Risk-adapted Therapy in HPV-positive Oropharyngeal Cancer Using Circulating Tumor (ct) HPV DNA Profiling (ReACT 2.0)

Inclusion Criteria: * Participants must have histologically or cytologically confirmed, stage I, II, or III, HPV-associated oropharyngeal (tongue base or tonsil) squamous cell carcinoma, as defined by 2017 American Joint Committee on Cancer (AJCC), 8th edition staging. Participants with HPV-associated disease of unknown primary (cT0) are eligible. * Participants who undergo upfront surgery are permitted to enroll if their post-operative pathology necessitates that they receive adjuvant therapy. * Participants who undergo upfront induction chemotherapy with platinum-based therapy are eligible if they have less than a complete clinical or radiologic response to induction as judged by the treating investigator(s). * Participants with locoregionally recurrent disease are eligible if they completed definitive or curative-intent treatment and meet criteria 3.1, 6e below. * HPV status should be confirmed on tissue biopsy or cytologic sample by any of the following: (a) IHC staining for p16 with ≥70% expression, and/or (b) DNA testing (PCR or ISH) for high-risk subtypes 16, 18, 31, 33, or 35. * Tumor tissue available for PD-L1 CPS testing. * Age 18 years or older at the time of informed consent. * Eastern Cooperative Oncology Group (ECOG) performance status ≤1. * Intermediate or high-risk HPV+ disease defined by any one of the following: * TTMV-HPV DNA score \>200 at baseline and failure to clear by \>95% by week 4-5 of treatment * undetectable or low (≤200) TTMV-HPV DNA…