Testosterone recovery to normal levels after long-term term androgen-deprivation therapy and radiotherapy significantly improved overall survival in patients with high-risk prostate cancer, according to data presented at the 2025 ASCO Genitourinary Cancers Symposium.¹

Long-term data from the phase III PCS4 trial, which randomly assigned 515 patients to receive either 18 or 36 months of androgen-deprivation therapy in combination with radiotherapy, demonstrated a 46% reduction in mortality risk among patients whose testosterone levels recovered to normal (hazard ratio [HR] = 0.54, P < .001). In addition, patients who underwent 18 months of androgen-deprivation therapy had a higher likelihood of testosterone recovery (57%) than did those who received 36 months (44.3%), though the duration of the therapy itself did not seem to directly impact overall survival. These findings add to the growing body of evidence supporting a more nuanced approach to androgen-deprivation therapy duration and endocrine recovery in prostate cancer management, authors of the study emphasized.

“In high-risk prostate cancer treated with long-term androgen-deprivation therapy and radiotherapy, testosterone recovery to normal levels is associated with a significant improvement in overall survival,” said lead study author Abdenour Nabid, MD, of the Centre Hospitalier Universitaire de Sherbrooke in Canada.

As Dr. Nabid explained, prolonged androgen-deprivation therapy has historically been associated with persistent hypogonadism, raising concerns about its long-term metabolic, cardiovascular, and quality-of-life effects. For this study, Dr. Nabid and colleagues analyzed data from the PCS4 trial, which originally enrolled 630 patients who received either 18 or 36 months of androgen-deprivation therapy in combination with radiotherapy. Of them, 515 patients met the criteria for final analysis, having completed their prescribed duration of androgen-deprivation therapy and possessing adequate baseline and follow-up testosterone measurements.

Study Methods

The PCS4 trial prospectively collected serum testosterone levels at baseline and throughout follow-up, spanning more than 22 years. The median follow-up duration was over 17 years, with more than 6,500 testosterone measurements analyzed.

Patients whose testosterone levels failed to return to normal after androgen-deprivation therapy were generally older and more likely to have diabetes and a higher clinical stage at baseline. Despite these differences, other clinical characteristics did not seem to differ significantly between those who recovered testosterone and those who did not.

Among the 515 patients included in the final analysis, 52% achieved testosterone recovery to normal levels. A significantly higher proportion of patients given 18 months of androgen-deprivation therapy (57%) recovered testosterone compared with those in the 36-month cohort (44%), suggesting a potential duration-dependent effect of androgen-deprivation therapy on long-term endocrine recovery (P = .006). Among those regaining testosterone, the median time to testosterone recovery was 3.6 years.

Overall Survival

As Dr. Nabid reported, patients who achieved testosterone recovery demonstrated a significant overall survival benefit, the study’s primary endpoint. Overall survival rates at 10 and 15 years were 76% and 44%, respectively, compared with 55% and 30% for those who did not achieve testosterone recovery (P < .001). The global hazard ratio for mortality was 0.54 (P < .001), indicating a 46% reduction in the risk of death associated with testosterone recovery.

“The Kaplan-Meier survival curves demonstrated a persistent and widening separation over time between those who recovered testosterone and those who did not,” stated Dr. Nabid.

Significant differences in mortality risk remained when stratified by androgen-deprivation therapy duration:

• 18-month androgen-deprivation therapy cohort: hazard ratio = 0.51 (95% confidence interval [CI] = 0.39–0.66, P < .001)
• 36-month androgen-deprivation therapy cohort: hazard ratio = 0.58 (95% CI = 0.40–0.84, P = .004).

Multivariable analysis confirmed testosterone recovery as an independent predictor of overall survival (HR = 0.69; P = .001), with consistent significance in both androgen-deprivation therapy duration cohorts. Of note, the time to testosterone recovery did not significantly impact overall survival (HR = 0.97; P = .41), suggesting that achieving testosterone normalization itself, rather than the speed of such recovery, may be the critical factor.

Furthermore, there was no significant difference in prostate cancer–specific mortality between patients recovering testosterone and those who did not (11.9% vs 13.5%, P = .58), suggesting the increased mortality in patients with persistent hypogonadism may be likely the result of causes unrelated to cancer. Competing risk analysis confirmed this finding, said Dr. Nabid.

The duration of androgen-deprivation therapy (18 vs 36 months) did not seem to independently impact overall survival. This finding may further underscore the importance of testosterone recovery—not androgen-deprivation therapy duration alone—in influencing long-term outcomes.

According to Dr. Nabid, these results provide evidence that restoring testosterone to normal levels after androgen-deprivation therapy may confer a survival advantage, warranting further exploration into strategies for mitigating prolonged androgen-deprivation therapy–induced hypogonadism. Although androgen-deprivation therapy remains a cornerstone of high-risk prostate cancer management, added Dr. Nabid, efforts to optimize endocrine recovery after treatment should be considered. Prospective trials assessing strategies to promote testosterone recovery while maintaining oncologic efficacy are warranted to guide future therapeutic decision-making, he concluded.

Expert Point of View

Michael J. Morris, MD, FASCO, Prostate Cancer Section Head at Memorial Sloan Kettering Cancer Center, New York, provided a nuanced perspective on the long-term follow-up data from the PCS4 trial, which demonstrated an association between testosterone recovery and improved overall survival in patients with high-risk prostate cancer undergoing androgen-deprivation therapy with radiotherapy. While acknowledging the significance of the findings, Dr. Morris offered some words of caution.

“This was a very interesting presentation on an important trial with long-term follow-up data,” Dr. Morris told The ASCO Post. “Although the observation between the relationship of testosterone recovery and improved overall survival was intriguing and gives one food for thought, the observation itself is not practice-changing.”

Dr. Morris continued: “The patients who experienced recovered testosterone levels were generally in better shape than those who did not. So, testosterone recovery might be a surrogate for other factors relating to general health that improve overall survival rather than testosterone recovery itself,” he explained.

Although the findings highlight an interesting and provocative association, they primarily generate new questions rather than establish a definitive basis for changing clinical practice, Dr. Morris noted. Future studies will be needed to determine whether testosterone recovery itself plays a mechanistic role in survival outcomes or simply reflects underlying patient health status.

DISCLOSURE: Dr. Nabid reported financial relationships with Sumitomo Pharma Oncology, TerSera, Astellas Pharma, and Bayer. Dr. Morris has reported advisory relationships with Flare Therapeutics, Z-Alpha Therapeutics, Arvinas, Convergent Therapeutics, Lantheus, Amgen, Ambrx, and Wren Pharmaceutical.

REFERENCE

1. Nabid A, Carrier N, Martin AG, et al: 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. 2025 ASCO Genitourinary Cancers Symposium. Abstract 310. Presented February 13, 2025.