This prospective, multicentre, intra-patient comparator study assessed urinary radioactivity, and patient-level and region-level detection rates (DR) with PSMA-PET radiopharmaceuticals, 18F-piflufolastat (18F-DCFPyL) and 18F-flotufolastat (18F-rhPSMA-7.3) in patients with biochemical recurrence (BCR) of prostate cancer to evaluate the hypothesis that lower urinary radioactivity is observed with 18F-flotufolastat. Patients with low PSA (≤0.5 ng/mL) BCR ≥6 months post-prostatectomy with undetectable PSA post-surgery, scheduled for standard-of-care 18F-piflufolastat PSMA-PET were enrolled. Patients underwent PET/CT 60 minutes post-18F-piflufolastat (9 mCi) administration, and a second PET/CT on the same scanner 1–10 days later, 60 minutes post-18F-flotufolastat (8 mCi) administration. The primary endpoint was the difference in urinary radioactivity (SUVmean) between the radiopharmaceuticals. Secondary endpoints included patient-level and region-level DR for each radiopharmaceutical, assessed by two blinded readers (a third resolved disagreements, allowing majority reads). Fifty-five evaluable patients (mean PSA, 0.28 ng/mL) were enrolled. Median bladder SUVmean was significantly higher with 18F-piflufolastat (29.0; interquartile range, 18.9–40.8) than 18F-flotufolastat (10.9; interquartile range, 6.0–18.5; p < 0.001 [Wilcoxon signed-rank test]). Majority read patient-level DR were 27.3

BACKGROUND:The objective of this cluster randomized controlled trial was to determine the feasibility and safety of an intensive (systolic blood pressure [SBP] <120 mm Hg) versus usual care (SBP <140 mm Hg) approach to SBP control in patients with renal cell or thyroid cancer initiating VEGFR (vascular endothelial growth factor)-tyrosine kinase inhibitors. METHODS:A phase II site-based cluster randomized controlled trial compared intensive SBP control to usual care, incorporating a centralized BP advisory core to guide BP management. Patients underwent home BP monitoring and study visits at baseline, 1, 2, 3, and 6 months. SBP was compared between the 2 study arms using bootstrapped CIs. Common Terminology Criteria for Adverse Events and patient-reported outcomes were summarized. RESULTS:Overall, 61 patients with renal cell (n=58) or thyroid cancer (n=3) from 10 sites were enrolled; 30 at 5 sites were randomized to intensive SBP control and 31 at 5 sites to usual care. A lower SBP was observed in the intensive SBP control arm compared with usual care, with mean differences of -12.2 (95% CI, -18.1 to -7.0) mm Hg at 1 month, -7.6 (95% CI, -15.3 to -0.4) mm Hg at 3 months, and -6.9 (95% CI, -19.3 to 6.0) mm Hg at 6 months. In the usual care arm, Grade 3 Common Terminology Criteria for Adverse Events for kidney injury (n=4), hypotension (n=3), and dyspnea (n=2) were numerically greater compared with the intensive SBP control (n=1, 2, and 0, respectively). Patient-reported outcomes were largely similar between the 2 groups. CONCLUSIONS:This first-ever randomized controlled trial of SBP control in an active cancer population demonstrates the feasibility, safety, and tolerability of intensive SBP control with VEGFR tyrosine kinase inhibitors. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT04467021.

TPS272 Background: Prostate-specific membrane antigen (PSMA)-targeting positron emission tomography (PET) radiopharmaceuticals enable early detection of metastatic and recurrent prostate cancer (PCa). High urinary radioactivity of some PSMA-PET agents can affect interpretation of scans in the pelvic region (prostate/prostate bed [PB]; pelvic lymph nodes [PLN]). 18 F-Piflufolastat and 18 F-flotufolastat are FDA-approved, mainly renally cleared, diagnostic PSMA-PET agents; data suggest 18 F-flotufolastat has lower urinary radioactivity than 18 F-piflufolastat, but no clinical differences have been confirmed by head-to-head intra-patient studies. The present study will directly compare the urinary radioactivity of 18 F-piflufolastat with 18 F-flotufolastat in men with low prostate-specific antigen (PSA) biochemical recurrence (BCR) of PCa after radical prostatectomy (RP). Methods: This multicenter, prospective, intra-patient comparator study will include men (≥ 18 years old) with low PSA (≤ 0.5 ng/mL) BCR of PCa who have had RP ≥ 6 months before enrollment (with undetectable PSA post surgery) and are due to have routine 18 F-piflufolastat PET. Men who have had prior 18 F-piflufolastat PET or salvage therapy, or with conditions affecting urinary output, will be excluded. Eligible patients will undergo 18 F-piflufolastat PET followed by 18 F-flotufolastat PET ≥ 24 hours but ≤ 10 days later. No diuretic will be administered for scanning purposes. Each radiopharmaceutical will be administered as a single intravenous bolus per approved US prescribing information (USPI). Scanning (with the same scanner for both scans) will start 50–90 minutes post injection of 18 F-piflufolastat and 50–70 minutes post injection of 18 F-flotufolastat. Each patient will be their own control. The primary endpoint will be difference in mean standardized uptake value (SUV mean ) between 18 F-piflufolastat and 18 F-flotufolastat as assessed in volumes of interest drawn on the urinary bladder. Secondary endpoints for both agents will include detection rates: at the patient level (overall; by baseline PSA); for local recurrences in PB subregions; and for PLN lesions. For secondary endpoints, PET scans will be interpreted per product-specific USPI by 2 specially trained, blinded, central readers (a third reader will adjudicate disagreements). Safety will be monitored until 24 hours after the second scan. Around 60 men will be screened and ≥ 52 with evaluable PET scans for both agents will be included in the primary analysis. The primary endpoint will be assessed for normality and a difference in SUV mean will be tested using 2-sided paired tests (Wilcoxon signed-rank test [non-normal]; t-test [normal]). All further endpoints, including safety, will be summarized descriptively. The trial has been open for enrollment since 10/24. Clinical trial information: NCT06604442 .

e17044 Background: Abiraterone acetate (AA) is a CYP17 inhibitor, an enzyme required for androgen biosynthesis. AA is an approved first-line treatment for metastatic PC (mPC). A first-in-human trial demonstrated inadequate testosterone (T) suppression with AA monotherapy, leading to its subsequent development in combination with GnRH analogues. We conducted a single arm, phase II trial of pts with mPC treated with AA+Prednisone (AAP) following the discontinuation of GnRH therapy. We previously reported on the primary endpoint, demonstrating successful suppression of T levels with AA monotherapy. This report presents results on the time to luteinizing hormone (LH) normalization and survival outcomes. Methods: We conducted a single arm, phase II study for pts with mPC treated with AAP following GnRH analogue discontinuation. Primary endpoint of T suppression was reported previously. Secondary endpoints included time-to-LH normalization, progression-free survival (PFS) and overall survival (OS). Adverse events were monitored throughout the trial period and graded according to CTCAE V5.0. Pts were followed until radiographic/clinical progression/death; LH levels were monitored every 12-weeks; normalization was defined as LH above 1.2 IU/L. PFS was defined as the time (weeks) from study enrollment and GnRH analogue discontinuation until progression or death, while OS was defined as the time to death (weeks) from any cause. We used Kaplan-Meier analysis to evaluate survival outcomes and Cox regression for multivariable modeling. Results: Between November 2018 and September 2019, 31 pts were enrolled to the study; we previously reported demographics. Median PFS was 119 weeks (95% CI: 87.1-182.1); median OS was not reached (95% CI: 163-NR); median follow up was 229 weeks. In multivariable subgroup analysis, ECOG PS of 2 compared to less than 2 was associated with shorter OS (HR: 17.8, p<0.05). The median time-to-LH normalization was 21 weeks (95% CI 15-27). Most common AEs included fatigue (n=4) hot flashes (n=5) and hypokalemia (n=2); all AEs were grade 1 except grade 3 fatigue (n=1), grade 2 hyperglycemia, (n=1) gr 2 prostatic obstruction (n=1). No treatment discontinuation due to AEs was observed. Conclusions: AAP used alone following GnRH discontinuation in pts with mPC successfully suppressed T and produced encouraging survival outcomes with an acceptable safety profile. Clinical trial information: NCT03565835 .

BACKGROUND AND OBJECTIVE:The rs4680 single-nucleotide polymorphism (SNP) of the COMT gene leads to a reduction in dopamine clearance, resulting in better mood and a decrease in symptoms in noncancer populations, but its influence on quality of life (QOL) during cancer treatment is undefined. We hypothesized that in comparison to wildtype (WT) COMT, the rs4680 SNP is associated with better QOL among men with metastatic hormone-sensitive prostate cancer receiving androgen deprivation therapy ± docetaxel (ADT ± D). METHODS:In this post hoc analysis, we tested the association between COMT rs4680 status and Functional Assessment of Cancer Therapy-Prostate (overall QOL), Functional Assessment of Chronic Illness Therapy-Fatigue, and Brief Pain Inventory scores at baseline and at 3, 6, 9, and 12 mo using Fisher's exact test and the Wilcoxon rank-sum test. Blood samples for genotyping were collected before treatment initiation. KEY FINDINGS AND LIMITATIONS:COMT SNP data were available for 550/790 men. Across the overall cohort, 3-mo pain severity was lower for rs4680 versus WT COMT (0.5 vs 1.25; p = 0.04). In the ADT arm, rs4680 versus WT COMT was associated with better overall QOL at 6 mo (128.9 vs 118.5; p = 0.04), less pain at 3 mo (no pain: 70.4% vs 41.5%; p = 0.01), and less pain interference at 3 mo (no interference: 76% vs 51.3%; p = 0.03), 6 mo (75% vs 48.7%; p = 0.02), and 9 mo (83.3% vs 52%; p = 0.02), with similar fatigue scores. Patients in the ADT + D arm had similar QOL regardless of COMT status. CONCLUSIONS AND CLINICAL IMPLICATIONS:Patients with the COMT rs4680 SNP experienced less pain and better global QOL after starting ADT alone. This is the first study to show that inherited genetic traits may influence treatment tolerability in men with prostate cancer.

447 Background: The evolving treatment landscape in mRCC since the advent of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) has rendered the role of CN unclear. We sought to quantify CN utilization in the US over the past two decades and assess factors that affect equitable access to CN. Methods: We performed an analysis of the National Inpatient Sample database, using ICD-9 and ICD-10 diagnostic and procedure codes to identify mRCC patients undergoing CN from 2006 to 2021. We calculated annual CN utilization rates, stratified by demographic and socioeconomic factors. We then performed univariable and directed acyclic graph-guided multivariable logistic regression analyses to determine the effect of demographic, socioeconomic, and clinical factors on CN utilization rates. Results: There has been a significant decrease in CN utilization in 2021 compared to 2006 (8.7% vs. 15.8%; OR 0.51, 95% CI 0.42-0.61), consistent across all demographic and socioeconomic groups. Factors associated with decreased CN utilization include Black race (OR 0.70, 95% CI 0.64-0.76), Hispanic race (OR 0.87, 95% CI 0.80-0.95), female gender (OR 0.94, 95% CI 0.90-0.98), being a Medicare (aOR 0.69, 95% CI 0.64-0.73) or Medicaid beneficiary (aOR 0.59, 95% CI 0.54-0.64), lowest income quartile (aOR 0.84, 95% CI 0.78-0.90), Southern US location (aOR 0.83, 95% CI, 0.74-0.93), and treatment in small-sized (aOR 0.57, 95% CI 0.51-0.63) or rural hospitals (aOR 0.33, 95% CI 0.27-0.40). CN utilization has significantly decreased during the ICI era compared to the TKI era (OR 0.69, 95% CI 0.64-0.75). Conclusions: CN utilization has steadily declined across the US over the past two decades, reflecting the uncertainty surrounding its role in mRCC management as new systemic therapies emerge. Access to CN is marked by significant demographic and socioeconomic disparities. Defining the evolving role of CN in the current mRCC treatment era and addressing these disparities is crucial to optimize patient outcomes. Characteristic Univariable analysis(OR [95% CI]) p -value Multivariable analysis(aOR [95% CI]) p -value Black race (ref. White) 0.70 (0.64-0.76) <0.001 - - Hispanic race (ref. White) 0.87 (0.80-0.95) 0.001 - - Female gender (ref. male) 0.94 (0.90-0.98) 0.008 - - 1 st quartile income (ref. 4 th quartile) 0.79 (0.73-0.85) <0.001 0.84 (0.78-0.90) <0.001 Medicare (ref. private insurance) 0.55 (0.53-0.58) <0.001 0.69 (0.64-0.73) <0.001 Medicaid (ref. private insurance) 0.58 (0.54-0.63) <0.001 0.59 (0.54-0.64) <0.001 Southern US (ref. Northeastern US) 0.82 (0.73-0.92) 0.001 0.83 (0.74-0.93) 0.002 Small hospital (ref. large hospital) 0.56 (0.50-0.62) <0.001 0.57 (0.51-0.63) <0.001 Rural hospital (ref. urban teaching hospital) 0.32 (0.27-0.38) <0.001 0.33 (0.27-0.40) <0.001

Prostate cancer remains a significant source of morbidity and mortality worldwide, with metastatic castration-sensitive disease (mCSPC) representing a complex therapeutic challenge. This review explores how a deeper understanding of the androgen receptor axis has shifted mCSPC management from monotherapy to more intense treatment. We discuss emerging data on triplet regimens, targeted therapies, and the role of local treatment. Randomized trials have shown that adding docetaxel or androgen receptor signaling inhibitors (ARSIs) to androgen deprivation therapy (ADT) improves survival. Triplet therapy (ADT, docetaxel, and an ARSI) improves outcomes in patients with high-volume disease compared to ADT and docetaxel alone, although comparisons to ADT plus ARSI doublet therapy are ongoing. The early use of targeted radionuclides, biomarker-driven therapies, and metastasis-directed radiotherapy has also emerged, potentially refining treatment personalization in clinical practice. Current guidelines recommend ADT combined with an ARSI, with the addition of docetaxel reserved for high-volume disease. Future research aims to optimize intensity, inform biomarker-driven strategies, and reduce toxicity. Advancements in management of mCSPC underscore the importance of a multimodal, personalized approach to improve outcomes.

BACKGROUND AND OBJECTIVE:The evolving treatment landscape in metastatic renal cell carcinoma (mRCC) since the advent of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) has rendered the role of cytoreductive nephrectomy (CN) unclear. We sought to quantify CN utilization in the USA over the past two decades and assess factors that affect access to CN. METHODS:We analyzed the National Inpatient Sample database from 2006 to 2021, identifying mRCC patients who underwent CN using International Classification of Diseases (ICD)-9 and ICD-10 codes. Annual CN utilization rates were calculated and stratified by demographic and socioeconomic factors. Univariable and multivariable logistic regression analyses, guided by directed acyclic graphs, were performed to assess the factors influencing CN utilization. KEY FINDINGS AND LIMITATIONS:CN utilization declined significantly in 2021 compared with that in 2006 (8.7% vs 15.8%; odds ratio [OR] 0.51, 95% confidence interval [CI] 0.42-0.61), a trend observed across all demographic groups. Reduced CN utilization was associated with Black (OR 0.70, 95% CI 0.64-0.76) and Hispanic (OR 0.87, 95% CI 0.80-0.95) race, female gender (OR 0.94, 95% CI 0.90-0.98), Medicare (adjusted OR [aOR] 0.69, 95% CI 0.64-0.73) or Medicaid (aOR 0.59, 95% CI 0.54-0.64) insurance, lower income (aOR 0.84, 95% CI 0.78-0.90), Southern US location (aOR 0.83, 95% CI 0.74-0.93), and treatment at small (aOR 0.57, 95% CI 0.51-0.63) or rural (aOR 0.32, 95% CI 0.26-0.38) hospitals. CN utilization declined further in the ICI (2018-2021) era compared with the TKI era (2006-2017; OR 0.69, 95% CI 0.64-0.75). CONCLUSIONS AND CLINICAL IMPLICATIONS:CN utilization has decreased progressively in the USA, coinciding with the emergence of novel systemic therapies. Several demographic and socioeconomic factors are associated with differential CN utilization. These findings underscore the need for further research to clarify the role of CN in the evolving mRCC therapeutic landscape.

Purpose:Although African American (AA) patients are disproportionately affected by prostate cancer, they are often underrepresented in oncology clinical trials. The SPOTLIGHT study (NCT04186845) assessed the novel diagnostic positron emission tomography radiopharmaceutical, 18F-flotufolastat (18F-rhPSMA-7.3), in patients with recurrent prostate cancer. The proportion of AA patients enrolled in SPOTLIGHT (17%) was greater than typically enrolled in oncology trials (8.5%) and was representative of the US population (14%). This post hoc analysis of SPOTLIGHT evaluates the diagnostic performance of 18F-flotufolastat in AA patients. Methods and Materials:Patients underwent positron emission tomography/computed tomography 50 to 70 minutes after intravenous administration of 296 MBq 18F-flotufolastat. Three blinded readers evaluated all images, with the majority read (agreement of ≥2 readers) result reported here. Standard of truth (SoT) was established with histopathology or correlative imaging. Data from AA patients were evaluated to determine the 18F-flotufolastat overall detection rate (DR), positive predictive value (PPV), and verified DR (VDR). VDR (SoT-verified) is equivalent to DR × PPV. Results:In total, 61 of 366 (17%) patients were AAs. Although baseline characteristics were broadly similar, fewer AA patients (56%) had undergone prostatectomy than non-AA patients (82%). The patient-level DR was 93% (57/61) in AA patients, increasing from 67% at prostate-specific antigen <0.5 ng/mL to 100% at prostate-specific antigen ≥10 ng/mL. Patient-level DR was marginally lower in all other patients (87%, 264/305). However, when stratifying by prior treatment, DRs were similar across ethnic groups in postprostatectomy patients, but in patients with intact prostates, AA patients had higher prostate DR than non-AA patients. SoT-verification (predominantly with conventional imaging [79%]) gave a VDR of 64% and PPV of 68% in AA patients, versus 55% and 64%, respectively, in all other patients. Conclusions:18F-Flotufolastat DRs were marginally higher in AA patients than in all other patients enrolled in SPOTLIGHT. High VDR and PPV were also achieved in AA patients from across all participating centers, indicating the broad applicability of newly US Food and Drug Administration-approved 18F-flotufolastat to the US population as a whole.

Context: Treatment decision-making (TDM) for patients with localized (LPC) or locally advanced (LAPC) prostate cancer is complex, and post-treatment decision regret (DR) is common. The factors driving TDM or predicting DR remain understudied. Objective: Two systematic literature reviews were conducted to explore the factors associated with TDM and DR. Evidence acquisition: Three online databases, select congress proceedings, and gray literature were searched (September 2022). Publications on TDM and DR in LPC/LAPC were prioritized based on the following: 2012 onward, >= 100 patients, journal article, and quantitative data. The Preferred Reporting Items Reviews and Meta-analyses guidelines were followed. Influential factors were those with p < 0.05; for TDM, factors described as "a decision driver", "associated", "influential", or "significant"were also included. The key factors were determined by number of studies, consistency of evidence, and study quality. Evidence synthesis: Seventy-five publications (68 studies) reported TDM. Patient participation in TDM was reported in 34 publications; overall, patients preferred an active/shared role. Of 39 influential TDM factors, age, ethnicity, external factors (physician recommendation most common), and treatment characteristics/toxicity were key. Forty-nine publications reported DR. The proportion of patients experiencing DR varied by treatment type: 7-43% (active surveillance), 12-57% (radical prostatectomy), 1-49% (radiotherapy), 28-49% (androgen-deprivation therapy), and 21-47% (combination therapy). Of 42 significant DR factors, treatment toxicity (sexual/urinary/bowel dysfunction), patient role in TDM, and treatment type were key. Conclusions: The key factors impacting TDM were physician recommendation, age, ethnicity, and treatment characteristics. Treatment toxicity and TDM approach were the key factors influencing DR. To help patients navigate factors influencing TDM and to limit DR, a shared, consensual TDM approach between patients, caregivers, and physicians is needed. Patient summary: We looked at factors influencing treatment decision-making (TDM) and decision regret (DR) in patients with localized or locally advanced prostate cancer. The key factors influencing TDM were doctor's recommendation, patient age/ethnicity, and treatment side effects. A shared, consensual TDM approach between patients and doctors was found to limit DR. (c) 2024 The Author(s). Published by Elsevier B.V. on behalf of European Association of Urology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

e17107 Background: Genitourinary (GU) cancers significantly impact United States (US) public health, not just in mortality but also in premature deaths. We evaluated the potential years of life lost (PYLL) due to these cancers (prostate, kidney, bladder, testicular, penile, and others) from 1975 to 2017 using the SEER database and stratified it across racial groups. Methods: From 1975 to 2017, GU cancers were identified using SEER*Stat 8.4.2 using ICD-10 CM codes. We analyzed premature deaths and calculated PYLL as [Life expectancy minus (age at diagnosis + survival time)]. Due to non-homogeneity, the Kruskal-Wallis test (α = 5%) was employed for subgroup PYLL analysis. Spearman correlation coefficient (ρ) assessed the relationship between the year of diagnosis and PYLL. Analyses were conducted using SAS OnDemand. Results: Of the 1,715,763 GU cancer cases (1975-2017), 235,279 had premature deaths, totaling 2,406,551.20 PYLL. Testicular cancer showed the highest median PYLL (33.3 years) compared to other sites, followed by penile cancer with a median PYLL of 12.2 years. Non-Hispanic (NH) Blacks had higher PYLL for prostate, kidney, ureteral, and bladder cancers (p<0.05), while Hispanics had higher PYLL for penile and testicular cancers (p<0.0001). ρ value for PYLL and year of diagnosis was 0.23. Conclusions: Our study reveals a substantial impact of GU cancers on premature mortality and PYLL in the US. Despite the lower prevalence, testicular and penile cancers contribute significantly to PYLL, likely related to younger age at diagnosis. Racial disparities were evident, with NH-Blacks and Hispanics experiencing higher PYLL for specific GU cancers compared to other racial groups. These findings underscore the pressing need for targeted interventions to address disparities and enhance GU cancer management and prevention outcomes. [Table: see text]

294 Background: Pts newly diagnosed with LPC/LAPC must contemplate many factors to make tx decisions that may later lead to regret. We conducted literature reviews exploring factors associated with pt TDM and DR. Methods: Databases (Ovid Medline, Ovid Embase, Cochrane Library), select congress proceedings and gray literature were searched (12 Sept 2022). Publications (pubs) on pt TDM and tx DR in LPC/LAPC were included following systematic literature review methods and selected based on the following criteria: 2012 onward, ≥100 pts, journal article, and quantitative data. Study quality was assessed by risk of bias tools (NICE STA guidance; Newcastle-Ottawa). Influential factors were those with p<0.05; for TDM, factors described as “a decision driver,” “associated,” “influential,” or “significant” were also included. Key factors were determined under consideration of number of studies, consistency of evidence, and study quality. Results: 75 pubs (68 studies) reported TDM (12 countries; 68% North America [NA] 25% Europe [E]). Pt TDM participation was reported in 34 pubs; overall, pts preferred an active/shared role. Of 39 influential TDM factors, those related to baseline demographics, health and disease, external factors (doctor recommendation most common), and tx goals/attributes were key (Table). 49 pubs reported DR (12 countries; 59% NA, 29% E). DR was assessed at 2 weeks to 6 years post-tx. Not tx specific DR (23 studies), was felt by 8-48% of pts. Regret associated with specific tx (18 studies) was felt by 7-43% (active surveillance), 12-57% (radical prostatectomy), 1-49% (radiotherapy), 28-49% (androgen deprivation therapy), and 21-47% (combination therapy) of pts. Of 42 significant DR factors, tx toxicity (sexual/urinary/bowel dysfunction), pt role in TDM, and making an informed tx decision were key (Table). Conclusions: DR is common in pts with LPC/LAPC. To help pts navigate factors influencing TDM and limit risk of DR, a shared consensual TDM approach between pts, caregivers, and healthcare professionals is needed. [Table: see text]

Introduction In patients with intermediate-risk non-muscle–invasive bladder cancer (IR NMIBC), measurable disease by marker lesions provides an opportunity to assess on-target efficacy of novel therapies. FGFR3/2 alterations are frequent in NMIBC and FGFR inhibition may be beneficial to patients with IR NMIBC with FGFR3/2 alterations. Erdafitinib is an oral selective pan-FGFR tyrosine kinase inhibitor approved to treat locally advanced or metastatic urothelial cancer in adults with FGFR3/2 alterations who have progressed during or following ≥1 line of platinum-containing chemotherapy. We report a longer follow-up of an exploratory marker lesion cohort of patients with IR NMIBC (Cohort 3) from the multicohort phase 2 THOR-2 study (NCT04172675) of erdafitinib in patients with NMIBC with FGFR3/2 alterations. Methods Patients were ≥18 years, with histologically confirmed IR NMIBC with FGFR3/2 alterations and recurrent IR disease. All previous tumors must have been grade 1-2, Ta/T1, with no previous carcinoma in situ, a <5% risk of progression for 2 years, and a >50% risk of recurrence using the EORTC risk calculator. Patients had all visible bladder tumors resected by transurethral resection except for one 5-10mm marker tumor. Patients received oral erdafitinib at 6 mg daily in 28-day cycles. Surveillance cystoscopy was performed at 3 months and if complete response (CR) was achieved, urine cytology was performed. Patients with partial response (PR) or CR ≤3 months after starting treatment continued erdafitinib for maximum 2 years or until high-risk disease recurrence, intolerable toxicity, consent withdrawal, investigator decision, or study closure. Exploratory end points included CR rate,;duration of response (DOR), best overall response, and safety. Results At data cutoff (27-Jun-2023; median follow-up 10.0 months), 18 patients were enrolled (median age: 63.5 years [range, 47-77]; tumor stage: n=13 Ta, n=5 not staged) and received erdafitinib for median duration 7.1 months (range, 0.7-17.4). Fifteen patients had CR (CR rate, 83.3%); 2 had PR (11.1%); median time to response was 1.15 months; 1 had high grade recurrence (Table). In 17 responders, median DOR was 12.8 months, with 12 responses ongoing, 3 censored, 2 ending with recurrence (1 low-grade; 1 high-grade) (Figure). Most common treatment-emergent adverse events (TEAEs): hyperphosphatemia (100%; n=18), diarrhea (83.3%; n=15), dry mouth (72.2%; n=13), dry skin (50.0%; n=9), dysgeusia (50.0%; n=9). Grade 3 TEAEs (n=1 each): abdominal pain, diarrhea, dysuria, and gastritis. Seven grade 1 treatment-related central serous retinopathy events were reported in 3 (16.7%) patients; events resolved in 1 patient (ongoing in 2). Three (16.7%) patients discontinued due to treatment-related TEAEs. No deaths were reported. Conclusions In this marker lesion study of an FGFR-targeted therapy, erdafitinib demonstrated efficacy in all treated patients with IR NMIBC with FGFR alterations. Safety data were consistent with the known safety profile of erdafitinib.

BACKGROUND. Metastases are the hallmark of lethal cancer, though underlying mechanisms that drive metastatic spread to specific organs remain poorly understood. Renal cell carcinoma (RCC) is known to have distinct sites of metastases, with lung, bone, liver, and lymph nodes being more common than brain, gastrointestinal tract, and endocrine glands. Previous studies have shown varying clinical behavior and prognosis associated with the site of metastatic spread; however, little is known about the molecular underpinnings that contribute to the differential outcomes observed by the site of metastasis. METHODS. We analyzed primary renal tumors and tumors derived from metastatic sites to comprehensively characterize genomic and transcriptomic features of tumor cells as well as to evaluate the tumor microenvironment at both sites. RESULTS. We included a total of 657 tumor samples (340 from the primary site [kidney] and 317 from various sites of metastasis). We show distinct genomic alterations, transcriptomic signatures, and immune and stromal tumor microenvironments across metastatic sites in a large cohort of patients with RCC. CONCLUSION. We demonstrate significant heterogeneity among primary tumors and metastatic sites and elucidate the complex interplay between tumor cells and the extrinsic tumor microenvironment that is vital for developing effective anticancer therapies.

TPS5118 Background: Novel androgen receptor pathway inhibitors (ARPIs) improve overall survival (OS) in patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC) in conjunction with testosterone suppression (TS) relative to TS alone. However, the duration of treatment required to derive clinical benefit is unclear, as is whether continuous treatment is requisite for optimal cancer outcomes. Favorable PSA declines have been associated with prolonged OS in clinical trials testing TS + ARPIs. We thus designed this single-arm Phase 2 trial to test the hypothesis that pts who achieve exceptional response to upfront TS + ARPI can suspend treatment, allowing for T recovery and improvement in quality of life while maintaining favorable clinical outcomes. Methods: Eligible pts had mHSPC by conventional imaging with PSA ≥ 5 ng/ml and T ≥ 150 ng/dl (or not known to have been hypogonadal) prior to starting treatment, have been receiving TS for 540-750 days and ARPI for ≥ 360 days, and have achieved PSA < 0.2 ng/ml (stable or falling for 3 consecutive measurements) with castrate T <50 ng/dl at the time of enrollment. Intermittent ADT for biochemical recurrence prior to mHSPC diagnosis, prior local therapy, prior radiation to metastatic sites, and up to 6 cycles of docetaxel in mHSPC are permitted. Pts who underwent surgical castration, received ARPI prior to mHSPC diagnosis, or are receiving experimental treatment for mHSPC or participating in a clinical trial that does not allow for TS or ARPI interruption are excluded. After enrollment, pts discontinue both TS and ARPI and are followed with PSA and T levels every 3 months, conventional CT/MRI and bone scan at least every 6 months, and FACT-P questionnaire for patient-reported outcomes every 6 months. Treatment re-initiation triggers are PSA increase to ≥ 5 ng/ml, radiographic change (progressive disease per modified RECIST 1.1 on CT/MRI or unconfirmed progressive disease per PCWG3 on bone scan), or symptoms attributable to prostate cancer. Subsequent management is per physician discretion. The primary endpoint is remaining treatment-free with eugonadal T (> 150 mg/dl) 18 months after the start of treatment interruption, with 75 pts to be enrolled to differentiate 18-month treatment free rates of 0.30 (null hypothesis) and 0.45 (alternative hypothesis). Secondary endpoints include time to eugonadal T, duration off treatment, and changes in patient-reported outcomes. Exploratory endpoints include radiographic progression-free survival, time to next treatment, OS, and correlation of tissue- and blood-based biomarkers with clinical endpoints. The study was activated in July 2022 and accrual is ongoing throughout the NCTN. Support: U10CA180821, U10CA180882, UG1CA189823, https://acknowledgments.alliancefound.org , Veracyte Inc. Clinical trial information: NCT05241860 .

Background and objective: Neoadjuvant cisplatin-based chemotherapy prior to radical cystectomy (RC) improves overall survival (OS) in muscle-invasive bladder cancer (MIBC). However, many patients are cisplatin ineligible; therefore, new treatment options are needed. Nivolumab without/with lirilumab prior to RC was investigated in cisplatin-ineligible patients in this phase 1b trial (NCT03532451) to determine its safety/feasibility. Methods: Patients with localized MIBC received two doses of nivolumab (480 mg) alone (cohort 1) or with lirilumab (240 mg; cohort 2) prior to RC. Cohorts were enrolled sequentially. The key eligibility criteria were cT2-4aN0-1M0 stage and cisplatin ineligibility/refusal. The primary endpoint was the rate of grade (G) >= 3 treatment-related adverse events (TRAEs) as per Common Terminology Criteria for Adverse Events version 5.0. The key secondary endpoints included the proportion of patients who underwent RC >6 wk after the last dose, CD8+ T-cell density change between pretreatment transurethral resection of bladder tumor (TURBT) and post-treatment RC, ypT0N0, 2N0 rates, 2-yr recurrence-free survival (RFS), and OS. Key findings and limitations: Among 43 patients enrolled (n = 13, cohort 1; n = 30, cohort 2), 13 and 29 completed intended neoadjuvant therapy, respectively, in cohorts 1 and 2, and 41 underwent RC. The median time from the last dose to RC was 4 wk. The G3 TRAEs occurred in 0% (90% confidence interval [CI] 0-21%) of patients in cohort 1 and 7% (90% CI 1-20%) in cohort 2; all these TRAEs resolved and no G4/5 TRAEs occurred. No patient had delayed RC for >6 wk. In cohorts 1 and 2, ypT0N0 rates for patients with MIBC and RC were 17% and 21%, 2N0 rates were 25% and 32%, 2-yr RFS rates were 73% and 71%, and 2-yr OS rates were 82% and 89%, respectively. CD8+ Tcell density increased significantly from TURBT to RC in cohort 2. Conclusions and clinical implications: Neoadjuvant nivolumab-based immunotherapy was safe, feasible, and well tolerated in cisplatin-ineligible patients with MIBC. Although ypT0N0 rates were lower than expected, 2-yr survival rates seem to be comparable with those of other neoadjuvant immunotherapy trials. Nivolumab is being evaluated in the CA-017-078 trial (NCT03661320). Patient summary: For patients with muscle-invasive bladder cancer unable to receive cisplatin-based chemotherapy, treatment with nivolumab without and with lirilumab prior to radical cystectomy was safe, feasible, and well tolerated. Nivolumab-based immunotherapy showed lower pathologic response rates than but similar survival rates to other neoadjuvant immunotherapy trials. (c) 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Molecular profiling of clear cell renal cell carcinoma (ccRCC) tumors of patients in a clinical trial has identified distinct transcriptomic signatures with predictive value, yet data in non-clear cell variants (nccRCC) are lacking. We examined the transcriptional profiles of RCC tumors representing key molecular pathways, from a multi -institutional, real -world patient cohort, including ccRCC and centrally reviewed nccRCC samples. ccRCC had increased angiogenesis signature scores compared with the heterogeneous group of nccRCC tumors, while cell cycle, fatty acid oxidation/AMPK signaling, and fatty acid synthesis/pentose phosphate signature scores were increased in one or more nccRCC subtypes. Among both ccRCC and nccRCC tumors, T effector scores statistically correlated with increased immune cell infiltration and were more commonly associated with immunotherapy-related markers (PD-L1 + /TMB hi /MSI hi ). In conclusion, this study provides evidence of differential gene transcriptional profiles among ccRCC versus nccRCC tumors, providing insights for optimizing personalized and histology -specific therapeutic strategies for patients with advanced RCC.

Background Apalutamide plus androgen-deprivation therapy (ADT) improved outcomes in metastatic castration-sensitive prostate cancer (mCSPC) and non-metastatic castration-resistant PC (nmCRPC) in the Phase 3 randomised TITAN and SPARTAN studies, respectively, and maintained health-related quality of life (HRQoL). Apalutamide treatment effect by patient age requires assessment. Methods Post-hoc analysis assessed patients receiving 240 mg/day apalutamide (525 TITAN and 806 SPARTAN) or placebo (527 TITAN and 401 SPARTAN) with ongoing ADT, stratified by age groups. Prostate-specific antigen declines, radiographic progression-free survival, metastasis-free survival, overall survival (OS), HRQoL and safety were assessed using descriptive statistics, Kaplan-Meier method, Cox proportional-hazards model and mixed-effects model for repeated measures. Results Hazard ratios (95% confidence intervals) generally favoured apalutamide plus ADT versus ADT alone across all endpoints regardless of age; e.g., OS values were 0.57 (0.40–0.80), 0.70 (0.54–0.91) and 0.74 (0.40–1.39) (TITAN) and 0.39 (0.19–0.78), 0.89 (0.69–1.16) and 0.81 (0.58–1.15) (SPARTAN) in patients aged <65, 65–79 and ≥80 years. Regardless of age, apalutamide also maintained HRQoL and was tolerated well with a potential trend in rates of adverse events increasing with age. Limitations include post-hoc nature and variability in sample size of age groups. Conclusions Apalutamide plus ADT was an effective and well-tolerated option maintaining HRQoL in patients with mCSPC and nmCRPC regardless of age. Clinical trial registration TITAN (NCT02489318); SPARTAN (NCT01946204).

Introduction Although radical cystectomy (RC) has remained a mainstay for management of cT2-3 urothelial carcinoma (UC), contemporary evidence indicates that bladder-preserving trimodal therapy (TMT) may offer similar oncologic outcomes in select patients with muscle-invasive bladder cancer (MIBC). Traditionally reserved for patients unsuitable for surgical intervention, the significant morbidity and mortality linked to RC have led to a growing adaptation of TMT as a viable and effective alternative for definitive treatment with curative intent. In this study, we aim to present our institutional experience with TMT in a racially diverse population. Methods A single-center retrospective cohort study was performed to identify all patients who underwent radiation therapy (RT) for MIBC (cT2-T3) UC from 2012-2021 at our institution. All patients who underwent RT with or without concurrent chemotherapy with curative intent after diagnostic TUBT, with or without re-staging TURBT were included. Patient demographic (age, sex, race) and clinicopathologic data (stage, presence of hydronephrosis, concurrent carcinoma in-situ (CIS)) were extracted from the medical record.; Primary outcomes were response to TMT (complete response [CR], partial response [PR], progression) and recurrence-free and overall survival. Response was determined based on the first surveillance imaging, cystoscopy, or TURBT after completion of TMT. Results 47 patients underwent TMT with radiation therapy performed at our institution during the study period. One patient was excluded from the analysis due to primary oncologic care at an outside hospital with records not available for review. 39.1% were Latino/Hispanic, 19.6% of patients were Black/Non-Hispanic, and 26.1% were White/Non-Hispanic. 47.8% were female and 91.3% underwent concurrent chemotherapy with RT. 32 (69.6%), 9 (19.6%), and 5 (10.9%) patients experienced CR, PR and progression after TMT, respectively (Table 1). Median and mean follow-up times were 25.8 and 40.4 months, respectively. Overall, 27 (58.7%) patients were disease-free at the time of last follow-up, of which 74.1% were still alive. Of those alive at last follow-up, 97.0% had an intact bladder. 13 were alive with disease (28.3%) and 7 (15.2%) were deceased with disease. Conclusions With a recent growing body of evidence supporting TMT as a viable alternative to RC as definitive management for MIBC in select patients, we report our institutional experience describing outcomes over a 2-year follow-up period. In concordance with prior reports, TMT offers favorable tumor response rates for patients seeking definitive therapy for cT2-3UC. Extended follow-up is needed to assess the durability of response and long-term survival after TMT.