Clinical trialPhase 3Prostate cancer

Improved Survival with Enzalutamide in Biochemically Recurrent Prostate Cancer

N Engl J Med · 20261068 patients (1:1:1 randomisation)

Shore ND, Luz MdA, De Giorgi U, Gleave M, Gotto GT, Pieczonka CM, et al. N Engl J Med. 2026. 394:563-575

Study type: Clinical trial
Study name: EMBARK
Phase: Phase 3
Design: Randomised phase 3 trial with three groups (1:1:1 randomisation); final overall survival analysis
Sample size: 1068 patients (1:1:1 randomisation)
Source: N Engl J Med · 2026
Trial registration: NCT02319837

In plain words

This study looked at patients who, after their first treatment for prostate cancer, had only a rise in PSA (biochemical recurrence) and were at high risk. The results showed that adding enzalutamide to hormone therapy with leuprolide raised the chance of being alive after 8 years (about 79% versus 70%). Enzalutamide on its own did not lead to better survival than leuprolide on its own. The choice of treatment should be made with the treating doctor, taking into account the side effects and each patient's situation.

Key results

78.9% vs 69.5%

8-year overall survival: combination group vs leuprolide alone

95% CI 73.9 to 83.1 vs 64.0 to 74.3

0.60

Hazard ratio for death (combination vs leuprolide alone)

95% CI 0.44 to 0.80; P<0.001

73.1%

8-year overall survival with enzalutamide monotherapy

95% CI 67.6 to 77.9

0.83

Hazard ratio for death (monotherapy vs leuprolide alone)

95% CI 0.63 to 1.10; P=0.19 (difference not significant)

Drugs in this study:Enzalutamide (Xtandi)Leuprolide (Lupron/Eligard)

Dose and schedule cards

Enzalutamide ± leuprolide (EMBARK)

High-risk biochemical recurrence after prostatectomy and/or radiotherapy: PSA doubling time of 9 months or less, PSA ≥1 ng/mL after prostatectomy or at least 2 above the nadir after radiotherapy alone, no metastases on conventional imaging, and unsuitable for salvage radiotherapyEach drug’s schedule in the tableOn the page “Prostate cancer” · Backbone hormone therapy, high-risk localized disease and biochemical recurrence

Drug	Dose	Route	Schedule
Enzalutamide	160 mg once daily	Oral, with or without food; swallow whole	Daily
Leuprolide	3-month formulation (22.5 mg)	IM or SC	Every 12 weeks

Cycle schedule: Enzalutamide daily; leuprolide every 12 weeks
Duration: Until radiographic progression or toxicity; treatment pause from week 37 if the week-36 PSA is below 0.2 ng/mL

The FDA label allows enzalutamide in this setting with or without a GnRH analog, but an overall survival advantage was shown only for the combination with leuprolide. If PSA is undetectable after 36 weeks, treatment is suspended and resumed when PSA reaches ≥2.0 ng/mL (after prostatectomy) or ≥5.0 (after primary radiotherapy).

On the page “Prostate cancer” · Backbone hormone therapy, high-risk localized disease and biochemical recurrence

Non-metastatic castration-sensitive prostate cancer with high-risk biochemical recurrence (EMBARK)

After radical prostatectomy and/or radiotherapy; with or without a GnRH analogueCycle length: ContinuousOn the page “Enzalutamide (Xtandi)” · Standard dosing (FDA label)

After radical prostatectomy and/or radiotherapy; with or without a GnRH analogue

Drug	Dose	Route	Schedule
Continuous
Enzalutamide	160 mg	Oral	Once daily, every day (with or without food)

Cycle length: Continuous
Duration: Treatment may be paused if PSA is undetectable (below 0.2 ng/mL) after 36 weeks

Restart: PSA 2.0 ng/mL or more after radical prostatectomy, or 5.0 ng/mL or more after primary radiotherapy.

On the page “Enzalutamide (Xtandi)” · Standard dosing (FDA label)

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Combination group (enzalutamide + leuprolide)

Enzalutamide 160 mg (4 × 40 mg capsules) orally once daily with leuprolide, one intramuscular or subcutaneous injection every 12 weeks (355 patients).

Treatment suspension in all three groups: if PSA at week 36 was undetectable (less than 0.2 ng/mL), treatment was stopped at week 37 and restarted when PSA reached ≥2.0 ng/mL (after prostatectomy) or ≥5.0 ng/mL (without prostatectomy); otherwise treatment continued until radiographic progression, new therapy or unacceptable toxicity.

2Leuprolide-alone group

Matching placebo once daily with leuprolide every 12 weeks (358 patients).

3Enzalutamide monotherapy group

Enzalutamide 160 mg orally once daily without leuprolide, open-label (355 patients).

Source of the regimen details: ClinicalTrials.gov NCT02319837 and the FDA label for XTANDI (DailyMed)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

1068 men with high-risk biochemical recurrence after definitive therapy (radical prostatectomy and/or radiotherapy) who were not candidates for salvage radiotherapy: PSA doubling time 9 months or less; PSA ≥1 ng/mL after prostatectomy or at least 2 ng/mL above the nadir after radiotherapy alone; testosterone ≥150 ng/dL; no metastases on conventional imaging (centrally confirmed). Prior neoadjuvant/adjuvant hormone therapy (maximum 36 months and at least 9 months before enrolment) was allowed.

Endpoints

Primary endpoint: metastasis-free survival, comparing the combination group with the leuprolide-alone group. Overall survival was an alpha-controlled key secondary endpoint. Updated results of prespecified secondary endpoints, including time to first use of new antineoplastic therapy and time to first symptomatic skeletal event, were summarised descriptively. Progression-free survival on first subsequent therapy was also reported descriptively as an exploratory endpoint.

Safety and side effects

Safety findings were consistent with the primary metastasis-free survival analysis. Per the FDA label (entire treatment period): grade 3 or higher adverse events 46% with enzalutamide + leuprolide, 50% with enzalutamide alone and 43% with placebo + leuprolide; permanent discontinuation because of adverse events 21%, 18% and 10%. The most common reason for discontinuation was fatigue. No new safety signal was seen.

Clinical significance and place in guidelines

This final analysis shows that in high-risk biochemically recurrent prostate cancer, the combination of enzalutamide and leuprolide significantly improves overall survival in addition to metastasis-free survival, whereas enzalutamide monotherapy was not superior to leuprolide alone in overall survival. Approval status and formal clinical guideline recommendations should be checked separately.

Limitations

The abstract does not provide enough information on patient numbers and adverse event details. Results of the other secondary endpoints and the exploratory endpoint were reported descriptively. More details are available in the full text of the paper.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.