While both options are supported by clinical evidence, few studies exist to guide this decision in patients with poor-prognosis disease, a group characterized by high disease burden and aggressive biology, making the optimal sequencing strategies uncertain. At the same time, circulating tumor DNA (ctDNA) is a recently established real-time prognostic adjunct but has mostly been evaluated in first-line, taxane-naïve mCRPC patients.
To address this gap, we conducted a multicenter open-label phase 2b study that enrolled patients with poor-prognosis mCRPC and mixed prior ARPI exposure, and randomized them to receive cabazitaxel or an ARPI immediately following progression on docetaxel to assess the primary endpoint of clinical benefit at 12 weeks, with secondary endpoints including radiographic progression-free survival (rPFS), overall survival (OS), and PSA50 response. Importantly, we collected serial blood samples from 100 patients at baseline (pre-treatment), after 12 weeks on treatment, and at disease progression (totaling 192 samples). We then applied our custom targeted DNA sequencing assay to both cell-free DNA (cfDNA) and patient-matched leukocyte DNA.
This study aimed to address three principal questions:
- To compare the clinical efficacy of cabazitaxel versus ARPIs in patients with poor-prognosis mCRPC who have progressed on docetaxel.
- Whether ctDNA can identify patients more likely to benefit from cabazitaxel compared to an ARPI.
- Whether genomic features such as ctDNA fraction (ctDNA%) or key gene alterations serve as prognostic or predictive biomarkers in this treatment-refractory, poor-prognosis population.
As expected, higher pretreatment ctDNA% was associated with reduced rPFS and OS, confirming its prognostic value; however, the effect size appeared attenuated compared with earlier-line settings. This diminished prognostic stratification likely reflects the compound treatment resistance and limited life expectancy characteristic of the trial population. Baseline ctDNA% was not predictive of differential treatment response, but among the prostate cancer driver genes assessed, deleterious PTEN alterations (in 37.9% of patients) were strongly associated with reduced OS, a finding which was validated through meta-analysis with a similarly designed randomized clinical trial. These results further corroborate existing retrospective and prospective evidence demonstrating that PTEN loss is linked to poorer survival outcomes and adverse prognosis in patients with mCRPC.
In conclusion, neither cabazitaxel nor ARPI treatment was associated with clearly favorable outcomes; however, both remain viable therapeutic options for patients with poor-prognosis mCRPC. These findings underscore that prior ARPI exposure is likely the strongest predictor of limited benefit from subsequent ARPI therapy following docetaxel. A higher pretreatment ctDNA% and deleterious PTEN alterations were associated with poor treatment outcomes. We also would like to extend our sincere gratitude to the patients, their families, and caregivers for their invaluable contributions and unwavering support throughout this study.
Written by: Karan Parekh,1 Kim van der Zande,2 Sarah W S Ng,1 Cameron Herberts,1 Edmond M Kwan,3 Gillian Vandekerkhove,1 Vincent van der Noort,4 Milou P H Busard,5 Aart Beeker,6 Pieter van den Berg,7 Jeantine M de Feijter,8 Vincent Dezentje,8 Paul Hamberg,9 Danny Houtsma,10 Suzan Ras,9 Metin Tascilar,11 Rebecca D Tutuhatunewa-Louhanepessy,2 Yi Jou Ruby Liao,1 Sofie H Tolmeijer,1 Gráinne Donnellan,1 Kim N Chi,12 Alexander W Wyatt,13 Wilbert Zwart,14 Andries M Bergman15
- Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, BC, Canada.
- Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands; Department of Oncogenomics, Netherlands Cancer Institute, Amsterdam, The Netherlands.
- Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, BC, Canada; Eastern Health Clinical School, Monash University, Melbourne, VIC, Australia; Biomedicine Discovery Institute Cancer Program, Prostate Cancer Research Group, Department of Anatomy and Developmental Biology, Monash University, Melbourne, VIC, Australia.
- Department of Biometrics, Netherlands Cancer Institute, Amsterdam, The Netherlands.
- Department of Radiology and Nuclear Medicine, Netherlands Cancer Institute, Amsterdam, The Netherlands.
- Department of Medical Oncology, Spaarne Gasthuis, Hoofddorp, The Netherlands.
- Department of Medical Oncology, Tergooi, Hilversum, The Netherlands.
- Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
- Department of Medical Oncology, Vlietland Gasthuis, Schiedam, The Netherlands.
- Department of Internal Medicine, Haga Hospital, The Hague, The Netherlands.
- Department of Medical Oncology, Isala, Zwolle, The Netherlands.
- Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, BC, Canada; Department of Medical Oncology, BC Cancer, Vancouver, British Columbia, Canada.
- Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, BC, Canada; Clinical Cancer Genomics Program and Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, British Columbia, Canada.
- Department of Oncogenomics, Netherlands Cancer Institute, Amsterdam, The Netherlands; Oncode Institute, Utrecht, The Netherlands.
- Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands; Department of Oncogenomics, Netherlands Cancer Institute, Amsterdam, The Netherlands; Department of Medical Oncology, Amsterdam University Medical Center, Amsterdam, The Netherlands.