The therapeutic landscape for renal cell carcinoma (RCC) and urinary tract cancer (UTC) has transformed dramatically, creating complexity in treatment selection and sequencing. The 2025 Advanced Urologic Cancer Consensus Conference was convened to establish evidence‐based expert consensus recommendations for optimal management. A multidisciplinary panel of 51 experts participated in a modified Delphi process addressing questions developed through iterative consensus‐building covering RCC and UTC management. Voting occurred before and after the conference, and analyses focused on postmeeting responses. Consensus was defined as ≥75% agreement, with strong consensus as >90%. Strong consensus was found on the use of adjuvant pembrolizumab for higher risk RCC (pathologic T2 [pT2], grade 4; pT3–pT4, any grade; pTXN1; or fully resected metastatic disease) and on neoadjuvant therapy before cystectomy for localized UTC. There was strong consensus on the use of enfortumab vedotin plus pembrolizumab as frontline therapy for metastatic UTC and the use of platinum‐based chemotherapy postprogression in biomarker‐negative UTC. For RCC, there was consensus on the role of single‐agent vascular endothelial growth factor receptor–tyrosine kinase inhibitor therapy after progression on frontline immune checkpoint inhibitor/vascular endothelial growth factor receptor–tyrosine kinase inhibitor therapy or dual immune checkpoint inhibitor therapy. However, there was a lack of consensus on other critical areas in the management of RCC and UTC. The 2025 Advanced Urologic Cancer Consensus Conference provides evidence‐informed guidance for complex clinical scenarios while identifying critical research priorities. The group recognizes that the lack of consensus across multiple areas highlights the need for improved patient selection and prospective studies enabling optimal combination and sequencing approaches. This iterative annual process will address evolving treatment paradigms to optimize outcomes.

PURPOSE:Precision medicine has revolutionized oncology; however, tumor biomarkers are not reflective of the heterogeneous cancer population. We evaluated NRG Oncology prostate cancer (PCa) clinical trials for demographic differences among patients with optional biospecimen collection (BC) consent and biospecimen submission (BSub). METHODS:Data from 19 NRG PCa clinical trials closed before 2015 were analyzed. Patients who consented to BC and completed BSub were evaluated by race, ethnicity, median income, area deprivation index (ADI; categorized as highest v lowest three quartiles), age at enrollment, site, and year of enrollment. T/chi-square tests were used for continuous/categorical variables, respectively, followed by logistic regression. RESULTS:Of the 15,648 randomized patients eligible for BC, 11,796 (75%) had specimens submitted. In all, 4,598 (82.2%) of 5,597 eligible patients consented for optional BC in nine clinical trials with a separate BC consent process (consent rates by race/ethnicity: 74.1% Black, 72.8% Hispanic/Latino, 83.8% White). A smaller proportion of Black and Hispanic/Latino patients consented to optional BC compared with those who did not (12.1% v 19.5% Black, P < .0001; 3.5% v 5.8% Hispanic, P = .0006). In univariable logistic regression models, high ADI (more socioeconomic disadvantage) was associated with a decreased likelihood for optional BC consent (odds ratio [OR], 0.67 [95% CI, 0.55 to 0.82]; P = .02), but not a decreased likelihood for BSub (OR, 0.74 [95% CI, 0.53 to 1.04]; P = .08). Multivariable models demonstrated that Black/Hispanic/Latino patients were less likely to consent to optional BC, and Black patients were less likely to have BSub (P < .05 for all). CONCLUSION:White/non-Hispanic patients and those with less socioeconomic disadvantage were more likely to consent to optional BC, whereas Black patients were less likely to have BSub. Targeted solutions are needed to improve biorepository representation so that precision medicine approaches better reflect the cancer population.

BACKGROUND:Delays in initiating radiation therapy for cervical cancer are common and may contribute to poorer outcomes. However, the pace of stage progression remains uncertain, limiting the development of quality targets and mitigation strategies. METHODS:We conducted a prospective cohort study of women with cervical cancer treated with radiation in Botswana between 2012 and 2019. We used an instrumental variable (IV) approach based on seasonal variation in access to treatment to estimate the causal effect of treatment delay on cancer stage progression. The month of cancer diagnosis served as a natural source of variation, with women diagnosed during end-of-year holiday disruptions (November-February) experiencing longer delays on average than women at other times of the year. Using two-stage weighted models of mean delay and mean cancer stage at time of treatment, we estimated the average time required for cervical cancer stage to progress (eg, IIIA to IIIB). To contextualize findings we examined the association between cancer stage at treatment initiation and overall survival. RESULTS:Among 763 eligible participants, 494 were diagnosed during routine access periods and 269 during delayed periods. The mean time to treatment initiation was longer (IV partial F statistic 13.1) in the delayed access group (12.4 weeks) compared to the routine access group (11.2 weeks). The groups were otherwise well-balanced. In the primary analysis, cervical cancer stage progression was estimated to occur over a mean of 8.6 weeks (95% CI: 7.1-10.9). Modeled time to stage progression differed by HIV status (p <0.001) with estimated 7.6 weeks (95% CI: 6.4-9.2) for women with HIV and 8.7 weeks (95% CI: 6.1-15.3) for women without HIV. Stage increase was associated with 38% (95% CI: 33 to 44%) reduction in survival time. CONCLUSIONS:Modest treatment delays commonly encountered in routine care were associated with measurable cervical cancer progression likely decreasing survival. Initiating treatment within four weeks from diagnosis minimizes the risk of stage progression.

Since the introduction of the Vesical Imaging-Reporting and Data System (VI-RADS), MRI has become an important imaging modality in the management of patients with bladder cancer. Its excellent diagnostic performance for determining muscle invasion in bladder cancer has been supported by numerous prospective and retrospective studies. Nevertheless, there needs to be continued improvement of the diagnostic performance of VI-RADS and sustained efforts to address remaining unmet clinical needs within the field of bladder cancer. In this paper, we highlight several such areas, some of which are actively being investigated. These include (1) whether to use intravenous contrast media or not (multiparametric vs. biparametric MRI), (2) quantitative metrics to enhance assessment of muscle invasion, (3) anatomic locations that come with pitfalls in staging, (4) introduction of bladder MRI image quality, (5) neoadjuvant chemotherapy VI-RADS (nacVI-RADS) and other considerations needed in the treatment response assessment after systemic therapies, (6) need for wider adoption, training, and implementation, and (7) application of artificial intelligence.

Given the recent explosion in the number and diversity of novel targeted systemic therapies, many future advances in cancer treatment may result from improving the therapeutic ratio of radiotherapy (RT) by exploiting combinations of RT and novel targeted systemic therapies. Despite the abundance of preclinical models suggesting that new agents can improve the efficacy of RT, early-phase clinical trials have not demonstrated expected synergies or even additive efficacy between RT and these agents, particularly in trials of concurrent immunotherapy/RT. This underscores the ongoing need to develop well-formulated and well-executed early-phase clinical trials in this space that are based on sound science and are well-positioned to discern the optimal ways to combine these treatment modalities. What are the barriers to the completion of early-phase clinical trials combining RT and drugs?

Purpose/Objective(s) Radiotherapy (RT) +/- androgen deprivation therapy (ADT) plays a key role in salvage therapy of prostate cancer (PC) recurrent after radical prostatectomy. However, not all patients benefit, and there is an unmet need for biomarkers to distinguish responders from non-responders (defined as those with second biochemical failure after salvage). We hypothesized that somatic mutations in primary PC are correlated with response to salvage RT+ADT. Materials/Methods We retrospectively identified 718 consecutive PC patients treated with post-operative RT at a single institution from 1992-2013, of whom 40 were treated with salvage RT+ADT and had formalin-fixed, paraffin-embedded prostatectomy and matched normal tissues available for DNA extraction. The indication for salvage therapy was biochemical failure after an undetectable post-operative PSA in 72%, gross local recurrence in 17%, and persistently elevated PSA after surgery in 11%. Median RT dose was 64.8 Gy, and all patients received concurrent ADT. Whole exome sequencing (WES) was performed to an average depth of 162X (r, 70.7-219). We tested for association between somatic mutations and clinical outcomes using the log-rank test and Cox proportional hazards model. Results Median age at salvage was 64.5 yrs. High quality WES data was available in 31 patients. With a median follow-up of 122 months (range = 29-248), 16 experienced second biochemical failure after salvage while 15 did not. Median time to second biochemical failure was 82.3 months (range = 1.2-140). Overall tumor mutational burden (TMB) was 3.3 mutations/Mb (range = 1.4-12.9). TMB among those with second biochemical failure was 3.8 vs. 2.8 among those without (p = 0.22). The most common mutations detected in the overall cohort were ALEC (n = 6) and CUX1 (n = 5). The presence of mutations in BRCA2, CASZ1, SYNE1, and AFDN was significantly correlated with second biochemical failure after salvage RT+ADT (see Table 1). Local failure after salvage occurred in 3 patients and was correlated with AFDN mutation (p = 0.0002). In contrast, none of the patients with mutations in WIZ (n = 4) or FOXA1 (n = 3), experienced second biochemical failure during follow-up. Conclusion Using WES analysis, we found that mutations in BRCA2, CASZ1, SYNE1, and AFDN correlated with second biochemical failure after salvage therapy with RT+ADT. These findings require validation in larger cohorts, but suggest that somatic mutations could potentially serve as predictive biomarkers for post-prostatectomy salvage therapy.

INTRODUCTION:We aimed to evaluate population-based outcomes of chemoradiation therapy (CRT) for muscle-invasive bladder cancer given a lack of population-based data, particularly in older adults. MATERIALS AND METHODS:We conducted observational analyses using SEER-Medicare based on the CRT protocol in the control arm of SWOG/NRG 1806. We included adults aged 66-89 years with T2-T4a N0 M0 urothelial bladder cancer treated with radiation and concurrent chemotherapy (cisplatin, gemcitabine, or 5-FU + mitomycin C) within 90 days of transurethral resection of bladder tumor (TURBT) from 2000 to 2017. We examined progression-free (PFS), cancer-specific (CSS), and overall survival (OS) using claims-based proxies and the Kaplan-Meier method. Associations of baseline characteristics with outcomes were evaluated using Cox regression. RESULTS:A total of 283 patients were included. Median age was 78 years (IQR 73-82), and tumor stage was T2 in 247 (87%) patients. Median follow-up was 26.0 months. At five years, PFS was 47%, CSS was 53%, and OS was 35%. On multivariable analysis, female sex (HR 1.74) was associated with increased risk of cancer-specific mortality (CSM), while higher education level (HR 0.37 for <14% without high school education versus >29%) was associated with reduced CSM. DISCUSSION:Notwithstanding the limitations of SEER-Medicare, in observational analyses designed to evaluate outcomes of a hypothetical single-arm trial, CRT was associated with lower CSS and OS than reported in prior clinical trials. Additional studies are required to determine if this is related to the efficacy or completeness of CRT in population-based practices or differences between trial and non-trial populations.

PURPOSE:177Lu-PSMA-617 (LuPSMA) is an effective radiopharmaceutical therapy for patients with metastatic castration-resistant prostate cancer. While LuPSMA can treat disseminated disease, additional localized control of metastatic disease may be required. Metastasis-targeted external beam radiation therapy (M-EBRT) can be an effective adjunct. However, the indications, efficacy, and safety/toxicity of combining M-EBRT with LuPSMA are unclear. Here, we report our experience with M-EBRT in patients receiving LuPSMA and assess M-EBRT's ability for local disease control and palliation. METHODS AND MATERIALS:This retrospective institutional review board-exempted study reviewed patients treated with LuPSMA at a multi-institutional academic cancer center within the first 2 years after United States Food and Drug Administration's approval, receiving contemporaneous M-EBRT. Clinical factors driving the use of M-EBRT were analyzed. RESULTS:Treatment courses of 261 patients receiving LuPSMA were reviewed; 52 patients received M-EBRT contemporaneously. M-EBRT was administered for intracranial/epidural disease (n = 22/52; 42%), bone pain palliation (n = 17/52; 33%), prevention of pathological fractures (n = 12/52; 23%), and 12% (n = 6/52) for various other indications. M-EBRT timing varied among patients, with 54% (n = 28/52) receiving M-EBRT before, 27% (n = 14/52) after, and 13% (n = 7/52) during LuPSMA therapy. EBRT was mostly well tolerated, although lymphopenia was commonly experienced. Most patients (n = 32/52; 62%) had symptom relief following M-EBRT. Symptom relief post-M-EBRT was 68%, 85%, and 50%, and mortality rates were 32%, 29%, and 57% for patients receiving EBRT before, during, and after LuPSMA treatment, respectively, albeit not statistically significant (P > .23). Prostate-specific antigen (PSA)50 (decrease in PSA by 50% during treatment) response in this patient population was 41% compared with 50% in the general LuPSMA population, but the magnitude of PSA response was heterogeneous (P = .27). CONCLUSIONS:In our experience, M-EBRT was used effectively with LuPSMA therapy for local tumor control and symptom management, especially for localized osseous and central nervous system lesions, and with good tolerability. M-EBRT may be an important adjunct treatment modality that facilitates the initiation and/or continuation of LuPSMA.

384 Background: RTOG 0521 was a randomized trial of radiotherapy (RT) and 24 months of androgen deprivation (ADT) with and without docetaxel (D) in high risk prostate cancer. We sought to evaluate whether post RT PSA was prognostic of outcomes and predictive of the benefit of D. We hypothesized that patients with a higher post RT PSA derive a benefit from D while those with a lower post RT PSA would derive no benefit. Methods: Patients treated on RTOG 0521 received 72-75.6 Gy in 40-42 fractions 8 weeks after starting ADT. In the experimental arm, D was started 28 days after RT. Per protocol, a PSA was to be drawn within 28 days after completion of RT (PRT-PSA). Hazard ratios (HRs) for PRT-PSA (>/≤ median level) were estimated by Cox proportional hazards regression for overall survival (OS) and Fine-Gray competing risks regression for prostate specific mortality (PCSM) and distant metastasis (DM), adjusting for baseline characteristics. As a sensitivity analysis for non-proportional hazards, HRs were estimated with follow up censored at 10 years. Results: PRT-PSA was available in 276/563 patients (114/281 in ADT alone and 162/282 in the ADT+D arm). PRT-PSA was drawn at a median of 15 days from the completion of RT and 120 days from randomization. 25% of patients had a PRT-PSA >0.1 ng/L. Patients with PSA >0.1 ng/mL had worse OS (HR 2.39, 95% confidence interval [CI] 1.51-3.79), PCSM (HR 3.78, 95% CI 1.87-7.62), and DM (HR 3.54, 95% CI 1.99-6.31) (all p<0.001). Baseline characteristics including Gleason score, T-stage, pretreatment PSA, performance status, and age were similar between patients with a PRT-PSA >0.1 and ≤ 0.1 ng/mL. In patients with PRT-PSA >0.1 ng/mL, there was no benefit seen with the addition of D to ADT alone in terms of OS (HR 1.06, p=0.88), PCSM (HR 0.97, p=0.96), or DM (HR 1.16, p=0.75). In patients with PRT-PSA ≤0.1 ng/mL, there was a benefit from the addition of D to ADT alone in terms of OS (HR 0.55, p=0.03) and PCSM (HR 0.36, p=0.02) but no significant benefit in terms of DM (HR 0.74, p=0.40). Results were similar in the sensitivity analysis for patients with PRT-PSA >0.1 ng/mL (OS HR 1.36, p=0.42; PCSM HR 1.71, p=0.39) and patients with PRT-PSA ≤0.1 ng/mL (OS HR 0.41, p=0.003; PCSM HR 0.26, p=0.006). Conclusions: PRT-PSA was prognostic of OS, DMFS, and DM in patients with high risk prostate cancer treated with RT and long term ADT +/- D. Despite having a worse prognosis, patients with PRT-PSA >0.1 ng/mL did not benefit from the addition of D while those with PRT-PSA ≤ 0.1 ng/mL had an OS and PCSM benefit from D. Clinical trial information: NCT00288080 . PRT-PSA (ng/mL) ADT, event/total ADT+D, event/total Adjusted HR (95% CI) Adjusted HR (95% CI)-10 y OS ≤0.1 28/79 31/127 0.55 (0.32-0.95) 0.41 (0.23-0.73) >0.1 21/35 18/35 1.06 (0.51-2.19) 1.36 (0.64-2.88) PCSM ≤0.1 13/79 7/127 0.36 (0.15-0.87) 0.26 (0.10-0.67) >0.1 15/35 11/35 0.97 (0.29-3.21) 1.71 (0.51-5.70) DM ≤0.1 14/79 16/127 0.74 (0.37-1.50) 0.75 (0.37-1.50) >0.1 16/35 16/35 1.16 (0.47-2.85) 1.09 (0.43-2.75)

4602 Background: TMT is a curative treatment option for pts with MIBC. Plasma circulating tumor DNA (ctDNA) is associated with treatment response and clinical outcomes following cystectomy for MIBC, but the association of plasma ctDNA with treatment response and clinical outcomes in pts treated with TMT is poorly understood. We hypothesize that ctDNA dynamics are correlated with clinical outcomes in pts with MIBC treated with TMT. Methods: Pts with MIBC who received TMT at Dana-Farber/Brigham and Women’s Cancer Center or Massachusetts General Hospital, consented to a research protocol, and underwent ctDNA evaluation with the commercially available Signatera assay were included in the analysis. Individual chart review was performed to collect demographic and clinical data. Results: A total of 67 pts had at least one ctDNA evaluation and were included in this analysis. Cohort characteristics are summarized in Table 1. Forty-eight pts had at least one ctDNA evaluation prior to TMT, and 17 (35%) were ctDNA(+). Of the pts who were ctDNA(+) prior to TMT, 12 had at least one post-TMT ctDNA evaluation and 7 of 12 (58%) converted to ctDNA(-). Thirty-one pts were ctDNA(-) prior to TMT: 24 (77%) have had ≥1 post-TMT ctDNA evaluation and all 24 remained ctDNA(-) at the first post-TMT evaluation (median 8 weeks after TMT completion). Of the 55 pts with ≥1 post-TMT ctDNA result, 46 (84%) have remained ctDNA(-) during subsequent follow-up and do not have clinical evidence of recurrence (median number of ctDNA evaluation, 2; median follow up, 44 weeks). Nine pts had a ctDNA(+) result in the post-TMT setting: 5 were also ctDNA(+) prior to TMT, 2 did not have a pre-TMT ctDNA assessment but were ctDNA(+) at first-post TMT assessment, and 2 were ctDNA(-) before and initially after TMT but subsequently converted to ctDNA(+). Of these 9 ctDNA(+) cases, 6 pts (67%) have developed clinical evidence of metastatic disease to date with a median lead time of 5.3 weeks (range, 0-27 weeks) between first ctDNA(+) assessment and clinical evidence of metastatic disease. Overall, the sensitivity of plasma ctDNA testing in the post-TMT setting was 100% and the specificity was 94%. Conclusions: Most pts with MIBC treated with TMT in this cohort were ctDNA(-) following TMT and did not develop evidence of recurrent invasive or metastatic disease. Pts with ctDNA(+) status in the post-TMT setting frequently developed clinical evidence of metastatic disease. Larger cohorts with longer follow-up will be required to determine whether ctDNA status may be useful in guiding clinical decisions in MIBC pts undergoing TMT. No. of Pts 67 Median Age (Yrs) 75 M:F 59:8 T3-4 (%) 16 (24%) ≥N1 (%) 3 (4%) Presence of variant histology (%) 13 (19%) Received neoadjuvant chemotherapy (%) 12 (18%) Received concurrent chemotherapy (%) 61 (91%) Median RT dose (Gy) 55 Median length of follow up (weeks) 39

Introduction Detection of genomic alterations and the presence of molecular residual disease (MRD) through the assessment of peripheral blood circulating tumor DNA (ctDNA) has important clinical relevance in muscle-invasive (MIBC) and advanced bladder cancer patients. Similarly, analysis of tumor DNA within patient urine specimens (utDNA) presents an intriguing option to optimize clinical care and investigate tumor biology in NMIBC patients. We investigated the utility of utDNA to characterize the genomic landscape and monitor MRD status in longitudinally collected urine samples from NMIBC patients treated with durvalumab containing regimens in the previously reported HCRN GU16-243: ADAPT-BLADDER Trial (Hahn N et al, Eur Urol 2023). Methods Baseline peripheral blood mononuclear cell and longitudinal urine samples at baseline, 3-month, 6-month, tumor recurrence (if observed), and 24-month (if available) time points were collected from BCG-unresponsive NMIBC patients treated with durvalumab monotherapy (D), durvalumab plus BCG (D + BCG), or durvalumab plus external beam radiation therapy (D + EBRT) in the HCRN 16-243: ADAPT-BLADDER Trial. utDNA mutations, copy number aberrations, tumor mutational burden (TMB), and MRD status were assessed by the PredicineWES+ and PredicineBEACON MRD assays respectively. Mutational, copy number aberrations, and TMB data were summarized in graphical form. Associations between post-treatment utDNA MRD status and clinical outcomes were assessed by generalized estimating equation (GEE) regression testing. Results Sixty-six utDNA samples from 26 patients were collected. Sixty-five (98.5%) samples were sufficient for analysis (Baseline n=25; 3-month n=19; 6-month n=16; recurrence n=1; 24-month n=4). Baseline utDNA was detectable in all (100%) patients with a median of 75 genomic alterations per sample, a median TMB of 1.4 muts/Mb (IQR 0.6 – 3.5), and a median tumor fraction (TF) of 21.0% (IQR 9.9 – 37.0). Frequent alterations in TERT, TP53, KMT2D, ARID1A, ATM, RB1, ERBB2, KDM6A, CDKN2A, and MDM2 were detected. Following treatment, MRD remained detectable in 36 (90%) samples (3-month – 17/19 (90%); 6-month – 15/16 (94%); recurrence – 1/1 (100%); 24-month – 3/4 (75%)) with 4 samples (10%) demonstrating undetectable MRD. In a multivariate GEE analysis, TF declined from baseline to cycle 4 (p=0.057), and to cycle 8 (p=0.039). TF was significantly lower in patients with RFS durations greater than 12 months, p < 0.001. Collection of utDNA specimens in additional treatment cohorts is ongoing. Conclusions Detection and monitoring of utDNA MRD proved feasible in this initial investigation in BCG-unresponsive NMIBC patients treated with durvalumab containing regimens. Post-treatment utDNA MRD was detected in most samples. Post-treatment reduction of utDNA tumor fraction was associated with durable clinical benefit. Validation of the utility of utDNA MRD status as a novel biomarker of response in NMIBC patients is ongoing in larger randomized prospective trials.

To evaluate whether pretreatment multiparametric MRI features can predict biochemical recurrence in patients with localized prostate cancer treated with radiation therapy of curative intent. This retrospective single-institution study analyzed patients with prostate cancer who underwent primary radiotherapy between January 2015 and December 2019. All patients underwent pretreatment multiparametric MRI, with or without endorectal coil. Clinical, pathological and MRI features were assessed, with emphasis on qualitative and quantitative imaging characteristics. Univariate binary logistic regression identified significant predictors of recurrence. Variables showing significance (p < 0.05) were included in forward stepwise logistic regression analysis. The primary endpoint was biochemical recurrence, defined by Phoenix criteria. The study included 54 patients (mean age 76.57 ± 7.77 years), with 10 patients (18.5

113 Background: Oligometastatic prostate cancer (omPCa) is an understudied entity, historically defined as ≤5 non-visceral metastases. However, its true prevalence in the molecular diagnostic imaging (MDI) era is unknown. Therapeutic clinical trials in advanced PCa based on conventional imaging modalities (CIM) complicate the ability to extrapolate findings to omPCa. Consequently, there is not a standard treatment approach; radiation therapy (RT) recommendations can vary widely. We sought to evaluate management and outcomes of de novo omPCa patients treated with RT in a multi-institutional cohort. Methods: Patients presenting with de novo omPCa (≤5 non-visceral lesions, allowance for >5 per physician discretion) diagnosed via CIM and/or MDI across 7 participating institutions were identified. Demographic/clinical data were collected. Clinical outcomes, including disease progression (any biochemical recurrence or distant failure) and survival were assessed. Progression-free survival (PFS) and overall survival (OS) were determined using the Kaplan-Meier method. Results: 163 patients treated with RT between 2015-2024 were analyzed (clinical data at diagnosis; Table). Over half of patients (90/163, 55%) were diagnosed using MDI, the remainder via CIM. 7% of patients presented with pelvic lymph nodes (LNs) only, 2% with non-regional LNs, 42% with bone only disease, and the remainder with a combination. Most patients (161/163) received systemic therapy. Of 131 patients with details, 39% received androgen deprivation therapy (ADT) alone, the remainder received ADT + androgen receptor signaling inhibitor (n=51); 8 also received docetaxel. 4% of patients received prostate RT alone, 5% of patients received prostate + pelvic RT, 17% of patients received metastasis-directed RT only, 36% of patients received prostate + pelvic + metastasis-directed RT, and 38.7% of patients received prostate + metastasis-directed RT. 152 patients had full follow-up (FU) details available. Median FU from time of omPCa diagnosis was 31 months (range, 3-229). Twenty-two patients developed distant metastases (outside of documented OM). Five-year OS from time of diagnosis was 91% (95%CI 80,97). Five-year PFS after RT was 51% (95%CI 30,68) with median PFS of 74 months (95%CI 41, not reached). Conclusions: In this contemporary real-world cohort, nearly all patients with de novo omPCa received systemic therapy and ~75% were treated with at least prostate + metastasis-directed RT. Identification of omPCa included both MDI and CIM, reflecting real-world patterns. Further analysis incorporating additional institutions, oligorecurrent and oligoprogressive patients is ongoing, and will evaluate the association of treatment characteristics on progression at last FU. Characteristic Age Gleason score PSA Number of lesions Median, range 68 (44-92) 8 (6-10) 17 (2-2670) 2 (1-8)

BACKGROUND:We aim to evaluate whether increased lymph node yield at prostatectomy (RP) is associated with improved outcomes in NRG/RTOG 9601, a randomized clinical trial of men who underwent either radiation (RT) alone or RT + bicalutamide for PSA elevation following RP for pT2/T3 prostate cancer. METHODS:We reviewed available pathology reports for patients in NRG/RTOG 9601 to determine the nodal count at RP. Cox proportional hazards models were used to assess effect of lymph nodes yield, arm (RT alone or RT + bicalutamide), Gleason score, positive margins, and seminal vesicle invasion on the following endpoints: times to local and distant failure and overall and disease-specific survival. RESULTS:Of 760 patients, 552 (73%, 276 in each arm) had complete data available. Median node count in the entire cohort was 6 (range: 0-33, IQR: 3-9). There were no significant differences between arms in terms of patient demographic or clinical characteristics, including total lymph nodes removed in either arm. There was no significant association between total lymph nodes and overall or disease-specific survival with both arms combined and when adjusting for arm. Notably, interaction analysis revealed that in seminal vesicle invasion, there was a significant association between lymph node yield and OS and DSS (HR = 0.91, 95% CI: 0.83-0.99, p = 0.034; HR = 0.87, 95% CI: 0.77-0.99, p = 0.029, respectively). CONCLUSIONS:Although lymph node yield in NRG/RTOG 9601 did not show association with adverse outcomes in the entire cohort or either arm alone, there was significant association between lymph node yield and adverse outcomes when seminal vesicle invasion was present. The therapeutic benefit of extensive lymph node dissection remains uncertain but could be more relevant in higher risk patients.

418 Background: Research on the genetic profile of cribriform pattern (CP) and intraductal carcinoma (IDC) subtypes of aggressive prostate cancer (PCa) is limited. We evaluated germline mutations in CP/IDC PCa patients receiving radiation therapy (RT) to assess the role of familial high-risk (FHR) and DNA damage repair (DDR) mutations associated with these pathologies and clinical outcomes. Methods: This multi-institutional study included CP/IDC PCa patients treated with RT who consented to germline whole exome sequencing (WES). WES data was annotated using Ensembl Variant Predictor, ClinVar, and OncoKB to identify pathogenic/oncogenic mutations. Mutational frequencies were calculated in R. Clinical data and disease progression (biochemical recurrence [BCR], local relapse [LR], distant metastases [DM]) were assessed. Gene and clinical outcome associations were evaluated using the Kaplan-Meier method and log-rank test (p < 0.05 for significance, Benjamini-Hochberg FDR of 0.1 used for multiple hypothesis testing). Results: Of 1,392 CP/IDC patients treated with RT between 2010-2024, 80 had germline sequencing, and 49 had WES data (12 CP, 24 IDC, 13 CP+IDC); 45 were localized at diagnosis (28 high-, 16 intermediate-, 1 low-risk). Median age at diagnosis was 64 years. 39 (80%) received RT post-radical prostatectomy (RP, salvage) and 10 (20%) for intact prostate (definitive). Median follow-up (FU, months) was 64.5 after diagnosis and 60.3 after RT. At last FU post-RT, 14 (29%) exhibited BCR, 12 (24%) had LR, and 9 (18%) had DM, with progression rates of 83% in CP and IDC, and 77% in CP+IDC. Five-year OS from diagnosis was 94.8% (95% CI, 80.4-98.7), and BCR-free survival (defined as no BCR post-salvage or post-definitive RT) was 69% (95% CI, 47.8-83). Of the 98 FHR and 280 DDR genes analyzed, 4 (8%) and 20 (40%) patients had confirmed mutations, respectively. Of the 24 patients with germline mutations, 20 (83%) had IDC pathology. DDR mutations associated with improved BCR-free survival, HR 0.14, 95%CI 0.03-0.70, p=0.007. Notably, 19 patients had a pathogenic MSH3 deletion, which was associated with improved BCR-free survival, HR 0.17, 95%CI 0.03-0.83, p=0.02. Additionally, 20 patients had pathogenic stop-gains/deletions, 17 (85%) of whom had IDC pathology. Five oncogene mutations were identified in DDR genes ATR, TP53 and ATM, and tumor suppressor genes SHDA and DPYS previously implicated in PCa, all in IDC samples. Conclusions: Pathogenic germline mutations, particularly DDR variants, are significantly associated with aggressive IDC pathology. Continued evaluation in non-CP/IDC patients undergoing RT is needed to examine associations between mutations, subtypes, and outcomes. Mutations in DDR genes, such as MSH3 deletion, were linked to improved BCR-free survival, highlighting the potential role of DDR alterations in therapeutic response of RT patients with aggressive PCa subtypes.

BACKGROUND AND OBJECTIVE:Innovations have improved outcomes in advanced prostate cancer (PC). Nonetheless, we continue to lack high-level evidence on a variety of topics that greatly impact daily practice. The 2024 Advanced Prostate Cancer Consensus Conference (APCCC) surveyed experts on key questions in clinical management in order to supplement evidence-based guidelines. Here we present voting results for questions from APCCC 2024. METHODS:Before the conference, a panel of 120 international PC experts used a modified Delphi process to develop 183 multiple-choice consensus questions on eight different topics. Before the conference, these questions were administered via a web-based survey to the voting panel members ("panellists"). KEY FINDINGS AND LIMITATIONS:Consensus was a priori defined as ≥75% agreement, with strong consensus defined as ≥90% agreement. The voting results show varying degrees of consensus, as discussed in this article and detailed in the Supplementary material. These findings do not include a formal literature review or meta-analysis. CONCLUSIONS AND CLINICAL IMPLICATIONS:The voting results can help physicians and patients navigate controversial areas of clinical management for which high-level evidence is scant or conflicting. The findings can also help funders and policymakers in prioritising areas for future research. Diagnostic and treatment decisions should always be individualised on the basis of patient and cancer characteristics, and should incorporate current and emerging clinical evidence, guidelines, and logistic and economic factors. Enrolment in clinical trials is always strongly encouraged. Importantly, APCCC 2024 once again identified important gaps (areas of nonconsensus) that merit evaluation in specifically designed trials.

BACKGROUND AND OBJECTIVE:This publication represents a summary of the updated 2025 European Association of Urology (EAU) guidelines for muscle-invasive and metastatic bladder cancer (MMIBC). The aim is to provide practical recommendations on the clinical management of MMIBC with a focus on diagnosis, treatment, and follow-up. METHODS:For the 2025 guidelines, new and relevant evidence was identified, collated, and appraised via a structured assessment of the literature. Databases searched included Medline, EMBASE, and the Cochrane Libraries. Recommendations within the guidelines were developed by the panel to prioritise clinically important care decisions. The strength of each recommendation was determined according to a balance between desirable and undesirable consequences of alternative management strategies, the quality of the evidence (including the certainty of estimates), and the nature and variability of patient values and preferences. KEY FINDINGS AND LIMITATIONS:The key recommendations emphasise the importance of thorough diagnosis, treatment, and follow-up for patients with MMIBC. The guidelines stress the importance of a multidisciplinary approach to the treatment of MMIBC patients and the importance of shared decision-making with patients. The key changes in the 2025 muscle-invasive bladder cancer (MIBC) guidelines include the following: a new recommendation for the use of susceptible FGFR3 alterations to select patients with unresectable or metastatic urothelial carcinoma for treatment with erdafitinib; significant adaption and update of the recommendations for pre- and postoperative radiotherapy and sexual organ-preserving techniques in women; new recommendation related to radical cystectomy and extent of lymph node dissection based on the results of the SWOG trial; recommendation related to hospital volume; new recommendations for salvage cystectomy after trimodality therapy and for the management of all patients who are candidates for trimodality bladder-preserving treatment in a multidisciplinary team setting using a shared decision-making process; significant adaption and update to the recommendation for adjuvant nivolumab in selected patients with pT3/4 and/or pN+ disease not eligible for, or who declined, adjuvant cisplatin-based chemotherapy; and addition of a new recommendation for metastatic disease regarding the antibody-drug conjugate trastuzumab deruxtecan in case of HER2 overexpression; in addition, removal of the recommendations on sacituzumab govitecan as the manufacturer has withdrawn the US Food and Drug Administration approval for this product; update of the follow-up of MIBC; and full update of the management algorithms of MIBC. CONCLUSIONS AND CLINICAL IMPLICATIONS:This overview of the 2025 EAU guidelines offers valuable insights into risk factors, diagnosis, classification, treatment, and follow-up of MIBC patients and is designed for effective integration into clinical practice.

Purpose NRG/RTOG 1115 was a phase 3 trial evaluating the addition of orteronel, a CYP17A1 inhibitor, to radiation therapy (RT) plus androgen deprivation therapy (ADT) in men with high-risk prostate cancer. Methods and Materials The study was designed to evaluate overall survival for 900 men with high-risk prostate cancer (Gleason 9-10, prostate specific antigen (PSA) > 20, or clinical stage T2 or higher with Gleason ≥ 8). Patients were randomized 1:1 to standard of care (SOC) therapy (RT plus 2 years of ADT) or SOC plus 2 years of orteronel. RT entailed image guided conventionally fractionated dose-escalated external beam RT to the prostate and pelvis to 45 Gy using intensity modulated RT with either intensity modulated RT (to 79.2 Gy) or brachytherapy boost. Health-related quality of life (HRQOL) was measured using the Expanded Prostate cancer Index Composite (EPIC), Patient-Reported Outcome Measurement Information System (PROMIS) fatigue, and EQ-5D. Accrual was halted early because of discontinuation of orteronel development and the trial redesigned to focus on a composite biochemical failure endpoint. Results There were a total of 231 eligible randomized patients. Only 29% in the orteronel arm received ≥80% of the planned dose. With median follow-up of 6.2 years, the cumulative incidence of grade 3+ adverse events was higher on orteronel than on the standard arm (P < .001; hazard ratio [HR], 2.32; 95% CI, 1.52-3.47) with 5-year estimates of 59.0% and 35.1%, respectively. No significant differences in overall survival (P = .28; HR, 0.71; 95% CI, 0.39-1.32) or biochemical failure (P = .56; HR, 0.84; 95% CI, 0.47-1.51) were observed. Use of orteronel had a transient negative impact on all prostate cancer-specific QOL domains of the EPIC, but did not increase the magnitude of decline once RT started and had minimal impact on other HRQOL measures. Conclusions The addition of orteronel to RT and ADT did not result in significant improvement in any efficacy outcomes, although information was limited by poor drug tolerance and early termination of accrual, thus limiting statistical power.