Surrogate Endpoints Useful in Study of Treatments for Prostate Cancer

In prostate cancer patients, a PSA nadir value of > 0.5 ng/mL after radiation therapy and androgen deprivation therapy can identify patients at a high risk of death.

In men with unfavorable-risk prostate cancer, a prostate-specific antigen (PSA) nadir value of greater than 0.5 ng/mL after radiation therapy (RT) and androgen deprivation therapy (ADT) can identify patients at a high risk of death, according to a new analysis. This surrogate marker could be used to design future trials aimed at improving outcomes in these men.

“While biochemical recurrence [BCR] is often managed with salvage ADT, there are no randomized studies to our knowledge to show that ADT in this setting prolongs survival,” wrote study authors led by Trevor J. Royce, MD, of Brigham and Women’s Hospital and Dana-Farber Cancer Institute in Boston. “Also, BCR is associated with but does not necessarily mean a patient will experience prostate cancer–specific mortality because many men will die from competing risks.” Surrogate endpoints for prostate cancer–specific mortality that occur before clinical recurrence could help find candidates for trials evaluating strategies to prolong life with more advanced disease.

The new study evaluated four candidate surrogates: PSA failure, PSA nadir > 0.5 ng/mL, PSA doubling time < 9 months, and interval to PSA failure < 30 months. A total of 206 men with unfavorable-risk prostate cancer treated between 1995 and 2001 were randomized to RT alone or RT followed by 6 months of ADT; of those, this analysis included 157 men with minimal or no comorbidities who were followed for a median of 16.49 years. The results were published in JAMA Oncology.

A total of 110 men (70%) died during the follow-up period. Three of the four candidate surrogates-excluding PSA failure-met all the Prentice criteria for surrogacy. On an adjusted analysis, men who received RT alone had a hazard ratio (HR) to have a PSA nadir > 0.5 ng/mL of 1.72 (95% CI, 1.17–2.52; P = .01) compared with those who received ADT. For PSA doubling time < 9 months, the adjusted HR was 2.06 (95% CI, 1.29–3.28; P = .003), and for interval to PSA failure < 30 months, the HR was 1.76 (95% CI, 1.06–2.92; P = .03).

The researchers also calculated the proportion of the treatment effect (PTE) explained by the surrogate; a score of 100% would signify that all of the treatment effect is explained by that surrogate endpoint. The PSA nadir > 0.5 ng/mL fared best, with a PTE of 103.86%; the PTE was 43.09% for PSA doubling time < 9 months, and 41.26% for PSA failure < 30 months.

“The clinical importance of this finding is that it provides an opportunity for patient selection for clinical entry at a time when the patient is still responding to but has not yet declared as having failed primary therapy,” the authors wrote. Specifically, men treated with a conventional RT dose and ADT whose PSA nadir does not fall below that cutoff of 0.5 ng/mL could be candidates for trials investigating treatments designed to prolong survival in metastatic and castration-resistant prostate cancer.

“By enriching the study cohort with men who have achieved a surrogate endpoint for all-cause mortality, one can enhance the likelihood that the study will be able to answer the question of whether survival is prolonged when novel treatment is added,” they concluded.