Shortened Course of Radiation Therapy After Trans-oral Robotic Surgery in Patients With HPV-Mediated Oropharyngeal Squamous Cell Carcinoma.

Step 1 Registration: Pre-Operative Eligibility

Inclusion Criteria:

* Participant aged ≥ 18 years.
* Diagnosis of oropharyngeal squamous cell carcinoma.
* Eligible to receive transoral robotic surgery.
* If status is known, p16 positivity or HPV positivity by in situ hybridization on pathological sampling of lymph node or primary oropharyngeal tumor. If status not known at the time of step-1 registration, otherwise eligible participants may be enrolled and HPV/p16 status must be determined prior to step-2 registration.
* Pre-operative TTMV-HPV DNA test collected or is planned to be collected. Pre-operative TTMV-HPV DNA may be collected anytime up until the day of surgery as long as it is prior to surgery.

  * Standard of care tests completed within 60 days of registration may be used for screening.
  * Tests results are not required to confirm eligibility for step 1 registration.
* ECOG Performance Status ≤ 2
* Able to provide informed consent and willing to sign an approved consent form that conforms to federal and institutional guidelines.

Exclusion Criteria:

* History of prior mucosal head and neck cancer treated with radiation therapy
* Prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of this study
* Participant has smoked cigarettes within 1 month of registration
* Prior systemic anti-cancer therapy or any investigational therapy ≤ 14 days or within five half-lives prior to starting study treatment, whichever is shorter.
* Known distant metastatic disease.
* Current evidence of any condition that would, in the Investigator's judgment, contraindicate the participant's participation in the clinical study due to safety concerns or compliance with clinical study procedures (e.g., infection/inflammation, intestinal obstruction, unable to swallow medication, \[participants may not receive the drug through a feeding tube\], social/ psychological issues, etc.)
* Medical, psychiatric, cognitive, or other conditions that may compromise the participant's ability to understand the participant information, give informed consent, comply with the study protocol or complete the study.

Step 2 Registration - Experimental Arm

Inclusion Criteria:

* Completion of trans-oral robotic surgery.
* Pre- and post-operative TTMV-HPV DNA test results obtained.
* P16 positivity or HPV positivity by in situ hybridization on pathological sampling of lymph node or primary oropharyngeal tumor
* For participants of childbearing potential: Negative pregnancy test or evidence of permanent surgical sterilization. The post-menopausal status will be defined as having been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:

  * \< 50 years of age:

    * Amenorrheic for ≥ 12 months following cessation of exogenous hormonal treatments; and
    * Luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution
  * ≥ 50 years of age:

    * Amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments; or
    * Had radiation-induced menopause with last menses \>1 year ago; or
    * Had chemotherapy-induced menopause with last menses \>1 year
* Participants of childbearing potential must agree to use a highly effective method of contraception as described in Section 5.5.2.

Exclusion Criteria:

* Meets ALL of the following criteria for low-risk disease (Note: participants may meet some without being excluded):

  * Pre-operative TTMV-HPV DNA positive
  * Post-operative TTMV-HPV DNA negative
  * Disease: pT1 with ≤ 1 lymph nodes OR pT2N0
  * \<10 pack year smoking
  * No extranodal extension
  * Negative surgical margins
  * No perineural invasion
  * No lymphovascular invasion
* Meets ANY of the following criteria for high-risk:

  * Post-operative TTMV-HPV DNA positive
  * Surgical margin positive --\>1 mm extranodal extension --≥ 5 lymph nodes
* Current evidence of any condition that would, in the Investigator's judgment, contraindicate the participant's participation in the clinical study due to safety concerns or compliance with clinical study procedures (e.g., infection/inflammation, intestinal obstruction, unable to swallow medication, \[participants may not receive the drug through a feeding tube\], social/ psychological issues, etc.)

Step 2 Registration - Exploratory Arm Inclusion Criteria

* Completion of trans-oral robotic surgery.
* Pre- and post-operative TTMV-HPV DNA test results obtained.
* Meets ANY of the following criteria:
* Post-operative TTMV-HPV DNA positive or indeterminate
* Surgical margin positive
* \>1 mm extranodal extension
* ≥5 lymph nodes
* Pre-operative TTMV-HPV DNA score of ≤ 50
* For participants of child bearing potential: Negative pregnancy test or evidence of permanent surgical sterilization. The post-menopausal status will be defined as having been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:

  * \< 50 years of age:

    * Amenorrheic for ≥ 12 months following cessation of exogenous hormonal treatments; and
    * Luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution
  * ≥ 50 years of age:

    * Amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments; or
    * Had radiation-induced menopause with last menses \>1 year ago; or
    * Had chemotherapy-induced menopause with last menses \>1 year
* Participants of childbearing potential must agree to use a highly effective method of contraception as described in Section 5.5.2.

Exclusion Criteria

* Pre-operative TTMV-HPV DNA score of \> 50.
* Current evidence of any condition that would, in the Investigator's judgment, contraindicate the participant's participation in the clinical study due to safety concerns or compliance with clinical study procedures (e.g., infection/inflammation, intestinal obstruction, unable to swallow medication, \[participants may not receive the drug through a feeding tube\], social/ psychological issues, etc.).