Men with metastatic castration-resistant prostate cancer should be treated primarily with second-generation hormonal drugs, which offer a better response to treatment and a longer life expectancy than chemotherapy. However, the effect depends on the mutations the patient’s tumor carries. This is shown by the results of the ProBio study, led by researchers at Karolinska Institutet in Sweden. The results are published in Natural medicine.
Every year, about 2,500 men in Sweden are diagnosed with metastatic prostate cancer. Initially, all are treated with testosterone blockade to prevent testosterone from activating the androgen receptor, the gene that primarily fuels cancer cell growth. Over time, the cancer cells develop resistance and become so-called castration-resistant cells. This requires the use of new drugs – usually chemotherapy or second-generation hormonal drugs (abiraterone/enzalutamide) that block the androgen receptor. These drugs are called androgen receptor pathway inhibitors, or ARPis. Although these drugs have been available for more than a decade, there has been no head-to-head comparison from a randomized trial.
For the first time, we compared these treatments with each other and also analyzed the DNA of cancer cells to find out which drug works best for different people.
Johan Lindberg, Senior Researcher, Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet
Blood contains so-called cell-free DNA from dead cells, which happens all the time in healthy people and is perfectly normal. In cancer patients, some of the cell-free DNA comes from cancer cells and is called circulating tumor DNA (ctDNA). Analyzing ctDNA can show what changes, or mutations, are present in a person’s tumor. The ProBio study aims to use knowledge of the tumor’s genetic signature to provide the best treatment. The idea is to be able to identify patients whose tumors are particularly sensitive or resistant to certain treatments through ongoing analysis.
“This is a self-learning system that can continuously improve the treatment of men with metastatic prostate cancer,” says Martin Eklund, professor of epidemiology in the same department. “We are also collecting information about regions of the genome that are important in prostate cancer.”
The current substudy involved 193 patients with metastatic castration-resistant prostate cancer. They were randomly assigned to receive either chemotherapy or ARPi, which was compared to a control group where the doctor decided which treatment was best. The ARPi group responded the longest to treatment (a median of 11.1 months versus 6.9 for chemotherapy and 7.4 for the control group). Survival in the ARPi group was also significantly longer – a median of 38.7 months versus 21.7 months and 21.8 months, respectively.
The effectiveness of ARPi varies depending on the patient’s genetic profile. For example, no significant short-term differences were observed between treatments in patients whose tumors had mutations in the p53 gene, which occur in about 45% of men with metastatic prostate cancer. However, the study data suggest that this group may also have better survival if they received ARPi rather than chemotherapy.
“Our study shows that it is possible to ensure that each patient receives the best treatment based on the genetic profile of the tumor,” says Henrik Grönberg, Professor of Cancer Epidemiology, MEB, Karolinska Institutet. “Everyone talks about precision medicine, but studies like ProBio are needed to understand how biomarkers can help patients.”
The ProBio study involves researchers and doctors from 31 hospitals, ten of which are in Sweden and the others in Belgium, Norway and Switzerland. The study is funded by the ALF, the Swedish Cancer Society, the Swedish Research Council and the pharmaceutical companies AstraZeneca and Janssen.
Several of the authors are shareholders or board members or have reported receiving honoraria from various pharmaceutical companies. Johan Lindberg is listed as an inventor on a Swedish patent application for a method used in the study, which is intended to be made freely available under a GPL 3.0 license.