Review of Second-Generation Androgen Receptor Inhibitor Therapies and Their Role in Prostate Cancer Management

Seyed Behzad Jazayeri; Abhishek Srivastava; Neal Shore

Disclosures

Curr Opin Urol. 2022;32(3):283-291. 

In This Article

Abstract and Introduction

Abstract

Purpose of Review: We review the published literature on the indications of second-generation androgen receptor inhibitors, Poly(ADP-Ribose) Polymerase (PARP) inhibitors, combination therapies, and their evolution throughout the advanced prostate cancer continuum.

Recent Findings: Enzalutamide trials have published data supporting its use in metastatic hormone-sensitive prostate cancer (mHSPC), nonmetastatic castration-resistant prostate cancer (nmCRPC), and metastatic castration-resistant prostate cancer (mCRPC). Apalutamide trials have supported its indication for mHSPC and nmCRPC. Darolutamide trials currently support its use for nmCRPC. Abiraterone trials have supported its use in mCRPC and mHSPC. Olaparib and rucaparib have shown clinical benefit in heavily pretreated patients with mCRPC and DNA repair mutation genes.

Summary: Phase 3 trials and peer-reviewed literature demonstrate that enzalutamide, apalutamide, and darolutamide prolong overall survival (OS) in men with nmCRPC. Abiraterone, enzalutamide, and apalutamide improve OS in men with mHSPC. Abiraterone and enzalutamide have data supporting improvement in OS in men with mCRPC

Introduction

In 2021, it was estimated that 248 530 United States men would be diagnosed with prostate cancer, and 34 130 men would die from the disease.[1] The treatment paradigm in advanced prostate cancer is evolving, and the Food and Drug Administration (FDA) has approved multiple treatment options for patients with advanced prostate cancer, including hormonal therapies, targeted therapies, immunotherapy, chemotherapy, radiopharmaceuticals, Poly (ADP-Ribose) Polymerase (PARP) inhibitors, and bone-modifying drugs. The evolving optimization of treatment has been to judiciously sequence and/or combine therapeutics with novel mechanisms of action while assuredly targeting the androgen receptor, and thus affecting prostate cancer cell proliferation.

Androgen receptor inhibitors have been investigated, refined, and innovated for prostate cancer treatment since the 1960 s.[2,3] The first generation, or 'vintage,' androgen receptor inhibitors include bicalutamide, flutamide, and nilutamide, and had limited efficacy because of their less potent competitive androgen receptor inhibition, explaining their potential to perform as agonists over time, explaining PSA decline upon drug withdrawal.[3] This lack of potency led to the development of second-generation androgen receptor inhibitors and androgen synthesis inhibitors.

Historically, the mainstay treatment of mPC has been androgen deprivation therapy (ADT) through either medical or surgical castration. Unfortunately, almost all patients progress to a castration resistance biology with disease progression over time. Although castration-resistant prostate cancer (CRPC) cells may proliferate without androgen stimulation, the androgen receptor signaling pathway is invariably essential and active in these cells.[4] Multiple mechanisms, including mutations in the androgen receptor gene mutation or amplification, overexpression of androgen receptor co-regulatory molecules, and splice variants, are believed to play a role in the castration resistance state.[5] Second-generation androgen receptor inhibitors competitively inhibit the androgen receptor itself, and thus prevent translocation of the androgen receptor complex inside the nucleus and prevent gene modification and the downstream impact of the androgen receptor complex.[2] Multiple clinical trials are in progress, which will evaluate the role of androgen receptor inhibitors in different clinical settings, in combination with other therapeutics, and in adjuvant or neoadjuvant settings. A list of selected ongoing clinical trials is presented in Table 1. For the purpose of this review, we will focus on the FDA-approved second-generation androgen receptor inhibitors: enzalutamide, apalutamide, darolutamide, and the androgen synthesis inhibitor: abiraterone acetate, and PARP inhibitors Olaparib and rucaparib.

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