Prostate cancer hormonal therapy and peptides — the GnRH-axis pharmacology that anchors modern androgen deprivation

Why this dossier exists

Prostate cancer hormonal therapy is the indication where peptide pharmacology built the foundation of an entire treatment paradigm and then handed half of the modern intensification package to small-molecule chemistry. The molecular target — pituitary GnRH receptors that gate luteinizing hormone secretion and therefore testicular androgen production — is reached almost exclusively by peptide drugs: the decapeptide agonists leuprolide, goserelin, triptorelin, and histrelin, and the synthetic peptide antagonists degarelix and relugolix. The downstream axis the peptides shut down is the same axis that Charles Huggins disrupted surgically in 1941 when he and Clarence Hodges published the founding paper of hormonal cancer therapy (Huggins and Hodges, Cancer Research 1941, 1:293; Nelson, Cancer Res 2016, 76(2):186–187) — the work that earned Huggins the 1966 Nobel Prize in Physiology or Medicine and remains, eight and a half decades later, the conceptual spine of every line of metastatic-prostate-cancer treatment.

US prostate cancer incidence and mortality remain substantial. The American Cancer Society projected approximately 299,010 new diagnoses and 35,250 deaths in 2024, with incidence rising approximately 3% per year overall and approximately 5% per year for advanced-stage disease over the prior decade (American Cancer Society, Cancer Facts & Figures 2024). The androgen dependence Huggins characterized in 1941 — castration produces dramatic regression of metastatic prostate cancer, androgen administration produces flare — licenses every modern hormonal therapy. The molecular biology has filled in: prostate adenocarcinomas express the androgen receptor (AR), depend on testosterone and dihydrotestosterone signaling for proliferation and survival, and resist initial therapy through AR-axis reactivation rather than AR-axis bypass for most of the castration-resistant disease that follows.

This dossier walks the peptide pharmacology that anchors androgen deprivation therapy (ADT) — the GnRH agonist class for medical castration, the GnRH antagonist class as the modern alternative, and the cardiovascular and skeletal cross-links that peptide users encounter when prostate cancer enters the differential. The downstream small-molecule classes — AR-axis-targeting agents (abiraterone, enzalutamide, apalutamide, darolutamide), antiandrogens (bicalutamide, flutamide), and the bone-protective antiresorptives — sit alongside the peptide layer rather than displacing it. The peptide axis is structural; the small molecules intensify against the floor the peptides provide.