Background: Rolapitant is a highly selective competitive long acting NK-1 receptor antagonist that demonstrated efficacy and safety 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 HEC. Methods: Randomized phase 3 double-blind active-control study. 555 cisplatin-naïve subjects treated with HEC (≥60 mg/m² cisplatin) were randomized 1:1 to receive either (1) rolapitant + granisetron + dexamethasone or (2) placebo + granisetron + dexamethasone. The primary endpoint was complete response (CR=no emesis and no rescue medication) in the delayed phase (>24-120 hrs) post-chemotherapy. Secondary endpoints included CR during the acute (0-24 hrs) and overall (0-120 hrs) phases. Treatment comparisons were performed using a Mantel-Haenszel chi-square test; to control for the type1 error, testing for the key secondary endpoints was conducted in a stepwise fashion. Subjects recorded episodes of emesis, nausea and rescue medication using a subject diary during 0-120 hours post-chemotherapy. Results: There were 544 evaluable subjects. Subjects in the rolapitant group had a significantly higher CR rate for the primary study endpoint during the delayed phase (70.1% vs 61.9%, p=0.043) compared to control. CR rates were also higher in rolapitant group for acute and overall phases (83.4% vs 79.5%, p=0.233; 67.5% vs 60.4%, p=0.084, respectively). The rolapitant group achieved higher rates of no nausea (maximum Visual Analog scale <5mm, 0-100mm) in both the delayed and overall phases compared to control (58.3% vs 46.9%, p=0.007; 55.0% vs 44.0%, p=0.009, 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 HEC in a global phase 3 study. Clinical trial information: NCT01500213.