Triplet versus doublet therapy in patients with metastatic hormone-sensitive prostate cancer

Triplet versus doublet therapy in patients with metastatic hormone-sensitive 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 Article Triplet versus doublet therapy in patients with metastatic hormone-sensitive prostate cancer Keita Hayakawa, Takashi Ueda, Masahiro Iehara, Yusuke Gabata, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8360739/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 16 Mar, 2026 Read the published version in Scientific Reports → Version 1 posted 11 You are reading this latest preprint version Abstract Background First-line treatment options for patients with metastatic hormone-sensitive prostate cancer (HSPC) are divided into two groups: androgen receptor signaling inhibitor (ARSI)-based doublet therapy and triplet therapy (which includes chemotherapy in addition to doublet therapy). However, differences in therapeutic efficacy between the two groups remain unclear. The aim of the study was to perform a comparative analysis between the two groups and to identify predictors of treatment response. Methods We retrospectively recruited 500 patients with mHSPC treated with doublet or triplet therapy from our hospital and affiliated hospitals between 2013 and 2025. The cohort of patients with mHSPC treated with doublet therapy received ABI, ENZ, or APA in combination with a luteinizing hormone-releasing hormone analog, such as androgen deprivation therapy (ADT). The cohort of those treated with triplet therapy received darolutamide plus ADT and docetaxel. Cox logistic regression analysis was performed to identify prognostic factors of overall survival in patients with mHSPC. Propensity score matching was used to adjust the clinical background of patients. Results The outcome (prostate-specific antigen-progression-free survival, second progression-free survival, and overall survival (OS)) of triplet therapy was significantly better than that of doublet therapy in matched high-risk patients with mHSPC. Univariate and multivariate analyses of OS in matched patients with high-risk mHSPC treated with triplet or doublet therapy suggested that treatment choice (triplet or doublet), pretreatment LDH levels, and presence of Gleason pattern 5 influenced OS in patients with high-risk mHSPC. Subgroup analysis suggested that LDH levels and the presence of Gleason pattern 5 may be predictive factors of the treatment of patients with mHSPC. Conclusions Our results showed that triplet therapy achieved a better outcome than doublet therapy in patients with mHSPC. Biological sciences/Cancer Health sciences/Oncology docetaxel darolutamide abiraterone acetate apalutamide enzalutamide metastatic hormone-sensitive prostate cancer Figures Figure 1 Figure 2 Figure 3 Introduction A variety of treatment options are available for patients with metastatic hormone-sensitive prostate cancer (mHSPC). In the National Comprehensive Cancer Network (NCCN) guidelines, first-line treatment options for patients with mHSPC are divided into two groups: androgen receptor signaling inhibitor (ARSI)-based doublet therapy and triplet therapy (1). ARSI-based doublet therapy is a combined therapy of androgen deprivation therapy (ADT) and ARSI: abiraterone acetate plus prednisolone (ABI), enzalutamide (ENZ), and apalutamide (APA). The superiority of doublet therapy to ADT for patients with mHSPC has been demonstrated in a clinical study (2-4). In triplet therapy, patients with mHSPC are administered docetaxel, a cytotoxic chemotherapeutic agent, in addition to the drugs of doublet therapy. Although triplet therapy is presumed to be superior to doublet therapy from the amount of medication, the adverse events (AEs) of docetaxel should be considered. Although some reports of network meta-analysis have suggested that triplet therapy may be superior to doublet therapy in overall survival (OS) of patients with mHSPC, no direct comparison between triplet and doublet therapies has been reported (5-7). Several studies have reported the clinical parameters that affect the efficacy of treatment of patients with mHSPC (8, 9). We previously reported that the histological presence of Gleason pattern 5 (GS5) in the primary tumor may affect the efficacy of ARSI-based doublet therapy of patients with mHSPC. There are few reports on the clinical factors affecting the efficacy of triplet therapy in patients with mHSPC. Previously, we reported a prognostic model for patients with mHSPC treated with ABI using clinical factors including lactate dehydrogenase (LDH) and primary GS5 (10, 11). The purpose of this study was to compare the treatment outcome (prostate-specific antigen-progression-free survival (PSA-PFS), second progression-free survival (PSF2), and OS) between patients treated with triplet and those treated with ARSI-based doublet therapy and to identify the clinical parameters affecting their efficacy. Material and Methods Patients and treatments We retrospectively recruited 500 patients with mHSPC treated with doublet or triplet therapy from our hospital and affiliated hospitals between December 2013 and August 2025. The cohort of patients with mHSPC treated with doublet therapy received ABI (1000 mg/day) plus prednisolone (5 mg/day) or ENZ (160 mg/day) or APA (240 mg/day) in combination with a luteinizing hormone-releasing hormone analog such as ADT. The cohort of those treated with triplet therapy received darolutamide (1200 mg/day) plus ADT and docetaxel (75 mg/m 2 every 3 weeks for six cycles). Bone metastasis was assessed by bone scintigraphy. Visceral and lymph node metastases were assessed by computed tomography (CT). High-risk mHSPC was defined according to the LATITUDE risk stratification (patients with mHSPC and at least two of the following factors: Gleason score (GS) at the primary lesion ≥8, ≥3 in bone lesions, or presence of visceral metastasis). Drug selection and dose adjustments were made at the physicians' discretion. Cutoffs of PSA and LDH were defined as 4.0 ng/mL and 220 IU/L, respectively. We obtained approval for this study from the Institutional Review Board (IRB) of Kyoto Prefectural University of Medicine. This study complied with the Declaration of Helsinki. The requirement for written informed consent was waived, considering the retrospective nature of the study. Opt-out information was provided to the patients on the website of our hospital and affiliated hospitals. Statistical Analysis Chi‐square and Wilcoxon rank‐sum tests were used to compare the two groups. Kaplan–Meier analysis, along with the log‐rank test, was employed to estimate the differences in time events between the two groups. Cox proportional hazards models were used to investigate factors associated with PFS. Propensity score matching was used to adjust for clinical background differences between groups. Age at diagnosis in years, performance status, pretreatment PSA and LDH levels, Gleason pattern 5, presence of bone, visceral, and lymph node metastasis, and observation period were used in the propensity score matching. We used SAS JMP, Version 17, for all statistical analyses with a significance threshold set at P < 0.05. Results Clinical characteristics of patients with mHSPC treated with doublet and triplet therapy The clinical characteristics of the overall cohort in this study are shown in Table 1. A total of 424 patients with mHSPC were treated with doublet therapy (doublet cohort) (180 patients with ABI, 113 patients with APA, and 131 patients with ENZ), and 76 patients with mHSPC were treated with triplet therapy (triplet cohort). The observation period of the triplet cohort was significantly shorter than that of the doublet cohort (P < 0.0001). The average age of the triplet cohort was significantly higher than that of the doublet cohort (P < 0.0001). Detailed data on sequential therapy following PSA progression are provided in Supplementary Table S1. AEs and PSA kinetics of doublet and triplet therapies for patients with mHSPC AEs occurred in patients with mHSPC treated with doublet and triplet therapies are shown in Supplementary Table S2. Each AE in patients was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5. The details of AEs for each treatment are shown in Supplementary Table S3. In the triplet therapy group, 67 of 76 patients (88.2%) experienced some form of AE, whereas in the doublet therapy group, 70 of 424 patients (16.5%) had AEs. In the triplet therapy group, grade 3 or grade 4 neutropenia was observed in 45 patients, and febrile neutropenia was observed in 20 patients. Forty patients were able to complete all six cycles of docetaxel. Although both doublet and triplet therapies achieved a reduction of ≥90% from baseline PSA levels (≥90% PSA decline; Supplementary Table S4),grade 3 or higher AEs were more frequent in 50 patients in the triplet therapy group (50 patients: 65.8%) than in the doublet therapy group (16 patients: 3.8%). Comparison of outcome (PSA-PFS, PSF2, and OS) in matched patients with high-risk mHSPC treated with doublet and triplet therapies Although ABI is indicated only for patients with high-risk mHSPC, triplet and other doublet (APA or ENZ) therapy is indicated for all patients with mHSPC regardless of LATTITUDE risk stratification. We extracted patients with high-risk mHSPC from the overall cohort to compare the outcome between triplet and doublet therapies under the same conditions. Propensity score matching was used to adjust the difference in backgrounds between the triplet and doublet cohorts (Supplementary Table S5). The outcome (PSA-PFS, PFS2, and OS) of triplet therapy was significantly better than that of doublet therapy in matched patients with high-risk mHSPC (Figure 1). Univariate and multivariate analyses of OS and PSA-PFS in matched patients with high-risk mHSPC treated with triplet or doublet therapy suggested that treatment choice (triplet or doublet), presence of Gleason pattern 5, and pretreatment LDH levels might influence OS in patients with high-risk mHSPC (Table 2). Comparison of outcome (PSA-PFS, PSF2, and OS) in matched patients with mHSPC treated with doublet (ENZ or APA) and triplet therapy Previously, we suggested that ENZ and APA may be superior to ABI in the treatment outcome of patients with mHSPC, especially with Gleason pattern 5 at the primary site (11). Next, we compared the outcome of triplet therapy with that of doublet therapy, except for ABI in patients with mHSPC. We adjusted the difference in background, including LATTITUDE risk stratification between triplet therapy and the ENZ or APA cohort (Supplementary Table S6). Although PSA-PFS of patients with mHSPC treated with triplet therapy was significantly longer than that of those treated with APA or ENZ, no significant difference was observed in PSF2 or OS between the two groups (Figure 2). Subgroup analysis of patients with mHSPC treated with doublet or triplet therapy based on LDH levels From the results above, we hypothesized that pretreatment LDH levels and the presence of Gleason pattern 5 at the primary site may be clinical parameters affecting the efficacy of doublet or triplet therapy in patients with mHSPC. To confirm the hypothesis, we performed subgroup analysis by dividing the two groups according to pretreatment LDH levels and the presence of Gleason pattern 5. Although PSA-PFS and OS of patients with mHSPC treated with triplet therapy were significantly longer than those treated with doublet therapy in the subgroup with high LDH levels (>220 IU/L), no significant difference was observed between triplet and doublet therapies in the subgroup with low LDH levels (≦220 IU/L) (Figure 3). In addition, PSA-PFS and OS of patients with mHSPC treated with triplet therapy were significantly longer than those treated with doublet therapy in the subgroup with the presence of Gleason pattern 5 (Supplementary Figure S1). These results suggested that triplet therapy may be superior to doublet therapy in the outcome of mHSPC with Gleason pattern 5 or high LDH levels. Discussion The ARASENS trial demonstrated the superiority in treatment outcome of patients with mHSPC treated with darolutamide-based triplet therapy to those treated with placebo and docetaxel (12). However, the efficacy of adding docetaxel to ARSI-based doublet therapy remains unclear. In the present study, we retrospectively compared the outcome (PSA-PFS, PSF2, and OS) between patients with mHSPC treated with ARSI-based doublet therapy (ABI, APA, and ENZ) and those treated with triplet therapy. We found that the outcome of patients with mHSPC treated with triplet therapy was significantly better than those treated with ARSI-based doublet therapy. Although PSA-PFS and OS of patients with mHSPC treated with triplet therapy were significantly longer than of those treated with doublet therapy in the subgroup with high LDH levels (>220 IU/L), no significant difference was observed between triplet and doublet therapies in the subgroup with low LDH levels (≦220 IU/L). The same results were also observed when classified according to the presence of Gleason pattern 5. These results suggested that triplet therapy may achieve better outcomes than ARSI-based doublet therapy in patients with mHSPC and high LDH levels or Gleason pattern 5. Although triplet therapy achieved a high PSA responsive rate (67%) , it also caused a high incidence rate of AEs (AE >G3: 70.5%) in the ARASENS trial (13). The most common AEs in triplet therapy were neutropenia in the ARASENS trial. The recovery time of patients with mHSPC treated with triplet therapy was significantly prolonged in patients aged over 79 (14). As expected, the incidence rate of AEs (>G3) in patients with mHSPC treated with triplet therapy was significantly higher than in those treated with doublet therapy in the present study. To tailor individual treatment strategies for patients with mHSPC in clinical practice, both the outcome and AEs of triplet therapy should be considered. Older patients with mHSPC (≧80 years old) with low LDH levels (≦220 IU/L) or without Gleason pattern 5 may be suitable for doublet therapy. In Japanese health insurance treatments, triplet therapy for patients with mHSPC means a darolutamide-based regimen, and doublet therapy corresponds to an ABI, APA, or ENZ-based regimen. In several countries other than Japan, other ARSIs (ABI, APA, and ENZ) than darolutamide can be administered to patients with mHSPC as triplet therapy, and darolutamide can be administered as doublet therapy. Previous network meta-analysis suggested that the darolutamide-based triplet showed the best outcomes in terms of OS (15). The differences in response to ARSIs may result from race, as Japanese patients with mHSPC show better response to bicalutamide than other races (16). The efficacy of these ARSIs in doublet and triplet therapies for Japanese patients with mHSPC should be compared in future studies. Our study suggested that high LDH levels (>220 IU/L) or the presence of Gleason pattern 5 in patients with mHSPC was associated with resistance to ARSI-based doublet therapy. A higher level of LDH is associated with poorer outcomes in patients with mHSPC (17) (9). LDH plays a role in tumor proliferation, invasion, and metastasis in colorectal cancers (18). An immunohistochemical study suggested that LDH overexpression may be associated with poor differentiation. High LDH levels (>220 IU/L) in patients with mHSPC may be associated with poor differentiation of prostate cancer, which is resistant to androgen blockade therapy, including ARSI-based doublet therapy. Untreated prostate cancer contains a mix of androgen receptor (AR)-dependent and AR-independent cells (19, 20), which forms the rationale for triplet therapy using drugs with different mechanisms of action. In prostate cancers that include Gleason pattern 5, many adverse prognostic gene mutations are present (21), and a high number of cells resistant to hormonal therapy exist. This is believed to underline the results observed in the present study. This study has several limitations. Because it was a retrospective study with a small cohort, selection and confounding biases may be present. A prospective study with a larger cohort is needed to exclude these biases. Furthermore, the observation period was very short, especially in patients with mHSPC treated with triplet therapy. We plan to perform a study with a longer observation period. In conclusion, triplet therapy achieved better outcomes (PSA-PFS, PSF2, and OS) than doublet therapy in patients with mHSPC with high LDH levels (>220 IU/L) or Gleason pattern 5. These results could be useful in clinical practice for treating patients with mHSPC. Declarations Data availability statement The datasets used and analyzed during this study are available from the corresponding author upon reasonable request. Funding statement The authors did not receive any financial support for the work presented in this manuscript. Co nflict of interest The authors have no actual or potential conflicts of interest to declare. Osamu Ukimura received honoraria from Jansen Pharmaceutical and AstraZeneca. Ethics approval statement This study was approved by the Institutional Review Boards of Kyoto Prefectural University of Medicine (ERB-C-1071-2). The study was conducted in accordance with the principles of the Declaration of Helsinki. Patient consent statement The requirement for written informed consent was waived owing to the retrospective nature of this study. Patients were provided with opt-out information on the website. Permission to reproduce material from other sources Not applicable. Clinical trial registration Not applicable. Acknowledgements This study is based on the results from our hospital and its affiliated hospitals. We express our gratitude to the urologists from affiliated hospitals who contributed to this study: Hiroaki Miyashita, So Ushijima, Yuki Harada, Ryosuke Tamai, and Takenori Miyamoto, Department of Urology, Omihachiman Community Medical Center; Jintetsu So, Takeshi Yamada, Ryota Ogura, Yuya Minato, and Tsubasa Mitsuoka, Department of Urology, Japanese Red Cross Daini Hospital; Hiroki Matsubara and Mineyuki Kato, Department of Urology, Kyoto Yamashiro General Medical Center; Yasuhiro Yamada, Shunsuke Hotta, and Yutaro Oda, Department of Urology, Kyoto Okamoto Memorial Hospital; Naruhiro Kayukawa and Yuta Inoue, Department of Urology, Kyoto Kuramaguchi Medical Center; Tsuyoshi Iwata, Hirokazu Ishida, and Madoka Miyamoto, Department of Urology, Kyoto Min-Iren Chuo Hospital; Kazuya Mikami, Nobukazu Onishi, Yuki Ota, Yuji Okusa, Mai Ujihara, and Yuta Asakawa, Department of Urology, Japanese Red Cross Daiichi Hospital; Jun Ajiki, Department of Urology, Maizuru Medical Center; Eiji Taniguchi and Yuji Okusa, Department of Urology, North Medical Center Kyoto Prefectural University of Medicine; Kimihiro Yano, Department of Urology, Uji Takeda Hospital; Shunji Harikai, and Yoshiyuki Ida, Department of Urology, Fujinomiya City General Hospital; Terukazu Nakamura, Akihisa Ueno, Kotaro Iwamoto, Ryo Nishigaki, and Takaaki Dezao, Department of Urology, Saiseikai Suita Hospital; Yusuke Gabata, Department of Urology, Aiseikai Yamashina Hospital; Motohiro Kanazawa, Toshiya Takamura, and Koto Kojima, Department of Urology, Kyoto Chubu Medical Center; Shuichi Tahara, Kai Inoue, and Hisaya Tajima, Department of Urology, Ayabe City Hospital; Mitsuhiko Inaba, and Satoshi Sako, Department of Urology, Kyoto Saiseikai Hospital; Kei Suzuki, Masahiro Iehara, and Suhei Ito, Department of Urology, Fukuchiyama City Hospital; Takeshi Nomoto, and Yuya Yagi, Department of Urology, Maizuru Kyosai Hospital; Munehiro Ohashi, and Asa Okamoto, Department of Urology, Kyoto Tanabe Central Hospital; and Teruki Shimizu, Keisuke Tsuji, and Haruki Kishida, Department of Urology, Matsushita Memorial Hospital. We would like to thank Editage (www.editage.com) for English language editing References NCCN Guidelines Version 2. (2026). Fizazi, K. et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. N Engl. J. Med. 377 (4), 352–360 (2017). Davis, I. D. et al. Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. N Engl. J. Med. 381 (2), 121–131 (2019). Chi, K. N. et al. Apalutamide in Patients With Metastatic Castration-Sensitive Prostate Cancer: Final Survival Analysis of the Randomized, Double-Blind, Phase III TITAN Study. J. Clin. Oncol. 39 (20), 2294–2303 (2021). Riaz, I. B. et al. First-line Systemic Treatment Options for Metastatic Castration-Sensitive Prostate Cancer: A Living Systematic Review and Network Meta-analysis. JAMA Oncol. 9 (5), 635–645 (2023). Wang, S. S. et al. Network meta-analysis of combination strategies in metastatic hormone-sensitive prostate cancer. Asian J. Androl. 26 (4), 402–408 (2024). Hoeh, B. et al. Triplet or Doublet Therapy in Metastatic Hormone-sensitive Prostate Cancer Patients: An Updated Network Meta-analysis Including ARANOTE Data. Eur. Urol. Focus . 11 (2), 386–390 (2025). Lowentritt, B. et al. Comparison of prostate-specific antigen response in patients with metastatic castration-sensitive prostate cancer initiated on apalutamide or abiraterone acetate: A retrospective cohort study. Urol. Oncol. 41 (5), 252 (2023). e19- e27. Narita, S. et al. Prognostic model for second progression-free survival and overall survival in patients with high-risk metastatic hormone-sensitive prostate cancer treated with abiraterone acetate and androgen deprivation therapy. Prostate 85 (1), 73–81 (2025). Ueda, T. et al. Predictive factors for the efficacy of abiraterone acetate therapy in high-risk metastatic hormone-sensitive prostate cancer patients. World J. Urol. 40 (12), 2939–2946 (2022). Ueda, T. et al. Screening for Predictive Factors of Efficacy of Second-Generation Androgen Receptor Axis-Targeted Agents in Patients With High-Risk Metastatic Hormone-Sensitive Prostate Cancer. Prostate 85 (6), 524–530 (2025). Smith, M. R. et al. Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer. N Engl. J. Med. 386 (12), 1132–1142 (2022). Saad, F. et al. Deep Prostate-specific Antigen Response following Addition of Apalutamide to Ongoing Androgen Deprivation Therapy and Long-term Clinical Benefit in SPARTAN. Eur. Urol. 81 (2), 184–192 (2022). Usui, K. et al. Short-term outcomes of triplet therapy in metastatic hormone-sensitive prostate cancer in older adults: a retrospective, single-center real-world cohort study. Int. Urol. Nephrol. (2025). Jian, T. et al. Systemic triplet therapy for metastatic hormone-sensitive prostate cancer: A systematic review and network meta-analysis. Front. Pharmacol. 13 , 955925 (2022). Shiota, M. et al. Association of Missense Polymorphism in HSD3B1 With Outcomes Among Men With Prostate Cancer Treated With Androgen-Deprivation Therapy or Abiraterone. JAMA Netw. Open. 2 (2), e190115 (2019). Li, F. et al. Association between lactate dehydrogenase levels and oncologic outcomes in metastatic prostate cancer: A meta-analysis. Cancer Med. 9 (19), 7341–7351 (2020). Koukourakis, M. I., Giatromanolaki, A., Sivridis, E., Gatter, K. C. & Harris, A. L. Tumour Angiogenesis Research G. Lactate dehydrogenase 5 expression in operable colorectal cancer: strong association with survival and activated vascular endothelial growth factor pathway–a report of the Tumour Angiogenesis Research Group. J. Clin. Oncol. 24 (26), 4301–4308 (2006). Cabanos, H. F. & Hata, A. N. Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer. Cancers (Basel) ; 13 (11). (2021). Graf, R. P. et al. Predictive Genomic Biomarkers of Hormonal Therapy Versus Chemotherapy Benefit in Metastatic Castration-resistant Prostate Cancer. Eur. Urol. 81 (1), 37–47 (2022). Velho, P. I. et al. Molecular Characterization and Clinical Outcomes of Primary Gleason Pattern 5 Prostate Cancer After Radical Prostatectomy. JCO Precis Oncol. ; 3 . (2019). Tables Table 1 Characteristics of the entire cohort. Hormone therapy Triplet (n = 76) Doublet (n = 424) p-Value (Triplet vs. Doublet) ABI (n = 180) APA (n = 113) ENZ (n = 131) Median age at diagnosis years (range) 72 (49–87) 74 (53–94) 77 (56–93) 76 (54–89) < 0.0001 Performance status (ECOG) ≧ 1, n (%) 13 (17.3) 54 (30.9) 32 (28.8) 47 (59.4) 0.0082 Median pretreatment PSA level (ng/mL) 195(0.76–12978) 436 (2.324–24201) 109.508 (0.307–8756) 112.4 (2.58–8413) 0.0451 Median pretreatment LDH (U/L) 195 (100–3456) 198 (39.3–2405) 189 (90–441) 191.5 (14.5–874) 0.0371 Gleason pattern 5, n (%) 49 (64.4) 122 (68.9) 63 (55.7) 71 (54.1) 0.3776 High risk of LATITUDE criteria, n (%) 63 (82.9) 172 (96.1) 68 (60.2) 67 (51.5) 0.0393 Presence of bone metastasis, n (%) 65 (85.5) 165 (92.1) 96 (84.9) 111 (84.7) 0.5636 Presence of visceral metastasis, n (%) 16 (21.0) 50 (27.9) 25 (22.3) 22 (16.9) 0.7015 Presence of lymph node metastasis, n (%) 52 (69.3) 141 (78.7) 69 (61.0) 82 (62.5) 0.8475 Median observation period month (range) 9 (3–28) 34 (3–82) 21 (3–60) 18.5 (3–57) < 0.0001 Table 2 Univariate and multivariate analyses for overall survival in matched patients with high-risk mHSPC. Univariate analysis Multivariable analysis HR (95% CI) p-value HR (95% CI) p-value Triplet or doublet 13.7 (1.79–104) 0.012 12.1 (1.55–95.1) 0.018 Performance status (ECOG) 14.3 (1.55–87.2) 0.0073 - - Pretreatment PSA level 1.26 (0.063–10.1) 0.8540 - - Presence of GS5 - 0.017 - 0.037 Pretreatment LDH 2987 (40.78-828657) 0.0023 142 (2.85–15279) 0.013 Presence of bone metastasis - 0.9993 - - Presence of visceral metastasis 0.80 (0.22–2.88) 0.73 - - Presence of lymph node metastasis 0.99 (0.31–3.17) 0.99 - - Additional Declarations No competing interests reported. Supplementary Files supportinginformation.docx Supporting Information Supplementary Figure S1. Kaplan–Meier estimates of PSA progression-free survival and overall survival in matched patients with high-risk mHSPC and GS5 (left) and without GS5 (right). Supplementary Table S1. Sequential therapy following PSA progression. Supplementary Table S2. Adverse events occurring in patients with mHSPC. Supplementary Table S3. Adverse events in each treatment group. Supplementary Table S4. PSA kinetics in patients with mHSPC. Supplementary Table S5.Characteristics of matched patients with high-risk mHSPC (triplet vs. doublet). Supplementary Table S6. Characteristics of matched patients with mHSPC (triplet vs. APA or ENZ). Cite Share Download PDF Status: Published Journal Publication published 16 Mar, 2026 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 29 Jan, 2026 Reviews received at journal 26 Jan, 2026 Reviewers agreed at journal 18 Jan, 2026 Reviewers agreed at journal 18 Jan, 2026 Reviews received at journal 12 Jan, 2026 Reviewers agreed at journal 11 Jan, 2026 Reviewers invited by journal 08 Jan, 2026 Editor invited by journal 17 Dec, 2025 Editor assigned by journal 15 Dec, 2025 Submission checks completed at journal 15 Dec, 2025 First submitted to journal 14 Dec, 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-8360739","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":572720384,"identity":"e97eba26-b1f7-49cc-ba19-35829127884a","order_by":0,"name":"Keita Hayakawa","email":"","orcid":"","institution":"Kyoto Prefectural University of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Keita","middleName":"","lastName":"Hayakawa","suffix":""},{"id":572720386,"identity":"0334517a-8611-4511-9422-747a989984f2","order_by":1,"name":"Takashi Ueda","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7ElEQVRIiWNgGAWjYLACHgYbAxDN2IAkhEc1mEgzYGAjUcthdC14gD0Dj+GDNzXnjfnlmw8wztxxmEG3gfnhBwaZO3hs4TE2nHPstplkG1sC48YzhxnMDrAZSzDwPMOtRf6NmTQP220bg2M8BowP2w7XbzvAYAYUP4zPFvPfPP/OwbUAbWH/RkiLGTNv2wEzsJaNYC08BGw5wFYsObcv2ViyLS3h4Mwz6Qxmh3mKJRLw+IW9gXnjhzff7Az7mQ8ffNi7w5rB7Hj7xg8fe3CHGAo4AI4YZiBO7DlAnBakuPxBrJZRMApGwSgYAQAAIqZODbuzqa0AAAAASUVORK5CYII=","orcid":"","institution":"Kyoto Prefectural University of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Takashi","middleName":"","lastName":"Ueda","suffix":""},{"id":572720387,"identity":"3e972919-2c0c-4c6e-820a-7986b4d60d98","order_by":2,"name":"Masahiro Iehara","email":"","orcid":"","institution":"Kyoto Prefectural University of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Masahiro","middleName":"","lastName":"Iehara","suffix":""},{"id":572720390,"identity":"34146998-3549-4fb9-a154-17b54a92b1a4","order_by":3,"name":"Yusuke Gabata","email":"","orcid":"","institution":"Kyoto Prefectural University of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yusuke","middleName":"","lastName":"Gabata","suffix":""},{"id":572720391,"identity":"1bb04ff1-9cb1-4f08-b911-da1c5f744238","order_by":4,"name":"Junki Murashita","email":"","orcid":"","institution":"Kyoto Prefectural University of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Junki","middleName":"","lastName":"Murashita","suffix":""},{"id":572720392,"identity":"f53288e9-dbdb-4e90-a9b9-20c792aff4e0","order_by":5,"name":"Hikaru Takahashi","email":"","orcid":"","institution":"Kyoto Prefectural University of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Hikaru","middleName":"","lastName":"Takahashi","suffix":""},{"id":572720393,"identity":"98e5d575-e10b-42f0-a395-db0a9c3d1699","order_by":6,"name":"Yumiko Saito","email":"","orcid":"","institution":"Kyoto Prefectural University of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yumiko","middleName":"","lastName":"Saito","suffix":""},{"id":572720394,"identity":"da319f1c-e304-4fde-9009-9ec8af4170e0","order_by":7,"name":"Yasuhiro Yamada","email":"","orcid":"","institution":"Kyoto Prefectural University of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yasuhiro","middleName":"","lastName":"Yamada","suffix":""},{"id":572720395,"identity":"d8c68d90-18e0-4cb4-b109-7db8d8059782","order_by":8,"name":"Masatsugu Miyashita","email":"","orcid":"","institution":"Kyoto Prefectural University of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Masatsugu","middleName":"","lastName":"Miyashita","suffix":""},{"id":572720396,"identity":"62ce3fb8-1a7c-42b0-9028-c617a634bc51","order_by":9,"name":"Takumi Shiraishi","email":"","orcid":"","institution":"Kyoto Prefectural University of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Takumi","middleName":"","lastName":"Shiraishi","suffix":""},{"id":572720397,"identity":"1065811d-863d-4160-9098-54560e8fba52","order_by":10,"name":"Atsuko Fujihara","email":"","orcid":"","institution":"Kyoto Prefectural University of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Atsuko","middleName":"","lastName":"Fujihara","suffix":""},{"id":572720398,"identity":"3af2137d-38ca-4ad2-8163-bef397dad5fb","order_by":11,"name":"Masayoshi Okumi","email":"","orcid":"","institution":"Kyoto Prefectural University of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Masayoshi","middleName":"","lastName":"Okumi","suffix":""},{"id":572720399,"identity":"c6c9d7cf-bbcd-4780-a9dc-7dcc03d5c0d2","order_by":12,"name":"Fumiya Hongo","email":"","orcid":"","institution":"Kyoto Prefectural University of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Fumiya","middleName":"","lastName":"Hongo","suffix":""},{"id":572720400,"identity":"ef519a9c-eb75-48df-b60c-f62abbb6bd50","order_by":13,"name":"Osamu Ukimura","email":"","orcid":"","institution":"Kyoto Prefectural University of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Osamu","middleName":"","lastName":"Ukimura","suffix":""}],"badges":[],"createdAt":"2025-12-15 01:23:06","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8360739/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8360739/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-026-44627-w","type":"published","date":"2026-03-16T15:57:34+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":100126549,"identity":"fafc8c92-7b66-48ac-acac-471918b0cd3f","added_by":"auto","created_at":"2026-01-13 09:25:12","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":252115,"visible":true,"origin":"","legend":"","description":"","filename":"tripletvsdoublet.docx","url":"https://assets-eu.researchsquare.com/files/rs-8360739/v1/3e86d43a051b610ff66a585e.docx"},{"id":100126574,"identity":"a8ffc18e-951c-4fc2-a42a-dfa17e43b7fd","added_by":"auto","created_at":"2026-01-13 09:25:14","extension":"json","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":14801,"visible":true,"origin":"","legend":"","description":"","filename":"96d240ede9b24f0d8b94e926ab7bcd5b.json","url":"https://assets-eu.researchsquare.com/files/rs-8360739/v1/c01d37ad3eea071245cccde8.json"},{"id":100126572,"identity":"5584f398-b363-454a-bf3a-3ed86b51079a","added_by":"auto","created_at":"2026-01-13 09:25:14","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":124638,"visible":true,"origin":"","legend":"","description":"","filename":"supportinginformation.docx","url":"https://assets-eu.researchsquare.com/files/rs-8360739/v1/8a379882015220f20b83131b.docx"},{"id":100366380,"identity":"f2cda971-eb1a-4202-85dd-47e555990685","added_by":"auto","created_at":"2026-01-16 07:56:17","extension":"xml","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":71274,"visible":true,"origin":"","legend":"","description":"","filename":"96d240ede9b24f0d8b94e926ab7bcd5b1enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-8360739/v1/0858680b9a8a331b60a5a855.xml"},{"id":100126540,"identity":"e74bae0d-7e22-4e5c-a0c1-3a40367378d5","added_by":"auto","created_at":"2026-01-13 09:25:12","extension":"png","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":16056,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8360739/v1/1a40772b3433b0e166619451.png"},{"id":100126527,"identity":"dd3741a3-941f-4cf5-b628-cc698f68f2be","added_by":"auto","created_at":"2026-01-13 09:25:11","extension":"jpeg","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":297837,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8360739/v1/4b7fce49d4eeff34b62189ec.jpeg"},{"id":100126496,"identity":"2e578868-e48c-4796-9cec-c2b8e3fe1ca9","added_by":"auto","created_at":"2026-01-13 09:25:01","extension":"jpeg","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":222405,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8360739/v1/92c99d6dcf1e09cba4873153.jpeg"},{"id":100126575,"identity":"40133692-e6c8-4570-ad89-4a1c2ea4f2c6","added_by":"auto","created_at":"2026-01-13 09:25:14","extension":"jpeg","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":99606,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8360739/v1/5a79d7a16369d5ddc779c9e2.jpeg"},{"id":100126559,"identity":"729089ea-8bb1-439d-be24-3cbba64a4363","added_by":"auto","created_at":"2026-01-13 09:25:13","extension":"jpeg","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":287454,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage5.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8360739/v1/40deb6b091626da04736a09c.jpeg"},{"id":100126500,"identity":"e7af4f27-4017-4863-a676-38a0f2852664","added_by":"auto","created_at":"2026-01-13 09:25:01","extension":"png","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":6530,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8360739/v1/59acf2567d7655451dd9de31.png"},{"id":100126513,"identity":"6ae29f36-7ef7-47ea-bf9e-fb075c1f13cb","added_by":"auto","created_at":"2026-01-13 09:25:09","extension":"png","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":73758,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8360739/v1/0f436e3cc9fc0be9cc4e740f.png"},{"id":100366497,"identity":"244a5c93-41d4-4e4f-9f99-4931a5380d65","added_by":"auto","created_at":"2026-01-16 07:56:19","extension":"png","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":54638,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8360739/v1/3f8d43a9e8ca5bd84f9fcb51.png"},{"id":100126526,"identity":"48f4b337-07c4-491c-8376-30010565acc4","added_by":"auto","created_at":"2026-01-13 09:25:11","extension":"png","order_by":12,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":25275,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-8360739/v1/b57b3b1eb0a7560a77cc7154.png"},{"id":100126551,"identity":"3cc2a8d3-a740-4a78-b148-12cada6bdd22","added_by":"auto","created_at":"2026-01-13 09:25:13","extension":"png","order_by":13,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":67067,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-8360739/v1/2f5a65897388030671e0e851.png"},{"id":100126578,"identity":"4e15ee65-e691-4621-9824-94bce6b406c2","added_by":"auto","created_at":"2026-01-13 09:25:14","extension":"xml","order_by":14,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":67818,"visible":true,"origin":"","legend":"","description":"","filename":"96d240ede9b24f0d8b94e926ab7bcd5b1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8360739/v1/3fa4efc24bbbfb54455093a7.xml"},{"id":100126499,"identity":"e4c996ed-8807-4d4d-bb44-dd568afebf59","added_by":"auto","created_at":"2026-01-13 09:25:01","extension":"html","order_by":15,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":79172,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8360739/v1/8bbb47f11cd87b19f8a03246.html"},{"id":100126529,"identity":"4e300dba-4e3d-43e2-b553-593fd092c7d1","added_by":"auto","created_at":"2026-01-13 09:25:11","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":79177,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier estimates of PSA progression-free survival, second progression-free survival, and overall survival in matched patients with high-risk mHSPC (triplet (n=50) vs. doublet (ABI=26, APA=8, ENZ=16)).\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8360739/v1/d5d50cb51bb20a508e3beb47.png"},{"id":100366571,"identity":"8f39ab17-1f0c-4839-b1bb-3c6ed0639661","added_by":"auto","created_at":"2026-01-16 07:56:22","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":88740,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier estimates of PSA progression-free survival, second progression-free survival, and overall survival in matched patients with mHSPC (triplet (n=48) vs. doublet (APA=20, ENZ=28)).\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8360739/v1/1811c9d7a63c128c28f68bc4.png"},{"id":100126534,"identity":"7f5543c2-f6cf-4e53-89d8-e088af6fc1c2","added_by":"auto","created_at":"2026-01-13 09:25:11","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":91653,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier estimates of PSA progression-free survival and overall survival in matched high-risk mHSPC patients with high (\u0026gt;220) (left) and low (\u0026lt;220) (right) LDH levels.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8360739/v1/95341dda0a75eb9d1226e6a5.png"},{"id":105223323,"identity":"1543cab4-5e7e-4362-abe0-3e69fb2fad9a","added_by":"auto","created_at":"2026-03-23 16:03:50","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1092945,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8360739/v1/c714c489-6387-462a-9f6c-80d2ddd7f1c9.pdf"},{"id":100126555,"identity":"1c11f7cc-193d-4e18-aa05-3a07302bdbf7","added_by":"auto","created_at":"2026-01-13 09:25:13","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":124638,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupporting Information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSupplementary Figure S1. Kaplan–Meier estimates of PSA progression-free survival and overall survival in matched patients with high-risk mHSPC and GS5 (left) and without GS5 (right).\u003c/p\u003e\n\u003cp\u003eSupplementary Table S1. Sequential therapy following PSA progression.\u003c/p\u003e\n\u003cp\u003eSupplementary Table S2. Adverse events occurring in patients with mHSPC.\u003c/p\u003e\n\u003cp\u003eSupplementary Table S3. Adverse events in each treatment group.\u003c/p\u003e\n\u003cp\u003eSupplementary Table S4. PSA kinetics in patients with mHSPC.\u003c/p\u003e\n\u003cp\u003eSupplementary Table S5.Characteristics of matched patients with high-risk mHSPC (triplet vs. doublet).\u003c/p\u003e\n\u003cp\u003eSupplementary Table S6. Characteristics of matched patients with mHSPC (triplet vs. APA or ENZ).\u003c/p\u003e","description":"","filename":"supportinginformation.docx","url":"https://assets-eu.researchsquare.com/files/rs-8360739/v1/79d24c156c84c96e4ed34501.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Triplet versus doublet therapy in patients with metastatic hormone-sensitive prostate cancer","fulltext":[{"header":"Introduction","content":"\u003cp\u003eA variety of treatment options are available for patients with metastatic hormone-sensitive prostate cancer (mHSPC). In the National Comprehensive Cancer Network (NCCN) guidelines, first-line treatment options for patients with mHSPC are divided into two groups: androgen receptor signaling inhibitor (ARSI)-based doublet therapy and triplet therapy (1). ARSI-based doublet therapy is a combined therapy of androgen deprivation therapy (ADT) and ARSI: abiraterone acetate plus prednisolone (ABI), enzalutamide (ENZ), and apalutamide (APA). The superiority of doublet therapy to ADT for patients with mHSPC has been demonstrated in a clinical study\u0026nbsp;(2-4). In triplet therapy, patients with mHSPC are administered docetaxel, a cytotoxic chemotherapeutic agent, in addition to the drugs of doublet therapy. Although triplet therapy is presumed to be superior to doublet therapy from the amount of medication, the adverse events (AEs) of docetaxel should be considered. Although some reports of network meta-analysis have suggested that triplet therapy may be superior to doublet therapy in overall survival (OS) of patients with mHSPC, no direct comparison between triplet and doublet therapies has been reported\u0026nbsp;(5-7).\u003c/p\u003e\n\u003cp\u003eSeveral studies have reported the clinical parameters that affect the efficacy of treatment of patients with mHSPC (8, 9). We previously reported that the histological presence of Gleason pattern 5 (GS5) in the primary tumor may affect the efficacy of ARSI-based doublet therapy of patients with mHSPC. There are few reports on the clinical factors affecting the efficacy of triplet therapy in patients with mHSPC. Previously, we reported a prognostic model for patients with mHSPC treated with ABI using clinical factors including lactate dehydrogenase (LDH) and primary GS5\u0026nbsp;(10, 11).\u003c/p\u003e\n\u003cp\u003eThe purpose of this study was to compare the treatment outcome (prostate-specific antigen-progression-free survival (PSA-PFS), second progression-free survival (PSF2), and OS) between patients treated with triplet and those treated with ARSI-based doublet therapy and to identify the clinical parameters affecting their efficacy.\u003c/p\u003e"},{"header":"Material and Methods","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePatients and treatments\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe retrospectively recruited 500 patients with mHSPC treated with doublet or triplet therapy from our hospital and affiliated hospitals between December 2013 and August 2025.\u0026nbsp;The cohort of patients with mHSPC treated with doublet therapy received ABI (1000\u0026nbsp;mg/day)\u0026nbsp;plus\u0026nbsp;prednisolone (5 mg/day)\u0026nbsp;or ENZ (160\u0026nbsp;mg/day) or APA (240\u0026nbsp;mg/day)\u0026nbsp;in combination with a luteinizing hormone-releasing hormone analog such as ADT. The cohort of those treated with triplet therapy received darolutamide (1200\u0026nbsp;mg/day) plus ADT and docetaxel (75 mg/m\u003csup\u003e2\u003c/sup\u003e every 3 weeks for six cycles). Bone metastasis\u0026nbsp;was assessed by bone scintigraphy. Visceral and lymph node metastases were assessed\u0026nbsp;by\u0026nbsp;computed tomography (CT).\u0026nbsp;High-risk mHSPC was defined according to the LATITUDE risk stratification (patients with mHSPC and\u0026nbsp;at least two of\u0026nbsp;the following factors: Gleason score (GS)\u0026nbsp;at the primary lesion\u0026nbsp;≥8, ≥3 in bone lesions, or presence of visceral metastasis). Drug selection and dose adjustments were made at the physicians' discretion. Cutoffs of PSA and LDH were defined as 4.0 ng/mL and 220 IU/L, respectively.\u003c/p\u003e\n\u003cp\u003eWe obtained approval for this study from the Institutional Review Board (IRB) of Kyoto Prefectural University of Medicine. This study complied with the Declaration of Helsinki.\u0026nbsp;The requirement for written informed consent was waived, considering the retrospective nature of the study. Opt-out information was provided to the patients on the website of our hospital and affiliated hospitals.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eStatistical Analysis\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eChi‐square and Wilcoxon rank‐sum tests were used to compare the two groups. Kaplan–Meier analysis, along with the log‐rank test, was employed to estimate the differences in time events between the two groups. Cox proportional hazards models were used to investigate factors associated with PFS. Propensity score matching was used to adjust for clinical background differences between groups. Age at diagnosis in years, performance status, pretreatment PSA and LDH levels, Gleason pattern 5, presence of bone, visceral, and lymph node metastasis, and observation period were used in the propensity score matching. We used SAS JMP, Version 17, for all statistical analyses with a significance threshold set at P \u0026lt; 0.05.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eClinical characteristics of patients with mHSPC treated with doublet and triplet therapy\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe clinical characteristics of the overall cohort in this study are shown in Table 1. A total of 424 patients with mHSPC were treated with doublet therapy (doublet cohort) (180 patients with ABI, 113 patients with APA, and 131 patients with ENZ), and 76 patients with mHSPC were treated with triplet therapy (triplet cohort). The observation period of the triplet cohort was significantly shorter than that of the doublet cohort (P \u0026lt; 0.0001). The average age of the triplet cohort was significantly higher than that of the doublet cohort (P \u0026lt; 0.0001).\u0026nbsp;Detailed data on sequential therapy following PSA progression are provided in Supplementary Table S1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAEs and PSA kinetics of doublet and triplet therapies for patients with mHSPC\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAEs occurred in patients with mHSPC treated with doublet and triplet therapies are shown in Supplementary Table S2. Each AE in patients was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5. The details of AEs for each treatment are shown in Supplementary Table S3. In the triplet therapy group, 67 of 76 patients (88.2%) experienced some form of AE, whereas in the doublet therapy group, 70 of 424 patients (16.5%) had AEs. In the triplet therapy group, grade 3 or grade 4 neutropenia was observed in 45 patients, and febrile neutropenia was observed in 20 patients. Forty patients were able to complete all six cycles of docetaxel. Although both doublet and triplet therapies achieved a reduction of \u0026ge;90% from baseline PSA levels (\u0026ge;90% PSA decline; Supplementary Table S4),grade 3 or higher AEs were more frequent in 50 patients in the triplet therapy group (50 patients: 65.8%) than in the doublet therapy group (16 patients: 3.8%).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComparison of outcome (PSA-PFS, PSF2, and OS) in matched patients with high-risk mHSPC treated with doublet and triplet therapies\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAlthough ABI is indicated only for patients with high-risk mHSPC, triplet and other doublet (APA or ENZ) therapy is indicated for all patients with mHSPC regardless of LATTITUDE risk stratification. We extracted patients with high-risk mHSPC from the overall cohort to compare the outcome between triplet and doublet therapies under the same conditions. Propensity score matching was used to adjust the difference in backgrounds between the triplet and doublet cohorts (Supplementary Table S5). The outcome (PSA-PFS, PFS2, and OS) of triplet therapy was significantly better than that of doublet therapy in matched patients with high-risk mHSPC (Figure 1). Univariate and multivariate analyses of OS and PSA-PFS in matched patients with high-risk mHSPC treated with triplet or doublet therapy suggested that treatment choice (triplet or doublet), presence of Gleason pattern 5, and pretreatment LDH levels might influence OS in patients with high-risk mHSPC (Table 2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComparison of outcome (PSA-PFS, PSF2, and OS) in matched patients with mHSPC treated with doublet (ENZ or APA) and triplet therapy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePreviously, we suggested that ENZ and APA may be superior to ABI in the treatment outcome of patients with mHSPC, especially with Gleason pattern 5 at the primary site (11). Next, we compared the outcome of triplet therapy with that of doublet therapy, except for ABI in patients with mHSPC. We adjusted the difference in background, including LATTITUDE risk stratification between triplet therapy and the ENZ or APA cohort (Supplementary Table S6). Although PSA-PFS of patients with mHSPC treated with triplet therapy was significantly longer than that of those treated with APA or ENZ, no significant difference was observed in PSF2 or OS between the two groups (Figure 2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSubgroup analysis of patients with mHSPC treated with doublet or triplet therapy based on LDH levels\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;From the results above, we hypothesized that pretreatment LDH levels and the presence of Gleason pattern 5 at the primary site may be clinical parameters affecting the efficacy of doublet or triplet therapy in patients with mHSPC. To confirm the hypothesis, we performed subgroup analysis by dividing the two groups according to pretreatment LDH levels and the presence of Gleason pattern 5. Although PSA-PFS and OS of patients with mHSPC treated with triplet therapy were significantly longer than those treated with doublet therapy in the subgroup with high LDH levels (\u0026gt;220 IU/L), no significant difference was observed between triplet and doublet therapies in the subgroup with low LDH levels (≦220 IU/L) (Figure 3). In addition, PSA-PFS and OS of patients with mHSPC treated with triplet therapy were significantly longer than those treated with doublet therapy in the subgroup with the presence of Gleason pattern 5 (Supplementary Figure S1). These results suggested that triplet therapy may be superior to doublet therapy in the outcome of mHSPC with Gleason pattern 5 or high LDH levels.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe ARASENS trial demonstrated the superiority in treatment outcome of patients with mHSPC treated with darolutamide-based triplet therapy to those treated with placebo and docetaxel (12). However, the efficacy of adding docetaxel to ARSI-based doublet therapy remains unclear. In the present study, we retrospectively compared the outcome (PSA-PFS, PSF2, and OS) between patients with mHSPC treated with ARSI-based doublet therapy (ABI, APA, and ENZ) and those treated with triplet therapy. We found that the outcome of patients with mHSPC treated with triplet therapy was significantly better than those treated with ARSI-based doublet therapy. Although PSA-PFS and OS of patients with mHSPC treated with triplet therapy were significantly longer than of those treated with doublet therapy in the subgroup with high LDH levels (\u0026gt;220 IU/L), no significant difference was observed between triplet and doublet therapies in the subgroup with low LDH levels (≦220 IU/L). The same results were also observed when classified according to the presence of Gleason pattern 5. These results suggested that triplet therapy may achieve better outcomes than ARSI-based doublet therapy in patients with mHSPC and high LDH levels or Gleason pattern 5.\u003c/p\u003e\n\u003cp\u003eAlthough triplet therapy achieved a high PSA responsive rate (67%) , it also caused a high incidence rate of AEs (AE \u0026gt;G3: 70.5%) in the ARASENS trial (13). The most common AEs in triplet therapy were neutropenia in the ARASENS trial. The recovery time of patients with mHSPC treated with triplet therapy was significantly prolonged in patients aged over 79 (14). As expected, the incidence rate of AEs (\u0026gt;G3) in patients with mHSPC treated with triplet therapy was significantly higher than in those treated with doublet therapy in the present study. To tailor individual treatment strategies for patients with mHSPC in clinical practice, both the outcome and AEs of triplet therapy should be considered. Older patients with mHSPC (≧80 years old) with low LDH levels (≦220 IU/L) or without Gleason pattern 5 may be suitable for doublet therapy.\u003c/p\u003e\n\u003cp\u003eIn Japanese health insurance treatments, triplet therapy for patients with mHSPC means a darolutamide-based regimen, and doublet therapy corresponds to an ABI, APA, or ENZ-based regimen. In several countries other than Japan, other ARSIs (ABI, APA, and ENZ) than darolutamide can be administered to patients with mHSPC as triplet therapy, and darolutamide can be administered as doublet therapy. Previous network meta-analysis suggested that the darolutamide-based triplet showed the best outcomes in terms of OS (15). The differences in response to ARSIs may result from race, as Japanese patients with mHSPC show better response to bicalutamide than other races (16). The efficacy of these ARSIs in doublet and triplet therapies for Japanese patients with mHSPC should be compared in future studies.\u003c/p\u003e\n\u003cp\u003eOur study suggested that high LDH levels (\u0026gt;220 IU/L) or the presence of Gleason pattern 5 in patients with mHSPC was associated with resistance to ARSI-based doublet therapy. A higher level of LDH is associated with poorer outcomes in patients with mHSPC (17) (9). LDH plays a role in tumor proliferation, invasion, and metastasis in colorectal cancers (18). An immunohistochemical study suggested that LDH overexpression may be associated with poor differentiation. High LDH levels (\u0026gt;220 IU/L) in patients with mHSPC may be associated with poor differentiation of prostate cancer, which is resistant to androgen blockade therapy, including ARSI-based doublet therapy. Untreated prostate cancer contains a mix of androgen receptor (AR)-dependent and AR-independent cells (19, 20), which forms the rationale for triplet therapy using drugs with different mechanisms of action. In prostate cancers that include Gleason pattern 5, many adverse prognostic gene mutations are present (21), and a high number of cells resistant to hormonal therapy exist. This is believed to underline the results observed in the present study.\u003c/p\u003e\n\u003cp\u003eThis study has several limitations. Because it was a retrospective study with a small cohort, selection and confounding biases may be present. A prospective study with a larger cohort is needed to exclude these biases. Furthermore, the observation period was very short, especially in patients with mHSPC treated with triplet therapy. We plan to perform a study with a longer observation period.\u003c/p\u003e\n\u003cp\u003eIn conclusion, triplet therapy achieved better outcomes (PSA-PFS, PSF2, and OS) than doublet therapy in patients with mHSPC with high LDH levels (\u0026gt;220 IU/L) or Gleason pattern 5. These results could be useful in clinical practice for treating patients with mHSPC.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and analyzed during this study\u0026nbsp;are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors did not receive any financial support for the work presented in this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCo\u003c/strong\u003e\u003cstrong\u003enflict of\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no actual or potential conflicts of interest to declare.\u003c/p\u003e\n\u003cp\u003eOsamu Ukimura received honoraria from Jansen Pharmaceutical and AstraZeneca.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Institutional Review Boards of Kyoto Prefectural University of Medicine (ERB-C-1071-2). The study was conducted in accordance with the principles of the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatient consent statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe requirement for written informed consent was waived owing to the retrospective nature of this study. Patients were provided with opt-out information on the website.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePermission to reproduce material from other sources\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial registration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is based on the results from our hospital and its affiliated hospitals. We express our gratitude to the urologists from affiliated hospitals who contributed to this study: Hiroaki Miyashita, So Ushijima, Yuki Harada, Ryosuke Tamai, and Takenori Miyamoto, Department of Urology, Omihachiman Community Medical Center; Jintetsu So, Takeshi Yamada, Ryota Ogura, Yuya Minato, and Tsubasa Mitsuoka, Department of Urology, Japanese Red Cross Daini Hospital; Hiroki Matsubara and Mineyuki Kato, Department of Urology, Kyoto Yamashiro General Medical Center; Yasuhiro Yamada, Shunsuke Hotta, and Yutaro Oda, Department of Urology, Kyoto Okamoto Memorial Hospital; Naruhiro Kayukawa and Yuta Inoue, Department of Urology, Kyoto Kuramaguchi Medical Center; Tsuyoshi Iwata, Hirokazu Ishida, and Madoka Miyamoto, Department of Urology, Kyoto Min-Iren Chuo Hospital; Kazuya Mikami, Nobukazu Onishi, Yuki Ota, Yuji Okusa, Mai Ujihara, and Yuta Asakawa, Department of Urology, Japanese Red Cross Daiichi Hospital; Jun Ajiki, Department of Urology, Maizuru Medical Center; Eiji Taniguchi and Yuji Okusa, Department of Urology, North Medical Center Kyoto Prefectural University of Medicine; Kimihiro Yano, Department of Urology, Uji Takeda Hospital; Shunji Harikai, and Yoshiyuki Ida, Department of Urology, Fujinomiya City General Hospital; Terukazu Nakamura, Akihisa Ueno, Kotaro Iwamoto, Ryo Nishigaki, and Takaaki Dezao, Department of Urology, Saiseikai Suita Hospital; Yusuke Gabata, Department of Urology, Aiseikai Yamashina Hospital; Motohiro Kanazawa, Toshiya Takamura, and Koto Kojima, Department of Urology, Kyoto Chubu Medical Center; Shuichi Tahara, Kai Inoue, and Hisaya Tajima, Department of Urology, Ayabe City Hospital; Mitsuhiko Inaba, and Satoshi Sako, Department of Urology, Kyoto Saiseikai Hospital; Kei Suzuki, Masahiro Iehara, and Suhei Ito, Department of Urology, Fukuchiyama City Hospital; Takeshi Nomoto, and Yuya Yagi, Department of Urology, Maizuru Kyosai Hospital; Munehiro Ohashi, and Asa Okamoto, Department of Urology, Kyoto Tanabe Central Hospital; and Teruki Shimizu, Keisuke Tsuji, and Haruki Kishida, Department of Urology, Matsushita Memorial Hospital.\u003c/p\u003e\n\u003cp\u003eWe would like to thank Editage (www.editage.com) for English language editing\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eNCCN Guidelines Version 2. (2026).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFizazi, K. et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. \u003cem\u003eN Engl. J. Med.\u003c/em\u003e \u003cb\u003e377\u003c/b\u003e (4), 352\u0026ndash;360 (2017).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDavis, I. D. et al. Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. \u003cem\u003eN Engl. J. Med.\u003c/em\u003e \u003cb\u003e381\u003c/b\u003e (2), 121\u0026ndash;131 (2019).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChi, K. N. et al. Apalutamide in Patients With Metastatic Castration-Sensitive Prostate Cancer: Final Survival Analysis of the Randomized, Double-Blind, Phase III TITAN Study. \u003cem\u003eJ. Clin. Oncol.\u003c/em\u003e \u003cb\u003e39\u003c/b\u003e (20), 2294\u0026ndash;2303 (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRiaz, I. B. et al. First-line Systemic Treatment Options for Metastatic Castration-Sensitive Prostate Cancer: A Living Systematic Review and Network Meta-analysis. \u003cem\u003eJAMA Oncol.\u003c/em\u003e \u003cb\u003e9\u003c/b\u003e (5), 635\u0026ndash;645 (2023).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang, S. S. et al. Network meta-analysis of combination strategies in metastatic hormone-sensitive prostate cancer. \u003cem\u003eAsian J. Androl.\u003c/em\u003e \u003cb\u003e26\u003c/b\u003e (4), 402\u0026ndash;408 (2024).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHoeh, B. et al. Triplet or Doublet Therapy in Metastatic Hormone-sensitive Prostate Cancer Patients: An Updated Network Meta-analysis Including ARANOTE Data. \u003cem\u003eEur. Urol. Focus\u003c/em\u003e. \u003cb\u003e11\u003c/b\u003e (2), 386\u0026ndash;390 (2025).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLowentritt, B. et al. Comparison of prostate-specific antigen response in patients with metastatic castration-sensitive prostate cancer initiated on apalutamide or abiraterone acetate: A retrospective cohort study. \u003cem\u003eUrol. Oncol.\u003c/em\u003e \u003cb\u003e41\u003c/b\u003e (5), 252 (2023). e19- e27.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNarita, S. et al. Prognostic model for second progression-free survival and overall survival in patients with high-risk metastatic hormone-sensitive prostate cancer treated with abiraterone acetate and androgen deprivation therapy. \u003cem\u003eProstate\u003c/em\u003e \u003cb\u003e85\u003c/b\u003e (1), 73\u0026ndash;81 (2025).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eUeda, T. et al. Predictive factors for the efficacy of abiraterone acetate therapy in high-risk metastatic hormone-sensitive prostate cancer patients. \u003cem\u003eWorld J. Urol.\u003c/em\u003e \u003cb\u003e40\u003c/b\u003e (12), 2939\u0026ndash;2946 (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eUeda, T. et al. Screening for Predictive Factors of Efficacy of Second-Generation Androgen Receptor Axis-Targeted Agents in Patients With High-Risk Metastatic Hormone-Sensitive Prostate Cancer. \u003cem\u003eProstate\u003c/em\u003e \u003cb\u003e85\u003c/b\u003e (6), 524\u0026ndash;530 (2025).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSmith, M. R. et al. Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer. \u003cem\u003eN Engl. J. Med.\u003c/em\u003e \u003cb\u003e386\u003c/b\u003e (12), 1132\u0026ndash;1142 (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSaad, F. et al. Deep Prostate-specific Antigen Response following Addition of Apalutamide to Ongoing Androgen Deprivation Therapy and Long-term Clinical Benefit in SPARTAN. \u003cem\u003eEur. Urol.\u003c/em\u003e \u003cb\u003e81\u003c/b\u003e (2), 184\u0026ndash;192 (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eUsui, K. et al. Short-term outcomes of triplet therapy in metastatic hormone-sensitive prostate cancer in older adults: a retrospective, single-center real-world cohort study. \u003cem\u003eInt. Urol. Nephrol.\u003c/em\u003e (2025).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJian, T. et al. Systemic triplet therapy for metastatic hormone-sensitive prostate cancer: A systematic review and network meta-analysis. \u003cem\u003eFront. Pharmacol.\u003c/em\u003e \u003cb\u003e13\u003c/b\u003e, 955925 (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShiota, M. et al. Association of Missense Polymorphism in HSD3B1 With Outcomes Among Men With Prostate Cancer Treated With Androgen-Deprivation Therapy or Abiraterone. \u003cem\u003eJAMA Netw. Open.\u003c/em\u003e \u003cb\u003e2\u003c/b\u003e (2), e190115 (2019).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi, F. et al. Association between lactate dehydrogenase levels and oncologic outcomes in metastatic prostate cancer: A meta-analysis. \u003cem\u003eCancer Med.\u003c/em\u003e \u003cb\u003e9\u003c/b\u003e (19), 7341\u0026ndash;7351 (2020).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKoukourakis, M. I., Giatromanolaki, A., Sivridis, E., Gatter, K. C. \u0026amp; Harris, A. L. Tumour Angiogenesis Research G. Lactate dehydrogenase 5 expression in operable colorectal cancer: strong association with survival and activated vascular endothelial growth factor pathway\u0026ndash;a report of the Tumour Angiogenesis Research Group. \u003cem\u003eJ. Clin. Oncol.\u003c/em\u003e \u003cb\u003e24\u003c/b\u003e (26), 4301\u0026ndash;4308 (2006).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCabanos, H. F. \u0026amp; Hata, A. N. Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer. \u003cem\u003eCancers (Basel)\u003c/em\u003e ;\u003cb\u003e13\u003c/b\u003e(11). (2021).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGraf, R. P. et al. Predictive Genomic Biomarkers of Hormonal Therapy Versus Chemotherapy Benefit in Metastatic Castration-resistant Prostate Cancer. \u003cem\u003eEur. Urol.\u003c/em\u003e \u003cb\u003e81\u003c/b\u003e (1), 37\u0026ndash;47 (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVelho, P. I. et al. Molecular Characterization and Clinical Outcomes of Primary Gleason Pattern 5 Prostate Cancer After Radical Prostatectomy. \u003cem\u003eJCO Precis Oncol.\u003c/em\u003e ;\u003cb\u003e3\u003c/b\u003e. (2019).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":" \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 \u003cdiv class=\"SimplePara\"\u003eCharacteristics of the entire cohort.\u003c/div\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\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 \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cdiv class=\"SimplePara\"\u003eHormone therapy\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cdiv class=\"SimplePara\"\u003eTriplet (n\u0026thinsp;=\u0026thinsp;76)\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003eDoublet (n\u0026thinsp;=\u0026thinsp;424)\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e \u003cdiv class=\"SimplePara\"\u003ep-Value\u003c/div\u003e \u003cdiv class=\"SimplePara\"\u003e(Triplet vs. Doublet)\u003c/div\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003eABI (n\u0026thinsp;=\u0026thinsp;180)\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003eAPA (n\u0026thinsp;=\u0026thinsp;113)\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003eENZ (n\u0026thinsp;=\u0026thinsp;131)\u003c/div\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eMedian age at diagnosis years (range)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e72 (49\u0026ndash;87)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e74 (53\u0026ndash;94)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e77 (56\u0026ndash;93)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e76 (54\u0026ndash;89)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u0026lt;\u0026thinsp;0.0001\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003ePerformance status (ECOG)\u0026thinsp;≧\u0026thinsp;1, n (%)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e13 (17.3)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e54 (30.9)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e32 (28.8)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e47 (59.4)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.0082\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eMedian pretreatment PSA level (ng/mL)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e195(0.76\u0026ndash;12978)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e436 (2.324\u0026ndash;24201)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e109.508 (0.307\u0026ndash;8756)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e112.4 (2.58\u0026ndash;8413)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.0451\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eMedian pretreatment LDH (U/L)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e195 (100\u0026ndash;3456)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e198 (39.3\u0026ndash;2405)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e189 (90\u0026ndash;441)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e191.5 (14.5\u0026ndash;874)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.0371\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eGleason pattern 5, n (%)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e49 (64.4)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e122 (68.9)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e63 (55.7)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e71 (54.1)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.3776\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eHigh risk of LATITUDE criteria, n (%)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e63 (82.9)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e172 (96.1)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e68 (60.2)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e67 (51.5)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.0393\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003ePresence of bone metastasis, n (%)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e65 (85.5)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e165 (92.1)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e96 (84.9)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e111 (84.7)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.5636\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003ePresence of visceral metastasis, n (%)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e16 (21.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e50 (27.9)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e25 (22.3)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e22 (16.9)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.7015\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003ePresence of lymph node metastasis, n (%)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e52 (69.3)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e141 (78.7)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e69 (61.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e82 (62.5)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.8475\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eMedian observation period month (range)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e9 (3\u0026ndash;28)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e34 (3\u0026ndash;82)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e21 (3\u0026ndash;60)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e18.5 (3\u0026ndash;57)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u0026lt;\u0026thinsp;0.0001\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003cbr/\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 \u003cdiv class=\"SimplePara\"\u003eUnivariate and multivariate analyses for overall survival in matched patients with high-risk mHSPC.\u003c/div\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=\"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\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003eUnivariate analysis\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003eMultivariable analysis\u003c/div\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003eHR (95% CI)\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003ep-value\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003eHR (95% CI)\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003ep-value\u003c/div\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eTriplet or doublet\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e13.7 (1.79\u0026ndash;104)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.012\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e12.1 (1.55\u0026ndash;95.1)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.018\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003ePerformance status (ECOG)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e14.3 (1.55\u0026ndash;87.2)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.0073\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003ePretreatment PSA level\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e1.26 (0.063\u0026ndash;10.1)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.8540\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003ePresence of GS5\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.017\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.037\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003ePretreatment LDH\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e2987 (40.78-828657)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.0023\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e142 (2.85\u0026ndash;15279)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.013\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003ePresence of bone metastasis\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.9993\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003ePresence of visceral metastasis\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.80 (0.22\u0026ndash;2.88)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.73\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003ePresence of lymph node metastasis\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.99 (0.31\u0026ndash;3.17)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.99\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e-\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003cbr/\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":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"docetaxel, darolutamide, abiraterone acetate, apalutamide, enzalutamide, metastatic hormone-sensitive prostate cancer","lastPublishedDoi":"10.21203/rs.3.rs-8360739/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8360739/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFirst-line treatment options for patients with metastatic hormone-sensitive prostate cancer (HSPC) are divided into two groups: androgen receptor signaling inhibitor (ARSI)-based doublet therapy and triplet therapy (which includes chemotherapy in addition to doublet therapy). However, differences in therapeutic efficacy between the two groups remain unclear. The aim of the study was to perform a comparative analysis between the two groups and to identify predictors of treatment response.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe retrospectively recruited 500 patients with mHSPC treated with doublet or triplet therapy from our hospital and affiliated hospitals between 2013 and 2025. The cohort of patients with mHSPC treated with doublet therapy received ABI, ENZ, or APA in combination with a luteinizing hormone-releasing hormone analog, such as androgen deprivation therapy (ADT). The cohort of those treated with triplet therapy received darolutamide plus ADT and docetaxel. Cox logistic regression analysis was performed to identify prognostic factors of overall survival in patients with mHSPC. Propensity score matching was used to adjust the clinical background of patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe outcome (prostate-specific antigen-progression-free survival, second progression-free survival, and overall survival (OS)) of triplet therapy was significantly better than that of doublet therapy in matched high-risk patients with mHSPC. Univariate and multivariate analyses of OS in matched patients with high-risk mHSPC treated with triplet or doublet therapy suggested that treatment choice (triplet or doublet), pretreatment LDH levels, and presence of Gleason pattern 5 influenced OS in patients with high-risk mHSPC. Subgroup analysis suggested that LDH levels and the presence of Gleason pattern 5 may be predictive factors of the treatment of patients with mHSPC.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOur results showed that triplet therapy achieved a better outcome than doublet therapy in patients with mHSPC.\u003c/p\u003e","manuscriptTitle":"Triplet versus doublet therapy in patients with metastatic hormone-sensitive prostate cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-13 09:23:33","doi":"10.21203/rs.3.rs-8360739/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-01-29T08:11:35+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-26T12:59:16+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"264589503173749592609608994341169181060","date":"2026-01-18T23:57:22+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"241348293934059523777409936563584472452","date":"2026-01-18T10:06:32+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-12T06:04:24+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"183159471361047225655734681197039261362","date":"2026-01-11T10:36:45+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-01-08T11:48:54+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-12-17T12:58:24+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-12-15T14:55:04+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-12-15T14:52:44+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-12-15T00:50:17+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f647b0de-6092-4878-9723-ea7693ce7860","owner":[],"postedDate":"January 13th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":60939666,"name":"Biological sciences/Cancer"},{"id":60939667,"name":"Health sciences/Oncology"}],"tags":[],"updatedAt":"2026-03-23T16:01:03+00:00","versionOfRecord":{"articleIdentity":"rs-8360739","link":"https://doi.org/10.1038/s41598-026-44627-w","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2026-03-16 15:57:34","publishedOnDateReadable":"March 16th, 2026"},"versionCreatedAt":"2026-01-13 09:23:33","video":"","vorDoi":"10.1038/s41598-026-44627-w","vorDoiUrl":"https://doi.org/10.1038/s41598-026-44627-w","workflowStages":[]},"version":"v1","identity":"rs-8360739","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8360739","identity":"rs-8360739","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}