A 68-year-old man with histologically confirmed localized prostate cancer (Gleason score 7, PSA 12 ng/mL) and no distant metastases is counselled for androgen deprivation therapy (ADT) as part of multimodal treatment. Which drug is the first-line choice for long-term hormonal suppression in this patient?

Explanation

## First-Line ADT in Prostate Cancer **Key Point:** Gonadotropin-releasing hormone (GnRH) agonists (leuprolide, goserelin, buserelin) are the gold-standard first-line agents for androgen deprivation therapy in intermediate- and high-risk localized prostate cancer and metastatic disease. ### Mechanism of Action GnRH agonists cause initial stimulation followed by downregulation of pituitary GnRH receptors, resulting in: - Suppression of luteinizing hormone (LH) secretion - Reduction of testicular testosterone production to castrate levels (<50 ng/dL) - Sustained androgen suppression over months with depot formulations ### Why Leuprolide is First-Line | Feature | Leuprolide | Bicalutamide Monotherapy | Finasteride | Estramustine | |---------|-----------|--------------------------|-------------|-------------| | **Testosterone suppression** | Complete (castrate) | Incomplete; requires LHRH agonist | Partial (5α-reductase inhibitor only) | Partial | | **Clinical efficacy** | Proven in RCTs | Inferior monotherapy; used as adjunct | Inadequate as monotherapy | Obsolete | | **Onset** | 1–3 weeks (depot) | 2–4 weeks | Weeks to months | Weeks | | **Duration** | 1–3 months (depot) | Daily oral | Daily oral | Daily oral | | **Flare phenomenon** | Yes (initial surge) | No | No | No | **High-Yield:** Leuprolide (and other GnRH agonists) achieve **complete androgen blockade** when combined with antiandrogens (bicalutamide) in high-risk disease; monotherapy with bicalutamide is insufficient for primary ADT. **Clinical Pearl:** Flare phenomenon (transient rise in testosterone and LH) occurs 1–3 days after first GnRH agonist injection; antiandrogen is given 1 week before and continued 2–4 weeks after to prevent clinical flare (bone pain, urinary obstruction). **Tip:** In exam questions, distinguish: - **Monotherapy ADT** → GnRH agonist alone (standard) - **Combined ADT** → GnRH agonist + antiandrogen (for high-risk or metastatic disease) - **Antiandrogen monotherapy** → bicalutamide alone (only in early, low-risk disease or as flare prevention) [cite:Harrison 21e Ch 89]