Background: Rolapitant is a highly selective competitive long acting NK-1 receptor antagonist that demonstrated efficacy in a large randomized phase 2 dose-finding study. This study evaluated the 200 mg dose for efficacy and safety in the prevention of CINV in subjects receiving MEC. Methods: Randomized phase 3 double-blind active-control study. 1,369 chemo-naïve patients treated with MEC (cyclophosphamide, doxorubicin, epirubicin, carboplatin, irinotecan, daunorubicin or cytarabine) were randomized 1:1 to either (1) rolapitant + granisetron + dexamethasone or (2) placebo + granisetron + dexamethasone. The primary endpoint was complete response (CR=no emesis and no rescue medication) in delayed phase (>24-120 hrs) post-chemo. Secondary endpoints included CR in acute (0-24 hrs) and overall (0-120 hrs) phases. Treatment comparisons were performed using Mantel-Haenszel chi-square test; to control for type 1 error testing for key secondary endpoints was conducted in a stepwise fashion. Subjects recorded episodes of emesis, nausea and rescue medication using a diary during 0-120 hrs post-chemo. Results: There were 1,344 evaluable patients (>50% received anthracycline-cyclophosphamide therapy). Subjects in rolapitant group had a significantly higher CR rate for the primary study endpoint during delayed phase compared to control (71.3% vs 61.6%, p<0.001, respectively). CR rates were also higher in rolapitant group for acute and overall phases (83.5% vs 80.3%, p=0.143; 68.6% vs 57.8%, p<0.001, respectively). The rolapitant group achieved higher rates of complete protection (no emesis, no rescue medication and maximum nausea VAS <25mm) in both delayed and overall phases compared to control (64.3% vs 56.9%, p=0.006; 62.0% vs 53.2%, p=0.001, respectively). AE rates were similar across both groups. Conclusions: Rolapitant in combination with a 5-HT3 receptor antagonist and dexamethasone was well-tolerated and demonstrated superior efficacy over control in the primary endpoint of the prevention of delayed CINV in subjects receiving MEC in a global phase 3 study. Clinical trial information: NCT01500226.