{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T09:12:11Z","timestamp":1788772331268,"version":"build-2803163510"},"reference-count":28,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T00:00:00Z","timestamp":1788566400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Background and Objectives: Treatment-emergent neuroendocrine prostate cancer (t-NEPC) is an aggressive resistance phenotype arising during metastatic castration-resistant prostate cancer (mCRPC). Because metastatic biopsy is not routinely feasible in advanced disease, real-world data on clinically defined t-NEPC\/aggressive-variant prostate cancer (AVPC)-like disease remain limited. We aimed to characterize the clinical features, treatment patterns, survival outcomes, and prognostic factors of this clinically defined phenotype. Materials and Methods: We retrospectively reviewed 354 patients with prostate cancer treated at our institution between 2010 and 2020. Seventy-four patients with mCRPC who were clinically identified as having a t-NEPC\/AVPC-like phenotype and had a treatment plan for platinum- and\/or etoposide-based neuroendocrine-directed systemic therapy were included. Overall survival (OS) and radiographic progression-free survival (rPFS) were estimated using the Kaplan\u2013Meier method, and prognostic factors were evaluated using Cox regression analyses. Results: At clinical identification of the phenotype, the median age was 66.4 years, and visceral metastases were present in 67.6% of patients, most commonly in the liver (55.4%). Median intervals from prostate cancer diagnosis and CRPC onset to clinical identification of the phenotype were 47.5 and 22.7 months, respectively. Neuroendocrine-directed therapy was initiated in 72 patients; platinum\u2013etoposide was the most common first-line regimen (n = 41, 55.4%). Median OS was 4.4 months (95% confidence interval [CI], 2.9\u20135.8), and median rPFS was 3.5 months (95% CI, 2.7\u20134.2). In an exploratory, unadjusted analysis, median OS did not differ significantly between doublet chemotherapy and monotherapy (7.0 vs. 3.5 months; p = 0.167). Gleason score \u22659, hemoglobin &lt;12 g\/dL, and albumin &lt;3.5 g\/dL were independently associated with inferior OS. Conclusions: The clinically defined t-NEPC\/AVPC-like phenotype was associated with an aggressive clinical course and poor survival. Earlier recognition, improved biomarker-based diagnostic strategies, and more effective therapeutic approaches are needed.<\/jats:p>","DOI":"10.3390\/medicina62091702","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T08:07:06Z","timestamp":1788768426000},"page":"1702","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Clinical Characteristics and Survival Outcomes of a Clinically Defined Treatment-Emergent Neuroendocrine\/Aggressive-Variant Prostate Cancer Phenotype: A Retrospective Study"],"prefix":"10.3390","volume":"62","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2004-7741","authenticated-orcid":false,"given":"Hakan","family":"Taban","sequence":"first","affiliation":[{"name":"Medical Oncology Clinic, Medical Park Ankara Hospital, 06680 Ankara, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4984-1049","authenticated-orcid":false,"given":"Sercan","family":"Aksoy","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Hacettepe University Cancer Institute, 06230 Ankara, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6924-9467","authenticated-orcid":false,"given":"Deniz Can","family":"G\u00fcven","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Hacettepe University Cancer Institute, 06230 Ankara, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5460-4895","authenticated-orcid":false,"given":"Burak Yasin","family":"Akta\u015f","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Hacettepe University Cancer Institute, 06230 Ankara, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5848-3381","authenticated-orcid":false,"given":"Feride","family":"Y\u0131lmaz","sequence":"additional","affiliation":[{"name":"Medical Oncology Clinic, Samsun Education and Research Hospital, 55090 Samsun, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9153-6921","authenticated-orcid":false,"given":"Ferit","family":"Aslan","sequence":"additional","affiliation":[{"name":"Medical Oncology Clinic, Medical Park Ankara Hospital, 06680 Ankara, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5884-4669","authenticated-orcid":false,"given":"Mustafa","family":"Erman","sequence":"additional","affiliation":[{"name":"Department of Preventive Oncology, Hacettepe University Cancer Institute, 06230 Ankara, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,5]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","unstructured":"European Association of Urology (2026). EAU Guidelines on Prostate Cancer, EAU Guidelines Office. [Edn. Presented at the EAU Annual Congress London 2026 ed.]."},{"key":"ref_3","unstructured":"National Comprehensive Cancer Network (2026, July 08). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Prostate Cancer. Version 5. Available online: https:\/\/www.nccn.org\/professionals\/physician_gls\/pdf\/prostate.pdf."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1002\/pros.24664","article-title":"Diagnosis and management of neuroendocrine prostate cancer","volume":"84","author":"Chan","year":"2024","journal-title":"Prostate"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"IJE20","DOI":"10.2217\/ije-2019-0008","article-title":"Treatment-Emergent Neuroendocrine Prostate Cancer: Molecularly Driven Clinical Guidelines","volume":"6","author":"Clermont","year":"2019","journal-title":"Int. J. Endocr. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"T67","DOI":"10.1530\/ERC-21-0140","article-title":"Therapy considerations in neuroendocrine prostate cancer: What next?","volume":"28","author":"Beltran","year":"2021","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.ejca.2019.08.011","article-title":"Clinical features of neuroendocrine prostate cancer","volume":"121","author":"Conteduca","year":"2019","journal-title":"Eur. J. Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1016\/j.euo.2024.12.014","article-title":"Emergence of Neuroendocrine Tumors in Patients Treated with Androgen Receptor Pathway Inhibitors for Metastatic Prostate Cancer: A Systematic Review and Meta-analysis","volume":"8","author":"Parent","year":"2025","journal-title":"Eur. Urol. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2492","DOI":"10.1200\/JCO.2017.77.6880","article-title":"Clinical and Genomic Characterization of Treatment-Emergent Small-Cell Neuroendocrine Prostate Cancer: A Multi-institutional Prospective Study","volume":"36","author":"Aggarwal","year":"2018","journal-title":"J. Clin. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"320","DOI":"10.5858\/arpa.2019-0434-RA","article-title":"Morphologic Spectrum of Neuroendocrine Tumors of the Prostate: An Updated Review","volume":"144","author":"Hu","year":"2020","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4103\/aja202467","article-title":"Divergences in neuroendocrine prostate cancer frequency as recognized by anatomic pathologists, clinicians, and basic scientists","volume":"27","author":"Iczkowski","year":"2025","journal-title":"Asian J. Androl."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3621","DOI":"10.1158\/1078-0432.CCR-12-3791","article-title":"Platinum-Based Chemotherapy for Variant Castrate-Resistant Prostate Cancer","volume":"19","author":"Aparicio","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3383","DOI":"10.1200\/JCO.2013.54.3553","article-title":"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","volume":"32","author":"Wang","year":"2014","journal-title":"J. Clin. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Baude, J., Niogret, J., Jacob, P., Bardet, F., Desmoulins, I., Zanetta, S., Kaderbhai, C., Galland, L., Mayeur, D., and Delattre, B. (2024). Carboplatin and Etoposide for the Treatment of Metastatic Prostate Cancer with or without Neuroendocrine Features: A French Single-Center Experience. Cancers, 16.","DOI":"10.3390\/cancers16020280"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1038\/s41391-022-00524-7","article-title":"A phase 2 trial of avelumab in men with aggressive-variant or neuroendocrine prostate cancer","volume":"25","author":"Brown","year":"2022","journal-title":"Prostate Cancer Prostatic Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.1200\/JCO.2007.12.4487","article-title":"Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: Recommendations of the Prostate Cancer Clinical Trials Working Group","volume":"26","author":"Scher","year":"2008","journal-title":"J. Clin. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.ejca.2008.10.026","article-title":"New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1)","volume":"45","author":"Eisenhauer","year":"2009","journal-title":"Eur. J. Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3346","DOI":"10.1002\/cncr.28890","article-title":"Simple prognostic score for metastatic castration-resistant prostate cancer with incorporation of neutrophil-to-lymphocyte ratio","volume":"120","author":"Templeton","year":"2014","journal-title":"Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e7334","DOI":"10.1002\/cam4.7334","article-title":"Survival by first-line therapy and prognostic group among men with metastatic castration-resistant prostate cancer","volume":"13","author":"Caram","year":"2024","journal-title":"Cancer Med."},{"key":"ref_20","first-page":"101038","article-title":"Epidemiology and treatments of neuroendocrine prostate cancer in a large commercially insured population in the US","volume":"45","author":"Vassilev","year":"2025","journal-title":"Cancer Treat. Res. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e161858","DOI":"10.1172\/JCI161858","article-title":"A clinical-grade liquid biomarker detects neuroendocrine differentiation in prostate cancer","volume":"132","author":"Zhao","year":"2022","journal-title":"J. Clin. Investig."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1007\/s13691-025-00812-8","article-title":"Early emergence of neuroendocrine prostate cancer during triplet therapy for high-volume metastatic castration-sensitive prostate cancer","volume":"15","author":"Nakamura","year":"2026","journal-title":"Int. Cancer Conf. J."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Zhang, Q., Han, Y., Zhang, Y., Liu, D., Ming, J., Huang, B., and Qiu, X. (2021). Treatment-Emergent Neuroendocrine Prostate Cancer: A Clinicopathological and Immunohistochemical Analysis of 94 Cases. Front. Oncol., 10.","DOI":"10.3389\/fonc.2020.571308"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Taban, H., Erman, M., Guven, D.C., Aktas, B.Y., Yilmaz, F., Ya\u015far, S., Yildirim, H.C., Aslan, F., and Aksoy, S. (2025). Prognostic Nutritional Index and a Blood-Based Prognostic Tool in Prostate Cancer Treated with Abiraterone, Enzalutamide or Cabazitaxel. Medicina, 61.","DOI":"10.3390\/medicina61061105"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"8279","DOI":"10.1038\/s41598-021-87441-2","article-title":"Novel, non-invasive markers for detecting therapy induced neuroendocrine differentiation in castration-resistant prostate cancer patients","volume":"11","author":"Bhagirath","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2548975","DOI":"10.1080\/07853890.2025.2548975","article-title":"Mechanisms of neuroendocrine differentiation in castration-resistant prostate cancer and advances in the treatment of neuroendocrine prostate cancer","volume":"57","author":"Shao","year":"2025","journal-title":"Ann. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1007\/s11912-025-01643-9","article-title":"Emerging Therapeutic Targets of Neuroendocrine Prostate Cancer","volume":"27","author":"Zhu","year":"2025","journal-title":"Curr. Oncol. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"108255","DOI":"10.1016\/j.pharmthera.2022.108255","article-title":"Current and emerging therapies for neuroendocrine prostate cancer","volume":"238","author":"Alabi","year":"2022","journal-title":"Pharmacol. Ther."}],"container-title":["Medicina"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1648-9144\/62\/9\/1702\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T08:58:35Z","timestamp":1788771515000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1648-9144\/62\/9\/1702"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,5]]},"references-count":28,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["medicina62091702"],"URL":"https:\/\/doi.org\/10.3390\/medicina62091702","relation":{},"ISSN":["1648-9144"],"issn-type":[{"value":"1648-9144","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,5]]}}}