Prognosis and Treatment Response in Aggressive-variant Prostate Cancer and Treatment-related Neuroendocrine Prostate Cancer: A Systematic Review and Meta-analysis

Martino Pedrani¹, Giuseppe Salfi², Giovanna Pecoraro³, Marialuisa Puglisi⁴, Fabio Turco¹, Luigi Tortola¹, Vasile Urechie⁵, Gianmarco Leone⁶, Hui-Ming Lin¹, Ursula Vogl¹, Jessica Barizzi⁷, Giorgio Treglia⁸, Marco Cuzzocrea⁹, Gaetano Paone¹⁰, Ping Lai¹¹, Jean Philippe Theurillat¹¹, Thomas Zilli¹², Silke Gillessen¹³, Sara Merler¹⁴, Ricardo Pereira Mestre¹⁵

Affiliations

¹ Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland.
² Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland; Institute of Oncology Research, Bellinzona, Switzerland.
³ Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland; Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.
⁴ Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland; School of Specialization in Medical Oncology, G. Barresi Department of Human Pathology, University of Messina, Messina, Italy.
⁵ Department of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.
⁶ Cancer Institute, Department of Oncology, University College London, London, UK; Garvan Institute of Medical Research, Darlinghurst, Australia; St. Vincent's Clinical School, University of New South Wales, Sydney, Australia.
⁷ Laboratory of Genetics and Molecular Pathology, Institute of Pathology, Ente Ospedaliero Cantonale, Locarno, Switzerland.
⁸ Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland; Nuclear Medicine Clinic, Imaging Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland; Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
⁹ Nuclear Medicine Clinic, Imaging Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland.
¹⁰ Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland; Nuclear Medicine Clinic, Imaging Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland.
¹¹ Institute of Oncology Research, Bellinzona, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland.
¹² Nuclear Medicine Clinic, Imaging Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland; Department of Radiation Oncology, Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland; Faculty of Medicine, University of Geneva, Geneva, Switzerland.
¹³ Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland; Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
¹⁴ Oncology Department, San Maurizio Central Hospital, Bolzano, Italy.
¹⁵ Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland; Institute of Oncology Research, Bellinzona, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland. Electronic address: ricardo.pereiramestre@eoc.ch.

PMID: 41672832
DOI: 10.1016/j.euo.2026.01.011

Free article

Review

Prognosis and Treatment Response in Aggressive-variant Prostate Cancer and Treatment-related Neuroendocrine Prostate Cancer: A Systematic Review and Meta-analysis

Martino Pedrani et al. Eur Urol Oncol. 2026.

Free article

. 2026 Feb 10:S2588-9311(26)00032-5.

doi: 10.1016/j.euo.2026.01.011. Online ahead of print.

Authors

Affiliations

¹ Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland.
² Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland; Institute of Oncology Research, Bellinzona, Switzerland.
³ Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland; Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.
⁴ Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland; School of Specialization in Medical Oncology, G. Barresi Department of Human Pathology, University of Messina, Messina, Italy.
⁵ Department of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.
⁶ Cancer Institute, Department of Oncology, University College London, London, UK; Garvan Institute of Medical Research, Darlinghurst, Australia; St. Vincent's Clinical School, University of New South Wales, Sydney, Australia.
⁷ Laboratory of Genetics and Molecular Pathology, Institute of Pathology, Ente Ospedaliero Cantonale, Locarno, Switzerland.
⁸ Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland; Nuclear Medicine Clinic, Imaging Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland; Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
⁹ Nuclear Medicine Clinic, Imaging Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland.
¹⁰ Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland; Nuclear Medicine Clinic, Imaging Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland.
¹¹ Institute of Oncology Research, Bellinzona, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland.
¹² Nuclear Medicine Clinic, Imaging Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland; Department of Radiation Oncology, Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland; Faculty of Medicine, University of Geneva, Geneva, Switzerland.
¹³ Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland; Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
¹⁴ Oncology Department, San Maurizio Central Hospital, Bolzano, Italy.
¹⁵ Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland; Institute of Oncology Research, Bellinzona, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland. Electronic address: ricardo.pereiramestre@eoc.ch.

PMID: 41672832
DOI: 10.1016/j.euo.2026.01.011

Abstract

Background and objective: Aggressive-variant prostate cancer (AVPC) is an umbrella term that encompasses clinically defined AVPC (c-AVPC), molecularly defined AVPC (m-AVPC), and treatment-related neuroendocrine PC (t-NEPC), which represent a spectrum of metastatic castration-resistant PC phenotypes with poor clinical outcomes. Despite its clinical relevance, AVPC definitions remain heterogeneous and treatment guidelines are lacking. Our aim was to elucidate AVPC prognosis and treatment responsiveness across definitions.

Methods: We conducted a systematic literature search of PubMed, Embase, and Scopus up to September 15, 2025. Our meta-analysis included studies reporting survival outcomes and treatment responses for patients with AVPC.

Key findings and limitations: From 1518 records, 40 studies (including 10 abstracts) were analyzed. In comparison to non-AVPC, c-AVPC/m-AVPC was associated with shorter progression-free survival (PFS; hazard ratio [HR] 2.72, 95% confidence interval [CI] 1.54-4.81; I² = 0%) and overall survival (OS; HR 2.81, 95% CI 1.87-4.22; I² = 36%). Platinum-based chemotherapy (PBC) outperformed non-platinum regimens, with higher objective response rates in the overall AVPC cohort (46% vs 19%; p < 0.01) and in the c-AVPC/m-AVPC (41% vs 16%; p = 0.04) and t-NEPC (49% vs 22%; p < 0.01) subgroups. In c-AVPC/m-AVPC, PBC was associated with longer PFS (HR 0.39, 95% CI 0.24-0.62; I² = 0%) and OS (HR 0.40, 95% CI 0.23-0.68; I² = 0%) according to evidence from mixed-design studies. For t-NEPC, data were insufficient for meta-analytic comparison of PFS and OS by PBC use.

Conclusions and clinical implications: AVPC encompasses distinct subsets of advanced PC that are associated with higher risk of progression and death on standard PC therapies. Platinum-based chemotherapy was associated with better response rates across AVPC subtypes and appears to confer a survival benefit in c-AVPC and m-AVPC. Future studies should focus on molecularly informed classification frameworks that include genomics, histology, and advanced imaging to optimize patient stratification and guide targeted therapies.

Keywords: Aggressive-variant prostate cancer; Meta-analysis; Neuroendocrine prostate cancer; Predictive; Prostate carcinoma; Small-cell carcinoma; Survival; Systematic review.

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Prognosis and Treatment Response in Aggressive-variant Prostate Cancer and Treatment-related Neuroendocrine Prostate Cancer: A Systematic Review and Meta-analysis

Affiliations

Prognosis and Treatment Response in Aggressive-variant Prostate Cancer and Treatment-related Neuroendocrine Prostate Cancer: A Systematic Review and Meta-analysis

Authors

Affiliations

Abstract

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LinkOut - more resources

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