Background: PHERGain is assessing the feasibility of a CT-free treatment based on a dual HER2 blockade with trastuzumab and pertuzumab (HP) in patients (pts) with HER2[+] EBC using a PET-based, pathologic complete response (pCR)-adapted strategy. In an earlier analysis of this study, a total of 227 (79.7%) of 285 pts included in group B were PET-responder (RX), of whom 86 of 227 (37.9%, 95% CI, 31.6 to 44.5; p<0.0001) achieved a pCR, reaching the first primary endpoint (Perez-Garcia JM, Lancet Oncol 2021). Methods: Details of the trial design and study population have been previously reported. Here, we present the results of the second primary endpoint, 3-year iDFS, among pts included in group B who underwent surgery based on an intent-to-treat (ITT) analysis. In brief, group B included centrally-confirmed, stage I-IIIA, HER2[+] EBC pts that were initially treated with HP (± endocrine therapy), introducing CT in pts without PET response after two treatment cycles and/or pCR. The binomial design tested the null hypothesis that the true 3-year iDFS rate was ≤89.0% against the alternative that the 3-year iDFS was >95%. We estimated that enrolling 284 pts in group B would provide 80% power at a nominal level of one-sided α of 0.025, assuming a 25% dropout rate. Results: Between June 26, 2017 and April 24, 2019, 356 pts were randomly assigned (71 pts in group A and 285 pts in group B) and 63 (89.0%) and 267 (93.7%) pts proceeded to surgery in groups A and B, respectively. In group B, the 3-year iDFS rate for the ITT population was 95.4% (95% CI, 92.8 to 98), meeting the second primary endpoint (p<0.001). After a median follow-up of 43.3 months (range, 2.4-63.0), a total of 12 iDFS events were reported, including eight distant recurrences (3.0%), three locoregional ipsilateral recurrences (1.1%), and one non-related death (0.4%). Among group B/PET-RX pts with pCR that did not receive CT as part of study treatment (n = 86), only one patient had an invasive event (locoregional ipsilateral recurrence) for a 3-year iDFS rate of 98.8% (95% CI, 96.3 to 100.0). Treatment-related adverse events (AEs) and serious adverse events (SAEs) were higher in pts allocated to group A than to group B (grade ≥3, 61.8% vs. 32.9% [p<0.001]; SAEs, 27.9% vs. 13.8% [p=0.01]). Group B/PET-RX pts with pCR presented the lowest incidence of treatment-related grade ≥3 AEs (1.2%) without any SAEs. No treatment-related deaths were reported. Conclusions: Among HER2[+] EBC pts, a PET-based, pCR-adapted strategy was associated with a substantial 3-year iDFS. These results appear comparable to those reported in several studies for the combination of neoadjuvant CT and dual HER2 blockade. This strategy identifies about a third of HER2[+] EBC pts who may safely omit CT with significantly reduced toxicity. Clinical trial information: NCT5732164.