Detecting a Survival Benefit to Dose Escalation—Reply

In Reply We thank Dr Zakeri and colleagues for their interest in the NRG/RTOG 0126 trial. After design, how a clinical trial plays out depends on accurate projections of several key parameters. As mentioned by Zakeri et al and described in the report, the overall survival (OS) was much better than anticipated, owing largely to better-than-expected prostate cancer prognosis. This result, in turn, has major bearing on the hazard ratio (HR) for the composite end point of OS. Indeed, the benefit on OS is bounded, and a simplified way to conceptualize this, similar to the argument by Zakeri et al, is that the HR of the composite outcome is a weighted average of effects on constituent end points:

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