Table 3 Eligibility criteria for the CompARE trial

1. Oropharyngeal squamous cell carcinoma (OPSCC) in the base of the tongue and tonsil (includes bilateral tumours) with a multidisciplinary team recommendation for treatment with definitive concurrent chemoradiotherapy

2. All OPC T4 or N3 (HPV-pos and HPV-neg) or all HPV-neg OPC T1–T4, N1–N3, or T3–4, N0 or HPV-pos OPC T1-T4 with N2b-N3 nodes and who are smokers ≥ 10 pack years current or previous smoking history

3. Minimum life expectancy of 3 months

4. Eastern Cooperative Oncology Group (ECOG) performance status 0–1

5. Body weight of > 30 kg

6. Adequate renal function, estimated glomerular filtration rate (eGFR) > 50 mL/min calculated using Cockcroft-Gault formula

7. Adequate bone marrow function (absolute neutrophil count (ANC) ≥ 1.5 × 109/L, haemoglobin ≥ 9.0 g/dL and platelets ≥ 100 × 109/L)

8. Adequate liver function, i.e. serum bilirubin ≤ 1.5 times the upper limit of normal (ULN), AST (SGOT)/ALT (SGPT) ≤ 2.5 × institutional upper limit of normal

9. Prothrombin time (PT) ≤ 1.5 × ULN or international normalised ratio (INR) ≤ 1.5

10. Magnesium ≥ lower limit of normal

11. No cancers in previous 5 years, except for basal cell carcinoma of the skin and cervical intra-epithelial neoplasia (CIN)

12. Aged 18–70

13. Written informed consent given for the trial

14. Surgically resectable disease if being randomised to all four arms

15. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:

 a. Women < 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinising hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilisation (bilateral oophorectomy or hysterectomy).

 b. Women ≥ 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses > 12 months ago, had chemotherapy-induced menopause with last menses > 12 months ago, or underwent surgical sterilisation (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy).

16. Willingness to comply with the protocol for the duration of the study, including undergoing treatment and scheduled visits and examinations including follow-up

1. All T1–T2, N0 OPC (HPV-pos or HPV-neg)

2. HPV-positive patients who are T1–T3, N0–N2c non-smokers or T1–T3, N0–N2c smokers with ≤ 10 pack years or T1–T2, N0–N2a smokers with ≥ 10 pack years

3. Unfit for chemoradiotherapy regimens

4. Creatinine clearance < 50 mL/min

5. Treatment with any of the following, prior to randomisation: (a) any investigational medicinal products (IMP) within 30 days; (b) any other chemotherapy, immunotherapy, or anticancer agents within 3 weeks; (c) major surgical procedure (as defined by the investigator) within 4 weeks, unless for diagnostic purposes; and (d) concurrent use of hormonal therapy for non-cancer-related conditions (e.g. hormone replacement therapy is acceptable)

6. History of allergic reactions or hypersensitivity to any of the IMPs and excipients used in this trial

7. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhoea, or any subject known to have evidence of acute or chronic hepatitis B, hepatitis C, human immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase the risk of incurring AEs or compromise the ability of the subject to give written informed consent

8. Women who are pregnant or breast-feeding. Women of childbearing potential must have a negative pregnancy test performed within 7 days prior to randomisation

9. Men or women who are not prepared to practise methods of contraception of proven efficacy during treatment and for 6 months following the end of treatment

10. Any condition that, in the opinion of the investigator, would interfere with the evaluation of study treatment or interpretation of patient safety or study results

11. Additional exclusion criteria for arm 5 only

12. Any previous treatment with PD-L or PD-L1 inhibitor, including durvalumab

13. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab; the following are exceptions to this criterion: injections (e.g. intra articular injection), systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent, and steroids as premedication for hypersensitivity reactions (e.g. CT scan, premedication)

14. Active or prior documented autoimmune or inflammatory disorders including inflammatory bowel disease, e.g. colitis or Crohn’s disease, diverticulitis (with the exception of diverticulosis), systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome (granulomatosis with polyangiitis, Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis, etc.). The following are exceptions to this criterion: patients with vitiligo or alopecia, patients with hypothyroidism (e.g. following Hashimoto syndrome) stable on hormone replacement, any chronic skin condition that does not require systemic therapy, patients without active disease in the last 5 years may be included but only after consultation with the study physician, and patients with celiac disease controlled by diet alone

15. History of active primary immunodeficiency

16. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA

17. History of allogeneic organ transplant

18. Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving durvalumab. Inactivated viruses, such as those in the influenza vaccine, are permitted.