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Background and Objective: Persistent prostatic specific antigen (PSA) represents a poor prognostic factor for recurrence after radical prostatectomy (RP). However, the impact of persistent PSA on oncologic outcomes in patients undergoing salvage RP is unknown. To investigate the impact of persistent PSA after salvage RP on long-term oncologic outcomes., Material and Methods: Patients who underwent salvage RP for recurrent prostate cancer between 2000 and 2021 were identified from twelve high-volume centers. Only patients with available PSA after salvage RP were included. Kaplan-Meier analyses and multivariable Cox regression models were used to test the effect of persistent PSA on biochemical recurrence (BCR), metastasis and any death after salvage RP. Persistent PSA was defined as a PSA-value ≥ 0.1 ng/ml, at first PSA-measurement after salvage RP., Results: Overall, 580 patients were identified. Of those, 42% (n = 242) harbored persistent PSA. Median follow-up after salvage RP was 38 months, median time to salvage RP was 64 months and median time to first PSA after salvage RP was 2.2 months. At 84 months after salvage RP, BCR-free, metastasis-free, and overall survival was 6.6 vs. 59%, 71 vs. 88% and 77 vs. 94% for patients with persistent vs. undetectable PSA after salvage RP (all p < 0.01). In multivariable Cox models persistent PSA was an independent predictor for BCR (HR: 5.47, p < 0.001) and death (HR: 3.07, p < 0.01)., Conclusion: Persistent PSA is common after salvage RP and represents an independent predictor for worse oncologic outcomes. Patients undergoing salvage RP should be closely monitored after surgery to identify those with persistent PSA., (© 2023. The Author(s).)

Prostate cancer treatment resistance is a significant challenge facing the field. Genomic and transcriptomic profiling have partially elucidated the mechanisms through which cancer cells escape treatment, but their relation toward the tumor microenvironment (TME) remains elusive. Here we present a comprehensive transcriptomic landscape of the prostate TME at multiple points in the standard treatment timeline employing single-cell RNA-sequencing and spatial transcriptomics data from 120 patients. We identify club-like cells as a key epithelial cell subtype that acts as an interface between the prostate and the immune system. Tissue areas enriched with club-like cells have depleted androgen signaling and upregulated expression of luminal progenitor cell markers. Club-like cells display a senescence-associated secretory phenotype and their presence is linked to increased polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) activity. Our results indicate that club-like cells are associated with myeloid inflammation previously linked to androgen deprivation therapy resistance, providing a rationale for their therapeutic targeting., Competing Interests: Competing interests C.T.A.P.’s employer may gain commercially from licensing data to Artera AI. G.A. received personal fees, grants, and travel support from Janssen and Astellas Pharma; personal fees or travel support from Pfizer, Novartis/AAA, Bayer Healthcare Pharmaceuticals, AstraZeneca, and Sanofi-Aventis; in addition, G.A.’s former employer, The Institute of Cancer Research, receives royalty income from abiraterone and G.A. receives a share of this income through the Institute’s Rewards to Discoverers Scheme. G.A. has received research funding (institutional) from Janssen, Astellas Pharma, and Novartis. All other authors declare no potential conflicts of interest., (© 2024. The Author(s).)

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.)

Objective: To investigate the effect of a dietary supplement containing fermented soy on PSA, IPSS, changes in prostate volume and prostate cancer (PCa) development after a 6-month challenge in men at increased risk of PCa and negative previous biopsies. MATERIALS AND METHODS: Patients with an elevated risk of PCa, defined by either 1 of the following criteria: PSA >3 ng/mL, suspect lesion at digital rectal examination (DRE), suspect lesion at transrectal ultrasound (TRUS)/magnetic resonance imaging (MRI) and previous negative prostate biopsies (at least 8 cores) within 12 months before inclusion. Statistical analysis was carried out using a non-parametric 1-sided paired Wilcoxon rank sum test, chi-square test, and Fisher's exact test., Results: In this trial, 94 patients were eligible for analysis. A PSA response was detected in 81% of the cases. In 25.8% (24/93) of patients, a decrease of at least 3 points on the IPSS was observed. The median prostate volume did not statistically change after 6 months (P = .908). Patients with PSA modulation required fewer investigations and had fewer positive biopsies (P <.001) and significantly fewer ISUP ≥3 lesions (P = .02)., Conclusion: We observed a significantly lower PSA level after a 6-month challenge with a fermented soy-containing supplement, and an effect on IPSS in a subset of patients. Prescribing a fermented soy supplement in patients with an increased PCa risk could lead to a better selection of patients at real increased risk of having occult PCa., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Salvage radical prostatectomy (sRP) yields poor functional outcomes and relatively high complication rates. Gleason score (GS) 6 prostate cancer (PCa) has genetic and clinical features showing little, if not absent, metastatic potential. However, the behavior of GS 6 PCa recurring after previous PCa treatment including radiotherapy and/or ablation has not been investigated., Objective: To evaluate the oncological outcomes of sRP for radio- and/or ablation-recurrent GS 6 PCa., Design, Setting, and Participants: Retrospective data of sRP for recurrent PCa after local nonsurgical treatment were collected from 14 tertiary referral centers from 2000 to 2021., Intervention: Prostate biopsy before sRP and sRP., Outcome Measurements and Statistical Analysis: A survival analysis was performed for pre-sRP biopsy and sRP-proven GS 6. Concordance between PCa at pre-sRP biopsy and sRP histology was assessed., Results and Limitations: We included GS 6 recurrent PCa at pre-sRP biopsy (n = 142) and at sRP (n = 50), as two cohorts. The majority had primary radiotherapy and/or brachytherapy (83.8% of GS 6 patients at pre-sRP biopsy; 78% of GS 6 patients at sRP) and whole-gland treatments (91% biopsy; 85.1% sRP). Biopsy GS 6 10-yr metastasis, cancer-specific survival (CSS), and overall survival (OS) were 79% (95% confidence interval [CI] 61-89%), 98% (95-99%), and 89% (78-95%), respectively. Upgrading at sRP was 69%, 35.5% had a pT3 stage, and 13.4% had positive nodes. The sRP GS 6 10-yr metastasis-free survival, CSS, and OS were 100%, 100%, and 90% (95% CI 58-98%) respectively; pT3 and pN1 disease were found in 12% and 0%, respectively. Overall complications, high-grade complications, and severe incontinence were experienced by >50%, >10%, and >15% of men, respectively (in both the biopsy and the sRP cohorts). Limitations include the retrospective nature of the study and absence of a centralized pathological review., Conclusions: GS 6 sRP-proven PCa recurring after nonsurgical primary treatment has almost no metastatic potential, while patients experience relevant morbidity of the procedure. However, a significant proportion of GS 6 cases at pre-sRP biopsy are upgraded at sRP. In the idea not to overtreat, efforts should be made to improve the diagnostic accuracy of pre-sRP biopsy., Patient Summary: We investigated the oncological results of salvage radical prostatectomy for recurrent prostate cancer of Gleason score (GS) 6 category. We found a very low malignant potential of GS 6 confirmed at salvage radical prostatectomy despite surgical complications being relatively high. Nonetheless, biopsy GS 6 was frequently upgraded and had less optimal oncological control. Overtreatment for recurrent GS 6 after nonsurgical first-line treatment should be avoided, and efforts should be made to increase the diagnostic accuracy of biopsies for recurrent disease., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

A new chemical scaffold with antagonistic activity towards the androgen receptor (AR) was identified. The parent compound, (3-Methoxy-N-[1-methyl-2-(4-phenyl-1-piperazinyl)-2-(2-thienyl)ethyl]benzamide) referred to as MEL-6, binds in the ligand binding pocket of AR and induces an antagonistic conformation of the ligand binding domain, even in presence of the antagonist-to-agonist switch mutations W741C, T877A and F876L-T877A. MEL-6 has antiproliferative effects on several AR positive prostate cancer cell lines. We further identified AR as the specific target of MEL-6 since it demonstrates little effect on other steroid receptors. In LNCaP cells it also inhibits the androgen-regulated transcriptome. These findings identify MEL-6 as a promising candidate for treatment of patients with prostate tumors that have become resistant to current clinically used AR antagonists. Analytical studies on the chemical composition of MEL-6 identified the presence of four isomers (two enantiomeric pairs), among which one isomer is responsible for the antiandrogenic activity. We therefore developed a synthetic route towards the selective preparation of the active enantiomeric pair. Various MEL-6-like analogues had improved metabolic stability while maintaining antiandrogenic activity. Metabolite identification of MEL-6 derivatives pinpointed N-dealkylation of the piperazine as the main mode for inactivation by liver enzymes. For further structural optimization, MEL-6 derivatives were purchased or synthesized having alterations on the N-phenyl group of the piperazine, the benzoyl group and additionally substituting the thiophen-2-yl ring of MEL-6 to a phenyl ring. This optimization process resulted in compound 12b with sustained AR inhibition and a 4-fold increased half-life due to the 1-(5-chloro-2-methylphenyl)-piperazine substitution, thienyl-to-phenyl substitution and chloro in para-position of the benzoyl group., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. 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.)

Purpose: Isolated recurrence in remnants of the seminal vesicles (SV) after treatment of primary prostate cancer (PCa) has become a more frequent entity with the widespread use of more sensitive next-generation imaging modalities. Salvage vesiculectomy is hypothesized to be a worthwhile management option in these patients. The primary goal of this study is to describe the surgical technique of this new treatment option. Secondary outcomes are peri- and post-operative complications and early oncological outcomes., Methods: Retrospective multicenter study, including 108 patients with solitary recurrence in the SV treated between January 2009 and June 2022, was performed. Patients with local recurrences outside the SVs or with metastatic disease were excluded. Both SVs were resected using a robot-assisted or an open approach. In selected cases, a concomitant lymphadenectomy was performed., Results: Overall, 31 patients (29%) reported complications, all but one grade 1 to 3 on the Clavien-Dindo Scale. A median PSA decrease of 2.07 ng/ml (IQR: 0.80-4.33, p < 0.001), translating into a median PSA reduction of 92% (IQR: 59-98%) was observed. At a median follow-up of 14 months, freedom from secondary treatment was 54%. Lymphadenectomy had a significant influence on PSA reduction (p = 0.018)., Conclusion: Salvage vesiculectomy for PCa recurrence limited to the SV is a safe procedure with excellent PSA response and is a potential curative treatment in a subset of patients. A concomitant lymphadenectomy can best be performed in all patients that did not underwent one at primary treatment., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Metastasis-directed therapy (MDT) is performed to delay systemic treatments for oligorecurrent disease after primary prostate cancer (PCa) treatment., Objective: The aim of this study was to identify the predictors of therapeutic response of MDT for oligorecurrent PCa., Design, Setting, and Participants: bicentric, retrospective study, including consecutive patients who underwent MDT for oligorecurrent PCa after radical prostatectomy (RP; 2006-2020) was conducted. MDT encompassed stereotactic body radiation therapy (SBRT), salvage lymph node dissection (sLND), whole-pelvis/retroperitoneal radiation therapy (WP[R]RT), or metastasectomy., Outcome Measurements and Statistical Analysis: ndpoints were 5-yr radiographic progression-free survival (rPFS), metastasis-free survival (MFS), palliative androgen deprivation treatment (pADT)-free survival, and overall survival (OS) together with prognostic factors for MFS following primary MDT. Survival outcomes were studied by Kaplan-Meier survival and univariable Cox regression (UVA)., Results and Limitations: A total of 211 MDT patients were included; 122 (58%) developed a secondary recurrence. Salvage lymph node dissection was performed in 119 (56%), SBRT in 48 (23%), and WP(R)RT in 31 (15%) of the cases. Two patients received sLND + SBRT and one received sLND + WPRT. Eleven (5%) patients received metastasectomies. The median follow-up since RP was 100 mo, while follow-up after MDT was 42 mo. The 5-yr rPFS, MFS, androgen deprivation treatment(-free survival, castration-resistant prostate cancer-free survival, CSS, and OS after MDT were 23%, 68%, 58%, 82%, 93%, and 87% respectively. There was a statistically significant difference between cN1 (n = 114) and cM+ (n = 97) for 5-yr MFS (83% vs 51%, p < 0.001), pADT-free survival (70% vs 49%, p = 0.014), and CSS (100% vs 86%, p = 0.019). UVA was performed to assess the risk factors (RFs) for MFS in cN1 and cM+. Alpha was set at 10%. RFs for MFS in cN1 were lower initial prostate-specific antigen (PSA) at the time of RP (hazard ratio [95% confidence interval] 0.15 [0.02-1.02], p = 0.053], pN stage at RP (2.91 [0.83-10.24], p = 0.096), nonpersisting PSA after RP (0.47 [0.19-1.12], p = 0.089), higher PSA at primary MDT (2.38 [1.07-5.24], p = 0.032), and number of positive nodes on imaging (1.65 [1.14-2.40], p < 0.01). RFs for MFS in cM+ were higher pathological Gleason score (1.86 [0.93-3.73], p = 0.078), number of lesions on imaging (0.77 [0.57-1.04], p = 0.083), and cM1b/cM1c (non-nodal metastatic recurrence; 2.62 [1.58-4.34], p < 0.001)., Conclusions: Following MDT, 23% of patients were free of a second recurrence at 5-yr follow-up. Moreover, cM+ patients had significantly worse outcomes in terms of MFS, pADT-free survival, and CSS. The RFs for a metastatic recurrence can be used for counseling patients, to inform prognosis, and potentially select candidates for MDT., Patient Summary: In this paper, we looked at the outcomes of using localized, patient-tailored treatment for imaging-detected recurrent prostate cancer in lymph nodes, bone, or viscera (maximum five recurrences on imaging). Our results showed that targeted treatment of the metastatic lesions could delay the premature use of hormone therapy., (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.)

In metastatic castration-sensitive prostate cancer (mCSPC), disease volume plays an integral role in guiding treatment recommendations, including selection of docetaxel therapy, metastasis-directed therapy, and radiation to the prostate. Although there are multiple definitions of disease volume, they have commonly been studied in the context of metastases detected via conventional imaging (CIM). One such numeric definition of disease volume, termed oligometastasis, is heavily dependent on the sensitivity of the imaging modality. We performed an international multi-institutional retrospective review of men with metachronous oligometastatic CSPC (omCSPC), detected via either advanced molecular imaging alone (AMIM) or CIM. Patients were compared with respect to clinical and genomic features using the Mann-Whitney U test, Pearson's χ 2 test, and Kaplan-Meier overall survival (OS) analyses with a log-rank test. A total of 295 patients were included for analysis. Patients with CIM-omCSPC had significantly higher Gleason grade group (p = 0.032), higher prostate-specific antigen at omCSPC diagnosis (8.0 vs 1.7 ng/ml; p < 0.001), more frequent pathogenic TP53 mutations (28% vs 17%; p = 0.030), and worse 10-yr OS (85% vs 100%; p < 0.001). This is the first report of clinical and biological differences between AMIM-detected and CIM-detected omCSPC. Our findings are particularly important for ongoing and planned clinical trials in omCSPC. PATIENT SUMMARY: Metastatic prostate cancer with just a few metastases only detected via newer scanning methods (called molecular imaging) is associated with fewer high-risk DNA mutations and better survival in comparison to metastatic cancer detected via conventional scan methods., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

A possible link between diet and cancer has long been considered, with growing interest in phytochemicals. Soy isoflavones have been associated with a reduced risk of prostate cancer in Asian populations. Of the soy isoflavones, genistein and daidzein, in particular, have been studied, but recently, equol as a derivative has gained interest because it is more biologically potent. Different mechanisms of action have already been studied for the different isoflavones in multiple conditions, such as breast, gastrointestinal, and urogenital cancers. Many of these mechanisms of action could also be demonstrated in the prostate, both in vitro and in vivo. This review focuses on the known mechanisms of action at the cellular level and compares them between genistein, daidzein, and equol. These include androgen- and estrogen-mediated pathways, regulation of the cell cycle and cell proliferation, apoptosis, angiogenesis, and metastasis. In addition, antioxidant and anti-inflammatory effects and epigenetics are addressed.

Background: Prostate cancer (PCa) patients treated with androgen deprivation therapy (ADT) have an increased fracture risk. Exploring biomarkers for early bone loss detection is of great interest., Methods: Pre-planned substudy of the ARNEO-trial (NCT03080116): a double blind, randomised, placebo-controlled phase 2 trial performed in high-risk PCa patients without bone metastases between March 2019 and April 2021. Patients were 1:1 randomised to treatment with gonadotropin-releasing hormone antagonist (degarelix) + androgen receptor signalling inhibitor (ARSI; apalutamide) versus degarelix + matching placebo for 12 weeks prior to prostatectomy. Before and following ADT, serum and 24-h urinary samples were collected. Primary endpoints were changes in calcium-phosphate homeostasis and bone biomarkers., Findings: Of the 89 randomised patients, 43 in the degarelix + apalutamide and 44 patients in the degarelix + placebo group were included in this substudy. Serum corrected calcium levels increased similarly in both treatment arms (mean difference +0.04 mmol/L, 95% confidence interval, 0.02; 0.06), and parathyroid hormone and 1,25-dihydroxyvitamin D 3 levels decreased. Bone resorption markers increased, and stable calcium isotope ratios reflecting net bone mineral balance decreased in serum and urine similarly in both groups., Interpretation: This exploratory substudy suggests that 12 weeks of ADT in non-metastatic PCa patients results in early bone loss. Additional treatment with ARSI does not seem to more negatively influence bone loss in the early phase. Future studies should address if these early biomarkers are able to predict fracture risk, and can be implemented in clinical practice for follow-up of bone health in PCa patients under ADT., Funding: Research Foundation Flanders; KU Leuven; University-Hospitals-Leuven., Competing Interests: Declaration of interests LA participated on advisory boards for Galapagos/Gilead, Simple Pharma and Merck. LA receives a Senior Clinical Investigator Fellowship from Flanders Research Foundation (FWO 1800923N). AE is founder of the Osteolabs GmbH, Kiel, Germany. EC received consulting fees from DiaSorin, IDS, Fujirebio, Nittobo, bioMérieux and Werfen. SJ received consulting fees and support for attending meetings, honoraria for lectures and participated in monitoring and advisory boards of Ipsen, Bayer, Astellas, Janssen and Ferring., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Metastatic castration-sensitive prostate cancer (mCSPC) is commonly classified into high- and low-volume subgroups which have demonstrated differential biology, prognosis, and response to therapy. Timing of metastasis has similarly demonstrated differences in clinical outcomes; however, less is known about any underlying biologic differences between these disease states. Herein, we aim to compare transcriptomic differences between synchronous and metachronous mCSPC and identify any differential responses to therapy., Patients and Methods: We performed an international multi-institutional retrospective review of men with mCSPC who completed RNA expression profiling evaluation of their primary tumor. Patients were stratified according to disease timing (synchronous versus metachronous). The primary endpoint was to identify differences in transcriptomic profiles between disease timing. The median transcriptomic scores between groups were compared with the Mann-Whitney U test. Secondary analyses included determining clinical and transcriptomic variables associated with overall survival (OS) from the time of metastasis. Survival analysis was carried out with the Kaplan-Meier method and multivariable Cox regression., Results: A total of 252 patients were included with a median follow-up of 39.6 months. Patients with synchronous disease experienced worse 5-year OS (39% versus 79%; P < 0.01) and demonstrated lower median androgen receptor (AR) activity (11.78 versus 12.64; P < 0.01) and hallmark androgen response (HAR; 3.15 versus 3.32; P < 0.01). Multivariable Cox regression identified only high-volume disease [hazard ratio (HR) = 4.97, 95% confidence interval (CI) 2.71-9.10; P < 0.01] and HAR score (HR = 0.51, 95% CI 0.28-0.88; P = 0.02) significantly associated with OS. Finally, patients with synchronous (HR = 0.47, 95% CI 0.30-0.72; P < 0.01) but not metachronous (HR = 1.37, 95% CI 0.50-3.92; P = 0.56) disease were found to have better OS with AR and non-AR combination therapy as compared with monotherapy (P value for interaction = 0.05)., Conclusions: We have demonstrated a potential biologic difference between metastatic timing of mCSPC. Specifically, for patients with low-volume disease, those with metachronous low-volume disease have a more hormone-dependent transcriptional profile and exhibit a better prognosis than synchronous low-volume disease., Competing Interests: Disclosure PAS reports stocks from Merck and Pfizer. AH reports employment, stock/other ownership interests with Veracyte. YL reports employment with Veracyte. VF reports travel/accommodations/expenses covered by Ipsen. AH reports honoraria, travel/accommodations/expenses covered by UroToday; consulting/advisory role with AstraZeneca and MSD. DYS is a consultant for Isoray; also reports being a consultant and carrying out research for BioProtect. AES reports consulting/advisory role for and receiving honoraria from Astellas Pharma; is on the speaker’ bureau and reports receiving honoraria from Tempus; reports receiving honoraria from Bayer, Janssen Biotech, Blue Earth Diagnostics, Decipher Biosciences, Myovant Sciences, and Lantheus Medical Imaging. FF reports carrying out consulting/advisory role for Janssen Biotech, Astellas Pharma, Foundation Medicine, Exact Sciences, Bristol-Myers Squibb, Varian Medical Systems, Novartis, Roivant, Bayer, Myovant Sciences, Tempus, and POINT Biopharma; reports performing consulting/advisory role or has stock/other ownership interests in Serimmune, BlueStar Genomics, and Artera; and receives research funding from Zenith Epigenetics. DS reports consulting/advisory role with AstraZeneca, Bayer, Boston Scientific, Janssen, Novartis, Myovant, Pfizer, GammaTile, Elekta, and Varian. KP reports consulting/advisory role with CUE Biopharma, GloriousMed Technology, and Akrevia Therapeutics; reports leadership, travel/accommodations/expenses, and stock/other ownership interests with CUE Biopharma; stock/other ownership interests with Keystone Biopharma; stock/other ownership interests with Medsyn Biopharma, Oncopia Therapeutics; and research funding from Progenics. SG reports consulting/advisory role with Bayer, MSD Oncology, Amgen, Pfizer, Bristol-Meyers Squibb, Telix Pharmaceuticals, AAA HealthCare, Orion, Novartis, Modra Pharmaceuticals, Myriad Genetics, AstraZeneca, TOLREMO, Silvio Grasso Consulting, WebMD/Medscape, ESMO, Swiss Academy of Multidisciplinary Oncology, Swiss group for Clinical Cancer Research, German-speaking European School of Oncology, Radiotelevisione Svizzera Italiana, and ProteoMediX; also reports travel/accommodations/expenses covered by AstraZeneca. GA reports consulting/advisory role, speakers’ bureau, travel/accommodations/expenses, honoraria, research funding from Janssen-Cilag; consulting/advisory role with Veridex, Novartis, Millennium; consulting/advisory role, speakers’ bureau, travel/accommodations/expenses covered by Ventana Medical Systems; consulting/advisory role, speakers’ bureau, travel/accommodations/expenses, honoraria from Astellas Pharma; consulting/advisory role, travel/accommodations/expenses covered by Medivation, Abbott Laboratories, ESSA, Bayer, and Pfizer; consulting/advisory role and is on the speaker’s bureau for AstraZeneca; consulting/advisory role, speakers’ bureau, travel/accommodations/expenses covered by Ferring; is on the speakers’ bureau for Takeda, Sanofi, Ipsen; has received ICR rewards to inventors of abiraterone acetate (patent/royalty/other intellectual property); and reports research funding from Arno Therapeutics and Innocrin Pharma. NDJ reports honoraria, consulting/advisory role, speakers’ bureau, research funding, travel/accommodations/expenses covered by Sanofi and Janssen; honoraria, consulting/advisory role, speakers’ bureau, and research funding from Astellas Pharma; honoraria and consulting/advisory role with Bayer; consulting/advisory role with Clovis Oncology and EUSA Pharma; reports consulting/advisory role with and research funding from Pfizer; is on the speakers’ bureau for Pierre Fabre, Ferring, and Merck; is on the speakers’ bureau and received research funding from AstraZeneca; and research funding from Novartis. TL reports consulting/advisory role with Janssen Oncology; research funding from Ventana Medical Systems, Deep Bio, AIRA Matrix, and Exact Sciences. ED reports employment and stock/other ownership interests with Veracyte. CS reports consulting/advisory role and research funding from Sanofi, Janssen Biotech, Astellas Pharma, Bayer, and Pfizer; consulting/advisory role with Genentech/Roche, AstraZeneca, Amgen, Lilly, and POINT Biopharma; stock/other ownership interest, patents/royalties/other intellectual property with Leuchemix; patents/royalties/other intellectual property with Exelixis; and research funding from Dendreon. PTT reports consulting/advisory role with Astellas Pharma, Regeneron, GenomeDx, Dendreon, Noxopharm, Janssen, Myovant Sciences, AstraZeneca; research funding from Astellas Pharma; consulting/advisory role, travel/accommodations/expenses, honoraria, and research funding from RefleXion Medical; consulting/advisory role and research funding from Bayer Health; and patent (Compounds and Methods of Use in Ablative Radiotherapy. Patent filed 3/9/2012. PCT/US2012/028475. PCT/WO/2012/122471). PO reports consulting/advisory role with Janssen-Cilag, Bayer, Astellas Pharma, Curium Pharma, Telix Pharmaceuticals, and Novartis; research funding from Bayer and Varian Medical Systems; and travel/accommodations/expenses covered by Ferring. All other authors have declared no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Salvage radical prostatectomy (sRP) is a potentially curative option for locally radiorecurrent prostate cancer (PCa) but is associated with significant morbidity. Therefore, the European Association of Urology (EAU) guidelines recommend restricting sRP to a favorable-prognosis group according to the EAU criteria, but these have been validated considering only biochemical recurrence (BCR). Our aim was to test these criteria in a large, multicenter, contemporary cohort. We retrospectively reviewed 1265 patients who underwent sRP at 14 referral centers (2000-2021), stratified by compliance with the EAU criteria. Our primary outcome was metastasis-free survival (MFS). We included 1030 men, of whom 221 (21.5%) fully met the EAU recommended criteria for sRP and 809 (78.5%) did not. The EAU-compliant group experienced more favorable pathological and functional outcomes (79% vs 63% wearing no pads at 1 yr; p < 0.001) and had significantly better MFS (90% vs 76% at 5 yr; p < 0.001), prostate-specific antigen-free survival (55% vs 38% at 5 yr; p < 0.001), and overall survival (89% vs 84% at 5 yr; p = 0.01). This was verified by Cox regression analysis for MFS (hazard ratio 1.84, 95% confidence interval 1.13-2.99; p = 0.01). We found that adherence to the EAU criteria is associated with a lower risk of BCR and, more importantly, of metastasis after surgery. PATIENT SUMMARY: We looked at outcomes of surgical removal of the prostate for prostate cancer recurrence after radiotherapy or other nonsurgical treatments according to whether or not patients met the European Association of Urology (EAU) criteria for this surgery. We found that men who did not meet the criteria had a higher risk of metastasis and their benefit from surgery might be significantly less than for patients who do meet the EUA criteria., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: High-risk prostate cancer (PCa) patients have a high risk of biochemical recurrence and metastatic progression following radical prostatectomy (RP)., Objective: To determine the efficacy of neoadjuvant degarelix plus apalutamide before RP compared with degarelix with a matching placebo., Design, Setting, and Participants: ARNEO was a randomized, placebo-controlled, phase II neoadjuvant trial before RP performed between March 2019 and April 2021. Eligible patients had high-risk PCa and were amenable to RP., Intervention: Patients were randomly assigned at a 1:1 ratio to degarelix (240-80-80 mg) + apalutamide (240 mg/d) versus degarelix + matching placebo for 3 mo followed by RP. Prior to and following neoadjuvant treatment, pelvic 18 F-PSMA-1007 positron emission tomography (PET)/magnetic resonance imaging (MRI) was performed., Outcome Measurements and Statistical Analysis: The primary endpoint was the difference in proportions of patients with minimal residual disease (MRD; = residual cancer burden (RCB) ≤0.25 cm 3 at final pathology). Secondary endpoints included differences in prostate-specific antigen responses, pathological staging, and change in TNM stage on prostate-specific membrane antigen (PSMA) PET/MRI following hormonal treatment. Biomarkers (immunohistochemical staining on prostate biopsy [PTEN, ERG, Ki67, P53, GR, and PSMA] and PSMA PET/MRI-derived characteristics) associated with pathological response (MRD and RCB) were explored., Results and Limitations: Patients were randomized to neoadjuvant degarelix + apalutamide (n = 45) or degarelix + matching placebo (n = 44) for 12 wk and underwent RP. Patients in the degarelix + apalutamide arm achieved a significantly higher rate of MRD than those in the control arm (38% vs 9.1%; relative risk [95% confidence interval] = 4.2 [1.5-11], p = 0.002). Patients with PTEN loss in baseline prostate biopsy attained significantly less MRD (11% vs 43%, p = 0.002) and had a higher RCB at final pathology (1.6 vs 0.40 cm 3 , p < 0.0001) than patients without PTEN loss. Following neoadjuvant hormonal therapy, PSMA PET-estimated tumor volumes (1.2 vs 2.5 ml, p = 0.01) and maximum standardized uptake value (SUVmax; 4.3 vs 5.7, p = 0.007) were lower in patients with MRD than in patients without MRD. PSMA PET-estimated volume and PSMA PET SUVmax following neoadjuvant treatment correlated significantly with RCB at final pathology (both p < 0.001)., Conclusions: In high-risk PCa patients, neoadjuvant degarelix plus apalutamide prior to RP results in a significantly improved pathological response (MRD and RCB) compared with degarelix alone. Our trial results provide a solid hypothesis-generating basis for neoadjuvant phase 3 trials, which are powered to detect differences in long-term oncological outcome following neoadjuvant androgen receptor signaling inhibitor therapy., Patient Summary: In this study, we looked at the difference in pathological responses in high-risk prostate cancer patients treated with degarelix plus apalutamide or degarelix plus matching placebo prior to radical prostatectomy. We demonstrated that patients treated with degarelix plus apalutamide achieved a significantly better tumor response than patients treated with degarelix plus matching placebo. Long-term follow-up is required to determine whether improved pathological outcome translates into better oncological outcomes., (Copyright © 2022 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Despite growing interest in metastasis-directed therapy (MDT) for prostate cancer (PCa), little is known regarding the feasibility and effectiveness of surgical metastasectomy for isolated lesions. We performed a narrative review of the available evidence supporting metastasectomy for M1b-c lesions in men diagnosed with oligometastatic or oligorecurrent PCa. The case series and case reports we identified indicate that surgical MDT is a safe and feasible treatment option for well-selected patients with a small number of PCa metastases diagnosed via molecular imaging. It is difficult to draw evidence-based conclusions regarding the survival benefit of metastasectomy; however, metastasectomy might lead to a prostate-specific antigen response and could potentially delay systemic therapy in patients with oligometastatic PCa. Prospective studies incorporating novel imaging are needed to better establish the role of metastasectomy for patients with metastatic PCa. PATIENT SUMMARY: We reviewed the evidence on surgical removal of prostate cancer lesions that have spread to the organs (eg, liver and lung) or bone, which are called metastases. Limited results show that this approach is feasible and has favorable outcomes in selected patients., (Copyright © 2022 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objectives: Several retrospective studies have shown that salvage bilateral pelvic lymph node dissection (sLND) is a valid treatment option in the setting of oligorecurrent nodal prostate cancer following radical prostatectomy. Little is known about the optimal template of such sLND in patients with strictly unilateral pelvic recurrence on PET-CT imaging. In this study, we investigated whether a unilateral pelvic sLND could be sufficient in such a setting., Methods: We retrospectively collected data of patients treated with sLND between 2010 and 2019 at the University Hospitals, Leuven. Patients were included if they developed recurrence following radical prostatectomy, characterized by ≤3 unilateral pelvic lymph node metastases on Choline or PSMA PET-CT and received a super-extended bilateral pelvic sLND as first metastasis-directed therapy. As a primary endpoint, we investigated in how many cases a unilateral sLND would have been sufficient., Results: In total, 44 patients with strictly unilateral pelvic recurrence were treated with super-extended bilateral pelvic sLND. In 5 out of 44 (11%) patients, histological examination showed presence of prostate cancer in the contralateral hemi-pelvis. In the group with a single positive node on imaging prior to sLND, only 1 out of 27 (3%) patients had contralateral disease at final pathology. No one (0%) in this group subsequently developed recurrence in the contralateral hemi-pelvis following sLND., Conclusions: In conclusion, this study suggests that unilateral pelvic sLND could be sufficient in patients with a single unilateral pelvic lymph node recurrence on PET/CT imaging., (© 2022 The Japanese Urological Association.)

Background: To construct a model based on magnetic resonance imaging (MRI) features and histological and clinical variables for the prediction of pathology-detected extracapsular extension (pECE) in patients with prostate cancer (PCa)., Methods: We performed a prospective 3 T MRI study comparing the clinical and MRI data on pECE obtained from patients treated using robotic-assisted radical prostatectomy (RARP) at our institution. The covariates under consideration were prostate-specific antigen (PSA) levels, the patient's age, prostate volume, and MRI interpretative features for predicting pECE based on the Prostate Imaging-Reporting and Data System (PI-RADS) version 2.0 (v2), as well as tumor capsular contact length (TCCL), length of the index lesion, and prostate biopsy Gleason score (GS). Univariable and multivariable logistic regression models were applied to explore the statistical associations and construct the model. We also recruited an additional set of participants-which included 59 patients from external institutions-to validate the model., Results: The study participants included 184 patients who had undergone RARP at our institution, 26% of whom were pECE+ (i.e., pECE positive). Significant predictors of pECE+ were TCCL, capsular disruption, measurable ECE on MRI, and a GS of ≥7(4 + 3) on a prostate biopsy. The strongest predictor of pECE+ is measurable ECE on MRI, and in its absence, a combination of TCCL and prostate biopsy GS was significantly effective for detecting the patient's risk of being pECE+. Our predictive model showed a satisfactory performance at distinguishing between patients with pECE+ and patients with pECE-, with an area under the ROC curve (AUC) of 0.90 (86.0-95.8%), high sensitivity (86%), and moderate specificity (70%)., Conclusions: Our predictive model, based on consistent MRI features (i.e., measurable ECE and TCCL) and a prostate biopsy GS, has satisfactory performance and sufficiently high sensitivity for predicting pECE+. Hence, the model could be a valuable tool for surgeons planning preoperative nerve sparing, as it would reduce positive surgical margins., (© 2022. The Author(s).)

Introduction: Abiraterone acetate + prednisone (AAP) and docetaxel have proven their efficacy in the treatment of patients with newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC) in clinical trials. However, real-world data are scarce. The goal of this study is to evaluate real-world data on the efficacy and safety of these therapies in mHSPC patients., Patients and Methods: Records of 93 patients from 21 different centres were retrospectively reviewed. Primary and secondary endpoints were radiographic and PSA progression-free survival (RPFS - PSA-PFS) and cancer specific and overall survival (CSS - OS), respectively. Adverse events (AEs) were evaluated according to the Common Terminology Criteria for Adverse Events version 5.0. Differences in oncological outcome and AEs were evaluated between three treatment groups: ADT only (N=26) - ADT + AAP (N=48) - ADT + docetaxel (N=19). Survival analysis was performed using Kaplan-Meier statistics., Results: Median RPFS was 13 months (95% confidence interval [CI]: 9-17) for ADT only, 21 months (95% CI: 19-23) for ADT + AAP and 12 months (95% CI: 11-14) for ADT + docetaxel (p = 0.004). The 1-year PSA-PFS, CSS and OS were 73.5%, 90.7% and 88.7%, respectively, with no significant differences between the three groups. Adverse events of grade 3 or higher were not observed more frequently., Conclusion: Retrospective real-world data show a significantly longer RPFS for mHSPC patients treated with ADT + AAP compared to ADT only or ADT + docetaxel at short-term follow-up. This can aid in counselling of mHSPC patients in daily clinical practice.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. The initial STOMP and ORIOLE trial reports suggested that metastasis-directed therapy (MDT) in oligometastatic castration-sensitive prostate cancer (omCSPC) was associated with improved treatment outcomes. Here, we present long-term outcomes of MDT in omCSPC by pooling STOMP and ORIOLE and assess the ability of a high-risk mutational signature to risk stratify outcomes after MDT. The primary end point was progression-free survival (PFS) calculated using the Kaplan-Meier method. High-risk mutations were defined as pathogenic somatic mutations within ATM , BRCA1 / 2 , Rb1 , or TP53 . The median follow-up for the whole group was 52.5 months. Median PFS was prolonged with MDT compared with observation (pooled hazard ratio [HR], 0.44; 95% CI, 0.29 to 0.66; P value < .001), with the largest benefit of MDT in patients with a high-risk mutation (HR high-risk, 0.05; HR no high-risk, 0.42; P value for interaction: .12). Within the MDT cohort, the PFS was 13.4 months in those without a high-risk mutation, compared with 7.5 months in those with a high-risk mutation (HR, 0.53; 95% CI, 0.25 to 1.11; P = .09). Long-term outcomes from the only two randomized trials in omCSPC suggest a sustained clinical benefit to MDT over observation. A high-risk mutational signature may help risk stratify treatment outcomes after MDT.

This report presents a 56-yr-old man in good general health status, newly diagnosed with a cT3b, cN1, cM1b, International Society of Urological Pathology grade group 3, low-volume (CHAARTED criteria), low-risk (LATITUDE criteria) metastatic prostate cancer. Staging was performed with conventional imaging: a computed tomography (CT) scan showed the presence of two enlarged lymph nodes on the left, close to the external iliac vessels. In addition, a suspicious 15-mm metastatic lesion was detected in the left pubic bone. This lesion was confirmed on the bone scan, without further metastatic lesions. In the context of a clinical trial, after an initial course of androgen deprivation therapy (ADT), the patient was treated with robot-assisted radical prostatectomy and extended pelvic lymph node dissection (histopathological examination: ypT3b pN1 R1). Postprostatectomy radiation therapy was delivered on prostatic bed (70Gy), pelvic lymph node area (54Gy), and pubic bone (51Gy). ADT was scheduled for a total period of 36 mo. Currently, the patient is still receiving ADT, which will be completed within 6 mo. The last prostate-specific antigen level was undetectable. The discussion is focused on the following three open questions: (1) Would molecular imaging (eg, prostate-specific membrane antigen positron emission tomography/CT) change the therapeutic approach to the patient? (2) Is there a role for local treatment in the metastatic setting? (iii) Should metastasis-directed therapy be considered for this patient? PATIENT SUMMARY: The optimal management of patients newly diagnosed with oligometastatic prostate cancer remains challenging. The fields of staging with modern imaging and therapy with novel treatment options are evolving rapidly. In particular, the role of a prostate-specific membrane antigen positron emission tomography/computed tomography scan for primary staging, the impact of a local treatment on the prostate, and the effect of direct therapies on the metastases represent important open questions in this intriguing field., (Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Prostate cancer (PCa) is the most frequent cancer in men. The prognosis of PCa is heterogeneous with many clinically indolent tumors and rare highly aggressive cases. Reliable tissue markers of prognosis are lacking. Active cholesteryl ester synthesis has been associated with prostate cancer aggressiveness. Sterol-O-Acyl transferases (SOAT) 1 and 2 catalyze cholesterol esterification in humans., Objective: To investigate the value of SOAT1 and SOAT2 tissue expression as prognostic markers in high risk PCa., Patients and Methods: Formalin-fixed paraffin-embedded tissue samples from 305 high risk PCa cases treated with radical prostatectomy were analyzed for SOAT1 and SOAT2 protein expression by semi-quantitative immunohistochemistry. The Kaplan-Meier method and Cox proportional hazards modeling were used to compare outcome., Main Outcome Measure: Biochemical recurrence (BCR) free survival., Results: SOAT1 expression was high in 73 (25%) and low in 219 (75%; not evaluable: 13) tumors. SOAT2 was highly expressed in 40 (14%) and at low levels in 249 (86%) samples (not evaluable: 16). By Kaplan-Meier analysis, we found significantly shorter median BCR free survival of 93 months (95% confidence interval 23.6-123.1) in patients with high SOAT1 vs. 134 months (112.6-220.2, Log-rank p < 0.001) with low SOAT1. SOAT2 expression was not significantly associated with BCR. After adjustment for age, preoperative PSA, tumor stage, Gleason score, resection status, lymph node involvement and year of surgery, high SOAT1 but not SOAT2 expression was associated with shorter BCR free survival with a hazard ratio of 2.40 (95% CI 1.57-3.68, p < 0.001). Time to clinical recurrence and overall survival were not significantly associated with SOAT1 and SOAT2 expression CONCLUSIONS: SOAT1 expression is strongly associated with BCR free survival alone and after multivariable adjustment in high risk PCa. SOAT1 may serve as a histologic marker of prognosis and holds promise as a future treatment target., (© 2021. The Author(s).)

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.)

Background: The optimal definition and prognostic significance of persistently elevated prostate-specific antigen (PSA) after salvage lymph node dissection (sLND) for node-only recurrent prostate cancer (PCa) remain unknown., Objective: To assess the definition and clinical implications of persistently elevated PSA after sLND for node-only recurrent PCa after radical prostatectomy., Design, Setting, and Participants: The study included 579 patients treated with sLND at 11 high-volume centers between 2000 and 2016., Outcome Measurements and Statistical Analysis: We assessed the linear relationship between the first PSA after sLND and death from PCa. Different definitions of PSA persistence were included in a multivariable model predicting cancer-specific mortality (CSM) after surgery to identify the best cutoff value. We investigated the association between PSA persistence and oncologic outcomes using multivariable regression models. Moreover, the effect of early androgen deprivation therapy (ADT) after sLND was tested according to PSA persistence status and estimated risk of CSM., Results and Limitations: We found an inverse relationship between the first PSA after sLND and the probability of cancer-specific survival. PSA persistence defined as first postoperative PSA ≥0.3 ng/ml provided the best discrimination accuracy (C index 0.757). According to this cutoff, 331 patients (57%) experienced PSA persistence. The median follow-up for survivors was 48 mo (interquartile range 27-74). After adjusting for confounders, men with persistently elevated PSA had higher risk of clinical recurrence (hazard ratio [HR] 1.61), overall mortality (HR 2.20), and CSM (HR 2.59; all p < 0.001) after sLND. Early ADT administration after sLND improved survival only for patients with PSA persistence after surgery (HR 0.49; p = 0.024). Similarly, when PSA persistence status was included in multivariable models accounting for pathologic features, early ADT use after sLND was beneficial only for patients with a predicted risk of CSM at 5 yr of >10%., Conclusions: PSA persistence after sLND independently predicts adverse prognosis, with the best discrimination accuracy for CSM provided by a definition of PSA ≥ 0.3 ng/ml. We showed that when stratifying patients by final pathology results and PSA persistence status, early ADT use after sLND was beneficial only for patients with PSA persistence or with a calculated 5-yr risk of CSM of >10%, which could be useful as we await results from ongoing prospective trials., Patient Summary: We found that for patients with prostate cancer who had lymph nodes removed after their cancer recurred, persistently elevated prostate-specific antigen (PSA) levels predict poorer prognosis. We showed that a PSA level of ≥0.3 ng/ml provides the best accuracy in identifying patients with worse prognosis. This may help to improve risk stratification after lymph node removal and allow physicians to optimize treatment strategies after surgery., (Copyright © 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Molecular drivers of metastasis in patients with high-risk localized prostate cancer are poorly understood. Therefore, we aim to study molecular drivers of metastatic progression in patients with high-risk prostate cancer. A retrospective matched case-control study of two clinico-pathologically identical groups of patients with high-risk prostate cancer was undertaken. One group developed metastatic recurrence (n = 19) while the other did not (n = 25). The primary index tumor was identified by a uro-pathologist, followed by DNA and RNA extraction for somatic copy-number aberration (SCNA) analysis and whole-transcriptome gene expression analysis. In vitro and in vivo studies included cell line manipulation and xenograft models., The integrative CNA and gene expression analyses identified an increase in Antizyme Inhibitor 1 (AZIN1) gene expression within a focal amplification of 8q22.3, which was associated with metastatic recurrence of patients with high-risk prostate cancer in four independent cohorts. The effects of AZIN1 knockdown were evaluated, due to its therapeutic potential. AZIN1 knockdown effected proliferation and metastatic potential of prostate cancer cells and xenograft models. RNA sequencing after AZIN1 knockdown in prostate cancer cells revealed upregulation of genes coding for collagen subunits. The observed effect on cell migration after AZIN1 knockdown was mimicked when exposing prostate cancer cells to bio-active molecules deriving from COL4A1 and COL4A2. Our integrated CNA and gene expression analysis of primary high-risk prostate cancer identified the AZIN1 gene as a novel driver of metastatic progression, by altering collagen subunit expression. Future research should further investigate its therapeutic potential in preventing metastatic recurrence., Implications: AZIN1 was identified as driver of metastatic progression in high-risk prostate cancer through matrikine regulation., (©2022 American Association for Cancer Research.)

Competing Interests: Conflicts of interest The authors have nothing to disclose.

Objectives: PSMA-PET has become the PET technique of choice to localise the site of biochemically recurrent prostate cancer (PCa). With hybrid PET/MRI, the advantages of MRI are added to molecular characteristic of PET. The aim of this study was to investigate the incremental value of PET/MR versus PET/CT in patients with biochemically recurrent PCa by head-to-head comparison., Methods: Thirty-four patients with biochemically recurrent PCa were prospectively included. They underwent [ 68 Ga]Ga-PSMA-11 PET/CT, followed by simultaneous PET/MR. All PET (PET CT , PET MR ), CT and MR images were evaluated for number of lesions and location. The number of lesions at specific sites was compared using Wilcoxon-sign-rank test. For PET, the maximum and mean standardised uptake values (SUVs) were calculated for each lesion compared using a two-sided paired t test., Results: PET CT and PET MR scans were positive in 19 and 20 patients, detecting 73 and 79 lesions respectively. All lesions detected on PET CT were also detected on PET MR . CT and MRI only were positive in 14 and 17 patients, detecting 38 and 50 lesions, respectively, which was significantly lower than PET CT and PET MR respectively. Combined interpretation showed more lesions on PET/MR than on PET/CT (88 vs 81). No significant difference in detection of presence of local recurrence nor distant metastases was found. SUV mean and SUV max values were significantly higher on PET MR than on PET CT in local recurrence and lymph node metastases., Conclusions: [ 68 Ga]Ga-PSMA-11 PET/MR was able to detect biochemically recurrent PCa at least as accurately as PET/CT for local recurrence, lymph node metastasis and distant metastasis., Key Points: • PSMA PET/MRI detects the location of biochemical recurrence at least as accurately as PET/CT. • Substitution of PET/CT by PET/MRI adds sensitivity in PSMA lesion detection also in the setting of distant recurrence due to both the MR and TOF PET components., (© 2021. European Society of Radiology.)

Background: Patients with prostate-specific antigen (PSA) persistence are at the increased risk of disease progression. The aim of our study was to evaluate the impact of early salvage therapy on oncological outcomes in patients with persistent PSA after radical prostatectomy (RP)., Methods: Within a single tertiary centre database, we identified men with persistent (≥ 0.1 ng/ml) versus undetectable (< 0.1 ng/ml) PSA 4-8 weeks after RP for high-risk prostate cancer (HRPCa). The cumulative incidence function was used to estimate cancer-specific survival (CSS) and clinical progression-free survival (CPFS). The Kaplan-Meier method was used to estimate overall survival (OS). The effects on oncological outcomes of salvage radiotherapy (SRT) ± androgen deprivation therapy (ADT) vs. ADT monotherapy were tested in the subgroup of patients with persistent PSA., Results: Of 414 consecutive patients who underwent RP for HRPC, 125 (30.2%) had persistent PSA. Estimated 10-year CPFS, CSS and OS for men with persistent vs. undetectable PSA were 63.8% vs. 93.5%, 78.5% vs. 98.3% and 54% vs. 83.2% (all p < 0.0001), respectively. In men with persistent PSA, ADT alone was associated with higher risk (hazard ratio (HR) for worse CSS (HR 3.9, p = 0.005) and OS (HR 4.7, p < 0.0001) but not for CP (HR 1.6, p = 0.2) when compared with SRT ± ADT., Conclusion: In patients who underwent RP for HRPCa, persistent PSA was associated with poor oncological outcomes. Early SRT ± ADT resulted in significantly improved CSS and OS in men with persistent PSA comparing with early androgen deprivation monotherapy., (© 2021. Federación de Sociedades Españolas de Oncología (FESEO).)

Background: Despite the curative intent of radical prostatectomy (RP) (+/- radiotherapy (RT)), 30% of the clinically localized prostate cancer (CaP) patients will develop rising PSA (prostate specific antigen). In absence of clinical recurrence, there is a lack of effective treatment strategies in order to control the disease at its earliest (micro)metastatic stage. The aim of this study was to assess safety, tolerability, and biochemical response of off-label Radium-223 (Xofigo) treatment in CaP patients with PSA relapse following maximal local therapy., Methods: We conducted a prospective, single arm, single center open-label, pilot study with Radium-223 in CaP patients with rising PSA (>0.2 ng/ml) following RP + adjuvant/salvage RT. Negative staging with 68 Ga-PSMA-11 PET/CT and whole-body MRI was mandatory at time of inclusion. Patients were eligible if they exhibited adverse clinico-pathological features predictive of significant recurrence. Safety, tolerability, biochemical progression (defined as PSA increase >50% from PSA nadir) and clinical recurrence were assessed., Results: In total, 23 patients were screened of whom 8 patients were included is the study. Radium-223 treatment was safe with no serious treatment related adverse events. One patient developed grade 3 lymphopenia. All patients rapidly developed PSA progression (median PSA progression-free survival: 5.5 months). Eventually all patients experienced clinical recurrence (median clinical recurrence-free survival 11.0 months) of whom only 2 patients developed skeletal recurrence., Conclusions: Radium-223 in patients with PSA relapse following maximal local treatment without clinical metastases is safe. However, the clinical benefit of Ra-223 in this setting is doubtful as significant oncological benefit is lacking., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Patients with high-risk prostate cancer treated with curative intent are at an increased risk of biochemical recurrence, metastatic progression and cancer-related death compared with patients treated for low-risk or intermediate-risk disease. Thus, these patients often need multimodal therapy to achieve complete disease control. Over the past two decades, multiple studies on the use of neoadjuvant treatment have been performed using conventional androgen deprivation therapy, which comprises luteinizing hormone-releasing hormone agonists or antagonists and/or first-line anti-androgens. However, despite results from these studies demonstrating a reduction in positive surgical margins and tumour volume, no benefit has been observed in hard oncological end points, such as cancer-related death. The introduction of potent androgen receptor signalling inhibitors (ARSIs), such as abiraterone, apalutamide, enzalutamide and darolutamide, has led to a renewed interest in using neoadjuvant hormonal treatment in high-risk prostate cancer. The addition of ARSIs to androgen deprivation therapy has demonstrated substantial survival benefits in the metastatic castration-resistant, non-metastatic castration-resistant and metastatic hormone-sensitive settings. Intuitively, a similar survival effect can be expected when applying ARSIs as a neoadjuvant strategy in high-risk prostate cancer. Most studies on neoadjuvant ARSIs use a pathological end point as a surrogate for long-term oncological outcome. However, no consensus yet exists regarding the ideal definition of pathological response following neoadjuvant hormonal therapy and pathologists might encounter difficulties in determining pathological response in hormonally treated prostate specimens. The neoadjuvant setting also provides opportunities to gain insight into resistance mechanisms against neoadjuvant hormonal therapy and, consequently, to guide personalized therapy., (© 2021. Springer Nature Limited.)

Purpose: Salvage radical prostatectomy is rare due to the risk of postoperative complications. We compare salvage Retzius-sparing robotic assisted radical prostatectomy (SRS-RARP) with salvage standard robotic assisted radical prostatectomy (SS-RARP)., Materials and Methods: A total of 72 patients across 9 centers were identified (40 SRS-RARP vs 32 SS-RARP). Demographics, perioperative data, and pathological and functional outcomes were compared using Student's t-test and ANOVA. Cox proportional hazard models and Kaplan-Meier curves were constructed to assess risk of incontinence and time to continence. Linear regression models were constructed to investigate postoperative pad use and console time., Results: Median followup was 23 vs 36 months for SRS-RARP vs SS-RARP. Console time and estimated blood loss favored SRS-RARP. There were no differences in complication rates or oncologic outcomes. SRS-RARP had improved continence (78.4% vs 43.8%, p <0.001 for 0-1 pad, 54.1% vs 6.3%, p <0.001 for 0 pad), lower pads per day (0.57 vs 2.03, p <0.001), and earlier return to continence (median 47 vs 180 days, p=0.008). SRS-RARP was associated with decreased incontinence defined as >0-1 pad (HR 0.28, 95% CI 0.10-0.79, p=0.016), although not when defined as >0 pad (HR 0.56, 95% CI 0.31-1.01, p=0.053). On adjusted analysis SRS-RARP was associated with decreased pads per day. Lymph node dissection and primary treatment with stereotactic body radiation therapy were associated with longer console time., Conclusions: SRS-RARP is a feasible salvage option with significantly improved urinary function outcomes. This may warrant increased utilization of SRS-RARP to manage men who fail nonsurgical primary treatment for prostate cancer.

Context: There is an urgent need to develop novel treatment strategies in patients with unfavorable intermediate- and high-risk localized prostate cancer (PCa) to optimize the outcome of these patients. Androgen receptor signaling inhibitors (ARSI) have demonstrated a survival benefit in metastatic hormonesensitive and castration-resistant PCa. A similar benefit might be expected in the localized setting., Objective: To perform a systematic review about the role of neoadjuvant ARSI in unfavorable intermediate and high-risk localized PCa., Evidence Acquisition: We performed a systematic review of the following databases: MEDLINE (PubMed), EMBASE, Cochrane Library and Web of Science. Publications of ASCO were consulted to identify meeting abstract with early results of ongoing trials. This systematic review was performed and reported in accordance with the PRISMA guidelines., Evidence Synthesis: Pathological complete response (pCR) following neoadjuvant ARSI treatment was observed in 4%-13% of the patients. Minimal residual disease response ranged from 36% to 73.9% when defined as residual cancer burden < 0.25 cm 3 at final pathology and from 8% to 20% when defined as the diameter of the remaining tumor < 5 mm. Despite intense neoadjuvant ARSI treatment, residual pT3 disease was observed in 48%-76% of the patients. In contrast, positive surgical margins (PSM) were present in only 5%-22%. Only one trial reported BCR following neoadjuvant ARSI therapy (44% BCR at a median follow-up of 4 years)., Conclusion: Despite intense neoadjuvant ARSI therapy, pCR is rarely attained and high proportions of pT3 disease are still observed at final pathology. In contrast, promising results are obtained in terms of PSMs. Long-term survival outcomes are eagerly awaited., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

In patients with prostate cancer who have a high risk of pelvic nodal disease, the use of elective whole pelvis radiotherapy is still controversial. Two large, randomised, controlled trials (RTOG 9413 and GETUG-01) did not show a benefit of elective whole pelvis radiotherapy over prostate-only radiotherapy. In 2020, the POP-RT trial established the role of elective whole pelvis radiotherapy in patients who have more than a 35% risk of lymph node invasion (known as the Roach formula). POP-RT stressed the importance of patient selection. In patients with cN1 (clinically node positive) disease or pN1 (pathologically node positive) disease, the addition of whole pelvis radiotherapy to androgen deprivation therapy significantly improved survival compared with androgen deprivation therapy alone, as shown in large, retrospective studies. This patient population might increase in the future because use of the more sensitive prostate-specific membrane antigen PET-CT will become the standard staging procedure. Additionally, the SPORTT trial suggested a benefit of whole pelvis radiotherapy in biochemical recurrence-free survival in the salvage setting. A correct definition of the upper field border, which should include the bifurcation of the abdominal aorta, is key in the use of pelvic radiotherapy. As a result of using modern radiotherapy technology, severe late urinary and intestinal toxic effects are rare and do not seem to increase compared with prostate-only radiotherapy., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objectives: To develop and validate a model to predict 12-month continence status after robot-assisted radical prostatectomy (RARP) from preoperative and 3-month postoperative data; this model could help in informing patients on their individualised risk of urinary incontinence (UI) after RP in order to choose the best treatment option., Patients and Methods: Data on 9421 patients in 25 Belgian centres were prospectively collected (2009-2016) in a compulsory regional database. The primary outcome was the prediction of continence status, using the International Consultation on Incontinence Urinary Incontinence Short Form (ICIQ-UI-SF) at 12-months after RARP. Linear regression shrinkage was used to assess the association between preoperative 3-month postoperative characteristics and 12-month continence status. This association was visualised using nomograms and an online tool., Results: At 12 months, the mean (sd) score of the ICIQ-UI-SF questionnaire was 4.3 (4.7), threefold higher than the mean preoperative score of 1.4. For the preoperative model, high European Association of Urology risk classification for biochemical recurrence (estimate [Est.] 0.606, se 0.165), postoperative radiotherapy (Est. 1.563, se 0.641), lower preoperative European Organisation for Research and Treatment of Cancer quality of life questionnaire 30-item core (EORCT QLQ-C30)/quality of life (QoL) score (Est. -0.011, se 0.003), higher preoperative ICIQ-UI-SF score (Est 0.214, se 0.018), and older age (Est. 0.058, se 0.009), were associated with a higher 12-month ICIQ-UI-SF score. For the 3-month model, higher preoperative ICIQ-UI-SF score (Est. 0.083, se 0.014), older age (Est. 0.024, se 0.007), lower 3-month EORCT QLQ-C30/QoL score (Est. -0.010, se 0.002) and higher 3-month ICIQ-UI-SF score (Est. 0.562, se 0.009) were associated with a higher 12-month ICIQ-UI-SF score., Conclusions: Our models set the stage for a more accurate counselling of patients. In particular, our preoperative model assesses the risk of UI according to preoperative and early postoperative variables. Our postoperative model can identify patients who most likely would not benefit from conservative treatment and should be counselled on continence surgery., (© 2020 The Authors BJU International © 2020 BJU International Published by John Wiley & Sons Ltd.)

Purpose: To assess the intermodality and intertracer variability of gallium-68 ( 68 Ga)- or fluorine-18 ( 18 F)-labeled prostate-specific membrane antigen (PSMA) positron emission tomography (PET) and biparametric magnetic resonance imaging (bpMRI)-based gross tumor volume (GTV) delineation for focal boosting in primary prostate cancer., Methods: Nineteen prospectively enrolled patients with prostate cancer underwent a PSMA PET/MRI scan, divided into a 1:1 ratio between 68 Ga-PSMA-11 and 18 F-PSMA-1007, before radical prostatectomy (IWT140193). Four delineation teams performed manual contouring of the GTV based on bpMRI and PSMA PET imaging, separately. Index lesion coverage (overlap%) and interobserver variability were assessed. Furthermore, the distribution of the voxelwise normalized standardized uptake values (SUV%) was determined for the majority-voted (>50%) GTV (GTV majority ) and whole prostate gland to investigate intertracer variability. The median patientwise SUV% contrast ratio (SUV%-CR, calculated as median GTV majority SUV% / median prostate gland without GTV majority SUV%) was calculated according to the tracer used., Results: A significant difference in overlap% favoring PSMA PET compared with bpMRI was found in the 18 F subgroup (median, 63.0% vs 53.1%; P = .004) but was not present in the 68 Ga subgroup (32.5% vs 50.6%; P = .100). Regarding interobserver variability, measured Sørensen-Dice coefficients (0.58 vs 0.72) and calculated mean distances to agreement (2.44 mm vs 1.22 mm) were statistically significantly lower and higher, respectively, for the 18 F cohort compared with the 68 Ga cohort. For the bpMRI-based delineations, the median Sørensen-Dice coefficient and mean distance to agreement were 0.63 and 1.76 mm, respectively. Median patientwise SUV%-CRs of 1.8 (interquartile range [IQR], 1.6-2.7) for 18 F-PSMA and 3.3 (IQR, 2.7-5.9) for 68 Ga-PSMA PET images were found., Conclusions: Both MRI and PSMA PET provided consistent intraprostatic GTV lesion detection. However, the PSMA tracer seems to have a major influence on the contour characteristics, owing to an apparent difference in SUV% distribution in the prostate gland., (Copyright © 2020 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Background: Salvage radical prostatectomy (sRP) historically yields poor functional outcomes and high complication rates. However, recent reports on robotic sRP show improved results. Our objectives were to evaluate sRP oncological outcomes and predictors of positive margins and biochemical recurrence (BCR)., Methods: We retrospectively collected data of sRP for recurrent prostate cancer after local nonsurgical treatment at 18 tertiary referral centers in United States, Australia and Europe, from 2000 to 2016. SM and BCR were evaluated in a univariate and multivariable analysis. Overall and cancer-specific survival were also assessed., Results: We included 414 cases, 63.5% of them performed after radiotherapy. Before sRP the majority of patients had biopsy Gleason score (GS) ≤7 (55.5%) and imaging negative or with prostatic bed involvement only (93.3%). Final pathology showed aggressive histology in 39.7% (GS ≥9 27.6%), with 52.9% having ≥pT3 disease and 16% pN+. SM was positive in 29.7%. Five years BCR-Free, cancer-specific survival and OS were 56.7%, 97.7% and 92.1%, respectively. On multivariable analysis pathological T (pT3a odds ratio [OR] 2.939, 95% confidence interval [CI] 1.469-5.879; ≥pT3b OR 2.428-95% CI 1.333-4.423) and N stage (pN1 OR 2.871, 95% CI 1.503-5.897) were independent predictors of positive margins. Pathological T stage ≥T3b (OR 2.348 95% CI 1.338-4.117) and GS (up to OR 7.183, 95% CI 1.906-27.068 for GS >8) were independent predictors for BCR. Limitations include the retrospective nature of the study and limited follow-up., Conclusions: In a contemporary series, sRP showed promising oncological control in the medium term despite aggressive pathological features. BCR risk increased in case of locally advanced disease and higher GS. Future studies are needed to confirm our findings., (Copyright © 2020. Published by Elsevier Inc.)

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.)

Objective: To investigate whether the new prostate cancer grade groups model provides significant predictive value and better patient stratification on tumor progression after radical prostatectomy compared with the former Gleason grading models., Methods: Men treated at a tertiary center by radical prostatectomy between 2005 and 2017 were analyzed. The outcomes of interest were clinical progression-free and cancer-specific survival. Multivariate Cox regression analysis, C-index and decision curve analysis were carried out using three-tier (Gleason score 6, 7 and 8-10), four-tier (Gleason score 6, 7, 8 and 9-10) and new grade groups model., Results: In total, 1759 men were included in the analysis. At a median of 87 months (interquartile range 51-134 months) of follow up, clinical progression was detected in 78 (4.4%) and cancer-related death in 42 (2.4%) patients. The hazard ratio of clinical progression-free was 2.3, 5.7, 5.2 and 29.5; the hazard ratio of cancer-specific survival was 1.7, 3.2, 4.8 and 11.8 in the grade groups 2-5, relative to grade group 1, respectively. The grade groups model had higher C-index in comparison with four- and three-tier grading models for clinical progression-free survival 0.88 versus 0.85 versus 0.83 and for cancer-specific survival 0.82 versus 0.80 versus 0.80, respectively. In the decision curve analysis, the grade groups model shows marginally better net benefit on clinical progression-free and cancer-specific survival., Conclusions: The new model shows better performance in comparison with former Gleason grading models on the prediction of long-term oncological outcomes., (© 2021 The Japanese Urological Association.)

Context: The prognosis and optimal management of pN0/pN1 patients with persistently elevated prostate-specific antigen (PSA) 6-8 wk after radical prostatectomy (RP) remain unclear., Objective: To perform a systematic review of oncologic outcomes and effectiveness of salvage therapies in men with a detectable PSA level after RP., Evidence Acquisition: A systematic review was performed in May 2020. A total of 2374 articles were screened, and 25 studies including 5217 men were selected and included in the systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines., Evidence Synthesis: PSA persistence was most commonly defined as PSA >0.1 ng/ml. PSA persistence was significantly correlated with disease aggressiveness and associated with worse oncologic outcomes than in men with undetectable PSA levels. The 5-yr recurrence-free survival rates varied from 21.5% to 67.0%. The ≥10-yr cancer-specific survival was 75-88%. Salvage radiotherapy ± androgen deprivation therapy was associated with improved survival outcomes. Risk stratification according to pathologic features, PSA levels/kinetics, and genomic classifier may aid in personalization of treatment. The usefulness of molecular imaging in this setting remains underevaluated. Main limitations of this systematic review are the retrospective design of the included studies and the lack of randomized controlled trials (RCTs) focusing on this specific population., Conclusions: PSA persistence after RP is strongly correlated with poor oncologic outcomes. Our review suggests a benefit from immediate radiotherapy; however, current evidence is still low. Indication of subsequent therapies should be based on individual discussions, taking into account all the prognostic factors and the efficacy/toxicity imbalance of proposed treatment. Results from ongoing RCTs are awaited to state on the role of more intensified systemic therapy in this population., Patient Summary: Patients with a detectable prostate-specific antigen level after surgery are at high risk of subsequent progression. Immediate radiotherapy might improve survival outcomes. Further research into the role of molecular imaging and genomic classifier is needed in this patient population., (Copyright © 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: This study proposes optimal tracer-specific threshold-based window levels for PSMA PET-based intraprostatic gross tumour volume (GTV) contouring to reduce interobserver delineation variability., Methods: Nine 68 Ga-PSMA-11 and nine 18 F-PSMA-1007 PET scans including GTV delineations of four expert teams (GTV manual ) and a majority-voted GTV (GTV majority ) were assessed with respect to a registered histopathological GTV (GTV histo ) as the gold standard reference. The standard uptake values (SUVs) per voxel were converted to a percentage (SUV%) relative to the SUV max . The statistically optimised SUV% threshold (SOST) was defined as those that maximises accuracy for threshold-based contouring. A leave-one-out cross-validation receiver operating characteristic (ROC) curve analysis was performed to determine the SOST for each tracer. The SOST analysis was performed twice, first using the GTV histo contour as training structure (GTV SOST-H ) and second using the GTV majority contour as training structure (GTV SOST-MA ) to correct for any limited misregistration. The accuracy of both GTV SOST-H and GTV SOST-MA was calculated relative to GTV histo in the 'leave-one-out' patient of each fold and compared with the accuracy of GTV manual ., Results: ROC curve analysis for 68 Ga-PSMA-11 PET revealed a median threshold of 25 SUV% (range, 22-27 SUV%) and 41 SUV% (40-43 SUV%) for GTV SOST-H and GTV SOST-MA , respectively. For 18 F-PSMA-1007 PET, a median threshold of 42 SUV% (39-45 SUV%) for GTV SOST-H and 44 SUV% (42-45 SUV%) for GTV SOST-MA was found. A significant pairwise difference was observed when comparing the accuracy of the GTV SOST-H contours with the median accuracy of the GTV manual contours (median, - 2.5%; IQR, - 26.5-0.2%; p = 0.020), whereas no significant pairwise difference was found for the GTV SOST-MA contours (median, - 0.3%; IQR, - 4.4-0.6%; p = 0.199)., Conclusions: Threshold-based contouring using GTV majority -trained SOSTs achieves an accuracy comparable with manual contours in delineating GTV histo . The median SOSTs of 41 SUV% for 68 Ga-PSMA-11 PET and 44 SUV% for 18 F-PSMA-1007 PET form a base for tracer-specific window levelling., Trial Registration: Clinicaltrials.gov ; NCT03327675; 31-10-2017.