Background: Bispecific antibodies (bsAbs) are emerging as a protein-based therapeutic strategy for directing T-cell-mediated cytotoxicity in a tumor antigen-specific manner, typically by binding to both tumor antigen and the CD3 receptor on T cells. REGN5678 is a human IgG4-based, first-in-class costimulatory bsAb designed to target prostate tumors by bridging prostate specific membrane antigen expressing tumor cells with the costimulatory receptor, CD28, on T cells, and providing amplified T-cell receptor-CD3 complex-mediated T-cell activation within the tumor through the activation of CD28 signaling. At the tumor site, REGN5678 may synergize with PD-1 inhibitors. In mouse models, REGN5678 in combination with PD-1 antibody has improved anti-tumor activity compared with either therapy alone (Skokos et al CRI/CICON 2019; oral, session 3). This study evaluates the safety and anti-tumor activity of REGN5678 alone and in combination with cemiplimab in patients with metastatic castration-resistant prostate cancer (mCRPC) who progressed after prior therapy. Methods: This is an open label, Phase I/II, first-in-human study evaluating safety, tolerability, pharmacokinetics (PK), and anti-tumor activity of REGN5678 alone and in combination with cemiplimab in treatment-experienced mCRPC (NCT03972657). For inclusion, patients must have received at least two approved therapies for metastatic disease, including a second-generation hormonal agent. REGN5678 is administered weekly and cemiplimab (350 mg) is administered once every 3 weeks. During dose escalation, a 3-week safety lead-in of REGN5678 monotherapy will be administered prior to the addition of cemiplimab. Study therapies are administered until disease progression, intolerable adverse events, withdrawal of consent, or study withdrawal criterion is met. The primary objectives in dose escalation are to evaluate safety, tolerability, and PK of REGN5678 alone and in combination with cemiplimab. Expansion cohort(s) will be enrolled once a REGN5678/cemiplimab recommended Phase II dose is determined. During the expansion phase, the primary trial objective is to assess clinical activity, as measured by objective response rate of REGN5678 in combination with cemiplimab per modified Prostate Cancer Working Group 3 criteria. This study is currently open to enrollment. Clinical trial information: NCT03972657.