Androgen Receptor Signaling Inhibitors (ARSIs)
Mechanism of Action
- Target the androgen receptor (AR) pathway, the main driver of prostate cancer growth.
- They block androgen receptor activation or prevent androgen synthesis, thereby inhibiting AR-mediated transcription and prostate cancer proliferation.
Key Agents
| Drug | Mechanism | Indications | Key Toxicities / Monitoring |
|---|---|---|---|
| Abiraterone acetate (Zytiga®, Yonsa®) | Irreversible inhibitor of CYP17A1 (17α-hydroxylase, 17,20-lyase) → ↓ androgen biosynthesis (testes, adrenal, tumor) | mCSPC (with prednisone), mCRPC (post- or pre-docetaxel) | Mineralocorticoid excess (hypertension, hypokalemia, fluid retention), hepatotoxicity; must give prednisone; taken on empty stomach |
| Enzalutamide (Xtandi®) | Potent AR antagonist; inhibits AR binding, nuclear translocation, and DNA binding | mCSPC, mCRPC | Fatigue, hypertension, falls, seizures, drug–drug interactions (CYP3A4 inducer) |
| Apalutamide (Erleada®) | AR antagonist; prevents AR nuclear translocation and binding to DNA | Non-metastatic CRPC, mCSPC | Rash, hypothyroidism, fractures, falls, fatigue |
| Darolutamide (Nubeqa®) | Structurally distinct AR antagonist with low CNS penetration | Non-metastatic CRPC, mCSPC (with docetaxel + ADT) | Fatigue, less CNS toxicity (lower seizure risk); monitor liver function |
Clinical Notes for Pharmacists
- All ARSIs are given orally and require strict adherence.
- Abiraterone requires co-administration with prednisone to counteract mineralocorticoid excess.
- Food effect: abiraterone must be taken on empty stomach; others can be taken without regard to food.
- Monitor for cardiovascular risk, bone health, drug interactions, and quality-of-life symptoms (fatigue, hot flashes, sexual dysfunction).
- ARSIs are often sequenced with chemotherapy or PARP inhibitors depending on disease stage and mutations.
Synonyms
ARSIs