ALPALAT

Indications

• Locally advanced prostate cancer at high risk of disease progression
• Prostate cancer (specialist use only)
• Metastatic prostate cancer with the aim of retaining sexual function

Dosage

Adults: 150 mg once daily for advanced prostate cancer, or 50 mg once daily to be started at the same time as surgical castration or at least 3 days before gonadorelin therapy. Dose adjustments may be necessary based on side effects.

Mechanism of action

Apalutamide acts as an antagonist of the androgen receptor (AR) by binding directly to its ligand-binding domain, leading to disrupted AR signaling. This binding inhibits DNA binding and AR-mediated gene transcription, preventing the translocation of AR from the cytoplasm to the nucleus and reducing the availability of AR to interact with androgen response elements. Its main metabolite, N-desmethyl apalutamide, has a lesser potency.

Pharmacodynamics

In studies involving androgen receptor-overexpressing LNCaP cells, apalutamide demonstrated a significantly higher affinity for the AR compared to bicalutamide, particularly in cells with resistance mutations. Animal studies indicated that apalutamide effectively reduced tumor volume and increased apoptosis in prostate cancer models. It also has been shown to increase the QTc interval in a concentration-dependent manner, indicating a potential cardiac effect.

Pharmacokinetics

Apalutamide is absorbed following oral administration, with peak plasma concentrations occurring within 4 to 5 hours. It undergoes extensive metabolism, primarily via hepatic enzymes. The drug and its metabolites are excreted mainly in feces. The elimination half-life is approximately 3 to 6 days. Caution is advised in patients with hepatic impairment, as there is an increased risk of accumulation.

Contra-indications

• History or risk of seizures

Adverse effects

• Fatigue
• Rash
• Hot flush
• Decreased appetite
• Nausea
• Oedema
• Breast tenderness
• Chest pain
• Seizures (discontinue permanently)
• QT interval prolongation
• Photosensitivity reaction

Interactions

• Moderate: calcium channel blockers (e.g., amlodipine, felodipine, nicardipine, etc.) - decreases exposure
• Unknown: antiepileptics - decreases exposure
• Unknown: valproate - decreases exposure
• Unknown: non-sedating antihistamines - decreases exposure

Precautions

• History or risk of QT-interval prolongation
• Recent cardiovascular disease
• Caution in hepatic impairment (moderate to severe)
• Caution in renal impairment (severe)
• Consider periodic liver function tests
• Risk of photosensitivity

Pregnancy

Not indicated in pregnancy; potential risk to the fetus.

Breast-feeding

Not recommended during breastfeeding.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Apalutamide 60 mg tablets (Erleada)

Mechanism of action

Persistent androgen receptor (AR) signaling is a common feature of castration-resistant prostate cancer (CRPC), attributed to AR gene amplification, AR gene mutation, increased AR expression, or increased androgen biosynthesis in prostate tumors. Apalutamide is an antagonist of AR that binds directly to the ligand-binding domain of the AR with the IC50 of 16 nM. Upon binding, apalutamide disrupts AR signalling, inhibits DNA binding, and impedes AR-mediated gene transcription. Apalutamide impairs the translocation of AR from the cytoplasm to the nucleus thus reducing the concentrations of AR available to interact with the androgen response elements (AREs). Upon treatment with apalutamide, AR was not recruited to the DNA promoter regions. Its main metabolite, N-desmethyl apalutamide, is a less potent inhibitor of AR, and exhibited one-third of the activity of apalutamide in an in vitro transcriptional reporter assay.

Pharmacodynamics

In androgen receptors (AR)-overexpressing LNCaP cells, apaludatamide was reported to have a 7 to 10-fold greater affinity to the AR than bicalutamide. Additionally, apalutamide still possesses total antagonistic activity in AR-overexpressing cell lines with bicalutamide-resistance mutations such as T878A and W741C. In castrate mice with LNCaP/AR(cs) tumors, apalutamide produced tumor regression (defined by >50% regression in tumor volume) in 8 mice compared to only 1 for bicalutamide. The apalutamide-treated tumors also have a 60% decrease in proliferative index and a 10-fold increase in apoptotic rate compared with vehicle. In an open-label, uncontrolled, multicenter, single-arm dedicated QT study in 45 patients with CRPC, an exposure-QT analysis suggested a concentration-dependent increase in QTcF for apalutamide and its active metabolite. Apalutamide demonstrated antitumor activity in the mouse xenograft models of prostate cancer, where it decreased tumor cell proliferation and reduced tumor volume.