Follow-up Analysis of Intermediate-risk Prostate Cancer Patients Staged With Psma PET/CT

Follow-up Analysis of Intermediate-risk Prostate Cancer Patients Staged With Psma PET/CT | 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 Follow-up Analysis of Intermediate-risk Prostate Cancer Patients Staged With Psma PET/CT Sara Damiani, Priscilla Guglielmo, Guya Mansi, Sara Calzolai Lettieri, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9347158/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 Objective. Radiolabelled PSMA PET/CT has demonstrated high diagnostic accuracy in staging patients with intermediate-risk prostate cancer (PCa). However, its role on long-term prognosis and outcome prediction in this risk-group remains poorly defined. This study aimed to evaluate survival outcomes and identify prognostic factors in intermediate-risk PCa patients staged with PSMA PET/CT before primary treatment. Methods. This is a retrospective, multicenter study of patients diagnosed with intermediate-risk PCa, both favourable (FIR) and unfavorable (UIR), who were staged using radiolabeled PSMA PET/CT to evaluate the extent of the disease before initiating appropriate treatment (either surgery, radiotherapy or systemic treatment), in the period between 2021 and 2024. Primary endpoints were biochemical recurrence (BCR) and radiological recurrence (RR). Survival was assessed using Kaplan-Meier analysis and log-rank tests. The event-free survival was established by using the time between PET/CT examination and the occurrence of the events. All statistical analyses were performed with MedCalc® version 23.3.7 and STATA 18.0/SE. Results. A total of 148 patients were enrolled across all the centers, 112 patients were treated exclusively with local treatment strategies (n = 84 surgery, n = 28 radiotherapy) and 36 with the addition or only with systemic treatment. After a median follow-up of 25 months, 30 (20.3%) patients experienced BCR and 15 (10.1%) RR. UIR patients showed significantly higher PSMA-positivity (20.8% vs 5.6%, p = 0.007) and significantly shorter BCR-free survival compared to FIR (p = 0.039). Extraprostatic PET-positivity (N + or M+) was associated with a trend toward poorer BCR and RR outcomes (p = 0.08). Within the intraprostatic PRIMARY score, score 5 nearly doubled the RR rate compared to score 4 (15.9% vs 8.2%). Main limitations include the retrospective design and relatively short follow-up. Conclusions. PSMA PET/CT may provide early prognostic information in patients with intermediate risk PCa. While its yield in FIR is marginal, molecular staging in UIR effectively identifies aggressive phenotypes at higher risk for early treatment failure, supporting its use to guide treatment intensification in this subgroup. prostate cancer intermediate-risk PSMA PET prognosis Figures Figure 1 1. INTRODUCTION Prostate cancer (PCa) represents one of the most frequently diagnosed malignancies among men worldwide, with a broad spectrum of clinical behavior ranging from indolent to aggressive disease. The growing incidence of this condition underscores its significance in routine clinical practice [ 1 ]. The risk-based classification adopted by current international guidelines, such as European Association of Urology (EAU) and National Comprehensive Cancer Network (NCCN) guidelines, comprises three different subgroups: low-, intermediate- and high-risk [ 2 , 3 ]. Our study focuses on the intermediate-risk cohort, a group characterized by great heterogeneity in terms of oncological features and outcomes and, therefore, can be further classified into favorable and unfavorable subgroups. The former category includes patients with an International Society of Urological Pathology (ISUP) grade group 1–2, prostate-specific antigen (PSA) < 10 ng/mL, cT1-2a and < 50% biopsy cores positive [ 4 ]. The latter, on the other hand, includes patients with ISUP grade group 2 and PSA levels between 10 and 20 ng/mL, or ISUP grade group 3 disease, a clinical stage cT1–2c and ≥ 50% biopsy positive cores [ 5 ]. This distinction has crucial clinical implications, as patients belonging to the unfavorable intermediate-risk group are characterized by a higher likelihood of adverse pathological features and disease progression. According to current guidelines, prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) is recommended as imaging modality for initial staging, because of its superior sensitivity and specificity compared with conventional techniques. Its use is increasingly advocated in patients with intermediate- and high-risk PCa [ 2 , 6 ]. Most available studies have evaluated heterogeneous cohorts, often including patients with high-risk disease [ 7 ]. In previous studies conducted by our group, patients with unfavorable intermediate-risk disease showed a higher incidence of PSMA positivity than those with favorable diseases [ 8 , 9 ]. Therefore, accurate staging in this population is essential to guide treatment selection and optimize clinical management, ultimately improving outcomes. However, evidence regarding the prognostic value of PSMA PET/CT at diagnosis remains limited in the intermediate-risk population. The aim of this multicenter retrospective study was to evaluate the prognostic impact of PSMA PET/CT at initial staging in patients with intermediate-risk PCa, focusing on biochemical and radiological outcomes, to address this gap in scientific literature. 2. PATIENTS AND METHODS 2.1 Study cohort Retrospective data were collected from the Nuclear Medicine Units of the Humanitas group (IRCCS Rozzano, Gavazzeni in Bergamo and Istituto Catanese in Catania), between 2021 and 2024. This represents a sub-analysis from a larger cohort of patients previously included in other recently published papers [ 8 , 9 ], with different endpoints. Eligibility criteria were: (1) age > 18 years; (2) patients with a well-established diagnosis of intermediate-risk PCa (ISUP grade: 2 or 3) according to the D’Amico classification [ 10 ] and (3) availability of baseline [⁶⁸Ga]Ga-PSMA-11 or [¹⁸F]F-PSMA-1007 PET/CT. Exclusion criteria were as follows: (1) previous history of other oncological diseases; (2) previous radiation treatments, androgen-based therapies, or chemotherapies; and (3) missing or unavailable clinical and follow-up data. This study was conducted in accordance with the principles of the Declaration of Helsinki (1964) and received approval from the Ethical Committee (n.169/24, date: 19.03.2024). 2.2 Image acquisition and analysis Image acquisition followed the methodology already explained in previous papers [ 8 , 9 ]. All PSMA PET/CT images were reviewed by two nuclear medicine physicians with at least 5 years of experience with this imaging modality. Positivity criteria were established in accordance with previously published papers [ 8 , 9 ]. Moreover, the PRIMARY score was collected in accordance with the definition provided by Emmet et al. [ 11 ]. 2.3 Follow-up The outcomes were assessed by FUP data obtained from institutional medical records and included biochemical recurrence (BCR), radiological recurrence (RR) and all-cause mortality. BCR was defined according to the previous treatment: after radical prostatectomy it is generally defined as at least two consecutive PSA measurements of ≥ 0.2 ng/ml [ 12 ], after radiation therapy as a PSA rise of ≥ 2.0ng/mL above the nadir, following the Phoenix criteria [ 13 ]. Radiological recurrence (RR), instead, was defined as the detection of disease on magnetic resonance imaging (MRI) or PSMA PET/CT during follow-up. Time to RR was calculated as the time interval between the date of PSMA PET/CT and the occurrence of a radiological recurrence identified at radiological/nuclear medicine procedures. 2.4 Statistical analysis Due to the limited observational period, the primary purpose of the present study was to assess “early” BCR and “early” RR in a cohort of intermediate-risk PCa patients referring to the Humanitas group’s hospitals for initial staging with PSMA PET/CT, further distinguishing between the favorable (FIR) and unfavorable (UIR) intermediate-risk subgroups. A secondary endpoint was to determine the additional prognostic value provided by the PRIMARY Score in this clinical setting. Descriptive statistics regarding patient, imaging, and tumor characteristics were provided for the whole population. Continuous variables were expressed as medians and interquartile ranges (IQR). Categorical variables were presented as absolute frequencies and proportions. The comparison of independent continuous variables was performed using the non-parametric Mann-Whitney U test. The association between categorical variables (e.g., risk groups, PET findings, and PRIMARY score) was assessed using the Pearson chi-square test or Fisher’s exact test, as appropriate. Survival analysis was conducted using the Kaplan-Meier method to estimate BCR-free and RR-free survival rates. Differences between survival curves were compared using the Log-rank test. Statistical significance was set at a p-value < 0.05. Statistical analyses were performed using MedCalc® version 23.3.7 and STATA 18.0/SE. 3. RESULTS Data from 148 patients across the three centres were included in the analysis. According to the EAU risk stratification, favourable and unfavourable intermediate-risk disease accounted for 71 (48.0%) and 77 (52.0%) patients, respectively. The indication for PSMA PET in the FIR group was defined in accordance with multidisciplinary decision. Baseline characteristics of the study population are summarized in Table 1 . Table 1 Baseline characteristics of the study population. Risk group FIR UIR Total Test N 71 (48.0%) 77 (52.0%) 148 (100.0%) Age 70.240 72.730 71.195 0.261 PSA_baseline 6.220 7.300 6.670 0.001 PRIMARY score 1 12 (16.9%) 4 (5.2%) 16 (10.8%) 2A 7 (9.9%) 0 (0.0%) 7 (4.7%) 2B 3 (4.2%) 4 (5.2%) 7 (4.7%) 3 8 (11.3%) 5 (6.5%) 13 (8.8%) 4 27 (38.0%) 34 (44.2%) 61 (41.2%) 5 14 (19.7%) 30 (39.0%) 44 (29.7%) Treatment type Surgery 47 (66.2%) 37 (48.1%) 84 (56.8%) HIFU 5 (7.0%) 1 (1.3%) 6 (4.1%) ADT 0 (0.0%) 6 (7.8%) 6 (4.1%) RT 15 (21.1%) 13 (16.9%) 28 (18.9%) RT + ADT 3 (4.2%) 20 (26.0%) 23 (15.5%) TURP + ADT 1 (1.4%) 0 (0.0%) 1 (0.7%) ADT = androgen deprivation therapy; HIFU = high-intensity focused ultrasound; RT = radiotherapy; TURP = transurethral resection of the prostate. Patients in the UIR group presented higher median baseline PSA levels compared with those belonging to the FIR one (median 7.3 vs 6.2 ng/mL, p = 0.003). No significant difference was observed in median age between the two groups (UIR: 72.7 vs. FIR: 70.2 years, p = 0.14). Regarding treatment, 84 (56.8%) patients underwent radical prostatectomy (± lymphadenectomy) only, while 51 (34.5%) received radiotherapy with or without systemic treatment, with no statistically significant difference in treatment distribution between the two risk groups. The remaining 8.7% was treated with systemic treatment. All patients underwent PET/CT at initial staging, with 60 (40.5%) receiving a [ 68 Ga]Ga-PSMA-11 and 88 (59.5%%) undergoing [ 18 F]F-PSMA-1007 imaging. PSMA uptake was monofocal in 102 (68.9%) patients, with no significant difference between FIR and UIR groups (p = 0.297). Overall, 20/148 (13.5%) patients showed a positive PSMA PET/CT scan for extraprostatic disease. In particular, pelvic lymph node involvement (N+) was detected in 11 (7.4%) patients, while distant metastases (M+) were in 15 (10.1%) and the combination of both in 6 (4.0%). Of these 20 patients with positive PSMA PET/CT scan for extraprostatic disease, seven had surgery, ten had RT + systemic therapy and the remaining three had only systemic treatment. In the subgroup analysis, UIR patients exhibited a significantly higher prevalence of PSMA-PET positivity compared to the FIR counterpart (20.8% vs. 5.6%; p = 0.007). Notably, the diagnostic yield for extraprostatic disease was substantially higher in the UIR group for both nodal (14.3% vs. 0%) and distant metastatic involvement (14.3% vs. 5.6%). After a median FUP period of 25 months (5–55 mo.), 30 (20.3%) patients experienced BCR, 15 (10.1%) RR, while all but one were still alive (death related to other causes). All oncological outcomes are summarized in Table 2 . Table 2 Oncological outcomes (BCR, RR, median BCR-free survival and median RR-free survival) according to intermediate-risk subclassification. Outcome Favorable (FIR) (N = 71) Unfavorable (UIR) (N = 77) p-value Median clinical follow-up, months 27.1 22.0 BCR, n (%) 10 (14.1%) 20 (26.0%) 0.072 BCR-free survival at 24 months 92.9% 78.2% BCR-free survival at 48 months 73.7% 47.7% 0.039 RR, n (%) 6 (8.5%) 9 (11.7%) 0.514 RR-free survival at 24 months 94.4% 88.9% RR-free survival at 48 months 80.8% 61.8% 0.406 Five out of 15 (33.3%) with distant metastases and 3/11 (27.3%) with lymph node involvement at PSMA PET/CT had a BCR. At survival analysis (log-rank test), a positive PSMA PET/CT scan for pelvic lymph nodes strong trend toward shorter BCR-free survival, although not statistically significant (p = 0.069). Notably, positive M-status at initial staging was significantly associated with shorter RR-free survival (p = 0.023). It is visually shown in Fig. 1 . No significant difference was observed in the median FUP time between the two groups (FIR: 27.1 months vs. UIR: 22.0 months). BCR was more frequent in the UIR group compared to the FIR one (26.0%, n = 20/77 vs. 14.1%, n = 10/71, p = 0.072). Kaplan-Meier analysis confirmed a significantly shorter BCR-free survival for UIR patients (p = 0.039). Accordingly, RR experience was reported at a higher rate in UIR patients with respect to patients belonging to the FIR cohort (n = 6/71; 8.5% vs. n = 9/77; 11.7%, respectively; p = 0.51). Survival analysis did not show any significant impact of the primary treatment modality on clinical outcomes. Patients treated with radical prostatectomy only (n = 84) and those who received radiotherapy with or without systemic treatment (n = 51) exhibited comparable survival probabilities. Specifically, no statistically significant difference was observed for BCR-free survival (log-rank test, p = 0.34) or for RR-free survival (log-rank test, p = 0.92). The Kaplan-Meier curves for both treatment groups remained closely aligned throughout the FUP period. At Kaplan-Meier analysis, the PRIMARY score showed a trend toward stratification for RR, although it did not reach formal statistical significance (log-rank test, p = 0.095). No significant stratification was observed for BCR-free survival (p = 0.14). However, a distinct prognostic divergence between PRIMARY 4 and PRIMARY 5 was found. Despite both being high-probability categories, patients with a score of 5 showed a numerically higher burden of recurrence compared to score 4. Specifically, for RR, the event rate nearly doubled from 8.2% (n = 5/61) in score 4 to 15.9% (n = 7/44) in score 5. Based on the abovementioned findings, the relationship between the baseline intraprostatic PRIMARY score and the presence of extraprostatic disease on PSMA PET/CT was investigated. These findings are represented in Table 3 . A distinct clinical trend was observed, although it did not reach formal statistical significance across the six score categories. Notably, all 11 cases of regional lymph node involvement (N+) occurred exclusively in patients with a PRIMARY score of 4 (n = 4; 6.6%) or 5 (n = 7; 15.9%), with no N+ events recorded in scores 1 through 3 (Fisher’s exact test, p = 0.311). Similarly, synchronous distant metastases (M+) were predominantly concentrated in the highest score categories, with 13 out of 15 M+ cases (86.6%) harbored by patients with a PRIMARY score of 4 or 5 (Fisher’s exact test, p = 0.53). Table 3 Distribution of extraprostatic PSMA-positivity (N and M status) across intraprostatic PRIMARY Score categories. PRIMARY score 1 2A 2B 3 4 5 Total Test N 16 (10.8%) 7 (4.7%) 7 (4.7%) 13 (8.8%) 61 (41.2%) 44 (29.7%) 148 (100.0%) PET_N N0 (Negative) 16 (100.0%) 7 (100.0%) 7 (100.0%) 13 (100.0%) 57 (93.4%) 37 (84.1%) 137 (92.6%) 0.311 N+ (Positive) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 4 (6.6%) 7 (15.9%) 11 (7.4%) PET_M M0 (Negative) 16 (100.0%) 6 (85.7%) 7 (100.0%) 12 (92.3%) 55 (90.2%) 37 (84.1%) 133 (89.9%) 0.539 M+ (Positive) 0 (0.0%) 1 (14.3%) 0 (0.0%) 1 (7.7%) 6 (9.8%) 7 (15.9%) 15 (10.1%) 4. DISCUSSION To the best of our knowledge, this is the first multicenter investigation specifically designed to shift the focus from the well-established diagnostic accuracy of PSMA PET/CT toward its prognostic signal in an exclusive cohort of intermediate-risk PCa patients. While previous literature has extensively focused on diagnostic performance [ 6 – 9 , 14 ], our data expands the clinical utility of this molecular imaging modality by exploring its potential in predicting early BCR-free survival and RR-free survival. This study provides the first evidence regarding the ability of this modality to stratify the risk of early treatment failure in patients with intermediate-risk PCa, a population where management decisions remain particularly challenging. In our cohort, according to PET/CT positivity, BCR occurred in 19.5% (n = 25/128) of N0M0 patients and 33.3% (n = 5/15) of those with distant metastases, independently from the nodal status (NxM+). Interestingly, no BCR events were recorded in the small N + M0 subgroup (n = 5); however, this finding must be interpreted with caution due to the limited sample size and potential selection bias regarding immediate treatment intensification in PET-positive nodal disease. RR occurred in 12/128 (9.4%), 0/5 (0.0%), and 3/15 (20.0%) patients, respectively to N0M0, N + M0 and NxM+ groups. Our results partially align with the findings of Cerci et al. [ 7 , 15 ], who identified PSMA PET/CT positivity as a primary predictor of treatment failure. However, unlike their study which included high-risk patients, a population for which PSMA PET is already recommended in international guidelines [ 2 , 3 , 7 , 16 ], our focus on the intermediate-risk population addresses a more nuanced clinical challenge where treatment decisions are often influenced by the subtle balance between oncological safety and over-treatment. PET/CT positivity was correlated with a rate of BCR with 25.0% of cases, while its negativity was associated with a rate of recurrence of 19.5%. It means that a positive PSMA PET increases the risk of BCR of about 5.5%. Notably, 10 out of the 25 BCR events observed in PSMA-negative patients occurred within the FIR subgroup. This finding underscores the limited clinical yield of PSMA PET/CT in this specific population, confirming that molecular imaging provides negligible added value for both primary risk stratification and prognostic assessment in FIR disease, but further information should be done to confirm this assumption. Conversely, another crucial aspect was the rate of recurrence in PET-positive patients; 100% of BCR and RR events recorded in the N + M+ population occurred exclusively in the UIR subgroup. A major finding of our study is the stark difference in PET positivity rates between risk subgroups. Patients in the UIR group demonstrated a significantly higher rate of extraprostatic disease compared to the FIR group (20.8% vs 5.6%, p = 0.007). Specifically, 14.3% of UIR patients harbored nodal involvement (N+) and 14.3% presented distant metastases (M+). This confirms that UIR disease represents a more aggressive biological entity, justifying a more intensive staging workup with PSMA-targeted imaging in this population. These results are consistent with the risk hierarchy reported in recent literature, as the work by Miller et al., which identified extraprostatic disease in 5.9% of FIR, 8.2% of UIR and 14.0% of high-risk patients, while providing even more robust evidence for the unfavorable category [ 17 ]. Although high-risk populations would expectedly yield even higher positivity rates, the 20.8% detection rate observed in our UIR subgroup represents a non-negligible clinical result. Recent studies have shown that up to 15.0% of patients with intermediate-risk PCa present extraprostatic disease detected on PSMA PET imaging [ 18 ]. Still, an important issue highlighted by several studies is the lack of a homogeneous consensus among different guidelines regarding the recommendations for the use of this imaging modality in this risk group, as recently reviewed by Carll et al. [ 19 ]. This lack of consensus is also reflected in the limited number of studies specifically focusing on this patient subgroup, which however is the most prevalent, accounting for up to 65.0% of all PCa cases [ 20 ]. Our findings in the UIR subgroup, which showed a 26.0% BCR rate within only 2 years, are particularly noteworthy when compared to contemporary high-risk PCa series reporting a 60.0% cumulative BCR incidence over 8 years [ 21 ]. Although our current follow-up is limited, the early recurrence signal observed in UIR patients suggests a clinical trajectory that may eventually mirror the aggressive behavior typically associated with high-risk disease as the observation period extends. This suggests that the traditional intermediate-risk classification may underestimate the true metastatic potential of the UIR subgroup, which PSMA PET/CT accurately re-stratifies and upstages toward a high-risk phenotype. Baseline N+ status showed a trend toward shorter BCR-free survival (p = 0.069), while baseline M+ status was associated with shorter RR-free survival (p = 0.023), with only the latter reaching statistical significance. This finding must be interpreted considering the median follow-up of 25 months. In intermediate-risk PCa, biochemical recurrence can occur years after treatment; the emergence of these trends at only two years suggests that with extended follow-up, PSMA PET/CT parameters are likely to become robust predictors of long-term failure. Regarding treatment strategies, our analysis showed no significant differences in BCR-free or RR-free survival between patients undergoing radical prostatectomy and those receiving radiotherapy (with or without systemic treatment). In a cohort accurately staged with PSMA PET/CT, the choice between surgery and radiation can be safely based on patient comorbidities and quality-of-life considerations (median age of the present population was 71 years) as both modalities offer comparable medium-term disease control. However, the identification of a high-risk BCR phenotype via PSMA PET/CT remains crucial for providing a critical window for therapeutic optimization, as recently demonstrated by the EMBARK trial. The EMBARK study demonstrated that patients with a PSA doubling time of ≤ 9 months significantly benefit from systemic intensification (e.g., enzalutamide plus leuprolide) plus local therapies, resulting in superior metastasis-free survival compared to standard androgen deprivation alone [ 22 ]. Therefore, the prognostic signal of initial PSMA PET/CT staging is paramount not only for primary treatment selection but also for identifying those intermediate-risk patients who may eventually require aggressive salvage strategies or systemic intensification. The secondary endpoint of this study was to identify imaging biomarkers capable of predicting treatment failure. While the PRIMARY score was originally developed to improve the diagnostic performance of PSMA PET/CT for the detection of intraprostatic lesions[ 23 ], we explored its potential as a prognostic and predictive tool within intermediate-risk setting, as already stated in a previous paper [ 9 ]. Our analysis indicates that in this specific cohort, the PRIMARY score did not provide a statistically significant prognostic stratification for BCR-free survival (p = 0.14), suggesting a potential predictive value, while a limited prognostic one. It remains unclear whether the lack of formal significance reflects a genuine biological limitation of the PRIMARY score, or if it represents a type II error. The latter is highly plausible given the relatively low event rate and the skewed distribution of scores toward high-probability findings (score 4 and 5), which inherently limits the statistical power to detect subtle differences in oncological outcomes within an intermediate-risk population. However, a noteworthy clinical pattern emerged regarding its predictive value for nodal involvement. Although the association between higher PRIMARY scores and nodal status did not reach statistical significance (p = 0.311), it is clinically striking that 100% of N+ patients exhibited a PRIMARY score of 4 or 5, whereas no nodal metastases were detected in the PRIMARY 1–3 subgroups. This observation suggests that higher PRIMARY scores may reflect biological features associated with an increased likelihood of metastatic spread. Furthermore, considering the RR, the event rate nearly doubled from 8.2% (5/61) in score 4 to 15.9% (7/44) in score 5, which suggests that a PRIMARY score of 5, often characterized by higher SUVmax or more extensive intraprostatic involvement, may act as a marker for a higher risk phenotype even among intermediate-risk patients. 4.1 Limitations This study has some limitations that should be acknowledged. First, its retrospective design may have introduced inherent selection bias, due to the presence of some missing data. Follow-up duration, although adequate to capture early biochemical and radiological outcomes, remains relatively limited for drawing conclusions on long-term oncological endpoints, such as overall survival. Treatment heterogeneity also makes the definition of BCR inhomogeneous. Finally, although the study focused specifically on a specific cohort of patients, the sample size may limit the generalizability of the results and preclude robust subgroup analyses, as well as multivariable evaluation. Indeed, multivariable analysis was not performed. Larger studies with longer FUP are required to validate its value for risk stratification and outcome prediction. 5. CONCLUSIONS In conclusion, PSMA PET/CT at initial staging effectively stratifies intermediate-risk PCa, revealing a high metastatic burden in UIR patients which is largely absent in the FIR subgroup. This advanced imaging modality shows a promising prognostic value in this cohort of patients. The PRIMARY score shows promise as a biological indicator of metastatic potential, though its formal prognostic power remains to be fully validated in larger, prospective cohorts with longer follow-up. Moreover, the inclusion of PSMA PET/CT, as a diagnostic imaging modality, is strongly recommended in future clinical trials. Declarations Funding: the authors declare that the manuscript has not received any funding. Financial or non-financial interests: the authors declare no financial interest. Study-specific approval by the appropriate ethics committee for research involving humans and/or animals: This study was con­ducted in accordance with the principles of the Declaration of Helsinki (1964) and received approval from the Ethical Committee (n.169/24, date: 19.03.2024). Informed consent: the informed consent was collected from all patients involved. AUTHORSHIP: All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Sara Damiani, Priscilla Guglielmo, Guya Mansi, Sara Calzolai Lettieri, Giulia Giacoppo, Demetrio Aricò, Lucia Setti, Alessia Artesani, Giovanni Lughezzani, Angelo Porreca, Antonio Selvaggio, Laura Evangelista. The first draft of the manuscript was written by Sara Damiani and Laura Evangelista and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. References Fillon M. Rates of advanced prostate cancer continue to increase. CA Cancer J Clin. 2020;70:427–9. https://doi.org/10.3322/caac.21641 . Cornford P, Van Den Bergh RCN, Briers E, Van Den Broeck T, Brunckhorst O, Darraugh J et al. EAU-EANM-ESTRO-ESUR-ISUP-SIOG Guidelines on Prostate Cancer-2024 Update. Part I: Screening, Diagnosis, and Local Treatment with Curative Intent [Internet]. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). 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Refining the definition of biochemical failure in the era of stereotactic body radiation therapy for prostate cancer: The Phoenix definition and beyond: Definition of BCF in Prostate SBRT. Radiotherapy and Oncology. Volume 166. Elsevier Ireland Ltd; 2022. pp. 1–7. https://doi.org/10.1016/j.radonc.2021.11.005 . Hagens MJ, Luining WI, Jager A, Donswijk ML, Cheung Z, Wondergem M, et al. The Diagnostic Value of PSMA PET/CT in Men with Newly Diagnosed Unfavorable Intermediate-Risk Prostate Cancer. J Nuclear Med Soc Nuclear Med Inc. 2023;64:1238–43. https://doi.org/10.2967/jnumed.122.265205 . Cerci JJ, Fanti S, Lobato EE, Kumar R, Kunikowska J, Al-Ibraheem A, et al. 68 Ga-PSMA-11 PET/CT for Initial Staging of Unfavorable Intermediate-Risk and High-Risk Prostate Cancer Predicts Overall Survival: An IAEA Multicenter Study. J Nuclear Med [Internet]. 2026. https://doi.org/10.2967/jnumed.125.271173 . jnumed.125.271173. Gillessen S, Turco F, Davis ID, Efstathiou JA, Fizazi K, James ND et al. Management of Patients with Advanced Prostate Cancer. Report from the 2024 Advanced Prostate Cancer Consensus Conference (APCCC). Eur Urol. Elsevier B.V.; 2025. pp. 157–216. https://doi.org/10.1016/j.eururo.2024.09.017 Miller SR, Gonzalez RT, Jackson WC, Caram MEV, Tsao PA, Stensland K, et al. Rates of PSMA PET Staging and Positivity in Newly Diagnosed Prostate Cancer in a National Health Care System. J Nuclear Med Soc Nuclear Med Inc. 2025;66:75–83. https://doi.org/10.2967/jnumed.124.268555 . Mazzone E, Cannoletta D, Quarta L, Chen DC, Thomson A, Barletta F, et al. A Comprehensive Systematic Review and Meta-analysis of the Role of Prostate-specific Membrane Antigen Positron Emission Tomography for Prostate Cancer Diagnosis and Primary Staging before Definitive Treatment. Eur Urol. 2025;87:654–71. https://doi.org/10.1016/j.eururo.2025.03.003 . Carll J, Shi W, Perera M, Lawrentschuk N, Chengodu T, Woon D. Guideline of guidelines: PSMA PET in staging newly diagnosed intermediate-risk prostate cancer. BJU Int John Wiley Sons Inc. 2025;800–4. https://doi.org/10.1111/bju.16872 . Harryman WL, Hinton JP, Sainz R, Gard JMC, Ryniawec JM, Rogers GC, et al. Intermediate risk prostate tumors contain lethal subtypes. Front Urol Front Media SA. 2024. https://doi.org/10.3389/fruro.2024.1487873 . Das S, Luu M, Terris M, Klaassen Z, Kane CJ, Amling C, et al. Contemporary risk of biochemical recurrence after radical prostatectomy in the active surveillance era. Urol Oncol. 2024;42. https://doi.org/10.1016/j.urolonc.2024.02.010 . :175.e1-175.e8. Freedland SJ, de Almeida Luz M, De Giorgi U, Gleave M, Gotto GT, Pieczonka CM, et al. Improved Outcomes with Enzalutamide in Biochemically Recurrent Prostate Cancer. New Engl J Med Mass Med Soc. 2023;389:1453–65. https://doi.org/10.1056/nejmoa2303974 . Emmett L, Buteau J, Papa N, Moon D, Thompson J, Roberts MJ, et al. The Additive Diagnostic Value of Prostate-specific Membrane Antigen Positron Emission Tomography Computed Tomography to Multiparametric Magnetic Resonance Imaging Triage in the Diagnosis of Prostate Cancer (PRIMARY): A Prospective Multicentre Study. Eur Urol. 2021;80:682–9. https://doi.org/10.1016/j.eururo.2021.08.002 . Supplementary Files Supplementarymaterial.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. 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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-9347158","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":622272125,"identity":"585f6fb7-fac7-4642-a91a-55c4e84aba09","order_by":0,"name":"Sara Damiani","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABA0lEQVRIie2PMUsDMRiG3xI4l+Ctcbn+hcANVir6Q1wOhLslcSyCgp3SSbre5l/xDNjl2jmjLp06HLh0OMTvxIJgI+3WIQ8hvJA8eb8AgcDBEn0vPDe0yS4AbDelKknYXelg/EfBf0p/Mn9vMLq4Oj6aV/a8bXEqdPXiboeIRbZVkXWRCiyuteE3mdVG4qykoOoCJ6VHQQ7RM0wbKGn1mAZzXTCWwnalP12ydc88aBOvpB20G+XT4tKjwOURtdCzgm4i2ihjavH9xS2jQbaYkbKS1aNJuaypTr0WXNRvnsFy5prRnX6aqrRZt0kiZyr9UPfDJJ54Buv4fcT/hEAgEAjszxelHl2qKlZZqwAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0009-0004-2622-8123","institution":"Humanitas University","correspondingAuthor":true,"prefix":"","firstName":"Sara","middleName":"","lastName":"Damiani","suffix":""},{"id":622272127,"identity":"1aff1f5e-f41c-4bb9-9fae-fef41be2503f","order_by":1,"name":"Priscilla Guglielmo","email":"","orcid":"","institution":"Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy","correspondingAuthor":false,"prefix":"","firstName":"Priscilla","middleName":"","lastName":"Guglielmo","suffix":""},{"id":622272130,"identity":"cc7a553d-8572-4dc6-9a15-f21586db1a67","order_by":2,"name":"Guya Mansi","email":"","orcid":"","institution":"Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy","correspondingAuthor":false,"prefix":"","firstName":"Guya","middleName":"","lastName":"Mansi","suffix":""},{"id":622272134,"identity":"f0620762-4791-4b4b-93bd-a237e644efa2","order_by":3,"name":"Sara Calzolai Lettieri","email":"","orcid":"","institution":"Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy","correspondingAuthor":false,"prefix":"","firstName":"Sara","middleName":"Calzolai","lastName":"Lettieri","suffix":""},{"id":622272135,"identity":"2ecd99e1-fa6a-4058-84fa-01c38122ec87","order_by":4,"name":"Giulia Giacoppo","email":"","orcid":"","institution":"Nuclear Medicine Unit, Humanitas Istituto Clinico Catanese, Catania, Italy","correspondingAuthor":false,"prefix":"","firstName":"Giulia","middleName":"","lastName":"Giacoppo","suffix":""},{"id":622272139,"identity":"00e903f3-20b6-465e-9372-c10c451b4f14","order_by":5,"name":"Demetrio Aricò","email":"","orcid":"","institution":"Nuclear Medicine Unit, Humanitas Istituto Clinico Catanese, Catania, Italy","correspondingAuthor":false,"prefix":"","firstName":"Demetrio","middleName":"","lastName":"Aricò","suffix":""},{"id":622272141,"identity":"d1a5e02d-96d1-45c8-83db-109f81f4d7ad","order_by":6,"name":"Lucia Setti","email":"","orcid":"","institution":"Nuclear Medicine Unit, Humanitas Gavazzeni, Bergamo, Italy","correspondingAuthor":false,"prefix":"","firstName":"Lucia","middleName":"","lastName":"Setti","suffix":""},{"id":622272142,"identity":"2535d321-b662-4e02-a094-b7e8676a869f","order_by":7,"name":"Alessia Artesani","email":"","orcid":"","institution":"Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy","correspondingAuthor":false,"prefix":"","firstName":"Alessia","middleName":"","lastName":"Artesani","suffix":""},{"id":622272143,"identity":"8e2eab72-423b-4bdc-b351-0ec5279b5a53","order_by":8,"name":"Giovanni Lughezzani","email":"","orcid":"","institution":"Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy","correspondingAuthor":false,"prefix":"","firstName":"Giovanni","middleName":"","lastName":"Lughezzani","suffix":""},{"id":622272144,"identity":"7ad61ca7-8d35-4764-a001-a8652077e9c8","order_by":9,"name":"Angelo Porreca","email":"","orcid":"","institution":"Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy","correspondingAuthor":false,"prefix":"","firstName":"Angelo","middleName":"","lastName":"Porreca","suffix":""},{"id":622272145,"identity":"53383089-29a6-4d9e-97c9-824695012da6","order_by":10,"name":"Antonio Selvaggio","email":"","orcid":"","institution":"Nuclear Medicine Unit, Humanitas Istituto Clinico Catanese, Catania, Italy","correspondingAuthor":false,"prefix":"","firstName":"Antonio","middleName":"","lastName":"Selvaggio","suffix":""},{"id":622272146,"identity":"3cf9ea9f-e601-4acb-8f8c-7aa35287f53a","order_by":11,"name":"Laura Evangelista","email":"","orcid":"","institution":"Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy","correspondingAuthor":false,"prefix":"","firstName":"Laura","middleName":"","lastName":"Evangelista","suffix":""}],"badges":[],"createdAt":"2026-04-07 15:27:43","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9347158/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9347158/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107377946,"identity":"2a56e949-97f6-4f27-a3fb-00f6bb13b68a","added_by":"auto","created_at":"2026-04-21 01:32:44","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":332396,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier curves for BCR-free survival according to PSMA PET/CT nodal status (N0 vs. N+) and for RR-free survival according to PSMA PET/CT metastatic status (M0 vs. M+).\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-9347158/v1/13d17708a9670a312caf269b.png"},{"id":107862655,"identity":"e3402af4-8d64-4446-87e3-25c3656cb2b3","added_by":"auto","created_at":"2026-04-27 05:56:49","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":744432,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9347158/v1/52b008f6-a9dc-436f-b112-27eaa2355555.pdf"},{"id":107486910,"identity":"8f24f2e6-8f90-4730-846a-170e4fcc0270","added_by":"auto","created_at":"2026-04-22 02:39:15","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":19772,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarymaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-9347158/v1/a78b45d161d677c5ddc5ca47.docx"}],"financialInterests":"","formattedTitle":"\u003cp\u003eFollow-up Analysis of Intermediate-risk Prostate Cancer Patients Staged With Psma PET/CT\u003c/p\u003e","fulltext":[{"header":"1. INTRODUCTION","content":"\u003cp\u003eProstate cancer (PCa) represents one of the most frequently diagnosed malignancies among men worldwide, with a broad spectrum of clinical behavior ranging from indolent to aggressive disease. The growing incidence of this condition underscores its significance in routine clinical practice [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The risk-based classification adopted by current international guidelines, such as European Association of Urology (EAU) and National Comprehensive Cancer Network (NCCN) guidelines, comprises three different subgroups: low-, intermediate- and high-risk [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Our study focuses on the intermediate-risk cohort, a group characterized by great heterogeneity in terms of oncological features and outcomes and, therefore, can be further classified into favorable and unfavorable subgroups. The former category includes patients with an International Society of Urological Pathology (ISUP) grade group 1\u0026ndash;2, prostate-specific antigen (PSA)\u0026thinsp;\u0026lt;\u0026thinsp;10 ng/mL, cT1-2a and \u0026lt;\u0026thinsp;50% biopsy cores positive [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. The latter, on the other hand, includes patients with ISUP grade group 2 and PSA levels between 10 and 20 ng/mL, or ISUP grade group 3 disease, a clinical stage cT1\u0026ndash;2c and \u0026ge;\u0026thinsp;50% biopsy positive cores [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. This distinction has crucial clinical implications, as patients belonging to the unfavorable intermediate-risk group are characterized by a higher likelihood of adverse pathological features and disease progression.\u003c/p\u003e \u003cp\u003e According to current guidelines, prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) is recommended as imaging modality for initial staging, because of its superior sensitivity and specificity compared with conventional techniques. Its use is increasingly advocated in patients with intermediate- and high-risk PCa [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Most available studies have evaluated heterogeneous cohorts, often including patients with high-risk disease [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. In previous studies conducted by our group, patients with unfavorable intermediate-risk disease showed a higher incidence of PSMA positivity than those with favorable diseases [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Therefore, accurate staging in this population is essential to guide treatment selection and optimize clinical management, ultimately improving outcomes. However, evidence regarding the prognostic value of PSMA PET/CT at diagnosis remains limited in the intermediate-risk population.\u003c/p\u003e \u003cp\u003eThe aim of this multicenter retrospective study was to evaluate the prognostic impact of PSMA PET/CT at initial staging in patients with intermediate-risk PCa, focusing on biochemical and radiological outcomes, to address this gap in scientific literature.\u003c/p\u003e"},{"header":"2. PATIENTS AND METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Study cohort\u003c/h2\u003e \u003cp\u003eRetrospective data were collected from the Nuclear Medicine Units of the Humanitas group (IRCCS Rozzano, Gavazzeni in Bergamo and Istituto Catanese in Catania), between 2021 and 2024. This represents a sub-analysis from a larger cohort of patients previously included in other recently published papers [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], with different endpoints.\u003c/p\u003e \u003cp\u003eEligibility criteria were: (1) age\u0026thinsp;\u0026gt;\u0026thinsp;18 years; (2) patients with a well-established diagnosis of intermediate-risk PCa (ISUP grade: 2 or 3) according to the D\u0026rsquo;Amico classification [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] and (3) availability of baseline [⁶⁸Ga]Ga-PSMA-11 or [\u0026sup1;⁸F]F-PSMA-1007 PET/CT.\u003c/p\u003e \u003cp\u003eExclusion criteria were as follows: (1) previous history of other oncological diseases; (2) previous radiation treatments, androgen-based therapies, or chemotherapies; and (3) missing or unavailable clinical and follow-up data. This study was conducted in accordance with the principles of the Declaration of Helsinki (1964) and received approval from the Ethical Committee (n.169/24, date: 19.03.2024).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Image acquisition and analysis\u003c/h2\u003e \u003cp\u003eImage acquisition followed the methodology already explained in previous papers [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAll PSMA PET/CT images were reviewed by two nuclear medicine physicians with at least 5 years of experience with this imaging modality. Positivity criteria were established in accordance with previously published papers [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Moreover, the PRIMARY score was collected in accordance with the definition provided by Emmet et al. [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Follow-up\u003c/h2\u003e \u003cp\u003eThe outcomes were assessed by FUP data obtained from institutional medical records and included biochemical recurrence (BCR), radiological recurrence (RR) and all-cause mortality.\u003c/p\u003e \u003cp\u003eBCR was defined according to the previous treatment: after radical prostatectomy it is generally defined as at least two consecutive PSA measurements of \u0026ge;\u0026thinsp;0.2 ng/ml [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], after radiation therapy as a PSA rise of \u0026ge;\u0026thinsp;2.0ng/mL above the nadir, following the Phoenix criteria [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRadiological recurrence (RR), instead, was defined as the detection of disease on magnetic resonance imaging (MRI) or PSMA PET/CT during follow-up. Time to RR was calculated as the time interval between the date of PSMA PET/CT and the occurrence of a radiological recurrence identified at radiological/nuclear medicine procedures.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Statistical analysis\u003c/h2\u003e \u003cp\u003eDue to the limited observational period, the primary purpose of the present study was to assess \u0026ldquo;early\u0026rdquo; BCR and \u0026ldquo;early\u0026rdquo; RR in a cohort of intermediate-risk PCa patients referring to the Humanitas group\u0026rsquo;s hospitals for initial staging with PSMA PET/CT, further distinguishing between the favorable (FIR) and unfavorable (UIR) intermediate-risk subgroups. A secondary endpoint was to determine the additional prognostic value provided by the PRIMARY Score in this clinical setting.\u003c/p\u003e \u003cp\u003eDescriptive statistics regarding patient, imaging, and tumor characteristics were provided for the whole population. Continuous variables were expressed as medians and interquartile ranges (IQR). Categorical variables were presented as absolute frequencies and proportions. The comparison of independent continuous variables was performed using the non-parametric Mann-Whitney U test. The association between categorical variables (e.g., risk groups, PET findings, and PRIMARY score) was assessed using the Pearson chi-square test or Fisher\u0026rsquo;s exact test, as appropriate.\u003c/p\u003e \u003cp\u003eSurvival analysis was conducted using the Kaplan-Meier method to estimate BCR-free and RR-free survival rates. Differences between survival curves were compared using the Log-rank test. Statistical significance was set at a p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05. Statistical analyses were performed using MedCalc\u0026reg; version 23.3.7 and STATA 18.0/SE.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. RESULTS","content":"\u003cp\u003eData from 148 patients across the three centres were included in the analysis. According to the EAU risk stratification, favourable and unfavourable intermediate-risk disease accounted for 71 (48.0%) and 77 (52.0%) patients, respectively. The indication for PSMA PET in the FIR group was defined in accordance with multidisciplinary decision. Baseline characteristics of the study population are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics of the study population.\u003c/p\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=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"5\" nameend=\"c6\" namest=\"c2\"\u003e \u003cp\u003eRisk group\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eFIR\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eUIR\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eTotal\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003eTest\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003eN\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e71 (48.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e77 (52.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e148 (100.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003eAge\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e70.240\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e72.730\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e71.195\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.261\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003ePSA_baseline\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.220\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.300\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.670\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003ePRIMARY score\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003e1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (16.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (5.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16 (10.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003e2A\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (9.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7 (4.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003e2B\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (4.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (5.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7 (4.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003e3\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (11.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (6.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13 (8.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003e4\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27 (38.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e34 (44.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e61 (41.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003e5\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (19.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e30 (39.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e44 (29.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003eTreatment type\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSurgery\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e47 (66.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e37 (48.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e84 (56.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHIFU\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (7.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (1.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6 (4.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eADT\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 (7.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6 (4.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRT\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (21.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13 (16.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e28 (18.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRT\u0026thinsp;+\u0026thinsp;ADT\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (4.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20 (26.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e23 (15.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTURP\u0026thinsp;+\u0026thinsp;ADT\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (1.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (0.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eADT\u0026thinsp;=\u0026thinsp;androgen deprivation therapy; HIFU\u0026thinsp;=\u0026thinsp;high-intensity focused ultrasound; RT\u0026thinsp;=\u0026thinsp;radiotherapy; TURP\u0026thinsp;=\u0026thinsp;transurethral resection of the prostate.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003ePatients in the UIR group presented higher median baseline PSA levels compared with those belonging to the FIR one (median 7.3 vs 6.2 ng/mL, p\u0026thinsp;=\u0026thinsp;0.003). No significant difference was observed in median age between the two groups (UIR: 72.7 vs. FIR: 70.2 years, p\u0026thinsp;=\u0026thinsp;0.14). Regarding treatment, 84 (56.8%) patients underwent radical prostatectomy (\u0026plusmn;\u0026thinsp;lymphadenectomy) only, while 51 (34.5%) received radiotherapy with or without systemic treatment, with no statistically significant difference in treatment distribution between the two risk groups. The remaining 8.7% was treated with systemic treatment.\u003c/p\u003e \u003cp\u003eAll patients underwent PET/CT at initial staging, with 60 (40.5%) receiving a [\u003csup\u003e68\u003c/sup\u003eGa]Ga-PSMA-11 and 88 (59.5%%) undergoing [\u003csup\u003e18\u003c/sup\u003eF]F-PSMA-1007 imaging. PSMA uptake was monofocal in 102 (68.9%) patients, with no significant difference between FIR and UIR groups (p\u0026thinsp;=\u0026thinsp;0.297).\u003c/p\u003e \u003cp\u003eOverall, 20/148 (13.5%) patients showed a positive PSMA PET/CT scan for extraprostatic disease. In particular, pelvic lymph node involvement (N+) was detected in 11 (7.4%) patients, while distant metastases (M+) were in 15 (10.1%) and the combination of both in 6 (4.0%). Of these 20 patients with positive PSMA PET/CT scan for extraprostatic disease, seven had surgery, ten had RT\u0026thinsp;+\u0026thinsp;systemic therapy and the remaining three had only systemic treatment.\u003c/p\u003e \u003cp\u003eIn the subgroup analysis, UIR patients exhibited a significantly higher prevalence of PSMA-PET positivity compared to the FIR counterpart (20.8% vs. 5.6%; p\u0026thinsp;=\u0026thinsp;0.007). Notably, the diagnostic yield for extraprostatic disease was substantially higher in the UIR group for both nodal (14.3% vs. 0%) and distant metastatic involvement (14.3% vs. 5.6%).\u003c/p\u003e \u003cp\u003eAfter a median FUP period of 25 months (5\u0026ndash;55 mo.), 30 (20.3%) patients experienced BCR, 15 (10.1%) RR, while all but one were still alive (death related to other causes). All oncological outcomes are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eOncological outcomes (BCR, RR, median BCR-free survival and median RR-free survival) according to intermediate-risk subclassification.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFavorable (FIR) (N\u0026thinsp;=\u0026thinsp;71)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eUnfavorable (UIR) (N\u0026thinsp;=\u0026thinsp;77)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMedian clinical follow-up, months\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBCR, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (14.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20 (26.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.072\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBCR-free survival at 24 months\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e92.9%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e78.2%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBCR-free survival at 48 months\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e73.7%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e47.7%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.039\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRR, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (8.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (11.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.514\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRR-free survival at 24 months\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e94.4%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e88.9%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRR-free survival at 48 months\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e80.8%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e61.8%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.406\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eFive out of 15 (33.3%) with distant metastases and 3/11 (27.3%) with lymph node involvement at PSMA PET/CT had a BCR. At survival analysis (log-rank test), a positive PSMA PET/CT scan for pelvic lymph nodes strong trend toward shorter BCR-free survival, although not statistically significant (p\u0026thinsp;=\u0026thinsp;0.069). Notably, positive M-status at initial staging was significantly associated with shorter RR-free survival (p\u0026thinsp;=\u0026thinsp;0.023). It is visually shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eNo significant difference was observed in the median FUP time between the two groups (FIR: 27.1 months vs. UIR: 22.0 months). BCR was more frequent in the UIR group compared to the FIR one (26.0%, n\u0026thinsp;=\u0026thinsp;20/77 vs. 14.1%, n\u0026thinsp;=\u0026thinsp;10/71, p\u0026thinsp;=\u0026thinsp;0.072). Kaplan-Meier analysis confirmed a significantly shorter BCR-free survival for UIR patients (p\u0026thinsp;=\u0026thinsp;0.039).\u003c/p\u003e \u003cp\u003eAccordingly, RR experience was reported at a higher rate in UIR patients with respect to patients belonging to the FIR cohort (n\u0026thinsp;=\u0026thinsp;6/71; 8.5% vs. n\u0026thinsp;=\u0026thinsp;9/77; 11.7%, respectively; p\u0026thinsp;=\u0026thinsp;0.51).\u003c/p\u003e \u003cp\u003eSurvival analysis did not show any significant impact of the primary treatment modality on clinical outcomes. Patients treated with radical prostatectomy only (n\u0026thinsp;=\u0026thinsp;84) and those who received radiotherapy with or without systemic treatment (n\u0026thinsp;=\u0026thinsp;51) exhibited comparable survival probabilities. Specifically, no statistically significant difference was observed for BCR-free survival (log-rank test, p\u0026thinsp;=\u0026thinsp;0.34) or for RR-free survival (log-rank test, p\u0026thinsp;=\u0026thinsp;0.92). The Kaplan-Meier curves for both treatment groups remained closely aligned throughout the FUP period.\u003c/p\u003e \u003cp\u003eAt Kaplan-Meier analysis, the PRIMARY score showed a trend toward stratification for RR, although it did not reach formal statistical significance (log-rank test, p\u0026thinsp;=\u0026thinsp;0.095). No significant stratification was observed for BCR-free survival (p\u0026thinsp;=\u0026thinsp;0.14).\u003c/p\u003e \u003cp\u003eHowever, a distinct prognostic divergence between PRIMARY 4 and PRIMARY 5 was found. Despite both being high-probability categories, patients with a score of 5 showed a numerically higher burden of recurrence compared to score 4. Specifically, for RR, the event rate nearly doubled from 8.2% (n\u0026thinsp;=\u0026thinsp;5/61) in score 4 to 15.9% (n\u0026thinsp;=\u0026thinsp;7/44) in score 5.\u003c/p\u003e \u003cp\u003eBased on the abovementioned findings, the relationship between the baseline intraprostatic PRIMARY score and the presence of extraprostatic disease on PSMA PET/CT was investigated. These findings are represented in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. A distinct clinical trend was observed, although it did not reach formal statistical significance across the six score categories. Notably, all 11 cases of regional lymph node involvement (N+) occurred exclusively in patients with a PRIMARY score of 4 (n\u0026thinsp;=\u0026thinsp;4; 6.6%) or 5 (n\u0026thinsp;=\u0026thinsp;7; 15.9%), with no N+ events recorded in scores 1 through 3 (Fisher\u0026rsquo;s exact test, p\u0026thinsp;=\u0026thinsp;0.311). Similarly, synchronous distant metastases (M+) were predominantly concentrated in the highest score categories, with 13 out of 15 M+ cases (86.6%) harbored by patients with a PRIMARY score of 4 or 5 (Fisher\u0026rsquo;s exact test, p\u0026thinsp;=\u0026thinsp;0.53).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDistribution of extraprostatic PSMA-positivity (N and M status) across intraprostatic PRIMARY Score categories.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"10\"\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=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\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=\"9\" nameend=\"c10\" namest=\"c2\"\u003e \u003cp\u003ePRIMARY score\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e2A\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2B\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eTest\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003eN\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (10.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (4.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e7 (4.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e13 (8.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e61 (41.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e44 (29.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e148 (100.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003ePET_N\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eN0 (Negative)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (100.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (100.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e7 (100.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e13 (100.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e57 (93.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e37 (84.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e137 (92.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.311\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eN+ (Positive)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4 (6.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e7 (15.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e11 (7.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003ePET_M\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eM0 (Negative)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (100.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (85.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e7 (100.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12 (92.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e55 (90.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e37 (84.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e133 (89.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.539\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eM+ (Positive)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (14.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 (7.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6 (9.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e7 (15.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e15 (10.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"4. DISCUSSION","content":"\u003cp\u003eTo the best of our knowledge, this is the first multicenter investigation specifically designed to shift the focus from the well-established diagnostic accuracy of PSMA PET/CT toward its prognostic signal in an exclusive cohort of intermediate-risk PCa patients. While previous literature has extensively focused on diagnostic performance [\u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], our data expands the clinical utility of this molecular imaging modality by exploring its potential in predicting early BCR-free survival and RR-free survival.\u003c/p\u003e \u003cp\u003eThis study provides the first evidence regarding the ability of this modality to stratify the risk of early treatment failure in patients with intermediate-risk PCa, a population where management decisions remain particularly challenging.\u003c/p\u003e \u003cp\u003eIn our cohort, according to PET/CT positivity, BCR occurred in 19.5% (n\u0026thinsp;=\u0026thinsp;25/128) of N0M0 patients and 33.3% (n\u0026thinsp;=\u0026thinsp;5/15) of those with distant metastases, independently from the nodal status (NxM+). Interestingly, no BCR events were recorded in the small N\u0026thinsp;+\u0026thinsp;M0 subgroup (n\u0026thinsp;=\u0026thinsp;5); however, this finding must be interpreted with caution due to the limited sample size and potential selection bias regarding immediate treatment intensification in PET-positive nodal disease. RR occurred in 12/128 (9.4%), 0/5 (0.0%), and 3/15 (20.0%) patients, respectively to N0M0, N\u0026thinsp;+\u0026thinsp;M0 and NxM+ groups.\u003c/p\u003e \u003cp\u003eOur results partially align with the findings of Cerci et al. [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], who identified PSMA PET/CT positivity as a primary predictor of treatment failure. However, unlike their study which included high-risk patients, a population for which PSMA PET is already recommended in international guidelines [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], our focus on the intermediate-risk population addresses a more nuanced clinical challenge where treatment decisions are often influenced by the subtle balance between oncological safety and over-treatment.\u003c/p\u003e \u003cp\u003ePET/CT positivity was correlated with a rate of BCR with 25.0% of cases, while its negativity was associated with a rate of recurrence of 19.5%. It means that a positive PSMA PET increases the risk of BCR of about 5.5%. Notably, 10 out of the 25 BCR events observed in PSMA-negative patients occurred within the FIR subgroup. This finding underscores the limited clinical yield of PSMA PET/CT in this specific population, confirming that molecular imaging provides negligible added value for both primary risk stratification and prognostic assessment in FIR disease, but further information should be done to confirm this assumption.\u003c/p\u003e \u003cp\u003eConversely, another crucial aspect was the rate of recurrence in PET-positive patients; 100% of BCR and RR events recorded in the N\u0026thinsp;+\u0026thinsp;M+ population occurred exclusively in the UIR subgroup.\u003c/p\u003e \u003cp\u003eA major finding of our study is the stark difference in PET positivity rates between risk subgroups. Patients in the UIR group demonstrated a significantly higher rate of extraprostatic disease compared to the FIR group (20.8% vs 5.6%, p\u0026thinsp;=\u0026thinsp;0.007). Specifically, 14.3% of UIR patients harbored nodal involvement (N+) and 14.3% presented distant metastases (M+). This confirms that UIR disease represents a more aggressive biological entity, justifying a more intensive staging workup with PSMA-targeted imaging in this population.\u003c/p\u003e \u003cp\u003eThese results are consistent with the risk hierarchy reported in recent literature, as the work by Miller et al., which identified extraprostatic disease in 5.9% of FIR, 8.2% of UIR and 14.0% of high-risk patients, while providing even more robust evidence for the unfavorable category [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAlthough high-risk populations would expectedly yield even higher positivity rates, the 20.8% detection rate observed in our UIR subgroup represents a non-negligible clinical result.\u003c/p\u003e \u003cp\u003eRecent studies have shown that up to 15.0% of patients with intermediate-risk PCa present extraprostatic disease detected on PSMA PET imaging [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Still, an important issue highlighted by several studies is the lack of a homogeneous consensus among different guidelines regarding the recommendations for the use of this imaging modality in this risk group, as recently reviewed by Carll et al. [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. This lack of consensus is also reflected in the limited number of studies specifically focusing on this patient subgroup, which however is the most prevalent, accounting for up to 65.0% of all PCa cases [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOur findings in the UIR subgroup, which showed a 26.0% BCR rate within only 2 years, are particularly noteworthy when compared to contemporary high-risk PCa series reporting a 60.0% cumulative BCR incidence over 8 years [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Although our current follow-up is limited, the early recurrence signal observed in UIR patients suggests a clinical trajectory that may eventually mirror the aggressive behavior typically associated with high-risk disease as the observation period extends. This suggests that the traditional intermediate-risk classification may underestimate the true metastatic potential of the UIR subgroup, which PSMA PET/CT accurately re-stratifies and upstages toward a high-risk phenotype.\u003c/p\u003e \u003cp\u003eBaseline N+ status showed a trend toward shorter BCR-free survival (p\u0026thinsp;=\u0026thinsp;0.069), while baseline M+ status was associated with shorter RR-free survival (p\u0026thinsp;=\u0026thinsp;0.023), with only the latter reaching statistical significance. This finding must be interpreted considering the median follow-up of 25 months. In intermediate-risk PCa, biochemical recurrence can occur years after treatment; the emergence of these trends at only two years suggests that with extended follow-up, PSMA PET/CT parameters are likely to become robust predictors of long-term failure.\u003c/p\u003e \u003cp\u003eRegarding treatment strategies, our analysis showed no significant differences in BCR-free or RR-free survival between patients undergoing radical prostatectomy and those receiving radiotherapy (with or without systemic treatment). In a cohort accurately staged with PSMA PET/CT, the choice between surgery and radiation can be safely based on patient comorbidities and quality-of-life considerations (median age of the present population was 71 years) as both modalities offer comparable medium-term disease control. However, the identification of a high-risk BCR phenotype via PSMA PET/CT remains crucial for providing a critical window for therapeutic optimization, as recently demonstrated by the EMBARK trial. The EMBARK study demonstrated that patients with a PSA doubling time of \u0026le;\u0026thinsp;9 months significantly benefit from systemic intensification (e.g., enzalutamide plus leuprolide) plus local therapies, resulting in superior metastasis-free survival compared to standard androgen deprivation alone [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Therefore, the prognostic signal of initial PSMA PET/CT staging is paramount not only for primary treatment selection but also for identifying those intermediate-risk patients who may eventually require aggressive salvage strategies or systemic intensification.\u003c/p\u003e \u003cp\u003eThe secondary endpoint of this study was to identify imaging biomarkers capable of predicting treatment failure. While the PRIMARY score was originally developed to improve the diagnostic performance of PSMA PET/CT for the detection of intraprostatic lesions[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], we explored its potential as a prognostic and predictive tool within intermediate-risk setting, as already stated in a previous paper [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Our analysis indicates that in this specific cohort, the PRIMARY score did not provide a statistically significant prognostic stratification for BCR-free survival (p\u0026thinsp;=\u0026thinsp;0.14), suggesting a potential predictive value, while a limited prognostic one. It remains unclear whether the lack of formal significance reflects a genuine biological limitation of the PRIMARY score, or if it represents a type II error. The latter is highly plausible given the relatively low event rate and the skewed distribution of scores toward high-probability findings (score 4 and 5), which inherently limits the statistical power to detect subtle differences in oncological outcomes within an intermediate-risk population.\u003c/p\u003e \u003cp\u003eHowever, a noteworthy clinical pattern emerged regarding its predictive value for nodal involvement. Although the association between higher PRIMARY scores and nodal status did not reach statistical significance (p\u0026thinsp;=\u0026thinsp;0.311), it is clinically striking that 100% of N+ patients exhibited a PRIMARY score of 4 or 5, whereas no nodal metastases were detected in the PRIMARY 1\u0026ndash;3 subgroups. This observation suggests that higher PRIMARY scores may reflect biological features associated with an increased likelihood of metastatic spread. Furthermore, considering the RR, the event rate nearly doubled from 8.2% (5/61) in score 4 to 15.9% (7/44) in score 5, which suggests that a PRIMARY score of 5, often characterized by higher SUVmax or more extensive intraprostatic involvement, may act as a marker for a higher risk phenotype even among intermediate-risk patients.\u003c/p\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e4.1 Limitations\u003c/h2\u003e \u003cp\u003eThis study has some limitations that should be acknowledged. First, its retrospective design may have introduced inherent selection bias, due to the presence of some missing data. Follow-up duration, although adequate to capture early biochemical and radiological outcomes, remains relatively limited for drawing conclusions on long-term oncological endpoints, such as overall survival. Treatment heterogeneity also makes the definition of BCR inhomogeneous. Finally, although the study focused specifically on a specific cohort of patients, the sample size may limit the generalizability of the results and preclude robust subgroup analyses, as well as multivariable evaluation. Indeed, multivariable analysis was not performed. Larger studies with longer FUP are required to validate its value for risk stratification and outcome prediction.\u003c/p\u003e \u003c/div\u003e"},{"header":"5. CONCLUSIONS","content":"\u003cp\u003eIn conclusion, PSMA PET/CT at initial staging effectively stratifies intermediate-risk PCa, revealing a high metastatic burden in UIR patients which is largely absent in the FIR subgroup. This advanced imaging modality shows a promising prognostic value in this cohort of patients. The PRIMARY score shows promise as a biological indicator of metastatic potential, though its formal prognostic power remains to be fully validated in larger, prospective cohorts with longer follow-up. Moreover, the inclusion of PSMA PET/CT, as a diagnostic imaging modality, is strongly recommended in future clinical trials.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eFunding: the authors declare that the manuscript has not received any funding.\u003c/p\u003e\n\u003cp\u003eFinancial or non-financial interests: the authors declare no financial interest.\u003c/p\u003e\n\u003cp\u003eStudy-specific approval by the appropriate ethics committee for research involving humans and/or animals:\u0026nbsp;This study was con\u0026shy;ducted in accordance with the principles of the Declaration of Helsinki (1964) and received approval from the Ethical Committee (n.169/24, date: 19.03.2024).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eInformed consent: the informed consent was collected from all patients involved.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAUTHORSHIP:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Sara Damiani, Priscilla Guglielmo, Guya Mansi, Sara Calzolai Lettieri, Giulia Giacoppo, Demetrio Aric\u0026ograve;, Lucia Setti, Alessia Artesani, Giovanni Lughezzani, Angelo Porreca, Antonio Selvaggio, Laura Evangelista. The first draft of the manuscript was written by Sara Damiani and Laura Evangelista and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eFillon M. Rates of advanced prostate cancer continue to increase. 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Elsevier B.V.; 2025. pp. 157\u0026ndash;216. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.eururo.2024.09.017\u003c/span\u003e\u003cspan address=\"10.1016/j.eururo.2024.09.017\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMiller SR, Gonzalez RT, Jackson WC, Caram MEV, Tsao PA, Stensland K, et al. Rates of PSMA PET Staging and Positivity in Newly Diagnosed Prostate Cancer in a National Health Care System. J Nuclear Med Soc Nuclear Med Inc. 2025;66:75\u0026ndash;83. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.2967/jnumed.124.268555\u003c/span\u003e\u003cspan address=\"10.2967/jnumed.124.268555\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMazzone E, Cannoletta D, Quarta L, Chen DC, Thomson A, Barletta F, et al. A Comprehensive Systematic Review and Meta-analysis of the Role of Prostate-specific Membrane Antigen Positron Emission Tomography for Prostate Cancer Diagnosis and Primary Staging before Definitive Treatment. Eur Urol. 2025;87:654\u0026ndash;71. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.eururo.2025.03.003\u003c/span\u003e\u003cspan address=\"10.1016/j.eururo.2025.03.003\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCarll J, Shi W, Perera M, Lawrentschuk N, Chengodu T, Woon D. Guideline of guidelines: PSMA PET in staging newly diagnosed intermediate-risk prostate cancer. BJU Int John Wiley Sons Inc. 2025;800\u0026ndash;4. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1111/bju.16872\u003c/span\u003e\u003cspan address=\"10.1111/bju.16872\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHarryman WL, Hinton JP, Sainz R, Gard JMC, Ryniawec JM, Rogers GC, et al. 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The Additive Diagnostic Value of Prostate-specific Membrane Antigen Positron Emission Tomography Computed Tomography to Multiparametric Magnetic Resonance Imaging Triage in the Diagnosis of Prostate Cancer (PRIMARY): A Prospective Multicentre Study. Eur Urol. 2021;80:682\u0026ndash;9. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.eururo.2021.08.002\u003c/span\u003e\u003cspan address=\"10.1016/j.eururo.2021.08.002\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":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":"prostate cancer, intermediate-risk, PSMA PET, prognosis","lastPublishedDoi":"10.21203/rs.3.rs-9347158/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9347158/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e \u003cb\u003eObjective.\u003c/b\u003e Radiolabelled PSMA PET/CT has demonstrated high diagnostic accuracy in staging patients with intermediate-risk prostate cancer (PCa). However, its role on long-term prognosis and outcome prediction in this risk-group remains poorly defined. This study aimed to evaluate survival outcomes and identify prognostic factors in intermediate-risk PCa patients staged with PSMA PET/CT before primary treatment.\u003c/p\u003e \u003cp\u003e \u003cb\u003eMethods.\u003c/b\u003e This is a retrospective, multicenter study of patients diagnosed with intermediate-risk PCa, both favourable (FIR) and unfavorable (UIR), who were staged using radiolabeled PSMA PET/CT to evaluate the extent of the disease before initiating appropriate treatment (either surgery, radiotherapy or systemic treatment), in the period between 2021 and 2024.\u003c/p\u003e \u003cp\u003ePrimary endpoints were biochemical recurrence (BCR) and radiological recurrence (RR). Survival was assessed using Kaplan-Meier analysis and log-rank tests. The event-free survival was established by using the time between PET/CT examination and the occurrence of the events. All statistical analyses were performed with MedCalc\u0026reg; version 23.3.7 and STATA 18.0/SE.\u003c/p\u003e \u003cp\u003e \u003cb\u003eResults.\u003c/b\u003e A total of 148 patients were enrolled across all the centers, 112 patients were treated exclusively with local treatment strategies (n\u0026thinsp;=\u0026thinsp;84 surgery, n\u0026thinsp;=\u0026thinsp;28 radiotherapy) and 36 with the addition or only with systemic treatment. After a median follow-up of 25 months, 30 (20.3%) patients experienced BCR and 15 (10.1%) RR. UIR patients showed significantly higher PSMA-positivity (20.8% vs 5.6%, p\u0026thinsp;=\u0026thinsp;0.007) and significantly shorter BCR-free survival compared to FIR (p\u0026thinsp;=\u0026thinsp;0.039). Extraprostatic PET-positivity (N\u0026thinsp;+\u0026thinsp;or M+) was associated with a trend toward poorer BCR and RR outcomes (p\u0026thinsp;=\u0026thinsp;0.08). Within the intraprostatic PRIMARY score, score 5 nearly doubled the RR rate compared to score 4 (15.9% vs 8.2%). Main limitations include the retrospective design and relatively short follow-up.\u003c/p\u003e \u003cp\u003e \u003cb\u003eConclusions.\u003c/b\u003e PSMA PET/CT may provide early prognostic information in patients with intermediate risk PCa. While its yield in FIR is marginal, molecular staging in UIR effectively identifies aggressive phenotypes at higher risk for early treatment failure, supporting its use to guide treatment intensification in this subgroup.\u003c/p\u003e","manuscriptTitle":"Follow-up Analysis of Intermediate-risk Prostate Cancer Patients Staged With Psma PET/CT","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-21 01:32:40","doi":"10.21203/rs.3.rs-9347158/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":"5ff6a3b6-7972-4a97-bb3f-bd5447afba58","owner":[],"postedDate":"April 21st, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-04-27T05:56:39+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-21 01:32:40","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9347158","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9347158","identity":"rs-9347158","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}