## First-Line Hormonal Therapy in Metastatic Prostate Cancer **Key Point:** GnRH agonists (leuprolide, goserelin, triptorelin) are the gold standard first-line agents for hormone-naïve metastatic prostate cancer, either as monotherapy or combined with an antiandrogen. ### Mechanism of Action Leuprolide is a GnRH agonist that causes initial LH surge (flare reaction) followed by sustained suppression of testosterone production to castrate levels (<50 ng/dL). ### Why Leuprolide is Preferred 1. **Proven survival benefit** in metastatic disease when combined with external beam radiation (EBRT) in intermediate/high-risk localized disease 2. **Cost-effective** compared to newer agents 3. **Well-established** long-term safety profile 4. **Rapid testosterone suppression** to castrate levels within 2–4 weeks 5. **Standard of care** per NCCN and EAU guidelines for hormone-naïve metastatic disease ### Combination Therapy (CAB) Often combined with an antiandrogen (bicalutamide, flutamide) for the first 2–4 weeks to block the initial testosterone flare and prevent clinical deterioration ("flare reaction"). **High-Yield:** In hormone-naïve metastatic prostate cancer, GnRH agonist ± antiandrogen is standard. Newer agents (enzalutamide, abiraterone) are reserved for castration-resistant disease (CRPC). **Clinical Pearl:** The flare reaction (transient rise in testosterone and symptoms) is a recognized complication; antiandrogen co-therapy mitigates this risk in the first 2–4 weeks. ### Timeline of Treatment Escalation ```mermaid flowchart TD A[Hormone-Naïve Metastatic PCa]:::outcome --> B[GnRH agonist ± Antiandrogen]:::action B --> C{Progression?}:::decision C -->|No| D[Continue ADT]:::action C -->|Yes| E[Castration-Resistant PCa]:::outcome E --> F[Add Abiraterone or Enzalutamide]:::action F --> G{Further progression?}:::decision G -->|Yes| H[Chemotherapy or Novel agents]:::action ```
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