PORTOS as a Predictive Biomarker to Help Personalize Radiotherapy Dose in the Postoperative Setting, in the SAKK 09/10 Trial - Alan Dal Pra
December 5, 2022
Alan Dal Pra, MD, Associate Professor, Director, Clinical Research Program, Medical Director, Radiation Oncology Lennar Coral Gables, Radiation Oncology Department, University of Miami Miller School of Medicine
Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts
ASTRO 2022: Prognostic and Predictive Performance of a 24-Gene Post-Operative Radiation Therapy Outcomes Score (PORTOS) in a Phase 3 Randomized Trial of Dose-Intensified Salvage Radiotherapy after Radical Prostatectomy (SAKK 09/10)
The Performance of a Genomic Classifier Score in the Phase 3 SAKK 09/10 in Patients with Biochemical Progression - Alan Dal Pra
ASTRO 2022: PSMA PET/CT–Based Atlas for Prostatic Bed Recurrence of Prostate Cancer after Radical Prostatectomy: Clinical Implications for Salvage Radiation Therapy
Prognostic Utility of Decipher® Prostate Genomic Classifier in the SAKK 09/10 Phase III Trial - Alan Dal Pra
ASTRO 2021: Performance of a Genomic Classifier Within a Phase 3 Randomized Trial of Dose Escalated Salvage Radiotherapy After Radical Prostatectomy
Alicia Morgans: Hi, I'm so excited to be here with Dr. Alan Dal Pra, who is from the Department of Radiation Oncology at the University of Miami where he is a radiation oncologist. Thank you so much for being here with me today.
Alan Dal Pra: Thank you very much, Alicia. It's a pleasure.
Alicia Morgans: Dr. Dal Pra, I'm so excited to talk with you about a presentation that you gave at ASTRO 2022 in which you assessed the PORTOS score in the SAKK 09/10 trial. Can you tell us a little bit about that?
Alan Dal Pra: All right. It's a pleasure to present our work that we presented at ASTRO this year on the prognostic and predictive performance of the 24-gene Post-Operative Radiation Therapy Outcome Score, the PORTOS signature in the phase 3 randomized clinical trial assessing dose escalation after radical prostatectomy, the SAKK 09/10 trial. These are my disclosures. Important for this work is to differentiate the different types of biomarkers. Here on the left you can see some of different categories of biomarkers according to the FDA. And for the purpose of this presentation, it's important to make that clear difference between the prognostic biomarkers, factors often measured before treatment to stratify and enrich a patient population that indicate a long-term outcome for patients untreated or receiving standard of care treatment independent of treatment received, whereas predictive biomarkers, they identify who's likely or unlikely to benefit from a specific treatment.
Prostate cancer biomarkers for nonmetastatic disease have been listed in national guidelines. Here we have the latest NCCN guideline. And you can see here there are no predictive biomarkers currently available. So the SAKK 09/10 trial was a phase 3 randomized clinical trial performing 24 centers in Switzerland, Germany, and Belgium randomizing 350 patients with biochemical progression. Patients were allocated to 64 versus 70 gray to the prostate bed. These patients did not receive hormonal therapy or elective treatment of the pelvis. At a median followup of six years, there was no difference in freedom from biochemical progression that was the primary endpoint of this study. So we have recently validated the prognostic performance of Decipher. So patients with a high Decipher had a two times more change of biochemical progression as compared to patients with low/intermediate risk Decipher. So Decipher was a strong prognostic marker, but did not predict a benefit from dose escalation.
As you can see here, we saw a comparable prognostic ability within the 64 and 70 gray arm without a significant interaction between Decipher status and radiotherapy dose. We next assess PORTOS. PORTOS is an expression signature of 24 genes related to DNA damage repair and immune pathways. PORTOS was published by George Zhao in The Lancet Oncology in 2016 suggesting that patients with high PORTOS, they may benefit from postoperative radiation therapy. So we assessed the samples of the patients included in the SAKK trial. After central review, the highest-grade tumors were profiled using the Decipher assay to generate the PORTOS score. The independent prognostic ability and interaction effects were examined using Cox, Fine, Gray or logistic multivariable analysis and interaction analysis. The endpoints we studied were biochemical progression, clinical progression-free survival, receipt of salvage hormonal therapy, and metastasis-free survival. We used the same thresholds for PORTOS as published in 2016. High PORTOS, high radiotherapy response, lower PORTOS, average radiotherapy response.
Of the 226 trial patients with transcriptome data, 16% had high PORTOS radiation response compared to 84% with lower PORTOS. So patients with high PORTOS were well balanced between the randomization arms. So what we saw. On the left, you can see the analytical cohort without differences in clinical progression between 64 and 70 gray arm. And on the right, all patients stratified by PORTOS score. There were no difference in clinical progression-free survival between lower PORTOS and higher PORTOS. Therefore, PORTOS was not a prognostic marker for clinical outcomes. However, when we assessed patients with lower versus higher PORTOS score as a function of radiotherapy dose, PORTOS was predictive of response to higher radiotherapy dose. Patients with higher PORTOS receiving 70 gray as opposed to 64 gray presented significantly better clinical progression-free survival, as you can see here. And the interaction of PORTOS status and radiotherapy dose was statistically significant in both unadjusted and adjusted tests for interaction.
Here you can see the bar plot representing the absolute clinical progression-free survival between dose-escalated and standard arms at five years stratified by PORTOS, suggesting that a very large benefit observed for dose escalation in higher PORTOS tumors. And we also saw a significant interaction between PORTOS status and radiotherapy dose for most of the clinical endpoints. So although there are strong prognostic biomarkers such as Decipher, we definitely need predictive biomarkers, biomarkers that can tell us which patients will respond to a specific type of therapy. How can we apply this data based on the 09/10 results? I think many people have decreased the dose to the prostate bed given the lack of difference between 64 and 70 gray in this phase 3 clinical trial. Therefore, PORTOS could help select patients for dose escalation versus the use of lower dose.
How to explain the dose escalation benefiting higher PORTOS tumors? I think this is very challenging because we are talking about a microscopic disease in the prostate bed. However, there are several interesting studies associating PORTOS and specific DNA repair pathways, hypoxia patterns also in imaging, and interestingly, differential immune profiling according to the PORTOS status. It's important to mention that this is a retrospective study of a phase 3 clinical trial, exploratory analysis, therefore further validation is needed. So in conclusion, in a phase 3 clinical trial testing radiotherapy dose intensification after prostatectomy, patient with high PORTOS scores had significantly better outcomes with dose-escalated radiotherapy, suggesting that higher doses could be considered in this subgroup of patients. We need further studies to validate PORTOS as the first biomarker to help personalize radiotherapy dose for these patients. I'd like to thank all the patients included in this clinical trial and all the outstanding team involved in this work. Thank you very much for your attention.
Alicia Morgans: Dr. Dal Pra, that was really, really interesting and so helpful because as you said, I think the field has moved in a direction where you're trying to avoid dose escalation if it's not going to be beneficial. And so from your perspective, how would we best assess PORTOS in further studies? Are there other studies where we can apply the PORTOS signature perhaps already completed, NRG studies or any settings where we can really test this before we think about potentially integrating this into our clinical practice and clinical process?
Alan Dal Pra: Yeah, this is a very important point because we need to validate these results and unfortunately we don't have many randomized clinical trials assessing dose escalation in this patient population. So I think we need to go towards real world data and retrospective studies, and this is ongoing. We are assessing some studies with different ranges of dose. So this definitely needs to be done.
Alicia Morgans: And I think that's great and we look forward to seeing that data. Now, if a clinician said, "Well, I really feel like at least it's reasonable to consider this as a factor as I see my patient in clinic," is the PORTOS score something that a doc can get in clinic today just like they can get a Decipher score? Or is this something that is still just reserved for clinical trials?
Alan Dal Pra: When a physician requests Decipher, he can request the PORTOS assay results and I think it could be used already for shared decision-making. There are several range of doses that we use in the postoperative setting and it's very interesting that we translate that knowledge to other tumor sites. When we talk about the treatment of micrometastatic disease in lung or other tumor sites, we never use such a high dose. So I think it's opening perhaps a new paradigm. We know that although the side effects for postoperative radiation are overall well tolerated, but some patients develop cystitis, some patients develop a stricture in the long term. So if we can find a better way to personalize treatment for these patient, that would be the ideal situation.
Alicia Morgans: Well, it's good to know that it's available if people want it, and certainly I think this is pretty compelling data even if only in a relatively small sample size, given some of the sample sizes that we see for radiation trials. What would your recommendations be to clinicians as they review this data and think about how they can best care for their patients in this setting?
Alan Dal Pra: So important to mention that this is a patient population without any evidence of local microscopic local recurrence in the prostate bed. Because in some situations we have to go a little bit higher and dose-escalate to those regions. However, when we are talking about in the absence of microscopic recurrence in the prostate bed, I think there's a dose range that you can use and perhaps using PORTOS can help radiation oncologists to define the best dose, or perhaps if patients have a high PORTOS score not to go to the lower end of dose and continue with around 66 to 70 gray dose to the prostate bed.
Alicia Morgans: I think that's great guidance. And as we saw, at least in this clinical trial population, it was not a majority of patients who had PORTOS high scores, so it won't be a majority of patients where we'd need to even have that dose escalation. And so really understanding in which patients this may be most beneficial is so helpful as we're trying to make those shared decisions with our patients. I sincerely appreciate the work that you've done and thank you so much for sharing it with us today.
Alan Dal Pra: Thank you very much for the opportunity.