Research Article: Progression-free survival outcomes of PARP inhibitors in ovarian cancer: an exploratory analysis of treatment heterogeneity based on organ vulnerability
Abstract:
PARP inhibitors are standard maintenance therapies for ovarian cancer (OC), but evidence regarding how baseline physiological vulnerability relates to heterogeneity in comparative treatment effectiveness—beyond molecular biomarkers—remains limited. This study applied a causal inference framework, benchmarked against established molecular associations, to explore whether organ vulnerability is associated with variation in progression-free survival (PFS) between PARP inhibitors.
In this retrospective study of 604 OC patients, we constructed an interpretable 0–3 organ vulnerability score (OVS) using routine pre-treatment laboratory indicators reflecting physiological reserve. A benchmark analysis in 280 patients with complete BRCA status evaluated whether the framework could reproduce established prognostic associations under real-world conditions. G-computation–based counterfactual survival standardization and causal forest analyses were applied to the full cohort to explore OVS-associated treatment heterogeneity, with directional reproducibility assessed in an independent external cohort (n = 58).
The estimated association between BRCA mutation status and PFS was directionally consistent with prior clinical evidence (HR = 0.685, 95% CI: 0.490–0.959; P = 0.028). In the full cohort, a significant treatment-by-OVS interaction was observed (interaction HR = 0.488, 95% CI: 0.293–0.813; P = 0.006). Among patients with low vulnerability (OVS 0–1, n = 479), olaparib was associated with a modest PFS advantage over niraparib (HR = 0.744, P = 0.030). In patients with high vulnerability (OVS 2–3, n = 125), the estimated relative benefit associated with olaparib was more pronounced (HR = 0.363, P < 0.001); however, these estimates are model-dependent and should not be interpreted as definitive comparisons. The directional heterogeneity pattern was qualitatively reproduced in the external cohort. Exploratory heterogeneity analysis further identified individual-level variation in estimated treatment response, including a subset with estimated relative benefit favoring niraparib.
This retrospective exploratory analysis suggests that baseline physiological vulnerability may be associated with heterogeneity in the relative effectiveness of PARP inhibitors. These findings are hypothesis-generating and lay the groundwork for prospective investigation into physiological vulnerability as a correlate of heterogeneous treatment response in real-world oncology populations.
Introduction:
PARP inhibitors are standard maintenance therapies for ovarian cancer (OC), but evidence regarding how baseline physiological vulnerability relates to heterogeneity in comparative treatment effectiveness—beyond molecular biomarkers—remains limited. This study applied a causal inference framework, benchmarked against established molecular associations, to explore whether organ vulnerability is associated with variation in progression-free survival (PFS) between PARP inhibitors.
Read more