ASCO 2022: Phase II, Double-Blind, Randomized Study of Salvage Radiation Therapy Plus Enzalutamide or Placebo for High-Risk PSA-Recurrent Prostate Cancer After Radical Prostatectomy: The SALV-ENZA Trial

( At the 2022 American Society of Clinical Oncology Annual Meeting held in Chicago and virtually, the poster session focused on Prostate, Testicular, and Penile cancers on Monday afternoon included a presentation from Dr. Phuoc T. Tran presenting results of the SALV-ENZA trial, a phase II study assessing salvage radiotherapy with or without enzalutamide for patients with high-risk PSA-recurrence following radical prostatectomy for prostate cancer.

The role of novel hormonal agents in prostate cancer has significantly evolved over the past decade: these agents were initially used in the post-chemotherapy metastatic castration resistant disease (mCRPC), followed by the pre-chemotherapy mCRPC space, metastatic castration sensitive disease, and now non-metastatic castration resistant and castration sensitive disease. Patients with high-risk biochemical recurrence following radical prostatectomy are at high risk of disease progression. As such, these authors sought to assess whether enzalutamide treatment, without androgen deprivation therapy, increases freedom-from-PSA-progression (FFPP) when combined with salvage radiation therapy (SRT) in men with recurrent prostate cancer post-radical prostatectomy (RP).

To do so, the authors enrolled men with biochemically recurrent prostate cancer after RP were enrolled. This double-blind, phase II, placebo-controlled, multicenter randomized men to SRT + placebo or SRT + enzalutamide in a 1:1 fashion (NCT02203695). The randomization was stratified by center, surgical margin status (R0 vs R1), PSA prior to salvage treatment (PSA ≥0.5 vs < 0.5 ng/mL), and pathologic Gleason sum (7 vs 8-10) using a minimization algorithm.

ASCO22_Phuoc T. Tran_0 

Following randomization, patients received either placebo or enzalutamide at standard doses (160 mg PO once daily) for 6 months. Following 2 months of study drug therapy, external beam radiotherapy to 66.6-70.2 Gy was administered to the prostate bed (no pelvic nodes). The primary endpoint was FFPP. The authors sought to assess the hypothesis of a 54% benefit (HR 0.44) in freedom-from-PSA-progression (FFPP). This resulted in a planned sample size of 96. Unfortunately, the trial was closed as of March 2020 after enrolling 86 men. In addition to FFPP, the authors assessed secondary endpoints including time to local recurrence (LR) within the radiation field, metastasis‐free survival (MFS), and safety as determined by frequency and severity of adverse events (AEs).

In total, 86 patients were randomized. The median pre-SRT PSA was 0.3 (range 0.06-4.6) ng/mL, 56/86 (65%) had extra-prostatic disease (pT3), 39/86 (45%) had Gleason Grade Group 4 or higher and 43/96 (50%) had positive surgical margins with differences between the two trial arms.

Over a median follow-up of 34 (range 0-52) months, FFPP was significantly improved with enzalutamide (compared to placebo) with a HR 0.40 [95% confidence interval (CI), 0.17-0.92, p-value = 0.026]. At the 2-year landmark, FFPP was 87.1% vs 68.1%, respectively.

ASCO22_Phuoc T. Tran_1 

Subgroup analyses demonstrate evidence of effect modification (p-value of interaction = 0.019) with a differential benefit of enzalutamide in men with pT3 (HR 0.22, 95%CI 0.07-0.69) vs pT2 disease (HR 1.54, 95%CI 0.43-5.47). There was also evidence of a greater benefit (p-value of interaction = 0.023) among those with positive surgical margins (HR 0.14, 95% CI 0.03-0.64) compared to those with negative margins (HR 1.00, 95% CI 0.36-2.76).

ASCO22_Phuoc T. Tran_2 

Event rates for secondary outcomes were insufficient for analysis. The most common adverse events were grade 1-2 fatigue (13% enzalutamide vs 9%) and urinary frequency (6 % enzalutamide vs 8%).

ASCO22_Phuoc T. Tran_3 

Thus, the authors conclude that the combination of salvage radiotherapy with enzalutamide monotherapy for men with PSA recurrent high-risk prostate cancer following RP is safe and delays PSA progression relative to salvage radiotherapy alone. Further work assessing longer-term outcomes and biomarkers for patient selection is ongoing.

Presented by: Phuoc T. Tran, MD, PhD, Professor and Vice Chair for Research of Radiation Oncology, University of Maryland Medical Center

Written by: Christopher J.D. Wallis, University of Toronto, Twitter: @WallisCJD during the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, June 3 – Mon, June 7, 2022.