Eur Urol. 2026 Oct 6:S0302-2838(26)02370-5. doi: 10.1016/j.eururo.2026.09.001. Online ahead of print.
ABSTRACT
BACKGROUND: Major adverse cardiovascular events (MACE) are a leading cause of noncancer death in men with prostate cancer (PCa). Androgen receptor pathway inhibitors (ARPIs) improve oncologic outcomes but may exacerbate cardiovascular risk. The Systematic Coronary Risk Evaluation 2(SCORE2) estimates 10-yr cardiovascular risk, yet its validity in men receiving treatment for PCa is untested.
OBJECTIVE: To evaluate the cardiovascular safety of ARPIs and other treatment intensification strategies within the STAMPEDE trial and assess SCORE2 performance.
DESIGN, SETTING, AND PARTICIPANTS: This post hoc analysis included patients allocated to the abiraterone acetate plus prednisolone (AAP), AAP plus enzalutamide (ENZ), docetaxel (DOC), zoledronic acid (ZA), and radiotherapy (RT) comparisons in STAMPEDE with linked health care records in England.
INTERVENTION: Treatment intensification with AAP, AAP plus ENZ, DOC, ZA, or prostate RT in addition to standard-of-care androgen deprivation therapy (ADT).
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: MACE were identified using prespecified International Classification of Diseases, 10th Revision, and Office of Population Censuses and Surveys Classification of Interventions and Procedures codes. Flexible parametric competing-risk models estimated cumulative incidence and subdistribution hazard ratios (SDHRs). SCORE2 discrimination and calibration were evaluated.
RESULTS AND LIMITATIONS: A total of 6292 men were included. The 5-yr cumulative MACE incidence with ARPI intensification was 9% in nonmetastatic (M0) disease and 7% in metastatic (M1) disease, comparable to ADT alone. ARPI intensification was not associated with a statistically significant increase in MACE risk (AAP: M0 SDHR 1.15 [95% confidence interval {CI} 0.80-1.67], M1 SDHR 1.36 [95% CI 0.87-2.10]; AAP plus ENZ: M0 SDHR 1.34 [95% CI 0.91-1.98], M1 SDHR 1.28 [95% CI 0.85-1.94]). Cardiovascular disease history was the strongest predictor of MACE. Among 5076 patients eligible for SCORE2 assessment, 4239 had complete baseline data. SCORE2 discrimination was modest (10-yr area under the curve 0.63 for M0 disease and 0.61 for M1 disease), and absolute cardiovascular risk was underestimated. Limitations included underrepresentation of patients with severe cardiovascular comorbidity.
CONCLUSIONS: No statistically significant increase in MACE was observed with ARPIs, DOC, ZA, or prostate RT compared with ADT alone. SCORE2 underestimated cardiovascular risk, supporting development of PCa-specific cardiovascular risk models.
PMID:42838799 | DOI:10.1016/j.eururo.2026.09.001