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Context: Many liquid biomarkers have entered clinical practice with the praise to improve the detection of clinically significant prostate cancer (csPCa), helping avoid unnecessary prostate biopsies., Objective: We aimed to assess the diagnostic accuracy of multianalyte biomarkers for csPCa detection using multiple thresholds., Evidence Acquisition: A comprehensive literature search was done through PubMed, Web of Science, and Scopus in March 2023 for prospective and retrospective studies reporting the diagnostic performance of liquid biomarkers for detecting csPCa. The outcomes of interest were the diagnostic performance of liquid biomarkers for csPCa detection and identification of optimal thresholds for each biomarker., Evidence Synthesis: Overall, 49 studies were eligible for this meta-analysis. Using each representative threshold based on the Youden Index, the pooled sensitivity and specificity for detecting csPCa were 0.85 and 0.37 for prostate cancer gene 3 (PCA3), 0.85 and 0.52 for prostate health index (PHI), 0.87 and 0.58 for four kallikrein (4K), 0.82 and 0.56 for SelectMDx, 0.85 and 0.54 for ExoDx, and 0.82 and 0.59 for mi prostate score (MPS), respectively. The diagnostic odds ratio was highest for 4K (8.84), followed by MPS (7.0) and PHI (6.28). According to the meta-analysis incorporating multiple thresholds, the corresponding sensitivity was 0.77 for 4K, 0.69 for PHI, and 0.63 for PCA3; specificity was 0.72 for PHI, 0.70 for 4K, and 0.69 for PCA3., Conclusions: Regarding the detection of csPCa, 4K had the highest diagnostic performance among the commercial liquid biomarkers. Based on the optimal thresholds calculated by the present meta-analysis, 4K had the highest sensitivity and PHI had the highest specificity for detecting csPCa. Nevertheless, clinical decision-making requires combination strategies between liquid and imaging biomarkers., Patient Summary: Novel biomarkers for prostate cancer detection were useful for more accurate diagnosis of clinically significant prostate cancer to avoid unnecessary biopsies., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Context: Active surveillance (AS) is a standard of care for patients with low-risk and selected intermediate-risk prostate cancer (PCa). Nevertheless, there is a lack of summary evidence on how to impact disease trajectory during AS., Objective: To assess which interventions prevent PCa progression effectively during AS., Evidence Acquisition: We queried PubMed, Scopus, and Web of Science databases to identify studies examining the impact of interventions aimed at slowing disease progression during AS. The primary endpoint was PCa progression, the definition of which must have included pathological upgrading. The secondary endpoint included treatment toxicities., Evidence Synthesis: We identified 22 studies, six randomized controlled trials and 16 observational studies, which analyzed the association between different interventions and PCa progression during AS. The interventions considered in the studies included 5-alpha reductase inhibitors (5-ARIs), statins, diet, exercise, chlormadinone, fexapotide triflutate (FT), enzalutamide, coffee, vitamin D3, and PROSTVAC. We found that administration of 5-ARIs was associated with improved progression-free survival (PFS; hazard ratio: 0.59; 95% confidence interval 0.48-0.72), with no increased toxicity signals. Therapies such as vitamin D3, chlormadinone, FT, and enzalutamide have shown some efficacy. However, these anticancer drugs have been associated with treatment-related adverse events in up to 88% of patients., Conclusions: The use of 5-ARIs in PCa patients on AS is associated with longer PFS. However, for the other interventions, it is difficult to draw clear conclusions based on the weak available evidence., Patient Summary: Patients with prostate cancer managed with active surveillance (AS) who are treated with 5-alpha reductase inhibitors have a lower risk of disease progression, with minimal adverse events. Other interventions require more studies to determine their efficacy and safety profile in men on AS., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Triplet therapy, androgen receptor signaling inhibitors (ARSIs) plus docetaxel plus androgen-deprivation therapy (ADT), is a novel guideline-recommended treatment for metastatic hormone-sensitive prostate cancer (mHSPC). However, the optimal selection of the patient most likely to benefit from triplet therapy remains unclear., Methods: We performed a systematic review, meta-analysis, and network meta-analysis to assess the oncologic benefit of triplet therapy in mHSPC patients stratified by disease volume and compare them with doublet treatment regimens. Three databases and meeting abstracts were queried in March 2023 for randomized controlled trials (RCTs) evaluating patients treated with systemic therapy for mHSPC stratified by disease volume. Primary interests of measure were overall survival (OS). We followed the PRISMA guideline and AMSTAR2 checklist., Results: Overall, eight RCTs were included for meta-analyses and network meta-analyses (NMAs). Triplet therapy outperformed docetaxel plus ADT in terms of OS in both patients with high-(pooled HR: 0.73, 95%CI 0.64-0.84) and low-volume mHSPC (pooled HR: 0.71, 95%CI 0.52-0.97). There was no statistically significant difference between patients with low- vs. high-volume in terms of OS benefit from adding ARSI to docetaxel plus ADT (p = 0.9). Analysis of treatment rankings showed that darolutamide plus docetaxel plus ADT (90%) had the highest likelihood of improved OS in patients with high-volume disease, while enzalutamide plus ADT (84%) had the highest in with low-volume disease., Conclusions: Triplet therapy improves OS in mHSPC patients compared to docetaxel-based doublet therapy, irrespective of disease volume. However, based on treatment ranking, triplet therapy should preferably be considered for patients with high-volume mHSPC while those with low-volume are likely to be adequately treated with ARSI + ADT., (© 2024. The Author(s).)

Context: Despite the lack of level 1 evidence, metastasis-directed therapy (MDT) is used widely in the management of metastatic prostate cancer (mPCa) patients. Data are continuously emerging from well-designed prospective studies., Objective: To summarise and report the evidence on oncological and safety outcomes of MDT in the management of mPCa patients., Evidence Acquisition: We searched the PubMed, Scopus, and Web of Science databases for prospective studies assessing progression-free survival (PFS), local control (LC), androgen deprivation therapy (ADT)-free survival (ADT-FS), overall survival (OS), and/or adverse events (AEs) in mPCa patients treated with MDT. A meta-analysis was performed for 1- and 2-yr PFS, LC, ADT-FS, OS, and rate of AEs. Meta-regression and sensitivity analysis were performed to account for heterogeneity and identify moderators., Evidence Synthesis: We identified 22 prospective studies (n = 1137), including two randomised controlled trials (n = 116). Two studies were excluded from the meta-analysis (n = 120). The estimated 2-yr PFS was 46% (95% confidence interval [CI]: 36-56%) or 42% (95% CI: 33-52%) after excluding studies using biochemical or ADT-related endpoints. The estimated 2-yr LC, ADT-FS, and OS were 97% (95% CI: 94-98%), 55% (95% CI: 44-65%), and 97% (95% CI: 95-98%), respectively. Rates of treatment-related grade 2 and ≥3 AEs were 2.4% (95% CI: 0.2-7%) and 0.3% (95% CI: 0-1%), respectively., Conclusions: MDT is a promising treatment strategy associated with favourable PFS, excellent LC, and a low toxicity profile that allows oligorecurrent hormone-sensitive patients to avoid or defer ADT-related toxicity. Integration of MDT with other therapies offers a promising research direction, in particular, in conjunction with systemic treatments and as a component of definitive care for oligometastatic PCa. However, in the absence of randomised trials, using MDT for treatment intensification remains an experimental approach, and the impact on OS is uncertain., Patient Summary: Direct treatment of metastases is a promising option for selected prostate cancer patients. It can delay hormone therapy and is being investigated as a way of intensifying treatment at the expense of manageable toxicity., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Preclinical studies have shown that the sympathetic nervous system is involved in the development of metastases, suggesting a potential antitumor effect of beta-blockers. These findings sparked a controversy over the past decade regarding the direction of the association between beta-blocker use and prostate cancer (PCa) mortality. To investigate this association, we conducted a systematic review and meta-analysis., Methods: The review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines to identify eligible studies. The primary outcome was PCa mortality in beta-blocker users versus nonusers, and overall survival was studied as a secondary endpoint. We assessed heterogeneity using the Cochrane Q test and quantified it using I 2 values. In the case of heterogeneity (Cochrane Q test p < 0.05 and I 2  > 50%), random-effect models were used to determine the association between beta-blockers use and survival outcomes., Results: Ten studies met our inclusion criteria and a total of 74,970 patients were included: 26,674 beta-blocker users and 48,326 nonusers. There was no statistically significant association between beta-blocker exposure and PCa mortality (hazard ratio [HR] 0.97; 95% confidence interval [CI] 0.87-1.09; p = 0.61). However, significant heterogeneity was found. Meta-regression analysis to explain heterogeneity showed no effect of any of the variables assessed (country, percentage of beta-blocker users, type of beta-blocker [selective and nonselective], study period, PCa stage and follow-up duration; all p > 0.05). We found similar results when we restricted the analysis to studies that include only patients with advanced PCa (HR 0.92; 95% CI 0.80-1.06; p = 0.24). Similarly, we found no association with overall survival (HR 1.02; 95% CI 0.94-1.10; p = 0.64). Meta-regression analysis was also performed, but none of the variables assessed explained the observed heterogeneity (all p > 0.05)., Conclusions: We found no association between beta-blockers use and overall survival or PCa mortality. This meta-analysis, which includes a considerable population and the most recent literature, provides important data for routine clinical care and patient counseling., (© 2023 Wiley Periodicals LLC.)

Context: It is unclear whether a magnetic resonance imaging (MRI)-targeted transperineal (TP) biopsy can improve the detection of clinically significant prostate cancer (csPCa)., Objective: To compare the MRI-targeted TP and transrectal (TR) approaches for csPCa detection., Evidence Acquisition: A literature search was conducted using the PubMed/Medline, Embase, and Web of Science databases to identify reports published until February 2023. The Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were followed to identify eligible studies. The primary outcome was the detection of csPCa (Gleason grade group ≥2). Sensitivity analyses were performed to investigate csPCa detection rates according to tumor location, Prostate Imaging Reporting and Data System (PI-RADS) score, and type of fusion (cognitive or software based)., Evidence Synthesis: Eleven studies met our inclusion criteria, and data from 3522 and 5140 patients who underwent, respectively, TR and TP MRI-targeted biopsies were reviewed. No statistically significant difference in the detection of csPCa was observed between the TR and TP approaches (odds ratio [OR] 1.11, 95% confidence interval [CI] 0.98-1.25; p = 0.1). When stratifying patients according to lesion location, the TP approach was associated with higher csPCa detection in case of anterior (OR 2.17, 95% CI 1.46-3.22; p < 0.001) and apical (OR 1.86, 95% CI 1.14-3.03; p = 0.01) lesions. In the subgroup analysis based on PI-RADS score, the TP approach was associated with higher csPCa detection (OR 1.57, 95% CI 1.07-2.29; p = 0.02) in PI-RADS 4 lesions. Conversely, no difference was found in PI-RADS 3 and 5 lesions (p > 0.05). The main limitation was the retrospective design of most included studies., Conclusions: No significant association was found between the prostate biopsy approach and csPCa detection rate when we considered all biopsy indications. The TP approach provides a detection advantage in anterior and apical tumors, arguing for a preferred use of the TP approach in these lesion locations., Patient Summary: The transperineal magnetic resonance imaging-targeted prostate biopsy approach appears to be more effective only for selected lesions. No clear benefit was seen for the transperineal approach in the overall population., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objective: To evaluate the efficacy of systemic therapies in patients with worse performance status (PS) treated for high-risk non-metastatic prostate cancer (PCa), metastatic hormone-sensitive PCa (mHSPC), and non-metastatic/metastatic castration-resistant PCa (nmCRPC/mCRPC), as there is sparse pooled data showing the effect of PS on oncological outcomes in patients with PCa., Methods: Three databases were queried in June 2022 for randomised controlled trials (RCTs) analysing patients with PCa treated with systemic therapy (i.e., adding androgen receptor signalling inhibitor [ARSI] or docetaxel [DOC] to androgen-deprivation therapy [ADT]). We analysed the oncological outcomes of patients with PCa with worse PS, defined as Eastern Cooperative Oncology Group PS ≥ 1, treated with combination therapies and compared these to patients with good PS. The main outcomes of interest were overall survival (OS), metastasis-free survival (MFS), and progression-free survival., Results: Overall, 25 and 18 RCTs were included for systematic review and meta-analyses/network meta-analyses, respectively. In all clinical settings, combination systemic therapies significantly improved OS in patients with worse PS as well as in those with good PS, while the MFS benefit from ARSI in the nmCRPC setting was more pronounced in patients with good PS than in those with worse PS (P = 0.002). Analysis of treatment ranking in patients with mHSPC revealed that triplet therapy had the highest likelihood of improved OS irrespective of PS; specifically, adding darolutamide to DOC + ADT had the highest likelihood of improved OS in patients with worse PS. Analyses were limited by the small proportion of patients with a PS ≥ 1 (19%-28%) and that the number of PS 2 was rarely reported., Conclusions: Among RCTs, novel systemic therapies seem to benefit the OS of patients with PCa irrespective of PS. Our findings suggest that worse PS should not discourage treatment intensification across all disease stages., (© 2023 The Authors. BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

Purpose: There are limited pooled data showing the impact of visceral metastasis on oncologic outcomes in metastatic prostate cancer patients treated with combination systemic therapies. We aimed to analyze and compare the efficacy of combination systemic therapies in metastatic hormone-sensitive prostate cancer and metastatic castration-resistant prostate cancer with or without visceral metastasis., Materials and Methods: Three databases were queried in July 2022 for randomized, controlled trials analyzing metastatic prostate cancer patients treated with combination systemic therapy (androgen receptor signaling inhibitor and/or docetaxel plus androgen deprivation therapy) to standard of care. We analyzed the association between presence of visceral metastases and efficacy of systemic therapies in metastatic hormone-sensitive prostate cancer and metastatic castration-resistant prostate cancer patients. The main and secondary outcomes of interest were overall survival and progression-free survival, respectively. Formal meta-analysis using fixed-effect model and network meta-analysis using random-effect model were conducted. We followed PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) and AMSTAR (A MeaSurement Tool to Assess systematic Reviews) guidelines., Results: Overall, 12 and 8 randomized, controlled trials were included for systematic review and meta-analyses/network meta-analyses, respectively. In metastatic hormone-sensitive prostate cancer patients, adding androgen receptor signaling inhibitor to standard of care improved overall survival in patients with visceral metastasis (pooled HR: 0.77, 95% CI: 0.64-0.94) as well as in those without (pooled HR: 0.66, 95% CI: 0.60-0.72; no differences in both across- and within-trial approach; P = .13 and P = .06, respectively). On the other hand, the progression-free survival benefit from androgen receptor signaling inhibitor + androgen deprivation therapy was significantly lower in patients with visceral metastasis using across-trial approach ( P = .03), while it did not reach statistical significance using within-trial approach ( P = .14). Analysis of treatment ranking in metastatic hormone-sensitive prostate cancer showed that darolutamide + docetaxel + androgen deprivation therapy had the highest likelihood of improved overall survival irrespective of visceral metastasis. In post-docetaxel metastatic castration-resistant prostate cancer patients, adding androgen receptor signaling inhibitor to androgen deprivation therapy significantly improved overall survival in both patients with visceral metastasis (pooled HR: 0.79, 95% CI: 0.63-0.98) and those without (pooled HR: 0.63, 95% CI: 0.55-0.72). No randomized, controlled trials reported the differential oncologic outcomes stratified by lung vs liver metastases., Conclusions: Despite aggressive clinical behavior and worse trajectory of metastatic hormone-sensitive prostate cancer and metastatic castration-resistant prostate cancer with visceral metastasis, the effectiveness of novel systemic therapies is similar in both metastatic hormone-sensitive prostate cancer and metastatic castration-resistant prostate cancer patients with and without visceral metastasis. Further well-designed studies with detailed visceral metastatic sites and number will enrich the clinical decision-making.

Purpose: Determining the frequency and distribution of pathogenic germline variants (PGVs) in Austrian prostate cancer (PCa) patients and to assess the accuracy of different clinical risk scores to correctly predict PGVs., Methods: This cross-sectional study included 313 men with advanced PCa. A comprehensive personal and family history was obtained based on predefined questionnaires. Germline DNA sequencing was performed between 2019 and 2021 irrespective of family history, metastatic or castration status or age at diagnosis. Clinical risk scores for hereditary cancer syndromes were evaluated and a PCa-specific score was developed to assess the presence of PGVs., Results: PGV presence was associated with metastasis (p = 0.047) and castration resistance (p = 0.011), but not with personal cancer history or with relatives with any type of cancer. Clinical risk scores (Manchester score, PREMM5 score, Amsterdam II criteria or Johns Hopkins criteria) showed low sensitivities (3.3-20%) for assessing the probability of PGV presence. A score specifically designed for PCa patients stratifying patients into low- or high-risk regarding PGV probability, correctly classified all PGV carriers as high-risk, whereas a third of PCa patients without PGVs was classified as low risk of the presence of PGVs., Conclusion: Application of common clinical risk scores based on family history are not suitable to identify PCa patients with high PGV probabilities. A PCa-specific score stratified PCa patients into low- or high-risk of PGV presence with sufficient accuracy, and germline DNA sequencing may be omitted in patients with a low score. Further studies are needed to evaluate the score., (© 2023. The Author(s).)

Mutations in the BRCA1 and BRCA2 tumour suppressor genes are associated with prostate cancer risk; however, optimal screening protocols for individuals with these mutations have been a subject of debate. Several prospective studies of prostate cancer incidence and screening among BRCA1/2 mutation carriers have indicated at least a twofold to fourfold increase in prostate cancer risk among carriers of BRCA2 mutations compared with the general population. Moreover, BRCA2 mutations are associated with more aggressive, high-grade disease characteristics at diagnosis, more aggressive clinical behaviour and greater prostate cancer-specific mortality. The risk for BRCA1 mutations seems to be attenuated compared with BRCA2. Prostate-specific antigen (PSA) measurement or prostate magnetic resonance imaging (MRI) alone is an imperfect indicator of clinically significant prostate cancer; therefore, BRCA1/2 mutation carriers might benefit from refined risk stratification strategies. However, the long-term impact of prostate cancer screening is unknown, and the optimal management of BRCA1/2 carriers with prostate cancer has not been defined. Whether timely localized therapy can improve overall survival in the screened population is uncertain. Long-term results of prospective studies are awaited to confirm the optimal screening strategies and benefits of prostate cancer screening among BRCA1/2 mutation carriers, and whether these approaches ultimately have a positive impact on survival and quality of life in these patients., (© 2023. Springer Nature Limited.)

The aim of our study was to determine the clinical utility of neutrophil-to-lymphocyte ratio (NLR) in predicting presence and prognosis of nodal involvement in patients treated with radical prostatectomy (RP) due to prostate cancer. This single-centre retrospective study included 205 patients treated with RP and lymphadenectomy between 2012 and 2018. Logistic regression and Kaplan-Meier analyses were performed to evaluate the prognostic value of preoperative NLR in terms of nodal spread and survival. Patients staged pN1 presented lower mean NLR (2.53 vs 3.86; p = 0.0025) compared to pN0 patients. On multivariable analysis of different haematological markers, only NLR exceeding the median (≥ 2.7) predicted pN1 (OR = 0.38; p = 0.0367) independently of biopsy grading and PSA. In internal validation (n = 31 pN1, n = 174 pN0) on the bootstrapped dataset using a spare cutoff of NLR ≥ 4.1 would allow sparing lymphadenectomy in 22.09% pN0 patients, missing 6.45% pN1 (NPV 92.66%; 95% CI 84.91-100%). Noticeably, in pN1 patients NLR ≥ 2.7 correlated with shorter overall survival (p = 0.0196), despite its association with reduced risk of pN1. High pre-prostatectomy NLR was negatively associated with pN1, yielding high NPV in internal validation. Simultaneously, high NLR in pN1 patients was associated with shorter survival., (© 2023. The Author(s).)

Context: Recent randomized controlled trials (RCTs) examined the role of adding androgen receptor signaling inhibitors (ARSIs), including abiraterone acetate (ABI), apalutamide, darolutamide (DAR), and enzalutamide (ENZ), to docetaxel (DOC) and androgen deprivation therapy (ADT) in patients with metastatic hormone-sensitive prostate cancer (mHSPC)., Objective: To analyze the oncologic benefit of triplet combination therapies using ARSI + DOC + ADT, and comparing them with available treatment regimens in patients with mHSPC., Evidence Acquisition: Three databases and meetings abstracts were queried in April 2022 for RCTs analyzing patients treated with first-line combination systemic therapy for mHSPC. The primary interests of measure were overall survival (OS) and progression-free survival (PFS). Subgroup analyses were conducted to assess the differential outcomes in patients with low- and high-volume disease as well as de novo and metachronous metastasis., Evidence Synthesis: Overall, 11 RCTs were included for meta-analyses and network meta-analyses (NMAs). We found that the triplet combinations outperformed DOC + ADT in terms of OS (pooled hazard ratio [HR]: 0.74, 95% confidence interval [CI]: 0.65-0.84) and PFS (pooled HR: 0.49, 95% CI: 0.42-0.58). There was no statistically significant difference between patients with low- and high-volume disease in terms of an OS benefit from adding an ARSI to DOC +ADT (both HR: 0.79; p = 1). Based on NMAs, triplet therapy also outperformed ARSI + ADT in terms of OS (DAR + DOC + ADT: pooled HR: 0.74, 95% CI: 0.55-0.99) and PFS (ABI + DOC + ADT: HR: 0.68, 95% CI: 0.51-0.91, and ENZ + DOC + ADT: HR: 0.70, 95% CI: 0.53-0.93). An analysis of treatment ranking among de novo mHSPC patients showed that triplet therapy had the highest likelihood of improved OS in patients with high-volume disease; however, doublet therapy using ARSI + ADT had the highest likelihood of improved OS in patients with low-volume disease., Conclusions: We found that the triplet combination therapy improves survival endpoints in mHSPC patients compared with currently available doublet treatment regimens. Our findings need to be confirmed in further head-to-head trials with longer follow-up and among various patient populations., Patient Summary: Our study suggests that triplet therapy with androgen receptor signaling inhibitor, docetaxel, androgen deprivation therapy prolongs survival in patients with metastatic hormone-sensitive prostate cancer compared with the current standard doublet therapy., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: Risk calculators (RC) aim to improve prebiopsy risk stratification. Their latest versions now include multiparametric magnetic resonance imaging (mpMRI) findings. For their implementation into clinical practice, critical external validations are needed., Methods: We retrospectively analyzed the patient data of 554 men who underwent ultrasound-guided targeted and systematic prostate biopsies at 2 centers. We validated the mpMRI-RCs of Radtke et al. (RC-R) and Alberts et al. (RC-A), previously shown to predict prostate cancer (PCa) and clinically significant PCa (csPCa). We assessed these RCs' prediction accuracy by analyzing the receiver-operating characteristics (ROC) curve and evaluated their clinical utility using Decision Curve Analysis (DCA), including Net-Benefit and Net-Reduction curves., Results: We found that the Area Under the ROC Curve (AUC) for predicting PCa was 0.681 [confidence interval (CI) 95% 0.635-0.727] for RC-A. The AUCs for predicting csPCa were 0.635 (CI 95% 0.583-0.686) for RC-A and 0.676 (CI 95% 0.627-0.725) for RC-R. For example, at a risk threshold of 12%, RC-A needs to assess 334 and RC-R 500 patients to detect one additional true positive PCa or csPCa patient, respectively. At the same risk threshold of 12%, RC-A only needs to assess 6 and RC-R 16 patients to detect one additional true negative PCa or csPCa patient., Conclusion: The mpMRI-RCs, RC-R and RC-A, are robust and valuable tools for patient counseling. Although they do not improve PCa and csPCa detection rates by a clinically meaningful margin, they aid in avoiding unnecessary prostate biopsies. Their implementation could reduce overdiagnosis and reduce PCa screening morbidity., (© 2022. The Author(s).)

Context: Prostate-specific membrane antigen positron emission tomography (PSMA-PET) has gained acceptance as a staging tool for prostate cancer (PCa). Recent reports suggest an association between PSMA PET and detection of clinically significant PCa (csPCa) on prostate biopsy., Objective: To assess the diagnostic accuracy of PSMA PET-targeted biopsy (PSMA-PET-TB) for csPCa detection., Evidence Acquisition: We searched PubMed, Web of Science, and Scopus in December 2021 to identify studies assessing the accuracy of PSMA-PET-TB for csPCa detection. A diagnostic meta-analysis was performed to calculate pooled sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of PSMA-PET-TB alone and in combination with magnetic resonance imaging (MRI)-TB for detecting csPCa., Evidence Synthesis: Overall, five prospective studies involving 497 patients were eligible for this meta-analysis. For csPCa detection, PSMA-PET-TB had pooled sensitivity, specificity, PPV, and NPV of 0.89 (95% confidence interval [CI] 0.85-0.93), 0.56 (95% CI 0.29-0.80), 0.69 (95% CI 0.58-0.79), and 0.78 (95% CI 0.50-0.93), respectively. Among the three studies assessing the PSMA-PET + MRI-TB strategy, the pooled sensitivity, specificity, PPV, and NPV for csPCa detection were 0.91 (95% CI 0.77-0.97), 0.64 (95% CI 0.40-0.82), 0.75 (95% CI 0.56-0.87), and 0.85 (95% CI 0.62-0.95), respectively. For lesions with a Prostate Imaging-Reporting and Data System (PI-RADS) score of 3, the sensitivity, specificity, PPV, and NPV were 0.69, 0.73, 0.48, and 0.86, respectively., Conclusions: PSMA-PET-TB appears to have favorable diagnostic accuracy for csPCa detection and combination with MRI seems to improve this. According to our meta-analysis, PSMA-PET has promising clinical application for detection of csPCa, namely in the case of PI-RADS 3 lesions. Further prospective studies are needed to explore the true clinical utility of a PSMA-PET-based diagnostic pathway., Patient Summary: Prostate-specific membrane antigen positron emission tomography (PSMA-PET) is a promising imaging method for detecting clinically significant prostate cancer and seems to have additional value to magnetic resonance imaging (MRI) for detection., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Context: Several recent randomised trials have evaluated the role of combination systemic treatment using androgen deprivation therapy (ADT) plus chemotherapy or an androgen receptor signaling inhibitor (ARSI) in patients with high-risk and/or unfavourable nonmetastatic prostate cancer (nmPC)., Objective: To assess the outcomes associated with adding combination systemic treatment to primary definitive local therapy in patients with high-risk and/or unfavourable nmPC., Evidence Acquisition: We queried the PubMed, Web of Science, and Scopus databases and conference abstracts to identify prospective randomised trials examining the value of adding chemotherapy or an ARSI to ADT and primary local therapy with curative intent for nmPC. The primary endpoints were overall survival (OS), cancer-specific survival (CSS), metastasis-free survival (MFS), and failure-free survival (FFS). Secondary endpoints included adverse events (AEs) and pathologic outcomes., Evidence Synthesis: We identified 15 randomised studies, of which nine evaluated chemohormonal and six investigated ARSI-based treatment strategies. In both radical prostatectomy (RP) and radiation therapy (RT) settings, addition of docetaxel to ADT was associated with significantly better CSS (pooled hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.49-0.95; p = 0.025), MFS (pooled HR 0.82, 95% CI 0.71-0.95; p = 0.008), and FFS (pooled HR 0.70, 95% CI 0.62-0.79; p < 0.001); the difference did not meet the conventional level of statistical significance for OS (pooled HR 0.86, 95% CI 0.73-1.01; p = 0.072). For patients treated with RT alone, docetaxel-based combination treatment did not meet the significance threshold set for OS (p = 0.3), CSS (p = 0.072), or MFS (p = 0.079), but the difference for FFS was statistically significant (pooled HR 0.72, 95% CI 0.63-0.84; p < 0.001). On network meta-analyses including RT studies, ARSI + ADT outperformed docetaxel + ADT for survival endpoints and had a more favourable AE profile., Conclusions: Intensification of systemic therapy with docetaxel or an ARSI in addition to ADT improves oncologic endpoints in high-risk and/or unfavourable nmPC treated with local definitive therapy. The highest efficacy was achieved with ARSI + ADT, specifically in patients treated with RT., Patient Summary: Our findings highlight that selected patients with high-risk nonmetastatic prostate cancer benefit from intensification of systemic therapy beyond hormonal treatment., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: To perform a systematic review and network meta-analysis to compare the efficacy and safety of currently available treatments for the management of metastatic hormone-sensitive prostate cancer (mHSPC), as there has been a paradigm shift with the use of next-generation androgen receptor inhibitors (ARIs) and docetaxel., Methods: Multiple databases were searched for articles published before May 2020 according to the Preferred Reporting Items for Systematic Review and Meta-analysis extension statement for network meta-analysis. Studies comparing overall/progression-free survival (OS/PFS) and/or adverse events (AEs) in patients with mHSPC were eligible., Results: Nine studies (N = 9960) were selected, and formal network meta-analyses were conducted. Abiraterone (hazard ratio [HR] 0.83, 95% credible interval [CrI] 0.76-0.90), docetaxel (HR 0.90, 95% CrI 0.82-0.98), and enzalutamide (HR 0.85, 95% CrI 0.73-0.99) were associated with significantly better OS than androgen-deprivation therapy (ADT), and abiraterone emerged as the best option. Abiraterone (HR 0.71, 95% CrI 0.67-0.76), apalutamide (HR 0.73, 95% CrI 0.65-0.81), docetaxel (HR 0.84, 95% CrI 0.78-0.90), and enzalutamide (HR 0.67, 95% CrI 0.63-0.71) were associated with significantly better PFS than ADT, and enzalutamide emerged as the best option. Abiraterone (HR 0.85, 95% CrI 0.78-0.93), apalutamide (HR 0.87, 95% CrI 0.77-0.98), and enzalutamide (HR 0.80, 95% CrI 0.73-0.88) were significantly more effective than docetaxel. Regarding AEs, apalutamide was the likely best option among the three ARIs. In patients with low-volume mHSPC, enzalutamide was the best option in terms of OS and PFS., Conclusions: All three ARIs are effective therapies for mHSPC; apalutamide was the best tolerated. All three seemed more effective than docetaxel. These findings may facilitate individualised treatment strategies and inform future comparative trials., (© 2021 The Authors. BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

Purpose: This study aimed to evaluate the efficacy of long-term neoadjuvant androgen-deprivation therapy (ADT) before radical prostatectomy (RP)., Methods: We conducted meta-analyses and network meta-analyses, which included randomized controlled trials that assessed patients with prostate cancer (PC) who received either short-term (<6 months) or long-term (≥6 months) neoadjuvant ADT before RP., Results: Thirteen articles with 2778 patients were eligible for analysis. Short-term neoadjuvant ADT was neither associated with biochemical recurrence (OR 1.19, 95% CI, 0.93-1.51, p  = 0.17), metastasis (OR 0.73, 95% CI, 0.45-1.19, p  = 0.21), nor overall mortality (OR 0.72, 95% CI 0.43-1.21, p  = 0.22); no study investigated survival outcomes in patients on long-term neoadjuvant ADT. In terms of pathologic outcomes, long-term neoadjuvant ADT was significantly associated with a reduced risk of positive surgical margin (SM) and an increased rate of organ-confined disease (OCD) compared to short-term neoadjuvant ADT (OR 0.56, 95% CI 0.39-0.80, p  = 0.001, and OR 1.48, 95% CI 1.10-1.99, p  = 0.009, respectively). These findings were confirmed in the network meta-analyses. Meanwhile, only a non-significant trend favoring long-term neoadjuvant ADT was observed for pathologic complete response (OR 1.98, 95% Crl 1.00-3.93)., Conclusion: Long-term neoadjuvant ADT was associated with more favorable pathologic outcomes, but whether these findings translate into favorable survival outcomes still remains unproven due to very limited evidence. Since there are no reliable survival data, long-term neoadjuvant ADT before RP should not be used in clinical practice until more robust evidence arises from ongoing trials.

Context: Degarelix is associated with high rates of injection site reaction. The US Food and Drug Administration approved relugolix, an oral gonadotropin-releasing hormone (GnRH) antagonist, for the treatment of advanced prostate cancer patients., Objective: This systematic review and network meta-analysis aimed to compare the efficacy and safety of relugolix versus degarelix., Evidence Acquisition: A systematic search was performed using major web databases for studies published before January 30, 2021, according to the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) extension statement for a network meta-analysis. Studies that compared the efficacy (12-mo castration rate with testosterone ≤50 ng/dl) and safety (adverse events [AEs]) of relugolix or degarelix and of the control group (GnRH agonists) were included. We used the Bayesian approach in the network meta-analysis., Evidence Synthesis: Four studies (n = 2059) met our eligibility criteria. The main efficacy analysis was conducted for two different treatments (relugolix and all doses of degarelix vs GnRH agonists); relugolix (risk ratio [RR] 1.09, 95% credible interval [CrI]: 0.95-1.23) and degarelix (RR 0.98, 95% CrI: 0.91-1.06) were not associated with different 12-mo castration rates. In the subgroup analysis, degarelix 480 mg was significantly associated with a lower castration rate (RR 0.46, 95% CrI: 0.07-0.92). In all efficacy ranking analyses, relugolix achieved the best rank. The safety analyses showed that relugolix (RR 0.99, 95% CrI: 0.6-1.6 and RR 0.72, 95% CrI: 0.4-1.3, respectively) and degarelix (RR 1.1, 95% CrI: 0.75-1.35 and RR 1.05, 95% CrI: 0.42-2.6, respectively) were not associated with either all AE or serious AE rates. In the ranking analyses, degarelix achieved the worst rank of all AEs and the best rank of serious AEs. Relugolix (RR 0.44, 95% CrI: 0.16-1.2) and degarelix (RR 0.74, 95% CrI: 0.37-1.52) were not associated with different cardiovascular event (CVE) rates; both were associated with lower CVE rates than GnRH agonists in the ranking analyses., Conclusions: We found that the efficacy and safety of relugolix are comparable with those of degarelix, albeit with no injection site reaction. Such data should be interpreted with caution until large-scale direct comparison studies with a longer follow-up are available., Patient Summary: We found that relugolix, an oral gonadotropin-releasing hormone (GnRH) antagonist, has comparable efficacy and safety with degarelix, a parenteral GnRH antagonist, for the treatment of advanced prostate cancer patients., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose of Review: To investigate the features and optimal management of pN+ cM0 prostate cancer (PCa) according to registry-based studies., Recent Findings: Up to 15% of PCa patients harbor lymph node invasion (pN+) at radical prostatectomy plus lymph node dissection. Nonetheless, the optimal management strategy in this setting is not well characterized., Summary: We performed a systematic review including n = 13 studies. Management strategies comprised 13 536 men undergoing observation, 11 149 adjuvant androgen deprivation therapy (aADT), 7,075 adjuvant radiotherapy (aRT) +aADT and 705 aRT. Baseline features showed aggressive PCa in the majority of men. At a median follow-up ranging 48-134months, Cancer-related death was 5% and overall-mortality 16.6%. aADT and aRT alone had no cancer-specific survival or overall survival advantages over observation only and over not performing aRT, respectively. aADT plus aRT yielded a survival benefit compared to observation and aADT, which in one study, were limited to certain intermediate-risk categories. Age, Gleason, Charlson score, positive surgical margins, pathological stage, and positive nodes number, but not prostate specific antigen, were most relevant prognostic factors. Our work further confirmed pN+ PCa is a multifaceted disease and will help future research in defining its optimal management based on different risk categories to maximize survival and patient's quality of life., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Grade group (GG) 4 prostate cancer (PC) is considered a single entity; however, there are questions regarding prognostic heterogeneity. This study assessed the prognostic differences among various Gleason scores (GSs) classified as GG 4 PC on biopsy before radical prostatectomy (RP)., Methods: We conducted a multicenter retrospective study, and a total of 1791 patients (GS 3 + 5: 190; GS 4 + 4: 1557; and GS 5 + 3: 44) with biopsy GG 4 were included for analysis. Biochemical recurrence (BCR)-free survival, cancer-specific survival, and overall survival were analyzed using the Kaplan-Meier method and the log-rank test. Logistic regression analysis was performed to identify factors associated with high-risk surgical pathologic features. Cox regression models were used to analyze time-dependent oncologic endpoints., Results: Over a median follow-up of 75 months, 750 patients (41.9%) experienced BCR, 146 (8.2%) died of any causes, and 57 (3.2%) died of PC. Biopsy GS 5 + 3 was associated with significantly higher rates of GS upgrading in RP specimens than GS 3 + 5 and GS 4 + 4. On multivariable analysis adjusted for clinicopathologic features, different GSs within GG 4 were significantly associated with BCR (p = 0.03) but not PC-specific or all-cause mortality. Study limitations include the lack of central pathological specimen evaluation., Conclusions: Patients with GG 4 at biopsy exhibited some limited biological and clinical heterogeneity. Specifically, GS 5 + 3 had an increased risk of GS upgrading. This can help individualize patients' counseling and encourage further study to refine biopsy specimen-based GG classification., (© 2021. The Author(s).)

Context: Although magnetic resonance imaging (MRI) is broadly implemented into active surveillance (AS) protocols, data on the reliability of serial MRI in order to help guide follow-up biopsy are inconclusive., Objective: To assess the diagnostic estimates of serial prostate MRI for prostate cancer (PCa) progression during AS., Evidence Acquisition: We systematically searched PubMed, Scopus, and Web of Science databases to select studies analyzing the association between changes on serial prostate MRI and PCa progression during AS. We included studies that provided data for MRI progression, which allowed us to calculate diagnostic estimates. We compared Prostate Cancer Radiological Estimation of Change in Sequential Evaluation (PRECISE) accuracy with institution-specific definitions., Evidence Synthesis: We included 15 studies with 2240 patients. Six used PRECISE criteria and nine institution-specific definitions of MRI progression. The pooled PCa progression rate, which included histological progression to Gleason grade ≥2, was 27%. The pooled sensitivity and specificity were 0.59 (95% confidence interval [CI] 0.44-0.73) and 0.75 (95% CI 0.66-0.84) respectively. There was significant heterogeneity between included studies. Depending on PCa progression prevalence, the pooled negative predictive value for serial prostate MRI ranged from 0.81 (95% CI 0.73-0.88) to 0.88 (95% CI 0.83-0.93) and the pooled positive predictive value ranged from 0.37 (95% CI 0.24-0.54) to 0.50 (95% CI 0.36-0.66). There were no significant differences in the pooled sensitivity (p = 0.37) and specificity (p = 0.74) of PRECISE and institution-specific schemes., Conclusions: Serial MRI still should not be considered a sole factor for excluding PCa progression during AS, and changes on MRI are not accurate enough to indicate PCa progression. There was a nonsignificant trend toward improved diagnostic estimates of PRECISE recommendations. These findings highlight the need to further define the optimal triggers and timing of biopsy during AS, as well as the need for optimizing the quality, interpretation, and reporting of serial prostate MRI., Patient Summary: Our study suggests that serial prostate magnetic resonance imaging (MRI) alone in patients on active surveillance is not accurate enough to reliably rule out or rule in prostate cancer progression. Other clinical factors and biomarkers along with serial MRI are required to safely tailor the intensity of follow-up biopsies., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: To evaluate the predictive and prognostic value of the Systemic Immune-inflammation Index (SII) in a large cohort of patients treated with radical prostatectomy (RP) for clinically non-metastatic prostate cancer (PCa)., Methods: We retrospectively analyzed our multicenter database comprising 6,039 consecutive patients. The optimal preoperative SII cut-off value was assessed with the Youden index calculated on a time-dependent receiver operating characteristic (ROC) curve. Logistic regression and Cox regression analyses were used to investigate the association of SII with pathologic features and biochemical recurrence (BCR), respectively. The discriminatory ability of the models was evaluated by calculating the concordance-indices (C-Index). The clinical benefit of the implementation of SII in clinical decision making was assessed using decision curve analysis (DCA)., Results: Patients with high preoperative SII (≥ 620) were more likely to have adverse clinicopathologic features. On multivariable logistic regression analysis, high preoperative SII was independently associated with extracapsular extension (odds ratio [OR] 1.16, P = 0.041), non-organ confined disease (OR 1.18, P = 0.022), and upgrading at RP (OR 1.23, P < 0.001). We built two Cox regression models including preoperative and postoperative variables. In the preoperative multivariable model, high preoperative SII was associated with BCR (hazard ratio [HR] 1.34, 95% CI 1.15-1.55, P < 0.001). In the postoperative multivariable model, SII was not associated with BCR (P = 0.078). The addition of SII to established models did not improve their discriminatory ability nor did it increase the clinical net benefit on DCA., Conclusion: In men treated with RP for clinically nonmetastatic PCa, high preoperative SII was statistically associated with an increased risk of adverse pathologic features at RP as well as BCR. However, it did not improve the predictive accuracy and clinical value beyond that obtained by current predictive and prognostic models. SII together with a panel of complementary biomarkers is praised to help guide decision-making in clinically nonmetastatic PCa., Competing Interests: Conflict of interest None of the authors have conflicts of interest to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: To summarize the available evidence on the survival and pathologic outcomes after deferred radical prostatectomy (RP) in men with intermediate- and high-risk prostate cancer (PCa)., Methods: The PubMed database and Web of Science were searched in November 2020 according to the PRISMA statement. Studies were deemed eligible if they reported the survival and pathologic outcomes of patients treated with deferred RP for intermediate- and high-risk PCa compared to the control group including those patients treated with RP without delay., Results: Overall, nineteen studies met our eligibility criteria. We found a significant heterogeneity across the studies in terms of definitions for delay and outcomes, as well as in patients' baseline clinicopathologic features. According to the currently available literature, deferred RP does not seem to affect oncological survival outcomes, such as prostate cancer-specific mortality and metastasis-free survival, in patients with intermediate- or high-risk PCa. However, the impact of deferred RP on biochemical recurrence rates remains controversial. There is no clear association of deferring RP with any of the features of aggressive disease such as pathologic upgrading, upstaging, positive surgical margins, extracapsular extension, seminal vesicle invasion, and lymph node invasion. Deferred RP was not associated with the need for secondary treatments., Conclusions: Owing to the different definitions of a delayed RP, it is hard to make a consensus regarding the safe delay time. However, the current data suggest that deferring RP in patients with intermediate- and high-risk PCa for at least around 3 months is generally safe, as it does not lead to adverse pathologic outcomes, biochemical recurrence, the need for secondary therapy, or worse oncological survival outcomes., (© 2021. The Author(s).)

Background: Serum albumin-to-globulin ratio (AGR) has been shown to be associated with poor prognosis in different malignancies. In this study we aimed to evaluate the predictive value of preoperative AGR for oncological outcomes in patients with radiation recurrent prostate cancer (PCa) treated with salvage radical prostatectomy (SRP)., Methods: A retrospective review of 214 consecutive patients with radiation recurrent PCa who underwent SRP at five referral centers. Levels of albumin and globulin were obtained before SRP and used to calculate the preoperative AGR level. The optimal cut off value of preoperative AGR was 1.4. Univariable and multivariable Cox regression analyses were performed., Results: Overall 89 (41.6%) patients had a low preoperative AGR. Low serum AGR was associated with biochemical recurrence (BCR) in univariable Cox regression analysis (HR 1.60, 95%CI 1.06-2.43, P=0.026). When adjusted for the effects of established preoperative and postoperative clinicopathologic confounders in different multivariable Cox regression models, this association did not retain its statistical significance. Moreover, preoperative AGR was not associated with metastasis free survival (P=0.21), overall survival (P=0.91) or cancer specific survival (P=0.61)., Conclusions: In patients with radiation recurrent PCa undergoing SRP, low preoperative AGR was associated with the risk of BCR only in univariable analysis. There was no association with metastasis or survival outcomes. Further studies are needed to evaluate this biomarker in the setting of primary PCa and to identify the patients most likely to benefit from a local therapy.

Purpose: To examine the predictive and prognostic value of preoperative Systemic Immune-inflammation Index (SII) in patients with radio-recurrent prostate cancer (PCa) treated with salvage radical prostatectomy (SRP)., Materials and Methods: This multicenter retrospective study included 214 patients with radio-recurrent PCa, treated with SRP between 2007 and 2015. SII was measured preoperatively (neutrophils × platelets/lymphocytes) and the cohort was stratified using optimal cut-off. Uni- and multivariable logistic and Cox regression analyses were performed to evaluate the predictive and prognostic value of SII as a preoperative biomarker., Results: A total of 81 patients had high preoperative SII (≥ 730). On multivariable logistic regression modeling, high SII was predictive for lymph node metastases (OR 3.32, 95% CI 1.45-7.90, p = 0.005), and non-organ confined disease (OR 2.55, 95% CI 1.33-4.97, p = 0.005). In preoperative regression analysis, high preoperative SII was an independent prognostic factor for cancer-specific survival (CSS; HR 10.7, 95% CI 1.12-103, p = 0.039) and overall survival (OS; HR 8.57, 95% CI 2.70-27.2, p < 0.001). Similarly, in postoperative multivariable models, SII was associated with worse CSS (HR 22.11, 95% CI 1.23-398.12, p = 0.036) and OS (HR 5.98, 95% CI 1.67-21.44, p = 0.006). Notably, the addition of SII to preoperative reference models improved the C-index for the prognosis of CSS (89.5 vs. 80.5) and OS (85.1 vs 77.1)., Conclusions: In radio-recurrent PCa patients, high SII was associated with adverse pathological features at SRP and survival after SRP. Preoperative SII could help identify patients who might benefit from novel imaging modalities, multimodal therapy or a closer posttreatment surveillance., (© 2021. The Author(s).)

Purpose: Although the Prostate Imaging-Reporting and Data System™ version 2 (PI-RADS™ v2) is a reliable diagnostic tool for significant prostate cancer, less is known about the prognostic significance of the structured reporting scheme for estimating oncologic outcomes after treatment. We aimed to synthesize the available evidence regarding the association of PI-RADS v2 score and risk of biochemical recurrence (BCR) among patients undergoing primary definitive treatment for prostate cancer., Materials and Methods: We systematically queried the PubMed® and Web of Science™ databases to identify studies addressing the association between the PI-RADS v2 and treatment outcomes. We included studies through November 2020 that assessed the independent prognostic significance of PI-RADS v2. After assessing risk of bias and quality, we conducted a formal meta-analysis to estimate the pooled effects of prostate magnetic resonance imaging (MRI) classification on the risk of BCR., Results: We identified 9 and 7 eligible studies including 2,274 and 1,215 patients for the systematic review and meta-analysis, respectively. Eight were conducted in the context of radical prostatectomy and 1 post-radiation. Among patients treated with radical prostatectomy, higher PI-RADS v2 scores were significantly associated with risk of BCR (pooled HR 3.06, 95% CI 2.16-4.33; p <0.01). There was no significant heterogeneity among studies. For all studies, PI-RADS v2 score remained significantly associated with BCR (pooled HR 3.19, 95% CI 2.28-4.45; p <0.01)., Conclusions: Prostate MRI findings assessed with the PI-RADS v2 classification were independently associated with risk of BCR after definitive local therapy, primarily based on data from radical prostatectomy. These findings support the prognostic significance of MRI, in addition to its role in prostate cancer diagnosis.

Purpose of Review: Artificial intelligence has made an entrance into mainstream applications of daily life but the clinical deployment of artificial intelligence-supported histological analysis is still at infancy. Recent years have seen a surge in technological advance regarding the use of artificial intelligence in pathology, in particular in the diagnosis of prostate cancer., Recent Findings: We review first impressions of how artificial intelligence impacts the clinical performance of pathologists in the analysis of prostate tissue. Several challenges in the deployment of artificial intelligence remain to be overcome. Finally, we discuss how artificial intelligence can help in generating new knowledge that is interpretable by humans., Summary: It is evident that artificial intelligence has the potential to outperform most pathologists in detecting prostate cancer, and does not suffer from inherent interobserver variability. Nonetheless, large clinical validation studies that unequivocally prove the benefit of artificial intelligence support in pathology are necessary. Regardless, artificial intelligence may soon automate and standardize many facets of routine work, including qualitative (i.e. Gleason Grading) and quantitative measures (i.e. portion of Gleason Grades and tumor volume). For the near future, a model where pathologists are enhanced by second-review or real-time artificial intelligence systems appears to be the most promising approach., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: Male infertility has been shown to be associated with different maladies. The present systematic review and meta-analysis aimed to summarize the available evidence on the association between male infertility or childlessness and prostate cancer., Recent Findings: The PubMed, Web of Science, and Scopus databases were searched according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. Studies were deemed eligible if they compared males with known infertility or childlessness to the control group including fertile males with regards to the diagnosis of prostate cancer. Overall, ten studies met our eligibility criteria. Three studies found that infertility was associated with higher risk of prostate cancer, four studies - with a reduced risk of prostate cancer, and three studies found no association. The forest plot revealed that infertility was not associated with prostate cancer (odds ratio [OR]: 1.26, 95% confidence interval [CI] 0.63-2.54; P = 0.5). Infertility was not associated with high (OR: 1.44, 95% CI 0.54-3.83; P = 0.5) or low (OR: 0.99, 95% CI 0.43-2.27; P = 0.9) grade prostate cancer., Summary: Infertility or childlessness were not associated with the risk of prostate cancer. The significant heterogeneity between the included studies supports the need for more granular research to guide/fine tune early detection guidelines based on fertility., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: With the growing adoption of active surveillance clinical parameters that can tailor the intensity of monitoring are increasingly needed. Therefore, we aimed to evaluate the prognostic value of negative followup biopsy for reclassification and upgrading in prostate cancer patients managed with active surveillance., Materials and Methods: The PubMed®, Web of Science TM , and Scopus® databases were queried to identify relevant studies published until November 2020 according to the Preferred Reporting Items for Systematic Review and Meta-analysis statement. We performed a formal meta-analysis for the reclassification and upgrading in the full cohort and selected subgroups., Results: We identified 13 and 9 studies eligible for the systematic review and meta-analysis, respectively. A total of 2,628 patients were included in the meta-analysis. Any negative followup biopsy was associated with significantly lower risk of reclassification (HR 0.46, 95% CI 0.39-0.55; p <0.01), and upgrading (HR 0.54, 95% CI 0.44-0.66; p <0.01). For the confirmatory biopsy subgroup, the results remained significant for reclassification (HR 0.44, 95% CI 0.36-0.55; p <0.01) and upgrading (HR 0.55, 95% CI 0.42-0.73; p <0.01). These patterns remained robust among patients with only Gleason Grade prognostic group 1 (reclassification HR 0.47, 95% CI 0.39-0.57; p <0.01; upgrading HR 0.54, 95% CI 0.42-0.69; p <0.01)., Conclusions: A negative followup biopsy is associated with an approximately 50% decrease in the risk of future reclassification and upgrading. Incorporation of the negative followup biopsy into current protocols should allow for personalized active surveillance tailoring and more precise decision making.

Introduction: There are questions regarding whether grade group (GG) 4 prostate cancer (PC) is heterogeneous in terms of prognosis. We assessed prognostic differences in PC patients within GG 4 treated with radical prostatectomy (RP)., Material and Methods: Biochemical recurrence (BCR)-free, cancer-specific, and overall survival were analyzed in 787 PC patients with GG 4 based on RP pathology (Gleason score (GS) 3 + 5: 189, GS 4 + 4: 500, and GS 5 + 3: 98). Logistic regression analysis was performed to assess factors predictive of high-risk surgical pathological features. Cox regression models were used to evaluate potential prognostic factors of survival., Results: Within a median follow-up of 86 months, 378 patients (48.0%) experienced BCR and 96 patients (12.2%) died, 42 of whom (5.3%) died of PC. GS 5 + 3 was significantly associated with worse BCR-free and cancer-specific survival, as well as higher positive surgical margin, lymph node metastasis, extraprostatic extension, and non-organ-confined disease rates, than GS 3 + 5 and higher positive surgical margin, lymph node metastasis, extraprostatic extension, and non-organ-confined disease rates than GS 4 + 4 (P < 0.05). GS 4 + 4 was significantly associated with worse BCR-free survival and higher extraprostatic extension, and non-organ-confined disease rates than GS 3 + 5 (P < 0.05). Inclusion of the different Gleason patterns improved the discrimination of a model for prediction of all survival outcomes compared to standard prognosticators., Conclusions: There is considerable heterogeneity within GG 4 in terms of oncological and surgical pathological outcomes. Primary and secondary Gleason patterns should be considered to stratify high-risk PC patients after RP., Competing Interests: Declaration of competing interest None of the authors have conflicts of interest to disclose., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: This systematic review and meta-analysis was conducted to assess the prognostic differences between different Gleason patterns in patients with prostate cancer (PC) within Internal Society of Urological Pathology (ISUP) grade group 4 (GG 4)., Evidence Acquisition: PUBMED and Scopus databases were searched for articles published prior to December 2019 according to the Preferred Reporting Items for Systematic Review and Meta-analysis statement. Studies were deemed eligible if they compared overall survival (OS), cancer-specific survival (CSS), and surgical pathological outcomes in PC patients categorized as ISUP GG 4 (Gleason Score [GS] 4+4 vs. GS 3+5 or GS 5+3). Formal meta-analyses were performed for these outcomes., Evidence Synthesis: Ten studies with 42,041 patients were eligible for the systematic review and eight studies with 36,250 patients for meta-analysis. The treatment type of included study was three surgery and three radiotherapy. The other four studies included many kinds of treatments such as surgery, radiotherapy, androgen deprivation therapy, and chemotherapy. GS 4+4 was significantly associated with better OS (pooled hazard ratio (HR): 0.52, 95% confidential interval (CI): 0.29-0.91) than GS 3+5 or GS 5+3. Positive surgical margin rates were significantly lower with GS 4+4 than GS 3+5 and GS 5+3 (odds ratio [OR] 0.70/95% CI 0.64-0.77 and OR 0.70/95% CI 0.56-0.87, respectively). In contrast, different Gleason patterns in ISUP GG 4 were not significantly associated with CSS (pooled HR: 0.77, 95% CI: 0.56-1.06)., Conclusions: GS 4+4 in patients with PC was associated with better OS and positive surgical margin rates. It seems likely that there is heterogeneity within ISUP GG 4. However, caution should be exercised in interpreting the conclusions drawn from this study, given the limitations of the study, which include the heterogeneity of the population of interest and the retrospective nature of the primary data evaluated.

Purpose: Androgen deprivation therapy is a standard therapy for some patients with localized and almost all patients with metastatic prostate cancer. Although several clinical cohort studies have identified an impact of androgen deprivation therapy on cognitive function, the previous reviews were not able to perform a well designed quantitative synthesis to summarize the risk of dementia and/or Alzheimer disease. Consequently there is still a lack of systematic review and meta-analysis regarding the impact of this risk including more recent studies., Materials and Methods: We conducted a systematic review and meta-analysis of the literature assessing the differential incidence of dementia and/or Alzheimer disease as outcomes in patients with prostate cancer who did vs did not receive androgen deprivation therapy. We queried PubMed® and Web of Science™ databases from January 1 to 3, 2020. We used random or fixed effects meta-analytic models in the presence or absence of heterogeneity per the I 2 statistic. We performed 6 meta-analyses for all cause dementia, Alzheimer disease and all cause dementia or Alzheimer disease according to the duration of androgen deprivation therapy (up to 12 or more than 12 months)., Results: A total of 14 studies were selected after considering inclusion and exclusion criteria. Nine of them reported all cause dementia (ie all types of dementia including Alzheimer disease), with 8 reporting Alzheimer disease. Five studies assessed these outcomes according to the duration of androgen deprivation therapy. The risk of new onset dementia (all cause) and Alzheimer disease was higher in patients with prostate cancer who received androgen deprivation therapy compared to those who did not (HR 1.21, 95% CI 1.11-1.33 and HR 1.16, 95% CI 1.09-1.24). The risk of dementia (all cause) was higher in patients with prostate cancer who received androgen deprivation therapy for more than 12 months (HR 1.36, 95% CI 1.07-1.72); however, for those who had less than 12 months of androgen deprivation therapy exposure the difference was not statistically significant 1.06 (95% CI 0.77-1.28). There was no association between the androgen deprivation therapy duration and the risk of Alzheimer disease (HR 1.21, 95% CI 0.97-1.51 for exposure up to 12 months and HR 1.39, 95% CI 0.69-2.79 for exposure greater than 12 months)., Conclusions: Men who receive androgen deprivation therapy for prostate cancer have an increased risk of dementia and/or Alzheimer disease compared to men who do not receive androgen deprivation therapy; this was more pronounced when androgen deprivation therapy was given longer than 12 months.

Purpose: This systematic review and meta-analysis aimed to assess the prognostic impact of intraductal carcinoma of the prostate in patients with prostate cancer., Materials and Methods: A systematic search was performed according to the Preferred Reporting Items for Systematic Review and Meta-Analysis statement. We searched PubMed®, Web of Science™, the Cochrane Library and Scopus® up to October 2019. The end points were biochemical recurrence-free, cancer specific and overall survival., Results: We identified 32 studies with 179,766 patients. A total of 31 studies containing 179,721 patients with localized and advanced prostate cancer were eligible for meta-analysis. In localized prostate cancer intraductal disease was associated with adverse outcomes including lower biochemical recurrence-free survival (pooled HR 2.09, 95% CI 1.75-2.50) and cancer specific survival (pooled HR 2.93, 95% CI 2.25-3.81). In advanced prostate cancer overall survival was lower in patients with vs without intraductal disease (pooled HR 1.75, 95% CI 1.43-2.14). Subgroup analysis by specimen type revealed that intraductal carcinoma of the prostate is a significant negative prognostic factor in both biopsies and prostatectomy specimens. Moreover, subgroup analyses based on the histopathological definitions of intraductal carcinoma of the prostate indicated that intraductal disease was significantly associated with lower biochemical recurrence-free, cancer specific and overall survival for almost all definitions., Conclusions: Intraductal disease is a histopathological feature of biologically and clinically aggressive prostate cancer. It confers worse oncologic outcomes in both localized and advanced prostate cancer, whether assessed in biopsy or prostatectomy specimen. The pathologist should assess for and report on the presence of intraductal disease in all prostate specimens. The urologist and radiation oncologist should consider this adverse feature in their clinical decision making.

Introduction: The aim of this review was to summarize the available evidence on the role of metastasis-directed therapy (MDT) and/or prostate-targeted therapy (PTT) in the setting of oligometastatic prostate cancer (PCa)., Evidence Acquisition: We searched PubMed, the Web of Science, and the Cochrane Library databases. The following keywords were used: ("prostate cancer" OR "prostate carcinoma" OR "prostate neoplasm" OR "prostate tumor") AND ("oligometastatic" OR "oligometastasis" OR "PSMA") AND ("surgery" OR "prostatectomy" OR "radical prostatectomy" OR "cytoreductive" OR "local treatment" OR "radiotherapy" OR "stereotactic" OR "stereotaxic") AND ("survival" OR "mortality")., Evidence Synthesis: After evaluating the selection criteria, 81 studies were evaluated for our endpoints. We included 22 studies for PTT of synchronous mPCa. There have been no randomized studies on cytoreductive prostatectomy (cRP). Four prospective studies showed that cRP was feasible but did not contribute to a positive effect on overall survival (OS). Regarding PTT-radiotherapy, two randomized controlled phase 3 trials showed that OS was improved in men with a low metastatic burden. Regarding MDT of metachronous lymph node recurrence, we included 29 retrospective studies. For MDT of oligometastases, we included 30 studies. One randomized phase 2 trial showed that androgen deprivation therapy-free survival improved with stereotactic body radiation therapy compared to that with surveillance; however, benefits on OS remain unclear., Conclusions: We performed a comprehensive overview of the current literature on MDT and PTT. The feasibility of MDT and PTT is supported by several retrospective studies. Nevertheless, there remains a lack of high-quality trials to prove its survival benefits. Results from ongoing prospective trials data are awaited.

Purpose of Review: Prostate cancer (PCa) is the most commonly diagnosed cancer in men. Poor specificity and sensitivity of total PSA often results in over and sometimes underdetection/treatment. Therefore, more specific and sensitive biomarkers for the detection and monitoring especially of clinically significant PCa as well as treatment-specific markers are much sought after. In this field, urine has emerged as a promising noninvasive source of biomarkers., Recent Findings: RNA-based biomarkers are the most extensively studied type of urinary nucleic acids. ERG-Score/MiPS (Mi-Prostate Score) and SelectMDx might be considered as additional parameters together with clinical and imaging modalities to decrease unnecessary biopsies. miR Sentinel Tests could make it possible to accurately detect the presence of cancer and to distinguish low-grade from high-grade disease. In men with previous negative biopsies, PCA3 may suggest the need to repeat biopsy., Summary: The definitive role of these markers and their clinical benefit needs future validation.

Introduction: This manuscript aims to give an overview of current diagnostic, staging, and prognostic markers for prostate cancer (PCa) and discuss emerging approaches. The widespread use of PSA for early detection led to improved survival but at the cost of over-diagnosis, often associated with over-treatment and its adverse events. There is thus an unmet need for new markers to sustainably improve the diagnosis and risk assessment, thereby providing a more accurate treatment decision for each individual patient., Areas Covered: Promising new molecular serum (PSA, PHI, 4Kscore®), urine (Progensa®, SelectMDx®, MiPS) and tissue-based markers (Ki-67, Prolaris®, ConfirmMDx®, Oncotype Dx®, Decipher®, Promark®) will be discussed in this review., Expert Opinion: Over-diagnosis and difficulties in prognosticating clinical outcome among patients with similar histological and clinical parameters often lead to over- or under-treatment. New markers will probably be used with clinical and histopathological features as well as imaging diagnostics to capture the comprehensive biology and clinical behavior of PCa. New biomarkers open the avenue to avoid mpMRI with targeted biopsy in the future, thereby sparing risks and pitfalls associated with this approach. Before this utopia becomes reality, the panel of technologically complementary markers need to prove that they are better, cheaper, and faster than current strategies.

Objective: To analyse the accuracy of high preoperative PSA levels for predicting transitional zone incidental PCa (TZ-PCa) in men with very large prostates., Materials and Methods: Perioperative data from 375 consecutive patients who underwent endoscopic enucleation of the prostate (EEP) for benign prostatic obstruction between July 2013 and December 2018 were retrospectively reviewed. Patients were stratified into three groups according to the preoperative PSA level: low-PSA (< 4 ng/mL), intermediate-PSA (4 ≤ PSA < 10 ng/mL) and high-PSA (≥ 10 ng/mL). Men in each group were propensity score matched by age, 5α-reductase inhibitor (5-ARI) use, prostate volume and mpMRI. The TZ-PCa incidence rate was retrospectively compared by preoperative PSA level in a propensity score model including all predetermined variables., Results: Age, prostate volume, 5-ARI use were similar between patient groups. The median PSA levels in the low-, intermediate- and high-PSA groups were 3 [2.3; 3.4], 6.6 [5.3; 8.1] and 12.7 [11; 16.7] ng/mL, respectively. The median prostate volume was > 100 grams in all groups (108, 105 and 120 cc, respectively). The T1a-Gleason 6 incidental TZ-PCa rate was statistically comparable between the three groups (3.4, 5.1 and 8.6% in the low-, intermediate- and high-PSA groups, respectively). The detection rate of clinically significant TZ-PCa was low for preoperative PSA levels > 4 ng/mL (1.7%); with no difference between the intermediate- and high-PSA groups., Conclusion: In men with large glands, the clinically significant incidental TZ-PCa detection rate was similar regardless of the preoperative PSA level stratum. Such details may help with patient counselling during BPH surgical management.

BackgroundThe relative cardiovascular safety of gonadotropin-releasing hormone (GnRH) antagonists compared with GnRH agonists in men with prostate cancer and known atherosclerotic cardiovascular disease remains controversial.MethodsIn this international, multicenter, prospective, randomized, open-label trial, men with prostate cancer and concomitant atherosclerotic cardiovascular disease were randomly assigned 1:1 to receive the GnRH antagonist degarelix or the GnRH agonist leuprolide for 12 months. The primary outcome was the time to first adjudicated major adverse cardiovascular event (composite of death, myocardial infarction, or stroke) through 12 months.ResultsBecause of slower-than-projected enrollment and fewer-than-projected primary outcome events, enrollment was stopped before the 900 planned participants were accrued. From May 3, 2016, to April 16, 2020, a total of 545 patients from 113 sites across 12 countries were randomly selected. Baseline characteristics were balanced between study groups. The median age was 73 years, 49.8% had localized prostate cancer; 26.3% had locally advanced disease, and 20.4% had metastatic disease. A major adverse cardiovascular event occurred in 15 (5.5%) patients assigned to degarelix and 11 (4.1%) patients assigned to leuprolide (hazard ratio, 1.28 [95% CI, 0.59-2.79]; P=0.53).ConclusionsPRONOUNCE (A Trial Comparing Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Advanced Prostate Cancer and Cardiovascular Disease) is the first, international, randomized clinical trial to prospectively compare the cardiovascular safety of a GnRH antagonist and a GnRH agonist in patients with prostate cancer. The study was terminated prematurely because of the smaller than planned number of participants and events, and no difference in major adverse cardiovascular events at 1 year between patients assigned to degarelix or leuprolide was observed. The relative cardiovascular safety of GnRH antagonists and agonists remains unresolved. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02663908.