Prostate cancer (PC) remains the most common noncutaneous cancer in American men and the second leading cause of cancer related deaths in the Unites States.1 Worldwide, PC is the second most common noncutaneous cancer with an estimated 1.4 million new cases and 375,000 deaths, ranking as the fifth leading cause of cancer related deaths among men in 2020.2 The incidence is rising again after 2 decades of decline, particularly of regional-stage and distant-stage PC. Initial treatment with curative intent for clinically significant cancers is either radical prostatectomy (RPE) or radiation therapy (RT).3, 4, 5 For intermediate-risk localized disease, focal treatment such as high intensity focused ultrasound (HIFU) is increasingly used as the adverse events reported are low while having good oncological outcome.6

Despite advancements in screening, diagnosis, and treatment strategies, a significant proportion of up to 53% of patients will develop biochemical recurrence (BCR).7,8 Initial tumor characteristics such as Gleason score and presence of metastases are predictors for recurrent disease.4 BCR is defined as a rise in prostate-specific antigen (PSA) levels: PSA ≥0.2 ng/mL with a second confirmatory PSA of at least 0.2 ng/mL after RPE,9 or a PSA ≥2 ng/mL above nadir after RT.10 Early and accurate detection and localization of recurrent disease is critical, allowing clinicians to tailor treatment strategies, such as salvage RT, androgen deprivation therapy (ADT), or early systemic chemotherapy, to the individual patient's needs, thus potentially improving outcomes and prolonging survival.

Conventional imaging with computed tomography (CT), magnetic resonance imaging (MRI), and bone scintigraphy have certain shortcomings, particularly at low PSA levels when recurrent disease volume may be low.11,12 Despite the high soft tissue contrast on MRI, MRI has limited sensitivity and specificity after RPE as postsurgical changes may mimic recurrent disease such as seminal vesicle remnants, or after RT when postradiation changes make it challenging to differentiate between prostatic zones, and benign and malignant tissue.13,14 Nonlocalized and small-volume disease are difficult to detect on CT or MRI with a sensitivity of only 57% for lymph node metastases of 5-6 mm.15, 16, 17, 18 Bone scintigraphy might be false negative in early bone metastases.19

Molecular imaging with positron emission tomography (PET) combined with either CT or MRI using radiopharmaceuticals that target prostate-specific membrane antigen (PSMA) has revolutionized imaging of PC. In a large cohort of 1007 patients with BCR PC, a high sensitivity of 79.7% was seen for 68Ga-PSMA11,20 even at low PSA levels.21,22 The most recent version 1.2023 of the National Comprehensive Cancer Network (NCCN) guideline has included PSMA-targeted PET/CT or PET/MRI for the localization of BCR PC.