Liquid Biopsy in Progressing Prostate Cancer Patients Starting Docetaxel with or Without Enzalutamide: A Biomarker Study of the PRESIDE Phase 3b Trial - Beyond the Abstract
The PRESIDE (NCT02288247) randomized trial demonstrated prolonged progression-free survival (PFS) with enzalutamide beyond progression in metastatic castration-resistant prostate cancer (mCRPC) patients starting docetaxel, suggesting enzalutamide-sensitive clones remain at docetaxel initiation. Concerns about the magnitude and heterogeneity of this benefit across unselected patients have limited clinical implementation.
In the article titled "Liquid Biopsy in Progressing Prostate Cancer Patients Starting Docetaxel with or Without Enzalutamide: A Biomarker Study of the PRESIDE Phase 3b Trial", we explored the clinical implications of liquid biopsy in 157 mCRPC patients undergoing treatment in the PRESIDE trial and consenting participation the biomarker sub-study. We evaluated the association between circulating tumor DNA (ctDNA) prior to and after one cycle (C2D1) of docetaxel with or without enzalutamide with PFS and whether a pre-treatment AR-based liquid biopsy resistance-biomarker (LBRB, plasma AR gain and/or circulating tumor cells expressing AR splice-variant 7, CTC AR-V7) identifies patients who benefit from continuing enzalutamide. We also performed an exploratory analysis of progression samples to characterize docetaxel resistance. Sequential plasma DNA samples were characterised with a prostate-cancer bespoke next-generation sequencing capture panel (PCF_SELECT), and circulating tumor cells were assessed for AR-V7 detection (Epic Sciences, USA).
Key findings highlighted that patients with detectable ctDNA before starting docetaxel after progression to enzalutamide had significantly shorter PFS compared to those without ctDNA. Furthermore, patients who demonstrated persistence or an increase in ctDNA at C2D1 were more likely to experience earlier progression. Interestingly, those negative for the LBRB had a substantial PFS benefit from continuing enzalutamide with docetaxel, while biomarker-positive patients did not. Additionally, we identified alterations in cell cycle genes, such as CDK4 and CDK6, at progression to docetaxel, which could play a role in docetaxel resistance in mCRPC and could represent a therapeutic opportunity for prolonging docetaxel benefit.
This study underscores the utility of liquid biopsy in guiding treatment decisions in mCRPC, providing early insights into treatment effectiveness, and identifying potential genomic drivers of resistance. These findings offer a foundation for personalized treatment strategies with the potential to improve outcomes for patients with advanced prostate cancer.
By integrating liquid biopsy biomarkers into clinical practice, we can enhance treatment strategies and ultimately improve therapeutic outcomes in mCRPC. Future studies should validate these findings for overall survival and explore targeted therapies aimed at overcoming docetaxel resistance mechanisms identified through this study.
Written by: Maria Ruiz-Vico,1 Daniel Wetterskog,2 Francesco Orlando,3 Suparna Thakali,2 Anna Wingate,2 Anuradha Jayaram,2 Paolo Cremaschi,2 Osvaldas Vainauskas,2 Nicole Brighi,2 Daniel Castellano-Gauna,4 Lennart Åström,5 Vsevolod B Matveev,6 Sergio Bracarda,7 Adil Esen,8 Susan Feyerabend,9 Elżbieta Senkus,10 Marta López-Brea Piqueras,11 Santosh Gupta,12 Rick Wenstrup,12 Gunther Boysen,13 Karla Martins,13 Kenneth Iwata,14 Simon Chowdhury,15 Georgia Gourgioti,13 Alexis Serikoff,13 Enrique Gonzalez-Billalabeitia,16 Axel S Merseburger,17 Francesca Demichelis,3 Gerhardt Attard2
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