The latest findings from a landmark phase III PCS4 trial demonstrate that testosterone recovery to normal levels following long-term androgen-deprivation therapy (ADT) and radiotherapy significantly improves survival outcomes in high-risk prostate cancer patients. The study, presented at the 2025 ASCO Genitourinary Cancers Symposium, revealed a striking 46% reduction in mortality risk among patients who achieved testosterone recovery.
Key Study Findings
The trial, which followed 515 patients for over 17 years, compared outcomes between 18- and 36-month ADT regimens combined with radiotherapy. Results showed that 52% of patients achieved testosterone recovery to normal levels, with a median recovery time of 3.6 years. Notably, patients receiving 18 months of ADT showed higher recovery rates (57%) compared to those on 36-month treatment (44.3%).
Overall survival rates at the 10- and 15-year marks were substantially higher in patients who recovered testosterone levels: 76% and 44% respectively, compared to 55% and 30% in non-recoverers (P < .001). The global hazard ratio for mortality was 0.54 (P < .001).
Clinical Implications and Patient Characteristics
Lead study author Dr. Abdenour Nabid of the Centre Hospitalier Universitaire de Sherbrooke emphasized that patients who failed to recover testosterone levels were generally older, more likely to have diabetes, and presented with higher clinical stage disease at baseline. However, the speed of testosterone recovery did not significantly impact overall survival (HR = 0.97; P = .41).
Cancer-Specific Mortality and Treatment Duration
Interestingly, prostate cancer-specific mortality showed no significant difference between recovery groups (11.9% vs 13.5%, P = .58), suggesting that increased mortality in patients with persistent hypogonadism may stem from non-cancer causes. The duration of ADT itself did not independently influence overall survival.
Expert Perspective
Dr. Michael J. Morris, Prostate Cancer Section Head at Memorial Sloan Kettering Cancer Center, offered a measured interpretation of the findings. While acknowledging their significance, he cautioned that testosterone recovery might serve as a surrogate marker for overall health status rather than a direct survival factor.
"The patients who experienced recovered testosterone levels were generally in better shape than those who did not," Dr. Morris noted. "So, testosterone recovery might be a surrogate for other factors relating to general health that improve overall survival rather than testosterone recovery itself."
Future Directions
These findings suggest the need for a more nuanced approach to ADT duration and endocrine recovery in prostate cancer management. Dr. Nabid called for prospective trials to evaluate strategies that promote testosterone recovery while maintaining oncologic efficacy, potentially reshaping future therapeutic decision-making in high-risk prostate cancer treatment.
