Clinical Trial

. 2025 May;36(5):572-582.

doi: 10.1016/j.annonc.2025.01.017. Epub 2025 Feb 13.

Predicting dose response to prostate cancer radiotherapy: validation of a radiation signature in the randomized phase III NRG/RTOG 0126 and SAKK 09/10 trials

A Dal Pra¹, P Ghadjar², H M Ryu³, J A Proudfoot³, S Hayoz⁴, J M Michalski⁵, D E Spratt⁶, Y Liu³, C Schär⁴, A M Berlin⁷, D R Zwahlen⁸, J P Simko⁹, T Hölscher¹⁰, J A Efstathiou¹¹, B Polat¹², H M Sandler¹³, G Hildebrandt¹⁴, M B Parliament¹⁵, A-C Mueller¹⁶, I S Dayes¹⁷, L Plasswilm¹⁸, R J M Correa¹⁹, J M Robertson²⁰, T G Karrison²¹, E Davicioni³, W A Hall²², F Y Feng⁹, A Pollack²³, G N Thalmann²⁴, P L Nguyen²⁵, D M Aebersold²⁶, P T Tran²⁷, S G Zhao²⁸

Affiliations

¹ Department of Radiation Oncology, University of Miami/Sylvester Comprehensive Cancer Center, Miami, USA. Electronic address: alan.dalpra@med.miami.edu.
² Department of Radiation Oncology, Charité Universitätsmedizin Berlin, Berlin, Germany.
³ Veracyte Inc., San Diego, USA.
⁴ SAKK Coordinating Center, Bern, Switzerland.
⁵ Washington University School of Medicine, Saint Louis, USA.
⁶ University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, USA.
⁷ University Health Network-Princess Margaret Hospital, Toronto, Canada.
⁸ Department of Radiation Oncology, Kantonsspital Winterthur, Winterthur, Switzerland.
⁹ University of California San Francisco, San Francisco, USA.
¹⁰ Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, Dresden, Germany.
¹¹ Massachusetts General Hospital Cancer Center, Boston, USA.
¹² Department of Radiation Oncology, University Hospital Wuerzburg, Wuerzburg, Germany.
¹³ Cedars-Sinai Medical Center, Los Angeles, USA.
¹⁴ Department of Radiation Oncology, University Hospital Rostock, Rostock, Germany.
¹⁵ University of Alberta, Edmonton, Canada.
¹⁶ Department of Radiation Oncology, Eberhard Karls University, Tübingen, Germany.
¹⁷ Juravinski Cancer Centre at Hamilton Health Sciences, Hamilton, Canada.
¹⁸ Department of Radiation Oncology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
¹⁹ London Health Sciences Centre, London, Canada.
²⁰ William Beaumont Hospital, Royal Oak, USA.
²¹ NRG Oncology Statistics and Data Management Center, Philadelphia, USA.
²² Medical College of Wisconsin, Milwaukee, USA.
²³ Department of Radiation Oncology, University of Miami/Sylvester Comprehensive Cancer Center, Miami, USA.
²⁴ Department of Urology, Bern University Hospital, Bern, Switzerland.
²⁵ Dana Farber Cancer Institute, Boston, USA.
²⁶ Department of Radiation Oncology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland.
²⁷ Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, USA. Electronic address: phuoc.tran@som.umaryland.edu.
²⁸ Department of Human Oncology, University of Wisconsin, Madison, USA. Electronic address: shgzhao@humonc.wisc.edu.

PMID: 39986927
PMCID: PMC12034480 (available on 2026-05-01)
DOI: 10.1016/j.annonc.2025.01.017

Clinical Trial

Predicting dose response to prostate cancer radiotherapy: validation of a radiation signature in the randomized phase III NRG/RTOG 0126 and SAKK 09/10 trials

A Dal Pra et al. Ann Oncol. 2025 May.

. 2025 May;36(5):572-582.

doi: 10.1016/j.annonc.2025.01.017. Epub 2025 Feb 13.

Authors

Affiliations

¹ Department of Radiation Oncology, University of Miami/Sylvester Comprehensive Cancer Center, Miami, USA. Electronic address: alan.dalpra@med.miami.edu.
² Department of Radiation Oncology, Charité Universitätsmedizin Berlin, Berlin, Germany.
³ Veracyte Inc., San Diego, USA.
⁴ SAKK Coordinating Center, Bern, Switzerland.
⁵ Washington University School of Medicine, Saint Louis, USA.
⁶ University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, USA.
⁷ University Health Network-Princess Margaret Hospital, Toronto, Canada.
⁸ Department of Radiation Oncology, Kantonsspital Winterthur, Winterthur, Switzerland.
⁹ University of California San Francisco, San Francisco, USA.
¹⁰ Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, Dresden, Germany.
¹¹ Massachusetts General Hospital Cancer Center, Boston, USA.
¹² Department of Radiation Oncology, University Hospital Wuerzburg, Wuerzburg, Germany.
¹³ Cedars-Sinai Medical Center, Los Angeles, USA.
¹⁴ Department of Radiation Oncology, University Hospital Rostock, Rostock, Germany.
¹⁵ University of Alberta, Edmonton, Canada.
¹⁶ Department of Radiation Oncology, Eberhard Karls University, Tübingen, Germany.
¹⁷ Juravinski Cancer Centre at Hamilton Health Sciences, Hamilton, Canada.
¹⁸ Department of Radiation Oncology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
¹⁹ London Health Sciences Centre, London, Canada.
²⁰ William Beaumont Hospital, Royal Oak, USA.
²¹ NRG Oncology Statistics and Data Management Center, Philadelphia, USA.
²² Medical College of Wisconsin, Milwaukee, USA.
²³ Department of Radiation Oncology, University of Miami/Sylvester Comprehensive Cancer Center, Miami, USA.
²⁴ Department of Urology, Bern University Hospital, Bern, Switzerland.
²⁵ Dana Farber Cancer Institute, Boston, USA.
²⁶ Department of Radiation Oncology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland.
²⁷ Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, USA. Electronic address: phuoc.tran@som.umaryland.edu.
²⁸ Department of Human Oncology, University of Wisconsin, Madison, USA. Electronic address: shgzhao@humonc.wisc.edu.

PMID: 39986927
PMCID: PMC12034480 (available on 2026-05-01)
DOI: 10.1016/j.annonc.2025.01.017

Abstract

Background: The SAKK 09/10 trial randomized biochemically recurrent prostate cancer patients to salvage radiation 64 Gy versus 70 Gy, and the NRG/RTOG 0126 randomized intermediate-risk prostate cancer patients to definitive radiation 70.2 Gy versus 79.2 Gy. We investigated a previously developed Post-Operative Radiation Therapy Outcomes Score (PORTOS) to identify preferential benefit from radiation dose escalation (DE).

Materials and methods: PORTOS was evaluated in patients enrolled in SAKK 09/10 and NRG/RTOG 0126 with available tissue that passed quality control (n = 226, 215). PORTOS was evaluated in the published post-operative groups in SAKK 09/10 and in tertiles in NRG/RTOG 0126 as cut-offs had not been established for biopsy samples and definitive radiation patients. Clinical and molecular correlates in a real-world dataset of 42 407 prostatectomy and 31 107 biopsy samples were also analyzed.

Results: In SAKK 09/10, the biomarker-treatment interaction was statistically significant between PORTOS (lower versus higher) and treatment arm for clinical progression-free survival. Only patients in the higher PORTOS group benefited from DE. In NRG/RTOG 0126, in patients with a lower tertile PORTOS, there was no difference in Phoenix biochemical failure (BF). However, for patients in the average and higher tertile PORTOS range, there was a significant benefit for DE for Phoenix BF. An interaction test indicated a significant difference in benefit for DE between higher and lower PORTOS groups. PORTOS was not strongly associated with clinicopathological variables in either trial or the large real-world dataset. In the latter, PORTOS was modestly associated with hypoxia signatures and strongly associated with immune signatures and subtypes.

Conclusion: In the SAKK 09/10 and RTOG 0126 randomized controlled trials, we demonstrated that PORTOS can potentially identify a subset of patients who benefit from DE, a subgroup that cannot be identified using clinicopathological or prognostic variables. These results suggest that PORTOS could be used clinically as a predictor of radiation response.

Keywords: biomarkers; prostate cancer; radiation dose response.

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Conflict of interest statement

Disclosure

Dr. Dal Pra declares research support from Veracyte, consulting fees and Scientific Advisory Board from Pfizer and Merck, support for attending meetings and/or travel from Global Congress on Prostate Cancer and ASTRO/CARO meeting, Medical Director at University of Miami. Dr. Davicioni declares employee of Veracyte, stock or stock options received from Veracyte. Dr. Dayes declares: participation on a Data Safety Monitoring Board or Advisory Board with a $1,500 Payment. Dr. Efstathiou declares consulting fees received from Blue Earth Diagnostics, Boston Scientific, AstraZeneca, Lantheus/Progenics, Astellas/Pfizer, payment or honoraria from Elekta, IBA, Genentech, UpToDate, Participation on a Data Safety Monitoring Board or Advisory Board for Merck, Roivant Pharma, Myovant Sciences, EMD Serono, Bayer Healthcare, Pfizer, Janssen, Progenics Pharmaceuticals, Gilead, Lantheus, Blue Earth Diagnostics, Angiodynamics, Clarity Pharmaceuticals, Board member (unpaid): Massachusetts Prostate Cancer Coalition (MPCC); American College of Radiation Oncology (ACRO); Radiation Oncology Institute (ROI). Dr. Hall declares grants or contracts from NIH, NCI, WE Care, Bobbie Nick Voss Foundation, Advancing a Healthier Wisconsin, royalties or licenses received from Sonoptima Inc (patent license), consulting fees received from Aktis Oncology, Sonoptima Inc, payment or honoraria for lectures received from Elekta to institution, support for attending meetings and/or travel from Elekta AB to institution, patents planned, issued, or pending number Patent 63/483,252, Vice Chair, Atlantic MR Linac Elekta Consortium, stock or stock options from Sonoptima Inc. Dr. Parliament declares support from the American College of Radiology. Dr. Pollack declares grants or contracts from Varian Medical Systems. Mr. Proudfoot and Dr. Ryu declare stock or stock options from Veracyte, Veracyte employees. Dr. Sandler declares support from the American College of Radiology in the form of institutional support in my role as GU committee chair during the conduct of the RTOG 0126 trial, support for attending meetings and/or travel to ASTRO has provided support for Board of Director from ASTRO as the current president. Dr. Simko declares stock or stock options received from Protean Biodiagnostics, Inc. Dr. Spratt declares payment or honoraria for lectures from Astellas, AstraZeneca, Bayer, Boston Scientific, Janssen, Novartis, Pfizer [personal fees], leadership or fiduciary role for NCCN, NCI GU Steering. Dr. Tran declares a patent for 9114158 issued to Natsar Pharmaceuticals with royalties paid from Natsar Pharmaceuticals [self], consulting fees received from NATSAR Pharmaceuticals, Johnson and Johnson, Regeneron, Bayer Healthcare, and Reflexion Medical Inc., personal fees from Johnson and Johnson, Regeneron, Bayer Healthcare, and Reflexion Medical Inc [self], support for attending meetings and/or travel from Reflexion Medical Inc, Bayer, Lantheus and J&J, leadership or fiduciary role as Cancer Research Senior Editor, NRG GU Translational Science Chair, ASTRO Research Funding Development Committee Chair. Dr. Zhao declares a patent on PORTOS licensed to Veracyte, other unrelated patents licensed to Veracyte, and a spouse who is an employee of Artera, who was a previous employee of Exact Sciences with stock. All remaining authors have declared no conflicts of interest.

References

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Predicting dose response to prostate cancer radiotherapy: validation of a radiation signature in the randomized phase III NRG/RTOG 0126 and SAKK 09/10 trials

Affiliations

Predicting dose response to prostate cancer radiotherapy: validation of a radiation signature in the randomized phase III NRG/RTOG 0126 and SAKK 09/10 trials

Authors

Affiliations

Abstract

Conflict of interest statement

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous