Plasma Epigenomics in mCRPC: Predicting PSMA-Targeted Therapy
Jacob E. Berchuck, MD, discusses research on plasma epigenomic profiling in metastatic castration-resistant prostate cancer.
Jacob E. Berchuck, MD, assistant professor, Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, discusses his research on plasma epigenomic profiling in metastatic castration-resistant prostate cancer (mCRPC). His abstract, "Plasma epigenomic profiling to reveal molecular correlates of response and resistance to 177Lu-PSMA-617 in metastatic castration-resistant prostate cancer (mCRPC),” was presented at the 2025 American Society of Clinical Oncology Annual Meeting and addresses a critical unmet clinical need in the evolving landscape of advanced solid tumor treatments.
Berchuck highlights the exciting advent of novel therapeutic classes, such as antibody-drug conjugates, radioligand therapies, and bispecific antibodies, all designed to target specific tumor cell surface antigens. While these therapies offer significant promise by precisely binding to tumor cells and initiating antitumor activity, a challenge exists: how to optimally select the right treatment for the right patient at the right time, especially as multiple drugs targeting various cell surface antigens become available.
This study specifically focused on prostate-specific membrane antigen (PSMA) in mCRPC. The goal was to explore whether advanced liquid biopsy technologies could predict or assess in real-time the expression of these crucial drug targets within individual patient tumors. Furthermore, the research aimed to gain deeper insights into the specific tumor features that either correlate with a favorable response to the corresponding drug or contribute to resistance.
“We are going to be left with this hopefully good challenge in the coming years of having multiple drugs targeting multiple different cell surface targets in specific tumor types. The challenge is going to be, how do we choose the right treatment for the right person at the right time? That's really what we sought to do in this study, specifically in the context of PSMA with metastatic prostate cancer,” he shares.
The investigation involved patients with mCRPC who underwent PSMA PET scans and subsequently received 177Lu-PSMA-617, an FDA-approved radioligand therapy. A primary goal was to elucidate the molecular underpinnings explaining the varied patient responses to this drug.
The study showed that patients whose tumors exhibited high expression of PSMA experienced more favorable responses to 177Lu-PSMA-617. Overall, this research underscores the potential of liquid biopsy to refine patient selection and provide real-time molecular insights for personalized cancer therapy.
“Patients whose tumors had high expression of PSMA, the drug target, had a more favorable response…this was sort of a nice clinical grounding of seeing what we expect to see, because we know from PET scans that high PSMA expression correlates with favorable response, and we saw the same thing in an unbiased analysis, that high expression of PSMA as measured in the plasma was one of the genes that was most strongly associated with favorable outcomes, or response to Pluvicto,” Berchuck adds.
