Prostate-specific antigen (PSA) nadir greater than 0.5 ng/mL may serve as a surrogate marker to identify men with localized prostate cancer at high risk of mortality, according to an analysis recently published in JAMA Oncology.1
“It’s really an opportunity for the whole clinical community to change the way they design clinical trials; instead of waiting for somebody to present to them with failure—which is what we do now, and losing perhaps important time—you can actually enroll them into trials earlier at the time of PSA nadir,” Anthony V. D’Amico, MD, PhD, of the department of radiation oncology at Brigham and Women’s Hospital and Dana-Farber Cancer Institute in Boston, Massachusetts, and senior author of the study, told Cancer Therapy Advisor.
PSA Nadir as a Surrogate Marker for Increased Risk of Mortality
This analysis used data from a clinical trial that randomly assigned 206 men with unfavorable-risk, localized prostate cancer to receive radiation therapy (RT) alone or RT plus androgen-deprivation therapy (ADT) for 6 months. A centralized genitourinary pathologist conducted all pathology.
Follow-up occurred every 3 months for 2 years, then every 6 months for an additional 3 years, and yearly thereafter. History, physical exam, serum PSA, and a digital rectal exam were performed at each visit. At the time of PSA failure, patients underwent a bone scan and CT or MRI of the pelvis. Salvage ADT was recommended to men whose PSA rose to about 10 ng/mL. The median follow-up was 16.62 years.
In this analysis, data from a cohort of 157 men with limited or no comorbidities were evaluated for an association between 4 metrics that met all 4 Prentice criteria for surrogacy and all-cause mortality. The metrics were PSA nadir greater than 0.5 mg/mL, PSA doubling time less than 9 months, interval to PSA failure less than 30 months, and PSA failure.
The Prentice criteria were: 1) decreased risk of all-cause mortality significantly associated with RT plus ADT therapy in an unadjusted Cox model, 2) the surrogate must be present in significantly fewer men who received RT and ADT in an unadjusted logistic regression analysis, 3) increased risk of all-cause mortality significantly associated with the surrogate in an unadjusted Cox model, and 4) when the surrogate is included in an adjusted Cox model, treatment with RT plus ADT was no longer associated with a decreased risk of all-cause mortality and the surrogate is significantly associated with an increased risk of mortality.
Of the 4 metrics, PSA nadir greater than 0.5 ng/mL demonstrated the strongest association with all-cause mortality with an adjusted hazard ratio (aHR) of 1.72 (95% CI, 1.17-2.52; P = .01) and a treatment effect value of 103.86%. The other metrics associated with all-cause mortality were PSA doubling time less than 9 months (aHR, 2.06; 95% CI, 1.29-3.28; P = .003) with a treatment effect of 43.09%, and interval to PSA failure less than 30 months (aHR, 1.76; 95% CI, 1.06-2.92; P = .03) with a treatment effect of 41.26%.