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Diagnostic Performance and Clinical Impact of Gallium-68 Prostate-Specific Membrane Antigen (PSMA) PET/CT Imaging in Early Relapsed Prostate Cancer after Radical Therapy: Phase 3, Prospective, Multicenter Study (IAEA-PSMA Study)

Introduction: Biochemical recurrence (BCR) is a major clinical challenge in patients with Prostate Cancer (PCa), as rising PSA occurs in about 20-30% of patients treated with radical prostatectomy and up to 60% in patients treated primarily with radiotherapy. Patients may have local recurrence in the pelvis or in distant sites. The location and burden of recurrent disease is mandatory in guiding subsequent therapies. Standard practice for BCR in PCa includes computed tomography and bone scintigraphy, both known for limited diagnostic performance. The use of positron emission tomography (PET) with prostate-specific membrane antigen (PSMA) was introduced in clinical practice in the past few years due to its better accuracy. The present phase 3, prospective, multicentric, international study was planned to evaluate the diagnostic performance and clinical impact of [68Ga]Ga-PSMA-11 PET/CT in evaluating patients with biochemical recurrent PCa; the study was promoted and supported by the IAEA. 
 
Methods: Patients with PCa who have undergone primary definitive treatment and presented with rising PSA levels were recruited to the study. Overall 17 centers from 15 countries (Azerbaijan, Brazil, Colombia, India, Israel, Italy, Jordan, Lebanon, Malaysia, Mexico, Pakistan, Poland, South Africa, Turkey, and Uruguay) were involved. Images and data were centrally reviewed; data were collected and assessed for site of findings ([68Ga]Ga-PSMA-11 pathologic uptake), positivity rate (percentage of patients with a positive [68Ga]Ga-PSMA-11 PET/CT) and impact on patient management. Regarding PET findings, a composite reference standard was used, including pathology, correlative imaging, PSA response; regarding management, the reference included changes in the treating physician’s documented clinical plans before and after PET; all patients have at least 6 months clinical follow-up. 
 
Results: 1198 patients were prospectively enrolled between November 2017 and December 2019; 1004 patients had complete data for final evaluation. [68Ga]Ga-PSMA-11 PET/CT was positive in 654/1004 patients (65.1%); lesions were identified as: prostate/prostatic bed only in 13.7% of the cases; pelvic lymph nodes only in 20.5%, and with any metastatic disease in 27.0%. There was a correlation between [68Ga]Ga-PSMA-11 PET/CT positivity and Gleason score (p<0.001): detection rate was 371/613 (60.5%) in patients with Gleason 7, 130/196 (66.3%) in Gleason 8, 140/180 (77.8%) in Gleason 9 and 13/15 (86.7%) in Gleason 10. There was also statistically significant correlation between lesions identified by [68Ga]Ga-PSMA-11 PET/CT and PSA values (p<0.001): detection rate was 21/41 (51.2%) for PSA <0.2, 84/188 (44.7%) for PSA between 0.2-0.5, 124/232 (53.4%) for PSA 0.5-1.0, 158/235 (67.2%) for PSA ≥1 and <2, 171/206 (83.0%) for PSA ≥2 and <4, and 96/102 (94,1%) in PSA 4 to 10. Finally, treatment was modified based on PET PSMA results in 56.8% of patients. The [68Ga]Ga-PSMA-11 PET/CT positivity rate was consistent and not statistically different among the different countries. 
 
Conclusion: This is the largest multicenter international prospective trial on [68Ga]Ga-PSMA-11 PET/CT, and it confirmed the capability of [68Ga]Ga-PSMA-11 PET /CT to detect local and metastatic recurrence in most men with BCR. Based on imaging results, most men had a change in treatment approach. This study demonstrates the reliability of [68Ga]Ga-PSMA-11 PET/CT in PCa BCR, and the worldwide feasibility of such imaging approach. 
 
Funding Statement: The study was promoted and supported by the IAEA. 
 
Declaration of Interests: The authors have no conflict of interest. 
 
Ethics Approval Statement: All centers obtained local ethical clearance for prospective recruitment of patients and data collection, according to national regulations.