Outcome of Patients with PSMA PET/CT Screening Failure by VISION Criteria and Treated with 177Lu-PSMA: A Multicenter Retrospective Analysis

Selection of patients for treatment with prostate-specific membrane antigen (PSMA)–targeted therapy is somewhat controversial. There are those who have suggested that no selection is necessary and those who have suggested that tight imaging-based selection criteria are required. What is optimal, what is required, and what is practical are all different questions. Given the importance of the VISION trial (the only trial demonstrating overall survival benefit with PSMA-targeted therapy), findings in this trial will be examined in some detail (1). Of note, the VISION trial enrolled patients with at least 1 metastatic lesion present on baseline contrast-enhanced CT, MRI, or bone scanning obtained no more than 28 d before beginning study therapy. Thus, metastatic disease on conventional imaging was required. In addition, patients must have progressed after one or more androgen axis inhibitors (e.g., abiraterone, enzalutamide, darolutamide, or apalutamide) and at least one taxane-based chemotherapy. Approximately 41% of VISION participants were previously treated with 2 taxane regimens. What were the eligibility criteria relative to PSMA PET/CT imaging in VISION? First, all patients must have had a centrally read Ga-PSMA-11 PET/CT scan for trial entry. Second, a metastatic lesion (one or more) that was PSMA PET–positive was required. PSMA PET positivity was determined by uptake in the lesion at an intensity level greater than that in the liver. There was no SUV cutoff requirement; potential metastatic lesions in each patient were compared with liver uptake by a centralized PET reading. There were no size criteria for metastatic PSMA PET–positive lesions. Importantly, the patients screened for the VISION trial had additional imaging-based exclusion criteria. Patients were excluded if there were PSMA PET–negative lesions (uptake less than in liver) measuring at least 1 cm in solid organs, at least 2.5 cm in lymph nodes, or at least 1 cm in a bone lesion with a soft-tissue component. Assessment was by contrast-enhanced CT combined with the PET/CT findings. These negative selection criteria are quite important and helped to exclude patients harboring lesions with low levels of PSMA expression. During the VISION design phase, there was a strong desire to avoid using 2 PET scans as a requirement for trial entry, knowing that the VISION entry criteria would likely be cited by regulatory authorities considering Lu-PSMA-617 as an approved therapy. In the United States, and many other areas of the world, obtaining reimbursement for 2 distinct types of PET scans was deemed potentially problematic. Thus, for practical reasons, F-FDG PET scans were not used in the VISION entry criteria. In the plenary session at the 2021 American Society of Clinical Oncology meeting, the discussant questioned whether PSMA-based imaging was required for selection of patients (2). This discussion followed the initial presentation of the VISION trial. Of the 1,003 patients screened with PET/CT, 49 (4.9%) had no PSMA-positive metastatic lesions. Of the 954 patients with PSMA PET metastatic lesions, 87 patients were excluded because PSMA-negative metastases were also detected. All told, only about 13% of patients were excluded because of PET imaging criteria. Given the overall survival benefit with a hazard ratio of 0.62 relative to control (hazard ratio, 0.62; 95% CI, 0.52–0.74), it is likely that had the VISION trial been conducted on non–PSMA PET-selected patients, the overall survival benefit would still have been statistically significant; that is, the CIs would not have crossed 1.0. Thus, questioning the requirement for PSMA PET selection for Lu-PSMA-617 is reasonable. Have any investigators used PSMA-targeted therapies without regard to PSMA PET selection? The answer is yes. Data on non– PSMA-selected patients have been presented from studies using Lu J591, Ac J591, PSMA bispecific antibodies, a PSMA antibody–drug conjugate, and PSMA-targeted chimeric antigen receptor T cells. J591 is a monoclonal antibody that binds to PSMA and has been used to target either Lu or Ac (3,4). The J591 radiopharmaceutical studies have not compared PSMA PET–selected and non–PSMA PET-selected patients; thus, it is not possible to determine how important selection might be to patient outcomes. The bispecific antibodies pasotuxizumab (also called AMG 212) and AMG 160 have also been studied in non–PSMA PET-selected patients (5,6). What is clearly noted is that many patients not selected by PSMA PET appear to respond to these treatments. Some meaningful responses have also been seen in the PSMA antibody–drug conjugate studies (7) and in patients treated with chimeric antigen receptor T cells (8). All in all, given the absence of long-term survival data and the absence of PSMA PET selection compared with non–PSMA PET selection, it is speculative to conclude that PSMA PET Received May 6, 2022; revision accepted May 16, 2022. For correspondence or reprints, contact Oliver Sartor (osartor@tulane.edu). Published online May 26, 2022. COPYRIGHT© 2022 by the Society of Nuclear Medicine andMolecular Imaging. DOI: 10.2967/jnumed.122. 264128