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.
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.
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.
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.
European urology oncology. 2026 Feb 10 [Epub ahead of print]
Martino Pedrani, Giuseppe Salfi, Giovanna Pecoraro, Marialuisa Puglisi, Fabio Turco, Luigi Tortola, Vasile Urechie, Gianmarco Leone, Hui-Ming Lin, Ursula Vogl, Jessica Barizzi, Giorgio Treglia, Marco Cuzzocrea, Gaetano Paone, Ping Lai, Jean Philippe Theurillat, Thomas Zilli, Silke Gillessen, Sara Merler, Ricardo Pereira Mestre
Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland., Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland; Institute of Oncology Research, Bellinzona, Switzerland., Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland; Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy., 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., Department of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA., 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., Laboratory of Genetics and Molecular Pathology, Institute of Pathology, Ente Ospedaliero Cantonale, Locarno, Switzerland., 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., Nuclear Medicine Clinic, Imaging Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland., Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland; Nuclear Medicine Clinic, Imaging 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., 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., Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland; Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland., Oncology Department, San Maurizio Central Hospital, Bolzano, Italy., 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: .