Background: Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) has superior diagnostic accuracy for detecting regional and distant metastases compared to conventional imaging (CT, bone scan, and MRI) in men with prostate cancer. This has the potential to guide definitive radiation therapy (dRT) patient selection and planning. Whether the use of improved diagnostic accuracy imaging improves patient outcomes remains to be demonstrated in clinical trials. Methods: This multi-institutional phase III randomized clinical trial (PSMA-dRT, NCT04457245) was designed to randomize 312 men with unfavorable intermediate-risk or high-risk prostate cancer 1.08:1 between receiving (n=162) and not receiving (n=150) a PSMA PET/CT prior to starting dRT. Treating radiation oncologists incorporated the PSMA PET/CT into radiotherapy planning. All other imaging modalities were allowed in the control arm. There were no prespecified androgen deprivation therapy (ADT) or dRT dose and volumes protocols. The primary endpoint was 5-year progression-free survival (PFS). Results: 54 patients were randomized between November 2020 and December 2021 (25 to PSMA PET/CT and 29 to control). The trial closed early following FDA approval and insurance coverage of PSMA PET/CT, since treatment without PSMA PET/CT in the control group was no longer acceptable for many patients and physicians. Among patients staged with PSMA PET/CT in the intervention group, 14 patients (58.3%) had localized miT2b-cN0M0 disease, 6 (25.0%) had locally advanced disease (miT3a-bN0M0), 3 (12.5%) had regional disease (miN1M0), and 1 (4.2%) had nodal and distant disease (miN1M1b). Four patients (16.7%) were upstaged relative to their staging at time of randomization. All three patients with miN1M0 disease received pelvic lymph node irradiation as part of their dRT course. The patient with miN1M1b disease received upfront ADT with abiraterone acetate and prednisone followed by consolidative radiotherapy to the prostate and pelvic lymph nodes. With a median follow-up of 21 months (interquartile range: 17.6-26.3 months), there were no cases of biochemical failure (PSA >2 ng/mL above nadir), radiographic or biopsy-proven recurrence, salvage therapy, or prostate cancer death in either arm. Two-year PFS was 93.8% in the PSMA PET/CT arm (due to 2 non prostate cancer deaths) and 100% in the control arm. There was no significant difference in PFS between the PSMA PET/CT and control arms (P=0.13). Conclusions: PSMA PET/CT upstaged 17% of patients compared to prior baseline staging, which allowed for more accurate treatment planning. Due to early termination, this trial was underpowered to assess the effect of PSMA PET/CT on PFS. PSMA-dRT is currently under submission for complete enrollment and data pooling at German sites. Clinical trial information: NCT04457245.