THE CLINICAL UNMET NEED
The combination of new expensive drugs with moderate effects and the lack of predictive treatment markers will lead to an unsustainable situation in metastatic castrate resistant prostate cancer (mCRPC). The need for systematic evaluation of treatment predictive markers is evident and urgent. With the development of technology to analyze circulating tumor DNA (ctDNA) we now have a powerful tool to assess molecular biomarkers in mCRPC and test these in the context of a randomized controlled trial.
Probio is an outcome-adaptive, multi-arm, open-label, multiple assignment randomized biomarker driven platform trial in patients with metastatic castration-resistant prostate cancer. Patients will be randomized to control or experimental treatment arms. Patients in the control arm will receive standard of care following national guidelines. Patients in the experimental arm will be randomized to treatments based on a biomarker signature. The predefined biomarker signatures are tumor properties or mutations in genes/pathways with previously known prognostic value in prostate cancer treatment response. The biomarker signatures are identified using a ctDNA panel specifically designed for prostate cancer.
Conceptual figure of the ProBio study design. The colors of the mCRPC patients represent patients with different biomarker signatures. After written informed consent, blood is drawn and plasma is enriched. Extraction is performed to obtain cell-free DNA from plasma and germline DNA from white blood cells. A fraction of the cell-free DNA from plasma originates form dying cancer cells, so called circulating tumor DNA. Targeted sequencing is conducted to analyze somatic alterations and relevant germline variants. This information is condensed into a biomarker signature report which in turn is applied for randomization of the study participants. The randomization takes the biomarker signature into account in the treatment arms. In the control arm standard of care is given according to national guidelines without knowledge about the biomarker signatures. Progression (disease relapse) is evaluated according to established international standards (Prostate Cancer Working Group version 3). Study participants who progress are reanalyzed and rerandomized. Outcomes data is continuously used to update the randomization probabilities to identify treatment–biomarker signature combinations that "graduate" (superior vs. standard of care) or are terminated for futility.