PSMA-PET predicts patient responses to Ac-225-based RPT

F-18 prostate-specific membrane antigen (PSMA)-1007 PET/CT scans can predict early treatment responses in prostate cancer patients scheduled for actinium-225 (Ac-225) PSMA-I&T radiopharmaceutical therapy (RPT), a group in Germany has reported.

The finding is an important step for further development of a promising new treatment option for advanced metastatic castration-resistant prostate cancer (mCRPC), noted Liam Widjaja, MD, of Ludwig Maximilian University Hospital in Munich, Germany, and colleagues.

“These preliminary results may lay the foundation for future studies using molecular imaging-derived biomarkers to identify patients that benefit from Ac-225 PSMA RPT,” the group wrote. The study was published January 29 in the Journal of Nuclear Medicine.

Despite encouraging results with beta-emitting PSMA-directed RPTs such as lutetium-177 (Lu-177) PSMA-617 (Pluvicto, Novartis), options are limited for patients whose disease progresses after receiving the treatment, the authors explained. Alternatively, researchers are developing alpha radiation-emitting therapeutics such as Ac-225 PSMA-I&T, which induces heavier and denser cellular damage at tumor sites.

Overall, however, there is a critical unmet need for reliable predictive markers that can identify patients at risk of treatment failure before initiating these treatments, Widjaja and colleagues noted. To that end, in this study, the group investigated the predictive value of pretherapeutic PSMA-1007 PET/CT scans for identifying early disease progression.

The researchers analyzed PSMA-1007 PET/CT scans of 26 patients with mCRPC (median age, 72) scheduled for Ac-225 PSMA-I&T treatment. All patients had progressed despite numerous previous treatments, including androgen deprivation therapy, next-generation antihormonal agents, chemotherapy, and Lu-177 PSMA-617.

The study authors first segmented all metastases on the PET/CT scans to calculate standard uptake values (SUVs). They then correlated these parameters with relative prostate-specific antigen (PSA) changes in patients after two cycles of Ac-225 PSMA-I&T. In addition, they explored predictive values for early progressive disease (defined as a PSA increase of more than 25%) after two cycles, and progression-free survival (PFS).

Representative case example of patient responding to Ac-225 PSMA RPT. (A) Baseline F-18 PSMA-1007 PET/CT with maximum-intensity projection (MIP), CT (top), PET (center), and fused PET/CT (bottom). This patient demonstrated high PSMA expression on pretherapeutic PET as can be seen in representative metastasis in second thoracic vertebral body (indicated by arrows) with averaged mean standardized uptake value (SUV_mean) of 8.44 (median of all patients, 6.8). In line with high SUV_mean and only moderate tumor burden, PSMA-TLQ was low (38.9 mL; median of all patients, 150.4 mL). After two cycles of Ac-225 PSMA RPT, PSA declined from 20.5 to 9.0 μg/L (−56.1%). (B) Follow-up F-18 PSMA-1007 PET/CT with MIP, CT (top), PET (center), and fused PET/CT (bottom). In line with biochemical response, there was partial response with decline of PSMA-TV from 328.42 to 150.34 mL (−54.2%). This patient achieved PFS of 167 days (median of all patients, 107 days) and overall survival of 592 days (median of all patients, 275 days), which was in line with high SUVmean and low PSMA-TLQ on baseline PET.Journal of Nuclear MedicineAccording to the analysis, maximum SUV (SUV_max [p = 0.031]) and mean SUV (SUV_mean [p = 0.046]) correlated significantly with PSA change after two cycles. SUV_mean emerged as the strongest predictor for prolonged PFS (hazard ratio [HR], 0.501; p = 0.006) with SUV_max also trending toward significance (HR, 0.914; p = 0.054), Widjaja et al reported. Patients with a high SUV_mean achieved a longer median PFS of 134 days compared with 39 days in patients with low SUV_mean (HR, 0.369; P = 0.041).

“In patients scheduled for Ac-225 PSMA-I&T RPT, SUVmean on pretherapeutic F-18 PSMA-1007 PET/CT is predictive for early treatment response,” the researchers wrote.

The investigators noted that patients in the study had extensive tumor burden identified on the pretherapeutic F-18 PSMA-1007 PET/CT scans and that they manually segmented a total of 2,776 metastases. This was extremely time-consuming, and while it enabled profound PET-based tumor characterization, it highlights the need for more sophisticated and time-saving approaches, such as software programs, they suggested.

Nonetheless, Ac-225 PSMA-I&T RPT shows promise as a “last-line therapy,” the group wrote.

“Our results need further validation in substantially larger, preferably prospective, studies,” the authors concluded.

The full study is available here.