A post hoc analysis of the phase 3 EMBARK trial has demonstrated that the majority of men with high-risk biochemically recurrent prostate cancer achieve full testosterone recovery following treatment suspension, according to findings presented at the 2025 American Urological Association Annual Meeting in Las Vegas.
The analysis, presented by Dr. Stephen J. Freedland, professor of urology at Cedars-Sinai in Los Angeles, examined testosterone recovery kinetics in patients who received either enzalutamide (Xtandi) plus leuprolide acetate or placebo plus leuprolide acetate and had their treatment suspended after achieving good PSA responses.
"One of the unique aspects of EMBARK was that after 9 months of treatments, PSA was measured, and if patients got a really good PSA response—less than 0.2 [ng/mL]—treatment was suspended," explained Dr. Freedland. "We know ongoing castration/low testosterone levels can impact quality of life and lead to other poor outcomes."
Testosterone Recovery Rates and Timing
The analysis revealed that more than 80% of patients in both treatment groups achieved full testosterone recovery (defined as >175 ng/dL) after treatment suspension. Remarkably, over 98% of patients experienced at least partial recovery, with only 2% or fewer showing no recovery at all.
The median time to first occurrence of testosterone recovery was 8.3 months (range, 0-36.0 months) in the enzalutamide plus leuprolide acetate arm compared to 5.9 months (range, 0-47.1 months) in the placebo plus leuprolide arm. The mean recovery times were 8.9 months and 8.0 months, respectively.
Age-Related Differences in Recovery
When stratified by age, the analysis showed important differences between younger and older men:
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For men under 70 years: 89% in the enzalutamide plus leuprolide group and 92% in the placebo plus leuprolide group achieved full testosterone recovery. Notably, all patients in this younger age group showed at least some testosterone recovery.
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For men 70 years or older: 78% in the enzalutamide plus leuprolide group and 84% in the placebo plus leuprolide group achieved full recovery.
"Importantly, no patients in the younger age group had no recovery at all," Dr. Freedland emphasized during his presentation.
EMBARK Trial Design and Patient Population
The EMBARK trial enrolled patients with prostate cancer who had high-risk biochemical recurrence, characterized by:
- PSA level of at least 1 ng/mL after radical prostatectomy or at least 2 ng/mL above the nadir for primary external beam radiation therapy
- PSA doubling time of 9 months or less
- No metastases on bone scan or CT/MRI
- Baseline testosterone level of at least 150 ng/dL
Patients were randomized 1:1:1 to receive enzalutamide plus leuprolide acetate, placebo plus leuprolide acetate, or enzalutamide monotherapy. The primary endpoint was metastasis-free survival for the combination therapy versus leuprolide alone.
At the 36-week mark, patients whose PSA levels dropped below 0.2 ng/mL had their treatment suspended, and testosterone levels were subsequently measured every 12 weeks.
Clinical Implications
These findings have significant implications for prostate cancer treatment strategies, particularly regarding intermittent hormone therapy approaches. The high rates of testosterone recovery suggest that temporary hormone therapy suspension may be a viable strategy to improve quality of life while maintaining treatment efficacy.
"In summary, what we showed is EMBARK, for those who got to the treatment suspension—which was the majority of patients—that with time, the testosterone recovers...and the vast majority of patients do ultimately develop return of testosterone," Dr. Freedland concluded.
The results provide reassurance to clinicians and patients that testosterone levels can recover after androgen deprivation therapy, potentially reducing long-term side effects associated with continuous hormone suppression while still effectively managing prostate cancer.
