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.
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.
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.
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.
NCT03910660.
Journal for immunotherapy of cancer. 2026 May 11*** epublish ***
Rahul Aggarwal, Jingsong Zhang, Paul Monk, Xinhua Zhu, Rob Jones, Mark Linch, Dan Costin, Johann de Bono, Lawrence I Karsh, Daniel P Petrylak, Li Zhang, Rashmi Deshpande, Pascal Borderies, Jiaoti Huang, Vincent O'Neill, Moses Donkor, Scott Tagawa
University of California San Francisco, San Francisco, California, USA ., Moffitt Cancer Center, Tampa, Florida, USA., Ohio State University James Cancer Hospital, Columbus, Ohio, USA., Northwell Health Cancer Institute, New Hyde Park, New York, USA., Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow, UK., UCL, London, UK., Center for Cancer Care, White Plains Hospital, White Plains, New York, USA., Royal Marsden Hospital Sutton, London, UK., AdventHealth Urology, Denver, Colorado, USA., Yale Cancer Center, New Haven, Connecticut, USA., University of California San Francisco, San Francisco, CA, USA., BioXcel Therapeutics, New Haven, Connecticut, USA., Duke University, Durham, North Carolina, USA., Weill Cornell Medicine, New York, New York, USA.