An Evidenced-Based Prior for Estimating the Treatment Effect of Phase III Randomized Trials in Oncology

Purpose: The primary results of phase III oncology trials may be challenging to interpret, given that such results are generally based on meeting P-value thresholds. The probability of whether a treatment is beneficial, although a more intuitive summary of the results, is not provided by most trials. In this study, we developed and released a user-friendly tool that calculates the probability that a treatment studied in a phase III oncology trial is beneficial using published summary statistics. Methods: We curated the primary time-to-event outcomes of 415 phase III, superiority design, therapeutic randomized controlled trials of oncologic treatments enrolling 338,600 patients and published between 2004 and 2020. A phase III oncology-specific prior probability distribution for the treatment effect was developed based on an estimated three-component zero-mean mixture distribution of the observed z-scores. Using this prior, we computed the probability of any benefit (hazard ratio < 1) and the probability of clinically meaningful benefit (hazard ratio < 0.8) for each trial. The distribution of signal-to-noise ratios of phase III oncology trials was compared with that of 23,551 randomized trials from the Cochrane Database of Systematic Reviews. Results: The signal-to-noise ratios of phase III oncology trials tended to be much larger than randomized trials from the Cochrane database. Still, the median power of phase III oncology trials was only 49% (IQR, 14% to 95%), and the power was less than 80% in 65% of trials. Using the developed phase III, oncology-specific prior, only 53% of trials claiming superiority (114 of 216) had a ≥ 90% probability of providing clinically meaningful benefits. Conversely, the probability that the experimental arm was superior to the control arm (HR < 1) exceeded 90% in 17% of trials interpreted as having no benefit (34 of 199). Conclusion: By enabling computation of contextual probabilities for the treatment effect from summary statistics, our robust, highly practical tool, now posted on a user-friendly webpage, can aid the wider oncology community in the interpretation of phase III trials. ### Competing Interest Statement A.D.S. reports honoraria from Sermo. P.M. reports honoraria for scientific advisory board membership for Mirati Therapeutics, Bristol-Myers Squibb, and Exelixis; consulting fees from Axiom Healthcare; non branded educational programs supported by DAVA oncology, Exelixis, and Pfizer, leadership or fiduciary roles as a Medical Steering Committee Member for the Kidney Cancer Association and a Kidney Cancer Scientific Advisory Board Member for KCCure; and research funding from Takeda, Bristol-Myers Squibb, Mirati Therapeutics, and Gateway for Cancer Research. Z.R.M. reports employment at Insitro. No other authors report any conflicts of interest. ### Funding Statement Supported in part by Cancer Center Support (Core) grant P30CA016672 from the National Cancer Institute to The University of Texas MD Anderson Cancer Center and by the Sabin Family Fellowship Foundation (E.B.L. and P.M.). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Data were obtained from published trials and available at ClinicalTrials.gov. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The underlying dataset, code for the development of the prior, and code for computing posterior probability are provided in the Supplement. A freely available webpage has been created for users to compute the probabilities at a given level of hazard ratio based on trial summary statistics.