Enzalutamide Fails to Improve Survival in High-Risk Prostate Cancer

Adding enzalutamide (Xtandi) to androgen deprivation therapy (ADT) and radiotherapy did not significantly improve metastasis-free survival (MFS) or overall survival (OS) among patients with high-risk localized or locally advanced prostate cancer, according to findings from the phase 3 ENZARAD trial (ANZUP 1303; NCT02446444) published in the Journal of Clinical Oncology.¹

After a median follow-up of 92 months, the 8-year MFS rates based on conventional imaging were 74% with enzalutamide and 72% with a nonsteroidal antiandrogen (NSAA; HR, 0.88; 95% CI, 0.67-1.15; P = .34). Investigators reported no significant improvement in MFS or OS with enzalutamide in the overall study population.

A prespecified subgroup analysis suggested a potential benefit among patients who received planned pelvic lymph node radiotherapy. Among these 324 patients, enzalutamide was associated with a lower risk of metastasis or death compared with NSAA treatment (HR, 0.47; 95% CI, 0.29-0.76; adjusted P = .004).¹

These findings provide additional context for treatment intensification in high-risk prostate cancer, suggesting that the benefit of adding an androgen receptor pathway inhibitor may depend on disease characteristics and the planned radiation field.

“With differences in cancer risk status, treatment approaches, and regional practice, no set of features can be declared as predictive of response given the unmeasured bias imparted by the clinicians when selecting pelvic radiotherapy initially that is unprotected by randomization. These data, however, do generate hypotheses and [provide] a training set to be prospectively tested for validation in other studies [that] have completed accrual…” wrote Williams et al.

ENZARAD Trial Design and Findings

ENZARAD was an open-label, randomized phase 3 study evaluating whether adding enzalutamide to standard ADT and radiotherapy could improve outcomes for patients with high-risk localized or locally advanced prostate cancer. The trial enrolled 802 patients who were randomly assigned to receive definitive prostate radiotherapy and 24 months of ADT with either enzalutamide at 160 mg daily for 24 months or an older NSAA for 6 months.¹

The primary end point was MFS based on conventional imaging, including computed tomography and technetium-99m bone scintigraphy. Pelvic lymph node radiation was required for patients with clinically node-positive disease and optional for those with node-negative disease.

Across the study population, investigators reported 207 MFS events, including 98 in the enzalutamide group and 109 in the NSAA group. At 8 years, OS rates were also similar between treatment groups, at 83% and 80%, respectively (HR, 0.87; 95% CI, 0.63-1.20; P = .40).¹

The safety findings were comparable, with grade 3 to 5 adverse events reported in 185 patients in each treatment group.

Implications for Treatment Intensification

The subgroup findings suggest that patients receiving pelvic radiation may have a different response to androgen receptor pathway intensification than the broader high-risk population. However, the investigators' primary analysis did not demonstrate a significant MFS or OS advantage with enzalutamide across all patients.

The results build on previous findings of androgen signaling blockade in high-risk prostate cancer, which also examined ENZARAD alongside the PRESTO (NCT03009981) and EMBARK (NCT02319837) trials.² Those studies explored treatment intensification in different prostate cancer settings, underscoring the importance of evaluating treatment strategies within the appropriate patient populations.

Overall, the updated ENZARAD findings indicate that adding 2 years of enzalutamide to ADT and radiotherapy does not provide a significant long-term survival advantage for all patients with high-risk localized or locally advanced prostate cancer. Further consideration of the pelvic radiation subgroup may help clarify which patients could benefit from intensified androgen receptor blockade.

REFERENCES

1. Williams S, Sweeney CJ, Thomas H, et al. ENZARAD (ANZUP 1303): Phase 3 trial of enzalutamide with androgen deprivation therapy and radiation therapy in high-risk localized or locally advanced prostate cancer. J Clin Oncol. Published online October 24, 2026. doi:10.1200/JCO-26-01794.

2. Nguyen PL, Sweeney CJ, Stockler MR, et al. Randomised phase 3 trial of androgen deprivation therapy (ADT) with radiation therapy with or without enzalutamide for high risk, clinically localised, and locally advanced prostate cancer: ENZARAD (ANZUP 1303). Presented at: ESMO Congress 2025; October 17-21, 2025; Berlin, Germany. Abstract LBA86.