Background: Effective therapies remain a currently unmet need for neuroendocrine prostate cancer (NEPC). Preclinical synergy in small cell cancer, and clinical tolerability led to the conduct of a multicenter phase II trial of lenvatinib and pembrolizumab combination. Patients and Methods: Eligible patients had histologically proven prostate cancer with radiologic evidence of metastases and at least one of the following: A) Small-cell or NEPC morphology B) Positive staining for chromogranin and synaptophysin C) Presence of visceral metastases or high volume disease (> 4 sites of metastases) and a PSA< 5ng/ml.D) Serum chromogranin A level > 5× upper limit of normal (ULN) and/or serum neuron specific enolase (NSE) > 2× ULN. E) RB1 deletions or mutations F) Trans-differentiated carcinoma. Maximum of 2 prior chemotherapy regimens were allowed. Performance status of 0-1 and normal marrow, renal and liver function were required. Primary endpoint was 6-month progression free survival (PFS). Secondary objectives included radiologic PFS, safety, overall survival (OS), overall response rate (ORR) and duration of response (DOR). Treatment consisted of lenvatinib orally daily at a starting dose of 20 mg daily and intravenous pembrolizumab 200 mg every 21 days. Imaging was conducted every 9 weeks for the first 4 assessments and then every 12 weeks thereafter. PSA was monitored on day 1 of each cycle. Results: 45 patients were enrolled; of which 4 (9%) were African American. Median age was 69 years (range- 37-88 years), 16 (36%) had Gleason > 8, 30 (67%) had small cell/NEPC, 1 had transdifferentiated histology (2%). 18 (40%) patients had liver metastases and 39 (87%) had measurable disease. 6 (13%) patients were chemotherapy naïve and 28 (62%) had received prior platinum-based therapy.  5 patients had grade 3 or 4 immune related adverse events. No treatment related deaths were noted. Of 40 response evaluable patients 10 (25%) had a partial response and 18 (45%) demonstrated stable disease. 10 patients (25%) were progression free at 6 months. The median PFS and OS were 3.9 (2.9-6.0) and 8.0 (5.9-12.3) months respectively. Conclusion: The combination of lenvatinib and pembrolizumab demonstrated promising efficacy in a patient population that currently has no therapeutic options. Clinical trials.gov: NCT04848337