While Prognostic, BCR May Not Be a Strong Surrogate End Point for Prostate Cancer Survival

In a recent study published in the Journal of Clinical Oncology, researchers found that biochemical recurrence (BCR) was not a reliable surrogate end point for overall survival (OS) in patients with localized prostate cancer (PCa).

BCR is a measure of great prognostic importance for patients with PCa; however, past analyses on surrogate end points and the utility of BCR have produced inconsistent results. To address the controversies surrounding its relevance for OS in patients with PCa, researchers conducted a meta-analysis across 11 randomized studies to evaluate the utility of BCR as a surrogate end point.

Their focus was on interventions that had been measured in various randomized studies and that benefited BCR-based outcomes: radiation therapy (RT) dose escalation, short-term androgen deprivation therapy (ADT), and the prolongation of ADT after short-term therapy.

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The primary objective of their analysis was determining the efficacy of time to BCR (TTBCR) as a surrogate intermediate clinical endpoint (ICE) for OS in patients with localized PCa treated with RT—with or without ADT. Additionally, the authors explored whether changing the censoring mechanism had any differential effects on the surrogacy results.

To evaluate the utility of BCR, the Prentice criteria were used. These benchmarks include: (1) treatment should significantly affect the true end point and (2) the ICE; (3) ICE and the true end point have a significant association; and (4) the treatment effect on the true end point is mediated by the effect of the treatment on ICE.

TTBCR was measured as the time from random assignment to BCR or the onset of ADT without recurrence or any cancer-specific death. Biochemical recurrence-free survival (BCRFS) was defined as the time from random assignment to BCR or death of any kind. OS refers to the time from random assignment to death.

A total of 10,741 patients were included: 3639 were treated on trials evaluating RT dose escalation, 3930 on trials evaluating ADT use, and 3772 on trials of ADT prolongation. Patients had a median age of 70 years, a median baseline PSA of 11.1 ng/mL, and follow-ups were conducted on an average of 9.2 years between all groups.

RT dose escalation, the addition of short-term ADT, as well as the prolongation of ADT all significantly reduced the hazard of BCR ([HR, 0.71; 95% CI, 0.63-0.79], [HR, 0.53; 95% CI, 0.48-0.59], and [HR, 0.54; 95% CI, 0.48-0.61], respectively). Although RT dose escalation had no significant effect on OS, both short-term and prolonged ADT showed significantly improved OS outcomes ([HR, 0.91; 95% CI, 0.84-0.99] and [HR, 0.86; 95% CI, 0.78-0.94], respectively).

The 3rd Prentice criterion was achieved across all 3 groups. At 48 months, BCR was linked to shorter OS across each group (HR, 2.46; HR, 1.51; and HR, 2.31). After adjusting for BCR at 48 months, however, the authors reported there were no significant treatment effects on OS. Associations between BCRFS and OS were low to moderate, with between Kendall's tau values falling from 0.59 and 0.69, and those between TTBCR and OS were low, ranging from 0.23 and 0.41. The 4th Prentice criterion was not achieved consistently within any group.

Although BCRFS and TTBCR are prognostic, neither measure successfully met the surrogacy criteria. Given that the Prentice criteria were not fully attained, the researchers concluded, “Overall, these results strongly suggest that BCR-based end points should not be the primary end point of any randomized trial in localized PCa.”

Reference

Roy S, Romero T, Michalski JM, et al. Biochemical recurrence surrogacy for clinical outcomes after radiotherapy for adenocarcinoma of the prostate. J Clin Oncol. Published online August 28, 2023. doi: 10.1200/JCO.23.00617