Intermediate clinical endpoints as surrogates for overall survival after salvage prostatectomy

To evaluate biochemical recurrence-free survival (BRFS) and metastasis-free survival (MFS) as potential intermediate clinical endpoints (ICEs) for overall survival (OS) in patients undergoing salvage radical prostatectomy (sRP).

Evaluable patients were selected from a retrospective dataset, resulting in a cohort of 879 patients with recurrent, non-metastatic, hormone-sensitive prostate cancer treated with sRP at 13 centres. ICE surrogacy was evaluated using a two-stage approach: (i) at the individual-patient level by fitting Clayton copula models and estimating Kendall's $\tau$ ( $\tau$ >0.7 indicating a strong association) and (ii) at the centre level, by fitting weighted linear regression of 5-year OS on 3-year BRFS and MFS.

The two-step analysis included 759 patients for BRFS (366 events) and 476 for MFS (137 events), with median follow-up of 37 months (95% confidence interval [CI] 36-42 months) and 34 months (95% CI 31-37 months), respectively. At the individual-patient level, MFS showed a strong association with OS (Kendall's $\tau$ 0.85, 95% CI 0.82-0.88), which was not observed for BRFS (Kendall's $\tau$ 0.63, 95% CI 0.56-0.69). At the centre level, neither 3-year BRFS (R² = 0.15; slope = 0.34, P = 0.2) nor 3-year MFS (R² = 0.21; slope = 0.26, P = 0.14) predicted 5-year OS with sufficient explanatory power. Limitations include the fact that centre-level analysis was based on single-arm associations rather than on treatment-effect surrogacy across arms, and retrospective data collection.

The BRFS should not be used as a surrogate endpoint in the sRP setting. MFS requires further validation in future prospective studies to confirm its association with OS. Patient-reported outcomes, such as quality-of-life and treatment-related toxicity, should be considered in parallel with OS.