Treatment options for metastatic castration-resistant prostate cancer (mCRPC) include androgen receptor pathway inhibitors (ARPIs), taxanes, radium-223, Lu-PSMA, poly (ADP-ribose) polymerase inhibitors, and immunotherapy in select patients. Resistance to ARPIs and hormone-based therapies has been associated with AR-ligand-binding domain mutations that can lead to promiscuous stimulation by other steroid hormones. There is a need to explore alternative targets and develop next-generation ARPIs or combination therapies that overcome this resistance. We describe the rationale and design of the randomized phase III trials OMAHA-003 (NCT06136624) and OMAHA-004 (NCT06136650), which will evaluate the efficacy and safety of opevesostat, a steroidogenesis inhibitor, versus ARPI switch in previously treated mCRPC. Results may support opevesostat as a potential new treatment option for mCRPC.Clinical trial registration: www.clinicaltrials.gov identifiers are NCT06136624 and NCT06136650.

Background The internet, including websites and large language models (LLMs), is an increasingly important information resource for medical patients. However, information quality varies, potentially leading to misinformation. Andrological patients may particularly rely on online sources due to the sensitive nature of their conditions.Objectives To assess the prevalence and quality of internet research among andrological patients and evaluate common online sources for comprehensibility, readability, and accuracy.Materials and Methods Patients (n = 283) at four German andrological centers completed a questionnaire on their online information behavior between November 2022 and October 2023. Common online sources were objectively evaluated using the DISCERN tool and Flesch readability index in 2023. Popular LLMs were also assessed in October 2024 and compared to traditional websites.Results 67% (n = 190/283) of andrological patients seek medical information before appointments, primarily using the internet (52%, n = 148/283) and general practitioners (49%, n = 139/283). Patients under 50 predominantly use online sources (60%, n = 74/122). Official medical association websites and Wikipedia are preferred, but 30% also use commercial sites (n = 91/283). In general, most common websites and LLMs provide sufficient information but lack easy comprehensibility and readability.Discussion The study highlights the widespread use of online resources by andrological patients and emphasizes the importance of high-quality medical information. While online tools show promise, the value of physician-patient communication remains irreplaceable and cannot be replaced by chatting with LLMs.Conclusion Official medical association should provide accurate and easily understood information for andrological patients. Efforts to improve the online media literacy and communication skills of medical personnel are necessary.Trial Registration Number The study was registered in the German WHO primary registry, the German Clinical Trials Register (DRKS) (Number: DRKS00029651).

TPS5135 Background: Opevesostat (MK-5684; ODM-208) is an oral, nonsteroidal inhibitor of cytochrome P450 11A1 (CYP11A1), a catalyst of the first and rate-limiting step of steroid biosynthesis. Opevesostat showed antitumor activity in participants with heavily pretreated mCRPC in the phase 1/2 CYPIDES trial. The randomized, open-label, phase 3 OMAHA-004 trial (NCT06136650) is designed to evaluate the efficacy and safety of opevesostat in participants with mCRPC after a prior ARPI. Methods: Eligible participants have mCRPC that progressed during androgen deprivation therapy ≤6 months before screening and on or after 1 ARPI for metastatic or nonmetastatic hormone-sensitive prostate cancer (HSPC) or CRPC for ≥8 weeks (≥14 weeks with bone progression). Prior ARPI plus docetaxel for HSPC is permitted if participants received no more than 6 cycles of docetaxel without radiographic disease progression. Approximately 1314 participants will be randomized 1:1 to opevesostat 5 mg orally twice-daily plus dexamethasone 1.5 mg and fludrocortisone 0.1 mg orally once daily or abiraterone acetate 1000 mg orally once daily plus prednisone 5 mg orally twice daily (if prior enzalutamide, darolutamide, or apalutamide) or enzalutamide 160 mg orally once-daily (if prior abiraterone). Stratification factors are metastatic site (bone only vs liver vs other), androgen receptor ligand binding mutation (AR-LBDm) status (positive vs negative), and prior docetaxel treatment for HSPC (yes vs no). Once the predefined enrollment threshold for participants with either mutation status (AR-LBDm-positive, ~400 participants or AR-LBDm-negative, ~914 participants) is met, no additional participants with that mutation status will be permitted to enroll. The protocol was amended to use radiographic progression-free survival per Prostate Cancer Working Group 3 (PCWG3)-modified RECIST v1.1 by blinded independent central review (BICR), analyzed separately in participants with AR-LBDm–positive and –negative disease, as the primary end point and overall survival as a key secondary end point. Other secondary end points include time to initiation of first subsequent anticancer therapy or death, objective response rate and duration of response per PCWG3-modified RECIST v1.1 by BICR, time to pain progression; time to prostate-specific antigen (PSA) progression, PSA response rate, time to first symptomatic skeletal-related event, and safety and tolerability. Enrollment is ongoing. Clinical trial information: NCT06136650 .

BACKGROUND AND OBJECTIVE:Aquablation and laser enucleation of the prostate (LEP) are treatments for alleviation of lower urinary tract symptoms (LUTS) that have not yet been directly compared in a prospective randomized trial. This study was designed to evaluate these treatments in terms of LUTS improvement and safety in men with large prostates. METHODS:WATER III is an investigator-initiated, international, multicenter, nonblinded, prospective noninferiority trial that includes randomized and nonrandomized participants. Eligible patients had moderate to severe LUTS and a large prostate volume (80-180 ml). The primary efficacy endpoint was the change in International Prostate Symptom Score (IPSS) from baseline to 3 mo. The primary safety endpoint was the incidence of Clavien-Dindo (CD) grade ≥2 or persistent CD grade 1 complications that had not resolved by 3 mo. Bayesian analyses were used to assess noninferiority. KEY FINDINGS AND LIMITATIONS:A total of 202 men were enrolled in the study, of whom 186 underwent surgery (98 Aquablation, 88 LEP). At 3 mo, data were available for 170 patients, including 66 randomized and 104 nonrandomized men. Both treatments showed similar mean IPSS improvement at 3 mo: -12.9 ± 6.9 with Aquablation versus -13.1 ± 7.5 with LEP, with an estimated difference of 0.93 (95% credible interval [CrI] -1.48 to 3.53) and noninferiority probability of >0.999. The incidence of CD grade ≥2/persistent grade 1 complications was 40.8% in the Aquablation group versus 56.8% in the LEP, with an estimated difference of -9.4% (95%CrI -31.8% to 12.9%; noninferiority probability 0.952). Retrograde ejaculation was less frequent after Aquablation (14.8% vs 77.1%; p < 0.001). Persistent stress urinary incontinence (SUI) was absent following Aquablation versus 9.3% after LEP (p < 0.05). CONCLUSIONS AND CLINICAL IMPLICATIONS:Aquablation demonstrated noninferior short-term LUTS relief and similar safety compared to LEP, with superior ejaculation preservation and avoidance of SUI in short-term follow-up.

PURPOSE:Systematic biopsy (SB) remains recommended in addition to MRI-targeted biopsy (TB) because TB alone may miss clinically significant prostate cancer (sPC). We evaluated the spatial distribution of sPC and clinically insignificant prostate cancer (iPC) detected by SB in relation to MRI lesions and assessed the effect of perilesional template (PLT) in terms of cancer detection. MATERIALS AND METHODS:We retrospectively analyzed 1043 men who underwent combined transperineal MRI/TRUS fusion biopsy. Spatial distribution between MRI lesions and cancer-positive SB cores was calculated. Hypothetical PLTs with 5, 10, and 15 mm were modeled. Radical prostatectomy (RP) whole-mount histopathology served as the reference standard. RESULTS:sPC was detected in 521/1043 (50.0%) men. SB alone identified sPC in 98 patients. The mean distance to the nearest sPC core was significantly shorter than for iPC (7.8 vs. 12.4 mm; p < 0.001). Cumulative sPC detection increased up to approximately 10 mm from the lesion border and plateaued thereafter, whereas iPC detection increased linearly beyond 10 mm. A 10mm-PLT would have detected 94.3% of all cancers and avoided 3.7% of iPC diagnoses, while missing 2.5% of sPC. Extending the margin to 15 mm did not meaningfully improve sPC detection but increased iPC detection. Use of 10mm-PLT would have resulted in 10.5% upgrades to sPC in RP compared to 5.9% in the TB + SB cohort. CONCLUSIONS:sPC is spatially concentrated near MRI lesions, whereas iPC is more widely distributed. A 10mm-PLT captures most sPC and provides an empirical basis for the guideline-recommended perilesional margin. Prospective validation is required before SB can be safely replaced.

Background and objective Treatment landscape in advanced prostate cancer (PC) is evolving. There is limited understanding of the factors influencing decision-making for genetic/genomic testing and the barriers to recommending testing and treatment in international real-world clinical practice following the approval of poly-adenosine diphosphate-ribose polymerase inhibitors (PARPi) for metastatic castration-resistant PC (mCRPC). This work aims to assess genetic/genomic testing patterns and methods, including for homologous recombination repair mutation (HRRm), and treatment decisions among physicians caring for patients with PC across the USA, Europe, and Asia. Methods A cross-sectional online survey of physicians treating patients with advanced PC was administered in the USA, France, Germany, Italy, Spain, UK, Japan, and China. Physicians were recruited (from August to December 2022) via clinical panels and provided informed consent. Survey questions covered factors influencing HRRm testing and treatment decision-making. Key findings and limitations Physicians reported that 50% of patients with mCRPC are recommended for HRRm testing, and among those recommended for testing, 60% are recommended for BRCA1/2 mutation testing and 65% go on to receive HRRm testing. Overall proportions of patients recommended for testing increased following PARPi approval (from 20% to 50%) and following updated practice guidelines (from 25% to 50%). Perceived barriers to the use of genetic/genomic testing included patient refusal, lack of insurance/reimbursement, and lack of availability of adequate tissue for testing. Conclusions and clinical implications Overall, testing rates increased following PARPi approval and updated clinical practice guidelines; yet, there was a wide variation in the proportions of patients with mCRPC recommended for testing, and perceived barriers to testing remain, suggesting unmet needs for patients and physicians. Patient summary We surveyed physicians globally about their experience in treating patients with advanced prostate cancer and genetic testing. Physicians reported that half of patients are recommended for genetic testing, which varied across countries. We conclude that barriers to testing remain for patients and physicians.

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Objective:To investigate whether storage or voiding symptoms respond more favourably to the use of Kranus Lutera, the first app-based digital therapeutic for male lower urinary tract symptoms (LUTS), using detailed item-level analysis of the IPSS questionnaire. Materials and Methods:The present data represent a post-hoc analysis of the results of the BEST trial, a randomized controlled study evaluating the efficiency of the digital therapy Kranus Lutera. The study period lasted 12 weeks, conducted between 04/2023 and 11/2023. We assessed the mean change from baseline to 12 weeks for each of the seven IPSS items. Voiding symptoms (items 1, 3, 5 and 6) and storage symptoms (items 2, 4 and 7) were analysed separately. Results:Participants using the digital therapeutic demonstrated statistically significant improvements across all IPSS items. Compared to the control group, the intervention group showed a significant and clinically relevant improvement in the primary endpoint (IPSS), with an overall reduction of -7.0 points (95% CI: -8.1 to -5.9, p < 0.0001). Notably, improvements in storage symptoms were consistently larger than those in voiding symptoms. The analysis of individual IPSS questions showed the greatest changes in the overall cohort for questions 1, 2 and 7 (each p < 0.0001). Patients with the single diagnosis BPH (N40) showed the greatest score reduction in questions 2 and 5 (each p < 0.0001), patients with OAB (N32.8) in questions 2, 4 and 7 (each p < 0.0001) and patients with BPH and OAB (N40 + N32.8) in questions 2, 3 and 7 (question 2 and 3 p < 0.0001, question 7 p = 0.0015). According to the analysis of individual IPSS questions, the greatest improvements were observed in frequency, nocturia and the feeling of incomplete bladder emptying. Conclusion:These findings suggest that a structured app-based therapeutic may exert a stronger effect on storage symptoms than voiding symptoms in men with LUTS. This study confirms the value of the digital therapy as an integral part of the standard care for patients with male LUTS.

INTRODUCTION:The goal of our study was to generate a standardized assessment of postoperative complications and functional results in patients undergoing salvage lymph node dissection (sLND) in a multimodal setting with prior primary therapy and possibly multiple courses of radiation due to nodal-recurrent prostate cancer. PATIENTS AND METHODS:This study included 173 patients that underwent sLND between 2005 and 2019. Postoperative complications were reported according to Clavien-Dindo-Classification (CDC). Health-related quality of life (QoL) was assessed prospectively using a validated questionnaire (EORTC QLQ-C30). Postoperative urinary incontinence was quantified with the assessment of pad usage and the ICIQ-SF questionnaire. RESULTS:The any-grade complication rate after sLND was 67% (n = 115 patients). A total of patients (n = 42) had severe postoperative complications (CDC grade ≥IIIa). No grade V complications were reported. The number of lymph nodes removed was higher in patients with any-grade complications (median 32 versus 25, p = 0.03), while the number of lymph node metastases was higher in patients with severe complications (median 7 versus 3, p = 0.03). However, no clinical parameter was independently associated with complications. A total of 56% patients did not require any pads postoperatively. Median postoperative ICIQ-SF score was 5 and was higher in patients with any prior radiation (median 6 versus 0, p = 0.03). Radical prostatectomy as primary therapy (p = 0.01) and any prior radiation (p = 0.01) were independent predictors of any incontinence. Patients' QoL was rated as moderate, with an impairment in QoL in 39% of the follow-up cohort. CONCLUSION:SLND is a treatment option in selected patients with nodal-recurrent prostate cancer with considerable complication rates and possible functional impairments that need to be discussed with the patient when balancing the indication for this metastasis-directed treatment option.

Introduction Androgen receptor (AR) somatic mutation activation is a resistance mechanism to AR-directed therapies (ADT) in metastatic castration-resistant prostate cancer (mCRPC). Upstream targeting of androgen biosynthesis may provide a therapeutic advantage over available AR-directed therapies in patients with mCRPC. Opevesostat (MK-5684; ODM-208) is an oral, nonsteroidal inhibitor of cytochrome P450 11A1 (CYP11A1), a catalyst of the first and rate-limiting step of steroid biosynthesis. By blocking the first step of the enzymatic pathway, opevesostat has the potential to inhibit all steroid hormones involved in AR signaling activation. In the phase 1/2 CYPIDES study, opevesostat had antitumor activity in patients with heavily pretreated mCRPC, especially in those with AR ligand binding domain (AR-LBD) mutations. The randomized, open-label, phase 3 MK-5684-004 trial (NCT06136650) will evaluate the efficacy and safety of opevesostat versus abiraterone or enzalutamide in patients with molecularly unselected mCRPC previously treated with 1 prior NHA. Methods Eligible patients have mCRPC that progressed during ADT ≤6 months before screening and during/after 1 NHA for hormone-sensitive prostate cancer or non-mCRPC. Approximately 1500 patients (375 with, 1125 without AR-LBD mutations) will be randomly assigned 1:1 to receive opevesostat 5 mg PO BID + dexamethasone 1.5 mg and fludrocortisone 0.1 mg PO QD or abiraterone acetate 1000 mg PO QD (if prior enzalutamide/darolutamide/apalutamide) or enzalutamide 160 mg PO QD (if prior abiraterone). Primary end points are radiographic PFS per PCWG3-modified RECIST v1.1 by BICR and OS in AR-LBD mutation–positive and –negative disease, separately. Secondary end points include time to initiation of first subsequent anticancer therapy or death; ORR and DOR per PCWG3-modified RECIST v1.1 by BICR; and safety. Recruitment is ongoing.© 2024 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was previously presented at the 2024 ASCO Annual Meeting. All rights reserved.

ObjectivesMolecular tumor boards (MTBs) have become an integral component of precision oncology, yet data on their real-world impact in urologic cancers are limited. This study aimed to characterize the molecular landscape of urologic malignancies presented to the MTB at the University Medical Center Freiburg and to evaluate the frequency and clinical relevance of genomic alterations across tumor entities.MethodsWe retrospectively analyzed 118 patients with histologically confirmed urologic tumors presented at the Freiburg MTB between Januar 2019 and December 2024. Comprehensive molecular profiling was performed using next-generation sequencing (TruSight Oncology 500 or whole exome sequencing). Data were analyzed for mutation frequency, tumor mutational burden (TMB), and co-occurrence patterns, and integrated with clinical data to guide therapy recommendations.ResultsSomatic mutations were identified in 90.6% of cases. Frequent alterations included TP53, BRCA2, KMT2D, and ATM, with DNA damage response and chromatin remodeling pathways commonly affected. Prostate cancers showed high rates of BRCA2 and APC co-mutations, indicating potential benefit from combined PARP and Wnt-targeted therapies. In bladder and upper tract urothelial carcinomas (UTUC), KMT2C co-occurred with genes such as SPTA1 and LRP1B, suggesting a hypermutated, immunoresponsive phenotype. Renal tumors frequently harbored alterations in VHL, PBRM1, and SETD2. Rare entities such as penile and testicular tumors displayed distinct mutation patterns, including BRCA1/2 and MMR gene alterations.ConclusionsComprehensive molecular profiling in a MTB setting reveals distinct and therapeutically relevant mutational patterns across urologic cancers. These data support the integration of MTBs into clinical workflows and highlight the potential of co-mutational signatures to guide personalized treatment strategies.

Background and objective:Stimulated Raman histology (SRH) offers promising near-real-time tissue visualization for intraoperative pathology assessment. We present preliminary results from the ROBOSPEC study, with a focus on the accuracy of results obtained via an integrated artificial intelligence (AI) tool. Methods:ROBOSPEC is a prospective, single-arm pilot study involving patients with prostate cancer undergoing robot-assisted radical prostatectomy (RARP). Probes from the RP specimens from the first 18 patients with intermediate-risk or high-risk prostate cancer were collected bilaterally from the dorsolateral sides of the prostate and examined with frozen section with hematoxylin and eosin staining (cryo-HE), SRH imaging (NIO laser imaging system, Invenio Imaging, Santa Clara, CA, USA). A previously published New York University AI algorithm (NYU-AI) that is based on the Inception-ResNet-v2 CNN architecture was used to generate three-color overlays to assist in interpretation. SRH images were reviewed by blinded urologists using this AI-enhanced output. Key findings and limitations:NYU-AI identified positive surgical margins in 22% of patients, with no statistically significant difference in comparison to cryo-HE (p > 0.05). Patient-based analysis yielded sensitivity and a negative predictive value (NPV) of 1.0, specificity of 0.93, and a positive predictive value of 0.75. Sample-based analysis showed similar performance, with specificity of 0.97 and identical sensitivity and NPV. These findings indicate strong diagnostic agreement between NYU-AI and conventional intraoperative pathology. Limitations of the study include the small patient cohort, the single-center design, previous training of the NYU-AI tool on prostate biopsy and periprostatic surgical-bed samples, and the lack of testing of interobserver agreement. Conclusions and clinical implications:Our preliminary findings support the potential of SRH with NYU-AI for intraoperative detection of positive surgical margins during RARP. Implementation of this technique should be further discussed after more studies have been conducted. Patient summary:We looked at an artificial intelligence program using a method called stimulated Raman histology to assess the cancer status of the cutting margin during robot-assisted surgery to remove the prostate. Our preliminary results show that this method could be an alternative to the current standard as it provides accurate and faster results.

Background and objective:Lymph node-positive (pN1) prostate cancer (PCa) is a heterogeneous disease, and a clear definition of prognostic groups is urgently needed. We aimed to assess cancer-related mortality (CRM) in different prognostic groups of pN1 patients, created based on the pathological PCa characteristics and number of positive lymph nodes (LN+). Methods:We conducted a retrospective, multicentre cohort study including 894 patients with pN1 disease treated at 15 European high-volume centres. Independent predictors for CRM were identified and pooled. A prognostic model was constructed for the prediction of CRM, accounting for death from other causes as a competing risk. The 10-yr cumulative risk of mortality was assessed. Key findings and limitations:Our model was based on pT stage (pT2-3a vs pT3b-4), surgical margin (SM) status (positive vs negative), and number of LN+ (1-4 vs >4), and included three prognostic groups. The favourable-prognosis group includes patients with pT2-3a and one to four LN+, or pT3b-4 with negative SM status. The intermediate-prognosis group included patients with pT2-3a disease and more than four LN+, or pT3b-4 disease, one to four LN+, and positive SM status. Patients in the poor-prognosis group had all three high-risk factors present. The C-index of this model was 0.73. The 10-yr cumulative CRM rates were 12% (95% confidence interval: 7.3-16%), 32% (24-40%), and 58% (40-76%), respectively, with significant differences between groups (hazard ratio 2.2-6.4, p < 0.005). Conclusions and clinical implications:The pN1 patient population is extremely heterogeneous, with an increased risk of death from PCa rather than death from other causes. In this group of patients, primary cancer characteristics (pT stage, number of LN+, and SM status) still represent the driving factors of CRM. Patient summary:Men with positive lymph nodes on pathology have an increased risk of dying from prostate cancer, rather than from other causes. Our proposed model stratifies patients into groups with different cancer-related prognosis and may aid in personalised clinical decision-making in a postoperative setting.

BACKGROUND:Metastatic castration-resistant prostate cancer (mCRPC) remains a therapeutic challenge. Poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPi) combined with new hormonal agents (NHA) offer novel treatment options. OBJECTIVE:This review summarizes the current status of PARPi + NHA combination therapy in mCRPC. MATERIALS AND METHODS:Summary of relevant phase II and III trials on PARPi + NHA and the G‑BA (Gemeinsame Bundesausschuss) decision as well as the current S3 guideline recommendations. RESULTS:PARPi + NHA demonstrated improved efficacy compared to NHA alone in an all-comers population that received prior androgen deprivation therapy (ADT) or docetaxel therapy. In particular the subgroup of patients with homologous recombination repair (HRR) and breast cancer (BRCA) 1/2 mutations had the best outcomes. Olaparib + abiraterone, talazoparib + enzalutamide, and niraparib + abiraterone are approved combinations, expanding treatment options in mCRPC. CONCLUSION:PARPi + NHA represent a significant advance in mCRPC therapy. Molecular genetic testing for HRR mutations, especially BRCA 1/2, is crucial for treatment planning.