Cross-resistance among novel androgen receptor signaling inhibitors in non-metastatic castration-resistant prostate cancer

Cross-resistance among novel androgen receptor signaling inhibitors in non-metastatic castration-resistant prostate cancer | 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 Cross-resistance among novel androgen receptor signaling inhibitors in non-metastatic castration-resistant prostate cancer Takuya Oishi, Naoki Fujita, Yohei Kawashima, Masanao Shinohara, and 13 more This is a preprint; it has not been peer reviewed by a journal.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-6935071/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 14 Sep, 2025 Read the published version in International Journal of Clinical Oncology → Version 1 posted 5 You are reading this latest preprint version Abstract Background Sequential therapy with different novel androgen receptor signaling inhibitors (ARSIs) is a possible treatment option for patients who have increased prostate-specific antigen (PSA) levels. The aim of the present study was to investigate cross-resistance among ARSIs and its predictors in non-metastatic castration-resistant prostate cancer (nmCRPC). Methods In this multicenter retrospective study, we evaluated 75 patients with nmCRPC who had progressed after treatment with one ARSI and were subsequently treated with a second ARSI. The primary endpoint was cross-resistance among ARSIs, which was identified by comparing PSA responses to treatment with first and second ARSIs. The secondary endpoints were changes in PSA doubling time (PSADT) from diagnosis of nmCRPC to initiation of treatment with a second ARSI and predictors of PSA non-responsiveness to treatment with that second ARSI. Results The rates of any PSA response, PSA decline ≥ 50%, and PSA decline ≥ 90% to treatment with a second ARSI were significantly lower than those to the first ARSI administered (45% vs. 88%, P < 0.001; 9.3% vs. 71%, P < 0.001; 2.7% vs. 33%, P < 0.001; respectively). The PSADT shortened to some degree in 31 patients (41%). According to multivariable analysis, only PSADT before initiation of treatment with a second ARSI was significantly associated with no PSA response to treatment with that second ARSI. Conclusions We identified significant cross-resistance among ARSIs in patients with nmCRPC. The PSADT before initiation of treatment with a second ARSI may be useful for predicting the efficacy of treatment with a second ARSI. cross-resistance non-metastatic castration-resistant prostate cancer novel androgen receptor signaling inhibitor predictor prostate-specific antigen response sequential therapy Figures Figure 1 Figure 2 Figure 3 Introduction Prostate cancer (PC) is one of the commonest malignancies among men worldwide [ 1 ]. Androgen deprivation therapy (ADT) is the gold standard primary treatment both for patients who develop recurrence after radical treatments and for patients with unresectable or metastatic PC [ 2 ]. While a greater proportion of such patients initially respond to ADT, numerous patients eventually develop castration-resistant PC (CRPC) [ 3 ]. Non-metastatic CRPC (nmCRPC) frequently progresses to metastatic CRPC (mCRPC), an incurable condition with a poor prognosis [ 4 ]. Although the introduction of novel androgen receptor signaling inhibitors (ARSIs) has dramatically changed the landscape of systemic treatment for nmCRPC [ 5 – 7 ], many patients evidence increases in prostate-specific antigen (PSA) before progression to mCRPC despite receiving treatment with novel ARSIs [ 8 – 10 ]. Sequential therapy with different novel ARSIs is a possible treatment option for such patients [ 10 ]. However, cross-resistance among novel ARSIs compromises the efficacy of treatment with a second ARSI [ 11 , 12 ]. Although several studies that focused solely on abiraterone acetate and enzalutamide have reported cross-resistance in a mCRPC setting [ 12 – 15 ], whether this phenomenon occurs with other ARSIs in a nmCRPC setting remains unclear. Moreover, the predictors of cross-resistance have not yet been determined. The PSA doubling time (PSADT) reflects disease status and predicts PSA response to PC treatments [ 16 , 17 ]. However, it changes over time, reflecting the current aggressiveness of the disease [ 18 , 19 ]. Thus, we hypothesized that the PSADT immediately before initiation of treatment with a second ARSI might predict PSA response more accurately than that before diagnosis of nmCRPC. The primary aim of the present study was to investigate cross-resistance among novel ARSIs in patients with nmCRPC. The secondary aims were to determine the safety of treatment with the first and second ARSIs administered, changes in PSADT from diagnosis of nmCRPC to initiation of treatment with a second ARSI, and predictors of PSA non-responsiveness to treatment with a second ARSI. Patients and methods Ethics statement The current study was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the ethics committees of the Hirosaki University Graduate School of Medicine (Authorization Number: 2019-099-2 and 2021-158-1) and all hospitals included in this study. Written informed consent was not obtained because of the public disclosure of study information (opt-out approach). Patient selection In this multicenter retrospective study, we assessed data of 325 consecutive patients with nmCRPC treated between June 2001 and January 2025 at the 12 participating hospitals. Of the 325 patients, 232 received novel ARSIs, including abiraterone acetate, enzalutamide, apalutamide, and darolutamide, in any line of nmCRPC treatment. Of the 232 patients, 97 were subsequently treated with a second ARSI before progression to mCRPC. We excluded three patients for whom information on the efficacy of treatment with a second ARSI was missing, and 19 patients who had discontinued treatment with the first ARSI because of adverse events (AEs) or other reasons in the absence of evidence of disease progression. Ultimately, 75 patients were included in this study (Fig. 1 ). nmCRPC was defined as PSA > 1 ng/mL, castrate testosterone concentrations < 50 ng/dL, and the absence of metastatic lesions on conventional imaging (computed tomography or bone scintigraphy) [ 20 ]. Evaluation of variables The following variables were analyzed: age and Eastern Cooperative Oncology Group performance status at time of initiation of treatment with a second ARSI, PSA concentrations at initial diagnosis and initiation of treatment with a second ARSI, biopsy Gleason score, history of radical treatment, clinical node stage at diagnosis of nmCRPC, and PSADT. The Sloan Kettering method was used to calculate PSADT: this requires at least three PSA concentrations of 0.2 ng/mL or greater taken at least 1 month apart within 12 months before the diagnosis of nmCRPC [ 21 ] and before the initiation of treatment with a second ARSI. AEs associated with novel ARSI treatment were evaluated using the Common Terminology Criteria for Adverse Events version 5.0. Treatment All patients included in this study had undergone ADT, including bilateral orchiectomy and luteinizing hormone-releasing hormone agonists or antagonists, throughout their PC treatment. The specific novel ARSIs for treatment of nmCRPC were selected at the clinician’s discretion. Outcomes The primary endpoint was cross-resistance among novel ARSIs. Because there is no robust definition of cross-resistance, the rates of any PSA response, PSA decline ≥ 50%, and PSA decline ≥ 90% were compared between the first and second ARSIs administered. The secondary endpoints were the safety of treatment with the first and second ARSIs administered, changes in PSADT from diagnosis of nmCRPC to initiation of treatment with a second ARSI, and identification of predictors of PSA non-responsiveness to treatment with a second ARSI. Statistical analysis SPSS version 29.0 (IBM Corp., Armonk, NY, USA) and GraphPad Prism 9 (GraphPad Software, San Diego, CA, USA) were used for the statistical analyses. Quantitative variables are expressed as medians with interquartile ranges. Differences in quantitative variables between the two groups were analyzed using the Mann–Whitney U test. Categorical variables were compared using Fisher’s exact test or the χ 2 test. Correlations between variables were analyzed using Spearman’s rank correlation coefficients. The changes in PSADT from diagnosis of nmCRPC to initiation of treatment with a second ARSI were analyzed using the paired t -test. The optimal PSADT cutoff value for no PSA response to treatment with a second ARSI was calculated using a receiver operating characteristic curve. Univariable and multivariable logistic regression analyses were performed to identify factors that were significantly associated with PSA non-responsiveness to treatment with a second ARSI. Statistical significance was set at P < 0.05. Results Patients’ characteristics The median age at initiation of treatment with a second ARSI was 79 years. The median PSADT before diagnosis of nmCRPC was 3.6 months. Almost all patients had a PSADT < 10 months (n = 68, 93%), 56 (83%) of them having a particularly rapid PSADT (< 6 months). Of the 75 patients, 36 had received docetaxel and/or vintage hormone therapy, such as bicalutamide, flutamide, estramustine phosphate, or ethinylestradiol, for treatment of nmCRPC prior to treatment with a first ARSI; the median number of such treatments was 1.0 (Table 1 ). Table 1 summarizes the patients’ characteristics. Table 1 Patients’ characteristics All, n = 75 Age, years 79 (73–83) Performance status ≥ 1 27 (36%) PSA at initial diagnosis, ng/mL 28 (11–77) PSA at initiation of second ARSI treatment, ng/mL 3.7 (1.8–9.9) Biopsy Gleason score ≥ 9 35 (47%) Clinical stage at initial diagnosis cT4 7 (9.3%) cN1 15 (20%) History of radical treatment 41 (55%) Prostatectomy 27 (36%) Radiation therapy 14 (19%) Clinical N stage at diagnosis of nmCRPC cN1 11 (15%) Therapy prior to first ARSI treatment None 39 (52%) Docetaxel 4 (5.3%) Vintage hormone therapy 34 (45%) Number of therapies prior to first ARSI treatment 1 21 (28%) 2 11 (15%) ≥ 3 4 (5.3%) PSADT before diagnosis of nmCRPC, months 3.6 (2.5–5.6) PSADT before initiation of second ARSI treatment, months 4.3 (2.2–6.7) 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. Sequential therapy of novel ARSIs The ARSI most frequently used first was enzalutamide (n = 30, 40%), followed by darolutamide (n = 24, 32%), abiraterone acetate (n = 13, 17%), and apalutamide (n = 8, 11%). The ARSI most frequently used second was abiraterone acetate (n = 22, 29%), followed by enzalutamide (n = 21, 28%), apalutamide (n = 17, 23%), and darolutamide (n = 15, 20%) (Fig. S1 ). Primary endpoint After exclusion of 15 patients who were still receiving treatment with a second ARSI at the time of analysis, the median duration of treatment with a second ARSI was significantly shorter than that of treatment with the first ARSI (Fig. 2 a; 5.5 vs. 13 months, respectively, P < 0.001). Waterfall plots of changes in PSA 3 months after initiation of treatment with the first and second ARSIs in all patients are shown in Fig. 2 b and c, respectively. Significantly fewer patients achieved any PSA response to treatment with their second ARSI than to treatment with their first ARSI (Fig. 2 d; 45% vs. 88%, respectively, P < 0.001). The rates of PSA decline ≥ 50% and ≥ 90% during treatment with a second ARSI were significantly lower than those during treatment with the first ARSI (Fig. 2 e and f; 9.3% vs. 71%, P < 0.001; 2.7% vs. 33%, P < 0.001; respectively). Secondary endpoints The rates of any grade AEs associated with novel ARSI treatment did not differ significantly between treatment with the first and second ARSIs (32% vs. 20%, respectively, P = 0.094). Similarly, the rates of grade ≥ 3 AEs did not differ significantly between treatment with the first and second ARSIs (1.3% vs. 1.3%, respectively, P = 1.000). The PSADT before diagnosis of nmCRPC was significantly and positively correlated with that before initiation of treatment with a second ARSI (Fig. 3 a; P = 0.001). The PSADT did not differ significantly between before diagnosis of nmCRPC and initiation of treatment with a second ARSI (Fig. 3 b; median 3.6 vs. 4.3 months, P = 0.499). Of the 75 patients, 31 (41%) evidenced some degree of shortening of PSADT during treatment with the first ARSI. The median change in PSADT from diagnosis of nmCRPC to initiation of treatment with a second ARSI was 0.6 months (interquartile range [IQR]: -1.9–2.5 months); this difference is not significant (Fig. 3 c; P = 0.542). The optimal cutoff values of PSADT before diagnosis of nmCRPC and before initiation of treatment with a second ARSI were 2.8 and 6.6 months, respectively. According to univariable analyses, PSADT before diagnosis of nmCRPC was not significantly associated with PSA non-responsiveness to treatment with a second ARSI, as was true of other well-known prognostic factors, whereas PSADT before initiation of treatment with a second ARSI was significantly associated with PSA non-responsiveness to treatment with that second ARSI (Table 2 ). According to multivariable analysis, only PSADT before initiation of treatment with a second ARSI was significantly and independently associated with PSA non-responsiveness to treatment with that second ARSI (Table 3 ). Table 2 Results of univariable analyses for PSA non-responsiveness to second ARSI therapy Factor P value Odds ratio 95% CI Age Continuous 0.876 0.995 0.937–1.057 Performance status ≥ 1 0.773 0.870 0.337–2.247 PSA at initial diagnosis Continuous 0.091 0.993 0.986–1.001 PSA at initiation of second ARSI treatment Continuous 0.125 0.955 0.900–1.013 Biopsy Gleason score ≥ 9 0.362 0.635 0.240–1.685 Clinical N stage at diagnosis of nmCRPC cN1 0.210 0.429 0.114–1.614 Therapy prior to first ARSI treatment Positive 0.752 0.864 0.348–2.146 PSADT before diagnosis of nmCRPC < 2.8 month 0.607 1.307 0.472–3.619 PSADT before initiation of second ARSI treatment < 6.7 month 0.039 3.128 1.062–9.211 ARSI, androgen receptor signaling inhibitor; CI, confidence interval; nmCRPC, non-metastatic castration-resistant prostate cancer; PSA, prostate-specific antigen; PSADT, prostate-specific antigen doubling time. Table 3 Results of multivariable analysis for PSA non-responsiveness to second ARSI therapy Factor P value Odds ratio 95% CI PSA at initiation of second ARSI treatment Continuous 0.325 0.983 0.950–1.017 Biopsy Gleason score ≥ 9 0.405 0.645 0.229–1.813 PSADT before initiation of second ARSI treatment < 6.6 month 0.047 3.169 1.016–9.888 ARSI, androgen receptor signaling inhibitor; CI, confidence interval; PSA, prostate-specific antigen; PSADT, prostate-specific antigen doubling time. Discussion To the best of our knowledge, the present study is the first to evaluate cross-resistance among ARSIs in patients with nmCRPC. Our results suggest that the efficacy of second ARSIs is significantly poorer than that of first ARSIs, indicating significant cross-resistance among ARSIs. Moreover, a shorter PSADT before diagnosis of nmCRPC was not associated with efficacy of the second ARSI administered, whereas a shorter PSADT before initiation of treatment with the second ARSI was significantly associated with poorer efficacy of the second ARSI, suggesting that evaluation of disease aggressiveness before initiation of treatment with a second ARSI is important in predicting a response to treatment with a second ARSI. In the present study, we identified significant cross-resistance among ARSIs in patients with nmCRPC. Although there are no available data concerning cross-resistance in the nmCRPC setting, the findings of several previous studies that have evaluated cross-resistance between abiraterone acetate and enzalutamide in a mCRPC setting support our findings [ 12 – 15 ]. However, the underlying mechanisms are complicated and not fully understood. Although the chemical structures of abiraterone acetate and darolutamide differ from those of apalutamide and enzalutamide [ 22 ], these ARSIs share the same resistance mechanisms [ 23 – 25 ]: androgen receptor (AR)-dependent mechanisms (e.g., AR gene mutations and amplifications, alteration of pathways involved in crosstalk with AR signaling, systemic and intratumoral androgen biosynthesis up-regulation, and splice variants such as AR-variant 7), and AR-independent mechanisms (e.g., immune system deregulation, glucocorticoid receptor overexpression, and neuroendocrine transformation) [ 11 , 26 ]. Thus, failure after treatment with a first ARSI may also be followed by failure of treatment with a second ARSI. As for nmCRPC, some of the aforementioned mechanisms have also been reported [ 27 ], supporting the results of the present study. Docetaxel may serve as an alternative for patients whose disease progresses after ARSI treatment [ 28 ]; however, there is no published evidence for this in the nmCRPC setting. Thus, further study is needed to establish the optimal treatment sequence in patients with nmCRPC. Although the issue of cross-resistance among ARSIs has emerged as a major concern, the predictors of efficacy of treatment with a second ARSI have not yet been identified. In the current study, we found that the PSADT did not change significantly from diagnosis of nmCRPC to initiation of treatment with a second ARSI (Fig. 3 c). However, in 41% of patients, the PSADT was shortened to some degree during treatment with a first ARSI. Additionally, the PSADT before diagnosis of nmCRPC was not associated with the efficacy of treatment with a second ARSI, whereas the PSADT before initiation of treatment with a second ARSI was significantly associated with the efficacy of that second ARSI. Up to now, data on biomarkers that predict responses to ARSIs have been limited. It has been proposed that the AR-variant 7 predicts poor responses to ARSIs [ 29 ]. Moreover, a whole-genomics and whole-transcriptomics study in ARSI-treated patients with mCRPC has demonstrated that tumor mutational burden, structural variants, tandem duplications, and deletions are enriched in poor responders to ARSI therapy [ 30 ]. Thus, these genetic changes may be promising biomarkers for ARSI responsiveness; however, the associated cost and facility restrictions prohibit their use in clinical practice. By contrast, the PSADT is easy to calculate and less costly, potentially making the PSADT before initiation of treatment with a second ARSI a simple biomarker for cross-resistance among ARSIs. This study had several limitations. First, the patient cohort was relatively small. Second, its retrospective design precluded definitive conclusions because we were unable to control for selection bias and other unmeasured confounders. Finally, the cohort was too small to allow comparison of the safety and efficacy of individual ARSIs. Conclusions We have identified cross-resistance among ARSIs in patients with nmCRPC. The PSADT before initiation of treatment with a second ARSI may be useful for predicting the efficacy of that second ARSI. Declarations 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. None of the other authors have any conflicts of interest to declare. 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. Acknowledgments 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 Dr Trish Reynolds, MBBS, FRACP, from Edanz ( https://jp.edanz.com/ac ) for editing a draft of this manuscript. 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Cite Share Download PDF Status: Published Journal Publication published 14 Sep, 2025 Read the published version in International Journal of Clinical Oncology → Version 1 posted Editorial decision: Major revisions 15 Jul, 2025 Reviewers agreed at journal 01 Jul, 2025 Reviewers invited by journal 01 Jul, 2025 Editor assigned by journal 21 Jun, 2025 First submitted to journal 19 Jun, 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6935071","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":478868068,"identity":"00ec2379-145a-4a85-8c95-f4d1e5792c81","order_by":0,"name":"Takuya Oishi","email":"","orcid":"","institution":"Hirosaki University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Takuya","middleName":"","lastName":"Oishi","suffix":""},{"id":478868069,"identity":"810ce3ce-fd34-4460-a0c0-d2d6f44d1fe3","order_by":1,"name":"Naoki Fujita","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0001-8284-9582","institution":"Hirosaki University Graduate School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Naoki","middleName":"","lastName":"Fujita","suffix":""},{"id":478868070,"identity":"f024e849-c794-4184-ad43-712eba0c3de0","order_by":2,"name":"Yohei Kawashima","email":"","orcid":"","institution":"Ageo Central General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yohei","middleName":"","lastName":"Kawashima","suffix":""},{"id":478868071,"identity":"38d92de1-5533-4749-90aa-98879ebff4b5","order_by":3,"name":"Masanao Shinohara","email":"","orcid":"","institution":"Ageo Central General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Masanao","middleName":"","lastName":"Shinohara","suffix":""},{"id":478868072,"identity":"97d48329-e509-46cf-b4dd-26b4e980e947","order_by":4,"name":"Ryuji Tabata","email":"","orcid":"","institution":"Sano Kosei General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ryuji","middleName":"","lastName":"Tabata","suffix":""},{"id":478868073,"identity":"ed4325f8-769f-4ab0-a47d-4839be6200bb","order_by":5,"name":"Fumiya Yoneyama","email":"","orcid":"","institution":"Hirosaki University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Fumiya","middleName":"","lastName":"Yoneyama","suffix":""},{"id":478868074,"identity":"ec020d64-c17f-47f3-998d-8c21e2359cb2","order_by":6,"name":"Ryuma Tanaka","email":"","orcid":"","institution":"Hirosaki University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Ryuma","middleName":"","lastName":"Tanaka","suffix":""},{"id":478868075,"identity":"68c63eb6-d73b-4ee4-ad4c-2bdbd794b4a9","order_by":7,"name":"Hikari Miura","email":"","orcid":"","institution":"Hirosaki University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Hikari","middleName":"","lastName":"Miura","suffix":""},{"id":478868076,"identity":"f2f171a4-6a21-4525-ac88-a301a0c0398e","order_by":8,"name":"Kyo Togashi","email":"","orcid":"","institution":"Hirosaki University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Kyo","middleName":"","lastName":"Togashi","suffix":""},{"id":478868077,"identity":"b96a26fa-0f93-401b-a21d-58dd3973d876","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":478868078,"identity":"28444ed1-1679-466a-811d-0c7c40fbb7e9","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":478868079,"identity":"24942184-33bc-4af2-9986-5f97eeda7e2f","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":478868080,"identity":"68467ed1-3d71-459b-bef0-323c708afb84","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":478868081,"identity":"33d02f46-328d-4437-a5ac-0ceeed0dfa99","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":478868082,"identity":"9cd3f29d-2834-4c09-8e09-99bd2b6d4b04","order_by":14,"name":"Satoshi Sato","email":"","orcid":"","institution":"Ageo Central General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Satoshi","middleName":"","lastName":"Sato","suffix":""},{"id":478868083,"identity":"59084888-42ff-4b28-9d9e-e692414ce5a7","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":478868084,"identity":"02e75103-de0d-4a6a-8a6a-7378755bab37","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":"2025-06-20 04:10:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6935071/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6935071/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10147-025-02881-4","type":"published","date":"2025-09-14T15:57:09+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":85992939,"identity":"884c5c34-7912-4c8c-b83a-3de95e61b720","added_by":"auto","created_at":"2025-07-04 05:36:27","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":59648,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSelection of the study patients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFlow chart showing numbers of included and excluded patients. AE, adverse event; ARSI, androgen receptor signaling inhibitor; nmCRPC, non-metastatic castration-resistant prostate cancer.\u003c/p\u003e","description":"","filename":"Slide1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6935071/v1/71adf2c6e25e6dcada4cae68.jpg"},{"id":85992922,"identity":"d794f619-e0a3-42ff-8d64-5db950cea33a","added_by":"auto","created_at":"2025-07-04 05:36:26","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":127833,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCross-resistance among novel ARSIs\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eUsing the Mann–Whitney U test, the duration of novel ARSI treatment was compared between treatment with a first and a second ARSI (\u003cstrong\u003ea\u003c/strong\u003e). Waterfall plots of PSA change 3 months after initiation of treatment with first and second ARSIs (\u003cstrong\u003eb\u003c/strong\u003e and \u003cstrong\u003ec\u003c/strong\u003e, respectively). The rates of any PSA response (\u003cstrong\u003ed\u003c/strong\u003e) and PSA decline ≥ 50% (\u003cstrong\u003ee\u003c/strong\u003e) and ≥ 90% (\u003cstrong\u003ef\u003c/strong\u003e) were compared between treatment with first and second ARSIs using Fisher’s exact test or the χ\u003csup\u003e2\u003c/sup\u003e test. ARSI, androgen receptor signaling inhibitor; PSA, prostate-specific antigen.\u003c/p\u003e","description":"","filename":"Slide2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6935071/v1/d5fed176cab3e49cedd0ea86.jpg"},{"id":85992935,"identity":"a25331dd-d63e-4f49-b9d7-256dfa4983ac","added_by":"auto","created_at":"2025-07-04 05:36:27","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":79919,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eChanges in PSADT from diagnosis of nmCRPC to initiation of treatment with a second ARSI\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCorrelations between PSADT before diagnosis of nmCRPC and before initiation of treatment with a second ARSI were analyzed using Spearman’s rank correlation coefficients (\u003cstrong\u003ea\u003c/strong\u003e). PSADTs before diagnosis of nmCRPC and initiation of treatment with a second ARSI were compared using the Mann–Whitney U test (\u003cstrong\u003eb\u003c/strong\u003e). Changes in PSADT from diagnosis of nmCRPC to initiation of treatment with a second ARSI were analyzed using the paired t-test (\u003cstrong\u003ec\u003c/strong\u003e). The blue and red lines respectively indicate an increase and decrease in PSADT during first ARSI treatment. ARSI, androgen receptor signaling inhibitor; nmCRPC, non-metastatic castration-resistant prostate cancer; PSADT, prostate-specific antigen doubling time.\u003c/p\u003e","description":"","filename":"Slide3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6935071/v1/5ff016273fcfad46b6de23b3.jpg"},{"id":91817653,"identity":"c88c2857-0980-4e21-811e-714dc8c61c4d","added_by":"auto","created_at":"2025-09-22 07:00:12","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1067531,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6935071/v1/2b90c4ee-b51e-4764-9627-1bf1d1af746e.pdf"},{"id":85993780,"identity":"e0309d48-ddfa-432e-8f3c-b8b31f64abae","added_by":"auto","created_at":"2025-07-04 05:44:27","extension":"pptx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":273148,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFig. S1 Sequential therapy of novel ARSIs\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe sequence of administration of novel ARSIs is shown using a Sankey diagram. Abi, abiraterone acetate; Apa, apalutamide; ARSI, androgen receptor signaling inhibitor; Dar, darolutamide; Enz, enzalutamide.\u003c/p\u003e","description":"","filename":"FigS.pptx","url":"https://assets-eu.researchsquare.com/files/rs-6935071/v1/7b1a23e932131d9d8f17f701.pptx"}],"financialInterests":"","formattedTitle":"Cross-resistance among novel androgen receptor signaling inhibitors in non-metastatic castration-resistant prostate cancer","fulltext":[{"header":"Introduction","content":"\u003cp\u003eProstate cancer (PC) is one of the commonest malignancies among men worldwide [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Androgen deprivation therapy (ADT) is the gold standard primary treatment both for patients who develop recurrence after radical treatments and for patients with unresectable or metastatic PC [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. While a greater proportion of such patients initially respond to ADT, numerous patients eventually develop castration-resistant PC (CRPC) [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eNon-metastatic CRPC (nmCRPC) frequently progresses to metastatic CRPC (mCRPC), an incurable condition with a poor prognosis [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Although the introduction of novel androgen receptor signaling inhibitors (ARSIs) has dramatically changed the landscape of systemic treatment for nmCRPC [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], many patients evidence increases in prostate-specific antigen (PSA) before progression to mCRPC despite receiving treatment with novel ARSIs [\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Sequential therapy with different novel ARSIs is a possible treatment option for such patients [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. However, cross-resistance among novel ARSIs compromises the efficacy of treatment with a second ARSI [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Although several studies that focused solely on abiraterone acetate and enzalutamide have reported cross-resistance in a mCRPC setting [\u003cspan additionalcitationids=\"CR13 CR14\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], whether this phenomenon occurs with other ARSIs in a nmCRPC setting remains unclear. Moreover, the predictors of cross-resistance have not yet been determined.\u003c/p\u003e \u003cp\u003eThe PSA doubling time (PSADT) reflects disease status and predicts PSA response to PC treatments [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. However, it changes over time, reflecting the current aggressiveness of the disease [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Thus, we hypothesized that the PSADT immediately before initiation of treatment with a second ARSI might predict PSA response more accurately than that before diagnosis of nmCRPC.\u003c/p\u003e \u003cp\u003eThe primary aim of the present study was to investigate cross-resistance among novel ARSIs in patients with nmCRPC. The secondary aims were to determine the safety of treatment with the first and second ARSIs administered, changes in PSADT from diagnosis of nmCRPC to initiation of treatment with a second ARSI, and predictors of PSA non-responsiveness to treatment with a second ARSI.\u003c/p\u003e"},{"header":"Patients and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eEthics statement\u003c/h2\u003e \u003cp\u003e The current study was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the ethics committees of the Hirosaki University Graduate School of Medicine (Authorization Number: 2019-099-2 and 2021-158-1) and all hospitals included in this study. Written informed consent was not obtained because of the public disclosure of study information (opt-out approach).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003ePatient selection\u003c/h3\u003e\n\u003cp\u003e In this multicenter retrospective study, we assessed data of 325 consecutive patients with nmCRPC treated between June 2001 and January 2025 at the 12 participating hospitals. Of the 325 patients, 232 received novel ARSIs, including abiraterone acetate, enzalutamide, apalutamide, and darolutamide, in any line of nmCRPC treatment. Of the 232 patients, 97 were subsequently treated with a second ARSI before progression to mCRPC. We excluded three patients for whom information on the efficacy of treatment with a second ARSI was missing, and 19 patients who had discontinued treatment with the first ARSI because of adverse events (AEs) or other reasons in the absence of evidence of disease progression. Ultimately, 75 patients were included in this study (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). nmCRPC was defined as PSA\u0026thinsp;\u0026gt;\u0026thinsp;1 ng/mL, castrate testosterone concentrations\u0026thinsp;\u0026lt;\u0026thinsp;50 ng/dL, and the absence of metastatic lesions on conventional imaging (computed tomography or bone scintigraphy) [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003eEvaluation of variables\u003c/h3\u003e\n\u003cp\u003eThe following variables were analyzed: age and Eastern Cooperative Oncology Group performance status at time of initiation of treatment with a second ARSI, PSA concentrations at initial diagnosis and initiation of treatment with a second ARSI, biopsy Gleason score, history of radical treatment, clinical node stage at diagnosis of nmCRPC, and PSADT. The Sloan Kettering method was used to calculate PSADT: this requires at least three PSA concentrations of 0.2 ng/mL or greater taken at least 1 month apart within 12 months before the diagnosis of nmCRPC [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] and before the initiation of treatment with a second ARSI. AEs associated with novel ARSI treatment were evaluated using the Common Terminology Criteria for Adverse Events version 5.0.\u003c/p\u003e\n\u003ch3\u003eTreatment\u003c/h3\u003e\n\u003cp\u003eAll patients included in this study had undergone ADT, including bilateral orchiectomy and luteinizing hormone-releasing hormone agonists or antagonists, throughout their PC treatment. The specific novel ARSIs for treatment of nmCRPC were selected at the clinician\u0026rsquo;s discretion.\u003c/p\u003e\n\u003ch3\u003eOutcomes\u003c/h3\u003e\n\u003cp\u003eThe primary endpoint was cross-resistance among novel ARSIs. Because there is no robust definition of cross-resistance, the rates of any PSA response, PSA decline\u0026thinsp;\u0026ge;\u0026thinsp;50%, and PSA decline\u0026thinsp;\u0026ge;\u0026thinsp;90% were compared between the first and second ARSIs administered.\u003c/p\u003e \u003cp\u003eThe secondary endpoints were the safety of treatment with the first and second ARSIs administered, changes in PSADT from diagnosis of nmCRPC to initiation of treatment with a second ARSI, and identification of predictors of PSA non-responsiveness to treatment with a second ARSI.\u003c/p\u003e \u003cdiv id=\"Sec8\" 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 the statistical analyses. Quantitative variables are expressed as medians with interquartile ranges. Differences in quantitative variables between the two groups were analyzed using the Mann\u0026ndash;Whitney U test. Categorical variables were compared using Fisher\u0026rsquo;s exact test or the χ\u003csup\u003e2\u003c/sup\u003e test. Correlations between variables were analyzed using Spearman\u0026rsquo;s rank correlation coefficients. The changes in PSADT from diagnosis of nmCRPC to initiation of treatment with a second ARSI were analyzed using the paired \u003cem\u003et\u003c/em\u003e-test. The optimal PSADT cutoff value for no PSA response to treatment with a second ARSI was calculated using a receiver operating characteristic curve. Univariable and multivariable logistic regression analyses were performed to identify factors that were significantly associated with PSA non-responsiveness to treatment with a second ARSI. 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=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u0026rsquo; characteristics\u003c/h2\u003e \u003cp\u003eThe median age at initiation of treatment with a second ARSI was 79 years. The median PSADT before diagnosis of nmCRPC was 3.6 months. Almost all patients had a PSADT\u0026thinsp;\u0026lt;\u0026thinsp;10 months (n\u0026thinsp;=\u0026thinsp;68, 93%), 56 (83%) of them having a particularly rapid PSADT (\u0026lt;\u0026thinsp;6 months). Of the 75 patients, 36 had received docetaxel and/or vintage hormone therapy, such as bicalutamide, flutamide, estramustine phosphate, or ethinylestradiol, for treatment of nmCRPC prior to treatment with a first ARSI; the median number of such treatments was 1.0 (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e summarizes the patients\u0026rsquo; characteristics.\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; characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll, n\u0026thinsp;=\u0026thinsp;75\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\u003e79 (73\u0026ndash;83)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePerformance status\u0026thinsp;\u0026ge;\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27 (36%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSA at initial diagnosis, ng/mL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28 (11\u0026ndash;77)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSA at initiation of second ARSI treatment, ng/mL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.7 (1.8\u0026ndash;9.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBiopsy Gleason score\u0026thinsp;\u0026ge;\u0026thinsp;9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35 (47%)\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 \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\u003e7 (9.3%)\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\u003e15 (20%)\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\u003e41 (55%)\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\u003e27 (36%)\u003c/p\u003e \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\u003e14 (19%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical N stage at diagnosis of nmCRPC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\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\u003e11 (15%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTherapy prior to first ARSI treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e39 (52%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDocetaxel\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (5.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVintage hormone therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34 (45%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of therapies prior to first ARSI treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21 (28%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (15%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge; 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (5.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSADT before diagnosis of nmCRPC, months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.6 (2.5\u0026ndash;5.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSADT before initiation of second ARSI treatment, months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.3 (2.2\u0026ndash;6.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\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 \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eSequential therapy of novel ARSIs\u003c/h2\u003e \u003cp\u003eThe ARSI most frequently used first was enzalutamide (n\u0026thinsp;=\u0026thinsp;30, 40%), followed by darolutamide (n\u0026thinsp;=\u0026thinsp;24, 32%), abiraterone acetate (n\u0026thinsp;=\u0026thinsp;13, 17%), and apalutamide (n\u0026thinsp;=\u0026thinsp;8, 11%). The ARSI most frequently used second was abiraterone acetate (n\u0026thinsp;=\u0026thinsp;22, 29%), followed by enzalutamide (n\u0026thinsp;=\u0026thinsp;21, 28%), apalutamide (n\u0026thinsp;=\u0026thinsp;17, 23%), and darolutamide (n\u0026thinsp;=\u0026thinsp;15, 20%) (Fig. \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003ePrimary endpoint\u003c/h2\u003e \u003cp\u003eAfter exclusion of 15 patients who were still receiving treatment with a second ARSI at the time of analysis, the median duration of treatment with a second ARSI was significantly shorter than that of treatment with the first ARSI (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003ea; 5.5 vs. 13 months, respectively, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Waterfall plots of changes in PSA 3 months after initiation of treatment with the first and second ARSIs in all patients are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003eb and c, respectively. Significantly fewer patients achieved any PSA response to treatment with their second ARSI than to treatment with their first ARSI (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003ed; 45% vs. 88%, respectively, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The rates of PSA decline\u0026thinsp;\u0026ge;\u0026thinsp;50% and \u0026ge;\u0026thinsp;90% during treatment with a second ARSI were significantly lower than those during treatment with the first ARSI (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003ee and f; 9.3% vs. 71%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; 2.7% vs. 33%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; respectively).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eSecondary endpoints\u003c/h2\u003e \u003cp\u003eThe rates of any grade AEs associated with novel ARSI treatment did not differ significantly between treatment with the first and second ARSIs (32% vs. 20%, respectively, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.094). Similarly, the rates of grade\u0026thinsp;\u0026ge;\u0026thinsp;3 AEs did not differ significantly between treatment with the first and second ARSIs (1.3% vs. 1.3%, respectively, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.000).\u003c/p\u003e \u003cp\u003eThe PSADT before diagnosis of nmCRPC was significantly and positively correlated with that before initiation of treatment with a second ARSI (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e3\u003c/span\u003ea; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001). The PSADT did not differ significantly between before diagnosis of nmCRPC and initiation of treatment with a second ARSI (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e3\u003c/span\u003eb; median 3.6 vs. 4.3 months, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.499). Of the 75 patients, 31 (41%) evidenced some degree of shortening of PSADT during treatment with the first ARSI. The median change in PSADT from diagnosis of nmCRPC to initiation of treatment with a second ARSI was 0.6 months (interquartile range [IQR]: -1.9\u0026ndash;2.5 months); this difference is not significant (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e3\u003c/span\u003ec; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.542).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe optimal cutoff values of PSADT before diagnosis of nmCRPC and before initiation of treatment with a second ARSI were 2.8 and 6.6 months, respectively. According to univariable analyses, PSADT before diagnosis of nmCRPC was not significantly associated with PSA non-responsiveness to treatment with a second ARSI, as was true of other well-known prognostic factors, whereas PSADT before initiation of treatment with a second ARSI was significantly associated with PSA non-responsiveness to treatment with that second ARSI (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). According to multivariable analysis, only PSADT before initiation of treatment with a second ARSI was significantly and independently associated with PSA non-responsiveness to treatment with that second ARSI (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\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\u003eResults of univariable analyses for PSA non-responsiveness to second ARSI therapy\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=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" 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\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\u003eOdds 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=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.876\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.995\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.937\u0026ndash;1.057\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePerformance status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.773\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.870\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.337\u0026ndash;2.247\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSA at initial diagnosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eContinuous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.091\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.993\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.986\u0026ndash;1.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSA at initiation of second ARSI treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eContinuous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.955\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.900\u0026ndash;1.013\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBiopsy Gleason score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.362\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.635\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.240\u0026ndash;1.685\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical N stage at diagnosis of nmCRPC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ecN1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.210\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.429\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.114\u0026ndash;1.614\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTherapy prior to first ARSI treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.752\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.864\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.348\u0026ndash;2.146\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSADT before diagnosis of nmCRPC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;2.8 month\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.607\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.307\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.472\u0026ndash;3.619\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSADT before initiation of second ARSI treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;6.7 month\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.039\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.128\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.062\u0026ndash;9.211\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eARSI, androgen receptor signaling inhibitor; CI, confidence interval; 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\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eResults of multivariable analysis for PSA non-responsiveness to second ARSI therapy\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=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" 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\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\u003eOdds 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\u003ePSA at initiation of second ARSI treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eContinuous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.325\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.983\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.950\u0026ndash;1.017\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBiopsy Gleason score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.405\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.645\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.229\u0026ndash;1.813\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSADT before initiation of second ARSI treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;6.6 month\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.047\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.169\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.016\u0026ndash;9.888\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eARSI, androgen receptor signaling inhibitor; CI, confidence interval; 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 \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo the best of our knowledge, the present study is the first to evaluate cross-resistance among ARSIs in patients with nmCRPC. Our results suggest that the efficacy of second ARSIs is significantly poorer than that of first ARSIs, indicating significant cross-resistance among ARSIs. Moreover, a shorter PSADT before diagnosis of nmCRPC was not associated with efficacy of the second ARSI administered, whereas a shorter PSADT before initiation of treatment with the second ARSI was significantly associated with poorer efficacy of the second ARSI, suggesting that evaluation of disease aggressiveness before initiation of treatment with a second ARSI is important in predicting a response to treatment with a second ARSI.\u003c/p\u003e \u003cp\u003eIn the present study, we identified significant cross-resistance among ARSIs in patients with nmCRPC. Although there are no available data concerning cross-resistance in the nmCRPC setting, the findings of several previous studies that have evaluated cross-resistance between abiraterone acetate and enzalutamide in a mCRPC setting support our findings [\u003cspan additionalcitationids=\"CR13 CR14\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. However, the underlying mechanisms are complicated and not fully understood. Although the chemical structures of abiraterone acetate and darolutamide differ from those of apalutamide and enzalutamide [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], these ARSIs share the same resistance mechanisms [\u003cspan additionalcitationids=\"CR24\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]: androgen receptor (AR)-dependent mechanisms (e.g., AR gene mutations and amplifications, alteration of pathways involved in crosstalk with AR signaling, systemic and intratumoral androgen biosynthesis up-regulation, and splice variants such as AR-variant 7), and AR-independent mechanisms (e.g., immune system deregulation, glucocorticoid receptor overexpression, and neuroendocrine transformation) [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Thus, failure after treatment with a first ARSI may also be followed by failure of treatment with a second ARSI. As for nmCRPC, some of the aforementioned mechanisms have also been reported [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], supporting the results of the present study. Docetaxel may serve as an alternative for patients whose disease progresses after ARSI treatment [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]; however, there is no published evidence for this in the nmCRPC setting. Thus, further study is needed to establish the optimal treatment sequence in patients with nmCRPC.\u003c/p\u003e \u003cp\u003eAlthough the issue of cross-resistance among ARSIs has emerged as a major concern, the predictors of efficacy of treatment with a second ARSI have not yet been identified. In the current study, we found that the PSADT did not change significantly from diagnosis of nmCRPC to initiation of treatment with a second ARSI (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e3\u003c/span\u003ec). However, in 41% of patients, the PSADT was shortened to some degree during treatment with a first ARSI. Additionally, the PSADT before diagnosis of nmCRPC was not associated with the efficacy of treatment with a second ARSI, whereas the PSADT before initiation of treatment with a second ARSI was significantly associated with the efficacy of that second ARSI. Up to now, data on biomarkers that predict responses to ARSIs have been limited. It has been proposed that the AR-variant 7 predicts poor responses to ARSIs [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Moreover, a whole-genomics and whole-transcriptomics study in ARSI-treated patients with mCRPC has demonstrated that tumor mutational burden, structural variants, tandem duplications, and deletions are enriched in poor responders to ARSI therapy [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Thus, these genetic changes may be promising biomarkers for ARSI responsiveness; however, the associated cost and facility restrictions prohibit their use in clinical practice. By contrast, the PSADT is easy to calculate and less costly, potentially making the PSADT before initiation of treatment with a second ARSI a simple biomarker for cross-resistance among ARSIs.\u003c/p\u003e \u003cp\u003eThis study had several limitations. First, the patient cohort was relatively small. Second, its retrospective design precluded definitive conclusions because we were unable to control for selection bias and other unmeasured confounders. Finally, the cohort was too small to allow comparison of the safety and efficacy of individual ARSIs.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eWe have identified cross-resistance among ARSIs in patients with nmCRPC. The PSADT before initiation of treatment with a second ARSI may be useful for predicting the efficacy of that second ARSI.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eConflicts of interest disclosure\u003c/h2\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. None of the other authors have any conflicts of interest to declare.\u003c/p\u003e\n\u003ch2\u003eEthics approval\u003c/h2\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\u003ch2\u003eAuthors\u0026rsquo; contribution\u003c/h2\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\n\u003ch2\u003eAcknowledgments\u003c/h2\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 Dr Trish Reynolds, MBBS, FRACP, from Edanz (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://jp.edanz.com/ac\u003c/span\u003e\u003c/span\u003e) for editing a draft of this manuscript.\u003c/p\u003e\n\u003ch2\u003eData Availability Statement\u003c/h2\u003e\n\u003cp\u003eThe 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.\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. 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Nat Commun 14:1968 \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41467-023-37647-x\u003c/span\u003e\u003cspan address=\"10.1038/s41467-023-37647-x\" 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":"cross-resistance, non-metastatic castration-resistant prostate cancer, novel androgen receptor signaling inhibitor, predictor, prostate-specific antigen response, sequential therapy","lastPublishedDoi":"10.21203/rs.3.rs-6935071/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6935071/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eSequential therapy with different novel androgen receptor signaling inhibitors (ARSIs) is a possible treatment option for patients who have increased prostate-specific antigen (PSA) levels. The aim of the present study was to investigate cross-resistance among ARSIs and its predictors in non-metastatic castration-resistant prostate cancer (nmCRPC).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eIn this multicenter retrospective study, we evaluated 75 patients with nmCRPC who had progressed after treatment with one ARSI and were subsequently treated with a second ARSI. The primary endpoint was cross-resistance among ARSIs, which was identified by comparing PSA responses to treatment with first and second ARSIs. The secondary endpoints were changes in PSA doubling time (PSADT) from diagnosis of nmCRPC to initiation of treatment with a second ARSI and predictors of PSA non-responsiveness to treatment with that second ARSI.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe rates of any PSA response, PSA decline\u0026thinsp;\u0026ge;\u0026thinsp;50%, and PSA decline\u0026thinsp;\u0026ge;\u0026thinsp;90% to treatment with a second ARSI were significantly lower than those to the first ARSI administered (45% vs. 88%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; 9.3% vs. 71%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; 2.7% vs. 33%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; respectively). The PSADT shortened to some degree in 31 patients (41%). According to multivariable analysis, only PSADT before initiation of treatment with a second ARSI was significantly associated with no PSA response to treatment with that second ARSI.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eWe identified significant cross-resistance among ARSIs in patients with nmCRPC. The PSADT before initiation of treatment with a second ARSI may be useful for predicting the efficacy of treatment with a second ARSI.\u003c/p\u003e","manuscriptTitle":"Cross-resistance among novel androgen receptor signaling inhibitors in non-metastatic castration-resistant prostate cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-04 05:36:21","doi":"10.21203/rs.3.rs-6935071/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revisions","date":"2025-07-16T02:49:30+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2025-07-01T08:11:17+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-07-01T07:22:05+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-21T07:18:22+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Journal of Clinical Oncology","date":"2025-06-20T00:08:50+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":"July 4th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-09-22T06:51:29+00:00","versionOfRecord":{"articleIdentity":"rs-6935071","link":"https://doi.org/10.1007/s10147-025-02881-4","journal":{"identity":"international-journal-of-clinical-oncology","isVorOnly":false,"title":"International Journal of Clinical Oncology"},"publishedOn":"2025-09-14 15:57:09","publishedOnDateReadable":"September 14th, 2025"},"versionCreatedAt":"2025-07-04 05:36:21","video":"","vorDoi":"10.1007/s10147-025-02881-4","vorDoiUrl":"https://doi.org/10.1007/s10147-025-02881-4","workflowStages":[]},"version":"v1","identity":"rs-6935071","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6935071","identity":"rs-6935071","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}