A phase 2 single-arm study testing SBRT, adenosine signaling modulation, and immune checkpoint inhibition for men with hormone-sensitive oligometastatic prostate cancer (SBRT-AMICO).
Authors: Lacuna Kristine Peregrino , Lee Shing M , Stein Mark N. , Ahmad Noor , Runcie Karie , Wei Alexander Z , Spina Catherine S. 
Published: January 2024

TPS240 Background: Oligometastatic hormone-sensitive prostate cancer (omHSPC) represents a distinct disease state that can benefit from local therapy. For patients (pts) with metachronous omHSPC, metastasis-directed therapy (MTD) demonstrates benefit in prospective studies. In the randomized phase 2 STOMP trial of MDT versus observation, MDT improved ADT-free survival.1 In the randomized phase 2 ORIOLE trial of MDT with stereotactic body radiation therapy (SBRT) versus observation, MDT improved PFS (HR = 0.30; 95% CI, 0.11-0.81; P = .002).2 MDT may improve cancer-specific outcomes and delay initiation of ADT, offering a significant impact on quality of life. Further investigation is needed to determine the optimal approach for omHSPC, especially in the era of advanced imaging (PSMA-PET). Radiation induces immunogenic cell death, releasing intracellular ATP that is rapidly metabolized by ectonucleases CD39 and CD73, creating free adenosine. Within the tumor microenvironment, adenosine binds to receptors A2AR and A2BR to promote immunosuppression, which blunts the anti-tumor immune response.3,4 The adenosine signaling pathway is an attractive target for therapeutic intervention in the context of metastasis-directed radiotherapy. Methods: SBRT-AMICO is a single-arm phase 2 trial testing the combination of a CD73 inhibitor (AB680), A2AR/A2BR inhibitor (AB928), and anti-PD-1 (AB122) with metastasis-directed SBRT for omHSPC. Eligible pts have newly diagnosed mHSPC including 1-3 asymptomatic metastases, who received prior primary PC treatment, unexposed to ADT within 6 months (mo), with a PSA 0.5-50 ng/mL and PSADT ≤ 15 mo. Pts initiate treatment with AB680 100mg IV q2 weeks + AB928 150mg PO daily, on Week 1. SBRT (1-5 fractions depending on size/location per AAPM Task Group 101) will be administered starting Week 4. AB122 240mg IV q2 weeks, will start within 1 week of completing SBRT. AB680, AB928, and AB122 will continue until progression, unacceptable toxicity, or death. The primary endpoint is progression of disease at 6 mo (per PCWG3/RECIST 1.1). The design evaluates for an improvement in progression of disease at 6 mo, from 80% (per experimental arm from ORIOLE) to 95%. Using a Simon Two-Stage Minimax design (α = 0.1, power = 0.8), 14 pts will be enrolled in Stage 1. If 13/14 are progression-free at 6 mo, 9 pts will be enrolled in Stage 2. The null hypothesis is rejected if 21/23 pts are progression-free at 6 mo. Secondary endpoints include PSA response, ADT-free survival, time to pain progression, and safety. Paired tumor biopsies and peripheral blood will be collected from all pts to evaluate immunologic changes before, during, and after treatment. The study opened to accrual 7/2023. 1. Ost et al. J Clin Oncol, 2018. 2. Phillips et al. JAMA Oncol, 2020. 3. Sek et al. Int J Mol Sci, 2018. 4. Hasko et al. Arterioscler Thromb Vasc Biol, 2012. Clinical trial information: NCT05915442 .