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Background Small cell neuroendocrine prostate cancer (SCNC) is a lethal subset of prostate cancer with limited treatment options. Talabostat, an oral small molecule inhibitor of dipeptidyl peptidases (DPP4 and DPP 8/9) triggers the inflammasome to alert and prime immune cells, leading to induction of interleukin (IL)-18 and IL-1ß, bridging innate and adaptive immunity. Talabostat was evaluated in a phase 2 study in combination with pembrolizumab in patients with SCNC.Methods Patients were required to have centrally confirmed histologic evidence of de novo or treatment-emergent SCNC and progression on ≥1 prior line of systemic therapy. Patients received pembrolizumab (200 mg intravenous every 21 days) + BXCL701 0.2 mg orally two times per day for a week, with step-up to 0.3 mg two times per day on days 8–14, and 0.3 mg two times per day on days 1–14 of subsequent cycles. The primary endpoint was the composite response rate (CRR). Biomarkers including levels of DPP 8/9 expression and association with clinical outcomes were analyzed in a post hoc fashion.Results 34 patients were enrolled, including 21 (62%) with visceral metastases. Patients had received a median of 3 prior lines of systemic treatment, including 19 (56%) and 18 (53%) of patients who received prior platinum and taxane chemotherapy, respectively. In the response evaluable subset (n=30), the CRR was 20% (95% CI 7.7% to 38.6%) and the objective response rate was 13% (95% CI 3.8% to 30.7%). The median duration of objective response was 9.0 months. All responders had tumors with low tumor mutational burden and/or microsatellite stability. The median radiographic progression-free survival was 2.1 months (95% CI 1.9 to 4.2). The median overall survival (OS) was 13.7 months (95% CI 7.0 to unevaluable) and the 12-month OS rate was 54.1% (95% CI 34.2% to 70.3%). The most frequently occurring treatment-related adverse events of any grade severity were fatigue (41%), hypotension (29%), dizziness (21%), pruritus (24%), nausea (15%), and diarrhea (15%). Baseline levels of DPP9 tumor stromal expression were associated with response.Conclusions Talabostat plus pembrolizumab demonstrates preliminary anti-tumor activity in patients with relapsed SCNC. Further evaluation in a randomized study is warranted to assess the contribution of talabostat in this high-risk disease subset.Trial registration number NCT03910660.