Background: ¹⁸F-labeled prostate-specific membrane antigen (PSMA) positron emission tomography (PET) ligands offer a longer half-life and improved spatial resolution compared with ⁶⁸Ga-PSMA. Here, we report the detection rate (DR) of ¹⁸F-rhPSMA-7.3, a novel high affinity theranostic PET ligand with potential for low bladder activity. Methods: SPOTLIGHT (NCT04186845) assessed the coprimary endpoints of patient level Correct Detection Rate (CDR - % of all patients scanned with ≥1 true positive lesion) and region level Positive Predictive Value (all PET positive regions combined) of ¹⁸F-rhPSMA-7.3 using histopathology and/or conventional imaging as a composite Standard of Truth (SoT). These metrics were also evaluated in a subset of patients with a histopathology-only SoT. Prespecified statistical thresholds of at least 36.5% and 62.5% were set for CDR and PPV, respectively. Overall DR stratified by PSA was also documented. Men with prostate cancer recurrence underwent PET 50-70 minutes after IV administration of 296 MBq ¹⁸F-rhPSMA-7.3. Image guided biopsies of PET lesions took place ≤60 days post-PET and any confirmatory imaging took place ≤90 days. Three blinded central readers evaluated the scans with majority read accepted as final interpretation. A separate Truth Panel established SoT for each patient. Results: The overall DR in the 389 men (median [range] PSA, 1.10 [0.03-134.6] ng/mL) who had an evaluable ¹⁸F-rhPSMA-7.3 scan is 83% by majority read (See Table). In the 366 men (median [range] PSA, 1.27 [0.03-134.6] ng/mL) with a composite SoT, the patient level CDR is 56.8% (95% CI, 51.6-62.0), meeting the prespecified threshold. The region level PPV is 59.7% (54.7-64.7), not meeting the prespecified threshold. In the subset of patients with a histopathology-only SoT, the patient level CDR and region level PPV are higher at 81.2% (69.9-89.6) and 71.6% (62.5-80.7), respectively. Both of these values would have met the prespecified thresholds. Conclusions:¹⁸F-rhPSMA-7.3 has a clinically meaningful CDR that meets the prespecified threshold. While the region level PPV does not meet the prespecified threshold, the data in patients with a composite SoT are limited by the high proportion of prostate/bed scans (92%) that relied on conventional imaging, a suboptimal SoT. For the subset of patients with the more robust histopathology SoT for at least one region per patient, a high PPV is seen and the lower bound of the 95% CI would have exceeded the prespecified threshold. Together, these data support the clinical utility of ¹⁸F-rhPSMA-7.3 PET in men with recurrent prostate cancer across a wide PSA range. Clinical trial information: NCT04186845.