Pharmacologic synergy versus independent action in androgen receptor-axis-targeted agent-docetaxel triplet therapy for metastatic hormone-sensitive prostate cancer: a copula-based analysis

• Triplet therapy benefits in metastatic prostate cancer match independent drug action predictions. • Observed survival outcomes were inferior or equivalent to model-predicted counterfactuals. • Drug-matched analyses reduced discrepancies, supporting independent rather than synergistic effects. • Findings challenge necessity of universal upfront triplet therapy for all eligible patients. • Sequential or selective treatment strategies may preserve efficacy while reducing toxicity. Triplet therapy combining androgen deprivation therapy (ADT), docetaxel, and androgen receptor-axis-targeted agents (ARATs) has exhibited survival benefits in metastatic hormone-sensitive prostate cancer (mHSPC). Whether these benefits originate from pharmacologic synergy or independent drug action (IDA) remains unclear. Using reconstructed individual patient data from phase III trials, we applied a copula-based independent-action model to compare observed triplet outcomes with counterfactual predictions derived from docetaxel- and ARAT-based doublets. The primary analysis used weak positive dependence (θ = 0.24), with sensitivity analyses across a plausible range. The triplet, docetaxel-doublet, and ARAT-doublet cohorts comprised 138/355, 206/355, and 637/1,667 events/patients for rPFS, respectively. The observed triplet outcomes did not exceed independent-action predictions (observed/predicted Hazard ration [HR] 1.39; 95% Confidence Interval [95% CI] 1.12–1.74), with excellent concordance in curve shape ( r = 0.99) and a difference of restricted mean survival time (ΔRMST) of 4.47 months favoring the prediction. Drug-matched analyses using abiraterone further reduced the discrepancy (HR 1.16; 95% CI 0.93–1.44; ΔRMST 2.93 months). Across the full plausible dependence range (θ = 0.08–0.40), findings remained consistent (HR 1.35–1.44). For overall survival, observed/predicted differences were larger (HR 1.87; 95% CI 1.61–2.17; r = 0.97; ΔRMST 7.59 months), but these results were considered exploratory due to substantial confounding from postprogression therapies. These findings did not identify any population-level benefit of triplet therapy that clearly exceeded predictions under an independent-action model, although synergistic effects at the individual-patient level cannot be excluded. These findings support selective or sequential treatment strategies to optimize the benefit-toxicity balance in appropriate patient populations.