PORTOS Biomarker Guides Radiation Dose Escalation in Prostate Cancer Treatment - George Zhao & Alan Dal Pra
February 27, 2025
Alicia Morgans is joined by Alan Dal Pra and George Zhao to discuss updates to the PORTOS Trial. PORTOS is a gene signature developed to predict radiation therapy benefit in prostate cancer, built on Veracyte's Decipher® platform using 24 genes to calculate radiation response. The signature has been validated in two randomized trials - SAKK 09/10 in the post-operative setting and RTOG 0126 in the definitive setting. In both trials, PORTOS successfully identified patients who benefited from radiation dose escalation, with higher PORTOS scores correlating with greater benefit. Molecular analysis revealed associations with hypoxia and immune response pathways. The speakers highlight that PORTOS represents the first biomarker validated in multiple randomized trials as predicting radiation dose response in any cancer, providing level 1b evidence that can guide personalized treatment decisions.
Biographies:
Shuang (George) Zhao, MD, Physician Scientist, Assistant Professor, Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI
Alan Dal Pra, MD, Radiation Oncologist, The University of Miami, Miami, FL
Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts
Biographies:
Shuang (George) Zhao, MD, Physician Scientist, Assistant Professor, Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI
Alan Dal Pra, MD, Radiation Oncologist, The University of Miami, Miami, FL
Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts
Related Content:
ASCO GU 2025: Gene Signature Predictor of Dose-response to Prostate Radiation: Validation of PORTOS in Phase III Trials
ASCO GU 2025: Discussant: Optimizing (radiotherapy) Treatment for High-risk Prostate Cancers
PORTOS as a Predictive Biomarker to Help Personalize Radiotherapy Dose in the Postoperative Setting, in the SAKK 09/10 Trial - Alan Dal Pra
ASCO GU 2025: Gene Signature Predictor of Dose-response to Prostate Radiation: Validation of PORTOS in Phase III Trials
ASCO GU 2025: Discussant: Optimizing (radiotherapy) Treatment for High-risk Prostate Cancers
PORTOS as a Predictive Biomarker to Help Personalize Radiotherapy Dose in the Postoperative Setting, in the SAKK 09/10 Trial - Alan Dal Pra
Read the Full Video Transcript
Alicia Morgans: Hi, I'm so excited to be here at GU ASCO 2025. I am here today with Alan Dal Pra and George Zhao to talk about updates to the PORTOS Trial. And George, you had a wonderful oral presentation at this year's GU ASCO. Can you tell me a little bit about the background, the impetus for the data that you ended up presenting?
George Zhao: Absolutely. So PORTOS is actually a gene signature that we developed almost a decade ago with Dr. Felix Feng. And the goal of it was to predict who benefited from radiation therapy in general. Fortunately, we were able to work with Veracyte, who has the Decipher platform on which we built the signature, and finally have investigated it in two randomized trials, RTOG 0126 and SAKK 09/10.
Alicia Morgans: Wonderful. So can you tell me a little bit about this study design, about this score that was developed?
Alan Dal Pra: So the SAKK Trial was a trial that investigated dose escalation in the post-operative setting. Historically, based on retrospective studies, we knew that a higher dose of radiation to the prostate bed would have a potential benefit, but this has never been tested in prospective studies. So the SAKK Trial compared 64 Gray to 70 Gray in the post-operative setting.
After more than six years of median follow-up, there was no difference in terms of biochemical control. So that was a great opportunity for us not only to validate Decipher, but also PORTOS. So 226 samples were available from this trial that passed quality control. And we saw, very interestingly, that those patients who had a high PORTOS, they derived a much higher benefit from dose escalation, potentially then giving a very important signal that PORTOS can be used as a predictor of dose response in the post-operative setting.
Alicia Morgans: Wonderful. And just to be clear, PORTOS is really calculated from this Decipher-based assay, Veracyte's Decipher assay? Can you speak to that a little bit, George?
George Zhao: Right, exactly. So the Veracyte assay has many, many thousands of genes on it. And Decipher uses 22 of them to calculate the Decipher score. PORTOS uses 24 different genes to calculate a radiation response score.
Alicia Morgans: Wonderful. So, tell me, what did you find and what did you present at GU ASCO?
George Zhao: Absolutely. So in the SAKK Trial that Alan just described, we found that the PORTOS score actually predicted who benefited from dose escalation in the post-operative setting. So patients with a higher PORTOS score had more benefit from escalation to 70 Gray, whereas patients with a lower PORTOS score, there was no difference between 70 versus 64 Gray.
In addition, we also looked in RTOG 0126, which was a randomized trial by NRG RTOG, looking at definitive radiation dose escalation in patients that did not have surgery, and instead, had primary radiation therapy. These were all men with intermediate-risk prostate cancer, and they were randomized to 70.2 Gray versus 79.2 Gray. And the overall study was positive for 79.2 Gray benefiting this overall population of intermediate-risk prostate cancer patients.
However, what we found is we looked at PORTOS in this study and patients with a lower PORTOS in the lower one third of PORTOS scores actually had no benefit from dose escalation, whereas patients in the middle and higher thirds of PORTOS scores were the ones that derived all of the benefit from dose escalation in the definitive setting.
Alicia Morgans: Wow. I mean, really, I think, very useful in this application of radiation. I wonder, Alan, if you can tell us a little bit about what you think about in terms of clinical applications and if there's anything that we can draw when it comes to use of systemic therapy in these situations as well?
Alan Dal Pra: Yeah, I think that's a very important point in terms of the biological processes that are involved in the high PORTOS and perhaps George can talk a little bit more about that later. But I think in terms of clinical applications, we can ask ourselves, how can we use PORTOS? So I think not only the primary setting, but I feel that more in the post-operative setting, we'll have a more important role because there is a trend towards lowering the total dose based on the SAKK Trial.
So perhaps for those patients that have a high PORTOS, we need to be aware that we should not lower the dose. We should still keep with a higher dose around 70 Gray to the prostate bed. Of course, there are so many factors involved when we think in terms of dosimetric parameters, but that's only one of the examples where PORTOS can be clinically useful.
Alicia Morgans: Absolutely. And George, Alan just alluded to the kind of pathways and the things that PORTOS might be sort of demonstrating are involved in some of these processes. Can you tell us a little bit about the molecular biology and the understanding that we may have of the pathways involved here?
George Zhao: So in addition to these two trials, we also looked at PORTOS in a larger real-world database from the clinical use of the Decipher test in both biopsy and prostatectomy patients. And this accounts to almost 70,000 or 80,000 total samples. And what we found was a modest association with hypoxia-related pathways, which makes sense given the known impact of hypoxia on radiation resistance.
What was a little bit more surprising was that the strongest associations were with immune response pathways and subtypes. And the interaction between the immune system and radiation has long been studied and is an area of active research. And so this is a very interesting biological finding on the mechanisms of how PORTOS is able to predict who benefits from dose escalation.
Alicia Morgans: Wonderful. So Alan, from your perspective, what are next steps? Where do we go from here in terms of further understanding PORTOS or perhaps, using it more commonly in clinical practice?
Alan Dal Pra: First of all, having that overview, I like very much the concept of evidence-based medicine from David Sackett, putting three major factors when we are defining the treatment decision. Which is the best available evidence? And then there's the question of how to validate all these biomarkers in precision medicine in terms of the best available evidence. And PORTOS, now with this trial, has a level 1b of evidence according to the criteria.
Then we have the physician's experience and the patient values and expectations. So this leads to the evidence-based medicine, shared decision making, that is the personalized care. So on top of that, we have dosimetric factors and everything related to radiation that we are becoming better and better with radiation technology. So I think it's another tool that you can put on the table in order to help better treat our patients.
Alicia Morgans: Wonderful. And George, from your perspective, anything that you would want to add in terms of next steps? Because getting that 1b in the guidelines, that's already really, really exciting to contribute as a team and all the work that you've done. Where do you go from here?
George Zhao: So we're actually looking at PORTOS in a number of other clinical trials in conjunction with Veracyte. In addition, Dan Spratt is designing the next-generation post-operative trial at NRG Oncology, which will hopefully incorporate PORTOS.
Alicia Morgans: Wonderful. So to each of you, I'll take you one at a time. What is your message to listeners, bottom line, and I guess concluding thought? Go ahead, Alan.
Alan Dal Pra: I think this is very exciting because not only dosimetric factors that have predicted better response to radiation, but now we're understanding more and more the biology of the tumor. So not only with prognostic, and finally with predictive biomarkers that can lead us to specific and better treatments.
Alicia Morgans: Exciting. And George?
George Zhao: So this is actually the first biomarker that's been validated in multiple randomized trials as predicting radiation dose response, not just in prostate cancer, but actually in any cancer. So I'm a little biased, but I think that's a pretty big step forward for our field.
Alicia Morgans: Wonderful. Well, I sincerely congratulate you two, as well as, of course, the teams that you brought together to help understand this signature and help implement it into the guidelines. I really look forward to future discussions and seeing where all of this goes. Thank you both.
George Zhao: Thank you.
Alicia Morgans: Hi, I'm so excited to be here at GU ASCO 2025. I am here today with Alan Dal Pra and George Zhao to talk about updates to the PORTOS Trial. And George, you had a wonderful oral presentation at this year's GU ASCO. Can you tell me a little bit about the background, the impetus for the data that you ended up presenting?
George Zhao: Absolutely. So PORTOS is actually a gene signature that we developed almost a decade ago with Dr. Felix Feng. And the goal of it was to predict who benefited from radiation therapy in general. Fortunately, we were able to work with Veracyte, who has the Decipher platform on which we built the signature, and finally have investigated it in two randomized trials, RTOG 0126 and SAKK 09/10.
Alicia Morgans: Wonderful. So can you tell me a little bit about this study design, about this score that was developed?
Alan Dal Pra: So the SAKK Trial was a trial that investigated dose escalation in the post-operative setting. Historically, based on retrospective studies, we knew that a higher dose of radiation to the prostate bed would have a potential benefit, but this has never been tested in prospective studies. So the SAKK Trial compared 64 Gray to 70 Gray in the post-operative setting.
After more than six years of median follow-up, there was no difference in terms of biochemical control. So that was a great opportunity for us not only to validate Decipher, but also PORTOS. So 226 samples were available from this trial that passed quality control. And we saw, very interestingly, that those patients who had a high PORTOS, they derived a much higher benefit from dose escalation, potentially then giving a very important signal that PORTOS can be used as a predictor of dose response in the post-operative setting.
Alicia Morgans: Wonderful. And just to be clear, PORTOS is really calculated from this Decipher-based assay, Veracyte's Decipher assay? Can you speak to that a little bit, George?
George Zhao: Right, exactly. So the Veracyte assay has many, many thousands of genes on it. And Decipher uses 22 of them to calculate the Decipher score. PORTOS uses 24 different genes to calculate a radiation response score.
Alicia Morgans: Wonderful. So, tell me, what did you find and what did you present at GU ASCO?
George Zhao: Absolutely. So in the SAKK Trial that Alan just described, we found that the PORTOS score actually predicted who benefited from dose escalation in the post-operative setting. So patients with a higher PORTOS score had more benefit from escalation to 70 Gray, whereas patients with a lower PORTOS score, there was no difference between 70 versus 64 Gray.
In addition, we also looked in RTOG 0126, which was a randomized trial by NRG RTOG, looking at definitive radiation dose escalation in patients that did not have surgery, and instead, had primary radiation therapy. These were all men with intermediate-risk prostate cancer, and they were randomized to 70.2 Gray versus 79.2 Gray. And the overall study was positive for 79.2 Gray benefiting this overall population of intermediate-risk prostate cancer patients.
However, what we found is we looked at PORTOS in this study and patients with a lower PORTOS in the lower one third of PORTOS scores actually had no benefit from dose escalation, whereas patients in the middle and higher thirds of PORTOS scores were the ones that derived all of the benefit from dose escalation in the definitive setting.
Alicia Morgans: Wow. I mean, really, I think, very useful in this application of radiation. I wonder, Alan, if you can tell us a little bit about what you think about in terms of clinical applications and if there's anything that we can draw when it comes to use of systemic therapy in these situations as well?
Alan Dal Pra: Yeah, I think that's a very important point in terms of the biological processes that are involved in the high PORTOS and perhaps George can talk a little bit more about that later. But I think in terms of clinical applications, we can ask ourselves, how can we use PORTOS? So I think not only the primary setting, but I feel that more in the post-operative setting, we'll have a more important role because there is a trend towards lowering the total dose based on the SAKK Trial.
So perhaps for those patients that have a high PORTOS, we need to be aware that we should not lower the dose. We should still keep with a higher dose around 70 Gray to the prostate bed. Of course, there are so many factors involved when we think in terms of dosimetric parameters, but that's only one of the examples where PORTOS can be clinically useful.
Alicia Morgans: Absolutely. And George, Alan just alluded to the kind of pathways and the things that PORTOS might be sort of demonstrating are involved in some of these processes. Can you tell us a little bit about the molecular biology and the understanding that we may have of the pathways involved here?
George Zhao: So in addition to these two trials, we also looked at PORTOS in a larger real-world database from the clinical use of the Decipher test in both biopsy and prostatectomy patients. And this accounts to almost 70,000 or 80,000 total samples. And what we found was a modest association with hypoxia-related pathways, which makes sense given the known impact of hypoxia on radiation resistance.
What was a little bit more surprising was that the strongest associations were with immune response pathways and subtypes. And the interaction between the immune system and radiation has long been studied and is an area of active research. And so this is a very interesting biological finding on the mechanisms of how PORTOS is able to predict who benefits from dose escalation.
Alicia Morgans: Wonderful. So Alan, from your perspective, what are next steps? Where do we go from here in terms of further understanding PORTOS or perhaps, using it more commonly in clinical practice?
Alan Dal Pra: First of all, having that overview, I like very much the concept of evidence-based medicine from David Sackett, putting three major factors when we are defining the treatment decision. Which is the best available evidence? And then there's the question of how to validate all these biomarkers in precision medicine in terms of the best available evidence. And PORTOS, now with this trial, has a level 1b of evidence according to the criteria.
Then we have the physician's experience and the patient values and expectations. So this leads to the evidence-based medicine, shared decision making, that is the personalized care. So on top of that, we have dosimetric factors and everything related to radiation that we are becoming better and better with radiation technology. So I think it's another tool that you can put on the table in order to help better treat our patients.
Alicia Morgans: Wonderful. And George, from your perspective, anything that you would want to add in terms of next steps? Because getting that 1b in the guidelines, that's already really, really exciting to contribute as a team and all the work that you've done. Where do you go from here?
George Zhao: So we're actually looking at PORTOS in a number of other clinical trials in conjunction with Veracyte. In addition, Dan Spratt is designing the next-generation post-operative trial at NRG Oncology, which will hopefully incorporate PORTOS.
Alicia Morgans: Wonderful. So to each of you, I'll take you one at a time. What is your message to listeners, bottom line, and I guess concluding thought? Go ahead, Alan.
Alan Dal Pra: I think this is very exciting because not only dosimetric factors that have predicted better response to radiation, but now we're understanding more and more the biology of the tumor. So not only with prognostic, and finally with predictive biomarkers that can lead us to specific and better treatments.
Alicia Morgans: Exciting. And George?
George Zhao: So this is actually the first biomarker that's been validated in multiple randomized trials as predicting radiation dose response, not just in prostate cancer, but actually in any cancer. So I'm a little biased, but I think that's a pretty big step forward for our field.
Alicia Morgans: Wonderful. Well, I sincerely congratulate you two, as well as, of course, the teams that you brought together to help understand this signature and help implement it into the guidelines. I really look forward to future discussions and seeing where all of this goes. Thank you both.
George Zhao: Thank you.