Real-world trends in the use and outcomes of novel androgen receptor signaling inhibitor therapy in patients with non-metastatic castration-resistant prostate cancer: A multicenter retrospective study

Real-world trends in the use and outcomes of novel androgen receptor signaling inhibitor therapy in patients with non-metastatic castration-resistant prostate cancer: A multicenter retrospective study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Real-world trends in the use and outcomes of novel androgen receptor signaling inhibitor therapy in patients with non-metastatic castration-resistant prostate cancer: A multicenter retrospective study Fumiya Yoneyama, Naoki Fujita, Yohei Kawashima, Masanao Shinohara, and 13 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6441263/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 08 Jul, 2025 Read the published version in International Journal of Clinical Oncology → Version 1 posted 5 You are reading this latest preprint version Abstract Background: Although three phase III trials demonstrated significant oncological benefits of novel androgen receptor signaling inhibitors (ARSIs) in patients with non-metastatic castration-resistant prostate cancer (nmCRPC), trends in novel ARSI use have been sparsely documented. Moreover, the safety and oncological benefits of novel ARSIs in real-world nmCRPC settings remain unclear. Methods: This multicenter retrospective study evaluated 318 consecutive patients with nmCRPC treated between 2001 and 2024. Trends in the use of novel ARSIs were analyzed. Adverse events associated with novel ARSIs were assessed using the Common Terminology Criteria for Adverse Events version 5.0. Multivariable Cox proportional hazards regression analyses were conducted to evaluate the effects of novel ARSIs on metastasis-free survival (MFS) and overall survival (OS). Results: The median age and follow-up period after nmCRPC diagnosis were 77 years and 46 months, respectively. Of the 318 patients, 231 (73%) received novel ARSI treatment at some point during nmCRPC management. First-line use of novel ARSIs gradually increased following their initial approval for nmCRPC in 2014. The rate of first-line novel ARSI use was significantly higher in 2020–2024 than in 2014–2019 (68% vs. 33%, P < 0.001). The incidence rates of any-grade and grade ≥3 adverse events associated with novel ARSIs were 23% and 2.2%, respectively. After adjusting for confounding variables, novel ARSIs were independently and significantly associated with prolonged MFS and OS. Conclusions: Novel ARSIs have become a primary treatment strategy for nmCRPC in real-world settings, demonstrating both safety and significant oncological benefits. nmCRPC novel ARSI oncological outcomes real-world safety trends Figures Figure 1 Figure 2 Figure 3 Introduction Prostate cancer (PC) is among the most common malignancies in men worldwide [ 1 ]. Androgen deprivation therapy (ADT) is the gold standard primary treatment for patients with recurrence after radical prostatectomy or radiotherapy, as well as for those with unresectable or metastatic PC [ 2 ]. However, most such patients eventually develop a castration-resistant phenotype. Non-metastatic castration-resistant PC (nmCRPC) often progresses to metastatic CRPC (mCRPC), an incurable disease with poor prognosis [ 3 ]. Three previous phase III trials demonstrated significant oncological benefits of novel androgen receptor signaling inhibitors (ARSIs)—enzalutamide, darolutamide, and apalutamide—compared with placebo [ 4 – 6 ]. Although a real-world study reported increased use of novel ARSIs in metastatic hormone-sensitive PC (mHSPC) [ 7 , 8 ], trends in novel ARSI use for nmCRPC have been sparsely documented [ 9 – 11 ]. Moreover, the safety and oncological benefits of novel ARSIs in real-world nmCRPC settings remain unclear. The present study was performed to evaluate real-world trends in novel ARSI use and the safety and oncological benefits of these drugs in patients with nmCRPC. Patients and Methods Ethics statement This study adhered to the principles of the Declaration of Helsinki and was approved by the ethics committees of the Hirosaki University Graduate School of Medicine (authorization number: 2019-099-1 and 2021-158-2) and all participating hospitals. The requirement for written informed consent was waived because of the use of a public disclosure of study information (opt-out approach). Patient selection This multicenter retrospective study included 318 consecutive patients with nmCRPC treated between June 2001 and December 2024 at 12 hospitals. nmCRPC was defined as a prostate-specific antigen (PSA) concentration of > 1 ng/mL, castrate testosterone concentration of < 50 ng/dL, and no metastatic lesions on conventional imaging (computed tomography or bone scintigraphy) [ 12 ]. The patients were categorized into two groups: those treated with any novel ARSI—enzalutamide, apalutamide, abiraterone acetate, or darolutamide—at any point during nmCRPC treatment (novel ARSI group) and those who were not (control group). Evaluation of variables The following variables were analyzed: age at nmCRPC diagnosis, initial PSA concentration, biopsy Gleason score, clinical tumor (T) and node (N) stages at initial diagnosis, history of radical treatment, time of nmCRPC diagnosis, clinical N stage at nmCRPC diagnosis, and PSA doubling time (PSADT). The PSADT was calculated using the Sloan Kettering method, which requires at least three PSA concentrations of ≥ 0.2 ng/mL measured at least 1 month apart within 12 months before the nmCRPC diagnosis [ 13 ]. Adverse events (AEs) associated with novel ARSI therapy were assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Treatment All patients in this study received ADT, which included bilateral orchiectomy or luteinizing hormone-releasing hormone agonists/antagonists throughout their PC treatment. In Japan, the clinical use of enzalutamide, abiraterone acetate, apalutamide, and darolutamide for nmCRPC has been available since May 2014, September 2014, March 2019, and January 2020, respectively. The choice of ARSIs for nmCRPC treatment was at the clinician’s discretion. Statistical analysis SPSS version 29.0 (IBM Corp., Armonk, NY, USA) and GraphPad Prism 9 (GraphPad Software, San Diego, CA, USA) were used for statistical analyses. Quantitative variables were presented as median with interquartile range, and differences between the two groups were analyzed using the Mann–Whitney U test. Categorical variables were compared using the chi-squared test. The optimal PSADT cutoff for metastasis-free survival (MFS) was determined using a receiver operating characteristic curve. MFS and overall survival (OS) were assessed using the Kaplan–Meier method and compared using the log-rank test. Univariable and multivariable Cox proportional hazards regression analyses were conducted to evaluate the effects of novel ARSI on MFS and OS. These outcomes were calculated from the date of nmCRPC diagnosis to the date of the first event or last follow-up. Statistical significance was set at P < 0.05. Results Patients’ background The median age and follow-up period after nmCRPC diagnosis were 77 years and 46 months, respectively. Of the 318 patients, 231 (73%) were treated with novel ARSIs during any line of nmCRPC treatment. In the control group, 80 (92%) patients received vintage hormone therapies and/or chemotherapy. No significant differences were observed in patient background characteristics between the two groups, except for the clinical N stage at initial diagnosis and the time of nmCRPC diagnosis (Table 1 ). Table 1 Patients’ backgrounds All n = 318 Control group n = 87 Novel ARSI group n = 231 P value Age, years 77 (72–82) 76 (72–82) 77 (72–83) 0.395 Initial PSA, ng/mL 27 (11–83) 23 (10–57) 28 (11–100) 0.184 Biopsy Gleason score ≥ 8 218 (69%) 57 (66%) 161 (70%) 0.474 Clinical stage at initial diagnosis cT4 52 (16%) 11 (13%) 41 (18%) 0.272 cN1 74 (23%) 14 (16%) 60 (26%) 0.020 cT4 or cN1 93 (29%) 19 (22%) 74 (32%) 0.075 History of radical treatment 168 (53%) 44 (51%) 124 (54%) 0.621 Prostatectomy 113 (36%) 30 (34%) 83 (36%) Radiation therapy 55 (17%) 14 (16%) 41 (18%) Diagnosis of nmCRPC before 2014 54 (17%) 36 (41%) 18 (7.8%) < 0.001 Clinical N stage at nmCRPC diagnosis cN1 81 (26%) 23 (26%) 58 (25%) 0.808 PSADT, months 3.7 (2.2–6.2) 4.2 (2.2–7.4) 3.5 (2.2–5.9) 0.250 Follow-up period, months 46 (27–71) 42 (28–70) 46 (27–71) All data are presented as n (%) or median (interquartile range). ARSI, androgen receptor signaling inhibitor; nmCRPC, non-metastatic castration-resistant prostate cancer; PSA, prostate-specific antigen; PSADT, prostate-specific antigen doubling time. The median PSADT was 3.7 months. The optimal PSADT cutoff for MFS was 3 months (Fig. S1 ), with 41% of patients classified as having a rapid PSADT (< 3 months). Trends in use of novel ARSIs Of the 231 patients in the novel ARSI group, 137 were treated with first-line ARSIs. The most used ARSI as first-line therapy was darolutamide (n = 66, 48%), followed by enzalutamide (n = 43, 31%), abiraterone acetate (n = 17, 12%), and apalutamide (n = 11, 8.0%). Following the initial approval of novel ARSIs for nmCRPC treatment in Japan in 2014, their use as first-line therapy gradually increased (Fig. 1 a). The rate of first-line novel ARSI use among patients diagnosed with nmCRPC between 2020 and 2024 was significantly higher than among patients diagnosed between 2014 and 2019 (68% vs. 33%, P < 0.001) (Fig. 1 b). By 2014, the rate of novel ARSI use in any line reached 69%, and it remained consistently above 60% thereafter (Fig. 1 c). Among the 264 patients diagnosed with nmCRPC after 2014, 213 (81%) were treated with novel ARSIs in any line of nmCRPC treatment. However, the rates of novel ARSI use in any line were not significantly different between patients diagnosed with nmCRPC in 2020–2024 and those diagnosed in 2014–2019 (84% vs. 77%, P = 0.113) (Fig. 1 d). AEs associated with novel ARSIs In the novel ARSI group, 231 patients were treated with a total of 364 ARSIs, including enzalutamide (n = 117), abiraterone acetate (n = 71), apalutamide (n = 55), and darolutamide (n = 121), across any line of nmCRPC treatment. The incidence rates of any-grade and grade ≥ 3 AEs associated with novel ARSIs were 23% and 2.2%, respectively (Fig. 2 a). The most common any-grade AE was general malaise or fatigue (n = 25, 6.9%), followed by skin rash (n = 20, 5.5%) (Fig. 2 b). The most frequent grade ≥ 3 AE was skin rash (n = 3, 0.8%), followed by hypertension (n = 2, 0.5%) (Fig. 2 c). Among the 364 ARSIs, 23 (6.3%) were discontinued because of AEs associated with novel ARSIs. Oncological outcomes At the end of follow-up, 57 (66%) patients in the control group and 71 (31%) in the novel ARSI group experienced mCRPC progression. The median MFS was 31 months in the control group and 92 months in novel ARSI group. Similarly, 53 (61%) and 67 (29%) patients in the control and novel ARSI groups, respectively, died of any cause. The median OS was 56 months in the control group and 99 months in the novel ARSI group. The MFS and OS were significantly longer in the novel ARSI group than in the control group ( P < 0.001 for both) (Fig. 3 a and b). In the univariable analyses, age, history of radical treatment, time of nmCRPC diagnosis, clinical N stage at nmCRPC diagnosis, PSADT, and novel ARSI therapy were significantly associated with MFS (Table S1 ). Similarly, PSADT and novel ARSI therapy were significantly associated with OS in the univariable analyses (Table S2 ). After adjusting for confounding variables, age, PSADT, and novel ARSI therapy were independently and significantly associated with MFS. PSADT and novel ARSI therapy were also independently and significantly associated with OS (Table 2 ). Table 2 Multivariable analysis of metastasis-free survival and overall survival Metastasis-free survival Factor P value Hazard ratio 95% CI Age Continuous 0.020 0.968 0.942–0.995 History of radical treatment Positive 0.061 1.447 0.983–2.131 Time of nmCRPC diagnosis Before 2014 0.552 0.873 0.557–1.367 Clinical N stage at nmCRPC diagnosis cN1 0.069 1.467 0.970–2.219 PSADT < 3 months < 0.001 2.285 1.551–3.366 Novel ARSI therapy Received < 0.001 0.288 0.192–0.432 Overall survival Factor P value Hazard ratio 95% CI Age Continuous 0.119 1.024 0.994–1.055 Time of nmCRPC diagnosis Before 2014 0.879 0.964 0.603–1.541 PSADT < 3 months < 0.001 2.320 1.558–3.454 Novel ARSI therapy Received < 0.001 0.416 0.275–0.631 CI, confidence interval; nmCRPC, non-metastatic castration-resistant prostate cancer; PSADT, prostate-specific antigen doubling time; ARSI, androgen receptor signaling inhibitor. Discussion This study examined real-world trends in the use of novel ARSIs and their safety and oncological benefits in patients with nmCRPC in Japan. The findings revealed a gradual increase in first-line use of novel ARSIs after 2014, with 81% of patients diagnosed with nmCRPC after 2014 receiving novel ARSIs in any line of treatment. Furthermore, novel ARSIs contributed to significantly improved oncological outcomes while maintaining an acceptable safety profile. These results suggest that novel ARSIs have become a primary treatment strategy in the real-world setting, reflecting their efficacy and safety in the novel ARSI era. Although three phase III trials demonstrated the significant survival benefits of novel ARSIs in patients with nmCRPC [ 6 , 5 , 4 ], their real-world utilization remains unclear. The present study showed that the rates of first-line novel ARSI use gradually increased after their initial approval for nmCRPC treatment in 2014, reaching 83% in 2022 (Fig. 1 a), while rates of novel ARSI use in any line consistently exceeded 60% after 2014 (Fig. 1 c). By contrast, several studies reported underutilization of novel ARSIs in nmCRPC. Swami et al. conducted a retrospective study in the United States, revealing that only 21% of patients received first-line novel ARSIs, even among those with a PSADT of ≤ 4 months [ 9 ]. Similarly, Wang et al. reported that only 6.4% of patients with nmCRPC in China received novel ARSIs based on electronic medical records [ 10 ]. Moreover, a retrospective observational study investigating real-world treatment patterns among veterans with nmCRPC demonstrated that only 13% of patients received novel ARSIs in first-line treatment [ 11 ]. Although the use of novel ARSIs gradually increased over time [ 11 , 9 , 14 ], its rate remained < 25% in 2018–2020 [ 9 ]. Because ARSI therapy is expensive, costing approximately $ 10,000 per month [ 15 ], differences in the rates of novel ARSI use between Japan and other countries might be influenced by health insurance systems. In Japan, the entire population is covered by a universal health insurance system with a maximum copayment of 10–30%. Additionally, a high-cost medical expense benefit system in Japan may further promote the use of novel ARSIs [ 16 ]. Beyond cost, patient characteristics, including age, frailty, and comorbidities, may influence treatment selection [ 8 ]. Further studies are needed to evaluate global trends in the use of novel ARSIs in patients with nmCRPC. The present study demonstrated less frequent AEs and lower discontinuation rates (Fig. 2 A) than those reported in three phase III trials [ 4 , 6 , 5 ], likely reflecting differences between clinical trial settings and real-world data. However, the rates observed in this study were consistent with another real-world study. A large retrospective cohort study in the United States found that among 870 patients with nmCRPC treated with novel ARSIs, 24.9% experienced any-grade of AEs, and 10–15% discontinued ARSI treatment because of AEs [ 17 ]. By contrast, other real-world studies reported higherAE rates, ranging from 52–57% [ 18 , 19 ]. These discrepancies may result from differences in evaluated agents, treatment lines, and ARSI dosing. Overall, novel ARSIs appear to be safely used in nmCRPC, with acceptable AE and discontinuation rates. Although previous studies focusing on patients with mHSPC or mCRPC demonstrated the real-world effects of novel ARSIs on oncological outcomes [ 20 – 22 ], data on their effects in nmCRPC in real-world settings remain sparse. Our earlier study, which included a relatively small cohort (n = 178), showed an improved MFS and OS in patients treated with novel ARSIs. The present study, with an expanded database of 318 patients and a median follow-up period of 46 months, confirmed the significant survival benefits of novel ARSIs (Table 2 ). Notably, while patients in the control groups of the three phase III trials received ADT alone [ 6 , 5 , 4 ], 92% of patients in the control group of this study were treated with vintage hormone therapies and/or chemotherapy. By contrast, a real-world study in Canada involving 233 patients with nmCRPC did not find a prolonged OS in patients treated with novel ARSIs [ 21 ]. These discrepancies highlight the need for further studies to evaluate the real-world effects of novel ARSIs on oncological outcomes in patients with nmCRPC. This study had several limitations. First, its retrospective design precluded definitive conclusions because we were unable to control for selection bias and other unmeasured confounders. Second, the time from nmCRPC diagnosis to initiation of novel ARSI treatment varied among patients, which may have influenced the outcomes. Finally, the study did not compare the safety and efficacy of individual ARSIs. Conclusions Novel ARSIs have become a primary treatment strategy for nmCRPC in real-world settings, supported by their demonstrated safety and oncological benefits. Declarations Acknowledgment This work was supported by a Grant-in-Aid for Scientific Research (No. 25K12244) from the Japan Society for the Promotion of Science. We thank Angela Morben, DVM, ELS, from Edanz (https://jp.edanz.com/ac), for editing a draft of this manuscript. Conflicts of interest disclosure Shingo Hatakeyama received honoraria from Janssen Pharmaceutical K.K., Astellas Pharma Inc., AstraZeneca K.K., Ono Pharmaceutical Co., Ltd., Bayer AG, Pfizer Inc., Bristol-Myers Squibb, Merck Biopharma Co., Ltd., Kaneka Corporation, and Nipro Corporation. The other authors have no conflicts of interest to declare. Data Availability Statement The data sets generated and/or analyzed during the current study are not publicly available due to ethical restrictions but are available from the corresponding author on reasonable request. Ethics approval This study adhered to the principles of the Declaration of Helsinki and was approved by the ethics committees of the Hirosaki University Graduate School of Medicine (authorization number: 2019-099-1 and 2021-158-2) and all participating hospitals. Informed consent The requirement for written informed consent was waived because of the use of a public disclosure of study information (opt-out approach). Authors’ contribution NF: project development, data collection, data analysis, acquisition of funding, and manuscript writing. FY, YK, SM, RT, RT, TO, HM, KT, KO, HH, TT, DN, YS, and SS: data collection. CO and SH: supervision. All authors: manuscript review and editing. References Sung H, Ferlay J, Siegel RL et al (2021) Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 71:209–249. 10.3322/caac.21660 Kluth LA, Shariat SF, Kratzik C et al (2014) The hypothalamic-pituitary-gonadal axis and prostate cancer: implications for androgen deprivation therapy. 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Int Urol Nephrol 56:3719–3725. 10.1007/s11255-024-04116-3 Supplementary Files Fig.S.pptx Fig. S1 Optimal cutoff point of PSADT for MFS The optimal cutoff point of PSADT for MFS was calculated using a receiver operating characteristic curve. PSADT, prostate-specific antigen doubling time; MFS, metastasis-free survival. TableS1UnivariableanalysesforMFS.docx TableS2UnivariableanalysesforOS.docx Cite Share Download PDF Status: Published Journal Publication published 08 Jul, 2025 Read the published version in International Journal of Clinical Oncology → Version 1 posted Editorial decision: Major revisions 21 May, 2025 Reviewers agreed at journal 23 Apr, 2025 Reviewers invited by journal 22 Apr, 2025 Editor assigned by journal 17 Apr, 2025 First submitted to journal 13 Apr, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Medicine","correspondingAuthor":false,"prefix":"","firstName":"Kyo","middleName":"","lastName":"Togashi","suffix":""},{"id":446127101,"identity":"2dcce707-2ec3-4663-9029-6f78fdbe0fc9","order_by":9,"name":"Kazutaka Okita","email":"","orcid":"","institution":"Hirosaki University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Kazutaka","middleName":"","lastName":"Okita","suffix":""},{"id":446127102,"identity":"049471da-f075-4be0-9282-8c6ae51aadb1","order_by":10,"name":"Hirotaka Horiguchi","email":"","orcid":"","institution":"Hirosaki University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Hirotaka","middleName":"","lastName":"Horiguchi","suffix":""},{"id":446127103,"identity":"618f3dea-a757-476e-b2b0-cd4bb879bb24","order_by":11,"name":"Toshikazu Tanaka","email":"","orcid":"","institution":"Hirosaki University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Toshikazu","middleName":"","lastName":"Tanaka","suffix":""},{"id":446127104,"identity":"b147ce89-c552-4428-b5d4-6f8124a59635","order_by":12,"name":"Daisuke Noro","email":"","orcid":"","institution":"Hirosaki University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Daisuke","middleName":"","lastName":"Noro","suffix":""},{"id":446127105,"identity":"ef101185-4f94-462e-9d02-bfb5b3142407","order_by":13,"name":"Yuichiro Suzuki","email":"","orcid":"","institution":"Hirosaki University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yuichiro","middleName":"","lastName":"Suzuki","suffix":""},{"id":446127106,"identity":"066a05cf-d157-40e6-ab5e-1df3171da398","order_by":14,"name":"Satoshi Sato","email":"","orcid":"","institution":"Ageo Central General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Satoshi","middleName":"","lastName":"Sato","suffix":""},{"id":446127107,"identity":"67020182-7333-4730-bd42-7a92c62ddd24","order_by":15,"name":"Chikara Ohyama","email":"","orcid":"","institution":"Hirosaki University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Chikara","middleName":"","lastName":"Ohyama","suffix":""},{"id":446127108,"identity":"3c9f0bb7-49d0-4f6a-b565-5fae6ce77eff","order_by":16,"name":"Shingo Hatakeyama","email":"","orcid":"","institution":"Hirosaki University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Shingo","middleName":"","lastName":"Hatakeyama","suffix":""}],"badges":[],"createdAt":"2025-04-13 22:28:23","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6441263/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6441263/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10147-025-02827-w","type":"published","date":"2025-07-08T15:57:18+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":82123127,"identity":"cd90ecbc-8576-405d-b178-261f24098c32","added_by":"auto","created_at":"2025-05-07 03:31:54","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":134821,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTrends in the use of novel ARSIs\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe rates of novel ARSI use in \u003cstrong\u003e(a) \u003c/strong\u003efirst-line treatment and \u003cstrong\u003e(c) \u003c/strong\u003eany line of treatment for nmCRPC are shown. The rates of novel ARSI use in \u003cstrong\u003e(b)\u003c/strong\u003efirst-line\u003cstrong\u003e \u003c/strong\u003etreatment and \u003cstrong\u003e(d) \u003c/strong\u003eany line of treatment were compared using the chi-squared test. ARSI, androgen receptor signaling inhibitor; nmCRPC, non-metastatic castration-resistant prostate cancer; DTX, docetaxel.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6441263/v1/9b737ade0da6d1357a95e595.jpg"},{"id":82121540,"identity":"33567e4c-f864-4b26-9eca-932c707c57b2","added_by":"auto","created_at":"2025-05-07 03:23:54","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":60664,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSafety of novel ARSI therapy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(a)\u003c/strong\u003e Rates of any-grade and grade ≥3 AEs. Details of \u003cstrong\u003e(b) \u003c/strong\u003eany-grade and \u003cstrong\u003e(c) \u003c/strong\u003egrade ≥3 AEs. ARSI, androgen receptor signaling inhibitor; AE, adverse event.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6441263/v1/c34d7b99a68686913b24f313.jpg"},{"id":82121547,"identity":"561599f9-56d6-4562-9a2b-c4e9f6131842","added_by":"auto","created_at":"2025-05-07 03:23:54","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":57960,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eOncological outcomes of novel ARSI therapy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(a) \u003c/strong\u003eMetastasis-free survival\u003cstrong\u003e \u003c/strong\u003eand \u003cstrong\u003e(b) \u003c/strong\u003eoverall survival after nmCRPC diagnosis were evaluated using the Kaplan–Meier method and compared using the log-rank test. ARSI, androgen receptor signaling inhibitor; nmCRPC, non-metastatic castration-resistant prostate cancer.\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6441263/v1/d8c4d3aa97e4ec0734db0c11.jpg"},{"id":86699348,"identity":"779de4e9-2228-4c6b-b7d7-818129d8bed6","added_by":"auto","created_at":"2025-07-14 16:08:05","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1076364,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6441263/v1/f4205534-d9a3-44d1-896f-687a9718e0a8.pdf"},{"id":82124716,"identity":"8114e1a7-142b-45aa-914c-1bd4b46b06ce","added_by":"auto","created_at":"2025-05-07 03:39:54","extension":"pptx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":49387,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFig. S1 Optimal cutoff point of PSADT for MFS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe optimal cutoff point of PSADT for MFS was calculated using a receiver operating characteristic curve. PSADT, prostate-specific antigen doubling time; MFS, metastasis-free survival.\u003c/p\u003e","description":"","filename":"Fig.S.pptx","url":"https://assets-eu.researchsquare.com/files/rs-6441263/v1/2f1439016f7f4128a5fb5d0e.pptx"},{"id":82121542,"identity":"8798df20-6355-499a-ba37-48174a2cf225","added_by":"auto","created_at":"2025-05-07 03:23:54","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":20266,"visible":true,"origin":"","legend":"","description":"","filename":"TableS1UnivariableanalysesforMFS.docx","url":"https://assets-eu.researchsquare.com/files/rs-6441263/v1/965996f0d68277804dc6fe63.docx"},{"id":82121551,"identity":"5538f1b2-c6ba-42b2-b298-f932be17ee55","added_by":"auto","created_at":"2025-05-07 03:23:54","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":20267,"visible":true,"origin":"","legend":"","description":"","filename":"TableS2UnivariableanalysesforOS.docx","url":"https://assets-eu.researchsquare.com/files/rs-6441263/v1/e758c7f7d1fd9d5e06ab118b.docx"}],"financialInterests":"","formattedTitle":"Real-world trends in the use and outcomes of novel androgen receptor signaling inhibitor therapy in patients with non-metastatic castration-resistant prostate cancer: A multicenter retrospective study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eProstate cancer (PC) is among the most common malignancies in men worldwide [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Androgen deprivation therapy (ADT) is the gold standard primary treatment for patients with recurrence after radical prostatectomy or radiotherapy, as well as for those with unresectable or metastatic PC [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. However, most such patients eventually develop a castration-resistant phenotype.\u003c/p\u003e \u003cp\u003eNon-metastatic castration-resistant PC (nmCRPC) often progresses to metastatic CRPC (mCRPC), an incurable disease with poor prognosis [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Three previous phase III trials demonstrated significant oncological benefits of novel androgen receptor signaling inhibitors (ARSIs)\u0026mdash;enzalutamide, darolutamide, and apalutamide\u0026mdash;compared with placebo [\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Although a real-world study reported increased use of novel ARSIs in metastatic hormone-sensitive PC (mHSPC) [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], trends in novel ARSI use for nmCRPC have been sparsely documented [\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Moreover, the safety and oncological benefits of novel ARSIs in real-world nmCRPC settings remain unclear.\u003c/p\u003e \u003cp\u003eThe present study was performed to evaluate real-world trends in novel ARSI use and the safety and oncological benefits of these drugs in patients with nmCRPC.\u003c/p\u003e"},{"header":"Patients and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eEthics statement\u003c/h2\u003e \u003cp\u003e This study adhered to the principles of the Declaration of Helsinki and was approved by the ethics committees of the Hirosaki University Graduate School of Medicine (authorization number: 2019-099-1 and 2021-158-2) and all participating hospitals. The requirement for written informed consent was waived because of the use of a public disclosure of study information (opt-out approach).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003ePatient selection\u003c/h3\u003e\n\u003cp\u003eThis multicenter retrospective study included 318 consecutive patients with nmCRPC treated between June 2001 and December 2024 at 12 hospitals. nmCRPC was defined as a prostate-specific antigen (PSA) concentration of \u0026gt;\u0026thinsp;1 ng/mL, castrate testosterone concentration of \u0026lt;\u0026thinsp;50 ng/dL, and no metastatic lesions on conventional imaging (computed tomography or bone scintigraphy) [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The patients were categorized into two groups: those treated with any novel ARSI\u0026mdash;enzalutamide, apalutamide, abiraterone acetate, or darolutamide\u0026mdash;at any point during nmCRPC treatment (novel ARSI group) and those who were not (control group).\u003c/p\u003e\n\u003ch3\u003eEvaluation of variables\u003c/h3\u003e\n\u003cp\u003eThe following variables were analyzed: age at nmCRPC diagnosis, initial PSA concentration, biopsy Gleason score, clinical tumor (T) and node (N) stages at initial diagnosis, history of radical treatment, time of nmCRPC diagnosis, clinical N stage at nmCRPC diagnosis, and PSA doubling time (PSADT). The PSADT was calculated using the Sloan Kettering method, which requires at least three PSA concentrations of \u0026ge;\u0026thinsp;0.2 ng/mL measured at least 1 month apart within 12 months before the nmCRPC diagnosis [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Adverse events (AEs) associated with novel ARSI therapy were assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.\u003c/p\u003e\n\u003ch3\u003eTreatment\u003c/h3\u003e\n\u003cp\u003eAll patients in this study received ADT, which included bilateral orchiectomy or luteinizing hormone-releasing hormone agonists/antagonists throughout their PC treatment. In Japan, the clinical use of enzalutamide, abiraterone acetate, apalutamide, and darolutamide for nmCRPC has been available since May 2014, September 2014, March 2019, and January 2020, respectively. The choice of ARSIs for nmCRPC treatment was at the clinician\u0026rsquo;s discretion.\u003c/p\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eSPSS version 29.0 (IBM Corp., Armonk, NY, USA) and GraphPad Prism 9 (GraphPad Software, San Diego, CA, USA) were used for statistical analyses. Quantitative variables were presented as median with interquartile range, and differences between the two groups were analyzed using the Mann\u0026ndash;Whitney U test. Categorical variables were compared using the chi-squared test. The optimal PSADT cutoff for metastasis-free survival (MFS) was determined using a receiver operating characteristic curve. MFS and overall survival (OS) were assessed using the Kaplan\u0026ndash;Meier method and compared using the log-rank test. Univariable and multivariable Cox proportional hazards regression analyses were conducted to evaluate the effects of novel ARSI on MFS and OS. These outcomes were calculated from the date of nmCRPC diagnosis to the date of the first event or last follow-up. Statistical significance was set at \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u0026rsquo; background\u003c/h2\u003e \u003cp\u003eThe median age and follow-up period after nmCRPC diagnosis were 77 years and 46 months, respectively. Of the 318 patients, 231 (73%) were treated with novel ARSIs during any line of nmCRPC treatment. In the control group, 80 (92%) patients received vintage hormone therapies and/or chemotherapy. No significant differences were observed in patient background characteristics between the two groups, except for the clinical N stage at initial diagnosis and the time of nmCRPC diagnosis (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatients\u0026rsquo; backgrounds\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;318\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eControl group\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;87\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNovel ARSI group\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;231\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e77 (72\u0026ndash;82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e76 (72\u0026ndash;82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e77 (72\u0026ndash;83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.395\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInitial PSA, ng/mL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27 (11\u0026ndash;83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23 (10\u0026ndash;57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e28 (11\u0026ndash;100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.184\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBiopsy Gleason score\u0026thinsp;\u0026ge;\u0026thinsp;8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e218 (69%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e57 (66%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e161 (70%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.474\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical stage at initial diagnosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ecT4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e52 (16%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (13%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e41 (18%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.272\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ecN1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e74 (23%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (16%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e60 (26%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.020\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ecT4 or cN1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e93 (29%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19 (22%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e74 (32%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.075\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistory of radical treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e168 (53%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e44 (51%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e124 (54%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.621\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProstatectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e113 (36%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30 (34%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e83 (36%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRadiation therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e55 (17%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (16%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e41 (18%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiagnosis of nmCRPC before 2014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e54 (17%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36 (41%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18 (7.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical N stage at nmCRPC diagnosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ecN1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e81 (26%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23 (26%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e58 (25%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.808\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSADT, months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.7 (2.2\u0026ndash;6.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.2 (2.2\u0026ndash;7.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.5 (2.2\u0026ndash;5.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.250\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFollow-up period, months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e46 (27\u0026ndash;71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e42 (28\u0026ndash;70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e46 (27\u0026ndash;71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eAll data are presented as n (%) or median (interquartile range). ARSI, androgen receptor signaling inhibitor; nmCRPC, non-metastatic castration-resistant prostate cancer; PSA, prostate-specific antigen; PSADT, prostate-specific antigen doubling time.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe median PSADT was 3.7 months. The optimal PSADT cutoff for MFS was 3 months (Fig. \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e), with 41% of patients classified as having a rapid PSADT (\u0026lt;\u0026thinsp;3 months).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eTrends in use of novel ARSIs\u003c/h3\u003e\n\u003cp\u003eOf the 231 patients in the novel ARSI group, 137 were treated with first-line ARSIs. The most used ARSI as first-line therapy was darolutamide (n\u0026thinsp;=\u0026thinsp;66, 48%), followed by enzalutamide (n\u0026thinsp;=\u0026thinsp;43, 31%), abiraterone acetate (n\u0026thinsp;=\u0026thinsp;17, 12%), and apalutamide (n\u0026thinsp;=\u0026thinsp;11, 8.0%). Following the initial approval of novel ARSIs for nmCRPC treatment in Japan in 2014, their use as first-line therapy gradually increased (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003ea). The rate of first-line novel ARSI use among patients diagnosed with nmCRPC between 2020 and 2024 was significantly higher than among patients diagnosed between 2014 and 2019 (68% vs. 33%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003eb).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eBy 2014, the rate of novel ARSI use in any line reached 69%, and it remained consistently above 60% thereafter (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003ec). Among the 264 patients diagnosed with nmCRPC after 2014, 213 (81%) were treated with novel ARSIs in any line of nmCRPC treatment. However, the rates of novel ARSI use in any line were not significantly different between patients diagnosed with nmCRPC in 2020\u0026ndash;2024 and those diagnosed in 2014\u0026ndash;2019 (84% vs. 77%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.113) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003ed).\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eAEs associated with novel ARSIs\u003c/h2\u003e \u003cp\u003eIn the novel ARSI group, 231 patients were treated with a total of 364 ARSIs, including enzalutamide (n\u0026thinsp;=\u0026thinsp;117), abiraterone acetate (n\u0026thinsp;=\u0026thinsp;71), apalutamide (n\u0026thinsp;=\u0026thinsp;55), and darolutamide (n\u0026thinsp;=\u0026thinsp;121), across any line of nmCRPC treatment. The incidence rates of any-grade and grade\u0026thinsp;\u0026ge;\u0026thinsp;3 AEs associated with novel ARSIs were 23% and 2.2%, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003ea). The most common any-grade AE was general malaise or fatigue (n\u0026thinsp;=\u0026thinsp;25, 6.9%), followed by skin rash (n\u0026thinsp;=\u0026thinsp;20, 5.5%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003eb). The most frequent grade\u0026thinsp;\u0026ge;\u0026thinsp;3 AE was skin rash (n\u0026thinsp;=\u0026thinsp;3, 0.8%), followed by hypertension (n\u0026thinsp;=\u0026thinsp;2, 0.5%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003ec). Among the 364 ARSIs, 23 (6.3%) were discontinued because of AEs associated with novel ARSIs.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eOncological outcomes\u003c/h2\u003e \u003cp\u003eAt the end of follow-up, 57 (66%) patients in the control group and 71 (31%) in the novel ARSI group experienced mCRPC progression. The median MFS was 31 months in the control group and 92 months in novel ARSI group. Similarly, 53 (61%) and 67 (29%) patients in the control and novel ARSI groups, respectively, died of any cause. The median OS was 56 months in the control group and 99 months in the novel ARSI group.\u003c/p\u003e \u003cp\u003eThe MFS and OS were significantly longer in the novel ARSI group than in the control group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001 for both) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e3\u003c/span\u003ea and b). In the univariable analyses, age, history of radical treatment, time of nmCRPC diagnosis, clinical N stage at nmCRPC diagnosis, PSADT, and novel ARSI therapy were significantly associated with MFS (Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e). Similarly, PSADT and novel ARSI therapy were significantly associated with OS in the univariable analyses (Table \u003cspan refid=\"MOESM2\" class=\"InternalRef\"\u003eS2\u003c/span\u003e). After adjusting for confounding variables, age, PSADT, and novel ARSI therapy were independently and significantly associated with MFS. PSADT and novel ARSI therapy were also independently and significantly associated with OS (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMultivariable analysis of metastasis-free survival and overall survival\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMetastasis-free survival\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFactor\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHazard ratio\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eContinuous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.968\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.942\u0026ndash;0.995\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistory of radical treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.061\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.447\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.983\u0026ndash;2.131\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime of nmCRPC diagnosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBefore 2014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.552\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.873\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.557\u0026ndash;1.367\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical N stage at nmCRPC diagnosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ecN1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.069\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.467\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.970\u0026ndash;2.219\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSADT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;3 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.285\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.551\u0026ndash;3.366\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNovel ARSI therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReceived\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.288\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.192\u0026ndash;0.432\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eOverall survival\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFactor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHazard ratio\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eContinuous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.119\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.024\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.994\u0026ndash;1.055\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime of nmCRPC diagnosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBefore 2014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.879\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.964\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.603\u0026ndash;1.541\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSADT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;3 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.320\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.558\u0026ndash;3.454\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNovel ARSI therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReceived\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.416\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.275\u0026ndash;0.631\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eCI, confidence interval; nmCRPC, non-metastatic castration-resistant prostate cancer; PSADT, prostate-specific antigen doubling time; ARSI, androgen receptor signaling inhibitor.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study examined real-world trends in the use of novel ARSIs and their safety and oncological benefits in patients with nmCRPC in Japan. The findings revealed a gradual increase in first-line use of novel ARSIs after 2014, with 81% of patients diagnosed with nmCRPC after 2014 receiving novel ARSIs in any line of treatment. Furthermore, novel ARSIs contributed to significantly improved oncological outcomes while maintaining an acceptable safety profile. These results suggest that novel ARSIs have become a primary treatment strategy in the real-world setting, reflecting their efficacy and safety in the novel ARSI era.\u003c/p\u003e \u003cp\u003eAlthough three phase III trials demonstrated the significant survival benefits of novel ARSIs in patients with nmCRPC [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], their real-world utilization remains unclear. The present study showed that the rates of first-line novel ARSI use gradually increased after their initial approval for nmCRPC treatment in 2014, reaching 83% in 2022 (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003ea), while rates of novel ARSI use in any line consistently exceeded 60% after 2014 (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003ec). By contrast, several studies reported underutilization of novel ARSIs in nmCRPC. Swami et al. conducted a retrospective study in the United States, revealing that only 21% of patients received first-line novel ARSIs, even among those with a PSADT of \u0026le;\u0026thinsp;4 months [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Similarly, Wang et al. reported that only 6.4% of patients with nmCRPC in China received novel ARSIs based on electronic medical records [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Moreover, a retrospective observational study investigating real-world treatment patterns among veterans with nmCRPC demonstrated that only 13% of patients received novel ARSIs in first-line treatment [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Although the use of novel ARSIs gradually increased over time [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], its rate remained\u0026thinsp;\u0026lt;\u0026thinsp;25% in 2018\u0026ndash;2020 [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Because ARSI therapy is expensive, costing approximately \u003cspan\u003e$\u003c/span\u003e10,000 per month [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], differences in the rates of novel ARSI use between Japan and other countries might be influenced by health insurance systems. In Japan, the entire population is covered by a universal health insurance system with a maximum copayment of 10\u0026ndash;30%. Additionally, a high-cost medical expense benefit system in Japan may further promote the use of novel ARSIs [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Beyond cost, patient characteristics, including age, frailty, and comorbidities, may influence treatment selection [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Further studies are needed to evaluate global trends in the use of novel ARSIs in patients with nmCRPC.\u003c/p\u003e \u003cp\u003eThe present study demonstrated less frequent AEs and lower discontinuation rates (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003eA) than those reported in three phase III trials [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], likely reflecting differences between clinical trial settings and real-world data. However, the rates observed in this study were consistent with another real-world study. A large retrospective cohort study in the United States found that among 870 patients with nmCRPC treated with novel ARSIs, 24.9% experienced any-grade of AEs, and 10\u0026ndash;15% discontinued ARSI treatment because of AEs [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. By contrast, other real-world studies reported higherAE rates, ranging from 52\u0026ndash;57% [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. These discrepancies may result from differences in evaluated agents, treatment lines, and ARSI dosing. Overall, novel ARSIs appear to be safely used in nmCRPC, with acceptable AE and discontinuation rates.\u003c/p\u003e \u003cp\u003eAlthough previous studies focusing on patients with mHSPC or mCRPC demonstrated the real-world effects of novel ARSIs on oncological outcomes [\u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], data on their effects in nmCRPC in real-world settings remain sparse. Our earlier study, which included a relatively small cohort (n\u0026thinsp;=\u0026thinsp;178), showed an improved MFS and OS in patients treated with novel ARSIs. The present study, with an expanded database of 318 patients and a median follow-up period of 46 months, confirmed the significant survival benefits of novel ARSIs (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Notably, while patients in the control groups of the three phase III trials received ADT alone [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], 92% of patients in the control group of this study were treated with vintage hormone therapies and/or chemotherapy. By contrast, a real-world study in Canada involving 233 patients with nmCRPC did not find a prolonged OS in patients treated with novel ARSIs [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. These discrepancies highlight the need for further studies to evaluate the real-world effects of novel ARSIs on oncological outcomes in patients with nmCRPC.\u003c/p\u003e \u003cp\u003eThis study had several limitations. First, its retrospective design precluded definitive conclusions because we were unable to control for selection bias and other unmeasured confounders. Second, the time from nmCRPC diagnosis to initiation of novel ARSI treatment varied among patients, which may have influenced the outcomes. Finally, the study did not compare the safety and efficacy of individual ARSIs.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eNovel ARSIs have become a primary treatment strategy for nmCRPC in real-world settings, supported by their demonstrated safety and oncological benefits.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by a Grant-in-Aid for Scientific Research (No. 25K12244) from the Japan Society for the Promotion of Science. We thank Angela Morben, DVM, ELS, from Edanz (https://jp.edanz.com/ac), for editing a draft of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest disclosure\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eShingo Hatakeyama received honoraria from Janssen Pharmaceutical K.K., Astellas Pharma Inc., AstraZeneca K.K., Ono Pharmaceutical Co., Ltd., Bayer AG, Pfizer Inc., Bristol-Myers Squibb, Merck Biopharma Co., Ltd., Kaneka Corporation, and Nipro Corporation. The other authors have no conflicts of interest to declare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data sets generated and/or analyzed during the current study are not publicly available due\u0026nbsp;to\u0026nbsp;ethical restrictions but are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study adhered to the principles of the Declaration of Helsinki and was approved by the ethics committees of the Hirosaki University Graduate School of Medicine (authorization number: 2019-099-1 and 2021-158-2) and all participating hospitals.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed consent\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe requirement for written informed consent was waived because of the use of a public disclosure of study information (opt-out approach).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNF: project development, data collection, data analysis, acquisition of funding, and manuscript writing. FY, YK, SM, RT, RT, TO, HM, KT, KO, HH, TT, DN, YS, and SS: data collection. CO and SH: supervision. All authors: manuscript review and editing.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSung H, Ferlay J, Siegel RL et al (2021) Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 71:209\u0026ndash;249. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3322/caac.21660\u003c/span\u003e\u003cspan address=\"10.3322/caac.21660\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKluth LA, Shariat SF, Kratzik C et al (2014) The hypothalamic-pituitary-gonadal axis and prostate cancer: implications for androgen deprivation therapy. 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Int Urol Nephrol 56:3719\u0026ndash;3725. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s11255-024-04116-3\u003c/span\u003e\u003cspan address=\"10.1007/s11255-024-04116-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijco","sideBox":"Learn more about [International Journal of Clinical Oncology](http://link.springer.com/journal/10147)","snPcode":"10147","submissionUrl":"https://www.editorialmanager.com/ijco/default2.aspx","title":"International Journal of Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"nmCRPC, novel ARSI, oncological outcomes, real-world, safety, trends","lastPublishedDoi":"10.21203/rs.3.rs-6441263/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6441263/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eAlthough three phase III trials demonstrated significant oncological benefits of novel androgen receptor signaling inhibitors (ARSIs) in patients with non-metastatic castration-resistant prostate cancer (nmCRPC), trends in novel ARSI use have been sparsely documented. Moreover, the safety and oncological benefits of novel ARSIs in real-world nmCRPC settings remain unclear.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eThis multicenter retrospective study evaluated 318 consecutive patients with nmCRPC treated between 2001 and 2024. Trends in the use of novel ARSIs were analyzed. Adverse events associated with novel ARSIs were assessed using the Common Terminology Criteria for Adverse Events version 5.0. Multivariable Cox proportional hazards regression analyses were conducted to evaluate the effects of novel ARSIs on metastasis-free survival (MFS) and overall survival (OS).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eThe median age and follow-up period after nmCRPC diagnosis were 77 years and 46 months, respectively. Of the 318 patients, 231 (73%) received novel ARSI treatment at some point during nmCRPC management. First-line use of novel ARSIs gradually increased following their initial approval for nmCRPC in 2014. The rate of first-line novel ARSI use was significantly higher in 2020–2024 than in 2014–2019 (68% vs. 33%, \u003cem\u003eP \u003c/em\u003e\u0026lt; 0.001). The incidence rates of any-grade and grade ≥3 adverse events associated with novel ARSIs were 23% and 2.2%, respectively. After adjusting for confounding variables, novel ARSIs were independently and significantly associated with prolonged MFS and OS.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eNovel ARSIs have become a primary treatment strategy for nmCRPC in real-world settings, demonstrating both safety and significant oncological benefits.\u003c/p\u003e","manuscriptTitle":"Real-world trends in the use and outcomes of novel androgen receptor signaling inhibitor therapy in patients with non-metastatic castration-resistant prostate cancer: A multicenter retrospective study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-07 03:23:49","doi":"10.21203/rs.3.rs-6441263/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revisions","date":"2025-05-21T04:45:22+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2025-04-23T14:30:19+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-04-22T06:53:56+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-04-17T06:03:54+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Journal of Clinical Oncology","date":"2025-04-13T18:28:10+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijco","sideBox":"Learn more about [International Journal of Clinical Oncology](http://link.springer.com/journal/10147)","snPcode":"10147","submissionUrl":"https://www.editorialmanager.com/ijco/default2.aspx","title":"International Journal of Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"077aeaf1-9427-4e36-8e0c-4bdb226eabf3","owner":[],"postedDate":"May 7th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-07-14T16:00:32+00:00","versionOfRecord":{"articleIdentity":"rs-6441263","link":"https://doi.org/10.1007/s10147-025-02827-w","journal":{"identity":"international-journal-of-clinical-oncology","isVorOnly":false,"title":"International Journal of Clinical Oncology"},"publishedOn":"2025-07-08 15:57:18","publishedOnDateReadable":"July 8th, 2025"},"versionCreatedAt":"2025-05-07 03:23:49","video":"","vorDoi":"10.1007/s10147-025-02827-w","vorDoiUrl":"https://doi.org/10.1007/s10147-025-02827-w","workflowStages":[]},"version":"v1","identity":"rs-6441263","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6441263","identity":"rs-6441263","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}