Epigenomic cfDNA may accurately assess PSMA expression, Lu-PSMA response in mCRPC

Recent data suggest that comprehensive epigenomic cell-free DNA (cfDNA) profiling via a non-invasive blood test may serve as a surrogate for tumor prostate-specific membrane antigen (PSMA) expression as well as a predictive biomarker for response to Lutetium-PSMA in patients with metastatic castration-resistant prostate cancer (mCRPC).

Jacob E. Berchuck, MD

The findings were presented at the 6th Annual Congress of the International Society of Liquid Biopsy in Denver, Colorado and at the 2024 American Association for Cancer Research (AACR) Special Conference In Cancer Research: Liquid Biopsy in San Diego, California.¹

“For the estimated 120,000 men in the USA living with advanced metastatic prostate cancer, which has spread to other parts of the body and no longer responds to hormone treatment, Lutetium-PSMA is an important FDA-approved treatment option, and requires a PSMA-PET scan to confirm tumor PSMA expression,” said senior author Jacob E. Berchuck, MD, assistant professor in the Department of Hematology and Medical Oncology at the Winship Cancer Institute of Emory University, Atlanta, Georgia, in a news release on the findings.² “Our study highlights the potential of epigenomic profiling from a simple blood draw to provide a real-time, non-invasive readout of PSMA expression that corresponds with treatment response, which is an important finding given that PSMA-PET is not equally accessible across the USA and across the globe.”

For the study, the investigators retrospectively assessed 45 patients with mCRPC who were treated with 177Lu-PSMA-617. Plasma was obtained from each patient at the time of PSMA PET scan. This was compared with PET images to quantify SUVmean, which according to the authors is “the radiographic feature that most strongly correlates with response to Lutetium-PSMA.”

The investigators then trained and validated a model to predict PSMA PET SUVmean using enhancer and promoter signal at the FOLH1 locus, both of which demonstrated robust activity in patients with mCRPC compared with healthy volunteers. Training cohort samples all had ctDNA% of 3 or higher.

The authors then compared hazard ratios (HRs) between predicted PSMA measurements from liquid biopsy and recorded PET-PSMA measurements across 4 clinical end points. Overall, the 2 measurements were comparable across all measures.

This included PSA progression-free survival, which had an actual HR of 0.41 (0.17-0.99; P = .0489) and a predicted HR of 0.41 (0.17-0.99; P = .0499). Clinical-radiographic PFS was also comparable, with an actual HR of 0.28 (0.12-0.69; P = .0058) and a predicted HR of 0.30 (0.12-0.73; P = .0080). For time to next treatment following Lu-PSMA, the actual HR was 0.29 (0.11-0.67; P = .0058) vs a predicated HR of 0.27 (0.11-0.66; P = .0045). Additionally, the actual HR for overall survival was 0.23 (0.09-0.63; P = .0038) compared with a predicted HR of 0.31 (0.12-0.84; P = .021).

Further, data showed that patients who were in the top tertile of plasma PSMA predicted expression demonstrated significantly improved clinical outcomes vs the bottom 2 tertiles.

According to the authors, these findings “highlight the potential of epigenomic cfDNA profiling” in prostate cancer, but still need validation in a larger cohort.

“This is both an exciting and promising era for precision medicine in prostate cancer, with more than 70 new medicines in clinical development against 25 cell surface targets, including PSMA,” concluded Rehan Verjee, co-founder and CEO of Precede Bio, in the news release.² “Our platform’s capability to resolve target expression from a simple blood draw, as we have done in this study for PSMA, underscores the opportunity that we see for Precede Biosciences to play an important role in enabling the success of these emerging medicines.”

References

1. Ravi P, D’Ippolito A, Wurster J, et al. Determination of tumor PSMA expression and response to Lutetium-PSMA in men with prostate cancer using a novel epigenomic liquid biopsy platform. Presented at: 2024 American Association for Cancer Research (AACR) Special Conference In Cancer Research: Liquid Biopsy (AACR LBx 2024). November 13 to 16, 2024. San Diego, California. Poster B002. Accessed November 26, 2024

2. Precede Biosciences Presents New Data at AACR LBx 2024 Demonstrating an Accurate Readout of Tumor PSMA Expression and Stratification of Response to Lutetium-PSMA in Men with mCRPC from a Simple Blood Test. News release. Precede Biosciences, Inc. November 15, 2024. Accessed November 26, 2024. https://www.globenewswire.com/news-release/2024/11/16/2982317/0/en/Precede-Biosciences-Presents-New-Data-at-AACR-LBx-2024-Demonstrating-an-Accurate-Readout-of-Tumor-PSMA-Expression-and-Stratification-of-Response-to-Lutetium-PSMA-in-Men-with-mCRPC-.html