Men diagnosed with metastatic castration-resistant prostate cancer should primarily receive treatment with second-generation hormone therapies, as these provide a more favorable treatment response and increased life expectancy compared to chemotherapy. However, the efficacy of these treatments is influenced by the specific mutations present in the patient’s tumor, as highlighted by new findings from the ProBio study, which was led by researchers at the Karolinska Institutet in Sweden. These results are published in Nature Medicine.
Each year, approximately 2,500 men in Sweden are found to have metastatic prostate cancer. Initially, all patients undergo testosterone suppression to stop testosterone from stimulating the androgen receptor, which is primarily responsible for cancer cell growth. Over time, cancer cells may develop resistance, leading to what is known as castration-resistant cancer. As a result, new treatments are required, which can be either chemotherapy or second-generation hormone therapies (such as abiraterone or enzalutamide) that target the androgen receptor. These are collectively referred to as Androgen Receptor Pathway inhibitors, or ARPi. Despite the availability of these drugs for over a decade, there hasn’t been a direct comparison from a randomized trial until now.
“For the first time, we have performed a side-by-side comparison of these treatments and analyzed the cancer cells’ DNA to determine which option is most effective for different patients,” explains Johan Lindberg, a senior researcher at the Department of Medical Epidemiology and Biostatistics (MEB) at Karolinska Institutet.
The blood contains what is known as cell-free DNA from cells that have died—a natural occurrence in healthy individuals. In cancer patients, a portion of this cell-free DNA comes from cancer cells, referred to as circulating tumor DNA (ctDNA). By examining ctDNA, researchers can identify the mutations present in a patient’s tumor. The goal of the ProBio study is to leverage this genetic information to optimize treatment. The aim is to distinguish patients whose tumors are particularly responsive or resistant to specific treatments through ongoing analyses.
“This creates a self-learning platform to continuously enhance treatment for men with metastatic prostate cancer,” states Martin Eklund, Professor of Epidemiology at the same department. “We are also gathering insights about which areas of the genome are critical in prostate cancer.”
The current sub-study involved 193 men with metastatic castration-resistant prostate cancer, randomly assigned to receive either chemotherapy or ARPi, compared to a control group where treatment was based on the physician’s choice. The ARPi group showed the longest response duration to treatment (a median of 11.1 months in comparison to 6.9 months for chemotherapy and 7.4 months for the control group). Survival in the ARPi group was also notably longer, with a median of 38.7 months compared to 21.7 months for chemotherapy and 21.8 months for the controls.
The effectiveness of ARPi varied depending on the patient’s genetic makeup. For instance, there was no marked difference in short-term treatment responses among patients with mutations in the p53 gene, which is found in about 45% of men with metastatic prostate cancer. Nevertheless, study data suggests that this group may have improved survival rates with ARPi compared to chemotherapy.
“Our research indicates that it is feasible to ensure each patient receives the optimal treatment based on their tumor’s genetic profile,” states Henrik Grönberg, Professor of Cancer Epidemiology at MEB, Karolinska Institutet. “While precision medicine is a popular concept, studies like ProBio are essential for understanding how biomarkers can benefit patients.”
ProBio involves participation from researchers and clinicians across 31 hospitals, 10 of which are located in Sweden, with additional sites in Belgium, Norway, and Switzerland. Funding for the study comes from ALF, the Swedish Cancer Society, the Swedish Research Council, as well as from pharmaceutical companies AstraZeneca and Janssen.
Several authors have disclosed that they hold shares or are board members and have reported receiving payments from various pharmaceutical companies. Johan Lindberg has also been listed as an inventor on a Swedish patent application related to a method utilized in the study, which is intended to be made publicly available under a GPL 3.0 license. For a detailed list of conflicts of interest, please refer to the scientific publication.
