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

OBJECTIVES

If randomized controlled trials can be successfully emulated using real-world data (RWD), confidence in the validity of RWD for estimating treatment effects for questions that have not been assessed in trials increases. We used routinely collected administrative and clinical national linked datasets from England to emulate the PR07 trial for high-risk prostate cancer patients, which compared the effects of radiotherapy added to hormone therapy (RT+HT) within 8 weeks of randomization (the "grace period") and hormone therapy (HT) only on all-cause mortality. We highlight methodological choices required and challenges encountered in emulating this trial.

STUDY DESIGN AND SETTING

Patients diagnosed with prostate cancer from 2014 to 2020 were identified from the routine national linked datasets. Diagnosis was taken as the time zero. As few patients initiated radiotherapy within 8 weeks of diagnosis, we considered target trials with grace periods of 4-6 months. Estimands of interest were hazard ratios (HRs) and survival probabilities over 7 years. The cloning-censoring-and-weighting (CCW) approach was used to control for measured confounding and to allow for the grace period. We also used an extension (the "landmark-CCW" approach), in which we consider several time-origins post-diagnosis, enabling us to use a grace period of 8 weeks as in PR07.

RESULTS

A total of 2,690 patients were eligible for inclusion in the emulated trial. The CCW analysis using a grace period of 6 months gave an estimated HR of 0.48 (95% confidence interval [CI]: 0.34-0.60) and 7-year survival estimates of 80.7% (95% CI: 74.3-87.0) for the RT+HT strategy and 65.6% (95% CI: 62.8-68.1) for HT only strategy, and corresponding risk difference of 15.1% (95% CI: 11.5-18.9). The corresponding HR from the landmark-CCW approach was 0.58 (95% CI: 0.51-0.65) and with survival estimates of 80.7% (95% CI: 77.7-83.8) for RT+HT strategy and 69.8% (95% CI: 68.2-71.4) for the HT only strategy, and a risk difference of 10.9% (95% CI: 6.3-15.9).

CONCLUSION

Our findings from the emulated trial using RWD are broadly consistent with those from PR07, with RT+HT estimated to result in better survival compared to HT only. However, the findings were not replicated exactly, with PR07 reporting an HR of 0.77 (95% CI: 0.61-0.98) over 7 years of follow-up. Differences may be in part due to challenges in defining time zero and allowing for a treatment grace period of the same duration as in PR07. Our study considered ways in which these challenges can be addressed, and our findings affirm the utility of RWD for estimating treatment effects.

PLAIN LANGUAGE SUMMARY

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.