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)

(UroToday.com) The 2022 American Society for Radiation Oncology (ASTRO) Annual Meeting held in San Antonio, TX between October 23rd and 26th, 2022 was host to a session evaluating new insights into post-prostatectomy radiotherapy. Dr. Dal Pra presented his group’s work evaluating the prognostic and predictive performance of a 24-gene post-operative radiation therapy outcomes score (PORTOS) in a phase III randomized trial of dose-intensified salvage radiotherapy after radical prostatectomy (SAKK 09/10).

 

Dr. Dal Pra began his presentation by highlighting the differences between prognostic and predictive biomarkers. Prognostic biomarkers indicate the long-term outcomes for patients untreated or receiving standard of care treatment, independent of treatment received. Conversely, predictive biomarkers identify who is likely or unlikely to benefit from a specific treatment. As per the most recent NCCN Prostate Cancer Guidelines, numerous prognostic biomarkers exist; however, to date, there are no predictive biomarkers available.

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The SAKK 09/10 was a multicenter, randomized phase III trial performed across 24 centers in Switzerland, Germany, and Belgium. This trial included 350 patients with biochemical progression (PSA 0.1 – 2.0 ng/ml) who were randomized to 64 Gy versus 70 Gy to the prostate bed. These patients did not receive ADT or pelvic nodal radiotherapy. This trial did not find a difference in freedom from biochemical progression at a median follow up of 6 years.1

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In a subsequent publication, Dal Pra et al. were able to validate the Decipher® score as a strong prognostic marker, but it did not predict the benefit from dose escalation. As demonstrated in the first figure below, patients with a low/intermediate Decipher® score had a better prognosis compared to those with high Decipher® scores. The subsequent two figures below demonstrate similar outcomes across the dose escalation regimens, with no statistically significant interaction between the Decipher® status and the radiotherapy dose given.2

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Can PORTOS act as a predictive biomarker? PORTOS is an expression signature of 24 DNA damage repair and immune pathway genes. Patients with high PORTOS scores have been shown to potentially benefit from post-operative radiotherapy in a matched, retrospective analysis.3

In this study, Dal Pra et al. included patients from the SAKK 09/10 phase 3 trial (NCT01272050). After central review, the highest-grade tumors were profiled using the Decipher whole-transcriptome assay (Veracyte, San Diego, CA) to generate PORTOS. The independent prognostic ability and interaction effects were examined with Cox, Fine, and Grey models, or logistic multivariable and interaction analyses. The endpoints of interest included biochemical progression, clinical progression-free survival, receipt of salvage hormone therapy, and metastasis-free survival endpoints. Categorical analyses used the published thresholds for PORTOS radiotherapy response (High PORTOS, higher radiotherapy response versus Low PORTS score, average radiotherapy response) used by Zhao et al.3

Out of the 226 patients with transcriptomic data, 16.4% had a high PORTOS score. Baseline variables including age, WHO performance status, pre-operative PSA, and proportion of positive surgical margins, extraprostatic extension, seminal vesicle invasion, lymphovascular invasion, and lymphadenectomy type were well-balanced between the specimens with low and high PORTOS scores. There were similarly no significant differences in the radical prostatectomy pathologic parameters and radiotherapy technique administered (3D-CRT versus IMRT/rotational techniques).

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The PORTOS score was found to not be prognostic of clinical progression-free survival rates as demonstrated below:

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However, PORTOS score was noted to be predictive of response to higher radiotherapy dose, with patients in the higher PORTOS group having significantly improved clinical progression free survival rates with dose escalation to 70 Gy, compared to 64 Gy (HR: 0.19, 95% CI: 0.05 – 0.70, p=0.01). Conversely in the lower PORTOS group, patients receiving 64 Gy had superior clinical progression free survival rates compared to those receiving 70 Gy (HR: 1.78, 95% CI: 1.02 – 3.11, p=0.04).

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The predictive ability of PORTOS was not limited to clinical progression free survival outcomes, but also a biochemical failure, metastasis-free, and progression-free survival rates.

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In his discussion, Dr. Dal Pra noted that although there are strong prognostic biomarkers such as Decipher®, we urgently need predictive biomarkers. How do we explain the dose-escalation benefits in higher PORTOS tumors? He hypothesized that this is likely due to differences in DNA Damage Repair pathways, differential immune profiling, and difference in hypoxia levels. He noted that in view of the SAKK 09/10 trial results, PORTOS could help select patients for dose-escalation (e.g. 70 Gy) versus lower doses to the prostate bed. He did note that these results are based on a retrospective exploratory analysis of a phase III trial and that further validation is required.

Dr. Dal Pra concluded as follows:

  • In a phase III trial testing radiotherapy dose intensification after radical prostatectomy, patients with higher PORTOS scores had significantly better outcomes with dose-escalated radiotherapy, suggesting that higher doses could be considered in this subgroup.
  • Further studies are warranted to validate PORTOS as the first predictive biomarker to help personalize radiotherapy dose in the postoperative setting.

Presented by: Alan Dal Pra, MD, Associate Professor, Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida, USA

Written by: Rashid Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2022 Annual American Society for Radiation Oncology (ASTRO) Meeting, San Antonio, TX, October 23 – 26, 2022


References:
1. Ghadjar P., Hayoz S., Bernhard J., et al. Dose-intensified Versus Conventional-dose Salvage Radiotherapy for Biochemically Recurrent Prostate Cancer After Prostatectomy: The SAKK 09/10 Randomized Phase 3 Trial. Eur Urol. 2021;80(3):306-315.
2. Dal Pra et al. Validation of the Decipher genomic classifier in patients receiving salvage radiotherapy without hormone therapy after radical prostatectomy - an ancillary study of the SAKK 09/10 randomized clinical trial. Ann Oncol. 2022;33(9):950-958
3. Zhao S., Chang L., Spratt D., et al. Development and validation of a 24-gene predictor of response to postoperative radiotherapy in prostate cancer: a matched, retrospective analysis. Lancet Oncol. 2016;17(11):1612-1620



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