bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor genomic landscape in smokers compared to non-smoker patients with locally advanced or metastatic urothelial carcinoma.
Authors: Tripathi Nishita , Sayegh Nicolas , Jo Yeonjung , Li Haoran , Nussenzveig Roberto , Haaland Benjamin , Thomas Vinay Mathew , Gupta Sumati , Sirohi Deepika , Swami Umang , Agarwal Neeraj , Maughan Benjamin L. 
Published: February 2022

554 Background: Cigarette smoking is a known risk factor for bladder cancer. Smokers have been reported to have greater ERCC2-Signature mutations and APOBEC-Signature 13 mutations when compared to non-smokers in a TCGA based study (PMID: 33849962). Our objective was to assess the frequency of targetable genomic alterations in smokers (current or past) vs never smokers patients (pts) with locally advanced or metastatic urothelial carcinoma (mUC). Methods: In this IRB approved retrospective study, smokers vs non-smokers pts with mUC undergoing tumor comprehensive genomic profiling (CGP) from CLIA-certified laboratory were included. Genes with alterations (GA) in < 5% pts and variants of unknown significance were excluded from the analysis. A chi square test was used to compare gene frequency aberration and the analysis was adjusted for false discovery using Benjamini-Hochberg (BH) correction. The median number of genomic aberrations per pt was compared using Wilcoxon rank-sum test. Results: 137 pts were eligible and included. Smokers (n=70) and non-smokers (n=67): median age, 67 vs 68 years; male vs female: 55/15 vs 42/25. The genomic aberrations enriched in smokers and non-smokers are shown in the table. The most common GA observed in smokers were TERT, TP53, CDKN2B, RB1 and KDM6A; and non-smokers were TERT, TP53, CDKN2B, PIK3CA and RB1 (Table). Tumor mutation burden and the frequency of genomic aberrations per pt were similar in both groups. Conclusions: Herein, we independently validate the findings by Walasek, Almassi et. al. (abstract B20, AACR 2020) of no significant difference in the tumor GA between smokers vs non-smokers pts with advanced urothelial carcinoma, despite high prevalence of targetable genomic aberrations in both cohorts. Future directions should include the investigation of epigenomic changes and transcriptomic profiling to further elucidate the effect of smoking on bladder cancer.[Table: see text]
Systematic literature review (SLR) and network meta-analysis (NMA) of first-line therapies (1L) for locally advanced/metastatic urothelial carcinoma (la/mUC).
Authors: Bloudek Lisa , Hepp Zsolt , McKay Caroline , Derleth Christina Louise , LIll Jennifer Susan , Lenero Enrique , Wright Phoebe , Ramsey Scott David , Sullivan Sean D. , Devine Beth 
Published: February 2022

570 Background: Standard of care (SOC) for 1L la/mUC is gemcitabine plus cisplatin (GC) or carboplatin (GCa), but the landscape is evolving with new therapies emerging. To compare outcomes of other approved/investigational 1L regimens with SOC in the context of recently published data on newer therapies, we updated a previously reported SLR/NMA of phase 2/3 randomized control trials. Methods: The SLR was conducted in line with PRISMA and NICE guidelines (01/2000-05/2020; updated 06/2020-06/2021). Three networks were formed: cisplatin (cis)-eligible/mixed eligibility; cis-ineligible (strict; studies including cis-ineligible patients only); and cis-ineligible (wide; expanded to also include study arms with an investigator’s choice of carboplatin in KEYNOTE-361, IMvigor130, and DANUBE). Comparative efficacy and safety were assessed under a Bayesian framework. Overall survival (OS) and progression-free survival (PFS) with 1L la/mUC regimens vs SOC (GC/GCa) are reported. Results: Among 2,312 citations identified, 55 unique trials were selected for data extraction. Of these, the NMA included 11 studies in the cis-eligible/mixed, 6 in the cis-ineligible (strict), and 8 in the cis-ineligible (wide) network. The NMA excluded therapies that were not effective or adopted in clinical practice; 6 maintenance trials were excluded due to differences in design precluding comparisons. Median OS in the SOC arms was 13.2 mo (95% confidence interval [CI] 12.4-14.0) for cis-eligible/mixed, 9.7 mo (95% CI 6.7-12.8) for cis-ineligible (strict), and 12.0 mo (95% CI 10.4-13.5) for cis-ineligible (wide); median PFS was 6.6 mo (95% CI 6.3-6.9) for cis-eligible/mixed and 5.6 mo (95% CI 5.0-6.3) for both cis-ineligible strict and wide. OS and PFS were similar to SOC across therapies in each network: hazard ratios (HR) ranged 0.7-1.4 for OS for cis-eligible/mixed, 0.9-1.4 for cis-ineligible (strict), and 0.8-1.4 for cis-ineligible (wide) (Table); HR for PFS ranged 0.5-1.6 for cis-eligible/mixed and 0.8-1.1 for both cis-ineligible strict and wide networks; all credible intervals (CrI) crossed or were close to 1. Conclusions: In this updated SLR/NMA, survival outcomes were similar and remained poor among established and emerging 1L la/mUC therapies, despite inclusion of recent trial data. This further highlights the unmet need in this population.[Table: see text]
Heterogeneity of BCG unresponsive bladder cancer clinical trials limits patients’ access to novel therapeutics.
Authors: Chandra Michael , Sundi Debasish , Pohar Kamal S. , Carson William Edgar , Li Roger 
Published: February 2022

572 Background: Effective therapies for patients with non-muscle invasive bladder cancer that recurs or progresses after Bacille Calmette-Guérin (BCG) are lacking. This unmet need is the focus of many drug development efforts, reflected in many completed/ongoing/planned clinical trials for patients with BCG unresponsive bladder cancer. Though BCG unresponsive criteria are well defined, enrollment criteria are variable such that, even at centers with several open trials in this space, a given patient with BCG unresponsive bladder cancer might not qualify for any. To understand the scope of this dilemma, we systematically analyzed enrollment criteria for all BCG unresponsive protocols registered on ClinicalTrials.gov to quantify heterogeneity in enrollment criteria and to determine what proportion of trials were inclusive to patients meeting U.S. Food and Drug Administration (FDA) BCG unresponsive criteria. Methods: The ClinicalTrials.gov search tool was queried for relevant trials using the terms ‘bladder cancer’ ‘non-muscle invasive bladder cancer’ and ‘BCG’. Previously published review articles were cross-referenced to ensure that search results were comprehensive. Inclusion and exclusion criteria for the resulting 28 protocols pertaining to distinct categories such as performance status, laboratory parameters, co-morbidities, active medications, and prior therapies were recorded. Based on enrollment criteria, the trial was assessed to fully inclusive or not to patients considered to be BCG unresponsive by the 2018 FDA criteria. Results: Of 28 trials, 15 (54%) had inclusion/exclusion criteria that were consistent with (inclusive of patients that met) the BCG unresponsive bladder cancer definition. 13 (48%) of 27 trials that specified performance status excluded patients with ECOG > 2 (or KPS equivalent). The most common disease specific exclusion for patients with BCG unresponsive bladder cancer was a requirement for stage Tis (carcinoma in situ, CIS), which pertained to 5 (18%) of trials. Conclusions: Enrollment criteria for patients with BCG unresponsive bladder cancer are highly variable. Nearly half of patients who meet stringent criteria for this disease state do not qualify for clinical trials in this area. For patients who desire to enroll in clinical trials, this restricts access to novel agents. For bladder cancer treating physicians and regulatory bodies, this also hinders comparisons across agents.
CYCLONE 2: A phase 2/3, randomized, placebo-controlled study of abiraterone acetate plus prednisone with or without abemaciclib in patients with metastatic castration-resistant prostate cancer.
Authors: Smith Matthew Raymond , Agarwal Neeraj , Todenhöfer Tilman , Piulats Josep M. , Lee Jae-Lyun , Trepiakas Redas , Rao Arpit , Horvath Lisa , Lithio Andrew , Johnston Erica L. , Hulstijn Maarten , Nacerddine Karim , Sweeney Christopher 
Published: February 2022

TPS198 Background: Despite recent advances, nearly all patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) experience disease progression and cancer-specific mortality. Persistent or reactivated androgen receptor (AR) signaling and/or activation of pathways in cross-talk with AR signaling are key drivers of mCRPC progression. Evidence suggests that AR signaling promotes translation of D-type cyclins resulting in cyclin-dependent kinase 4 and 6 (CDK4&6) activation and cell cycle progression. Abemaciclib is an oral selective inhibitor of CDK4&6 dosed on a continuous schedule, that is FDA-approved in combination with endocrine therapy or as monotherapy to treat HR+, HER2- metastatic breast cancer pts. Preclinical studies with prostate cancer cell lines and xenograft models showed that abemaciclib induces cell cycle arrest and tumor growth inhibition. The hypothesis is that addition of abemaciclib to AR targeted therapy may be an effective treatment for mCRPC pts. Methods: CYCLONE 2 (NCT03706365) is a phase 2/3, randomized, double-blind, multicenter, placebo-controlled study to assess the safety and efficacy of abemaciclib in combination with abiraterone acetate plus prednisone (AA+P) in pts with mCRPC. CYCLONE 2 is an adaptive study which is designed in three parts. Part 1 is a 30-patient safety lead-in to determine the recommended phase 2 dose (RP2D; 150 mg or 200 mg, twice daily) of abemaciclib in combination with AA (1000 mg, once daily) + P (5 mg, twice daily). In part 2, 150 pts are randomized 1:1 to AA+P with abemaciclib at the RP2D or placebo. The study expands to enroll an additional 170 pts in Part 3 if prespecified expansion criteria are met at a planned adaptive interim analysis performed by an independent data monitoring committee (IDMC). Pts with mCRPC evidenced by radiographic and/or PSA progression during continuous ADT are eligible. Prior docetaxel for mHSPC is permitted. Systemic anti-cancer therapy for mCRPC and prior novel hormonal agents are exclusionary. The primary objective is radiographic progression free survival (rPFS; per RECIST1.1 for soft tissue and PCWG3 for bone). Secondary objectives include safety, objective response rate, duration of response, time to symptomatic and PSA progression, overall survival, and pharmacokinetics. Status: Enrollment in Part 1 & 2 is completed. Based on the recommendation from the IDMC, Part 3 was opened in June 2021 and enrolls pts from about 112 sites across 12 countries. Clinical trial information: NCT03706365.
Relugolix in combination with abiraterone acetate, apalutamide, or docetaxel in men with advanced prostate cancer (aPC): A phase 1, three-part, open-label, parallel-cohort study.
Authors: De La Cerda Jose , Migoya Elizabeth , Brown Bruce , Lu Sophia , Zohren Fabian , Tutrone Ronald F. , Dunshee Curtis 
Published: February 2022

TPS207 Background: Androgen deprivation therapy (ADT) with gonadotropin-releasing hormone (GnRH) analogs or receptor antagonists is a cornerstone of prostate cancer treatment. As disease progresses, agents with complementary mechansims are co-prescribed with ADT to suppress extra-testicular testosterone production or block androgen receptors on cancer cells. Relugolix (120 mg) is an oral non-peptide GnRH receptor antagonist approved in the US for the treatment of aPC. In the phase 3 study, relugolix maintained suppression of testosterone to castration levels in 96.7% of men for up to 48 weeks (wks), with superiority to leuprolide acetate. Relugolix was well tolerated and associated with a 54% lower risk of major adverse cardiovascular events relative to leuprolide acetate (Shore N, NEJM 2020;382;23). To formally assess the safety and tolerability of combination treatment with relugolix, a phase 1 study in men with aPC has been undertaken. Methods: This is a three-part, open-label, parallel-cohort safety and tolerability study of relugolix in combination with abiraterone acetate in men with metastatic castration-sensitive prostate cancer (mCSPC) or metastatic castration-resistant prostate cancer (mCRPC) (Part 1), apalutamide in men with mCSPC or non-metastatic catration-resistant prostate cancer (nmCRPC) (Part 2), or docetaxel in men with mCSPC or mCRPC (Part 3). Each part of the study consists of a 45-day screening period, a 12-wk primary study treatment period and a 40-wk safety extension treatment period. All of the men are required to have been treated with leuprolide acetate or a GnRH receptor antagonist (eg, degarelix) in combination with abiraterone acetate for a minimum of 12 wks, apalutamide for a minimum of 6 wks, or docetaxel for a minimum of one treatment cycle prior to the baseline (Day 1) visit. Men will be transitioned from leuprolide acetate or degarelix to relugolix (120 mg [Part 1 and 3] or 240 mg [Part 2] once daily after a single loading dose of 360 mg); on the approximate date the next analog or antagonist injection is scheduled; treatment with each combination treatment will continue as previously prescribed. Hence, the study will provide safety and tolerability of relugolix and the three different combination agents for up to 1 year and in addition, will provide safety and tolerability data as men transition from injectable leuprolide acetate or degarelix to oral treatment with relugolix. Enrollment into the study began in March 2021. A protocol amendment was approved in July 2021 to include Part 2 and Part 3 of the study and to add the 40-wk safety extension treatment period. Screening for Part 2 was initiated in August 2021 and for Part 3 it is expected to initiate in January 2022. Clinical trial information: NCT04666129.
KEYNOTE-365 cohorts E and F: Phase 1b/2 study of pembrolizumab + lenvatinib combination therapy in patients with adenocarcinoma metastatic castration-resistant prostate cancer (mCRPC) or treatment-emergent neuroendocrine mCRPC (t-NE).
Authors: Kramer Gero , Shore Neal D. , Joshua Anthony M. , Li Xin Tong , Poehlein Christian Heinrich , Schloss Charles , De Bono Johann S. , Yu Evan Y. 
Published: February 2022

TPS215 Background: Standard of care for noncurative adenocarcinoma mCRPC is docetaxel or the next-generation hormonal agents (NHAs) abiraterone and enzalutamide. However, approximately 20% of patients develop t-NE after treatment for adenocarcinoma mCRPC; t-NE is associated with shorter survival, and it has no standard of care beyond combination platinum chemotherapy. The vascular endothelial growth factor (VEGF)/fibroblast growth factor receptor (FGFR) inhibitor lenvatinib inhibits proliferation and angiogenesis in preclinical models of adenocarcinoma prostate cancer. The phase 2 KEYNOTE-199 trial showed some antitumor activity with pembrolizumab monotherapy in docetaxel-pretreated patients with adenocarcinoma mCRPC. VEGF/FGFR inhibition combined with PD-1 inhibition may have enhanced benefit in mCRPC, for adenocarcinoma and possibly as a new treatment option for t-NE. Methods: KEYNOTE-365 (NCT02861573) is a nonrandomized, open-label, multicohort, phase 1b/2 trial designed to evaluate different pembrolizumab combination therapies in several patient populations with mCRPC. Cohort E will enroll patients with confirmed adenocarcinoma of the prostate without small cell histology, per investigator. Cohort F will enroll patients with t-NE (≥1% neuroendocrine cells in a recent biopsy specimen confirmed by central histology review). Each cohort will include patients who previously received docetaxel treatment for mCRPC. Prior treatment with ≤2 NHAs (for hormone-sensitive metastatic prostate cancer [mHSPC] or mCRPC) and 1 other chemotherapy for mCRPC is permitted. Additionally, enrollment in cohort F requires prostate cancer progression within 6 months of starting an NHA (for mHSPC or mCRPC) and within < 6 cycles of docetaxel for mCRPC. Each cohort will enroll 40-100 patients with Eastern Cooperative Oncology Group performance status score of 0 or 1. Both cohorts will receive pembrolizumab 200 mg IV every 3 weeks + oral lenvatinib 20 mg once daily until disease progression, withdrawal of consent, prespecified alanine aminotransaminase or aspartate aminotransaminase level increase, or other discontinuation event. Primary end points are safety and tolerability, prostate-specific antigen (PSA) response rate, and objective response rate (ORR) per RECIST v1.1 by blinded independent central review (BICR). Secondary end points include time to PSA progression; ORR and radiographic progression-free survival per Prostate Cancer Working Group 3 (PCWG3)–modified RECIST v1.1 by BICR; duration of response and disease control rate per RECIST v1.1 and PCWG3-modified RECIST v1.1 by BICR; and overall survival. These cohorts of KEYNOTE-365 are enrolling in Australia, Germany, New Zealand, Spain, and the United States. Clinical trial information: NCT02861573.
DASL-HiCaP: Darolutamide augments standard therapy for localized very high-risk cancer of the prostate (ANZUP1801). a randomized phase 3 double-blind, placebo-controlled trial of adding darolutamide to androgen deprivation therapy and definitive or salvage radiation.
Authors: McBride Sean Matthew , Niazi Tamim , Williams Scott , Davis Ian D. , Stockler Martin R. , Martin Andrew James , Bracken Karen , Roncolato Felicia T. , Horvath Lisa , Sengupta Shomik , Martin Jarad , Lim Tee , Hughes Simon , McDermott Raymond S. , Catto James W.F. , Kelly Paul J. , Parulekar Wendy R. , Morgan Scott Carlyle , Rendon Ricardo A. , Sweeney Christopher ,   Australia and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP)
Published: February 2022

TPS284 Background: Radiation therapy (RT), plus androgen deprivation therapy (ADT) with a luteinizing hormone releasing hormone analog (LHRHA), is standard of care for men with very high-risk localized prostate cancer (PC), or with very high-risk features and persistent PSA after radical prostatectomy (RP). Despite this, incurable distant metastases develop within 5 years in 15% of men with very high-risk features. Darolutamide is a structurally distinct oral androgen receptor antagonist with low blood-brain-barrier penetration, a demonstrated favorable safety profile, and low potential for drug-drug interactions. Our aim is to determine the efficacy of adding darolutamide to ADT and RT in the setting of either primary definitive therapy, or salvage therapy for very high-risk PC. Methods: This study is a randomized (1:1), phase 3, placebo-controlled, double-blind international trial for men planned for RT who have very high-risk localized PC on conventional imaging; or very high-risk features with PSA persistence or rise within one year following RP. The trial is stratified by: RP; use of adjuvant docetaxel; pelvic nodal involvement. 1100 participants will be randomized to darolutamide 600 mg or placebo twice daily for 96 weeks in combination with SOC: LHRHA for 96 weeks, plus RT starting week 8-24 from randomization. Participants are allowed nonsteroidal antiandrogen in addition to LHRHA for up to 90 days prior to randomization. Early treatment with up to 6 cycles of docetaxel completed at least 4 weeks prior to RT is permitted. The primary endpoint is metastasis-free survival (ICECaP-validated), with secondary endpoints overall survival, PC-specific survival, PSA-progression free survival, time to subsequent hormonal therapy, time to castration-resistance, frequency and severity of adverse events, health related quality of life, fear of recurrence. Tertiary endpoints include incremental cost-effectiveness, and identification of prognostic and/or predictive biomarkers of treatment response, safety, and resistance to study treatment. Clinical trial information: NCT04136353.
Trial in progress: A phase 2, randomized, open-label study of trilaciclib with first-line, platinum-based chemotherapy and avelumab maintenance in untreated patients with locally advanced or metastatic urothelial carcinoma (PRESERVE 3).
Authors: Sonpavde Guru P. , Grivas Petros , Milowsky Matthew I. , Galsky Matt D. , Malik Rajesh K. , Beelen Andrew Paul 
Published: February 2022

TPS585 Background: Trilaciclib is an intravenous (IV) CDK4/6 inhibitor that has been shown to help protect hematopoietic stem and progenitor cells from chemotherapy (CT)-induced damage (myeloprotection) via transient cell cycle arrest. Trilaciclib is approved in the US to decrease the incidence of CT-induced myelosuppression (CIM) in adult patients with extensive-stage small cell lung cancer receiving certain treatment regimens. An exploratory phase 2 study (NCT02978716) in patients with triple-negative breast cancer showed improved overall survival (OS) in patients receiving trilaciclib prior to CT vs CT alone, regardless of PD-L1 expression. The aim of this exploratory, randomized, open-label, multicenter, phase 2 trial (PRESERVE 3; NCT04887831) is to assess whether trilaciclib administered with standard-of-care platinum-based CT and avelumab maintenance can improve antitumor efficacy and reduce CIM versus CT and avelumab without trilaciclib, in patients with locally advanced or metastatic urothelial carcinoma (mUC). Methods: Adult patients with measurable disease per RECIST v1.1, no prior systemic treatment for mUC, and ECOG performance status ≤2 will be randomized 1:1 to receive gemcitabine 1000 mg/m2 plus cisplatin 70 mg/m2 or carboplatin area under the curve 4.5 (± trilaciclib 240 mg/m2 IV over 30 minutes, ≤4 hours prior to CT) in 21-day cycles. Patients will receive 4–6 cycles of CT. Those without progressive disease per RECIST v1.1 can receive avelumab 800 mg maintenance therapy (± trilaciclib) in 14-day cycles until disease progression, unacceptable toxicity, investigator/patient decision, or end of trial. Patients will be followed for survival. The sample size was calculated to support the primary endpoint of progression-free survival (PFS), using a stratified log-rank test accounting for two stratification factors (visceral metastasis and platinum agent [cisplatin/carboplatin]). 63 PFS events will be required to achieve 77% power to detect a hazard ratio of 0.6 with a 2-sided significance of 0.2, corresponding to a median PFS of 11.7 months for the trilaciclib arm. Assuming a 10-month enrollment period, final PFS analysis approximately 22 months after the first randomization, and 5% loss to follow-up, 90 patients are required for randomization. PFS will be analyzed in the intention-to-treat population. Secondary endpoints include objective response rate, disease control rate, PFS during maintenance, OS, multilineage myeloprotective effects, and safety/tolerability. Exploratory endpoints will assess pharmacodynamic parameters, including those related to immune-based mechanisms, and efficacy by CDK4/6-dependence. Enrollment opened in June 2021. As of September 29, 2021, 8 sites are open, and 1 patient randomized. Clinical trial information: NCT04887831.