{"entity":{"id":"prostate-nepc","kind":"cancer","name":"Neuroendocrine and small-cell prostate cancer","aka":["NEPC","Treatment-emergent neuroendocrine prostate cancer","t-NEPC","Small-cell carcinoma of the prostate","Aggressive variant prostate cancer"],"tldr":"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.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Prostate_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Prostate_cancer"},{"label":"NCCN Guidelines: Prostate Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459"}],"tags":["subtype-page"],"related":[],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"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"],"standardOfCare":[{"setting":"Small-cell or predominantly neuroendocrine","approach":"Cisplatin or carboplatin with etoposide, as for small-cell lung cancer; continue androgen deprivation; brain imaging.","refs":["platinum-etoposide","cisplatin","carboplatin","etoposide","androgen-deprivation"],"guideline":{"version":"NCCN Guidelines: Prostate Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459"}},{"setting":"Mixed adenocarcinoma and neuroendocrine, or aggressive variant","approach":"Carboplatin plus docetaxel or cabazitaxel, then platinum with etoposide; clinical trial enrolment preferred.","refs":["carboplatin","docetaxel","cabazitaxel","cytotoxic-chemotherapy"],"guideline":{"version":"NCCN Guidelines: Prostate Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459"}},{"setting":"Recognition and biopsy","approach":"Biopsy any progression with low PSA, visceral metastases or PSMA-negative FDG-avid lesions; test for mismatch repair deficiency (pembrolizumab) and HRR genes.","refs":["psma-pet","pet","pembrolizumab"]},{"setting":"Trials","approach":"DLL3 T-cell engagers (tarlatamab), EZH2 inhibitors and aurora kinase inhibitors against the lineage switch; lurbinectedin borrowed from small-cell lung cancer.","refs":["tarlatamab","dll3","mevrometostat","ezh2","lurbinectedin"]}],"stateOfArt":["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."],"history":[{"year":1977,"title":"Small-cell carcinoma of the prostate first described","refs":["sclc"]},{"year":2011,"title":"Beltran finds AURKA and MYCN amplification in neuroendocrine prostate cancer","refs":["myc"]},{"year":2016,"title":"Divergent clonal evolution from adenocarcinoma shown by sequencing","refs":[]},{"year":2017,"title":"RB1 and TP53 loss drive lineage plasticity in models","refs":["tp53"]},{"year":2018,"title":"Aggarwal: 17 percent of men on potent hormone therapy have neuroendocrine features at biopsy","refs":["castration-resistance"]},{"year":2024,"title":"Tarlatamab shows activity against DLL3-positive neuroendocrine prostate cancer","refs":["tarlatamab","dll3"]}],"pipeline":["tarlatamab","mevrometostat","lurbinectedin","ifinatamab-deruxtecan"],"openProblems":["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."],"parent":"prostate"},"route":"/cancers/prostate-nepc/","neighbours":{"cancer":[{"id":"prostate","kind":"cancer","name":"Prostate cancer","route":"/cancers/prostate/"},{"id":"sclc","kind":"cancer","name":"Small-cell lung cancer","route":"/cancers/sclc/"}],"pathway":[{"id":"myc","kind":"pathway","name":"MYC","route":"/pathways/myc/"}],"target":[{"id":"dll3","kind":"target","name":"DLL3","route":"/targets/dll3/"},{"id":"ezh2","kind":"target","name":"EZH2","route":"/targets/ezh2/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"}],"term":[{"id":"castration-resistance","kind":"term","name":"Castration-resistant prostate cancer (CRPC)","route":"/terms/castration-resistance/"}],"drug":[{"id":"cabazitaxel","kind":"drug","name":"Cabazitaxel","route":"/drugs/cabazitaxel/"},{"id":"carboplatin","kind":"drug","name":"Carboplatin","route":"/drugs/carboplatin/"},{"id":"cisplatin","kind":"drug","name":"Cisplatin","route":"/drugs/cisplatin/"},{"id":"docetaxel","kind":"drug","name":"Docetaxel","route":"/drugs/docetaxel/"},{"id":"etoposide","kind":"drug","name":"Etoposide","route":"/drugs/etoposide/"},{"id":"ifinatamab-deruxtecan","kind":"drug","name":"Ifinatamab deruxtecan","route":"/drugs/ifinatamab-deruxtecan/"},{"id":"lurbinectedin","kind":"drug","name":"Lurbinectedin","route":"/drugs/lurbinectedin/"},{"id":"mevrometostat","kind":"drug","name":"Mevrometostat","route":"/drugs/mevrometostat/"},{"id":"pembrolizumab","kind":"drug","name":"Pembrolizumab","route":"/drugs/pembrolizumab/"},{"id":"platinum-etoposide","kind":"drug","name":"Platinum + etoposide (EP / CE)","route":"/drugs/platinum-etoposide/"},{"id":"tarlatamab","kind":"drug","name":"Tarlatamab","route":"/drugs/tarlatamab/"}],"technology":[{"id":"androgen-deprivation","kind":"technology","name":"Androgen deprivation & AR pathway inhibitors","route":"/technologies/androgen-deprivation/"},{"id":"cytotoxic-chemotherapy","kind":"technology","name":"Cytotoxic chemotherapy","route":"/technologies/cytotoxic-chemotherapy/"},{"id":"pet","kind":"technology","name":"PET (positron emission tomography)","route":"/technologies/pet/"},{"id":"psma-pet","kind":"technology","name":"PSMA PET","route":"/technologies/psma-pet/"}]}}