Key result
ARPI intensification does not increase MACE risk compared to ADT alone in prostate cancer.
Why the study?
Major adverse cardiovascular events are a leading cause of noncancer death in men with prostate cancer, and the cardiovascular safety of androgen receptor pathway inhibitors and other treatment intensification strategies is uncertain.
Does treatment intensification with ARPIs, docetaxel, zoledronic acid, or radiotherapy increase major adverse cardiovascular events in men with high-risk localized or metastatic prostate cancer on androgen deprivation therapy?
RCT (n=6,292)
Yes
Does treatment intensification with ARPIs, docetaxel, zoledronic acid, or radiotherapy increase major adverse cardiovascular events in men with high-risk localized or metastatic prostate cancer on androgen deprivation therapy?
Hazard Ratio: 1.15 (95% CI 0.8–1.67)
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“General population risk scores that we've been recommended to use are not ideally predicting who is at an increased risk for developing a major adverse cardiovascular event. Until we have better risk scores, we need to be extremely proactive as clinicians and oncologists at getting our patients on risk-lowering therapies, including statins and appropriate blood pressure monitoring and management, and get them plugged into primary care providers and cardiologists, because we know those do lower the risk of cardiovascular events.”
“Treatment intensification with docetaxel, abiraterone acetate + prednisone +/- enzalutamide, or prostate radiotherapy did not significantly increase the rate of MACEs. The addition of an ARPI to ADT did not modify the MACE risk across subgroups. A trend towards higher MACE events was observed with ARPI intensification (ADT + enzalutamide).”
“We've known for some time that androgen deprivation therapy has consequences, metabolic consequences for patients, and that's associated with increased cardiovascular risk. And we know that it has effects on musculoskeletal integrity. For example, this has led us to study this in much more detail at population level, and we've been lucky enough to have the STAMPEDE trial, and we have a large coordinated translational science program which enables us to analyze the data from the trial.”
Treatment intensification for high-risk prostate cancer does not significantly increase MACE risk compared to ADT alone, but standard SCORE2 models underestimate cardiovascular risk in this population.
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.
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El‐Taji et al. (2026) conducted an RCT in High-risk localized or metastatic prostate cancer (n=6,292). Androgen receptor pathway inhibitors (ARPIs) and other treatment intensifications vs. Standard-of-care androgen deprivation therapy (ADT) alone was evaluated on Major adverse cardiovascular events (MACE) (SDHR 1.15, 95% CI 0.80-1.67). ARPI intensification did not significantly increase MACE risk compared to ADT alone in nonmetastatic (SDHR 1.15; 95% CI 0.80-1.67) or metastatic (SDHR 1.36; 95% CI 0.87-2.10) prostate cancer.
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