Is metastasis-free survival a valid surrogate for OS in localized prostate cancer?

Metastasis-free survival (MFS) is still a good proxy for overall survival (OS) as endpoint in the current era, wherein patients have more access to docetaxel and other treatments for metastatic castrate-resistant prostate cancer (mCRPC), according to a study.

“Prior work from the Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP) consortium (ICECaP-1) demonstrated that MFS is a valid surrogate for OS in localized prostate cancer,” the authors said. “This was based on data from patients treated predominantly before 2004, prior to docetaxel being available for the treatment of metastatic castrate-resistant prostate cancer (mCRPC).”

The present study validated surrogacy in a more contemporary era (ICECaP-2) with greater availability of docetaxel and other systemic therapies for mCRPC. Trials with individual patient data (IPD) after publication of ICECap-1, with an assessment of adjuvant/salvage therapy for localized prostate cancer, and MFS and OS data were eligible for ICECaP-2.

The authors defined MFS as distant metastases or death from any cause and OS as death from any cause. They also evaluated surrogacy using a meta-analytic two-stage validation model, with an R² ≥ 0.7 defined a priori as clinically relevant.

Fourteen trials with a total of 15,164 IPD were included in ICECaP-2, with 70 percent of patients treated after 2004. The median follow-up was 8.3 years. In ICECaP-2, the median survival following metastasis was 3.1 years, which was greater than the 1.9 years in ICECaP-1.

Kendall’s tau for surrogacy condition 1 was 0.92 for MFS with OS at the patient level. At the trial level, R² from weighted linear regression (WLR) of 8-year OS on 5-year MFS was 0.73 (95 percent confidence interval [CI], 0.53‒0.82). R² for condition 2 was 0.83 (95 percent CI, 0.64‒0.89) from WLR of log(hazard ratio [HR])-OS on log(HR)-MFS. The surrogate threshold effect on OS was an HR(MFS) of 0.81.

These findings support “the use of MFS as the primary outcome measure for ongoing adjuvant trials in localized prostate cancer,” the authors said.