Therapeutic Innovations in Advanced Prostate Cancer: A Real-World Comparative Effectiveness Evaluation

Abstract

Background: Metastatic prostate cancer is a major source of cancer mortality among US men. Since 2015, the treatment landscape for metastatic hormone-sensitive prostate cancer (mHSPC) has expanded to include four guideline-endorsed doublet regimens combining androgen deprivation therapy (ADT) with docetaxel or one of three androgen receptor pathway inhibitors (ARPIs)—abiraterone, apalutamide, or enzalutamide—yet no head-to-head randomized trial has compared these regimens. In metastatic castration-resistant prostate cancer (mCRPC), lutetium-177 PSMA-617 (Lu-PSMA) and cabazitaxel are both used after progression on docetaxel and an ARPI, but their comparative survival benefit has not been established in US practice. Real-world evidence is needed to inform first-line selection, sequencing, and value assessment.Objective: To estimate the real-world comparative effectiveness and cost-effectiveness of contemporary doublet therapies for mHSPC and the comparative effectiveness of Lu-PSMA versus cabazitaxel for mCRPC in a US population. Methods: Two real-world comparative effectiveness analyses were conducted using the Komodo Health administrative claims database and the target trial emulation framework, and a decision-analytic cost-effectiveness model was built from the Aim 1 outputs. Aim 1 identified 9,141 men with mHSPC who initiated ADT with abiraterone, apalutamide, enzalutamide, or docetaxel. Overlap propensity score weighting with Cox proportional hazards models estimated overall survival (OS) and progression-free survival (PFS), while Fine-Gray competing risk models estimated time to mCRPC progression (TTP), and time to next treatment initiation (TTNT). Aim 2 populated a three-state partitioned survival cost-effectiveness model with the propensity-weighted survival curves from Aim 1 to estimate lifetime costs and quality-adjusted life-years (QALYs) for each regimen from the US healthcare sector perspective, with probabilistic sensitivity analysis. Aim 3 identified men with mCRPC who received Lu-PSMA or cabazitaxel following prior docetaxel and at least one ARPI; average treatment effect in the treated (ATT) propensity score weighting and weighted Cox models estimated OS and PFS. Results: In Aim 1, all three ARPI doublets demonstrated superior PFS versus docetaxel (abiraterone aHR 0.60, 95% CI 0.55–0.66; apalutamide aHR 0.64, 95% CI 0.56–0.73; enzalutamide aHR 0.57, 95% CI 0.51–0.64), with comparable OS across regimens and no significant differences among ARPIs. Time to mCRPC progression and time to next treatment also favored ARPI doublets. In Aim 2, abiraterone yielded 5.37 QALYs at $716,701 and was the most cost-effective option across all evaluated willingness-to-pay thresholds; docetaxel was dominated by abiraterone, apalutamide was dominated by enzalutamide, and the incremental cost-effectiveness ratio for enzalutamide versus abiraterone was $1,214,802 per QALY. In Aim 3, Lu-PSMA was associated with significantly longer OS (aHR 0.87, 95% CI 0.76–0.99) and PFS (aHR 0.41, 95% CI 0.36–0.46) compared with cabazitaxel. Conclusions: ARPI doublets are the preferred first-line treatment for mHSPC, with abiraterone offering superior value driven by generic availability. In post-docetaxel, post-ARPI mCRPC, Lu-PSMA improves both overall and progression-free survival relative to cabazitaxel. These findings provide real-world comparative evidence to inform clinical decision-making, value assessment, and Inflation Reduction Act drug price negotiation.