Understanding randomized controlled trial generalizability through an embedded molecular diagnostics trial.

Abstract

Purpose: Issues with randomized controlled trial (RCT) generalizability are well described, but whether these result from differences in patient management across contexts remains unknown. We studied management of patients with high-risk prostate cancer after radical prostatectomy (RP) inside and outside of an RCT evaluating the impact of a genomic classifier (GC) on post-RP treatment decision-making (Genomics in Michigan Impacting Observation of Radiation [G-MINOR]; NCT02783950).

Materials and methods: 338 patients enrolled in G-MINOR, and propensity score matched eligible but non-enrolled patient cohorts (pre-trial and trial contemporary) from the Michigan Urological Surgery Improvement Collaborative (MUSIC), in which the trial was embedded, were compared for rates and time to secondary treatment (adjuvant or salvage therapy) after prostatectomy.

Results: Among 338 patients in the G-MINOR cohort, 69 (31 adjuvant, 38 salvage) received secondary treatment, compared with 266 (183 adjuvant, 83 salvage) and 104 (60 adjuvant, 44 salvage) in the 1,014 contemporary and 338 pre-trial matched MUSIC cohorts. Time to secondary treatment was significantly shorter in the MUSIC cohort across all comparisons. For example, matching G-MINOR to synchronous MUSIC patients demonstrated 84% vs 74% estimated 2-year treatment-free survival for trial and "real world" patients, respectively (p < 0.001).

Conclusions and relevance: Controlling for key clinicopathologic factors, patients in the G-MINOR RCT and MUSIC cohorts were managed differently, even after stratifying by genomic risk. These findings suggest challenges in RCT generalizability extend beyond the representativeness of trial participants. Differences in management may also explain why divergent patient outcomes are observed in RCTs vs real-world settings.