SUMMARY

• Apalutamide is an androgen receptor (AR) inhibitor that binds directly to the ligand - binding domain of the AR. Apalutamide inhibits AR nuclear translocation, inhibits DNA binding, and impedes AR-mediated transcription.^1-3 A major metabolite, N-desmethyl apalutamide, is a less potent inhibitor of AR, and exhibited one-third the activity of apalutamide in an in vitro transcriptional reporter assay.⁴ Apalutamide administration caused decreased tumor cell proliferation and increased apoptosis leading to decreased tumor volume in mouse xenograft models of prostate cancer.^2,3

BACKGROUND

Role of Androgen in Castration-Sensitive Prostate Cancer and Castration-Resistant Prostate Cancer

Prostate cancer is an androgen-driven disease.⁵ Androgens bind to androgen receptors, which activate the androgen receptor signaling pathway and causes prostate cancer tumor growth.^6,7

Androgen-sensitive cancer, including metastatic castrationsensitive prostate cancer (mCSPC), responds to treatment that decreases androgen levels.^8,9 Androgen deprivation therapies (ADTs), such as treatment with gonadotropin-releasing hormone agonists/antagonists or bilateral orchiectomy, decrease androgen production in the testes, but do not affect androgen production by the adrenals or in the tumor tissue itself. Some patients will inevitably develop resistance to ADT and progress to castration-resistant prostate cancer (CRPC).^7,10

Castration resistance can develop through several different molecular events, which can include oncogene activation, tumor suppressor gene inactivation, apoptosis evasion, intratumoral androgen production, and aberrant AR activation.^11,12 ARs in tumor cells exposed to ADT undergo selective alterations that result in aberrant AR reactivation, which results in the AR pathway remaining active despite decreased amounts of androgenic ligands.¹¹ These alterations include the following: AR amplification and subsequent AR protein over-expression, increasing the likelihood of AR binding proximity with scarce androgens; AR phosphorylation that may sensitize AR to lower concentrations of androgens; promiscuous binding, where mutations in AR can increase sensitivity or decrease specificity of ligand binding, allowing activation with binding of other steroid hormones and AR antagonists; and AR splice variants, which can produce truncated AR proteins that are constitutively active independent of ligand stimulation. ¹¹

These mechanisms allow cancer cells to evade apoptosis, promoting tumor cell growth and ultimately resulting in progression to CRPC.¹¹

CLINICAL pharmacology

Mechanism of Action

Apalutamide is an orally administered AR inhibitor that binds directly to the ligand-binding domain of the AR. Apalutamide inhibits AR nuclear translocation, inhibits DNA binding, and impedes AR-mediated transcription.^1-3 A major metabolite, N-desmethyl apalutamide, is a less potent inhibitor of AR, and exhibited one-third the activity of apalutamide in an in vitro transcriptional reporter assay.⁴ Apalutamide administration caused decreased tumor cell proliferation and increased apoptosis leading to decreased tumor volume in mouse xenograft models of prostate cancer.^2,3

AR Binding

Apalutamide retains full antagonist activity in the setting of increased AR expression. Apalutamide (half maximal inhibitory concentration [IC₅₀] =16 nmol/L) binds to AR with 7- to 10-fold greater affinity than bicalutamide (median IC₅₀=160 nmol/L) and competes for the same binding site in the ligand-binding pocket of the receptor. The binding of apalutamide is selective for AR vs for other nuclear hormone receptors (eg, estrogen, progesterone, or glucocorticoid receptors).^1,2

Effect on Overexpressing Prostate Cancer Cells

In laboratory engineered CRPC cells, apalutamide antagonized androgen-mediated induction or repression of mRNA expression levels for 13 endogenous genes. When used to treat CRPC cells in the absence of the synthetic androgen R1881, apalutamide does not show agonist activity.^1,2

Effect on Cell Proliferation

Apalutamide does not stimulate the growth of prostate cancer cells (as mediated through antagonism of AR) and antagonizes the proliferative effect of R1881.^1,2

Effect on Nuclear AR

Apalutamide reduces the concentration of nuclear AR available to bind to androgen response elements. The decrease in nuclear AR is not related to turnover or stability, as apalutamide does not alter steady-state levels of AR. Apalutamide does not facilitate AR binding to androgen response elements in DNA. Apalutamide competes with R1881 and prevents AR from binding to promoter regions.^1,2

Effects in Castration-Sensitive Prostate Cancer and CRPC Models

In preclinical models, apalutamide induced partial or complete regression in both
castration-sensitive prostate cancer and CRPC xenograft models.^2,3

GABA_A Receptor Antagonist

Antiandrogens are functional antagonists of Gamma-aminobutyric acid (GABA)_A receptors, known to cause seizures in preclinical species and humans. Apalutamide weakly binds to GABA_A in radioligand binding assays (IC₅₀=3.0 µmol/L and 2.7 µmol/L, respectively) and could potentially antagonize GABA_A at therapeutic dose levels.^1,2

Antiandrogenic Activity in Noncastrate Animals

In adult male dogs, after 28 days of treatment with apalutamide 10 mg/kg/day, a 3-fold reduction in the weight of dog prostates was seen with a lack of glandular secretory activity, similar to that seen in prostates of sexually immature or castrate animals.^1,2

In a murine xenograft model of human CRPC, treatment with apalutamide 10 mg/kg/day stabilized tumor growth, whereas 75% of animals treated with apalutamide 30 mg/kg/day had tumors that regressed by >50% compared to the initial volume, similar to regressions seen in castrated mice.^1,2

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 27 August 2024.