Incomplete testosterone suppression with luteinizing hormone‐releasing hormone agonists: does it happen and does it matter?

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Previous reports, with small numbers of patients, have described the problem of incomplete testosterone suppression (>1.1 or 1.7 nmol/L) with LHRH agonists. Various predisposing factors have been suggested: different drug agents and patient factors such as age, pretreatment testosterone levels and weight. Such incomplete testosterone suppression has been shown in one small report to be associated with increased PSA failure rates and in another report in those with metastases, with worse survival. This study used testosterone assays that are more accurate at low levels than those used in most previous reports in a large dataset of 2196 men, and confirmed incomplete testosterone suppression (breakthrough) rates >1.7 nmol/L of 3.4% and >1.1 nmol/L of 6.6%. We showed that younger age was strongly associated with the risk of breakthrough, with a minor effect of increasing body mass index. Repeated breakthroughs were more common (16%) in those who had already had one breakthrough. Interim measures of cancer control (PSA kinetics during LHRH therapy) were inferior in those with a breakthrough, and those with breakthroughs between 1.1 and 1.7 nmol/L had worse long‐term biochemical control rates. OBJECTIVES To describe breakthrough rates above castrate levels of testosterone, in a population‐based series of men undergoing adjuvant luteinizing hormone‐releasing hormone (LHRH) agonist therapy with curative radiation therapy. To explore the predisposing factors for such breakthroughs and their impact on subsequent outcomes. PATIENTS AND METHODS All men treated for prostate cancer between 1998 and 2007 with curative radiation in the province of British Columbia, Canada were potentially eligible ( n = 11 752). Of these, 2196 fulfilled the eligibility criteria. Serial testosterone measurements were obtained during continuous LHRH therapy. Breakthrough rates >1.1 nmol/L and >1.7 nmol/L were calculated for each LHRH injection and for each patient course. Predisposing factors were identified, and early surrogates of oncological outcome (neoadjuvant nadir and post‐treatment nadir) were determined. RESULTS The risk of a breakthrough >1.1 nmol/L was 6.6%, and >1.7 nmol/L was 3.4% per patient course and 5.4% and 2.2% per LHRH injection (inclusive ranges). Repeated breakthroughs occurred in 16% of patients. Younger men were more liable to breakthroughs ( P < 0.001). Early PSA kinetic surrogates of cancer control were inferior in those with breakthroughs. Neither overall biochemical non‐evidence of disease (bNED) nor survival were compromised, although subgroup analysis showed inferior 5‐year bNED in those with breakthroughs of 1.1–1.7 nmol/L vs those without (58% vs 73%, respectively; P = 0.048). CONCLUSIONS Breakthroughs with LHRH agonists occur occasionally per injection, but occur commonly per patient course of treatment, and adversely affect early surrogate measures of outcome. The monitoring of testosterone levels during therapy is therefore advised.