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.
The Prostate. 2022 Dec 23 [Epub ahead of print]
María P Fernandez-Perez, Enrique Perez-Navarro, Teresa Alonso-Gordoa, Vicenza Conteduca, Albert Font, Sergio Vázquez-Estévez, Aránzazu González-Del-Alba, Daniel Wetterskog, Emmanuel S Antonarakis, Begona Mellado, Ovidio Fernandez-Calvo, María J Méndez-Vidal, Miguel A Climent, Ignacio Duran, Enrique Gallardo, Angel Rodriguez Sanchez, Carmen Santander, Maria I Sáez, Javier Puente, Julian Tudela, Alberto Martínez, Maria J López-Andreo, José Padilla, Rebeca Lozano, David Hervas, Jun Luo, Ugo de Giorgi, Daniel Castellano, Gerhardt Attard, Enrique Grande, Enrique Gonzalez-Billalabeitia
Department of Haematology and Medical Oncology, Hospital Universitario Morales Meseguer, IMIB, Murcia, Spain., Department of Medical Oncology, Instituto de Investigación, Hospital Universitario 12 de Octubre, Madrid, Spain., Department of Medical Oncology, Hospital Ramón y Cajal, Madrid, Spain., Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) "Dino Amadori" IRCCS, Meldola, Italy., Department of Medical Oncology, Catalan Institute of Oncology, Badalona Applied Research Group in Oncology (BARGO), Badalona, Spain., Department of Medical Oncology, H. Universitario Lucus Augusti, Lugo, Spain., Department of Medical Oncology, H.U. Son Espases, Palma de Mallorca, Spain., University College London Cancer Institute, Paul O'Gorman Building, London, UK., Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Department of Medical Oncology, IDIBAPS, Hospital Clinic, Universidad de Barcelona, Barcelona, Spain., Department of Medical Oncology, Complejo Hospitalario Universitario Ourense, Orense, Spain., Department of Medical Oncology, Hospital Universitario Reina Sofía (HURS), Maimonides Institute for biomedical research of Córdoba (IMIBIC), Córdoba, Spain., Servicio de Oncología Médica, Instituto Valenciano de Oncología, Valencia, Spain., Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain., Department of Medical Oncology, Servicio de Oncología Médica, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Sabadell, Spain., Department of Medical Oncology, Hospital Universitario de León, León, Spain., Department of Medical Oncology, Hospital Universitario Miguel Servet, Zaragoza, Spain., Medical Oncology Intercenter Unit, Regional and Virgen de la Victoria University Hospitals, IBIMA, Málaga, Spain., Department of Medical Oncology, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), CIBERONC, Madrid, Spain., Department of Pathology, Hospital Morales Meseguer, Murcia, Spain., Biobanco de la región de Murcia, IMIB, Nodo 3, Murcia, Spain., Department of Molecular Biology, SAI-IMIB-Universidad de Murcia, Murcia, Spain., Prostate Cancer Clinical Research Unit, Spanish National Cancer Research Centre, Madrid, Spain., Data Science Unit, Instituto de Investigación Sanitaria La Fe, Valencia, Spain., Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., MD Anderson Cancer Center Madrid, Madrid, Spain.