bluuebunny/crossref_metadata_2025 huggingface dataset:
Pulmonary arterial hypertension associated with protein kinase inhibitors: a pharmacovigilance–pharmacodynamic study
Authors: Cornet Lucie , Khouri Charles , Roustit Matthieu , Guignabert Christophe , Chaumais Marie-Camille , Humbert Marc , Revol Bruno , Despas Fabien , Montani David , Cracowski Jean-Luc
Published: March 2019

The pathophysiology of pulmonary arterial hypertension (PAH) induced by protein kinase inhibitors (PKIs) remains unclear. To gain knowledge into this rare and severe pathology we performed a study combining a pharmacovigilance approach and the pharmacodynamic properties of PKIs.

A disproportionality analysis on the World Health Organization pharmacovigilance database VigiBase using the reporting odds ratio (ROR) and 95% confidence interval was first performed. Then, we identified the most relevant cellular targets of interest through a systematic literature review and correlated the pharmacovigilance signals with the affinity for the different PKIs. We further performed a hierarchical cluster analysis to assess patterns of binding affinity.

A positive disproportionality signal was found for dasatinib, bosutinib, ponatinib, ruxolitinib and nilotinib. Five non-receptor protein kinases significantly correlate with disproportionality signals: c-Src (r=0.79, p=0.00027), c-Yes (r=0.82, p=0.00015), Lck (r=0.81, p=0.00046) and Lyn (r=0.80, p=0.00036), all belonging to the Src protein kinase family, and TEC (r=0.85, p=0.00006). Kinases of the bone morphogenetic protein signalling pathway also seem to play a role in the pathophysiology of PKI-induced PAH. Interestingly, the dasatinib affinity profile seems to be different from that of other PKIs in the cluster analysis.

The study highlights the potential role of the Src protein kinase family and TEC in PAH induced by PKIs. This approach combining pharmacovigilance and pharmacodynamics data allowed us to generate some hypotheses about the pathophysiology of the disease; however, the results have to be confirmed by further studies.
PACE: Analysis of acute toxicity in PACE-B, an international phase III randomized controlled trial comparing stereotactic body radiotherapy (SBRT) to conventionally fractionated or moderately hypofractionated external beam radiotherapy (CFMHRT) for localized prostate cancer (LPCa).
Authors: Van As Nicholas John , Brand Douglas , Tree Alison , Ostler Peter James , Chu William , Loblaw Andrew , Ford Daniel , Tolan Shaun P. , Jain Suneil , Martin Alexander Stephen , Staffurth John , Brown Stephanie , Burnett Stephanie M. , Duffton Aileen , Griffin Clare , Hinder Vicki , Morrison Kirsty , Naismith Olivia Frances , Hall Emma ,   On behalf of the PACE investigators
Published: March 2019

1

Background: External beam radiotherapy (EBRT) is a curative treatment for LPCa. Large randomised controlled trials (RCTs) have shown moderately hypofractionated regimens (2.5–3 Gy/fraction(f)) as non-inferior to conventionally fractionated regimens (2 Gy/f). PACE-B aims to demonstrate non-inferiority of SBRT compared to CFMHRT for biochemical or clinical failure. Compared to CFMHRT, SBRT reduces patient (pt) attendances but compressed overall treatment time may influence acute toxicity severity. Methods: PACE is a phase III open-label multiple-cohort RCT. Men with LPCa, stage T1-T2, ≤ Gleason 3 + 4, PSA ≤ 20 ng/mL, unsuitable for surgery or preferring EBRT, were eligible for the PACE-B cohort. Between 08/12-01/18, 874 pts (38 centres) were randomised (1:1) to SBRT or CFMHRT. SBRT dose was 36.25 Gy/5f in 1-2 weeks (wks), CFMHRT as 78 Gy/39f over 7.5 wks, or 62 Gy/20f in 4 wks. Androgen deprivation therapy was not permitted. Clinician reported acute toxicity was assessed at baseline, 2-weekly during CFMHRT and at 2, 4, 8 & 12 wks post-treatment. Key toxicity outcomes were worst grade 2+ Radiation Therapy Oncology Group (RTOG) genitourinary (GU) and gastrointestinal (GI) acute toxicities, compared by Chi-square test with alpha 0.05 divided between the two measures. Results: By per protocol analysis n=430 received CFMHRT, n=414 received SBRT. Key characteristics seen in the CFMHRT and SBRT groups respectively were: mean age: 69.5 vs 69.3 years; T-stage ≥T2b: 51.8% vs 56.6%; Gleason Score 3+4: 80.2% vs 85.0%; PSA 10-20 ng/mL: 30.9% vs 31.6%. RTOG G2+ toxicity was not significantly different for GI events (CMFHRT 52/430 (12.1%) vs SBRT 42/414 (10.1%), p=0.368), nor GU events (CFMHRT 117/430 (27.2%) vs SBRT 96/414 (23.2%), p=0.179). Conclusions: Despite an accelerated treatment schedule, RTOG assessments show similar rates of acute GI and GU toxicity for SBRT and CFHFRT. Pt follow-up in PACE-B continues and results of late toxicity and biochemical/clinical failure are awaited. Clinical trial information: NCT01584258.
Brachytherapy use for favorable-risk prostate cancer continues to decline in both academic and community centers despite superior survival compared to dose-escalated external beam radiation therapy.
Authors: Nguyen Kevin H. , Patel Sagar Anil , Lee Alan K. , Venkat Puja , Chang Albert
Published: March 2019

105

Background: Several studies have highlighted the decline in brachytherapy (BT) utilization for localized prostate cancer, possibly due to reduced reimbursement, decreased provider efficiency, and decline in operative training. We sought to evaluate the most contemporary trends in BT versus dose-escalated external beam radiation therapy (DE-EBRT) use, as well as its impact on survival. Methods: We identified 134,713 men in the National Cancer Database with favorable risk prostate cancer (Gleason 6-7, clinical stage T1-2, and PSA < 20 ng/mL) who were treated with BT or DE-EBRT alone from 2004 to 2014. Multivariable logistic regression was used to identify independent determinants of treatment modality. Overall survival (OS) was compared between modalities using Kaplan-Meier and log-rank tests in propensity score-matched cohorts adjusted for age, race, comorbidities, year of diagnosis, and treatment facility. Results: The 10-year OS rate was higher for BT compared to DE-EBRT (BT 74.5%, DE-EBRT 68.2%, P< .0001). However, consistent with prior analyses, BT use decreased significantly from 59.3% in 2004 to 34.7% in 2014 ( P value for trend < .0001), with a corresponding rise in EBRT. The rate of decline was similar in academic and community centers; however, BT was consistently more often utilized in the community (63% in 2004, 61% in 2014). On multivariable analysis, BT was least likely to be used in men who were black (vs. white or Asian), treated at an academic (vs. community) center, and insured by Medicaid (vs. Medicare or private). Conclusions: Nationally, despite its superior survival and cost-effectiveness, prostate brachytherapy continues to be superseded by DE-EBRT in favorable risk prostate cancer, especially in men treated at academic centers and insured by Medicaid, with striking racial disparities. Payment reform, patient/provider education, and more robust resident training in prostate brachytherapy are urgently needed to help reverse this trend and ensure equal access to this efficacious treatment modality.
MRI-TRUS fusion-guided biopsy in obese patients: Does it reduce risk of prostate cancer upgrade on final pathology compared to systematic 12-core biopsy?
Authors: Gold Samuel A , Bloom Jonathan , Lebastchi Amir H , Hale Graham , Mehralivand Sherif , Sanford Thomas , Choyke Peter L. , Turkbey Baris , Pinto Peter A.
Published: March 2019

110

Background: Epidemiologic data suggests a link between obesity and increased risk of aggressive prostate cancer (PCa). Therefore, the accurate detection of prostate cancer is paramount in obese men. We sought to characterize the PCa lesions seen on multiparametric magnetic resonance imaging (mpMRI) in both obese (OB) and non-obese (nOB) patients. In addition, we examined whether obesity affects the accuracy of fusion biopsy (FBx) versus systematic biopsy (SBx). Methods: Data from patients who underwent FBx, SBx, or both, and subsequent prostatectomy at a single institution between 2007-2017 were reviewed. Men were stratified into three groups based on body mass index (BMI): normal weight (18.5-24.9), overweight (25.0-29.9), and obese (≥30.0). mpMRIs were analyzed to determine prostate size, lesion size, lesion location, and evidence of ≥T3 disease. FBx and SBx were compared to prostatectomy specimens. These variables were then analyzed between the OB and nOB groups. Results: 487 patients were included: 109 (19%) normal weight, 266 (48%) overweight, and 185 (33%) obese. No statistical differences were noted in age, PSA, or clinical stage. mpMRI showed similar prostate size, index and total lesion diameter, lesion location, and Prostate Imaging Reporting and Data System (PIRADS) score between BMI categories. In OB patients, FBx was better able to predict final Gleason score (GS) than SBx, 60% vs 47%, p = 0.0474, OR 1.67 (1.00-2.80). The rate of upgrading after SBx was higher for OB men versus nOB men, 44% vs 34%, p = 0.034, OR 1.52 (1.01-2.29). However, risk of upgrading returned to that of nOB men with FBx, 20% vs 17%, p = 0.538, OR 1.21 (0.658-2.23). Conclusions: FBx is a more accurate measure of the true GS in OB patients than SBx, and there is a significantly greater risk of underrepresenting PCa on SBx in OB patients. These findings were not associated with differences in prostate sizes and lesion characteristics on mpMRI. This suggests that obesity may cause technical challenges with prostate biopsies that may be overcome by improved visualization and targeting of FBx.
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

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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]
Eltanexor (KPT-8602), a second-generation selective inhibitor of nuclear export (SINE) compound, in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Zhang Jingsong , Chism David D. , Tagawa Scott T. , Monk Paul , Alter Robert S. , Reichman William , Senapedis William , Baloglu Erkan , Shacham Sharon , Kauffman Michael G.
Published: March 2019

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Background: Overexpression of exportin 1 (XPO1) in malignant cells increases the nuclear export/inactivation of tumor suppressor proteins (eg. p53), and promotes the translation of eIF4E-bound oncoprotein mRNAs (eg. c-MYC). XPO1 inhibition reduces total androgen receptor levels, including ARv7, and may re-sensitize prostate cancer (PC) cells to androgen deprivation therapy. Selinexor, the first-in-human SINE compound, showed anticancer activity in patients (pts) with mCRPC. Eltanexor (ELTA), a second-generation SINE compound, showed promising anticancer activity in preclinical models of PC, including in abiraterone (ABI) resistant cell lines. Therefore, ELTA ± ABI was evaluated in mCRPC. Methods: This was part of a phase 1/2 study to determine the safety, preliminary efficacy, and recommended phase 2 doseof ELTA in pts with advanced cancers. Pts with mCRPC received oral ELTA once daily for 5 days per week over a 28-day cycle in 4 cohorts: single-agent (20 mg; n=7 or 30 mg; n=6) or in combination with ABI (20 mg; n=13 or 30 mg; n=4). Pts may have prior exposure to chemotherapy. Pts receiving ELTA + ABI had prior response to ABI then progressed. Response was evaluated by PCWG3 / RECIST v1.1. Results: As of 17 Sept 2018, 30 pts were treated with ELTA ± ABI with a median age of 71 and a median of 4 prior regimens; (87% ABI, 60% enzalutamide, and 57% chemotherapy). Twenty-one pts with mCRPC were evaluable for efficacy: 2 partial response (10%), 15 stable disease (71%), and 4 progressive disease (19%). The median treatment duration is 75.5 days; 4 pts still on treatment. Treatment-related adverse events (TRAEs) occurring in ≥30% of the pts: fatigue (67%; 13% Gr≥3), nausea (63.3%; 0% Gr≥3), decreased appetite (57%; 0% Gr≥3), diarrhea (47%; 3% Gr≥3), weight decreased (43%; 3% Gr≥3), vomiting (37%; 7% Gr≥3), anemia (33%; 7% Gr≥3), and dysgeusia (33%; 0% Gr≥3). The 2 Gr4 TRAEs were neutropenia and elevated AST. Conclusions: ELTA± ABI is well-tolerated with AEs mostly limited to Gr 1/2 and demonstrates preliminary anti-tumor activity in patients with mCRPC. With enrollment complete, these results warrant further investigation of ELTA ± ABIin mCPRC. Clinical trial information: NCT02649790.
Outcomes of the patients with pT0 on first protocol biopsy during active surveillance for early prostate cancer: From the PRIAS-JAPAN study.
Authors: Kato Takuma , Sugimoto Mikio , Kakehi Yoshiyuki , Yamaguchi Akito , Yokomizo Akira , Shinohara Nobuo , Matsumoto Ryuji , Mitsuzuka Koji , Kume Haruki , Nakamura Masaki , Egawa Shin , Sasaki Hiroshi ,   PRIAS JAPAN Study Group
Published: March 2019

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Background: We assessed the outcomes of the patients with pT0 on first protocol biopsy during active surveillance(AS) from the analysis Japanese cohort forming part of the Prostate Cancer Research International: Active Surveillance (PRIAS) study. Methods: PRIAS-JAPAN started in January 2010. 39 institutions are participating in this study. The inclusion criteria for the PRIAS study are as follows: clinical stage T1c/T2, PSA ≤ 10 ng/ml, PSA density (PSAD) < 0.2 ng/ml per milliliter, one or two positive biopsy cores, and Gleason score (GS) ≤ 6 at initial diagnostic biopsy.In this analysis, we defined the patients presenting no reclassification with cancer after first protocol biopsy as NR-CA group and the patients presenting no reclassification showing pT0 as NR-noCA group. We compared AS remaining rate, pathological outcomes in extra biopsy and second protocol biopsy at 4 years between two groups. Results: First protocol biopsy was performed on 514 patients. 191 patients were in NR-noCA group and 199 patients were in NR-CA group. Patients background of NR-noCA group was as follows: Median age was 68, median PSA was 5.6ng/ml, and median prostate volume was 38.4cc. T1c were in 183 and T2a were in 8. At the time of first protocol biopsy, there was no significant differences about PSA parameters and pathological factors between NR-noCA group and NR-CA group. Also, extra biopsy performing rate (NR-noCA group vs NR-CA group; 5.75% vs 7.53%) and implementation rate of second protocol biopsy at 4 years (75.6% vs 63.6%) showed no significant differences. On second protocol biopsy, number of cancer positive cores were significantly smaller and rate of pT0 was higher in NR-noCA group. After five years, both group showed comparable AS remaining rate (76.9 vs 75.3%). Thirty eight patients of NR-noCA group selected definitive therapy and surgery was the most frequently chosen treatment option. Conclusions: Although rate of pT0 on second biopsy was higher in NR-noCA group, there was no significant difference between both groups in AS remaining rate. The patients in NR-noCA group tended to choose surgery as a definitive therapy. Clinical trial information: UMIN000002874.
Prostate cancer-derived anti-GRP78 autoantibodies compromise the blood-brain barrier and accelerate atherosclerosis progression in vivo.
Authors: Al-Hashimi Ali , Shayegan Bobby , Austin Richard , Won Kevin Doyoon
Published: March 2019

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Background: Pathological conditions of prostate cancer (PCa) drive the translocation of the endoplasmic reticulum-resident chaperone, GRP78, to the cell surface (cs) where it acts as an antigenic protein with signaling properties. In PCa, csGRP78 drives the production of anti-GRP78 autoantibodies (AutoAbs) that engage csGRP78 and promote PCa survival/progression. New studies now demonstrate csGRP78 expression on endothelial cells (EC) that line the arterial vasculature and the blood-brain barrier (BBB) suggesting that these AutoAbs can affect other systems in the body. Based on this, we investigated how the engagement of anti-GRP78 AutoAbs to csGRP78 on EC can contribute to EC-dysfunction that can promote atherosclerosis and compromise the integrity of the BBB. Methods: Anti-GRP78 AutoAbs were purified from PCa patients (St. Joseph’s Healthcare Hamilton); human aortic EC and the ApoE -/- mouse model were used for in vitro and in vivo investigations, respectively. EC or mice were treated with anti-GRP78 AutoAbs or IgG control (60µg/mL); EC-dysfunction was investigated by measuring attachment protein expression, in vitro. In vivo evaluation was carried out by studying atherosclerotic plaque progression (immunohistochemistry; aorta); the BBB integrity was examined using the Evans Blue dye. Results: Mice injected with anti-GRP78 AutoAbs, and not human IgG, demonstrated larger atherosclerotic plaque volume and hallmarks of a leaky BBB. In terms of a mechanism, in vitro studies demonstrated that treating EC with anti-GRP78 AutoAbs resulted in activation of the NFκB pathway that led to increased expression of attachment proteins. All these effects were reversed by using a recombinant molecule that interfere with the binding of the AutoAb to csGRP78. Conclusions: We have identified anti-GRP78 AutoAb as a driver of EC-dysfunction that promote atherosclerotic plaque progression and damage to the BBB. Our results indicate that interfering with anti-GRP78 AutoAb:csGRP78 complex can reverse the pathological effects of the AutoAbs. This novel data suggests that patient-derived anti-GRP78 autoantibodies systemically drive pathologies, other than cancer, in vivo.
Overall survival by race in chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone acetate or enzalutamide.
Authors: McNamara Megan Ann , George Daniel J. , Ramaswamy Krishnan , Lechpammer Stanislav , Mardekian Jack , Schultz Neil M. , Wang Li , Baser Onur , Huang Ahong , Freedland Stephen J.
Published: March 2019

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Background: Prostate cancer (PC) is the most common malignancy among US men and the 2nd leading cause of cancer-related death. African Americans (AAs) have higher mortality from mCRPC than Whites (W). Despite this disparity, a small prior study suggested AAs may have better PSA response to abiraterone acetate (ABAC) than Ws, though radiographic progression did not differ. We evaluated overall survival (OS) in AA vs W chemotherapy-naïve (CN) mCRPC patients (Ps) treated with ABAC or enzalutamide (ENZ). Methods: This was a retrospective study that used the Veterans Health Administration (VHA) database. Male PC Ps (≥18 years) who had surgical or medical castration were identified from Apr 1, 2013 to Mar 31, 2018. The index date was the first prescription claim date for ABAC or ENZ following castration. Ps had no chemotherapy for 12 months pre-index date and had continuous VA health plan enrollment for ≥12 months pre- and post-index date. Ps were followed until death or disenrollment. Unadjusted and Kaplan-Meier survival analyses adjusted for demographic and clinical characteristics were used to calculate survival time, and multivariate Cox proportional hazards models assessed the relationship between race and OS. Results: This study included 2,123 W and 787 AA mCRPC Ps with mean ages of 74 and 71 years, respectively. The median follow‐up time was 570 days and 561 days for AA and W, respectively. AA were more prone to comorbid hypertension (77.1% vs 67.1%; p<.0001), type II diabetes (38.1% vs 29.3%; p<.0001), and liver damage or abnormality (8.8% vs 5.2%; p=0.0003) than W . From the unadjusted analysis, the median Kaplan-Meier estimated OS was 910 days for AAs and 784 days for Ws; AAs had better OS than Ws (HR=0.887; 95%CI [0.790-0.996]). From the adjusted analysis, the median Kaplan-Meier estimated OS was 918 days for AAs and 781 days for Ws; AAs still had better OS (HR=0.826; 95%CI [0.732-0.933]). Conclusions: This large retrospective study provides the first evidence that AA CN mCRPC Ps may have better OS with ABAC or ENZ than W Ps. Trials are needed to validate this finding and explore the mechanisms of racial disparities in outcomes with new hormonal therapies.
Pembrolizumab for metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel: Updated analysis of KEYNOTE-199.
Authors: Antonarakis Emmanuel S. , Goh Jeffrey C. , Gross-Goupil Marine , Vaishampayan Ulka N. , Piulats Josep M. , De Wit Ronald , Alanko Tuomo , Fukasawa Satoshi , Tabata Kenichi , Feyerabend Susan , Berger Raanan , Wu Haiyan , Kim Jeri , Poehlein Christian Heinrich , De Bono Johann S.
Published: March 2019

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Background: Previously presented data from cohorts (C) 1-3 of the phase 2 KEYNOTE-199 study (n = 258; NCT02787005) showed that pembrolizumab monotherapy had antitumor activity and acceptable safety in patients (pts) with mCRPC previously treated with next-generation hormonal agents (NHAs; eg, abiraterone, enzalutamide) and docetaxel. Activity was observed for both PD-L1–positive and negative cohorts and in RECIST-measurable and bone-predominant disease. We present data from KEYNOTE-199 C1, C2, and C3 based on longer-follow-up. Methods: C1 enrolled 133 pts with RECIST-measurable, PD-L1–positive disease, C2 enrolled 66 pts with RECIST-measurable, PD-L1–negative disease, and C3 enrolled 59 pts with nonmeasurable, bone-predominant disease. All pts had ECOG PS 0-2 and received ≥1 NHA and 1-2 prior chemotherapies including docetaxel. Pembrolizumab 200 mg Q3W was given for 35 cycles or until PD or intolerable toxicity. Response was assessed Q9W in yr 1, then Q12W. Primary end point was ORR per RECIST v1.1 by central review. Key secondary end points included DCR (CR + PR + SD ≥6 mo), duration of response (DOR), OS, and safety. Results: Median follow-up as of Aug 21, 2018, was 9.5 mo in C1, 7.9 mo in C2, and 14.1 mo in C3. ORR (95% CI) was 5% (2-11) in C1 and 3% ( < 1-11) in C2. DCR was 10% in C1, 9% in C2, and 22% in C3 per RECIST v1.1. Median (range) DOR was not reached (1.9-21.8+ mo) in C1 and 10.6 mo (4.4-16.8) in C2; KM estimates of DOR ≥12 mo were 71% and 50%. Median (95% CI) OS was 9.5 mo (6.4-11.9) in C1, 7.9 mo (5.9-10.2) in C2, and 14.1 (10.8-17.6) in C3. 12-mo OS rates were 41% in C1, 35% in C2, and 62% in C3; 18-mo rates were 30%, 21%, and 36%. Grade 3-5 drug-related AE rates were 15% in C1, 14% in C2, and 17% in C3. There were 2 drug-related deaths (n = 1 each sepsis and pneumonitis). Conclusions: Pembrolizumab shows antitumor activity and disease control with acceptable safety in RECIST-measurable and bone-predominant mCRPC previously treated with NHAs and docetaxel. Responses are durable, and the observed OS benefit is promising. Clinical trial information: NCT02787005.
Next generation N-terminal domain androgen receptor inhibitors with improved potency and metabolic stability in castration-resistant prostate cancer models.
Authors: Le Moigne Ronan , Zhou Han-Jie , Mawji Nasrin R , Banuelos C. Adriana , Wang Jun , Jian Kunzhong , Virsik Peter , Andersen Raymond J , Sadar Marianne
Published: March 2019

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Background: EPI-506, pro-drug of EPI-002, was a first-in-class oral small molecule from the Aniten family of compounds, which inhibit androgen receptor (AR) activity by binding to the N-terminal domain of the AR. EPI-506 was tested in a Phase 1 study in men with metastatic castration-resistant prostate cancer (mCRPC) resistant to current therapies and demonstrated a favorable tolerability profile with signs of moderate efficacy. Metabolic vulnerabilities in the chemical scaffold of EPI-506 were identified and new Aniten molecules, EPI-7170 and EPI-7245 , with improved potency, metabolic stability and pharmaceutical properties have been generated. Methods: Chemical structure activity relationships were developed in order to increase molecule potency in cellular and in vivo assays, while metabolic stability improvements were assessed in in vitro ADME assays and in animal pharmacokinetic studies. In addition, the on-target activity and selectivity was also optimized using a variety of cellular experiments. Results: Next generation Anitens demonstrated a 10-20 fold improvement on AR-driven cellular potency, with IC50’s of 0.5-1 uM when compared to 10-12 uM for EPI-002. In vitro proliferation assays demonstrated on target activity, with an IC50 ~ 2 uM in LNCaP and > 10 uM in the AR-independent cell model PC-3. EPI-7170 was also active in AR-V7-driven LNCaP95 cells. The antiproliferative effect was in alignment with the inhibitory effect on a subset of AR driven genes. In vivo activity in castrated mice bearing LNCaP tumors showed tumor growth inhibition of approximately 70%. While EPI-7170 represents a major advance, subsequent chemistry efforts led to the generation of EPI-7245 and other next generation Anitens which exhibit IC50’s < 500 nM and favorable ADME and PK profiles. Conclusions: Promising next-generation Aniten compounds have been identified. Major chemistry efforts led to the identification of several Anitens with > 10-20 fold improvements in cellular potency compared to EPI-506 which are also metabolically stable. IND-selection preclinical studies are underway on the most promising Aniten’s with an IND submission planned shortly.