Results from the randomized phase II trial designated NRG/RTOG 3506, also known as STEEL, show that enhanced androgen receptor blockade using enzalutamide alongside salvage radiotherapy improves progression-free survival in high-risk prostate cancer patients experiencing biochemical relapse. Presented at the 2026 American Society for Radiation Oncology Annual Meeting in Boston, the trial evaluated 188 patients enrolled between April 2019 and August 2022.
RTOG 3506 Trial Results for Enzalutamide in High-Risk Prostate Cancer
The primary end point was progression-free survival (PFS), defined as the first biochemical failure or clinical failure. Because participating clinical sites utilized assays with varying lower limits of detection and case report forms could not reliably capture an undetectable PSA, investigators analyzed biochemical failure at a threshold of 0.2 ng/mL or higher. According to Posadas, this analysis was post hoc, with full details slated for the complete manuscript.
Patient Demographics and Treatment Adherence Patterns
The trial population comprised 188 randomly assigned patients, with 90 allocated to the enzalutamide arm and 98 to standard androgen deprivation therapy (ADT). The median patient age was 64 years. Black patients accounted for 11.2% of the total cohort, though distribution skewed toward the experimental arm at 16.7% compared with 6.1% in the standard arm, requiring race to be included in adjusted statistical models.
Investigators characterized the study population as high risk. Approximately 45.2% of participants had pT3b disease, 21.8% had pN1 disease, roughly 61% exhibited a Gleason score of 8 to 10, and 71.8% presented with more than one aggressive feature. The overall median pre-salvage radiation therapy PSA was 0.605 ng/mL, registering higher in the enzalutamide arm at 0.785 ng/mL versus 0.565 ng/mL in the standard arm.
While standard gonadotropin-releasing hormone analog therapy was completed per protocol by 78% of the enzalutamide group and 81% of the standard group, sustaining the oral study drug proved more challenging. Posadas noted that 53% of patients completed enzalutamide treatment per protocol, 18% discontinued therapy due to adverse events, and approximately one-third received less than 80% of the planned dose.
Clinical Insight: Despite nearly half of the patients stopping enzalutamide early, researchers observed a persistent progression-free survival benefit favoring the intensified blockade arm.
Efficacy Outcomes and Adverse Events
At a median follow-up of 33.1 months, the trial demonstrated a progression-free survival benefit favoring enzalutamide, yielding a hazard ratio of 0.62 (80% CI, 0.42 to 0.91; one-sided P = .052). At the two-year mark, PFS reached 88% in the enzalutamide arm compared with 79% in the standard ADT arm. Following adjustment for age, race, and aggressive disease features, the hazard ratio shifted to 0.54 (80% CI, 0.36 to 0.80; two-sided P = .04).
Safety analyses indicated that grade 3 adverse events occurred in 30% of patients receiving enzalutamide versus 19% of those on standard ADT. Grade 4 adverse events were documented in 2% of the enzalutamide group and 4% of the standard group, with zero grade 5 events recorded. Specific toxicities included grade 3 or 4 decreased lymphocyte counts in 15% versus 5% of patients, and grade 3 or 4 hypertension in 8% versus 5%. Treatment-related cardiac events remained rare across both treatment arms, and no seizures were reported, noting that the trial protocol explicitly excluded patients with a history of seizure.
Did You Know? The STEEL trial data build upon long-term investigations like NRG/RTOG 9601 and systematic reviews evaluating optimal androgen suppression durations with postoperative radiotherapy.
Future Directions for Intensified AR Blockade Trials
Posadas concluded that these hypothesis-generating findings support advancing to a phase 3 clinical trial evaluating intensified androgen receptor blockade combined with salvage radiotherapy. Future study designs should incorporate metastasis-free survival as the primary end point, establish regimens specifically optimized for patient adherence, and capture PSA data utilizing explicit undetectable values.
Frequently Asked Questions About the STEEL Trial
What was the primary end point of the STEEL trial?
The primary end point was progression-free survival, defined as the first biochemical failure or clinical failure.
How was biochemical failure defined in the analysis?
Investigators analyzed biochemical failure at a threshold of a detectable PSA of 0.2 ng/mL or higher, a post hoc decision necessitated by varying assay limits of detection across participating sites.
What were the main adherence challenges with enzalutamide?
Only 53% of patients completed the enzalutamide treatment per protocol, with 18% stopping due to adverse events and about one-third receiving less than 80% of the planned dose.
Were there any safety concerns regarding seizures?
No seizures were reported during the trial, though the study protocol excluded patients who had a prior history of seizure.
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