Background: Immune checkpoint inhibitors have limited single agent activity in microsatellite-stable mCRPC. ¹⁷⁷Lu-PSMA-617 (Lu) is a PSMA-targeting radioligand therapy that has demonstrated promising anti-tumor activity. We sought to determine whether a single dose of Lu can induce an immunogenic priming effect to improve outcomes of men with mCRPC subsequently treated with pembrolizumab (P). Methods: We undertook a phase 1b, single arm trial enrolling chemotherapy-naïve mCRPC patients (pts) with progression (PD) on at least one prior androgen signaling inhibitor (NCT03805594). Pts were required to have ≥ 3 PSMA-avid lesions on ⁶⁸Ga-PSMA-11 PET and measurable disease by RECIST 1.1 criteria. No genomic selection was undertaken. Pts were enrolled sequentially on one of three schedules: A) Single dose of Lu (7.4 GBq) followed by initiation of P (200 mg IV q 3 weeks) 28 days later; B) Lu x 1 dose given concomitantly with first P administration; C) Lu x 1 dose given on C2D1 following initiation of P on C1D1. Pts were treated with P until confirmed radiographic or clinical PD. The primary endpoint was safety; key secondary endpoints included PSA response, objective response rate by RECIST 1.1 criteria (ORR), median duration of response (DOR), and radiographic progression-free survival (rPFS). Results: 18 pts were enrolled, 6 per schedule. The median age was 64 (range 51 – 80) and 44% of pts had visceral metastases. The median baseline number of PSMA-avid metastatic lesions was 20 (range 6 – 50+). Six pts (33%) had progressed on prior abiraterone, 4 (22%) on enzalutamide, and 8 (44%) on both. There were no dose-limiting toxicities and one Grade ≥ 3 treatment-related adverse event (AE) (inflammatory arthritis, schedule B). There were no grade ≥ 3 hematologic AEs. The ORR was 8/18 (44%) and median DOR has not been reached (range 1.9+ – 15.9+ months). Four pts (2 on schedule A, 1 on schedule B, 1 on schedule C) with durable partial responses remain on study treatment for 5.4+, 8.9+, 9.2+, and 17.8+ months, respectively. The median rPFS was 6.5 months (95% CI: 2.5 – 9.8). PSA30, PSA50, and PSA90 response rates were 44%, 28%, and 17%, respectively. Fourteen pts (78%), including all durable responders, had somatic genomic data available. One (7%) harbored a DNA repair mutation (BRCA1, non-responder), none were MSI-high, and all carried low tumor mutational burden (≤ 5 mutations/MB). Single cell sequencing of the immune microenvironment from paired metastatic tumor biopsies is underway. Conclusions:¹⁷⁷Lu-PSMA-617 as a priming dose followed by pembrolizumab was well tolerated and leads to durable responses in a subset of mCRPC without high mutational burden or microsatellite instability, suggesting a possible immunogenic priming effect of radioligand therapy. Further evaluation of the combination is ongoing in a phase 2 study. Clinical trial information: NCT03805594