Failure of a LHRH agonist in metastatic prostate cancer: a case report and review of literature

Background: Androgen deprivation therapy (ADT) is the cornerstone of advanced prostate cancer treatment, aiming to achieve castrate testosterone levels. Luteinizing hormone-releasing hormone (LHRH) agonists are widely used, but intrinsic resistance, although rare, may pose significant therapeutic challenges. Case presentation: We report a 75-year-old man with de novo low-volume metastatic prostate cancer who experienced unusual refractoriness to LHRH agonist therapy. Despite correct administration of leuprolide and good treatment adherence, testosterone levels did not drop and instead progressively increased over five months. This occurred concurrently with a marked PSA decline following the addition of the androgen receptor pathway inhibitor (ARPI) apalutamide. Drug-drug interactions, pharmacological interference, and other common causes of treatment resistance were ruled out. Upon switching to the LHRH antagonist degarelix, adequate testosterone suppression was rapidly achieved. Discussion: This case highlights a rare biochemical failure of LHRH agonist therapy, possibly due to primary resistance or inadequate receptor desensitization. The concomitant use of an ARPI masked ADT failure by suppressing PSA despite elevated testosterone. This case emphasizes the still relevant need for periodic testosterone monitoring to ensure effective hormonal suppression.