Background: African Americans (AA) are at higher risk for prostate cancer death compared to other ethnic groups in the United States. Early immune-based therapy prolonged overall survival in men with mCRPC and appears to be more pronounced in AA compared to Caucasian men. We sought to explore efficacy of PD-L1 inhibition in AA men with mCRPC. Methods: AA men > 18 years of age and had developed mCRPC on next generation hormonal therapies (NHTs) were eligible for this study. Patients received avelumab 10mg/kg IV every 2 weeks while remaining on NHTs until clinical or radiographic disease progression. This pilot, single-arm phase 2 prospective study was designed to enroll 13 patients with primary endpoint to assess > 50% reduction in PSA (PSA50). Radiographic assessments were planned every 12 weeks until progression or two years, whichever came first. Results: Of the eight patients enrolled, there were three screen-failures: +hepatitis titer (n = 1), rapid clinical deterioration (n = 1) and not confirmed CRPC (n = 1). Median age at time of enrollment was 62 (54-73) with median PSA 7.2 (3.6 – 8.63). Five patients received at least one dose of avelumab and remained on abiraterone acetate with steroid (n = 4) or enzalutamide (n = 1). Median duration on NHTs prior to enrollment was 364 days (95% CI, 260.9-467.1). Median time from screening to cycle 1 was 8 days (3-14). One patient withdrew consent after a single dose of avelumab. Two patients had rapid clinical progression within 8 weeks of starting avelumab. One patient received 9 cycles of avelumab and progressed. One patient experienced a grade 4 adverse event after 2 doses of avelumab with clinical progression during treatment delay. None of the five enrolled patients achieved a PSA50. The median time on study to PSA progression was 35 days (95 CI%, 0-94.8) with median time to radiographic progression of 44 days (95 CI%, 0-118.5). Adverse events occurred in 80% (n = 4/5) of cases. One of the 11 reported grade 3/4 adverse events was related to study drug (G3 hyperglycemia). The study was closed to further accrual prior to the pre-planned completion due to safety concerns related to lack of efficacy of study intervention and rapid clinical progression. Conclusions: The addition of avelumab did not demonstrate clinical activity in AA men with mCRPC who progressed on abiraterone acetate or enzalutamide. The short time interval between PSA progression and radiographic and/or clinical progression is concerning and notable to be much shorter than previously reported pivotal phase III trials. This suggests potential for very significant clinical implications regarding not only future clinical trial designs but also clinical management in this underrepresented ethnicity. We will report updated analysis with longer follow-up (NCT03770455). Clinical trial information: NCT03770455