Serial Liquid Biopsies Reveal Therapy Resistance in Metastatic Prostate Cancer

Metastatic Prostate cancer can rapidly adapt under treatment, making it difficult to detect resistance before clinical progression. Genomic results from archival tumor tissue may no longer reflect the active disease, complicating timely therapy selection. Liquid biopsy enables real-time tracking of tumor evolution through blood-based analysis. Researchers now report that serial blood testing reveals recurrent androgen receptor alterations associated with poorer outcomes across multiple therapies.

At the University of Miami Miller School of Medicine’s Sylvester Comprehensive Cancer Center, investigators evaluated serial liquid biopsies that analyze circulating tumor DNA (ctDNA) to monitor disease evolution in metastatic castration‑resistant prostate cancer (mCRPC). The approach tracks how fragments of tumor DNA in the bloodstream change under therapeutic pressure. By repeatedly sampling over a treatment course, it aims to provide a contemporaneous view of molecular drivers that emerge as resistance develops.

In a real‑world analysis, paired ctDNA samples were examined before treatment initiation and after treatment discontinuation, a period commonly associated with progression. The study included more than 1,700 patients and drew on a large linked clinical–genomic database. The multi‑center collaboration involved Sylvester, the University of California San Diego Moores Cancer Center, the University of California San Francisco, Scripps Research Institute and Guardant Health, Inc., and the project was developed and initiated at UC San Diego.

Across treatment groups, overall mutation burden increased after therapy, consistent with selective pressure from modern regimens. Alterations in the androgen receptor (AR) emerged consistently after androgen receptor pathway inhibitors, PARP inhibitors and taxane chemotherapy, including AR amplifications and mutations that maintain receptor activity. The presence of AR alterations was associated with shorter overall survival, faster treatment discontinuation and earlier need for subsequent therapy. Among patients treated with PARP inhibitors, some tumors developed BRCA reversion mutations that restore DNA repair, and additional resistance‑associated changes were observed in genes such as TP53, EGFR and PIK3CA.

Findings were published on February 26, 2026, in Clinical Cancer Research. The authors report that a single genomic test at diagnosis may be insufficient for managing advanced disease and support use of real‑time molecular testing to guide more personalized care. The results also support continued development of next‑generation therapies, including androgen receptor degraders and rational combinations designed to overcome resistance.

“This work highlights the power of real-time molecular monitoring to inform precision medicine in advanced prostate cancer. As we develop the next generation of therapies, including novel AR-targeted agents and rational combinations, understanding how tumors evolve under treatment pressure will be critical to delivering the right drug to the right patient at the right time,” said Rana McKay, M.D., Associate Director of Clinical Research and Professor of Medicine, Urology, and Radiation Medicine and Applied Sciences at the Moores Cancer Center at UC San Diego.

“Serial ctDNA testing gives us a moving picture, not a snapshot. That has real implications for precision oncology,” said Chinmay T. Jani, M.D., Chief Fellow, Hematology and Oncology, at Sylvester Comprehensive Cancer Center.

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University of Miami Miller School of Medicine’s Sylvester Comprehensive Cancer Center