Journal of Clinical Oncology October 24, 2026

ENZARAD (ANZUP 1303): Phase 3 Trial of Enzalutamide With Androgen Deprivation Therapy and Radiation Therapy in High-Risk Localized or Locally Advanced Prostate Cancer

Scott Williams, Christopher J. Sweeney, Hayley Thomas, Blossom Mak, Alison Zhang, et al.

Bottom Line

In men with high-risk localized or locally advanced prostate cancer, adding 24 months of enzalutamide to definitive radiotherapy and standard androgen deprivation therapy did not significantly improve metastasis-free survival or overall survival.

Key Findings

1. After a median follow-up of 92 months, 207 metastasis-free survival events on conventional imaging were reported (98 in the enzalutamide arm and 109 in the standard NSAA arm).

2. The 8-year metastasis-free survival rate was 74% with enzalutamide versus 72% with the older NSAA drug, failing to meet statistical significance (HR 0.88, 95% CI 0.67-1.15; P=0.34).

3. No significant improvement in overall survival was observed with the addition of enzalutamide.

4. A prespecified subgroup analysis of 324 patients undergoing planned pelvic nodal radiotherapy suggested a possible metastasis-free survival benefit with enzalutamide (HR 0.47, 95% CI 0.29-0.76; adjusted P=0.004).

5. Grade 3 to 5 adverse events were perfectly balanced between the two groups, occurring in 185 participants in each treatment arm.

Study Design

Design

Randomized Phase 3 Trial

Open-Label

Sample

802

Patients

Duration

92 mo

Median

Setting

Multicenter

Population Men with high-risk localized or locally advanced prostate cancer

Intervention Definitive prostate radiotherapy, 24 months of androgen deprivation therapy, and enzalutamide (160 mg daily for 24 months)

Comparator Definitive prostate radiotherapy, 24 months of androgen deprivation therapy, and a first-generation nonsteroidal antiandrogen (NSAA) for 6 months

Outcome Metastasis-free survival on conventional imaging (MFS-CI)

Study Limitations

• The trial utilized an open-label design, which could introduce bias in adverse event reporting and subjective endpoint assessments.

• Because the primary study endpoint was not met, the statistically significant findings within the pelvic radiation subgroup are strictly hypothesis-generating and require independent prospective confirmation.

• The study cohort was highly heterogeneous, enrolling lower-risk participants who may not have required intensified systemic therapy, thereby potentially diluting benefits for patients with more aggressive disease phenotypes.

• The study compared 24 months of enzalutamide to 6 months of an older nonsteroidal antiandrogen, introducing a significant disparity in the duration of targeted androgen receptor blockade.

Clinical Significance

The ENZARAD trial establishes that uniformly intensifying standard androgen deprivation therapy and definitive radiotherapy with 24 months of enzalutamide does not offer a significant oncologic benefit for unselected patients with high-risk localized or locally advanced prostate cancer. The lack of overall benefit suggests that blanket aggressive systemic escalation in this population does not translate to survival gains and may only increase financial toxicity and side effect burdens. However, the strong hypothesis-generating benefit observed in patients requiring pelvic nodal irradiation (HR 0.47) underscores the ongoing need to identify specific, ultra-high-risk subgroups (such as node-positive patients) who might actually benefit from intensified androgen receptor pathway inhibition.

Historical Context

For over a decade, the standard of care for high-risk localized prostate cancer has been long-term androgen deprivation therapy (ADT) combined with definitive radiotherapy. Following the paradigm-shifting success of next-generation androgen receptor signaling inhibitors (such as enzalutamide, abiraterone, and apalutamide) in metastatic castrate-resistant and metastatic hormone-sensitive settings, investigators hypothesized that moving these agents into earlier, localized settings would eradicate micro-metastatic disease and improve cure rates. While trials like STAMPEDE successfully demonstrated a survival benefit for adding abiraterone to ADT in high-risk non-metastatic disease, the ENZARAD (ANZUP 1303) trial's failure to show a broad benefit with enzalutamide highlights nuanced biological differences among high-risk cohorts. It emphasizes that meticulous patient selection remains critical as ongoing trials (like DASL-HiCaP and PROTEUS) continue to refine the role of treatment intensification in localized disease.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Enzalutamide was added to standard androgen deprivation therapy (ADT) in the ENZARAD trial. How does the mechanism of action of enzalutamide differ from traditional ADT with a GnRH agonist like leuprolide, and why was dual therapy initially hypothesized to be synergistic?

Key Response

GnRH agonists work centrally to suppress testicular testosterone production, but the adrenal glands continue to produce weak androgens, and prostate cancer cells can synthesize their own intratumoral androgens. Enzalutamide is a next-generation androgen receptor signaling inhibitor (ARSI) that directly binds the androgen receptor (AR), inhibiting its nuclear translocation and DNA binding. The hypothesis was that blocking both the primary ligand source (ADT) and the receptor itself (enzalutamide) would completely abrogate AR signaling and prevent resistance, though this trial showed no survival benefit in this specific localized setting.

Resident

A 68-year-old patient with high-risk localized prostate cancer is scheduled for definitive radiotherapy and 24 months of standard ADT. He asks if he should also receive enzalutamide, having read about its success in metastatic disease. Based on the ENZARAD trial, how should you counsel him regarding the efficacy and potential toxicities of adding enzalutamide to his regimen?

Key Response

Based on the ENZARAD trial, the resident should counsel the patient that adding enzalutamide to standard ADT and radiation therapy for high-risk localized disease does not significantly improve metastasis-free or overall survival. Furthermore, it exposes the patient to unnecessary and potentially severe toxicities associated with enzalutamide, such as significant fatigue, cognitive impairment, hypertension, and an increased risk of falls. The standard of care remains definitive RT with standard ADT.

Fellow

The negative results of ENZARAD contrast with the STAMPEDE trial arms, which demonstrated a metastasis-free survival benefit when adding abiraterone to ADT and RT in high-risk non-metastatic prostate cancer. How can we biologically and clinically reconcile these differing outcomes with two different next-generation androgen axis inhibitors?

Key Response

Reconciling these trials requires nuanced interpretation of both drug mechanisms and trial populations. Biologically, abiraterone inhibits CYP17A1, fundamentally halting extragonadal and intratumoral androgen synthesis, whereas enzalutamide antagonizes the receptor. Clinically, STAMPEDE's 'high-risk' cohort included a substantial proportion of node-positive (N1) patients and those with very high-risk features who likely harbored micrometastases, a population that benefits greatly from treatment intensification. ENZARAD's population may have had a lower overall risk profile, meaning standard RT + ADT already achieved maximal local and systemic control, leaving no room for enzalutamide to demonstrate a measurable additive survival benefit.

Attending

The failure of ENZARAD to show a survival benefit challenges the paradigm that 'more is better' in oncology. As an attending leading a multidisciplinary tumor board, what broader lessons does this negative trial provide regarding the limits of maximal androgen blockade and the competing risks of non-cancer mortality in this localized demographic?

Key Response

This trial highlights the critical concept of the therapeutic index and the ceiling of oncologic benefit in localized disease. Local control with modern radiotherapy combined with standard ADT is already highly effective. Escalating systemic therapy with enzalutamide adds significant toxicity in an older population where competing causes of death (e.g., cardiovascular disease, exacerbated by ADT/enzalutamide) often outpace prostate cancer mortality. The lesson is that without a high enough risk of distant micrometastatic failure, treatment intensification merely amplifies side effects and non-cancer mortality without improving overall survival.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The ENZARAD trial utilized metastasis-free survival (MFS) as a primary endpoint, a validated surrogate for overall survival in localized prostate cancer. In a negative trial for a population with high competing non-cancer mortality risks, how does the choice of MFS impact the statistical interpretation of the intervention's true oncologic efficacy, and what specific competing risk analyses are critical here?

Key Response

MFS includes both the development of metastases and death from any cause. In an older population receiving a potentially toxic drug like enzalutamide, increased non-cancer deaths (e.g., cardiovascular events) could artificially depress the MFS curve for the intervention arm, masking a potential reduction in actual metastatic events. To validate the negative findings, researchers must perform rigorous competing risk regressions (such as the Fine-Gray model) separating prostate cancer-specific metastasis/death from non-cancer mortality, ensuring that the lack of MFS benefit reflects a true lack of anti-tumor efficacy rather than just an increase in treatment-related mortality.

Journal Editor

As a peer reviewer evaluating the ENZARAD manuscript, a major contemporary concern is stage migration due to advanced imaging. Since the trial spanned the transition from conventional imaging to PSMA PET staging, how does this heterogeneity threaten the validity of the 'high-risk localized' classification, and what sensitivity analyses would you demand to evaluate the robustness of the negative result?

Key Response

Many patients in ENZARAD were likely staged with conventional CT/bone scans, meaning a subset may have harbored occult micrometastases that a modern PSMA PET would classify as M1. Paradoxically, if enzalutamide failed to show a benefit even in a 'contaminated' cohort that included occult M1 disease (where ARSIs usually excel), it strongly reinforces the negative finding for M0 disease. However, the reviewer should demand a sensitivity analysis stratified by staging modality (conventional vs. PSMA PET) to ensure the lack of benefit is consistent and to clarify exactly which modern patient phenotype these results apply to.

Guideline Committee

Current NCCN and EAU guidelines recommend radiation therapy plus 1.5 to 3 years of ADT for high-risk localized prostate cancer, while allowing the addition of abiraterone for very high-risk/node-positive disease based on STAMPEDE. Given the definitive negative results of ENZARAD, how should guidelines formally address the use of enzalutamide in this setting, and what level of evidence supports this update?

Key Response

The ENZARAD trial provides Level 1 evidence (Phase 3 RCT) that enzalutamide should NOT be added to standard ADT and definitive RT for high-risk localized (M0) prostate cancer due to a lack of MFS/OS benefit and increased toxicity. Guidelines should be updated to explicitly include a strong recommendation against the off-label use of enzalutamide in this specific setting. This clarification is vital to distinguish it from the guideline-supported use of abiraterone in very high-risk/N1 disease, thereby preventing unwarranted therapeutic extrapolation by clinicians.

Clinical Landscape

Noteworthy Related Trials

2018

RTOG 0521 Trial

n = 612 · JCO

Tested

Docetaxel + ADT + radiotherapy

Population

Patients with high-risk localized prostate cancer

Comparator

ADT + radiotherapy

Endpoint

Overall survival

Key result: The addition of docetaxel to ADT and radiotherapy improved overall survival and disease-free survival in high-risk localized prostate cancer.

2022

STAMPEDE Trial

n = 1,974 · Lancet

Tested

Abiraterone acetate + prednisolone + ADT

Population

Patients with high-risk non-metastatic prostate cancer

Comparator

ADT alone

Endpoint

Metastasis-free survival

Key result: Adding abiraterone to ADT significantly improved metastasis-free survival and overall survival.

2023

ATLAS Trial

n = 1,503 · Lancet Oncol

Tested

Apalutamide + ADT + radiotherapy

Population

Patients with high-risk localized or locally advanced prostate cancer

Comparator

Bicalutamide + ADT + radiotherapy

Endpoint

Metastasis-free survival

Key result: Apalutamide combined with ADT and radiotherapy significantly improved metastasis-free survival compared to the control group.

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