Background: Survival rates for patients with metastatic colorectal cancer (mCRC) are low. Current front-line therapy includes a combination of irinotecan/5-fluorouracil/leucovorin (FOLFIRI) ± bevacizumab. Veliparib (Vel) is a potent, competitive poly (ADP-ribose) polymerase (PARP)-1/2 inhibitor that enhances the activity of irinotecan in pre-clinical models. This study assessed if addition of oral Vel concurrent to FOLFIRI, with the goal to potentiate irinotecan activity, improves survival in patients with previously untreated mCRC. Methods: This is a randomized, blinded, phase 2 study (NCT02305758) comparing Vel (200 mg BID administered for 7 days of each 14-day cycle) to placebo (PBO), each in combination with FOLFIRI. Bevacizumab was allowed in both arms. Endpoints were progression-free survival (PFS), overall survival (OS), objective response rate (ORR) by RECIST 1.1, duration of overall response (DOR), safety and tolerability. Results: As of October 31, 2017, 130 patients were randomized to receive either Vel (n= 65) or PBO (n= 65). Median PFS was 12 vs 11 months (Vel vs PBO) [HR = 0.94 (95% CI: 0.60, 1.48)]. Median OS was 25 vs 27 months (Vel vs PBO) [HR = 1.26 (95% CI: 0.74, 2.16)]. There were 27 OS events each in the Vel and PBO arms. ORR was 56.9% (Vel) and 61.5% (PBO). Median DOR was 11.1 vs 9.4 months (Vel vs PBO) [HR = 0.73 (95% CI: 0.38, 1.40)]. Common adverse events (AE) (in ≥20% patients) assessed as related to Vel that did not differ from Vel to PBO arm were nausea, fatigue, and vomiting. Grade 3/4 AE (in ≥5% patients) assessed as related to Vel (for Vel vs PBO) include neutropenia (22% vs 11%), diarrhea (5% vs 9%), nausea (8% vs 2%), and asthenia (6% vs 0%). SAE assessed as related to Vel (for Vel vs PBO) include febrile neutropenia (3% vs 3%) and diarrhea (2% vs 3%). All grade hematopoietic cytopenias were more common with Vel than PBO (79% vs 52%, p= 0.003). Two treatment-emergent AE deaths occurred in each Vel and PBO arm. 14% of patients in Vel arm and 15% in PBO arm prematurely discontinued treatment due to AEs. Conclusions: Vel added on to FOLFIRI ± bevacizumab demonstrated similar efficacy as FOLFIRI ± bevacizumab in frontline mCRC patients. Overall, there were no unexpected safety concerns. Clinical trial information: NCT02305758