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Published on: March 6, 2018
Exploratory Time-Dependent Patterns in Estimated Treatment Effect of Talazoparib Plus Enzalutamide in HRR
Shugo Yajima1,2, Soichiro Yoshida2, Wei Chen2
1Department of Urology, National Cancer Center Hospital East, Chiba, Japan.
Objectives:
Talazoparib plus enzalutamide improved overall survival (OS) in the biomarker-unselected TALAPRO-2 population, but OS benefit was not statistically significant in the homologous recombination repair (HRR) non-deficient or unknown subgroup, whereas radiographic progression-free survival (rPFS) was prolonged. We explored time-dependent patterns in estimated treatment effects in this subgroup.
Methods:
Approximate individual-level data for 636 patients were reconstructed from published Kaplan-Meier curves; original trial-level patient data were unavailable. The proportional hazards assumption was assessed using Schoenfeld residuals and log-log plots. Interval-specific hazard ratios (HRs) were estimated using piecewise Cox models. A treatment-by-log(time + 1) interaction was evaluated formally. Sensitivity analyses included alternative interval schemes, landmark analyses, restricted mean survival time (RMST), and descriptive application of the same piecewise framework to the HRR-deficient subgroup.
Results:
The proportional hazards assumption was not rejected for OS (p = 0.63) or rPFS (p = 0.37). For OS, the 36-48-month interval showed a nominally lower hazard with talazoparib (HR 0.59; 95% confidence interval [CI] 0.36-0.97; nominal p = 0.039). For rPFS, the lowest HR occurred at 0-6 months (HR 0.56; 95% CI 0.37-0.86; p = 0.008). Treatment-by-log(time + 1) interactions were not statistically significant for OS (p = 0.44) or rPFS (p = 0.12).
Conclusions:
This reconstructed-data post hoc analysis suggested exploratory time-dependent patterns in effect estimates without formal evidence of a time-varying treatment effect. Findings are descriptive, hypothesis-generating, and should not be extrapolated to molecularly confirmed HRR-proficient disease.
Trial Registration:
ClinicalTrials.gov: NCT03395197.
