bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human epidermal growth factor receptor 2 (HER2) and fibroblast growth factor receptor 3 (FGFR3) mutations to reveal biological pathways in urothelial carcinoma.
Authors: Chu Carissa Ellen , De Jesus Escano Manuel , Yip Wesley , Jiang Song , Iyer Gopa , Al-Ahmadie Hikmat A. , Goh Alvin C. , Dalbagni Guido , Bochner Bernard H. , Solit David B. , Pietzak Eugene J. 
Published: February 2022

567 Background: Human epidermal growth factor receptor 2 (HER2) (gene name: ERBB2) is a member of the epidermal growth factor receptor (EGFR) family and when mutated, associated with higher grade and stage of localized bladder cancer. Two HER2-targeted antibody-drug conjugates (ADC), trastuzumab emtansine and trastuzumab deruxtecan, are currently approved by the Food and Drug Administration (FDA) for use in gastric/breast cancers with promising application in urothelial carcinoma. Fibroblast growth factor receptor 3 ( FGFR3) is the target of another FDA-approved tyrosine kinase inhibitor erdafitinib and generally associated with more favorable prognosis as well as upper tract carcinoma. The purpose of this study is to characterize ERBB2 and FGFR3 mutations in a prospectively collected cohort of urothelial cancers. Methods: Patients with localized upper or lower tract urothelial carcinoma diagnosed between 2014 and 2020 who underwent a targeted exome sequencing panel of up to 468 cancer genes were identified. If multiple tumors were sequenced, only the diagnostic specimen was included. Analysis of gene alterations, frequency, and associated co-mutations was performed. Descriptive statistics were used to compare baseline patient characteristics. Results: 381 unique ERBB2 or FGFR3 mutated urothelial carcinoma specimens were included in this study. Of note, ERBB2 and FGFR3 mutations were essentially mutually exclusive and included 122 (66%) ERBB2 mutated tumors and 259 (34%) FGFR3 mutated tumors. Patients with tumors harboring FGFR3 mutations were younger (median 70 years IQR 60-76 vs. 74 years IQR 66-78, p<0.05), while patients with ERBB2 mutated tumors were more likely to be male (85% vs 73%, p<0.05). At the time of diagnosis, ERBB2 tumors were more likely to present with advanced (pT2 or higher) disease compared to FGFR3 mutated tumors (48% vs 24%). ERBB2 mutated tumors were more likely associated with RB1, P53, and ARID1A mutations, while FGFR3 mutated tumors were more likely associated with CDKN2A/B and STAG2 mutations (Table). Conclusions: These data highlight divergent biological pathways for patients with targetable mutations in ERBB2 and FGFR3 and are consistent with prior findings in non-muscle invasive bladder cancer. ERBB2 mutated tumors are associated with male gender, more aggressive pathological features and co-mutations with RB1, P53, and ARID1A.[Table: see text]
Recurrence patterns in bladder cancer patients with no residual disease (pT0N0) at radical cystectomy.
Authors: Ladi Seyedian Seyedeh Sanam , Douglawi Antoin , Lee Ryan , Alsyouf Muhannad , Ghoreifi Alireza , Bhanvadia Sumeet , Schuckman Anne K. , Djaladat Hooman , Daneshmand Siamak 
Published: February 2022

576 Background: Bladder cancer patients can achieve no residual disease status at the time of radical cystectomy (RC) following transurethral resection (TURBT) alone (pT0) or neoadjuvant chemotherapy (NAC) (ypT0). This population has favorable survival potential, yet limited data is available on their oncological outcomes. We examined the recurrence patterns in these patients and the implications for post-operative surveillance. Methods: A retrospective review of our IRB-approved bladder cancer database identified patients who underwent RC between 2000 - 2019 and were found to have no residual disease (pT0N0). The primary outcome was recurrence-free survival (RFS). Results: A total of 234 patients with a median age of 67 years were included. NAC was used in 89 (38%) patients and 145 (62%) cases were rendered pT0 following TURBT alone. After a median follow up of 44 months, 6/145 (4%) pT0 patients and 10/89 (11.2%) ypT0 cases developed a recurrence. None of the pT0 patients with previous history of clinical Ta/Tis disease had a recurrence after RC. The median time to recurrence was 9 months. All but one of the recurrences in the ypT0 group were within 2 years of cystectomy, while half of the recurrences in the pT0 group occurred after 2 years. Patients with ypT0 had worse 2- and 5-year RFS compared to the pT0 group (85% and 84% vs. 99% and 95%, respectively; p=0.003). Variant histology was noted in 49 (21%) patients and the recurrence rate was higher in this subgroup compared to those with pure urothelial carcinoma (12.2% vs. 5.4%, p = 0.02). Lung metastasis and involvement of distant organs, while rare, was noted at similar rates in both groups (Table). On univariate Cox regression analysis of RFS, clinical T stage > 3 (HR: 6.5, 95%CI: 2.4 – 17.3, p<0.001) and NAC (HR: 4.3, 95%CI: 1.5 – 12.5, p = 0.007) were associated with increased risk of recurrence. Conclusions: Most patients with pT0N0 pathology at the time of cystectomy are cured however metastasis can still develop up to 4 years after surgery. Patients achieving ypT0 after NAC exhibit worse prognosis and shorter times to recurrence, and closer follow-up may be considered.[Table: see text]
Evaluation of tumor genomic variants in Japanese patients with metastatic castration-sensitive prostate cancer (mCSPC) treated with apalutamide: Protocol of a phase 4 study (CUARTET).
Authors: Uemura Hirotsugu , Kamoto Toshiyuki , Uemura Hiroji , Masumori Naoya , Terada Naoki , Akamatsu Shusuke , Koroki Yosuke , Ono Shintaro , Ito Miku , Matsuyama Hideyasu 
Published: February 2022

TPS196 Background: Apalutamide is an oral non-steroidal, potent, and highly selective androgen receptor antagonist. Alterations in androgen signaling, DNA repair, and other pathways impact on castration sensitivity and outcomes of androgen antagonists. Currently, there is limited data on the types or effects of variants in prostate cancer (PC)-related genes among Japanese mCSPC (castration-naïve or castration-sensitive) patients treated with apalutamide. Methods: CUARTET is a collaborative phase 4 study with a primary objective of evaluating genomic variants in 73 PC driver genes during apalutamide treatment and hence identify potential biomarkers. Men aged ≥20 years with mCSPC scheduled to start apalutamide at 20 participating institutions will be eligible. Patients previously treated with abiraterone, docetaxel, enzalutamide, apalutamide or darolutamide, are ineligible, as are those who received androgen-deprivation therapy or combined androgen blockade for >6 months before registration or neoadjuvant/adjuvant hormonal therapy for >36 months. The primary endpoint is the changes in genomic variants of 73 PC driver genes between pre- and post-treatment of apalutamide. Secondary endpoints, stratified by baseline genomic variants, include the proportion of patients with nadir prostate–specific antigen (PSA) ≤0.2 ng/mL, PSA–progression-free survival (PFS), PFS, overall survival, time to castration resistance, and PFS2. Other planned outcomes include safety, incidence/severity of apalutamide-related skin rash stratified by single nucleotide polymorphisms or human leukocyte antigen typing, and clinical outcomes in patients with only distant lymph node metastases. The first patient was enrolled in December 2020, and it is expected to enroll 100 patients during the 1.5-year registration period. Eighty-one patients have been enrolled in this study by July 2021. The patients will be followed up for a maximum of 4.5 years. Interim analyses are planned after the last patient has been registered. Results of CUARTET are expected to reveal the genomic variants, including those in androgen signaling-related genes, that are potentially involved in acquired resistance to apalutamide. The results will reveal biomarkers to aid treatment decision making for mCSPC patients, including the treatment options following apalutamide. Clinical trial information: NCT04601441.
PEARLS: A multicenter phase II/III trial of extended field radiotherapy for androgen-sensitive prostate cancer patients with PSMA‐avid pelvic and para-aortic lymph nodes at presentation.
Authors: Murray Julia , Cruickshank Clare , Bird Thomas , Bell Philip , Braun John , Chuter Dave , Davda Reena , Ferreira Miguel Reis , Griffin Clare , Hujairi Nabil , Melcher Alan , Miles Elizabeth , Naismith Olivia , Rekowski Jan , Staffurth John , Syndikus Isabel , Tree Alison , Wilkins Anna , Hall Emma 
Published: February 2022

TPS199 Background: Optimal management for lymph node (LN) positive prostate cancer has not yet been determined. With the emerging role of PSMA-PET/CT in diagnostic staging, identification of this disease status is increasing. The superior border for prostate nodal radiotherapy is variable across different centres. PEARLS (CRUK/19/016) aims to show that extending the radiotherapy field to cover the para-aortic LN (up to L1/L2 vertebral interspace) can improve outcomes for prostate cancer patients with PSMA-avid pelvic LN at presentation. The trial is registered: ISRCTN36344989. Methods: PEARLS is a multi‐stage randomised controlled trial. Men with histologically confirmed prostate cancer with PSMA‐avid nodal disease within the pelvis +/‐ para‐aortic region receiving androgen deprivation therapy +/‐ androgen receptor targeted therapy or docetaxel chemotherapy are eligible. Two cohorts defined by extent of LN disease determined by PSMA‐PET/CT will be recruited: cohort A (pelvic LN at or below the L4/L5 vertebral interspace) and cohort B (para-aortic LN below L1/L2 vertebral interspace). Patients are randomly allocated (1:1) to standard field (dependent on cohort) intensity modulated radiotherapy (IMRT) (control) or extended-field IMRT (experimental) in 20 fractions over 4 weeks. In the control group, cohort A will receive 60Gy to the prostate and 44Gy to the pelvis with an integrated boost of 51Gy to PSMA-avid LN and cohort B will receive 60Gy to the prostate only. In the experimental group, participants in both cohorts will receive 60Gy to the prostate and 44Gy to the pelvis and para‐aortic region with an integrated boost of 51Gy to involved LN. In phase II, the primary endpoint is lower gastrointestinal RTOG grade 2+ toxicity at week 18 from start of radiotherapy. Assuming acceptable toxicity in the first 75 participants receiving extended-field IMRT, the study will move to phase III where the primary endpoint is metastasis‐free survival. The trial aims to recruit 714 patients with pelvic LN to detect a hazard ratio of 0.62 in favour of extended-field IMRT and a further 179 patients with para‐aortic LN disease. The trial was launched in the UK on 25 June 2021. Phase II will be conducted in 20 NHS Trusts across the UK. Clinical trial information: ISRCTN36344989.
A randomized, controlled, phase 3 study of darolutamide in addition to androgen deprivation therapy (ADT) versus ADT alone in metastatic hormone-sensitive prostate cancer (ARANOTE).
Authors: KP Haresh , Vjaters Egils , Castellano Daniel , Olmos David , Shore Neal D. , Nevalaita Liina , Testa Isabella , Kappeler Christian , Kuss Iris , Saad Fred 
Published: February 2022

TPS200 Background: Previous randomized, phase 3 trials have shown the efficacy of adding docetaxel, abiraterone acetate, enzalutamide, or apalutamide to ADT in improving overall survival and/or radiologic progression-free survival (rPFS) in patients with metastatic hormone-sensitive prostate cancer (mHSPC). However, these combinations are associated with an increased risk of adverse events (eg, fatigue, rash, and cardiovascular events). Darolutamide is a structurally distinct and highly potent androgen receptor inhibitor. In the ARAMIS study, darolutamide has been shown to significantly reduce the risk of death by 31% and have a favorable safety profile in men with nonmetastatic castration-resistant prostate cancer. It has a low incidence of central nervous system−related adverse events, which may be explained by its distinct low blood−brain barrier penetration. Darolutamide has also been shown to have a low potential for drug−drug interactions, allowing flexibility with concomitant medications. ARANOTE will evaluate the efficacy and safety of darolutamide plus ADT in patients with mHSPC (NCT04736199). Methods: ARANOTE is an international, multicenter (ex-US), randomized, double-blind, placebo-controlled, phase 3 study in patients with histologically or cytologically confirmed adenocarcinoma of the prostate and documented metastatic disease by conventional imaging (eg, computed tomography or magnetic resonance imaging) who started ADT ≤12 weeks before randomization. In total, 555 patients will be randomized 2:1 to darolutamide 600 mg twice daily or placebo, plus ADT. Patients will be stratified by the presence of visceral metastases, assessed by central review, and prior local therapy. Patients will be evaluated every 12 weeks for efficacy, safety, and quality of life (using the FACT-P questionnaire) during treatment and active follow-up post treatment. For long-term follow-up, patients will be contacted by telephone every 12 weeks. The primary endpoint is rPFS; secondary endpoints include overall survival, time to castration-resistant prostate cancer, time to prostate-specific antigen progression, and safety. Recruitment is ongoing, and the first patient first visit was on February 23, 2021. The estimated study completion date is September 2025. Clinical trial information: NCT04736199.
A single-arm, open-label, phase 2 study evaluating pacritinib for patients with biochemical recurrence after definitive treatment for prostate cancer: Blast study.
Authors: Kilari Deepak , Szabo Aniko , Hall William A. , Nelson Ariel Ann , Johnson Scott , Giever Thomas A. , Burfeind John , Tolat Parag , Bylow Kathryn A. , Iczkowski Kenneth , Sun Yunguang , Rui Hallgeir , Thomas James P. , Nevalainen Marja 
Published: February 2022

TPS220 Background: Androgen deprivation therapy (ADT) achieved with gonadotropin releasing hormone (GnRH) agonist or antagonist is considered the standard of care for men with prostate cancer (PC) who develop biochemical recurrence (BCR) after definitive treatment. ADT is associated with significant adverse effects in this asymptomatic population, and hence there is an unmet need for alternate non-hormonal options. Androgen receptor (AR) and its variants (AR-V) are persistently expressed in the majority of the cells in recurrent PCs and drives PC growth. Jak2-Stat5 signaling has been shown to sustain PC cell viability and is critical for PC tumor growth. Stat5 activation in PC at the time of surgery predicts early PC recurrence. Our investigation of the molecular targets downstream of Jak2-Stat5 signaling have revealed the AR gene as a critical target, and the Jak2-Stat5 pathway represents a target to inhibit expression of diverse AR and AR-V species and thereby control of PC growth. Pacritinib (PAC) is a novel JAK2 inhibitor that suppresses wild-type Jak2 in cell-based assays and has demonstrated promising antitumor activity in myelofibrosis. We hypothesize that PAC inhibition of Jak2-Stat5 signaling will induce biochemical responses in men with recurrent PC by depleting AR and AR-V. Methods: BLAST (NCT04635059) is a single arm, open-label, phase 2 study of PAC (200mg BID) for patients with PC who underwent definitive treatment and developed BCR. Eligibility criteria include histologically confirmed PC, BCR with a PSA doubling time ≤ 9 months, PSA > 0.5 ng/mL, and serum testosterone > 150 ng/dL. 46 subjects will be enrolled with a primary objective to assess the effect of PAC on time to PSA progression. The primary endpoint is six-month PSA progression free survival per PCWG3 criteria. The null hypothesis that the median PSA-progression-free survival is six months will be tested against a one-sided alternative for the six-month PSA-progression-free survival probability exceeding 50%. Secondary endpoints include time to subsequent therapy, safety and toxicity. Exploratory endpoints include effect of PAC on geriatric domains. An interim analysis will be performed when 10 patients have been treated and followed for six months. Accrual began in July 2021. Clinical trial information: NCT04635059.
Talapro-3: A phase 3, double-blind, randomized study of enzalutamide (ENZA) plus talazoparib (TALA) versus placebo plus enza in patients with DDR gene mutated metastatic castration-sensitive prostate cancer (mCSPC).
Authors: Agarwal Neeraj , Azad Arun , Fizazi Karim , Mateo Joaquin , Matsubara Nobuaki , Shore Neal D. , Chakrabarti Jayeta , Chen Hsiang-Chun , Lanzalone Silvana , Niyazov Alexander , Saad Fred ,   For the TALAPRO-3 investigational group
Published: February 2022

TPS221 Background: TALA is a poly(ADP-ribose) polymerase inhibitor (PARPi) approved as monotherapy for germline BRCA1/2-mutated HER 2-negative advanced breast cancer. PARPi have demonstrated substantial clinical efficacy in metastatic castration-resistant prostate cancers (mCRPC) with alterations in DNA damage response (DDR) genes involved directly or indirectly in homologous recombination repair (HRR). Phase 3 study findings (de Bono et al. N Engl J Med. 2020;382:2091-2102) resulted in the approval of olaparib for mCRPC. ENZA is an androgen receptor (AR) inhibitor and established therapy for mCSPC. Since PARP activity has been shown to support AR function, PARP inhibition is expected to increase sensitivity to AR-directed therapies. In addition, AR blockade downregulates HRR gene regulation, which has been hypothesized to induce a “ BRCAness ” phenotype . A phase 2 study of TALA monotherapy (TALAPRO-1) demonstrated robust antitumor activity in men with heavily pretreated, HRR-mutated mCRPC . The Phase 3, double-blind, randomized trial TALAPRO-3 (NCT04821622) herein presented will compare the combination of TALA plus ENZA versus placebo plus ENZA in men with mCSPC with DDR/HRR alterations. Methods: Approximately 550 patients with mCSPC harboring DDR/HRR alterations will be randomized to TALA (0.5 mg once daily) plus ENZA (160 mg once daily) or placebo (once daily) plus ENZA (160 mg once daily). Key eligibility criteria include age ≥18 years; histological diagnosis of prostate cancer; alterations in 12 DDR/HRR genes known to sensitize to PARPi ( ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C); and metastatic disease (no brain metastases). Primary endpoint is rPFS (time to radiographic progression in soft tissue per RECIST 1.1 or in bone per PCWG3 criteria by investigator, or death). Secondary endpoints include overall survival, safety, and patient-reported outcomes. Patient recruitment is planned at approximately 285 sites in 27 countries, including the US and Europe, South America, South Africa, and Asia-Pacific. Clinical trial information: NCT04821622.
Window-of-opportunity clinical trial platform for evaluation of novel treatment strategies in renal cell cancer (WIRE).
Authors: Sipple Jamal A N , Thomas Martin G , Mossop Helen , Wason James , Gallagher Ferdia , Chhabra Anita , Warren Anne , Stone John , Venugopal Balaji , Oades Grenville , Welsh Sarah Joanne , Stewart Grant D. 
Published: February 2022

TPS406 Background: Renal cell cancer (RCC) is the 7th commonest cancer in the UK. The WIRE trial ‘exploits’ a window-of-opportunity between clear cell RCC diagnosis and nephrectomy to use vascular endothelial growth factor tyrosine kinase inhibitors, PARP inhibitors, and immune checkpoint inhibitor therapies in isolation and in combination. WIRE aims to provide biological proof-of-mechanism of these therapies, and build on encouraging pre-clinical evidence of DNA damage response inhibition to be an effective future therapeutic strategy in RCC. Methods: WIRE is a phase II, multi-IMP, multi-arm, non-randomised clinical trial featuring a Bayesian adaptive design with five treatment arms, and three recruitment stages per arm. The treatment groups: cediranib, cediranib and olaparib, olaparib, durvalumab, and durvalumab and olaparib form the initial set of therapy options with the opportunity for additional treatments to be deployed on this platform-trial in future. The primary endpoint for the first three arms is tumour capillary permeability, measured using multiparametric MRI, defined as a 30% reduction in Ktrans compared to pre-treatment. Whereas in the remaining two arms the primary endpoint is changed to intra-tumoural CD8 positive T cells, defined as an increase of 30% cell count compared to pre-treatment. Up to 76 evaluable participants will be recruited. Monotherapy arms will recruit a maximum of 12 participants each, whereas a maximum of 20 participants will be recruited into each dual-therapy arm. Participants are assigned to the current recruiting arm for treatment lasting between 14 and 28 days before proceeding with standard-of-care nephrectomy. Participants will undergo a biopsy and imaging before and after treatment for primary endpoint analysis, alongside blood and urine collections for translational endpoints. A final two follow-up visits are scheduled before concluding the trial pathway. Rapid interim analysis will follow at the end of a recruitment stage to determine whether to cease recruitment to the current treatment arm due to biological response, or due to futility – defined as lacking in promising evidence for proof of mechanism. Alternatively, if more data is required, recruitment will continue within the same treatment arm until the next interim analysis, where endpoints are re-examined. This highly-efficient design accelerates the exploration of multiple therapies with a strong emphasis on determining early proof-of-mechanism. Promising therapies can then be taken forward to later phase trials in RCC with greater confidence. Clinical trial information: NCT03741426.