bluuebunny/crossref_metadata_2025 huggingface dataset:
Bunocephalus hertzi, a new banjo catfish from the upper Rio Paraná basin, Brazil (Siluriformes: Aspredinidae), with the redescription of Bunocephalus larai Ihering, 1930
Authors: ESGUÍCERO ANDRÉ L. H. , CASTRO RICARDO M. C. , PEREIRA THIAGO N. A.
Published: February 2020

Bunocephalus hertzi, new species, is described from two tributaries of the upper Rio Paraná basin. Because the type series of B. larai (the only other species of Bunocephalus in the basin) is lost, a redescription of B. larai is also provided herein. Bunocephalus larai and B. hertzi can be distinguished from all its congeners, except B. minerim, by the absence of an epiphyseal bar (vs. present). From B. minerim, both species can be distinguished by the presence of 10 principal caudal-fin rays (vs. 9). Bunocephalus hertzi can be differentiated from B. larai by the longer coracoid process size (11.9–16.2% vs. 6.7–9.8% SL), shorter maxillary barbel (just reaching the pectoral fin origin; 54.6–67.4% vs. 73.7–84.6% HL) and skull ornamentation represented by five bony protuberances between the posterior end of the occipital and the origin of the dorsal fin (vs. four bony protuberances).
The association between serum adipocyte fatty acid–binding protein and 3-month disability outcome after aneurysmal subarachnoid hemorrhage
Authors: Luo Yong-Gang , Han Bing , Sun Tong-Wen , Liu Xianzhi , Liu Jun , Zhang Jun
Published: February 2020

Background

Adipocyte fatty acid–binding protein (FABP4) is an adipokine that plays an important role in development of cardiovascular and metabolic diseases. The aim of this study was to assess the 3-month prognostic value of serum levels of FABP4 in Chinese patients with aneurysmal subarachnoid hemorrhage (aSAH) on hospital admission.

Methods

This was a prospective observational study from a stroke treatment center in Zhengzhou, China. From October 2016 to May 2018, patients with aSAH who were hospitalized within 24 h were included. In addition, 202 age- and gender-matched healthy volunteers were assigned to the healthy control group. At admission, serum levels of FABP4 were measured, and patients’ characteristics, Hunt–Hess grade, and modified Fisher grade evaluated. At 3-month follow-up, functional outcome (Glasgow Outcome Scale score; dichotomized as poor [score 1–3] or good [score 4–5]) and all-cause mortality were recorded. Univariate and multivariate logistic regression models were used to investigate the association of FABP4 with the two endpoints.

Results

A total of 418 patients with aSAH were included in this study. The median age was 58 years (interquartile range, 49–66 years), and 57.9% were women. FABP4 serum levels were related to Hunt–Hess score (r[Spearman] = 0.381;P < 0.001). Patients with a poor outcome and non-survivors had significantly increased serum FABP4 levels on admission (P < 0.001 for all). In multivariate logistic regression analysis, FABP4 was an independent predictor of poor outcome and mortality, with increased risks of 7% (odds ratios 1.07, 95% confidence interval [CI] 1.02–1.13;P = 0.001) and 5% (odds ratio 1.05, 95% CI, 1.01–1.12;P = 0.003), respectively. Receiver operating characteristics to predict functional outcome and mortality were significantly different between conventional risk factors (difference area under the curve 0.024, 95% CI 0.018–0.032) and FABP4 plus conventional risk factors (area under the curve 0.015, 95%CI 0.011–0.020). After FABP4 was added to the existing risk factors, mortality was better reclassified and was associated with the net reclassification improvement statistic (P = 0.009), while poor outcome was better reclassified and associated with both the integrated discrimination improvement and net reclassification improvement statistics (P < 0.05 for all).

Conclusions

Elevated serum FABP4 levels were related to poor outcome and mortality in a cohort of patients with aSAH.
Niraparib in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and biallelic DNA-repair gene defects (DRD): Correlative measures of tumor response in phase II GALAHAD study.
Authors: Smith Matthew Raymond , Fizazi Karim , Sandhu Shahneen Kaur , Kelly William Kevin , Efstathiou Eleni , Lara Primo , Yu Evan Y. , George Daniel J. , Chi Kim N. , Saad Fred , Summa Jason , Freedman Jamie M. , Mason Gary , Espina Byron M. , Zhu Eugene , Ricci Deborah S. , Snyder Linda A. , Simon Jason S. , Cheng Shinta , Scher Howard I.
Published: February 2020

118

Background: Niraparib, a highly potent and selective poly (ADP-ribose) polymerase inhibitor (PARPi) received breakthrough designation by US FDA for treatment of pts with BRCA1,2 mutant mCRPC who progressed on taxane and androgen receptor-targeted therapy. Circulating tumor cells (CTC) detection associates with poor outcomes, with declining counts consistent with improved survival [1,2]. Methods: GALAHAD study assessed niraparib (300 mg daily) in pts with mCRPC+DRD (NCT02854436). Patients with non-measurable soft tissue disease by RECIST 1.1 were required to have a baseline CTC count ≥1 cell/7.5 mL blood. CTC response was defined as CTC conversion to <5 for pts with baseline CTC≥5 and CTC drop to 0 post-baseline for pts with ≥1 baseline CTC. Alkaline phosphatase (ALP) was collected at each monthly cycle. Results: For primary efficacy population of pts with BRCA1/2 mutations, the objective response rate (ORR) by RECIST 1.1 criteria was 41.4%. CTC response rates for this population were as high as ORR regardless of measurability (Table). Time to CTC response for each CTC responder will be shown. Radiographic progression-free survival (rPFS) durations were similar for patients with a measurable disease response and patients with CTC conversion. Median duration of treatment for responders of any type was 6.7mo (range: 2–27). DRD status, both BRCA and non- BRCA, for each responder will also be discussed. Trends in disease burden and markers of bone metabolism will also be quantitatively explored including 24% pts who were on treatment for at least one cycle who had ≥25% decreased unfractionated ALP from baseline. Conclusions: Niraparib showed clinical activity with CTC response and decline in ALP levels in mCRPC pts having biallelic BRCA mutations, which further supports its recent breakthrough designation. Clinical trial information: NCT02854436. [Table: see text]
Adenosine receptor blockade with ciforadenant +/- atezolizumab in advanced metastatic castration-resistant prostate cancer (mCRPC).
Authors: Harshman Lauren Christine , Chu Michael , George Saby , Hughes Brett Gordon Maxwell , Carthon Bradley Curtis , Fong Lawrence , Merchan Jaime R. , Kwei Long , Hotson Andrew N. , Mobasher Mehrdad , Miller Richard A.
Published: February 2020

129

Background: Adenosine, generated by the ectonucleotidase CD73, mediates immunosuppression within the tumor microenvironment by triggering adenosine 2A receptors (A2AR) on immune cells. Tumor CD73 expression may be prognostic in prostate cancer. We evaluated the clinical activity of adenosine blockade using A2AR antagonist, ciforadenant, with or without the anti-PDL-1 antibody, atezolizumab (atezo), in advanced mCRPC patients (pts) in an ongoing phase 1 trial. Methods: Eligibility required measurable disease and up to 5 prior systemic therapies. Prior anti- PD-(L)1 was allowed. Ciforadenant was administered orally BID as monotherapy at 50-200mg or 100mg in combination with atezo 840mg IV Q 2 weeks (wks). Safety and efficacy were evaluated by CTCAE4, RECIST1.1 and PCWG2. Serum was obtained for measurement of cytokines. Results: Of 33 enrolled pts, 10 received ciforadenant monotherapy and 23 in combination with atezo. As of 10/21/19, 14 pts are evaluable for response and described further. Median prior therapies is 3 (range 2-6) with median follow-up 10.8 (4-33) wks. Metastatic burden included 4 node only, 2 bone plus node, and 8 visceral metastases. Five pts experienced tumor regression: 2 ciforadenant monotherapy (tumor reductions 12%, 17%); and 3 combination (tumor reductions 4%, 27%, 42%). The pt with a partial response had PSA decline from 98 ng/mL to <1. Eight pts had stable disease (SD) for a clinical benefit rate (SD + PR) of 8/14 (57%). Median duration of disease control was 24 wks. Study treatment was well tolerated with two Gr3/4 adverse events (AEs) of fatigue (1) and anorexia (1). The most common Gr1/2 AEs were fatigue and nausea. Serum TNFα levels increased by 4-8 wks on therapy in 12/13 pts. Baseline levels of soluble VCAM-1, which has been implicated in metastatic spread/more aggressive disease, were higher in pts with tumor regression (771 ± 109 ng/mL, n=4) than pts with tumor growth (544 ± 62 ng/mL, n=5, p<0.05). Conclusions: Results from this phase 1 study show mCRPC can be sensitive to A2AR blockade with ciforadenant. Cytokine changes provide evidence of treatment-induced inflammatory response, which may predict efficacy. Data on all 33 enrolled pts will be presented. Clinical trial information: NCT02655822.
Feasibility and oncologic outcome of salvage surgery in isolated seminal vesical remnants after radical prostatectomy.
Authors: Pfister David , Haidl Friederike , Nestler Tim , Paffenholz Pia , Heidenreich Axel
Published: February 2020

137

Background: Improved imaging modalities identify metastatic prostate cancer earlier. Atypical and oligometastatic disease is identified more often. Thus a more individual treatment approach in oligometastatic prostate cancer is getting more popular. We demonstrate our results in recurrent disease in seminal vesical remnants after radical prostatectomy and radiotherapy. Methods: A total of 33 patients underwent open resection of locoregional recurrence in seminal vesicals. In case of suspicious 68Ga-PSMA-PET findings in the small pelvis an additional ipsilateral lymph node dissection was performed in 10 patients. 11 patients already received hormone treatment fulfilling the definition of castration resistant prostate cancer. Age, PSA-DT, PSA, time to recurrence after primary treatment resection status were used in a uni and multivariate-cox regression analysis for biochemical relapse after surgery. Results: Median patient age at time of salvage surgery was 70(57-77) years. Median PSA and PSA-DT was 2.79(0.4-61.54)ng/ml and 5.4(1.6-20.1)months respectively. Median surgical time and hospital stay was 132 (75-313)min and 5.5(4-13)days. Median progression-free survival was 29 (8-47) months. After a mean follow-up of 22 months (3-68) months three patients died 8, 14, and 40 months after salvage surgery. In a univariable cox-regression analyses age at time of surgery, preoperative PSA and the time from primary treatment to salvage surgery have been identified as significant parameters for biochemichal relapse. Only the interval from primary to salvage surgery was significant with a Hazard ratio of 1.008 (95%-CI 1.001-1.015, p=0,018) in multivariate analysis. 4 adjunctive surgeries (Ureterovericoneostomy n=3 and one nephrectomy) were needed due to local progressive disease. Conclusions: Seminal vesicle resection is feasible with no significant intra and postoperative complications even in CRPC. Although there is a good median progression-free survival after 5 years almost all patients had biochemical or systemic relapse. Salvage surgery must be seen as prevention for local symptoms, to our experience most often postrenal ipsilateral obstruction.
Intermediate atypical carcinoma (IAC): A discrete subtype of metastatic castration-resistant prostate cancer (mCRPC) suggesting that treatment-associated small cell/neuroendocrine prostate cancer (t-SCNC) may evolve from mCRPC adenocarcinoma (adeno)—Results from the SU2C/PCF/AACR West Coast Prostate Cancer Dream Team (WCDT).
Authors: Small Eric Jay , Aggarwal Rahul Raj , Friedl Verena , Weinstein Alana , Thomas George V. , True Lawrence D. , Foye Adam , Beer Tomasz M. , Rettig Matthew , Gleave Martin , Evans Christopher P. , Alumkal Joshi J. , Reiter Robert Evan , Lara Primo , Chi Kim N. , Feng Felix Y , Bailey Adina , Stuart Josh , Huang Jiaoti
Published: February 2020

158

Background: A subset of mCRPC patients (pts) that develop resistance to next-gen androgen signaling inhibitors are subsequently found to harbor t-SCNC. We have undertaken a longitudinal prospective biopsy (bx) study to clinically and molecularly characterize these pts. Methods: Eligible pts underwent an image-guided mCRPC bx at one of 5 WCDT centers. Tissue was both frozen and formalin fixed/paraffin embedded (FFPE). FFPE tissue was used for targeted next generation sequencing (NGS) and independent pathologic review by 3 pathologists. Frozen specimens underwent laser capture micro-dissection prior to RNA sequencing (seq). Machine learning was used to derive histology-specific expression signatures. Linear Discriminant Analysis (LDA) was applied to the RNA seq data from the first 131 bx using 3 observed histologic subtypes as labels to test for an intermediate subtype. Results: Of 391 mCRPC metastasis (53% bone, 26% node, 12% liver, 9% other soft tissue), 295(75%) yielded cancer. Overall, 89% of the bx contained a single histologic subtype: pure adeno in 156(53%); pure t-SCNC in 35(12%). A novel morphologically distinct subtype, IAC, with features of both tSCNC and adeno was seen in 72(24%). Samples comprised of two subtypes made up 32(11%) of all bx. Overall, 50(17%) of bx had a t-SCNC component. TP53 and/or RB1 loss of function variants were significantly more frequent in t-SCNC. NGS revealed no difference between adeno and IAC. LDA classified IAC as intermediate between adeno and t-SCNC 93% of the time, across 100 bootstrap replicates, significantly better than the 33% expected by chance (p <10−17). Conclusions: Nearly half of mCRPC bx exhibit non-adeno features with t-SCNC found in 17%. IAC is a reproducible mCRPC histologic subtype found in 24% of bx, with a gene expression signature that is intermediate to adeno and t-SCNC, and targeted NGS results similar to adeno. Understanding the role of IAC in disease evolution and resistance is critical for improving outcomes in mCRPC. Clinical trial information: NCT02432001.
Radiotherapy (RT) guided by ultra‐small superparamagnetic iron oxide (USPIO)-contrast MRI staging for patients with advanced or recurrent prostate cancer.
Authors: Li Yun Rose , Dattoli Michael J. , Barentsz Jelle , Roach Mack
Published: February 2020

218

Background: Aggressive treatment of oligometastatic PC may prolong survival in selected patients. USPIO-contrast MRI is potentially more sensitive in detecting early lymph node (LN) metastases than PET. Methods: This retrospective study explores the safety and utility of USPIO-guided RT in 69 patients with advanced/recurrent PC treated at 2 US institutions. All USPIO-MRIs were completed at RadboudUMC and interpreted by expert radiologists. Age, Stage, Gleason score, PSA, prior therapy, duration of androgen-deprivation (ADT), cause of death, details of RT, and adverse events (AEs) were collected by chart review. Biochemical recurrence (BCR) was defined as PSA Nadir plus 2.0 (RT) or PSA>0.2 (radical prostatectomy, RP). Patients received external beam radiation (RT) to involved nodal basins (+/-prostate/prostate bed) with either a simultaneous integrated or sequential boost to USPIO(+) nodes. All patients received >6 months of ADT. Overall (OS) and BCR free-survival (BCRFS) were calculated using Cox-PH models in R. Results: Between 2007-18, 69 patients with de novo or recurrent PC were found to have USPIO(+) LNs and received USPIO-guided RT; median age was 62. The majority of patients presented after BCR following RP (N=28), definitive RT (N=27) or RP and post-op RT (N=6). Prior to USPIO-MRI, 20/69 patients had cN1 disease based on abdominal-pelvic CT/MRI, Bone Scan, Prostascint-scan, and F18 Choline, Axumin or PSMA PET/CT. The mean(median)USPIO(+) LNs was 5.2(3) Range=[1-32]. Patients had (+)pelvic (95%), para-aortic (43%), and/or peri-rectal LNs (19%). At median follow up of 29.5(44.6) Range=[5-127] months, OS was 58/69 (84%) and 11/11 patients died of PC. At last follow up, 40 patients remained BCR-free (BCRFS not reached). The median time to BCR (N=29) was 25.9 months after USPIO-guided RT. For patients with follow-up imaging, recurrences were predominantly out-of-field (outside of elective LN fields or in osseous sites). No patients experienced >CTCAE grade 2 AEs. Conclusions: In this cohort of 69 patients with predominantly recurrent PC, USPIO-directed RT was well-tolerated, feasible and resulted in encouraging biochemical control rates.
Impact of 68Ga-PSMA-11 PET on the management of biochemically recurrent prostate cancer in a prospective single-arm clinical trial.
Authors: Fendler Wolfgang , Ferdinandus Justin , Calais Jeremie , Eiber Matthias , Flavell Robert R. , Mishoe Ashley , Feng Felix Y , Nguyen Hao Gia , Reiter Robert Evan , Rettig Matthew , Gartmann Jeannine , Smith Raven , Small Eric Jay , Slavik Roger , Carroll Peter , Herrmann Ken , Czernin Johannes , Hope Thomas ,   The PSMA PET Reader Group
Published: February 2020

292

Background: Prostate-specific membrane antigen ligand positron emission tomography (PSMA PET) induced management changes in up to every second patient in smaller clinical trials. We aim to determine the impact of 68Ga-PSMA-11 PET/CT on management of biochemically recurrent prostate cancer in a large prospective cohort. Methods: We report management changes following PSMA PET, a secondary endpoint of a prospective multicenter trial in men with prostate cancer biochemical recurrence (NCT02940262 and NCT03353740). Pre-PET, Post-PET and Post-Treatment Questionnaires were sent to referring physicians recording working clinical summaries, intended and implemented therapeutic and diagnostic management. Results: Intended management change occurred in 260/382 (68%) patients. Intended change was considered major in 176/382 (46%) patients. Management pathway aligned with PET findings, i.e. change towards local/focal therapy for locoregional disease (54/126 patients, 44%) and towards systemic therapy or combination approaches for metastatic disease (106/153 patients, 69%). Intended management was implemented in 160/206 (78%) patients. Perceived site of disease was unknown in 259/382 (68%) patients before and 111/382 (29%) patients after PSMA PET. A total of 150 intended diagnostic tests, mostly CT (n=43, 29%) and bone Scans/NaF-PET (n=52, 35%), were prevented by PSMA PET. A total of 73 tests, mostly biopsies (n=44, 60%) requested by the study protocol, were triggered. Conclusions: Disease localization by PSMA PET translated into management changes in more than half of patients with biochemical recurrence of prostate cancer. More than twice as many diagnostic tests were prevented than triggered following PET. Clinical trial information: NCT02940262 and NCT03353740.
Efficacy and toxicity according to hormone therapy used in the CHHiP trial.
Authors: Tree Alison , Griffin Clare , Hall Emma , Dearnaley David P. ,   on behalf of the CHHiP Investigators
Published: February 2020

316

Background: CHHiP (CRUK/06/016) is a multicentre randomised controlled trial which investigated the use of moderately hypofractionated radiotherapy (RT) dose schedules for treatment of localised prostate cancer. 97% of participants (pts) had concurrent androgen deprivation therapy (ADT). Luteinising Hormone Releasing Hormone analogues (LHRHa) and bicalutamide 150mg (BIC) daily were permitted. This exploratory analysis investigates whether both ADT regimens show similar efficacy and whether BIC has the propensity to preserve erectile function. Methods: In CHHiP, 2700 pts received LHRH and 403 BIC, median duration 5.6 months. The primary endpoint was biochemical or clinical failure (BCF). ADT groups were compared with Cox regression adjusted forage, NCCN risk group, Gleason score,T-stage and stratified by RT dose. A key secondary endpoint was erectile function assessed by clinicians (LENTSOM subjective erectile function for vaginal penetration score) and pts (single items within UCLA-PCI and EPIC-50 questionnaires) at 2 years. 195/875 (22%) pts were excluded from this toxicity analysis as they had erectile dysfunction pre-ADT (grade (G) 3/4 LENTSOM). A chi square trend test compared ADT regimens. Results: Baseline demographics were similar except BIC pts were significantly younger (median 67 years BIC, 69 years LHRHa). With a median follow-up of 9.2 years, there was no evidence of a difference in BCF with an adjusted hazard ratio 0.95 (95% CI 0.75-1.20), p = 0.657. Eight year BCF rates were 80.7% (95%CI 79.0-82.2) and 80.3% (95%CI 75.8-84.0) for LHRHa and BIC pts respectively. At two years, LENTSOM erectile function was significantly worse (p < 0.0001) for LHRHa pts with 93/585 (16%), 95/585 (16%) and 125/585 (21%) G2, G3 and G4, compared to 3/68 (4%), 5/68 (7%) and 9/68 (13%) in BIC. At 2 years, the ability to have an erection, as reported by pts, was graded poor and very poor in 73/278 (26%) and 57/278 (21%) LHRHa pts and 5/23 (22%) and 4/23 (17%) in BIC pts (p = 0.584). Conclusions: There was no evidence of a difference in efficacy according to ADT received. BIC preserved clinician assessed (LENTSOM) erectile function at 2 years but patient reported outcomes did not show statistically significant differences with type of ADT. Clinical trial information: 97182923.
Prognostic factors in advanced seminoma: An analysis from the IGCCCG Update Consortium.
Authors: Beyer Joerg , Collette Laurence , Daugaard Gedske , De Wit Ronald , Tryakin Alexey , Albany Costantine , Stahl Olof , Fizazi Karim , Gietema Jourik A. , De Giorgi Ugo , Hansen Aaron Richard , Feldman Darren R. , Cafferty Fay , Tandstad Torgrim , Garcia del Muro Xavier , Huddart Robert A. , Sweeney Christopher , Necchi Andrea , Assele Samson , Gillessen Silke ,   for the IGCCCG Update Consortium
Published: February 2020

386

Background: Extrapulmonary visceral metastases were the only adverse prognostic factor among 660 advanced seminomas in the original classification of the International Germ Cell Cancer Collaborative Group (IGCCCG) treated between 1975 and 1990 and published 1997. Outcomes may have improved with current era management and additional prognostic factors may exist. Methods: To update the original IGCCCG classification, an international consortium (30 centers/groups) provided data on 2458 advanced seminoma patients treated with cisplatin- and etoposide-based first-line chemotherapy between 1990 and 2015 in prospective cohorts or clinical trials. Progression-free (PFS) and overall survival (OS) probabilities were calculated. CART analysis was used to identify prognostic factors inside original IGCCCG good risk group to further refine the classification. Among eligible 2302 patients with full data, a training set of 1509 patients (1437 good risk and 72 intermediate risk) was used for model building. An independent set of 793 patients was set aside for validation. Primary endpoints were PFS and OS at 5 years. Results: Compared with the 1997 IGCCCG benchmarks, the 5-year PFS rates increased to 88.7% (87.2 - 89.9%) and 78.4% (69.6 - 84.9%) in good and intermediate IGCCCG patients. The corresponding 5-year OS rates were 95.4% (94.4 - 96.2%) and 87.2% (79.2 - 92.2%). CART analysis identified LDH with a cut-point of 2.5 x ULN as the single most significant prognostic factor in good risk patients with 5-y PFS rates of 92.1% (90.3 - 93.6%) and 79.2% (74.2 - 83.4%) in low and high LDH subgroups. (HR = 2.90, P < .0001). Good risk patients with LDH above 2.5 x ULN (313 of 1411 patients) performed similarly to the intermediate IGCCCG patients; hCG was not independently prognostic. Conclusions: In this modern era series, the original IGCCCG still significantly discriminates between "good” and "intermediate" risk metastatic seminoma, but with significantly improved PFS and OS in both risk groups. LDH at a cut-off point of 2.5 x ULN further refines this classification and identifies men with intermediate risk seminoma in the absence of extrapulmonary visceral metastases. This refinement will be relevant to improve future seminoma care.
Treatment of high-grade non-muscle invasive bladder carcinoma by standard number and dose of BCG instillations versus reduced number and standard dose of BCG instillations: Results of the phase III clinical trial (NIMBUS).
Authors: Grimm Marc-Oliver , van der Heijden Toine , Colombel Marc , Martinez Pineiro Luis , Muilwijk Tim , Babjuk Marek , Turkeri Levent N. , Palou-Redorta Joan , Patel Anup , Bjartell Anders , Caris Christien , Schipper Raymond , Witjes Wim ,   EAU Research Foundation NIMBUS Study Group
Published: February 2020

436

Background: Intravesical instillation of BCG is an accepted strategy to prevent recurrence of non muscle invasive bladder cancer (NMIBC). However, the optimal number of instillations is unknown. NIMBUS assessed whether a reduced number/standard dose BCG instillations is not inferior to standard number and dose BCG in patients with high-grade (HG) NMIBC. The primary endpoint was time to first recurrence. Methods: The aim was to enroll 824 BCG naïve patients with HG Ta-T1 NMIBC +/- CIS. NIMBUS was an international randomized not blinded trial to establish therapeutic equivalence defined as the lower part of the Confidence Interval (CI) (using one-sided 2.5% level of significance) being higher than a HR (hazard experimental/hazard standard) of 0.75 for recurrence. The treatment arms were: Standard: Induction cycle BCG weekly wks 1-6; maintenance cycles at months 3,6,12 (wks 1,2,3) and Reduced: Induction cycle at wks 1,2,6; maintenance cycles at months 3,6,12 (wks 1,3). Safety was evaluated at yearly intervals by the IDMC and in case inferiority was shown, defined as the upper part of the CI (one-sided 2.5% level) lower than a HR of 0.75, an advice to stop the trial would be given. Results: Available data at July 1, 2019 were analyzed for the IDMC meeting. A total of 345 patients were recruited from Germany (149), the Netherlands (109), France (64), Belgium (22) and Spain (1). Prognostic factors at initial resection were Ta/T1: 46/54%; primary/recurrent disease: 92/8%; single/multiple lesions: 57/43% and concomitant CIS/no CIS: 27/73%. The intention to treat analysis showed a clear difference in time to and number of recurrences between treatment arms: 27% in the reduced arm versus 12% in the standard arm. Known prognostic factors were evenly distributed between arms. Additional safety analyses were performed showing a HR of 0.40 [95% CI: 0.24-0.67]. Conclusions: Safety analysis showed that the reduced frequency schedule of BCG was inferior to the standard frequency schedule for time to first recurrence according to the previously defined stop criterion. Recruitment of patients was stopped immediately. Clinical trial information: NTR4011.
The National Radium-223 Dichloride Audit Group: Data from patients in United Kingdom oncology centers with metastatic castration-resistant prostate cancer treated with radium-223 dichloride.
Authors: Randhawa Manreet , Stratton Irene , Jones Robert J. ,   National Radium-223 Audit Group
Published: February 2020

59

Background: Clinicians in 20 UK oncology centres comprise the National Radium-223 Dichloride Audit group which is evaluating treatment patterns and outcomes in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) treated with Radium-223 dichloride (Xofigo). Methods: Pts first treated with Xofigo from September 2017 were included and demographics, treatment, clinical, biochemical and outcome data collected prospectively. Analysis was carried out using frequency tables, univariate and survival analysis. Results: We report the outcomes on the first 100 pts in 4 centres with good quality data. Median values of each characteristic including 25th and 75th percentiles are as follows: Age at diagnosis = 67 years (62-72), weight = 83.5kgs (73.6-92.8), Hb = 139g/L (118 – 136), WCC = 7.3X109/L (5.7 – 8.7), plt count = 252x109/L (208 – 290), ALP = 128U/L (96-263) and PSA = 42.1ug/L (21.5 – 125.7). A majority of pts had an ECOG PS of 0-1. The number of pts having Xofigo as 1st, 2nd, 3rd and 4th line treatment was 15, 64, 20 and 1 respectively. There was a statistically significant decline in median weight, Hb, WCC, plt count and ALP and a rise in PSA between cycle 1 and cycle 6. Thirty eight pts did not complete 6 cycles with 31 of these (82%) discontinuing due to disease progression. The prevalence of adverse events was 5% (20/100). Twenty nine pts had a skeletal event by 12 months. There was no change in the WHO analgesic score, QOL scores or ECOG PS between treatment 1 and 6. Thirty nine pts had subsequent lines of treatment with 31 of these having only 1 line of treatment. Median overall survival was 363 days (95% CI 312-426 days). Conclusions: The ongoing National Radium-223 Dichloride Audit records data from approximately 600 mCRPC pts treated across the UK in routine clinical NHS care. To our knowledge, it is the first prospective analysis of such pts and the largest in assessing treatment patterns, outcomes and quality of life data in addition to standard biochemical and clinical parameters. Further multivariate analysis will be presented and the implications of the licensing change of Xofigo will be illustrated in the final analysis.
A multicenter retrospective study to evaluate real-world clinical outcomes in patients with metastatic renal cell carcinoma (mRCC) and brain metastasis treated with ipilimumab and nivolumab.
Authors: Brown Landon Carter , Desai Kunal , Kao Chester , Kinsey Emily Noelle , Healy Patrick , Kephart Julie , Harrison Michael Roger , Ramalingam Sundhar , Armstrong Andrew J. , George Daniel J. , Martin Allison , Allman Kimberly D. , Wood Laura S. , Wei Wei , Garcia Jorge A. , Gilligan Timothy D. , Gupta Shilpa , Rini Brian I. , Ornstein Moshe Chaim , Zhang Tian
Published: February 2020

637

Background: The combination of ipilimumab & nivolumab (I+N) followed by maintenance nivolumab has improved outcomes in patients (pts) with mRCC. Little is known about the outcomes in mRCC pts with brain metastasis. In this multicenter retrospective analysis, we present a real-world experience in pts with brain metastasis treated with I+N. Methods: Pts with mRCC and brain metastases treated with I+N at the Duke Cancer Institute and Cleveland Clinic were identified. Pt characteristics were summarized with descriptive statistics. Fisher’s exact test was used to determine predictors of response (alpha 0.05). Results: From 10/2017 to 2/2019, 17 pts received I+N for mRCC with brain metastases. Median age was 60; 29% were female. IMDC risk was 18%/59%/24% favorable/intermediate/poor, and 77% were clear cell histology. Pts received I+N as either first-line (65%) or ≥ second-line (35%) therapy. Of the pts evaluable for response: objective response rate (ORR) was 42% [0% CR]; with 29% achieving stable disease and 18% progressive disease as their best response. Median duration on therapy was 13 weeks. 59% of pts developed an immune-related adverse event (AE). The most common reason for treatment discontinuation was disease progression (47%) followed by AEs (18%). There were no significant predictors of any radiographic response category (PR, SD, or PD) among variables assessed (gender, IMDC risk, histology, presence of bone metastasis, line of therapy, or presence of irAE). Of note, 50% (3/6) patients treated in the second-line or greater setting experienced a PR. Conclusions: In our real-world cohort of mRCC patients with brain metastasis, I+N is clinically effective. Further investigation is warranted in this population given exclusion from prior clinical trials.
Depth of response (DepOR) analysis and correlation with clinical outcomes from JAVELIN Renal 101.
Authors: Voss Martin H , Motzer Robert J. , Albiges Laurence , Rini Brian I. , Schmidinger Manuela , Larkin James M. G. , Haanen John B. A. G. , Kollmannsberger Christian K. , Campbell Matthew T. , Grimm Marc-Oliver , Pal Sumanta K. , Gravis Gwenaelle , Atkins Michael B. , Huang Bo , Chudnovsky Aleksander , di Pietro Alessandra , Thomaidou Despina , Choueiri Toni K.
Published: February 2020

690

Background: In the phase 3 JAVELIN Renal 101 trial (NCT02684006), avelumab + axitinib (A+Ax) significantly improved progression-free survival (PFS) in patients (pts) with advanced renal cell carcinoma (aRCC) compared with sunitinib (S); median PFS (mPFS) in the A+Ax arm was 13.8 mo (95% CI, 11.1 mo, not estimable [NE]) vs 8.4 mo (95% CI, 6.9, 11.1) in the S arm (HR, 0.69; 95% CI, 0.56, 0.84; P < 0.001) (Motzer NEJM 2019). Here, we report on the correlation of PFS with DepOR at early imaging timepoints. Methods: Data from pts in both arms were analyzed based on blinded independent central review (BICR) per RECIST 1.1. Tumor shrinkage or growth was categorized by best percent change in target lesions on imaging obtained up to 13 wk: shrinkage ≥0% to < 30%, ≥30% to < 60%, and ≥60% and growth > 0% to < 20%. Pts without progressive disease and who had not died at or prior to 13 wk after randomization were included in the landmark analysis. PFS data were analyzed for each category. A Cox multivariate landmark analysis was conducted for PFS for pts in the A+Ax arm, with DepOR as a continuous variable. Results: Results are reported on the basis of the first interim analysis, with a minimum follow-up of 6.0 mo in all pts. The table shows the proportion of pts in each shrinkage category and PFS outcomes according to best percent change in target lesions at the 13-wk landmark. After adjusting for prognostic covariates, Cox multivariate analyses showed a meaningful association between DepOR and PFS for pts in the A+Ax arm, consistent with the results observed in each shrinkage category. Conclusions: Greater tumor shrinkage at early imaging timepoints was associated with longer PFS in JAVELIN Renal 101. Clinical trial information: NCT02684006 .[Table: see text]
Phase I/II trial of enzalutamide (Enz) plus mifepristone (Mif) for metastatic castration-resistant prostate cancer (mCRPC).
Authors: Serritella Anthony , Shevrin Daniel H. , Heath Elisabeth I. , Wade James Lloyd , Martinez Elia , Karrison Theodore , Stadler Walter Michael , Szmulewitz Russell Zelig
Published: February 2020

91

Background: Resistance to androgen receptor (AR) targeted therapies is common in mCRPC. Glucocorticoid receptor (GR) expression increases with AR inhibition in patients (pts) and blockade of GR signaling inhibits CRPC growth in preclinical models when combined with AR blockade. We thus conducted a phase I/II open label trial of Enz combined with Mif, a GR, AR, and progesterone receptor antagonist for pts with mCRPC to assess the feasibility and impact on disease progression with dual AR/GR antagonism. Methods: The phase I dose escalation portion assessed the safety of the two-drug combination and a recommended phase II dose (R2PD) was determined based on safety, pharmacokinetic and endocrine assessments. In the phase II portion, patients (pts) received 12 weeks of Enz (160mg/day) followed by randomization to Enz alone or Enz plus Mif with PSA-progression free survival (PFS) as the primary endpoint. 42 pts were to randomize to each arm to provide 80% power to detect a hazard ratio of 0.6, with a one-sided alpha of 0.1; there was a planned interim futility analysis after 50% of progression events. Results: 106 pts (18 phase I/88 phase II) were enrolled. Pts had a median age of 70 (range 53-89) and baseline PSA of 12.8 (range 0.1-755). 34% of pts received prior docetaxel. The RP2D was 120mg/day Enz and 300mg/day Mif. In phase II, 33 patients were randomized to each arm, with well-balanced baseline demographics. 22 pts were not randomized (15 due to disease progression, 2 due to toxicity, and 5 due to the interim study analysis). The interim analysis showed no difference between arms in PSA-PFS (hazard ratio = 1.34, p=0.395), 12-month PSA-PFS of 31% in both arms, and per-protocol, the trial was stopped. Toxicities were similar in the arms, e.g. fatigue (12% vs. 14%), hot flashes (6% vs. 5%), and pain (4% vs. 4%). Conclusions: The addition of Mif to Enz following a 12-week Enz lead-in did not delay time to PSA progression. Further analyses of secondary endpoints, including translational biomarkers such as hormone levels, GR/AR-v7 expression in circulating tumor cells and cell free DNA analyses are ongoing. Clinical trial information: NCT02012296.
Phase III study of pembrolizumab (pembro) plus docetaxel and prednisone for enzalutamide (enza)- or abiraterone acetate (abi)–pretreated patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): KEYNOTE-921.
Authors: Petrylak Daniel Peter , Shore Neal D. , Bennamoun Mostefa , Ratta Raffaele , Piulats Josep M. , Li Ben , Schloss Charles , Fizazi Karim
Published: February 2020

TPS262

Background: Docetaxel is an established treatment for pts with mCRPC. Pembro, a PD-1 inhibitor, showed single-agent antitumor activity in mCRPC. In the phase 1b/2 KEYNOTE-365 study (NCT02861573), docetaxel + pembro and prednisone showed activity in pts treated with abi or enza for mCRPC, warranting further evaluation. Methods: KEYNOTE-921 (NCT03834506) is a phase 3 trial to evaluate efficacy and safety of pembro + docetaxel and prednisone in chemotherapy-naive pts who progressed with enza or abi therapy for mCRPC. An estimated 1000 pts will be randomly assigned 1:1 to receive docetaxel 75 mg/m2 IV every 3 weeks (Q3W) + prednisone/prednisolone orally 5 mg twice daily (BID) and pembrolizumab 200 mg IV Q3W or docetaxel 75 mg/m2 IV Q3W + prednisone/prednisolone 5 mg orally BID + placebo IV Q3W. Treatment will be stratified by previous next-generation hormone agent (abi or enza) and metastases location (bone only, liver, other). Adults (≥18 years) with histologically or cytologically confirmed mCRPC who progressed with androgen deprivation therapy (or postbilateral orchiectomy) ≤6 months of screening, have ECOG PS 0 or 1, and have adequate organ function are eligible. Pts must have experienced either progression after ≥8 weeks (≥14 weeks for bone progression) or intolerance after ≥4 weeks of abi or enza (but not both) in a chemotherapy-naive mCRPC state. Pts will be required to provide tissue for biomarker analysis. Responses will be assessed by CT or MRI and radionuclide bone imaging per Prostate Cancer Working Group 3 (PCWG3)–modified RECIST v1.1 by blinded independent central review (BICR) Q9W during the first year and Q12W thereafter. Treatment will continue with docetaxel and prednisone for up to 10 cycles and with pembro for up to 35 cycles or until disease progression, unacceptable toxicity, or consent withdrawal. Primary end points are rPFS by BICR and OS. Secondary end points are time to initiation of subsequent anticancer therapy or death, PSA response rate, time to PSA progression, ORR and DOR per PCWG3-modified RECIST v1.1 assessed by BICR, and safety. Accrual began May 2, 2019. Clinical trial information: NCT03834506.
A randomized phase II study of erdafitinib (ERDA) versus intravesical chemotherapy (IC) in patients with high-risk nonmuscle invasive bladder cancer (HR-NMIBC) with FGFR mutations or fusions, who recurred after Bacillus Calmette-Guérin (BCG) therapy.
Authors: Steinberg Gary D. , Palou-Redorta Joan , Gschwend Juergen E. , Tran Ben , Loriot Yohann , Daneshmand Siamak , Roupret Morgan , Santiago-Walker Ademi E. , Switzky Julie C. , Major Christopher , Baig Mahadi , Xia Qi , Catto James WF
Published: February 2020

TPS603

Background: ERDA, an oral pan-FGFR inhibitor, is approved by the US FDA for metastatic urothelial carcinoma (mUC) with susceptible FGFR3 or FGFR2 gene alterations and progressed on/ or after at least 1 line of prior platinum-containing chemotherapy (PCC) including within 12 months of neoadjuvant/adjuvant PCC.1 Around 40% of patients with bladder cancer present with HR-NMIBC. First-line BCG therapy fails in 30-40% of patients and subsequent treatment options are limited. This study is designed to evaluate recurrence-free survival (RFS) following treatment with ERDA vs IC in patients with FGFR positive HR-NMIBC who recurred after BCG therapy. Methods: This is an open-label, multicenter, randomized, phase 2, safety and efficacy study of ERDA in adults with histologically confirmed HR-NMIBC and FGFR mutations or fusions. Inclusion criteria: ECOG status ≤1, adequate bone marrow, liver, renal function, and ineligibility for or declining cystectomy, with no history of prior FGFR inhibitors. Patients will be enrolled into 1 of 3 cohorts. Cohort 1 (n=240): high-grade disease Ta/T1 lesion (papillary only) with disease recurrence after BCG therapy will be randomized to ERDA or IC (investigator choice: gemcitabine or mitomycin C); Cohort 2 (n=20): carcinoma in situ (CIS) with/without papillary disease to receive ERDA monotherapy; Cohort 3 (n=20): marker lesion study in patients with intermediate-risk papillary disease only to receive ERDA monotherapy. Dose will be maintained at 8 mg, up-titrated to 9 mg, or withheld based on phosphate levels. Primary endpoint: Cohort 1- RFS; Secondary endpoints: Cohort 1 - time to progression and disease worsening, disease-specific survival (invasive bladder cancer), overall survival, RFS rate at 6, 12, 24 months, and RFS on subsequent anticancer therapy (RFS2). An IDMC will be commissioned for Cohort 1. Exploratory endpoints: Cohort 2- complete response (CR) rate at 6 months; Cohort 3- CR in marker lesion. Patients will be enrolled at sites in ~14 countries. EudraCT: 2019-002449-39. Loriot Y et al. N Engl J Med. 2019;381:338-48. Clinical trial information: 2019-002449-39.
Cell cycLe inhibitiON to target the EVolution of urOthelial cancer (CLONEVO): A single-arm, open-label window-of-opportunity trial of neoadjuvant abemaciclib in platinum-ineligible muscle invasive bladder cancer patients.
Authors: Nauseef Jones , Vlachostergios Panagiotis J. , Molina Ana M. , Nanus David M. , Sternberg Cora N. , McClure Timothy D , Scherr Douglas , Martin M. Laura , Inghirami Giorgio , Elemento Olivier , Tagawa Scott T. , Faltas Bishoy Morris
Published: February 2020

TPS606

Background: The standard of care for clinically localized muscle-invasive bladder cancer (MIBC) is neoadjuvant platinum-based combination chemotherapy followed by radical cystectomy (RC). Up to 40% of patients (pts) are ineligible to receive cisplatin and proceed to RC without any neoadjuvant therapy. We and others have demonstrated enrichment of molecular alterations in cell cycle genes in MIBC, including copy number losses of CDKN2A in 41% of pts. Abemaciclib is a unique CDK4/6 inhibitor with single agent activity and a target kinome distinct from other CDK4/6 inhibitors. We have demonstrated that CRISPR knockout of CDKN2A increases susceptibility to abemaciclib in bladder cancer cell lines. Beyond tumor-intrinsic effects, abemaciclib also modulates the tumor microenvironment (TME) via upregulating human endogenous retroviral elements and increasing T cell infiltration. Methods: Cell cycLe inhibitiON to target the EVolution of urOthelial cancer (CLONEVO) is a single arm, window-of-opportunity trial of neoadjuvant abemaciclib which will evaluate tumor cell and TME changes in response to abemaciclib. Enrolled pts must be ineligible for platinum-based neoadjuvant therapy for resectable MIBC. Pts receive abemaciclib (200 mg BID PO) for 4 weeks prior to RC. Tumor tissue collected via transurethral resection of bladder tumor (TURBT) and residual tumor at RC undergo single cell RNA sequencing and whole-exome sequencing. Patient-derived organoids and xenografts are generated for a co-clinical trial of abemaciclib alone or in combination. The primary endpoint is the measurement of changes in cell cycle dynamics. Secondary objectives are assessment of toxicity via NCI CTCAE v 5.0 and pathologic downstaging of MIBC. We will perform targeted sequencing of a panel of cell cycle genes in serial plasma and urine cell free DNA to evaluate changes in the variant allele fractions of somatic alterations. The novel design of this trial allows dynamic in vivo assessment of tumor changes and creates a new paradigm for studying tumor evolution in real time. Clinical trial information: NCT03837821.
PIVOT-09: A phase III randomized open-label study of bempegaldesleukin (NKTR-214) plus nivolumab versus sunitinib or cabozantinib (investigator's choice) in patients with previously untreated advanced renal cell carcinoma (RCC).
Authors: Tannir Nizar M. , Agarwal Neeraj , Pal Sumanta K. , Cho Daniel C. , Formiga Maria , Guo Jun , George Daniel J. , Tagliaferri Mary Ann , Singel Stina Mui , O'Keeffe Bridget A. , Hannah Alison L. , Balbas Minna , Penkov Konstantin
Published: February 2020

TPS763

Background: Bempegaldesleukin (BEMPEG; NKTR-214) is a first-in-class interleukin-2 (IL-2) receptor pathway agonist that activates and expands effector T cells and natural killer cells in the tumor microenvironment and increases tumor PD-L1 expression, making BEMPEG a promising agent for combination with immune checkpoint inhibitors. In a phase 1/2 study, BEMPEG plus nivolumab (NIVO) demonstrated an encouraging objective response rate (ORR) in first-line advanced RCC (46%) and a manageable safety profile. BEMPEG plus NIVO offers a potential novel immunooncology treatment option for patients with advanced RCC. Methods: A global, multicenter, randomized, open-label phase 3 study is evaluating the efficacy and safety of BEMPEG plus NIVO vs investigator’s choice of tyrosine kinase inhibitor (TKI; sunitinib [SUNI] or cabozantinib [CABO]) in patients with previously untreated advanced or metastatic RCC with a clear-cell component. Patients must not have had prior systemic therapy (including neoadjuvant, adjuvant or vaccine therapy) for RCC. Key exclusion criteria include active brain metastasis and autoimmune disease requiring systemic immunosuppressive agents. Approximately 600 patients will be randomized 1:1 to receive 0.006 mg/kg BEMPEG plus 360 mg NIVO intravenously every 3 weeks or TKI (50 mg SUNI [4 weeks on, 2 weeks off schedule] or 60 mg CABO; orally each day). Patients will be stratified by International Metastatic RCC Database Consortium (IMDC) prognostic score (0 [favorable risk] vs 1-2 [intermediate risk] vs 3-6 [poor risk]) and TKI choice (SUNI vs CABO). Primary objectives are ORR by blinded independent central review (BICR) and overall survival in the IMDC intermediate/poor risk population and the intention-to-treat (ITT) population. Secondary objectives are progression-free survival by BICR in the IMDC intermediate/poor risk population and the ITT population, safety, PD-L1 expression as a predictive biomarker, and quality of life. Enrollment is ongoing. Clinical trial information: NCT03729245.