Long-Term Outcomes and Genetic Predictors of Response to Metastasis-Directed Therapy Versus Observation in Oligometastatic Prostate Cancer: Analysis of STOMP and ORIOLE Trials

Abstract

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The initial STOMP and ORIOLE trial reports suggested that metastasis-directed therapy (MDT) in oligometastatic castration-sensitive prostate cancer (omCSPC) was associated with improved treatment outcomes. Here, we present long-term outcomes of MDT in omCSPC by pooling STOMP and ORIOLE and assess the ability of a high-risk mutational signature to risk stratify outcomes after MDT. The primary end point was progression-free survival (PFS) calculated using the Kaplan-Meier method. High-risk mutations were defined as pathogenic somatic mutations within ATM, BRCA1/2, Rb1, or TP53. The median follow-up for the whole group was 52.5 months. Median PFS was prolonged with MDT compared with observation (pooled hazard ratio [HR], 0.44; 95% CI, 0.29 to 0.66; P value < .001), with the largest benefit of MDT in patients with a high-risk mutation (HR high-risk, 0.05; HR no high-risk, 0.42; P value for interaction: .12). Within the MDT cohort, the PFS was 13.4 months in those without a high-risk mutation, compared with 7.5 months in those with a high-risk mutation (HR, 0.53; 95% CI, 0.25 to 1.11; P = .09). Long-term outcomes from the only two randomized trials in omCSPC suggest a sustained clinical benefit to MDT over observation. A high-risk mutational signature may help risk stratify treatment outcomes after MDT.

Trial registration: ClinicalTrials.gov NCT01558427 NCT02680587.

FIG 1.

CONSORT diagram demonstrating screening, inclusion, and sequenced sample breakdown. MDT, metastasis-directed therapy; NGS, next-generation sequencing.

FIG 2.

Time-to-event outcomes of MDT versus observation. Time-to-event outcomes demonstrate improvements in PFS with MDT over observation, but no differences in rPFS, time to CRPC, or OS. CRPC, castration-resistant prostate cancer; HR, hazard ratio; MDT, metastasis-directed therapy; NR, not reached; OS, overall survival; PFS, progression-free survival; rPFS, radiographic progression-free survival.

FIG 3.

PFS stratified by treatment arm for those (A) with and (B) without a high-risk mutation stratified by treatment arm. MDT resulted in improvements in PFS in those both with and without a high-risk mutation, however, with a potential differential benefit resulting in relatively larger improvements in PFS in those with a high-risk mutation treated with MDT. (C) PFS and (D) rPFS in those treated with MDT stratified by high-risk mutation status. High-risk mutational status was prognostic for both PFS and rPFS in those treated with MDT, with longer times to events in those without a high-risk mutation. HiRi, high-risk; MDT, metastasis-directed therapy; OS, overall survival; PFS, progression-free survival; rPFS, radiographic progression-free survival.