Radiotherapy plus Long-term Adjuvant Androgen Deprivation with a Luteinizing Hormone-releasing Hormone Antagonist Versus Agonist in Patients with Very High-risk Localized or Locally Advanced Prostate Cancer: The EORTC GUCG-1414 Phase 3 Randomized Trial.

BACKGROUND AND

OBJECTIVE

External beam radiotherapy (EBRT) combined with long-term androgen deprivation therapy (ADT) is standard for high-risk prostate cancer. EORTC 1414 compared ADT with a luteinizing hormone-releasing hormone (LHRH) antagonist (degarelix) or an LHRH agonist in patients who received EBRT.

METHODS

Between 2017 and 2023, 379 patients with prostate cancer with at least two high-risk features (prostate-specific antigen [PSA] ≥20 ng/ml, Gleason score ≥8, cN1, or cT3-4) and stage M0 on conventional imaging or stage M1a/b (n = ≤3 lesions) on advanced imaging were enrolled. Patients were randomized to receive 18, 24, or 36 mo of ADT (degarelix, n = 190; LHRH agonist, n = 189) with pelvic EBRT and treatment of all metastases. Owing to low accrual, the primary endpoint was changed from progression-free survival (PFS) to the PSA nadir response (<0.1 vs ≥0.1 ng/ml) within 6 mo after EBRT.

KEY FINDINGS AND LIMITATIONS: Median age was 72 yr. A PSA nadir of <0.1 ng/ml was achieved by 60% of patients in the agonist arm and 52% in the degarelix arm (odds ratio 0.73, 95% confidence interval 0.43-1.22; p = 0.9). Two-year PFS was 88% in both arms. Adverse events occurred in 89% of agonist and 88% of degarelix patients. Among 41 patients with baseline cardiovascular (CV) disease, four in the agonist arm and one in the degarelix group experienced a CV event. Two CV-related deaths occurred in the agonist arm. Degarelix improved lower urinary tract symptoms, particularly in patients with a baseline International Prostate Symptom Score of ≥13. Limitations include early closure and insufficient power to assess PFS.

CONCLUSIONS AND CLINICAL IMPLICATIONS: Degarelix did not improve the PSA nadir response within 6 mo after EBRT in comparison to LHRH agonists, but was associated with lower incidence of CV events among patients with pre-existing CV disease.