios Sociales e Igualdad (España), Fundación CRIS contra el Cáncer, Fernández-Pérez, M. P., Pérez-Navarro, Enrique, Alonso Gordoa, Teresa, Conteduca, Vicenza, Font Pous, Albert, Vázquez-Estévez, Sergio, González del Alba, Aránzazu, Wetterskog, Daniel, Antonarakis, Emmanuel S., Mellado González, Begoña, Fernández-Calvo, Ovidio, Méndez-Vidal, María J., Climent, Miguel A., Durán, Ignacio, Gallardo, Enrique, Rodríguez Sánchez, Ángel, Santander, Carmen, Sáez, María Isabel, Puente Vázquez, Javier, Tudela, Julián, Martínez, Alberto, López-Andreo, María J., Padilla, José, Lozano, Rebeca, Hervas, David, Luo, Jun, de Giorgi, Ugo, García-Castellanos, Daniel, Attard, Gerhardt, Grande, Enrique, González-Billalabeitia, E., Astellas Pharma, Instituto de Salud Carlos III, Ministerio de Sanidad, Servicios Sociales e Igualdad (España), Fundación CRIS contra el Cáncer, Fernández-Pérez, M. P., Pérez-Navarro, Enrique, Alonso Gordoa, Teresa, Conteduca, Vicenza, Font Pous, Albert, Vázquez-Estévez, Sergio, González del Alba, Aránzazu, Wetterskog, Daniel, Antonarakis, Emmanuel S., Mellado González, Begoña, Fernández-Calvo, Ovidio, Méndez-Vidal, María J., Climent, Miguel A., Durán, Ignacio, Gallardo, Enrique, Rodríguez Sánchez, Ángel, Santander, Carmen, Sáez, María Isabel, Puente Vázquez, Javier, Tudela, Julián, Martínez, Alberto, López-Andreo, María J., Padilla, José, Lozano, Rebeca, Hervas, David, Luo, Jun, de Giorgi, Ugo, García-Castellanos, Daniel, Attard, Gerhardt, Grande, Enrique, and González-Billalabeitia, E.
- 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.
- Published
- 2023