Inferences About Drug Safety in Phase III Trials in Oncology: Examples From Advanced Prostate Cancer

Abstract

Background: Safety is a central consideration when choosing between multiple medications with similar efficacy. We aimed to evaluate whether adverse event (AE) profiles of 3 such drugs in advanced prostate cancer could be distinguished based on published literature.

Methods: We assessed consistency in AE reporting, AE risk in placebo arms, and methodology used for risk estimates and quantification of statistical uncertainty in randomized placebo-controlled phase III trials of apalutamide, enzalutamide, and darolutamide in advanced prostate cancer.

Results: Seven included clinical trials enrolled a total of 9215 participants (range = 1051-1715 per trial) across 3 prostate cancer disease states. Within disease states, baseline patient characteristics appeared similar between trials. Of 54 distinct AE types in total, only 3 (fatigue, hypertension, and seizure) were reported by all 7 trials. Absolute risks of AEs in the placebo arms differed systematically and more than twofold between trials, which was associated with visit frequency and resulted in different degrees of uncertainty in AE profiles between trials. No trial used inferential methodology to quantify statistical uncertainty in AE risks, but 6 of 7 trials drew overall conclusions. Two trials concluded that there was no elevated AE risk because of the intervention, including the trial of darolutamide, which had the greatest statistical uncertainty.

Conclusions: Rigorous comparison of drug safety was precluded by heterogeneity in AE reporting, variation in AE risks in the placebo arms, and lack of inferential statistical methodology, underscoring considerable opportunities to improve how AE data are collected, analyzed, and interpreted in oncology trials.

Figure 1.

Adverse event (AE) types reported across trials and risk of AE by type and trial in the placebo arms. All AEs of any grade reported in the articles are shown. Light gray indicates AEs that were not reported.

Figure 2.

Adverse event (AE) risks in the placebo arms of each trial, by type of adverse event. The plot shows absolute risks of AEs of any grade; ratios above the plot indicate the relative risk of AEs, comparing between placebo arms of the different trials. Plotted are only AE types reported by at least 6 of the 7 trials; ratios between trials include all AE types. CI = confidence interval; mCRPC = metastatic castration-resistant prostate cancer; mCSPC = metastatic castration-sensitive prostate cancer; nmCRPC = nonmetastatic castration-resistant prostate cancer.

Figure 3.

Uncertainty in relative risk estimates per trial. The plots show the width of the confidence intervals (CIs) for adverse events (AEs) of any grade reported by at least 6 of the 7 trials (except seizures because of the low absolute risk) for comparisons of relative risks of AEs between drug and placebo arm. Ratios above the plot indicate the relative width of confidence intervals comparing between trials, based on all AE types.