Emulating an existing trial of treatments for prostate cancer using real-world data: challenges and lessons learned

Clinical trials are the best way to test whether treatments work, but they are expensive, take years to complete, and focus on narrow research questions. If we can use real-world data (RWD) such as patient health records to mimic these trials, we may be able to answer additional medical questions relevant to patients who are prescribed these medications. This study aimed to see if we could recreate the results of a past clinical trial (PR07) using national health data from England. The PR07 trial looked at two treatments for high-risk prostate cancer: hormone therapy (HT) alone and radiotherapy added to hormone therapy (RT+HT) within 8 weeks of starting the study. This trial was chosen for several reasons. It included high-risk patients who were studied for up to 7 years, meaning that there was enough information to study survival outcomes. Being a major UK-based trial, it was useful for comparing with the data recorded in UK national health data. The trial also allowed some flexibility in when treatment started, which was an interesting factor to examine. Its main goal was to see if adding radiotherapy to hormone therapy provided extra benefits to patients. We wanted to see whether the trial results were replicated using the UK health data. If results were replicated, it would provide confidence in further exploration of questions not covered by the trial. In a trial, randomization time is the point where doctors allocate patients to one of the treatments being assessed, usually 1 new treatment and 1 control treatment. Patients in the study are then followed up from that point. However, defining a starting point in a non-trial setting, using UK national health data, is not as straightforward. In the PR07 trial, patients started RT+HT within 8 weeks of randomization. In the UK datasets, we use diagnosis as a starting point, because it is available for both treatment groups. However, very few patients started RT+HT within 8 weeks of diagnosis. To address this, we allowed for longer periods of 4-6 months from diagnosis for RT+HT initiation. Recent developments provided statistical methods for estimating the cause-effect relationship between treatment received and survival patterns. In this study, we show how these approaches can be used to estimate survival patterns if all patients had RT+HT within 4-6 months from diagnosis compared with if no patients had any RT within 4-6 months. We account for the different treatment initiation times and the main differences between the RT+HT and HT only patients. Using these methods, we estimate that RT+HT has an 11%-15% higher survival rate at 7 years compared to HT only. We discuss similarities and differences between these findings and those in the original PR07 trial.