ctDNA and Recurrence Risk for Adjuvant De-Escalation in HPV-Positive Oropharyngeal Carcinoma

Importance The De-escalated Adjuvant Radiation Therapy (DART) phase 3 randomized clinical trial (RCT) showed that in patients with human papillomavirus (HPV)−associated oropharyngeal squamous cell carcinoma, postoperative minimal residual disease (MRD), detected through circulating tumor HPV DNA (ctHPVDNA), was associated with a higher risk of disease progression. When considered along with pathologic factors, postoperative ctHPVDNA assessment may improve patient selection for adjuvant treatment de-escalation; however, more data are needed to demonstrate how it may be used in personalizing treatment intensity. Objective To determine the association of postoperative MRD status with progression-free survival (PFS) after surgery for HPV-associated oropharyngeal squamous cell carcinoma. Design, Setting, and Participants This was a secondary analysis of the DART RCT, which was conducted from October 2016 to August 2020 in multiple sites in the US. Participants from the de-escalated adjuvant radiation therapy group and the standard of care group with available blood specimen data were included. Reports from 3-month posttreatment surveillance visits were used to assess associations and outcomes. Data analyses were performed from March 2023 to March of 2025. Interventions The DART group received 30 to 36 Gy of radiation therapy in 1.5 to 1.8 Gy twice daily, plus docetaxel, 15 mg/m 2 , on days 1 and 8. The standard of care group received 60 Gy with or without weekly cisplatin, 40 mg/m 2 . Main Outcome and Measure PFS. Results The analysis included 140 patients (mean [SD] age, 59.1 [8.4] years; 12 [8.6%] females and 128 [91.4%] males; 97 [69.3%] with no smoking history); characteristics were similar to the overall DART RCT population. Of these, 17 patients (12.1%) had postoperative MRD (13 of 96 [13.5%] receiving DART and 4 of 44 [9.1%] receiving standard of care). For all patients, postoperative MRD positivity was strongly associated with worsened PFS at 24 months (MRD positivity, 69.5%; MRD negativity, 95.9%; hazard ratio [HR], 0.19; 95% CI, 0.06-0.59). MRD positivity was associated with PFS when evaluating only those patients in the DART group, where 24-month PFS was 68.4% compared to 92.6% for MRD-negative patients (HR, 0.28; 95% CI, 0.08-0.93). Three months after completion of all treatment, 8 of 117 patients (6.8%) had detectable ctHPVDNA, whereas 109 of 117 (93.2%) did not, and detection was highly associated with PFS (HR, 20.48; 95% CI, 6.91-60.67). Conclusions and Relevance This secondary analysis of the DART RCT found that patients with detectable ctHPVDNA after surgery had a higher risk of disease progression. When added to the pathologic factors considered, ctHPVDNA assessment may improve selection of patients for treatment de-escalation. In addition, the 3-month posttreatment time point, early in surveillance, may identify a sizable portion of patients with progression and may guide intervention and surveillance after surgery for HPV-associated oropharyngeal squamous cell carcinoma. Trial Registration ClinicalTrials.gov Identifier: NCT02908477