## First-Line Hormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer (mHSPC) **Key Point:** GnRH agonists (e.g., leuprolide, goserelin) ± nonsteroidal antiandrogen (NSAA) are the first-line standard for androgen deprivation therapy (ADT) in metastatic hormone-sensitive prostate cancer. **Mechanism:** - **GnRH agonist**: Suppresses LH and FSH, reducing testicular testosterone production - **Antiandrogen**: Blocks androgen receptor at tissue level - **Combined approach** (maximal androgen blockade, MAB): Synergistic effect; reduces clinical progression **Evidence & Dosing:** - **Leuprolide**: 7.5 mg IM monthly or 22.5 mg IM every 3 months - **Bicalutamide** (NSAA): 50 mg daily added to GnRH agonist - SWOG 8894 and subsequent trials support MAB in metastatic disease - Improves overall survival and delays progression to castration-resistant prostate cancer (CRPC) - Typical duration: Continuous until progression to CRPC **Clinical Pearl:** Antiandrogen withdrawal response may occur if patient progresses on MAB; consider flutamide or bicalutamide withdrawal before escalating therapy. **High-Yield:** GnRH agonists are first-line; newer agents (abiraterone, enzalutamide) are reserved for CRPC or added upfront in high-risk mHSPC (per LATITUDE/STAMPEDE trials).
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