Potential Surrogate for All-Cause Mortality Risk in Localized Prostate Cancer



In a study reported in JAMA Oncology, Trevor J. Royce, MD, of Harvard Radiation Oncology Program, Brigham and Women’s Hospital, and colleagues found that a prostate-specific antigen (PSA) nadir > 0.5 ng/mL may be a dominant risk factor for all-cause mortality after radiation therapy and androgen-deprivation therapy in men with localized unfavorable-risk prostate cancer.

The study involved analysis of four candidate surrogate markers for all-cause mortality risk in men who had participated in a randomized trial of radiation therapy plus 6 months of androgen-deprivation therapy vs radiation therapy: PSA failure, PSA nadir > 0.5 ng/mL, PSA doubling time < 9 months, and PSA failure at < 30 months. In the trial, conducted between 1995 and 2001, radiation therapy plus androgen-deprivation therapy was shown to improve overall survival vs radiation therapy.

Surrogates for mortality risk had to satisfy the following four (Prentice) criteria: (1) treatment with radiation therapy plus androgen-deprivation therapy had to be significantly associated with a reduced risk in an unadjusted Cox model; (2) the surrogate had to be significantly less common in men randomized to radiation therapy plus androgen-deprivation therapy in unadjusted logistic regression analysis; (3) the surrogate had to be significantly associated with an increased risk of mortality in an unadjusted Cox model; and (4) the reduction in mortality risk with radiation therapy plus androgen-deprivation therapy had to lose significance when the surrogate was included in an adjusted Cox model, with the surrogate remaining significantly associated with mortality risk.

Surrogates Identified

The analysis was performed in 157 study patients (of the total of 206) who had minimal or no comorbidity. Median follow-up was 16.49 years.

Among the candidates, PSA nadir > 0.5 ng/mL (adjusted hazard ratio [aHR] = 1.72, P = .01), PSA doubling time < 9 months (aHR = 2.06, P = .003), and PSA failure at < 30 months (aHR = 1.76, P = .03) met all criteria, including remaining significant in adjusted analysis for all-cause mortality, whereas treatment group (radiation therapy plus androgen-deprivation therapy vs radiation therapy) no longer remained significant (P ≥ .27); PSA failure did not remain significant in the adjusted analysis (aHR = 1.47, P = .10) and thus did not meet the criteria for surrogacy.

Analysis of the three surrogates using proportion of treatment effect metrics showed that proportion of treatment effect values were 103.86% for PSA nadir > 0.5 ng/mL, 43.09% for PSA doubling time < 9 months; and 41.26% for PSA failure within 30 months. Thus, the findings indicated that PSA nadir > 0.5 ng/mL could be considered the optimal surrogate measure for all-cause mortality risk in the radiation therapy plus androgen-deprivation therapy group.

The investigators concluded: “A PSA nadir value of greater than 0.5 ng/mL following radiation and androgen deprivation therapy appears to identify men prior to PSA failure who are at high risk for death. This could be used to select men for entry at the time of PSA nadir onto randomized trials evaluating the impact on survival of salvage androgen deprivation therapy with or without agents shown to prolong survival in men with castrate-resistant metastatic prostate cancer.” ■

Royce TJ, et al: JAMA Oncol. January 12, 2017 (early release online).



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