The incidence of prostate cancer (PCa) has risen rapidly around the world. Androgen deprivation therapy (ADT) is commonly employed in the treatment of advanced PCa. Nevertheless, the advent of castration-resistant prostate cancer (CRPC) following ADT is a major clinical challenge because the recurrent disease would not respond well to alternative therapies (Katzenwadel and Wolf, 2015). In recent years, the CRPC treatment landscape has sensibly revolutionized, with many new hormonal therapies targeting either testosterone production or directly acting upon the androgen receptor (AR), including abiraterone, enzalutamide, apalutamide and darolutamide (Abramenkovs et al., 2022, Cafaro et al., 2020, Wilson et al., 2022, Yanagisawa et al., 2022).

The efficacy of those aforementioned next-generation hormonal agents (NHA) was evaluated in multiple previous studies respectively and the application has been approved by the main regulatory agencies including the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of different phenotypes CRPC (Bastos and Antonarakis, 2019, Berruti et al., 2023, Rathkopf and Scher, 2018). Most CRPC survivors —those who went through NHA treatment and are expected to live beyond the immediate future —are older adults who commonly have cardiovascular (CV) risk factors and/or CV comorbidities, which can make treatment decisions more complicated and further increase CV risks. This indicated that CRPC patients with co-existing CV disease, as well as cardiac risk factors, must be cautious when choosing optimal treatment for CRPC. However, the lack of a head-to-head comparison of drug safety among the four NHAs (abiraterone, enzalutamide, apalutamide, and darolutamide) made it difficult to help the clinical practice precisely. The primary analysis of former studies addressed the need for more information on the safety of NHA to better inform patient-specific treatment decisions. Thus in the present study, we conducted a systematic review and network meta-analysis of clinical studies using these NHAs to evaluate the relative risk of CV disease.