Definition
- Target the CYP17A1 enzyme (17α-hydroxylase and 17,20-lyase) to block androgen production in testes, adrenal glands, and tumor tissue.
- Unlike ADT via LHRH analogs/antagonists (which only suppress testicular androgens), these agents also reduce extragonadal androgen production.
Main Agent in Clinical Use
Abiraterone acetate (Zytiga®, Yonsa®)
- Indications:
- Metastatic castration-sensitive prostate cancer (mCSPC) – with ADT.
- Metastatic castration-resistant prostate cancer (mCRPC) – with ADT, both pre- and post-chemotherapy.
Mechanism of Action
- CYP17A1 inhibition → ↓ androgen precursors (DHEA, androstenedione) → ↓ testosterone and DHT levels.
- Also decreases glucocorticoid synthesis → ↑ ACTH → mineralocorticoid excess (fluid retention, hypertension, hypokalemia).
Dosing & Administration
- Standard dose: Abiraterone acetate 1000 mg PO once daily (on empty stomach) + prednisone 5 mg PO BID (Zytiga®) or 5 mg daily (Yonsa® has different bioavailability).
- Continue concurrent ADT (LHRH agonist/antagonist or orchiectomy).
- Take ≥1 hour before or 2 hours after meals (food increases absorption up to 10-fold).
Adverse Effects
- Mineralocorticoid excess: Hypertension, hypokalemia, edema.
- Hepatotoxicity: ↑ AST/ALT; rare fulminant hepatic failure.
- Fatigue, arthralgia, diarrhea.
- Cardiac: Fluid overload, arrhythmias (use caution in CHF).
- Other: Hot flashes, cough.
Monitoring
| Parameter | Frequency |
|---|---|
| LFTs (AST/ALT, bilirubin) | Baseline, every 2 weeks × 3 months, then monthly |
| BP, potassium | Baseline, monthly (more often if high risk) |
| PSA, testosterone | Every 1–3 months |
| Signs of fluid overload | Each visit |
Drug Interactions
- CYP3A4 substrate – avoid strong inhibitors/inducers.
- Moderate inhibitor of CYP2D6 – may ↑ exposure to CYP2D6 substrates (e.g., some β-blockers, SSRIs, opioids).
- Avoid with food due to ↑ absorption risk.
Special Populations
- Hepatic impairment:
- Child-Pugh B: Reduce dose to 250 mg daily.
- Child-Pugh C: Avoid use.
- Renal impairment: No dose adjustment for mild/moderate; limited data in severe.
- Pregnancy: Contraindicated.
Practice Pearls
- Prednisone is essential to prevent mineralocorticoid excess and adrenal insufficiency.
- Counsel on empty stomach requirement.
- For patients with uncontrolled hypertension, hypokalemia, or CHF, stabilize first before starting.
- Continue ADT to maintain castrate testosterone levels.
Key Takeaway:
Androgen synthesis inhibitors like abiraterone complement ADT by blocking extra-testicular androgen production, improving survival in both hormone-sensitive and castration-resistant prostate cancer. Close monitoring for hepatic toxicity, mineralocorticoid excess, and drug interactions is essential for safe use.