bluuebunny/crossref_metadata_2025_split huggingface dataset:
Incidence of hypocalcemia in patients with castration-resistant prostate cancer treated with denosumab: Data from a non-inferiority phase III trial assessing prevention of symptomatic skeletal events (SSE) with denosumab administered every four weeks (q4w) versus every 12 weeks (q12w)—SAKK 96/12 (REDUSE).
Authors: Gillessen Silke , Von Moos Roger Anton Fredy , Hayoz Stefanie , Hawle Hanne , Cathomas Richard , Rothermundt Christian Alexander , Anchisi Sandro , Mueller Andreas , Wehrhahn Tobias , Burmeister Henning , Stoll Susanna , Llado Anna , Borner Markus M. , Pedrazzini Augusto , Huber-Tribolet Urs Sebastian , Bohanes Pierre Oliver , Winterhalder Ralph C. , Fuhrer Andrea Corinne , Schaer Corinne , Templeton Arnoud J. 
Published: March 2019

139 Background: DN given q4w has shown superiority in delaying skeletal related events over q4w zoledronic acid (ZA). Recently it has been demonstrated that ZA q12w is non-inferior to ZA q4w. The objective of REDUSE is to show non-inferiority for DN q12w versus q4w in terms of SSE. Here we present an interim analysis for the secondary endpoint HC. Methods: Patients (pts) with castration resistant prostate cancer (planned N=690) were randomized 1:1 to DN q4w (Arm A) vs q12w (Arm B) after a 16 week induction phase with application q4w. All pts received vitamin D (ViD) 400 U and calcium (Ca) 500 mg daily. Measurement of corrected serum-Ca was mandatory before each DN injection. This interim analysis was performed after 3.5 years of accrual. Men who received ≥ 1 dose of DN were considered evaluable. Results: 383 pts were evaluable. HC occurred in 28.7% during the first 16 weeks (DN q4w for all pts) and 30.2% afterwards. After the induction phase HC occurred in 40.2% in Arm A and in 20.3% in Arm B. Grade 3 (2.1%) and 4 (1.1%) HC were rare, most frequently occurring in the first 16 weeks. After 1 year of treatment, the incidence of HC was lower in both arms (A: 30.8%, B: 18.7%). A clinically relevant difference for HC was noted between the two arms after the induction phase (table). Conclusions: In our trial nearly 30% of all men treated with DN experienced HC in the q4w induction phase despite mandatory supplementation of calcium and ViD and measurement of Ca. This rate was considerably higher than reported in the registration trials of DN (13%). After induction treatment the incidence of HC is considerably lower in the q12w arm compared to q4w. This suggests that DN given q12w has a more favorable long time toxicity profile (HC) compared to DN q4w. Change in HC grade after week 16 (week 1 – 12: DN q4w Arm A+B), thereafter q4w in Arm A and q12w in Arm B. Clinical trial information: NCT02051218. [Table: see text]
Final analysis of phase III LATITUDE study in patients (pts) with newly diagnosed high-risk metastatic castration-naïve prostate cancer (NDx-HR mCNPC) treated with abiraterone acetate + prednisone (AA+P) added to androgen deprivation therapy (ADT).
Authors: Fizazi Karim , Tran Namphuong , Fein Luis Enrique , Matsubara Nobuaki , Rodríguez Antolín Alfredo , Ozguroglu Mustafa , Ye Dingwei , Feyerabend Susan , Protheroe Andrew , Sulur Giri , Luna Yesenia , Li Susan , Mundle Suneel , Chi Kim N. 
Published: March 2019

141 Background: The first and second interim analyses (IA1 and IA2) of the LATITUDE study in NDx-HR mCNPC pts with addition of AA+P to ADT vs placebo (PBO)+ADT showed significant benefit in the coprimary endpoints of overall survival (OS) and radiographic progression free survival (rPFS), and secondary endpoints. Final OS analysis and updated safety results are presented. Methods: 1,199 pts were randomized (1:1) to AA (1 g QD) + P (5 mg QD) + ADT or PBO + ADT. Primary endpoint of OS and secondary endpoints were assessed (stratified proportional hazards model), and adverse events (AEs) were summarized from final analysis, which was planned for around 852 total death events. Results: Final analysis was conducted after a median follow-up of 51.8 mo (~22 mo from IA1) and 618 deaths were observed (275 [46%] in AA+P and 343 [57%] in PBO). Treatment was ongoing for 157 (26.3%) pts in AA+P; 72 (12.0%) crossed over from PBO to AA+P, of which 59 (81.9%) remained on treatment. AA+P treatment continued to show significant OS benefits vs PBO (HR: 0.7, 95% CI: 0.6-0.8; p<0.0001), along with significant improvements in secondary endpoints (table). Serious AEs were reported in 32.2% pts in AA+P and 25.1% in PBO. Grade 3/4 AEs of special interest (AA+P vs PBO; %) were hypertension (21.9 vs 10.5), hypokalemia (11.7 vs 1.7), hepatotoxicity (8.9 vs 3.5), cardiac disorders (3.9 vs 1) and fluid retention (0.8 vs 1). Conclusions: The final analysis continues to demonstrate a significant OS advantage of combining AA+P to ADT in NDx-HR mCNPC pts. These efficacy findings and AE profiles are consistent with IA1 and IA2 and reinforce AA+P as a standard of care in NDx-HR mCNPC pts. Clinical trial information: NCT01715285. [Table: see text]
Genomic drivers of poor prognosis and enzalutamide resistance in metastatic castration-resistant prostate cancer.
Authors: Chen William S. , Aggarwal Rahul Raj , Zhang Li , Zhao Shuang , Beer Tomasz M. , Quigley David A , Foye Adam , Playdle Denise , Lloyd Paul , Rettig Matthew , Gleave Martin , Evans Christopher P. , Lara Primo , Kothari Vishal , Chi Kim N. , Reiter Robert Evan , Maher Christopher , Feng Felix Y , Small Eric Jay , Alumkal Joshi J. ,   West Coast Prostate Cancer Dream Team
Published: March 2019

146 Background: Metastatic castration-resistant prostate cancer (mCRPC) is the lethal form of the disease. Several recent efforts have identified genomic alterations in mCRPC, but the clinical implications of these alterations have not been fully elucidated. We conducted a prospective cohort study (n = 101) using whole genome sequencing (WGS) to analyze the association between key driver gene alterations and overall survival. We also performed whole-transcriptome RNA sequencing (RNA-seq) analyses to identify potential mechanisms of enzalutamide resistance in mCRPC. Methods: Metastasis biopsies were obtained in 101 mCRPC patients as part of the multi-institutional West Coast Prostate Cancer Dream Team project. Samples underwent WGS and RNA-seq. The resulting mutation, copy number, and structural variant calls were integrated to determine functional copy number status of candidate genes for downstream clinical analyses. We performed univariate and multivariable analyses to assess the prognostic significance of candidate genomic events with respect to overall survival. To nominate and investigate genomic pathways associated with enzalutamide resistance, we performed expression-based gene set enrichment analysis followed by cross-sectional enrichment and survival analyses related to the top nominated pathway. Results: RB1 loss was associated with poor overall survival (median 14.1 vs. 42.0 months, p < 0.001). When we compared enzalutamide resistant versus naïve samples using gene set enrichment analysis, we identified the Wnt/beta-catenin pathway as the top differentially expressed pathway in enzalutamide-resistant patients. Furthermore, CTNNB1 (beta-catenin) activating mutations were exclusive to enzalutamide-resistant patients (p = 0.013) and predictive of poor overall survival (median 13.6 vs. 41.7 months, p < 0.001). Conclusions: Impaired survival in mCRPC patients is associated with RB1 loss, identified by integrated genomic analysis of CRPC metastasis biopsies. Among men with mCRPC that was enzalutamide-resistant, the Wnt/beta-catenin pathway is nominated as an important predictive (and potentially therapeutic) pathway.
Higher blood–brain barrier penetration of [14C]apalutamide and [14C]enzalutamide compared to [14C]darolutamide in rats using whole-body autoradiography.
Authors: Zurth Christian , Sandman Steffen , Trummel Dagmar , Seidel Dietrich , Nubbemeyer Reinhard , Gieschen Hille 
Published: March 2019

156 Background: Darolutamide ([14C]Daro) is an investigational oral androgen receptor antagonist, structurally distinct from enzalutamide ([14C]Enza) and apalutamide ([14C]Apa). In a retrospective analysis of the ARADES database, central nervous system (CNS)-related adverse events (AEs) were not linked with Daro (Fizazi, et al. 2015). CNS-related AEs have been observed with Enza and Apa, eg, fatigue, mental impairment, and seizure (Hussain et al, 2018; Smith et al, 2018). In preclinical studies, low blood–brain barrier (BBB) penetration of Daro was observed, suggesting low impact on the CNS. To understand the different CNS effects, we report in vivo tissue distribution data in rats with [14C]-labeled Apa compared to previously presented [14C]Enza and [14C]Daro distribution data (Zurth, ASCO GU 2018) using quantitative whole-body autoradiography (QWBA). Methods: Male rats were orally dosed with 10 mg/kg [14C]Apa under similar experimental conditions as previously reported for [14C]Daro or [14C]Enza, prior to QWBA. One animal was sacrificed at each timepoint: (tmax) 3h, 8h, and 24h post-dose. Timepoint selection was based on a single oral Apa dose pharmacokinetic study in rats. Results: Apa displayed good absorption and homogeneous distribution throughout the body early post-dose, comparable to previous observations for Enza and Daro. As observed for [14C]Enza, [14C]Apa remained constant in the body (t1/2 ~4h vs ~3h) up to 8h post-dose, whereas [14C]Daro was eliminated from all tissues (t1/2 ~1h). High concentrations of [14C]Apa persisted in the brain for up to 8h, although concentrations were ~2-fold lower than previously reported for [14C]Enza. [14C]Daro brain concentrations were near the lower limit of quantification, and ~26x and 46x lower than [14C]Apa and [14C]Enza brain concentrations, respectively. Conclusions: The current preclinical study demonstrated moderate BBB penetration for Apa, similar to the previous Enza data, whereas Daro displayed > 25-fold lower BBB penetration, suggesting that Daro may be less likely to induce CNS-related AEs, which is expected to be confirmed by data from the ARAMIS study.
A phase I/II study of proxalutamide (GT0918), a potent androgen receptor blocker, in patients with mCRPC progressed after both hormonal therapy and chemotherapy.
Authors: Vogelzang Nicholas J. , Levin Richard , Chu David T. , Gabrail Nashat Y. , Nordquist Luke T. , Stein Mark N. , Dave Harish P. , Zhang Phoebe , Zhou Karl 
Published: March 2019

169 Background: GT0918 is a new chemical entity of androgen receptor (AR) blocker. A phase I/II study was conducted to identify dose-limiting toxicities (DLTs) and to assess safety, tolerability, and PK of GT0918 in pts with mCRPC who have progressed on standard of care (SoC) and experimental therapies in the United States. Methods: Patients (pts) with histologically confirmed mCRPC who had progressed after both hormonal therapy (abiraterone or/and enzalutamide) and chemotherapy (e.g., docetaxel) were eligible. GT0918 was administered once daily orally for 28 consecutive days, followed by a 7-day off-treatment period for PK analysis. The first 28-days on treatment (cycle 1) was defined as DLT period. Pts continued on receiving GT0918 thereafter until they experienced one of following events of intolerable toxicities, disease progression or withdrew consent. Results: 35 pts were enrolled to GT0918-US-1001 trial with 6 dose escalations of study drug defined in protocol: 50 mg (n = 3), 100 mg (n = 6), 200 mg (n = 6), 300 mg (n = 7), 400 mg (n = 7) and 500 mg (n = 6). All pts progressed on multiple lines of therapies including but limited to bicalutamide, abiraterone, enzalutamide, docetaxel, cabazitaxel, radium 223, sipuleucel T and pembrolizumab. No DLT was observed and MTD has not been reached. GT0918 related adverse events (AEs) were less than 10% and grade 1 or 2 as per CTCAE v4.03, including fatigue, nausea, dizziness, loss of appetite, back pain, hot flush, hypercholesterolemia, anemia, constipation, etc. Two events of grade 3 fatigue and one event of grade 4 elevated creatine kinase (CK) were reported. Stable disease by imaging scans at 24 weeks by dose group were; 1/50 mg, 1/100mg, and 4/400mg. Three pts on 500mg finished 3 cycles and continue on the treatment (as 10/15/18). PSA decreases were also seen among pts at 500mg dose level for 4 cycles. Conclusions: GT0918 administrated orally once a day is well tolerated and resulted in SD in late-stage pts. No DLT has occurred to date (at 500 mg) and dose escalation is planned to 600 mg or higher. Extended/Ph II trial will further evaluate safety and efficacy of GT0918 in mCRPC pts. Clinical trial information: NCT02826772.
Keynote-365 cohort b: Pembrolizumab (pembro) plus docetaxel and prednisone in abiraterone (abi) or enzalutamide (enza)-pretreated patients (pts) with metastatic castrate resistant prostate cancer (mCRPC).
Authors: Massard Christophe , Retz Margitta , Hammerer Peter , Quevedo Fernando , Fong Peter C.C. , Berry William R. , Gurney Howard , Piulats Josep M. , Joshua Anthony , Linch Mark David , Kolinsky Michael , Romano Emanuela , Sridhar Srikala S. , Conter Henry Jacob , Augustin Marinela , Wu Haiyan , Schloss Charles , Poehlein Christian Heinrich , Yu Evan Y. 
Published: March 2019

170 Background: Pembro had antitumor activity as monotherapy in pretreated advanced mCRPC (KEYNOTE-028; KEYNOTE-199). KEYNOTE-365 (NCT02861573) is a phase 1b/2 umbrella study testing combinations in mCRPC; we report early results from cohort B combining pembro + docetaxel in mCRPC. Methods: Pts who failed or became intolerant to ≥4 weeks of abi or enza in the pre-chemotherapy mCRPC state received pembro 200 mg IV with docetaxel 75 mg/m2 IV Q3W plus prednisone 5 mg orally twice daily. Pts also progressed within 6 months prior to screening as determined by either PSA progression or radiologic progression in bone or soft tissue. Response was evaluated by PSA levels Q3W and imaging Q9W for first year and Q12W thereafter. Primary end points: safety and PSA response rate (confirmed PSA decline ≥50%). Key secondary end points: investigator-determined ORR (RECIST v1.1), disease control rate (DCR: CR+PR+SD ≥6 mo), time to PSA progression, rPFS, and OS. Results: 72 pts (median age 68 years; PD-L1+ 29%; visceral disease 36%; measurable disease 50%) initiated pembro + docetaxel. Median (95% CI) follow-up was 10 (8-12) mo. Efficacy is outlined in table below. Treatment-related AEs occurred in 69 (96%) pts; most frequent (≥30%) were alopecia (43%), fatigue (40%), and diarrhea (39%). Grade 3-5 treatment-related AEs occurred in 27 (38%) pts, including 2 deaths due to treatment-related AEs (pneumonitis). Conclusions: Combination of pembro + docetaxel/prednisone has activity in pts with mCRPC previously failing anti-hormonal therapy. Observed safety profile for the combination was consistent with known safety profile of each component. Clinical trial information: NCT02861573. [Table: see text]
Pembrolizumab in men with heavily treated metastatic castration-resistant prostate cancer (mCRPC).
Authors: Tucker Matthew D , Zhu Jason , Berry William R. , Ramalingam Sundhar , Zhang Tian , Harrison Michael Roger , Wu Yuan , Healy Patrick , George Daniel J. , Armstrong Andrew J. 
Published: March 2019

172 Background: Pembrolizumab is approved for patients with metastatic, microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) solid tumors who have progressed on prior therapy and have no satisfactory treatment options. However, very few men with PC were included in these initial studies. We evaluated the clinical activity of pembro in a cohort of men with mCRPC and their responses based on molecular genotype. Methods: We performed a retrospective, IRB-approved review of all men with mCRPC in the Duke Cancer Center who were treated with pembro in order to define the duration of therapy, time to PSA-progression, and imaging responses according to prior/concurrent therapy and by molecular subtypes. Results: We identified 51 men who received ≥1 cycle of pembro for mCRPC. Of these, 86% (44/51) had ≥3 prior lines of therapy after ADT, including abiraterone (88%), docetaxel (86%), enzalutamide (enza, 80%), and sipuleucel-T (74%). Somatic tumor sequencing was available in 18/51 men (35%). We found that 16% (8/51) had a ≥50% confirmed PSA decline with pembro, with 8% (4/51) having ≥90% PSA decline. Two of 4 had mutations in LRP1b, one of whom also had MSH2loss and was MSI-H and TMB-high; of the other 2 patients, one had no actionable mutations and the other had no genetic testing available. Fifty-nine percent (30/51) of men were treated with concurrent therapy with pembro (most commonly enza); however, all patients with PSA responses who were concurrently treated with enza had prior documented PSA progression on enza. Overall, the median time to discontinuation of treatment was 5.8 months (mo), median PSA-PFS, defined as a 25% increase in PSA from baseline, was 1.4 mo, and median OS was 6.7 mo. Among patients with ≥50% PSA decline, duration of response ranged from 3.7 to 16.3 mo with 5 patients with ongoing responses. Conclusions: In a heavily pre-treated population of men with mCRPC, pembrolizumab was associated with a ≥50% PSA decline in 16% (8/51) of men, including a dramatic ≥90% PSA response in 8% (4/51), two of whom harbored LRP1b mutations, one also with MSH2loss and a MSI-H tumor. Large prospective studies with genomic testing are needed to identify men with the greatest chance for response to immunotherapy.
GATA2 exosomal mRNA: A novel urine biomarker for the diagnosis of clinically significant prostate cancer.
Authors: Woo Jungreem , Santasusagna Sandra , Leiby Benjamin , Yadav Kamlesh K , Dominguez-Andres Ana , Pippa Raffaella , Wang Kerith Ruoyao , Carceles-Cordon Marc , Fields Shannon , Weil Rachel , Stolovitzky Gustavo A. , Tewari Ashutosh , Lu-Yao Grace L. , Kelly William Kevin , Rodriguez-Bravo Veronica , Prats Josep Maria , Gomella Leonard G. , Domingo-Domenech Josep 
Published: March 2019

18 Background: Prostate specific antigen (PSA) detection in blood is widely used to screen for prostate cancer (PCa). However, PSA has limited utility in discriminating tumors at high risk of progression from indolent-low risk tumors, which leads to PCa overtreatment and highlights the need to identify better biomarkers for the detection of clinically significant PCa (Gleason Score; GS ≥ 7). Here, we introduce a novel mRNA GATA2 exosomal biomarker detected in urine useful to diagnose clinically significant PCa. Exosomes are 50-120 nm sized vesicles shed in body fluids that contain RNA, DNA, and protein that can be used as biomarkers to interrogate the health of the originating cells. GATA2 is a pioneer transcription factor specific to PCa, increased in aggressive tumors. Methods: To evaluate the predictive value of exosomal GATA2 mRNA levels for aggressive PCa, we isolated exosomes using ultracentrifugation in non-DRE urines from 128 males with elevated PSA serum levels (> 4ng/ml) and analyzed them according to their tissue biopsy result. Results: Importantly, prostate origin of GATA2 mRNA detected in urine exosomes was confirmed by observing that exosomal GATA2 mRNA levels significantly dropped after prostatectomy (p < 0.05). Most remarkably, GATA2 exosomal mRNA expression was significantly increased in PCa biopsy positive patients (n=88) when compared to biopsy negative males (n=28, p < 0.001). Furthermore, GATA2 levels in PCa patients were significantly associated with GS, but not with disease stage and PSA levels. Multivariable regression analysis showed that GATA2 exosomal mRNA levels are an independent factor for the diagnosis of aggressive PCa. Urine GATA2 exosome mRNA expression plus SOC (age and PSA) was associated with improved discrimination of GS ≥ 7 versus GS 6 and benign disease: AUC of SOC alone 0.59 (0.49-0.70, p value=0.083) vs SOC plus GATA2 AUC of 0.68 (95% CI, 0.58-0.78, p value=0.0004). Conclusions: The analysis of urine exosomal GATA2 mRNA in individuals with high PSA may help distinguish clinically significant PCa and reduce the number of patients that need biopsy. Future studies are focused on combining this biomarker to others, such as urine exosomal PCA3, already used in the clinic.
A retrospective analysis of treatment patterns in metastatic castration-resistant prostate cancer patients treated with radium-223.
Authors: Sartor A. Oliver , Appukkuttan Sreevalsa , Aubert Ronald E. , Weiss Jeffrey , Wang Joy , Simmons Stacey , Tsao Che-Kai 
Published: March 2019

180 Background: Radium-223 (RA-223) is the first FDA approved targeted alpha therapy that significantly improves overall survival (OS) in patients (pts) with metastatic castration resistant prostate cancer (mCRPC) with symptomatic bone metastases. There is limited real world data describing RA-223 current use. Methods: A retrospective patient chart review was done of men who received at least 1 cycle of Ra-223 for mCRPC in 10 centers throughout the US (4 academic, 6 private practices). All pts had a minimum follow-up of 4 months, or placed in hospice or death. Descriptive analyses for clinical characteristics and treatment outcomes were performed. Results: Among the 200 pts (mean age-73.6 years, mean Charlson comorbidity index-6.9) RA-223 was initiated on average 1.6 years from mCRPC diagnosis (first line use (1L)=38.5%, 2L=31.5% and ≥3L=30%). 78% completed 5-6 cycles of RA-223 with mean therapy duration of 4.2 months. Among all pts, 43% received RA-223 as monotherapy (no overlap with other mCRPC therapies) while 57% had combination therapy with either abiraterone or enzalutamide. Median OS following RA-223 initiation was 21.2 months (95% CI 19.6- 29.2). Table provides the RA-223 utilization by type of clinical practice. Conclusions: Utilization of RA-223 in this real world data set was distinct from clinical trial data. Most patients received RA-223 in combination with abiraterone or enzalutamide, therapies that were unavailable when the pilot trial was conducted. Median survival was 21.2 months. Real world use of RA-223 has evolved as newer agents have become FDA approved in bone-metastatic CRPC. Academic and community patterns of practice were more similar than distinct. [Table: see text]