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Background: The treatment paradigm for metastatic hormone-sensitive prostate cancer (mHSPC) patients is evolving. PET/CT now offers improved sensitivity and accuracy in staging. Recent randomized trial data supports escalated hormone therapy, local primary tumor therapy, and metastasis-directed therapy. The impact of combining such therapies into a multimodal approach is unknown. This Phase II single-arm clinical trial sponsored and funded by Veterans Affairs combines local, metastasis-directed, and systemic therapies to durably render patients free of detectable disease off active therapy., Methods: Patients with newly-diagnosed M1a/b prostate cancer (PSMA PET/CT staging is permitted) and 1-5 radiographically visible metastases (excluding pelvic lymph nodes) are undergoing local treatment with radical prostatectomy, limited duration systemic therapy for a total of six months (leuprolide, abiraterone acetate with prednisone, and apalutamide), metastasis-directed stereotactic body radiotherapy (SBRT), and post-operative fractionated radiotherapy if pT ≥ 3a, N1, or positive margins are present. The primary endpoint is the percent of patients achieving a serum PSA of < 0.05 ng/mL six months after recovery of serum testosterone ≥150 ng/dL. Secondary endpoints include time to biochemical progression, time to radiographic progression, time to initiation of alternative antineoplastic therapy, prostate cancer specific survival, health related quality-of-life, safety and tolerability., Discussion: To our knowledge, this is the first trial that tests a comprehensive systemic and tumor directed therapeutic strategy for patients with newly diagnosed oligometastatic prostate cancer. This trial, and others like it, represent the critical first step towards curative intent therapy for a patient population where palliation has been the norm., Trial Registration: Clinicaltrials.gov identifier: NCT03298087 (registration date: September 29, 2017).

Background: Ultrasensitive prostate-specific antigen (uPSA) has untapped potential for optimizing management following radical prostatectomy (RP) in terms of facilitating early salvage, minimizing overtreatment, and identifying those at risk of occult systemic disease., Objective: To test first postoperative uPSA for prediction of outcome in patients with adverse pathology after RP., Design, Setting, and Participants: Patients with extraprostatic extension and/or a positive margin who did not receive immediate adjuvant therapy., Outcome Measurements and Statistical Analysis: First uPSA was measured at 3 mo after RP. The study endpoints were biochemical relapse (BCR), defined as PSA ≥0.2ng/ml, bone metastasis-free survival (BMFS), prostate cancer-specific survival (PCSS), overall survival (OS), and salvage radiation therapy (SRT) success. Outcome results were compared using the Kaplan-Meier method and multivariate analysis (MVA)., Results and Limitations: The cohort consisted of 269 RP patients from 1991-2015 with median follow-up of 77 mo. Sensitivity analysis identified first postoperative uPSA of ≥0.03ng/ml as the optimal threshold for predicting BCR. First postoperative uPSA ≥0.03 versus <0.03ng/ml was associated with worse 5-yr BCR (86%, 95% confidence interval [CI] 71-93% vs 39%, 95% CI 25-51%; p<0.00001), 10-yr BMFS (75%, 95% CI 62-92% vs 95%, 95% CI 88-100%; p=0.0001), 10-yr PCSS (84%, 95% CI 73-96% vs 100%, 95% CI 100-100%; p=0.005), and 10-yr OS (81%, 95% CI 70-93% vs 98%, 95% CI 94-100%; p=0.009). On MVA, first postoperative uPSA ≥0.03ng/ml was an independent predictor of BCR (hazard ratio [HR] 9.4, 95% CI 5.8-15.4; p<0.00001) and the only predictor for BMFS (HR 9.7, 95% CI 2.1-44.6; p=0.0034), PCSS (HR 13.5, 95% CI 1.7-107.9; p=0.014), and OS (HR 5.0, 95% CI 1.4-18.3; p=0.014). Following SRT, first postoperative uPSA ≥0.03ng/ml independently predicted worse BMFS (HR 5.9, 95% CI 1.3-26.9; p=0.021), PCSS (HR 6.9, 95% CI 0.9-55.8; p=0.07), and OS (4.5, 95% CI 1.0-20.1; p=0.057). Limitations include the retrospective design and potential selection bias., Conclusions: First postoperative uPSA ≥0.03ng/ml independently predicts BCR, BMFS, PCSS, and OS better than traditional risk factors. SRT alone may be insufficient for patients with high-risk disease when first postoperative uPSA is ≥0.03ng/ml., Patient Summary: When the first postprostatectomy ultrasensitive prostate-specific antigen level is ≥0.03ng/ml, patients are at higher risk of recurrent and occult prostate cancer. They should be considered for early salvage radiotherapy, possibly with hormone therapy., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objectives: To examine the impact of positive surgical margin (PSM) laterality on failure after radical prostatectomy (RP). A PSM can influence local recurrence and outcomes after salvage radiation. Unlike intrinsic risk factors, a PSM is caused by intervention and thus iatrogenic failures may be elucidated by analyzing margin laterality as surgical approach is itself lateralized., Patients and Methods: We reviewed 226 RP patients between 1991 and 2013 with PSM. Data includes operation type, pre/postoperative PSA, surgical pathology, and margin type (location, focality, laterality). The median follow-up was 47 months. Biochemical recurrence after RP was defined as PSA≥0.1 ng/mL or 2 consecutive rises above nadir. Ninety-two patients received salvage radiation therapy (SRT). Failure after SRT was defined as any PSA≥0.2 ng/mL or greater than presalvage. Kaplan-Meier and Cox multivariate analyses compared relapse rates., Results: The majority of PSM were iatrogenic (58%). Laterality was associated with differences in median relapse: right 20 versus left 51 versus bilateral 14 months (P<0.01). Preoperative PSA, T-stage, Gleason grade, and laterality were associated with biochemical progression on univariate and multivariate analyses. Right-sided margins were more likely to progress than left (hazard ratio, 1.67; P=0.04). More right-sided margins were referred for SRT (55% right vs. 23% left vs. 22% bilateral), but were equally salvaged. Only T-stage and pre-SRT PSA independently influenced SRT success., Conclusions: Most PSM are iatrogenic, with right-sided more likely to progress (and sooner) than left sided. Margin laterality is a heretofore unrecognized independent predictor of biochemical relapse and hints at the need to modify the traditional unilateral surgical technique.

Purpose of Review: Novel tools have become available to the practicing urologist in recent years that endeavor to improve on commonly utilized prostate cancer (PCa) risk-stratification techniques. In this review, we provide an overview of these modalities in the context of active surveillance., Recent Findings: Multiparametric MRI (MP-MRI) has a rapidly growing body of evidence that suggests it provides the necessary sensitivity and negative predictive value to rule out clinically significant disease. MRI-guided targeted biopsy has the potential to improve detection of clinically significant cancers and for rebiopsy of patients with continued suspicion for PCa. Prostate-specific antigen isoforms and Prostate Health Index outperform PSA alone and improve risk stratification when combined with the established criteria, but need further prospective studies using template and MRI-targeted biopsies. Urinary biomarkers tend to fall short in predicting adverse pathology when used alone, but improve risk stratification when used in conjunction and with the established criteria. Finally, tissue biomarkers and gene assays allow patient-specific molecular and genetic characterization of cancer phenotype, showing significant promise in predicting adverse pathology, and in some cases have already been incorporated into and altered clinical practice., Summary: These novel modalities show remarkable promise in improving the risk stratification of patients with PCa, and as the body of evidence grows will likely become incorporated into major oncologic guidelines and standard urologic practice. Further prospective clinical studies are needed, as well as analysis of cost-effectiveness.

Purpose: Integrating ultrasensitive prostate specific antigen with surveillance in patients at high risk after radical prostatectomy potentially optimizes treatment by correctly identifying recurrence, promoting an early salvage strategy and minimizing overtreatment. We tested the power of postoperative ultrasensitive prostate specific antigen to identify eventual biochemical failure., Materials and Methods: We identified 247 patients at high risk with a median followup of 44 months who underwent radical prostatectomy from 1991 to 2013. Each patient had extraprostatic extension and/or a positive margin. Surgical technique, initial prostate specific antigen, pathology findings and postoperative prostate specific antigen were analyzed. The ultrasensitive prostate specific antigen assay threshold was 0.01 ng/ml. Conventional biochemical relapse was defined as prostate specific antigen 0.2 ng/ml or greater. Kaplan-Meier and Cox multivariate analyses were done to compare the rates of ultrasensitive prostate specific antigen recurrence and conventional biochemical relapse., Results: Sensitivity analysis revealed that ultrasensitive prostate specific antigen 0.03 ng/ml or greater was the optimal threshold to identify recurrence. A first postoperative ultrasensitive value of 0.03 ng/ml or greater, Gleason grade, T stage, initial prostate specific antigen and margin status predicted conventional biochemical relapse. On multivariate analysis only a first postoperative ultrasensitive value of 0.03 ng/ml or greater, Gleason grade and T stage independently predicted conventional biochemical relapse. First postoperative ultrasensitive prostate specific antigen 0.03 ng/ml or greater conferred the highest risk (HR 8.5, p < 0.0001) and identified conventional biochemical relapse with greater sensitivity than undetectable first conventional prostate specific antigen (70% vs 46%). Any postoperative prostate specific antigen 0.03 ng/ml or greater captured all failures missed by the first postoperative value (100% sensitivity) with accuracy (96% specificity). Defining failure at an ultrasensitive value of 0.03 ng/ml or greater yielded a median lead time advantage of 18 months (mean 24) over the conventional definition of prostate specific antigen 0.2 ng/ml or greater., Conclusions: Ultrasensitive prostate specific antigen 0.03 ng/ml or greater is an independent factor that identifies biochemical relapse more accurately than any traditional risk factors and confers a significant lead time advantage. This factor enables critical decisions on the timing of and indication for postoperative radiotherapy in patients at high risk after radical prostatectomy., (Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Conventional biopsy fails to detect the presence of some prostate cancers (PCas). Men with a prior negative biopsy but persistently elevated prostate-specific antigen (PSA) pose a diagnostic dilemma, as some harbor elusive cancer., Objective: To determine whether use of magnetic resonance-ultrasound (MR-US) fusion biopsy results in improved detection of PCa compared to repeat conventional biopsy., Design, Setting, and Participants: In a consecutive-case series, 105 subjects with prior negative biopsy and elevated PSA values underwent multiparametric magnetic resonance imaging (MRI) and fusion biopsy in an outpatient setting., Intervention: Suspicious areas on multiparametric MRI were delineated and graded by a radiologist; MR-US fusion biopsy was performed by a urologist using the Artemis device; targeted and systematic biopsies were obtained regardless of MRI result., Outcome Measurements and Statistical Analysis: Detection rates of all PCa and clinically significant PCa (Gleason ≥3+4 or Gleason 6 with maximal cancer core length ≥4 mm) were determined. The yield of targeted biopsy was compared to systematic biopsy. The ability of an MRI grading system to predict clinically significant cancer was investigated. Stepwise multivariate logistic regression analysis was performed to determine predictors of significant cancer on biopsy., Results and Limitations: Fusion biopsy revealed PCa in 36 of 105 men (34%; 95% confidence interval [CI], 25-45). Seventy-two percent of men with PCa had clinically significant disease; 21 of 23 men (91%) with PCa on targeted biopsy had significant cancer compared to 15 of 28 (54%) with systematic biopsy. Degree of suspicion on MRI was the most powerful predictor of significant cancer on multivariate analysis. Twelve of 14 (86%) subjects with a highly suspicious MRI target were diagnosed with clinically significant cancer., Conclusions: MR-US fusion biopsy provides improved detection of PCa in men with prior negative biopsies and elevated PSA values. Most cancers found were clinically significant., (Copyright © 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Madin-Darby canine kidney (MDCK) cells are immortalized epithelial cells that have been used extensively as a model system to study intracellular molecular trafficking, polarized expression, and secretion of proteins in various epithelia. In order to determine if MDCK cells might serve as a model to study molecular events within prostate epithelial cells, we have evaluated the polarized distribution of three prostate restricted proteins, PSMA, PSCA, and PSA, in situ, and in MDCK cells., Methods: Using immunofluorescence, confocal microscopy, cell surface biotinylation, antibody internalization, and biochemical assays we evaluated surface expression and secretion of three prostate restricted proteins expressed in MDCK cells. We compared these patterns of expression to results observed within prostatic epithelium., Results: We demonstrate that PSMA is localized primarily to the apical plasma membrane in both the prostatic epithelium and transfected MDCK cells, whereas PSCA is expressed in a non-polarized fashion. We also show that PSA is secreted predominantly from the apical surface of transfected MDCK cells, consistent with in vivo observations., Conclusions: Similar patterns of localization among MDCK and prostatic epithelial cells suggest that the mechanisms of polarized sorting within these cell types are conserved. Thus, MDCK cells offer a useful model system to study mechanisms of targeting of these proteins within the prostate., (Copyright 2003 Wiley-Liss, Inc.)

Purpose: p27 is an important cell cycle regulator, and decreased expression in radical prostatectomy specimens is associated with an increased risk of prostate specific antigen (PSA) failure. To our knowledge no prior study has shown that preoperative p27 status independently predicts recurrence after radical prostatectomy., Materials and Methods: The prostate needle biopsy specimens of 161 men treated with radical prostatectomy were examined for p27 expression using immunohistochemistry. Various p27 cut points were examined for their ability to separate patients into groups with different risk for time to biochemical recurrence following radical prostatectomy. The best p27 cut point was compared to other clinical variables (PSA, clinical stage, age, biopsy Gleason score and percent of prostate needle biopsy with cancer) on multivariate analysis to determine which variables independently predicted biochemical failure., Results: A p27 cut point of less than 45% positive staining cells resulted in significant preoperative risk stratification for time to PSA failure (HR 2.41, p = 0.010). On multivariate analysis serum PSA (HR 1.04, p = 0.011), biopsy Gleason score (HR 1.51, p = 0.011), percent of biopsy tissue with cancer (HR 10.01, p = 0.001) and less than 45% p27 positive cells (HR 2.44, p = 0.014) were all independent predictors of biochemical recurrence., Conclusions: Preoperative p27 expression is an independent predictor of time to biochemical recurrence following radical prostatectomy. Patients with less than 45% p27 positive cells in the prostate needle biopsy specimen have almost a 2.5-fold increased risk of biochemical recurrence. To our knowledge this study is the first to show that p27 status of the prostate needle biopsy specimen can be used before radical prostatectomy to predict biochemical failure.

Opinion statementPSMA-PET has been a practice-changing imaging biomarker for the management of men with PCa. Research suggests improved accuracy over conventional imaging and other PET radiotracers in many contexts. With multiple approved PSMA-targeting radiotracers, PSMA PET will become even more available in clinical practice. Its increased use requires an understanding of the prospective data available and caution when extrapolating from prior trial data that utilized other imaging modalities. Future trials leveraging PSMA PET for treatment optimization and management decision-making will ultimately drive its clinical utility.

PurposeThe sequencing of androgen-deprivation therapy (ADT) with radiotherapy (RT) may affect outcomes for prostate cancer in an RT-field size-dependent manner. Herein, we investigate the impact of ADT sequencing for men receiving ADT with prostate-only RT (PORT) or whole-pelvis RT (WPRT).Materials and methodsIndividual patient data from 12 randomized trials that included patients receiving neoadjuvant/concurrent or concurrent/adjuvant short-term ADT (4-6 months) with RT for localized disease were obtained from the Meta-Analysis of Randomized trials in Cancer of the Prostate consortium. Inverse probability of treatment weighting (IPTW) was performed with propensity scores derived from age, initial prostate-specific antigen, Gleason score, T stage, RT dose, and mid-trial enrollment year. Metastasis-free survival (primary end point) and overall survival (OS) were assessed by IPTW-adjusted Cox regression models, analyzed independently for men receiving PORT versus WPRT. IPTW-adjusted Fine and Gray competing risk models were built to evaluate distant metastasis (DM) and prostate cancer-specific mortality.ResultsOverall, 7,409 patients were included (6,325 neoadjuvant/concurrent and 1,084 concurrent/adjuvant) with a median follow-up of 10.2 years (interquartile range, 7.2-14.9 years). A significant interaction between ADT sequencing and RT field size was observed for all end points (P interaction < .02 for all) except OS. With PORT (n = 4,355), compared with neoadjuvant/concurrent ADT, concurrent/adjuvant ADT was associated with improved metastasis-free survival (10-year benefit 8.0%, hazard ratio [HR], 0.65; 95% CI, 0.54 to 0.79; P < .0001), DM (subdistribution HR, 0.52; 95% CI, 0.33 to 0.82; P = .0046), prostate cancer-specific mortality (subdistribution HR, 0.30; 95% CI, 0.16 to 0.54; P < .0001), and OS (HR, 0.69; 95% CI, 0.57 to 0.83; P = .0001). However, in patients receiving WPRT (n = 3,049), no significant difference in any end point was observed in regard to ADT sequencing except for worse DM (HR, 1.57; 95% CI, 1.20 to 2.05; P = .0009) with concurrent/adjuvant ADT.ConclusionADT sequencing exhibits a significant impact on clinical outcomes with a significant interaction with field size. Concurrent/adjuvant ADT should be the standard of care where short-term ADT is indicated in combination with PORT.

The androgen receptor (AR) antagonist enzalutamide is one of the principal treatments for men with castration-resistant prostate cancer (CRPC). However, not all patients respond, and resistance mechanisms are largely unknown. We hypothesized that genomic and transcriptional features from metastatic CRPC biopsies prior to treatment would be predictive of de novo treatment resistance. To this end, we conducted a phase II trial of enzalutamide treatment (160 mg/d) in 36 men with metastatic CRPC. Thirty-four patients were evaluable for the primary end point of a prostate-specific antigen (PSA)50 response (PSA decline ≥50% at 12 wk vs. baseline). Nine patients were classified as nonresponders (PSA decline

BackgroundInnovations in treatments, imaging, and molecular characterisation in advanced prostate cancer have improved outcomes, but there are still many aspects of management that lack high-level evidence to inform clinical practice. The Advanced Prostate Cancer Consensus Conference (APCCC) 2019 addressed some of these topics to supplement guidelines that are based on level 1 evidence.ObjectiveTo present the results from the APCCC 2019.Design, setting, and participantsSimilar to prior conferences, experts identified 10 important areas of controversy regarding the management of advanced prostate cancer: locally advanced disease, biochemical recurrence after local therapy, treating the primary tumour in the metastatic setting, metastatic hormone-sensitive/naïve prostate cancer, nonmetastatic castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, bone health and bone metastases, molecular characterisation of tissue and blood, inter- and intrapatient heterogeneity, and adverse effects of hormonal therapy and their management. A panel of 72 international prostate cancer experts developed the programme and the consensus questions.Outcome measurements and statistical analysisThe panel voted publicly but anonymously on 123 predefined questions, which were developed by both voting and nonvoting panel members prior to the conference following a modified Delphi process.Results and limitationsPanellists voted based on their opinions rather than a standard literature review or formal meta-analysis. The answer options for the consensus questions had varying degrees of support by the panel, as reflected in this article and the detailed voting results reported in the Supplementary material.ConclusionsThese voting results from a panel of prostate cancer experts can help clinicians and patients navigate controversial areas of advanced prostate management for which high-level evidence is sparse. However, diagnostic and treatment decisions should always be individualised based on patient-specific factors, such as disease extent and location, prior lines of therapy, comorbidities, and treatment preferences, together with current and emerging clinical evidence and logistic and economic constraints. Clinical trial enrolment for men with advanced prostate cancer should be strongly encouraged. Importantly, APCCC 2019 once again identified important questions that merit assessment in specifically designed trials.Patient summaryThe Advanced Prostate Cancer Consensus Conference provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference, which has been held three times since 2015, aims to share the knowledge of world experts in prostate cancer management with health care providers worldwide. At the end of the conference, an expert panel discusses and votes on predefined consensus questions that target the most clinically relevant areas of advanced prostate cancer treatment. The results of the voting provide a practical guide to help clinicians discuss therapeutic options with patients as part of shared and multidisciplinary decision making.

BackgroundMetastatic castration-resistant prostate cancer (mCRPC) is the lethal form of the disease. Several recent studies have identified genomic alterations in mCRPC, but the clinical implications of these genomic alterations have not been fully elucidated.ObjectiveTo use whole-genome sequencing (WGS) to assess the association between key driver gene alterations and overall survival (OS), and to use whole-transcriptome RNA sequencing to identify genomic drivers of enzalutamide resistance.Design, setting, and participantsWe performed survival analyses and gene set enrichment analysis (GSEA) on WGS and RNA sequencing results for a cohort of 101 mCRPC patients.Outcome measurements and statistical analysisOS was the clinical endpoint for all univariate and multivariable survival analyses. Candidate drivers of enzalutamide resistance were identified in an unbiased manner, and mutations of the top candidate were further assessed for enrichment among enzalutamide-resistant patients using Fisher's exact test.Results and limitationsHarboring two DNA alterations in RB1 was independently predictive of poor OS (median 14.1 vs 42.0mo; p=0.007) for men with mCRPC. GSEA identified the Wnt/β-catenin pathway as the top differentially modulated pathway among enzalutamide-resistant patients. Furthermore, β-catenin mutations were exclusive to enzalutamide-resistant patients (p=0.01) and independently predictive of poor OS (median 13.6 vs 41.7mo; p=0.025).ConclusionsThe presence of two RB1 DNA alterations identified in our WGS analysis was independently associated with poor OS among men with mCRPC. The Wnt/β-catenin pathway plays an important role in enzalutamide resistance, with differential pathway expression and enrichment of β-catenin mutations in enzalutamide-resistant patients. Moreover, β-catenin mutations were predictive of poor OS in our cohort.Patient summaryWe observed a correlation between genomic findings for biopsy samples from metastases from men with metastatic castration-resistant prostate cancer (mCRPC) and clinical outcomes. This work sheds new light on clinically relevant genomic alterations in mCRPC and provides a roadmap for the development of new personalized treatment regimens in mCRPC.

BackgroundNational Comprehensive Cancer Network guidelines consider 18F-fluciclovine PET-CT for prostate cancer biochemical recurrence localisation after radical prostatectomy, whereas European Association of Urology guidelines recommend prostate-specific membrane antigen (PSMA) PET-CT. To the best of our knowledge, no prospective head-to-head comparison between these tests has been done so far. The aim of this study was to compare prospectively paired 18F-fluciclovine and PSMA PET-CT scans for localising biochemical recurrence of prostate cancer after radical prostatectomy in patients with low prostate-specific antigen (PSA) concentrations (

PurposeTo evaluate 3T mpMRI characteristics of transition zone and peripheral zone index prostate cancer lesions stratified by Gleason Score and PI-RADSv2 with whole mount histopathology correlation.MethodsAn institution review board-approved, HIPAA-compliant single-arm observational study of 425 consecutive men with 3T mpMRI prior to radical prostatectomy from December 2009 to October 2016 was performed. A genitourinary radiologist and a genitourinary pathologist matched all lesions detected on whole mount histopathology with lesions concordant for size and location on 3T mpMRI. Differences in clinical, MRI parameters, and histopathology between transition zone and peripheral zone were determined and analyzed with χ2 and Mann-Whitney U test. AUC was measured.Results3T mpMRI detected 248/323 (76.7%) index lesions in peripheral zone and 75/323 (23.2%) in transition zone. Transition zone prostate cancer had higher median prostate-specific antigen (p = 0.001), larger tumor on 3T mpMRI (p = 0.001), lower proportions of PI-RADSv2 category 4 and 5 (p

PurposeWe sought to identify the clinical and magnetic resonance imaging variables predictive of biochemical recurrence after robotic assisted radical prostatectomy in patients who underwent multiparametric 3 Tesla prostate magnetic resonance imaging.Materials and methodsWe performed an institutional review board approved, HIPAA (Health Insurance Portability and Accountability Act) compliant, single arm observational study of 3 Tesla multiparametric magnetic resonance imaging prior to robotic assisted radical prostatectomy from December 2009 to March 2016. Clinical, magnetic resonance imaging and pathological information, and clinical outcomes were compiled. Biochemical recurrence was defined as prostate specific antigen 0.2 ng/cc or greater. Univariate and multivariate regression analysis was performed.ResultsBiochemical recurrence had developed in 62 of the 255 men (24.3%) included in the study at a median followup of 23.5 months. Compared to the subcohort without biochemical recurrence the subcohort with biochemical recurrence had a greater proportion of patients with a high grade biopsy Gleason score, higher preoperative prostate specific antigen (7.4 vs 5.6 ng/ml), intermediate and high D'Amico classifications, larger tumor volume on magnetic resonance imaging (0.66 vs 0.30 ml), higher PI-RADS® (Prostate Imaging-Reporting and Data System) version 2 category lesions, a greater proportion of intermediate and high grade radical prostatectomy Gleason score lesions, higher pathological T3 stage (all p

BackgroundThe current study was conducted to evaluate the performance of magnetic resonance (MR)-ultrasound-guided fusion biopsy in diagnosing clinically significant prostate cancer (csCaP).MethodsA total of 1042 men underwent multiparametric MR imaging (mpMRI) and fusion biopsy consecutively in a prospective trial (2009-2014). An expert reader graded mpMRI regions of interest (ROIs) as 1 to 5 using published protocols. The fusion biopsy device was used to obtain targeted cores from ROIs (when present) followed by a fusion image-guided, 12-core systematic biopsy in all men, even if no suspicious ROI was noted. The primary endpoint of the study was the detection of csCaP (ie, Gleason score ≥ 7).ResultsAmong 825 men with ≥ 1 suspicious ROI of ≥ grade 3, 289 (35%) were found to have csCaP. Powerful predictors of csCaP were ROI grade (grade 5 vs grade 3: odds ratio, 6.5 [P

PurposeIntegrating ultrasensitive prostate specific antigen with surveillance in patients at high risk after radical prostatectomy potentially optimizes treatment by correctly identifying recurrence, promoting an early salvage strategy and minimizing overtreatment. We tested the power of postoperative ultrasensitive prostate specific antigen to identify eventual biochemical failure.Materials and methodsWe identified 247 patients at high risk with a median followup of 44 months who underwent radical prostatectomy from 1991 to 2013. Each patient had extraprostatic extension and/or a positive margin. Surgical technique, initial prostate specific antigen, pathology findings and postoperative prostate specific antigen were analyzed. The ultrasensitive prostate specific antigen assay threshold was 0.01 ng/ml. Conventional biochemical relapse was defined as prostate specific antigen 0.2 ng/ml or greater. Kaplan-Meier and Cox multivariate analyses were done to compare the rates of ultrasensitive prostate specific antigen recurrence and conventional biochemical relapse.ResultsSensitivity analysis revealed that ultrasensitive prostate specific antigen 0.03 ng/ml or greater was the optimal threshold to identify recurrence. A first postoperative ultrasensitive value of 0.03 ng/ml or greater, Gleason grade, T stage, initial prostate specific antigen and margin status predicted conventional biochemical relapse. On multivariate analysis only a first postoperative ultrasensitive value of 0.03 ng/ml or greater, Gleason grade and T stage independently predicted conventional biochemical relapse. First postoperative ultrasensitive prostate specific antigen 0.03 ng/ml or greater conferred the highest risk (HR 8.5, p < 0.0001) and identified conventional biochemical relapse with greater sensitivity than undetectable first conventional prostate specific antigen (70% vs 46%). Any postoperative prostate specific antigen 0.03 ng/ml or greater captured all failures missed by the first postoperative value (100% sensitivity) with accuracy (96% specificity). Defining failure at an ultrasensitive value of 0.03 ng/ml or greater yielded a median lead time advantage of 18 months (mean 24) over the conventional definition of prostate specific antigen 0.2 ng/ml or greater.ConclusionsUltrasensitive prostate specific antigen 0.03 ng/ml or greater is an independent factor that identifies biochemical relapse more accurately than any traditional risk factors and confers a significant lead time advantage. This factor enables critical decisions on the timing of and indication for postoperative radiotherapy in patients at high risk after radical prostatectomy.

Background: Hemiablation is a less morbid treatment alternative for appropriately selected patients with unilateral prostate cancer (PCa). However, to the authors' knowledge, traditional diagnostic techniques inadequately identify appropriate candidates. In the current study, the authors quantified the accuracy for identifying hemiablation candidates using contemporary diagnostic techniques, including multiparametric magnetic resonance imaging (mpMRI) and MRI‐fusion with complete systematic template biopsy. Methods: A retrospective analysis of patients undergoing MRI and MRI‐fusion prostate biopsy, including full systematic template biopsy, prior to radical prostatectomy in a single tertiary academic institution between June 2010 and February 2018 was performed. Hemiablation candidates had unilateral intermediate‐risk PCa (Gleason score [GS] of 3+4 or 4+3, clinical T classification ≤T2, and prostate‐specific antigen level <20 ng/dL) on MRI‐fusion biopsy and 2) no contralateral highly or very highly suspicious Prostate Imaging Reporting and Data System version 2 (PI‐RADSv2) MRI lesions. Hemiablation candidates were inappropriately selected if pathologists identified contralateral GS ≥3+4 or high‐risk ipsilateral PCa on prostatectomy. The authors tested a range of hemiablation inclusion criteria and performed multivariable analysis of preoperative predictors of undetected contralateral disease. Results: Of 665 patients, 92 met primary hemiablation criteria. Of these 92 patients, 44 (48%) were incorrectly identified due to ipsilateral GS ≥3+4 tumors crossing the midline (21 patients), undetected distinct contralateral GS ≥3+4 tumors (20 patients), and/or ipsilateral high‐risk PCa (3 patients) on prostatectomy. The rate of undetected contralateral disease ranged from 41% to 48% depending on inclusion criteria. On multivariable analysis, men with anterior index tumors were found to be 2.4 times more likely to harbor undetected contralateral GS ≥3+4 PCa compared with men with posterior lesions (P < .05). Conclusions: Clinicians and patients must weigh the risk of inadequate oncologic treatment against the functional benefits of hemiablation. Further investigation into methods for improving patient selection for hemiablation is necessary. Even with contemporary diagnostic techniques, including magnetic resonance imaging (MRI), MRI‐fusion biopsy, and systematic template biopsy, appropriately identifying unilateral prostate cancer remains difficult. Nearly one‐half of hemiablation candidates based on preoperative radiographic, clinical, and pathologic factors harbored pathology, making them inappropriate for hemiablation in their radical prostatectomy specimen. [ABSTRACT FROM AUTHOR]

Purpose We assessed focal therapy eligibility in men who underwent multiparametric magnetic resonance imaging and targeted biopsy with correlation to whole mount histology after radical prostatectomy. Materials and Methods Subjects were selected from among the 454 men in whom targeted biopsy proven prostate cancer was derived from regions of interest on multiparametric magnetic resonance imaging from 2010 to 2016. Focal therapy eligibility was limited to a maximum Gleason score of 4 + 3 in regions of interest with or without other foci of low risk prostate cancer (Gleason score 3 + 3 and less than 4 mm). Men who did not meet NCCN® intermediate risk criteria were classified as ineligible for focal therapy. Of the 454 men 64 underwent radical prostatectomy and biopsy findings were compared to final pathology findings. Results Of the 454 men with a biopsy proven region of interest 175 (38.5%) were eligible for focal therapy. Fusion biopsy, which combined targeted and template biopsy, had 80.0% sensitivity (12 of 15 cases), 73.5% specificity (36 of 49) and 75.0% accuracy (48 of 64) for focal therapy eligibility. Targeted cores alone yielded 73.3% sensitivity (11 of 15 cases), 47.9% specificity (23 of 48) and 54.7% accuracy (35 of 64). Gleason score and extension across the midline differed in 4 and 9, respectively, of the 13 cases that showed discordant biopsy and whole mount histology. Conclusions Using intermediate risk eligibility criteria more than a third of men with a targeted biopsy proven lesion identified on multiparametric magnetic resonance imaging would have been eligible for focal therapy. Eligibility determined by fusion biopsy was concordant with whole mount histology in 75% of cases. Improved selection criteria are needed to reliably determine focal therapy eligibility. [ABSTRACT FROM AUTHOR]

Purpose Salvage radiotherapy (SRT) is the standard of care offered when postprostatectomy prostatespecific antigen (PSA) levels are ≥ 0.2 ng/mL. However, emerging evidence suggests that early SRT (ie, SRT delivered at PSA values < 0.2 ng/mL, but generally ≥ 0.05 ng/mL) improves oncologic outcomes. We evaluated the feasibility of improving referral rates for discussion of early SRT by using a dynamic registry that identifies through the electronic medical record patients with rising postprostatectomy PSA levels. Methods We developed an iteratively updated registry that identifies patients who fall within two postoperative PSA strata: ≥ 0.05 to < 0.1 ng/mL and ≥ 0.1 to < 0.2 ng/mL. We compared referral rates to radiation oncology during a 3-year period before use of this registry with those during a 1-year period after promotion of the registry in multidisciplinary tumor board settings. Results Before promotion of the registry, referral rates for patients with PSA values ≥ 0.05 to < 0.1 ng/mL and ≥ 0.1 to < 0.2 ng/mL were 35% and 65%, respectively. After promotion of the registry, referral rates within each stratum increased significantly to 82% and 94%, respectively (P < .05 for both by Fisher's exact test). The overall rate of referral for patients with PSA values ≥ 0.05 to < 0.2 ng/mL rose from 48% to 90% (P < .001). Conclusion The creation of a registry of patients with rising postprostatectomy PSA values can facilitate increased referral rates for early SRT without burdening providers with a clinical support tool embedded within the EMR itself. This is true even in the case of already high baseline rates of referral for early SRT. The changes reported herein most likely reflect a Hawthorne effect wherein the ability to track referrals rather than a direct function of the registry influenced practice patterns. Nonetheless, the registry provided an integral framework to allow for tracking. [ABSTRACT FROM AUTHOR]

Prostate cancer is a common malignancy in men, but its management is fraught with controversy owing to its variable biologic and clinical behavior. Despite evidence that PSA screening reduces prostate cancer specific metastasis and death, it has not gained acceptance by various health authorities. Nevertheless, recent advances in biomarker development potentially address many of the shortcomings of routine PSA testing alone, including improved specificity for the detection of clinically significant cancer, optimized risk stratification to aid clinical management decisions, and discovery of genetic variants that may guide optimized therapy of advanced disease. [ABSTRACT FROM AUTHOR]

The integration of prostate-specific membrane antigen positron emission tomography to the presurgical risk assessment improves the performance and reduces the difference with the postsurgical reference standard for biochemical recurrence–free survival risk assessment of patients with intermediate- to high-risk prostate cancer treated with radical prostatectomy and pelvic lymph node dissection. In the initial staging of patients with high-risk prostate cancer (PCa), prostate-specific membrane antigen positron emission tomography (PSMA-PET) has been established as a front-line imaging modality. The increasing number of PSMA-PET scans performed in the primary staging setting might be associated with decreases in biochemical recurrence (BCR)-free survival (BCR-FS). To assess the added prognostic value of presurgical PSMA-PET for BCR-FS compared with the presurgical Cancer of the Prostate Risk Assessment (CAPRA) and postsurgical CAPRA-Surgery (CAPRA-S) scores in patients with intermediate- to high-risk PCa treated with radical prostatectomy (RP) and pelvic lymph node dissection. This is a follow-up study of the surgical cohort evaluated in the multicenter prospective phase 3 imaging trial (n = 277; NCT03368547, NCT02611882, and NCT02919111). Each 68Ga-PSMA-11-PET scan was read by three blinded independent readers. PSMA-PET prostate uptake (low vs high), PSMA-PET extraprostatic disease (N1/M1), and CAPRA and CAPRA-S scores were used to assess the risk of BCR. Patients were followed after RP by local investigators using electronic medical records. BCR was defined by a prostate-specific antigen (PSA) level increasing to ≥0.2 ng/ml after RP or initiation of PCa-specific secondary treatment (>6 mo after surgery). Univariate and multivariable Cox models, and c-statistic index were performed to assess the prognostic value of PSMA-PET and for a comparison with the CAPRA and CAPRA-S scores. From December 2015 to December 2019, 277 patients underwent surgery after PSMA-PET. Clinical follow-up was obtained in 240/277 (87%) patients. The median follow-up after surgery was 32.4 (interquartile range 23.3–42.9) mo. Of 240 BCR events, 91 (38%) were observed. PSMA-PET N1/M1 was found in 41/240 (17%) patients. PSMA-PET prostate uptake, PSMA-PET N1/M1, and CAPRA and CAPRA-S scores were significant univariate predictors of BCR. The addition of PSMA-PET N1/M1 status to the presurgical CAPRA score improved the risk assessment for BCR significantly in comparison with the presurgical CAPRA score alone (c-statistic 0.70 [0.64–0.75] vs 0.63 [0.57–0.69]; p < 0.001). The C-index of the postsurgical model utilizing the postsurgical CAPRA-S score alone was not significantly different from the presurgical model combining the presurgical CAPRA score and PSMA-PET N1/M1 status (p = 0.19). Presurgical PSMA-PET was a strong prognostic biomarker improving BCR-FS risk assessment. Its implementation in the presurgical risk assessment with the CAPRA score improved the performance and reduced the difference with the reference standard (postsurgical CAPRA-S score). The use prostate-specific membrane antigen positron emission tomography improved the assessment of biochemical recurrence risk in patients with intermediate- and high-risk prostate cancer who were treated with radical prostatectomy and pelvic lymph node dissection. [ABSTRACT FROM AUTHOR]

Postoperative radiation therapy (RT) is an underused standard-of-care intervention for patients with prostate cancer and recurrence/adverse pathologic features after radical prostatectomy. Although stereotactic body RT (SBRT) is a well-studied and convenient option for definitive treatment, data on the postprostatectomy setting are extremely limited. The purpose of this study was to evaluate short-term physician-scored genitourinary (GU) and gastrointestinal (GI) toxicities and patient-reported outcomes after postprostatectomy SBRT. The SCIMITAR trial was a phase 2, dual-center, open-label, single-arm trial that enrolled patients with postoperative prostate-specific antigen >0.03 ng/mL or adverse pathologic features. Coprimary endpoints were 4-year biochemical recurrence–free survival, physician-scored acute and late GU and GI toxicities by the Common Terminology Criteria for Adverse Events (version 4.03) scale, and patient-reported quality-of-life (QOL) outcomes, as represented by the Expanded Prostate Cancer Index-26 and the International Prostate Symptom Score. Patients received SBRT 30 to 34 Gy/5 fractions to the prostate bed ± bed boost ± pelvic nodes with computed tomography (CTgRT) or magnetic resonance imaging guidance (MRgRT) in a nonrandomized fashion. Physician-scored toxicities and patient-reported QOL outcomes were collected at baseline and at 1, 3, and 6 months of follow-up. Univariable and multivariable analyses were performed to evaluate predictors of toxicities and QOL outcomes. One hundred participants were enrolled (CTgRT, n = 69; MRgRT, n = 31). The median follow-up was 29.5 months (CTgRT: 33.3 months, MRgRT: 22.6 months). The median (range) prostate bed dose was 32 (30-34) Gy. Acute and late grade 2 GU toxicities were both 9% while acute and late grade 2 GI toxicities were 5% and 0%, respectively. Three patients had grade 3 toxicity (n = 1 GU, n = 2 GI). No patient receiving MRgRT had grade 3 GU or grade ≥2 GI toxicity. Compared with CTgRT, MRgRT was associated with a 30.5% (95% confidence interval, 11.6%-49.5%) reduction in any-grade acute GI toxicity (P =.006). MRgRT was independently associated with improved any-grade GI toxicity and improved bowel QOL. Postprostatectomy SBRT was well tolerated at short-term follow-up. MRgRT may decrease GI toxicity. Longer toxicity and/or efficacy follow-up and randomized studies are needed. [ABSTRACT FROM AUTHOR]

Background: National Comprehensive Cancer Network guidelines consider 18F-fluciclovine PET-CT for prostate cancer biochemical recurrence localisation after radical prostatectomy, whereas European Association of Urology guidelines recommend prostate-specific membrane antigen (PSMA) PET-CT. To the best of our knowledge, no prospective head-to-head comparison between these tests has been done so far. The aim of this study was to compare prospectively paired 18F-fluciclovine and PSMA PET-CT scans for localising biochemical recurrence of prostate cancer after radical prostatectomy in patients with low prostate-specific antigen (PSA) concentrations (<2·0 ng/mL).Methods: This was a prospective, single-centre, open-label, single-arm comparative study done at University of California Los Angeles (Los Angeles, CA, USA). Patients older than 18 years of age with prostate cancer biochemical recurrence after radical prostatectomy and PSA levels ranging from 0·2 to 2·0 ng/mL without any prior salvage therapy and with a Karnofsky performance status of at least 50 were eligible. Patients underwent 18F-fluciclovine (reference test) and PSMA (index test) PET-CT scans within 15 days. Detection rate of biochemical recurrence at the patient level and by anatomical region was the primary endpoint. A statistical power analysis demonstrated that a sample size of 50 patients was needed to show a 22% difference in detection rates in favour of PSMA (test for superiority). Each PET scan was interpreted by three independent masked readers and a consensus majority interpretation was generated (two vs one) to determine positive findings. This study is registered with ClinicalTrials.gov, number NCT02940262, and is complete.Findings: Between Feb 26, 2018, and Sept 20, 2018, 143 patients were screened for eligibility, of whom 50 patients were enrolled into the study. Median follow-up was 8 months (IQR 7-9). The primary endpoint was met; detection rates were significantly lower with 18F-fluciclovine PET-CT (13 [26%; 95% CI 15-40] of 50) than with PSMA PET-CT (28 [56%; 41-70] of 50), with an odds ratio (OR) of 4·8 (95% CI 1·6-19·2; p=0·0026) at the patient level; in the subanalysis of the pelvic nodes region (four [8%; 2-19] with 18F-fluciclovine vs 15 [30%; 18-45] with PSMA PET-CT; OR 12·0 [1·8-513·0], p=0·0034); and in the subanalysis of any extrapelvic lesions (none [0%; 0-6] vs eight [16%; 7-29]; OR non-estimable [95% CI non-estimable], p=0·0078).Interpretation: With higher detection rates, PSMA should be the PET tracer of choice when PET-CT imaging is considered for subsequent treatment management decisions in patients with prostate cancer and biochemical recurrence after radical prostatectomy and low PSA concentrations (≤2·0 ng/mL). Further research is needed to investigate whether higher detection rates translate into improved oncological outcomes.Funding: None. [ABSTRACT FROM AUTHOR]

Abstract Background Multiparametric magnetic resonance imaging (mpMRI) undoubtedly affects the diagnosis and treatment of localized prostate cancer (CaP). However, clinicians need a better understanding of its accuracy and limitations in detecting individual CaP foci to optimize management. Objective To determine the per-lesion detection rate for CaP foci by mpMRI and identify predictors of tumor detection. Design, setting, and participants We carried out a retrospective analysis of a prospectively managed database correlating lesion-specific results from mpMRI co-registered with whole-mount pathology (WMP) prostatectomy specimens from June 2010 to February 2018. Participants include 588 consecutive patients with biopsy-proven CaP undergoing 3-T mpMRI before radical prostatectomy at a single tertiary institution. Outcome measurements and statistical analysis We measured mpMRI sensitivity in detecting individual CaP and clinically significant (any Gleason score ≥7) CaP foci and predictors of tumor detection using multivariate analysis. Results and limitations The final analysis included 1213 pathologically confirmed tumor foci in 588 patients with primarily intermediate- (75%) or high-risk (12%) CaP. mpMRI detected 45% of all lesions (95% confidence interval [CI] 42–47%), including 65% of clinically significant lesions (95% CI 61–69%) and nearly 80% of high-grade tumors. Some 74% and 31% of missed solitary and multifocal tumors, respectively, were clinically significant. The majority of missed lesions were small (61.1% ≤1 cm); 28.3% were between 1 and 2 cm, and 10.4% were >2 cm. mpMRI missed at least one clinically significant focus in 34% of patients overall, and in 45% of men with multifocal lesions. On multivariate analysis, smaller, low-grade, multifocal, nonindex tumors with lower prostate-specific antigen density were more likely to be missed. Limitations include selection bias in a prostatectomy cohort, lack of specificity data, an imperfect co-registration process, and uncertain clinical significance for undetected lesions. Conclusions mpMRI detects less than half of all and less than two-thirds of clinically significant CaP foci. The moderate per-lesion sensitivity and significant proportion of men with undetected tumor foci demonstrate the current limitations of mpMRI. Patient summary Magnetic resonance imaging of the prostate before surgical removal for prostate cancer finds less than half of all individual prostate cancer tumors. Large, solitary, aggressive tumors are more likely to be visualized on imaging. Take Home Message In this retrospective review of robotic radical prostatectomy specimens for prostate cancer processed using whole-mount pathology, 3-T multiparametric magnetic resonance imaging detected 45% of all individual prostate cancers and 65% of clinically significant tumors. Smaller, low-risk, nonindex, and multifocal tumors were more likely to be missed. [ABSTRACT FROM AUTHOR]

Objective: To determine whether multiparametric magnetic resonance imaging might improve the identification of patients with higher risk disease at diagnosis and thereby reduce the incidence of undergrading or understaging. Methods: We retrospectively reviewed the clinical records of 115 patients who underwent multiparametric magnetic resonance imaging before radical prostatectomy. We used Epstein's criteria of insignificant disease with and without a magnetic resonance imaging (MRI) parameter (apparent diffusion coefficient) to calculate sensitivity, specificity, as well as negative and positive predictive values [NPV and PPV] across varying definitions of clinically significant cancer based on Gleason grade and tumor volume (0.2 mL, 0.5 mL, and 1.3 mL) on whole-mount prostate specimens. Logistic regression analysis was performed to determine the incremental benefit of MRI in delineating significant cancer. Results: The majority had a prostate-specific antigen from 4.1-10.0 (67%), normal rectal examinations (90%), biopsy Gleason score ≤6 (68%), and ≤2 cores positive (55%). Of the 58 patients pathologically staged with Gleason 7 or pT3 disease at prostatectomy, Epstein's criteria alone missed 12 patients (sensitivity of 79% and NPV of 68%). Addition of apparent diffusion coefficient improved the sensitivity and NPV for predicting significant disease at prostatectomy to 93% and 84%, respectively. MRI improved detection of large Gleason 6 (≥1.3 mL, P = .006) or Gleason ≥7 lesions of any size (P <.001). Conclusion: Integration of MRI with existing clinical staging criteria helps identify patients with significant cancer. Clinicians should consider utilizing MRI in the decision-making process. [Copyright &y& Elsevier]

: ObjectivesIt is unclear why men who undergo radical prostatectomy (RP) and are found to have pathologically organ-confined disease develop prostate-specific antigen (PSA) recurrences. We previously found that patients with less than 45% of cells in the prostate needle biopsy specimen (PNBx) staining positive for the cell cycle regulator p27 had a significantly increased risk of biochemical recurrence after RP. We sought to determine whether p27 staining in the PNBx specimen might serve as a molecular marker for PSA failure in the subset of patients who develop PSA recurrence despite organ-confined disease at RP.: MethodsThe PNBx specimens of 161 men treated with RP between 1991 and 2000 were examined for p27 expression using immunohistochemistry. The p27 cutpoint of less than 45% expression was used to define the high and low-risk categories. Patients were separated into two groups for analysis: organ-confined (pT2 and negative surgical margins) and non-organ-confined (pT2 with positive surgical margins, pT3, pT4, or lymph node involvement). The mean and median follow-up for patients with organ-confined and non-organ-confined disease was 47 and 43 months and 42 and 38 months, respectively. Multivariate Cox proportional hazards analysis was used to examine the preoperative clinical variables that were the strongest predictors of biochemical recurrence after RP among each group.: ResultsAmong organ-confined patients, p27 expression was the only significant independent predictor of the time to biochemical recurrence after RP (hazard ratio 5.15, 95% confidence interval 1.41 to 18.83, P = 0.013). Among patients with non-organ-confined disease, the percentage of biopsy tissue with cancer, biopsy Gleason score, and PSA level were independent predictors of PSA recurrence. p27 expression was not a significant independent predictor of PSA recurrence among men with non-organ-confined disease.: Conclusionsp27 expression in the PNBx was a significant independent predictor of PSA failure for patients with pathologically organ-confined disease, but not for those with non-organ-confined disease. Patients with organ-confined disease but low p27 expression had a greater than fivefold risk of developing PSA recurrence than were men with high p27 expression, suggesting that p27 may be a molecular marker associated with micrometastatic disease at the time of RP. [Copyright &y& Elsevier]