ASCO 2025: Non-Androgen-Receptor–Driven Prostate Cancer: Updates in Biology, Classification, and Management

New Hope for Aggressive Prostate Cancer: Advances in Understanding and Treating Neuroendocrine Prostate Cancer

Revolutionary diagnostic tools and promising new therapies offer renewed hope for patients with treatment-resistant disease

What Patients Need to Know

For most men with prostate cancer, treatments targeting the androgen receptor (AR) pathway—including hormone therapy and newer drugs like enzalutamide and abiraterone—are highly effective. However, as these treatments have become more successful, doctors have observed an important but concerning phenomenon: some cancers develop resistance by essentially changing their identity. This transformation, called neuroendocrine prostate cancer (NEPC), represents one of the most aggressive forms of the disease.

At the recent 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, Dr. Himisha Beltran from Dana-Farber Cancer Institute presented groundbreaking research that offers new hope for patients facing this challenging diagnosis. Her presentation outlined significant advances in how doctors can detect, understand, and treat NEPC.

Understanding the Cancer's "Identity Switch"

NEPC occurs when prostate cancer cells undergo what scientists call "lineage plasticity"—essentially shedding their original prostate cancer identity and adopting characteristics of neuroendocrine cells. This phenomenon, known as lineage plasticity, occurs when tumors suppress their luminal adenocarcinoma characteristics and adopt a neuroendocrine phenotype.

10–20% of these treatment-resistant tumors are described as treatment-emergent neuroendocrine prostate cancer, t-NEPC because they present with expression of neuroendocrine phenotype and loss of AR expression. When this happens, the cancer no longer responds to hormone-based treatments and typically becomes more aggressive, often spreading to the liver and lungs rather than just bones.

The Challenge of Diagnosis

One of the biggest obstacles in treating NEPC has been accurate and timely diagnosis. While some clinicians report rarely encountering NEPC, others suggest that 15–20% of CRPC tumors may exhibit neuroendocrine features. This discrepancy exists because routine re-biopsies aren't typically performed, and there has been significant variability among pathologists due to lack of standardized evaluation criteria.

Dr. Beltran emphasized that doctors should consider a biopsy to look for NEPC in specific situations, including:

  • Aggressive disease with low or non-rising PSA levels
  • PSMA-negative lesions on PSMA PET/CT scans, particularly if they show up on FDG scans
  • History of mixed features on previous biopsies

Revolutionary Blood Test Breakthrough

Perhaps the most exciting development is the creation of NEMO (NEuroendocrine MOnitoring), a blood test that can detect NEPC without requiring a tissue biopsy. In this work, we present the NEuroendocrine detection and MOnitoring (NEMO) assay, a targeted DNA methylation sequencing panel designed for CRPC disease monitoring and neuroendocrine phenotype detection.

This innovative test works by analyzing cell-free DNA in blood plasma to identify specific methylation patterns that distinguish NEPC from regular prostate adenocarcinoma. "It not only picks up the neuroendocrine phenotype but also can pick up subtypes in the middle, as tumors transition from one subtype to the other," says Beltran.

The NEMO test provides two critical pieces of information:

  1. Tumor fraction: A measure of disease burden based on the ratio of tumor DNA to normal DNA in the blood
  2. Tumor type: Whether the cancer is adenocarcinoma or NEPC, reported as a score since patients may have a mixture

New Treatment Approach: Targeting DLL3

A major breakthrough in NEPC treatment involves targeting a protein called DLL3 (Delta-like ligand 3). DLL3 is a surface-expressed protein that is highly enriched in neuroendocrine prostate cancer (NEPC), with expression observed in approximately 77% of cases. Importantly, DLL3 is not found in normal prostate tissue or early-stage prostate cancer.

Tarlatamab is a bispecific T-cell engager targeting DLL3, a protein expressed in the majority of high-grade neuroendocrine cancers, including NEPC. This drug works by simultaneously binding to DLL3 on cancer cells and CD3 on immune T-cells, bringing them together to destroy the cancer.

Recent clinical trial results are encouraging: Tarlatamab demonstrated a 10.5% overall response rate in the general NEPC population and 22.2% in DLL3-positive tumors. While these numbers may seem modest, they represent meaningful progress for patients with very few treatment options.

Standardizing Diagnosis and Treatment

Dr. Beltran led a working group that developed new standardized criteria for diagnosing NEPC. This comprehensive approach includes:

  • Morphologic classification: Detailed examination of cell structure and appearance
  • Immunohistochemistry (IHC) profiling: Testing for specific protein markers
  • Proliferation index assessment: Measuring how rapidly cancer cells are dividing

For example, a cancer profile of "prostatic adenocarcinoma, AR-positive, NE-negative, Ki-67 20%" indicates less aggressive disease, while "small cell carcinoma, AR-negative, NE-positive, Ki-67 70%" reflects highly aggressive disease with poor outcomes.

Current Treatment Recommendations

For patients diagnosed with NEPC, current treatment approaches include:

  1. Continuing hormone therapy: Even though the cancer no longer depends on androgens, maintaining low testosterone levels is still recommended
  2. Platinum-based chemotherapy: Similar to treatments used for small cell lung cancer
  3. Clinical trials: Whenever possible, patients should consider enrolling in studies testing new treatments

Memorial Sloan Kettering Cancer Center (MSK) are confronting it with multiple new research projects and clinical trials... "No other program in the country really has this combination of laboratory experience, diagnostic tools, and therapeutic clinical trials to offer these patients, who otherwise have no standard treatment options," Dr. Morris says.

Looking to the Future

Several promising developments are on the horizon:

  • Additional DLL3-targeted therapies: Multiple drugs targeting this protein are in clinical trials
  • Combination approaches: Researchers are testing combinations of targeted therapy with immunotherapy
  • Liquid biopsies: Blood tests like NEMO may eventually replace tissue biopsies for diagnosis and monitoring
  • Precision medicine: Notably, it will be used in the Alliance A032102 trial (PREDICT: Precision Diagnostics in Prostate Cancer Treatment), in which patients are randomized based on actionable genomic alterations, including the presence of an NEPC signature.

What This Means for Patients

These advances represent a fundamental shift in how doctors understand and treat aggressive prostate cancer. For patients currently facing NEPC, these developments offer:

  • More accurate diagnosis through blood tests
  • Better understanding of disease biology
  • New targeted treatment options
  • Hope for improved outcomes

For patients with castration-resistant prostate cancer who haven't yet developed NEPC, these tools may enable earlier detection and intervention before the cancer becomes more aggressive.

Key Takeaways

Dr. Beltran concluded her presentation with several important messages:

  1. Increased awareness has improved diagnostic accuracy and understanding of NEPC biology
  2. NEPC remains challenging to diagnose due to its varied presentation
  3. Recognizing neuroendocrine features has important treatment implications
  4. New molecular tools, including blood tests, may improve detection
  5. Promising new therapies targeting DLL3 are under investigation
  6. Clinical trial participation should be considered whenever possible

While NEPC represents one of the most challenging forms of prostate cancer, these research advances provide genuine reasons for optimism. The combination of better diagnostic tools, deeper biological understanding, and promising new therapies suggests that outcomes for patients with this aggressive disease may improve significantly in the coming years.

Sources and Citations

  1. Beltran, H. (2025). Non-Androgen-Receptor–Driven Prostate Cancer: Updates in Biology, Classification, and Management. Presentation at American Society of Clinical Oncology (ASCO) 2025 Annual Meeting, Chicago, IL. Available at: https://www.urotoday.com/conference-highlights/asco-2025/asco-2025-prostate-cancer/161079-asco-2025-non-androgen-receptor-driven-prostate-cancer-updates-in-biology-classification-and-management.html
  2. Memorial Sloan Kettering Cancer Center. (April 4, 2025). Researching New Treatments for Neuroendocrine Prostate Cancer (NEPC). Available at: https://www.mskcc.org/news/new-treatments-for-neuroendocrine-prostate-cancer-nepc-focus-at-msk
  3. Alabi, B.R., et al. (2022). Current and emerging therapies for neuroendocrine prostate cancer. Pharmacology & Therapeutics, 240, 108298. Available at: https://www.sciencedirect.com/science/article/abs/pii/S0163725822001498
  4. Beltran, H., et al. (2021). Clinical and Biological Features of Neuroendocrine Prostate Cancer. Cancers, 13(6), 1434. PMC7990389. Available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC7990389/
  5. Wang, H.T., et al. (2014). Neuroendocrine Prostate Cancer (NEPC) Progressing From Conventional Prostatic Adenocarcinoma: Factors Associated With Time to Development of NEPC and Survival From NEPC Diagnosis—A Systematic Review and Pooled Analysis. Journal of Clinical Oncology, 32(30), 3383-3390. Available at: https://ascopubs.org/doi/10.1200/JCO.2013.54.3553
  6. Séguier, D., et al. (2025). Emergence of Neuroendocrine Tumors in Patients Treated with Androgen Receptor Pathway Inhibitors for Metastatic Prostate Cancer: A Systematic Review and Meta-analysis. European Urology Oncology, 8(2), 581-590. Available at: https://pubmed.ncbi.nlm.nih.gov/39824723/
  7. Paz-Ares, L., et al. (2023). Tarlatamab, a first-in-class DLL3-targeted bispecific T-cell engager, in recurrent small-cell lung cancer: an open-label, phase I study. Journal of Clinical Oncology, 41(16), 2893-2903. Available at: https://ascopubs.org/doi/10.1200/JCO.22.02823
  8. Ahn, M.J., et al. (2023). Tarlatamab for Patients with Previously Treated Small-Cell Lung Cancer. New England Journal of Medicine, 389(22), 2063-2075. Available at: https://www.nejm.org/doi/full/10.1056/NEJMoa2307980
  9. OncLive. (July 18, 2024). Tarlatamab Monotherapy Is Safe, Active in DLL3+ Neuroendocrine Prostate Cancer. Available at: https://www.onclive.com/view/tarlatamab-monotherapy-is-safe-active-in-dll3-neuroendocrine-prostate-cancer
  10. University of California San Diego. Tarlatamab in Advanced Delta-like 3 (DLL3)-Expressing Tumors Including Neuroendocrine Neoplasms. ClinicalTrials.gov Identifier: NCT06788938. Available at: https://clinicaltrials.ucsd.edu/trial/NCT06788938
  11. National Cancer Institute. (2023). Tarlatamab for Previously Treated Small Cell Lung Cancer. Available at: https://www.cancer.gov/news-events/cancer-currents-blog/2023/tarlatamab-previously-treated-sclc
  12. Aggarwal, R.R., et al. (2024). Phase 1b study of tarlatamab in de novo or treatment-emergent neuroendocrine prostate cancer (NEPC). Journal of Clinical Oncology, 42(16_suppl), 5012-5012. Available at: https://ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.5012
  13. Franceschini, G.M., et al. (2024). Noninvasive Detection of Neuroendocrine Prostate Cancer through Targeted Cell-free DNA Methylation. Cancer Discovery, 14(3), 424-447. Available at: https://aacrjournals.org/cancerdiscovery/article/14/3/424/734914/Noninvasive-Detection-of-Neuroendocrine-Prostate
  14. Dana-Farber Cancer Institute. (2024). Blood test distinguishes neuroendocrine subtype of advanced prostate cancer. Available at: https://www.dana-farber.org/newsroom/news-releases/2024/blood-test-distinguishes-neuroendocrine-subtype-of-advanced-prostate-cancer
  15. Drug Target Review. (January 11, 2024). Blood test developed that reliably detects NEPC. Available at: https://www.drugtargetreview.com/news/113606/blood-test-developed-that-reliably-detects-nepc/
  16. GenomeWeb. (January 12, 2024). Targeted Epigenetic-Based Early Cancer Assay Detects Aggressive Prostate Cancer. Available at: https://www.genomeweb.com/sequencing/targeted-epigenetic-based-early-cancer-assay-detects-aggressive-prostate-cancer
  17. ScienceDaily. (September 24, 2024). Blood test distinguishes neuroendocrine subtype of advanced prostate cancer. Available at: https://www.sciencedaily.com/releases/2024/01/240110120221.htm
  18. UroToday. Non-Invasive Detection of Neuroendocrine Prostate Cancer Through Targeted Cell-Free DNA Methylation - Himisha Beltran & Francesca Demichelis. Available at: https://www.urotoday.com/categories-media/2462-centers-of-excellence/translational-science-in-prostate-cancer-coe/3995-non-invasive-detection-of-neuroendocrine-prostate-cancer-through-targeted-cell-free-dna-methylation-himisha-beltran-francesca-demichelis.html
ASCO 2025: Non-Androgen-Receptor–Driven Prostate Cancer: Updates in Biology, Classification, and Management

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