Inferences about drug safety in phase III trials in oncology: Examples from advanced prostate cancer Journal Article

Authors: Drago, J. Z.; Gönen, M.; Thanarajasingam, G.; Sacks, C. A.; Morris, M. J.; Kantoff, P. W.; Stopsack, K. H.
Article Title: 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. © The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please email:
Journal Title: JNCI: Journal of the National Cancer Institute
Volume: 113
Issue: 5
ISSN: 0027-8874
Publisher: Oxford University Press  
Date Published: 2021-05-01
Start Page: 553
End Page: 561
Language: English
DOI: 10.1093/jnci/djaa134
PUBMED: 32857839
PROVIDER: scopus
PMCID: PMC8096372
Notes: Article -- Export Date: 1 June 2021 -- Source: Scopus
Citation Impact
MSK Authors
  1. Michael Morris
    392 Morris
  2. Mithat Gonen
    824 Gonen
  3. Philip Wayne Kantoff
    159 Kantoff
  4. Joshua Drago
    10 Drago