Statins augment survival in prostate cancer patients on an ARPI

Among prostate cancer patients receiving treatment with the androgen receptor pathway inhibitor (ARPI) apalutamide, those who also use statins appear to have longer overall survival (OS), according to a study.

Analysis of data from the phase III TITAN and SPARTAN trials showed that statin exposure was associated with better OS among patients treated with apalutamide (TITAN: hazard ratio [HR], 0.53, 95 percent confidence interval [CI], 0.32–0.87; SPARTAN: HR, 0.54, 95 percent CI, 0.39–0.74) but not among those who received placebo (TITAN: HR, 0.65, 95 percent CI, 0.38–1.13; SPARTAN: HR, 1.16, 95 percent CI, 0.76–1.77). [JAMA Netw Open 2025;8:e2527988]

The 3-year OS rates for statin-exposed vs unexposed patients were 81 percent vs 67 percent in the apalutamide arm of the TITAN trial (difference, 14 percent, 95 percent CI, 5–22) and 86 percent vs 78 percent in the apalutamide arm of the SPARTAN trial (difference, 8 percent, 95 percent CI, 3–13).

However, statin-exposed patients had a more than twofold greater risk of grade 3 or higher cardiac adverse events (AEs) than unexposed patients in both the apalutamide (5.8 percent vs 2.1 percent; subdistribution HR, 2.62, 95 percent CI, 1.35–5.08) and placebo (4.5 percent vs 1.2 percent; subdistribution HR, 2.36, 95 percent CI, 0.96–5.84) arms. This finding was consistent in both trials.

The increased risk of grade 3 or greater cardiac AEs seen among statin-exposed patients could reflect a spurious association or reverse causality due to residual confounding, the investigators noted. These patients may already have a higher pre-existing burden of cardiac or noncardiac comorbidity, although the study data did not capture this underlying risk with sufficient detail, they added.

“Furthermore, use of statins in these patients might reflect a measure to mitigate cardiac AEs (ie, an indication bias) and minimize noncancer-related deaths among patients treated with intensified hormonal therapy using ARPIs like apalutamide,” the investigators said. [JACC CardioOncol 2024;6:835-846; J Urol 2020;203:1109-1116]

They discussed the science behind the observed survival benefit from using statins in patients with relatively earlier stages of advanced prostate who were taking apalutamide, citing lipid-lowering and nonlipid-lowering mechanisms. [Prostate Cancer Prostatic Dis 2022;25:641-649; Medicine (Baltimore) 2015;94:e1644]

“The cholesterol-mediated mechanisms are postulated to involve cell signalling processes related to androgen receptors (ARs) and epidermal growth factor receptors, while noncholesterol-mediated mechanisms are related to the downregulating effect of statins on cell proliferation and adhesion, angiogenesis, and inflammation and selective upregulation of apoptosis in tumour cells,” the investigators said. [Curr Urol Rep 2008;9:189-196; Nat Rev Cancer 2005;5:930-942]

They also highlighted a possible interaction between metformin and statins in metastatic hormone sensitive prostate cancer, with the two drugs often simultaneously used in patients with metabolic syndromes. [Cardiovasc Diabetol 2018;17:1-22]

The analysis included 2,187 patients, of which 1,288 received apalutamide (517 in TITAN, 770 in SPARTAN) and 900 received placebo. The median age was 65 years in TITAN and 70 years in SPARTAN. About a third of the overall population (34.2 percent) were exposed to statins. The statin-exposed group was older and had a higher BMI compared with the unexposed group.

“Given the post hoc exploratory nature of the study, the findings are at best hypothesis generating and need further validation in additional studies,” the investigators said.