PSMA status of CTCs could guide mCRPC therapy

BY JOHN SCHIESZER PROSTATE-SPECIFIC membrane antigen (PSMA) expression on circulating tumor cells (CTCs) in men with metastatic castration-resistant prostate cancer (mCRPC) is heterogeneous and increases upon disease progression during treatment with abiraterone or enzalutamide, investigators reported at the European Society for Medical Oncology’s 2022 Congress in Paris.

In a retrospective analysis of 97 men treated with abiraterone or enzalutamide in the multicenter PROPHECY trial, Andrew J. Armstrong, MD, of the Duke Cancer Institute Center for Prostate and Urologic Cancers in Durham, North Carolina, and colleagues demonstrated that prostate cancer CTC PSMA status provides useful prognostic information that informs therapeutic decision-making.

“Given that PSMA-negative disease is also quite aggressive, it is important to understand which patients have significant disease that lacks the target both prior to treatment and during treatment in order to optimize care delivery and predict resistance and also to develop better therapies for these men,” Dr Armstrong said. “In addition, men with more intense and homogeneous

PSMA expression by PSMA PET/CT have better outcomes with PSMAdirected radioligand therapy, and if we can better identify these men through a liquid biopsy, this would be a significant advance in facilitating precision medicine for men with advanced prostate cancer.”

In the current study, the overall CTC prevalence prior to treatment with abiraterone or enzalutamide in the mCRPC setting was 80%, with 55% of patients harboring PSMA-positive CTCs, Dr Armstrong’s team reported in a poster presentation. On progression during treatment, CTCs were present in 88% of patients, with PSMA expression detected in 68% of them. In an analysis limited to men with PSMApositive CTC cells and whose disease progressed despite treatment, 34% had PSMA expression on more than 50% of their CTCs at progression compared with 14% at baseline, according to the investigators. Thus, PSMA CTC expression is fairly uniform in some men and heterogeneous in others, and some lacked PSMA detection despite having many detectable CTCs. After adjusting for multiple variables, PSMA positivity at the optimal threshold of 2 or more CTCs per mL was associated with a significant 3-fold increased risk for death and a nonsignificant 2.3-fold increased risk for radiographic progression compared with PSMA negativity (fewer than 2 CTCs per mL).

For the study, Dr Armstrong and colleagues used a novel liquid biopsy assay developed by Epic Sciences. The investigators explained that the assay analyzes cellular parameters such as PSMA protein expression and cell morphology to differentiate candidate CTCs from surrounding white blood cells.

“This is really the first study to evaluate clinical outcomes of a PSMA-CTC assay in the context of potent [androgen receptor] therapy and mCRPC patients, and we anticipate that this PSMA liquid biopsy could be helpful to enable precision medicine approaches going forward, and will lead to planned trials in the context of PSMA targeted therapies,” Dr Armstrong said.

He added, “This assay is non-invasive and could be repeated over time to track response and update prognosis as well.”

Oncologists acknowledged the potentially important role that prostate cancer CTC PSMA status could have in treating patients. Klaus Pantel, MD, of the Department of Tumor Biology at University Medical Center HamburgEppendorf in Hamburg, Germany, said the findings are a significant advance toward better understanding when best to adopt PSMA-targeted therapies. “Our group published already about the heterogeneity of PSMA expression on CTCs some years ago, but we did not include clinical follow-up information,” Dr Pantel said. “It is important to know for urologists and radiologists that PSMA expression is heterogeneous because PSMA is being used as a diagnostic and therapeutic target in prostate cancer.”

Howard Scher, MD, Chief of the Genitourinary Oncology Service within the Sidney Kimmel Center for Urologic and Prostate Cancers at Memorial Sloan Kettering Cancer Center in New York, agreed that the latest findings are an important contribution. “The results suggest that the detection of PSMA-expressing circulating tumor cells predicts for sensitivity to PSMA-directed radionuclide therapy,” Dr Scher said. ■