Whether cabazitaxel or an androgen receptor pathway inhibitor (ARPI) is the optimal treatment option for poor-prognosis metastatic castration-resistant prostate cancer (mCRPC), progressing on docetaxel, remains unclear.
There are limited prospective data supporting a preference for one of these treatments and few candidate biomarkers to inform individual patient management. This study aims to compare the clinical efficacy of cabazitaxel versus ARPIs in patients with poor-prognosis mCRPC who have progressed on docetaxel, and to evaluate the prognostic and predictive utility of circulating tumor DNA (ctDNA) in this treatment-refractory population.
A multicenter, open-label, phase 2b trial randomized poor-prognosis mCRPC patients to an ARPI (1000 mg abiraterone plus prednisone or 160 mg enzalutamide daily) or cabazitaxel (25 mg/m2 every 3 wk plus prednisone daily). The primary endpoint was the clinical benefit rate (CBR) at 12 wk. The secondary endpoints included radiographic progression-free survival (rPFS), overall survival (OS), and PSA50 response. Genomic analyses on plasma utilized targeted cell-free DNA sequencing at baseline, 12 wk, and progression.
In total, 106 patients were randomized. The CBR at 12 wk was 62.3% (66/106), with no difference between treatments (p = 0.54). Between groups, rPFS and OS (median follow-up of 30.9 mo) were not different. PSA50 was higher in the ARPI arm (47.2%) than in the cabazitaxel arm (26.9%; p = 0.04). Prior ARPI exposure (in 37.7%) predicted inferior outcomes on ARPIs but not on cabazitaxel. Adverse events of grade ≥3 were more frequent with cabazitaxel (65.4% vs 30.2%). A high baseline ctDNA fraction correlated with reduced rPFS and OS; plasma AR copy number status was not associated with outcomes, but PTEN alterations were linked with shorter OS (hazard ratio: 1.9, multivariable p = 0.02).
No significant differences in CBR or time-to-event endpoints were observed between cabazitaxel and ARPIs. However, prior ARPI exposure, a higher baseline ctDNA fraction, and PTEN alterations were strongly prognostic.
European urology oncology. 2025 Sep 30 [Epub ahead of print]
Karan Parekh, Kim van der Zande, Sarah W S Ng, Cameron Herberts, Edmond M Kwan, Gillian Vandekerkhove, Vincent van der Noort, Milou P H Busard, Aart Beeker, Pieter van den Berg, Jeantine M de Feijter, Vincent Dezentje, Paul Hamberg, Danny Houtsma, Suzan Ras, Metin Tascilar, Rebecca D Tutuhatunewa-Louhanepessy, Yi Jou Ruby Liao, Sofie H Tolmeijer, Gráinne Donnellan, Kim N Chi, Alexander W Wyatt, Wilbert Zwart, Andries M Bergman, OSTRICh Investigators and the Dutch Uro-Oncology Study Group (DUOS16107)
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. Electronic address: ., Department of Oncogenomics, Netherlands Cancer Institute, Amsterdam, The Netherlands; Oncode Institute, Utrecht, The Netherlands. Electronic address: ., 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. Electronic address: .
PubMed http://www.ncbi.nlm.nih.gov/pubmed/41033927