Clinically relevant drug–drug interaction risks in patients with advanced prostate cancer treated with second-generation androgen receptor inhibitors: an interdisciplinary perspective

Expansion of therapeutic options for progressive prostate cancer, particularly the use of second-generation androgen receptor inhibitors (SGARIs) in earlier therapy lines, has led to a significant increase in patient survival. The longer time to progression and, consequently, the higher number of treatment lines involving this pharmacological class in an elderly patient population with high prevalence of comorbidity and polypharmacy creates a substantial risk of adverse drug-drug interactions.

This review examines the pharmacokinetic and pharmacogenetic characteristics of modern SGARIs: apalutamide, enzalutamide, and darolutamide, as well as the mechanisms of their drug-drug interactions at the level of cytochrome P450 isoenzymes and transporter proteins. Particular attention is paid to clinically significant interactions with anticoagulants, antiarrhythmic agents, lipid-lowering drugs, and glucose-lowering medications.

It is demonstrated that therapy with enzalutamide (a strong inducer of CYP3A4, CYP2C9, and CYP2C19) and apalutamide (an inducer of CYP3A4 and CYP2C9) can reduce systemic exposure of a wide range of concomitant medications, including drugs used to treat cardiovascular diseases, diabetes mellitus, and anticoagulants. This may lead to loss of their clinical efficacy and is associated with a high risk of clinically significant drug-drug interactions. Darolutamide, which is neither an inducer nor an inhibitor of key cytochrome P450 isoenzymes, demonstrates minimal potential for pharmacokinetic interactions and is characterized by a more predictable safety profile in patients with polypharmacy.

Assessment of the comorbidity burden and the risk of drug-drug interactions is a critically important element during selection of therapy based on SGARIs. For patients with prostate cancer receiving multiple concomitant medications, especially those with a narrow therapeutic window (anticoagulants, antiarrhythmics, anticonvulsants), darolutamide may be the preferred choice due to its low potential for drug interactions.