Leuprolide Acetate With Enzalutamide or Placebo Is Associated With Full Testosterone Recovery in Prostate Cancer

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Treatment with the combination of enzalutamide (Xtandi) and leuprolide acetate or placebo plus leuprolide acetate led to full testosterone recovery after suspension of treatment at 36 weeks in patients with prostate cancer, according to a post hoc analysis of the phase 3 EMBARK trial (NCT02319837).

The results were presented at the 2025 American Urological Association Annual Meeting in Las Vegas, Nevada, by Stephen J. Freedland, MD, professor of urology at Cedars-Sinai in Los Angeles, California.

“One of the unique aspects of EMBARK was that after 9 months of treatments, PSA [prostate-specific antigen] was measured, and if patients got a really good PSA response—less than 0.2 [ng/mL]—treatment was suspended. We know ongoing castration/low testosterone levels can impact quality of life and lead to other poor outcomes. The question was, how quickly does testosterone recover? What percent of people ultimately do recover their testosterone, and particularly as a function of age, because we know that older patients have a slower time to recovery. The purpose of this post hoc analysis was to look at the kinetics of testosterone recovery during the off-treatment cycle,” Freedland said in his presentation.

EMBARK enrolled patients with prostate cancer who had high-risk biochemical recurrence. Patients had a screening 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, had a PSA doubling time of 9 months or less, no metastases on bone scan or CT/MRI, and a testosterone level of at least 150 ng/dL. The primary end point was metastasis-free survival (MFS) by blinded independent central review (BICR) for enzalutamide plus leuprolide acetate vs leuprolide acetate alone. Secondary end points included MFS by BICR for enzalutamide monotherapy vs leuprolide acetate alone, time to PSA progression, time to first use antineoplastic therapy, and overall survival. Safety was an additional secondary end point.

Patients were randomly assigned 1:1:1 to enzalutamide plus leuprolide acetate, placebo plus leuprolide acetate, and enzalutamide monotherapy. At 36 weeks, if a patient’s PSA level was lower than 0.2 ng/mL, treatment was suspended. Testosterone levels were measured every 12 weeks. “Normal” testosterone was defined as greater than 175 ng/mL. In his presentation, Freedland explained that the EMBARK study entry criterion was a testosterone level of at least 150 ng/dL.

Freedland reported that the median time to first occurrence of testosterone recovery to greater than 175 ng/dL was 8.3 months (range, 0-36.0 months) in the enzalutamide plus leuprolide acetate arm vs 5.9 months (range, 0-47.1 months) in the placebo plus leuprolide arm. Mean time to first occurrence of testosterone recovery to greater than 175 ng/dL was 8.9 months (± SD=5.0) in the enzalutamide plus leuprolide acetate arm vs 8.0 months (± SD=5.1) in the placebo plus leuprolide arm. More than 80% of patients in both groups had a full recovery of testosterone, and more 98% of patients had at least partial recovery. Two percent or fewer had no recovery of testosterone.

The investigators stratified their findings by men younger than 70 and men 70 years of age or older. In the enzalutamide plus leuprolide acetate group, the median time to first occurrence of testosterone recovery to greater than 175 ng/dL was 8.3 months (range, 0-36.0 months) in men younger than 70 and 8.3 months (range, 1.9-30.4 months) in men 70 years of age or older. In the placebo plus leuprolide acetate group, the median time to first occurrence of testosterone recovery to greater than 175 ng/dL was 5.7 months (range, 2.8-24.8 months) in men younger than 70 and 8.1 months (range, 0-47.1 months) in men 70 years of age or older. Eighty-nine percent and 92% of patients younger than 70 years of age achieved full recovery of testosterone in the enzalutamide plus leuprolide acetate vs placebo plus leuprolide acetate group, respectively.

“Importantly, no patients in the younger age group had no recovery at all,” Freedland noted.

Seventy-eight percent and 84% of patients 70 years of age or older achieved full recovery of testosterone in the enzalutamide plus leuprolide acetate vs placebo plus leuprolide acetate group, respectively.

“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,” Freedland said in his concluding remarks.

Reference

Freedland SJ, Tutrone R, Saad F, et al. Testosterone recovery following treatment suspension of enzalutamide plus leuprolide or leuprolide alone in patients with high-risk biochemically recurrent prostate cancer: embark post hoc analysis. J Urol. 2025;213(5S):e506. doi:10.1097/01.JU.0001109880.25183.6b.03