In Reply We thank Dr Baker for his Letter and agree that an optimal way to select men at highest risk for death, as well as for entry onto randomized clinical trials assessing the impact on survival of adding androgen deprivation therapy to novel agents shown to overcome castration resistance, is by combining prostate-specific antigen (PSA) nadir greater than 0.5 ng/mL with other important prostate cancer prognostic factors shown to have independent prognostic significance on multivariable analysis in which the end point is time to death. In our multivariable model that included age and known prostate cancer prognostic factors as covariates, which was appended in the Supplement (available online only), we reported adjusted hazard ratios (AHRs) and showed that increasing age (AHR, 1.08; 95% CI, 1.04-1.66; P < .001) in addition to PSA nadir greater than 0.5 ng/mL (AHR, 1.72; 95% CI, 1.17-2.52; P = .01) was significantly associated with the risk of death.1 The established prostate cancer prognostic factor2 Gleason score 7 and 8 to 10 as compared with 6 was not significant, with P values of .05 and .08, respectively, in the multivariable model; other established prognostic factors such as PSA level and clinical stage were also not significant (P = .24 and .50, respectively). Therefore, when selecting men at the highest risk for death it appears that PSA nadir greater than 0.5 ng/mL identified the most at-risk population and that established prognostic factors such as PSA level, clinical stage, and Gleason score do not add significantly to this risk assessment in men. Regarding age, it is expected that with increasing age survival would shorten but adding a drug that is aimed at killing prostate cancer is unlikely to change the impact of increasing age on the risk of death because the association of increasing age and increased risk of death is likely driven by competing risks.3 The reason we added additional covariates in our model was stated in the Methods section of our study: “because men were not stratified by comorbidity prior to randomization, we also included age and known PC [prostate cancer] prognostic factors—specifically PSA, Gleason score, and T stage—in the adjusted model because we only evaluated the subset of 157 men with no or minimal comorbidity, given that PSA failure has been shown to be associated with an increased risk of ACM [all-cause mortality] only in men with no or minimal comorbidity.4”5(p654) As a result, our conclusion was that PSA nadir greater than 0.5 ng/mL “appears” to be a surrogate. This is the reason why we suggested the use of PSA greater than 0.5 ng/mL only as a patient selection factor to identify men for future randomized clinical trials who are at high risk for death if they are treated in accordance with current standards of practice, and not for immediate use as a surrogate end point for death without further validation.
Royce TJ, Chen M, D’Amico AV. Validity of Surrogate End Points for Prostate Cancer—Reply. JAMA Oncol. 2018;4(1):130–131. doi:10.1001/jamaoncol.2017.2506
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