Supplemental Xtandi Does Not Improve Metastasis-Free Survival in High-Risk Prostate Cancer

The addition of two years of Xtandi (enzalutamide) to standard androgen deprivation therapy (ADT) and high-dose radiation therapy did not significantly improve metastasis-free survival (MFS) for patients with high-risk clinically localized or locally advanced prostate cancer, according to data from the phase 3 ENZARAD (ANZUP 1303) trial which were shared in a presentation from the 2025 ESMO Congress.

After a median follow-up of eight years, in the overall unselected population, MFS was 74% for patients receiving Xtandi versus 72% for those receiving a conventional non-steroidal anti-androgen (NSAA), investigators shared.

“The trial did not show a meaningful MFS benefit for Xtandi in unselected high-risk localized prostate cancer, but for patients with positive lymph nodes on computed tomography or magnetic resonance imaging or other indications for pelvic radiation, the data support considering the addition of Xtandi,” Dr. Paul L. Nguyen said in the presentation

Nguyen is currently a senior physician and director of Genitourinary Radiation Oncology at Dana-Farber Cancer Institute, in Boston, Massachusetts, where he also serves as a professor of radiation oncology at Harvard Medical School.

Despite the lack of a broad MFS benefit, research identified certain patients that derived substantial advantage from Xtandi. Among patients with clinical N1 disease, five-year MFS reached 87% with Xtandi versus 77% for NSAA, indicating that targeted intensification may be warranted in carefully selected patients.

Overall survival (OS) and prostate cancer-specific survival (PCSS) remained high across both study arms, with eight-year OS at 83% versus 80% and PCSS at 97% versus 96% for Xtandi versus NSAA. Progression-free survival (PFS) was modestly improved with Xtandi, with eight-year PFS of 67% versus 62%.

ENZARAD Phase 3 Trial: Design and Eligibility Criteria in High-Risk Prostate Cancer

The trial was designed as an international, investigator-initiated phase 3 study to determine whether adding Xtandi to high-dose radiation and two years of ADT improves outcomes in high-risk prostate cancer.

Participants were randomized to receive either 160 milligrams (mg) of Xtandi daily for 24 months or conventional NSAA for six months, with all patients receiving luteinizing hormone-releasing hormone agonist therapy for 24 months. Radiation therapy was delivered to the prostate at plus a brachytherapy boost.

The trial enrolled 802 participants across eight countries from March 2014 to June 2018, with a median follow-up of eight years. Baseline characteristics reflected a typical high-risk population, though only 11% were N1 by conventional imaging. The primary end point, MFS, was assessed by conventional imaging (CT, MRI, or bone scan), with prostate-specific membrane antigen–positron emission tomography-only lesions insufficient to define events.

The primary end point was changed from overall survival to MFS in June 2020 due to lower-than-expected death rates in contemporary trials, with events confirmed by a blinded central review committee.

Safety Outcomes from the Phase 3 ENZARAD Trial

Side effects reflected the known safety profile of Xtandi. Grade 1/2 events occurred in 210 patients on Xtandi versus 206 NSAA patients, grade 3/4 in 182 versus 181, and grade 5 in 3 versus 4, respectively.

Fatigue was more common in the Xtandi arm (337 patients grade 1/2, 16 patients grade 3/4) compared with NSAA (315 patients, 6 patients), while hot flashes were reported in 308 versus 278 patients at grade 1/2. Nervous system events were higher with Xtandi (177 patients grade 1/2, 25 patients grade 3/4) versus NSAA (122 patients, 15 patients), and psychiatric events occurred in 178 versus 169 patients.

Metabolic and nutritional events, respiratory events, hypertension, infections, and liver enzyme elevations were observed in both arms, predominantly grade 1/2. Cardiac events, falls, fractures, thromboembolic events, seizures, and deaths from other causes occurred at similar rates across arms.

Subgroup Analyses and Comparison to Previous Trials

Patients with regional lymph node involvement experienced fewer events with Xtandi compared with NSAA, and those receiving pelvic nodal irradiation similarly derived benefit. Very high-risk patients did not demonstrate significant interaction with treatment. Age and geographic region did not modify treatment effect on MFS. Exploratory analyses revealed a range of outcomes based on eligibility criteria. Patients with clinical N1 disease and Gleason 9-10 had five-year MFS of 87% with Xtandi versus 74% with NSAA, while better prognostic patients had five-year MFS of 86% versus 90% and OS of 90% versus 91%.

Comparisons with the STAMPEDE trial indicate ENZARAD findings in N1 patients are consistent with prior results using Zytiga (abiraterone). Differences in baseline patient characteristics explain why the overall MFS benefit in the full cohort was not significant.

Nguyen noted, “The benefit in clinical N1 is consistent with STAMPEDE, but ENZARAD enrolled more favorable patients, and our findings were essentially the same as STAMPEDE for N1 patients.”

Reference

1. “Randomised phase 3 trial of androgen deprivation therapy (ADT) with radiation therapy with or without enzalutamide for high risk, clinically localised prostate cancer: ENZARAD (ANZUP 1303),” by Dr. Paul L. Nguyen. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA86.

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