Targeting the androgen receptor signaling pathway in advanced prostate cancer

Abstract

Disclaimer In an effort to expedite the publication of articles related to the COVID-19 pandemic, AJHP is posting these manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. Purpose This article summarizes current androgen receptor (AR)–directed therapies that have received regulatory approval for the treatment of advanced prostate adenocarcinoma (herein referred to as prostate cancer, PC). Summary PC is an androgen-dependent malignancy in which ligands including testosterone and dihydrotestosterone bind to AR, initiating androgen-AR complex translocation to the nucleus followed by AR-mediated transcription of target genes. Androgen deprivation therapy (ADT), including gonadotropin hormone–releasing hormone (GnRH) agonists with or without AR antagonists (antiandrogens), GnRH antagonists, or bilateral orchiectomy, forms the backbone of treatment for patients with metastatic castration-naive PC and/or castration-resistant PC (CRPC). ADT is also an option for high-risk, early-stage PC after prostatectomy and/or radiation. While ADT is often very effective as initial therapy, resistance ultimately develops despite suppression of gonadal and/or adrenal androgens, leading to CRCPC, which is characterized by mechanisms such as reactivation of the AR signaling pathway, AR overexpression, and gene mutations in the ligand-binding domain of AR that lead to disease progression, resulting in increased symptom burden and ultimately death. However, disease in patients with CRPC is still dependent on androgen signaling, and these patients continue on ADT to maintain a castrate level of serum testosterone. Novel hormonal therapies including agents that target AR directly (eg, AR antagonists) are often added to ADT in this setting. Targeting the AR signaling pathway led to the development of second-generation AR antagonists, examples of which include enzalutamide, apalutamide, and darolutamide. These agents do not exhibit partial agonism or possess a higher affinity for AR and are not postulated to improve survival outcomes relative to their first-generation counterparts for patients with CRPC. Lastly, the emergence of ADT, including second-generation AR antagonists, has led to the development of supportive care for treatment-related adverse effects. Conclusion Major advances have been made in targeting the AR signaling pathway in patients with advanced PC. Further studies are warranted to identify the optimal sequencing of therapies to maximize treatment benefit. Mitigation of treatment-related adverse effects presents new opportunities to advance clinical pharmacy practice.

Prostate cancer research: tools, cell types, and molecular targets

“…In later stages, prostate cancer can no longer be adequately managed, and effective treatment is limited. Patients with disseminated disease as indicated by rising PSA can be treated by targeting AR ( 67 ). However, many would fail, and the cancer becomes resistant to anti-androgen therapies.…”

Molecular Anatomy of Prostate Cancer and Its Implications in Active Surveillance and Early Intervention Strategies

“…In the luminal layer, the AR pathway maintains differentiation and secretion functions and blocks the cell cycle [151]. Ligand binding induces conformational changes that liberate the AR from heat shock proteins and expose its ligand-binding domain, which contains a nuclear localization signal [152,153]. The ligand-bound AR subsequently forms dimers and undergoes phosphorylation, which are translocated to the nucleus.…”

Ligand‐gated ion channels as potential biomarkers for ADT‐mediated cognitive decline in prostate cancer patients

“…ADT delays disease progression and improves the efficacy of standard-of-care treatments, including chemotherapy and external beam radiation therapy. 1,2 The use of first-generation antiandrogens such as bicalutamide and nilutamide for total androgen blockade 3 and second-generation oral antiandrogens namely, abiraterone acetate and enzalutamide has exhibited survival advantages in prostate cancer patients. [4][5][6] Despite proven efficacy, ADT treatment results in notable side effects, including hot flashes, sexual dysfunction, osteoporosis, cardiovascular disease, insulin resistance, muscle atrophy, and obesity, negatively impacting quality of life.…”

“…Androgen deprivation therapy (ADT) is the most common treatment for loco‐regional and advanced‐stage prostate cancer. ADT delays disease progression and improves the efficacy of standard‐of‐care treatments, including chemotherapy and external beam radiation therapy 1,2 . The use of first‐generation antiandrogens such as bicalutamide and nilutamide for total androgen blockade 3 and second‐generation oral antiandrogens namely, abiraterone acetate and enzalutamide has exhibited survival advantages in prostate cancer patients 4–6 .…”