TPS7086 Background: Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) remains a standard of care first-line (1L) treatment for patients (pts) with DLBCL. However, poor outcomes persist for certain DLBCL pt subgroups, including those with high-risk features: activated B-cell-like (ABC) cell of origin (5-yr progression-free survival PFS/overall survival OS 48%/56%), MYC and BCL2 rearrangements (median OS 15 months), or International Prognostic Index IPI score 4–5 (5-yr PFS/OS 46%/54%). Improving outcomes through effective 1L treatment continues to be important, highlighted by the dismal prognosis in pts who are primary refractory (2-yr OS 24%) or who relapse early after 1L treatment (4-yr OS 30%). Odronextamab, a CD20×CD3 bispecific antibody, showed encouraging efficacy (objective response rate 52%; complete response CR rate 31%; 47% maintained CR at 2 years) and generally manageable safety as a monotherapy in pts with heavily pretreated relapsed/refractory DLBCL, including in pts who were anti-CD20 antibody refractory (Ph 2 ELM-2 study; Ayyappan, et al. ASH 2023). These data provide the rationale to evaluate the efficacy and safety of odronextamab plus CHOP (O-CHOP) vs R-CHOP in pts with previously untreated DLBCL. Methods: OLYMPIA-3 (NCT06091865) is a Ph 3, randomized, open-label, multicenter study of O-CHOP vs R-CHOP in pts with previously untreated DLBCL and intermediate- or high-risk features. The study consists of Part 1A (dose escalation), Part 1B (dose optimization), and Part 2 (randomized controlled). Part 1A will assess the safety of O-CHOP. In Part 1B, pts will be randomized 1:1 to one of two O-CHOP regimens, selected based on Part 1A results. In Part 2, pts will be randomized 1:1 to O-CHOP or R-CHOP, with odronextamab dosing dependent on Part 1 results, and R-CHOP given per standard practice. Intravenous odronextamab will be administered weekly from Cycle (C) 1 Day (D) 8 until C5D8, with step-up dosing during C1 and C2, then every 2 weeks until the end of C6. CHOP will be administered in six 21-day cycles, starting on C1D1. Key inclusion criteria: aged ≥18 years; untreated CD20+ DLBCL; ECOG PS ≤2; and IPI score ≥2. Pts with central nervous system lymphoma, Grade ≥3 peripheral neuropathy, or an active infection are excluded. The primary endpoints are the incidence of dose-limiting toxicities, and incidence and severity of treatment-emergent adverse events (Part 1), and PFS by independent central review (Part 2). Part 2 key secondary endpoints are event-free survival and CR rate (both by independent central review), as well as OS. Other secondary endpoints are minimal residual disease (by ctDNA) and patient-reported outcomes (EORTC QLQ-C30, FACT-LymS, PGIS, PGIC, and EQ-5D-5L). The trial is currently recruiting and is expected to enroll up to 64 pts in Part 1 and ~840 pts in Part 2 at ~200 global sites. Clinical trial information: NCT06091865 .