Precision medicine: promising results from ProBio trial
Last year, researchers from Karolinska Institutet and SciLifeLab introduced routine diagnostic testing of cell-free DNA for patients with metastatic prostate cancer (see 2023 news article). The test was originally developed for the ProBio (Prostate Biomarkers) trial. The first results from this trial have now been published in Nature Medicine.
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 arm, where the treating oncologist chooses treatment. The trial uses 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.
”This has been an important collaboration for the last 10 years. Johan’s group is one of our first collaborators and it is great to see the progress, starting from a concept and seeing the assays, tools and processes that have been developed now being used for clinical trials for creating a patient benefit. This is precision medicine in action,” says Valtteri Wirta, Platform Scientific Director at Clinical Genomics.
Better results with novel hormonal therapies
All men diagnosed with metastatic prostate cancer are initially treated with testosterone blockade to prevent testosterone from activating the androgen receptor, the main gene that fuels the growth of cancer cells. Eventually, resistance will occur. Patients who progress to the castration-resistant phase of the disease 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 compared to those treated with chemotherapy or those in the control group. Those treated with ARPI also experienced improved overall survival.
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 whereas for TP53 mutated patients there was no difference between ARPI and chemotherapy. However, the study suggests that even this group may 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.
“The whole trial was designed to evolve over time with new or improved biomarkers and treatment options. 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 DNA obtained from plasma 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.
In short, ProBio shows that using genetic information to guide treatment can significantly improve patient outcomes, providing renewed hope for those battling advanced prostate cancer.
