Background: BXCL701 (talabostat), oral small molecule inhibitor of dipeptidyl peptidases (DPP)—primarily DPP8/9 & DPP4—triggers inflammasome to alert and prime immune cells, leading to induction of IL-18 & IL-1ß, bridging innate & adaptive immunity. BXCL701 is evaluated in a Phase 2 study in combination with pembrolizumab, in mCRPC patients with SCNC phenotype. SCNC is highly proliferative and aggressive with limited duration of response to platinum-based chemotherapy. Here are reported the results of the Phase 2a after enrollment of 32 patients for the SCNC cohort. The final results will be presented at the Symposium. Methods: Phase 2a patients with any SCNC histopathological features, either de novo or treatment-emergent including mixed SCNC, required to have progression by PCWG3 on ≥1 prior line of cytotoxic chemotherapy (patients who either have refused chemotherapy or are considered unsuitable for chemotherapy also permitted entry with prior approval by sponsor). Patients receive pembrolizumab (200 mg IV q3week) + BXCL701 0.2 mg BID on days 1-7 with step-up to 0.3 mg BID on days 8-14, and 0.3 mg BID on days 1-14 of subsequent cycles. Primary endpoint is Composite Response, either objective response by RECIST 1.1 or PSA₅₀ or CTC count conversion from ≥5/7.5 mL to <5/7.5 mL from baseline. Study uses a Simon 2-stage minimax design with 15 evaluable patients in stage 1 and 13 in stage 2. Baseline markers and changes in relevant immune effector cells also evaluated. Results: As of 10/11/2022, 32 patients have been accrued, 27 of which are evaluable. 16 patients (59%) are treatment-emergent SCNC and 11 (41%) are de novo SCNC. 19 patients (70%) received prior platinum chemotherapy. BXCL701 in combination with pembrolizumab continues to demonstrate acceptable tolerability without evidence of increased immune-related AEs compared to historic controls with checkpoint inhibitors. Adverse Events consistent with cytokine activation were observed (hypotension, fever, fatigue). In the previously reported 15 evaluable SCNC patients, 5 were composite responders, including 4 RECIST responders with a median duration of response of 39 weeks (range 9-45 weeks). 2/5 responders still actively receiving treatment and median duration of follow up is 48.3 weeks (range 1.9-88 weeks). All responders are MSS and/or low TMB. Enrollment is ongoing and 9 patients are actively receiving treatment at abstract submission. Final data for 28 evaluable patients will be presented at the Symposium. Conclusions: Oral BXCL701 in combination with pembrolizumab demonstrates encouraging anti-tumor activity with durability of response in late-line, refractory mCRPC SCNC for which there is currently no standard of care. BXCL701 BID dosing continues to demonstrate an acceptable safety profile. Clinical trial information: NCT03910660.