Prostate cancer screening in Switzerland: a literature review and consensus statement from the Swiss Society of Urology.

Over a decade ago, the United States Preventive Services Taskforce (USPSTF) recommended against prostate-specific antigen (PSA)-based screening for prostate cancer in all men, which considerably influenced prostate cancer screening policies worldwide after that. Consequently, the world has seen increasing numbers of advanced stages and prostate cancer deaths, which later led the USPSTF to withdraw its initial statement. Meanwhile, the European Union has elaborated a directive to address the problem of implementing prostate cancer screening in "Europe's Beating Cancer Plan". In Switzerland, concerned urologists formed an open Swiss Prostate Cancer Screening Group to improve the early detection of prostate cancer. On the 20th of September 2023, during the annual general assembly of the Swiss Society of Urology (SGU/SSU) in Lausanne, members positively voted for a stepwise approach to evaluate the feasibility of implementing organised prostate cancer screening programs in Switzerland. The following article will summarise the events and scientific advances in the last decade during which evidence and promising additional modalities to complement PSA-based prostate cancer screening have emerged. It also aims to provide an overview of contemporary strategies and their potential harms and benefits.

Opportunistic Prostate Cancer Screening with Biparametric Magnetic Resonance Imaging (VISIONING).

BACKGROUND: This study investigates the use of biparametric magnetic resonance imaging (bpMRI) as primary opportunistic screening for prostate cancer (PCa) without using a prostate-specific antigen (PSA) cut-off. OBJECTIVE: The primary endpoint was to assess the efforts and effectiveness of identifying 20 participants with clinically significant prostate cancer (csPCa) using bpMRI. DESIGN, SETTING, AND PARTICIPANTS: Biopsy-naïve men aged over 45 yr were included. All participants underwent 3 Tesla bpMRI, PSA, and digital rectal examination (DRE). Targeted-only biopsy was performed in participants with Prostate Imaging Reporting and Data System (PI-RADS) ≥3. Men with negative bpMRI but suspicious DRE or elevated PSA/PSA density had template biopsies. Preintended protocol adjustments were made after an interim analysis for PI-RADS 3 lesions: no biopsy and follow-up MRI after 6 mo and biopsy only if lesions persisted or upgraded. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Biopsy results underwent a comparison using Fisher's exact test and univariable logistic regression to identify prognostic factors for positive biopsy. RESULTS AND LIMITATIONS: A total of 229 men were enrolled in this study, of whom 79 underwent biopsy. Among these men, 77 displayed suspicious PI-RADS lesions. PCa was detected in 29 participants (12.7%), of whom 21 had csPCa (9.2%). Biparametric MRI detected 21 csPCa cases, while PSA and DRE would have missed 38.1%. Protocol adjustment led to a 54.6% biopsy reduction in PI-RADS 3 lesions. Overall, in this cohort of men with a median PSA value of 1.26 ng/ml, 10.9 bpMRI scans were needed to identify one participant with csPCa. A major limitation of the study is the lack of a control cohort undergoing systematic biopsies. CONCLUSIONS: Opportunistic screening utilising bpMRI as a primary tool has higher sensitivity in detecting csPCa than classical screening methods. PATIENT SUMMARY: Screening with biparametric magnetic resonance imaging (bpMRI) and targeted biopsy identified clinically significant prostate cancer in every 11th man, regardless of the prostate-specific antigen (PSA) levels. Preselecting patients based on PSA >1 ng/ml and a positive family history of prostate cancer, as well as other potential blood tests may further improve the effectiveness of bpMRI in this setting.

Outcomes of robot-assisted laparoscopic extended pelvic lymph node dissection for prostate Cancer.

INTRODUCTION: Extended pelvic lymph node dissection (ePLND) in men undergoing robot-assisted laparoscopic radical prostatectomy (RARP) is a widely used procedure. However, little is known about anatomical site-specific yields and subsequent metastatic patterns in these patients. PATIENTS AND METHODS: Data on a consecutive series of 1107 patients undergoing RARP at our centre between 2004 and 2018 were analysed. In men undergoing LN dissection, the internal, external and obturator nodes were removed and sent in separately. We performed an analysis of LN yields in total and for each anatomical zone, patterns of LN metastases and complications. Oncological outcome in pN+ disease was assessed including postoperative PSA persistence and survival. RESULTS: A total of 823 ePLNDs were performed in the investigated cohort resulting in 98 men being diagnosed as pN+ (8.9%). The median (IQR) LN yield was 19 (14-25), 10 (7-13) on the right and 9 (6-12) on the left side (P < 0.001). A median of six (4-8) LNs were retrieved from the external, three (1-6) from the internal iliac artery, and eight (6-12) from the obturator fossa. More men had metastatic LNs on the right side compared to the left (41 vs. 19). Symptomatic lymphoceles occurred exclusively in the ePLND group (2.3% vs. 0%, p = 0.04). Postoperatively, 47 (47.9%) of men with pN+ reached a PSA of < 0.1µg/ml. There was no association between a certain pN+ region and postoperative PSA persistence or BCRFS. The estimated cancer specific survival rate at 5 years was 98.5% for pN+ disease. CONCLUSION: Robot-assisted laparoscopic ePLND with a high LN yield and low complication rate is feasible. However, we observed an imbalance in more removed and positive LNs on the right side compared to the left. A high rate of postoperative PSA persistence and early recurrence in pN+ patients might indicate a possibly limited therapeutical value of the procedure in already spread disease. Yet, these men demonstrated an excellent survival.

Focal therapy with high-intensity focused ultrasound for prostate cancer: 3-year outcomes from a prospective trial.

OBJECTIVE: To assess the oncological and functional outcomes of focal high-intensity focused ultrasound (HIFU) in treating localised prostate cancer (PCa), a 3-year prospective study was undertaken using periodic post-ablation saturation biopsies. PATIENTS AND METHODS: Men with two or fewer lesions of grade group (GG) ≤3 PCa were eligible for participation. Additional criteria included a prostate-specific antigen (PSA) level of ≤15 ng/mL, clinical T1c-T2, and a life expectancy of ≥10 years. The primary endpoint was failure-free survival (FFS), defined as absence of clinically significant PCa (csPCa) in- or out-of-field on protocol-mandated saturation biopsy, no whole-gland or systemic salvage treatment, PCa metastasis, or PCa-related death. Results are reported using two distinct definitions of csPCa: (i) the presence of any GG ≥2 and (ii) any GG ≥3 or core involvement of ≥6 mm. Secondary endpoints were functional patient-reported outcome measures addressing urinary, sexual, and bowel function. RESULTS: A total of 91 patients were included: six (7%) with GG1 and 85 (93%) with GG ≥2. In all, 83 (91%) underwent at least one follow-up biopsy. Biopsy attendance at 6, 12, and 36 months was 84%, 67%, and 51%, respectively. The FFS at these time points for any GG ≥2 PCa was 79% (95% confidence interval [CI] 80-88%), 57% (95% CI 48-69%) and 44% (95% CI 34-56%), respectively. Using the second definition, FFS were 88% (95% CI 81-95%), 70% (95% CI 61-81%) and 65% (95% CI 55-77%), respectively. The 3-year cancer-specific survival was 100%, and freedom from metastasis was 99%. Magnetic resonance imaging (MRI) (negative predictive value of up to 89%, 95% CI 84-93%) and relative decrease of PSA values (P = 0.4) performed poorly in detecting residual disease. Urinary and bowel assessment returned to baseline questionnaire scores within 3 months. In all, 17 (21%) patients reported meaningful worsening in erectile function. A significant decrease of PCa related anxiety was observed. CONCLUSIONS: Focal HIFU treatment for localised PCa shows excellent functional outcomes with half of the patients remaining cancer-free after 3 years. Whole-gland treatment was avoided in 81%. Early follow-up biopsies are crucial to change or continue the treatment modality at the right time, while the use of MRI and PSA in detecting PCa recurrence is uncertain.

Prospective Multicenter Validation of the Stockholm3 Test in a Central European Cohort.

BACKGROUND: It has been shown that the Stockholm3 test decreases overdetection of prostate cancer (PCa) while retaining the ability to detect clinically significant PCa (csPCa) in a Swedish population. However, the test includes potentially population-specific testing of single-nucleotide polymorphisms and has yet not been validated outside Scandinavia. OBJECTIVE: To assess the performance of the Stockholm3 test in discriminating csPCa in a Central European cohort undergoing prostate biopsy (PBx). DESIGN, SETTING, AND PARTICIPANTS: This prospective multicenter validation study was conducted from August 2020 to September 2022 at two centers in Switzerland and one center in Germany. The study involved 342 men undiagnosed with PCa who were scheduled for PBx after prostate-specific antigen (PSA) testing and subsequent magnetic resonance imaging (MRI) of the prostate. Before PBx, participants had a blood sample taken for Stockholm3 testing. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was the accuracy of the Stockholm3 test in detecting csPCa (International Society of Urological Pathology grade group [GG] ≥2) according to the area under the receiver operating characteristic curve (AUC), sensitivity, and specificity, and the clinical consequences of using the model. RESULTS AND LIMITATIONS: The Stockholm3 test with a cutoff of 11% for csPCa detection had sensitivity of 92.3% (95% confidence interval [CI] 86.9-95.9%), specificity of 32.6% (95% CI 26.0-39.8%), a positive predictive value of 53.2% (95% CI 47.0-59.2%), and a negative predictive value of 83.6% (95% CI 73-91.2%). It showed superior discrimination for csPCa (AUC 0.77, 95% CI 0.72-0.82) in comparison to PSA (AUC 0.66, 95% CI 0.61-0.72; p < 0.001). Using a Stockholm3 cutoff of 11%, PBx could have been omitted for 73 men (21.0%), and 12/154 (8%) csPCa and 2/72 (2.8%) GG >2 cases would have been missed. Limitations include population selection bias. CONCLUSIONS: Our results show favorable clinical outcomes for the blood-based Stockholm3 biomarker test in a Central European patient cohort. PATIENT SUMMARY: The Stockholm3 blood test shows better accuracy in predicting prostate cancer than the more common PSA (prostate-specific antigen) test.

Transperineal template saturation and conventional biopsy for stage prediction in prostate cancer.

OBJECTIVE: To evaluate the performance of risk calculators (RCs) predicting lymph node invasion (LNI) and extraprostatic extension (EPE) in men undergoing transperineal magnetic resonance imaging/transrectal ultrasound (TRUS)-fusion template saturation biopsy (TTSB) and conventional systematic TRUS-guided biopsy (SB). PATIENTS AND METHODS: The RCs were tested in a consecutive cohort of 645 men undergoing radical prostatectomy with extended pelvic LN dissection between 2005 and 2019. TTSB was performed in 230 (35.7%) and SB in 415 (64.3%) men. Risk of LNI and EPE was calculated using the available RCs. Discrimination, calibration, and clinical usefulness stratified by different biopsy techniques were assessed. RESULTS: Lymph node invasion was observed in 23 (10%) and EPE in 73 (31.8%) of cases with TTSB and 53 (12.8%) and 158 (38%) with SB, respectively. RCs showed an excellent discrimination and acceptable calibration for prediction of LNI based on TTSB (area under the curve [AUC]/risk estimation: Memorial Sloan Kettering Cancer Center [MSKCC]-RC 0.79/-4%, Briganti (2012)-RC 0.82/-4%, Gandaglia-RC 0.81/+6%). These were comparable in SB (MSKCC-RC 0.78/+2%; Briganti (2012)-RC 0.77/-3%). Decision curve analysis (DCA) revealed a net benefit at threshold probabilities between 3% and 6% when TTSB was used. For prediction of EPE based on TTSB an inferior discrimination and variable calibration were observed (AUC/risk estimation: MSKCC-RC 0.71/+8% and Martini (2018)-RC 0.69/+2%) achieving a net benefit on DCA only at risk thresholds of >17%. Performance of RCs for prediction of LNI and EPE based on SB showed comparable results with a better performance in the DCA for LNI (risk thresholds 1-2%) and poorer performance for EPE (risk threshold >20%). This study is limited by its retrospective single-institution design. CONCLUSIONS: The potentially more accurate grading ability of TTSB did not result in improved performance of preoperative RCs. Prediction tools for LNI proved clinical usefulness while RCs for EPE did not.

Do Swiss urologists and Swiss internists screen themselves and their relatives for prostate cancer? A questionnaire study.

PURPOSE: Prostate-specific antigen (PSA) screening for men at risk of prostate cancer is controversial. The current recommendation is to raise awareness of prostate cancer and offer PSA screening in accordance with shared decision- making. Whether the possibility of a PSA screen is discussed with the patient depends on the treating physician, but data on physicians' attitudes towards PSA screening are scarce. This study aimed to examine internists' and urologists' personal PSA screening activity as an indicator of their attitude towards PSA screening. MATERIALS AND METHODS: Members of the Swiss Society of Urology and the Swiss Society of General Internal Medicine were asked in 08/2020 to anonymously complete an online survey about personal PSA screening behaviour for themselves, their fathers, brothers and partners. Categorical and continuous variables were compared by chi-squared tests and t-tests, respectively. RESULTS: In total, 190/295 (response rate: 64%) urologists and 893/7400 (response rate: 12%) internists participated in the survey. Of the participants, 297/1083 (27.4%) were female. Male urologists >50 years of age screened themselves more often than male internists >50 years of age (89% vs 70%, p <0.05). Furthermore, urologists reported recommending screening statistically significantly more often than internists to their brother, father or partner regardless of their sex (men: 38.1% vs 18.5%; p <0.05; women: 81.8% vs 32.2%; p <0.05).   CONCLUSIONS: Most participating male physicians >50 years of age have screened themselves for prostate cancer. Furthermore, PSA screening of relatives was significantly associated with the urology specialty. The reasons physicians screen themselves substantially more often than the public and why male and female urologists as well as male internists perform PSA screening more frequently in their private environment than female internists should be further examined.

Therapy decisions after diagnosis of prostate cancer in men with negative prostate MRI.

BACKGROUND: To investigate the clinical implications of magnetic resonance imaging (MRI) negative prostate cancer (PCa) in a cohort of men undergoing transperineal prostate biopsy. METHODS: We included all men without prior diagnosis of PCa undergoing transperineal template saturation ± fusion-guided targeted biopsy of the prostate between November 2014 and March 2018. Before biopsy, all patients underwent MRI and biopsies were performed irrespective of imaging results. Baseline characteristics, imaging, biopsy results, and follow-up information were retrieved from the patient charts. Patients were classified as either MRI negative (Prostate Imaging Reporting and Data System [PIRADS] ≤ 2) or positive (PIRADS ≥ 3). ISUP grade group 1 was defined as clinically nonsignificant (nsPCa) and ≥2 as clinically significant PCa (csPCa). Primary outcome was the individual therapeutic decision after diagnosis of PCa stratified according to MRI visibility. Secondary outcomes were the sensitivity and specificity of MRI, and the urooncological outcomes after radical prostatectomy (RP). RESULTS: From 515 patients undergoing prostate biopsy, 171 (33.2%) patients had a negative and 344 (66.8%) a positive MRI. Pathology review stratified for MRI negative and positive cases revealed nsPCa in 27 (15.8%) and 32 (9.3%) and csPCa in 26 (15.2%) and 194 (56.4%) of the patients, respectively. The rate of active treatment in the MRI negative was lower compared with the MRI positive cohort (12.3% vs. 53.2%; odd ratio [OR] = 0.12; p < 0.001). While men with negative MRI were more likely to undergo active surveillance (AS) than MRI positive patients (18.1% vs. 10.8%; OR = 1.84; p = 0.027), they rarely underwent RP (6.4% vs. 40.7%, OR = 0.10; p < 0.001). Logistic regression revealed that a negative MRI was independently protective for active treatment (OR = 0.32, p = 0.014). The specificity, sensitivity, negative, and positive predictive value of MRI for detection of csPCa were 49.2%, 88.2%, 56.4%, and 84.8%, respectively. The rate of adverse clinicopathological outcome features (pT3/4, ISUP ≥4, or prostate-specific antigen [PSA]-persistence) following RP was 4.7% for men with MRI negative compared to 17.4% for men with MRI positive PCa (OR = 3.1, p = 0.19). CONCLUSION: Only few men with MRI negative PCa need active cancer treatment at the time of diagnosis, while the majority opts for AS. Omitting prostate biopsies and performing a follow-up MRI may be a safe alternative to reduce the number of unnecessary interventions.

External Validation of the Prostate Biopsy Collaborative Group Risk Calculator and the Rotterdam Prostate Cancer Risk Calculator in a Swedish Population-based Screening Cohort.

Background: External validation of risk calculators (RCs) is necessary to determine their clinical applicability beyond the setting in which these were developed. Objective: To assess the performance of the Rotterdam Prostate Cancer RC (RPCRC) and the Prostate Biopsy Collaborative Group RC (PBCG-RC). Design setting and participants: We used data from the prospective, population-based STHLM3 screening study, performed in 2012-2015. Participants with prostate-specific antigen ≥3 ng/ml who underwent systematic prostate biopsies were included. Outcome measurements and statistical analysis: Probabilities for clinically significant prostate cancer (csPCa), defined as International Society of Urological Pathology grade ≥2, were calculated for each participant. External validity was assessed by calibration, discrimination, and clinical usefulness for both original and recalibrated models. Results and limitations: Out of 5841 men, 1054 (18%) had csPCa. Distribution of risk predictions differed between RCs; median risks for csPCa using the RPCRC and PBCG-RC were 3.3% (interquartile range [IQR] 2.1-7.1%) and 20% (IQR 15-28%), respectively. The correlation between RC risk estimates on individual level was moderate (Spearman's r = 0.55). Using the RPCRC's recommended risk threshold of ≥4% for finding csPCa, 36% of participants would get concordant biopsy recommendations. At 10% risk cut-off, RCs agreed in 23% of cases. Both RCs showed good discrimination, with areas under the curves for the RPCRC of 0.74 (95% confidence interval [CI] 0.72-0.76) and the PBCG-RC of 0.70 (95% CI 0.68-0.72). Calibration was adequate using the PBCG-RC (calibration slope: 1.13 [95% CI 1.03-1.23]), but the RPCRC underestimated the risk of csPCa (calibration slope: 0.73 [0.68-0.79]). The PBCG-RC showed a net benefit in a decision curve analysis, whereas the RPCRC showed no net benefit at clinically relevant risk threshold levels. Recalibration improved clinical benefit, and differences between RCs decreased. Conclusions: Assessment of calibration is essential to ensure the clinical value of risk prediction tools. The PBCG-RC provided clinical benefit in its current version online. On the contrary, the RPCRC cannot be recommended in this setting. Patient summary: Predicting the probability of finding prostate cancer on biopsy differed between two assessed risk calculators. After recalibration, the agreement of the models improved, and both were shown to be clinically useful.

68Ga-PSMA-11 PET/MRI versus multiparametric MRI in men referred for prostate biopsy: primary tumour localization and interreader agreement.

BACKGROUND: Magnetic resonance imaging (MRI) is recommended by the European Urology Association guidelines as the standard modality for imaging-guided biopsy. Recently positron emission tomography with prostate-specific membrane antigen (PSMA PET) has shown promising results as a tool for this purpose. The aim of this study was to compare the accuracy of positron emission tomography with prostate-specific membrane antigen/magnetic resonance imaging (PET/MRI) using the gallium-labeled prostate-specific membrane antigen (68Ga-PSMA-11) and multiparametric MRI (mpMRI) for pre-biopsy tumour localization and interreader agreement for visual and semiquantitative analysis. Semiquantitative parameters included apparent diffusion coefficient (ADC) and maximum lesion diameter for mpMRI and standardized uptake value (SUVmax) and PSMA-positive volume (PSMAvol) for PSMA PET/MRI. RESULTS: Sensitivity and specificity were 61.4% and 92.9% for mpMRI and 66.7% and 92.9% for PSMA PET/MRI for reader one, respectively. RPE was available in 23 patients and 41 of 47 quadrants with discrepant findings. Based on RPE results, the specificity for both imaging modalities increased to 98% and 99%, and the sensitivity improved to 63.9% and 72.1% for mpMRI and PSMA PET/MRI, respectively. Both modalities yielded a substantial interreader agreement for primary tumour localization (mpMRI kappa = 0.65 (0.52-0.79), PSMA PET/MRI kappa = 0.73 (0.61-0.84)). ICC for SUVmax, PSMAvol and lesion diameter were almost perfect (≥ 0.90) while for ADC it was only moderate (ICC = 0.54 (0.04-0.78)). ADC and lesion diameter did not correlate significantly with Gleason score (ρ = 0.26 and ρ = 0.16) while SUVmax and PSMAvol did (ρ = - 0.474 and ρ = - 0.468). CONCLUSIONS: PSMA PET/MRI has similar accuracy and reliability to mpMRI regarding primary prostate cancer (PCa) localization. In our cohort, semiquantitative parameters from PSMA PET/MRI correlated with tumour grade and were more reliable than the ones from mpMRI.

Association of Open vs Robot-Assisted Radical Cystectomy With Mortality and Perioperative Outcomes Among Patients With Bladder Cancer in Sweden.

Importance: Mortality rates resulting from bladder cancer have remained unchanged for more than 30 years. The surgical community has put hope in robot-assisted radical cystectomy (RARC) with intracorporeal urinary diversion (ICUD) in an effort to improve surgical outcomes and bladder cancer survival without strong supporting evidence. Objective: To evaluate perioperative, safety, and survival outcome differences between RARC with ICUD and open radical cystectomy (ORC). Design, Setting, and Participants: This nationwide population-based cohort study used data from the Swedish National Register of Urinary Bladder Cancer and population-based Cause of Death Register, which includes clinical information on tumor characteristics, treatment, and survival and covers approximately 97% of patients with urinary bladder cancer in Sweden. All patients who underwent radical cystectomy for bladder cancer in any hospital between January 2011 and December 2018 were included. Follow-up data were collected until December 2019. Data analysis was conducted from June to December 2020. Exposures: RARC or ORC. Main Outcomes and Measures: The main outcomes were all-cause and cancer-specific mortality between RARC and ORC, compared using propensity score matching. Secondary outcomes were differences in perioperative outcomes after the different surgical approaches. Results: Throughout the observation period, 889 patients underwent RARC and 2280 patients underwent ORC at 24 Swedish hospitals. The median (IQR) age was 71 (66-76) years and 2386 patients (75.3%) were men. After a median (IQR) follow-up of 47 (28-71) months, the 5-year cancer-specific mortality rates were 30.2% (variance, 1.59) for ORC and 27.6% (variance, 3.12) for RARC, and the overall survival rates were 57.7% (variance, 2.46) for ORC and 61.4% (variance, 5.11) for RARC. In the propensity score-matched analysis, RARC was associated with a lower all-cause mortality (hazard ratio, 0.71; 95% CI, 0.56-0.89; P = .004). Compared with ORC, RARC was associated with a lower estimated blood loss (median [IQR] 150 [100-300] mL vs 700 [400-1300] mL; P < .001), intraoperative transfusion rate (odds ratio [OR], 0.05; 95% CI, 0.03-0.08; P < .001), and shorter length of stay (median [IQR], 9 [6-13] days vs 13 [10-17] days; P < .001), and with a higher lymph node yield (median [IQR], 20 [15-27] lymph nodes vs 14 [8-24] lymph nodes; P < .001) and 90-day rehospitalization rate (OR, 1.28; 95% CI, 1.02-1.60; P = .03). The RARC group, compared with the ORC group had lower risk of Clavien-Dindo grade III or higher complications (OR, 0.62; 95% CI, 0.43-0.87; P = .009). Conclusions and Relevance: These findings suggest that compared with ORC, RARC with ICUD was associated with a lower overall mortality rate, fewer high-grade complications, and more favorable perioperative outcomes.

Clinical Trial Protocol for ProBio: An Outcome-adaptive and Randomised Multiarm Biomarker-driven Study in Patients with Metastatic Prostate Cancer.

ProBio is an outcome-adaptive, multiarm, multiple-assignment randomised, biomarker-driven platform trial in men with metastatic castration-resistant prostate cancer. Here we describe the amended clinical protocol, focusing on expansion of the trial to include patients with de novo metastatic hormone-sensitive prostate cancer.

Increased Pathway Complexity Is a Prognostic Biomarker in Metastatic Castration-Resistant Prostate Cancer.

Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease, characterized by common and rare driver gene alterations that provide a selective growth advantage for progressing tumour cells. We hypothesized that the number of distinct gene driver alteration-affected pathways or gene classes was associated with poor prognosis in patients initiating androgen receptor signalling inhibitors (ARSi). We performed a post hoc analysis of an amalgamated baseline circulating tumour DNA (ctDNA) mutational landscape dataset of ARSi-treated men with mCRPC (n = 342). We associated the detected hotspot, pathogenic, and/or high impact protein function-affecting perturbations in 39 genes into 13 pathways. Progression-free (PFS) and overall survival (OS) were analysed using Kaplan-Meier curves and multivariate Cox regression models. Driver gene alterations were detected in 192/342 (56.1%) evaluable patients. An increased number of affected pathways, coined pathway complexity index (PCI), resulted in a decremental PFS and OS, and was independently associated with prognosis once ≥3 pathway or gene classes were affected (PFS HR (95%CI): 1.7 (1.02-2.84), p = 0.04, and OS HR (95%CI): 2.5 (1.06-5.71), p = 0.04). Additionally, visceral disease and baseline PSA and plasma ctDNA levels were independently associated with poor prognosis. Elevated PCI is associated with poor ARSi outcome and supports comprehensive genomic profiling to better infer mCRPC prognosis.

Diagnostic performance of 68Ga-PSMA-11 PET/MRI-guided biopsy in patients with suspected prostate cancer: a prospective single-center study.

PURPOSE: Ultrasound-guided biopsy (US biopsy) with 10-12 cores has a suboptimal sensitivity for clinically significant prostate cancer (sigPCa). If US biopsy is negative, magnetic resonance imaging (MRI)-guided biopsy is recommended, despite a low specificity for lesions with score 3-5 on Prostate Imaging Reporting and Data System (PIRADS). Screening and biopsy guidance using an imaging modality with high accuracy could reduce the number of unnecessary biopsies, reducing side effects. The aim of this study was to assess the performance of positron emission tomography/MRI with 68Ga-labeled prostate-specific membrane antigen (PSMA-PET/MRI) to detect and localize primary sigPCa (ISUP grade group 3 and/or cancer core length ≥ 6 mm) and guide biopsy. METHODS: Prospective, open-label, single-center, non-randomized, diagnostic accuracy study including patients with suspected PCa by elevation of prostate-specific antigen (PSA) level and a suspicious lesion (PIRADS ≥3) on multiparametric MRI (mpMRI). Forty-two patients underwent PSMA-PET/MRI followed by both PSMA-PET/MRI-guided and section-based saturation template biopsy between May 2017 and February 2019. Primary outcome was the accuracy of PSMA-PET/MRI for biopsy guidance using section-based saturation template biopsy as the reference standard. RESULTS: SigPCa was found in 62% of the patients. Patient-based sensitivity, specificity, negative and positive predictive value, and accuracy for sigPCa were 96%, 81%, 93%, 89%, and 90%, respectively. One patient had PSMA-negative sigPCa. Eight of nine false-positive lesions corresponded to cancer on prostatectomy and one in six false-negative lesions was negative on prostatectomy. CONCLUSION: PSMA-PET/MRI has a high accuracy for detecting sigPCa and is a promising tool to select patients with suspicion of PCa for biopsy. TRIAL REGISTRATION: This trial was retrospectively registered under the name "Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI) Guided Biopsy in Men with Elevated PSA" (NCT03187990) on 06/15/2017 ( https://clinicaltrials.gov/ct2/show/NCT03187990 ).

Head-to-head Comparison of Conventional, and Image- and Biomarker-based Prostate Cancer Risk Calculators.

BACKGROUND: A new generation of risk calculators (RCs) for prostate cancer (PCa) incorporating magnetic resonance imaging (MRI) data have been introduced. However, these have not been validated externally, and their clinical benefit compared with alternative approaches remains unclear. OBJECTIVE: To assess previously published PCa RCs incorporating MRI data, and compare their performance with traditional RCs (European Randomized Study of Screening for Prostate Cancer [ERSPC] 3/4 and Prostate Biopsy Collaborative Group [PBCG]) and the blood-based Stockholm3 test. DESIGN, SETTING, AND PARTICIPANTS: RCs were tested in a prospective multicenter cohort including 532 men aged 45-74 yr participating in the Stockholm3-MRI study between 2016 and 2017. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The probabilities of detection of clinically significant PCa (csPCa) defined as Gleason score ≥3 + 4 were calculated for each patient. For each RC and the Stockholm3 test, discrimination was assessed by area under the curve (AUC), calibration by numerical and graphical summaries, and clinical usefulness by decision curve analysis (DCA). RESULTS AND LIMITATIONS: The discriminative ability of MRI RCs 1-4 for the detection of csPCa was superior (AUC 0.81-0.87) to the traditional RCs (AUC 0.76-0.80). The observed prevalence of csPCa in the cohort was 37%, but calibration-in-the-large predictions varied from 14% to 63% across models. DCA identified only one model including MRI data as clinically useful at a threshold probability of 10%. The Stockholm3 test achieved equivalent performance for discrimination (AUC 0.86) and DCA, but was underpredicting the actual risk. CONCLUSIONS: Although MRI RCs discriminated csPCa better than traditional RCs, their predicted probabilities were variable in accuracy, and DCA identified only one model as clinically useful. PATIENT SUMMARY: Novel risk calculators (RCs) incorporating imaging improved the ability to discriminate clinically significant prostate cancer compared with traditional tools. However, all but one predicted divergent compared with actual risks, suggesting that regional modifications be implemented before usage. The Stockholm3 test achieved performance comparable with the best MRI RC without utilization of imaging.

Effect of information on prostate biopsy history on biopsy outcomes in the era of MRI-targeted biopsies.

PURPOSE: To describe the predictive value of information on previous benign biopsy for the outcome of MRI-targeted biopsies. METHODS: An exploratory analysis was conducted using data from a prospective, multicenter, paired diagnostic study of 532 men undergoing diagnostics for prostate cancer during 2016-2017. All men underwent 1.5 T MRI; systematic prostate biopsies; and MRI-targeted biopsies to MRI lesions with Prostate Imaging Reporting and Data System version 2, PI-RADS ≥ 3. The main outcome was numbers of detected prostate cancer characterized by grade group (GG) where GG ≥ 2 defined clinically significant cancer (csPCa). RESULTS: Men with previous biopsies had significantly more often negative MRI (26% vs. 17%, p < 0.05) compared to men without previous biopsies. Men with previous biopsies showed higher rates of benign biopsies (41% vs. 26%, p < 0.05) and lower rates of GG2 (17% vs. 30%, p < 0.05) and GG ≥ 3 (5% vs. 10%, p < 0.05) cancer. Biopsy-naïve men had higher proportions of highly suspicious MRI lesions (PIRADS 5; p < 0.05) and a higher proportion of significant cancer in those lesions (p = 0.05). In multivariate regression analysis, a previous benign prostate biopsy was associated with less than half the odds of csPCa (OR 0.38; 95% CI 0.20-0.71). CONCLUSION: In this large prospective multicenter trial, we showed that men with a previous prostate biopsy had higher proportions of MRIs without lesions and lower proportion of highly suspicious lesions than biopsy-naïve men. Further, biopsy-naïve men showed higher detection of clinically significant cancer when using MRI-targeted biopsies. Also, in the era of MRI-targeted biopsy strategies, biopsy history should be carefully considered in biopsy decisions. TRIAL REGISTRATION: NCT02788825 (ClinicalTrials.gov). Date of registration June 2, 2016.

Morbidity and mortality after robot-assisted radical cystectomy with intracorporeal urinary diversion in octogenarians: results from the European Association of Urology Robotic Urology Section Scientific Working Group.

OBJECTIVES: To evaluate the postoperative complication and mortality rate following laparoscopic radical cystectomy (RARC) with intracorporeal urinary diversion (ICUD) in octogenarians. PATIENTS AND METHODS: We conducted a retrospective analysis comparing postoperative complication and mortality rates depending on age in a consecutive series of 1890 patients who underwent RARC with ICUD for bladder cancer between 2004 and 2018 in 10 European centres. Outcomes of patients aged <80 years and those aged ≥80 years were compared with regard to postoperative complications (Clavien-Dindo grading) and mortality rate. Cancer-specific mortality (CSM) and other-cause mortality (OCM) after surgery were calculated using the non-parametric Aalen-Johansen estimator. RESULTS: A total of 1726 patients aged <80 years and 164 aged ≥80 years were included in the analysis. The 30- and 90-day rate for high-grade (Clavien-Dindo grades III-V) complications were 15% and 21% for patients aged <80 years compared to 11% and 13% for patients aged ≥80 years (P = 0.2 and P = 0.03), respectively. In a multivariable logistic regression analysis adjusting for pre- and postoperative variables, age ≥80 years was not an independent predictor of high-grade complications (odds ratio 0.6, 95% confidence interval 0.3-1.1; P = 0.12). The non-cancer-related 90-day mortality was 2.3% for patients aged ≥80 years and 1.8% for those aged <80 years, respectively (P = 0.7). The estimated 12-month CSM and OCM rates for those aged <80 years were 8% and 3%, and for those aged ≥80 years, 15% and 8%, respectively (P = 0.009 and P < 0.001). CONCLUSIONS: The minimally invasive approach to RARC with ICUD for bladder cancer in well-selected elderly patients (aged ≥80 years) achieved a tolerable high-grade complication rate; the 90-day postoperative mortality rate was driven by cancer progression and the non-cancer-related rate was equivalent to that of patients aged <80 years. However, an increased OCM rate in this elderly group after the first year should be taken into account. These results will support clinicians and patients when balancing cancer-related vs treatment-related risks and benefits.

Robot-assisted intracorporeal orthotopic bladder substitution after radical cystectomy: perioperative morbidity and oncological outcomes - a single-institution experience.

OBJECTIVE: To report a single-institution experience with totally intracorporeal neobladder urinary diversion (UD) after robot-assisted laparoscopic radical cystectomy (RARC). PATIENTS AND METHODS: A total of 158 patients underwent totally intracorporeal neobladder UD after RARC between 2003 and 2016. Patient demographics, intraoperative and pathological data, 30- and 90-day perioperative mortality and complications were recorded. Complications were classified according to the modified Clavien-Dindo classification. The 5-year overall (OS) and cancer-specific survival (CSS) rates were estimated by Kaplan-Meier plots. RESULTS: Most of the patients were male (84%) and had clinical T Stage ≤2 (87%). The mean operation time was 359 (SD ±98) min, with a median (range) estimated blood loss of 300 (50-2200) mL. Most of the men (86%) received a nerve-sparing procedure and 38% of the females an organ-sparing approach. A lymph node dissection was performed in 156 (99%) patients, with a median (range) yield of 23 (7-48) nodes. Conversion to open surgery occurred in five patients (3%). We recorded negative margins in 156 patients (99%). The median (range) follow-up was 34 (1-170) months, with 30- and 90-day mortality rates of 0%. Clavien-Dindo Grade III-IV complications occurred in 29 of 158 (18%) patients at 30-days and in eight of 158 (5%) between 30-90 days, resulting into a 90-day overall high-grade complication rate of 23%. The unadjusted estimated 5-years recurrence-free survival, CSS and OS rates were 70%, 72%, and 71%, respectively. CONCLUSION: In our present series the complication and oncological results were similar to open RC series, suggesting that RARC followed by totally intracorporeal neobladder UD is a safe and feasible alternative.

Apalutamide in combination with autophagy inhibitors improves treatment effects in prostate cancer cells.

BACKGROUND: ARN-509 (Apalutamide) is a unique androgen receptor (AR) antagonist for the treatment of castration-resistant (CR) prostate cancer (PC). It inhibits AR nuclear translocation, DNA binding and transcription of AR gene targets. As dysregulation of autophagy has been detected in PC, the targeting of autophagy is a potential approach to overcome early therapeutic resistance. Therefore, we investigated the characteristics of autophagic response to ARN-509 treatment and evaluated the potential effect of a combination with autophagy inhibition. METHODS: Human prostate cancer cells (LNCaP) were cultivated in a steroid-free medium. Cells were treated with ARN-509 (50 µM) alone or in combination with the autophagy inhibitors 3-methyladenine (3MA, 5 mM) or chloroquine (Chl, 20 µM) or with ATG5 siRNA knock-down. Cell viability and apoptosis were measured by flow cytometry and fluorescence microscopy. Autophagy was monitored by immunohistochemistry, AUTOdot and immunoblotting (WES). RESULTS: Treatment with ARN-509 led to cell death of up to 37% with 50 µM and 60% with 100 µM by day 7. The combination of 50 µM ARN-509 with autophagy inhibitors produced a further increase in cell death by day 7. Immunostaining results showed that ARN-509 induced autophagy in LNCaP cells as evidenced by elevated levels of ATG5, Beclin 1 and LC3 punctuation and by an increase in the LC3-II band detected by WES. Autophagic flux was restored by the treatment of cells with Chl, intensifying the LC3-II band. These findings were further supported by an enhanced autophagosome punctuation observed by Autodot staining. CONCLUSIONS: These data demonstrate that treatment with ARN-509 leads to increased autophagy levels in LNCaP cells. Furthermore, in combination with autophagy inhibitors, ARN-509 provided a significantly elevated antitumor effect, thus providing a new therapeutic approach potentially translatable to patients.