The ProBio trial: molecular biomarkers for advancing personalized treatment decision in patients with metastatic castration-resistant prostate cancer

Alessio Crippa, Bram De Laere, Andrea Discacciati, Berit Larsson, Jason T Connor, Erin E Gabriel, Camilla Thellenberg, Elin Jänes, Gunilla Enblad, Anders Ullen, Marie Hjälm-Eriksson, Jan Oldenburg, Piet Ost, Johan Lindberg, Martin Eklund, Henrik Grönberg, Alessio Crippa, Bram De Laere, Andrea Discacciati, Berit Larsson, Jason T Connor, Erin E Gabriel, Camilla Thellenberg, Elin Jänes, Gunilla Enblad, Anders Ullen, Marie Hjälm-Eriksson, Jan Oldenburg, Piet Ost, Johan Lindberg, Martin Eklund, Henrik Grönberg

Abstract

Background: Multiple therapies exist for patients with metastatic castration-resistant prostate cancer (mCRPC). However, their improvement on progression-free survival (PFS) remains modest, potentially explained by tumor molecular heterogeneity. Several prognostic molecular biomarkers have been identified for mCRPC that may have predictive potential to guide treatment selection and prolong PFS. We designed a platform trial to test this hypothesis.

Methods: The Prostate-Biomarker (ProBio) study is a multi-center, outcome-adaptive, multi-arm, biomarker-driven platform trial for tailoring treatment decisions for men with mCRPC. Treatment decisions in the experimental arms are based on biomarker signatures defined as mutations in certain genes/pathways suggested in the scientific literature to be important for treatment response in mCRPC. The biomarker signatures are determined by targeted sequencing of circulating tumor and germline DNA using a panel specifically designed for mCRPC.

Discussion: Patients are stratified based on the sequencing results and randomized to either current clinical practice (control), where the treating physician decides treatment, or to molecularly driven treatment selection based on the biomarker profile. Outcome-adaptive randomization is implemented to early identify promising treatments for a biomarker signature. Biomarker signature-treatment combinations graduate from the platform when they demonstrate 85% probability of improving PFS compared to the control arm. Graduated combinations are further evaluated in a seamless confirmatory trial with fixed randomization. The platform design allows for new drugs and biomarkers to be introduced in the study.

Conclusions: The ProBio design allows promising treatment-biomarker combinations to quickly graduate from the platform and be confirmed for rapid implementation in clinical care.

Trial registration: ClinicalTrials.gov Identifier NCT03903835. Date of registration: April 4, 2019. Status: Recruiting.

Keywords: Clinical trial platform; Genetic biomarker; Precision medicine; Prostate cancer.

Conflict of interest statement

Henrik Grönberg has received honoraria for giving talks at Janssen, Bayer, and Astellas. All other authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1
Genomic profiling in the ProBio platform trial. Two 10-ml tubes of blood are drawn from each study participant and plasma is enriched. Extraction is performed to obtain cell-free DNA from plasma and germline DNA from white blood cells. Targeted sequencing is applied on both cell-free and germline DNA using the ProBio-panel. The ProBio panel covers mutations in 78 genes, structural variants in 11 genes and allows for interrogation of genome-wide copy-number alterations, microsatellite instability, and hypermutation. Sequence data is processed using an in-house developed bioinformatics infrastructure (https://autoseq-docs.readthedocs.io). All variants are manually examined to remove false positive calls. This information is condensed into a report which contains the biomarker profile for subsequent randomization of the study participants. Study participants that progress are reanalyzed and re-randomized
Fig. 2
Fig. 2
Study design of the ProBio platform trial. Participants who meet the inclusion criteria and agreed to participate in the study are genotyped and their biomarker profile is derived. Based on their biomarker subgroup combination they are randomized to either the control group (standard-of-care) or one of the active arms. Patients are regularly followed through the study. Their outcome data is used to adapt the randomization probabilities, assigning more patients to more beneficial therapies within a biomarker signature. Upon the first progression in the study, patients will be re-genotyped and re-randomized to an alternative arm based on their updated biomarker profile
Fig. 3
Fig. 3
Life cycle of the ProBio platform trial. After written informed consent, the biomarker subgroup combination of the patient is determined and used for randomization to either the control group (standard of care) or one of the experimental arms. Outcome data are updated monthly throughout the trial and will be used to calculate the probabilities of superiority for the active arms over the control group for each biomarker signature of interest. Based on the selected threshold, a decision to continue enrollment or to terminate (for futility or superiority) each treatment-biomarker signature will be made. As treatment-biomarker signatures leave the platform, new treatments can possibly entry in the study. The outcome data is also used to update the randomization probabilities within the biomarker subgroup combinations. Graduating treatment-biomarker signatures will enter a confirmatory trial to validate the hypotheses generated from the platform

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