Androgen receptor pathway inhibitors and drug-drug interactions in prostate cancer

Abstract

Prostate cancer represents a major global health challenge, necessitating efficacious therapeutic strategies. Androgen receptor pathway inhibitors (ARPIs) have become central to prostate cancer treatment, demonstrating significant effectiveness in both metastatic and non-metastatic contexts. Abiraterone acetate, by inhibiting androgen synthesis, deprives cancer cells androgens necessary for growth, while second-generation androgen receptor (AR) antagonists disrupt AR signaling by blocking AR binding, thereby impeding tumor progression. Given the predominance of prostate cancer in the elderly, who often present with multiple comorbidities requiring complex pharmacological regimens, the potential for drug-drug interactions with ARPIs is a critical concern. These interactions, particularly through pathways like CYP2D6 inhibition by abiraterone and CYP3A4 induction by enzalutamide and apalutamide, necessitate a thorough understanding to optimize therapeutic outcomes and minimize adverse effects. This review aims to delineate the efficacy of ARPIs in prostate cancer management and elucidate their interaction with common medications, highlighting the importance of vigilant drug management to optimize patient care.

Keywords: abiraterone acetate; apalutamide; darolutamide; drug-drug interaction; enzalutamide; prostate cancer.

Figure 1

Mechanism of androgen receptor signaling inhibitors and their effect on cytochrome P450 enzymes. Abiraterone acetate blocks the conversion of steroid precursors to DHEA by inhibiting CYP17A1 in adrenal gland and tumor tissue. Abiraterone also suppresses the activity of 3β-hydroxysteroid dehydrogenase/isomerase, an enzyme necessary for the production of DHT. Enzalutamide, apalutamide, and darolutamide inhibit the competitive binding of androgen to the androgen receptor, AR nuclear translocation, DNA binding and coactivator recruitment. AA, abiraterone acetate; AR, androgen receptor; BCRP, breast cancer resistance protein; CYP, cytochrome P450 (CYP) enzymes; DHEA, dehydroepiandrosterone; DHT, dihydrotestosterone; MRP, multidrug resistance protein; OATP, organic anion-transporting polypeptide; OCTN, organic cation transporters novel; PEPT1, intestinal peptide transporter 1; P-gp, P-glycoprotein.