A phase 2, multicenter, parallel-group, open-label study of vudalimab (XmAb20717), a PD-1 x CTLA-4 bispecific antibody, alone or in combination with chemotherapy or targeted therapy in patients with molecularly defined subtypes of metastatic castration-resistant prostate cancer.
Authors: Stein Mark N. , Dorff Tanya B. , Goodman Oscar B. , Thomas Roby Antony , Silverman Michael H. , Guo Matthew , Aversa Catherine R , Clynes Raphael , Hickingbottom Barbara , Shorr Jolene S 
Published: June 2022

TPS5097 Background: Although immune checkpoint inhibitor (ICI) monotherapy has shown limited clinical benefit in patients with metastatic castration-resistant prostate cancer (mCRPC), better outcomes have been observed with combination anti-PD-1/CTLA-4 therapy. In addition, whereas response rates are low in unselected mCRPC populations, tumors with selected molecular characteristics, including those associated with aggressive variant disease, CDK12 inactivation, and microsatellite instability high (MSI-H) status, have shown increased sensitivity to ICIs. Finally, altering the tumor microenvironment to promote antitumor immunity by combining ICIs with chemotherapy or targeted agents also has potential to increase clinical benefit. Vudalimab (XmAb20717) is a humanized bispecific monoclonal antibody that simultaneously targets PD-1 and CTLA-4 and binds preferentially to PD-1/CTLA-4 dual-positive cells. In a Phase 1 study, vudalimab monotherapy was generally well-tolerated and associated with complete and partial responses in patients with multiple tumor types, including mCRPC. This Phase 2 study is designed to evaluate the safety and antitumor activity of vudalimab in combination with other anticancer agents or alone in subgroups of mCRPC patients with and without specific tumor molecular subtypes. Methods: This multicenter, open-label study is being conducted at approximately 20 sites in the United States. Patients with mCRPC that progressed following treatment with ≥ 2 prior lines of anticancer therapy are enrolled into the following parallel cohorts based on the presence or absence of molecular abnormalities from prior sequencing of metastatic tumor: aggressive variant (Cohort 1), homologous recombination deficient or CDK12 mutation positive PARP inhibitor progressor (Cohort 2) or PARP inhibitor naïve (Cohort 3), MSI-H or mismatch repair deficient (Cohort 4), and no targetable mutation (Cohort 5). All patients will receive vudalimab 10 mg/kg intravenously every 2 weeks. Cohorts 1, 2, and 5 (n = 20 each) also will receive carboplatin AUC 4 + cabazitaxel 20 mg/m2 (or docetaxel 60 mg/m2, if not received prior) every 3 weeks; Cohort 3 (n = 20) also will receive olaparib 300 mg 2x/day; and Cohort 4 (n = 5) will receive vudalimab monotherapy. The primary objective is to evaluate the safety/tolerability of treatment based on adverse events. Secondary objectives include evaluating objective response (RECIST 1.1, as modified by PCWG3), radiographic progression-free survival, and PSA response. Exploratory objectives include assessing pharmacodynamic activity in peripheral blood and tumor, and correlations of response with cohort-specific molecular tumor characteristics. Enrollment has been initiated. Clinical trial information: NCT05005728.