Precision medicine: results from ProBio trial
(Note: This text is adopted from SciLifeLab Communications, read the story at SciLifeLab News)
ProBio (Prostate Biomarkers) is an innovative randomized clinical trial with the goal of advancing precision medicine for metastatic prostate cancer. All patients in the trial are profiled to identify the somatic alterations that drive the growth of the cancer cells. Based on somatic alterations (biomarkers) in a predefined set of cancer genes, a patient is randomized either to one of the experimental arms or to the control armusing a self-learning randomization approach to identify effective biomarker and treatment combinations as quickly as possible. The approach ensures that fewer patients receive treatments that are unlikely to be effective, maximizing the overall benefits of the study. Over time, the study will adapt by discarding or adding treatments or biomarkers.
“The first publication from the ProBio trial demonstrates that it is possible to establish and execute an efficient adaptive biomarker-driven trial and that such a trial can generate novel results to improve treatment selection for men with metastatic prostate cancer,” says Johan Lindberg, researcher at SciLifeLab and Karolinska Institutet. He continues, “ProBio is an adaptive platform trial. This means that we are testing multiple biomarkers and treatments at the same time. We are also collaborating with pharma to test new promising drugs. This publication is the first of many.”
Cancer commonly occurs due to DNA damage, either from aging or external factors like smoking, that accumulates over time and causes cells to grow uncontrollably. While all prostate cancers start in the same organ, the specific mutations in a tumor’s DNA vary, leading to different behaviors and outcomes. By applying DNA sequencing to analyze these mutations, the research group can identify which genes are affected and how this might influence treatment.
Better results with novel hormonal therapies
All men diagnosed with metastatic prostate cancer are initially treated with testosterone blockade to prevent activation of the androgen receptor, which fuels the growth of cancer cells. Eventually, resistance will occur and patients then have the option to receive either chemotherapy or second-generation hormone drugs that target the androgen receptor (abbreviated ARPI – Androgen Receptor Pathway Inhibitors). The publication in Nature Medicine demonstrates that patients receiving ARPI had significantly better outcomes and iproved overall survival compared to those treated with chemotherapy or those in the control group.
The benefit of ARPI was particularly evident in patients with specific genetic profiles. Patients without mutations in TP53 and the androgen receptor benefitted the most. However, the study suggests that all patients groups experience improved overall survival, therefore the recommendation is that all newly diagnosed patients with metastatic castrate resistant prostate cancer should obtain ARPI as first line treatment.
What comes next?
The initial findings from the ProBio trial are promising and pave the way for further research into additional biomarkers and treatment combinations. This research will hopefully lead to more personalized and effective treatment strategies for prostate cancer. However, for this to succeed, sensitive biomarker detection is crucial.
“One particular challenge is that important copy number alterations (biomarkers) cannot be reliably detected in a sample from a patient if the fraction of cancer DNA is very low. As this is common when working with liquid biopsies and circulating tumor we solved this by developing a new algorithm, jumble, that significantly improves the sensitivity compared to other bioinformatic tools.” says Markus Mayrhofer, Bioinformatician at NBIS, SciLifeLab.
DOI: 10.1038/s41591-024-03204-2
