Rosuvastatin and Darolutamide Interaction
Yes, there is a clinically significant drug-drug interaction between rosuvastatin and darolutamide that requires dose adjustment or alternative statin selection. Darolutamide increases rosuvastatin exposure approximately 5-fold through inhibition of BCRP, OATP1B1, and OATP1B3 transporters, substantially elevating the risk of statin-associated muscle toxicity including rhabdomyolysis 1, 2.
Mechanism of Interaction
Darolutamide inhibits multiple drug transporters that are critical for rosuvastatin clearance, specifically breast cancer resistance protein (BCRP), organic anion-transporting polypeptide 1B1 (OATP1B1), and OATP1B3 1, 2.
Rosuvastatin relies heavily on these transporters for hepatic uptake and active efflux, making it particularly vulnerable to this interaction compared to other statins 3, 4.
Phase I clinical studies demonstrated that concomitant darolutamide increased rosuvastatin AUC and Cmax by approximately 5-fold 1, 2.
Clinical Evidence of Harm
A case report documented rhabdomyolysis in a patient receiving rosuvastatin 40 mg daily with darolutamide, presenting with lower extremity weakness, myalgia, and marked creatine phosphokinase elevation during week 11 of treatment 3.
The patient was receiving five times the maximum recommended dose when accounting for the interaction, as the recommended limit is 5 mg rosuvastatin daily during concomitant darolutamide use 3.
Clinical symptoms and CPK elevation resolved following rosuvastatin discontinuation, confirming the causal relationship 3.
Management Recommendations
If rosuvastatin must be continued with darolutamide:
Limit rosuvastatin dose to a maximum of 5 mg daily to account for the 5-fold increase in exposure 3.
Monitor closely for muscle-related symptoms including myalgia, weakness, and dark urine, particularly in the first 3 months of combination therapy 3.
Check baseline and periodic creatine phosphokinase (CPK) levels, especially if symptoms develop 3.
Preferred alternative approach:
Switch to a statin with lower interaction potential such as atorvastatin, pravastatin, fluvastatin, or pitavastatin, which are not significantly affected by BCRP/OATP inhibition 5.
Rosuvastatin, pravastatin, fluvastatin, and pitavastatin do not require dose adjustment with other cardiovascular drugs that don't affect these specific transporters 5.
Important Clinical Context
The ARAMIS trial data showed no increased adverse events in statin users versus non-users overall, but this analysis did not specifically examine rosuvastatin or account for dose adjustments that may have been made 6.
Most ARAMIS participants (98.4%) had comorbidities and were taking multiple medications, with lipid-modifying agents used in 34.5% of patients 6.
The interaction risk is specific to BCRP/OATP substrates - darolutamide showed no clinically relevant effects on CYP3A4 substrates (midazolam) or P-gp substrates (dabigatran) 1, 2.
Common Pitfalls to Avoid
Do not assume all statins interact similarly with darolutamide - the interaction is specific to rosuvastatin due to its unique dependence on BCRP/OATP transporters for clearance 3, 2.
Do not continue high-dose rosuvastatin (>5 mg) with darolutamide without dose reduction, as this substantially increases rhabdomyolysis risk 3.
Recognize that older male patients with multiple medications (the typical nmCRPC population) are at particularly high risk for statin-related muscle toxicity 5.
Monitor blood pressure closely as darolutamide itself increases hypertension risk (13.7% vs 9.2% with placebo), which may complicate cardiovascular management in patients requiring statins 7.