Is it safe to use darolutamide (androgen receptor inhibitor) and atorvastatin (HMG-CoA reductase inhibitor) together in patients with prostate cancer and cardiovascular disease?

Darolutamide and Atorvastatin Combination Safety

The combination of darolutamide and atorvastatin can be used together with appropriate dose limitation and monitoring, but atorvastatin should be limited to a maximum of 10 mg daily due to darolutamide's inhibition of drug transporters that significantly increase statin exposure.

Key Drug Interaction Mechanism

• Darolutamide inhibits breast cancer resistance protein (BCRP) and organic anion-transporting polypeptides (OATP), which are critical for the clearance of statins including atorvastatin 1
• This inhibition leads to elevated statin concentrations in the blood, substantially increasing the risk of muscle toxicity and rhabdomyolysis 1
• While the available evidence specifically documents this interaction with rosuvastatin (where a patient on rosuvastatin 40 mg developed rhabdomyolysis when combined with darolutamide), atorvastatin shares similar transporter-mediated clearance pathways 1

Recommended Dosing Strategy

Atorvastatin should be limited to a maximum of 10 mg daily when co-administered with darolutamide, extrapolating from established guidelines for similar transporter-mediated interactions 2

• The American Heart Association recommends that atorvastatin doses >10 mg daily are not recommended when combined with agents that inhibit OATP1B1 and other transporters without close monitoring 2
• This conservative approach is justified given that a patient receiving rosuvastatin 40 mg (five times the recommended maximum of 5 mg with darolutamide) developed confirmed rhabdomyolysis 1

Essential Monitoring Requirements

Monitor creatine phosphokinase (CPK) levels and assess for muscle symptoms at baseline and regularly during treatment:

• Obtain baseline CPK before initiating combination therapy 2
• Monitor for myalgia, muscle weakness, or lower extremity weakness at each clinical encounter 1
• Check CPK levels if any muscle symptoms develop 2, 1
• Advanced age increases the risk of muscle toxicity with this combination 3

Management of Muscle Toxicity

Discontinue both medications immediately if muscle symptoms develop with elevated CPK:

• The documented case of rhabdomyolysis showed clinical improvement and CPK normalization only after rosuvastatin cessation 1
• Do not attempt dose reduction first—complete discontinuation of the statin is recommended when rhabdomyolysis is suspected 3
• Symptoms may include lower extremity weakness, myalgia, and markedly elevated CPK levels 1

Alternative Statin Considerations

While not extensively studied with darolutamide specifically, consider that:

• Pravastatin, fluvastatin, and pitavastatin have less reliance on BCRP and OATP transporters compared to atorvastatin 2
• However, no specific safety data exists for these alternatives with darolutamide, so the same cautious approach with low doses and close monitoring should apply

Critical Clinical Context

• Patients with metastatic hormone-sensitive prostate cancer receiving darolutamide often have cardiovascular comorbidities requiring statin therapy 4, 5
• Darolutamide itself is associated with increased cardiovascular events and hypertension in prostate cancer patients, making cardiovascular risk management essential 4
• The benefit-risk assessment must weigh the cardiovascular protection from statins against the real risk of severe muscle toxicity 4

Common Pitfalls to Avoid

• Do not use standard atorvastatin doses (20-80 mg) with darolutamide—this substantially increases rhabdomyolysis risk 1
• Do not assume the interaction is negligible because darolutamide is a "mild" CYP3A4 inducer—the clinically significant interaction occurs through transporter inhibition, not CYP metabolism 1, 6
• Do not overlook baseline renal function—impaired renal function further increases the risk of statin accumulation and toxicity 1