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A fire deficit persists across diverse North American forests despite recent increases in area burned

The feasibility of tumor-infiltrating lymphocyte expansion in non-clear cell renal cell carcinoma.

580 Background: The treatment landscape for non-clear cell renal cell carcinoma (nccRCC) lacks personalized therapeutic options. Although adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) has been explored in the treatment of other solid tumors, its potential feasibility and role in nccRCC remains unclear. This study aims to evaluate the feasibility of TIL expansion in nccRCC tumors. Methods: In this IRB-approved study conducted at Moffitt Cancer Center, tumor fragments collected from patients with nccRCC were cultured for 4 weeks in media supplemented with high-dose IL-2 (6000 IU/mL). After the 4-week period, assessments were made of TIL expansion, TIL phenotype, and reactivity to autologous tumor, measured by IFNγ secretion. The percent of T-cell phenotypes among expanded TILs were compared using a paired Student's t-test for normally distributed data and a Wilcoxon signed-rank test for non-normally distributed data. Differences in TIL measures by histologic subtype and TNM staging were analyzed using Kruskal-Wallis testing, while tumor size and patient clinicodemographic data were evaluated with standard linear regression. Results: A total of 16 patients underwent nephrectomy with curative intent for high risk, localized nccRCC. Most patients were male (68.8%) with a median age at time of surgery of 60.3 years (Interquartile Range [IQR]: 50.4-63.9). Histologically, 9 tumors were classified as papillary type 1, two as papillary type 2, one as chromophobe, one as Xp11.2 translocation, and three as unclassified. TILs were successfully grown in all 16 samples, with an average of 47.3% (range: 6.25-100.0) of fragments successfully expanded. The average TIL yield per fragment was 1.24 x 10 7 cells (range: 1.60 x 10 6 – 2.75 x 10 7 ). Reactivity of TILs to autologous tumors was observed in 81.25% of samples. Across each TIL measure, no differences were noted among nccRCC histology subtypes, TNM status, or tumor size. A histologic breakdown of TIL and phenotypic data is provided in the table. Conclusions: In this study, all 16 nccRCC tumor fragments expanded TILs with viable reactivity and marked predominance of T-cells. These results suggest the novel potential for TIL-based therapy in nccRCC histologic subtypes and warrant further investigation. nccRCC TIL expansion measures and phenotype breakdown. Primarily CD3 + T-cells expanded (p=0.01), with a higher proportion of CD4 + T-cells than CD8 + T-cells (p=0.004). Measure, mean ± SD Papillary nccRCC (n=11) Non-Papillary nccRCC (n=5) % Fragment Expanded 54.8 ± 26.7 29.3 ± 19.8 Total TIL Per Fragment 1.2 x 10 7 ± 8.2 x 10 6 1.4 x 10 7 ± 1.0 x 10 7 % Reactive Fragments 65.2 ± 26.8 43.0 ± 46.2 % CD56 + of TIL Expansion 14.1 ± 26.2 9.8 ± 4.6 % CD3 + of TIL Expansion 80.7 ± 26.3 88.5 ± 3.4 % CD4 + of TIL Expansion 50.3 ± 22.6 66.9 ± 18.1 % CD8 + of TIL Expansion 22.5 ± 17.5 12.0 ± 10.2

Real-world treatment patterns and outcomes in advanced prostate cancer: A cohort study using the prostate cancer disease observation (PRECISION) data platform.

59 Background: There are several real-world data sources for prostate cancer (PC), each with its own limitations; the most notable limitation is an incomplete picture of the multidisciplinary clinical management of PC. The PRECISION data platform, the largest, most comprehensive, and continually updated real-world evidence source on patients with advanced PC to date, tries to address this limitation and shed light on PC management in both urology and oncology practices in both academic and community settings in the US. The platform includes a wide variety of PC-specific data variables among patients with metastatic hormone-sensitive PC (mHSPC) and metastatic castration-resistant PC (mCRPC) treated across the US. This study aims to provide an overview of the characteristics, treatment patterns, and clinical outcomes among patients with mHSPC and mCRPC included in PRECISION to date. Methods: A retrospective cohort study that included patients with a diagnosis of mHSPC or mCRPC (index date) in PRECISION between 2018 and 2024 (cohorts could overlap). For each cohort, patient characteristics and treatment patterns were evaluated descriptively. Results: The PRECISION platform currently includes 72,855 and 33,538 patients with mHSPC and mCRPC, respectively. Among the mHSPC cohort, the mean ± standard deviation (SD) age was 74.5±9.4 years; 67% and 33% were treated at oncology and urology centers, respectively; 40% and 60% were from academic and community settings, respectively. The average ± SD time from mHSPC to mCRPC was 11.2±11.7 months. Overall, 77.6% of patients were treated with androgen-deprivation therapy (ADT), of whom 64.7% had ADT combined with androgen receptor pathway inhibitors (ARPIs) including abiraterone acetate, enzalutamide, and apalutamide. Among the mCRPC cohort, the mean ± SD age was 74.1±9.3 years; similar treatment setting patterns as mHSPC were observed. Overall, 74.6% initiated a first-line (1L) therapy on/after mCRPC diagnosis; 52.1% had 1L ARPIs, 16.2% 1L immunotherapy, and 4.6% 1L taxane chemotherapy. In addition, 2.2% of patients received the recently US FDA-approved therapy, lutetium-177 vipivotide tetraxetan, at some point during their mCRPC disease duration. Conclusions: This analysis provides key insights into the patients included in the PRECISION data platform. This multidisciplinary dataset provides a 70/30 split between oncology and urology centers, and a 40/60 split between academic and community settings. The observed clinical profile, treatment patterns, and outcomes comprise the most comprehensive representation of current treatment practice in the US. Future analyses of clinical outcomes with existing and novel therapies could contribute significantly to our understanding of opportunities to improve the treatment of patients with mHSPC and mCRPC in the US.

Treatment patterns and survival outcomes in metastatic castration-resistant prostate cancer in the Brazilian population: LACOG 1818.

27 Background: Prostate cancer is the second leading cause of cancer death in men worldwide. In Brazil, 75% of patients (pts) rely on the public healthcare system, where access to novel therapies is limited. This disparity may lead to significant differences in survival outcomes. The LACOG 1818 study aims to address this gap by evaluating survival outcomes and treatment patterns among Brazilian pts diagnosed with metastatic castration resistant prostate cancer (mCRPC) in different healthcare settings (public versus private). Methods: LACOG 1818 is a retrospective cohort that included Brazilian pts from 18 research sites diagnosed with mCRPC between Jan 2014 and Dec 2017. Data on pts demographics, clinicopathological features, treatment patterns, and overall survival (OS) were collected from medical records. The primary endpoint was cause-specific survival (CSS) estimated by Kaplan-Meier method. Comparisons between groups (public vs. private healthcare) were assessed by chi-square and the log-rank tests. Results: From Jan 2020 to Jan 2022, 582 eligible pts were included. The median age was 49 (26-53) years, 259 (45%) were white and 85 (15%) were black/brown. Most had bone metastases (n=499, 86%), followed by non-regional lymph-nodes (n=239, 41%). A total of 323 (55%) pts had public and 259 (45%) had private health coverage. The main modality of castration was biochemical castration (n=442, 76% [public 60% vs. private 96%; p<0.0001]), followed by bilateral orchiectomy (n=140, 24% [public 40% vs. private 4%; p<0.0001]). 499 pts had available data on systemic treatment for mCRPC: 473 (95%) received first line; 247 (49%) second line; and 147 (29%) ≥ 3 lines. 378 (65%) pts received a bone protector agent (63% in public vs. 68% in private; p <0.001). At median follow-up of 59 months (95% CI 54.3-62.1), median OS was 57.1 months (95% CI 47.0-65.2) in overall sample; 44.8 months (95% CI 36.0-57.1) in public versus 65.7 months (95% CI 59.8-79.1) in private (HR 1.4 [95%IC 1.1-1.8] p=0.0051). The median CSS was 73.8 months (95% CI 55.1.-NR) in public versus 102.4 months (95% CI 83.4-102.4) in private (HR 1.9 [95%IC 1.4-2.6] p<0.0001). Conclusions: LACOG 1818 study demonstrated significant disparities in treatment patterns and survival outcomes between public and private settings for Brazilian pts with mCRPC. Pts with private coverage had longer OS and CSS. These findings underscore the need for improved access to novel therapies and comprehensive cancer care in Brazil's public healthcare system to reduce survival disparities. Clinical trial information: NCT04962919 . Private Public P First-line N=221 N= 251 <0.0001 ARPI 132 (60%) 18 (7%) Antiandrogen 30 (13%) 127(51%) Chemotherapy 59 (27%) 106 (42%) Second-line N=132 N=110 <0.0001 ARPI 75 (57%) 25 (23%) Antiandrogen 5 (4%) 22 (20%) Chemotherapy 52 (39%) 63 (57%) ARPI= Antiandrogen receptor pathways inhibitor. Antiandrogen= bicalutamide, flutamide, cyproterone and DES.

Resonant inelastic X-ray scattering tools to count 5 f electrons of actinides and probe bond covalency

Abstract The actinides possess a complex electronic structure, making their chemical and physical properties among the least understood in the periodic table. Advanced spectroscopic tools, able to obtain deep insights into the electronic structure and binding properties of the actinides, are highly desirable. Here, we introduce two sensitive spectroscopic tools: one determines the number of localized 5 f electrons on an actinide atom, and another assesses the covalent character of actinide-ligand bonding. Both tools are based on the multiplet structure present in actinide M 4 edge core-to-core resonant inelastic X-ray scattering (CC-RIXS) maps. The spectral intensity of different many-body final-state multiplets directly depends on the local many-electron ground-state symmetry including the local 5  f spin configuration. By comparing U M 4 edge CC-RIXS data for 21 U, Np, Pu and Am compounds, we demonstrate the ability to compare the number of localized 5  f electrons and bond covalency across the actinide series.

A prognostic biomarker panel for chromophobe renal cell carcinoma using immunohistochemistry.

596 Background: The American Cancer Society estimates 14,390 deaths from kidney cancer in 2024 Chromophobe renal cell carcinoma (chRCC) is the third most common subtype of kidney cancer, and 5-10% of patients with chRCC develop metastatic disease. Being able to prognosticate which tumors are aggressive vs. indolent is a significant unmet need. Methods: All partial and radical nephrectomies performed at our institution between 2012-2018 were queried. Cases stage pT1a-pT3a N0M0 at the time of surgery with a minimum of three-year follow up were included. Cases were evaluated for recurrence after surgery. chRCC tissue microarrays (TMA) were constructed from formalin-fixed paraffin-embedded surgical specimens with five 2 mm cores obtained from each tumor. Biomarker choice was hypothesis driven based on publicly available TCGA data. Immunohistochemistry (IHC) was performed for each antibody (Ab) of interest per protocol, with appropriate positive and negative controls. A blinded genitourinary pathologist reviewed the slides and designated an average Immunoreactive Score for all 5 punches for each Ab. Log rank test was used to compare expression levels of recurrent disease to non-recurrent disease based on high and low biomarker expression. Survival analysis for 0-3 positive markers was performed using Log-rank test. Results: Forty-six patients were included in the TMA. Six had recurrent disease: two developed metastasis and four had local recurrences. Two recurrences were from pT1a primaries, two were from pT1b primaries, and two were from pT3a primaries. One metastasis developed from a pT1b primary and one from a pT3a primary. Median length of follow up was 70.5 months, median age at surgery was 54.5 years, median time to recurrence was 32 months, and median mass size was 4.1 cm. High expression of glucose transporter 1 (GLUT1; hazard ratio (HR) = 33.6, p = 0.02) and Claudin-7 (HR = 6.1, p = 0.02) and low expression of platelet derived growth factor receptor (PDGFR; HR = 7.9, p = 0.005) relative to the median was associated with metastatic disease. Recurrences also tended to have high expression of cluster of differentiation 10 (CD10). When markers were combined as a panel, having two to three positive markers was associated with decreased recurrence free survival (RFS) on univariate analysis. Median RFS was 23 months vs. 92 months for three vs. two positive markers, respectively (p < 0.0001). Conclusions: High expression of GLUT1, important in glycolysis, and the epithelial mesenchymal transitional markers CD10 and Claudin-7 and low PDGFR is a protein expression signature that may signal chRCC capable of recurrent or metastatic disease. This provides post-translational insight to proteins that may be important for chRCC invasion and metastasis. Biomarker analysis using IHC is readily and widely available for use. External validation in a larger cohort is currently underway.

Circulating tumor cell (CTC) expression patterns of cell surface targets in metastatic prostate cancer.

232 Background: Resistance to first-line Androgen Receptor Pathway Inhibitors (ARPI) in metastatic prostate cancer (mPC) is universal and can be driven by androgen receptor (AR) alterations driving constitutive AR signaling, or lineage state transitions that bypass AR and culminate in small cell/neuroendocrine PC (NEPC). Recent advances in cell surface targeted therapies, including radioligand therapies and antibody drug conjugates show promise for treatment of metastatic castrate-resistant prostate cancer (mCRPC). Circulating tumor cells (CTCs) are a minimally-invasive source of tumor material to track these known and novel targets for therapeutic development. We report differential expression of cell surface targets using the largest CTC RNA sequencing cohort of patients with mPC across lineage states and clinical outcomes. Methods: We isolated CTCs using automated microfluidic technology on a 273-sample cohort from patients with histologically confirmed mPC. CTCs purified via anti-EpCAM conjugated magnetic beads were analyzed via RNA-seq. We examined CTC gene expression of cell surface targets, including PSMA, TROP2, B7H3, DLL3, stratified by: disease category (metastatic castration sensitive PC [mCSPC], mCRPC or NEPC), metastatic site (bone +/- lymph nodes, liver, other visceral), and prior ARPI treatment. Results: CTCs from patient with mCRPC showed high expression of canonical adenocarcinoma cell surface targets STEAP1 , KLK2 and FOLH1 (PSMA) and epithelial TACSTD2 (TROP2), intermediate tumor immune checkpoint cell surface protein CD276 (B7H3), and low expression of NEPC targets DLL3 and SSTR2 . CTCs from NEPC patients, as expected, demonstrated lower expression of most adenocarcinoma targets and a trend towards higher DLL3 and SSTR2 and associates with worse OS regardless of disease site in multivariate analysis (HR 4.76 [1.09-8.44], p=0.011). CTCs from patients with mCSPC had highest TACSTD2 (p=0.0076) and a trend towards lower DLL3 expression. When comparing metastatic sites, CTCs from non-NEPC mCRPC patients with liver metastases had significantly higher expression of DLL3 (p=0.012) compared to bone or non-liver visceral metastases and can be detected in high-risk adenocarcinomas though expression is heterogeneous. Conversely, CTCs from mCRPC with liver metastases had lower TACSTD2 expression (p=0.039). Prior ARPI therapy associated with lower TACSTD2 (p=0.025) and a trend toward higher DLL3 in patients with early evidence of lineage transition. Conclusions: We report differential cell surface target expression across lineage states and disease sites using novel CTC RNA-seq and single CTC phenotyping. Altered target expression was observed in PC lineage transitions. These findings have implications for treatment response towards surface targeted therapies, and future studies will utilize these biomarkers to explore mechanisms of response and resistance.

Extracellular DNA in patients with urothelial carcinoma of the bladder.

834 Background: Higher concentration of extracellular DNA (ecDNA) in plasma of subjects with various cancers is associated with worse prognosis. The association of ecDNA and its subcellular origin – nuclear DNA (ncDNA) and mitochondrial DNA (mtDNA) with urothelial carcinoma of the bladder (BC) is unexplored. Deoxyribonuclease (DNase) can cleave ecDNA and modulate the observed association. The objective of this study was to identify the potential differences in ecDNA, ncDNA, mtDNA and DNase between patients with non-muscle-infiltrating BC (NMIBC) and muscle-infiltrating BC (MIBC) compared to controls. Methods: We analyzed a population of 62 individuals with BC (44 males, median age 67.5 years), 20 had Ta stage, 26 T1 stage (NMIBC) and 16 T2–T3 stage (MIBC). The control group consisted of 15 males and 6 females without history of cancer, median age 67.3 years. EcDNA was quantified fluorometrically after isolation from double centrifuged plasma. The subcellular origin of ecDNA was analyzed using quantitative real time PCR targeting specific nuclear and mitochondrial sequences. DNase activity was assessed using the single radial enzyme diffusion method. For statistical analysis, basic nonparametric tests were used. Results: In patients with BC compared to controls, we identified significantly higher ecDNA (median 15.0 v 11.7 ng/ml, P=.021) and ncDNA (median 4707 v 2136 GE/ml, P=.0046), but not mtDNA and DNase. Moreover, we determined a higher activity of DNase (median 2.3 vs 1.9 ng/ml, P=.0084) in subjects with NMIBC (Ta+T1) v MIBC. By mutual comparisons of all subgroups, following significant differences were recognized: ecDNA and ncDNA in MIBC v controls (P=.0065 and P=.0127, respectively) and DNase for Ta v MIBC (P=.0177). In addition, we detected a significant correlation on a stage of BC and rising ecDNA concentrations (P=.0076). Conclusions: In this study, we showed higher plasma ecDNA and ncDNA in patients with MIBC than controls and lower DNase activity in MIBC compared to NMIBC. The ecDNA concentrations increased with rising tumor stage. These results suggest a possible diagnostic and a likely prognostic value of ecDNA and DNase in BC. Further studies will focus on a potential association between plasma ecDNA and urinary ecDNA, which are assessed non-invasively and more frequently. This study was supported by the Ministry of Education, Science, Research and Sport of the Slovak Republic (grant number : VEGA 1/0090/22), the Slovak Research and Development Agency (grant number: APVV-22-0231) and OncoReSearch. Key Words: Bladder Cancer. Extracellular DNA. Nuclear DNA. Mitochondrial DNA. Nuclease.

A primary quantum current standard based on the Josephson and the quantum Hall effects

Racial differences in organic anion transport proteins (OATP) and outcome in castration resistant prostate cancer treated with AR pathway inhibitors in Alliance A031201: A phase III trial.

246 Background: Serum androgen levels are prognostic in mCRPC and genetic variation in androgen metabolism may drive these effects. OATPs, encoded by genes of the solute carrier organic anion (SLCO) family, govern the uptake of steroids. We hypothesize variation in androgen uptake may drive differential outcomes on ARPI therapy. A secondary analysis was the contribution of race to prevalence and outcome with the variants. Methods: A031201 was a randomized phase 3 trial in progressive mCRPC by Prostate Cancer Working Group 2 (PCWG2) criteria. Patients (pts) were randomized 1:1 to enzalutamide (ENZ) or ENZ plus abiraterone (AAP) at standard doses. Castrating therapy was maintained. The primary endpoint was overall survival (OS). Secondary endpoint was radiographic-free survival (rPFS). Germline DNA was genotyped for SLCO2B1 in 772 men from A031201 using a validated melting assay. 458 ENZ/AAP). Race is self-reported. Proportional hazards model was used to determine if variants predict OS/rPFS. Results: Two SLCO2B1 variants were analyzed (rs12422149 – GG (82% prevalence) vs AA allele (2% prevalence), and rs1789693 AA (prevalence 43%) vs TT allele (prevalence 13%). 105 (11%) Black patients were genotyped for rs1789693, prevalence of AA was 9%, with median rPFS 67 mos, OS of 67 mos; 50% had TT, median rPFS 16 mos (HR = 3.25 (95% CI 1.16-9.12) OS was 23 mos (hazard ratio for death 2.60 95% CI1.01-6.68). Hazard ratios for homo and heterozygotes are shown (Table). Conclusions: In black men, variations in OATP may contribute to differences in outcome when treated with ARPI therapy. Further study of these interactions with other factors is warranted. Clinical trial information: NCT01949337 . Outcome by genotype. Genotype Median in Months (95% CI) Hazard Ratio (95% CI) SLCO2B1_rs1789693 OS Black (n = 102)AA 67 (52, -) (n = 9)AT 36 (27, 53) (n = 42)TT 23 (20,42) (n = 51) Referent (ref)AT vs. AA 2.02 (0.78,5.26)TT vs. AA 2.60 (1.01, 6.68) White (n = 772; 5 undetermined (und))AA 35 (32-37) (n = 322)AT 36 (22, 39) (n = 346)TT 31 (27,43) (n = 99) RefAT vs. AA 1.01 (0.85,1.21)TT vs. AA 0.99(0.75-1.30) rPFS Black (n = 102)AA 67 (31, NR) (n = 9)AT 23 (17, 39) (n = 42)TT 16 (13,26) (n = 51) RefAT vs. AA 2.84 (1.00,8.07)TT vs. AA 3.25 (1.16, 9.12) White (n = 772; 5 und)AA 23 (20, 27) (n = 322)AT 23 (20, 25) (n = 346)TT 26 (17, 34) (n = 99) RefAT vs. AA 1.02 (0.86,1.21)TT vs. AA 0.85 (0.65, 1.12) SLCO2B1_rs12422149 OS Black (n = 102; 1 und)GG 36 (26,52) (n = 74)AG 26 (21, NR) (n = 27)AA NR (n = 0) RefAG vs GG 0.96 (0.56, 1.66)AA vs GG NE White (n = 772; 3 und)GG 34 (32,37) (n = 630)AG 36 (32, 44) (n = 125)AA 42 (25,NR) (n = 14) RefAG vs. GG 0.91 (0.72, 1.66)AA vs. GG 0.70 (0.35-1.41) rPFS Black (n = 102; 1 und)GG 23 (17,39) (n = 74)AG 20 (13, NR) (n = 27)AA NR (n = 0) RefAG vs GG 1.04 (0.61, 1.78) AA vs GG NE White (n = 772; 3 und)GG 23 (20,25) (n = 630)AG 22 (18, 26) (n = 125)AA 34 (14,NR) (n = 14) RefAG vs GG 1.07 (0.86, 1.3) AA vs. GG 0.63 (0.32,1.27) NR=not reached; NE= Not estimable.

Cabozantinib (C) ± atezolizumab (A) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Expansion cohorts from the open-label phase 1b COSMIC-021 study.

145 Background: The phase 3 CONTACT-02 study significantly improved PFS and showed a trend in OS benefit with C+A vs a second novel hormone therapy (NHT) in mCRPC pts with soft tissue metastases (mets). We report outcomes from similar pts in the randomized mCRPC expansion cohorts of COSMIC-021 evaluating the contribution of adding A to C vs C alone. Methods: Pts with mCRPC with extrapelvic visceral or nodal mets who progressed on one prior NHT were randomized to receive C (60 mg QD), A (1200 mg IV Q3W), or C (40 mg QD) + A (1200 mg IV Q3W). Cohort A (n=10) was terminated early (lacked objective responses). The primary and secondary endpoints were investigator-assessed ORR per RECIST v1.1 and safety, respectively. Efficacy outcomes by blinded independent radiology committee (BIRC) were also assessed. Flow cytometry and proteomic profiling were performed on baseline and on-treatment samples. Results: A total of 101 pts were randomized to C (n=51) and C+A (n=50); median age was 70 y in both groups, 75%/72% had bone mets, 20%/24% had liver mets, and 31%/24% received docetaxel for mCSPC. ORR by BIRC (Table) and investigator (C: 20%, 95% CI, 10–33; C+A: 22%, 95% CI, 12–36) were similar between groups. Although PFS by BIRC was similar (Table, HR, 0.96; 95% CI, 0.59–1.58), the KM estimate of pts without events at 12 mo was higher with C+A (25.8% vs 14.0%). Compared with C, C+A group had longer DOR (~2-fold), fewer pts with progressive disease (PD) as best response, a numerically higher median OS (HR, 0.91; 95% CI, 0.57–1.46), more pts with PSA response with longer duration of response (median mo [95% CI], NE [6.24, NE] vs 6.93 [4.63, NE]), and prolonged time to PSA progression (Table). In the liver mets subgroup, median PFS and OS were longer with C+A vs C (PFS: HR, 0.44; 95% CI, 0.15–1.34, 5.7 vs 2.5 mo; OS: HR, 0.25; 95% CI, 0.08–0.77, 14.7 vs 5.0 mo). Grade 3–4 treatment-related adverse events occurred in 51% and 58% in C and C+A, respectively; no grade 5 events occurred. Differential regulation of activated CD8 T cells, myeloid-derived suppressor cells, and immune response and apoptosis-related proteins were observed with C+A vs C or A. Conclusions: C and C+A demonstrated clinical activity in pts with mCRPC and extrapelvic soft tissue mets, with no new safety signals. These exploratory data from randomized cohorts suggest an additive effect of A to C with a prolonged DOR in C+A vs C; additive clinical benefits were noted in pts with liver mets. Clinical trial information: NCT03170960 . Efficacy outcomes by BIRC. C (n=51) C+A (n=50) ORR, % (95% CI) 12 (4–24) 14 (6–27) Complete / partial response, n (%) 0 / 6 (12) 0 / 7 (14) Stable disease / PD, n (%) 33 (65) / 9 (18) 31 (62) / 6 (12) DCR, n (%) 39 (76) 38 (76) Median DOR (95% CI), mo 4.3 (2.8–NE) 10.6 (6.7–NE) PSA response, n (%) 5 (12%) 8 (20%) Median time to PSA progression (95% CI), mo 3.5 (1.7–5.7) 5.6 (2.7–NE) Median PFS, mo 6.7 5.5 Median OS, mo 13.8 15.6 NE, not evaluable for KM estimates.

Real world comparison of time-to-next-treatment (TTNT), time-to-castration-resistance (TTCR), and overall survival (OS) among patients with <i>BRCA1/2</i> positive and homologous recombination repair (HRR) negative metastatic castration-sensitive prostate cancer (mCSPC).

77 Background: Patients with mCSPC harboring genetic alterations in HRR genes, particularly BRCA1/2 , may experience aggressive disease course and adverse clinical outcomes. This study compared real-world TTNT, TTCR, and OS between patients with BRCA1/2+ and HRR- mCSPC. Methods: Data from oncology centers included in the US-based Flatiron Health-Foundation Medicine, Inc. Metastatic PC Clinico-Genomic Database (1/1/2011–12/31/2022) were evaluated. Patients with mCSPC who received an HRR alteration test and initiated first-line (1L) treatment for mCSPC after 1/1/2018 (index date) were included. Patients with ≥1 positive test for BRCA1/2 ( BRCA1/2 +) and those with no positive test for any HRR alteration (HRR-; 8 alterations) were assessed for TTNT (time from index to start of subsequent treatment for PC), an indicator of clinical/non-clinical performance, TTCR (time from index to prostate-specific antigen increase on therapy or clinician documentation), and OS (time from initial PC diagnosis to death). Baseline characteristics (12 months pre-index) were balanced between cohorts using inverse-probability of treatment weighting. Outcomes between BRCA1/2+ and HRR- patients were compared using weighted Kaplan-Meier analyses. Hazard ratios (HRs), 95% confidence intervals (CIs) and nominal p-values were generated using weighted Cox proportional hazards models. Results: A total of 149 BRCA1/2+ and 1,042 HRR- patients with mCSPC were included. Weighted baseline characteristics were balanced. The median age was 70 years in both cohorts; 60.4% of BRCA1/2+ and 61.2% HRR- patients were White. Abiraterone acetate was most used in 1L ( BRCA1/2 +: 30.2%; HRR-: 30.7%). By 24 months after 1L initiation, a significantly higher proportion of BRCA1/2+ patients progressed to next treatment than HRR- patients (69.7% vs. 56.8%; HR: 1.45 [95% CI: 1.10, 1.92], p=0.009). Median TTNT was shorter in the BRCA1/2+ cohort (10.9 months) than HRR- cohort (18.7 months). By 24 months, a significantly higher proportion of BRCA1/2+ patients progressed to castration resistance than HRR- (72.2% vs. 61.4%; HR: 1.46 [95% CI: 1.16, 1.84], p=0.001). Median TTCR was shorter among the BRCA1/2 + cohort than HRR- cohort (12.9 months vs. 16.9 months). Numerically fewer BRCA1/2+ patients survived 24 months after PC diagnosis (80.6%) than the HRR- cohort (85.4%; HR: 1.46 [95% CI: 0.99, 2.14], p=0.054). Conclusions: This study demonstrates worse outcomes for patients with BRCA1/2+ mCSPC, particularly more rapid treatment changes and progression to mCRPC by 24 months. Given that BRCA1/2 alterations are the most prevalent HRR alterations observed in men with PC, these results support early identification and a need for more effective therapies for this population.

Cryo-EM structures of the BAF-Lamin A/C complex bound to nucleosomes

Abstract Barrier-to-autointegration factor (BAF) associates with mitotic chromosomes and promotes nuclear envelope assembly by recruiting proteins, such as Lamins, required for the reconstruction of the nuclear envelope and lamina. BAF also mediates chromatin anchoring to the nuclear lamina via Lamin A/C. However, the mechanism by which BAF and Lamin A/C bind chromatin and affect the chromatin organization remains elusive. Here we report the cryo-electron microscopy structures of BAF-Lamin A/C-nucleosome complexes. We find that the BAF dimer complexed with the Lamin A/C IgF domain occupies the nucleosomal dyad position, forming a tripartite nucleosomal DNA binding structure. We also show that the Lamin A/C Lys486 and His506 residues, which are reportedly mutated in lipodystrophy patients, directly contact the DNA at the nucleosomal dyad. Excess BAF-Lamin A/C complexes symmetrically bind other nucleosomal DNA sites and connect two BAF-Lamin A/C-nucleosome complexes. Although the linker histone H1 competes with BAF-Lamin A/C binding at the nucleosomal dyad region, the two BAF-Lamin A/C molecules still bridge two nucleosomes. These findings provide insights into the mechanism by which BAF, Lamin A/C, and/or histone H1 bind nucleosomes and influence chromatin organization within the nucleus.

Sociodemographic disparities in treatment (tx) patterns and clinical outcomes among real-world patients (pts) with locally advanced/metastatic urothelial carcinoma (la/mUC) in the US.

707 Background: Sociodemographic disparities in la/mUC pt population include worse survival outcomes observed among certain pt subgroups. This study evaluates disparities among la/mUC pts receiving systemic therapies overall and those initiating an antibody drug conjugate in the real world. Methods: This descriptive, retrospective cohort study used US Flatiron Health electronic health record–derived de-identified database. Pts aged ≥ 18 yrs were grouped into cohorts C1 (all pts with la/mUC) and C2 (2L+ sacituzumab govitecan [SG] or 1L+ enfortumab vedotin [EV]) with tx initiation on/after Jan 2017 and Dec 2019, respectively; data cutoff for both cohorts was July 2024. Pt demographics and clinical outcomes (overall survival [OS] and time to tx discontinuation [TTD]) were calculated overall and by race. Socioeconomic status (SES) index was calculated using Yost index score (1 = lowest category; 5 = highest). Predictors of survival were assessed using Cox proportional hazards model. Results: C1 comprised 5102 pts. Most were White (68%) followed by Other race (11%), Black (5%), and Asian (1%); 15% were missing race. The racial distribution among C2 (N = 767) was similar to C1. Median age across C1 and C2 was similar (74 and 73 yrs, respectively), with Black pts being the youngest in both cohorts (median ages in C1 and C2: 70 and 65 yrs, respectively). Across both cohorts, Black and Asian pts, respectively, had the greatest proportion of pts in the lowest SES index group (C1: 36.7% and 13.3%; C2: 43.6% and 22.2%). In C1, median TTD (95% CI) was 3.0 (2.8-3.0) mos and was similar across all races. In C2, median TTD was higher for Asian (6.8 [4.2-NR] mos) and Black pts (6.5 [2.3-8.1] mos) and lowest for Other race (3.1 [1.9-4.3] mos). Median OS (95% CI) was 13.3 (12.6-13.9) mos in C1 and 11.9 (10.4-12.9) mos in C2. In both C1 and C2, Asian pts had the longest survival (median OS: 25.2 [11.9-41.9] and 14.0 [9.3-NR] mos, respectively) and Black pts had the shortest survival (median OS: 11.2 [9.2-15.9] and 11.4 (6.9-20.5] mos, respectively). Exploratory Univariate Cox modeling (limited by small sample size) suggested older age, history of smoking, treatment in community setting, de novo metastatic diagnosis, and ECOG score ≥ 2 are factors associated with low survival in C1 and only history of smoking and ECOG score ≥ 2 in C2. Conclusions: In this real-world study of treated pts with la/mUC, sample sizes, especially in C2, further research is needed to understand disparities and pt-centric factors that may impact tx decisions, TTD patterns, and reasons for discontinuation to define and address the unmet medical needs of these pts.

Evaluation of de novo oligometastatic prostate cancer patients managed with radiation therapy: A multi-institution, real-world dataset.

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

Efficacy of targeted therapies (TT) after HIF-2⍺ inhibitor-based treatment in advanced renal cell carcinoma (aRCC).

508 Background: Hypoxia-inducible factor 2⍺ (HIF) inhibitors are active in renal cell carcinoma refractory to prior treatment with tyrosine kinase inhibitors (TKI) and immunotherapy, including anti-PD-1 monotherapy or combinations with anti-CTLA-4, and represent a new therapeutic option. However, the efficacy of TT after HIF-2⍺ inhibitors has not been assessed. Methods: A retrospective review of medical records from aRCC patients (pts) treated with HIF-2a inhibitors at five academic institutions was conducted. Pts who received subsequent treatment with TT were identified to collect outcomes in terms of best radiological response by RECIST 1.1 criteria (BRR), time to treatment failure (TTF), defined as treatment failure can be defined as one or a combination of events, including disease progression, discontinuation of treatment due to toxicity, or death from any cause; and overall survival (OS). This work was approved by an ethics board and all patients provided approval. Results: Data of 35 pts were available: 30 (85%) were male and 18 (51%) were metastatic at diagnosis. IMDC risk group was favorable, intermediate and poor in 11 (31%), 20 (57%) and 4 (11%) pts, respectively. Belzutifan was administered as monotherapy in 27 (77%) and in combination in 8 (22%) pts. Regarding first subsequent TT, 30 (85%) received TKI and 5 (14%) received mammalian target of rapamycin (mTOR). TT post HIF-2a was administered as second-line, third-line, fourth-line and beyond fourth-line in 3 (8%), 4 (9%), 18 (51%) and 10 (28%) pts, respectively. Treatment was interrupted due to progression in 28 (80%), 1 (3%) discontinued due to toxicity and 7 (20%) remained on treatment after data cut-off. Median follow-up was was 19 months.Median TTF on subsequent TT was 5.74 months (95% CI: 2.82–8.00). Median OS was 10,49 months (95% CI: 6,13-NR) with 17% pts alive at 1 year from the initiation of subsequent TT. Investigator-assessed BRR to subsequent TT was available for 33 out of 35 pts. Partial response and stable disease were observed in 7 (20%) and 12 (34%), respectively. Progressive disease was observed in 14 (40%) pts. Conclusions: Both VEGF/VEGFR and mTOR inhibitors have activity following HIF-2α blockade. However, 40% of patients will be refractory to treatment. This highlights the need for new drugs with distinct mechanisms of action.

Loss-of-function mutations in the dystonia gene THAP1 impair proteasome function by inhibiting PSMB5 expression

Abstract The 26S proteasome is a multi-catalytic protease that serves as the endpoint for protein degradation via the ubiquitin-proteasome system. Proteasome function requires the concerted activity of 33 distinct gene products, but how the expression of proteasome subunits is regulated in mammalian cells remains poorly understood. Leveraging coessentiality data from the DepMap project, here we characterize an essential role for the dystonia gene THAP1 in maintaining the basal expression of PSMB5 . PSMB5 insufficiency resulting from loss of THAP1 leads to defects in proteasome assembly, impaired proteostasis and cell death. Exploiting the fact that the toxicity associated with loss of THAP1 can be rescued upon exogenous expression of PSMB5, we define the transcriptional targets of THAP1 through RNA-seq analysis and perform a deep mutational scan to systematically assess the function of thousands of single amino acid THAP1 variants. Altogether, these data identify THAP1 as a critical regulator of proteasome function and suggest that aberrant proteostasis may contribute to the pathogenesis of THAP1 dystonia.

Real-world analysis of the efficacy and safety of enfortumab vedotin in patients with locally advanced or metastatic urothelial carcinoma: A multicenter retrospective study.

712 Background: We investigated the efficacy and safety enfortumab vedotin (EV) in patients with locally advanced or metastatic urothelial carcinoma in real-world practice. Methods: This multicenter retrospective study included 419 patients treated for locally advanced or metastatic urothelial carcinoma between April 2004 to April 2024. The patients were categorized into the following three groups: 87 patients who underwent first-line chemotherapy and sequential chemotherapy alone (chemo-alone group), 217 patients who underwent maintenance immunotherapy or second-line immunotherapy after first-line chemotherapy (chemo-ICI group) and 115 patients who were treated with EV after first-line chemotherapy and immunotherapy (chemo-ICI-EV group). The primary outcome was the comparison of progression-free survival (PFS) of first-line therapy and overall survival (OS) from first-line therapy between the three treatment groups. Secondary outcomes included the efficacy and safety in the chemo-ICI-EV group focusing on skin adverse events (AEs). Results: The OS from first-line therapy was significantly longer in the chemo-ICI-EV group than that in the other groups. There was no significant difference in the first-line PFS of first-line therapy between the three groups. A multivariable Cox regression analysis showed the administration of EV was significantly associated with prolonged OS. Skin AEs were observed in 69 (60%) as a major adverse event. The PFS and OS in the patients with skin AEs was significantly longer than in the patients without skin AEs despite the reduced dose of EV. A multivariable Cox regression analysis showed that skin AEs were significantly associated with prolonged RFS and OS. Conclusions: The administration of EV significantly improved oncological outcomes in the real-world practice. Dose adjustment of EV may be key for long-term use and oncological outcomes.

Patient-reported outcomes (PROs) for tivozanib (TIVO) + nivolumab (NIVO) vs TIVO monotherapy in patients with renal cell carcinoma (RCC) following an immune checkpoint inhibitor (ICI): Results of the phase 3 TiNivo-2 study.

459 Background: The TiNivo-2 study assessed TIVO 0.89 mg + NIVO vs TIVO 1.34 mg in patients with RCC that progressed after ICI therapy. This study did not meet its primary endpoint of demonstrating a benefit of adding NIVO to TIVO vs TIVO after prior ICI exposure; however, clinically meaningful outcomes were observed with TIVO as a second-line (2L) and third-line (3L) treatment following ICI. In the intent-to-treat population, the median progression-free survival was 5.7 months (95% CI, 4.0-7.4) with TIVO + NIVO and 7.4 months (5.6-9.2) with TIVO (hazard ratio, 1.10; 95% CI, 0.84-1.43; P =.49), with fewer treatment-emergent adverse events in the TIVO + NIVO vs TIVO arm. Quality of life (QOL) data are reported here (NCT04987203). Methods: The Functional Assessment of Cancer Therapy Kidney Cancer Symptom Index–Disease-Related Symptoms (FKSI-DRS) and European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaires were administered at baseline (BL), day 1 of each cycle, and end of treatment. The PRO-evaluable set was defined as all randomized patients with a BL and ≥1 post-BL assessment. Descriptive statistics were provided for the FKSI-DRS and EORTC QLQ-C30 data. The number and percentage of patients categorized as having improved (I), stable (S), or deteriorated (D) QOL were summarized. Results: As of April 1, 2024, median follow-up was 12.0 months. Median duration (range) of treatment was 6·3 months (2.68-10.12) with TIVO + NIVO and 7·4 months (2.83-11.04) with TIVO. Completion rates for FKSI-DRS and EORTC QLQ-C30 were &gt;90% at BL and &gt;50% at week 24 (≈6 mo.) in each arm. Compliance rates for both instruments at BL and week 24 were &gt;90%. PRO results are presented in the table. Conclusions: There were no differences in the PRO outcomes between the combination therapy and monotherapy arms or between the 2 different TIVO doses. PRO data suggested that TIVO maintained the FKSI-DRS and EORTC QLQ-C30 mean scores from BL to week 24. In the TIVO arm, the proportion of patients who had improvement in FKSI-DRS and EORTC QLQ-C30 scores was numerically better in patients receiving 2L vs 3L treatment, while the portion of patients with a deterioration was smaller in the 2L than in the 3L. Clinical trial information: NCT04987203 . PRO variables TIVO + NIVO TIVO ITT 2L 3L ITT 2L 3L FKSI-DRSBL mean (SD) 28.8 (5.6) 29.5 (4.9) 27.6 (6.5) 29.3 (5.3) 29.1(5.5) 29.5 (5.0) Week 24 mean (SD) 29.9 (4.9) 30.1 (4.7) 29.5 (5.4) 29.4 (5.3) 29.3 (4.8) 29.6 (6.3) I/S/D, % 28.2/47.2/24.6 28.0/52.7/19.4 28.6/36.7/34.7 22.9/53.5/23.6 27.5/53.8/18.7 15.1/52.8/32.1 EORTC-QLQ-C30BL mean (SD) 63.4 (23.4) 65.0 (21.8) 60.5 (26.1) 66.2 (21.4) 67.1 (21.9) 64.9 (20.7) Week 24 mean (SD) 68.7 (17.4) 68.7 (16.1) 68.6 (20.6) 64.8 (21.1) 64.6 (20.7) 65.1 (22.4) I/S/D, % 27.7/48.9/23.4 27.8/52.2/20.0 27.7/42.6/29.8 21.3/53.7/25.0 23.0/56.3/20.7 18.4/49.0/32.7

Global, phase 3, open-label, single arm studies to evaluate the efficacy, safety, and pharmacokinetics of FP-014, 11.25 mg (triptorelin mesylate injection, 11.25 mg) and FP-014, 22.5 mg (triptorelin mesylate injection, 22.5 mg) in patients with advanced prostate cancer.

TPS284 Background: When given continuously, long-acting LH-RH agonist triptorelin is known to inhibit pituitary gonadotropin secretion and suppress testicular and ovarian steroidogenesis. Serum testosterone concentrations in males have been reduced to levels associated with castration (&lt; 50 ng/dL in serum). This effect is generally observed within two to four weeks after the start of treatment and is maintained as long as treatment continues. Induction and maintenance of castrate levels of serum testosterone concentrations in prostate cancer patients is a standard palliative treatment and slows cancer cell growth. FP-014 was formulated in N-methyl-2-pyrrolidone (NMP) and poly (D, L-lactide-co-glycolide) (PLGA) to control and sustain the release of bioactive triptorelin after subcutaneous administration. Two dosages of FP-014 are under investigation: 11.25 mg for three-month release, and 22.5 mg for six-month release. Methods: The FP-014 11.25 mg three-month formulation study and FP-014 22.5 mg six-month formulation study are designed for six months and 12 months, respectively, to evaluate the safety, efficacy, and pharmacokinetics of subcutaneously administered FP-014 (triptorelin mesylate) in subjects with advanced prostate cancer who are candidates for androgen ablation therapy. Subjects will receive up to 2 doses of long-acting FP-014 every three months with the 11.25 mg formulation or every six months with the 22.5 mg formulation. Results: Primary endpoints: 1. The percentage of patients with a serum testosterone concentration suppressed to castrate levels (&lt; 50 ng/dL) by Week 4 following the first SC injection of FP-. 2. The percentage of patients with serum testosterone concentration suppressed to castrate levels (&lt; 50 ng/dL) from Week 4 through Week 24 (11.25 mg formulation) or Week 48 (22.5 mg formulation). Secondary endpoints: 1. Mean acute-on-chronic changes in serum testosterone and LH levels prior to the second injection through 48-72 hours after the second injection of FP-014. 2. Mean change in serum LH levels. 3. Mean change in serum PSA levels. 4. The percentage of patients with: PSA relapse (defined as an increase in serum PSA of &gt; 50% PSA nadir) by End of Study after achieving serum PSA level ≤ 4 ng/mL post administration of FP-014; within normal limit serum PSA level (&lt; 4 ng/mL) by End of Study; the percentage of patients with enhanced serum testosterone concentration suppression to &lt; 20 ng/dL at Week 4 and at End of Study; and urinary signs and symptoms as assessed by International Prostate Symptom Score (I-PSS). Conclusion: Two Phase 3 studies are designed to evaluate the safety, efficacy, and pharmacokinetics of long-acting injectable FP-014 (triptorelin mesylate), aiming to demonstrate an alternative therapeutic option for patients with prostate cancer. Clinical trial information: TBD.