PURPOSE: Novel therapies are needed to extend survival in metastatic castration-resistant prostate cancer (mCRPC). Prostate-specific membrane antigen (PSMA), a cell surface antigen overexpressed in PC, provides a validated target. This dose-escalation study investigated the safety, efficacy, maximum tolerated dose (MTD), and recommended phase II dose (RP2D) for ²²⁵Ac-J591, anti-PSMA monoclonal antibody J591 radiolabeled with the alpha emitter actinium-225. METHODS: Following investigational new drug-enabling preclinical studies, we enrolled patients with progressive mCRPC that was refractory to or who refused standard treatment options (including androgen receptor pathway inhibitor and had received or been deemed ineligible for taxane chemotherapy). No selection for PSMA was performed. Patients received a single dose of ²²⁵Ac-J591 at one of seven dose-escalation levels followed by expansion at the highest dose. Primary end point of dose-escalation cohort was determination of dose-limiting toxicity (DLT) and RP2D. RESULTS: Radiochemistry and animal studies were favorable. Thirty-two patients received ²²⁵Ac-J591 in an accelerated dose-escalation design (22 in dose escalation, 10 in expansion). One patient (1 of 22; 4.5%) experienced DLT in cohort 6 (80 KBq/kg) but none in cohort 7; MTD was not reached, and RP2D was the highest dose level (93.3 KBq/kg). The majority of high-grade adverse events (AEs) were hematologic with an apparent relationship with administered radioactivity. Nonhematologic AEs were generally of low grade. Prostate-specific antigen (PSA) declines and circulating tumor cell (CTC) control were observed: 46.9% had at least 50% PSA decline at any time (34.4% confirmed PSA response), and protocol-defined CTC count response occurred in 13 of 22 (59.1%). CONCLUSION: To our knowledge, this is the first-in-human phase I dose-escalation trial of a single dose of ²²⁵Ac-J591 in 32 patients with pretreated progressive mCRPC demonstrated safety and preliminary efficacy signals. Further investigation is underway.

FDG PET/CT provides complementary metabolic information with greater sensitivity and specificity than conventional imaging modalities for evaluating local recurrence, nodal, and distant metastases in patients with cervical cancer. PET/CT can also be used in radiation treatment planning, which is the mainstay of treatment. With the implementation of various oncological guidelines, FDG PET/CT has been utilized more frequently in patient management and prognostication. Newer PET tracers targeting the tumor microenvironment offer valuable biologic insights to elucidate the mechanism of treatment resistance and tumor aggressiveness and identify the high-risk patients. Artificial intelligence and machine learning approaches have been utilized more recently in metastatic disease detection, response assessment, and prognostication of cervical cancer.

• ⁶⁸Ga-cyclotron (solid target) and ⁶⁸Ga-generator production methods are equivalent in detecting abnormal PSMA positive lesions. • The cyclotron produced, solid target ⁶⁸Ga, can be made in Ci quantities which will increase the isotope availability nationally and it can significantly decrease costs of tracer production to currently available generator systems. • High-volume production of ⁶⁸Ga may aid in the imaging of other organ studies. For instance, ⁶⁸Ga-DOTATATE PET/CT and ⁶⁸Ga-DOTATOC PET/CT for neuroendocrine tumors (NETs) and ⁶⁸Ga ventilation and perfusion PET/CT imaging for lung cancer.

Background: PSMA PET has emerged as a “gold standard” imaging modality for assessing prostate cancer metastases. However, it is not universally available, and this limits its impact. In contrast, whole-body MRI is much more widely available but misses more lesions. This study aims to improve the interpretation of whole-body MRI by comparing false negative scans retrospectively to PSMA PET. Methods: This study was a retrospective sub-analysis of a prospectively collected database of patients who participated in a clinical trial of PSMA PET/MRI comparing PSMA PET and whole-body MRI from 2018–2021. Subjects whose separately read PSMA PET and MRI diagnostic reports showed discrepancies (“false negative” MRI cases) were selected for sub-analysis. The cases were reviewed by the same attending radiologist who originally read the scans. The radiologist noted specific features on MRI indicating metastatic disease that were initially missed. Results: Of 263 cases, 38 (14%) met the inclusion criteria and were reviewed. Six classes of mpMRI false negatives were identified: anatomically normal (18, 47%), atypical MRI appearance (6, 16%), mischaracterization (1, 3%), undercall (6, 16%), obscured (4, 11%), and no abnormality on MRI (3, 8%). Considering that the atypical and undercalled cases could have been adjusted in retrospect, and that 4 additional cases had positive lesions to the same extent and 11 further cases had disease confined to the pelvis, only 11 (4%) of the original 263 would have had disease outside of a conventional radiation treatment plan. Conclusion: Notably, almost 50% of the cases, including most lymph node metastases, were anatomically normal using standard criteria. This suggests that current anatomic criteria for evaluating prostate cancer lymph node metastases are not ideal, and there is a need for improved criteria. In addition, 32% of cases involved some element of human interpretive error, and, therefore, improving reader training may lead to more accurate results.