Impact of testosterone recovery after androgen deprivation therapy on overall survival in patients with high-risk prostate cancer: Long-term data from a phase III trial.
Authors: Nabid Abdenour , Carrier Nathalie , Martin Andre-Guy , Bahary Jean-Paul , Vavassis Peter , Vass Sylvie , Bahoric Boris , Archambault Robert , Vincent Francois , Bettahar Redouane , Duclos Marie , Souhami Luis 
Published: February 2025

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Background:
To determine the potential impact of persistent hypogonadism on overall survival (OS) after prolonged androgen deprivation therapy (ADT) in patients (pts) with high-risk prostate cancer.
Methods:
From 10/2000 to 01/2008, 630 pts were randomised to pelvic radiotherapy (RT) plus 36 (310 pts) vs. 18 months (320 pts) of ADT. Serum testosterone (T) was prospectively collected at baseline, then regularly. We defined T recovery as a return of T to within the normal range value of each participating institution, regardless of whether it was initially normal or abnormal. Excluded from the analysis were pts not receiving exactly 18 or 36 months of ADT (48), or had no T measured at baseline or during follow-up (67). We compared OS between patients recovering or not T to a normal level using the log rank test. Multivariable analysis to predict OS included recovered T to a normal level, age, Zubrod, comorbidities, baseline PSA, Gleason score, stage and ADT duration.
Results:
515/630 pts had proper T data available (baseline and follow-up) and were retained for the analysis. The results are reported with a median follow-up of 17.4 years. Over a period of 22 years, 6587 T measurements were available. A total of 270/515 pts (52.4%) recovered T to normal level, 188/330 (57%) in the 18-month and 82/185 (44.3%) in the 36-month cohort, p=0.006. Pts not recovering T to a normal level were older, had higher clinical stage and diabetes. Among pts regaining T to a normal level, the median time to T recovery was 3.6 (IQR 2.9-4.9) years.10- and 15-year OS rates were 76% (71-81) and 44% (38-51) for pts recovering T vs. 55% (49-62) and 30% (24-36) for those who did not, p<0.001. A significant lower risk of death favoured pts recovering T when considering the global hazard ratio (HR) [HR (95% CI) = 0.54 (0.44-0.67), p<0.001]. Significant differences in HR for death are maintained for both 18-month [HR = 0.51 (0.39-0.66), p<0.001] and 36-month cohort [HR = 0.58 (0.40-0.84), p=0.004]. In multivariable analyses, the impact of T recovery remains significant for the risk of death [(HR = 0.69 (0.55-0.86), p=0.001], and also for the 18-month [HR = 0.70 (0.53-0.93), p=0.013] and the 36-month cohort [(HR = 0.61 (0.40-0.93), p=0.021]. In a multivariable model, among pts regaining T to a normal level, the time to T recovery had no impact on OS [HR = 0.97 (0.90-1.04), p=0.41]. Of note, there was no significant difference in the rate of death from prostate cancer between pts recovering or not T (11.9% vs. 13.5%, p=0.58). Competing risk analysis confirms this finding [sHR = 0.83 (0.51-1.35), p=0.57].
Conclusions:
In high-risk prostate cancer treated with RT and long-term ADT, T recovery to normal level is associated with a significant improvement in overall survival. The increased death rate in pts not recovering T is likely due to causes unrelated to prostate cancer. Clinical trial information:
NCT00223171
.