RADICAL PC-2: Routine Cardiology Referral in Prostate Cancer Corrected Risk Factors but Did Not Reduce Cardiac Events

KEY FINDINGS

• Trial: RADICAL PC-2 is the first large randomized trial of its kind in cardio-uro-oncology. It was conducted at 55 centres in 8 countries between 2015 and 2025; 2,487 patients diagnosed with prostate cancer within the past 12 months who had started ADT in the past 6 months or were due to start ADT within 1 month were randomized 1:1.
• Intervention: Routine referral to a cardiologist/internist in addition to usual care - lifestyle counselling, smoking cessation support, a target systolic blood pressure of ≤130 mmHg and initiation of a statin irrespective of baseline cholesterol level.
• Primary endpoint: The hierarchical composite endpoint favoured the intervention (win ratio 1.60; 95% CI 1.42-1.81) - but this superiority was driven almost entirely by cholesterol control (mean difference 12 mg/dL; 95% CI 9-15).
• No difference in hard clinical endpoints: At a median follow-up of 5.8 years, the subdistribution HR for the composite of cardiovascular death, myocardial infarction, stroke or heart failure was 1.08 (95% CI 0.79-1.49).
• Blood pressure: The difference remained clinically negligible - at close-out, mean SBP was 131.1 mmHg (intervention) versus 132.9 mmHg (usual care). Statin use was 63% versus 40% (p<0.001).
• Subgroup analysis: In those with a baseline total cholesterol >155 mg/dL (>4 mmol/L) the win ratio was 1.75; in those ≤4 mmol/L it was 1.21 (interaction p=0.016). In those with a baseline SBP ≥130 or DBP ≥80 mmHg the HR for hard events was 0.86, while in those with normal blood pressure it was 4.85 (95% CI 1.65-14.26; interaction p=0.003).
• Conclusion: A "refer everyone to cardiology" strategy does not work; a "refer selectively by risk profile" strategy appears meaningful.

Background: What Kills the Patient With Prostate Cancer?

Oncological survival figures in localized and locally advanced prostate cancer have improved markedly over the past two decades. The natural consequence of this improvement is that our patients are lost not to prostate cancer but to other causes. Foremost among those causes is cardiovascular disease.

There is a second layer to the equation: androgen deprivation therapy (ADT) actively worsens the cardiometabolic profile. An increase in body fat mass, a decrease in muscle mass, insulin resistance, dyslipidaemia and endothelial dysfunction are well-defined effects. When hypertension, diabetes and existing atherosclerotic disease - already common in this age group - are added to this picture, the cardiovascular dimension of uro-oncological follow-up becomes impossible to neglect.

The intuitive inference from this was: if we systematically direct every patient starting ADT to a cardiologist, we will reduce cardiovascular events. RADICAL PC-2 tested precisely this hypothesis - and showed that the intuition was not directly confirmed.

Study Design

RADICAL PC-2 (RAndomizeD Intervention for CArdiovascular and Lifestyle risk factors in Prostate Cancer patients) is a pragmatic randomized clinical trial derived from the 5,000-patient prospective RADICAL PC-1 cohort. It was conducted by the Population Health Research Institute (McMaster University / Hamilton Health Sciences); the results were presented at the European Society of Cardiology (ESC) Congress on 30 August 2026 and published simultaneously in JAMA Internal Medicine.

Key Results

Process measures: the intervention worked

As the protocol intended, statin use at trial close-out was 63% in the intervention arm and 40% in the usual care arm (p<0.001). In parallel, a significant reduction of 12 mg/dL (95% CI 9-15) in total cholesterol was achieved. In other words, the intervention genuinely changed the intermediate variable it targeted.

Blood pressure: the target was not reached

At close-out, mean systolic blood pressure was 131.1 mmHg (SD 16.9) in the intervention arm and 132.9 mmHg (SD 18.3) in the usual care arm. This difference of approximately 1.8 mmHg is too small to be expected to affect the incidence of cardiovascular events. This is a point that should not be overlooked when interpreting the trial's neutral result.

Hard endpoints: no difference

The subdistribution hazard ratio for the composite of cardiovascular death, myocardial infarction, stroke or heart failure was 1.08 (95% CI 0.79-1.49). The width of the confidence interval shows that neither a meaningful benefit nor a meaningful harm can be excluded statistically.

Subgroup analysis: the trial's real information is here

The prespecified subgroup analysis published simultaneously in JACC: CardioOncology is clinically more useful than the main publication in clarifying who will benefit from referral.

A finding to be read carefully: The higher cardiovascular event risk in the referral arm among patients with normal baseline blood pressure (sHR 4.85) is striking; however, the confidence interval is extremely wide (1.65-14.26), pointing to the statistical volatility to be expected in subgroup analyses. This finding should not be read as "cardiovascular intervention harms the patient without risk factors". The correct reading is this: in a patient without risk factors, no benefit from this intervention could be demonstrated - a hypothesis-generating, not confirmatory, observation.

Implications for Clinical Practice

1. Cardiovascular assessment when starting ADT is no longer optional

The trial's neutral primary clinical result does not mean that cardiovascular assessment is unnecessary. Quite the opposite: that only 40% of patients in the usual care arm were taking a statin shows how inadequately cardiovascular risk factors are treated in this population. Before starting ADT, a lipid profile, blood pressure, fasting glucose/HbA1c, smoking history and enquiry about existing cardiovascular disease should be standard.

2. The referral decision should be selective

The practical summary of the data is clear: automatically directing every patient receiving ADT to a cardiologist is a practice that consumes system resources without translating into hard endpoints. By contrast, patients with the following profile constitute the group that will benefit most from referral: those with a total cholesterol above approximately 155 mg/dL; those with a systolic blood pressure ≥130 mmHg or diastolic ≥80 mmHg; patients with diabetes (although it did not reach statistical significance, the effect estimate consistently favours benefit); and those with known atherosclerotic cardiovascular disease.

3. The urologist's role does not end with the referral

The trial's most instructive technical detail is that the blood pressure target was not reached. Having been referred does not mean the risk factor has been brought under control. During oncological follow-up the physician who sees the patient regularly is most often the urologist; monitoring whether blood pressure and lipid control are being maintained is a natural part of interdisciplinary care.

4. A statin alone is not a sufficient strategy

A 12 mg/dL fall in cholesterol is real and measurable; but over 5.8 years of follow-up it was not enough to separate the event curves. This is a reminder of the multi-component nature of cardiovascular risk management: blood pressure control, glycaemic control, smoking cessation, weight management and physical activity - all of these components must be addressed simultaneously in a patient under the metabolic burden of ADT.

5. The right framing in communication with the patient

The cardiovascular concerns of patients in whom ADT is to be started are legitimate and are frequently voiced. The message to convey from this trial is: hormone therapy can have effects on heart and vascular health; blood pressure, cholesterol and blood sugar will therefore be monitored closely throughout treatment. This is not a risk requiring the treatment to be abandoned; it is a situation that can be managed together, measured and corrected. Presenting cardiovascular risk management not as an obstacle to oncological treatment but as part of holistic care markedly increases the patient's adherence and trust.

Limitations of the Study

• The cost of the pragmatic design: Statin use reached 40% in the usual care arm too; contamination between arms may have narrowed the difference in effect.
• The failure to reach the blood pressure target limited the strength of the intervention and may partly explain the neutral result.
• Over a conduct period spanning ten years in eight countries, standard cardiovascular and oncological care changed considerably.
• The subgroup findings are hypothesis-generating; they are not confirmatory evidence and must be tested prospectively.
• The population is heterogeneous in terms of duration and type of ADT and co-administration with ARPIs.

Glossary

• ADT: Androgen deprivation therapy - hormone therapy suppressing testosterone in prostate cancer.
• Win ratio: A hierarchical statistical method comparing the components of a composite endpoint in order of importance; a value above 1 favours the intervention.
• sHR (subdistribution hazard ratio): A measure estimating event risk in the presence of competing risks (e.g. death from cancer).
• Pragmatic trial: A randomized trial conducted under real clinical conditions, close to everyday practice.
• ARPI: Androgen receptor pathway inhibitor (abiraterone, enzalutamide, apalutamide, darolutamide).

Conclusion

RADICAL PC-2 is the largest randomized intervention trial conducted to date in the field of cardio-uro-oncology, and it has given the field information that is different from what was expected but more valuable: in prostate cancer patients, routine, undifferentiated cardiology referral corrects risk factor measures but does not reduce cardiovascular events.

This result is not a failure but a calibration. Beneath the neutral primary endpoint lies a clear, clinically applicable message: cardiovascular assessment should be universal, cardiovascular referral should be selective. High cholesterol, high blood pressure, diabetes or known cardiovascular disease - if one of these four indicators is present, interdisciplinary collaboration is justified; if not, no benefit has been demonstrated.

To the extent that we can keep our prostate cancer patients alive longer oncologically, managing the other causes by which we lose them also becomes part of our treatment responsibility. RADICAL PC-2 shows how we can discharge that responsibility more rationally.

References

• Leong DP, Higano C, Cano Garcia C, et al. Specialist Referral for Cardiovascular Risk in Patients With Prostate Cancer: A Randomized Clinical Trial. JAMA Intern Med. 2026;e264773. doi:10.1001/jamainternmed.2026.4773
• Cano Garcia C, Pinthus J, Avezum A, et al. Identifying Patients With Prostate Cancer Who Benefit Most From Routine Cardiovascular Specialist Referral. JACC CardioOncol. 2026;S2666-0873(26)00290-5. doi:10.1016/j.jaccao.2026.08.001
• Clarke H. Cardiovascular referral improves risk-factor control in prostate cancer, but not clinical events. Urology Times. 2 September 2026.
• Population Health Research Institute / McMaster University. Cardiologist referrals improve cholesterol levels in prostate cancer patients, but may not be necessary for all. Press release, EurekAlert!, 30 August 2026.
• Population Health Research Institute. RADICAL PC-1 - Research Studies.
• Rationale and Design of RADICAL PC: A Trial of Cardioprotective Strategies in Prostate Cancer. JU Open Plus. 2026;4(5). doi:10.1097/JU9.0000000000000447