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 in a poster at ESMO Congress 2022.
In a retrospective analysis of 97 men treated with abiraterone or enzalutamide in the multicenter PROPHECY trial, prostate cancer CTC PSMA status provided useful prognostic information that informed 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,” said study author Andrew J. Armstrong, MD, of the Duke Cancer Institute Center for Prostate and Urologic Cancers in Durham, North Carolina.
“In addition, men with more intense and homogeneous PSMA expression by PSMA PET/CT have better outcomes with PSMA-directed 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 this 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. 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 PSMA-positive CTCs and whose disease progressed despite treatment, 34% had PSMA expression on more than 50% of their CTCs at progression compared with 14% at baseline. Thus, some men had fairly uniform PSMA CTC expression, while others had heterogeneous PSMA CTC expression or lacked PSMA detection on CTCs, 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 (less than 2 CTCs per mL).
For this 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 in 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.”
These findings are a significant advance toward better understanding when best to adopt PSMA-targeted therapies, according to Klaus Pantel, MD, of University Medical Center Hamburg-Eppendorf in Germany.
“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, of Memorial Sloan Kettering Cancer Center in New York, 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. “Further testing will need to be done of the PSMA-expressing CTC biomarker alone and in relation to PSMA PET imaging, with respect to the threshold level of expression and number of CTC meeting the criteria to predict outcomes.”
Disclosures: Epic Sciences and PCF/Movember provided funding for the study.
Gupta S, Halabi S, Yang Q, et al. The impact of PSMA positive circulating tumor cells in men with metastatic castrate-resistant prostate cancer (mCRPC). ESMO 2022, September 9-13, 2022. Poster 1365.
This article originally appeared on Renal and Urology News