A randomized phase 2 study of enhanced AR blockade with enzalutamide in high-risk patients with biochemical relapse undergoing salvage radiation: Final results from RTOG 3506 (STEEL).

156 Background: Patients with high-risk features who experience biochemical relapse (BCR) after radical prostatectomy (RP) benefit from the addition of androgen deprivation therapy (ADT) to salvage radiotherapy (SRT). We hypothesized that enhanced androgen receptor (AR) blockade (eARB) with enzalutamide would improve SRT outcomes for high-risk patients. Methods: Post-RP patients who had BCR (PSA ≥ 0.2 ng/mL) with at least 1 high-risk feature (Gleason 8-10, seminal vesicle invasion, pN1, persistent PSA >0.1 ng/mL after RP, and PSA ≥ 0.7 ng/mL) were eligible. Patients were randomized 1:1 to 24 months of standard ADT (sADT) with an LHRH analog (LHRHa) or eARB comprised of LHRHa + enzalutamide 160 mg daily. Progression free survival (PFS) was analyzed with progression defined as PSA ≥ 0.2 ng/mL or initiation of new therapy following SRT. Results: Between April 2019 and August 2022, 188 patients were enrolled. The patient characteristics were well balanced between the two arms. Median age was 64 years. Nodal involvement (pN1), pT3a-b, and Gleason 9 were noted in 22%, 77%, and 52% of patients, respectively. Over 70% had ≥2 aggressive features. Median follow-up time at the time of this report was 34.6 months. Prostatic fossa and pelvic SRT were mandatory. Para-aortic radiotherapy (RT), and lymph node and prostatic fossa lesion RT boosts were left at the discretion of the radiation oncologist. The SRT+eARB arm had better PFS when compared to the SRT+sADT arm (HR=0.62, 80% CI: 0.42-0.91, one-sided p=0.052). The rate of biochemical failure at 2 years was 19% (95% CI: 12-28) in the SRT+sADT arm as compared to 11% (95% CI: 5-18) in the SRT+eARB arm. Grade 3 adverse events (AEs) related to sADT vs. eARB were 19% vs. 30%, while Grade 4 AEs were 4% vs. 2%, respectively. The most common AEs (all grades, >15%) included hot flashes, fatigue, diarrhea, and decreased lymphocytes. The grade 3+ AEs (>3%) included decreased lymphocytes and hypertension. Conclusions: The addition of enzalutamide to standard ADT resulted in an improvement of PFS following SRT, warranting a phase 3 trial. The increase in toxicity was consistent with other studies of enzalutamide and did not identify new safety concerns. Clinical trial information: NCT03809000 .