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Evaluating the survival benefits of adjuvant immunotherapy in muscle-invasive urothelial carcinoma: A real-world experience.
750 Background: Despite current guidelines recommendations to administer adjuvant nivolumab following radical cystectomy (RC) in patients with adverse pathologies, regardless of prior neoadjuvant chemotherapy (NAC), evidence on the long-term efficacy of ICIs remains sparse. This study aims to evaluate the potential survival benefits of the two most common ICIs, Nivolumab and Pembrolizumab, in patients with muscle-invasive bladder cancer (MIBC) at a single institution. Methods: We queried our IRB-approved, prospectively maintained institutional RC database for all patients who underwent RC from January 2017 (following FDA approval for ICIs in MIBC) to July 2022. Patients with pT3-4a and/or N+ after RC, or ypT2-4a and/or N+ after NAC + RC, were included and categorized into two groups: those who received adjuvant ICI (ICI+) and those who did not (ICI-). Demographic, clinical, and survival data were retrieved from our database. Multivariable Cox regressions were performed to adjust for potential confounding variables. Results: A total of 191 patients were included, with 38 (19.9%) receiving adjuvant ICI (30 Nivolumab and 8 Pembrolizumab). The table outlines the patient characteristics, stratified by adjuvant ICI treatment. With a median follow up of 17.9 months, overall survival (OS) was 97.4% in the ICI+ group and 66.0% in the ICI- group (p = .003). Recurrence-free survival (RFS) was 84.2% and 67.9% in the ICI+ and ICI- groups, respectively (p=.206). in the ICI- group, 10 out of 49 (20.4%) recurrences were local or regional (i.e. urethral or ureteral), while all recurrences (N=6) in the ICI+ group were distant. Multivariable Cox regressions demonstrated that, after adjusting for age and pathological stage, adjuvant ICI was associated with significantly improved OS (HR = 0.08 [95%CI: 0.01, 0.59], p = .013), but not RFS (HR = 0.43 [95%CI: 0.18, 1.04], p = .062). Conclusions: Our results corroborated the beneficial effect of ICIs on OS. Although the improvement in RFS did not reach statistical significance, ICIs showed a trend toward positive clinical impact. A notable finding was the potential for ICIs to alter the recurrence pattern in MIBC. Although limited by a small sample size, this study represents one of the first real-world evaluations of adjuvant ICI efficacy in a single-institution cohort. Demographics and baseline clinical characteristics. ICI+ (N=38) ICI- (N=153) p Age (years) 68.7 ± 8.6 71.6 ± 10.4 .060 Sex (Male) 27 (71.1%) 118 (77.1%) .433 Charleson Comorbidity Index 0 9 (23.7%) 31 (20.3%) .886 1 6 (15.8%) 27 (17.6%) ≥ 2 23 (60.5%) 95 (62.1%) Pathological staging OC (< (y)pT2; pN0) 3 (7.9%) 29 (19.0%) .013 EV (> (y)pT2; pN0) 11 (28.9%) 67 (43.8%) LN+ (pN+) 24 (63.2%) 57 (37.2%) Neoadjuvant Chemotherapy (yes) 30 (79.0%) 85 (55.6%) .008
Real-world safety of first-line (1L) therapies for locally advanced or metastatic urothelial cancer (la/mUC) in the US.
759 Background: The 1L treatment landscape in la/mUC has evolved rapidly, encompassing platinum-based chemotherapy, immune checkpoint inhibitors (ICIs), and antibody-drug conjugates, and including monotherapy and combination regimens. Real-world data on adverse events (AEs) with novel 1L therapies are limited. This study aims to fill this evidence gap by comprehensively characterizing the incidence of real-world treatment-emergent AEs (rwTEAEs) with 1L regimens for la/mUC. Methods: This is a retrospective observational cohort study of patients (pts) in the nationwide Flatiron Health electronic health record–derived deidentified database. The study population included adults diagnosed with la/mUC who initiated 1L treatment with a regimen of interest (Table) since January 1, 2016. Machine learning was used to extract clinician documentation of a prespecified list of 30 rwTEAEs from 1L treatment initiation to the earliest of 90 days after last 1L dose, start of subsequent treatment, or death. Occurrence of rwTEAEs (overall incidence and exposure-adjusted rate based on treatment-months) was described across groups. Results: Of 5,235 pts who met study criteria, 73% were male, median age was 74 years (IQR, 66-80), 70% were White, 66% had ECOG PS of 0-1, and practice setting was community/academic/both in 79%/14%/7%. The most common rwTEAEs in the overall cohort were fatigue (71%), anemia (48%), nausea (48%), and loss of appetite (47%). When adjusted for time on treatment, relative rates of some rwTEAEs differed greatly from incidences (Table). Conclusions: These data aid in understanding the real-world safety of 1L treatment options for la/mUC and help inform the development of patient supportive care plans by population-based healthcare decision-makers. Time on treatment should be considered when interpreting the incidence of safety events. Incidence of rwTEAEs, % (rate per 1,000 person-months on treatment) Overall N=5,235 Enfortumab vedotin + pembrolizumabn=198 ICI monotherapy n=2,146 Cisplatin-based chemo without avelumab 1LMn=1,372 Carboplatin-based chemo without avelumab 1LMn=1,140 Cisplatin-based chemo with avelumab 1LMn=197 Carboplatin-based chemo with avelumab 1LMn=182 Fatigue 70.7 (266.6) 68.7 (234.3) 62.2 (172.0) 75.7 (406.9) 72.5 (380.4) 95.4 (371.3) 96.7 (375.5) Weight loss 34.6 (66.6) 47.0 (102.2) 32.9 (53.2) 33.0 (84.1) 32.5 (84.9) 51.8 (35.1) 48.4 (34.6) Diarrhea 30.7 (58.2) 45.0 (98.4) 30.2 (49.5) 27.8 (66.9) 29.5 (74.9) 40.6 (24.9) 40.7 (29.1) Rash 20.3 (35.6) 47.0 (108.7) 21.9 (33.5) 14.7 (32.5) 15.3 (34.4) 34.0 (20.1) 31.9 (20.8) Pruritus 14.5 (24.3) 36.9 (72.5) 19.9 (30.7) 6.1 (12.4) 7.8 (16.4) 23.4 (13.0) 21.4 (13.4) Peripheral neuropathy 5.2 (7.6) 17.7 (29.0) 3.6 (4.4) 5.3 (10.9) 3.8 (7.6) 16.8 (8.4) 6.6 (2.8) Hyperglycemia 3.9 (5.6) 8.6 (12.7) 3.4 (4.1) 3.9 (7.9) 2.7 (5.4) 9.1 (4.0) 5.5 (2.6) 1LM, 1L maintenance; chemo, chemotherapy.
Plasma proteome-based integrative prognostic nomogram in metastatic castrate-resistant prostate cancer (mCRPC).
225 Background: Currently non-specific clinical factors including non-tumor biology proteins (Alkaline Phosphatase-ALK, LDH, albumin) are used for identifying high, intermediate or low prognostic survival risk in mCRPC. We integrated these biomarkers with plasma proteins overexpressed exclusively in mCRPC to develop patient-centric nomograms for estimating 1,2 and 3-year (yr) overall survival (OS) probabilities. Methods: Proteomic profiling of plasma for 3072 proteins using Olink Explore NGS platform was performed in 32 local stage prostate cancer, 123 metastatic hormone-sensitive (mHSPC) and 157 mCRPC state samples (Total N=312) in a clinically annotated real-world cohort study that enrolled patients (pts) between 2020 and 2024. Protein assays were measured in normalized protein expression (NPX) units through a normalization process. We compared NPX values of all protein assays across all three cancer states to identify Differentially Expressed Proteins (DEPs) exclusively overexpressed in mCRPC using t-test with multiple corrections. Clinical outcome in the mCRPC was OS. A composite score was generated aggregating DEPs overexpressed in mCRPC with OS, by multiplying each individual DEP’s univariate-level survival Hazard Ratio (HR) coefficient with their corresponding NPX value. The composite score range for the mCRPC cohort (N=121 pts) was dichotomized above and below the cohort median as “High” and “Low” and evaluated for survival using Cox Proportional Hazard Regression along with current prognostic protein biomarkers (ALK, LDH, albumin) at the univariate followed by multi-variable analysis (MVA) for variables observed with univariate significance (P<0.05). Prognostic nomograms integrating MVA significant clinical factors with the DEP composite score was developed and performance of the nomogram with and without the composite score for estimating 1,2 and 3-years survival probabilities was determined using ROC curves and Area Under Curve (AUC). All analyses were conducted in RStudio. Results: Median OS of the mCRPC cohort (N=121) was 28 months (range: 0.3-45). There were 353/3072 DEPs exclusive to mCRPC and 19/353 DEPs were associated with OS (univariate P<0.05) (SCRN1, GP2, NFU1, DPY30, SNRPB2, KRT19, FKBP5, PGD, IL6, L3HYPDH, MYDGF, DH1, IQGAP2, TOMM20, YAP1, CLGN, IMMT, PKD2, PALM2). MVA Hazard Ratios (HR) with 95% CIs for nomogram input included: DEP score HR-3.48 (1.77-6.83; P<0.0003); LDH: HR-1.01 (1-1; P=0.13); ALK: HR-1 (1-1; P=0.000035); Albumin: HR-0.61 (0.24-1.51; P=0.28). AUCs for estimating mCRPC OS probabilities integrating the DEP score with current factors versus clinical factors alone increased to 0.87 from 0.85 (1-yr); to 0.78 from 0.73(2-yr) and to 0.79 from 0.70 (3-yr). Conclusions: A patient-centric approach using nomograms to estimate survival in mCRPC which includes novel protein classifiers can enhance current prognostication models.
Correlates of immunotherapy response in metastatic clear cell renal cell carcinoma from circulating cell-free epigenomes.
593 Background: Immune checkpoint inhibitors (ICIs) are a mainstay of treatment for metastatic clear cell renal cell carcinoma (mccRCC). With a growing number of treatment options for mccRCC, biomarkers are needed to guide treatment selection by predicting benefit from ICIs. Cell-free DNA (cfDNA)-based assays that measure tumor DNA in plasma are promising biomarkers for treatment response in several cancers, but their role in RCC remains unclear. Here, we tested whether epigenomic profiling of cell-free DNA can identify or predict radiographic responses to immunotherapy in mccRCC. Methods: Plasma samples were obtained from 180 patients (400 total samples collected, up to 4 samples per patient) with mccRCC enrolled in the DOD-funded Kidney Cancer Research Consortium ctDNA study (NCT04883827). Patients received an immune checkpoint inhibitor and were categorized as non-responders or responders based on CT scan results obtained at 3- or 6-months following treatment initiation. Cell-free chromatin immunoprecipitation sequencing (cfChIP-seq) was performed on patient plasma to profile H3K4me3, a histone modification associated with active gene promoters. DNA methylation was profiled with cell-free methylated DNA immunoprecipitation sequencing (cfMeDIP-seq). H3K4me3 signal at the promoters of ccRCC-associated genes variation between pre-treatment and on-treatment timepoints was assessed for non-responders and responders. We calculated changes in H3K4me3 signal for on- and pre-treatment plasma draws. We then compared these changes between non-responders and responders using the Wilcoxon sum-rank test. The immune cell types contributing to cfDNA were inferred from cfMeDIP-seq data. Results: Comparing pre- and on-treatment timepoints drawn between 1-5 months after starting therapy, cfDNA promoter H3K4me3 at RCC-associated genes was concordant with radiographic response in 10 of 11 patients (91%), with signal increasing from pre- to on-treatment samples in 6 of 7 non-responders (86%) and decreasing in 4 of 4 responders (100%). The median change in H3K4me3 differed significantly for non-responders and responders (p = 0.02). Analysis of cfDNA methylation profiles identified a higher proportion of memory CD8 T cell-derived cfDNA in non-responders compared to responders in pre-treatment samples (p = 0.003) Conclusions: This pilot study suggests that epigenomic profiling of cfDNA may identify pre-treatment and on-treatment biomarkers of ICI response. Profiling of larger cohorts is underway to test the generalizability of these findings.
Circulating tumor DNA levels and related kinetics as prognostic biomarkers for clinical outcomes in mCRPC: A post hoc analysis of CM 7DX.
252 Background: Liquid biopsy assays in mCRPC are utilized for treatment eligibility of PARP inhibitors (HRR) and Pembrolizumab (MSI High). These ctDNA targeted gene panels provide translational data beyond gene mutations. Tumor Fraction (TF), the percentage of cfDNA from tumor, is a promising prognostic efficacy biomarker in pre-chemo mCRPC, and a potential predictive biomarker to post-chemo PSMA radioligand therapy. Methods: We analyzed ctDNA run with Illumina-TSO500 from the CA209-7DX Ph3 mCRPC trial (Nivo+chemo vs. Chemo in chemo-naïve mCRPC) to determine: TF at baseline or changes at Cycle6 Day1 (C6D1). TF at each timepoint was determined through the maximum somatic allelic frequency. Results: We present a combined analysis of treatment arms as both showed similar association between clinical outcomes and TF levels as well as clearance. Out of 1030 ITT patients TF data was available for 527 (51%) patients. Patients in the highest TF tertile had TF of ≥4.6% and TF<0.3% for the lowest tertile. Patients in the lowest TF tertile had 10 months longer overall survival (OS) to the highest TF tertile (p<0.001). Patients in the highest TF tertile demonstrated higher hazard ratio for OS (HR 3.42,[2.34-4.98] p<0.001) and rPFS (HR 1.95 [1.47-2.59], p<0001) over lowest tertile. This differential was maintained across arms and indicates that TF is a strong prognostic biomarker. High TF outperformed common stratification factors (prior exposure to chemo in CSPC or novel ARPIs) for poor prognostication in a multivariate analysis. TF high patients have higher rates of AR-Amp/AR-LBD mutations (72.6%) than TF low (28.8%). Patients with TF clearance, defined as TF < 1% at C6D1 had 8 months mOS advantage over patients with a TF >1% at baseline and on-treatment. TF clearance strongly correlated with OS (HR=0.42 [0.28-0.62], p<0.001), rPFS benefit (HR=0.24 [0.17-0.34], p<0.001) and PSA response (28% vs. 62%) regardless of treatment arm. Conclusions: This data advocates for plasma TF as a robust prognostic biomarker and as a potential stratification opportunity in mCRPC clinical trials. TF clearance may act as an early indicator of treatment response and hence can be an important monitoring tool for mCRPC patient management. Clinical trial information: NCT04100018 .
Unraveling the dietary impact: Associations between ultra-processed foods and prostate cancer in a two-decade study.
135 Background: Prostate cancer is a leading cause of cancer-related morbidity in men, and emerging research suggests that dietary patterns, particularly involving processed foods, may play a role in its development. This study aims to explore the association between NOVA-classified food consumption and prostate cancer. Methods: Data from the National Health and Nutrition Examination Survey (NHANES 1999-2018) was analyzed. A sensitivity analysis was performed. Men aged 20 and older with a diagnosis of prostate cancer (n=731) and without any cancer (n=20,972) were contrasted. The mean daily caloric intake from various NOVA food categories was analyzed using independent t-tests, then corrected using Benjamini-Hochberg (p<0.05). Subgroup analyses were conducted via Welch two-sample t-tests for age and BMI, while Chi-Square tests were used for race, education level, birth country, and military status. Results: Men with prostate cancer had a higher intake of the following NOVA group 4 ultra-processed foods: “cakes, cookies pies, pancakes” (p=0.031), “ice cream, ice pops, and frozen yogurts” (p<0.001), “sugared breakfast cereals” (p<0.001). They also had a higher intake of certain group 1 unprocessed or minimally processed foods: “roots and tubers” (p=0.019) and “fruits including juices” (p<0.001). Men without cancer had a higher intake of certain NOVA 1 unprocessed or minimally processed foods: meat/poultry (p<0.001), grains (p=0.002), pasta (p=0.025). They also ate more oils (NOVA 2 processed culinary ingredients, p=0.003), NOVA 3 processed foods like cheese (p<0.001), and many NOVA 4 foods like salty snacks (p=0.002), pizza (p<0.001), sandwiches/hamburgers (p=0.030), potato products (p<0.001), sauces/dressing/gravies (p=0.001), soft drinks (p<0.001), and sweetened beverages (p<0.001). Subgroups analyses revealed a greater association with prostate cancer for people with older age, Non-Hispanic Black and Non-Hispanic White races, being US-born, having a higher education, and serving in the military. Conclusions: To our knowledge, this is the largest study evaluating dietary behavior in the context of food processing and prostate cancer prevalence. We identified a high risk dietary pattern associated with industrially processed, calorically dense, and high glycemic index foods; conversely, a low risk dietary pattern was associated with minimally processed Mediterranean diets and, interestingly, highly processed Western diets.
A phase 2/3 study of bicycle toxin conjugate zelenectide pevedotin (BT8009) targeting Nectin-4 in patients with locally advanced or metastatic urothelial cancer (la/mUC) (Duravelo-2).
TPS898 Background: Zelenectide pevedotin (zele; BT8009) is a Bicycle Toxin Conjugate (BTC), comprising a highly selective bicyclic peptide targeting Nectin-4 linked to the cytotoxin monomethyl auristatin E (MMAE) via a cleavable linker. Nectin-4 is an adhesion molecule commonly expressed in many tumor types, including la/mUC, and is a validated therapeutic target (Hoffman-Censits 2021). Zele has a low molecular weight and short plasma half-life, with potential to rapidly penetrate solid tumors and reduce toxicity by minimizing exposure to normal tissue (Rigby 2022). Results from the ongoing Phase 1/2 clinical trial of zele (NCT04561362) indicate preliminary antitumor activity and a tolerable safety profile in patients (pts) with advanced malignancies including UC (Baldini 2023). This global, open label, Phase 2/3 multicenter adaptive study aims to evaluate the safety and efficacy of zele as monotherapy, or combined with pembrolizumab (pembro), vs chemotherapy in pts with la/mUC (NCT06225596/BT8009-230; Duravelo-2). Methods: The trial will enroll n≤956 adult pts in 2 cohorts. Cohort 1 will include n≤641 previously untreated pts eligible for platinum-based chemotherapy. Cohort 2 will include n≤315 pts with ≥1 prior systemic therapy, excluding enfortumab vedotin or other MMAE-based therapy. Pts must have la/mUC of the renal pelvis, ureter, bladder, or urethra, ECOG performance status ≤2 (Cohort 1) or ≤1 (Cohort 2), and adequate organ function. Cohort 1 will be randomized 1:1:1 to receive: 1) zele 5 mg/m 2 on days [D]1, 8, and 15 + pembro 200 mg on D1; 2) zele 6 mg/m 2 on D1 and 8 + pembro 200 mg on D1; or 3) chemotherapy (gemcitabine + cisplatin / carboplatin, followed by avelumab maintenance in appropriate patients). Cohort 2 will be randomized 1:1 to receive: 1) zele 5 mg/m 2 on D1, 8, and 15 or 2) zele 6 mg/m 2 on D1 and 8. Cycle lengths will be 21D (28D for avelumab). After 30 pts in each dose arm have 9 weeks follow up, an interim analysis will determine the optimal dose of zele + pembro (Cohort 1) or zele monotherapy (Cohort 2) to be used for the rest of the study. An additional Cohort 2 arm, optimal dose of zele + pembro, will open after completion of the interim analysis. Discontinuation criteria include planned completion of therapy, progressive disease, and intolerable toxicity. Primary endpoints are progression-free survival (PFS; Cohort 1) and objective response rate (ORR; Cohort 2) assessed by blinded independent central review. Secondary endpoints are ORR (Cohort 1), PFS (Cohort 2), and overall survival, duration of response, disease control rate, safety/tolerability, and health-related quality of life (Cohorts 1 and 2). Pharmacokinetics, incidence/titers of antidrug antibodies, and tumor/peripheral biomarkers are exploratory endpoints. Efficacy endpoints will be assessed per RECIST v1.1. This study is actively recruiting. Clinical trial information: NCT06225596 .
Lewis Y antigen as a novel target for CAR (chimeric antigen receptor) T-cell therapy in patients with neuroendocrine prostate cancer.
217 Background: Neuroendocrine prostate cancers (NEPC) currently have no effective therapies. While CAR (Chimeric Antigen Receptor) T cell therapies targeting PSMA and PSCA receptors are currently in phase 1/2 studies in metastatic castrate-resistant prostate cancer (mCRPC), antigen targets for NEPC remain limited. Lewis Y antigen (LeY) is an oncofetal antigen expressed only in adult tumour cells and is considered a target for CAR T cell therapy in haematological, lung, ovarian and colon cancer. We previously found that LeY is a promising target for CAR T cell therapy in prostate cancer and that preconditioning LeY-directed CAR T cells with carboplatin further enhances tumour responses in mCRPC. We investigated if LeY can be used as a novel CAR T cell target for NEPC. Methods: The expression of the Lewis Y antigen was assessed in our patient-derived prostate cancer xenograft collection using immunohistochemistry (IHC). To assess the efficacy of LeY-CAR T cells, we used specimens established from a patient (Patient 508) with NEPC who had incurable metastatic disease and failed standard treatments. We generated CAR T cells from his peripheral blood mononuclear cells (PBMCs) to test their specificity and efficacy in vitro against established cell lines. Results: In our MURAL PDX collection of 59 prostate tumours, 81% (9/11) NEPCs expressed LeY antigen on IHC. Next, we successfully produced anti-LeY CAR T cells from the patient’s PBMCs using retroviral transduction. Flow cytometry verified efficient transduction of the CAR constructs. Previous studies found that a 1:1 ratio of CD4 + :CD8 + T cells improved outcomes following CAR T cell therapy 5,6 , so we further phenotyped patient T cells by flow cytometry. The CD4 + :CD8 + T cell ratio was nearly 1:1 (51.7% and 41.4% of total T cells, respectively). Next, we used an immunobead assay to investigate CAR-T specificity in releasing proinflammatory cytokines. Significant cytokine production was observed after a 4-hour co-culture with LeY+ human ovarian cancer cell line, OVCAR3, vs co-culture with control LeY- MDA-MB435 cells (p=0.0004), demonstrating the specificity of the CAR T cells.Lastly, we showed that patient CAR T cells effectively killed LeY+ cells (OVCAR3), but not control LeY- cells (MDA-MB435; p<0.0001). Tumour cell death was measured by the amount of released chromium following 16-hour co-culture. CAR T cells killed LeY+ target cells more effectively than their non-transduced equivalents at a range of effector-to-target ratios, with up to 15-fold increase in cell death. Conclusions: Our preclinical studies show that most NEPC tumors express the LeY antigen and that patient-derived CAR T cells specifically kill those cells. These findings identified a potential CAR T treatment target for NEPC for a phase 1/2 study.
Real-world community oncology-based treatment patterns for first line axitinib plus pembrolizumab in advanced renal cell carcinoma: Initial dosing, dose reductions and clinical outcomes.
487 Background: Axitinib (AXI) with pembrolizumab (PEM) is approved for first line (1L) treatment of advanced renal cell carcinoma (aRCC). This study provides real-world evidence of treatment patterns and outcomes in 1L aRCC patients treated in primarily community practice settings. Methods: This retrospective, multicenter, community oncologist-based chart review study used the Cardinal Health Oncology Provider Extended Network (OPEN). Patients with age ≥18 years, stage IV clear cell aRCC diagnosis, 1L AXI+PEM initiation between 22-Apr-2019 to 22-Feb-2024, and ≥6 months follow-up were included. Descriptive statistics were used to report demographics and treatment patterns. Duration of therapy (rwDOT) was defined as start date to discontinuation date of 1L AXI+PEM (any cause). Progression-free survival (rwPFS) was defined as start of 1L AXI+PEM to physician-reported progression or death. Results: Physicians (n=25) abstracted data for 300 patients, who were a median age of 66.7 years (interquartile range [IQR]: 60.0-72.8), 61.0% (n=183) male, 69.3% (n=208) White, and 11.3% (n=34) with sarcomatoid features. International Metastasis RCC Database Consortium risk groups for patients were 18.0% favorable, 59.3% intermediate, and 21.7% poor risk (n=3 unknown). Median follow-up overall was 12.3 (IQR: 8.1-21.6) months. Most patients (95%; n=285) started AXI at the initial recommended dose of 5 mg twice daily (BID; Table). Few patients (14.3%; n=43) required AXI dose reductions, with a median time to first AXI dose reduction of 2.3 months (IQR: 1.4-3.7), while 8.7% (n=26) of patients were able to dose escalate (7.3% [n=22] to 7 mg BID; 1.3% [n=4] to 10 mg BID). At data collection, 44.7% (n=134) of patients had discontinued AXI+PEM (78.7% due to progression; 7.8% due to adverse events). Median rwDOT of 1L AXI+PEM was 11.7 (IQR: 7.0-18.5) months and 12-month rwPFS was 74.3% (95% confidence interval: 68.3-79.4). Conclusions: This is one of the first comprehensive studies to describe real-world treatment patterns and clinical outcomes of 1L AXI+PEM for aRCC patients in the US community setting. The majority of patients were able to start 1L AXI+PEM at the FDA-recommended initial dose, with a minority of patients requiring dose reductions. Further prospective studies investigating the impact of 1L AXI+PEM treatment modification on clinical outcomes for aRCC are needed. Initial AXI regimen: 5 mg orally BID (n, %) 285, 95.0 Time from 1L initiation to first AXI decrease (months; median, IQR) 2.3, 1.4-3.7 Time from 1L initiation to first AXI increase (months; median, IQR) 0.5, 0.5-2.8 AXI dose/frequency after first decrease (n, %) 43, 14.3 3 mg orally BID 36, 83.7 2 mg orally BID 6, 14.0 Other ( 2 mg BID, 2 weeks on 1 week off) 1, 2.3 AXI dose/frequency after first increase (n, %) 26, 8.7 7 mg orally BID 22, 84.6 10 mg orally BID 4, 15.4
A natural language processing algorithm to extract MRI and biopsy-related phenotypes for prostate cancer patients.
356 Background: Extraction of data from unstructured medical records is a powerful but challenging tool for deriving novel information to drive research, improve clinical care and better inform guidelines. Here, we describe the creation and validation of a novel natural language processing (NLP) algorithm for extracting components of interest from biopsy and MRI reports for prostate cancer patients. Our algorithm specifically extracts the Gleason score from biopsy reports and maximum Prostate Imaging-Reporting and Data System (PI-RADS) score, Prostate-specific androgen (PSA) density, prostate volume, and prostate dimensions from MRI reports. Methods: MRI and biopsy pathology reports were extracted for a cohort of 155,570 patients diagnosed with prostate cancer between 1999 and 2024 either in the VA Cancer Registry System (VACRS) with prostate as their primary site of tumor or in the VA Corporate Data Warehouse with a relevant procedure or diagnosis code. These were annotated by a physician and a trained research scientist to generate data for the development and validation of our algorithm. Disagreements between annotators were adjudicated by a urologist. Our rule-based NLP algorithm was iteratively developed on 600 annotated and unannotated notes. The algorithm was validated on a manually annotated set of 250 MRI reports and 250 biopsy pathology notes from 378 patients at 78 VA centers for procedures between 2004 and 2024. Precision (true positives / (true positives + false positives)), recall (true positives / (true positives + false negatives)), and F1 score (2 * (precision * recall) / (precision + recall)) were computed to evaluate algorithm performance, with higher scores indicating better performance. Results: Our algorithm successfully extracted all five components from text reports with high precision and sensitivity. Item-level performance metrics for our algorithm on unseen data are reported in the table below. Post-hoc spot checking of algorithm performance on an additional sample of notes selected by procedure year revealed consistency of results across time for all components except prostate dimensions, for which a greater proportion of recent negative notes were false negatives. Further error analysis showed that many Gleason scores that our algorithm did not extract were repetitions of scores successfully extracted elsewhere in the note. Conclusions: Our NLP algorithm is able to derive structured data from medical reports with highly diverse formats with excellent accuracy and reliability. This approach has great potential to facilitate data extraction in a range of settings and to drive future research and clinical questions. Component Precision % Recall % F1 score % Gleason grade group 99.1 94.7 96.9 PI-RADS 95.5 92.7 94.1 PSA density 100.0 99.0 99.5 Prostate volume 96.9 94.5 95.7 Prostate dimensions 98.4 90.2 94.1
Evaluating the combined role of HHLA2 and PD-L1 as biomarkers in first-line nivolumab therapy in advanced clear cell renal cell carcinoma.
598 Background: PD-1 directed immune checkpoint inhibitors are effective in many tumor types, including kidney cancers. HHLA2 is a negative immune checkpoint, generally expressed on PD-L1 negative clear cell renal cell carcinomas (ccRCC) (Bhatt, et al. 2021). Therapeutics targeting either HHLA2 or its inhibitory receptor KIR3DL3 are in Phase I trials and predictive biomarkers are needed to help direct treatment. We previously reported that efficacy of nivolumab correlated with tumor PD-L1 status in patients with kidney cancer treated in the first line setting (GU16- 260; Atkins, et al. 2022). We hypothesize that HHLA2 expression in combination with PD-L1 expression may provide a clinically significant biomarker for resistance to PD-1 blockade in patients with advanced ccRCC. Methods: HHLA2 expression in tumor cells (TC) was assessed by immunohistochemistry coupled with image analysis algorithms in 63 pre-treatment primary ccRCC tissues from patients enrolled in the HCRN GU16-260 trial. TC PDL-1 positivity had been previously evaluated in this cohort (Atkins, 2022). TC HHLA2 expression in combination with TC PD-L1 expression was correlated with progression-free survival (PFS) and objective response rate (ORR). Results: Consistent with our prior reports, HHLA2 expression did not overlap with PD-L1 expression on tumor cells. TC HHLA2 expression in combination with TC PD-L1 expression identified three groups of patients with different clinical outcomes with regards to ORR (trend test p-value = 0.016) and PFS (trend test p-value = 0.024) (Table). Patients with positive (>0%) TC PD-L1 expression had the best outcomes (ORR=62.5%, median PFS=24.7 months); patients with negative TC PD-L1 expression and low (<61%) TC HHLA2 expression had intermediate outcomes (ORR=38.5%, median PFS=10.6 months) and patients with negative TC PD-L1 expression and high (≥61%) TC HHLA2 expression had the worst outcomes (ORR=12.5%, median PFS=3.5 months). Conclusions: Further investigation of the HHLA2/PD-L1 combined biomarker is warranted as it may be helpful in identifying patients that do not respond to anti-PD-1 therapy but could benefit from agents targeting the HHLA2/KIR3DL3 pathway. HHLA2 and PDL-1 category Number of patients(63 total) ORR PFS (median, months) TC PD-L1 >0% 16 62.5% 24.7 TC PD-L1 = 0% & TC HHLA2 <61% (low) 39 38.5% 10.6 TC PD-L1 = 0% & TC HHLA2 ≥61% (high) 8 12.5% 3.5 Trend test p-value 0.016 0.024
Survival disparities by race in advanced urothelial carcinoma (aUC): A real-world analysis.
668 Background: Retrospective population data suggest poorer survival for non-White aUC patients. However, data on survival disparities in the era of immuno- and targeted therapies is limited. Methods: This cohort study used Flatiron Health’s nationwide de-identified electronic health record (EHR)-derived database. 7,244 patients (pts) were identified. Pts who started systemic therapy for aUC from 1/1/2017 to 5/1/2024 and had a recorded race were included. Baseline demographics, including social determinants of health (SDOH) score, performance status (PS), disease characteristics, treatment history, and clinical outcomes were abstracted. Progression free survival (PFS) and overall survival (OS) were compared between Black, White and Asian patients via Kaplan-Meier log-rank analysis and Cox proportional hazards models. Independent sample t-tests and chi-square analyses were used for univariate comparisons. P-values < 0.05 were considered statistically significant. Results: A total of 2,388 pts with aUC were identified, with 1.4% Asian, 5.2% Black, 14.4% “other,” and 78.9% White. In 1L, 17.9% received immunotherapy (IO) monotherapy, 4.2% received enfortumab vedotin + pembrolizumab (EVP), 37.5% received carboplatin-based regimens (carbo), 27.8% cisplatin-based regimens (cis), and 12.5% other chemotherapy (p=0.317). ECOG PS>1 at diagnosis was associated with non-White race (p=0.022). Black patients received treatment at an academic center (41.0%) more often than White patients (25.6%; p<0.001). Black pts had lower SDOH score compared White (p<0.001). Asian (HR0.73, p=0.3) and Black (HR1.07, p=0.3) pts had similar PFS to White pts, as well as similar OS with HR0.85(p=0.4) and HR1.05(p=0.4), respectively. On Cox univariate analysis, there was no significant 1L PFS difference between White, Asian, and Black pts on cis (n=665, p=0.3), carbo (n=895, p=0.7), EVP (n= 25, p=0.8), or IO (n=428, p=0.3). OS was not significantly different by race for any 1L therapy. Conclusions: In a large real-world database, race did not affect overall aUC survival. Baseline characteristics and survival by race. Black (n=124) White (n=1884) Asian (n=33) Other (n=344) Sig (p) Baseline Characteristics ECOG PS 0-1 (%) 55.5 64.6 58.2 62.1 0.027 2-4 (%) 18.5 15.5 19.4 15.2 Academic treatment center (%) 36.6 25.9 13.4 13.2 <0.001 Mean SDOH score (0-5) 2.27 3.26 3.38 2.97 <0.001 1L Treatment IO (%) 23.8 16.4 20.0 17.5 0.317 EVP (%) 5.7 3.9 4.4 4.0 Carbo (%) 32.9 36.5 37.4 38.0 Cis (%) 27.4 29.2 27.8 29.8 Other (%) 10.2 14.0 10.4 10.7 Survival 1L mPFS (m) 5.2 4.6 5.1 4.2 0.300 mOS (m) 5.3 6.9 8.7 5.2 0.400 Sig values (p<0.05) in bold.
ETCTN 10483: Phase Ib trial of erdafitinib (E) combined with enfortumab vedotin (EV) following platinum and PD-1/L1 inhibitors for metastatic urothelial carcinoma (mUC) with FGFR3/2 genetic alterations (GAs).
808 Background: Erdafitinib (E) is an approved treatment in patients with mUCwith FGFR 3 GAs after progression on platinum-based chemotherapy (PBC). Enfortumab Vedotin (EV) is approved to treat patients with mUC following prior PBC and PD1/L1 inhibitors or as First-line therapy in combination with pembrolizumab. Retrospective studies suggest that the activity of EV is not compromised by FGFR 3/2 GAs. EV and erdafitinib have different mechanisms of activity and toxicities are mostly non-overlapping. Hence, there is rationale to evaluate the feasibility of combination EV and E, to overcome the difficulties of resistance and sequencing agents in mUC patients with FGFR 3/2 GAs. Methods: This is an ongoing, single arm, multicenter, Phase I, 3+3 design dose-escalation and expansion study of E+ EV combination evaluating the safety, tolerability, PK, and antitumor activity in patients with mUC harboring FGFR3/2 GAs who have progressed after platinum and/or PD1/L1 inhibitor therapies. Dose escalation phase aims to identify the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of EV in combination with fixed dose of E at 8 mg/day (table). Results: As of data cutoff, 9 patients were enrolled and completed dose limiting toxicity (DLT) period (1 st cycle) in the dose-escalation phase. Six patients were enrolled at DL1 with 1 DLT (skin rash) and 3 at DL2 (no DLT). The most common all grade treatment-related adverse events (TRAEs) included hyperphosphatemia (88%), mucositis (88%), high AST (88%), hypercalcemia (75%), palmar plantar erythrodysesthesia (75%), peripheral neuropathy (75%), alopecia (63%), diarrhea (63%), hypoalbuminemia (63%) and hypomagnesemia (63%). Grade 3 TRAEs included palmar plantar erythrodysesthesia (50%), anemia (17%), rash (17%), anorexia (17%) and paronychia (17%). One patient developed grade 4 Stevens-Johnson syndrome related to EV which subsequently improved. PK data are available for all 6 patients in DL1. The average steady-state Cmin of E and MMAE was 1430 ± 639 ng/mL and 1.4 ± 0.9 ng/ml, respectively, and the average Cmax of MMAE was 3.9 ± 0.9 ng/mL at DL1. All 9 patients are evaluable with 100% best objective rate, including 8 partial responses (PRs) and 1 complete response (CR). The mOS was NR (95% 17.1 months-NR), mPFS was 7.52 months (95% CT 5.55-NR) with median follow up of 22.7 months. The mDOR is 5.49 months. The RP2D of EV is 1.25 mg/kg in combination with E at 8 mg/day. Conclusions: E+EV combination is feasible and preliminarily exhibits promising antitumor activity. Dose expansion is ongoing at RP2D dose of EV with E. Clinical trial information: NCT04963153 . Dose Level (DL) Dose Cycle Length E EV Level -1 8 mg PO QD 0.75 mg/kg IV (maximum dose 75 mg) D1,8,15 28 days Level 1 8 mg PO QD 1 mg/kg IV (maximum dose 100 mg) D1,8,15 Level 2 8 mg PO QD 1.25 mg/kg IV (maximum dose 125 mg) D1,8,15
First-in-human phase 0 safety, imaging, pharmacokinetics, and dosimetry study of <sup>64</sup> Cu-PD-32766, a carbonic anhydrase IX (CAIX)-targeting peptide, in patients with clear cell renal cell carcinoma (ccRCC).
TPS605 Background: Carbonic Anhydrase (CA)IX is a type of carbonic anhydrase and is expected to be a useful target for detecting tumors with poor prognosis. Particularly in clear cell renal cell carcinoma, high CAIX expression has been reported in a large proportion of patients. In this study, we developed a novel radioligand agent called PD-32766 that specifically binds to CAIX and administered it to recurrent cases of clear cell renal cell carcinoma (ccRCC) patient. Safety, imaging, pharmacokinetics and dosimetry are evaluated. Methods: Between May 2024 and September 2024, PD-32766 labeled by positron-emitting 64Cu (64Cu-PD-32766) was intravenously administered at a dose of 148 MBq (±20%) to five patients with clear cell renal cell carcinoma who had either distant metastasis or local recurrence, and who met other eligibility criteria. PET/CT imaging was performed at 5, 60, 120, 240 minutes, 24, and 48 hours after administration, with vital signs, blood tests, and urinalysis performed as needed. The primary endpoint was the patient-level PET uptake positivity rate of target tumor regions. Secondary endpoints included the number of positive lesions, pharmacokinetics, estimated radiation dose, and the frequency and types of adverse events. This trial is registered under the jRCT trial identifier:jRCTs031240046. Results: 64Cu-PD-32766 demonstrated good tolerability, with no serious complications observed. The average patient-level PET uptake positivity rate at 120 minutes was 75%. The average lesion-level PET positivity rate was 96.2%. Tumor uptake was highest at 60, 120 minutes post-administration. The effective dose for whole body was 0.102±0.036 mSv/MBq. The stomach and small intestine had the highest absorbed doses among all organs, with 0.712±0.287 mGy/MBq and 0.304±0.067 mGy/MBq, respectively. Conclusions: 64Cu-PD-32766 demonstrated an excellent positivity rate in ccRCC patients with no significant adverse events and tolerated radiation dose to normal organs, proving high diagnostic capability and suggesting future therapeutic uses by labeling with therapeutic radionuclides. Clinical trial information: jRCTs031240046 .
Immune profiling at the single-cell level to evaluate the immune microenvironment in bladder cancer: Insights from non-muscle invasive and muscle-invasive disease.
842 Background: Advanced Bladder Cancer (BC) presents significant challenges due to its high incidence and limited treatment options. Most patients initially present with non-muscle invasive bladder cancer (NMIBC), managed with transurethral resection (TURBT) and Bacillus Calmette–Guerin (BCG) therapy. However, some cancers recur or develop resistance, progressing to muscle-invasive bladder cancer (MIBC), which is associated with high mortality and limited curative options. While radical cystectomy (RC) is the standard treatment for MIBC, it has considerable morbidity. Thus, there is a critical need for predictive tools to guide treatment decisions and novel therapeutic approaches. Immunotherapies show promise, but their efficacy remains constrained. Analyzing the immune infiltrate in BC may uncover mechanisms of resistance and identify new targets. Methods: We investigated the immune microenvironment in NMIBC and MIBC using high-dimensional single-cell analysis, including scRNAseq and Imaging Mass Cytometry (Cytomass). Tumor tissues were obtained from BC patients who underwent cystectomy or Trans urethral removal of bladder tumour (TURBT). We enrolled 7 NMIBC and 8 MIBC patients for scRNAseq, isolating CD45+ immune cells and CD45- epithelial and stromal cells using FACS. The samples were processed with 10X technology to reveal transcriptional landscapes. Additionally, we enrolled 5 NMIBC and 5 MIBC patients for Cytomass analysis, where tissue sections were snap-frozen, stained, and analyzed with the Hyperion system. Our primary endpoint was to identify differences in the composition of tumor and immune cells between NMIBC and MIBC. The study was funded by the Next Generation EU Plan - Piano Nazionale di Ripresa e Resilienza (PNRR-MAD-2022-12376756). Results: The cohort included 15 patients with clinically significant BC who underwent radical cystectomy or TURBT. scRNAseq analysis of patients revealed differences in immune cell abundance and activation states between NMIBC and MIBC samples, identifying distinct cell types and high intra-tumoral heterogeneity. Notable changes were observed tumor-infiltrating B cell lymphocytes, with different abundance in tumors depending on the cell subsets. Immature B cells were enriched in MIBC when compared to NMIBC, indicating a potential role in tumor progression. Cytomass analysis further highlighted modulations in immune cell activation and spatial localization between NMIBC and MIBC. Conclusions: Our findings demonstrate the utility of single-cell RNA sequencing in elucidating the immune landscape of BC and highlight significant immune changes between MIBC and NMIBC. This data enhances our understanding of immune composition and the role of specific immune subsets in BC, potentially informing clinical risk stratification and treatment decision-making.
Disease management costs and healthcare resource utilization by progression health state among patients with previously untreated locally advanced or metastatic urothelial cancer.
714 Background: Significant disease management cost (DMC) burden and healthcare resource utilization (HRU) have been reported for patients with advanced bladder cancer; however, available data were outdated. We estimated the real-world DMC and HRU for patients with locally advanced or metastatic urothelial carcinoma (la/mUC) receiving first-line (1L) treatment over time and by progression health state with more contemporary data. Methods: Patients aged ≥65 years with la/mUC receiving 1L treatment were identified from the SEER-Medicare linked database (2007–2019 [SEER]; 2007-2020 [Medicare]). Disease progression on 1L treatment was defined as the initiation of second-line treatment or the diagnosis of secondary malignancies. All-cause DMC and HRU were evaluated for all eligible patients during the pre-progression period, defined as the time from 1L initiation to date of progression or end of follow-up. For patients who progressed after 1L treatment, DMC and HRU were also assessed during the post-progression period, defined as the time from date of progression to end of follow-up. DMC were calculated as the sum of all-cause medical costs (inpatient [IP] + emergency room [ER] + outpatient [OP] costs + other medical costs not associated with these settings [e.g., skilled nursing facility]) and pharmacy (Rx) + drug administration costs, excluding the Rx and drug administration costs of la/mUC treatments. HRU included IP, ER, and OP visits, and use of radiation therapy and imaging. Costs and HRU were summarized on a per-patient per-month (PPPM) basis and stratified by time intervals: 0 to <12 months, 12 to <24 months, and 24+ months. All costs were inflated to 2023 US dollars. Results: Among the 1,145 patients with la/mUC who received 1L treatment, 872 (76.2%) progressed after 1L treatment. DMC (PPPM) post-progression were higher compared to pre-progression across all time intervals ($12,039 vs. $8,422 [0 to < 12 months], $5,994 vs. $3,119 [12 to <24 months], and $4,591 vs $1,743 [24+ months]) and decreased over successive time intervals for both pre- and post-progression health states. Similar findings in HRU indicate higher number of IP and OP visits in the post-progression state, except for OP visits during the 0 to <12 months interval. ER visits were similar in all but the 24+ months interval, where higher rates in the post-progression state were observed. Use of radiation therapy and imaging was higher in all intervals in the post-progression health state. Conclusions: DMC for la/mUC patients receiving 1L therapy were higher in the post-progression state compared with the pre-progression health state. The highest costs and HRU incurred within the first 12 months of 1L treatment initiation and disease progression. Contemporary time-varying DMC during progression health states is valuable to assess economic impact of new therapies.
Efficacy of nivolumab plus ipilimumab in T1aN0M0 renal cell carcinoma (RCC) patients: Results from 3-year follow-up of the phase 2 pilot study.
536 Background: Some patients with primary renal cell carcinoma (RCC) are not candidates for surgery or nephron-sparing interventions due to various factors, such as the presence of a functional single kidney with a central, high-complexity tumor. This study aimed to evaluate whether a combination of nivolumab and ipilimumab could eliminate the primary tumor in patients with T1aN0M0 RCC. Methods: This prospective, multicenter, phase 2 pilot study enrolled patients with biopsy-confirmed clear-cell RCC (cT1a) ≤4 cm, no metastases, and who were ineligible for surgery or nephron-sparing procedures. Patients were treated with ipilimumab (1 mg/kg) every 3 weeks for four doses, alongside nivolumab (240 mg) every 2 weeks for eight doses. The primary endpoint was the complete response rate. Simon's two-stage design was used, testing the null hypothesis of a true complete response rate of 11%. A type I error rate of 0.05 and a power of 0.9 were set, with the null hypothesis rejected if 3 or more responses were observed in 8 patients. Results: From February 2020 to June 2021, 8 patients were enrolled, with a median age of 77.9 years (range 73–89). The cohort was entirely Caucasian, predominantly male (75%), and 62.5% had centrally located tumors. Six patients had moderate to severe comorbidities. All patients completed the immunotherapy without experiencing grade ≥2 adverse events. After a median follow-up of 37.4 months (95% CI 31.7–44.5), no complete responses were observed. However, partial responses were seen in 4 patients (50%), with continued tumor reduction after therapy. The median tumor size decreased from 3.11 cm (range 2.2–3.9) to 1.89 cm (range 1.1–4.0). Tumor shrinkage was observed in 6 patients (75%), while 1 patient experienced a slight tumor enlargement (+0.5 cm, +13%) after 9 months. The 3-year progression-free survival rate was 100%. Data on 5-year overall survival will be reported later. Conclusions: Although complete tumor regression was not achieved, immunotherapy with nivolumab and ipilimumab led to significant and durable tumor shrinkage in two-thirds of T1aN0M0 RCC patients, with minimal toxicity, making it a viable option for patients with significant comorbidities. Further data on long-term survival are awaited. Clinical trial information: NCT04134182 .
Real-world comparison of cost and adherence between patients receiving low-dose versus standard-dose abiraterone acetate (AA) in a safety-net hospital.
54 Background: While the standard dose of AA (1,000 mg) is taken on an empty stomach, low-dose AA (250 mg with a low-fat meal) is also an option, with both listed as standard of care in national guidelines for the treatment of prostate cancer (PCa). We sought to evaluate the cost and adherence of low-dose AA (LDAA) versus standard-dose AA (SDAA) in a diverse population treated at the University of Illinois Chicago (UIC), a Chicago safety-net hospital. Methods: PCa patients treated at UIC who filled at least oneprescription for AA between April 2017 and September 2024 were identified retrospectively. Key data such as age, race, ethnicity, insurance status, disease stage, monthly copays, medication fill history, dates of disease progression or death, and adverse events were obtained. Chi square analysis was used to compare cost, adherence, progression-free survival (PFS), and adverse events between the two groups. Adherence was calculated as the number of 30-day fills divided by the number of months the patient was prescribed AA, expressed as a percentage. Results: We identified 138 patients who filled a prescription for AA during the study timeframe (Table). 72.5% were Black, 55.1% had Medicare as their primary insurance, and 35.5% had Medicaid as their primary insurance. 26.8% had localized disease upon starting AA while 73.2% had metastatic disease (Table 1). Patients receiving LDAA were less likely to have a monthly copay of $100 or greater at any point compared to those receiving SDAA (7.3% vs. 19.6%, p=0.04). The percentage of patients with less than 80% adherence was 4.9% for those receiving LDAA compared to 10.7% of those receiving SDAA, however this difference did not meet statistical significance (p=0.20). Adverse events were similar in both cohorts, with 13.4% of those receiving LDAA having discontinued the medication due to toxicities compared to 10.7% of those receiving SDAA (p=0.64). Median PFS was 23 months in the standard-dose group but was not reached in the low-dose group due to data immaturity. Conclusions: Patients receiving LDAA experienced lower financial burden than those receiving SDAA, as quantified by copays of $100 or greater. There was not a statistically significant difference between the two groups in adherence or rate of adverse events requiring discontinuation. Data on the impact of dose and clinical outcomes are ongoing and maturing. LDAA (n=82, median age 65) SDAA (n=56, median age 68) Total (n=138, median age 66) Medicare 42 (51.2%) 34 (60.7%) 76 (55.1%) Medicaid 32 (39.0%) 17 (30.4%) 49 (35.5%) Private or other insurance 8 (9.8%) 5 (8.9%) 13 (9.4%) Black, non-Hispanic 59 (72.0%) 41 (73.2%) 100 (72.5%) White, non-Hispanic 7 (8.5%) 8 (14.3%) 15 (10.9%) Hispanic of any race 14 (17.1%) 7 (12.5%) 21 (15.2%) Other race 2 (2.4%) 0 (0%) 2 (1.4%) Localized disease 27 (32.9%) 10 (17.9%) 37 (26.8%) Metastatic disease 55 (67.1%) 46 (82.1%) 101 (73.2%)
Final overall survival (OS) with talazoparib (TALA) + enzalutamide (ENZA) as first-line (1L) treatment in patients (pts) with homologous recombination repair (HRR)-deficient metastatic castration-resistant prostate cancer (mCRPC) in the phase 3 TALAPRO-2 trial.
LBA141 Background: Approximately one-quarter of advanced prostate cancers have alterations in DNA damage response genes directly or indirectly involved with HRR that can sensitize them to treatment with poly(ADP-ribose) polymerase inhibitors. The Phase 3 TALAPRO-2 trial met its primary endpoint, showing improved radiographic progression-free survival (rPFS) for TALA + ENZA vs placebo (PBO) + ENZA as 1L treatment in pts with mCRPC in the HRR-deficient cohort (cohort 2). At the first interim analysis, immature OS data favored TALA + ENZA vs PBO + ENZA. Here we report final OS data, a descriptive update of rPFS, and extended safety follow-up in cohort 2. Methods: Pts with HRR-deficient tumors were randomized 1:1 to ENZA 160 mg + either TALA 0.5 mg (0.35 mg if moderate renal impairment) or PBO once daily and stratified by prior abiraterone or docetaxel (yes/no) for castration-sensitive PC. Key eligibility criteria included asymptomatic or mildly symptomatic mCRPC, ECOG PS ≤1, ongoing androgen deprivation therapy, and no prior life-prolonging therapy for CRPC. The primary endpoint was rPFS by blinded independent central review. OS was an alpha-protected key secondary endpoint. To achieve statistical significance at the final OS analysis, the stratified log-rank 2-sided P value needed to be ≤0.024 using a group sequential design with O’Brien-Fleming spending function. Results: Overall, 399 pts were randomized (N=200, TALA + ENZA; N=199, PBO + ENZA). At data cutoff (Sept 3, 2024), 93 pts (46%) in the TALA + ENZA arm and 126 pts (63%) in the PBO + ENZA arm had died; median follow-up was 44.2 and 44.4 months, respectively. Hazard ratio (HR) for OS with TALA + ENZA vs PBO + ENZA was 0.622 (95% CI, 0.475–0.814; 2-sided P =0.0005); median OS (95% CI), 45.1 months (35.4–not reached) vs 31.1 months (27.3–35.4 months), respectively. In exploratory analyses, OS favored TALA + ENZA vs PBO + ENZA in pts with BRCA1/2 alterations (n=155; HR, 0.497; 95% CI, 0.318–0.776; P =0.0017) and pts without BRCA1/2 alterations (n=244; HR, 0.727; 95% CI, 0.516–1.024; P =0.0665). Updated rPFS data were consistent with the primary analysis, favoring the TALA + ENZA vs PBO + ENZA arm (HR, 0.468; 95% CI, 0.359–0.612; P <0.0001); median rPFS, 30.7 vs 12.3 months, respectively. Consistent with primary results, the most common grade 3–4 TEAEs with TALA + ENZA were anemia (43%) and neutropenia (20%). TEAEs were generally manageable; 26 pts (13%) discontinued TALA due to TEAEs. Conclusions: TALA + ENZA demonstrated a statistically significant and clinically meaningful improvement in OS vs ENZA. These data establish TALA + ENZA as a standard of care for 1L treatment in pts with HRR-deficient mCRPC. rPFS continued to favor TALA + ENZA. Safety was consistent with previous reports; no new safety signals were identified. Clinical trial information: NCT03395197 .
Deciphering immune-genomic markers of hyperprogression in patients (Pts) with metastatic urothelial cancer (mUC) treated with immune checkpoint inhibitors (ICIs).
840 Background: ICIs offer modest response rates (~20%) in mUC and there remains a critical need for validated biomarkers to predict patient benefit. Hyperprogressive disease (HPD), characterized by rapid tumor progression following ICI initiation, is a poorly understood phenomenon in mUC. No robust biomarkers currently exist to identify patients at risk for HPD, a condition that leads to unnecessary treatment and exacerbated toxicity. While patient factors associated with HPD have been studied, little is known about the tumor’s immune-genomic landscape in these cases. We investigate the immune-genomic features of mUC tumors associated with HPD to better understand and predict this response to ICI. Methods: We retrospectively analyzed 132 pts with mUC treated with atezolizumab or pembrolizumab between 2015-2023. All patients received at least 2 ICI cycles, and archival FFPE tumor samples were available for immune-genomic analysis. Pts were classified as responders (N=75, defined as complete/partial response or stable disease) or non-responders (N=57, progressive disease). HPD was defined as progression per RECIST within 14 weeks of ICI initiation. RNA was extracted from macrodissected FFPE samples, and transcriptomic profiling was performed using the Nanostring PanCancer IO 360 panel. Data were processed using nSolver 4.0 and nanostring data analysis service analyzed for differential gene expression. Receiver operator characteristic (ROC) analysis was conducted to assess the predictive power of immune signatures for HPD. Results: Of the 132 pts, 48 (36%) were classified as having HPD. Compared to non-responders without HPD, HPD tumors exhibited significant downregulation of immune signatures, including IFN Gamma, PD-L1, myeloid cells, and tumor inflammation signatures (TIS). Key chemokines and IFN downstream signaling were also downregulated (p-adj = 0.041). Single-gene analysis highlighted downregulation of CCL4 (logFC = -0.947, p = 0.00012), GBP1 (logFC = -0.8105, p = 0.00017), and NECTIN2 (logFC = -0.4792, p = 0.00032) in HPD tumors, though statistical significance was not reached after adjustment. ROC analysis demonstrated modest predictive power for HPD with AUCs of 0.66 for TIS and IFN Gamma, and 0.658 for the immunoproteasome. Conclusions: Our findings reveal a distinct immune-genomic profile in mUC tumors associated with HPD following ICI treatment, including reduced IFN Gamma, TIS, and myeloid cell signaling. These immune signatures may serve as potential biomarkers to identify pts at risk of HPD, warranting further validation in prospective trials. Ongoing analyses will continue to explore the genomic underpinnings of HPD and therapeutic resistance in mUC.