# Neuroendocrine and small-cell prostate cancer

Source: https://onco.cc/cancers/prostate-nepc/  
OnCo record `prostate-nepc` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Neuroendocrine prostate cancer is a form that has stopped depending on the androgen receptor, either from the start or after years of hormone therapy. It no longer shows up on PSA, spreads to the liver and brain, and is treated with the platinum chemotherapy used for small-cell lung cancer.

## Summary

Neuroendocrine prostate cancer includes rare de novo small-cell carcinoma and, far more often, treatment-emergent disease that arises when adenocarcinoma under prolonged androgen receptor blockade switches lineage, typically with combined loss of RB1 and TP53, PTEN loss, MYCN or AURKA amplification and loss of androgen receptor and PSA expression. It is suspected when disease progresses with a low or flat PSA, visceral or lytic bone metastases, raised chromogranin, neuron-specific enolase or lactate dehydrogenase, or FDG-avid but PSMA-negative lesions, and confirmed by biopsy showing small-cell morphology or synaptophysin and chromogranin staining. There is no approved therapy specific to it: platinum with etoposide, or carboplatin with docetaxel for mixed histology, is standard, with response rates of about half but brief duration, and androgen deprivation is usually continued. Immunotherapy adds little outside mismatch repair deficiency. DLL3 is expressed in most neuroendocrine prostate cancers, and the DLL3 T-cell engager tarlatamab, approved for small-cell lung cancer, is in trials here; EZH2 inhibitors and aurora kinase inhibitors are being tested against the lineage switch itself.

## Fields

- Kind: Cancer
- Last checked: 2026-09-25
- Also known as: NEPC; Treatment-emergent neuroendocrine prostate cancer; t-NEPC; Small-cell carcinoma of the prostate; Aggressive variant prostate cancer; Treatment-related neuroendocrine prostatic carcinoma; Small cell neuroendocrine carcinoma of the prostate; Small cell carcinoma of the prostate; Neuroendocrine prostatic carcinoma
- Tags: subtype-page
- Group: genitourinary
- Burden: Pure small-cell prostate cancer is under 1 percent of new diagnoses, but neuroendocrine features emerge in 10 to 20 percent of men treated with potent androgen receptor inhibitors; median survival after diagnosis is about a year.
- Subtypes: De novo small-cell carcinoma of the prostate; Treatment-emergent neuroendocrine prostate cancer (after androgen receptor pathway inhibitors); Mixed adenocarcinoma and neuroendocrine carcinoma; Aggressive variant prostate cancer (clinical definition, low PSA, visceral spread); Large-cell neuroendocrine carcinoma of the prostate
- Biomarkers: Synaptophysin, chromogranin and INSM1 staining; Loss of androgen receptor and PSA expression; Combined RB1 and TP53 loss; MYCN and AURKA amplification; DLL3 expression; Serum chromogranin A, neuron-specific enolase and lactate dehydrogenase; FDG PET-avid, PSMA PET-negative lesions

## Sections of this record

The page is a hub with ten sections in reading order; large sections have their own page. The same plan as JSON: https://onco.cc/api/v1/cancers/prostate-nepc/sections.json

- Overview (on the hub): The TL;DR, the family this cancer belongs to, the organ, who gets it and what the state of the art is. https://onco.cc/cancers/prostate-nepc/#overview [3 state-of-the-art points]
- Types and stages (on the hub): Anatomy, the subtypes and how they differ, how it is staged, and where advanced disease spreads. https://onco.cc/cancers/prostate-nepc/#what-it-is [5 subtypes]
- Symptoms and diagnosis (on the hub): How this cancer shows itself, how the diagnosis is confirmed, and the biomarkers clinicians test for. https://onco.cc/cancers/prostate-nepc/#finding-it [7 biomarkers]
- Treatment (on the hub): The standard of care by setting, the medicines, surgery and radiotherapy named in it, and the regimens behind them. https://onco.cc/cancers/prostate-nepc/#treating-it [4 settings, 4 decisions with options]
- Trials and papers (on the hub): Trials recruiting now, the landmark trials, the trials held by this cancer's subtypes, the key papers and what they mean, the latest literature, and the milestones year by year. https://onco.cc/cancers/prostate-nepc/#evidence [12 key papers, 6 milestones]
- Biology and targets (on the hub): The molecular landscape: the targets and how often each appears, the pathways, the mechanics stages and the preclinical models. https://onco.cc/cancers/prostate-nepc/#science [9 targets, 1 pathway]
- Countries and centres (own page): Cases by country, the UK and NHS pathway and other country lenses, the expert centres with trials on record, and the centres named on this cancer's subtypes. https://onco.cc/cancers/prostate-nepc/where-you-are/ [26 UK centres]
- Decisions and support (on the hub): The decisions you may face, the aids that walk through them, the warnings on record, the first sixty days and the questions to ask. https://onco.cc/cancers/prostate-nepc/#living-with-it [17 questions, 6 red cards]
- Pipeline and open problems (own page): Everything in development, the medicines held by this cancer's subtypes, the open problems and what is being done about them, the roadmaps, and what changed on this record. https://onco.cc/cancers/prostate-nepc/coming/ [11 medicines, 1 idea, 3 open problems]
- Data (own page): Every connected record, the notes, the JSON, Markdown and RDF twins, and where the record came from and when it was checked. https://onco.cc/cancers/prostate-nepc/data/ [62 connected records, 3 notes]

## Standard of care

- Small-cell or predominantly neuroendocrine: Cisplatin or carboplatin with etoposide, as for small-cell lung cancer; continue androgen deprivation; brain imaging. ([Platinum + etoposide (EP / CE)](https://onco.cc/drugs/platinum-etoposide/), [Cisplatin](https://onco.cc/drugs/cisplatin/), [Carboplatin](https://onco.cc/drugs/carboplatin/), [Etoposide](https://onco.cc/drugs/etoposide/), [Androgen deprivation & AR pathway inhibitors](https://onco.cc/technologies/androgen-deprivation/))
- Mixed adenocarcinoma and neuroendocrine, or aggressive variant: Carboplatin plus docetaxel or cabazitaxel, then platinum with etoposide; clinical trial enrolment preferred. ([Carboplatin](https://onco.cc/drugs/carboplatin/), [Docetaxel](https://onco.cc/drugs/docetaxel/), [Cabazitaxel](https://onco.cc/drugs/cabazitaxel/), [Cytotoxic chemotherapy](https://onco.cc/technologies/cytotoxic-chemotherapy/))
- Recognition and biopsy: Biopsy any progression with low PSA, visceral metastases or PSMA-negative FDG-avid lesions; test for mismatch repair deficiency (pembrolizumab) and HRR genes. ([PSMA PET](https://onco.cc/technologies/psma-pet/), [PET (positron emission tomography)](https://onco.cc/technologies/pet/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/))
- Trials: DLL3 T-cell engagers (tarlatamab), EZH2 inhibitors and aurora kinase inhibitors against the lineage switch; lurbinectedin borrowed from small-cell lung cancer. ([Tarlatamab](https://onco.cc/drugs/tarlatamab/), [DLL3](https://onco.cc/targets/dll3/), [Mevrometostat](https://onco.cc/drugs/mevrometostat/), [EZH2](https://onco.cc/targets/ezh2/), [Lurbinectedin](https://onco.cc/drugs/lurbinectedin/))

## State of the art

- Sequencing has shown that neuroendocrine prostate cancer evolves from the same clone as the adenocarcinoma rather than arising anew.
- DLL3 gives the disease its first surface target, borrowed from small-cell lung cancer.
- Lineage plasticity is now studied as a drug target in its own right.

## Open problems

- No approved therapy specific to the disease; every regimen is borrowed from lung cancer.
- No blood test reliably detects the lineage switch before it shows on scans.
- Whether androgen receptor blockade should be de-escalated to slow the switch.

## Notes

- This page is a tumour type, not a disease state. The WHO fifth edition gives treatment-related neuroendocrine prostatic carcinoma its own section inside the prostate chapter, rather than folding it into the classification's consolidated neuroendocrine chapter, because of its distinctive clinical and biological behaviour. It is defined there as tumours demonstrating complete neuroendocrine differentiation, or partial neuroendocrine differentiation with adenocarcinoma, following androgen deprivation therapy, and the definition covers both the primary and its metastases (Kench 2022).
- What a UK report will and will not do with it. Neuroendocrine carcinomas are not Gleason graded. The dataset in force does not ask for routine synaptophysin and chromogranin staining of ordinary prostate adenocarcinoma, because almost all of them show some neuroendocrine differentiation and there is not enough evidence that finding it changes treatment or prognosis; the stains are for tumours that already look neuroendocrine down the microscope. PSA and NKX3.1 are usually lost in these tumours, which is one of the reasons the PSA can stay low while the disease advances (RCPath G084).
- How common it is in the setting where it matters. Treatment-related neuroendocrine prostatic carcinoma is found in 10.5 to 17 percent of people with metastatic castration-resistant prostate cancer after treatment with androgen receptor signalling inhibitors (Kench 2022). The evidence is that these carcinomas arise by transformation of an existing adenocarcinoma rather than from neuroendocrine cells, which is what lineage plasticity means here and why it is a route to resistance rather than a second cancer.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Prostate_cancer
- Wikipedia: https://en.wikipedia.org/wiki/Prostate_cancer
- NCCN Guidelines: Prostate Cancer: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459
- Kench et al., Histopathology 2022: WHO Classification of Tumours fifth edition, evolving issues in the classification, diagnosis and prognostication of prostate cancer: https://doi.org/10.1111/his.14711
- Royal College of Pathologists G084: dataset for histopathology reports for prostatic carcinoma, version 4, October 2024: https://www.rcpath.org/static/8cc88604-2c8d-4df4-a99542df41c102af/G084-dataset-for-histopathology-reports-for-prostatic-carcinoma.pdf
- WHO Classification of Tumours, 5th edition: tumours of the prostate (IARC, 2022): https://tumourclassification.iarc.who.int/chapters/36

## Connected records

- cancers: [Ductal adenocarcinoma of the prostate](https://onco.cc/cancers/prostate-ductal-adenocarcinoma/), [Metastatic castration-resistant prostate cancer](https://onco.cc/cancers/prostate-mcrpc/), [Metastatic hormone-sensitive prostate cancer](https://onco.cc/cancers/prostate-mhspc/), [Non-metastatic castration-resistant prostate cancer](https://onco.cc/cancers/prostate-nmcrpc/), [Prostate cancer](https://onco.cc/cancers/prostate/), [Small-cell lung cancer](https://onco.cc/cancers/sclc/)
- terms: [Acinar adenocarcinoma of the prostate](https://onco.cc/terms/prostate-acinar-adenocarcinoma/), [Castration-resistant prostate cancer (CRPC)](https://onco.cc/terms/castration-resistance/), [Histologic transformation](https://onco.cc/terms/histologic-transformation/), [Neuroendocrine differentiation in prostate cancer](https://onco.cc/terms/neuroendocrine-differentiation/), [Radiographic progression-free survival (rPFS)](https://onco.cc/terms/radiographic-progression-free-survival/), [TNM staging for prostate cancer, and what changed in the 9th edition](https://onco.cc/terms/tnm-prostate-cancer/)
- key papers: [Androgen receptor pathway-independent prostate cancer is sustained through FGF signalling](https://onco.cc/key-papers/paper-bluemn-double-negative-prostate-fgf-mapk-cancer-cell-2017/), [Clinical and genomic characterisation of treatment-emergent small-cell neuroendocrine prostate cancer](https://onco.cc/key-papers/paper-aggarwal-t-sccpc-jco-2018/), [Combined tumour suppressor defects characterise clinically defined aggressive variant prostate cancers](https://onco.cc/key-papers/paper-aparicio-aggressive-variant-prostate-tumour-suppressors-ccr-2016/), [Detecting neuroendocrine prostate cancer through tissue-informed cell-free DNA methylation analysis](https://onco.cc/key-papers/paper-berchuck-cfdna-methylation-nepc-detection-ccr-2022/), [Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer](https://onco.cc/key-papers/paper-beltran-nepc-divergent-evolution-nat-med-2016/), [Molecular characterisation of neuroendocrine prostate cancer and identification of new drug targets](https://onco.cc/key-papers/paper-beltran-nepc-aurka-mycn-cancer-discov-2011/), [Molecular profiling stratifies diverse phenotypes of treatment-refractory metastatic castration-resistant prostate cancer](https://onco.cc/key-papers/paper-labrecque-mcrpc-phenotypes-jci-2019/), [MSH2 loss in primary prostate cancer](https://onco.cc/key-papers/paper-guedes-msh2-loss-primary-prostate-ccr-2017/), [Platinum-based chemotherapy for variant castration-resistant prostate cancer (aggressive variant criteria)](https://onco.cc/key-papers/paper-aparicio-aggressive-variant-ccr-2013/), [Proposed morphologic classification of prostate cancer with neuroendocrine differentiation](https://onco.cc/key-papers/paper-epstein-neuroendocrine-prostate-morphologic-classification-ajsp-2014/), [Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis and antiandrogen resistance](https://onco.cc/key-papers/paper-ku-rb1-trp53-lineage-plasticity-science-2017/), [SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer](https://onco.cc/key-papers/paper-mu-sox2-lineage-plasticity-science-2017/)
- pathways: [MYC](https://onco.cc/pathways/myc/)
- targets: [DLL3](https://onco.cc/targets/dll3/), [EZH2](https://onco.cc/targets/ezh2/), [SOX2](https://onco.cc/targets/sox2/), [TP53](https://onco.cc/targets/tp53/)
- drugs: [Cabazitaxel](https://onco.cc/drugs/cabazitaxel/), [Carboplatin](https://onco.cc/drugs/carboplatin/), [Cisplatin](https://onco.cc/drugs/cisplatin/), [Docetaxel](https://onco.cc/drugs/docetaxel/), [Etoposide](https://onco.cc/drugs/etoposide/), [Ifinatamab deruxtecan](https://onco.cc/drugs/ifinatamab-deruxtecan/), [Lurbinectedin](https://onco.cc/drugs/lurbinectedin/), [Mevrometostat](https://onco.cc/drugs/mevrometostat/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Platinum + etoposide (EP / CE)](https://onco.cc/drugs/platinum-etoposide/), [Tarlatamab](https://onco.cc/drugs/tarlatamab/)
- technologies: [Androgen deprivation & AR pathway inhibitors](https://onco.cc/technologies/androgen-deprivation/), [Cytotoxic chemotherapy](https://onco.cc/technologies/cytotoxic-chemotherapy/), [PET (positron emission tomography)](https://onco.cc/technologies/pet/), [PSMA PET](https://onco.cc/technologies/psma-pet/)
- roadmaps: [Prostate cancer roadmap: from Huggins and the discovery that a cancer can depend on a hormone, through the PSA epidemic and what it cost, the androgen receptor drugs, the DNA repair subset and PSMA, to a 2032 registry watch](https://onco.cc/roadmaps/prostate-roadmap/)
- ideas: [Watch for the cancer changing cell type before the biopsy says neuroendocrine, and act on it](https://onco.cc/ideas/idea-prostate-plasticity-surveillance-before-it-is-neuroendocrine/)
- biomarkers: [DLL3 expression](https://onco.cc/biomarkers/dll3-expression/), [Treatment-emergent neuroendocrine transformation (recognising it)](https://onco.cc/biomarkers/nepc-transformation/)

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JSON: https://onco.cc/api/v1/entities/prostate-nepc.json