ProBio is the first outcome-adaptive platform trial in prostate cancer utilizing a Bayesian framework to evaluate efficacy within predefined biomarker signatures across systemic treatments. Prospective circulating tumor DNA and germline DNA analysis was performed in patients with metastatic castration-resistant prostate cancer before randomization to androgen receptor pathway inhibitors (ARPIs), taxanes or a physician's choice control arm. The primary endpoint was the time to no longer clinically benefitting (NLCB). Secondary endpoints included overall survival and (serious) adverse events. Upon reaching the time to NLCB, patients could be re-randomized. The primary endpoint was met after 218 randomizations. ARPIs demonstrated ~50% longer time to NLCB compared to taxanes (median, 11.1 versus 6.9 months) and the physician's choice arm (median, 11.1 versus 7.4 months) in the biomarker-unselected or 'all' patient population. ARPIs demonstrated longer overall survival (median, 38.7 versus 21.7 and 21.8 months for taxanes and physician's choice, respectively). Biomarker signature findings suggest that the largest increase in time to NLCB was observed in AR (single-nucleotide variant/genomic structural rearrangement)-negative and TP53 wild-type patients and TMPRSS2-ERG fusion-positive patients, whereas no difference between ARPIs and taxanes was observed in TP53-altered patients. In summary, ARPIs outperform taxanes and physician's choice treatment in patients with metastatic castration-resistant prostate cancer with detectable circulating tumor DNA. ClinicalTrials.gov registration: NCT03903835 .
Nature medicine. 2024 Aug 20 [Epub ahead of print]
Bram De Laere, Alessio Crippa, Andrea Discacciati, Berit Larsson, Maria Persson, Susanne Johansson, Sanne D'hondt, R Bergström, Venkatesh Chellappa, Markus Mayrhofer, Mahsan Banijamali, Anastasijia Kotsalaynen, Céline Schelstraete, Jan Pieter Vanwelkenhuyzen, Marie Hjälm-Eriksson, Linn Pettersson, Anders Ullén, Nicolaas Lumen, Gunilla Enblad, Camilla Thellenberg Karlsson, Elin Jänes, Johan Sandzén, Peter Schatteman, Maria Nyre Vigmostad, Martha Olsson, Christophe Ghysel, Brieuc Sautois, Wendy De Roock, Siska Van Bruwaene, Mats Anden, Ingrida Verbiene, Daan De Maeseneer, Els Everaert, Jochen Darras, Bjørg Y Aksnessether, Daisy Luyten, Michiel Strijbos, Ashkan Mortezavi, Jan Oldenburg, Piet Ost, Martin Eklund, Henrik Grönberg, Johan Lindberg
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden., Health, Innovation and Research Institute (Clinical Trial Unit), University Hospital Ghent, Ghent, Belgium., National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden., Department of Urology, University Hospital Ghent, Ghent, Belgium., Department of Oncology, Capio Saint Göran's Hospital, Stockholm, Sweden., Department of Oncology, Länssjukhuset Ryhov, Jönköping, Sweden., Department of Oncology, Karolinska University Hospital, Stockholm, Sweden., Department of Oncology, Uppsala University Hospital, Uppsala, Sweden., Department of Oncology, University Hospital of Umeå, Umeå, Sweden., Department of Oncology, Sundsvalls sjukhus, Sundsvall, Sweden., Department of Oncology, Centralsjukhuset Karlstad, Karlstad, Sweden., Department of Urology, Onze Lieve Vrouwziekenhuis, Aalst, Belgium., Department of Oncology, Stavanger University Hospital, Stavanger, Norway., Department of Oncology, Centrallasarettet Växjö, Växjö, Sweden., Department of Urology, AZ Sint Jan Brugge AV, Bruges, Belgium., Department of Oncology, CHU de Liège - site Sart Tilman, Liège, Belgium., Department of Oncology, Ziekenhuis Oost- Limburg, Genk, Belgium., Department of Urology, AZ Groeninge, Kortrijk, Belgium., Department of Oncology, Länssjukhuset i Kalmar, Kalmar, Sweden., Department of Oncology, Falu lasarett, Falu, Sweden., Department of Oncology, AZ Sint-Lucas, Bruges, Belgium., Department of Oncology, Vitaz campus Sint-Niklaas Lodewijk, Sint-Niklaas, Belgium., Department of Urology, AZ Damiaan, Oostende, Belgium., Department of Oncology, Ålesund Hospital, Ålesund, Norway., Department of Oncology, Virga Jessa, Hasselt, Belgium., Department of Oncology, GZA Sint-Augustinus, Antwerpen, Belgium., Department of Urology, Universitätsspital Basel, Basel, Switzerland., Department of Oncology, Akershus University Hospital, Nordbyhagen, Norway., Department of Human Structure and Repair, Ghent University, Ghent, Belgium., Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. ., Department of Medical Epidemiology and Biostatistics, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden.