Phase II Randomized Study of Salvage Radiation Therapy Plus Enzalutamide or Placebo for High-Risk Prostate-Specific Antigen Recurrent Prostate Cancer After Radical Prostatectomy: The SALV-ENZA Trial

Abstract

Purpose: We sought to investigate whether enzalutamide (ENZA), without concurrent androgen deprivation therapy, increases freedom from prostate-specific antigen (PSA) progression (FFPP) when combined with salvage radiation therapy (SRT) in men with recurrent prostate cancer after radical prostatectomy (RP).

Patients and methods: Men with biochemically recurrent prostate cancer after RP were enrolled into a randomized, double-blind, phase II, placebo-controlled, multicenter study of SRT plus ENZA or placebo (ClinicalTrials.gov identifier: NCT02203695). Random assignment (1:1) was stratified by center, surgical margin status (R0 v R1), PSA before salvage treatment (PSA ≥ 0.5 v < 0.5 ng/mL), and pathologic Gleason sum (7 v 8-10). Patients were assigned to receive either ENZA 160 mg once daily or matching placebo for 6 months. After 2 months of study drug therapy, external-beam radiation (66.6-70.2 Gy) was administered to the prostate bed (no pelvic nodes). The primary end point was FFPP in the intention-to-treat population. Secondary end points were time to local recurrence within the radiation field, metastasis-free survival, and safety as determined by frequency and severity of adverse events.

Results: Eighty-six (86) patients were randomly assigned, with a median follow-up of 34 (range, 0-52) months. Trial arms were well balanced. The median pre-SRT PSA was 0.3 (range, 0.06-4.6) ng/mL, 56 of 86 patients (65%) had extraprostatic disease (pT3), 39 of 86 (45%) had a Gleason sum of 8-10, and 43 of 86 (50%) had positive surgical margins (R1). FFPP was significantly improved with ENZA versus placebo (hazard ratio [HR], 0.42; 95% CI, 0.19 to 0.92; P = .031), and 2-year FFPP was 84% versus 66%, respectively. Subgroup analyses demonstrated differential benefit of ENZA in men with pT3 (HR, 0.22; 95% CI, 0.07 to 0.69) versus pT2 disease (HR, 1.54; 95% CI, 0.43 to 5.47; P_interaction = .019) and R1 (HR, 0.14; 95% CI, 0.03 to 0.64) versus R0 disease (HR, 1.00; 95% CI, 0.36 to 2.76; P_interaction = .023). There were insufficient secondary end point events for analysis. The most common adverse events were grade 1-2 fatigue (65% ENZA v 53% placebo) and urinary frequency (40% ENZA v 49% placebo).

Conclusion: SRT plus ENZA monotherapy for 6 months in men with PSA-recurrent high-risk prostate cancer after RP is safe and delays PSA progression relative to SRT alone. The impact of ENZA on distant metastasis or survival is unknown at this time.

FIG 1.

CONSORT diagram of the SALV-ENZA trial. GBM, glioblastoma multiforme.

FIG 2.

Kaplan-Meier curves of PSA progression-free survival (FFPP) by enzalutamide versus placebo arms. FFPP, freedom from prostate-specific antigen progression; PSA, prostate-specific antigen.

FIG 3.

Forest plots of subgroup analysis for FFPP of enzalutamide versus placebo arms. Pathologic T-stage (pT3 v pT2) and surgical margin status (R1 v R0) displayed differential benefit from the addition of enzalutamide to salvage radiation. FFPP, freedom from prostate-specific antigen progression; HR, hazard ratio; MI, University of Michigan; OHSU, Oregon Health & Science University; PSA, prostate-specific antigen; SRT, salvage radiotherapy.

FIG 4.

Forest plots of gene expression signature subgroup analysis for FFPP of enzalutamide versus placebo arms. Selected signatures included Decipher risk group, ERG alteration, PAM50 subtype, ADT score, homologous recombination deficiency classifier, RB1 loss signature, Activated CD8 and T reg signatures, and p53 Hallmarks of Cancer signature. For RB1 loss signature (loss v intact), activated CD8 (higher v lower) T reg (higher v lower) signatures, and p53 hallmarks of cancer (higher v lower) signature values were split into ≤ median and > median for categorical survival analysis. Higher RB1 loss signatures scores were shown to predict DNA-level biallelic loss of RB. Higher activated CD8 activity and T reg signature scores characterize the intratumoral immune levels for activated CD8 and regulatory T cells, respectively. Higher p53 hallmark signature scores predict p53 tumor suppressor pathway activity. ADT, androgen deprivation therapy; FFPP, freedom from prostate-specific antigen progression; HR, hazard ratio; SRT, salvage radiotherapy.