Cardiovascular referral improves risk-factor control in prostate cancer, but not clinical events

Routine referral to a cardiologist or internist improved cholesterol control among patients with prostate cancer, although the intervention did not reduce cardiovascular death, myocardial infarction, stroke, or heart failure, according to results from the RADICAL PC-2 trial.¹

The findings, published in JAMA Internal Medicine, suggest that systematic cardiovascular risk-factor management can improve outcomes in patients with prostate cancer, specifically through better cholesterol control rather than a reduced risk of clinical cardiovascular events.¹ A prespecified subgroup analysis published in JACC: CardioOncology further suggested that patients with uncontrolled cholesterol or blood pressure may be more likely to benefit from intensified cardiovascular care.²

“Cardiovascular disease is a common cause of morbidity and mortality in patients with prostate cancer,” said lead author Darryl P. Leong, PhD, in correspondence with Urology Times®. “Cardiovascular risk factors are prevalent and often sub optimally treated in this population, and they may be worsened by androgen deprivation therapy [(ADT)]. This trial demonstrates that cardiologist or internist referral improves risk factor treatment and control, especially cholesterol. This might be most impactful in patients with diabetes or blood pressure >130/80 mm Hg.”

RADICAL PC-2 evaluates systematic cardiovascular care

RADICAL PC-2 (RAndomizeD Intervention for CArdiovascular and Lifestyle Risk Factors in Prostate Cancer Patients) was a pragmatic randomized clinical trial conducted at 55 sites across 8 countries between 2015 and 2025. The study enrolled 2487 patients with prostate cancer who had been diagnosed within the previous 12 months, had initiated ADT within the previous 6 months, or were expected to begin ADT within 1 month.

Patients were randomly assigned 1:1 to usual care alone or usual care plus referral to a cardiologist or internist. The intervention included lifestyle counseling, smoking-cessation advice, a target systolic blood pressure (SBP) of 130 mm Hg or lower, and statin therapy regardless of baseline cholesterol levels.

After a median follow-up of 5.8 years, the hierarchical composite primary outcome favored the intervention, with a win ratio of 1.60 (95% CI, 1.42 to 1.81). However, the difference was driven primarily by cholesterol control (mean difference, 12 mg/dL; 95% CI, 9 to 15 mg/dL) due to greater protocol-mandated statin use. At study close-out, 63% of patients in the intervention group were taking a statin compared with 40% of those receiving usual care (P < .001).

Mean SBP at close-out was 131.1 mm Hg (SD, 16.9) in the intervention group compared with 132.9 mm Hg (SD, 18.3) in the usual-care group.

Notably, there was no significant difference in the time to cardiovascular death, myocardial infarction, stroke, or heart failure. The subdistribution HR for the composite of these clinical events was 1.08 (95% CI, 0.79 to 1.49).

Patients with uncontrolled risk factors may benefit most

A prespecified subgroup analysis of the study sought to determine whether baseline cardiovascular risk could identify patients more likely to benefit from routine specialist referral.

The investigators found evidence of treatment-effect heterogeneity according to baseline total cholesterol. Among patients with total cholesterol greater than 4 mmol/L (approximately 155 mg/dL), the win ratio was 1.75 (95% CI, 1.51 to 2.03), compared with 1.21 (95% CI, 0.89 to 1.64) among those with cholesterol of 4 mmol/L or less (interaction P = .016).

Baseline blood pressure also modified the apparent treatment effect. Among patients with an SBP of at least 130 mm Hg or diastolic blood pressure of at least 80 mm Hg, the subdistribution HR for cardiovascular death, myocardial infarction, stroke, or heart failure was 0.86 (95% CI, 0.61 to 1.21). The corresponding estimate among patients with blood pressure below 130/80 mm Hg was 4.85 (95% CI, 1.65 to 14.26) (interaction P = .003).

The interaction according to diabetes status did not reach statistical significance (P = .054). However, the authors noted that “the intervention effect estimates suggested a potential difference by diabetes status,” with an estimated hazard ratio of 0.53 (95% CI, 0.24 to 1.15) among patients with diabetes and 1.25 (95% CI, 0.88 to 1.78) among those without diabetes.

According to the authors, these findings raise the possibility that patients with poorly controlled modifiable cardiovascular risk factors may be the most appropriate candidates for cardiovascular care referral.

Clinical implications remain focused on risk-factor management

For urologists, the results support continued attention to cardiovascular risk assessment when initiating and managing ADT.

“Patients with elevated total cholesterol benefited more from referral, mainly through better cholesterol control,” noted Cristina Cano Garcia, MD, FEBU, lead author of the subgroup analyses, in correspondence with Urology Times. “However, patients with elevated blood pressure (SBP ≥130 or DBP ≥80 mm Hg), and potentially diabetes, seem to benefit more from referral on hard cardiovascular outcomes.”

Cano Garcia added, “RADICAL PC2 strengthens the rationale for assessing cardiovascular risk factors in prostate cancer care. This assessment can guide cardiovascular specialist referral by risk profile, rather than by default for all patients.”

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