bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multi-institutional evaluation of the clinical outcomes and genomic correlates of African Americans with metastatic castration-sensitive prostate cancer (mCSPC).
Authors: Freeman Meredith MI , Jaeger Ellen , Zhu Jason , Phone Audrey , Nussenzveig Roberto , Caputo Sydney , Ravindranathan Deepak , Layton Jodi Lyn , Nandagopal Lakshminarayanan , Kessel Adam , Desai Arpita , Koshkin Vadim S , Basu Arnab , Bilen Mehmet Asim , Swami Umang , Garcia Jorge A. , Agarwal Neeraj , Burgess Earle F , Sartor A. Oliver , Barata Pedro C. 
Published: March 2021

17 Background: Prostate cancer incidence and mortality is higher in African American (AA) as compared with non-AA men. The outcomes of mCSPC have significantly improved through treatment intensification yet, AA representation in those studies was suboptimal. We aimed to report the clinical, treatment outcomes and genomic data of AA men with mCSPC. Methods: Retrospective analysis of consecutive AA men with mCSPC at six Academic Institutions. The primary objective was to report the baseline characteristics and treatment patterns of mCSPC AA patients. The secondary objectives included the germline and somatic data and the clinical outcomes including PSA response, progression-free survival and subsequent treatments. Results: A total of 71 patients, median age 63 years (range, 41-84) with 58% Gleason 8-10, initial PSA of 69.8 ng/mL (0.02-7650), 59% with de-novo and 55% with high-volume (CHAARTED criteria; 20% visceral) disease, were included in this analysis. Twenty-two patients (31%) were treated with androgen deprivation therapy (ADT; 67% prior to year 2017), while 24%, 45% and 3% received docetaxel (median 6 cycles), abiraterone acetate and enzalutamide, respectively. Two patients received triplet therapy with ADT/docetaxel plus abiraterone or enzalutamide. Undetectable PSA was achieved in 35% after a median of 8.9 months (1.8-22.3). Among patients with mCSPC who received radiation therapy to prostate (n = 8), 89% had low volume disease. At time of cut off, thirty-two patients developed CRPC and the estimated median time to CRPC was 2.9 years (95% CI, 1.6-4.2). Subsequent therapies (n = 29) included abiraterone acetate (41%), enzalutamide (24%), bicalutamide (10%), radium-223 (7%), chemotherapy (7%), sipuleucel-T (3%) and others (7%). Five patients (8%) had pathogenic germline alterations (n = 2 BRCA1; n = 1 HOXB13, PALB2 and PMS2). Additionally, the most common somatic alterations among tested patients (n = 27) included CDK12, SPOP, TMPRSS2-ERG fusion, and TP53, all in 11% frequency. Of note, n = 2 BRCA1 and n = 1 high MSI/TMB. Conclusions: In one of the largest reported cohorts to our knowledge, mCSPC AA presented with a high number of de-novo and high-volume disease and might harbor a different germline and somatic genomic profile. The outcomes were comparable to contemporary phase III trials with treatment intensification, yet 31% were treated with ADT. Despite the known limitations associated with retrospective analysis, these data support prior observations where AA might have better initial PSA responses to ADT-based strategies compared with Caucasians, requiring further validation.
Association of reductions in PSA screening across states with increased metastatic prostate cancer in the United States.
Authors: Sharma Vidit , Venkataramana Abhishek , Comulada W. Scott , Litwin Mark S. , Saigal Christopher 
Published: March 2021

228 Background: While PSA screening was found to reduce prostate cancer metastasis and mortality in a large European randomized trial, PSA screening has also resulted in over-treatment of prostate cancer with significant quality-of-life implications. As a result, the US Preventive Services Task Force (USPSTF) did not recommend PSA screening in 2008 and 2012. It is unknown if reductions in PSA screening were responsible for increased metastatic prostate cancer in the United States. We test this hypothesis by associating longitudinal variations across individual states in PSA screening with their incidence of metastatic prostate cancer at diagnosis from 2002 to 2016. Methods: Age-adjusted incidences of metastatic prostate cancer at diagnosis per 100,000 men were obtained from the North American Association of Central Cancer Registries in 2002 – 2016 for each state. Survey-weighted PSA screening estimates for each state were extracted from the Behavioral Risk Factor Surveillance System, which collects this information for men at least 40 years of age every 2 years from 2002 onward. PSA screening and metastasis data were collated as a multi-panel time series and then analyzed using a random-effects linear regression model with random effects at the state level. Results: There was significant variation between states in the percent of men age >40 years who reported ever receiving PSA screening (range 40.1% to 70.3%) and in the age-adjusted incidence of metastatic prostate cancer at diagnosis (range 3.3 to 14.3 per 100,000). From 2008 to 2016, the mean percentage of men screened decreased (61.8% to 50.5%) whereas the mean incidence of metastatic prostate cancer at diagnosis increased (6.4 to 9.0 per 100,000; Bonferroni adjusted p < 0.001 for both). A random-effects linear regression model demonstrated that longitudinal reductions across states in PSA screening were associated with increased metastatic prostate cancer (regression coefficient per 100,000 men: 14.9, 95% CI 12.3 – 17.5, p < 0.001). This indicated that states with larger declines in PSA screening had larger increases in the incidence of metastatic prostate cancer at diagnosis. Variation in PSA screening explained 27% of the longitudinal variation in metastatic prostate cancer within states. Conclusions: In the context of randomized trial data demonstrating a metastasis reduction with PSA screening, our study strengthens the epidemiologic evidence that reductions in PSA screening may explain some of the recent increase in metastatic prostate cancer at diagnosis in the United States. The trend of rising metastatic disease at diagnosis is a worrisome consequence that needs attention. Thus, we support shared-decision making policies, such as the 2018 USPSTF update, that may optimize PSA screening utilization to reduce the incidence of metastatic prostate cancer in the United States.
Concordance of BRCA1, BRCA2 (BRCA), and ATM mutations identified in matched tumor tissue and circulating tumor DNA (ctDNA) in men with metastatic castration-resistant prostate cancer (mCRPC) screened in the PROfound study.
Authors: Chi Kim N. , Barnicle Alan , Sibilla Caroline , Lai Zhongwu , Corcoran Claire , Williams J. Andrew , Barrett J Carl , Adelman Carrie A. , Qiu Ping , Easter Ashley , Dearden Simon , Harrington Elizabeth 
Published: March 2021

26 Background: Not all mCRPC patients have available or sufficient tissue for multigene molecular testing. In the Phase 3 PROfound study, olaparib significantly improved radiographic progression-free survival compared with physician’s choice of abiraterone or enzalutamide in men with homologous recombination repair (HRR)-gene-mutated mCRPC (de Bono et al. N Engl J Med 2020). Overall, 31% of patients’ tissue samples failed molecular screening during the study, showing the need for additional testing methods to detect patients with HRR-gene-mutated cancers. We evaluated the utility of plasma-derived ctDNA to identify deleterious BRCA and ATM mutations in screened patients from PROfound. Methods: Tumour samples were prospectively tested at Foundation Medicine, Inc (FMI) using an investigational next-generation sequencing test (based on FoundationOne CDx) to inform trial eligibility. Matched ctDNA samples were sequenced at FMI with the FoundationOne Liquid CDx assay. Tissue samples were clinically heterogeneous regarding location and timing of collection; plasma samples were collected as part of screening in PROfound. Results: 81% (503/619) of ctDNA samples tested yielded a result, of which 491 had a tumour result. BRCA and ATM status in tissue compared with ctDNA reported 81% (95% CI 75–87%) positive percentage agreement (PPA) and 92% (95% CI 89–95%) negative percentage agreement (NPA), with tissue as reference (Table). Further concordance and discordance measures will be presented. Conclusions: High concordance between tumour tissue and ctDNA supports the development of ctDNA testing as a minimally invasive method to identify patients with HRR-gene-mutated mCRPC and guide treatment decisions, particularly for those with insufficient tissue for genomic analyses. Clinical trial information: NCT02987543. [Table: see text]
Outcomes of first-line (1L) immuno-oncology (IO) combination therapies in metastatic renal cell carcinoma (mRCC): Results from the International mRCC Database Consortium (IMDC).
Authors: Gan Chun Loo , Dudani Shaan , Wells J Connor , Schmidt Andrew Lachlan , Bakouny Ziad , Szabados Bernadett , Parnis Francis , Wong Shirley , Lee Jae-Lyun , de Velasco Guillermo , Pal Sumanta K. , Davis Ian D. , Kanesvaran Ravindran , Wood Lori , Kollmannsberger Christian K. , McKay Rana R. , Beuselinck Benoit , Donskov Frede , Choueiri Toni K. , Heng Daniel Yick Chin 
Published: March 2021

276 Background: Ipilimumab and nivolumab (IPI-NIVO) and IO/vascular endothelial growth factor (VEGF) inhibitor combinations (IOVE) are now standard of care 1L treatment options for mRCC. However, there is limited head-to-head comparative evidence between these strategies. Methods: Using the IMDC dataset, patients treated with a 1L IOVE combination (pembrolizumab axitinib, avelumab axitinib and nivolumab cabozantinib) were compared with those treated with IPI-NIVO. The outcomes of interest were overall response rate (ORR), treatment duration (TD), time to next treatment (TTNT), and overall survival (OS). A preplanned subgroup analysis of the IMDC intermediate/poor risk population was conducted. Hazard ratios were adjusted for IMDC risk factors. Results: 723 patients were included for analysis (N=571 for IPI-NIVO and N=152 for IOVE). The median age was 60 in both groups. The proportion of patients with IMDC favorable, intermediate and poor risk disease in IPI-NIVO vs. IOVE groups were 9% vs. 33%, 58% vs. 53%, 33% vs. 14%, respectively. In the intermediate/poor risk groups (Table), ORR and median TD were lower and shorter in IPI-NIVO vs IOVE while no difference in median TTNT and OS was detected. The HR for death adjusting for IMDC criteria for IPI-NIVO vs. IOVE was 0.92 (95% CI 0.61-1.40, p=0.71). IMDC risk groups and the presence or absence of sarcomatoid histology, brain, liver or bone metastases were not associated with differences in OS between these treatments (all p>0.2). Patients that had dose delays or steroid use (defined as >40mg of prednisone equivalent/day) for immune related adverse events (irAEs) were associated with longer median TTNT (21.6 vs. 9.5 mons, p=0.02) and OS (NR vs. 44.4 mons, p=0.01) despite similar treatment durations (7.6 vs. 8.9 mons, p=0.77) compared to those without dose delays or steroid use. Conclusions: We were unable to detect any differences in OS between IPI-NIVO and IOVE regimens in the IMDC intermediate/poor risk groups and amongst various subgroups. Patients who experienced irAEs requiring dose delay or steroids had longer overall survival. [Table: see text]
Treatment sequence after first-line nivolumab plus ipilimumab or sunitinib monotherapy in patients with metastatic renal cell carcinoma (mRCC) using real-world data.
Authors: Geynisman Daniel M. , Faccone Jillian , Zhang Ying , Ejzykowicz Flavia , Stwalley Brian , Hamilton Melissa , Le Trong Kim , Huo Stephen 
Published: March 2021

288 Background: The introduction of second-line (2L) nivolumab (NIVO) in 2015 (CheckMate 025) and first-line (1L) NIVO plus ipilimumab (NIVO+IPI) in 2018 (CheckMate 214) revolutionized the management of mRCC in the US. This study sought to leverage real-world (RW) data by applying CheckMate 214 inclusion criteria to develop a RW comparator for the trial to assess treatment patterns and sequences in RW patients (pts) with mRCC after receiving 1L NIVO+IPI or sunitinib (SUN). Methods: This retrospective study identified pts with clear cell mRCC from the Flatiron Health EHR-derived de-identified database who received 1L NIVO+IPI or SUN monotherapy on or after December 2015. Pts must have met the strict selection criteria from CheckMate 214 for this analysis. Evaluation of 1L, 2L, and third-line (3L) therapies was stratified by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk (favorable [FAV] and intermediate/poor [I/P]). Results: Of 401 mRCC pts included in the study, 197 (49.1%) received NIVO+IPI and 204 (50.9%) received SUN as 1L therapy (Table). The median follow-up time was 10.1 months in NIVO+IPI pts and 20.2 months in SUN pts ( P < 0.0001). Among 66 (33.5%) NIVO+IPI pts who received 2L line therapy, the 2 most common therapies were cabozantinib (CABO; 50.0%), and pazopanib (PAZO; 12.1%). Among 119 (58.3%) SUN pts who received 2L therapy, the most common therapies were NIVO (48.7%), and PAZO (8.4%). The 2 most common 3L therapies were axitinib (AXI; 18.2%) or everolimus plus lenvatinib (EVE+LEN; 18.2%) for NIVO+IPI pts, and CABO (26.7%) or NIVO (15.0%) for SUN pts. The treatment sequence is similar between patients with FAV and I/P risk. Conclusions: In the RW setting, the treatment sequences after NIVO+IPI and SUN were largely similar across the IMDC risk groups. CABO was the most common therapy in 2L after NIVO+IPI in RW pts, and NIVO was the most common 2L therapy after SUN monotherapy, which was consistent with the sequence in the trial. [Table: see text]
Efficacy and safety of avelumab plus axitinib (A + Ax) versus sunitinib (S) in elderly patients with advanced renal cell carcinoma (aRCC): Extended follow-up results from JAVELIN Renal 101.
Authors: Tomita Yoshihiko , Motzer Robert J. , Choueiri Toni K. , Rini Brian I. , Miyake Hideaki , Uemura Hirotsugu , Albiges Laurence , Fujii Yosuke , Umeyama Yoshiko , Wang Jing , Mariani Mariangela , Schmidinger Manuela 
Published: March 2021

301 Background: In the phase III JAVELIN Renal 101 trial (NCT02684006), A + Ax demonstrated significantly longer progression-free survival (PFS) and a higher objective response rate (ORR) vs S in patients with previously untreated aRCC. The role of immune checkpoint + VEGFR inhibition in elderly patients remains unclear. Here we report the efficacy of A + Ax vs S by age group from the second interim analysis (IA) of overall survival (OS) and the safety of A + Ax by age group from the first IA. Methods: Patients were randomized 1:1 to receive A 10 mg/kg intravenously every 2 wk + Ax 5 mg orally twice daily or S 50 mg orally once daily for 4 wk (6-wk cycle). PFS and ORR per independent central review (RECIST 1.1), OS, and safety by age group (<65, ≥65 to <75, and ≥75 y) were assessed. Results: A total of 271/138/33 and 275/128/41 patients in each age group (<65, ≥65 to <75, and ≥75 y, respectively) were randomized to the A + Ax or S arm, respectively. The proportion of IMDC risk groups was generally well balanced between the A + Ax and S arm in each age group, although in the ≥75 y age group, the frequency of patients with intermediate risk was slightly higher in the A + Ax arm, and that of patients with favorable risk was slightly higher in the S arm. The percentages of patients with favorable/intermediate/poor risk in each age group were 19%/61%/19%, 28%/58%/13%, and 12%/76%/12% in the A + Ax arm vs 20%/63%/16%, 23%/60%/16%, and 24%/61%/15% in the S arm. At data cut-off (Jan 2019) for the second IA, median follow-up for OS and PFS was 19.3 vs 19.2 mo and 16.8 vs 15.2 mo for the A + Ax vs S arm, respectively. The table shows OS, PFS, and ORR by age group. In the A + Ax arm, the most common treatment-emergent adverse events (AEs) were diarrhea (62%/68%/42%), hypertension (49%/49%/55%), palmar-plantar erythrodysesthesia syndrome (37%/31%/15%), fatigue (37%/53%/30%), and nausea (34%/37%/21%) in each age group. Grade ≥3 treatment-emergent AEs and immune-related AEs were observed in 69%/74%/73% and 39%/40%/24% of patients in each age group, respectively. Conclusions: A + Ax demonstrated favorable efficacy across age groups, including patients aged ≥75 y. OS was still immature; follow-up for the final analysis is ongoing. The safety profile was generally consistent between age groups. Clinical trial information: NCT02684006 . [Table: see text]
Nivolumab + cabozantinib (NIVO+CABO) versus sunitinib (SUN) for advanced renal cell carcinoma (aRCC): Outcomes by sarcomatoid histology and updated trial results with extended follow-up of CheckMate 9ER.
Authors: Motzer Robert J. , Choueiri Toni K. , Powles Thomas , Burotto Mauricio , Bourlon Maria Teresa , Hsieh James J , Maruzzo Marco , Shah Amishi Yogesh , Suarez Cristina , Barrios Carlos H. , Richardet Martin Eduardo , Porta Camillo , Goh Jeffrey C. , Tomita Yoshihiko , Bedke Jens , Zhang Joshua , Simsek Burcin , Scheffold Christian , Gupta Saurabh , Apolo Andrea B. 
Published: March 2021

308 Background: First-line NIVO+CABO met primary and secondary efficacy endpoints by improving progression-free survival (PFS; HR 0.51, P < 0.0001), overall survival (OS; HR 0.60, P = 0.0010), and objective response rate (ORR; 55.7% vs 27.1%; P < 0.0001) vs SUN in patients (pts) with aRCC in CheckMate 9ER (Choueiri et al. ESMO 2020). Efficacy benefits with NIVO+CABO vs SUN were consistent across prespecified subgroups including by IMDC risk group, and regardless of tumor PD-L1 expression (database lock for primary analysis, March 30, 2020). Updated analyses are needed to establish durability of benefit with first-line NIVO+CABO and assess outcomes in aRCC pts with sarcomatoid features (sRCC)—an aggressive histologic subtype associated with poor prognoses. Methods: In this phase III open-label trial, adults with confirmed aRCC (with a clear cell component including those with sRCC) were randomized 1:1 (stratified by IMDC risk score, tumor PD-L1 expression, geographic region) to NIVO 240 mg IV Q2W + CABO 40 mg PO QD vs SUN 50 mg PO (4 weeks of 6-week cycles). The primary endpoint was RECIST v1.1-defined PFS by blinded independent central review (BICR) in all randomized (intent-to-treat [ITT]) pts; secondary endpoints included OS, ORR by BICR, and safety. Pts with and without sRCC were identified by local pathology report, and outcomes in these pts were evaluated via prespecified supportive subset analyses. Results: The presence of sRCC was assessed in ITT pts (N = 651) at enrollment. Overall, 75 (11.5%) pts had sRCC and 557 (85.6%) did not; sRCC status was not reported in 19 pts (2.9%). Overall, 34 vs 41 pts with sRCC were randomized to NIVO+CABO vs SUN, respectively. At a median follow-up of 18.1 months, NIVO+CABO improved PFS, OS, and ORR in sRCC pts vs SUN (Table). Notable PFS, OS, and ORR benefits were observed with NIVO+CABO vs SUN in the subgroup of pts without sRCC. Median PFS was doubled, the risk of death was lower, and ORR was consistently higher with NIVO+CABO vs SUN regardless of sarcomatoid status. Key updated PFS, OS, response, and safety outcomes in the ITT population and in pts with and without sRCC will be reported with additional follow-up based on a September 10, 2020 database lock. Conclusions: NIVO+CABO demonstrated improved efficacy and prolonged survival vs SUN in previously untreated aRCC pts regardless of sarcomatoid status. Updated results with extended follow-up will assess the durability of outcomes in this trial. Clinical trial information: NCT03141177 . [Table: see text]
Patterns of progression in patients treated with nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib (SUN) for first-line treatment of advanced renal cell carcinoma (aRCC) in CheckMate 214.
Authors: Tannir Nizar M. , Motzer Robert J. , Albiges Laurence , Plimack Elizabeth R. , George Saby , Powles Thomas , Donskov Frede , Rini Brian I. , Grünwald Viktor , Hammers Hans J. , Choueiri Toni K. , Gurney Howard , Tykodi Scott S. , Porta Camillo , Burotto Mauricio , Tomita Yoshihiko , Lee Chung-Wei , Tang Chad , McDermott David F. , McKay Rana R. 
Published: March 2021

313 Background: First-line NIVO+IPI demonstrates superior survival and response benefits in intent-to-treat (ITT) patients (pts) with aRCC after long-term follow-up in the phase 3 CheckMate 214 trial. Data are scarce on tumor relapse and patterns of disease progression with immuno-oncology agents in this setting. This exploratory analysis of CheckMate 214 characterizes patterns of progression with NIVO+IPI vs SUN with 4 years minimum follow-up. Methods: Pts with clear cell aRCC were randomized to NIVO+IPI Q3W×4 followed by NIVO monotherapy Q2W, or SUN QD×4 weeks (6-week cycle). Patterns of progression were characterized in ITT pts and analyzed post hoc using descriptive statistics. Progression patterns were defined by ≥ 20% target lesion growth (T), unequivocal progression of nontarget lesions (NT), and new lesion(s) (NL). Response and progression were assessed per independent radiology review committee via RECIST v1.1. Results: Radiographic progression (RP) was documented in 299/550 (54.4%) ITT pts with NIVO+IPI vs 289/546 (52.9%) with SUN. Among ITT pts with a confirmed response (objective response = 215/550 [39.1%, NIVO+IPI] vs 177/546 [32.4%, SUN]), 71/215 (33.0%) vs 84/177 (47.5%) pts experienced post-response RP with NIVO+IPI vs SUN; 8/59 (13.6%) vs 3/14 (21.4%) progressed after complete response, and 63/156 (40.4%) vs 81/163 (49.7%) progressed after partial response, respectively. The pattern of RP differed between arms (Table). With NIVO+IPI, 106/299 (35.5%) RPs resulted from NL only vs 74/289 (25.6%) with SUN, and this differential was more pronounced in pts with an initial confirmed response (36/71 [50.7%] vs 23/84 [27.4%]). Most NL-only RPs in initial responders occurred in a single organ (34/36 [94.4%] for NIVO+IPI; 20/23 [87.0%] for SUN) with the most common being lymph nodes (11/34 [32.4%]), brain (8/34 [23.5%]), and lung (5/34 [14.7%]) with NIVO+IPI, and lymph nodes (7/20 [35.0%]), brain (4/20 [20.0%]) and adrenal gland (3/20 [15.0%]) with SUN. Additional progression details, baseline characteristics, and key efficacy outcomes in progressors will be reported. Conclusions: Differential patterns of tumor relapse and disease progression were observed after long-term follow up of patients treated with NIVO+IPI vs SUN in CheckMate 214. NL-only progression occurred more often with NIVO+IPI vs SUN, in particular in the subset of pts who progressed post-response. These patterns may have therapeutic implications. Clinical trial information: NCT02231749 . [Table: see text]