{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T14:01:06Z","timestamp":1789999266581,"version":"4.0.1"},"reference-count":38,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T00:00:00Z","timestamp":1789862400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Androgen receptor pathway inhibitors (ARPIs) are widely used across prostate cancer disease states, but spontaneous-report safety signals may be distorted by co-administered therapies. We characterized ARPI-associated adverse event reporting in men aged 18\u201364 years with prostate cancer and tested whether robust signals persisted after accounting for documented docetaxel co-reporting. Methods: We analyzed deduplicated U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) reports from 2014 Q1 through 2026 Q1 in which abiraterone, enzalutamide, apalutamide, or darolutamide was the primary suspect drug. Disproportionality was assessed using ROR, PRR, chi-square, and Bayesian information component metrics. Priority signals were tested across three reference backgrounds, followed by symmetric exclusion of docetaxel-co-reported cases from the darolutamide group and the comparator. Results: Among 19,814 age- and disease-restricted background reports, 4919 involved an ARPI as the primary suspect. Docetaxel was co-reported in 27.8% of darolutamide reports. Darolutamide-associated decreased neutrophil count remained positive across all three reference backgrounds and was IC025-supported, yet both decreased neutrophil count and myelosuppression fell to zero events after documented docetaxel exclusion. Peripheral neuropathy persisted with 20 events. Enzalutamide-associated fatigue and dizziness were more strongly reported in patients aged \u2265 65 years. Conclusions: ARPIs showed distinct adverse event reporting patterns in men aged 18\u201364 years with prostate cancer. Disappearance of darolutamide-associated hematologic signals after documented docetaxel exclusion highlights the value of regimen-level sensitivity analyses in pharmacovigilance of combination cancer therapies. Persistent peripheral neuropathy requires external evaluation because residual confounding from unreported or prior neurotoxic treatment cannot be excluded.<\/jats:p>","DOI":"10.3390\/cancers18183049","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T12:50:03Z","timestamp":1789995003000},"page":"3049","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pharmacovigilance of Androgen Receptor Pathway Inhibitors in Prostate Cancer: The Impact of Docetaxel Co-Reporting"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8558-1654","authenticated-orcid":false,"given":"Onur","family":"Alkan","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, Istanbul Medeniyet University, G\u00f6ztepe Prof. Dr. S\u00fcleyman Yal\u00e7\u0131n City Hospital, Istanbul 34722, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]},{"given":"\u0130smail","family":"Nazl\u0131","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Istanbul Medeniyet University, G\u00f6ztepe Prof. Dr. S\u00fcleyman Yal\u00e7\u0131n City Hospital, Istanbul 34722, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6992-5461","authenticated-orcid":false,"given":"Ahmet","family":"Ba\u015fg\u00f6ze","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Istanbul Medeniyet University, G\u00f6ztepe Prof. Dr. S\u00fcleyman Yal\u00e7\u0131n City Hospital, Istanbul 34722, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"validation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Mahmut","family":"G\u00fcm\u00fc\u015f","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Istanbul Medeniyet University, G\u00f6ztepe Prof. Dr. S\u00fcleyman Yal\u00e7\u0131n City Hospital, Istanbul 34722, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"supervision","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,20]]},"reference":[{"key":"ref_1","first-page":"e70043","article-title":"Cancer statistics, 2026","volume":"76","author":"Siegel","year":"2026","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","first-page":"485","article-title":"Prostate cancer statistics, 2025","volume":"75","author":"Kratzer","year":"2025","journal-title":"CA Cancer J. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Sekhoacha, M., Riet, K., Motloung, P., Gumenku, L., Adegoke, A., and Mashele, S. (2022). Prostate cancer review: Genetics, diagnosis, treatment options, and alternative approaches. Molecules, 27.","DOI":"10.3390\/molecules27175730"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"30830","DOI":"10.18632\/oncotarget.8306","article-title":"Prediction of Mycoplasma hominis proteins targeting in mitochondria and cytoplasm of host cells and their implication in prostate cancer etiology","volume":"8","author":"Khan","year":"2017","journal-title":"Oncotarget"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1038\/nrurol.2014.91","article-title":"Prostate cancer in young men: An important clinical entity","volume":"11","author":"Salinas","year":"2014","journal-title":"Nat. Rev. Urol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1002\/cncr.32498","article-title":"Prostate cancer in young men: An emerging young adult and older adolescent challenge","volume":"126","author":"Bleyer","year":"2020","journal-title":"Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e70414","DOI":"10.1002\/hsr2.70414","article-title":"Exploring the epidemiological characteristics and survival analysis among prostate cancer patients under 50: A SEER-based population study","volume":"8","author":"Mali","year":"2025","journal-title":"Health Sci. Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1056\/NEJMoa1704174","article-title":"Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer","volume":"377","author":"Fizazi","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1056\/NEJMoa1207506","article-title":"Increased survival with enzalutamide in prostate cancer after chemotherapy","volume":"367","author":"Scher","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1056\/NEJMoa1405095","article-title":"Enzalutamide in metastatic prostate cancer before chemotherapy","volume":"371","author":"Beer","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1408","DOI":"10.1056\/NEJMoa1715546","article-title":"Apalutamide treatment and metastasis-free survival in prostate cancer","volume":"378","author":"Smith","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1056\/NEJMoa1903307","article-title":"Apalutamide for metastatic, castration-sensitive prostate cancer","volume":"381","author":"Chi","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1056\/NEJMoa1815671","article-title":"Darolutamide in nonmetastatic, castration-resistant prostate cancer","volume":"380","author":"Fizazi","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1056\/NEJMoa2119115","article-title":"Darolutamide and survival in metastatic, hormone-sensitive prostate cancer","volume":"386","author":"Smith","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1210\/jc.2011-2189","article-title":"Clinical and biochemical consequences of CYP17A1 inhibition with abiraterone given with and without exogenous glucocorticoids in castrate men with advanced prostate cancer","volume":"97","author":"Attard","year":"2012","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1038\/s41391-019-0195-5","article-title":"A review of prostate cancer treatment impact on the CNS and cognitive function","volume":"23","author":"Ryan","year":"2020","journal-title":"Prostate Cancer Prostatic Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1007\/s11523-023-00959-5","article-title":"Comparison of cerebral blood flow in regions relevant to cognition after enzalutamide, darolutamide, and placebo in healthy volunteers: A randomized crossover trial","volume":"18","author":"Williams","year":"2023","journal-title":"Target. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Uemura, H., Koroki, Y., Iwaki, Y., Imanaka, K., Kambara, T., Lopez-Gitlitz, A., Smith, A., and Uemura, H. (2020). Skin rash following administration of apalutamide in Japanese patients with advanced prostate cancer: An integrated analysis of the phase 3 SPARTAN and TITAN studies and a phase 1 open-label study. BMC Urol., 20.","DOI":"10.1186\/s12894-020-00689-0"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e359","DOI":"10.1111\/1346-8138.15510","article-title":"Fatal case of toxic epidermal necrolysis due to apalutamide used as a novel prostate cancer drug","volume":"47","author":"Endo","year":"2020","journal-title":"J. Dermatol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1200\/JCO.2019.37.7_suppl.156","article-title":"Higher blood\u2013brain barrier penetration of [14C]apalutamide and [14C]enzalutamide compared to [14C]darolutamide in rats using whole-body autoradiography","volume":"37","author":"Zurth","year":"2019","journal-title":"J. Clin. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Lee, J., Song, M., Leem, S., Kim, J.-Y., Shim, S.R., Kim, J.H., and Chung, B.I. (2025). Adverse events of androgen receptor pathway inhibitors in prostate cancer from real world data. PLoS ONE, 20.","DOI":"10.1371\/journal.pone.0335459"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1080\/14740338.2024.2442514","article-title":"A 13-years pharmacovigilance analysis of novel hormonal agents in prostate cancer using the FDA adverse event reporting system database","volume":"25","author":"Xiao","year":"2026","journal-title":"Expert Opin. Drug Saf."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1016\/j.clgc.2023.07.003","article-title":"Cardiovascular adverse events associated with new-generation androgen receptor pathway inhibitors for prostate cancer: A disproportionality analysis based on the FDA Adverse Event Reporting System","volume":"21","author":"Liu","year":"2023","journal-title":"Clin. Genitourin. Cancer"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Chen, Y., Huang, L., Li, W., Gu, H., and Chen, Y. (2025). Exploring skin adverse events and mechanisms of apalutamide using data mining algorithms and network pharmacology. Front. Pharmacol., 16.","DOI":"10.3389\/fphar.2025.1517874"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Liu, J., Liu, X., Zeng, H., Tong, Y., Chen, Z., and Dong, Z. (2025). Severe cutaneous adverse reactions associated with second-generation androgen receptor antagonists in prostate cancer patients. PLoS ONE, 20.","DOI":"10.1371\/journal.pone.0325448"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1200\/JCO.2026.44.7_suppl.206","article-title":"Evaluation of Toxicity Profiles of Next-Generation Androgen Receptor Pathway Inhibitors in the Geriatric Population: Analysis of the FAERS Database","volume":"44","author":"Esen","year":"2026","journal-title":"J. Clin. Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"13405","DOI":"10.1007\/s00210-026-05253-5","article-title":"Vigilance for Drug Safety of Darolutamide in the Cancer Therapies: A Disproportionality Analysis from the FDA Adverse Event Reporting System","volume":"399","author":"Wu","year":"2026","journal-title":"Naunyn-Schmiedeberg\u2019s Arch. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"102610","DOI":"10.1016\/j.clgc.2026.102610","article-title":"Safety Profile Comparison of Androgen Receptor Pathway Inhibitors: A Pharmacovigilance Signal Detection Analysis Using Disproportionality Methods and Age-Stratified Comparison of 37,875 FAERS Reports","volume":"24","year":"2026","journal-title":"Clin. Genitourin. Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e17045","DOI":"10.1200\/JCO.2026.44.16_suppl.e17045","article-title":"Pharmacovigilance Signals of Androgen Receptor Pathway Inhibitors in Non-Geriatric Men with Prostate Cancer: A FAERS Disproportionality Analysis","volume":"44","author":"Alkan","year":"2026","journal-title":"J. Clin. Oncol."},{"key":"ref_30","unstructured":"U.S. Food and Drug Administration (2026, July 12). FDA Adverse Event Reporting System (FAERS) Database, Available online: https:\/\/www.fda.gov\/drugs\/drug-approvals-and-databases\/fda-adverse-event-reporting-system-faers-database."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1002\/cpt.3701","article-title":"FDA Adverse Event Reporting System (FAERS) Essentials: A Guide to Understanding, Applying, and Interpreting Adverse Event Data Reported to FAERS","volume":"118","author":"Potter","year":"2025","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Cutroneo, P.M., Sartori, D., Tuccori, M., Crisafulli, S., Battini, V., Carnovale, C., Rafaniello, C., Capuano, A., Poluzzi, E., and Moretti, U. (2024). Conducting and Interpreting Disproportionality Analyses Derived from Spontaneous Reporting Systems. Front. Drug Saf. Regul., 3.","DOI":"10.3389\/fdsfr.2023.1323057"},{"key":"ref_33","unstructured":"International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (2026, July 20). Medical Dictionary for Regulatory Activities (MedDRA) Version 28.0. Available online: https:\/\/alt.meddra.org\/files_acrobat\/intguide_28_0_English.pdf."},{"key":"ref_34","first-page":"e23678","article-title":"A case of abiraterone-related hypokalemia leading to torsades de pointes and cardiac arrest","volume":"14","author":"Lee","year":"2022","journal-title":"Cureus"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1001\/jamaoncol.2017.3361","article-title":"Seizure rates in enzalutamide-treated men with metastatic castration-resistant prostate cancer and risk of seizure: The UPWARD study","volume":"4","author":"Slovin","year":"2018","journal-title":"JAMA Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1111\/bjd.19677","article-title":"The value of case reports and spontaneous reporting systems for pharmacovigilance and clinical practice","volume":"184","author":"Raschi","year":"2021","journal-title":"Br. J. Dermatol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1007\/s40264-023-01345-w","article-title":"Challenges and opportunities in accessing and analysing FAERS data: A call towards a collaborative approach","volume":"46","author":"Giunchi","year":"2023","journal-title":"Drug Saf."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"891","DOI":"10.2165\/00002018-200730100-00007","article-title":"Impact of safety alerts on measures of disproportionality in spontaneous reporting databases: The notoriety bias","volume":"30","author":"Pariente","year":"2007","journal-title":"Drug Saf."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/18\/3049\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T13:12:19Z","timestamp":1789996339000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/18\/3049"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,20]]},"references-count":38,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["cancers18183049"],"URL":"https:\/\/doi.org\/10.3390\/cancers18183049","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,20]]}}}