EMBARK data indicate large OS benefit with enzalutamide/ADT in prostate cancer

In patients with biochemically recurrent prostate cancer, combination treatment with enzalutamide (Xtandi) plus leuprolide emphatically improves overall survival (OS) compared with leuprolide alone, according to recently presented findings from the phase 3 EMBARK trial (NCT02319837).^1,2

The data were presented at the 2025 European Society for Medical Oncology Congress in Berlin, Germany and simultaneously published in the New England Journal of Medicine.

Previously published data from the EMBARK trial indicated that enzalutamide plus leuprolide and enzalutamide monotherapy were associated with improved metastasis-free survival (MFS) vs leuprolide alone in patients with high-risk biochemically recurrent prostate cancer for whom conventional imaging was negative for metastases. The HR for MFS with enzalutamide/leuprolide vs leuprolide alone was 0.42 (95% CI: 0.30-0.61, P < .001), and the HR for MFS for enzalutamide monotherapy vs leuprolide alone was 0.63 (95% CI: 0.46-0.87, P = .005). Both the enzalutamide/leuprolide combination and enzalutamide monotherapy were associated with improved time to prostate-specific antigen (PSA) progression, first use of new antineoplastic therapy, distant metastasis, and symptomatic progression.³

“Overall survival is a key alpha-protected secondary end point of EMBARK and was immature at the time of initial presentation,” explained Stephen J. Freedland, MD, a professor of urology at Cedars-Sinai in Los Angeles, California.

EMBARK included patients with a screening PSA level of at least 1 ng/mL following radical prostatectomy or at least 2 ng/mL above the nadir after primary external beam radiation therapy, a PSA doubling time of 9 months or less, no metastases on bone scan CT/MRI per central read, and a testosterone level of at least 150 ng/dL. Patients were stratified according to screening PSA level (≤ 10 ng/mL vs >10 ng/mL), PSA doubling time (≤ 3 months vs > 3 months to ≤9 months), and prior hormonal therapy (yes vs no). The primary end point was MFS by blinded independent central review (BICR) for combination enzalutamide/leuprolide vs leuprolide alone. Key secondary end points included MFS by BICR for enzalutamide monotherapy vs leuprolide alone, time to PSA progression, time to first use of new antineoplastic therapy, and OS. Other key secondary end points included time to first symptomatic skeletal event and safety, and PFS2 was an exploratory end point.

A total of 1068 patients were randomly assigned 1:1:1 to receive enzalutamide (160 mg orally once daily) plus leuprolide (225 mg IM every 12 weeks) (355 patients), placebo plus leuprolide (225 mg IM every 12 weeks) (358 patients), or enzalutamide monotherapy (160 mg orally once daily) (355 patients). Patients were assessed for PSA level at week 36; if PSA level was lower than 0.2 ng/mL, treatment was suspended at week 37 and PSA levels were monitored; treatment would resume if PSA levels reached predefined thresholds. Patients continued treatment if their PSA level was higher than 0.2 ng/mL. Safety follow-up was conducted 30 days following the final dose, and long-term follow-up every 12 weeks until final analysis looked at survival status, new antineoplastic therapies for prostate cancer, symptomatic skeletal events, and progression-free survival on first subsequent therapy (PFS2).

Freedland reported that with combination enzalutamide/leuprolide, the risk of death was 40.3% lower vs leuprolide alone. The 8-year OS rate was 78.9% (95% CI: 73.9-83.1) in the combination enzalutamide/leuprolide arm vs 69.5% (95% CI: 64.0-74.3) in the leuprolide-alone arm (HR, 0.597, 95% CI: 0.444-0.804, P = .0006).

“To our knowledge, this is the greatest survival benefit based upon hazard ratio ever seen in a prostate cancer global phase 3 trial based upon all patients in the study, not small little subsets,” Freedland said, prompting applause from attendees.

Freedland then turned to prespecified subgroup analysis of OS.

“When we looked at subsets, what we saw based upon predefined subsets is every single subset benefited. Though the numbers within these are small and don't always reach statistical significance, we could not identify any subset of patients that did not benefit from adding enzalutamide to ADT [androgen deprivation therapy],” Freedland said.

The investigators also evaluated OS with enzalutamide monotherapy, which was associated with a 17.0% lower risk of death vs leuprolide alone, which was not statistically significant.

Time to first use of new antineoplastic therapy favored combination enzalutamide/leuprolide vs leuprolide alone (HR, 0.374, 95% CI: 0.287-0.489, nominal P < .0001). Benefit with this end point was also observed in the enzalutamide monotherapy arm (HR, 0.570, 95% CI: 0.450-0.721, nominal P < .0001).

Turning to time to first symptomatic skeletal event with combination enzalutamide/leuprolide vs leuprolide alone, “We see, though the overall rates are relatively low, we do see significant benefits to enzalutamide combination relative to ADT alone with a hazard ratio of 0.4. And we actually see relatively similar benefits with enzalutamide monotherapy, interestingly, suggesting perhaps the lack of castration leading to high testosterone, aromatization to estrogen, that that may have added bone health benefits,” Freedland said.

Treatment with combination enzalutamide/leuprolide was associated with a statistically significant and clinically meaningful PFS2 vs leuprolide alone (HR, 0.563, 95% CI: 0.420-.755, nominal P < .0001). A statistically significant but lower PFS2 benefit was also seen with enzalutamide monotherapy (HR, 0.761, 95% CI: 0.581-0.998, nominal P = 0.0465).

Freedland then discussed adverse events.

“In terms of safety, importantly, we really didn't see any new safety signals relative to what had previously been reported included in the New England Journal of Medicine paper, which is nice to know with an additional 2 and a half years of follow up,” Freedland said. He noted that incidence of serious treatment-emergent AEs related to study drug was below 10% in all 3 treatment arms.

In his concluding remarks, Freedland commented, “These findings, in conjunction with the original results published 2 years ago, really show that enzalutamide with ADT is the standard of care for high-risk, biochemically recurrent prostate cancer patients.”

DISCLOSURES: Freedland noted that he is a consultant for Astellas Pharma and Pfizer.

REFERENCES

1. Shore ND, de Almeida Luz M, De Giorgi U, et al. Overall survival with enzalutamide in biochemically recurrent prostate cancer. Presented at: European Society for Medical Oncology Congress. October 17-21, 2025. Berlin, Germany. LBA87.

2. Shore ND, de Almeida Luz M, De Giorgi U, et al. Improved survival with enzalutamide in biochemically recurrent prostate cancer. N Engl J Med. Published online October 19, 2025. Accessed October 19, 2025. doi:10.1056/NEJMoa2510310

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