Clinical trialPhase 3Prostate cancer

Improved Outcomes with Enzalutamide in Biochemically Recurrent Prostate Cancer

N Engl J Med · 20231068 patients

Freedland SJ, de Almeida Luz M, De Giorgi U, Gleave M, Gotto GT, Pieczonka CM, et al. N Engl J Med. 2023. 389:1453-1465

A newer report of this study has been published: Improved Survival with Enzalutamide in Biochemically Recurrent Prostate Cancer (2026)

Study type: Clinical trial
Study name: EMBARK
Phase: Phase 3
Design: Randomised three-arm trial (enzalutamide versus placebo double-blind; monotherapy arm open-label)
Sample size: 1068 patients
Source: N Engl J Med · 2023
Trial registration: NCT02319837

In plain words

Sometimes after surgery or radiotherapy, the PSA rises again, and quickly, without any spread being seen on standard scans. In this study, adding enzalutamide tablets to hormone injections clearly lowered the chance of the cancer spreading, and in the final analysis it also helped patients live longer (alive after 8 years: about 79% versus 70%).

Key results

87.3% / 71.4% / 80.0%

5-year metastasis-free survival

Combination / leuprolide alone / monotherapy

HR 0.42

Metastasis or death: combination vs leuprolide

95% CI 0.30 to 0.61; P<0.001

HR 0.63

Metastasis or death: monotherapy vs leuprolide

95% CI 0.46 to 0.87; P=0.005

78.9% vs 69.5%

8-year overall survival (final analysis 2026)

Combination vs leuprolide alone; HR 0.60; 95% CI 0.44 to 0.80; P<0.001 (Shore et al., NEJM 2026; doi:10.1056/NEJMoa2510310)

73.1%

8-year overall survival: monotherapy

Versus leuprolide alone HR 0.83; P=0.19 (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

1Enzalutamide + leuprolide (355 patients)

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.

2Placebo + leuprolide (358 patients)

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

3Enzalutamide monotherapy (355 patients)

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, EMBARK clinical studies section)

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 (blinded independent central review) in the combination group versus leuprolide alone. Key secondary endpoint: metastasis-free survival in the monotherapy group versus leuprolide alone; overall survival (alpha-controlled key secondary endpoint); patient-reported outcomes and safety.

Safety and side effects

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.

No notable differences in quality-of-life measures were seen between the groups.

Clinical significance and place in guidelines

EMBARK led to FDA approval (November 2023) of enzalutamide for non-metastatic castration-sensitive prostate cancer with high-risk biochemical recurrence. The final analysis (2026) confirmed an overall survival benefit for the combination of enzalutamide and leuprolide; enzalutamide monotherapy was not significantly superior in overall survival.

Limitations

Staging was done with conventional imaging, and many of these patients have metastatic disease visible on PSMA PET; the role of PSMA PET-directed local therapy was not studied; the monotherapy arm was open-label.

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.