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Association between abnormal IMDC laboratory criteria after surgery and cancer-specific and overall survival in non-metastatic renal cell carcinoma: Potential biomarkers for adjuvant therapy patient selection.
567 Background: The International Metastatic RCC Database Consortium (IMDC) criteria are widely used for risk stratification in metastatic renal cell carcinoma (RCC), but their role in non-metastatic RCC is less defined, especially as a biomarker of recurrence. This study seeks to evaluate (1) the prevalence of IMDC abnormalities in non-metastatic RCC patients (nmRCCC), (2) the impact of nephrectomy on the normalization of these criteria, and (3) the association between post-operative IMDC abnormalities and oncological outcomes. Methods: Data from the Canadian Kidney Cancer Information System (CKCis) were analyzed to identify non-metastatic RCC patients diagnosed between January 2011 and April 2024 who underwent nephrectomy after diagnosis. Laboratory tests were evaluated preoperatively (within 6 months before surgery) and postoperatively (between 2 and 15 months). Univariable and multivariable analyses were performed to assess the association with overall survival, recurrence-free survival, and cancer-specific survival. Results: A total of 1,804 patients were analyzed, with 65.7% male and mean age was 62.5y. Tumors pathological characteristics were: pT1 (69.2%), pT2 (5.6%), pT3 (1.8%), pT4 (0.28%); tumors necrosis (21.8%); mean tumor size (4.7cm) and clear cell carcinoma (73.1%). Preoperative hemoglobin (Hb), neutrophils, platelets (Plt), and corrected calcium (Ca 2+ ) IMDC criteria abnormalities were identified in 19.4, 9.6, 4.3, and 3.2% of patients, respectively. After surgery, 45.4, 79.8, 80.4, and 76.9% of these abnormal cases normalized, respectively. Among patients with normal preoperative Hb, neutrophils, Plt, and Ca 2+ , 9.65, 4.4, 1.0, and 1.6% developed postoperative IMDC criteria abnormalities, respectively. In multivariate analysis, patients with normal Hb, neutrophils, and Ca 2+ , both pre- and postoperatively, had an increase in overall survival (OS) compared to those with abnormal postoperative values. Hazard ratios (HR[95%CI]) for increased OS were 3.6[2.8-4.7], 2.1[1.7-2.7] and 3.5[1.5-43.1], respectively, compared to those with abnormal postoperative values. Furthermore, those with normal Hb, neutrophils, Plt, and Ca 2+ , both pre- and postoperatively, had an increase in cancer-specific survival (CSS) with HR of 3.3, 4.3, 8.0 and 5.7 (p<0.05),indicating a significantly higher CSS probability than patients with abnormal postoperative values. Conclusions: Abnormal IMDC laboratory criteria are frequently found in nmRCC, especially anemia, and most normalize after surgery. Finding abnormal IMDC laboratory criteria post-surgery is associated with decreased CSS and OS. This knowledge may be useful in stratifying patients for intensified monitoring or for future adjuvant therapy clinical trials.
Apatinib monotherapy for pretreated advanced squamous cell carcinoma of the penis: A phase II trial.
8 Background: Treatment options for patients with advanced penile squamous cell carcinoma who have disease progression on systemic chemotherapy are scarce. Antiangiogenic drugs have shown antitumor effects in case series. This phase 2 trial evaluated the activity and safety of apatinib (a VEGF receptor inhibitor) in such patients. Methods: This investigator-initiated, single-arm, phase 2 trial was performed at a tertiary cancer center in Shanghai, China. Eligible patients had histologically confirmed penile squamous cell carcinoma, were not candidates for surgery with curative intent, had measurable disease, and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Patients were prescribed oral apatinib 500 mg daily with the option of dose reduction to manage adverse events. The primary endpoint was the investigator-assessed overall response rate (ORR) assessed in all patients who received at least one dose of study drug. Results: Between 2016 and 2023, we enrolled 23 patients, all of whom received at least one dose of study treatment. Of the 23 patients, sixteen had an ECOG performance status of 2. Only six patients had human papillomavirous-positive tumors. Five patients had a partial response (ORR=22% (95%CI: 10%-42%). Median Progression-Free Survival was 3.8 months and median overall survival was 7.2 months. Treatment-related adverse events of grade 3 or worse occurred in 7 (30%) of 23 patients. The most common grade 3 or 4 treatment-related adverse events were hand–foot syndrome (13%), hypertension (9%), and increase in serum alanine aminotransferase (ALT:9%). No treatment-related deaths occurred. Conclusions: Apatinib in pretreated advanced penile cancer showed limited efficacy with a manageable safety profile. A prospective study with apatinib in combination with immune checkpoint therapy is ongoing. Clinical trial information: 000021849.
A phase 2 trial of neoadjuvant futibatinib plus durvalumab for cisplatin-ineligible patients with <i>FGFR</i> overexpressing muscle-invasive bladder cancer.
TPS899 Background: There is an unmet need to develop neoadjuvant therapies for cisplatin-ineligible patients (pts) with muscle-invasive bladder cancer (MIBC). Neoadjuvant immune checkpoint inhibition (ICI) has shown promising early results in this population; however, > 2/3 pts did not achieve pathological complete response (pCR), a surrogate endpoint for improved survival. Fibroblast growth factor receptor inhibitor (FGFRi) may induce synergy with ICI through modulation of the tumor immune microenvironment. FGFR mRNA overexpression by RNA in situ hybridization (ISH) is an emerging biomarker that may predict responses to an FGFRi ± ICI. Futibatinib (FUTI) is an irreversible pan-FGFRi, and durvalumab (DURV) is an anti-PD-L1 antibody. Methods: This is a phase 2, single arm, multicenter study to evaluate the efficacy and safety of neoadjuvant FUTI + DURV before cystectomy. Pts with stage cT2 to cT4aN0M0, urothelial carcinoma predominant histology, cisplatin-ineligible by Galsky criteria, and FGFR1-3 mRNA expression ≥3+ by RNAscope ISH assay are eligible. Twenty-four pts will be treated with FUTI 20 mg PO daily and DURV 1500 mg IV on day 1 of every 28-day cycle for 3 cycles. The primary outcome is pCR (defined as ypT0N0). We hypothesize that FUTI + DURV will improve the pCR rate from 21% to 41%. This trial has 80% power to detect the alternative hypothesis while maintaining a one-sided α = 0.1. The study will begin with a safety lead-in period, during which 6 pts will be enrolled for dose-limiting toxicity (DLT) evaluations. After confirming safety (≤ 2 DLTs), another 18 pts will be enrolled. The study will be monitored for futility using a Bayesian Optimal Phase II design, including 2 interim analyses (12 and 18 pts). If there are ≥ 3 pCRs among the first 12 pts, we will continue enrollment. If there are ≥ 5 pCRs among the first 18 pts, the study will continue. When 24 evaluable pts are enrolled, we will reject the null hypothesis and conclude that the treatment is acceptable if there are ≥ 8 pCRs. The secondary endpoints include safety, pathologic downstaging rate, progression-free survival, and overall survival. Correlative studies will explore immune and molecular predictors of response and resistance in the tumor, blood, and urine. Clinical trial information: NCT06263153 .
Efficacy and safety of CAR-T cell therapy in penile and urethral carcinomas: A meta-analysis of preliminary clinical trials and case studies.
655 Background: Penile and urethral carcinomas are rare and aggressive cancers with limited treatment options, often leading to poor prognoses. Chimeric Antigen Receptor T-cell (CAR-T) therapy has shown promise in various malignancies, but its efficacy and safety in penile and urethral carcinomas remain under-explored. This meta-analysis aims to evaluate the preliminary clinical trials and case studies on CAR-T cell therapy in treating these rare carcinomas. Methods: The PubMed, Embase, Scopus and Cochrane databases were systematically searched from inception until June 2024 using relevant keywords. We performed proportional meta-analysis of untransformed proportions using Random Effects model in OpenMeta (version 5.3). The I 2 and X 2 statistics were used to evaluate inter-study heterogeneity. An I 2 value of >50% was considered significant heterogeneity. Subgroup analyses were performed to identify factors influencing treatment outcomes. Results: A total of 15 studies, including 10 clinical trials and 5 case reports, comprising 230 patients were included in the meta-analysis. The pooled overall response rate (ORR) was 42% (95% CI: 30%-55%), with a complete response rate (CRR) of 15% (95% CI: 8%-25%). Common adverse effects included cytokine release syndrome (CRS) (35%) and neurotoxicity (20%). Pre-existing comorbidities and prior treatments were significant factors affecting outcomes. No treatment-related mortality (TRM) was reported. Conclusions: CAR-T cell therapy demonstrates encouraging efficacy in penile and urethral carcinomas, with manageable safety profiles. While preliminary results are promising, larger and more comprehensive studies are needed to validate these findings and optimize treatment protocols.
Inclusion of patients with reduced performance status (ECOG 2 or higher) in FDA registrational trials for renal cell carcinoma (RCC).
453 Background: Clinical trials often use performance status indicators to include only those participants with good baseline functional status. The Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) and the Karnofsky Performance Scale (KPS) are two such scales that determine a cancer patient’s ability to perform common tasks. As a result, the study population does not accurately represent the real-world population. We evaluated the inclusion of patients with ECOG 2 or greater/ KPS less than 70 in RCC clinical trials leading to FDA approvals between 2014 and 2024. Methods: The US Food and Drug Administration (FDA) approvals for drugs approved in RCC and associated clinical evidence were collected from the FDA website from 2014-2024. Data from each registrational trial was searched in public databases using drug name, trial name, and registration number. The total number and percentage of participants in each ECOG/KPS category were recorded and analyzed. Results: The FDA approved 13 drugs and combinations for the treatment of RCC from 2014 - 2024. A cumulative total of 8731 participants were included in these trials, with only 24 (0.3%) participants with ECOG PS 2 or greater (KPS <70). Only 3 of the 13 trials included participants with ECOG 2 (KPS <70) with 2 trials having <1% ECOG 2 participants. Only CABOSUN trial had >10% enrolment of ECOG 2 participants. There was no participation of ECOG 3 in any of the trials. Of the total participants, over 70% belonged to ECOG score 0 or KPS 90-100 (excluding CheckMate 214 for which PS distribution data was unavailable). Conclusions: There is poor enrollment of participants with ECOG 2 and greater in registrational clinical trials for RCC. This limits the therapeutic options available for patients with poor PS and is not representative of the real-world population. Greater inclusion of poor PS patients is needed in future trials. Percentage enrollment of patients with reduced PS in registrational trials for RCC. Clinical trial Year Reduced PS% (ECOG 2 or higher/KPS <70) CABOSUN 2017 12.7% S-TRAC 2017 0.2% CheckMate 025 2015 0.4% LITESPARK-005, KEYNOTE-564, TIVO-3, CLEAR, CHECKMATE-9ER, JAVELIN Renal 101, KEYNOTE-426, CheckMate 214, METEOR, Lenvatinib+Everolimus 2016-2023 0.0%
Patterns of hospital admissions and readmissions due to immune-related adverse events in patients with genitourinary cancers.
462 Background: Immune checkpoint therapies (ICTs) improve survival in patients with genitourinary (GU) cancers, specifically renal cell carcinoma (RCC) and urothelial carcinoma (UC). However, they also lead to inflammation of normal host organs: immune-related adverse events (irAEs). Severe irAEs may lead to repetitive hospitalizations especially if refractory which affects patients’ ability to receive further anti-cancer therapy. We reasoned that identifying such irAEs may enable clinical quality improvement interventions to improve outcomes. Methods: All consecutive patients hospitalized under the Genitourinary Medical Oncology inpatient service at The University of Texas MD Anderson Cancer Center with irAEs over a 14-month period (June 2023 to August 2024) were evaluated. Readmission was defined as re-entry to any hospital within 30 days of an initial discharge. Patient characteristics, ICT regimens, irAE types, treatment strategies, time to outpatient follow-up, and clinical outcomes were analyzed. Results: Sixty-seven patients (n=53 male; n=14 female) were admitted at least once for an irAE. The median age was 69 years (IQR: 62.0-75.5). Male predominance was consistent with the sex distribution of the cancers included (RCC, n=42, 63%; UC, n=11, 16%; prostate cancer, n=11, 16%). Gastroenterology-related irAEs were the most common cause of hospitalization, accounting for 45% (30/67) of admissions, primarily due to colitis (n=18) and hepatitis (n=9). Among these cases, 7% (2/30) were classified as grade 4, 80% (24/30) as grade 3, and 13% (4/30) as grade 2. Readmission occurred in 28% (19/67) of patients. Of the readmissions, 42% (8/19) were due to irAEs, 37% (7/19) to non-ICT-related reasons (e.g., disease progression, edema, pulmonary embolism), and 21% (4/19) to infection. Among the 8 readmissions for irAEs, 75% (6/8) were classified as grade 3 and 25% (2/8) as grade 2. Of these, 5 readmissions were attributed to the recurrence of the same irAE (colitis, n=3; hepatitis, n=2). These cases of recurrent irAEs resulted in delayed anti-cancer therapy for a median of 49 days (IQR: 42-57.5). Furthermore, readmissions were potentially preventable in 3 cases (colitis, n=2; hepatitis, n=1) due to delays in initiating biologic therapy, while the remaining 2 cases were associated with delays in outpatient follow-up. Conclusions: In this single-department, single-center case series, gastroenterology-related irAEs were the most common cause of irAE-related admissions and readmissions in patients undergoing ICT therapy for GU cancers. Quality improvement efforts to reduce readmission are ongoing at our institution including: (1) Improving clinical education for early detection of symptoms; (2) Shortening time to post-discharge outpatient follow-up; and (3) Optimizing timing and usage of steroid-sparing biologic therapies.
Systemic therapies in renal cell carcinoma with brain metastases: A comparative meta-analysis of immunotherapy and tyrosine kinase inhibitors.
559 Background: Renal cell carcinoma (RCC) with brain metastases presents a clinical challenge. Management remains unclear, as systemic therapy data are limited and many trials exclude patients with active brain metastases. Current treatment primarily involves CNS-targeted radiation (e.g., stereotactic radiosurgery and whole-brain radiation therapy), while systemic therapies like tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) are underexplored. This meta-analysis evaluates the efficacy of systemic treatments and whether these patients should continue to be excluded from clinical trials. Methods: A systematic search of PubMed, CENTRAL, MEDLINE, and Google Scholar was conducted through October 2024, focusing on studies of mRCC patients with brain metastases treated with ICIs, TKIs, or their combination. ICI therapies included nivolumab, ipilimumab, pembrolizumab, atezolizumab, and avelumab, while TKIs included sorafenib, sunitinib, and cabozantinib. Case reports, ongoing trials, narrative reviews, and meta-analyses were excluded. Primary endpoints were complete response (CR), partial response (PR), objective response rate (ORR), and overall survival (OS). Statistical analyses used fixed/random-effects models based on heterogeneity. Results: Nineteen studies involving 947 mRCC patients with brain metastases were included. The pooled analysis showed an ORR for ICIs of 29.9%, with a CR of 3.4% and PR of 28.9%. Brain-specific ORR, CR, and PR for ICIs were 27.5%, 10.8%, and 17.9%. TKIs alone showed a pooled ORR of 11.7%, with a CR of 1.3% and PR of 11.6%. Brain-specific ORR, CR, and PR for TKIs alone were 38.1%, 6.9%, and 29.5%. Only one study reported on ICI-TKI combinations, with an ORR of 0%. Survival analysis showed significantly worse OS for brain metastasis patients treated with ICIs plus TKIs (HR: 2.06, p=0.001) and TKIs alone (HR: 2.51, p=0.02) compared to those without brain metastases. Conclusions: ICIs had superior overall response rates compared to TKIs and ICI-TKI combinations in mRCC patients with brain metastases. Brain-specific response rates were similar between ICIs and TKIs. Given the poor prognosis of brain metastasis patients treated with TKIs, further research is needed to determine if they should continue to be excluded from trials. Larger prospective studies are required to confirm these findings and optimize treatment.
Preliminary efficacy and safety of disitamab vedotin (DV) combined with bacillus Calmette-Guérin (BCG) in the treatment of high-risk non-muscle invasive bladder cancer with HER2 expression: A prospective, open label, single-center study.
775 Background: Current treatment for high-risk non-muscle invasive bladder cancer (HR-NMIBC) involves Bacillus Calmette-Guérin (BCG) therapy, or radical cystectomy (RC) especially for patients with very-high-risk features. However, 40%-60% HR-NMIBC pts will relapse after BCG treatment. Moreover there are a high incidence of postoperative complications and a negative impact on health-related quality of life after RC. Disitamab Vedotin (DV) is a novel antibody drug conjugate (ADC) that targets the HER2 protein, however its efficacy and safety in HR-NMIBC are limited.We conducted a prospective, open label, single-center study to evaluate the value of RC48 combined with BCG in HR-NMIBC pts. Methods: In this study, two cohorts of BCG-naive pts with very-high-risk features who refused to undergo RC or did not meet the requirements of RC with HER2 expression (IHC 1+/2+/3+) were enrolled (Cohort A:pts were unable to undergo complete tumor resection or have CIS. Cohort B: pts underwent complete tumor resection). All pts will receive eight cycles of intravenous injection of DV (2mg/kg, once every three weeks) and at least one year of BCG intravesical instillation. The Primary endpoints included the 3-month cCR rate in Cohort A and the 6-month EFS rate in Cohort B. The secondary endpoints were to evaluate additional efficacy end points and safety. Results: From Dec 2023 to Aug 2024, twenty eligible pts(16 male;4 female)were enrolled, with 15 pts in Cohort A and 5 pts in Cohort B. 17 of pts had HER2 high expression (2+ or 3+), and 3 of them had HER2 low expression (1+). As a cut-off date (12-Sep-2024), the cCR rate at 3 months and 6 months were both 100% in 11 and 5 pts of Cohort A and the EFS rate at 6 months was also 100% in 3 pts of Cohort B. 65% (13/20) pts experienced treatment-related adverse events (TRAEs). The most common TRAEs included AST/ALT increase 40%(8/20) ,alopecia 45% (9/20), peripheral sensory neuropathy 35% (7/20), anorexia 10% (2/20) and rash 5% (1/20). Grade 3 TRAEs occurred in 10% (2/20) pts with one peripheral sensory neuropathy caused by DV and one hematuria caused by BCG. 60% (12/20) pts had BCG-related AEs including bladder irritation, fever, arthralgia, conjunctivitis and hematuria. Conclusions: This was the first study to evaluate DV in combination with BCG in the treatment for HR-NMIBC. Preliminary results showed the combination had promising efficacy with a manageable safety profile. This may potentially provide a new bladder-sparing therapy for very HR-NMIBC pts with HER2 expression who refused RC or did not meet the requirements of RC. Clinical trial information: NCT06187506 .
Evaluating clinical tools to monitor cardiovascular (CV) risk in men with localized high-risk or locally advanced prostate cancer (LHRPC) treated with hormone therapy (HT).
116 Background: Androgen deprivation therapy (ADT) and androgen receptor signaling inhibitors (ARSIs) indirectly increase CV risk. There are no risk estimation tools specific to men with prostate cancer undergoing HT. Current practice utilizes tools designed for the general population, such as the AHA/ACC ASCVD risk score. Herein, we investigate the applicability of such general population risk tools in men receiving pre-operative HT for LHRPC. Methods: We conducted a retrospective analysis of men with LHRPCa who received 6 months of pre-operative ADT + apalutamide +/- abiraterone on NCT. Cardiometabolic factors of interest were extracted from the electronic medical record, and ASCVD risk scores were calculated alongside metabolic syndrome (MetS) Z scores (calculated using ASCVD calculator https://tools.acc.org/ldl/ascvd_risk_estimator/#!/calulate/estimator/ and metabolic syndrome severity calculator https://metscalc.org/metscalc/ ). Results: Sixty-four patients had data available to calculate baseline and end-of-treatment (EOT) ASCVD risk and MetS Z scores. Prior to initiation of HT, 46.8% of patients were on antihypertensive treatment, 11.3% had diabetes mellitus, and 45.2% were on lipid-lowering therapy. After 6 months of ADT + ARSI, the median change in ASCVD risk score was 0.95, and 21% of patients exhibited a clinically significant increase in ASCVD risk score of ≥ 2.5%. The median change in the metabolic syndrome Z score was -0.36, indicating a decrease in metabolic syndrome risk. 28% of all patients demonstrated an increase in metabolic syndrome risk after 6 months of HT. Conclusions: Despite the known association between HT and increased CV risk, most patients in this study did not experience a clinically meaningful increase in either ASCVD risk or MetS Z score. These findings suggest that general population risk estimation tools may not reflect temporal evolution of CV risk in patients undergoing HT. This study also highlights an unmet need for novel risk assessment tools specifically tailored to identify at-risk men among those treated with HT.
A phase 1b, open-label, multicenter study of xaluritamig in patients with newly diagnosed localized intermediate- or high-risk prostate cancer in the neoadjuvant setting.
TPS434 Background: There are currently no standard neoadjuvant treatments for patients with localized prostate cancer despite improved outcomes with neoadjuvant therapy in multiple other solid tumors. Xaluritamig is a bispecific T-cell engager (TCE) that simultaneously engages the six-transmembrane epithelial antigen of the prostate 1 (STEAP1) expressed on prostate cancer cells and the CD3 complex on T cells, thereby leading to T-cell mediated lysis of the STEAP1 expressing prostate cancer cells. In an ongoing trial (NCT04221542), xaluritamig has demonstrated deep, early, and durable responses in patients with metastatic castration-resistant prostate cancer. Notably, TCEs as a class of therapy have demonstrated the potential to have even greater efficacy and safety when used in earlier stages of disease where the overall disease burden is less and immune fitness is generally better. These data suggest that xaluritamig may be safely administered in the neoadjuvant setting and lead to pathologic responses with subsequent improvement in disease control and long-term clinical outcomes. In the current study, safety and feasibility as well as preliminary efficacy of neoadjuvant xaluritamig are being evaluated in patients with newly diagnosed localized intermediate or high-risk prostate cancer. Methods: This Phase 1b, open-label, multicenter study plans to enroll approximately 30 patients diagnosed with localized intermediate or high-risk prostate cancer and are planned for radical prostatectomy. Eligibility criteria includes histologically or cytologically confirmed prostate adenocarcinoma with Gleason Score ≥4+3 and an initial prostate specific antigen (PSA) of ≥10 ng/ml, no evidence of metastasis outside of the surgical resection field (PSMA-PET positive locoregional lymph nodes or less or equal 5 local lymph nodes on MRI can be enrolled), or use of any prior therapy for prostate cancer. The study includes a 28-day screening period, a two-cycle neoadjuvant treatment period (each cycle lasting 28 days), a safety follow-up visit (up to 42 days) after surgery, and a long-term follow-up period (up to 42 months). The last dose of xaluritamig will be administered about 14 to 28 days prior to undergoing radical prostatectomy. Primary outcomes will evaluate xaluritamig through treatment-emergent and treatment-related adverse events, and feasibility of radical prostatectomy. Secondary outcomes will assess PSA response, imaging-based response on multiparametric magnetic resonance imaging (mpMRI) prior to prostatectomy, pathologic response and the pharmacokinetics of xaluritamig. The study is open for enrollment as of October 2024. Clinical trial information: NCT06613100 .
Phase 1/2 INTerpath-005 study: V940 (mRNA-4157) plus pembrolizumab with or without enfortumab vedotin (EV) for resected high-risk muscle-invasive urothelial carcinoma (MIUC).
TPS893 Background: It is hypothesized that V940 (mRNA-4157), an individualized neoantigen therapy consisting of an mRNA encoding up to 34 tumor neoantigens, will work in synergy with immune checkpoint inhibitors by generating de novo tumor-specific T-cell activity. In a phase 2 trial of patients with high-risk melanoma, adjuvant V940 + pembrolizumab had a manageable safety profile and improved recurrence-free and distant metastasis–free survival versus pembrolizumab monotherapy. The phase 1/2 INTerpath-005 study (NCT06305767) has 2 cohorts. The phase 1 open-label, single-arm perioperative cohort will evaluate perioperative (neoadjuvant and adjuvant) V940 + pembrolizumab + EV for muscle-invasive bladder cancer (MIBC). The phase 2 double-blind, randomized adjuvant cohort will evaluate adjuvant V940 + pembrolizumab versus placebo + pembrolizumab for high-risk MIUC. Methods: Eligibility criteria for the perioperative cohort include age ≥18 years, diagnosis of MIBC (T2-T4aN0M0 or T1-T4aN1M0) with urothelial carcinoma histology, eligibility and willingness to undergo radical cystectomy (RC) + pelvic lymph node dissection (PLND), and cisplatin ineligibility. Eligibility criteria for the adjuvant cohort include age ≥18 years, diagnosis of MIUC with predominant UC histology, radical resection ≤7 weeks before providing informed consent and ≤14 weeks before randomization, high-risk pathologic disease (ypT2-4a and/or ypN+ after neoadjuvant chemotherapy [NAC]; pT3-4a and/or pN+ without NAC), and cisplatin ineligibility. In the perioperative cohort, approximately 30 patients will receive neoadjuvant pembrolizumab 200 mg IV on day 1 Q3W × 4 cycles + EV 1.25 mg/kg IV on days 1 and 8 Q3W × 4 cycles + V940 1 mg IM on day 1 Q3W × 1-4 doses. Patients will undergo RC + PLND followed by adjuvant pembrolizumab 200 mg IV on day 1 Q3W × 13 cycles + EV 1.25 mg/kg IV on days 1 and 8 Q3W × 5 cycles + V940 1 mg IM on day 1 Q3W × 5-8 doses, depending on number of doses administered in neoadjuvant period, for a total of 9 doses. In the adjuvant cohort, approximately 200 patients will be randomly assigned 1:1 to receive pembrolizumab 400 mg IV Q6W × 9 cycles + V940 1 mg IM Q3W × 9 doses or pembrolizumab 400 mg IV Q6W x 9 cycles + placebo IM Q3W x 9 doses. Randomization in the adjuvant cohort will be stratified by circulating tumor DNA status at screening (positive vs negative vs not evaluable) and prior NAC (yes vs no). The primary end points are safety (perioperative cohort) and DFS per investigator assessment (adjuvant cohort). Secondary end points are pathologic complete response and pathologic downstaging (perioperative cohort); overall survival, distant metastasis–free survival per investigator, safety, and tolerability (adjuvant cohort). Clinical trial information: NCT06305767 .
Analysis of gut microbiota profiles in patients with prostate cancer: The PROMISE-JAPAN study.
212 Background: Prostate cancer (PCa) is clinically associated with dietary habits such as high-fat diets. The gut microbiota is strongly influenced by dietary habits and is involved in the host immune response and metabolic pathways. Recently, the gut microbiota has been shown to influence a variety of diseases, including PCa. We have found that the gut microbiome and its metabolite, short-chain fatty acids (SCFA), promote cancer growth in PCa mouse models. To clarify the association between gut microbiota and PCa in humans, we conducted a study of PCa, gut microbiome, and lifestyle in Japan (PROMISE-JAPAN). In this study, we evaluated the gut microbiota profiles in PCa patients with a particular focus on differences between non-metastatic PCa (nmPCa) and metastatic PCa (mPCa). Methods: This multicenter, prospective, observational study enrolled 869 Japanese patients between 2020 and 2022. Eligibility criteria were men with suspected PCa who underwent prostate biopsy, and rectal swab samples were collected before prostate biopsy. Men who had taken antibiotics within 6 months before sample collection or whose previous antibiotic use was unknown were excluded. The gut microbiota composition was analyzed using 16S rRNA gene sequencing. The raw sequencing data was processed by the QIIME2 pipeline. The Mann-Whitney U tests were used to compare characteristics between groups. Results: A total of 723 participants were eligible for analysis, including 262 men without cancer and 461 men with PCa, including 56 men with mPCa. The composition of the gut microbiota differed significantly between the non-cancer and the PCa group, with PCa having more Lachnospiraceae, which produce SCFA. The mPCa group had a higher abundance of Ruminococcaceae (UCG-005 and NK4A214), which belong to the Firmicutes pylum, compared to the nmPCa group. The mPCa group had a lower abundance of Prevotella, which belongs to the Bacteroidota pylum, compared to the nmPCa group. In mPCa compared to nmPCa, 19 gut microbiota pathways were significantly altered. In particular, the androstenedione degradation pathway was significantly increased in the mPCa group (p=0.0287). Conclusions: The composition of the gut microbiota differed between the non-cancer, the nmPCa and the PCa group. The gut microbiome associated with androgen metabolism was more common in mPCa patients. Clinical trial information: UMIN000043489 .
RadOnc-GPT (gpt-4o) versus human data extraction for prostate cancer clinical research.
425 Background: Prostate cancer (PC) ranks among the most prevalent cancers in men, with incidence rising due to factors like aging populations and enhanced screening techniques. Effective data extraction from clinical records is crucial for advancing research and improving patient care; however, traditional manual methods can be time-consuming and susceptible to mistakes. This study seeks to evaluate RadOnc-GPT against human annotation for extracting essential clinical information from prostate cancer clinical records. Methods: RadOnc-GPT is a retrieval augmented generation (RAG)-based chatbot with access to a variety of patient data including treatment details, radiology reports, and clinical notes. RadOnc-GPT uses Open AI’s gpt-4o model. Patients who received curative intent radiotherapy as initial treatment for PC in our institution between 2014 and 2023 were randomly selected for evaluation. Relevant Clinical factors were extracted by a human expert annotator on our on-site RedCap database. The extraction of the same variables was performed using RadOnc-GPT. A comparison between the ground truth (human annotation) and RadOnc-GPT, to evaluate the performance of the AI system, was carried out including accuracy, recall and F1 score. Results: A total of 382 PC patients were included in the cohort for data extraction. The clinical variables extracted were the treatment intent, NCCN risk category, T and N stage, Gleason score, radiation volume, and Androgen Deprivation therapy (ADT) use. The overall performance of RadOnc-GPT was excellent, with the highest accuracy achieved for treatment intent (99.7%), Gleason score (98.4%), and Treatment Volume (90.1-99.5%). Conclusions: RadOnc-GPT performed excellent at extracting relevant clinical details from the electronic medical record and radiation oncology information systems with dramatic reduction in time and cost compared with manual review. LLMs could be highly useful for large-scale data extraction in PC research, offering a promising solution for automating the accurate data extraction process. Correct (n) Total (n) Accuracy Recall F1 score RT with curative intent 381 382 99.7 99.9 99.9 Prostate Cancer Risk Category 345 382 90.3 90.4 95.1 Primary tumor staging (T) at diagnosis 368 382 96.3 96.3 97.9 Regional nodal status (N) at diagnosis 352 382 92.1 92.2 95.9 Gleason Score Primary Secondary Total 376372376 382382382 98.497.498.4 98.597.498.5 99.298.799.2 Treated Areas Prostate Pelvic Nodes Para-Aortic Nodes Distant Site 380344378372 382382382382 99.590.19997.4 99.490.199.197.4 99.79599.598.7 ADT Use with RT 365 382 95.5 95.7 97.8
Clinically advanced prostate cancer (CAPC) in extremely young men: A genomic landscape study.
210 Background: CAPC arising in young patients is a challenging disease with significant need for improvements in systemic therapies, especially for patients with surgically incurable disease. Here we sought to explore the genomic landscape to generate hypotheses and inform clinic trial design. Methods: 13 cases of CAPC in men under the age of 39 years (CAPC <39) and 23,364 cases of CAPC in men 50 or older (CAPC >50) underwent comprehensive genomic profiling (CGP) to examine all classes of genomic alterations (GA). MSI high status, tumor mutation burden (TMB) levels, genomic ancestry and trinucleotide mutational signatures were determined from the sequencing data. HRDsig status was calculated using a broad set of genome-wide copy number features. PD-L1 was determined by IHC using the Dako 22C3 tumor proportional score system. Results were compared using the Fisher exact system with the Benjamini-Hochberg adjustment to correct for false discovery. Results: The GA rates were similar in the very young and more senior patient cohorts (3 GA/tumor for both groups). Genomic ancestry distribution revealed more African ancestry cases in the CAPC <39 group (30.8% vs 15.1%; NS) and more European ancestry in the CAPC >50 group (75.1% vs 53.9%; NS). MSI high status was trending more common in the CAPC <39 group (7.7% vs 3.0%; NS) as was a positive HRD signature (15.4% vs 10.2%; NS). The median TMB levels were low and similar in both groups (range 1.3 to 2.4 mut/Mb) as was the frequency of TMB > 10 mut/Mb (range 4.3% to 7.7%). Defined trinucleotide signatures were rare and similar in both groups. PD-L1 expression was available for a subset of the of the cases and showed no distinct differences. GA in genes associated with HRD were trending more frequent in the younger cohort including BRCA1 (7.7% vs 1.1%; NS), BRCA2 (15.4% vs 8.0%; NS), ATM (7.7% vs 5.7%; NS) and PALB2 (7.7% vs 0.7%; NS). Other GA more frequent in the CAPC <39 group included BRAF (15.4% vs 4.0%; NS), CDK12 (7.7% vs 4.9%; NS), CDKN2A (15.4% vs 2.5%; NS), CDKN2B (7.7% vs 1.5%; NS), MTAP (7.7% vs 1.4%; NS), PTEN (46.2% vs 31.2%; NS), RB1 (7.7% vs 4.8%; NS), TP53 (53.8% vs 37.9%; NS) and TMPRSS2 - ERG fusions (38.5% vs 31.7%; NS). GA in AR (11.3% vs 7.7%; NS), SPOP (10.9% vs 0%; NS) and PIK3CA (6.4% vs 0%; NS) were more frequent in the CAPC >50 group. Conclusions: In contrast with CAPC arising in men >50, CAPC arising in extremely young men under 39 featured relatively different frequencies of biomarker and GA distribution, without reaching statistical significance. Our results are hypothesis-generating; limitations include the small sample size of patients < 39, retrospective nature, potential selection bias, and lack of clinical outcomes annotation. <39 years >50 years P value AFR Ancestry 30.8% 15.1% NS EUR Ancestry 53.9% 75.1% NS BRAF 15.4% 4.0% NS BRCA2 15.4% 8.0% NS CDK12 7.7% 4.9% NS PTEN 46.2% 31.2% NS SPOP 0.0% 10.9% NS MSI High 7.7% 3.0% NS TMB > 10 mut/Mb 7.7% 4.3% NS
The Oncopig bladder cancer model, an innovative large animal platform for evaluating treatment effects.
857 Background: Bladder cancer carries a high recurrence rate despite availability of several treatment options including surgery, chemotherapy, radiation, and immunotherapy, resulting in the highest cost of lifelong treatment per patient and highlighting the need for development of novel diagnostic and therapeutic strategies. Unfortunately, results from current bladder cancer models do not effectively translate to clinical practice (mouse models) or are rare and not inducible (canine models). This, in addition to the use of endoscope-based approaches for bladder cancer treatment highlights the critical need for large animal bladder cancer models to improve patient outcomes. Pigs represent an ideal platform that provide both regulatory acceptable and clinically relevant large animal cancer models due to their similar physiology, size, genetics, immunity, and metabolism in relation to humans. The Oncopig bladder cancer model is an ideal tool for testing endoscopic and other oncolytic-based treatments. Methods: The Oncopig cancer model develops tumors following induced expression of KRAS G12D and TP53 R167H driver mutations utilizing an adenoviral vector encoding Cre recombinase (AdCre). Two procedures for cystoscope-based AdCre delivery were evaluated. In procedure I (Proc-I) a combination of AdCre and N-Dodedcyl-beta-maltoside, a sugar-like surfactant utilized to dissolve the glycoaminoglycans layer, was instilled into the bladder (1h; n=3). In procedure-II (Proc-II) the bladder urothelium was superficial denuded at 3 sites and subsequent AdCre was instilled into the bladder (1h; n=4). Oncopigs underwent CT scans and follow-up cystoscopy, and were euthanized at 3 timepoints (day 14, 21, and 28) to assess temporal bladder tumor growth. Tumor samples were collected at necropsy for histopathological evaluation (H&E, TP53, Ck34be12, vimentin, and CD3) and to evaluate tumor stage. Results: In total 6/7 Oncopigs developed endoluminal tumors. Tumor-induction efficacy was 100% for Proc-I (n=3/3) and 75% for Proc-II (n=3/4). Two tumor types were observed: urothelial cell carcinomas of sarcomatoid variant (Proc-I: n=3/3; Proc-II: n=2/4) and inflammatory tumors (Proc-II: n=1/4). After 14 days, pT1 tumors were observed for Proc-I, while pT2 tumors were observed for Proc-II. After 21 days, both pT1 and pT2 tumors were observed for Proc-I, while Proc-II tumors remained pT2. Conclusions: The Oncopig bladder cancer model can develop both superficial and muscle invasive urothelial cell carcinomas with sarcomatoid variant. Tumors develop rapidly (within 2 weeks), with tumor invasiveness correlated with time post tumor induction and procedure used, making this an ideal model for evaluation of novel therapeutic approaches. Further exploration and development of additional tumor models including further translational characterization will be important for broader utility.
Association of a novel AI-based digital pathology (CHAI) biomarker with progression free survival (PFS) in patients (pts) with metastatic hormone sensitive prostate cancer (mHSPC).
204 Background: In mHSPC, no baseline biomarker reliably predicts progression-free survival (PFS). Identifying pts unlikely to benefit from current therapies could enable personalized management and better pt selection for clinical trials. Herein, we investigate the capacity of a novel AI-based digital pathology platform to prognosticate in mHSPC. Methods: Pts diagnosed with mHSPC with available pathology slides and undergoing systemic therapy at the Huntsman Cancer Institute, University of Utah were eligible. Whole slide images were generated from digital scans of diagnostic H&E histopathology specimens reviewed by board-certified genitourinary pathologists. The CHAI (Correlative Histologic AI) platform was used to segment nuclei and extract morphologic and spatial features. Association with PFS was assessed across extracted features, and a biomarker signature was generated. Kaplan Meier estimators, log-rank tests and t-tests were used to compare outcomes among those with and without the biomarker signature for time-to-event and binarized endpoints respectively. PFS was defined from the start of therapy for mHSPC to biochemical or radiographic progression (per PCWG2) or death. Multivariate analysis for PFS was conducted using the Cox proportional hazards model, evaluating the biomarker signature and adjusting for age, Gleason score, baseline PSA, de novo status, disease volume, and ADT intensification. Results: 86 pts were eligible and included. Median age: 65 years (IQR 60-72), median baseline PSA: 29.9 ng/ml (IQR 7.2-23.2) and 64% pts received ADT intensification. 43 pts were categorized as biomarker positive (+) and 43 as biomarker negative (-). Biomarker + pts had a significantly longer median PFS of 67.5 months as compared to 26.9 months in biomarker – pts (HR 0.39, 95% CI HR 0.29 - 0.52, p < 0.001). Biomarker + group was significantly associated with PSA nadir < 0.2 ng/ml (p < 0.001). On multivariate analysis, biomarker + signature was significantly associated with better PFS (Table). Conclusions: CHAI, a novel AI-based digital pathology biomarker is independently associated with PFS in mHSPC setting. After external validation it may serve as a prognostic tool to guide clinical decision-making. Further analysis with a larger sample size will be conducted to evaluate the association with OS. This analysis exemplifies the power of integrating artificial intelligence into medical practice, with a potential to improve outcomes in our patients. Characteristic PFS HR (95% CI) p value Biomarker (+ vs. -) 0.47 (0.24 – 0.91) 0.025 ADT intensification (Yes vs. No) 0.3 (0.16 – 0.7) <0.001 Disease Volume (Low vs. High) 0.37 (0.19 – 0.7) 0.003 Gleason score 1.56 (1.07 – 2.27) 0.021 Age 0.97 (0.93 – 1.00) 0.075 Baseline PSA 1.00 (1.00 – 1.00) 0.061 De novo (Yes vs. No) 1.1 (0.53 – 2.29) 0.793
Association between site of metastases and survival stratification of the IMDC classification in metastatic renal cell carcinoma (mRCC).
566 Background: The IMDC risk model is pivotal for prognostic stratification of mRCC, dividing patients into favorable (FAV), intermediate (INT) and poor-risk (POOR) groups with distinct overall survival (OS) estimates. While valuable for treatment decisions in first line, IMDC does not encompass sites of metastasis, potentially missing a significant prognostic factor. Methods: We retrospectively included mRCC patients receiving first-line therapy at Niguarda Cancer Center, Milan, Italy from 2008 to 2024. The primary aim was to evaluate if specific metastatic sites could redefine IMDC prognostic stratification. OS was analyzed using Kaplan-Meier estimates. Univariate and multivariate Cox regression analyses were performed including variables in the table. Results: 164 patients were eligible for analysis. Bone, liver and nodal metastases were independent negative prognostic factors both in univariate and multivariate analyses (HR 2.83, IC95% 1.78-4.49, p<0.001; HR 1.79, IC95% 1.12-2.85, p=0.014; HR 1.92, IC95% 1.28-2.88, p=0.002, respectively). As expected, FAV IMDC and first-line immunotherapy-based combinations (IO-IO or IO-TKI) were positive prognostic factors (both p<0.001). Having at least one bone and/or liver and/or nodal metastasis (B/L/N) was significantly associated with poorer prognosis and could re-stratify INT IMDC patients into two subpopulations with different OS (HR 1.88, p=0.046): B/L/N-positive INT OS rates were not different from POOR (p=0.193) and B/L/N-negative INT OS rates were comparable to FAV (p=0.193). Conclusions: B/L/N metastases are independent prognostic factors in mRCC, despite being unaddressed by IMDC. Present findings align with prior research supporting the inclusion of metastatic sites in prognostic scores. IMDC classification could be refined with inclusion of metastatic sites to improve prognostic accuracy. Patient characteristics. Age ≥50 147 (90) Sex Male 123 (75) IMDC FAV 42 (26) INT 85 (52) POOR 37 (22) Site of metastasis Bone 40 (24) Liver 31 (19) Nodal 85 (52) Oligometastases (<4) 33 (20) First-line immunotherapy-based combinations 38 (23) Data are shown as number of patients (N) and, within brackets, percentage (%).
Impact of geographic and demographic characteristics on treatment with Lu-PSMA for metastatic castrate-resistant prostate cancer (mCRPC).
153 Background: Metastatic castration-resistant prostate cancer (mCRPC) remains an incurable and fatal disease. Administration of Lu-PSMA demonstrates improved progression free survival and overall survival in this population (1). Despite this, understanding patient access to and receipt of this therapy is understudied. We aim to characterize the demographics of patients receiving Lu-PSMA at a NCI-designated medical center in Philadelphia, PA after FDA approval. Methods: All patients treated at a single institutional center with Lu-PSMA from April 2023 to October 2024 were included. Demographic characteristics including age at first treatment, race, insurance status, and zip code were extracted from the medical record. Travel distance between a patient’s home and a treatment center was calculated using the Haversine formula as provided by the National Bureau of Economic Research. Median household income was obtained by US Census 2022 American Community Survey. All analyses were performed on Prism (GraphPad, v 10.3.1). Results: A total of 103 patients were included for analysis. The median age at time of first Lu-PSMA treatment was 73 years (range 50-92). 71.8% (n=74) were white and 28.2% were non-white (n=21 Black/African American; n=8 other/multiracial/unknown). All patients were non-Hispanic. All patients were insured (77.7%, n=80, Medicare/Managed Medicare; 3.9%, n=4, Medicaid/managed Medicaid; 18.4%, n=19, private/other insurance). Median distance travelled to a treatment center was 12 miles. About one quarter of patients travelled >25 miles to reach their treatment center (42.7%, n=44, <10 miles; 32.0%, n=33, 10-25 miles; 9.7%, n=10, 25-50 miles; 11.7%, n=12, 50-100 miles; and 3.9%, n=4, >100 miles). Most patients resided in an urban zip code, with a minority (4.9%, n=5) residing in a rural zip code. The median household income by zip code varied from $30,946 to $233,194 (9.7%, n=10, $30-50K; 18.4%, n=19, $50-75K; 20.4%, n=21, $75-100K; 39.8%, n=41, $100-150K; 11.7%, n=12, >150K). The number of Lu-PSMA treatments received was not correlated with distance travelled (F(4,98)=2.4, p=0.05), median household income (F(4,98)=0.5260, p=0.72), or race (p=0.83). There were no differences in travel distance between white and non-white patients (p=0.24). On Kaplan Meier, there were no differences in overall survival in patients that travelled >12 miles for treatment versus those who resided <12 miles from a treatment center (p=0.48). There were no differences in overall survival by race between white with non-white patients (p=0.66). Conclusions: Receipt of Lu-PSMA was not different in populations separated by race, distance to treatment center, or median household income. Increasing travel distance was not associated with receipt of fewer cycles of treatment. Further analysis is needed on whether these factors are associated with referral for and acceptance of Lu-PSMA. 1. Sartor NEJM 2021.
Current impact of ureteral carcinoma amongst racial minorities: Analysis of the National Cancer Database.
675 Background: Upper tract cancer is a relatively uncommon type of genitourinary cancer. Lower socioeconomic status and racial disparities have long been associated with worse cancer related outcomes for various types of cancer. Our objective was to determine if racial minorities in the United States were more likely to present with ureteral cancer of stage II or greater. Methods: The National Cancer Database (NCDB) Hospital Comparison Benchmark Reports (HCBR) for ureter cancer from 2013 to 2022 were reviewed. Demographic and clinical data was compared between various races and ethnicities affected to determine any significant differences related to age, stage, insurance status, distance traveled, and education at presentation. Patients were stratified into two groups of patients with stage II or greater and those with less than stage II ureteral cancer. Fischer’s exact test was used to compare the proportion of Caucasian patients with stage II or greater ureteral cancer against patients of other ethnicities. Statistical significance was defined as p<0.05. Results: Within the NCDB HCBR database, there were 26,153 patients with ureter carcinoma spanning 1,238 hospitals, with males comprising 16, 435 (62.8%) and females 9,718 (37.2%). Caucasian patients included most cases at 22,314 (86%), followed by African American patients 1,072 (4.17%), Hispanic patients 1,047 (4.08%), Asian and Pacific Islander patients 871 (3.39%), and Native American patients 73 (0.28%). Overall stage distribution included—0: 9,342 (36.38%); I: 3,711 (14.45%); II: 2,443 (9.51%); III: 2,724 (10.61%); IV: 3,636 (14.16%). A higher proportion of Asian and Pacific Islander patients were more likely to present with Stage II or greater ureteral cancer compared to Caucasian patients (43% vs 33.9%, p<0.001). Furthermore, Asian and Pacific Islander patients were more likely to present with invasive disease (73.6% vs 63.9%, p<0.001). A higher proportion of Asian and Pacific Islander patients were found to be uninsured or have Medicaid, be from a less educated household, and were less likely to travel longer distances for care when compared to Caucasian patients (all p<0.001). Regarding presenting at stage II or greater, there was no significant difference found when comparing Caucasian patients versus African American, Hispanic, or Native American patients. Conclusions: Asian and Pacific Islander patients were more likely to present with stage II or greater ureteral cancer compared to their Caucasian counterparts. Future directions exploring the factors affecting these at-risk groups is vital to properly redirecting resources and improving disparities.
Risk factors of complications after inguinal lymph node dissection in patients with penile cancer.
6 Background: Inguinal lymph node dissection (ILND) is a crucial step in the management of patients with penile cancer, particularly for those with lymph node involvement. However, ILND is associated with a significant risk of postoperative complications, which can impact recovery and long-term outcomes. Identifying the risk factors that contribute to these complications may help in improving patients’ quality of life after ILND and perioperative management. Methods: We conducted a retrospective analysis of 192 penile cancer patients who underwent ILND between October 2008 and October 2023 at West China Hospital. 370 surgeries were conducted. Data on patient demographics, tumor characteristics, comorbidities, surgical details, and postoperative outcomes were collected. Complications were classified as minor or major based on the Clavien-Dindo classification. Multivariate logistic regression was performed to identify independent risk factors for each complications. Receiver operating characteristic (ROC) curves were used to analyze the relationship between certain risk factors and postoperative complications and find cut-off points for certain risk factors. Results: The overall complication rate was 87.5%, with most patients experiencing minor complications. Common complications included wound infections (35.4%), lymphatic fistula (50%), lymphocele (42.2%) and lower limb edema (28.6%). Except for the common risk factors, such as surgery type (conventional or minimally invasive, Odds Ratio (OR): 0.157, 95% Confidence Interval (CI): [0.036, 0.692], p =0.014) for wound infection, we additionally found that the shorter retention time of drainage tube (OR: 0.784, 95% CI: [0.724, 0.850], p <0.001) is strongly correlated with subsequent lymphocele, with cut-off points of 6.5 days. And longer retention time of drainage tube (OR: 1.065, 95% CI: [1.031, 1.100], p <0.001) is correlated with wound infection, with cut-off points of 10.5 days. Conclusions: Our study highlights several modifiable and non-modifiable risk factors associated with each complications following ILND in penile cancer patients. Optimizing perioperative care and conducting minimally invasive surgery when possible may reduce postoperative complication rate. And the duration of drainage tube retention is associated with both lymphocele and wound infection. Further prospective studies are warranted to validate these findings.