NRG-GU005

Background

NRG-GU005: phase 3, international, open-label, randomized trial (136 centers, Asia/Canada/Europe/US; accrual Nov 2017–Jun 2022). N=698 men with localized intermediate-risk prostate cancer: cT1–T2b, Gleason 3+4 (grade group 2) with PSA <20 ng/mL, or Gleason 3+3 (grade group 1) with PSA 10–20 ng/mL. Tested whether ultrahypofractionated SBRT (5 fractions) is superior to moderately hypofractionated IMRT for both patient-reported bowel/urinary quality of life and disease control. Co-primary design powered for an 8% (urinary irritative/obstructive) and 10% (bowel) absolute reduction in EPIC-26 minimal clinically important decline (MCID) at 2 years and for a DFS HR of 0.62.

Results

INTERVENTIONS AND FOLLOW UP: Arm A: SBRT 36.25 Gy in 5 fractions (n=353)
Arm B: Moderately hypofractionated IMRT 70 Gy in 28 fractions or 60 Gy in 20 fractions (n=345)
Primary endpoint: Co-primary — frequency of EPIC-26 MCID in the urinary irritative/obstructive and bowel domains at 2 years, and DFS at 3 years
mFollow up: 3.2 years (range 0–6.5)
RESULTS: EPIC-26 urinary irritative/obstructive MCID at 2 y: 35.4% vs 33.7%, P=.68 (not met)
EPIC-26 bowel MCID at 2 y: 34.9% vs 43.8%, P=.03 (favors SBRT)
DFS at 3 y: 88.6% (95% CI 85.2–92.1) with SBRT vs 92.1% (95% CI 88.9–95.2) with MH-IMRT; 1-sided log-rank P<.001 — superiority of SBRT not demonstrated, interim futility boundary crossed
Local recurrence at 3 y: 1.2% vs 1.0%
OS at 3 y: 97% vs 97%
PSA failure: not significantly improved with SBRT
Other PRO domains: urinary incontinence at 1 y and 2 y and sexual function at 1 y favored SBRT

Adverse events

Genitourinary grade 3–4: 0.6% vs 2.5%, P=.04 (favors SBRT)
Gastrointestinal grade 3–4: NR
Treatment discontinuation: NR

Conclusions

Five-fraction SBRT at 36.25 Gy did not improve disease-free survival over moderately hypofractionated IMRT in intermediate-risk localized prostate cancer, and the DFS comparison crossed the interim futility boundary. SBRT did deliver a better patient experience: fewer clinically meaningful 2-year declines in bowel quality of life, better urinary continence and sexual function, and fewer grade 3–4 genitourinary events, with identical 3-year local recurrence (~1%) and overall survival (97%). SBRT is therefore best framed as a shorter, better-tolerated alternative rather than a more effective one.

Key Limitations

Open-label design with patient-reported co-primary endpoints, so response bias cannot be excluded. The SBRT dose (36.25 Gy/5) is at the low end of contemporary practice — several modern series use 40 Gy/5 — and the numerically higher PSA-failure rate may reflect underdosing rather than a limitation of ultrahypofractionation itself. DFS at 3 years is a short-horizon surrogate in a disease with a decade-plus natural history, and the trial was stopped for DFS futility at interim, limiting long-term biochemical and metastasis-free comparisons. Androgen deprivation use, rectal spacer use, and image-guidance technique were not uniform. Cohort was 80% White, limiting generalizability. Grade 3–4 gastrointestinal toxicity was not separately reported in the primary abstract.

Clinical Context

Both regimens are already accepted radiotherapy options; no new regulatory action attaches to this trial. NCCN, ASTRO/ASCO/AUA, and ESMO all endorse ultrahypofractionated SBRT as a standard external-beam option for low- and intermediate-risk localized prostate cancer, based largely on HYPO-RT-PC and PACE-B, which established non-inferior disease control and acceptable toxicity. NRG-GU005 was the first trial to test SBRT for superiority against moderately hypofractionated IMRT and did not achieve it, so SBRT should continue to be offered on the basis of convenience (5 visits vs 20–28) and favorable bowel/GU tolerability rather than improved cancer control. The findings argue for careful dose selection — 36.25 Gy may be insufficient for grade group 2 disease — and reinforce shared decision-making when counseling intermediate-risk patients.

References