Background: BXCL701 (talabostat), oral small molecule inhibitor of dipeptidyl peptidases (DPP)—primarily DPP 8/9 & DPP 4—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 1b/2 study in combination with pembrolizumab, in mCRPC patients with adenocarcinoma phenotype (and in small-cell neuroendocrine carcinoma). Most prostate cancers are classified as adenocarcinomas, characterized by expression of androgen receptor (AR) and PSA. The initial results on the phase 2a adenocarcinoma cohort were reported at ESMO 2021. Here are reported the updated safety and efficacy analyses after enrollment of 40 patients for the adenocarcinoma cohort. Methods: Phase 2a patients with adenocarcinoma required to have progression by PCWG3 on 1 or 2 androgen signaling inhibitor and ≥1 prior line of taxane chemotherapy. Patients received pembrolizumab (200 mg IV q21-days) + BXCL701 0.2 mg BID for a week 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 defined as RECIST 1.1 ± PSA₅₀± CTC count conversion. 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 9/27/21, 40 adenocarcinoma patients were enrolled (26 evaluable, 12 in active treatment). All had previously received taxane chemotherapy and first and/or second generation Androgen Deprivation Treatments and a median of 5 prior lines of therapy (range 1-11); 44% have bone only disease. Median follow-up duration is 12 weeks (range 1-54)/ 4+ cycles. Although follow-up was short, anti-tumor activity was observed. Composite Response rate was 23% (6/ 26 evaluable patients): 2 RECIST-defined confirmed PR + 1 unconfirmed PR (16%) and 63% disease control rate (defined as PR + SD + non-CR/ non-PD) in 19 patients with measurable disease; 16% PSA₅₀ (3 patients had ̃90% PSA decrease) in 31 patients with ≥1 post-baseline PSA measurement; 25% CTC conversion in 8 CTC evaluable patients. All responders showed decrease in tumor burden, 5/ 6 responders were Micro Satellite Stable. BXCL701 + pembrolizumab demonstrated acceptable tolerability without evidence of increased immune-related AEs compared to historic controls with checkpoint inhibitors. AEs consistent with cytokine activation were observed (hypotension, oedema, fever, fatigue). Conclusions: Oral BXCL701 in combination with pembrolizumab demonstrates encouraging anti-tumor activity in very late-line, refractory mCRPC adenocarcinoma. BXCL701 BID dosing continues to demonstrate an acceptable safety profile. Final phase 2a study results will be presented. Clinical trial information: NCT03910660.