Navigating New Horizons in Neuroendocrine Prostate Cancer

A rare but increasingly recognized challenge in prostate cancer treatment, neuroendocrine prostate cancer (NEPC) demands a shift in diagnostic and therapeutic approaches. Treatment-emergent NEPC (t-NEPC), appearing as a resistance mechanism to androgen receptor (AR) pathway inhibition, presents a formidable clinical challenge with particularly poor survival outcomes.¹ Recent advancements are focusing on identifying this phenotype and developing targeted therapies.

Understanding Neuroendocrine Prostate Cancer

Whereas de novo NEPC – meaning it’s present at initial diagnosis – is uncommon, representing less than 1% of all new prostate cancer diagnoses, t-NEPC is becoming more prevalent. Estimates suggest t-NEPC develops in approximately 10% to 15% of patients undergoing treatment for prostate cancer.¹ This transition is characterized by significant genomic alterations and often evades standard detection methods like PSA monitoring.

Identifying Patients at Risk: Biopsy Triggers

Determining which patients require a re-biopsy to assess for NEPC involves a “clinical gestalt,” considering several factors. Current National Comprehensive Cancer Network (NCCN) guidelines recommend a metastatic biopsy in the hormone-resistant setting for all patients with an accessible lesion, to assess for genomic alterations and histopathology.¹ Specific triggers include:

• Presence of liver metastases
• Disproportionately low PSA levels despite high disease burden
• Known RB1 mutation based on prior genomic testing
• PSMA-PET–negative disease with soft tissue involvement

The Role of Genomic Markers

Genomic markers play a crucial role in identifying NEPC and guiding treatment decisions. Key markers include:

• RB1 loss: Often associated with lineage plasticity and treatment resistance.
• TP53 loss: Another indicator of aggressive disease and potential benefit from platinum-based chemotherapy when combined with other alterations.
• PTEN loss: Frequently observed in aggressive variants.
• BRCA2 alterations: May indicate sensitivity to PARP inhibitors.
• Microsatellite Instability-High (MSI-H): Identifies patients who may benefit from immunotherapy.

Evolving Treatment Strategies

Treatment approaches are evolving beyond traditional androgen deprivation therapy. Platinum-based regimens, such as carboplatin, are increasingly being used, particularly in patients with RB1 or TP53 alterations.² A study by Corn et al. (2019) demonstrated potential benefit from cabazitaxel plus carboplatin in patients with metastatic castration-resistant prostate cancer, especially those with loss of two or more tumor suppressors.² Continued androgen receptor-targeted therapy is often maintained alongside platinum-based chemotherapy to address any remaining AR-responsive disease.

Emerging Targets: ADCs, T-Cell Engagers, and Beyond

Research is focused on identifying novel surface targets for antibody-drug conjugates (ADCs) and T-cell engagers. Promising targets include:

• DLL3: Clinical data suggests potential benefit from DLL3-targeted therapies, though expression can be heterogeneous.
• SEZ6: An emerging target showing promise in preclinical studies.
• CD46: Currently under investigation as a potential target for both adenocarcinoma and neuroendocrine prostate cancer.
• B7H3: Showing potential, similar to its use in small cell lung cancer.

The Future of Diagnosis: Liquid Biopsies

Liquid biopsies, including circulating tumor cells (CTCs) and cell-free DNA (cfDNA), are showing promise in detecting the transition to NEPC. Epigenetic profiling of cfDNA, in particular, appears effective in differentiating adenocarcinoma from neuroendocrine disease.¹ While clinical-grade assays are still under development, liquid biopsies offer a less invasive approach to monitoring disease progression and identifying treatment resistance.

Conclusion

Neuroendocrine prostate cancer remains a significant clinical challenge, but ongoing research is yielding new insights into its biology and treatment. Improved diagnostic strategies, coupled with the development of targeted therapies, offer hope for improving outcomes for patients with this aggressive disease. Continued focus on identifying and understanding the genomic drivers of NEPC is crucial for advancing personalized treatment approaches.

References

1. Aggarwal R. Neuroendocrine prostate cancer: spectrum, recognition, and management implications. Presented at: 19th Annual New York GU Cancers Congress®; March 13-14, 2026; New York, NY. https://www.cancernetwork.com/view/navigating-new-horizons-in-neuroendocrine-prostate-cancer
2. Corn PG, Heath EI, Zurita A, et al. Cabazitaxel plus carboplatin for the treatment of men with metastatic castration-resistant prostate cancers: a randomised, open-label, phase 1–2 trial. Lancet Oncol. 2019;20(10):1432-1443. https://doi.org/10.1016/S1470-2045(19)30408-5