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Background: De novo oligometastatic prostate cancer (omPCa) on prostate-specific membrane antigen (PSMA) positron emission tomography (PET) is a new disease entity and its optimal management remains unknown., Objective: To analyze the outcomes of patients treated with cytoreductive radical prostatectomy (cRP) for omPCa on PSMA-PET., Design, Setting, and Participants: Overall, 116 patients treated with cRP at 13 European centers were identified. Oligometastatic PCa was defined as miM1a and/or miM1b with five or fewer osseous metastases and/or miM1c with three or fewer lung lesions on PSMA-PET., Intervention: Cytoreductive radical prostatectomy., Outcome Measurements and Statistical Analysis: Thirty-day complications according to Clavien-Dindo, continence rates, time to castration-resistant PCa (CRPC), and overall survival (OS) were analyzed., Results and Limitations: Overall, 95 (82%) patients had miM1b, 18 (16%) miM1a, and three (2.6%) miM1c omPCa. The median prebiopsy prostate-specific antigen was 14 ng/ml, and 102 (88%) men had biopsy grade group ≥3 PCa. The median number of metastases on PSMA-PET was 2; 38 (33%), 29 (25%), and 49 (42%) patients had one, two, and three or more distant positive lesions. A total of 70 (60%) men received neoadjuvant systemic therapy, and 37 (32%) underwent metastasis-directed therapy. Any and Clavien-Dindo grade ≥3 complications occurred in 36 (31%) and six (5%) patients, respectively. At a median follow-up of 27 mo, 19 (16%) patients developed CRPC and eight (7%) patients died. The 1-yr urinary continence rate was 82%. The 2-yr CRPC-free survival and OS were 85.8% (95% confidence interval [CI] 78.5-93.7%) and 98.9% (95% CI 96.8-100%), respectively. The limitations include retrospective design and short-term follow-up., Conclusions: Cytoreductive radical prostatectomy is a safe and feasible treatment option in patients with de novo omPCa on PSMA-PET. Despite overall favorable oncologic outcomes, some of these patients have a non-negligible risk of early progression and thus should be considered for multimodal therapy., Patient Summary: We found that patients treated at expert centers with surgery for prostate cancer, with a limited number of metastases detected using novel molecular imaging, have favorable short-term survival, functional results, and acceptable rates of complications., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Objective: Pathological features in non-muscle-invasive bladder cancer specimens are pivotal in determining correct patients' therapeutic management. Sparse data exist regarding the importance of second opinion performed by an expert uropathologist. This study aimed to assess the importance of a second opinion by an expert uropathologist in the management of bladder cancer., Methods: The study relied on 272 bladder cancer specimens from 231 patients seeking a pathology second opinion after transurethral resection of the bladder for a clinical suspicion of bladder cancer, relapse, or second-look procedure. Pathology second opinion was offered by an experienced fellowship-trained uropathologist. Discrepancies were recorded considering primary tumor staging, the presence of muscularis propria, and the presence of histological variants. Cases were categorized as no significant discordance, major discordance without management change, and major discordance with management change according to the European Urology Association (EAU) guidelines., Key Findings and Limitations: Among 272 second opinion cases, 39% (108/272) had major discordance and 28% (75/272) had major discordance with change in management according to the EAU guidelines. Upstaging and downstaging were reported in 66 (24%) patients. Improper identification of the presence of muscularis propria was found in 46 (17%) cases, of which 11 (4%) were deemed clinically relevant. Differences regarding the presence of histological variants were diagnosed in 40 cases (15%), resulting in eight (3%) changes in clinical management. In ten specimens (4%), multiple clinically relevant discrepancies were found., Conclusions and Clinical Implications: The second opinion evaluation changed the clinical management in 25% of the cases. These results support the importance of specimen review by an expert uropathologist as a major driver in the correct bladder cancer management., Patient Summary: We investigated the importance of a second opinion performed by an expert uropathologist in the management of bladder cancer. We found that 25% had their treatment plan changed due to the revised pathological report., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: The role of local therapies including radical prostatectomy (RP) in prostate cancer (PCa) patients with clinical lymphadenopathies on prostate-specific membrane antigen (PSMA) positron emission tomography/computerized tomography (PET/CT) has scarcely been explored. Limited data are available to identify men who would benefit from RP; on the contrary, those more likely to benefit already have systemic disease., Objective: We aimed to assess the predictors of prostate-specific antigen (PSA) persistence in surgically managed PCa patients with lymphadenopathies on a PSMA PET/CT scan by integrating clinical, magnetic resonance imaging (MRI), and PSMA PET/CT parameters., Design, Setting, and Participants: We identified 519 patients treated with RP and extended lymph node dissection, and who received preoperative PSMA PET between 2017 and 2022 in nine referral centers. Among them, we selected 88 patients with nodal uptake at preoperative PSMA PET (miTxN1M0)., Outcome Measurements and Statistical Analysis: The outcome was PSA persistence, defined as a PSA value of ≥0.1 ng/ml at the first measurement after surgery. Multivariable logistic regression models tested the predictors of PSA persistence. Covariates consisted of biopsy International Society of Urological Pathology (ISUP) grade group, clinical stage at MRI, and number of positive spots at a PET/CT scan. A regression tree analysis stratified patients into risk groups based on preoperative characteristics., Results and Limitations: Overall, lymph node invasion (LNI) was detected in 63 patients (72%) and 32 (36%) experienced PSA persistence after RP. At multivariable analyses, having more than two lymph nodal positive findings at PSMA PET, seminal vesicle invasion (SVI) at MRI, and ISUP grade group >3 at biopsy were independent predictors of PSA persistence (all p < 0.05). At the regression tree analysis, patients were stratified in four risk groups according to biopsy ISUP grade, number of positive findings at PET/CT, and clinical stage at MRI. The model depicted good discrimination at internal validation (area under the curve 78%)., Conclusions: One out of three miN1M0 patients showed PSA persistence after surgery. Patients with ISUP grade 2-3, as well as patients with organ-confined disease at MRI and a single or two positive nodal findings at PET are those in whom RP may achieve the best oncological outcomes in the context of a multimodal approach. Conversely, patients with a high ISUP grade and extracapsular extension or SVI or more than two spots at PSMA PET should be considered as potentially affected by systemic disease upfront., Patient Summary: Our novel and straightforward risk classification integrates currently available preoperative risk tools and should, therefore, assist physician in preoperative counseling of men candidates for radical treatment for prostate cancer with positive lymph node uptake at prostate-specific membrane antigen positron emission tomography., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Although the therapeutic role of extended pelvic lymph node dissection (ePLND) in patients with prostate cancer (PCa) is still under debate, this procedure is recommended for staging purposes in selected cases. Nomograms for predicting lymph node invasion (LNI) do not account for prostate-specific membrane antigen (PSMA) positron emission tomography (PET) imaging, which is characterized by a high negative predictive value for nodal metastases., Objective: To externally validate models predicting LNI in patients with miN0M0 PCa at PSMA PET and to develop a novel tool in this setting., Design, Setting, and Participants: Overall, 458 patients with miN0M0 disease undergoing radical prostatectomy (RP) and ePLND at 12 centers between 2017 and 2022 were identified., Outcome Measurements and Statistical Analyses: Available tools were externally validated using calibration plots, the area under the receiver operating characteristic curve (AUC), and decision curve analyses to assess calibration, discrimination, and the net benefit. A novel coefficient-based model was developed, internally validated, and compared with available tools., Results and Limitations: Overall, 53 patients (12%) had LNI. The AUC was 69% for the Briganti 2012, 64% for the Briganti 2017, 73% for the Briganti 2019, and 66% for the Memorial Sloan Kettering Cancer Center nomogram. Multiparametric magnetic resonance imaging stage, biopsy grade group 5, the diameter of the index lesion, and the percentage of positive cores at systematic biopsy were independent predictors of LNI (all p ≤ 0.04). Internal cross-validation confirmed a coefficient-based model with AUC of 78%, better calibration, and a higher net benefit in comparison to the other nomograms assessed. Use of a 5% cutoff would have spared 47% ePLND procedures (vs 13% for the Briganti 2019 nomogram) at the cost of missing only 2.1% LNI cases . The lack of central review of imaging and pathology represents the main limitation., Conclusions: Tools for predicting LNI are associated with suboptimal performance for men with miN0M0 PCa. We propose a novel model for predicting LNI that outperforms available tools in this population., Patient Summary: Tools currently used to predict lymph node invasion (LNI) in prostate cancer are not optimal for men with negative node findings on PET (positron emission tomography) scans, leading to a high number of unnecessary extended pelvic lymph node dissection (ePLND) procedures. A novel tool should be used in clinical practice to identify candidates for ePLND to reduce the risk of unnecessary procedures without missing LNI cases., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: A significant proportion of patients with positive multiparametric magnetic resonance imaging (mpMRI; Prostate Imaging-Reporting and Data System [PI-RADS] scores of 3-5) have negative biopsy results., Objective: To systematically assess all prostate-specific antigen density (PSAD) values and identify an appropriate cutoff for identification of patients with positive mpMRI who could potentially avoid biopsy on the basis of their PI-RADS score., Design, Setting, and Participants: The study included a cohort of 1341 patients with positive mpMRI who underwent combined targeted and systematic biopsies., Outcome Measurements and Statistical Analysis: Multivariable logistic regression analysis (MVA) was used to assess the association between PSAD and the risk of clinically significant prostate cancer (csPCa, grade group ≥2) after adjusting for confounders. We used locally weighted scatterplot smoothing to explore csPCa risk according to PSAD and PI-RADS scores. PSAD utility was observed only for patients with PI-RADS 3 lesions, so we plotted the effect of each PSAD value as a cutoff for this subgroup in terms of biopsies saved, csPCa cases missed, and clinically insignificant PCa (ciPCa, grade group 1) cases not detected., Results and Limitations: Overall, 667 (50%) csPCa cases were identified. On MVA, PSAD independently predicted csPCa (odds ratio 1.57; p < 0.001). For PI-RADS ≥4 lesions, the csPCa risk was ≥40% regardless of PSAD. Conversely, among patients with PI-RADS 3 lesions, csPCa risk ranged from 0% to 60% according to PSAD values, and a PSAD cutoff of 0.10 ng/ml/cm 3 corresponded to a threshold probability of 10% for csPCa. Using this PSAD cutoff for patients with PI-RADS 3 lesions would have saved 32% of biopsies, missed 7% of csPCa cases, and avoided detection of 34% of ciPCa cases. Limitations include selection bias and the high experience of the radiologists and urologists involved., Conclusions: Patients with PI-RADS ≥4 lesions should undergo prostate biopsy regardless of their PSAD, while PSAD should be used to stratify patients with PI-RADS 3 lesions. Using a threshold probability of 10% for csPCa, our data suggest that the appropriate strategy is to avoid biopsy in patients with PI-RADS 3 lesions and PSAD <0.10 ng/ml/cm 3 . Our results also provide information to help in tailoring an appropriate strategy for every patient with positive mpMRI findings., Patient Summary: We investigated whether a cutoff value for PSAD (prostate-specific antigen density) could identify patients with suspicious prostate lesions on MRI (magnetic resonance imaging) who could avoid biopsy according to the PI-RADS score for their scan. We found that patients with PI-RADS ≥4 should undergo prostate biopsy regardless of their PSAD. A PSAD cutoff of 0.10 should be used to stratify patients with PI-RADS 3., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Family history (FH) of prostate cancer (PCa) is associated with an increased risk of PCa and adverse disease features. However, whether patients with localized PCa and FH could be considered for active surveillance (AS) remains controversial., Objective: To assess the association between FH and reclassification of AS candidates, and to define predictors of adverse outcomes in men with positive FH., Design, Setting, and Participants: Overall, 656 patients with grade group (GG) 1 PCa included in an AS protocol at a single institution were identified., Outcome Measurements and Statistical Analysis: Kaplan-Meier analyses assessed the time to reclassification (GG ≥2 and GG ≥3 at follow-up biopsies) overall and according to FH status. Multivariable Cox regression tested the impact of FH on reclassification and identified the predictors among men with FH. Men treated with delayed radical prostatectomy (n = 197) or external-beam radiation therapy (n = 64) were identified, and the impact of FH on oncologic outcomes was assessed., Results and Limitations: Overall, 119 men (18%) had FH. The median follow-up was 54 mo (interquartile range 29-84 mo), and 264 patients experienced reclassification. The 5-yr reclassification-free survival rate was 39% versus 57% for FH versus no FH (p = 0.006), and FH was associated with reclassification to GG ≥2 (hazard ratio [HR] 1.60, 95% confidence interval [CI] 1.19-2.15, p = 0.002). In men with FH, the strongest predictors of reclassification were prostate-specific antigen (PSA) density (PSAD), high-volume GG 1 (≥33% of cores involved or ≥50% of any core involved), and suspicious magnetic resonance imaging (MRI) of the prostate (HRs 2.87, 3.04, and 3.87, respectively; all p < 0.05). No association between FH, adverse pathologic features, and biochemical recurrence was observed (all p > 0.05)., Conclusions: Patients with FH on AS are at an increased risk of reclassification. Negative MRI, low disease volume, and low PSAD identify men with FH and a low risk of reclassification. Nonetheless, sample size and wide CIs entail caution in drawing conclusions based on these results., Patient Summary: We tested the impact of family history in men on active surveillance for localized prostate cancer. A significant risk of reclassification, but not adverse oncologic outcomes after deferred treatment, prompts the need for cautious discussion with these patients, without precluding initial expectant management., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

The PROpel trial assessed the combination of olaparib + abiraterone acetate (AA) plus prednisone and androgen deprivation therapy (ADT) versus AA plus prednisone and ADT alone as first-line treatment for metastatic castration-resistant prostate cancer (mCPRP). To contextualize the progression free survival (PFS) benefit in PROpel, we performed a systematic review and quasi-individual patient data network meta-analysis on randomized controlled trials of first-line hormonal treatments for mCPRC. Meta-analysis was performed for the PROpel control arm and PREVAIL (enzalutamide) and COU-AA-302 (AA) treatment arms. Kaplan-Meier PFS curves were digitally reconstructed and differences in restricted mean survival time (ΔRMST) were computed. Combination therapy yielded longer PFS (24-mo ΔRMST 1.5 mo, 95% confidence interval 0.6-2.4) in comparison to novel hormonal treatments alone. However, the lack of mature overall survival data, higher complication rates, and higher health care costs are limitations of combination therapy. Ultimately, combining treatments, rather than molecularly targeted sequencing in cases of failure, might not be justified in unselected patients with mCRPC., Patient Summary: A recent trial showed that for metastatic prostate cancer that does not respond to hormone treatment, combined therapy with two drugs (olaparib and abiraterone) may prolong survival free from cancer progression. We included these data in an analysis of three trials that confirmed a small benefit. This combination approach has higher complication rates and is more expensive, and longer-term results for overall survival are needed., (© 2023 Published by Elsevier B.V. on behalf of European Association of Urology.)

Intermediate clinical endpoints (ICEs) might aid in trial design and potentially expedite study results. However, little is known about the most informative ICE for patients receiving salvage radiation therapy (sRT) after radical prostatectomy. To investigate the most informative ICE for patients receiving sRT, we used a multi-institutional database encompassing patients treated at eight tertiary centers. Overall, 1301 men with node-negative disease who had not received any form of androgen deprivation therapy were identified. Associations of biochemical (BCR) and clinical recurrence (CR) within 1, 3, 5, and 7yr after surgery with the risk of overall mortality were evaluated using multivariable Cox regression analyses fitted at the landmark points of 1, 3, 5, and 7yr after sRT. The discriminative ability of each model for predicting overall survival (OS) was assessed using Harrell's c index. Median follow-up for survivors was 5.6yr (interquartile range 2.0-8.8). On multivariable analysis, progression to CR within 3yr from sRT (hazard ratio 4.19, 95% confidence interval 1.44-11.2; p= 0.008) was the most informative ICE for predicting OS (c index 0.78) compared to CR within 1, 5, and 7yr (c index 0.72, 0.75, and 0.71). In conclusion, progression to CR within 3yr after sRT, irrespective of the time of surgery, was the most informative ICE for prediction of OS. Our study is hypothesis-generating. If these results are confirmed in future prospective studies and surrogacy is met, this information could be applied for study design and could potentially expedite earlier release of results from ongoing randomized controlled trials. PATIENT SUMMARY: Clinical recurrence of prostate cancer within 3yr after salvage radiation therapy, irrespective of the time of radical prostatectomy, represents the most informative intermediate clinical endpoint for the prediction of overall survival. This information could be applied in the design of future studies and could potentially expedite earlier release of results from ongoing randomized controlled trials., (Copyright © 2019 European Association of Urology. All rights reserved.)

Background: The impact of positive surgical margins (PSMs) on the risk of metastases in prostate cancer (PCa) patients treated with radical prostatectomy (RP) is still debated., Objective: To identify PSM features associated with recurrence in a stage-by-stage analysis., Design, Setting, and Participants: A total of 1757 PCa patients treated with RP without neoadjuvant or adjuvant treatments between 2011 and 2017 were identified. Patients were stratified according to the presence of PSM and to margins characteristics in three groups: no versus favourable (single margin <3mm) versus unfavourable (≥3mm or multifocal margin) PSMs., Outcome Measurements and Statistical Analysis: Predictors of biochemical recurrence (BCR) and clinical recurrence (CR) were assessed using semiparametric Cox proportional hazard models., Results and Limitations: Overall, 285 (16%) patients had PSMs; 146 (51%) had a unifocal PSM, while 139 (49%) had a multifocal PSM. The median length of a PSM was 1mm. Overall, 120 (42%) versus 165 (58%) patients had favourable versus unfavourable PSMs. In patients with ≤pT3a and pathologic grade group ≤3 disease (n=1351), favourable (hazard ratio [HR]: 2.24; 95% confidence interval [CI]: 1.19-4.22) and unfavourable (HR: 2.68; 95% CI: 1.49-4.84) PSMs significantly increased the risk of BCR (p<0.01). However, they were not associated with CR (all p>0.05). Conversely, in patients with pT3b/4 and/or pathologic grade group 4-5 and/or pN1 (n=406), only an unfavourable PSM was associated with both BCR (HR: 2.96; 95% CI: 1.19-4.22) and CR (HR: 2.60; 95% CI: 1.07-6.30; all p≤0.04)., Conclusions: Although the presence of PSMs was associated with an increased risk of BCR in all stages, only men with adverse pathologic characteristics and an unfavourable PSM were at an increased risk of experiencing metastases as compared with their counterparts with no or a single margin shorter than 3mm., Patient Summary: In this study, we defined a new category of unfavourable positive surgical margins (namely, ≥3mm and/or multifocal), which confers a higher risk of developing metastasis in men with more aggressive pathologic features., (Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.)