A shorter course of radiotherapy (RT) after prostatectomy provides similar disease control and patient-reported outcomes as conventional fractionation at 5 years — but with a higher rate of physician-reported genitourinary (GU) toxicity, according to results from the phase 3 NRG-GU003 trial.

The findings extend earlier 2-year results supporting hypofractionated postprostatectomy radiotherapy (HYPORT) as an alternative to conventionally fractionated postprostatectomy radiotherapy (COPORT), while providing longer-term safety data.

Although the two regimens were similar in terms of patient-reported urinary and bowel symptoms at the 5-year mark, physician-reported grade 3 adverse events were twice as common with the hypofractionated approach, at 16% vs 7%. Most were renal or urinary disorders, according to findings presented at the American Society for Radiation Oncology (ASTRO) 2026 Annual Meeting in Boston.

“HYPORT remains noninferior to COPORT for late patient-reported urinary and bowel outcomes,” said lead investigator Mark Buyyounouski, MD, MS, of the Stanford Cancer Institute in Palo Alto, California.

He characterized the tradeoff as “increased physician-reported urinary toxicity for less treatment burden, with no lasting patient-reported difference.”

The shorter regimen cuts treatment visits by one third compared to conventional RT, potentially saving patients time and money, Buyyounouski noted.

Study discussant Sophia Kamran, MD, of Massachusetts General Hospital and Harvard Medical School in Boston, called moderate hypofractionation “a reasonable prostate bed radiation option.”

But she said the findings on late GU toxicity should inform shared decision-making — especially for relatively younger patients, who may face more years at risk for late events.

Reducing Treatment Burden

Postprostatectomy RT can provide another opportunity for cure in men with adverse pathologic features or a detectable or rising prostate-specific antigen (PSA) after surgery. However, it’s delivered after patients have already experienced the potential urinary and sexual consequences of prostatectomy and adds further treatment burden.

NRG-GU003 tested whether HYPORT, which eliminates 12 treatment visits, was noninferior to conventional fractionation for patient-reported urinary and bowel symptoms at 2 years. Overall, 296 patients with adverse pathologic features after prostatectomy and either an undetectable or detectable PSA were randomly assigned to HYPORT (62.5 Gy in 25 fractions) or COPORT (66.6 Gy in 37 fractions).

Patients were stratified by baseline Expanded Prostate Cancer Index Composite (EPIC) score and use of androgen deprivation therapy (ADT). Lymph-node radiation was not permitted; ADT for up to 6 months was allowed.

The trial met its coprimary endpoints — changes from baseline to 2 years in the urinary and bowel domains of the EPIC questionnaire. HYPORT was noninferior to COPORT for patient-reported GU and gastrointestinal symptoms at 2 years, with no significant difference for freedom from biochemical failure, a secondary endpoint.

At 5 years, the main new safety signal involved physician-reported toxicity. Grade 3 adverse events were more common with HYPORT than COPORT (16% vs 7%), including grade 3 renal or urinary disorders (12.7% vs 3.4%), driven by higher rates of noninfective cystitis (7% vs 0%) and hematuria (5.6% vs 0.7%). Grade 3 gastrointestinal toxicity was uncommon and did not differ significantly between groups (2.1% vs 0.7%). There were no grade 4 or 5 treatment-related toxicities.

However, patient-reported urinary and bowel outcomes remained similar between groups at the 5-year mark. The mean change from baseline in EPIC urinary score was -8.0 with HYPORT vs -5.7 with COPORT (P = .40), whereas bowel scores changed by -2.0 vs 0.6 (P = .12), indicating that the earlier bowel decline with HYPORT did not persist, Buyyounouski noted.

Disease control also remained similar. At 5 years, estimated progression rates were approximately 25% with HYPORT and 22% with COPORT (hazard ratio, 1.05; P = .70), and biochemical failure rates were 21% and 18%, respectively (P = .30).

At a median follow-up of 7 years, 31 deaths had been reported — 17 with HYPORT and 14 with COPORT — including four (13%) from prostate cancer.

Shared Decision-Making

Buyyounouski said the findings leave clinicians and patients weighing a modest increase in physician-reported toxicity against a substantial reduction in the number of treatment visits.

“The clinically relevant question is how much incremental risk HYPORT adds to the risks of surgery and postoperative radiation,” he said.

Kamran emphasized that the GU events should not be dismissed simply because the patient-reported domain scores remained similar.

“These are fairly…substantial toxicities,” she said. “These physician-attributed events matter, even though the available patient-reported domain scores did not separate.”

Kamran said HYPORT may be most appropriate for patients for whom an additional 2 weeks of daily radiation would pose a substantial logistical or financial burden.

“I feel comfortable offering this to patients who are older, in particular,” she noted.

Kamran cautioned that 5 years may not be sufficient to fully characterize late toxicity, particularly since many patients who receive postoperative radiation are relatively young, and GU effects can emerge years after treatment.

“We don’t know what’s going to happen beyond 5 years, at 10 years, or 15 years,” Kamran said.

She added that HYPORT is “a good treatment option,” but one that “definitely warrants a good discussion with the patients.”

The study was funded by the National Cancer Institute. Buyyounouski and Kamran reported having no relevant disclosures.