Background: Treatment of localized prostate cancer (PCa) with surgery or radiotherapy remains suboptimal with failure rates of 35-40%. Bruton’s Tyrosine Kinase (BTK) is seen elevated in PCa tissues compared to normal prostate tissue. Malignant B-cell density has been correlated with higher risk of aggressive PCa and mitigating that through the BTK has been proposed in mouse models. Ibrutinib is a potent BTK inhibitor which targets B-cell signaling pathways, has an established safety profile, and has been shown to inhibit in vivo prostate tumor growth pre-clinically. Therefore, we hypothesized that ibrutinib will augment anti-tumor immune responses through inhibiting tumor-intrinsic growth via blocking BTK B-cell signaling pathways, while also inducing favorable T-cell profiles in localized PCa. Methods: We performed a neoadjuvant clinical trial (NCT02643667) studying ibrutinib in PCa. Eligible patients had localized PCa with no prior treatment, and deemed suitable for undergoing a radical prostatectomy. Patients received 840mg/day oral ibrutinib for 28 days followed by a radical prostatectomy 7-12 days later. Patients were assessed 4 weeks after surgery. The primary objectives are to assess safety of ibrutinib and characterize B and T cell infiltration. Correlative pre- and post- treatment tissue and blood samples were collected; BTK and PD-L1 expression in tumor and immune-infiltrating immune cells will be examined, and BCR and TCR clonality and diversity will be evaluated. Results: 22 patients were registered and underwent treatment to date. 4 patients had early termination of ibrutinib treatment with 3 due to adverse effects and 1 due to discovery of surgically unresectable disease. A total of 21 of 22 patients received radical prostatectomies. There were no intra-operative complications attributed to ibrutinib. The treatment was generally well tolerated with 7.1% grade 3 treatment related adverse effects. 2% experienced a grade 4 treatment adverse effects of hepatic dysfunction. The most common grade 1-2 adverse effects were diarrhea (8.2%), fatigue (7.1%), and anemia (6.1%). The median follow-up time was 23.9 months. Median overall survival and median failure free survival have not been reached and the two-year milestone is 100%. Sample collection is complete and immune correlative analyses are ongoing. Safety/tolerability, clinical outcomes, and preliminary correlative data will be reported. Conclusions: This is the first clinical trial of ibrutinib in PCa, and lays the foundation for larger future studies. Clinical trial information: NCT02643667.