Outcomes after cytoreductive radical prostatectomy for de novo metastatic hormone-sensitive prostate cancer: survival and time to treatment intensification in a retrospective cohort

Outcomes after cytoreductive radical prostatectomy for de novo metastatic hormone-sensitive prostate cancer: survival and time to treatment intensification in a retrospective cohort | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Outcomes after cytoreductive radical prostatectomy for de novo metastatic hormone-sensitive prostate cancer: survival and time to treatment intensification in a retrospective cohort Yi Hong Li, Yi Sheng Lin, Yen Chuan Ou, Li Hua Huang, Wei Chun Weng, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7696870/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose: To evaluate whether cytoreductive radical prostatectomy (CRP) confers benefit beyond contemporary systemic therapy in men with de novo metastatic hormone-sensitive prostate cancer (mHSPC). Methods: Single-center retrospective cohort (2014–2022) comparing CRP plus systemic therapy versus systemic therapy alone. Primary endpoints were overall (OS) and cancer-specific survival (CSS); secondary endpoints were time to treatment intensification (“no-intensification survival”) and post-intensification progression-free survival (PFS). Kaplan–Meier/log-rank and Cox models were used; competing-risk methods estimated subdistribution hazard ratios (sHR) for intensification. Propensity-score matching (1:2; caliper 0.1) tested robustness. Results: Among 164 patients, 58 received CRP and 106 no local therapy; median follow-up was 30.6 months (36.2 among survivors). In the unmatched cohort, 5-year OS was 70.2% with CRP versus 35.4% without (univariable HR 0.24; multivariable HR 0.40; p=0.006), and 5-year CSS was 83.8% versus 49.6% (HR 0.20; p<0.001). CRP prolonged no-intensification survival (2-year 56.6% vs 33.6%; HR 0.46; log-rank p<0.001) and lowered the cumulative incidence of intensification (sHR 0.52; Gray’s p=0.003). Post-intensification PFS was similar (HR 0.89; p=0.67). After matching (CRP n=35; non-CRP n=51), 5-year OS was 55.0% versus 41.0% (p=0.027) and CSS 75.0% versus 54.0% (p=0.021). Conclusion: CRP integrated with systemic therapy was associated with improved OS/CSS and delayed treatment intensification without affecting outcomes after intensification, supporting CRP as a potential component of multimodal management in selected men; randomized trials are warranted. metastatic hormone-sensitive prostate cancer cytoreductive radical prostatectomy primary-tumour control treatment intensification overall survival cancer-specific survival propensity score matching competing risks Figures Figure 1 Figure 2 Figure 3 Introduction Management of de novo metastatic hormone-sensitive prostate cancer (mHSPC) has shifted from androgen-deprivation therapy (ADT) alone to treatment intensification with either an ARPI-based doublet (ADT + ARPI) or a triplet regimen incorporating docetaxel (ADT + docetaxel + ARPI), both endorsed in contemporary practice ( 1 – 5 ). Against this backdrop, the role of local therapy to the primary has re-emerged as a clinically relevant question. Randomised radiotherapy (RT) data have established that treating the prostate can confer benefit in low-volume mHSPC. In STAMPEDE (Arm H), prostate-directed RT improved overall survival in men with low metastatic burden, whereas the overall population showed no survival gain; HORRAD similarly suggested delayed biochemical/clinical failure without clear overall survival improvement ( 6 , 7 ). Current guidelines therefore endorse prostate RT as an option for carefully selected low-volume mHSPC, alongside intensified systemic therapy( 8 ). By contrast, evidence for cytoreductive radical prostatectomy (CRP) remains less mature and more controversial. Retrospective series and registry analyses have associated CRP with lower mortality and fewer local events, but these studies are limited by selection bias and were largely conducted in the pre-ARPI era( 9 ). Prospective surgical data include feasibility work (e.g., TRoMbone) and a randomised phase II trial in which radical local therapy—predominantly prostatectomy—added to ADT improved radiographic progression-free survival and three-year overall survival versus ADT alone, but definitive phase III evidence is pending ( 10 ). Importantly, most historical comparisons of local therapy versus systemic therapy were benchmarked against ADT monotherapy, which may underestimate (or obscure) the incremental value of CRP when layered onto modern systemic backbones. Technical considerations and uncertainty about incremental efficacy have also constrained broader adoption of CRP in routine practice. Consequently, high-quality, contemporary data are needed to clarify whether CRP adds clinically meaningful benefit beyond intensified systemic therapy and to define where any advantage accrues (e.g., prolonging the hormone-sensitive interval versus altering post-escalation trajectories). To address this gap, we conducted a single-centre retrospective cohort study comparing CRP plus systemic therapy with systemic therapy alone in men with de novo mHSPC treated in the ARPI era, prespecifying overall and cancer-specific survival as primary endpoints and evaluating decision-oriented secondary endpoints—time to treatment intensification and post-intensification progression-free survival—while applying multivariable adjustment and propensity-score matching. Methods Study Design and Patient Selection We conducted a retrospective cohort study of men with newly diagnosed metastatic prostate cancer at a single tertiary referral centre between 2014 and 2022. The study was approved by the Institutional Review Board, and a waiver of informed consent was obtained due to the retrospective design (IRB113020). Eligible patients had de novo metastatic disease at presentation (i.e., distant metastasis detected at the time of initial prostate cancer diagnosis) with histologically confirmed prostatic adenocarcinoma and no prior definitive local therapy to the prostate. Initial staging included cross-sectional imaging (CT with or without MRI) and technetium bone scintigraphy to confirm metastatic disease. To focus on the synchronous setting, we excluded patients with metachronous metastases (initially localized disease later progressing to metastasis). Additional exclusions were receipt of primary prostate radiotherapy as initial management (to isolate surgery vs no local therapy), absence of any cancer-directed therapy after diagnosis, death during the index hospitalization or within 1 month of diagnosis, <6 months of follow-up, or incomplete treatment/outcomes data. Transurethral resection of the prostate for symptom control was permitted. Patients were categorized according to management of the primary-tumour: the CRP group underwent cytoreductive radical prostatectomy with pelvic lymph node dissection as part of initial management; the non-CRP group received systemic therapy without local treatment of the prostate. The timing of surgery relative to systemic therapy was individualized; in most cases CRP was performed after a short course of androgen deprivation therapy (ADT; approximately 3–6 months). All CRP procedures were performed with curative intent by uro-oncologic surgeons using a robotic approach. Baseline Variables and Definitions Baseline clinicopathologic variables included age at diagnosis, body mass index (BMI), Eastern Cooperative Oncology Group (ECOG) performance status, and Charlson Comorbidity Index (CCI) as a composite measure of comorbidity burden. Tumor-related variables included initial serum PSA (iPSA), clinical T stage (cT) assessed by digital rectal examination and imaging, clinical nodal status (cN), and extent of metastatic disease (cM). Metastatic burden was categorized as low- versus high-volume using criteria aligned with CHAARTED definitions(11). Biopsy Gleason Grade Group was recorded (1–5) and analyzed as favorable/intermediate (Groups 2–3) versus high-grade (Groups 4–5) for selected models. Systemic Treatments and Treatment Intensification Systemic treatment data were abstracted for all patients, including receipt of ADT alone or ADT with treatment intensification (TI). In this study, TI referred to the addition of life-prolonging systemic therapy beyond ADT within the castration-sensitive phase, most commonly docetaxel or next-generation androgen receptor pathway inhibitors (ARPIs) such as abiraterone, enzalutamide, or apalutamide. For each patient, the occurrence and timing of TI initiation were captured. Systemic strategies evolved over the study period: ADT monotherapy predominated in earlier years, whereas combination regimens (ADT + docetaxel or ADT + ARPI) became increasingly common in fit patients following the dissemination of trial evidence. Follow-up typically included PSA testing every 1–3 months, routine clinical assessments, and imaging at the discretion of the treating team. Endpoints Primary endpoints were overall survival (OS)—defined as time from diagnosis to death from any cause—and cancer-specific survival (CSS)—defined as time from diagnosis to death attributable to prostate cancer. Cause of death was adjudicated from chart review and death certificates; non-cancer deaths were treated as competing events in CSS analyses. Secondary endpoints included: (1) No-intensification survival, defined as time from diagnosis to initiation of TI (KM analyses censored patients who died before intensification, and competing-risk analyses treated death before intensification as a competing event); and (2) Intensification progression-free survival (intensification PFS), defined among patients who received TI as time from TI start to radiographic or clinical progression, shift to second-line management or death. Progression was determined by rising PSA and/or imaging in the treating physician’s assessment. Statistical Analysis Baseline characteristics were compared between groups using Student’s t-test for normally distributed continuous variables, Mann–Whitney U test for non-normal variables (e.g., PSA), and chi-square or Fisher’s exact tests for categorical variables. Survival functions were estimated via Kaplan–Meier and compared using the log-rank test. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression. Variables with p<0.10 in univariable analysis or with established clinical relevance were considered for multivariable Cox models for OS; proportional hazards assumptions were evaluated and addressed as appropriate. Because death can preclude intensification, time to TI was also analyzed within a competing-risk framework using cumulative incidence functions (CIFs), with Gray’s test used for between-group comparisons and subdistribution hazard ratios reported where appropriate. To mitigate selection bias, we performed propensity score matching (PSM) for receipt of CRP using a logistic regression model incorporating baseline covariates. Nearest-neighbor matching without replacement at a 1:2 ratio (one CRP matched to two non-CRP patients) with a caliper width of 0.1 on the propensity score logit was used. Covariate balance after matching was evaluated using standardised mean differences (SMD), targeting SMD <0.10 for negligible imbalance; where residual imbalances persisted, they were noted and considered in interpretation. All analyses were conducted in R version 4.5.1 (R Foundation for Statistical Computing). Two-sided p<0.05 was considered statistically significant. Reporting followed STROBE guidelines for observational studies(12-14). Results Patient Characteristics A total of 164 patients with de novo mHSPC met eligibility criteria, of whom 58 (35.4%) underwent CRP and 106 (64.6%) received no local therapy to the prostate. The patient selection flow diagram is presented in Supplementary Figure S1. In the unmatched cohort (Table 1), CRP patients were younger (mean 68.9 vs 74.6 years, p<0.001), had fewer comorbidities (CCI 9.0 vs 10.3, p<0.001; noting that CCI includes 6 points for metastatic disease), and were more likely to have ECOG 0 performance status (98% vs 73%, p=0.002). They also presented with lower iPSA (median 79 vs 310 ng/mL, p<0.001) and were more frequently low-volume by CHAARTED criteria (59% vs 26%, p<0.001). High-grade disease (Grade Groups 4–5) was common in both cohorts but more prevalent in non-CRP (94% vs 81%, p=0.014). Clinical T and N stage distributions were broadly similar between groups. After PSM (CRP n=35; non-CRP n=51), covariate balance improved substantially, with most SMDs <0.10; small residual imbalances were observed for a minority of variables (Table 2). A Love plot and propensity score overlap (Supplementary Figures S2 and S3) demonstrated acceptable matching quality and common support. Overall and Cancer-Specific Survival At the time of analysis, median follow-up for the overall cohort was 30.6 months (36.2 months among survivors), and 58 deaths had occurred. Overall survival favored the CRP group (Figure 1A). The 5-year OS estimates were 70.2% for CRP and 35.4% for non-CRP. On univariable Cox analysis, CRP was associated with a 75% relative reduction in the hazard of death (HR 0.24, 95% CI 0.13–0.44, p<0.001). Adjustment for age, CCI, PSA, metastatic volume, Grade Group, and other covariates attenuated but preserved the association (adjusted HR 0.395, 95% CI 0.205–0.762, p=0.006), indicating an independent association with improved survival over systemic therapy alone (Table 3). Cancer-specific survival also favored CRP (Figure 1B), with higher 5-year CSS in the surgical cohort (83.8% vs 49.6% for non-CRP). The unadjusted hazard of prostate cancer–specific death was 80% lower with CRP (HR 0.20, 95% CI 0.09–0.45, p<0.001). To contextualize the treatment effect, we examined other covariates in OS models. Comorbidity burden (CCI) emerged as an independent predictor of mortality (multivariable HR per point 1.213, 95% CI 1.015–1.451, p=0.034). High-volume disease was associated with worse OS in univariable analysis (HR 2.269, p=0.002) and demonstrated a borderline association after adjustment (adjusted HR 1.733, 95% CI 0.98–3.07, p=0.058). In contrast, iPSA, cT stage, and Grade Group (4–5 vs 2–3) were not independently associated with OS after accounting for other variables, the latter showing only a trend (adjusted HR 2.31, p=0.081). Collectively, these findings suggest that disease extent and host comorbidity substantially influence prognosis and that the CRP benefit is observed on top of these factors. Treatment Intensification and Progression We next evaluated endpoints related to systemic therapy escalation. No-intensification survival (time from diagnosis to initiation of TI) was prolonged in CRP patients (Figure 1C). At 2 years, an estimated 56.6% of CRP patients remained without TI versus 33.6% of non-CRP patients (HR 0.46, 95% CI 0.32–0.67; log-rank p<0.001). To address the possibility that early death could confound the initiation of TI, we performed a competing-risk analysis for time to intensification (Figure 2). The cumulative incidence of TI remained substantially lower in the CRP group across follow-up; for example, by 1 year from diagnosis, approximately 45% of non-CRP patients had initiated additional therapy compared with around 20% of CRP patients. The subdistribution hazard for intensification was significantly reduced with CRP (sHR 0.52, 95% CI 0.34–0.80; Gray’s p=0.003). Additionally, a total of 14 patients had ADT withheld—13 in the CRP cohort and 1 in the non-CRP cohort—and none have resumed ADT as of the last follow-up. Of the CRP cases, 9 were managed with ADT alone and 4 received a short course of an ARPIs or chemotherapy; the non-CRP case had received ADT alone. Notably, the cumulative incidence of death without intensification was also lower among CRP patients—consistent with their superior OS—yet the between-group difference in TI remained statistically significant even when accounting for this competing event. These data suggest that CRP, alongside systemic therapy, is associated with improved survival and delayed treatment intensification, consistent with a longer time on ADT-based regimens before escalation. Among the 107 patients who ultimately underwent intensification (70 non-CRP; 37 CRP), intensification PFS (time from TI start to progression/death) did not differ significantly between groups (Figure 1D; p=0.67). Approximately 42% of patients in each group remained progression-free at 2 years following initiation of TI. This suggests that once disease biology mandates escalation to second-line systemic therapy, subsequent trajectories are broadly similar regardless of prior primary-tumor extirpation. Taken together with the no-intensification results, these findings support a model in which CRP primarily extends the pre-intensification interval and improves overall outcomes, rather than materially altering post-intensification disease course. Finally, a summary forest plot (Supplementary Figure S4) presents hazard ratios comparing CRP with non-CRP across prespecified endpoints. CRP was associated with a substantial reduction in overall mortality (HR 0.24), cancer-specific mortality (HR 0.20), and initiation of treatment intensification (HR 0.46), whereas the hazard for post-intensification progression was HR 0.89 and not statistically significant. Taken together, these findings indicate that in de novo mHSPC the principal benefit of CRP lies in improving survival and delaying escalation of systemic therapy, with no clear difference once intensification has commenced. A swimmer plot of individual timelines (Supplementary Figure S5) further illustrates this pattern: patients undergoing CRP more often exhibit prolonged stability on ADT, whereas those managed without local therapy more frequently require earlier escalation and progress more rapidly. Survival Outcomes in Matched Cohort To mitigate confounding by indication, we evaluated outcomes in the propensity score–matched cohort (CRP n=35; non-CRP n=51), which achieved good balance across baseline covariates (most standardised mean differences <0.10). Despite the smaller sample, CRP remained associated with superior survival. As shown in Figure 3 (OS, panel A; CSS, panel B), the 5-year OS was 55.0% for CRP versus 41.0% for non-CRP (p=0.027), and the 5-year CSS was 75.0% versus 54.0%, respectively (p=0.021). These differences correspond to hazard ratios 0.55 in favor of CRP. The persistence of benefit after matching supports that the survival advantage is not solely explained by baseline imbalances. Discussion In this contemporary single-centre cohort of men with de novo mHSPC, cytoreductive radical prostatectomy (CRP) integrated with optimized systemic therapy was associated with longer overall and cancer-specific survival and a materially delayed need for therapy intensification. These associations persisted after multivariable adjustment and propensity score matching, and were directionally consistent across Kaplan–Meier and competing-risk frameworks. Together, they support a model in which surgical cytoreduction extends the hormone-sensitive window—deferring escalation—while outcomes after escalation (post-intensification PFS) largely reflect systemic disease biology rather than prior local control. Relationship to prior evidence Population-based and institutional series first suggested survival advantages with local therapy in de novo metastatic disease, albeit with selection bias. Randomised prostate RT trials refined this view: HORRAD and STAMPEDE Arm H did not show an overall survival benefit in unselected populations, but STAMPEDE demonstrated improved OS in low-volume disease (HR 0.68, 95% CI 0.52–0.90), crystallizing volume-dependent benefit( 6 , 7 , 15 ). Our cohort included mixed volumes, with more low-volume patients in the CRP arm; nonetheless, the association with improved OS persisted after adjustment, consistent with reports that carefully selected surgical candidates—often oligometastatic—can achieve favorable long-term outcomes( 16 , 17 ). Meta-analytic estimates similarly suggest lower all-cause and cancer-specific mortality with prostatectomy in selected patients, while acknowledging heterogeneity and residual confounding( 18 ). Why absolute survival may exceed historical series Our absolute 5-year OS/CSS in the CRP group (~ 70%/84% unmatched; ~55%/75% matched) lies at the high end of older surgical series. Two shifts likely contribute. First, systemic therapy has modernized: our study period (2014–2022) captures increasingly routine ARPI use and earlier intensification, known to improve survival broadly in mHSPC. Second, when potent systemic therapy becomes prevalent in both arms of a comparison, the relative effect of local treatment can be “diluted,” as illustrated by the contrast between STAMPEDE (no routine abiraterone) and PEACE-1 (abiraterone widely allowed): the latter did not confirm an RT–OS advantage in low-volume disease, plausibly because stronger systemic therapy raised outcomes for all and reduced the incremental gain from local treatment( 8 ). Our findings sit within this contemporary context. Endpoints that refine decision-making We explicitly examined “no-intensification survival” (diagnosis to first systemic escalation beyond ADT) and post-intensification PFS—complementary, decision-oriented endpoints that are underreported in surgical series. CRP significantly prolonged the former; in competing-risk analyses treating death as a competing event, the subdistribution hazard for intensification remained lower with surgery (sHR = 0.52). By contrast, among patients who escalated, post-intensification PFS was comparable. This predominantly “front-loaded” effect refines expectations: CRP appears to buy time in the hormone-sensitive phase—plausibly by limiting metastatic seeding, removing resistant niches, and reducing local morbidity that disrupts systemic therapy—while once escalation is necessary, systemic disease biology governs subsequent trajectories. Clinical implications. For fit patients with favorable biology and clinicopathologic features—typically younger age, lower CCI, and lower-volume metastatic disease—CRP may be considered within a multimodal strategy with two realistic goals: (i) prolong the ADT-sensitive interval and defer intensification, thereby postponing cumulative ARPI/chemotherapy toxicity and resource use; and (ii) improve OS/CSS alongside optimized systemic therapy. The lack of advantage after intensification helps set expectations and emphasizes that CRP complements rather than replaces modern systemic regimens. In settings where real-world adoption of intensification remains incomplete, safe local cytoreduction that extends disease control on baseline therapy may be particularly meaningful. Limitations and ongoing trials. Residual confounding is possible despite adjustment and propensity matching; surgical candidates were younger, less comorbid, and more often low-volume. Treatment patterns evolved over time; increasing ARPI/triplet use may confound effect estimates. Median follow-up (~ 3 years) may underestimate late events, and patient-reported outcomes were not captured. We did not directly compare CRP with prostate RT; equipoise remains, and head-to-head randomised data are needed. Readouts from SWOG S1802 (systemic therapy ± definitive local treatment by surgery or prostate RT)( 19 ) and surgery-focused trials such as SIMCAP are expected to quantify incremental survival benefit( 20 ), clarify modification by metastatic burden and systemic backbone, and define how (and for whom) CRP should be incorporated into standard care. Conclusion In men with synchronous mHSPC treated in the ARPI era, cytoreductive radical prostatectomy, integrated with guideline-concordant systemic therapy, was associated with improved OS/CSS and a robust delay to treatment intensification, while post-intensification trajectories were similar between groups. These observational findings, consistent after multivariable adjustment and propensity matching, support CRP as a potential component of multimodal care for carefully selected patients and warrant confirmation in randomised trials. Abbreviations ADT = Androgen Deprivation Therapy ARPI = Androgen Receptor Pathway Inhibitor CRP = Cytoreductive Radical Prostatectomy RT = Radiotherapy OS = Overall Survival CSS = Cancer-Specific Survival PFS = Progression-Free Survival TI = Treatment Intensification sHR = Subdistribution Hazard Ratio PSA = Prostate-Specific Antigen iPSA = Initial Prostate-Specific Antigen ECOG = Eastern Cooperative Oncology Group CCI = Charlson Comorbidity Index BMI = Body Mass Index cT = Clinical T Stage cN = Clinical Nodal Status cM = Clinical Metastatic Stage PSM = Propensity Score Matching SMD = Standardised Mean Difference STROBE = Strengthening the Reporting of Observational Studies in Epidemiology KM = Kaplan–Meier CIF = Cumulative Incidence Function HR = Hazard Ratio CI = Confidence Interval SIMCAP = Surgery in Metastatic Carcinoma of Prostate (clinical trial acronym) Declarations Acknowledgements: The authors have no acknowledgements to declare. Declaration of Interests: The corresponding author has collected ICMJE Declaration of Interests forms from all co-authors. All authors declare no competing interests. Ethics Statement: This study was approved by the Institutional Review Board of Tungs’ Taichung MetroHarbor Hospital (Approval No. 113020). Given the retrospective design, the requirement for informed consent was waived. The study was conducted in accordance with the Declaration of Helsinki and all patient data were handled with confidentiality. Data Availability: The datasets generated and analyzed during the current study are not publicly available due to privacy regulations but are available from the corresponding author on reasonable request. De-identified summary data are presented within the article and supplementary files. Funding: This research received no external funding. It was supported by departmental resources only. Author Contributions: Study conception & design: Yi Sheng Lin, Yen Chuan Ou Data acquisition: Yi Hong Li, Yi Sheng Lin, Li Hua Huang, Wei Chun Weng Surgery & clinical oversight: Yi Sheng Lin, Li Hua Huang, Wei Chun Weng, Yen Chuan Ou Data analysis & interpretation: Yi Hong Li, Yen Chuan Ou Drafting of the manuscript: Yi Hong Li Critical revision of the manuscript: All authors Supervision & guarantor: Yi Sheng Lin, Yen Chuan Ou All authors approved the final version and agree to be accountable for all aspects of the work. References James ND, de Bono JS, Spears MR, Clarke NW, Mason MD, Dearnaley DP, et al. Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. N Engl J Med. 2017;377(4):338–51. Davis ID, Martin AJ, Stockler MR, Begbie S, Chi KN, Chowdhury S, et al. Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. N Engl J Med. 2019;381(2):121–31. Chi KN, Agarwal N, Bjartell A, Chung BH, Pereira de Santana Gomes AJ, Given R, et al. 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Investig Clin Urol. 2023;64(3):242–54. ClinicalTrials.gov. SWOG S1802: Standard systemic therapy with or without definitive treatment of the primary tumor 2018 [Available from: https://clinicaltrials.gov/ct2/show/NCT03678025. ClinicalTrials.gov. Phase 2.5 Multi-institution Randomized Prospective Clinical Trial Evaluating the Impact of Cytoreductive Radical Prostatectomy Combined With Best Systemic Therapy on Oncologic & Quality-of-Life Outcomes in Men With Newly Diagnosed Metastatic Prostate Cancer (SIMCAP) 2018 [Available from: https://clinicaltrials.gov/study/NCT03456843. Tables Table 1 and 2 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files SupplementaryFigureS1PRISMAFlowchart.jpg SupplementaryFigureS2LovePlot.png SupplementaryFigureS3Overlap.png SupplementaryFigureS4ForestplotHR.png SupplementaryFigureS5Swimmerplot.png SupplementaryLegends.docx Table1.docx Table2.docx Cite Share Download PDF Status: Posted Version 1 posted 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-7696870","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":525593394,"identity":"b37bd483-a083-47fb-ba6f-74b4ae03c1d9","order_by":0,"name":"Yi Hong Li","email":"","orcid":"","institution":"Tungs' Taichung MetroHarbor Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yi","middleName":"Hong","lastName":"Li","suffix":""},{"id":525593396,"identity":"5fc2daeb-a7f1-4b73-8acc-9a741ecf8aa4","order_by":1,"name":"Yi Sheng 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10:26:08","extension":"html","order_by":22,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":123980,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7696870/v1/76260c7c94903bd277969325.html"},{"id":93580978,"identity":"5d40c8c6-41d6-4877-9d1f-3d7e56538971","added_by":"auto","created_at":"2025-10-15 10:26:08","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":323362,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan–Meier survival curves in the overall cohort (N = 164; CRP 58, non-CRP 106).\u003c/strong\u003e\u003cbr\u003e\n(A) \u003cstrong\u003eOverall survival (OS)\u003c/strong\u003e and (B) \u003cstrong\u003ecancer-specific survival (CSS)\u003c/strong\u003ecomparing cytoreductive radical prostatectomy (CRP) vs no local therapy. (C) \u003cstrong\u003eNo-intensification survival\u003c/strong\u003e (time from diagnosis to initiation of treatment intensification [TI]) (\u003cstrong\u003edeath censored; groups compared by log-rank\u003c/strong\u003e); the corresponding competing-risk analysis is shown in Figure 2. (D) \u003cstrong\u003eIntensification progression-free survival (intensification PFS)\u003c/strong\u003e among patients who underwent TI (N = 107; CRP 37, non-CRP 70).\u003c/p\u003e","description":"","filename":"Figure1KM4endpoints.png","url":"https://assets-eu.researchsquare.com/files/rs-7696870/v1/7f30475c010f5ba538021ead.png"},{"id":93582575,"identity":"e02e04e5-56ac-4b54-a608-2e0fe1faad45","added_by":"auto","created_at":"2025-10-15 10:42:08","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":133855,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCumulative incidence of treatment intensification with death as a competing risk. (groups compared using Gray’s test with effect size from Fine–Gray sHRs)\u003c/strong\u003e\u003cbr\u003e\nStacked cumulative incidence functions (CIFs) for \u003cstrong\u003etime to treatment intensification [TI]\u003c/strong\u003e, with \u003cstrong\u003edeath before TI\u003c/strong\u003e modeled as a competing event. Solid lines denote TI; dashed lines denote death without TI.\u003c/p\u003e","description":"","filename":"Figure2TTICIF.png","url":"https://assets-eu.researchsquare.com/files/rs-7696870/v1/07ed5ea56b4d4d97f0068c61.png"},{"id":93581474,"identity":"70f4e2cf-e4bf-4347-85b2-17ea2b194464","added_by":"auto","created_at":"2025-10-15 10:34:08","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":30194,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan–Meier survival curves after propensity score matching (1:2, caliper 0.1).\u003c/strong\u003e\u003cbr\u003e\nMatched cohort sizes at diagnosis: \u003cstrong\u003eCRP 35, non-CRP 51\u003c/strong\u003e. (A) \u003cstrong\u003eOverall survival\u003c/strong\u003e; (B) \u003cstrong\u003ecancer-specific survival\u003c/strong\u003e.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-7696870/v1/31ac7a7b124cd0ac7ebcc040.png"},{"id":109308753,"identity":"931b026e-2904-422f-a3e0-289128abc0de","added_by":"auto","created_at":"2026-05-15 10:41:06","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":688714,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7696870/v1/ff5d0f8d-60d5-4285-9178-c5b07a423fa0.pdf"},{"id":93580984,"identity":"ed5ee324-4e76-41f7-bcf7-90d525333cce","added_by":"auto","created_at":"2025-10-15 10:26:08","extension":"jpg","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":112052,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFigureS1PRISMAFlowchart.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7696870/v1/7d6897b3eb2202f179817198.jpg"},{"id":93580985,"identity":"99b18d42-23c0-4d7a-a53a-25bc1d141727","added_by":"auto","created_at":"2025-10-15 10:26:08","extension":"png","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":153823,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFigureS2LovePlot.png","url":"https://assets-eu.researchsquare.com/files/rs-7696870/v1/de3b9614cecb4dd57194a212.png"},{"id":93580990,"identity":"a1676727-811d-4f0e-b9ff-2be798c8b9e7","added_by":"auto","created_at":"2025-10-15 10:26:08","extension":"png","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":87387,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFigureS3Overlap.png","url":"https://assets-eu.researchsquare.com/files/rs-7696870/v1/73f12d33c3cdc0fc7b670832.png"},{"id":93581477,"identity":"ef1d382c-4f34-4825-92f1-28f1468dcb82","added_by":"auto","created_at":"2025-10-15 10:34:08","extension":"png","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":110474,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFigureS4ForestplotHR.png","url":"https://assets-eu.researchsquare.com/files/rs-7696870/v1/4b3df208998c4b2e18e0c659.png"},{"id":93580993,"identity":"826ce3f6-4ef1-48c2-9f33-af0565da5295","added_by":"auto","created_at":"2025-10-15 10:26:08","extension":"png","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":411426,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFigureS5Swimmerplot.png","url":"https://assets-eu.researchsquare.com/files/rs-7696870/v1/d813d9fc0e43392215386cfd.png"},{"id":93580998,"identity":"261a50d3-9a2a-43bd-9e36-fbc203395670","added_by":"auto","created_at":"2025-10-15 10:26:08","extension":"docx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":54103,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryLegends.docx","url":"https://assets-eu.researchsquare.com/files/rs-7696870/v1/76b03be0d151a766abb28ab0.docx"},{"id":93580986,"identity":"6a5aa025-588c-4371-afd3-8442fcb8865d","added_by":"auto","created_at":"2025-10-15 10:26:08","extension":"docx","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":26426,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-7696870/v1/eec7b2ae30bef0ee145966b3.docx"},{"id":93581479,"identity":"3ef8832b-f2db-48d2-b892-8df6a27c2407","added_by":"auto","created_at":"2025-10-15 10:34:08","extension":"docx","order_by":8,"title":"","display":"","copyAsset":false,"role":"supplement","size":28700,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.docx","url":"https://assets-eu.researchsquare.com/files/rs-7696870/v1/a268c59eb8992a936c048a4e.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Outcomes after cytoreductive radical prostatectomy for de novo metastatic hormone-sensitive prostate cancer: survival and time to treatment intensification in a retrospective cohort","fulltext":[{"header":"Introduction","content":"\u003cp\u003eManagement of de novo metastatic hormone-sensitive prostate cancer (mHSPC) has shifted from androgen-deprivation therapy (ADT) alone to treatment intensification with either an ARPI-based doublet (ADT\u0026thinsp;+\u0026thinsp;ARPI) or a triplet regimen incorporating docetaxel (ADT\u0026thinsp;+\u0026thinsp;docetaxel\u0026thinsp;+\u0026thinsp;ARPI), both endorsed in contemporary practice (\u003cspan additionalcitationids=\"CR2 CR3 CR4\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Against this backdrop, the role of local therapy to the primary has re-emerged as a clinically relevant question.\u003c/p\u003e\u003cp\u003eRandomised radiotherapy (RT) data have established that treating the prostate can confer benefit in low-volume mHSPC. In STAMPEDE (Arm H), prostate-directed RT improved overall survival in men with low metastatic burden, whereas the overall population showed no survival gain; HORRAD similarly suggested delayed biochemical/clinical failure without clear overall survival improvement (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Current guidelines therefore endorse prostate RT as an option for carefully selected low-volume mHSPC, alongside intensified systemic therapy(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). By contrast, evidence for cytoreductive radical prostatectomy (CRP) remains less mature and more controversial. Retrospective series and registry analyses have associated CRP with lower mortality and fewer local events, but these studies are limited by selection bias and were largely conducted in the pre-ARPI era(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Prospective surgical data include feasibility work (e.g., TRoMbone) and a randomised phase II trial in which radical local therapy\u0026mdash;predominantly prostatectomy\u0026mdash;added to ADT improved radiographic progression-free survival and three-year overall survival versus ADT alone, but definitive phase III evidence is pending (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eImportantly, most historical comparisons of local therapy versus systemic therapy were benchmarked against ADT monotherapy, which may underestimate (or obscure) the incremental value of CRP when layered onto modern systemic backbones. Technical considerations and uncertainty about incremental efficacy have also constrained broader adoption of CRP in routine practice. Consequently, high-quality, contemporary data are needed to clarify whether CRP adds clinically meaningful benefit beyond intensified systemic therapy and to define where any advantage accrues (e.g., prolonging the hormone-sensitive interval versus altering post-escalation trajectories).\u003c/p\u003e\u003cp\u003eTo address this gap, we conducted a single-centre retrospective cohort study comparing CRP plus systemic therapy with systemic therapy alone in men with de novo mHSPC treated in the ARPI era, prespecifying overall and cancer-specific survival as primary endpoints and evaluating decision-oriented secondary endpoints\u0026mdash;time to treatment intensification and post-intensification progression-free survival\u0026mdash;while applying multivariable adjustment and propensity-score matching.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy Design and Patient Selection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe conducted a retrospective cohort study of men with newly diagnosed metastatic prostate cancer at a single tertiary referral centre between 2014 and 2022. The study was approved by the Institutional Review Board, and a waiver of informed consent was obtained due to the retrospective design (IRB113020). Eligible patients had de novo metastatic disease at presentation (i.e., distant metastasis detected at the time of initial prostate cancer diagnosis) with histologically confirmed prostatic adenocarcinoma and no prior definitive local therapy to the prostate. Initial staging included cross-sectional imaging (CT with or without MRI) and technetium bone scintigraphy to confirm metastatic disease. To focus on the synchronous setting, we excluded patients with metachronous metastases (initially localized disease later progressing to metastasis). Additional exclusions were receipt of primary prostate radiotherapy as initial management (to isolate surgery vs no local therapy), absence of any cancer-directed therapy after diagnosis, death during the index hospitalization or within 1 month of diagnosis, \u0026lt;6 months of follow-up, or incomplete treatment/outcomes data. Transurethral resection of the prostate for symptom control was permitted.\u003c/p\u003e\n\u003cp\u003ePatients were categorized according to management of the primary-tumour: the CRP group underwent cytoreductive radical prostatectomy with pelvic lymph node dissection as part of initial management; the non-CRP group received systemic therapy without local treatment of the prostate. The timing of surgery relative to systemic therapy was individualized; in most cases CRP was performed after a short course of androgen deprivation therapy (ADT; approximately 3\u0026ndash;6 months). All CRP procedures were performed with curative intent by uro-oncologic surgeons using a robotic approach.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBaseline Variables and Definitions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBaseline clinicopathologic variables included age at diagnosis, body mass index (BMI), Eastern Cooperative Oncology Group (ECOG) performance status, and Charlson Comorbidity Index (CCI) as a composite measure of comorbidity burden. Tumor-related variables included initial serum PSA (iPSA), clinical T stage (cT) assessed by digital rectal examination and imaging, clinical nodal status (cN), and extent of metastatic disease (cM). Metastatic burden was categorized as low- versus high-volume using criteria aligned with CHAARTED definitions(11). Biopsy Gleason Grade Group was recorded (1\u0026ndash;5) and analyzed as favorable/intermediate (Groups 2\u0026ndash;3) versus high-grade (Groups 4\u0026ndash;5) for selected models.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSystemic Treatments and Treatment Intensification\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSystemic treatment data were abstracted for all patients, including receipt of ADT alone or ADT with treatment intensification (TI). In this study, TI referred to the addition of life-prolonging systemic therapy beyond ADT within the castration-sensitive phase, most commonly docetaxel or next-generation androgen receptor pathway inhibitors (ARPIs) such as abiraterone, enzalutamide, or apalutamide. For each patient, the occurrence and timing of TI initiation were captured. Systemic strategies evolved over the study period: ADT monotherapy predominated in earlier years, whereas combination regimens (ADT + docetaxel or ADT + ARPI) became increasingly common in fit patients following the dissemination of trial evidence. Follow-up typically included PSA testing every 1\u0026ndash;3 months, routine clinical assessments, and imaging at the discretion of the treating team.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEndpoints\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePrimary endpoints were overall survival (OS)\u0026mdash;defined as time from diagnosis to death from any cause\u0026mdash;and cancer-specific survival (CSS)\u0026mdash;defined as time from diagnosis to death attributable to prostate cancer. Cause of death was adjudicated from chart review and death certificates; non-cancer deaths were treated as competing events in CSS analyses. Secondary endpoints included: (1) No-intensification survival, defined as time from diagnosis to initiation of TI (KM analyses censored patients who died before intensification, and competing-risk analyses treated death before intensification as a competing event); and (2) Intensification progression-free survival (intensification PFS), defined among patients who received TI as time from TI start to radiographic or clinical progression, shift to second-line management or death. Progression was determined by rising PSA and/or imaging in the treating physician\u0026rsquo;s assessment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBaseline characteristics were compared between groups using Student\u0026rsquo;s t-test for normally distributed continuous variables, Mann\u0026ndash;Whitney U test for non-normal variables (e.g., PSA), and chi-square or Fisher\u0026rsquo;s exact tests for categorical variables. Survival functions were estimated via Kaplan\u0026ndash;Meier and compared using the log-rank test. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression. Variables with p\u0026lt;0.10 in univariable analysis or with established clinical relevance were considered for multivariable Cox models for OS; proportional hazards assumptions were evaluated and addressed as appropriate.\u003c/p\u003e\n\u003cp\u003eBecause death can preclude intensification, time to TI was also analyzed within a competing-risk framework using cumulative incidence functions (CIFs), with Gray\u0026rsquo;s test used for between-group comparisons and subdistribution hazard ratios reported where appropriate. To mitigate selection bias, we performed propensity score matching (PSM) for receipt of CRP using a logistic regression model incorporating baseline covariates. Nearest-neighbor matching without replacement at a 1:2 ratio (one CRP matched to two non-CRP patients) with a caliper width of 0.1 on the propensity score logit was used. Covariate balance after matching was evaluated using standardised mean differences (SMD), targeting SMD \u0026lt;0.10 for negligible imbalance; where residual imbalances persisted, they were noted and considered in interpretation. All analyses were conducted in R version 4.5.1 (R Foundation for Statistical Computing). Two-sided p\u0026lt;0.05 was considered statistically significant. Reporting followed STROBE guidelines for observational studies(12-14).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003ePatient Characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 164 patients with de novo mHSPC met eligibility criteria, of whom 58 (35.4%) underwent CRP and 106 (64.6%) received no local therapy to the prostate. The patient selection flow diagram is presented in Supplementary Figure S1. In the unmatched cohort (Table 1), CRP patients were younger (mean 68.9 vs 74.6 years, p\u0026lt;0.001), had fewer comorbidities (CCI 9.0 vs 10.3, p\u0026lt;0.001; noting that CCI includes 6 points for metastatic disease), and were more likely to have ECOG 0 performance status (98% vs 73%, p=0.002). They also presented with lower iPSA (median 79 vs 310 ng/mL, p\u0026lt;0.001) and were more frequently low-volume by CHAARTED criteria (59% vs 26%, p\u0026lt;0.001). High-grade disease (Grade Groups 4\u0026ndash;5) was common in both cohorts but more prevalent in non-CRP (94% vs 81%, p=0.014). Clinical T and N stage distributions were broadly similar between groups.\u003c/p\u003e\n\u003cp\u003eAfter PSM (CRP n=35; non-CRP n=51), covariate balance improved substantially, with most SMDs \u0026lt;0.10; small residual imbalances were observed for a minority of variables (Table 2). A Love plot and propensity score overlap (Supplementary Figures S2 and S3) demonstrated acceptable matching quality and common support.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOverall and Cancer-Specific Survival\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt the time of analysis, median follow-up for the overall cohort was 30.6 months (36.2 months among survivors), and 58 deaths had occurred. Overall survival favored the CRP group (Figure 1A). The 5-year OS estimates were 70.2% for CRP and 35.4% for non-CRP. On univariable Cox analysis, CRP was associated with a 75% relative reduction in the hazard of death (HR 0.24, 95% CI 0.13\u0026ndash;0.44, p\u0026lt;0.001). Adjustment for age, CCI, PSA, metastatic volume, Grade Group, and other covariates attenuated but preserved the association (adjusted HR 0.395, 95% CI 0.205\u0026ndash;0.762, p=0.006), indicating an independent association with improved survival over systemic therapy alone (Table 3).\u003c/p\u003e\n\u003cp\u003eCancer-specific survival also favored CRP (Figure 1B), with higher 5-year CSS in the surgical cohort (83.8% vs 49.6% for non-CRP). The unadjusted hazard of prostate cancer\u0026ndash;specific death was 80% lower with CRP (HR 0.20, 95% CI 0.09\u0026ndash;0.45, p\u0026lt;0.001).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTo contextualize the treatment effect, we examined other covariates in OS models. Comorbidity burden (CCI) emerged as an independent predictor of mortality (multivariable HR per point 1.213, 95% CI 1.015\u0026ndash;1.451, p=0.034). High-volume disease was associated with worse OS in univariable analysis (HR 2.269, p=0.002) and demonstrated a borderline association after adjustment (adjusted HR 1.733, 95% CI 0.98\u0026ndash;3.07, p=0.058). In contrast, iPSA, cT stage, and Grade Group (4\u0026ndash;5 vs 2\u0026ndash;3) were not independently associated with OS after accounting for other variables, the latter showing only a trend (adjusted HR 2.31, p=0.081). Collectively, these findings suggest that disease extent and host comorbidity substantially influence prognosis and that the CRP benefit is observed on top of these factors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTreatment Intensification and Progression\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe next evaluated endpoints related to systemic therapy escalation. No-intensification survival (time from diagnosis to initiation of TI) was prolonged in CRP patients (Figure 1C). At 2 years, an estimated 56.6% of CRP patients remained without TI versus 33.6% of non-CRP patients (HR 0.46,\u0026nbsp;95% CI 0.32\u0026ndash;0.67;\u0026nbsp;log-rank p\u0026lt;0.001). To address the possibility that early death could confound the initiation of TI, we performed a competing-risk analysis for time to intensification (Figure 2). The cumulative incidence of TI remained substantially lower in the CRP group across follow-up; for example, by 1 year from diagnosis, approximately 45% of non-CRP patients had initiated additional therapy compared with around 20% of CRP patients. The subdistribution hazard for intensification was significantly reduced with CRP (sHR 0.52, \u0026nbsp;95% CI 0.34\u0026ndash;0.80; Gray\u0026rsquo;s p=0.003). Additionally, a total of 14 patients had ADT withheld\u0026mdash;13 in the CRP cohort and 1 in the non-CRP cohort\u0026mdash;and none have resumed ADT as of the last follow-up. Of the CRP cases, 9 were managed with ADT alone and 4 received a short course of an ARPIs or chemotherapy; the non-CRP case had received ADT alone. Notably, the cumulative incidence of death without intensification was also lower among CRP patients\u0026mdash;consistent with their superior OS\u0026mdash;yet the between-group difference in TI remained statistically significant even when accounting for this competing event. These data suggest that CRP, alongside systemic therapy, is associated with improved survival and delayed treatment intensification,\u0026nbsp;consistent with a longer time on ADT-based regimens before escalation.\u003c/p\u003e\n\u003cp\u003eAmong the 107 patients who ultimately underwent intensification (70 non-CRP; 37 CRP), intensification PFS (time from TI start to progression/death) did not differ significantly between groups (Figure 1D; p=0.67). Approximately 42% of patients in each group remained progression-free at 2 years following initiation of TI. This suggests that once disease biology mandates escalation to second-line systemic therapy, subsequent trajectories are broadly similar regardless of prior primary-tumor extirpation. Taken together with the no-intensification results, these findings support a model in which CRP primarily extends the pre-intensification interval and improves overall outcomes, rather than materially altering post-intensification disease course.\u003c/p\u003e\n\u003cp\u003eFinally, a summary forest plot (Supplementary Figure S4) presents hazard ratios comparing CRP with non-CRP across prespecified endpoints. CRP was associated with a substantial reduction in overall mortality (HR 0.24), cancer-specific mortality (HR 0.20), and initiation of treatment intensification (HR 0.46), whereas the hazard for post-intensification progression was HR 0.89 and not statistically significant. Taken together, these findings indicate that in de novo mHSPC the principal benefit of CRP lies in improving survival and delaying escalation of systemic therapy, with no clear difference once intensification has commenced.\u003c/p\u003e\n\u003cp\u003eA swimmer plot of individual timelines (Supplementary Figure S5) further illustrates this pattern: patients undergoing CRP more often exhibit prolonged stability on ADT, whereas those managed without local therapy more frequently require earlier escalation and progress more rapidly.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSurvival Outcomes in Matched Cohort\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo mitigate confounding by indication, we evaluated outcomes in the propensity score\u0026ndash;matched cohort (CRP n=35; non-CRP n=51), which achieved good balance across baseline covariates (most standardised mean differences \u0026lt;0.10). Despite the smaller sample, CRP remained associated with superior survival. As shown in Figure 3 (OS, panel A; CSS, panel B), the 5-year OS was 55.0% for CRP versus 41.0% for non-CRP (p=0.027), and the 5-year CSS was 75.0% versus 54.0%, respectively (p=0.021). These differences correspond to hazard ratios 0.55 in favor of CRP. The persistence of benefit after matching supports that the survival advantage is not solely explained by baseline imbalances.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this contemporary single-centre cohort of men with de novo mHSPC, cytoreductive radical prostatectomy (CRP) integrated with optimized systemic therapy was associated with longer overall and cancer-specific survival and a materially delayed need for therapy intensification. These associations persisted after multivariable adjustment and propensity score matching, and were directionally consistent across Kaplan\u0026ndash;Meier and competing-risk frameworks. Together, they support a model in which surgical cytoreduction extends the hormone-sensitive window\u0026mdash;deferring escalation\u0026mdash;while outcomes after escalation (post-intensification PFS) largely reflect systemic disease biology rather than prior local control.\u003c/p\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003eRelationship to prior evidence\u003c/h2\u003e\u003cp\u003e Population-based and institutional series first suggested survival advantages with local therapy in de novo metastatic disease, albeit with selection bias. Randomised prostate RT trials refined this view: HORRAD and STAMPEDE Arm H did not show an overall survival benefit in unselected populations, but STAMPEDE demonstrated improved OS in low-volume disease (HR 0.68, 95% CI 0.52\u0026ndash;0.90), crystallizing volume-dependent benefit(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Our cohort included mixed volumes, with more low-volume patients in the CRP arm; nonetheless, the association with improved OS persisted after adjustment, consistent with reports that carefully selected surgical candidates\u0026mdash;often oligometastatic\u0026mdash;can achieve favorable long-term outcomes(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Meta-analytic estimates similarly suggest lower all-cause and cancer-specific mortality with prostatectomy in selected patients, while acknowledging heterogeneity and residual confounding(\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003eWhy absolute survival may exceed historical series\u003c/h2\u003e\u003cp\u003eOur absolute 5-year OS/CSS in the CRP group (~\u0026thinsp;70%/84% unmatched; ~55%/75% matched) lies at the high end of older surgical series. Two shifts likely contribute. First, systemic therapy has modernized: our study period (2014\u0026ndash;2022) captures increasingly routine ARPI use and earlier intensification, known to improve survival broadly in mHSPC. Second, when potent systemic therapy becomes prevalent in both arms of a comparison, the relative effect of local treatment can be \u0026ldquo;diluted,\u0026rdquo; as illustrated by the contrast between STAMPEDE (no routine abiraterone) and PEACE-1 (abiraterone widely allowed): the latter did not confirm an RT\u0026ndash;OS advantage in low-volume disease, plausibly because stronger systemic therapy raised outcomes for all and reduced the incremental gain from local treatment(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Our findings sit within this contemporary context.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003eEndpoints that refine decision-making\u003c/h2\u003e\u003cp\u003eWe explicitly examined \u0026ldquo;no-intensification survival\u0026rdquo; (diagnosis to first systemic escalation beyond ADT) and post-intensification PFS\u0026mdash;complementary, decision-oriented endpoints that are underreported in surgical series. CRP significantly prolonged the former; in competing-risk analyses treating death as a competing event, the subdistribution hazard for intensification remained lower with surgery (sHR\u0026thinsp;=\u0026thinsp;0.52). By contrast, among patients who escalated, post-intensification PFS was comparable. This predominantly \u0026ldquo;front-loaded\u0026rdquo; effect refines expectations: CRP appears to buy time in the hormone-sensitive phase\u0026mdash;plausibly by limiting metastatic seeding, removing resistant niches, and reducing local morbidity that disrupts systemic therapy\u0026mdash;while once escalation is necessary, systemic disease biology governs subsequent trajectories.\u003c/p\u003e\u003cp\u003e\u003cb\u003eClinical implications.\u003c/b\u003e\u003c/p\u003e\u003cp\u003eFor fit patients with favorable biology and clinicopathologic features\u0026mdash;typically younger age, lower CCI, and lower-volume metastatic disease\u0026mdash;CRP may be considered within a multimodal strategy with two realistic goals: (i) prolong the ADT-sensitive interval and defer intensification, thereby postponing cumulative ARPI/chemotherapy toxicity and resource use; and (ii) improve OS/CSS alongside optimized systemic therapy. The lack of advantage after intensification helps set expectations and emphasizes that CRP complements rather than replaces modern systemic regimens. In settings where real-world adoption of intensification remains incomplete, safe local cytoreduction that extends disease control on baseline therapy may be particularly meaningful.\u003c/p\u003e\u003cp\u003e\u003cb\u003eLimitations and ongoing trials.\u003c/b\u003e\u003c/p\u003e\u003cp\u003eResidual confounding is possible despite adjustment and propensity matching; surgical candidates were younger, less comorbid, and more often low-volume. Treatment patterns evolved over time; increasing ARPI/triplet use may confound effect estimates. Median follow-up (~\u0026thinsp;3 years) may underestimate late events, and patient-reported outcomes were not captured. We did not directly compare CRP with prostate RT; equipoise remains, and head-to-head randomised data are needed. Readouts from SWOG S1802 (systemic therapy\u0026thinsp;\u0026plusmn;\u0026thinsp;definitive local treatment by surgery or prostate RT)(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e) and surgery-focused trials such as SIMCAP are expected to quantify incremental survival benefit(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e), clarify modification by metastatic burden and systemic backbone, and define how (and for whom) CRP should be incorporated into standard care.\u003c/p\u003e\u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003e In men with synchronous mHSPC treated in the ARPI era, cytoreductive radical prostatectomy, integrated with guideline-concordant systemic therapy, was associated with improved OS/CSS and a robust delay to treatment intensification, while post-intensification trajectories were similar between groups. These observational findings, consistent after multivariable adjustment and propensity matching, support CRP as a potential component of multimodal care for carefully selected patients and warrant confirmation in randomised trials.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eADT = Androgen Deprivation Therapy\u003c/p\u003e\n\u003cp\u003eARPI = Androgen Receptor Pathway Inhibitor\u003c/p\u003e\n\u003cp\u003eCRP = Cytoreductive Radical Prostatectomy\u003c/p\u003e\n\u003cp\u003eRT = Radiotherapy\u003c/p\u003e\n\u003cp\u003eOS = Overall Survival\u003c/p\u003e\n\u003cp\u003eCSS = Cancer-Specific Survival\u003c/p\u003e\n\u003cp\u003ePFS = Progression-Free Survival\u003c/p\u003e\n\u003cp\u003eTI = Treatment Intensification\u003c/p\u003e\n\u003cp\u003esHR = Subdistribution Hazard Ratio\u003c/p\u003e\n\u003cp\u003ePSA = Prostate-Specific Antigen\u003c/p\u003e\n\u003cp\u003eiPSA = Initial Prostate-Specific Antigen\u003c/p\u003e\n\u003cp\u003eECOG = Eastern Cooperative Oncology Group\u003c/p\u003e\n\u003cp\u003eCCI = Charlson Comorbidity Index\u003c/p\u003e\n\u003cp\u003eBMI = Body Mass Index\u003c/p\u003e\n\u003cp\u003ecT = Clinical T Stage\u003c/p\u003e\n\u003cp\u003ecN = Clinical Nodal Status\u003c/p\u003e\n\u003cp\u003ecM = Clinical Metastatic Stage\u003c/p\u003e\n\u003cp\u003ePSM = Propensity Score Matching\u003c/p\u003e\n\u003cp\u003eSMD = Standardised Mean Difference\u003c/p\u003e\n\u003cp\u003eSTROBE = Strengthening the Reporting of Observational Studies in Epidemiology\u003c/p\u003e\n\u003cp\u003eKM = Kaplan\u0026ndash;Meier\u003c/p\u003e\n\u003cp\u003eCIF = Cumulative Incidence Function\u003c/p\u003e\n\u003cp\u003eHR = Hazard Ratio\u003c/p\u003e\n\u003cp\u003eCI = Confidence Interval\u003c/p\u003e\n\u003cp\u003eSIMCAP = Surgery in Metastatic Carcinoma of Prostate (clinical trial acronym)\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u003c/strong\u003e The authors have no acknowledgements to declare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of Interests:\u003c/strong\u003e The corresponding author has collected ICMJE Declaration of Interests forms from all co-authors. All authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Statement:\u003c/strong\u003e This study was approved by the Institutional Review Board of\u0026nbsp;Tungs\u0026rsquo; Taichung MetroHarbor Hospital\u0026nbsp;(Approval\u0026nbsp;No. 113020). Given the retrospective design, the requirement for informed consent was waived. The study was conducted in accordance with the Declaration of Helsinki and all patient data were handled with confidentiality.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability:\u003c/strong\u003e The datasets generated and analyzed during the current study are not publicly available due to privacy regulations but are available from the corresponding author on reasonable request. De-identified summary data are presented within the article and supplementary files.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e This research received no external funding. It was supported by departmental resources only.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eStudy conception \u0026amp; design: Yi Sheng Lin, Yen Chuan Ou\u003c/p\u003e\n\u003cp\u003eData acquisition: Yi Hong Li, Yi Sheng Lin, Li Hua Huang, Wei Chun Weng\u003c/p\u003e\n\u003cp\u003eSurgery \u0026amp; clinical oversight: Yi Sheng Lin, Li Hua Huang, Wei Chun Weng, Yen Chuan Ou\u003c/p\u003e\n\u003cp\u003eData analysis \u0026amp; interpretation: Yi Hong Li, Yen Chuan Ou\u003c/p\u003e\n\u003cp\u003eDrafting of the manuscript: Yi Hong Li\u003c/p\u003e\n\u003cp\u003eCritical revision of the manuscript: All authors\u003c/p\u003e\n\u003cp\u003eSupervision \u0026amp; guarantor: Yi Sheng Lin, Yen Chuan Ou\u003c/p\u003e\n\u003cp\u003eAll authors approved the final version and agree to be accountable for all aspects of the work.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eJames ND, de Bono JS, Spears MR, Clarke NW, Mason MD, Dearnaley DP, et al. Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. N Engl J Med. 2017;377(4):338\u0026ndash;51.\u003c/li\u003e\n\u003cli\u003eDavis ID, Martin AJ, Stockler MR, Begbie S, Chi KN, Chowdhury S, et al. Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. N Engl J Med. 2019;381(2):121\u0026ndash;31.\u003c/li\u003e\n\u003cli\u003eChi KN, Agarwal N, Bjartell A, Chung BH, Pereira de Santana Gomes AJ, Given R, et al. Apalutamide for Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med. 2019;381(1):13\u0026ndash;24.\u003c/li\u003e\n\u003cli\u003eFizazi K, Foulon S, Carles J, Roubaud G, McDermott R, Fl\u0026eacute;chon A, et al. Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2\u0026thinsp;\u0026times;\u0026thinsp;2 factorial design. Lancet. 2022;399(10336):1695\u0026ndash;707.\u003c/li\u003e\n\u003cli\u003eSmith MR, Hussain M, Saad F, Fizazi K, Sternberg CN, Crawford ED, et al. Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer. N Engl J Med. 2022;386(12):1132\u0026ndash;42.\u003c/li\u003e\n\u003cli\u003eParker CC, James ND, Brawley CD, Clarke NW, Hoyle AP, Ali A, et al. Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. Lancet. 2018;392(10162):2353\u0026ndash;66.\u003c/li\u003e\n\u003cli\u003eBoev\u0026eacute; LMS, Hulshof M, Vis AN, Zwinderman AH, Twisk JWR, Witjes WPJ, et al. Effect on Survival of Androgen Deprivation Therapy Alone Compared to Androgen Deprivation Therapy Combined with Concurrent Radiation Therapy to the Prostate in Patients with Primary Bone Metastatic Prostate Cancer in a Prospective Randomised Clinical Trial: Data from the HORRAD Trial. Eur Urol. 2019;75(3):410\u0026ndash;8.\u003c/li\u003e\n\u003cli\u003eBossi A, Foulon S, Maldonado X, Sargos P, MacDermott R, Kelly P, et al. Efficacy and safety of prostate radiotherapy in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2 x 2 factorial design. Lancet. 2024;404(10467):2065\u0026ndash;76.\u003c/li\u003e\n\u003cli\u003evon Deimling M, Rajwa P, Tilki D, Heidenreich A, Pallauf M, Bianchi A, et al. The current role of precision surgery in oligometastatic prostate cancer. ESMO Open. 2022;7(6):100597.\u003c/li\u003e\n\u003cli\u003eSooriakumaran P, Wilson C, Rombach I, Hassanali N, Aning J, A DL, et al. Feasibility and safety of radical prostatectomy for oligo-metastatic prostate cancer: the Testing Radical prostatectomy in men with prostate cancer and oligo-Metastases to the bone (TRoMbone) trial. BJU Int. 2022;130(1):43\u0026ndash;53.\u003c/li\u003e\n\u003cli\u003eSweeney CJ, Chen YH, Carducci M, Liu G, Jarrard DF, Eisenberger M, et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. N Engl J Med. 2015;373(8):737\u0026ndash;46.\u003c/li\u003e\n\u003cli\u003evon Elm E, Altman DG, Egger M, Pocock SJ, G\u0026oslash;tzsche PC, Vandenbroucke JP. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet. 2007;370(9596):1453\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eAustin PC. An Introduction to Propensity Score Methods for Reducing the Effects of Confounding in Observational Studies. Multivariate Behav Res. 2011;46(3):399\u0026ndash;424.\u003c/li\u003e\n\u003cli\u003eFine JP, Gray RJ. A Proportional Hazards Model for the Subdistribution of a Competing Risk. Journal of the American Statistical Association. 1999;94(446):496\u0026ndash;509.\u003c/li\u003e\n\u003cli\u003eAli A, Hoyle A, Haran AM, Brawley CD, Cook A, Amos C, et al. Association of Bone Metastatic Burden With Survival Benefit From Prostate Radiotherapy in Patients With Newly Diagnosed Metastatic Prostate Cancer: A Secondary Analysis of a Randomized Clinical Trial. JAMA Oncol. 2021;7(4):555\u0026ndash;63.\u003c/li\u003e\n\u003cli\u003eRajwa P, Zattoni F, Maggi M, Marra G, Kroyer P, Shariat SF, et al. Cytoreductive Radical Prostatectomy for Metastatic Hormone-sensitive Prostate Cancer-Evidence from Recent Prospective Reports. Eur Urol Focus. 2023;9(4):637\u0026ndash;41.\u003c/li\u003e\n\u003cli\u003eCheng B, Li B, Fu J, Wang Q, Luo T, Li Z, et al. Evaluating the effectiveness of cytoreductive surgery in oligometastatic prostate cancer: insights from quantitative analysis and retrospective cohort studies. Int J Surg. 2025;111(1):122\u0026ndash;34.\u003c/li\u003e\n\u003cli\u003eChung DY, Kang DH, Jung HD, Lee JY, Kim DK, Ha JS, et al. Cytoreductive prostatectomy may improve oncological outcomes in patients with oligometastatic prostate cancer: An updated systematic review and meta-analysis. Investig Clin Urol. 2023;64(3):242\u0026ndash;54.\u003c/li\u003e\n\u003cli\u003eClinicalTrials.gov. SWOG S1802: Standard systemic therapy with or without definitive treatment of the primary tumor 2018 [Available from: https://clinicaltrials.gov/ct2/show/NCT03678025.\u003c/li\u003e\n\u003cli\u003eClinicalTrials.gov. Phase 2.5 Multi-institution Randomized Prospective Clinical Trial Evaluating the Impact of Cytoreductive Radical Prostatectomy Combined With Best Systemic Therapy on Oncologic \u0026amp; Quality-of-Life Outcomes in Men With Newly Diagnosed Metastatic Prostate Cancer (SIMCAP) 2018 [Available from: https://clinicaltrials.gov/study/NCT03456843.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"metastatic hormone-sensitive prostate cancer, cytoreductive radical prostatectomy, primary-tumour control, treatment intensification, overall survival, cancer-specific survival, propensity score matching, competing risks","lastPublishedDoi":"10.21203/rs.3.rs-7696870/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7696870/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose:\u003c/strong\u003e To evaluate whether cytoreductive radical prostatectomy (CRP) confers benefit beyond contemporary systemic therapy in men with de novo metastatic hormone-sensitive prostate cancer (mHSPC).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003eSingle-center retrospective cohort (2014–2022) comparing CRP plus systemic therapy versus systemic therapy alone. Primary endpoints were overall (OS) and cancer-specific survival (CSS); secondary endpoints were time to treatment intensification (“no-intensification survival”) and post-intensification progression-free survival (PFS). Kaplan–Meier/log-rank and Cox models were used; competing-risk methods estimated subdistribution hazard ratios (sHR) for intensification. Propensity-score matching (1:2; caliper 0.1) tested robustness.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003eAmong 164 patients, 58 received CRP and 106 no local therapy; median follow-up was 30.6 months (36.2 among survivors). In the unmatched cohort, 5-year OS was 70.2% with CRP versus 35.4% without (univariable HR 0.24; multivariable HR 0.40; p=0.006), and 5-year CSS was 83.8% versus 49.6% (HR 0.20; p\u0026lt;0.001). CRP prolonged no-intensification survival (2-year 56.6% vs 33.6%; HR 0.46; log-rank p\u0026lt;0.001) and lowered the cumulative incidence of intensification (sHR 0.52; Gray’s p=0.003). Post-intensification PFS was similar (HR 0.89; p=0.67). After matching (CRP n=35; non-CRP n=51), 5-year OS was 55.0% versus 41.0% (p=0.027) and CSS 75.0% versus 54.0% (p=0.021).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e CRP integrated with systemic therapy was associated with improved OS/CSS and delayed treatment intensification without affecting outcomes after intensification, supporting CRP as a potential component of multimodal management in selected men; randomized trials are warranted.\u003c/p\u003e","manuscriptTitle":"Outcomes after cytoreductive radical prostatectomy for de novo metastatic hormone-sensitive prostate cancer: survival and time to treatment intensification in a retrospective cohort","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-15 10:26:03","doi":"10.21203/rs.3.rs-7696870/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"be4cae53-7822-4e51-b970-cd405c8fff0e","owner":[],"postedDate":"October 15th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-05-15T10:40:28+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-15 10:26:03","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7696870","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7696870","identity":"rs-7696870","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}