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.
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.
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.
Cancer chemotherapy and pharmacology. 2026 May 20*** epublish ***
Eleonora Paganoni, Paola Sabbadini, Antonio D'Avolio, Jessica Cusato, Giovanna Motta, Letizia Galeasso, Roberto Filippi, Massimo Di Maio, Ilaria Depetris
Department of Oncology, University of Turin, Orbassano, Italy. ., Department of Oncology, University of Turin, Orbassano, Italy., Laboratory of Clinical Pharmacology and Pharmacogenetics, Department of Medical Sciences, University of Turin, Turin, Italy., Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, University of Turin, Turin, Italy., Division of Medical Oncology 1U, AOU Città della Salute e della Scienza di Torino, Turin, Italy.