The 2023 ASTRO annual meeting included a session on novel prognostication techniques for prostate cancer, featuring a presentation by Dr. Edlira Horjeti discussing an analysis of the ORIOLE trial, specifically the ability of PSMA-positive extracellular vesicles to predict disease recurrence in oligometastatic castration-sensitive prostate cancer treated with stereotactic ablative radiotherapy.
Stereotactic ablative radiation therapy improves oncological outcomes of oligometastatic castration-sensitive prostate cancer in the two randomized phase II clinical trials, ORIOLE1 and STOMP2:
Distant recurrence remains the primary cause of disease progression in oligometastatic castration sensitive prostate cancer treated with stereotactic ablative radiotherapy, and distant failure post treatment suggests the presence of metastatic disease undetected by imaging at diagnosis. Thus, predictive tools are necessary to identify those who will benefit from stereotactic ablative radiation therapy. Tumor derived extracellular vesicles are microscopic particles released naturally by tumor cells into biofluids, such as blood or urine, and contain molecular cargo (ie. RNA, DNA, proteins) reflecting tumor origin. Dr. Horjeti’s group was the first to demonstrate that plasma levels of prostate cancer-derived extracellular vesicles correlate with tumor burden and predict disease progression in oligometastatic prostate cancer after stereotactic ablative radiation therapy. At the ASTRO 2023 annual meeting, they presented results of a blinded validation study using plasma samples from the ORIOLE randomized phase 2 clinical trial, in addition to two other cohorts, in castration-sensitive patients.
Plasma samples were incubated with fluorescent antibodies against PSMA to label prostate cancer-derived extracellular vesicles. Concentrations of prostate cancer derived extracellular vesicles were measured by the device nanoscale flow cytometry, which enables quantification of extracellular vesicles from 1 microliter of plasma within 1 hour:3
For this study, there were 30 oligometastatic prostate cancer patients from the Baltimore ORIOLE trial, a 2:1 randomization to stereotactic ablative radiation therapy vs observation (NCT02680587), 47 from the Iridium Network, and 80 from Ghent University. Baseline PSMA+ prostate cancer-derived extracellular vesicles levels were measured by standardized and calibrated nanoscale flow cytometry using fluorescent PSMA antibodies. Median prostate cancer-derived extracellular vesicles levels was used as cut-off for low and high levels. Kaplan-Meier curves and Cox regression models were used to determine the association of prostate cancer-derived extracellular vesicles levels with clinical outcomes (PSA progression-free survival and radiographic distant progression free survival).
The baseline characteristics for patients included in this study are as follows:
There was no association observed between number of metastatic lesions or baseline PSA and plasma prostate cancer-derived extracellular vesicles levels:
High baseline levels of PSMA-positive extracellular vesicles were associated with shorter progression free survival in oligometastatic castration sensitive prostate cancer treated with stereotactic ablative therapy in both the Ghent/Iridium cohort and the ORIOLE trial patients:
Finally, the combination of PSA and PSMA positive extracellular vesicles identified long-term responders to stereotactic ablative therapy:
Dr. Horjeti noted that the main limitation of this study was the small sample size and retrospective nature of the design. However, this is the largest cohort of oligometastatic castration sensitive prostate cancer for biomarker analysis.
Dr. Horjeti concluded this presentation discussing the ability of PSMA-positive extracellular vesicles to predict disease recurrence in oligometastatic castration-sensitive prostate cancer treated with stereotactic ablative radiotherapy with the following take-home messages:
- Prostate cancer-derived extracellular vesicles are the first blood biomarker of tumor burden that can prognosticate the risk of disease recurrence in oligometastatic prostate cancer patients treated with stereotactic ablative radiation therapy
- Extracellular vesicles can help identify patients with long-term remission after stereotactic ablative therapy and delay the use of systemic therapy and the development of CRPC
- While biomarker-guided trials are warranted, our validation study strengthens the clinical value of prostate cancer-derived extracellular vesicles for personalized radiation therapy
Presented by: Edlira Horjeti, MD, Mayo Clinic, Rochester, MN
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2023 American Society of Radiation Oncology (ASTRO) Annual Meeting, San Diego, CA, Sun, Oct 1 – Wed, Oct 4, 2023.
References:
- Phillips R, Shi WY, Deek M, et al. Outcomes of Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer: The ORIOLE Phase 2 Randomized Clinical Trial. JAMA Oncol 2020 Mar 26;6(5):650-659.
- Ost P, Reynders D, Decaestecker K, et al. Surveillance of metastasis-directed therapy for oligometastatic cancer recurrence: A prospective, randomized, multicenter phase II trial. J Clin Oncol. 2018 Feb 10;36(5):446-453.
- Kim Y, van der Pol E, Arafa A, et al. Calibration and standardization for extracellular vesicle measurements by flow cytometry for translational prostate cancer research. Nanoscale. 2022 Jul 14;14(27):9781-9795.