ENZARAD Trial Shows Selective Gains for Node-Positive Prostate Cancer With Enzalutamide Intensification

The final results of the phase 3 ENZARAD study, presented at the European Society for Medical Oncology (ESMO) Congress 2025, reveal that intensifying androgen deprivation therapy (ADT) with enzalutamide does not significantly improve metastasis-free survival (MFS) in the overall population of men with high-risk localized or locally advanced prostate cancer. Conducted across eight countries and coordinated by the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP), the trial evaluated the long-term impact of adding the androgen receptor inhibitor to radiation and standard hormonal therapy.

After a median follow-up of eight years, MFS was 74% for patients treated with enzalutamide plus radiation and ADT, compared with 72% for those who received a conventional non-steroidal anti-androgen. Overall survival and prostate cancer–specific survival were also similar, at approximately 83% versus 80% and 97% versus 96%, respectively. Progression-free survival showed a modest improvement in favor of enzalutamide, reaching 67% versus 62%.

The trial enrolled 802 participants between 2014 and 2018, all receiving high-dose external beam radiation with or without a brachytherapy boost and two years of ADT using luteinizing hormone–releasing hormone agonists. Participants in the experimental arm received 160 mg of enzalutamide daily for 24 months, while those in the control arm received six months of conventional non-steroidal anti-androgen therapy. In 2020, the study adopted MFS as its primary endpoint, replacing overall survival due to low mortality rates in modern treatment settings.

Although the overall results did not favor enzalutamide for the broad patient population, subgroup analyses revealed a clear benefit for those with clinically node-positive (N1) disease or those receiving pelvic nodal irradiation. In these subgroups, five-year MFS reached 87% with enzalutamide compared with 77% in the control group, suggesting a selective advantage for more advanced regional disease. This pattern mirrors findings from the STAMPEDE platform, where intensified androgen receptor blockade similarly improved outcomes in node-positive cohorts.

Safety results reflected the known profile of enzalutamide. Rates of grade 3 or higher toxicities were comparable between treatment arms, but fatigue, neurologic effects, and psychiatric symptoms were more frequent among patients on enzalutamide.

Researchers from the Dana-Farber Cancer Institute and collaborating institutions concluded that broad adoption of enzalutamide for all high-risk localized prostate cancer cases is unwarranted. However, for patients with lymph node involvement or those already eligible for pelvic nodal radiation, targeted use of the agent alongside ADT and radiation appears justified.

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