Androgen receptor signaling inhibitors: post-chemotherapy, pre-chemotherapy and now in castration-sensitive prostate cancer

Abstract

Based on pioneering work by Huggins, Hodges and others, hormonal therapies have been established as an effective approach for advanced prostate cancer (PC) for the past 8 decades. However, it quickly became evident that androgen deprivation therapy (ADT) via surgical or medical castration accomplishes inadequate inhibition of the androgen receptor (AR) axis, with clinical resistance inevitably emerging due to adrenal and intratumoral sources of androgens and other mechanisms. Early efforts to augment ADT by adding adrenal-targeting agents (aminoglutethimide, ketoconazole) or AR antagonists (flutamide, bicalutamide, nilutamide, cyproterone) failed to achieve overall survival (OS) benefits, although they did exhibit some evidence of limited clinical activity. More recently, four new Androgen Receptor Signalling Inhibitors (ARSIs) successfully entered clinical practice. Specifically, the CYP17 inhibitor abiraterone acetate and the 2nd generation AR antagonists (enzalutamide, apalutamide and darolutamide) achieved OS benefits for PC patients, confirmed the importance of reactivated AR signaling in castration-resistant PC and validated important concepts that had been proposed in the field several decades ago but had remained so far unproven, including adrenal-targeted therapy and combined androgen blockade. The past decade has seen steady advances towards more comprehensive AR axis targeting. Now the question is raised whether we have accomplished the maximum AR axis inhibition possible or there is still room for improvement. This review, marking the 80-year anniversary of ADT and 10-year anniversary of successful ARSIs, examines their current clinical use and discusses future directions, in particular combination regimens, to maximize their efficacy, delay emergence of resistance and improve patient outcomes.

Celebrating the 80th anniversary of hormone ablation for prostate cancer

“…In 'Androgen receptor signaling inhibitors: postchemotherapy, pre-chemotherapy and now in castrationsensitive prostate cancer', Mitsiades & Kaochar (2021) ask 'Can a more comprehensive approach targeting all sources of androgenic stimulation delay emergence of resistance to ADT?' The development of CRPC was proposed to be caused by the low potency of AR antagonists and most likely prone to 'antagonist-to-agonist' conversion which was noticed in 15-30% CRPC treated patients (Kelly & Scher 1993, Leone et al 2018.…”

From Omics to Multi-Omics Approaches for In-Depth Analysis of the Molecular Mechanisms of Prostate Cancer

“…The driving role of AR signaling in early and late prostate cancer spurred the development and approval of drugs addressing specific steps of this pathway, including gonadotropin-releasing hormone (GnRH) analogues that centrally suppress androgen synthesis, the cytochrome P450 17A1 (CYP17A) inhibitor abiraterone acetate, which locally inhibits androgen synthesis in the testis, prostate and adrenal glands, and competitive antagonists, including enzalutamide, apalutamide and darolutamide, which inhibit AR function [ 15 , 16 , 17 , 18 , 19 ]. Unfortunately, therapy resistance often emerges, ultimately leading to metastatic CRPC (mCRPC) for which treatment with taxanes, poly (ADP-ribose) polymerase (PARP) inhibitors and alpha particle-emitting radiotherapy are used [ 15 , 20 ].…”

Evaluation of Interaction of Some Quinolone Derivatives on RSK-4 Using a Theoretical Model

“…[1] There are several molecular mechanisms involved in the proliferation of cancer; for example, prostate cancer progression is related to androgen receptor activation. [2] It is important to mention that although there are some androgen receptor inhibitor drugs, [3,4] in some cases, resistance to drug therapy (castrate-resistant prostate cancer) [5] has led to the search for new treatments for this clinical pathology. In this way, a benzenesulfonamide derivative (Y08060) was developed as a bromodomaincontaining protein 4 inhibitor for treating prostate cancer.…”