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SAN FRANCISCO — A gene signature panel could help identify men with localized prostate cancer who would benefit from radiotherapy dose escalation in both the definitive and salvage settings, according to the results of an analysis of two phase 3 randomized clinical trials.

The findings offer the first randomized evidence for a biomarker that can predict radiation response, said senior investigator and study presenter Shuang Zhao, MD, a radiation oncologist and researcher at the University of Wisconsin, Madison, Wisconsin.

The assay, dubbed the Post-Operative Radiation Therapy Outcomes Score (PORTOS), could help select patients who will likely benefit from escalated radiation doses while steering away men who likely won’t and may instead experience unnecessary toxicity from the higher dose, said Zhao, presenting at the American Society of Clinical Oncology’s 2025 Genitourinary Cancers Symposium.

PORTOS was developed by Zhao and his team using the Decipher Prostate gene expression assay from Veracyte, Inc. In previous work, the researchers identified the 24 genes most strongly associated with radiation response after biochemical failure following prostatectomy.

The new investigation aimed to further validate the association in both the postsurgical salvage setting and in men treated with upfront definitive radiation instead of surgery.

To do so, Zhao and his colleagues turned to two completed phase 3 trials. The first, NRG/RTOG 0126, showed a benefit for dose escalation from 70.2 Gy to 79.2 Gy for upfront radiotherapy. The second trial, SAKK 09/10, failed to a show benefit for dose escalation from 64 Gy to 70 Gy for post-operative salvage.

The team calculated PORTOS scores from tissue samples based on the trials and correlated the scores with patient outcomes.

Prostatectomy samples from SAKK 09/10 received either a low or high score, in line with previous publications. Biopsy samples from RTOG 0126, however, were evaluated in tertiles for low, average, or high scores.

Among 215 RTOG patients, dose-escalation made no difference in biochemical failure risk among those with lower PORTOS scores (subdistribution hazard ratio [sHR], 1.03; 95% CI, 0.45-2.36; P = .94). However, dose escalation significantly lowered the risk for biochemical failure in patients with mid-range (sHR, 0.45; P = .02) and high scores (sHR, 0.30; P = .009). 

Among the 226 SAKK patients, only high PORTOS scores were associated with a substantially better chance of clinical progression-free survival (HR, 0.19; P = .01). 

PORTOS scores were not associated with common clinical and pathologic variables, including Gleason grade, lymph node involvement, and several others. Scores were, however, associated with tumor hypoxia, tumor immune signatures, and molecular subtypes, which are known to be associated with radiation response.

Although SAKK did not show an overall benefit for dose escalation in the salvage setting, “PORTOS seemed to be able to identify a subset of patients who do benefit,” said Zhao.

And although RTOG did show an overall benefit for higher upfront definitive radiation doses, “PORTOS was able to identify a subset of patients who don’t need a dose escalation,” Zhao said.

Looking for ways to identify patients for dose escalation is important, said Edwin Posadas, MD, a prostate cancer specialist and researcher at Cedars-Sinai Medical Center, Los Angeles, who commented on the study. “I think emerging biomarkers such as PORTOS may help us to optimize selection and dosing for these patients.”

However, “there’s still a number of other variables that need to be considered, including patient-based variables and biology that will impact toxicity and outcomes for patients on the whole,” he said.

Zhao and his team are now investigating PORTOS in the setting of androgen deprivation therapy, elective nodal irradiation, and PSMA-PET and are looking to see if PORTOS can help with the decision between upfront surgery or radiation of localized prostate cancer.

The work was funded by the National Cancer Institute. Investigators included Veracyte employees. Zhao disclosed pending patent applications. Posadas is an advisor and speaker for Bayer and disclosed research funding from EnviroTherapetuics and Pfizer.

M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape Medical News. Email: aotto@mdedge.com.