Background: Human Papilloma Virus (HPV) oropharynx cancer (HPVOPC) is highly curative. Current standard of care treatment recommendations result in over treatment with chemoradiotherapy (CRT) across all stages of the disease and lead to significant long-term morbidity. The Quarterback (QB) trials (NCT01706939, QB1; NCT02945631, QB2a/2b) applied induction chemotherapy (IC) with modified Taxotere, cis-platinum and 5-fluorouracil (TPF) and reduced dose chemoradiotherapy (rdCRT) in very advanced HPVOPC. The primary endpoints were local regional control (LRC) and progression-free survival (PFS) at 3 years. Methods: Patients with locally advanced HPVOPC and High Risk (HR) features (radiographic ECE, T4 primary, ≥N2c disease or non-HPV16 HR genotype) or who were candidates for organ preservation were entered on sequential trials of 3 cycles of TPF IC followed by rdCRT to 5600 cGy with weekly carboplatin. The only variable in IC treatment were 3 sequential reductions of 5-fluorouracil from 800 to 500 mg/M²/day across the trials (QB1, QB2a/2b). Major inclusion criteria were: molecularly documented high risk HPV and ≤20 pack year smoking history. Patients were eligible for rdCRT if they had a significant clinical response to IC. The hypothesis for non-inferiority was that LRC and PFS at 3 years would be at least 85% and 80%, respectively, based on results from RTOG 1029. Analysis was limited to those patients who received or were randomized (QB1) to rdCRT. Results: Of 45 subjects treated with rdCRT, 35 (78%) had HR features. Overall survival (OAS) is 39 (87%), LRC 39 (87%), PFS 35 (78%) with a median follow up of 57m (range: 12-120). Kaplan Meyer 3 year LRC is 88% (95% CI: 79-99), PFS 86% (95 CI 76-97) and OS 93% (95% CI 86-100). 2 subjects (4%) developed an in-field non-HPV, p53 positive squamous cancer and 1 (2%) died. 1 subject (2%) died of non-HPV related disease (SLE); 2 (4%) developed distant metastases; 4 (9%) subjects are alive after recurrence. Disease specific survival is 40/43 (93%). 19 patients signed consent and did not receive rdCRT: 8 were randomized to standard dose (QB1), 2 withdrew consent, 5 had an inadequate response to IC and 4 were screen failures. All 15 treated with IC are alive and disease free. There are no treatment related deaths. Conclusions: TPF IC in HPVOPC with HR features, followed by rdCRT met its predetermined statistical goals for LRC, PFS and OAS. Treatment was tolerable and toxicity was manageable. Compared to other Phase 2 and 3 de-escalation trials this approach is reasonable, effective and feasible. QB1 demonstrated improved quality of life in rdCRT with 5600 cGy compared to standard chemoradiotherapy. Randomized trials to establish de-escalation as a standard of care are warranted. Further de-escalation of treatment to further reduce acute and long-term radiation toxicity in HR populations appears feasible. Clinical trial information: NCT01706939; NCT02945631.