The imipridone ONC201 is the first selective antagonist of the G protein-coupled receptor DRD2 for clinical oncology. ONC201 induces p53-independent apoptosis in newly diagnosed and recurrent glioblastoma in vitro, ex vivo, and in vivo. We performed a Phase II clinical trial that enrolled an initial cohort of 17 patients with recurrent, bevacizumab-naïve, IDH1/2 WT glioblastoma who received 625mg ONC201 every three weeks. One patient continues to have a durable objective response that has deepened over time, exhibiting an 92% regression by 92% after 15 months of therapy. Another patient remains disease-free 14 months after enrolling on this trial following a re-resection. Median OS was 41.6 weeks with an OS12 of 35%. No drug-related SAEs or treatment discontinuation due to toxicity occurred. Plasma PK at 2 hours post-dose was 2.6 ug/mL and serum prolactin induction was observed as a surrogate marker of target engagement. In addition to cytotoxic effects in tumor cells, DRD2 antagonism can induce the activation of NK and other immune cells. We found that immune effector levels in the serum correlated with the kinetics of the objective response. Preclinical studies have identified a DRD2+DRD5- tumor biomarker signature that is predictive of innate sensitivity to ONC201. Among the 15 available archival tumor tissue specimens, all had expression of DRD2 and 8/17 patients had low expression of DRD5. Patients with PFS>5 month had no detectable expression of DRD5 unlike those with PFS<5 months. In addition, 4/8 DRD2+DRD5- are still alive after >57 weeks and 0/7 DRD2+DRD5+ patients remain alive. In summary, ONC201 is a well tolerated novel therapy with potential anti-glioblastoma activity that may be associated with a predictive biomarker signature and immune activation. The pharmacodynamic activity and clinical efficacy of ONC201 continues to be explored in additional cohorts of glioblastoma patients at first recurrence (NCT02525692).