Enzalutamide plus leuprolide yields longest treatment break in EMBARK analysis

A post-hoc exploratory analysis of the phase 3 EMBARK trial (NCT02319837) evaluating duration of treatment suspension across all randomized patients found that enzalutamide (Xtandi) plus leuprolide acetate achieved a significantly longer median treatment suspension compared with leuprolide alone, supporting the concept of a treatment holiday strategy while maintaining the superior efficacy previously established for the combination regimen.

The findings were presented by Neal D. Shore, MD, FACS, director of research at START Carolinas/Carolina Urologic Research Center in Myrtle Beach, South Carolina, at the 2026 American Urological Association (AUA) Annual Meeting in Washington, DC.¹

EMBARK trial background

The EMBARK trial enrolled 1068 men with high-risk biochemically recurrent prostate cancer following prior definitive local therapy—radical prostatectomy, external beam radiation therapy (EBRT), or both—who had no evidence of metastases on conventional imaging (bone scan and CT/MRI per central read). Eligible patients had a screening prostate-specific antigen (PSA) level of at least 1 ng/mL after radical prostatectomy or at least 2 ng/mL above the post-external beam radiation therapy nadir, a PSA doubling time (PSADT) of 9 months or shorter, and serum testosterone of at least150 ng/dL. Patients with prior hormonal therapy within 9 months of randomization (or neoadjuvant/adjuvant therapy within 9 months, ≤36 months in duration for rising PSA) were excluded.^1,2

Patients were randomly assigned 1:1:1 to enzalutamide 160 mg orally once daily plus leuprolide acetate 22.5 mg intramuscularly every 12 weeks (n=355, blinded), placebo plus leuprolide acetate 22.5 mg intramuscularly every 12 weeks (n=358, blinded), or enzalutamide 160 mg orally once daily as monotherapy (n=355, open label). Randomization was stratified by screening PSA (≤10 ng/mL vs >10 ng/mL), PSADT (≤3 months vs >3 to ≤9 months), and prior hormonal therapy (yes vs no).^1,2

A distinctive feature of the EMBARK design was a planned treatment suspension at week 37 for patients whose PSA level had declined to lower 0.2 ng/mL. Treatment was suspended and PSA monitored; it was reinitiated if PSA level rose to at least 5.0 ng/mL without prior radical prostatectomy, or at least 2 ng/mL with prior radical prostatectomy. Patients whose PSA level had not reached less than 0.2 ng/mL by week 36 remained on assigned treatment. This strategy was designed to examine whether early, intensive hormonal therapy could induce durable disease control while permitting treatment breaks that might reduce the long-term toxicity burden associated with continuous androgen deprivation therapy (ADT).^1,2

Previously reported findings from EMBARK established that both enzalutamide-containing regimens significantly improved metastasis-free survival (MFS) compared with leuprolide alone: the combination arm demonstrated an HR for metastasis or death of 0.42 (95% CI, 0.30-0.61; P < .001), and enzalutamide monotherapy an HR of 0.63 (95% CI, 0.46-0.87; P = .005).² A subsequent overall survival (OS) analysis presented at the 2025 European Society for Medical Oncology Congress confirmed a significant OS benefit for the enzalutamide combination vs leuprolide alone (HR, 0.597; 95% CI, 0.444-0.804; P = .0006).³

Analytical approach for treatment suspension analysis

Previously published analyses of treatment suspension duration in EMBARK did not account for differing rates of treatment suspension across arms: 90% of patients in the enzalutamide combination group, 86% in the enzalutamide monotherapy group, and only 67% in the leuprolide alone group actually suspended treatment.¹ Because these prior analyses were restricted to patients who suspended treatment, they introduced potential selection bias by excluding patients who never suspended—a group disproportionately represented in the leuprolide alone arm.

The current post-hoc exploratory analysis included all randomized patients regardless of whether they had suspended treatment, using the intention-to-treat (ITT) population. Patients who did not suspend treatment were assigned a suspension duration of 0 months. This approach was designed to eliminate treatment suspension as a post-randomization factor and ensure an unbiased comparison across all 3 arms. Wilcoxon tests were used to compare enzalutamide combination vs leuprolide alone and enzalutamide monotherapy vs leuprolide alone; P-values are nominal given the ad hoc nature of the analyses.¹

Baseline characteristics

Baseline characteristics were well balanced across the 3 treatment groups in the ITT population. Median age was 69 years (range, 51-87 years) in the enzalutamide combination arm, 70 years (range, 50-92 years) in the leuprolide alone arm, and 69 years (range, 49-93 years) in the enzalutamide monotherapy arm. Median PSADT was 4.6 months (range, 0.9-9.6 months), 5.0 months (range, 1.1-10.8 months), and 5.0 months (range, 1.0-18.9), respectively. Median serum PSA was 5.0 ng/mL (range, 1.0-308.3), 5.5 ng/mL (range, 1.1-163.3), and 5.3 ng/mL (range, 1.1-37.0). ECOG performance status 0 was present in 92.4%, 93.9%, and 90.4% of patients, respectively. Prior primary definitive therapy—prostatectomy alone, radiation therapy alone, or both—was similarly distributed across arms.¹

Duration of treatment suspension across all randomized patients

In the ITT population, the median duration of treatment suspension was 17.0 months (range, 0-109.0 months) for the enzalutamide combination arm, 11.5 months (range, 0-110.9 months) for the leuprolide alone arm, and 8.8 months (range, 0-105.5 months) for the enzalutamide monotherapy arm.¹

The duration of treatment suspension was significantly longer for the enzalutamide combination arm vs leuprolide alone (P < .0001), representing a median difference of approximately 5.5 months. By contrast, the difference between enzalutamide monotherapy and leuprolide alone did not reach statistical significance (P = .381).¹

The distribution of treatment suspension duration also differed across groups. Patients in the leuprolide alone arm were most likely to have no treatment suspension at all—reflecting the lower PSA suppression rate in that arm. Patients in the enzalutamide combination arm were most likely to achieve a treatment suspension lasting at least 24 months, with this arm having the highest proportion of patients in the 24-month-or-longer suspension category. Patients in the enzalutamide monotherapy arm were most likely to experience a suspension lasting less than 12 months.¹

Conclusions and clinical implications

The analysis yielded 3 primary conclusions. First, despite the enzalutamide combination arm experiencing a nearly 6-month longer median treatment suspension than the leuprolide alone arm, the combination regimen still demonstrated superior OS—an observation that reinforces the depth of disease control achieved by early androgen receptor pathway inhibition. Second, the duration of treatment suspension was not significantly different between enzalutamide monotherapy and leuprolide alone in this all-patient ITT analysis. Third, treatment suspension most commonly lasted at least 2 years in the enzalutamide combination group, less than 1 year in the enzalutamide monotherapy group, and patients who received leuprolide alone were most likely to have no treatment suspension at all.¹

The investigators concluded that these findings support the potential for a treatment holiday strategy with enzalutamide combination therapy that maintains efficacy while reducing treatment burden in patients with high-risk biochemically recurrent prostate cancer. The ability to achieve extended off-treatment periods without compromising survival outcomes may have meaningful implications for patient quality of life and long-term tolerability of ADT, including reductions in exposure to adverse events such as bone loss, metabolic changes, and cardiovascular risk associated with continuous hormonal suppression.¹

References

1. Shore ND, Sieber P, De Giorgi U, et al. Duration of treatment suspension among all randomized patients in EMBARK. Presented at: 2026 American Urological Association Annual Meeting. May 15-18, 2026. https://www.auajournals.org/doi/10.1097/01.JU.0001191680.76138.83.05

2. Freedland SJ, de Almeida Luz M, De Giorgi U, et al; EMBARK Study. Improved outcomes with enzalutamide in biochemically recurrent prostate cancer. N Engl J Med. 2023;389(16):1453-1465. doi:10.1056/NEJMoa2303974

3. Shore ND, de Almeida Luz M, De Giorgi U, et al. EMBARK: overall survival with enzalutamide in biochemically recurrent prostate cancer. Ann Oncol. 2025;36(suppl 2):S1629-S1630. doi:10.1016/j.annonc.2025.09.103