Search

Poly-ADP ribose polymerase inhibitors (PARPi) are an emerging therapeutic option for the treatment of prostate cancer. Their primary mechanism of action is via induction of synthetic lethality in cells with underlying deficiencies in homologous recombination repair (HRR). In men with metastatic castrate-resistant prostate cancer (mCRPC) and select HRR pathway alterations, PARPi treatment has been shown to induce objective tumor responses as well as improve progression free and overall survival. Presently, there are two PARPi, olaparib and rucaparib, that are FDA approved in the treatment of mCRPC. Ongoing research is focused on identifying which HRR alterations are best suited to predict response to PARPi so that these therapies can be most effectively utilized in the clinic. While resistance to PARPi remains a concern, combination therapies may represent a mechanism to overcome or delay resistance.

467 Background: Neuroendocrine, small cell, or large cell carcinoma originating from the urothelium (uro-NE/SCC/LCC) is rare. Outcomes for metastatic disease are dismal. Treatment is extrapolated from small cell lung cancer, for which immune checkpoint inhibitors (ICIs) have modest activity. Preliminary activity has been reported with ICI for uro-NE. We aimed to compare real-world progression-free survival (PFS) and overall survival (OS) between ICI-containing and non-ICI-containing regimens in the first line (1L) metastatic setting for uro-NE/SCC/LCC. Methods: We performed a retrospective study at 11 cancer centers. Patients (pts) who received systemic therapy (2011-2021) for biopsy confirmed metastatic uro-NE/SCC/LCC were included. Pts with metastasis within 6 months of (neo)adjuvant chemotherapy (CT) (n=16) were excluded from 1L analyses. Results: 102 pts with metastatic uro-NE/SCC/LCC were evaluable. 17 (16.7%) had NE histology, 81 (79.4%) SCC, and 4 (3.9%) LCC. NE/SCC/LCC was mixed with urothelial histology in 19 (18.6%). Primary tumors were most often in the bladder (84.3%, n=86), less frequently upper tract (11.8%, n=12) or urethra (3.9%, n=4). 42 pts (41.2%) were previously treated for localized disease, the rest were de novo metastatic (n=60, 58.8%). Pts who received an ICI in any line (n=61) had significantly longer OS (p=0.038) than pts that never received an ICI (n=41). As shown in the table, in the 1L, ICI-containing regimens (n=33) resulted in significantly longer PFS, but not OS or ORR compared to non-ICI regimens (n=53). Subdividing 1L regimens into ICI without CT (n=14), CT without ICI (n=53), or ICI + CT (n=19), both PFS and OS were significantly different with similar ORR. ICI w/o CT had the longest median PFS and OS with an ORR 57.1% comparable to CT regimens. Of 61 pts that received ICI in any line, 14 (23.0%) had an immune-related adverse event of any grade; 11 (18.0%) received steroids. Conclusions: This is the largest ever report of ICI for metastatic uro-NE/SCC/LCC. ICIs were associated with improved outcomes with expected added toxicity. Further prospective investigation of ICI regimens is warranted. [Table: see text]

547 Background: Despite recent therapeutic advancements for patients with mUC, including checkpoint inhibitors (CPIs), anti-FGFR and antibody-drug conjugates (ADCs), biomarker data to predict therapeutic response and identify mechanisms of resistance remain limited. Ongoing randomized clinical trials evaluating the combination of CPIs and ADCs in these pts underscore the need to develop biomarkers to better understand who might best respond to these therapies. Here, we employ a liquid biopsy approach to molecularly characterize circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA), including those isolated with Trop-2, the target of the novel drug Sacituzumab Govitecan and Datopotamab Deruxtecan. Methods: 104 blood samples serially collected from pts being treated for mUC were used for CTC collection using anti-EpCAM and Trop-2 antibodies in parallel. CTCs were isolated and stained for immune markers PD-L1 and HLA I using the VERSA (Versatile Exclusion-based Rare Sample Analysis) platform. Plasma was isolated for paired analysis of CTC and ctDNA content. CTCs were analyzed for enumeration and single-cell protein analysis. Overall survival (OS) was defined from time of sample collection, and survival analyses were performed using the Kaplan-Meier method. Results: We observed significantly shorter OS in pts with higher CTC burden (≥ 20 CTCs/7.5 mL blood) in samples captured with either EpCAM (median 34.1 vs 3.1 mo, P < 0.01) or Trop-2 (median 34.1 vs 6.2 months, P < 0.01). Furthermore, EpCAM and Trop-2 CTC burdens were higher at progression timepoints relative to responding or stable timepoints, when stratified according to treatment modality (table). Inter and intra-patient heterogeneous PD-L1 and HLA I expression and co-expression was observed on CTCs although no significant differences were seen globally between EpCAM and Trop-2 CTCs. In a cohort of pts treated with CPIs, we observed dynamic phenotypic changes in the ratio of HLA:PD-L1 that differed between EpCAM and Trop-2 CTCs. ctDNA analysis identified concordant increases in tumor fraction and acquired genomic mutations. When examined longitudinally across individual pts, these findings in tandem with changes in enumeration, suggest the emergence of different CTC subpopulations that may serve as biomarkers of resistance. Conclusions: We identify the prognostic significance of CTC enumeration with parallel EpCAM and Trop-2 CTC isolation and demonstrate the utility of a liquid biopsy assay that can detect pharmacodynamic changes in CTC burden and immune marker expression throughout the course of treatment. [Table: see text]

247 Background: The mainstay of therapy in metastatic prostate cancer is androgen receptor (AR) signaling inhibition. However, the emergence of early castration resistance or neuroendocrine transformation is associated with poor prognosis. Reliable biomarkers are needed to identify these patients and guide selection of clinical therapy. Methods: mRNA was isolated from EpCAM-positive circulating tumor cells (CTCs) isolated from patients with CSPC, CRPC, or NEPC to measure expression of KLK2, KLK3 (PSA), TMPRSS2, FOLH1 (PSMA), synaptophysin ( SYP), and chromogranin ( CHGA). Post-hoc retrospective analysis of an institutional review board–approved prospective cohort (N = 98) was performed to identify patterns of gene expression. Samples were considered AR+ if 3 of 4 AR pathway genes ( TMPRSS2, KLK2, KLK3, and FOLH1) were positive, and were considered NE+ if either or both SYP or CHGA were positive. Blood samples from two prospective clinical trials of men with mCRPC treated with abiraterone and enzalutamide, respectively, were analyzed to confirm results. Longitudinal samples were collected from 17 patients (6 NEPC and 11 Adenocarcinoma) and cell free DNA was isolated and sequenced using a novel targeted exon panel. Results: AR and/or NE positive patients were found to have a median overall survival (OS) of 8.58 months as compared to a median OS of 29.6 months in the AR and NE negative population (p

e18524 Background: Treatment and survival disparities faced by Medicaid patients are documented for pancreatic, colon-rectosigmoid, and liver cancers at a national level. Studies show these disparities persist at academic medical centers. We assessed Medicaid treatment and survival outcomes among University of Wisconsin-Health (UWH) pancreatic, colon-rectosigmoid, and liver cancer patients to determine whether national trends persisted at this academic medical center. Methods: We included UWH registry data for 1567 pancreatic, 2313 colon-rectosigmoid, and 1027 liver cancer patients ages 18+ from 2004-2016. We performed multivariable logistic regression to estimate odds ratios (ORs) to assess insurance disparities in intended resection and Cox Proportional regression to estimate hazard ratios (HRs) to assess all-cause mortality disparities for each cancer, adjusting for age, sex, race/ethnicity, BMI, comorbidity, stage, rurality, and insurance. Results: Median overall survival was 6.5 months (range 0.1-147.5) for pancreatic, 12.8 months (0.1-167.5) for colon-rectosigmoid, and 12.5 months (0.1-168.7) for liver cancer patients. 3% of pancreatic, 5% of colon-rectosigmoid, and 9% of liver cancer patients had Medicaid Insurance. Medicaid patients were less likely to be older and non-Hispanic White than private insurance (private) patients for each cancer. Medicaid patients were diagnosed with more distant disease for colon-rectosigmoid and liver cancers and less distant disease for pancreatic cancer. Medicaid patients were less likely to receive surgery vs private patients for pancreatic (OR 0.41, 95% CI 0.16-1.08) and liver (OR 0.62, 0.26-1.49) cancers, though confidence intervals were wide. Insurance was not associated with surgery in colon-rectosigmoid cancer patients (OR 0.97, 0.48-1.97). Medicaid patients had a higher risk of death vs private patients for colon rectosigmoid cancer (HR 1.50, 1.12-2.01). Risk of death was modestly elevated for Medicaid vs private patients for pancreatic (HR 1.35, 0.97-1.87) but not liver (HR 1.07, 0.77-1.48) cancer. Conclusions: Medicaid pancreatic and liver cancer patients may be less likely to receive surgery than private patients in our one center study. Results suggested that Medicaid pancreatic and colon-rectosigmoid cancer patients may have a slightly elevated risk of death vs private patients, though this needs confirmation in larger samples. Future studies should explore at which local, state, and regional levels Medicaid pancreatic, colon-rectosigmoid, and liver cancer patients experience treatment and survival disparities vs private insurance patients. These studies, combined with Medicaid expansion studies, can guide healthcare leaders and policy makers to design context-appropriate interventions to reduce insurance-related disparities in cancer treatment and outcomes.

119 Background: Race and ethnicity-based treatment and survival disparities are documented for pancreatic cancer. Studies cite patient genetic, biological, and social factors and differences across treatment centers and geographical areas that may contribute to disparities. We investigated treatment and survival disparities for a cohort of 1,569 pancreatic cancer (PC) patients at the local level within a National Cancer Institute-designated comprehensive cancer center. Methods: Data from 1,569 PC patients aged over 18 diagnosed with adenocarcinoma, NOS or infiltrating duct carcinoma, NOS from 2004 to 2016 who received some or all of their care at the University of Wisconsin Carbone Cancer Center were included in the study. Sequential models of adjusted Cox proportional hazard regression were performed to describe the association between race/ethnicity and overall survival. Model I included age, sex and race/ethnicity; model II added BMI, Charlson Comorbidity Index and stage; model III added rurality, treatment course and payer. Treatment course, defined as the receipt of chemoradiation, surgery with/without chemoradiation, or no treatment, rurality, and insurance status were factors of interest. Results: 38.6% of patients were diagnosed with metastatic disease. Overall survival was 11.6 months. Non-Hispanic black (NHB) patients experienced an 88% increased risk of death (95% CI: 23%-188%) and patients categorized as other race/ethnicity experienced a 32% (10%-60%) increased risk of death compared to NH white (NHW) patients in model II. After adding treatment course and insurance status, the hazard ratio for NHB patients decreased to 1.41 (0.92-2.17) and other race/ethnicity patients decreased to 1.27 (1.05-1.53) compared to NHW Patients. Medicaid patients had an adjusted hazard ratio of 1.41 (1.01-1.95) and unknown/uninsured patients had an adjusted hazard ratio of 1.62 (1.71-4.02) compared to managed care patients. Incarcerated patients had an adjusted hazard ratio of 1.28 (0.98-1.67) compared to managed care patients. Conclusions: To reduce disparities across race/ethnicity and insurance status, organizations should invest in financial support programs for patients in need and monitor treatment courses for people of color, underinsured or uninsured patients to verify access to treatment, equitable treatment, and adherence to treatment guidelines. Future studies should investigate the contribution of clinician and healthcare system bias to race and ethnicity-based cancer disparities.

e19063 Background: Trends in oncology examine the influence of rural characteristics on cancer patient (pt) treatment and outcomes. Current definitions of rurality are broad and varied, with multiple standardized definitions. Few analyses exist to compare definitions and quality in assessing oncologic outcomes. We aim to determine which index is most suitable to define rurality in cancer research. Methods: 1,567 pancreatic cancer pts from the University of Wisconsin Cancer Registry, representing 84 Midwestern counties and 452 zip codes, were assigned rurality codes based on three indices spanning 1983-2013: Rural-Urban Continuum Code (RUCC), Rural-Urban Commuting Areas (RUCA), and Index of Relative Rurality (IRR). RUCC and IRR were assigned to pts at the county level and RUCA at the zip level. Pt rurality was compared across the three indices and over time via the median and interquartile range and inspected visually with violin plots. We compared indices with Spearman’s Rank Order Correlation (SROC). Results: RUCC 2003, RUCA 2004 (zip), and IRR 2000 were concordant in terms of metropolitan, micropolitan, and rural designations for 66.9% (1,049) of pancreatic cancer registry pts. The rural designation for almost one-third (489, 31.2%) of pts was discordant by one or two levels across the three indices (i.e. classified as metropolitan in one index and micropolitan or rural in another). SROC was 0.73 between RUCC 2003 and RUCA 2004 (zip) indices, 0.82 between IRR 2000 and RUCA 2004 (zip), and 0.85 between RUCC 2003 and IRR 2000. Across the 84 counties of registry pts’ residence, the median and interquartile range of RUCC decreased from 6 (3-7) in 1983 to 4 (2.25-6) in 2013 and of IRR decreased from 0.49 (0.44-0.53) in 2000 to 0.49 (0.43-0.53) in 2010. Across the 452 zip codes, RUCA decreased from 4 (1-10) in 1998 to 3 (1-8) in 2004. Pts’ median RUCC decreased from 3 (2-6) in 1983 to 3 (2-4) in 2013, median RUCA (zip) decreased from 2 (1-7) in 1990 to 1 (1-6) in 2000, and IRR remained constant at 0.42 (0.38-0.49) in 2000 and 2010. Conclusions: RUCC is preferable for state-level cancer studies incorporating rurality as it best distributes pts across the rural-urban interface compared to RUCA (skews urban) and IRR (skews central). County boundaries (RUCC) are consistent over time versus zip (RUCA) and census tract (RUCA). Our findings suggest that while the extremes of rural and urban are well-defined, rurality as a continuum is inconsistently measured. Researchers should continue to incorporate other measures of vulnerability to achieve health equity.