A 72-year-old man with castration-resistant prostate cancer (PSA progression despite 18 months of GnRH agonist therapy) and bone metastases presents for treatment escalation. Testosterone is <20 ng/dL. What is the preferred next-line hormonal agent?

Explanation

## Treatment of Castration-Resistant Prostate Cancer (CRPC) **Key Point:** Abiraterone acetate (CYP17 inhibitor) + prednisone is the preferred next-line hormonal agent for metastatic CRPC after GnRH agonist failure, offering superior survival benefit. ### Mechanism of Abiraterone Abiraterone inhibits CYP17A1 enzyme, blocking both 17α-hydroxylase and 17,20-lyase activities, thereby suppressing androgen synthesis at multiple sites: - Adrenal glands (primary source in CRPC) - Testes (residual) - Prostate cancer cells (intracrine production) ### Why Abiraterone is Preferred in CRPC | Feature | Abiraterone + Prednisone | Enzalutamide | Bicalutamide | Flutamide | |---------|--------------------------|--------------|--------------|----------| | **Mechanism** | CYP17 inhibitor | AR antagonist | AR antagonist | AR antagonist | | **Castrate-resistant efficacy** | ✓ Proven OS benefit | ✓ Proven OS benefit | ✗ Weak in CRPC | ✗ Outdated | | **Median OS gain** | 4.6 months (vs placebo) | 4.8 months (vs placebo) | Minimal | Minimal | | **Prednisone required** | Yes (mineralocorticoid effect) | No | No | No | | **Hepatotoxicity** | Low | Low | Moderate | **High** | | **First-line CRPC** | Yes | Yes (alternative) | No | No | **High-Yield:** Both abiraterone and enzalutamide are acceptable next-line agents for CRPC, but abiraterone is often preferred first due to: 1. Earlier approval in CRPC setting 2. Slightly more predictable pharmacokinetics 3. Less CNS penetration (fewer neurological side effects) 4. Established safety in elderly patients ### Management Algorithm for CRPC ```mermaid flowchart TD A[Hormone-Naïve Metastatic PCa]:::outcome --> B[GnRH agonist ± Antiandrogen]:::action B --> C{PSA/Imaging Progression?}:::decision C -->|No| D[Continue ADT]:::action C -->|Yes| E[Castration-Resistant PCa]:::outcome E --> F{Visceral Metastases?}:::decision F -->|No| G[Abiraterone + Prednisone OR Enzalutamide]:::action F -->|Yes| H[Docetaxel Chemotherapy]:::action G --> I{Further Progression?}:::decision I -->|Yes| J[Switch to Enzalutamide or Docetaxel]:::action ``` **Clinical Pearl:** Prednisone (5–10 mg daily) is essential with abiraterone to prevent hypokalemia and hypertension due to mineralocorticoid excess from shunting of steroid precursors to the 11β-hydroxylase pathway. **Warning:** Do NOT use bicalutamide or flutamide monotherapy in CRPC — they lack the potency needed and are associated with poor outcomes. Flutamide is largely obsolete due to hepatotoxicity.