bluuebunny/crossref_metadata_2025 huggingface dataset:
Immunomodulatory response to neoadjuvant nivolumab in non-metastatic clear cell renal cell carcinoma.
Authors: Singla Nirmish , Nirschl Thomas , Obradovic Aleksandar , Shenderov Eugene , Lombardo Kara A. , Liu Xiaopu , Pons Alice , Zarif Jelani , Rowe Steven P. , Trock Bruce J. , Hammers Hans J. , Bivalacqua Trinity , Pierorazio Phillip , Deutsch Julie S. , Lotan Tamara L. , Taube Janis M. , Ged Yasser , Gorin Michael A. , Allaf Mohamad E. , Drake Charles G.
Published: March 2023

708

Background: Novel perioperative strategies are needed to reduce recurrence rates in patients undergoing nephrectomy for high-risk, non-metastatic clear cell renal cell carcinoma (ccRCC). We sought to (1) elucidate the effects of PD-1 inhibition on primary tumor-infiltrating and circulating immune cell populations in ccRCC and (2) correlate tumor microenvironment and circulating immune cell compositions with response to anti-PD-1 therapy. Methods: We conducted a prospective, phase I trial of neoadjuvant nivolumab prior to nephrectomy in 15 evaluable patients with non-metastatic ccRCC. We leveraged tissue from this cohort to elucidate the effects of PD-1 inhibition on immune cell populations in ccRCC and correlate the evolving immune milieu with anti-PD-1 response using fluorescence-activated cell sorting, bulk RNA sequencing with protein activity inference, and enzyme-linked immunosorbent assay for circulating cytokines. Results: We found that nivolumab durably promotes a pro-inflammatory state within the primary tumor, as evidenced by a sustained increase in the effector T cell phenotype and decreased representation of regulatory T cell subsets. Baseline immune infiltration within the primary tumor including T effector and myeloid enrichment along with angiogenic depletion correlates with nivolumab responsiveness. Nivolumab increases CTLA-4 expression in the primary tumor, and subsequent nephrectomy increases circulating concentrations of sPD-L1, sPD-L3 (sB7-H3), and s4-1BB. Conclusions: Our findings form the basis to consider neoadjuvant immune checkpoint inhibition (ICI) for high-risk ccRCC while the tumor remains in situ and provide the rationale for perioperative strategies of novel ICI combinations. Clinical trial information: NCT02575222 .
Association of serum lactate dehydrogenase (LDH) isozyme with prognosis of patients with metastatic clear cell renal cell carcinoma (mCRCC).
Authors: Takeda Hayato , Kimura Go , Akatsuka Jun , Endo Yuki , Yanagi Masato , Mikami Hikaru , Hasegawa Hiroya , Katsu Akifumi , Funato Ryota , Taniuchi Mami , Toyama Yuka , Kondo Yukihiro
Published: March 2023

709

Background: LDH isozyme is a tetramer of two subunits, H chain and M chain, and is present in all living tissue. Five types of molecular forms characterize the LDH pattern, and tumor tissues relatively consist LDH-4 and LDH-5, composed with a high ratio of the M chain, compared to normal tissues. This study analyzed the association between LDH isozyme and prognosis of mCRCC after nephrectomy. Methods: Clinical records of mCRCC patients those who were initially diagnosed M0 disease at Nippon Medical School between 2012 and 2016 were retrospectively reviewed. LDH isozyme values before operation and at time of metastasis were checked. Isozyme patterns were classified into 6 types, LDH 1-5 dominant and common type, according to the most composed molecular form. Results: Out of 38 patients, 33 patients (87%) were male, 5 patients (13%) were female. Median age was 65 years old (36-87). pT1 was seen in 3 cases, pT2 in 4, pT3 in 27, and pT4 in 4. Pathological grade 2 were 9 cases, G3 in 21, and G4 in 8. As for the IMDC risk, favourable was 2 cases (5%), intermediate in 26 (68%) and poor in 10 (26%). Median LDH was 163 IU/L (113-317), and isozyme dominant pattern were as follows: LDH-2 in 9 cases (24%), LDH-3 in 6 (16%), LDH-4 in 4, LDH-5 in 11. 8 cases were common type, and no cases showed LDH-1 dominant. Median time from surgery to recurrence was 10 months (1-104), median follow-up period after recurrence was 18 months (4-72). 16 deaths occurred. No significant correlation was seen between pre-operative LDH isozyme pattern and pathological grade or pT stage. Pre-operative LDH isozyme did not correlate with the time to recurrence (p=0.7420). The median OS for LDH-4 dominant at the time of metastasis was 10.9 months, significantly shorter than other isozyme types (P=0.0134). Conclusions: LDH-4 dominant isozyme pattern at the time of recurrence has a short OS, proposing as a prognostic predictor in mRCC.
Evaluating the clinical utility of circulating tumor cells (CTC) profiling to predict selection of preferred therapeutic regimens in newly diagnosed or pretreated refractory renal cell carcinomas (RCC).
Authors: Vaishampayan Ulka N. , Taylor Jeremy MG , Alva Ajjai Shivaram , Shah Neha , Mhalsekar Anuja , Gosavi Rahul Ashok , Apurwa Sachin , Patil Darshana
Published: March 2023

717

Background: There is an unmet need for biomarkers enabling therapeutic selection and prediction of clinical outcomes in kidney cancer . We evaluated the feasibility and utility of profiling of circulating tumor cells (CTCs) via multiplexed fluorescence immunocytochemistry (ICC) to identify liquid biopsy biomarkers linked to treatment response (or resistance) in advanced RCC patients. In addition, transcriptome analysis for 20802 genes from exosomal RNA is planned to evaluate novel prognostic and predictive signatures. Methods: Patients with either untreated or pretreated advanced RCC were eligible prior to starting a new systemic therapy regimen. IRB approved written informed consent was obtained. Serial blood samples were collected at baseline, and at 3, 6, 12 and 24 months. Primary endpoint of the study was to detect the proportion of patients with RCC in whom CTCs can be detected and profiled. Secondary endpoints are to correlate the profiling and changes in CTC with response and clinical outcomes. The study will meet its primary endpoint if the assay provides adequate detection and profiling for at least 12 patients. With an overall sample size of 50 the width of a 95% confidence interval for the rate of providing a therapeutic intervention is guaranteed to be less than 26%. Results: 44 evaluable patients have been enrolled; 11 females, 33 males. Median age was 64 years (range 40-85 years). 38 white patients, 2 black patients and 4 of other ethnicity have been enrolled.16 patients were untreated, 22 were pretreated and 6 were undergoing adjuvant therapy post nephrectomy. 37 patients had clear cell histology, 4 non clear cell and 3 unclassified histology. 42 of the 44 (95.5%) patients had detectable CTCs in the baseline sample. 21 on treatment samples have been collected to date, with detectable CTCs in all except one sample. 53 of 65 samples (81.5%) demonstrated detection of at least one biomarker by ICC. VEGFA expression was the most commonly detected biomarker on ICC (detected in 28 of 63 samples). Conclusions: The primary endpoint was met, and feasibility of the test was demonstrated with 95% of the baseline samples showing CTC detection and 81.5% showing biomarker expression. This blood-based, non-invasive liquid biopsy demonstrated high sensitivity for detection of cancer cells, and presents a potential opportunity for biomarker profiling to predict therapeutic efficacy of conventional RCC therapeutic agents. Correlation of longitudinal CTC with clinical outcomes will be reported. Transcriptome analysis is under evaluation for novel prognostic and predictive signatures and will be reported.
Nivoswitch trial: Predictive value of PD-L1 in plasma and extracellular vesicles.
Authors: Sonnleithner JAdzia , Himbert Dirk , Zeuschner Philip , Hartmann Arndt , Grüllich Carsten , Ivanyi Philipp , Wirth Manfred , Staib Peter , Schostak Martin , Dargatz Philip , Müller Lothar , Grünwald Viktor , Junker Kerstin
Published: March 2023

718

Background: Predictive markers for immune checkpoint inhibition (ICI) in renal cell carcinoma patients are still missing. Until now, mainly primary tumor tissues have been analyzed to identify reliable markers including PD-L1, although distant metastases represent the therapy targets. Taking into account putative heterogeneity between primary tumors and metastases as well as dynamic changes during tumor progression and treatment, markers from liquid biopsies seem to be more suitable. The aim of this study was to investigate the predictive value of PD-L1 in plasma and on extracellular vesicles (EV) from plasma in the Nivoswitch trial. Methods: Plasma samples at randomization were obtained from 39 patients who received 3 months of tyrosine kinase inhibitor (TKI) therapy followed by random allocation to Nivolumab (“switch arm”) or continued TKI therapy (control arm) and during treatment (day 30). PD-L1 concentration was quantified by ELISA. EVs were isolated by ultracentrifugation or by using a commercial kit. They were characterized by Western blotting using cell specific, EV-specific markers as well as PD-L1 antibody. The data was analyzed by Mann Whitney and Kruskal Wallis tests as well as Kaplan Meier estimates. Results: PD-L1 was detected in plasma and EVs in all patients. PD-L1 plasma concentration was similar between response categories both in the overall cohort and the control (TKI) arm. In contrast, PD-L1 concentration in the “switch arm” was significantly lower in patients with objective response compared to patients with stable (p=0.028) or progressive disease (p=0.008) at day 0, whereas no significant difference occurred at day 30. Plasma PD-L1 levels during treatment (day 30 compared to day 0) did not show an association with therapy response in both arms. A trend towards better OS was found in patients with lower PD-L1 irrespective of treatment arm, but not for PFS. PD-L1 was detected on plasma EVs both by Western blotting as well as by ELISA, although the concentrations were too low for statistical analysis. Conclusions: In this study, plasma PD-L1 concentration did not show strong associations with clinical outcomes which might be caused by the rather small sample size and inherent heterogeneity of treatment. However, PD-L1 concentrations may have prognostic value confirming published data on tumor tissues. PD-L1 is detectable on EVs from plasma. Further studies should investigate the potential of EVs as biomarkers as well as their functional role in therapy response, especially in ICI. Clinical trial information: NCT02959554 .
Outcomes of first subsequent taxane (FST) therapy in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) who previously received docetaxel intensification (DI) for metastatic castration-sensitive prostate cancer (mCSPC).
Authors: Robin Gabrielle , Basappa Naveen S. , North Scott A. , Ghosh Sunita , Kolinsky Michael Paul
Published: March 2023

72

Background: The management of advanced prostate cancer continues to rapidly evolve, particularly with earlier use of survival prolonging therapies in mCSPC. Though approved prior to the use of intensification therapy in mCSPC, taxane-based chemotherapies remain a relevant option for pts with mCRPC. However, there is little evidence determining outcomes of taxane chemotherapies as FST in mCRPC pts who received DI in mCSPC. The purpose of this study is to compare outcomes between the survival prolonging taxanes, docetaxel (D) and cabazitaxel (C), as FST after DI. Methods: New patient consults seen at the Cross Cancer Institute from 1 July 2014 to 31 Dec 2020 were reviewed. Pts were considered eligible if they received DI for mCSPC and then received either D or C in mCRPC. Variables of interest were collected from the electronic medical record. The primary endpoint was ≥50% PSA response at 12 weeks relative to baseline for FST. Secondary endpoints included OS from mCSPC diagnosis, as well as PFS and OS from FST start date. PSA responses were compared using chi-squared test and time-based endpoints were compared using the Kaplan-Meier method. Results: 34 pts were identified: D = 22, C = 12 as FST. 91.2% of pts (D 95.5% vs C 83.3%) received FST in 2nd line mCRPC. Median age at diagnosis (63.1 vs 67.1 yrs, p = 0.236) and median time to CRPC (18.6 vs 14.2 mos, p = 0.079) were similar for D and C, respectively. Median time to FST (24.1 vs 34.6 mos, p = 0.036) and OS from mCSPC diagnosis (30.9 vs 52.7 mos, p = 0.002) were significantly shorter for pts receiving C vs D. PSA responses occurred in 40.9% of pts treated with D compared to 25.0% treated with C (p = 0.645). There was no significant difference in median PFS (2.7 vs 3.5 mos, p = 0.727) or median OS (11.4 vs 8.1 mos, p = 0.132) from time of FST for pts treated with D vs C, respectively. Conclusions: Both D and C demonstrated activity as FST after DI in mCSPC. Pts who received C had shorter time to FST and OS from mCSPC. The reasons for this may reflect clinician preference for C in pts with aggressive or rapidly progressing disease. No difference was found in PSA response, PFS, or OS from FST with D compared to C. While limited by its retrospective nature and small sample size, this study suggests that D is active as FST despite treatment with DI in mCSPC.
Clinical characteristics, tumor genomic and transcriptomic profiles of patients (pts) with metastatic renal cell carcinoma (mRCC) who developed venous thromboembolism (VTE).
Authors: Li Haoran , Sahu Kamal Kant Kant , Gebrael Georges , Chigarira Beverly , Mathew Thomas Vinay , Jo Yeonjung , Kumar Shruti Adidam , Nordblad Blake , Brundage James , Tripathi Nishita , Sayegh Nicolas , Swami Umang , Agarwal Neeraj , Maughan Benjamin L.
Published: March 2023

726

Background: VTE is a common complication in pts with mRCC. Identifying pts with mRCC at the highest risk of developing VTE may provide the rationale for initiating prophylactic anticoagulation. Methods: In this IRB-approved retrospective study, pts diagnosed with mRCC between 7/2012 and 7/2022 at Huntsman Cancer Institute at University of Utah were included. Variables evaluated were pts' clinical characteristics, treatment, and anticoagulation therapy. Pts with mRCC with VTE within 12 months after diagnosis were used as cases and those without VTE during the same period were used as control. The multivariable logistic model was used to assess risk factors of VTE. DeSeq2 analysis was implemented in Bioconductor Software to analyze differentially expressed genes based on the VTE. These results were subjected to gene ontology analysis in the TopGO software. All bioinformatic analysis was conducted in R-Studio, version 4.1.1. Results: Among 355 pts with mRCC, 53 pts developed VTE within 12 months after diagnosis (incidence rate: 14.9%). Pts of the two groups (with or without VTE) did not differ significantly when compared for age, gender, race, cytoreductive nephrectomy rate, clear cell histology, grade of tumor, IMDC risk factors (table). Pts who developed VTE had a higher BMI at diagnosis (31.7 vs. 29.1 kg/m2, p=0.03). In multivariate analysis, obesity (OR=1.06, [1.01-1.12], p=0.028) was associated with increased VTE risk. There was no significant difference of mutation rates in genomic panel. Transcriptomic analysis showed hormone metabolic, organic acid transport, extracellular matrix and structure organization (all p<0.0001) are among the most significantly elevated pathways associated with VTE. Correlation of genomic and transcriptomic data with occurrence of VTE will be presented in the meeting. Conclusions: In this real-world population of pts with mRCC, VTE is more commonly associated with mRCC than what was previously reported in clinical trials. These hypothesis generating data, upon external validation, may provide guidance for clinical use of prophylactic anticoagulation therapy in pts with mRCC.[Table: see text]
Mapping distribution of brain metastases in renal cell carcinoma (RCC) and association with clinical features.
Authors: Ged Yasser , Feinaj Ardit , Markowski Mark Christopher , Yerrapragada Anirudh , Elias Roy , Bettegowda Chetan , Singla Nirmish , Kamson David
Published: March 2023

727

Background: Brain metastases (BM) are frequently observed in metastatic RCC (mRCC) with a tendency to present with hemorrhagic BM. Distribution patterns of BM in RCC and associations with clinical outcomes are not well understood. Here we present a detailed distribution analysis in a surgically resected BM RCC cohort with a focus on clinically relevant associations. Methods: A retrospective analysis was performed on patients (pts) with mRCC who underwent craniotomy for BM at our institution. We reviewed gadolinium-enhanced MRI brain and CT head (if available) at the time of BM diagnosis. We assessed the presence of hemosiderin on MRI or hemorrhage on CT in the BM lesion and marked each at their corresponding anatomic location. Public brain atlases were used for distribution analysis. Overall survival (OS) from the date of BM diagnosis and CNS progression free survival (CNS-PFS) from the date of craniotomy were calculated. Results: A total of 67 BM were analyzed from 46 pts. 23 with synchronous BM, 9 with two and 6 with 3 concurrent BM. Most patients were male (n=35, 76%) with a median age at diagnosis of 63 years. Primary histology was clear cell in 42 pts (91%) and 10 pts (22%) had renal vein thrombosis (RVT) at primary diagnosis. IMDC scores at time of BM diagnosis were favorable in 20%, intermediate in 60% and poor in 20%. Hemosiderin (MRI) or hemorrhage (CT) was seen in 82% and 80% of BM, respectively. 55% of lesions were left sided, 45% frontal, 21% parietal, 18% occipital, 7% temporal and 6% cerebellar. Posterior circulation and posterior cerebral artery territories contained 42% and 34% of BM despite supplying only 30% and 16% of the brain volume, respectively. Patients with solitary BM had higher Karnofsky performance status (p=0.006) and lower disease burden (p=0.004) than those with multiple BM. Shorter CNS-PFS was seen in association with hemosiderin on MRI (log-rank p=0.04) and RVT in primary specimen (log-rank p=0.002). IMDC risk scores (log-rank p<0.001) predicted OS. On multivariable OS analysis, BM lateralized to the right (HR 2.6, p=0.06), hemosiderin in BM (HR 6.5, p=0.02) and IMDC risk groups (intermediate HR 2.9, poor risk HR 25.6, p<0.04) were independent prognostic factors for shorter OS. Conclusions: The above-presented lesion mapping method shows clinically relevant findings in RCC BM. Tumoral hemosiderin deposits appear a potential parameter to predict outcomes in RCC BM which deserve further study and validation.
Proposal for reclassification of upstaged T1 and T2 and pathological T3 RCC based on improved alignment of survival analyses.
Authors: Meagher Margaret , Cerrato Clara , Puri Dhruv , Liu Franklin , Shah Aastha , Ghassemzadeh Saeed , Dhanji Sohail , Wang Luke , Patil Dattatraya H , Saito Kazutaka , Yasuda Yosuke , Nasseri Ryan , Fujii Yasuhisa , Master Viraj A. , Derweesh Ithaar H
Published: March 2023

732

Background: Patients with pathologically upstaged tumors have worse survival outcomes than their non-upstaged matched counterparts. However, we do know that original clinical tumor staging does still predict outcomes. We sought to examine if pathologic upstaging incrementally may more rationally stratify cancer specific survival outcomes. Methods: Multi-institutional (Emory, TMDU, UCSD) retrospective analysis of patients with renal cell carcinoma who underwent partial or radical nephrectomy between 1998-2020. Patients were divided into cT1 upstaged to pT3 (cT1/pT3), cT2 non-upstaged (cT2/pT2), cT2 upstaged to pT3 (cT2/pT3), and cT3 non-upstaged (cT3/pT3). Patients were analyzed for demographics, clinical parameters, and post-surgical outcomes. Primary outcome was cancer specific mortality (CSM). Secondary outcomes were all cause mortality and recurrence free survival. Cox regression was utilized to analyze factors associated with outcomes. Kaplan Meier analysis (KMA) was performed to analyze 5-year cancer specific survival. ROC analysis was utilized to compare predictive value of AJCC 8th edition TNM staging vs proposed staging. Results: 1093 patients were analyzed (283 cT1/pT3, 237 cT2/pT2, 244 cT2/pT3, and 329 cT3/pT3). Median follow-up was 25.9 months. Cox regression demonstrated that cT2/pT3 (HR 2.7, p<0.001 vs. cT1/pT3 [referent]) and cT3/pT3 (HR 2.6, p<0.001 vs. cT1/pT3 [referent]) were significantly associated with worsened cancer specific mortality, while cT1/pT3 (HR 0.4, p<0.001 vs. cT3/pT3 [referent]) and cT2/pT2 (HR 0.4, p<0.001 vs. cT3/pT3 [referent]) were associated with improved cancer specific mortality. Based on this, we proposed to realign cT1/pT3 with cT2/pT2 and cT2/pT3 with cT3/pT3. KMA revealed significant differences in 5-year cancer specific survival (cT1/pT3 82%, cT2/pT2 81%, cT2/pT3 67%, and cT3/pT3 60%, p<0.001). There were significant differences in 5-year overall survival (cT1/pT3 63%, cT2/pT2 67%, cT2/pT3 49%, and cT3/pT3 49%, p<0.001), and 5-year recurrence free survival (cT1/pT3 80%, cT2/pT2 83%, cT2/pT3 70%, and cT3/pT3 59%, p<0.001) on KMA. ROC analysis revealed an AUC of 0.529 for CSM and AUC of 0.502 for ACM using the current AJCC 8th edition TNM staging. ROC analysis revealed an AUC of 0.597 for CSM and AUC of 0.545 for our new proposal. Conclusions: Our analysis suggests that cT1 tumors pathologically upstaged to pT3 behave more similarly to pT2 tumors. Further delineation of pathologically upstaged tumors may more rationally stratify cancer specific survival outcomes to guide patient counseling and clinical decision making.
The impact of homologous recombination repair (HRR) gene mutation status on treatment (tx) patterns and clinical outcomes among patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) in the United States (US).
Authors: Barata Pedro C. , Du Ella X. , Yang Hongbo , Xu Chunyi , Guo Helen , Cui Caroline , Nazari Jonathan , Niyazov Alexander
Published: March 2023

97

Background: There is a paucity of evidence that evaluates the impact of HRR mutation status on clinical outcomes in pts with mCRPC. This study assessed the real-world (rw) progression-free survival (rwPFS) based on HRR mutation status (HRR mutated [HRRm]), HRR wild type (HRRwt) among pts with mCRPC in the US. Methods: Data from pts with mCRPC initiating first line (1L) tx between 2016 and 2019 and known HRR status based on germline or tumor testing were retrospectively abstracted from medical charts by physicians in the US from 2021–2022. Pt demographic and clinical characteristics were summarized descriptively across subgroups by HRR status (HRRm vs HRRwt). HRRm was defined as a mutation in at least 1 of 12 genes of interest ( BRCA1, BRCA2, PALB2, ATM, ATR, CHEK2, FANCA, MLH1, MRE11A, NBN, RAD51C, CDK12), regardless of test type. RwPFS on 1L mCRPC tx was compared among pts with HRRm vs HRRwt genes and BRCA1/2 HRRm vs HRRwt genes using the Kaplan–Meier method and log-rank test. Results: A total of 80 physicians contributed data from charts of 130 pts (N=51 HRRm and N=79 HRRwt). Among pts with HRRm genes, 34 (67%) were positive for BRCA1 or BRCA2 mutations. In pts with known timing of testing (n=88), 33% were tested prior to initiation of 1L therapy and 67% after initiation of 1L therapy. In the 1L setting, novel hormonal therapy (NHT) was utilized in 29% of pts with HRRm vs 58% with HRRwt genes (P<0.01). Chemotherapy was utilized in 43% of pts with HRRm vs 34% with HRRwt genes (P=0.40); docetaxel was the most common agent, utilized in 26% vs 27% of pts with HRRm vs HRRwt genes. Median rwPFS on 1L tx was 19 months (95% CI: 11–NE) vs 31 months (95% CI: 23–NE), P=0.11, for pts with HRRm vs HRRwt genes, respectively. RwPFS for pts with BRCA1/2 HRRm genes (N=34) vs HRRwt genes was 19 months (95% CI: 11–NE) vs 31 months (95% CI: 23–NE), P=0.17. Conclusions: In this rw study, genomic testing was performed frequently in later stages of metastatic disease. Pts with HRRm genes had numerically shorter rwPFS on 1L standard therapies compared with HRRwt pts. While unmet needs exist to optimize mCRPC txs and prolong disease progression irrespective of HRRm mutation status, further studies are warranted to further elucidate the prognostic role of HRRm and BRCA1/2 mutations on clinical outcomes.
Survival outcomes of metastatic castration-resistant prostate cancer in Brazil (LACOG 1818).
Authors: Maluf Fernando Cotait , Martins Suelen P. S. , Silva Neto Deusdedit Cortêz Vieira , Werutsky Gustavo , Rinck Jr Jose Augusto , Bastos Diogo Assed , Rocha Roberto Odebrecht , Fay Andre P. , Fernandes Roni de Carvalho , Girardi Daniel da Motta , Araujo Daniel Vilarim , Mota Augusto C. A. , Lara Gongora Aline Bobato , Fernandes Bruno Melo , Alves Ana Caroline Fonseca , Sampaio Cristina de Deus Anjos Tavares , de Souza Andréa Lopes Ponte , de Jesus Rafaela Gomes , Gössling Gustavo Cartaxo de Lima , Soares Andrey
Published: March 2023

TPS272

Background: Treatment of metastatic castration-resistant prostate cancer (mCRPC) has been steadily evolving during the last decade, but access remains a significant issue in low- and middle-income countries (LMICs). As novel therapies emerge and translate into clinical practice, the gap in treatment patterns between patients who do or do not have access to these therapies is expected to increase. The resulting disparities in outcomes are likely to be more noticeable in countries with pronounced inequality, such as Brazil. In Brazil, while a minority of patients have private insurance and have access to nearly all available treatment options, approximately 75% of patients depend on the public health system, which is unable to afford most of the recent treatment innovations for mCRPC, such as novel hormonal agents (NHA) or PARP inhibitors. LACOG 1818 was developed to investigate and compare outcomes of patients with mCRPC treated at private and public hospitals in Brazil. Methods: LACOG 1818 (NCT04962919) is a retrospective multicentric study investigating disparities in cancer treatment and survival among public and private institutions in Brazil. Patients with mCRPC diagnosed within January 2014 and December 2017 will be included and their data will be abstracted from medical records. Primary endpoint is cause-specific survival, comparing patients from private and public institutions. We estimate that 299 events are needed to detect a hazard ratio of 0.75 indicating a lower risk of prostate cancer-related death for patients treated at private institutions with a power of 80% and a bicaudate significance level of 10%. Considering a follow up of 24 months and a median cause-specific survival of 20 months in patients from public institutions, 590 patients are planned to be included. Secondary endpoints include describing comorbidities, sociodemographic and clinicopathological characteristics of patients with mCRPC; comparing overall survival of patients with mCRPC treated at public and private institutions; comparing treatments patterns of patients with mCRPC treated at public and private institutions; and describing skeleton-related complications, bone-directed treatments, and admission rates. From January 2020 to August 2022, 244 of planned 590 patients have been enrolled in 7 Brazilian centers. Additional 12 centers are still planned to open before 2023. Results are expected in the first semester of 2023. Clinical trial information: NCT04962919 .
A phase II trial modifying metabolic syndrome and cardiovascular risk for patients with prostate cancer on ADT using a risk factor modification program and continuous Fitbit monitoring (ProTrio).
Authors: Hahn Andrew Warren , Slack Tidwell Rebecca , Thoman Whittney , Abdulla Amer , Koutroumpakis Efstratios , Aparicio Ana , Subudhi Sumit Kumar , Siddiqui Bilal Ahmed , Pilié Patrick Glen , Zurita Amado J. , Corn Paul Gettys , Laccetti Andrew Leonard , Jana Bagi RP , Basen-Engquist Karen , Logothetis Christopher
Published: March 2023

TPS273

Background: Prostate cancer is a disease of older age, and there is significant overlap with age-related illnesses. Androgens play a critical role in prostate cancer but also have been linked to cardiovascular (CV) disease, metabolic syndrome, bone health, and frailty. ADT is associated with an increased risk of CV events primarily due to increased rates of diabetes, dyslipidemia, and adverse changes in body composition. We assume that prostate cancer and age-related illnesses share biology with therapeutic implications in a subset of men. The ProTrio trial will test the hypothesis that a 16-week digital risk factor modification program will improve 10-year atherosclerotic cardiovascular disease (ASCVD) risk score as compared to usual care in men with potentially lethal prostate cancer receiving ADT. Methods: This single center, open-label, randomized phase II trial is evaluating a 16-week digital risk factor modification program, which includes an exercise prescription (150 minutes of titrated cardiovascular exercise and resistance exercise 2 times a week) with support via a smart phone application (Moving Analytics) and Fitbit, in patients with prostate cancer who are receiving ADT compared to usual care with Fitbit monitoring. Eligible patients are men receiving ADT +/- an androgen signaling inhibitor for at least 3 months prior to enrollment. The study will enroll to two cohorts: (1) distant metastatic disease and (2) biochemically recurrent or regional lymph node disease. Patients will be stratified according to their baseline ASCVD risk score. The primary endpoint is the difference in ASCVD risk score post-intervention. Secondary endpoints include difference in metabolic severity index z-score, PSA velocity, 6-minute walk, 5X Sit-to-Stand, body composition, physical activity measured by Fitbit, and health-related quality of life. Up to 100 patients will be enrolled in each cohort. A clinically relevant improvement in ASCVD score reduction is 2.5%. With 44 men per arm, after 12% dropout, we can detect an improvement of 2.5% vs. 0% at a 2-sided 5% significance level with 80% power assuming a standard deviation (SD) of 4.125%. A sample size adjustment is planned based on the SD of the first cohort to reach 44 patients. Each cohort will undergo futility analysis once half the men are enrolled. The study is enrolling at MD Anderson Cancer Center. Clinical trial information: NCT05054296 .
LuCAB: A phase I/II trial evaluating cabazitaxel in combination with [177Lu]Lu-PSMA-617 in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC)
Authors: Kostos Louise Kathleen , Buteau James Patrick , Kong Grace , Yeung Theresa , Di Iulio Juliana , Fahey Michael T , Fettke Heidi , Furic Luc , Hofman Michael S , Azad Arun
Published: March 2023

TPS278

Background: [177Lu]Lu-PSMA-617 was recently FDA-approved for use in the post-taxane, post-antiandrogen setting in pts with mCRPC. Despite conferring a survival benefit, for many the treatment response is short, and progression is inevitable. One of the likely mechanisms limiting the durability of responses to [177Lu]Lu-PSMA-617 is heterogeneity in tumor PSMA expression. This can be screened for visually using PSMA and FDG PET/CT scans and inspecting for discordant disease, however, micrometastatic disease is unable to be evaluated in this way. In addition, [177Lu]Lu-PSMA-617 may not effectively target micrometastatic disease due to the longer path length of beta emitters. Cabazitaxel has radiosensitizing properties that may enhance the cytotoxic effect of [177Lu]Lu-PSMA-617, whilst also treating any PSMA-negative disease. We hypothesize that the combination of [177Lu]Lu-PSMA-617 and cabazitaxel will be well tolerated and lead to more durable responses. Methods: This single-centre, single-arm phase I/II trial will enrol 32-38 pts with mCRPC to evaluate the safety and preliminary efficacy of cabazitaxel and [177Lu]Lu-PSMA-617 in combination. Up to 6 doses of [177Lu]Lu-PSMA-617 (7.4 GBq) will be administered intravenously every 6 weeks. Cabazitaxel will be given concurrently (dose range 12.5mg/m2 - 20mg/m2), on Day 2 and Day 23 of each 6-week cycle. The dose of cabazitaxel will be escalated using a traditional 3+3 design. Key eligibility criteria include a diagnosis of mCRPC with PSMA-positive disease on PSMA PET/CT (SUVmax ≥15), with no evidence of diffuse marrow disease or sites of discordance on FDG PET/CT. Pts must have progressed after prior docetaxel and a second-generation antiandrogen, have adequate bone marrow and organ function and an ECOG performance status of 0-1. The primary objective is to establish the maximum tolerated dose of cabazitaxel and [177Lu]Lu-PSMA-617. Secondary objectives include measuring the frequency and severity of adverse events, assessment of efficacy through PSA 50% response rate, radiographic and PSA progression-free survival, overall survival, objective tumor response rate, and evaluation of pain and health-related quality of life over the first 12 months. Bloods will be taken at baseline, during treatment and at progression for ctDNA analysis, the results of which will be correlated with baseline pt and disease characteristics, and response outcomes, to determine biomarkers of treatment response and resistance. Pt recruitment commenced in August 2022 and will continue for 18 months. Clinical trial information: NCT05340374 .
AlphaBet: A phase I/II trial evaluating the combination of radium-223 and [177Lu]Lu-PSMA-I&T in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Kostos Louise Kathleen , Buteau James Patrick , Yeung Theresa , Xie Sophia , Di Iulio Juliana , Cardin Anthony , Owen Katie , Fettke Heidi , Chin Kwang Y , Emmerson Brittany , Haskali Mohammad B , Parker Belinda , Furic Luc , Azad Arun , Hofman Michael S
Published: March 2023

TPS280

Background: [177Lu]Lu-PSMA-I&T (LuPSMA) is a small molecule radioligand that delivers radiation via beta-particulate emission to cells expressing prostate-specific membrane antigen (PSMA). Despite a survival benefit in mCRPC, responses for many are not durable, with the majority of pts developing progressive osseous disease. Due to the lack of crossfire radiation in micrometastatic disease, small cancer cell clusters in the bone marrow may not receive an adequate dose of radiation from 177Lu to induce cytotoxic double-stranded DNA breaks. Alpha-emitters have a shorter path length (≤100 µm) and higher linear energy transfer, making them better suited for treating micrometastatic disease. As a calcium-mimetic, radium-223 (223Ra) is a bone-specific alpha-emitter which targets osteoblastic bone metastases. We hypothesise that the combination of LuPSMA with 223Ra will be well tolerated and lead to improved response durability. Methods: This phase I/II, single-arm, single-centre study will enrol 36 patients with mCRPC who have progressed on a prior second-generation antiandrogen. Up to 6 cycles of LuPSMA (7.4 GBq) and 223Ra (28 kBq/kg - 55 kBq/kg) will be given intravenously every 6 weeks, along with background androgen deprivation and bone protective therapy. Key eligibility criteria include a diagnosis of mCRPC with at least two untreated bone metastases visible on bone scintigraphy and PSMA-positive disease on PSMA PET/CT (SUVmax ≥20). Sites of FDG-positive disease must be either PSMA-positive or have increased uptake on bone scan. Other eligibility criteria include an ECOG status of 0-2, and adequate bone marrow and organ function. Patients treated with more than one line of chemotherapy for metastatic prostate cancer are not eligible. Blood samples and biopsies will be taken at baseline, on treatment, and at progression to develop tumor- and immune-based biomarkers that predict treatment response and associated survival benefit. A traditional 3+3 dose-escalation model will be utilized initially, escalating the dose of 223Ra. The dose of LuPSMA will remain fixed. The co-primary objectives of this study are to determine the maximum tolerated dose of 223Ra when combined with LuPSMA, and the 50% PSA response rate. Secondary objectives include measuring the frequency and severity of adverse events, assessment of efficacy through overall, radiographic and PSA progression-free survival, overall survival, objective tumor response rate, and evaluation of pain and health-related quality of life. Enrolment commenced in September 2022 and will continue for 24 months. Clinical trial information: NCT05383079 .
AtezoCab: A phase II study of cabozantinib (C) in combination with atezolizumab (A) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) with non-measurable disease (NMD).
Authors: Swami Umang , Brown Julian , Turner Alena , Haaland Benjamin , Jones Kristen , Mathew Thomas Vinay , Sahu Kamal Kant Kant , Li Haoran , Phunrab Tenzin Kunsang , Batten Julia , Maxwell Lindsay , Lloyd Jennifer , Kohli Manish , Gupta Sumati , Thorne Kelli , Maughan Benjamin L. , Agarwal Neeraj
Published: March 2023

TPS295

Background: Preclinical studies and clinical observations suggest that C promotes an immune permissive environment, which might lead to synergistic effects from combination treatment with immune checkpoint inhibitors. In Cohort 6 of COSMIC-021 study, the combination of C and A showed encouraging clinical activity and acceptable tolerability in mCRPC pts who had radiographically progressed in soft tissue on or after novel hormonal treatment (NHT; PMID: 35690072). CONTACT-02 is a phase 3 study randomizing pts with mCRPC with measurable disease 1:1 to C+A or NHT (NCT04446117). The objective of this study is to specifically evaluate the safety and efficacy of C+A in pts with mCRPC with NMD. Methods: AtezoCab is an IRB approved, investigator-initiated, single-arm, single-center, open-label, non-randomized phase 2 study of C+A in mCRPC patients with NMD to assess disease control rate (DCR). Treatment: C 40 mg oral daily + A 1200 mg intravenously every 3 weeks. Treatment continues until progression or intolerable toxicities. Key inclusion criteria: ≥18 years age, mCRPC with histologically or cytologically confirmed adenocarcinoma without small cell histology, Eastern Cooperative Oncology Group performance status ≤ 2, adequate organ function, prior treatment with NHT, only NMD outside the pelvis (above aortic bifurcation) per RECIST 1.1 criteria. Key exclusion criteria: prior chemotherapy for mCRPC, prior treatment with C, immune checkpoint inhibitors or other systemic immunostimulatory agents, active or history of clinically significant autoimmune disease per treating physician, corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days before first dose of study treatment. Primary endpoint: Percentage of pts with disease control. DCR will be defined as the percentage of pts with confirmed response of any duration or stable disease or noncomplete response or nonprogressive disease for 24 weeks or longer per PCWG3-modified RECIST v1.1. Up to 33 pts will be enrolled for a total of 30 evaluable pts. This will ensure that DCR can be estimated via a 95% confidence interval (CI) with margin of error <0.18. The primary analysis CI on DCR will be based on Wilson’s approach. Secondary Endpoints: Progression-free survival (PSA and radiographic), PSA50% response rate, overall survival and safety. Tissue and blood samples will be collected for correlative studies. 7 patients have been enrolled. Clinical trial information: NCT05168618 .
Radiation therapy and irreversible electroporation for intermediate risk prostate cancer (RTIRE).
Authors: McClure Timothy D , Ballman Karla V. , Marciscano Ariel E. E. , Barbieri Christopher , Nagar Himanshu
Published: March 2023

TPS403

Background: The objective of the RTIRE clinical trial (NCT05345444) is to demonstrate the feasibility, safety, and early oncologic efficacy of combining MRI-guided stereotactic body radiation therapy (MRgSBRT) with irreversible electroporation (IRE) for men with intermediate-risk localized prostate cancer. Methods: Inclusion criteria: 1) Men aged ≥18, 2) ECOG 0 –1, 3) Histologically confirmed intermediate risk prostate cancer per NCCN guidelines, 4) Focal grade group 2 (GG2) or 3 (GG3) cancer in multi-parametric magnetic resonance imaging (mpMRI) target, 5) Gland size < 80cc, 6) Ability to undergo IRE, 7) Ability to receive MRI-guided SBRT, 8) Ability to complete the HRQOL assessment surveys, 9) Willingness to undergo 12 month follow up biopsy. Exclusion criteria: 1) Prior TURP, 2) Prior history of focal therapy, 3) Prior history of receiving pelvic radiotherapy, 4) Patient with history of inflammatory bowel disease, 5) History of bladder neck or urethral stricture. Study Design/Endpoints: This is a feasibility and safety study assessing the ability to perform IRE followed by real-time MRgSBRT. Subjects will undergo focal IRE followed by MRgSBRT (>6 weeks after IRE) to the prostate +/- seminal vesicles prescribed to 32.5 Gy in 5 fractions. The primary endpoint of the first portion of the trial is feasibility, defined as at least 80% of subjects (8 of 10 subjects) undergoing assessment at 12-weeks post-IRE and at 6-weeks post-MRgSBRT within 1 year from enrollment of the first subject. The expansion phase will include an additional 40 subjects to assess side effect profile and early oncologic efficacy (n=50) at 12 months post RTIRE. RTIRE has enrolled 8 subjects in 3 months and will proceed to the expansion phase. Secondary endpoints include: 1) short-term safety as measured by treatment-related adverse events, 2) oncologic efficacy as measured by number of subjects with presence of ≥GG2 cancer at 12 months post-RTIRE therapy, 3) health-related quality of life (HRQOL) as measured by Expanded Prostate Cancer Index Composite for Clinical Practice (EPIC-CP), International Prostate Symptom Score (IPSS), International Index of Erectile Function (IIEF-5) 4) post-RTIRE prostate-specific antigen (PSA) kinetics including time to PSA nadir and post-nadir PSA stability, 5) assessment of pre and post-RTIRE mpMRI changes to evaluate the area of necrosis and presence of residual tissue, 6) rates of biochemical and clinical progression and the need for secondary or adjuvant treatment following RTIRE. Clinical trial information: NCT05345444 .
The CONFIDENT-P trial: Clinical implementation of artificial intelligence assistance in prostate cancer pathology.
Authors: Flach Rachel , Stathonikos Nikolas , Nguyen Tri , ter Hoeve Natalie D , van Diest Paul J. , van Dooijeweert Carmen
Published: March 2023

TPS405

Background: Prostate cancer grading has been subject to variation, putting patients at risk for over- and under-treatment (Flach et al., 2022). As a response, development of artificial intelligence (AI) prostate cancer algorithms has been on the rise in the field of pathology. Despite promising results in retrospective studies, and several FDA-approved and CE-IVD certified algorithms on the market, prospective clinical implementation studies of AI are lacking. Moreover, uptake of digital pathology is currently insufficient due to high implementation costs (Ho et al., 2014). In this trial, we will explore the benefits of an AI-assisted pathology workflow in prostate cancer detection, while maintaining diagnostic safety standards. We will focus on reducing costly immunohistochemistry stains (IHC), which are currently used to aid in the diagnosis of prostate cancer. Methods: CONFIDENT-P is a SPIRIT-AI compliant single-centre, clinical trial, in a fully digital academic pathology laboratory. We will prospectively enroll 80 prostate cancer patients who undergo prostate needle biopsies. The pathology specimens will be pseudo-randomized to be assessed by a pathologist with- or without AI-assistance in a pragmatic (bi-)weekly sequential design, in a 1:1 allocation ratio. Patients are excluded when they are redirected for a second opinion to the UMC Utrecht. In the intervention group, pathologists will assess whole slide images (WSI) of the standard haematoxylin-eosin (HE)-stained sections assisted by the output of a CE-IVD approved prostate cancer detection and grading algorithm. In the control group, pathologists will assess HE WSI according to the current clinical workflow. If no tumour cells are identified or when the pathologist is in doubt, staining by immunohistochemistry (IHC) will be performed. Primary endpoint is the number of saved resources on IHC for detecting tumour cells, since this will clarify tangible cost savings that will help to build the business case for AI. We will compare the proportion of IHC-use in both arms, and calculate adjusted relative risks, using a log-binomial model. The sample size gives at least 80% power to detect a 30% difference in IHC usage, using a one-sided significance level of 5%. Enrolment is set to begin in November 2022. The ethics committee (MREC NedMec) waived the need of official ethical approval, as participants are not subjected to procedures and as they are not required to follow rules. Furthermore, they are not at risk of an inferior diagnosis. Trial registration is therefore applicable nor suitable.
A randomized phase II trial of neoadjuvant chemokine modulation in patients with localized prostate cancer undergoing radical prostatectomy.
Authors: Jatwani Karan , Farmer Bailey , Roy Arya Mariam , Slomba Ronald , Attwood Kristopher , Levine Ellis Glenn , Kauffman Eric , Kalinski Pawel , Guru Khurshid , Gopalakrishnan Dharmesh , Chatta Gurkamal S.
Published: March 2023

TPS406

Background: Most patients with high or very high risk localized prostate cancer (PCa) experience disease recurrence after radical prostatectomy (RP). Neoadjuvant androgen ablation has not improved high-risk pathological features or recurrence rates after RP.1 We reported the association between high intratumoral CD8+ T lymphocyte (CTL) density and improved survival post-RP, suggesting clinical benefit from neoadjuvant immunomodulation (NI).2 Analysis of the tumor immune microenvironment after NI may also provide key insights into potential therapeutic strategies in PCa. CTL/NK/Th1-recruiting chemokines (CCL5, CXCL9 and CXCL10) are downregulated while MDSC/Treg-attracting chemokines (CCL2, CCL22, and CXCL12) are upregulated in human PCa tissue.3 A large proportion of T cells in PCa are Tregs or dysfunctional CTLs and this immunosuppressive profile may be partly driven by COX-2 upregulation.4,5 A chemokine modulating regimen (CKM) of rintatolimod (TLR-3 ligand), aspirin (COX-2 inhibitor), and IFN-α favorably reprogrammed the chemokine profile and CTL/Treg ratio in human PCa explants.3 This combination has demonstrated safety in phase I/II trials across other tumor types, though it is unclear if IFN-α can be omitted without compromising efficacy.7-8 Methods: This is a three-arm, phase II trial where patients with localized PCa scheduled to undergo RP are randomized in 1:1:1 ratio to a 2-week regimen of neoadjuvant CKM triplet (rintatolimod + aspirin + IFN-α) vs CKM doublet (rintatolimod + aspirin) vs no CKM. Thirty patients will be enrolled to assess CD8+ T cell density in the RP specimen as the primary endpoint. Pathological and PSA responses, surgical margin positivity, and safety/toxicity of the CKM combinations will be secondary endpoints. Pre- and post-treatment density of various infiltrating T cell subtypes, MDSCs, chemokine and chemokine receptor profiles, immune checkpoint expression, immune-regulatory gene expression signatures, and peripheral blood immune cell landscape will be key exploratory endpoints. The trial is currently open with 11 patients enrolled. Clinical trial ID: NCT03899987 . References: 1) Scolieri MJ, J Urol 2000, 2) Clin Oncol 36, 2018: suppl; abstr 5068, 3) Muthuswamy R, Prostate 2016, 4) Sfanos KS, Prostate 2009, 5) Gupta S, Prostate 2000, 6) NCT01545141, 7) NCT02151448, 8) NCT02432378.