This study reports the results of a phase 1, first-in-human trial evaluating the safety and efficacy of prostate stem cell antigen (PSCA)-directed chimeric antigen receptor (CAR) T cell therapy in patients with metastatic castration-resistant prostate cancer (mCRPC). The trial aimed to assess the safety and dose-limiting toxicities (DLTs) of PSCA-CAR T cells, with secondary endpoints including CAR T cell persistence, disease response, and survival. The starting dose was 100 million (M) CAR T cells without lymphodepletion (LD), followed by LD in subsequent cohorts. No DLTs were observed at the starting dose, but a grade 3 cystitis was encountered at the second dose level (DL2), leading to the addition of a reduced LD regimen in the third cohort (DL3). No DLTs were observed in DL3. Cytokine release syndrome (CRS) of grade 1 or 2 occurred in 5 of 14 treated patients, and prostate-specific antigen (PSA) declines (>30%) were observed in 4 of 14 patients. Radiographic improvements were also noted in some patients. Dynamic changes in peripheral blood immune cell subsets, TCR repertoire diversity, and the tumor immune microenvironment were observed in a subset of patients. However, limited persistence of CAR T cells was observed beyond 28 days post-infusion. The study supports further clinical trials to optimize dosing and combination strategies to improve durable therapeutic outcomes.This study reports the results of a phase 1, first-in-human trial evaluating the safety and efficacy of prostate stem cell antigen (PSCA)-directed chimeric antigen receptor (CAR) T cell therapy in patients with metastatic castration-resistant prostate cancer (mCRPC). The trial aimed to assess the safety and dose-limiting toxicities (DLTs) of PSCA-CAR T cells, with secondary endpoints including CAR T cell persistence, disease response, and survival. The starting dose was 100 million (M) CAR T cells without lymphodepletion (LD), followed by LD in subsequent cohorts. No DLTs were observed at the starting dose, but a grade 3 cystitis was encountered at the second dose level (DL2), leading to the addition of a reduced LD regimen in the third cohort (DL3). No DLTs were observed in DL3. Cytokine release syndrome (CRS) of grade 1 or 2 occurred in 5 of 14 treated patients, and prostate-specific antigen (PSA) declines (>30%) were observed in 4 of 14 patients. Radiographic improvements were also noted in some patients. Dynamic changes in peripheral blood immune cell subsets, TCR repertoire diversity, and the tumor immune microenvironment were observed in a subset of patients. However, limited persistence of CAR T cells was observed beyond 28 days post-infusion. The study supports further clinical trials to optimize dosing and combination strategies to improve durable therapeutic outcomes.