Precision therapy for metastatic prostate cancer improves survival

Men with metastatic castration-resistant prostate cancer should be treated primarily with second-generation hormone drugs, which offer better treatment response and longer life expectancy than chemotherapy. However, the effect depends on which mutations the patient’s tumour carries. This is shown by results from the ProBio study, led by researchers at Karolinska Institutet in Sweden. The findings are published in Nature Medicine.

Every year, around 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 mainly fuels the growth of cancer cells. Over time, the cancer cells develop resistance and become so-called castration-resistant. This requires the use of new drugs – usually chemotherapy or second-generation hormone drugs (abiraterone/enzalutamide) that inhibit the androgen receptor. These are called Androgen Receptor Pathway inhibitors, or ARPi. Although these drugs have been available for over a decade, there is no direct comparison from a randomised trial until now.

“For the first time, we have compared these treatments with each other and also analysed the DNA of the cancer cells to find out which drug that works best for different individuals,” says Johan Lindberg, senior researcher at the Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet.

The bloodstream contains so-called cell-free DNA from cells that have died, something that happens all the time in healthy individuals and is perfectly normal. In patients with cancer, a fraction of the cell-free DNA originates from the cancer cells and is called circulating tumour DNA (ctDNA). By analysing ctDNA, it is possible to see what changes, or mutations, are present in a person’s tumour. The ProBio study aims to use knowledge of the tumour’s genetic signature to provide the best treatment. The idea is to be able to identify patients whose tumours are particularly sensitive or resistant to certain treatments through ongoing analyses.

“It creates a self-learning system to continuously improve treatment for men with metastatic prostate cancer,” says Martin Eklund, Professor of Epidemiology at the same department. “We are also gathering knowledge about which regions of the genome are important in prostate cancer.”

The current sub-study included 193 patients with metastatic castration-resistant prostate cancer. They were randomly chosen to receive either chemotherapy or ARPi, which was compared to a control group where the doctor decided on the best treatment. The ARPi group responded the longest to treatment (a median of 11.1 months compared with 6.9 for chemotherapy and 7.4 for the control group). Survival for the ARPi group was also significantly longer – a median of 38.7 months compared with 21.7 months and 21.8 months respectively.

The effectiveness of ARPi varied depending on the patient’s genetic profile. For example, there was no significant difference between the treatments in the short term in patients whose tumours had mutations in the p53 gene, which occurs in around 45 per cent of men with metastatic prostate cancer. However, data from the study suggest that this group may also have better survival if they receive ARPi rather than chemotherapy.

“Our study shows that it is possible to ensure that each patient receives the best treatment given the genetic profile of the tumour,” 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.”

ProBio involves researchers and doctors at 31 hospitals, ten of which are in Sweden and the rest in Belgium, Norway and Switzerland. The study is funded by 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 listed that they have received fees 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 licence. See the scientific article for a complete list of conflicts of interest.

Publication: “Androgen receptor pathway inhibitors and taxanes in metastatic prostate cancer: an outcome adaptive randomised platform trial”, Bram De Laere, Alessio Crippa, Andrea Discacciati, Berit Larsson, Maria Persson, Susanne Johansson, Sanne D’hondt, R. Bergström, Venkatesh Chellappa, Markus Mayrhofer, Mahsan Banijamali, Anastasijia Kotsalaynen, Céline Schelstraete, Jan Pieter Vanwelkenhuyzen, Marie Hjälm-Eriksson, Linn Pettersson, Anders Ullén, Nicolaas Lumen, Gunilla Enblad, Camilla Thellenberg Karlsson, Elin Jänes, Johan Sandzén, Peter Schatteman, Maria Nyre Vigmostad, Martha Olsson, Christophe Ghysel, Brieuc Sautois, Wendy De Roock, Siska Van Bruwaene, Mats Anden, Ingrida Verbiene, Daan De Maeseneer, Els Everaert, Jochen Darras, Bjørg Y. Aksnessether, Daisy Luyten, Michiel Strijbos, Ashkan Mortezavi, Jan Oldenburg, Piet Ost, Martin Eklund, Henrik Grönberg & Johan Lindberg, Nature Medicine, online 20 August 2024, doi: 10.1038/s41591-024-03204-2.