Background: Patients with intermediate and high-risk oropharyngeal cancer (OPC) have poorer response to standard treatment and poorer overall survival compared to low-risk OPC. The CompARE trial is designed to test alternative approaches to intensification of treatment for these patients to improve survival. Methods: CompARE is a pragmatic phase III open-label multicenter RCT with an adaptive multi-arm multi-stage design. Eligible OPC patients include those with; HPV negative, T1-T4, N1-N3 or T3-4, N0 or HPV positive current smokers (or ≥ 10 pack years previous smoking history) with T1-T4, N2b-N3. The primary outcome measure is overall survival. Secondary outcome measures include quality of life, toxicity, swallowing outcomes, feeding tube incidence, surgical complications and cost-effectiveness. The trial is powered to detect a hazard ratio of 0.69 (an improvement of 10% in OS at 3-years) requiring 128 control events. It is estimated that the study will take 6.5 years to recruit sufficient patients to experience the number of events needed. Planned interim futility analyses using event-free survival (EFS) will be performed when 70 and 114 control EFS events have occurred. Current treatment arms are; (1) control: standard treatment of 3-weekly cisplatin 100mg/m² or weekly 40mg/m² with Intensity Modulated Radiotherapy (IMRT) using 70Gy in 35F +/- neck dissection determined by clinical and radiological assessment 3-months post treatment. (3) IMRT 64Gy in 25F + cisplatin 100mg/m² day 1 of week 1 and week 5 or weekly 40mg/m²+/- neck dissection as per standard treatment. (4) Resection of primary + selective neck dissection followed by standard treatment. (5) One cycle of induction durvalumab 1500mg followed by standard treatment then durvalumab 1500mg every four weeks for a total of 6 months. Recruitment to arm (2) involving induction chemotherapy from the original protocol is suspended. Since July 2015, 42 patients have been randomised with 16 sites open to recruitment. The Data Monitoring Committee last reviewed progress and conduct of the trial in September 2016 and recommended continuation. ISRCTN Number: 41478539, CRUK CRUK/13/026 Clinical trial information: 41478539.