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APCCC Diagnostics 2025: New Fashion Blood Markers for Metastatic Prostate Cancer

(UroToday.com) The 2025 APCCC Diagnostics annual meeting featured a session on metastatic prostate cancer and a presentation by Dr. Elena Castro discussing new blood markers, including ctDNA, for metastatic disease.

Dr. Castro notes that “new fashion blood biomarkers” really means a liquid biopsy, with the following figure highlighting tumor features, clinical utility, and challenges of liquid biopsy:1
new fashion blood biomarkers” really means a liquid biopsy, with the following figure highlighting tumor features, clinical utility, and challenges of liquid biopsy
Dr. Castro highlighted that several studies have shown evidence that baseline circulating tumor cell enumeration has prognostic value in metastatic hormone sensitive prostate cancer (mHSPC) and metastatic castration resistant prostate cancer (mCRPC):Dr. Castro highlighted that several studies have shown evidence that baseline circulating tumor cell enumeration has prognostic value in mHSPC and mCRPC
Additionally, circulating tumor cell conversion (either from >= 5 to <= 5 or a 30% decrease) after 12 weeks of treatment is also a prognostic marker:
Additionally, circulating tumor cell conversion (either from >= 5 to <= 5 or a 30% decrease) after 12 weeks of treatment is also a prognostic marker
Dr. Castro also notes that AR-V7 expression in circulating tumor cells is prognostic in mCRPC. Dr. Armstrong and colleagues in the PROPHECY study2 evaluated circulating tumor cell AR-V7 detection as a poor prognostic indicator for the clinical efficacy of secondary hormone therapies. Among 118 men with mCRPC starting abiraterone or enzalutamide treatment, AR-V7 detection was independently associated with shorter progression free survival (HR 1.95, 95% CI 1.1 to 3.3) and overall survival (HR 4.2, 95% CI, 2.1 to 8.5) after adjusting for circulating tumor cell number and clinical prognostic factors:
Dr. Castro also notes that AR-V7 expression in circulating tumor cells is prognostic in mCRPC. Dr. Armstrong and colleagues [2] in the PROPHECY study evaluated circulating tumor cell AR-V7 detection as a poor prognostic indicator for the clinical efficacy of secondary hormone therapies. Among 118 men with mCRPC starting abiraterone or enzalutamide treatment, AR-V7 detection was independently associated with shorter progression free survival (HR 1.95, 95% CI 1.1 to 3.3) and overall survival (HR 4.2, 95% CI, 2.1 to 8.5) after adjusting for circulating tumor cell number and clinical prognostic factor
Dr. Castro emphasized that AR-V7 status also has differential impact on response to androgen receptor pathway inhibitors and taxanes:
Dr. Castro emphasized that AR-V7 status also has differential impact on response to androgen receptor pathway inhibitors and taxanes
We already know that there is limited response to a second androgen receptor pathway inhibitor in mCRPC without assessing the androgen receptor status. Still, perhaps a new generation of androgen receptor pathway inhibitors will have differential activity by androgen receptor status. Work presented by Dr. Fizazi at ESMO assessing the CYP11A1 inhibitor opevesostat showed that in patients with AR-ligand binding domain activating mutations, a PSA50 response was observed in 53% of patients. Conversely, in the AR-ligand binding domain of wild-type patients, a PSA50 response was observed in 15%. PSA30 responses were observed in 68% and 29% of patients, respectively:Work presented by Dr. Fizazi at ESMO assessing the CYP11A1 inhibitor opevesostat showed that in patients with AR-ligand binding domain activating mutations, a PSA50 response was observed in 53% of patients. Conversely, in the AR-ligand binding domain of wild-type patients, a PSA50 response was observed in 15%. PSA30 responses were observed in 68% and 29% of patients, respectively
Also at ESMO 2024, Dr. Rathkopf assessed the activity of the androgen receptor ligand-directed degrader BMS-986365, showing that clinical benefit was observed both in patients with androgen receptor ligand binding domain WT and mutant mCRPC:
Also at ESMO 2024, Dr. Rathkopf assessed the activity of the androgen receptor ligand-directed degrader BMS-986365, showing that clinical benefit was observed both in patients with androgen receptor ligand binding domain WT and mutant mCRPC
Dr. Castro then discussed ctDNA and cfDNA, emphasizing that ctDNA/cfDNA fraction correlates with other prognostic biomarkers and outcomes:3
Dr. Castro then discussed ctDNA and cfDNA, emphasizing that ctDNA/cfDNA fraction correlates with other prognostic biomarkers and outcomes
ctDNA dynamics have prognostic value in advanced prostate cancer, including ctDNA “conversion” after 4 weeks of treatment with an androgen receptor pathway inhibitor and ctDNA “conversion” after 6 weeks of 177Lu-PSMA therapy:
ctDNA dynamics have prognostic value in advanced prostate cancer, including ctDNA “conversion” after 4 weeks of treatment with an androgen receptor pathway inhibitor and ctDNA “conversion” after 6 weeks of 177Lu-PSMA therapy
There is high concordance between ctDNA and tissue analyses, and Dr. Castro notes that the detection of predictive biomarkers in ctDNA is now feasible. In the PROfound trial,4 of the 181 (73.9%) Cohort A patients who gave consent for plasma sample ctDNA testing, 139 (76.8%) yielded a result, and BRCA/ATM alterations were identified in 111 (79.9%). Of these, 73 patients received olaparib, and 38 received control. Radiographic progression free survival was longer in the olaparib group versus control (median 7.4 versus 3.5 months; HR 0.33, 95% CI 0.21-0.53), which was consistent with Cohort A ITT population (HR 0.34; 95% CI, 0.25-0.47):There is high concordance between ctDNA and tissue analyses, and Dr. Castro notes that detection of predictive biomarkers in ctDNA is now feasible. In the PROfound trial [4], of the 181 (73.9%) Cohort A patients who gave consent for plasma sample ctDNA testing, 139 (76.8%) yielded a result and BRCA/ATM alterations were identified in 111 (79.9%). Of these, 73 patients received olaparib and 38 received control. Radiographic progression free survival was longer in the olaparib group versus control (median 7.4 versus 3.5 months; HR 0.33, 95% CI 0.21-0.53), which was consistent with Cohort A ITT population (HR 0.34; 95% CI, 0.25-0.47)
Finally, Dr. Castro discussed that ctDNA can be used to monitor disease evolution, specifically early identification of treatment resistance to PARP inhibitors, which has been shown in the TRITON2 and TOPARP-B trials:
Finally, Dr. Castro discussed that ctDNA can be used to monitor disease evolution, specifically early identification of treatment resistant to PARP inhibitors, which has been shown in the TRITON2 and TOPARP-B trials
Work from Beltran et al.5 using whole-exome sequencing and whole-genome bisulfite sequencing of cfDNA and of matched metastatic tumor biopsies from patients with metastatic prostate adenocarcinoma and CRPC-neuroendocrine has identified CRPC-neuroendocrine features detectable in the circulation:Work from Beltran et al.5 using whole-exome sequencing and whole-genome bisulfite sequencing of cfDNA and of matched metastatic tumor biopsies from patients with metastatic prostate adenocarcinoma and CRPC-neuroendocrine has identified CRPC-neuroendocrine features detectable in the circulation
Additionally, this group has proposed the following model of prostate cancer progression towards CRCP-neuroendocrine differentiation:
Additionally, this group has proposed the following model of prostate cancer progression towards CRCP-neuroendocrine differentiation
Dr. Castro concluded her presentation discussing new blood markers, including ctDNA, for metastatic disease with the following take-home points:

  • New blood biomarkers provide additional information to “old fashion” biomarkers
  • These tests are non-invasive, thus, serial analyses are possible
  • We are now able to capture the relative contribution of metastases in different anatomical sites
  • New blood biomarkers are useful for monitoring response, resistance, and disease evolution
  • Additional clinical validation of these tools is needed

Presented by: Elena Castro, MD, PhD, Department of Medical Oncology Hospital Universitario 12 de Octubre, Madrid, Spain

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the Advanced Prostate Cancer Consensus Conference (APCCC) Diagnostics 2025 Annual Meeting, Virtual and Lugano, Switzerland, Thurs, Feb 27 – Fri, Feb 28, 2025.

References:
  1. Trujilo B, Wu A, Wetterskog, et al. Blood-based liquid biopsies for prostate cancer: Clinical opportunities and challenges. Br J Cancer. 2022 Nov;127(8):1394-1402.
  2. Armstrong AJ, Halabi S, Luo J, et al. Prospective multicenter validation of androgen receptor splice variant 7 and hormone therapy resistance in high-risk castration-resistant prostate cancer: The PROPHECY study. J Clin Oncol. 2019 May 1;37(13):1120-1129.
  3. Fonseca NM, Maurice-Dror C, Herberts C, et al. Prediction of plasma ctDNA fraction and prognostic implications of liquid biopsy in advanced prostate cancer. Nat Commun. 2024 Feb 29;15(1):1828.
  4. Matsubara N, de Bono J, Olmos D, et al. Olaparib efficacy in patients with metastatic castration-resistant prostate cancer and BRCA1, BRCA2, or ATM alterations identified by testing circulating tumor DNA. Clin Cancer Res. 2023 Jan 4;29(1):92-99.
  5. Beltran H, Romanel A, Conteduca V, et al. Circulating tumor DNA profile recognizes transformation to castration-resistant neuroendocrine prostate cancer. J Clin Invest. 2020 Apr 1;130(4):1653-1668.