The PRESIDE (NCT02288247) randomized trial demonstrated prolonged progression-free survival (PFS) with continuing enzalutamide beyond progression in metastatic castration-resistant prostate cancer (mCRPC) patients starting docetaxel. This study aims to test the associations of PFS and circulating tumor DNA (ctDNA) prior to and after one cycle (cycle 2 day 1 [C2D1]) of docetaxel and with a liquid biopsy resistance biomarker (LBRB; plasma androgen receptor [AR] gain and/or circulating tumor cells [CTCs] expressing AR splice variant 7 [CTC-AR-V7]) prior to continuation of enzalutamide/placebo.
Patients consenting to the biomarker substudy and donating blood before starting docetaxel with enzalutamide/placebo (N = 157) were included. Sequential plasma DNA samples were characterized with a prostate-cancer bespoke next-generation-sequencing capture panel (PCF_SELECT), and CTCs were assessed for AR-V7 (Epic Sciences, San Diego, CA, USA). Cox models, Kaplan-Meier, and restricted mean survival time (RMST) at 18 mo were calculated.
There was a significant association of worse PFS with pre-docetaxel ctDNA detection (N = 86 (55%), 8.1 vs 10.8 mo hazard ratio [HR] = 1.78, p = 0.004) or persistence/rise of ctDNA at C2D1 (N = 35/134, 5.5 vs 10.9 mo, HR = 1.95, 95% confidence interval [CI] = 1.15-3.30, p = 0.019). LBRB-positive patients (N = 62) had no benefit from continuing enzalutamide with docetaxel (HR = 0.78, 95% CI = 0.41-1.48, p = 0.44; RMST: 7.9 vs 7.1 mo, p = 0.50). Conversely, resistance biomarker-negative patients (N = 87) had significantly prolonged PFS (HR = 0.49, 95% CI = 0.29-0.82, p = 0.006; RMST: 11.5 vs 8.9 mo, p = 0.005). Eight patients were unevaluable. An exploratory analysis identified increased copy-number gains (CDK6/CDK4) at progression on docetaxel. Limitations included relatively low detection of CTC-AR-V7. Validation of impact on overall survival is required.
Liquid biopsy gives an early indication of docetaxel futility, could guide patient selection for continuing enzalutamide, and identifies cell cycle gene alterations as a potential cause of docetaxel resistance in mCRPC.
In the PRESIDE biomarker study, we found that detecting circulating tumor DNA in plasma after starting treatment with docetaxel (chemotherapy) for metastatic prostate cancer resistant to androgen deprivation therapy can predict early how long patients will take to respond to treatment. Patients negative for a liquid biopsy resistance biomarker (based on the status of androgen receptor (AR) gene and AR splice variant 7 in circulating tumor cells) benefit from continuing enzalutamide in combination with docetaxel, while patients positive for the resistance biomarker did not. Additionally, we identified alterations in the cell cycle genes CDK6 and CDK4 as a potential genetic cause of resistance to docetaxel, which may support testing of specific drugs targeting these alterations.
European urology oncology. 2024 Sep 10 [Epub ahead of print]
Maria Ruiz-Vico, Daniel Wetterskog, Francesco Orlando, Suparna Thakali, Anna Wingate, Anuradha Jayaram, Paolo Cremaschi, Osvaldas Vainauskas, Nicole Brighi, Daniel Castellano-Gauna, Lennart Åström, Vsevolod B Matveev, Sergio Bracarda, Adil Esen, Susan Feyerabend, Elżbieta Senkus, Marta López-Brea Piqueras, Santosh Gupta, Rick Wenstrup, Gunther Boysen, Karla Martins, Kenneth Iwata, Simon Chowdhury, Georgia Gourgioti, Alexis Serikoff, Enrique Gonzalez-Billalabeitia, Axel S Merseburger, Francesca Demichelis, Gerhardt Attard
Oncology Department, University College London Cancer Institute, London, UK; PhD Program in Biomedicine Research, Universidad Complutense de Madrid, Madrid, Spain; Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain., Oncology Department, University College London Cancer Institute, London, UK., Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy., Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain., Department of Immunology, Genetics and Pathology, University of Uppsala, Uppsala, Sweden., Department of Urology, Blokhin Cancer Research Center, Moscow, Russia., Medical Oncology, Azienda Ospedaliera Santa Maria, Terni, Italy., Department of Urology, Dokuz Eylul University, Konak, Turkey., Studienpraxis Urologie, Medius Klinik Nürtingen, Nürtingen, Germany., Department of Oncology and Radiotherapy, Medical University of Gdansk, Gdansk, Poland., Department of Medical Oncology, Marqués de Valdecilla University Hospital, Cantabria, Spain., Translational Research, Epic Sciences Inc, San Diego, CA, USA., Astellas Pharma Europe Ltd, Addlestone, UK., Astellas Pharma USA, Northbrook, IL, USA., Medical Oncology, Guy's and St Thomas' NHS Foundation Trust, King's College London, London, UK., PhD Program in Biomedicine Research, Universidad Complutense de Madrid, Madrid, Spain; Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain., Department of Urology, Universitätsklinikum Schleswig-Holstein, Lübeck, Germany., Oncology Department, University College London Cancer Institute, London, UK. Electronic address: .