A study using individual patient data from the SPARTAN and TITAN randomized clinical trials has found that statin exposure was associated with superior overall survival (OS) among all patients with advanced prostate cancer (PC) who were treated with apalutamide.
Cardiovascular AND prostate cancer benefits?
Statins play a pivotal role in cardiovascular risk prevention. [Cochrane Database Syst Rev 2013;doi:10.1001/jama.2013.281348] Beyond this major health benefit, a growing body of evidence suggests a possible role of statins in PC prevention or forestalling PC progression. [Prostate Cancer Prostatic Dis 2022;25:641-649] Statin use has been shown to be associated with lower PC-specific mortality among men undergoing androgen deprivation therapy, and pooled analyses of enzalutamide trials found that concurrent statin use was associated with improved OS in enzalutamide-treated patients with metastatic castration-resistant PC (mCRPC). [Eur Urol Focus 2017;3:212-220; Eur J Cancer 2022;170:285-295] Similarly, another pooled analysis reported longer OS among statin-exposed patients with mCRPC treated with abiraterone. [Eur J Cancer 2022;170:296-304]
“The effect of statins on patients treated with apalutamide, especially in earlier stages of advanced PC, such as metastatic hormone-sensitive PC [mHSPC] or nonmetastatic castration-resistant PC [nmCRPC] remains to be elucidated,” wrote the researchers. “In this study, we performed an individual patient data–based analysis of the SPARTAN and TITAN trials to determine the associations of statin exposure with OS and grade ≥3 cardiac adverse events [AEs] in patients with advanced PC treated with apalutamide.” [JAMA Netw Open 2025;8:e2527988]
SPARTAN and TITAN: Longer OS with statins in nmCRPC and mHSPC
The present study used individual data from 2,187 patients involved in the randomized, multicentre, phase III SPARTAN (n=1,148; median age, 70 years) and TITAN (n=1,039; median age, 65 years) trials investigating use of apalutamide in nmCRPC and mHSPC, respectively. Statin exposure was recorded in 44.1 and 23.3 percent of patients in the SPARTAN and TITAN trials, respectively. Compared with unexposed patients, patients with statin exposure were older and had higher body–mass index. A greater proportion of patients had history of diabetes, dyslipidaemia, hypertension, and vascular disorders in the statin-exposed group vs the unexposed group.
In the overall study cohort, statin exposure was associated with significantly improved OS (hazard ratio [HR], 0.67; 95 percent confidence interval [CI], 0.48–0.86). In patients who were treated with apalutamide, statin exposure was associated with a 42 percent reduction in the hazard of death (HR, 0.58; 95 percent CI, 0.42–0.92), while in the placebo group, statin exposure was associated with a 17 percent reduction in the hazard of death (HR, 0.83; 95 percent CI, 0.32–1.02).
“The study-level random variance was very low, suggesting lack of substantial interstudy heterogeneity,” noted the researchers. “In multivariable Cox proportional hazard regression model analysis in landmark populations, the findings were consistent with the primary analysis, with longer OS among statin-exposed subgroups treated with apalutamide in both SPARTAN and TITAN trials.”
…But more cardiac AEs – Why?
Among patients with statin exposure, grade ≥3 cardiac AEs were reported in 5.8 percent of patients in the apalutamide cohort and 4.5 percent of patients in the placebo cohort. In contrast, among patients without statin exposure, only 2.1 percent in the apalutamide and 1.2 percent in the placebo group had grade ≥3 cardiac AEs.
“Patients receiving statins had a higher risk of grade ≥3 cardiac AEs in both the apalutamide [subdistribution HR, 2.62; 95 percent CI, 1.35–5.08] and placebo [subdistribution HR, 2.36 [95 percent CI, 0.96–5.84] groups, which could reflect a spurious association or reverse causality due to residual confounding from higher preexisting burden of cardiac or noncardiac comorbidity, which was not captured with sufficient granularity in the data,” suggested the researchers.
Conclusion
The researchers emphasised that the findings were hypothesis-generating and required further validation in additional studies due to some limitations. Among them were inadequate power to detect between-group differences, higher risk of false discovery rates despite adjusting for multiple analyses, lack of information on serial serum cholesterol levels, residual unmeasured confounding, and residual selection bias. In addition, the possibility of patients being exposed to more than one class of concomitant medication was not explored in the analysis. “[Furthermore,] statin exposure may reflect health-seeking behaviours that may have independent survival benefits, including PC-specific outcomes, as such behaviours could also indicate better adherence to PC treatment leading to improved cancer-specific outcomes,” they added.
“In this cohort study, statin exposure was associated with longer OS in patients treated with apalutamide. Statin-exposed patients had a higher risk of grade ≥3 cardiac AEs, which may reflect their preexisting cardiovascular comorbidity,” summarized the researchers. “Overall, our findings should be interpreted with caution.”