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Introduction Approximately one million prostate biopsies are performed annually in the USA, and most are performed using a transrectal approach under local anaesthesia. The risk of postbiopsy infection is increasing due to increasing antibiotic resistance of rectal flora. Single-centre studies suggest that a clean, percutaneous transperineal approach to prostate biopsy may have a lower risk of infection. To date, there is no high-level evidence comparing transperineal versus transrectal prostate biopsy. We hypothesise that transperineal versus transrectal prostate biopsy under local anaesthesia has a significantly lower risk of infection, similar pain/discomfort levels and comparable detection of non-low-grade prostate cancer.Methods and analysis We will perform a multicentre, prospective randomised clinical trial to compare transperineal versus transrectal prostate biopsy for elevated prostate-specific antigen in the first biopsy, prior negative biopsy and active surveillance biopsy setting. Prostate MRI will be performed prior to biopsy, and targeted biopsy will be conducted for suspicious MRI lesions in addition to systematic biopsy (12 cores). Approximately 1700 men will be recruited and randomised in a 1:1 ratio to transperineal versus transrectal biopsy. A streamlined design to collect data and to determine trial eligibility along with the two-stage consent process will be used to facilitate subject recruitment and retention. The primary outcome is postbiopsy infection, and secondary outcomes include other adverse events (bleeding, urinary retention), pain/discomfort/anxiety and critically, detection of non-low-grade (grade group ≥2) prostate cancer.Ethics and dissemination The Institutional Review Board of the Biomedical Research Alliance of New York approved the research protocol (protocol number #18-02-365, approved 20 April 2020). The results of the trial will be presented at scientific conferences and published in peer-reviewed medical journals.Trial registration number NCT04815876.

Purpose: Clinical variables alone have limited ability to determine which patients will have recurrence after radical prostatectomy (RP). We evaluated the ability of locked multimodal artificial intelligence (MMAI) algorithms trained on prostate biopsy specimens to predict prostate cancer specific mortality (PCSM) and overall survival (OS) among patients undergoing radical prostatectomy with digitized RP specimens., Materials and Methods: The Prostate, Lung, Colorectal, and Ovarian Cancer Screening Randomized Controlled Trial randomized subjects from 1993-2001 to cancer screening or control. A subset of patients who underwent RP with available digitized histopathological images and subsequent survival data were identified. Distant metastasis (DM) and PCSM MMAIs originally trained on biopsy slides for patients undergoing radiation were evaluated for prediction of PCSM and OS. Cox proportional hazards modeling and Kaplan Meier survival curve analysis were utilized., Results: 1032 patients who underwent RP with median follow up of 17 years (IQR 14.3, 19.3 years) were identified. MMAI algorithms for PCSM and DM both predicted PCSM (HR 2.31, 95% confidence interval [CI] 1.6-3.35, p<0.001, and HR 1.96, 95% CI 1.35-2.85, p<0.001, respectively). Similarly, DM and PCSM MMAI predicted OS (HR 1.22, 95% CI 1.01-1.47, p=0.04 and HR 1.19, 95% CI 1.02-1.4, p=0.03)., Conclusions: Locked MMAI algorithms previously developed and validated on biopsy specimens from patients undergoing radiation for prostate cancer successfully predicted clinical outcomes when applied to RP specimens from patients treated with surgery. MMAI models and other biomarkers may help select patients who may benefit from post-operative treatment intensification with androgen deprivation therapy or radiation.

Background: Traditional nomograms can inform the presence of extraprostatic extension (EPE) but not laterality, which remains important for surgical planning, and have not fully incorporated multiparametric MRI data. We evaluated predictors of side-specific EPE on surgical pathology including MRI characteristics and developed side-specific EPE risk calculators., Methods: This was a retrospective cohort of patients evaluated with mpMRI prior to radical prostatectomy (RP) in our eleven hospital healthcare system from July 2018-November 2022. The dominant side was defined pre-operatively using a tiered system based on laterality of highest biopsy Gleason Grade Group (GG), highest PIRADS lesion, number of lesions, and cancer volume. Univariable and multivariable logistic regression were performed for overall EPE, dominant side EPE, and non-dominant side EPE. Internal validation with leave one out and calibration curves were completed., Results: EPE was identified in 53% (317/601) of patients at RP. Side-specific factors (PIRADS, GG, abutment) were only associated with EPE on their respective side. Final variables in the model associated with EPE on the dominant and non-dominant sides included age, log PSA density (PSAD), side-specific PIRADS 5, side-specific GG3-5, and percentage positivity of systematic cores. AUCs for dominant and non-dominant side EPE were 0.77 (95% CI 0.73-0.80) and 0.79 (95% CI 0.74-0.84), respectively. MRI-identified abutment and prostate health index (PHI) did not improve model discrimination. Risk calculators available online at https://rossnm1.shinyapps.io/PredictionOfEPELaterality/ ., Conclusions: PSA, side-specific PIRADS, side-specific GG, and percentage positivity of systematic cores were associated with side-specific EPE at RP and incorporated into a risk calculator to assist in surgical planning and nerve-sparing decisions at time of RP., Competing Interests: Competing interests: AER is engaged in consulting with American Society of Clinical Oncology (ASCO), Astellas, Bayer HealthCare Pharmaceuticals, Blue Earth Diagnostics, Janssen Biotech, Lantheus Medical Imaging, Myovant Sciences, NCCN, Pfizer, Tempus Health, and Veracyte. EMS is engaged in consulting with Astellas, Lantheus Medical Imaging, Pfizer. The other contributing authors have no conflicts of interest to declare. Ethics approval and consent to participate: The study was reviewed under IRB STU00214996 issued by Northwestern University. The study was performed in accordance with the Declaration of Helsinki., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: Finite courses of androgen deprivation therapy (ADT) are often utilized in men undergoing treatment for prostate cancer. Previous evidence suggests that timing of testosterone (T) recovery can be variable after ADT. Recently, an oral gonadotropin releasing-hormone (GnRH) antagonist, relugolix, has demonstrated more rapid T recovery than injectable GnRH agonists such as leuprolide. In this study, we sought to evaluate patient characteristics associated with T recovery in patients undergoing ADT of defined duration., Materials and Methods: The Northwestern Enterprise Data Warehouse was queried for men with prostate cancer who completed a course of ADT and subsequently had a testosterone lab performed. Testosterone recovery was evaluated for levels that reached above castrate (T > 50 ng/dl), partial recovery (T > 150 ng/dl), and full recovery (T ≥ 300 ng/dl)., Results: 388 men who received finite courses of ADT were identified (348 receiving leuprolide, 36 receiving relugolix, and 4 receiving degarelix). In multivariable Cox regression analysis, men who were prescribed GnRH antagonists (HR = 3.74, CI = 2.53-5.53, P ≤ 0.001) and who were younger (HR for 1 year increase in age = 0.96, CI = 0.95-0.98, P < 0.001) were more likely to achieve partial recovery. In a subgroup analysis, men who received extended ADT courses (>12 months) with a GnRH agonist had lower rates of partial T recovery (HR = 0.58, CI = 0.41-0.81, P = 0.001)., Conclusion: T recovery after ADT is variable with roughly one sixth of men remaining castrate. GnRH antagonist use and younger age are associated with higher rates of T recovery after ADT. Longer ADT courses were associated with worse T recovery rates., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ashley E. Ross, Alicia K. Morgans, Edward Schaeffer reports a relationship with Astellas Pharma Inc that includes: consulting or advisory. Ashley E. Ross, Alicia K. Morgans reports a relationship with AstraZeneca that includes: consulting or advisory. Ashley E. Ross, Alicia K. Morgans reports a relationship with Bayer Corporation that includes: consulting or advisory. Alicia K. Morgans reports a relationship with AAA that includes: consulting or advisory. Ashley E. Ross reports a relationship with Blue Earth Diagnostics that includes: consulting or advisory. Ashley E. Ross reports a relationship with Boston Scientific Corporation that includes: consulting or advisory. Ashley E. Ross reports a relationship with BillionToOne that includes: consulting or advisory. Alicia K. Morgans reports a relationship with Curium that includes: consulting or advisory. Alicia K. Morgans reports a relationship with Exelixis Inc that includes: consulting or advisory. Ashley E. Ross, Alicia K. Morgans reports a relationship with Janssen Pharmaceuticals Inc that includes: consulting or advisory. Ashley E. Ross, Alicia K. Morgans reports a relationship with Lantheus Medical Imaging Inc that includes: consulting or advisory. Alicia K. Morgans reports a relationship with Merck that includes: consulting or advisory. Alicia K. Morgans reports a relationship with MacroGenics Inc that includes: consulting or advisory. Ashley E. Ross, Alicia K. Morgans, Edward Schaeffer reports a relationship with Pfizer that includes: consulting or advisory. Ashley E. Ross, Alicia K. Morgans reports a relationship with Sumitomo Pharma America Inc that includes: consulting or advisory. Alicia K. Morgans reports a relationship with Novartis Pharmaceuticals Corporation that includes: consulting or advisory. Alicia K. Morgans reports a relationship with Telix Pharmaceuticals Limited that includes: consulting or advisory. Ashley E. Ross reports a relationship with Veracyte Inc that includes: consulting or advisory. If there are other authors, they 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 Inc. All rights reserved.)

Background and Objective: The extent of prostate cancer found on biopsy, as well as prostate cancer grade and genomic tests, can affect clinical decision-making. The impact of these factors on the initial management approach and subsequent patient outcomes for men with favorable-grade prostate cancer has not yet been determined on a population level. Our objective was to explore the association of Decipher 22-gene genomic classifier (GC) biopsy testing on the initial use of conservative management versus radical prostatectomy (RP) and to determine the independent effect of GC scores on RP pathologic outcomes., Methods: A total of 87 140 patients diagnosed with grade group 1 and 2 prostate cancer between 2016 and 2018 from the Surveillance, Epidemiology, and End Results registry data were linked to GC testing results (2576 tested and 84 564 untested with a GC). The primary endpoints of interest were receipt of conservative management or RP, pathologic upgrading (pathologic grade group 3-5), upstaging (pathologic ≥T3b), and adverse pathologic features (pathologic upgrading, upstaging, or lymph node invasion). Multivariable logistic regressions quantified the association of variables with outcomes of interest., Key Findings and Limitations: GC tested patients were more likely to have grade group 2 on biopsy (51% vs 46%, p < 0.001) and lower prostate-specific antigen (6.1 vs 6.3, p = 0.016). Conservative management increased from 37% to 39% and from 22% to 24% during 2016-2018 for the GC tested and untested populations, respectively. GC testing was significantly associated with increased odds of conservative management (odds ratio [OR] 2.1, 95% confidence interval [CI] 1.9-2.4, p < 0.001). The distribution of biopsy GC risk was as follows: 45% low risk, 30% intermediate risk, and 25% high risk. In adjusted analyses, higher GC (per 0.1 increment) scores (OR 1.24, 95% CI 1.17-1.31, p < 0.001) and percent positive cores (1.07, 95% CI 1.02-1.12, p = 0.009) were significantly associated with the receipt of RP. A higher GC score was significantly associated with all adverse outcomes (pathologic upgrading [OR 1.29, 95% CI 1.12-1.49, p < 0.001], upstaging [OR 1.31, 95% CI 1.05-1.62, p = 0.020], and adverse pathology [OR 1.27, 95% CI 1.12-1.45, p < 0.001]). Limitations include observational biases associated with the retrospective study design., Conclusions and Clinical Implications: Men who underwent GC testing were more likely to undergo conservative management. GC testing at biopsy is prognostic of adverse pathologic outcomes in a large population-based registry., Patient Summary: In this population analysis of men with favorable-risk prostate cancer, those who underwent genomic testing at biopsy were more likely to undergo conservative management. Of men who initially underwent radical prostatectomy, higher genomic risk but not tumor volume was associated with adverse pathologic outcomes. The use of genomic testing at prostate biopsy improves risk stratification and may better inform treatment decisions than the use of tumor volume alone., (Copyright © 2024. Published by Elsevier B.V.)

Background and Objective: We characterized tumor prostate-specific membrane antigen (PSMA) levels as a reflection of cancer biology and treatment sensitivities for treatment-naïve prostate cancer., Methods: We first correlated PSMA positron emission tomography (PET) maximum standardized uptake values (SUVmax) in primary prostate cancer with tumor FOLH1 (PSMA RNA abundance) to establish RNA as a proxy (n = 55). We then discovered and validated molecular pathways associated with PSMA RNA levels in two large primary tumor cohorts. We validated those associations in independent cohorts (18 total; 5684 tumor samples) to characterize the pathways and treatment responses associated with PSMA., Key Findings and Limitations: PSMA RNA abundance correlates moderately with SUVmax (ρ = 0.41). In independent cohorts, androgen receptor signaling is more active in tumors with high PSMA. Accordingly, patients with high PSMA tumors experienced longer cancer-specific survival when managed with androgen deprivation therapy for biochemical recurrence (adjusted hazard ratio [AHR] 0.54 [0.34-0.87]; n = 174). PSMA low tumors possess molecular markers of resistance to radiotherapy. Consistent with this, patients with high PSMA tumors experience longer time to recurrence following primary radiotherapy (AHR 0.50 [0.28-0.90]; n = 248). In the SAKK09/10 trial (n = 224), patients with high PSMA tumors who were managed with salvage radiotherapy experienced longer time to progression in the 64-Gy arm (restricted mean survival time [RMST] +7.60 [0.05-15.16]), but this effect was mitigated in the 70-Gy arm (RMST 3.52 [-3.30 to 10.33]). Limitations include using PSMA RNA as a surrogate for PET SUVmax., Conclusions and Clinical Implications: PSMA levels in treatment-naïve prostate cancer differentiate tumor biology and treatment susceptibilities. These results warrant validation using PET metrics to substantiate management decisions based on imaging., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

The National Comprehensive Cancer Network (NCCN) very low risk (VLR) category for prostate cancer (PCa) represents clinically insignificant disease, and detection of VLR PCa contributes to overdiagnosis. Greater use of magnetic resonance imaging (MRI) and biomarkers before patient selection for prostate biopsy (PBx) reduces unnecessary biopsies and may reduce the diagnosis of clinically insignificant PCa. We tested a hypothesis that the proportion of VLR diagnoses has decreased with greater use of MRI-informed PBx using data from our 11-hospital system. From 2018 to 2023, 351/3197 (11%) men diagnosed with PCa met the NCCN VLR criteria. The proportion of VLR diagnoses did not change from 2018 to 2023 (p = 0.8) despite an increase in the use of MRI-informed PBx (from 49% to 82%; p < 0.001). Of patients who underwent combined systematic and targeted PBx and were diagnosed with VLR disease, cancer was found in systematic PBx regions in 79% of cases and in targeted PBx regions in 31% of cases. When performing both systematic and targeted PBx, prebiopsy MRI-based risk calculators could limit VLR diagnosis by 41% using a risk threshold of >5% for Gleason grade group ≥3 PCa to recommend biopsy; the reduction would be 77% if performing targeted PBx only. These findings suggest that VLR disease continues to account for a significant minority of PCa diagnoses and could be limited by targeted PBx and risk stratification calculators. PATIENT SUMMARY: We looked at recent trends for the diagnosis of very low-risk (VLR) prostate cancer. We found that VLR cancer still seems to be frequently diagnosed despite the use of MRI (magnetic resonance imaging) scans before biopsy. The use of risk calculators to identify men who could avoid biopsy and/or biopsy only for lesions that are visible on MRI could reduce the overdiagnosis of VLR prostate cancer., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: There are limited data on PSMA PET/CT for workup of recurrence after radical prostatectomy (RP) at low PSA values. We evaluated a PSMA PET/CT cohort of patients with post-RP, focusing on patients with PSA < 0.5 ng/mL., Materials and Methods: We identified a retrospective cohort who underwent piflufolastat F-18 PSMA PET/CT across an 11 hospital system from July 2021 to February 2023. Prostate-specific membrane antigen (PSMA) positivity was determined by radiology reports. Univariable and multivariable logistic regression identified factors associated with suspicious PSMA activity., Results: Median PSA was 0.37 ng/mL (IQR, 0.15-1.29 ng/mL), with 49% of patients overall having at least 1 suspicious PSMA-avid lesion. Rates of scan positivity among patients with PSA < 0.2 and 0.2 to 0.5 ng/mL were 34% and 38%, respectively. Among all patients, 25% (104/415) had pelvic disease (prostate bed or N1) and 24% (100/415) had M1 disease. Among patients with PSA < 0.5 ng/mL, prior postoperative radiation was associated with suspicious PSMA activity. In the overall cohort, age, PSA at PSMA PET/CT, and RP Gleason grade were associated with PSMA positivity. PSADT, EAU risk, and CAPRA-S were all associated with suspicious PSMA activity., Conclusions: Over one-third of patients with PSAs < 0.2 ng/mL had imaging findings concerning for recurrence. Prior postoperative radiation was associated with higher rates of PSMA positivity among patients with PSA < 0.5 ng/mL, and half of patients with evidence of PSMA avid distant metastatic disease underwent metastasis-directed therapy. PET-PSMA imaging at low PSAs can be considered to inform salvage therapies.

Purpose: Current clinical risk stratification methods for localized prostate cancer are suboptimal, leading to over- and undertreatment. Recently, machine learning approaches using digital histopathology have shown superior prognostic ability in phase III trials. This study aims to develop a clinically usable risk grouping system using multimodal artificial intelligence (MMAI) models that outperform current National Comprehensive Cancer Network (NCCN) risk groups., Materials and Methods: The cohort comprised 9,787 patients with localized prostate cancer from eight NRG Oncology randomized phase III trials, treated with radiation therapy, androgen deprivation therapy, and/or chemotherapy. Locked MMAI models, which used digital histopathology images and clinical data, were applied to each patient. Expert consensus on cut points defined low-, intermediate-, and high-risk groups on the basis of 10-year distant metastasis rates of 3% and 10%, respectively. The MMAI's reclassification and prognostic performance were compared with the three-tier NCCN risk groups., Results: The median follow-up for censored patients was 7.9 years. According to NCCN risk categories, 30.4% of patients were low-risk, 25.5% intermediate-risk, and 44.1% high-risk. The MMAI risk classification identified 43.5% of patients as low-risk, 34.6% as intermediate-risk, and 21.8% as high-risk. MMAI reclassified 1,039 (42.0%) patients initially categorized by NCCN. Despite the MMAI low-risk group being larger than the NCCN low-risk group, the 10-year metastasis risks were comparable: 1.7% (95% CI, 0.2 to 3.2) for NCCN and 3.2% (95% CI, 1.7 to 4.7) for MMAI. The overall 10-year metastasis risk for NCCN high-risk patients was 16.6%, with MMAI further stratifying this group into low-, intermediate-, and high-risk, showing metastasis rates of 3.4%, 8.2%, and 26.3%, respectively., Conclusion: The MMAI risk grouping system expands the population of men identified as having low metastatic risk and accurately pinpoints a high-risk subset with elevated metastasis rates. This approach aims to prevent both overtreatment and undertreatment in localized prostate cancer, facilitating shared decision making.

Background: Accurate risk stratification is critical to guide management decisions in localized prostate cancer (PCa). Previously, we had developed and validated a multimodal artificial intelligence (MMAI) model generated from digital histopathology and clinical features. Here, we externally validate this model on men with high-risk or locally advanced PCa treated and followed as part of a phase 3 randomized control trial., Objective: To externally validate the MMAI model on men with high-risk or locally advanced PCa treated and followed as part of a phase 3 randomized control trial., Design, Setting, and Participants: Our validation cohort included 318 localized high-risk PCa patients from NRG/RTOG 9902 with available histopathology (337 [85%] of the 397 patients enrolled into the trial had available slides, of which 19 [5.6%] failed due to poor image quality)., Outcome Measurements and Statistical Analysis: Two previously locked prognostic MMAI models were validated for their intended endpoint: distant metastasis (DM) and PCa-specific mortality (PCSM). Individual clinical factors and the number of National Comprehensive Cancer Network (NCCN) high-risk features served as comparators. Subdistribution hazard ratio (sHR) was reported per standard deviation increase of the score with corresponding 95% confidence interval (CI) using Fine-Gray or Cox proportional hazards models., Results and Limitations: The DM and PCSM MMAI algorithms were significantly and independently associated with the risk of DM (sHR [95% CI] = 2.33 [1.60-3.38], p < 0.001) and PCSM, respectively (sHR [95% CI] = 3.54 [2.38-5.28], p < 0.001) when compared against other prognostic clinical factors and NCCN high-risk features. The lower 75% of patients by DM MMAI had estimated 5- and 10-yr DM rates of 4% and 7%, and the highest quartile had average 5- and 10-yr DM rates of 19% and 32%, respectively (p < 0.001). Similar results were observed for the PCSM MMAI algorithm., Conclusions: We externally validated the prognostic ability of MMAI models previously developed among men with localized high-risk disease. MMAI prognostic models further risk stratify beyond the clinical and pathological variables for DM and PCSM in a population of men already at a high risk for disease progression. This study provides evidence for consistent validation of our deep learning MMAI models to improve prognostication and enable more informed decision-making for patient care., Patient Summary: This paper presents a novel approach using images from pathology slides along with clinical variables to validate artificial intelligence (computer-generated) prognostic models. When implemented, clinicians can offer a more personalized and tailored prognostic discussion for men with localized prostate cancer., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background and Objective: Biochemical recurrence (BCR) after primary definitive treatment for prostate cancer (PCa) is a heterogeneous disease state. While BCR is associated with worse oncologic outcomes, risk factors that impact outcomes can vary significantly, necessitating avenues for risk stratification. We sought to identify prognostic risk factors at the time of recurrence after primary radical prostatectomy or radiotherapy, and prior to salvage treatment(s), associated with adverse oncologic outcomes., Methods: We performed a systematic review of prospective studies in EMBASE, MEDLINE, and ClinicalTrials.gov (from January 1, 2000 to October 16, 2023) according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines (CRD42023466330). We reviewed the factors associated with oncologic outcomes among patients with BCR after primary definitive treatment., Key Findings and Limitations: A total of 37 studies were included (total n = 10 632), 25 after prostatectomy (total n = 9010) and 12 after radiotherapy (total n = 1622). Following recurrence after prostatectomy, factors associated with adverse outcomes include higher pathologic T stage and grade group, negative surgical margins, shorter prostate-specific antigen doubling time (PSADT), higher prostate-specific antigen (PSA) prior to salvage treatment, shorter time to recurrence, the 22-gene tumor RNA signature, and recurrence location on molecular imaging. After recurrence following radiotherapy, factors associated with adverse outcomes include a shorter time to recurrence, and shorter PSADT or higher PSA velocity. Grade group, T stage, and prior short-term hormone therapy (4-6 mo) were not clearly associated with adverse outcomes, although sample size and follow-up were generally limited compared with postprostatectomy data., Conclusions and Clinical Implications: This work highlights the recommendations and level of evidence for risk stratifying patients with PCa recurrence, and can be used as a benchmark for personalizing salvage treatment based on prognostics., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Importance: Half of all carriers of inherited cancer-predisposing variants in BRCA1 and BRCA2 are male, but the implications for their health are underrecognized compared to female individuals. Germline variants in BRCA1 and BRCA2 (also known as pathogenic or likely pathogenic variants, referred to here as BRCA1/2 PVs) are well known to significantly increase the risk of breast and ovarian cancers in female carriers, and knowledge of BRCA1/2 PVs informs established cancer screening and options for risk reduction. While risks to male carriers of BRCA1/2 PVs are less characterized, there is convincing evidence of increased risk for prostate cancer, pancreatic cancer, and breast cancer in males. There has also been a rapid expansion of US Food and Drug Administration-approved targeted cancer therapies, including poly ADP ribose polymerase (PARP) inhibitors, for breast, pancreatic, and prostate cancers associated with BRCA1/2 PVs., Observations: This narrative review summarized the data that inform cancer risks, targeted cancer therapy options, and guidelines for early cancer detection. It also highlighted areas of emerging research and clinical trial opportunities for male BRCA1/2 PV carriers. These developments, along with the continued relevance to family cancer risk and reproductive options, have informed changes to guideline recommendations for genetic testing and strengthened the case for increased genetic testing for males., Conclusions and Relevance: Despite increasing clinical actionability for male carriers of BRCA1/2 PVs, far fewer males than female individuals undergo cancer genetic testing. Oncologists, internists, and primary care clinicians should be vigilant about offering appropriate genetic testing to males. Identifying more male carriers of BRCA1/2 PVs will maximize opportunities for cancer early detection, targeted risk management, and cancer treatment for males, along with facilitating opportunities for risk reduction and prevention in their family members, thereby decreasing the burden of hereditary cancer.

Objective: This study aimed to evaluate the association of dynamic contrast enhancement (DCE) with clinically significant prostate cancer (csPCa, Gleason Grade Group ≥2) and compare biparametric magnetic resonance imaging (bpMRI) and multiparametric MRI (mpMRI) nomograms., Subjects/patients and Methods: We identified a retrospective cohort of biopsy naïve patients who underwent pre-biopsy MRI separated by individual MRI series from 2018 to 2022. csPCa detection rates were calculated for patients with peripheral zone (PZ) lesions scored 3-5 on diffusion weighted imaging (DWI) with available DCE (annotated as - or +). bpMRI Prostate Imaging Reporting and Data System (PIRADS) (3 = 3-, 3+; 4 = 4-, 4+; 5 = 5-, 5+) and mpMRI PIRADS (3 = 3-; 4 = 3+, 4-, 4+; 5 = 5-, 5+) approaches were compared in multivariable logistic regression models. Nomograms for detection of csPCa and ≥GG3 PCa incorporating all biopsy naïve patients who underwent prostate MRI were generated based on available serum biomarkers [PHI, % free prostate-specific antigen (PSA), or total PSA] and validated with an independent cohort., Results: Patients ( n = 1010) with highest PIRADS lesion in PZ were included in initial analysis with 127 (12.6%) classified as PIRADS 3+ (PIRADS 3 on bpMRI but PIRADS 4 on mpMRI). On multivariable analysis, PIRADS 3+ lesions were associated with higher csPCa rates compared to PIRADS 3- (3+ vs. 3-: OR 1.86, p  = 0.024), but lower csPCa rates compared to PIRADS DWI 4 lesions (4 vs. 3+: OR 2.39, p  < 0.001). csPCa rates were 19% (3-), 31% (3+), 41.5% (4-), 65.9% (4+), 62.5% (5-), and 92.3% (5+). bpMRI nomograms were non-inferior to mpMRI nomograms in the development ( n  = 1410) and independent validation ( n  = 353) cohorts. Risk calculators available at: https://rossnm1.shinyapps.io/MynMRIskCalculator/., Conclusion: While DCE positivity by itself was associated with csPCa among patients with highest PIRADS lesions in the PZ, nomogram comparisons suggest that there is no significant difference in performance of bpMRI and mpMRI. bpMRI may be considered as an alternative to mpMRI for prostate cancer evaluation in many situations., Competing Interests: EMS is a consultant for Atria Academy of Science and Medicine, Early Medical, Lantheus, Pfizer, and PinnacleCare Health Advisors. AER is a consultant for Astellas, Astra Zeneca, Bayer HealthCare Pharmaceuticals, BillionToOne, Janssen Biotech, Lantheus, Myovant, Novartis, Pfizer, and Veracyte. These relationships are not related to the contents of this manuscript., (© 2024 The Author(s). BJUI Compass published by John Wiley & Sons Ltd on behalf of BJU International Company.)

Background and Objective: The transrectal biopsy approach is traditionally used to detect prostate cancer. An alternative transperineal approach is historically performed under general anesthesia, but recent advances enable transperineal biopsy to be performed under local anesthesia. We sought to compare infectious complications of transperineal biopsy without antibiotic prophylaxis versus transrectal biopsy with targeted prophylaxis., Methods: We assigned biopsy-naïve participants to undergo transperineal biopsy without antibiotic prophylaxis versus transrectal biopsy with targeted prophylaxis (rectal culture screening for fluoroquinolone-resistant bacteria and antibiotic targeting to culture and sensitivity results) through a multicenter, randomized trial. The primary outcome was post-biopsy infection captured by a prospective medical review and patient report on a 7-d survey. The secondary outcomes included cancer detection, noninfectious complications, and a numerical rating scale (0-10) for biopsy-related pain and discomfort during and 7-d after biopsy., Key Findings and Limitations: A total of 658 participants were randomized, with zero transperineal versus four (1.4%) transrectal biopsy infections (difference -1.4%; 95% confidence interval [CI] -3.2%, 0.3%; p = 0.059). The rates of other complications were very low and similar. Importantly, detection of clinically significant cancer was similar (53% transperineal vs 50% transrectal, adjusted difference 2.0%; 95% CI -6.0, 10). Participants in the transperineal arm experienced worse periprocedural pain (0.6 adjusted difference [0-10 scale], 95% CI 0.2, 0.9), but the effect was small and resolved by 7-d., Conclusions and Clinical Implications: Office-based transperineal biopsy is tolerable, does not compromise cancer detection, and did not result in infectious complications. Transrectal biopsy with targeted prophylaxis achieved similar infection rates, but requires rectal cultures and careful attention to antibiotic selection and administration. Consideration of these factors and antibiotic stewardship should guide clinical decision-making., Patient Summary: In this multicenter randomized trial, we compare prostate biopsy infectious complications for the transperineal versus transrectal approach. The absence of infectious complications with transperineal biopsy without the use of preventative antibiotics is noteworthy, but not significantly different from transrectal biopsy with targeted antibiotic prophylaxis., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Multiparametric prostate MRI (mpMRI) is being increasingly adopted for work-up of prostate cancer. For patients selected to omit biopsy, we identified factors associated with repeat MRI, eventual prostate biopsy, and subsequent detection of clinically significant prostate cancer (csPCa, Grade Group ≥2)., Methods: We identified biopsy-naïve men presenting with PSA 2-20 ng/mL (March 2018-June 2021) undergoing initial mpMRI with PIRADS 1-3 lesions who were not selected for biopsy with ≥6 months follow-up. We examined factors associated with repeat mpMRI, progression to biopsy, and subsequent detection of csPCa with univariable and multivariable logistic regression., Results: Of 1494 men, 31% (463/1494) did not pursue biopsy. PSA density (PSAD) ≤ 0.1, prostate health index (PHI) < 55, and PIRADS 1-2 were associated with omission of prostate biopsy. csPCa diagnosis-free survival was 97.6% (326/334) with median follow up of 23.1 months (IQR 15.1-34.6 months). Black race, PSA, PHI, PSA density, and PSA and PHI velocity were significant predictors of undergoing repeat mpMRI (15.6%, 52/334) and subsequent biopsy (8.4%, 28/334). 8 men were subsequently diagnosed with csPCa (N = 7 on prostate biopsy; N = 1 incidentally on holmium enucleation of prostate). All patients diagnosed with csPCa had PIRADS 4-5 on repeat mpMRI., Conclusions: The subsequent detection rate of csPCa among patients not initially biopsied after mpMRI was low at 2.4%. Decisions to omit biopsy after initial reassuring PHI, PSAD, and mpMRI appear safe with subsequent reassuring serum biomarkers and for cause mpMRI during follow-up., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Introduction: Hypogonadism is associated with frailty, lower health-related quality of life, decreased muscle mass, and premature mortality, which may predispose patients to poor postoperative outcomes. We aimed to determine the prevalence of hypogonadism in men undergoing radical cystectomy (RC) and whether hypogonadism and frailty are associated with adverse postoperative outcomes., Materials and Methods: The IBM MarketScan database was used to identify men who underwent RC between 2012 and 2021. Frailty was determined using published Hospital Frailty Risk Score ranges. Patients were considered to have hypogonadism if diagnosed within 5 years prior to RC. Length of stay (LOS), complications, emergency department (ED) visits and inpatient readmissions were compared. Sub-group analysis of men with hypogonadism was performed to determine the effect of testosterone replacement therapy (TRT) on clinical outcomes., Results: Among 3,727 men who underwent RC, 226 (6.1%) had a diagnosis of hypogonadism. Overall, 565 (15.2%) men were low-risk frailty, 2,214 (59.4%) intermediate-risk frailty, and 948 (25.4%) were high-risk frailty, and men with hypogonadism were significantly more frail compared to men without hypogonadism (P = 0.027). There was no significant difference in LOS, complications, or rate of ED visits and inpatient readmissions between cohorts (P > 0.05). However, high-risk frailty was associated with an increased risk of 90-day ED visit (HR 1.19, 95%CI 1.00-1.41, P = 0.049) and 90-day readmission (HR 1.60, 95%CI 1.29-1.97, P < 0.001) after RC. Among men with hypogonadism, 58 (25.7%) were on TRT. There was no significant difference in frailty, LOS, complications, or 90-day ED visits or 90-day inpatient readmissions between patient with hypogonadism prescribed TRT and those without TRT., Conclusions: These findings suggest that hypogonadism and preoperative frailty may be important to evaluate prior to undergoing RC., 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 Inc. All rights reserved.)

Introduction: Clinicians may offer patients with positive lymph nodes (pN1) and undetectable PSA following surgery for prostate cancer either observation or adjuvant therapy based on AUA, EAU, and NCCN guidelines considering standard PSA detection thresholds of <0.1ng/ml. Here we sought to investigate the outcomes of pN1 patients in the era of ultrasensitive PSA testing., Methods: We queried the Northwestern Electronic Data Warehouse for patients with prostate cancer who were pN1 at radical prostatectomy and followed with ultrasensitive PSA. Patients receiving neoadjuvant treatment were excluded. We compared clinical characteristics including age, race, pre-operative PSA, Gleason grade, tumor stage, surgical margins, and nodal specimens to identify factors associated with achievement and maintenance of an undetectable PSA (defined as <0.01 ng/mL). Statistics were performed using t-test, Mann-Whitney U test, chi-squared analysis, and logistic regression with significance defined as p<0.05., Results: From 2018-2023, 188 patients were included. Subsequently, 39 (20.7%) had a PSA decline to undetectable levels (<0.01 ng/mL) post-operatively at a median time of 63 days. Seven percent of these men (3/39) were treated with adjuvant RT + ADT with undetectable PSA levels. 13/39 (33.3%) had eventual rises in PSA to ≥0.01 ng/mL for which they underwent salvage RT with ADT. Overall, 23/39 (59%) patients achieved and maintained undetectable PSA levels without subsequent therapy at median follow-up of 24.2 mo. Compared to patients with PSA persistence after surgery or elevations to detectable levels (≥0.01 ng/mL), patients who achieved and maintained undetectable levels had lower Gleason grades (p=0.03), lower tumor stage (p<0.001), fewer positive margins (p=0.02), and fewer involved lymph nodes (p=0.02). On multivariable analysis, only primary tumor (pT) stage was associated with achieving and maintaining an undetectable PSA; pT3b disease was associated with a 6.6-fold increased chance of developing a detectable PSA (p=0.03)., Conclusion: Ultrasensitive PSA can aid initiation of early salvage therapy for lymph node positive patients after radical prostatectomy while avoiding overtreatment in a significant subset. 20% of patients achieved an undetectable PSA and over half of this subset remained undetectable after 2 years., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Aguiar, Li, Ho, Bennett, Li, Neill, Schaeffer, Patel and Ross.)

Implications: Our study illuminates the potential of deep learning in effectively inferring key prostate cancer genetic alterations from the tissue morphology depicted in routinely available histology slides, offering a cost-effective method that could revolutionize diagnostic strategies in oncology., (©2024 The Authors; Published by the American Association for Cancer Research.)

Objective: To compare clinically significant prostate cancer detection with TP-TBx utilizing software vs cognitive fusion. It is established that MRI prior to prostate biopsy improves detection of clinically significant cancer (csPCa, Grade Group ≥2). MRI/US fusion targeted biopsy via a transperineal approach (TP-TBx) is increasing in utilization due to the clean percutaneous approach that greatly reduces postbiopsy infection. However, the comparative effectiveness of formal software fusion over cognitive fusion remains under studied., Materials and Methods: We performed a retrospective multicenter study from June 2020 to July 2022 including age, race, prostate-specific antigen (PSA), prostate volume, PI-RADS, lesion size(s), number of cores sampled, indication (elevated PSA, prior negative, active surveillance) and anesthesia type. Surgeon preference determined use of cognitive (PrecisionPoint) vs software fusion techniques. Multivariable logistic regression determined factors associated with TP-TBx detection of csPCa., Results: We identified 490 patients (201 cognitive, 289 software fusion) who underwent TP-TBx. Patient age, PSA, number of targets, and PI-RADS were similar (all P > .05). Software fusion TP-TBx had 4 [95% confidence interval (CI) 3-5] more (estimated median difference) systematic cores sampled. csPCa was detected in 44% of all patients. In adjusted analysis, cognitive vs software fusion was similar in detection of csPCa (odds ratio 1.46, 95% CI 0.82-2.58)., Conclusion: Cognitive vs software fusion TP-TBx has similar csPCa detection, despite fewer systematic cores taken with cognitive fusion. The expense, additional time requirement, and similar outcomes of software fusion platforms confers higher value to cognitive TP-Bx., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: Few studies have explored the potential for pharmacological interventions to delay disease progression in patients undergoing active surveillance (AS). This preplanned transcriptomic analysis of patient samples from the ENACT trial aims to identify biomarkers in patients on AS who are at increased risk for disease progression or who may derive the greatest benefit from enzalutamide treatment., Patients and Methods: In the phase II ENACT (ClinicalTrials.gov identifier: NCT02799745) trial, patients on AS were randomly assigned 1:1 to 160 mg orally once daily enzalutamide monotherapy or continued AS for 1 year. Transcriptional analyses were conducted on biopsies collected at trial screening, year 1, and year 2. Three gene expression signatures were evaluated in samples collected at screening and in available samples from patients on AS at any time during surveillance (expanded cohort): Decipher genomic classifier, androgen receptor activity (AR-A) score, and Prediction Analysis of Microarray 50 (PAM50) cell subtype signature., Results: The Decipher genomic classifier score was prognostic; higher scores were associated with disease progression in the expanded cohort and AS arm of the expanded cohort. Patients with higher Decipher scores had greater positive treatment effect from enzalutamide as measured by time to secondary rise in prostate-specific antigen >25% above baseline. In patients treated with enzalutamide, higher AR-A scores and PAM50 luminal subtypes were associated with a greater likelihood of negative biopsy incidence at year 2., Conclusion: This analysis suggests that the Decipher genomic classifier may be prognostic for disease progression in AS patients with low- to intermediate-risk prostate cancer. Higher Decipher and AR-A scores, as well as PAM50 luminal subtypes, may also serve as biomarkers for treatment response.

The NCCN Guidelines for Prostate Cancer include recommendations for staging and risk assessment after a prostate cancer diagnosis and for the care of patients with localized, regional, recurrent, and metastatic disease. These NCCN Guidelines Insights summarize the panel's discussions for the 2024 update to the guidelines with regard to initial risk stratification, initial management of very-low-risk disease, and the treatment of nonmetastatic recurrence.

Purpose: We sought to develop and validate a prostate biopsy risk calculator for Black men and compare it with the Prostate Cancer Prevention Trial version 2.0, Prostate Biopsy Collaborative Group, and Kaiser Permanente Prostate Cancer Risk Calculators for the detection of Gleason Grade Group (GG) ≥ 2 prostate cancer (PCa)., Materials and Methods: We prospectively recruited 2 cohorts of men undergoing prostate biopsy from 5 facilities in Chicago. The first cohort was split into development (70%) and internal validation (30%) groups. The second was used for external validation. Iterative logistic regression was used to develop 3 models for predicting GG ≥ 2 PCa. Models were compared for discrimination using the C statistics, calibration curves, and net benefit curves. The frequency of unnecessary biopsies and missed PCas was compared at 10% and 30% risk thresholds., Results: The 2 cohorts included 393 and 292 Black men, respectively. Our first model, Mistry-Sun 1, used serum PSA and prior negative biopsy. Mistry-Sun 2 added abnormal digital rectal exam (DRE) and an interaction term with abnormal DRE and PSA to Mistry-Sun 1. Mistry-Sun 3 added prostate volume, abnormal DRE, and age to Mistry-Sun 1. The C statistics were 0.74, 0.74, and 0.78, respectively, and were similar to or higher than established calculators. At the 10% and 30% risk thresholds our models had the fewest unnecessary biopsies and an appropriate proportion of missed GG ≥ 2 PCas., Conclusions: Tailoring a risk calculator to detect clinically significant PCa in Black men may improve biopsy decision-making and outcomes compared to tools developed in non-Black populations.

This study aimed to assess the accuracy of intraprostatic tumor volume measurements on prostate-specific membrane antigen-targeted 18 F-DCFPyL PET/CT made with various segmentation methods. An accurate understanding of tumor volumes versus segmentation techniques is critical for therapy planning, such as radiation dose volume determination and response assessment. Methods: Twenty-five men with clinically localized, high-risk prostate cancer were imaged with 18 F-DCFPyL PET/CT before radical prostatectomy. The tumor volumes and tumor-to-prostate ratios (TPRs) of dominant intraprostatic foci of uptake were determined using semiautomatic segmentation (applying SUV max percentage [SUV%] thresholds of SUV30%-SUV70%), adaptive segmentation (using adaptive segmentation percentage [A%] thresholds of A30%-A70%), and manual contouring. The histopathologic tumor volume (TV-Histo) served as the reference standard. The significance of differences between TV-Histo and PET-based tumor volume were assessed using the paired-sample Wilcoxon signed-rank test. The Spearman correlation coefficient was used to establish the strength of the association between TV-Histo and PET-derived tumor volume. Results: Median TV-Histo was 2.03 cm 3 (interquartile ratio [IQR], 1.16-3.36 cm 3 ), and median TPR was 10.16%. The adaptive method with an A40% threshold most closely determined the tumor volume, with a median difference of +0.19 (IQR, -0.71 to +2.01) and a median relative difference of +7.6%. The paired-sample Wilcoxon test showed no significant difference in PET-derived tumor volume and TV-Histo using A40%, A50%, SUV40%, and SUV50% threshold segmentation algorithms ( P > 0.05). For both threshold-based segmentation methods, use of higher thresholds (e.g., SUV60% or SUV70% and A50%-A70%) resulted in underestimation of tumor volumes, and use of lower thresholds (e.g., SUV30% or SUV40% and A30%) resulted in overestimation of tumor volumes relative to TV-Histo and TPR. Manual segmentation overestimated the tumor volume, with a median difference of +2.49 (IQR, 0.42-4.11) and a median relative difference of +130%. Conclusion: Segmentation of intraprostatic tumor volume and TPR with an adaptive segmentation approach most closely approximates TV-Histo. This information might be used to guide the primary treatment of men with clinically localized, high-risk prostate cancer., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

The NCCN Guidelines for Prostate Cancer provide a framework on which to base decisions regarding the workup of patients with prostate cancer, risk stratification and management of localized disease, post-treatment monitoring, and treatment of recurrence and advanced disease. The Guidelines sections included in this article focus on the management of metastatic castration-sensitive disease, nonmetastatic castration-resistant prostate cancer (CRPC), and metastatic CRPC (mCRPC). Androgen deprivation therapy (ADT) with treatment intensification is strongly recommended for patients with metastatic castration-sensitive prostate cancer. For patients with nonmetastatic CRPC, ADT is continued with or without the addition of certain secondary hormone therapies depending on prostate-specific antigen doubling time. In the mCRPC setting, ADT is continued with the sequential addition of certain secondary hormone therapies, chemotherapies, immunotherapies, radiopharmaceuticals, and/or targeted therapies. The NCCN Prostate Cancer Panel emphasizes a shared decision-making approach in all disease settings based on patient preferences, prior treatment exposures, the presence or absence of visceral disease, symptoms, and potential side effects.

Purpose: To develop nomograms that predict the detection of clinically significant prostate cancer (csPCa, defined as ≥GG2 [Grade Group 2]) at diagnostic biopsy based on multiparametric prostate MRI (mpMRI), serum biomarkers, and patient clinicodemographic features., Materials and Methods: Nomograms were developed from a cohort of biopsy-naïve men presenting to our 11-hospital system with prostate specific antigen (PSA) of 2-20 ng/mL who underwent pre-biopsy mpMRI from March 2018-June 2021 (n = 1494). The outcomes were the presence of csPCa and high-grade prostate cancer (defined as ≥GG3 prostate cancer). Using significant variables on multivariable logistic regression, individual nomograms were developed for men with total PSA, % free PSA, or prostate health index (PHI) when available. The nomograms were both internally validated and evaluated in an independent cohort of 366 men presenting to our hospital system from July 2021-February 2022., Results: 1031 of 1494 men (69%) underwent biopsy after initial evaluation with mpMRI, 493 (47.8%) of whom were found to have ≥GG2 PCa, and 271 (26.3%) were found to have ≥GG3 PCa. Age, race, highest PIRADS score, prostate health index when available, % free PSA when available, and PSA density were significant predictors of ≥GG2 and ≥GG3 PCa on multivariable analysis and were used for nomogram generation. Accuracy of nomograms in both the training cohort and independent cohort were high, with areas under the curves (AUC) of ≥0.885 in the training cohort and ≥0.896 in the independent validation cohort. In our independent validation cohort, our model for ≥GG2 prostate cancer with PHI saved 39.1% of biopsies (143/366) while only missing 0.8% of csPCa (1/124) with a biopsy threshold of 20% probability of csPCa., Conclusions: Here we developed nomograms combining serum testing and mpMRI to help clinicians risk stratify patients with elevated PSA of 2-20 ng/mL who are being considered for biopsy. Our nomograms are available at https://rossnm1.shinyapps.io/MynMRIskCalculator/ to aid with biopsy decisions., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Management of localized or recurrent prostate cancer since the 1990s has been based on risk stratification using clinicopathological variables, including Gleason score, T stage (based on digital rectal exam), and prostate-specific antigen (PSA). In this study a novel prognostic test, the Decipher Prostate Genomic Classifier (GC), was used to stratify risk of prostate cancer progression in a US national database of men with prostate cancer., Methods: Records of prostate cancer cases from participating SEER (Surveillance, Epidemiology, and End Results) program registries, diagnosed during the period from 2010 through 2018, were linked to records of testing with the GC prognostic test. Multivariable analysis was used to quantify the association between GC scores or risk groups and use of definitive local therapy after diagnosis in the GC biopsy-tested cohort and postoperative radiotherapy in the GC-tested cohort as well as adverse pathological findings after prostatectomy., Results: A total of 572 545 patients were included in the analysis, of whom 8927 patients underwent GC testing. GC biopsy-tested patients were more likely to undergo active active surveillance or watchful waiting than untested patients (odds ratio [OR] =2.21, 95% confidence interval [CI] = 2.04 to 2.38, P < .001). The highest use of active surveillance or watchful waiting was for patients with a low-risk GC classification (41%) compared with those with an intermediate- (27%) or high-risk (11%) GC classification (P < .001). Among National Comprehensive Cancer Network patients with low and favorable-intermediate risk, higher GC risk class was associated with greater use of local therapy (OR = 4.79, 95% CI = 3.51 to 6.55, P < .001). Within this subset of patients who were subsequently treated with prostatectomy, high GC risk was associated with harboring adverse pathological findings (OR = 2.94, 95% CI = 1.38 to 6.27, P = .005). Use of radiation after prostatectomy was statistically significantly associated with higher GC risk groups (OR = 2.69, 95% CI = 1.89 to 3.84)., Conclusions: There is a strong association between use of the biopsy GC test and likelihood of conservative management. Higher genomic classifier scores are associated with higher rates of adverse pathology at time of surgery and greater use of postoperative radiotherapy.In this study the Decipher Prostate Genomic Classifier (GC) was used to analyze a US national database of men with prostate cancer. Use of the GC was associated with conservative management (ie, active surveillance). Among men who had high-risk GC scores and then had surgery, there was a 3-fold higher chance of having worrisome findings in surgical specimens., (© The Author(s) 2023. Published by Oxford University Press.)

BACKGROUND: Androgen deprivation therapy (ADT) with radiotherapy can benefit patients with localized prostate cancer. However, ADT can negatively impact quality of life, and there remain no validated predictive models to guide its use. METHODS: We used digital pathology images from pretreatment prostate tissue and clinical data from 5727 patients enrolled in five phase 3 randomized trials, in which treatment was radiotherapy with or without ADT, as our data source to develop and validate an artificial intelligence (AI)–derived predictive patient-specific model that would determine which patients would develop the primary end point of distant metastasis. The model used baseline data to provide a binary output that a given patient will likely benefit from ADT or not. After the model was locked, validation was performed using data from NRG Oncology/Radiation Therapy Oncology Group (RTOG) 9408 (n=1594), a trial that randomly assigned men to radiotherapy plus or minus 4 months of ADT. Fine–Gray regression and restricted mean survival times were used to assess the interaction between treatment and the predictive model and within predictive model–positive, i.e., benefited from ADT, and –negative subgroup treatment effects. RESULTS: Overall, in the NRG/RTOG 9408 validation cohort (14.9 years of median follow-up), ADT significantly improved time to distant metastasis. Of these enrolled patients, 543 (34%) were model positive, and ADT significantly reduced the risk of distant metastasis compared with radiotherapy alone. Of 1051 patients who were model negative, ADT did not provide benefit. CONCLUSIONS: Our AI-based predictive model was able to identify patients with a predominantly intermediate risk for prostate cancer likely to benefit from short-term ADT. (Supported by a grant [U10CA180822] from NRG Oncology Statistical and Data Management Center, a grant [UG1CA189867] from NCI Community Oncology Research Program, a grant [U10CA180868] from NRG Oncology Operations, and a grant [U24CA196067] from NRG Specimen Bank from the National Cancer Institute and by Artera, Inc. ClinicalTrials.gov numbers NCT00767286, NCT00002597, NCT00769548, NCT00005044, and NCT00033631.)

Background: Prostate cancer (PCa) is a clinically heterogeneous disease. The creation of an expression-based subtyping model based on prostate-specific biological processes was sought., Methods: Unsupervised machine learning of gene expression profiles from prospectively collected primary prostate tumors (training, n = 32,000; evaluation, n = 68,547) was used to create a prostate subtyping classifier (PSC) based on basal versus luminal cell expression patterns and other gene signatures relevant to PCa biology. Subtype molecular pathways and clinical characteristics were explored in five other clinical cohorts., Results: Clustering derived four subtypes: luminal differentiated (LD), luminal proliferating (LP), basal immune (BI), and basal neuroendocrine (BN). LP and LD tumors both had higher androgen receptor activity. LP tumors also had a higher expression of cell proliferation genes, MYC activity, and characteristics of homologous recombination deficiency. BI tumors possessed significant interferon γactivity and immune infiltration on immunohistochemistry. BN tumors were characterized by lower androgen receptor activity expression, lower immune infiltration, and enrichment with neuroendocrine expression patterns. Patients with LD tumors had less aggressive tumor characteristics and the longest time to metastasis after surgery. Only patients with BI tumors derived benefit from radiotherapy after surgery in terms of time to metastasis (hazard ratio [HR], 0.09; 95% CI, 0.01-0.71; n = 855). In a phase 3 trial that randomized patients with metastatic PCa to androgen deprivation with or without docetaxel (n = 108), only patients with LP tumors derived survival benefit from docetaxel (HR, 0.21; 95% CI, 0.09-0.51)., Conclusions: With the use of expression profiles from over 100,000 tumors, a PSC was developed that identified four subtypes with distinct biological and clinical features., Plain Language Summary: Prostate cancer can behave in an indolent or aggressive manner and vary in how it responds to certain treatments. To differentiate prostate cancer on the basis of biological features, we developed a novel RNA signature by using data from over 100,000 prostate tumors-the largest data set of its kind. This signature can inform patients and physicians on tumor aggressiveness and susceptibilities to treatments to help personalize cancer management., (© 2023 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: The utilization of MRI to risk stratify elevated PSA prior to prostate biopsy has been inconsistently adopted and varies considerably by practice setting. This study aims to evaluate the usage and performance of MRI as an advanced risk stratification tool of elevated PSA prior to biopsy and identify factors associated with differential utilization of MRI at a large academic setting with ready access to 3T multiparametric MRI of the prostate., Methods: A retrospective single-center study of 2900 men presenting with elevated PSA 2-20 ng/mL from 2018 through 2021 was conducted. We analyzed trends in MRI utilization and outcomes of prostate biopsy by MRI usage. Univariate and multivariate logistic regressions were performed to calculate odds ratios to identify patient- and provider-level predictors of MRI usage., Results: Rates of prebiopsy MRI utilization increased from 56% in 2018 to 89% in 2021 (p < 0.001). Prebiopsy MRI led to biopsy avoidance in 31% of men. MRI usage enhanced detection of clinically significant prostate cancer by 13% and reduced identification of Gleason Grade Group 1 disease by 3% and negative biopsies by 10% (p < 0.001). Men who received MRI were more likely to be younger than 75 years in age and have private or Medicare insurance, PSA >4 ng/mL, and PHI >27. In both univariate and multivariate analysis, black race and Medicaid insurance were associated with reduced MRI utilization (all p < 0.001). Urologic provider was an independent predictor of MRI usage (p < 0.001)., Conclusions: Use of MRI as a risk stratification tool for elevated PSA rose during this 4-year study period. Men who self-identify as black or men with Medicaid coverage have diminished rates of MRI usage. Considerable provider-level variability in MRI use was observed. Future research aimed at identifying factors affecting implementation of MRI as a routine risk assessment tool is warranted., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Genetic evaluation of men with advanced prostate cancer is recognized as imperative both to guide treatment decisions and to trigger cascade genetic testing of family members. Here we investigate utilization patterns of genetic testing among a contemporary cohort of men with advanced prostate cancer at our institution., Methods: We queried the Northwestern Electronic Data Warehouse from January 2021 to present for all men diagnosed with National Comprehensive Cancer Network high-risk/very high-risk, regional, or metastatic prostate cancer. Patients were excluded from analyses if treated at an outside institution and/or presented for a second opinion evaluation. Statistics were performed using t-test, Chi-squared test, and univariable and multivariable logistic regression with significance defined as p < 0.05., Results: Atotal of 320 men (52.5%) had local/regional disease and 290 (47.5%) had metastatic disease, 53 (18.3%) of whom had castrate resistant prostate cancer. Rates of germline genetic testing rate were low in patients with localized disease (9.4%) and metastatic disease (34.1%). Only 19 (35.8%) men diagnosed with metastatic castrate resistant prostate cancer underwent germline genetic evaluation. Germline testing was most frequently discussed or ordered by medical oncologists (52%) followed by urologists (20%). Men who underwent germline testing were younger (p < 0.001), more likely to have Medicaid or private insurance (p = 0.002), and more likely to have metastatic disease (p < 0.001). There were no statistically significant differences in baseline PSA, ethnicity, race, or castration sensitivity status. Age (odds ratio [OR]: 0.94, 95% confidence interval [CI]: 0.91-0.97, p < 0.001) and metastatic disease (OR: 5.71, 95% CI: 3.63-9.22, p < 0.001) were significant independent predictors of genetic testing on multivariable logistic regression., Conclusions: Here we report that utilization of genetic testing is associated with metastatic disease and inversely associated with age. Overall, utilization rates of genetic testing remain low in all patient groups, including in the metastatic castrate resistant setting, where genetic testing can identify patients with homologous recombination repair deficiency who may benefit from use of targeted therapeutics such as PARP inhibitors. Genetic testing in men with aggressive prostate cancer is critical and barriers to routine implementation of testing require further study to develop strategies to improve utilization rates., (© 2022 Wiley Periodicals LLC.)

Background: Pelvic fascia-sparing robotic-assisted radical prostatectomy (PFS-RARP) is a novel approach that spares the endopelvic fascia ventral to the prostate. The preservation of more native structures compared to conventional robotic-assisted radical prostatectomy (RARP) may lead to faster recovery of urinary function, fewer penile changes, and decreased inguinal hernia sequelae, but may have a higher risk for positive surgical margins and poorer cancer control. However, high-level evidence is absent. The PARTIAL trial is a surgical randomized controlled trial (RCT) aiming to bridge this evidence gap (NCT05155501)., Methods: We describe a prospective RCT with a projected enrollment of 600 men randomized to PFS-RARP vs. RARP. The primary outcome is cancer control (positive surgical margins and prostate-specific antigen failure) and secondary outcomes include health-related quality of life pertaining to urinary and sexual function, decision regret, and adverse events (30-day complications, inguinal hernias, penile shortening, and Peyronie's disease). The anticipated duration of trial participation is 24 months. Study participation is incentivized with the use of innovative methodologies such as a novel, two-stage informed consent and a validated web-based interface to monitor patient-reported symptoms and empower individuals to improve their recovery., Conclusion: If PFS-RARP is non-inferior to RARP in terms of cancer control and has better functional outcomes, it should be the surgical standard of care for men with localized prostate cancer. Using the innovative two-stage consent process, completion of the trial will not only provide much needed evidence on one of the most common cancer surgeries but also insight on improving surgical RCT methodology. Trial status This trial is registered at ClinicalTrials.gov (NCT05155501; first posted on December 13, 2021); Institutional approval number: WCM IRB # 21-07023781, BRANY's initial approval event ID # 186333. The trial is not yet recruiting., Competing Interests: Declaration of Competing Interest JCH: Consultant for Intuitive Surgical and Pfizer. All other authors declare having no other competing interests., (Copyright © 2023. Published by Elsevier Inc.)

BACKGROUND: The Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP) working group identified metastasis-free survival as a valid surrogate end point for overall survival (OS) for patients with localized prostate cancer. No comparably validated surrogate end points exist in advanced prostate cancer. METHODS: We searched for trials in advanced prostate cancer, defined as node-positive, metastatic castration-sensitive, nonmetastatic, or metastatic castration-resistant prostate cancer. Eligible randomized trials reported OS and one or more intermediate clinical end points, including biochemical failure (BF), clinical failure, biochemical failure–free survival (BFS), progression-free survival (PFS), and radiographic PFS. Candidacy for surrogacy was assessed by using the second condition of the meta-analytic approach; R2 was weighted by the inverse variance of the log intermediate clinical end point hazard ratio and defined as R2>0.70. RESULTS: A total of 143 randomized trials (n=75,601 patients) were included. No candidate end points met the criteria for surrogacy (R2 BF [n=28,922], 0.42 [95% confidence interval (CI), 0.18 to 0.64]; BFS [n=25,741], 0.57 [95% CI, 0.37 to 0.73]; clinical failure [n=22,616], 0.31 [95% CI, 0.075 to 0.56]; PFS [n=52,639], 0.50 [95% CI, 0.35 to 0.63]; and radiographic PFS [n=52,548], 0.50 [95% CI, 0.35 to 0.63]). Within preplanned subgroups according to castration-sensitive or castration-resistant disease or according to treatment type, neither BFS nor PFS consistently met criteria for surrogacy. Sensitivity analyses showed that candidacy for surrogacy of all end points tested did not change over time. CONCLUSIONS: Our aggregate screening method for surrogate end points in advanced prostate cancer showed that commonly used clinical end points are not clear valid surrogate end points for OS. (Funded by the Prostate Cancer Foundation and the National Cancer Institute.)

Background: Data on advanced prostate cancer (PCa) suggest more prior systemic therapies might reduce tumor immune responsiveness. In treatment-naïve primary PCa, recent work correlated intratumoral plasma cell content with enhanced tumor immune-responsiveness. We sought to identify features of localized PCa at a high risk of recurrence following local treatment with high plasma cell content to help focus future immune-based neoadjuvant trials., Methods: We performed retrospective analyses of molecular profiles from three independent cohorts of over 1300 prostate tumors. We used Wilcoxon Rank Sum to compare molecular pathways between tumors with high and low intratumoral plasma cell content and multivariable Cox proportional hazards regression analyses to assess metastasis-free survival., Results: We validated an expression-based signature for intratumoral plasma cell content in 113 primary prostate tumors with both RNA-expression data and digital image quantification of CD138+ cells (plasma cell marker) based on immunohistochemisty. The signature showed castration-resistant tumors (n = 101) with more prior systemic therapies contained lower plasma cell content. In high-grade primary PCa, tumors with high plasma cell content were associated with increased predicted response to immunotherapy and decreased response to androgen-deprivation therapy. Master regulator analyses identified upregulated transcription factors implicated in immune (e.g. SKAP1, IL-16, and HCLS1), and B-cell activity (e.g. VAV1, SP140, and FLI-1) in plasma cell-high tumors. Master regulators overactivated in tumors with low plasma cell content were associated with shorter metastasis-free survival following radical prostatectomy., Conclusions: Markers of plasma cell activity might be leveraged to augment clinical trial targeting and selection and better understand the potential for immune-based treatments in patients with PCa at a high risk of recurrence following local treatment., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Metastatic and high-risk localized prostate cancer respond to hormone therapy but outcomes vary. Following a pre-specified statistical plan, we used Cox models adjusted for clinical variables to test associations with survival of multi-gene expression-based classifiers from 781 patients randomized to androgen deprivation with or without abiraterone in the STAMPEDE trial. Decipher score was strongly prognostic (p<2×10 -5 ) and identified clinically-relevant differences in absolute benefit, especially for localized cancers. In metastatic disease, classifiers of proliferation, PTEN or TP53 loss and treatment-persistent cells were prognostic. In localized disease, androgen receptor activity was protective whilst interferon signaling (that strongly associated with tumor lymphocyte infiltration) was detrimental. Post-Operative Radiation-Therapy Outcomes Score was prognostic in localized but not metastatic disease (interaction p=0.0001) suggesting the impact of tumor biology on clinical outcome is context-dependent on metastatic state. Transcriptome-wide testing has clinical utility for advanced prostate cancer and identified worse outcomes for localized cancers with tumor-promoting inflammation., Competing Interests: All other authors declare no competing interests.

The genomic and immune landscapes of prostate cancer differ by self-identified race. However, few studies have examined the genome-wide copy number landscape and immune content of matched cohorts with genetic ancestry data and clinical outcomes. Here, we assessed prostate cancer somatic copy number alterations (sCNA) and tumor immune content of a grade-matched, surgically treated cohort of 145 self-identified Black (BL) and 145 self-identified White (WH) patients with genetic ancestry estimation. A generalized linear model adjusted with age, preoperative prostate-specific antigen (PSA), and Gleason Grade Group and filtered for germline copy number variations (gCNV) identified 143 loci where copy number varied significantly by percent African ancestry, clustering on chromosomes 6p, 10q, 11p, 12p, and 17p. Multivariable Cox regression models adjusted for age, preoperative PSA levels, and Gleason Grade Group revealed that chromosome 8q gains (including MYC) were significantly associated with biochemical recurrence and metastasis, independent of genetic ancestry. Finally, Treg density in BL and WH patients was significantly correlated with percent genome altered, and these findings were validated in the TCGA cohort. Taken together, our findings identify specific sCNA linked to genetic ancestry and outcome in primary prostate cancer and demonstrate that Treg infiltration varies by global sCNA burden in primary disease.

Background: Despite the historic association of higher prostate cancer volume with worse oncologic outcomes, little is known about the impact of tumor volume on cancer biology., Objective: To characterize the relationship between tumor volume (measured by percent positive cores [PPC]) and cancer biology (measured by Decipher genomic risk classifier [GC]) in men who underwent prostate biopsy., Design Setting and Participants: Prostate biopsies from 52 272 men profiled with Decipher captured in a population-based prospective tumor registry were collected from 2016 to 2021., Outcome Measurements and Statistical Analysis: The degree of distribution and correlation of PPC with a GC score across grade group (GG) strata were examined using the Mann-Whitney U test, Pearson correlation coefficient, and multivariable linear regression controlled for clinicopathologic characteristics., Results and Limitations: A total of 38 921 (74%) biopsies passed quality control (14 331 GG1, 16 159 GG2, 5661 GG3, 1775 GG4, and 995 GG5). Median PPC and GC increased with sequentially higher GG. There was an increasingly positive correlation ( r ) between PPC and GC in GG2-5 prostate cancer ( r [95% confidence interval {CI}]: 0.07 [0.5, 0.8] in GG2, 0.15 [0.12, 0.17] in GG3, 0.20 [0.15, 0.24] in GG4, and 0.25 [0.19, 0.31] in GG5), with no correlation in GG1 disease ( r  = 0.01, 95% CI [-0.001, 0.03]). In multivariable linear regression, GC was significantly associated with higher PPC for GG2-5 (all p  < 0.05) but was not significantly associated with PPC for GG1. Limitations include retrospective design and a lack of final pathology from radical prostatectomy specimens., Conclusions: Higher tumor volume was associated with worse GC for GG2-5 prostate cancer, whereas tumor volume was not associated with worse GC for GG1 disease. The finding that tumor volume is not associated with worse cancer biology in GG1 disease encourages active surveillance for most patients irrespective of tumor volume., Patient Summary: We studied the relationship between prostate cancer tumor volume and cancer biology, as measured by the Decipher genomic risk score, in men who underwent prostate biopsy. We found that tumor volume was not associated with worse cancer biology for low-grade prostate cancer. Our findings reassuringly support recent guidelines to recommend active surveillance for grade group 1 prostate cancer in most patients, irrespective of tumor volume., (© 2022 The Authors.)

The NCCN Guidelines for Prostate Cancer address staging and risk assessment after a prostate cancer diagnosis and include management options for localized, regional, recurrent, and metastatic disease. The NCCN Prostate Cancer Panel meets annually to reevaluate and update their recommendations based on new clinical data and input from within NCCN Member Institutions and from external entities. These NCCN Guidelines Insights summarizes much of the panel's discussions for the 4.2022 and 1.2023 updates to the guidelines regarding systemic therapy for metastatic prostate cancer.

Context: Men of African ancestry have demonstrated markedly higher rates of prostate cancer mortality than men of other races and ethnicities around the world. In fact, the highest rates of prostate cancer mortality worldwide are found in the Caribbean and Sub-Saharan West Africa, and among men of African descent in the USA. Addressing this inequity in prostate cancer care and outcomes requires a focused research approach that creates durable solutions to address the structural, social, environmental, and health factors that create racial disparities in care and outcomes., Objective: To introduce a conceptual model for evaluating racial inequities in prostate cancer care to facilitate the development of translational research studies and interventions., Evidence Acquisition: A collaborative review of literature relevant to racial inequities in prostate cancer care and outcomes was performed. Existing literature was used to highlight various components of the conceptual model to inform future research and interventions toward equitable care and outcomes., Evidence Synthesis: Racial inequities in prostate cancer outcomes are driven by a series of structural and social determinants of health that impact exposures, mediators, and outcomes. Social determinants of equity, such as laws/policies, economic systems, and structural racism, affect the inequitable access to environmental and neighborhood exposures, in addition to health care access. Although the incidence disparity remains problematic, various studies have demonstrated parity in outcomes when social and health factors, such as access to equitable care, are normalized. Few studies have tested interventions to reduce inequities in prostate cancer among Black men., Conclusions: Worldwide, men of African ancestry demonstrate worse outcomes in prostate cancer, a phenomenon driven largely by social factors that inform biologic, environmental, and health care risks. A conceptual model was presented that organizes the many factors that influence prostate cancer incidence and mortality. Within that framework, we must understand the current state of inequities in clinical prostate cancer practice, the optimal state of what equitable practice would be, and how achieving equity in prostate cancer care balances costs, benefits, and harms. More robust characterization of the sources of prostate cancer inequities should inform testing of ambitious and innovative interventions as we work toward equity in care and outcomes., Patient Summary: Men of African ancestry demonstrate the highest rates of prostate cancer mortality, which may be reduced through social interventions. We present a framework for formalizing the identification of the drivers of prostate cancer inequities to facilitate the development of interventions and trials to eradicate them., (Published by Elsevier B.V.)

Background: Prostate cancer (PC) screening guidelines have changed over the last decade to reduce overdiagnosis and overtreatment of low-grade disease. We sought to examine and attempt to explain how changes in screening strategies have impacted temporal trends in Gleason grade group (GG) PC at diagnosis and radical prostatectomy pathology., Methods: Using the Surveillance, Epidemiology, and End Results Registry database, we identified 438 432 men with newly diagnosed PC during 2010-2018. Temporal trends in incidence of GG at biopsy, radical prostatectomy pathology, prostate-specific antigen (PSA) level, and metastasis at diagnosis were examined. The National Health Interview Survey database was examined to evaluate trends in PSA-screening rates, and a literature review evaluating magnetic resonance imaging and biomarkers utilization during this period was performed., Results: Between 2010 and 2018, the incidence of low-grade PC (GG1) decreased from 52 to 26 cases per 100 000 (P < .001). The incidence of GG1 as a proportion of all PC decreased from 47% to 32%, and the proportion of GG1 at radical prostatectomy pathology decreased from 32% to 10% (P < .001). However, metastases at diagnosis increased from 3.0% to 5.2% (P < .001). During 2010-2013, PSA screening rates in men aged 50-74 years declined from 39 to 32 per 100 men and remained stable. Utilization rates of magnetic resonance imaging and biomarkers modestly increased from 7.2% in 2012 to 17% in 2019 and 1.3% in 2012 to 13% in 2019, respectively., Conclusions: We found a significant decrease in the diagnosis and treatment of GG1 PC between 2010 and 2018. Changes in PSA screening practices appear as the primary contributor. Public health efforts should be directed toward addressing the increase in the diagnoses of metastatic PC., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: B7 homolog 3 (B7-H3) is an immunomodulatory molecule that is highly expressed in prostate cancer (PCa) and belongs to the B7 superfamily, which includes PD-L1. Immunotherapies (antibodies, antibody-drug conjugates, and chimeric antigen receptor T cells) targeting B7-H3 are currently in clinical trials; therefore, elucidating the molecular and immune microenvironment correlates of B7-H3 expression may help to guide trial design and interpretation. The authors tested the interconnected hypotheses that B7-H3 expression is associated with genetic racial ancestry, immune cell composition, and androgen receptor signaling in PCa., Methods: An automated, clinical-grade immunohistochemistry assay was developed by to digitally quantify B7-H3 protein expression across 2 racially diverse cohorts of primary PCa (1 with previously reported transcriptomic data) and pretreatment and posttreatment PCa tissues from a trial of intensive neoadjuvant hormonal therapy., Results: B7-H3 protein expression was significantly lower in self-identified Black patients and was inversely correlated with the percentage African ancestry. This association with race was independent of the significant association of B7-H3 protein expression with ERG/ETS and PTEN status. B7-H3 messenger RNA expression, but not B7-H3 protein expression, was significantly correlated with regulatory (FOXP3-positive) T-cell density. Finally, androgen receptor activity scores were significantly correlated with B7-H3 messenger RNA expression, and neoadjuvant intensive hormonal therapy was associated with a significant decrease in B7-H3 protein expression., Conclusions: The current data underscore the importance of studying racially and molecularly diverse PCa cohorts in the immunotherapy era. This study is among the first to use genetic ancestry markers to add to the emerging evidence that PCa in men of African ancestry may have a distinct biology associated with B7-H3 expression., Lay Summary: B7-H3 is an immunomodulatory molecule that is highly expressed in prostate cancer and is under investigation in clinical trials. The authors determined that B7-H3 protein expression is inversely correlated with an individual's proportion of African ancestry. The results demonstrate that B7-H3 messenger RNA expression is correlated with the density of tumor T-regulatory cells. Finally, in the first paired analysis of B7-H3 protein expression before and after neoadjuvant intensive hormone therapy, the authors determined that hormone therapy is associated with a decrease in B7-H3 protein levels, suggesting that androgen signaling may positively regulate B7-H3 expression. These results may help to guide the design of future clinical trials and to develop biomarkers of response in such trials., (© 2022 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)