3313 - Trial in Progress: A Phase II Single-Arm Study Testing SBRT, Adenosine Signaling Modulation, and Immune Checkpoint Inhibition for Men with Hormone Sensitive Oligometastatic Prostate Cancer (SBRT-AMICO)

Purpose/Objective(s):

For men with metachronous oligometastatic hormone-sensitive metastatic prostate cancer (omHSPC), ablative stereotactic body radiation therapy (SBRT) has been shown to increase progression-free survival. Radiotherapy increases the intratumoral adenosine concentration and abundance of suppressive immune cells in the irradiated tumor, while activating the highly suppressive adenosine signaling pathway. In preclinical models, the addition of tumor irradiation to adenosine signaling modulators and an immune checkpoint inhibitor (ICI) has been shown to significantly improve tumor control. We launched a single-arm phase 2 clinical trial with the primary aim to evaluate the efficacy of targeted inhibition of adenosine signaling (CD73 inhibitor + A2AR/A2BR inhibitor) plus ICI (a-PD-1) in combination with metastasis-directed SBRT, as measured by biochemical recurrence-free survival (bRFS) at 12 months (PSA + 0.2ng/mL above the post-SBRT nadir). Secondary objectives include assessment of bRFS survival at 6 months, treatment response based on CT, nuclear bone scan, and PSMA-PET at 6 months, and safety and tolerability.

Materials/Methods:

Key inclusion criteria include men with prostate adenocarcinoma, PSA of 0.2-50 ng/mL, testosterone =125 ng/mL, who have undergone primary treatment with surgery and/or radiation (+/- hormone therapy), with 1-3 asymptomatic metastatic lesions diagnosed on PSMA-PET, at least one site amenable to biopsy. Patients may be allowed one prior line of systemic therapy, including investigational agents, for initial presentation of metastatic disease, and the therapy must be completed =3 months from enrollment. Key exclusion criteria include known brain metastases, spinal cord compression, or active autoimmune disease. Patients will start the CD73 inhibitor and A2AR/A2BR inhibitor 4 weeks (+ 1 week) prior to SBRT, and ICI within one week of completing SBRT. All three agents will continue for 32 months unless there is disease progression or an unacceptable adverse event. All patients will undergo pre- and on-treatment (2 weeks post-SBRT) biopsies of a single metastasis and serial blood collection. Kaplan-Meier analyses will be used to assess bRFS, compared to historical outcomes from SBRT monotherapy for PSMA-PET detected omHSPC. Biopsy tissue and peripheral blood will undergo single cell level analyses to investigate the local and systemic response to therapy, including single cell RNAseq and spectral flow cytometry, respectively.

Results: n/a

Conclusion: This phase 2 single-arm clinical trial is currently in accrual phase, with target enrollment of 23 patients, and a plan for expansion to additional sites. The Clinicaltrials.gov registry ID is NCT05915442.