<h3>Importance</h3> In retrospective studies,<sup>68</sup>Ga-PSMA-11 positron emission tomographic (PET) imaging improves detection of biochemically recurrent prostate cancer compared with conventional imaging. <h3>Objective</h3> To assess<sup>68</sup>Ga-PSMA-11 PET accuracy in a prospective multicenter trial. <h3>Design, Setting, and Participants</h3> In this single-arm prospective trial conducted at University of California, San Francisco and University of California, Los Angeles, 635 patients with biochemically recurrent prostate cancer after prostatectomy (n = 262, 41%), radiation therapy (n = 169, 27%), or both (n = 204, 32%) underwent<sup>68</sup>Ga-PSMA-11 PET. Presence of prostate cancer was recorded by 3 blinded readers on a per-patient and per-region base. Lesions were validated by histopathologic analysis and a composite reference standard. <h3>Main Outcomes and Measures</h3> Endpoints were positive predictive value (PPV), detection rate, interreader reproducibility, and safety. <h3>Results</h3> A total of 635 men were enrolled with a median age of 69 years (range, 44-95 years). On a per-patient basis, PPV was 0.84 (95% CI, 0.75-0.90) by histopathologic validation (primary endpoint, n = 87) and 0.92 (95% CI, 0.88-0.95) by the composite reference standard (n = 217).<sup>68</sup>Ga-PSMA-11 PET localized recurrent prostate cancer in 475 of 635 (75%) patients; detection rates significantly increased with prostate-specific antigen (PSA): 38% for &lt;0.5 ng/mL (n = 136), 57% for 0.5 to &lt;1.0 ng/mL (n = 79), 84% for 1.0 to &lt;2.0 ng/mL (n = 89), 86% for 2.0 to &lt;5.0 ng/mL (n = 158), and 97% for ≥5.0 ng/mL (n = 173,<i>P</i> &lt; .001). Interreader reproducibility was substantial (Fleiss κ, 0.65-0.78). There were no serious adverse events associated with<sup>68</sup>Ga-PSMA-11 administration. PET-directed focal therapy alone led to a PSA drop of 50% or more in 31 of 39 (80%) patients. <h3>Conclusions and Relevance</h3> Using blinded reads and independent lesion validation, we establish high PPV for<sup>68</sup>Ga-PSMA-11 PET, detection rate and interreader agreement for localization of recurrent prostate cancer. <h3>Trial Registration</h3> ClinicalTrials.gov identifiers:NCT02940262andNCT03353740

Assessment of 68Ga-PSMA-11 PET Accuracy in Localizing Recurrent Prostate Cancer