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 + pembrolizumab evaluated in a Phase 2 study, in mCRPC patients with SCNC. SCNC is highly proliferative and aggressive with limited duration of response to platinum-based chemotherapy. Final results of Phase 2a presented at ASCO GU 2023 (abstract #176) after enrollment of 28 evaluable SCNC patients. 7 (25%) patients achieved a composite response, primary endpoint of trial. In patients with measurable disease (n = 25), RECIST 1.1-defined partial response (PR) observed in 5 (20%) patients (4 confirmed PR + 1 uPR). Disease control rate (complete response + PR + stable disease) was 48% (12 patients). Median duration of response for both composite responses and RECIST-defined PRs was 6+ months as of data cutoff on 19-DEC-22. 6 / 34 patients (18%) in safety population experienced serious adverse events (SAEs) possibly related to BXCL701 or pembrolizumab, and 6 (18%) patients discontinued any drug due to an AE. No evidence found that BXCL701 potentiates immune-related AEs related to immune checkpoint inhibitors. DPP9 overexpression was identified as a potential predictive biomarker for BXCL701 response; biomarker evaluation is ongoing and additional findings will be presented at an upcoming medical meeting. Since SCNC cohort showed encouraging efficacy in Phase 2a, the Phase 2b portion of study was initiated to evaluate SCNC variant in a potential registrational randomized study. Methods: Patients with any SCNC histopathological features, either de novo or treatment-emergent including mixed SCNC, are randomized 2:1 to receive BXCL701 + pembrolizumab (n = 40) or BXCL701 monotherapy (n = 20). Patients are 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 Day 1) + BXCL701 or BXCL 701 alone (0.2 mg BID Days 1-7 with step-up to 0.3 mg BID Days 8-14, and 0.3 mg BID Days 1-14 of subsequent 21-day cycles). Primary endpoint is response rate defined by RECIST 1.1 criteria. Secondary objectives are ≥-50% decline in PSA from baseline, OS, duration of response, rPFS, and PSA PFS. Exploratory biomarkers and changes in relevant immune effector cells are also evaluated. Phase 2a activity threshold for accrual was met. ClinicalTrials.gov Identifier: NCT03910660. Clinical trial information: NCT03910660.