[en] 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 .
Disciplines :
Oncology
Author, co-author :
De Laere, Bram ; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden ; Department of Human Structure and Repair, Ghent University, Ghent, Belgium
Crippa, Alessio ; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
Discacciati, Andrea; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
Larsson, Berit; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
Persson, Maria; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
Johansson, Susanne; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
D'hondt, Sanne ; Health, Innovation and Research Institute (Clinical Trial Unit), University Hospital Ghent, Ghent, Belgium
Bergström, Rebecka ; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
Chellappa, Venkatesh; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
Mayrhofer, Markus; National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden
Banijamali, Mahsan; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
Kotsalaynen, Anastasijia; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
Schelstraete, Céline; Department of Urology, University Hospital Ghent, Ghent, Belgium
Vanwelkenhuyzen, Jan Pieter ; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden ; Department of Human Structure and Repair, Ghent University, Ghent, Belgium
Hjälm-Eriksson, Marie; Department of Oncology, Capio Saint Göran's Hospital, Stockholm, Sweden
Pettersson, Linn; Department of Oncology, Länssjukhuset Ryhov, Jönköping, Sweden
Ullén, Anders; Department of Oncology, Karolinska University Hospital, Stockholm, Sweden
Lumen, Nicolaas; Department of Urology, University Hospital Ghent, Ghent, Belgium
Enblad, Gunilla ; Department of Oncology, Uppsala University Hospital, Uppsala, Sweden
Thellenberg Karlsson, Camilla ; Department of Oncology, University Hospital of Umeå, Umeå, Sweden
Jänes, Elin; Department of Oncology, Sundsvalls sjukhus, Sundsvall, Sweden
Sandzén, Johan ; Department of Oncology, Centralsjukhuset Karlstad, Karlstad, Sweden
Schatteman, Peter; Department of Urology, Onze Lieve Vrouwziekenhuis, Aalst, Belgium
Nyre Vigmostad, Maria ; Department of Oncology, Stavanger University Hospital, Stavanger, Norway
Olsson, Martha; Department of Oncology, Centrallasarettet Växjö, Växjö, Sweden
Ghysel, Christophe; Department of Urology, AZ Sint Jan Brugge AV, Bruges, Belgium
Sautois, Brieuc ; Université de Liège - ULiège > Département des sciences cliniques
De Roock, Wendy; Department of Oncology, Ziekenhuis Oost- Limburg, Genk, Belgium
Van Bruwaene, Siska; Department of Urology, AZ Groeninge, Kortrijk, Belgium
Anden, Mats; Department of Oncology, Länssjukhuset i Kalmar, Kalmar, Sweden
Verbiene, Ingrida; Department of Oncology, Falu lasarett, Falu, Sweden
De Maeseneer, Daan ; Department of Oncology, AZ Sint-Lucas, Bruges, Belgium
Everaert, Els; Department of Oncology, Vitaz campus Sint-Niklaas Lodewijk, Sint-Niklaas, Belgium
Darras, Jochen; Department of Urology, AZ Damiaan, Oostende, Belgium
Aksnessether, Bjørg Y; Department of Oncology, Ålesund Hospital, Ålesund, Norway
Luyten, Daisy; Department of Oncology, Virga Jessa, Hasselt, Belgium
Strijbos, Michiel; Department of Oncology, GZA Sint-Augustinus, Antwerpen, Belgium
Mortezavi, Ashkan; Department of Urology, Universitätsspital Basel, Basel, Switzerland ; Department of Urology, Universitätsspital Zürich, Zürich, Switzerland
Oldenburg, Jan; Department of Oncology, Akershus University Hospital, Nordbyhagen, Norway
Ost, Piet; Department of Human Structure and Repair, Ghent University, Ghent, Belgium ; Department of Radiation Oncology, GZA Sint-Augustinus, Antwerpen, Belgium
Eklund, Martin ; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
Grönberg, Henrik ; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. henrik.gronberg@ki.se ; Prostatacancer Centrum, Capio S:t Görans Sjukhus, Stockholm, Sweden. henrik.gronberg@ki.se
Lindberg, Johan; Department of Medical Epidemiology and Biostatistics, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden
Vlaamse Liga Tegen Kanker KLBB - Krebsliga Beider Basel Cancerfonden Sverige Vetenskapsrådet
Funding text :
We thank all patients for their willingness to participate in this study. We thank the biobanks of the Karolinska Institutet (Stockholm, Sweden) and HIRUZ (Ghent, Belgium) for weekly processing of the biomaterial for genomic analysis. We also thank Clinical Genomics (Stockholm, Sweden) and National Bioinformatics Infrastructure Sweden (Uppsala, Sweden) for providing timely and cost-efficient DNA sequencing and analysis services. The ProBio consortium thanks the following funding organizations for the following awarded research grants: ALF Medicine (to H.G., 20190087), Swedish Cancer Society (to H.G., 211610P), Swedish Research Council (to H.G., 2021-00331), Krebsliga beider Basel (to A.M., KLbB-5580-02-2022) and Kom Op Tegen Kanker/Stand up to Cancer \u2013 Flemish Cancer Society (to P.O., STI.VLK.2020.0006.01; to B.D.L., STI.VLK.2022.0005.01). We extend our gratitude to all investigators, coworkers and staff involved in the ProBio trial. A complete list of ProBio consortium members is available in the .
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