Practical implications of androgen receptor inhibitors for prostate cancer treatment

Abstract

Antiandrogens have been used for the treatment of prostate cancer as a single agent or in combination with hormone deprivation therapy. New generation antiandrogens act like androgen receptor inhibitors (ARIs). Their binding complex blocks the pathways of cellular proliferation and differentiation of the prostate. Enzalutamide, apalutamide and darolutamide are the new ARIs that demonstrated acceptable tolerability and toxicity, both active in hormone-sensitive and castration-resistant prostate cancer (CRPC). There is no evidence of superiority of one drug over the other, therefore the therapeutic choice depends on the safety profile in relation to the individual patient, their comorbidities and clinical condition. ARIs have also shown promising results in association with new drugs that are active on patients with metastatic CRPC carrying the mutated breast cancer gene (BRCA). Before undergoing new antiandrogenic therapies, patients should be evaluated for cardiological and metabolic risk and possible drug interactions.

Keywords: Androgen receptor inhibitors; androgen deprivation therapy; antiandrogens; apalutamide; darolutamide; enzalutamide; prostate cancer.

Figure 1

Formalin-fixed, paraffin-embedded human prostate carcinoma stained with AR monoclonal antibody (image source: AR441 + DHTR/882, NeoBiotechnologies Inc. Union City, CA, USA). AR: androgen receptor

Figure 2

Multi-step inhibitory activity of ARIs against T at the AR level, intra-cytoplasmic AR translocation, and DNA-AR complex binding. AR: androgen receptor; ARI: AR inhibitor; T: testosterone; C: coactivator Note. Adapted from “Enzalutamide for the treatment of metastatic castration-resistant prostate cancer,” by Rodriguez-Vida A, Galazi M, Rudman S, Chowdhury S, Sternberg CN. Drug Des Devel Ther. 2015;9:3325–39 (https://doi.org/10.2147/DDDT.S69433). CC BY-NC.