Enzalutamide plus salvage radiotherapy associated with improved PFS in high-risk BCR

In men with high-risk biochemical recurrence after radical prostatectomy, adding enzalutamide (Xtandi) to salvage radiotherapy (SRT) and 24 months of a gonadotropin-releasing hormone (GnRH) analog was associated with improved progression-free survival (PFS), according to results from the randomized phase 2 RTOG 3506 (STEEL) trial.¹

Final results were presented at the 2026 American Society for Radiation Oncology (ASTRO) Annual Meeting in Boston, Massachusetts.

“Hormone therapy with salvage radiotherapy is a standard of care. The benefit is not uniform, and this is well known in the field,” said lead author , of Cedars-Sinai Medical Center in Los Angeles, California, during the presentation at ASTRO. “In RTOG 9601, 24 months of bicalutamide with SRT did improve overall survival—at 18 years, survival was 53% vs 43%.² However, the DADSPORT meta-analysis found that only a small overall survival effect existed, and any survival benefit appeared to be concentrated in men with higher risk disease, such as higher pre-radiotherapy PSAs or higher CAPRA scores.³ This tells us where it's most likely to matter [is] in men with high-risk features, and this is the population that we focused on in STEEL.”

STEEL trial design

STEEL (NCT03809000) was a multicenter randomized phase 2 trial led by the RTOG Foundation in partnership with Pfizer and Astellas Pharma, with sites in the US and Canada. Eligible patients had biochemical recurrence after radical prostatectomy, defined as a prostate-specific antigen (PSA) level of 0.2 ng/mL or higher (or 0.1 ng/mL or higher on an ultrasensitive assay), plus at least 1 aggressive feature. These included Gleason score 8 to 10, seminal vesicle invasion, pN1 disease, persistently elevated PSA after prostatectomy (>0.1 ng/mL), or PSA of 0.7 ng/mL or higher.

Patients were randomly assigned 1:1 to SRT plus 24 months of a GnRH analog, with or without enzalutamide 160 mg daily. Radiotherapy to both the prostatic fossa (66.6 to 70.2 Gy in 1.8-Gy fractions or 66 to 70 Gy in 2.0-Gy fractions) and the pelvic lymph nodes (45 to 50.4 Gy in 1.8 Gy fractions or 44 to 50 Gy in 2.0-Gy fractions) was mandatory. Para-aortic coverage and nodal boosts were optional. All patients received daily image guidance, and radiotherapy quality was centrally reviewed.

"So, the radiotherapy fields were much more contemporary than 9601," said Posadas, referring to the landmark NRG/RTOG 9601 trial.

The primary end point was PFS, defined as the first biochemical failure or clinical failure. The protocol originally defined biochemical failure as a detectable PSA of 0.05 ng/mL or higher. Posadas explained that participating sites used assays with different lower limits of detection and that case report forms could not reliably record an undetectable PSA. The investigators therefore analyzed biochemical failure at a threshold of 0.2 ng/mL or higher. Posadas described this analysis as post hoc and said the details will be reported in the full manuscript.

Patient population and adherence

The trial enrolled patients from April 2019 through August 2022. In total, 188 patients were randomly assigned: 90 to enzalutamide and 98 to standard ADT. Median age was 64 years, and 11.2% of patients were Black. More Black patients were assigned to the enzalutamide arm than to the standard arm (16.7% vs 6.1%), so race was included in adjusted models.

The population was high risk: 45.2% had pT3b disease, 21.8% were pN1, approximately 61% had Gleason score 8 to 10 disease, and 71.8% had more than 1 aggressive feature. Median pre-SRT PSA was 0.605 ng/mL overall and was higher in the enzalutamide arm (0.785 vs 0.565 ng/mL).

GnRH analog therapy was completed per protocol by 78% of the enzalutamide arm and 81% of the standard arm.

Posadas added, “As you might expect, enzalutamide was a little harder to sustain: 53% of the patients completed treatment per protocol, 18% stopped because of adverse events, and about a third received less than 80% of the planned dose.”

Efficacy and safety

At a median follow-up of 33.1 months, results showed a PFS benefit favoring the enzalutamide arm (HR, 0.62; 80% CI, 0.42 to 0.91; one-sided P = .052). At 2 years, PFS was 88% with enzalutamide and 79% on the standard arm. After adjustment for aggressive features, race, and age, the HR was 0.54 (80% CI, 0.36 to 0.80; 2-sided P = .04).

"The benefit persisted, though nearly half of the patients stopped enzalutamide early,” Posadas added.

Grade 3 adverse events (AEs) occurred in 30% of patients receiving enzalutamide vs 19% of those receiving standard ADT. Grade 4 AEs occurred in 2% vs 4%, and there were no grade 5 events. Grade 3 or 4 decreased lymphocyte count occurred in 15% vs 5% of patients, and grade 3 or 4 hypertension in 8% vs 5%.

Treatment-related cardiac events were rare in both arms. No seizures were reported, although the protocol excluded patients with a history of seizure.

"These hypothesis-generating results support a phase 3 trial of intensified AR blockade with salvage radiotherapy,” Posadas concluded. “I would suggest that the trial use metastasis-free survival as its end point and have a regimen designed for adherence and capture PSA data with explicit undetectable values.”

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REFERENCES

1. Posadas E, Gay HA, Pugh SL, et al. A Randomized Phase II Study of Enhanced AR Blockade with Enzalutamide In High-Risk Patients with Biochemical Relapse Undergoing Salvage Radiation: Final Results from RTOG 3506 (STEEL). Presented at: 2026 American Society for Radiation Oncology Annual Meeting. September 26 – 30, 2026. Boston, Massachusetts. Abstract 249

2. Lukka PR, Pugh SL, Shipley WU, et al. Long-Term Results of NRG/RTOG 9601, a Randomized Trial of Radiation With or Without Antiandrogens in Patients Receiving Salvage Prostate Bed Radiation Therapy Postprostatectomy. Int J Radiat Oncol Biol Phys. 2025;123(4):990-999. doi:10.1016/j.ijrobp.2025.07.1416

3. Burdett S, Fisher DJ, Tierney JF, et al. Duration of Androgen Suppression with Postoperative Radiotherapy (DADSPORT) for Nonmetastatic Prostate Cancer: A Collaborative Systematic Review and Meta-analysis of Aggregate Data. Eur Urol. 2025;88(3):277-290. doi:10.1016/j.eururo.2025.05.013