Advanced Prostate Cancer: Treatment and GnRH Evidence

What is advanced prostate cancer and how many men does it affect?

Prostate cancer is a malignant tumor of the prostate gland; it is considered advanced when it has spread beyond the organ or relapsed after local treatment, and it includes metastatic and castration-resistant disease. ICD-10 classifies it as C61. The 2024 European guidelines address localized disease, treatable with curative intent, separately from relapsing, metastatic and castration-resistant disease²⁴.

According to the GLOBOCAN 2022 estimates of the International Agency for Research on Cancer (IARC), prostate was the fourth most common cancer worldwide, with 7.3% of all new cases, behind lung (12.4%), female breast (11.6%) and colorectal (9.6%)¹. The same report counted close to 20 million new cancer cases and 9.7 million cancer deaths overall¹.

Diagnosis and staging: how it is detected

According to the 2024 European guideline, prostate cancer is found through a multistep, risk-based screening process; the goal is to find as many men as possible with a curable cancer². The same guideline states that active surveillance is the appropriate management for men with low-risk disease and for selected men with favorable intermediate risk, and that patients with positive lymph nodes (cN1) should be offered local treatment combined with long-term intensified hormonal treatment².

For diagnosis, the PRECISION trial (500 men with no prior biopsy) compared MRI before biopsy with standard ultrasound-guided biopsy: clinically significant cancer was detected in 38% with MRI-targeted biopsy vs 26% with standard biopsy (adjusted difference 12 percentage points; 95% CI 4 to 20), 28% of men did not need a biopsy, and 13 percentage points fewer clinically insignificant cancers were diagnosed³. For disease that is already advanced, staging and treatment follow the guidelines on relapsing and metastatic disease⁴⁵⁶.

Standard treatment today: what guidelines recommend

Guidelines from the European Association of Urology (EAU, 2024), the European Society for Medical Oncology (ESMO, 2026) and the American Urological Association with the Society of Urologic Oncology (AUA/SUO, 2023 amendment) cover advanced and metastatic prostate cancer⁴⁵⁶. The EAU guideline summarizes that men with metastatic disease now have new options: androgen receptor-targeted agents (ARTAs), ARTA plus chemotherapy combinations, PARP inhibitors, and therapies directed at prostate-specific membrane antigen (PSMA)⁴.

Androgen deprivation therapy (ADT), meaning lowering testosterone to castrate levels with a GnRH analog or an antagonist, remains the skeleton of treatment: the large modern trials test what is added to it. In CHAARTED (790 men with metastatic hormone-sensitive disease), six cycles of docetaxel at the start of ADT were associated with median overall survival of 57.6 vs 44.0 months with ADT alone (hazard ratio for death 0.61; 95% CI 0.47 to 0.80)¹². In LATITUDE, abiraterone plus prednisone vs ADT with placebos reduced the risk of death (hazard ratio 0.62; 95% CI 0.51 to 0.76), and radiographic progression-free survival was 33.0 vs 14.8 months¹³. In STAMPEDE (1917 men), there were 184 deaths with the combination vs 262 with ADT alone (hazard ratio 0.63)¹⁴. In ARASENS (1306 patients), darolutamide added to ADT and docetaxel lowered the risk of death by 32.5% (hazard ratio 0.68; 95% CI 0.57 to 0.80)¹⁵.

That does not mean ADT alone has disappeared. In the SWOG 9346 trial, which compared intermittent with continuous therapy in 1535 men with metastatic hormone-sensitive disease, median survival was 5.8 years with continuous therapy and 5.1 with intermittent (hazard ratio 1.10; 90% CI 0.99 to 1.23); the authors called the findings statistically inconclusive and could not rule out a 20% greater risk of death with intermittent therapy¹⁶.

What peptide research has shown on GnRH analogs

GnRH is a hypothalamic decapeptide. Peptide agonists, given continuously, desensitize the pituitary and lower testosterone; antagonists block it directly. The wider history of this drug class is in A century of therapeutic peptides and a review of approved oncology peptides is in Peptides in oncology; the gynecologic counterpart is in Endometriosis and GnRH analogs.

Leuprolide (leuprorelin). A peptide GnRH agonist. Its FDA label for Lupron Depot lists treatment of advanced prostate cancer¹⁹. In the 1984 Leuprolide Study Group trial (98 men on leuprolide and 101 on diethylstilbestrol, untreated metastatic disease), objective response was 86% with leuprolide and 85% with diethylstilbestrol; one-year survival was 87% vs 78% (P = 0.17). Diethylstilbestrol caused more painful gynecomastia, nausea and vomiting, edema and thromboembolism, and leuprolide caused more hot flashes; the authors concluded it was therapeutically equivalent with fewer side effects⁷.

Goserelin. Another peptide agonist. Its FDA label includes use with flutamide in locally confined stage T2b to T4 prostate cancer and palliative treatment of advanced carcinoma of the prostate²². In the EORTC trial (415 patients with locally advanced disease, 401 analyzed), adding goserelin for three years to radiotherapy was associated with 5-year overall survival of 79% vs 62% (P = 0.001) and, among surviving patients, disease-free status of 85% vs 48% (P < 0.001). In that study the group also received cyproterone for the first month to inhibit the transient rise in testosterone⁸.

Degarelix. A peptide GnRH antagonist, indicated according to its label for treatment of patients with advanced prostate cancer²⁰. In a 12-month phase 3 trial against leuprolide, testosterone stayed at castrate level (≤ 0.5 ng/mL) in 97.2%, 98.3% and 96.4% of the two degarelix groups and the leuprolide group, and on day 3 it was at that level in 96.1% and 95.5% with degarelix and in none with leuprolide⁹. The trade-off was injection-site reactions: 40% vs under 1%⁹ (35% in the label²⁰).

Relugolix (non-peptide). An oral GnRH antagonist; its label describes it as a nonpeptide antagonist indicated for adults with advanced prostate cancer²¹. In the HERO trial (622 men on relugolix and 308 on leuprolide, 48 weeks), 96.7% maintained castration vs 88.8% (difference 7.9 points; 95% CI 4.1 to 11.8). On day 4, 56.0% on relugolix were at castrate level vs 0% on leuprolide, and in a 184-patient subgroup mean testosterone 90 days after stopping was 288.4 ng/dL with relugolix and 58.6 ng/dL with leuprolide. Major adverse cardiovascular events were 2.9% vs 6.2% (hazard ratio 0.46; 95% CI 0.24 to 0.88)¹⁰. The trial was funded by the manufacturer¹⁰. It is the part of this story that most changes the narrative: the drug that beat a peptide in a head-to-head trial is not a peptide.

Safety: adverse effects and precautions

A review of ADT adverse effects lists loss of bone mineral density, metabolic changes (weight gain, decreased muscle mass, increased insulin resistance), decreased libido and sexual dysfunction, hot flashes, gynecomastia, anemia and fatigue; several observational studies suggest more diabetes and cardiovascular events, although most published studies report no greater cardiovascular mortality¹⁸. In a study of 50,613 men, among those surviving at least five years 19.4% of those who received ADT had a fracture vs 12.6% of those who did not (P < 0.001)¹⁷.

FDA labels add specific warnings. The leuprolide label lists tumor flare (transient worsening at the start), metabolic syndrome, cardiovascular diseases, effect on the QT/QTc interval, convulsions and severe cutaneous adverse reactions¹⁹. The goserelin label includes tumor flare, hyperglycemia and diabetes, cardiovascular diseases and QT/QTc²². The degarelix label lists hypersensitivity and QT prolongation; injection-site reactions were 35% and hot flashes 26%²⁰. The relugolix label lists QT prolongation and hypersensitivity; the most common reactions were hot flushes (54%), musculoskeletal pain (30%) and fatigue (26%), with increased glucose (44%) and triglycerides (35%) on laboratory tests²¹.

The cardiovascular question remains open. In PRONOUNCE (545 men with prostate cancer and atherosclerotic cardiovascular disease, 12 months), a major adverse cardiovascular event occurred in 5.5% with degarelix and 4.1% with leuprolide (hazard ratio 1.28; 95% CI 0.59 to 2.79; P = 0.53); the study stopped before enrolling the planned 900 and its authors concluded that the relative cardiovascular safety of antagonists and agonists remains unresolved¹¹.

Summary by drug

Frequently asked questions

What share of new cancers is prostate cancer? 7.3% of all new cancer cases worldwide in 2022, the fourth most common tumor¹.

Are there approved peptides for advanced prostate cancer? Yes: the FDA labels for leuprolide (Lupron Depot), goserelin (Zoladex) and degarelix (Firmagon) include advanced prostate cancer among their indications¹⁹²⁰²².

Do GnRH analogs cure prostate cancer? That has not been shown in the sources consulted. ADT is the backbone of treatment for advanced disease, and in modern trials the best survival results come from adding other drugs, such as docetaxel, abiraterone or darolutamide^12131415.

Is degarelix better than leuprolide? Degarelix achieved faster castration (96.1% and 95.5% vs none on day 3)⁹, but in the PRONOUNCE trial there was no significant difference in major cardiovascular events¹¹.

Is oral relugolix better than injectable peptides? In HERO it maintained castration in 96.7% vs 88.8% with leuprolide at 48 weeks and had fewer major cardiovascular events (2.9% vs 6.2%)¹⁰, but it is not a peptide and the cardiovascular comparison with degarelix has not been resolved¹¹²¹.

What are the most important adverse effects of ADT? Bone loss and fractures, metabolic changes, hot flashes, sexual dysfunction and fatigue; in a study of 50,613 men, fractures were 19.4% with ADT vs 12.6% without it¹⁷¹⁸.