TY - JOUR
T1 - A correlative biomarker study and integrative prognostic model in chemotherapy-naïve metastatic castration-resistant prostate cancer treated with enzalutamide
AU - Fernandez-Perez, María P.
AU - Perez-Navarro, Enrique
AU - Alonso-Gordoa, Teresa
AU - Conteduca, Vicenza
AU - Font, Albert
AU - Vázquez-Estévez, Sergio
AU - González-del-Alba, Aránzazu
AU - Wetterskog, Daniel
AU - Antonarakis, Emmanuel S.
AU - Mellado, Begona
AU - Fernandez-Calvo, Ovidio
AU - Méndez-Vidal, María J.
AU - Climent, Miguel A.
AU - Duran, Ignacio
AU - Gallardo, Enrique
AU - Rodriguez Sanchez, Angel
AU - Santander, Carmen
AU - Sáez, Maria I.
AU - Puente, Javier
AU - Tudela, Julian
AU - Martínez, Alberto
AU - López-Andreo, Maria J.
AU - Padilla, José
AU - Lozano, Rebeca
AU - Hervas, David
AU - Luo, Jun
AU - de Giorgi, Ugo
AU - Castellano, Daniel
AU - Attard, Gerhardt
AU - Grande, Enrique
AU - Gonzalez-Billalabeitia, Enrique
N1 - Publisher Copyright:
© 2022 The Authors. The Prostate published by Wiley Periodicals LLC.
PY - 2023/3
Y1 - 2023/3
N2 - 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.
AB - 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.
KW - AR gain
KW - AR-V7
KW - CTCs
KW - TMPRSS2-ERG
KW - enzalutamide
KW - prostate cancer
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U2 - 10.1002/pros.24469
DO - 10.1002/pros.24469
M3 - Article
C2 - 36564933
AN - SCOPUS:85145039209
SN - 0270-4137
VL - 83
SP - 376
EP - 384
JO - Prostate
JF - Prostate
IS - 4
ER -