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Meta-Analysis
. 2024 Jul 1;10(7):874-884.
doi: 10.1001/jamaoncol.2024.1549.

Cardiovascular Events and Androgen Receptor Signaling Inhibitors in Advanced Prostate Cancer: A Systematic Review and Meta-Analysis

Omar El-Taji  1   2   3 , Samih Taktak  4 , Craig Jones  1   2   3 , Mick Brown  1 , Noel Clarke  1   2   3 , Ashwin Sachdeva  1   2
Affiliations
Meta-Analysis

Cardiovascular Events and Androgen Receptor Signaling Inhibitors in Advanced Prostate Cancer: A Systematic Review and Meta-Analysis

Omar El-Taji et al. JAMA Oncol. .

Abstract

Importance: Cardiovascular (CV) events remain a substantial cause of mortality among men with advanced and metastatic prostate cancer (PCa). The introduction of novel androgen receptor signaling inhibitors (ARSI) has transformed the treatment landscape of PCa in recent years; however, their associated CV toxic effects remains unclear.

Objective: To assess the incidence of CV events with addition of ARSI to standard of care (SOC) in locally advanced (M0) and metastatic (M1) PCa.

Data sources: Systematic searches of PubMed, Scopus, Web of Science, EMBASE, and ClinicalTrials.gov were performed from inception up to May 2023.

Study selection: Randomized clinical trials of ARSI agents (abiraterone, apalutamide, darolutamide, enzalutamide) that reported CV events among individuals with M0 and M1, hormone-sensitive prostate cancer (HSPC) and castration-resistant prostate cancer (CRPC).

Data extraction and synthesis: A systematic review was performed in accordance with PRISMA guidance. Two authors screened and independently evaluated studies eligible for inclusion. Data extraction and bias assessment was subsequently performed.

Main outcomes and measures: A random-effects meta-analysis was performed to estimate risk ratios for the incidence of all grade and grade 3 or higher CV events (primary outcomes), in addition to hypertension, acute coronary syndrome (ACS), cardiac dysrhythmia, CV death, cerebrovascular event, and venous thromboembolism (secondary outcomes). Sources of heterogeneity were explored using meta-regression.

Results: There were 24 studies (n = 22 166 patients; median age range, 63-77 years; median follow-up time range, 3.9-96 months) eligible for inclusion. ARSI therapy was associated with increased risk of all grade CV event (risk ratio [RR], 1.75; 95% CI, 1.50-2.04; P < .001) and grade 3 or higher CV events (RR, 2.10; 95%, 1.72-2.55; P < .001). ARSI therapy also was associated with increased risk for grade 3 or higher events for hypertension (RR, 2.25; 95% CI, 1.74-2.90; P < .001), ACS (RR, 1.93; 95% CI, 1.43-1.60; P < .01), cardiac dysrhythmia (RR, 1.64; 95% CI, 1.23-2.17; P < .001), cerebrovascular events (RR, 1.86; 95% CI, 1.34-2.59; P < .001) and for CV-related death (RR, 2.02; 95% CI, 1.32-3.10; P = .001). Subgroup analysis demonstrated increased risk of all CV events across the disease spectrum (M0 HSPC: RR, 2.26; 95% CI, 1.36-3.75; P = .002; M1 HSPC: RR, 1.85; 95% CI, 1.47-2.31; P < .001; M0 CRPC: RR, 1.79; 95% CI, 1.13-2.81; P = .01; M1 CRPC: RR, 1.46; 95% CI, 1.16-1.83; P = .001).

Conclusions and relevance: This systematic review and meta-analysis found that the addition of ARSIs to traditional ADT was associated with increased risk of CV events across the prostate cancer disease spectrum. These results suggest that patients with prostate cancer should be advised about and monitored for the potential of increased risk of CV events with initiation of ARSI therapy alongside conventional hormonal therapy.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr El-Taji reported personal fees from Bayer outside the submitted work. Dr Jones reported personal fees from Janssen and Bayer outside the submitted work. Dr Clarke has received institutional consultancy or advisory fees from Astellas Pharma, Bayer, Ferring, Janssen-Cilag, and Sanofi; honoraria from Astellas Pharma, Bayer, Janssen-Cilag, and Sanofi; speaker bureau fees from Astellas Pharma, AstraZeneca, and Janssen-Cilag; and travel and accommodation expenses from Astellas Pharma, AstraZeneca, Bayer, Ferring, Ipsen, Janssen-Cilag, and Sanofi. Dr Sachdeva reported nonfinancial support from AIRAMatrix (travel costs) outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. PRISMA Flow Diagram
ARSI indicates androgen receptor signaling inhibitors. aFour trials from the STAMPEDE trial platform were reported across 2 reports.
Figure 2.
Figure 2.. Meta-Analysis of Relative Risk for All Grade Cardiovascular Events Associated With Commencement of Androgen Receptor Signaling Inhibitors (ARSI) Therapy
AG indicates groups A and G from the STAMPEDE trial; AJ, groups A and J from the STAMPEDE trial; CRPC, castration-resistant prostate cancer; HSPC, hormone-sensitive prostate cancer; M0, locally advanced; M1, metastatic; RR, risk ratio.
Figure 3.
Figure 3.. Meta-Analysis of Relative Risk for Grade 3 or Higher Cardiovascular Events Associated With Commencement of Androgen Receptor Signaling Inhibitors (ARSI) Therapy
AG indicates groups A and G from the STAMPEDE trial; AJ, groups A and J from the STAMPEDE trial; CRPC, castration-resistant prostate cancer; HSPC, hormone-sensitive prostate cancer; M0, locally advanced; M1, metastatic; RR, risk ratio.
Figure 4.
Figure 4.. Meta-Analysis of Relative Risk for Secondary Outcomes Associated With Commencement of Androgen Receptor Signaling Inhibitors (ARSI) Therapy
CRPC indicates castration-resistant prostate cancer; HSPC, hormone-sensitive prostate cancer; M0, locally advanced; M1, metastatic; RR, risk ratio.
See this image and copyright information in PMC

Comment in

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