bluuebunny/crossref_metadata_2025_split huggingface dataset:
Concomitant characterization of androgen receptor (AC) and immune checkpoints (ICs) in cell-free (cf) DNA and RNA from patients with metastatic castration resistant prostate cancer (mCRPC).
Authors: Pal Sumanta K. , Szeto Christopher , Reddy Sandeep K. , Nussenzveig Roberto , Lam Richard Y. , Scholz Mark C. , Agarwal Neeraj 
Published: March 2019

286 Background: Immunotherapy (IO) appears to benefit a subset of patients (pt) with mCPRC, with recent data showing disease control > 6 mo in 11% of patients (De Bono et al ASCO 2018). We interrogate cfDNA/cfRNA from pt with mCRPC to ascertain relationships between AR and IC markers, and offer preliminary correlation with response to IC inhibitors (ICIs). Methods: Pt in this series were on active therapy for mCRPC and received cfDNA/cfRNA assessment for 26 analytes using the CLIA-certified NantHealth LiquidGPS platform during the course of routine clinical care. For this assay, 10 mL of blood were separately collected in DNA and RNA stabilizing solutions, respectively. DNA was amplified via mutant allele-specific blocker or allele-specific PCR assays. Wild type (WT) DNA was PCR amplified in an area where mutations had not been detected, and allele fractions were determined by the ratio of mutant to WT alleles. RNA was reverse transcribed to cDNA using random hexamer primers and amplified via gene specific assays relative to a stably expressed housekeeping gene, beta actin. Results: 103 pt were tested, median age 74y (range, 51-95). Expression was elevated for AR in 41%, and for AR-V7 in 3% pt. cfRNA detected expression for PD-L1, CTLA4, LAG-3 and TIM-3 in 60%, 52%, 72%, and 81% pt respectively. There was no strong association between AR and PD-L1 expression (Rho = 0.03, P = 0.77), or coincidence of detectable levels (OR = 1.4, p = 0.43). AR expression weakly inversely correlated with expression of CTLA4, LAG-3 and TIM-3. In 2 pts responding to ICI therapy, markedly increased PD-L1 and CTLA4 expression was noted. Multiple additional pts are receiving ICIs and correlation between expression of AR/IC markers and response will be presented. Conclusions: Unlike within the tumor microenvironment,expression ofcirculating AR and IC markers are independent biomarkers offering potentially more specific insights into combination versus sequential strategies for AR-directed tx and IO. Our preliminary observation of elevated circulating IC makers in the context of ICI response in mCRPC will be assessed in a larger series.
Phase II trial enzalutamide and androgen deprivation therapy (ADT) with salvage radiation in men with high-risk PSA recurrent prostate cancer (PC): The STREAM trial.
Authors: Armstrong Andrew J. , Bitting Rhonda L. , Healy Patrick , George Daniel J. , Kim Sung , Mayer Tina M. , Winters Carolyn , Riggan Colleen , Rasmussen Julia , Wilder Rhonda , Anand Monika , Stein Mark N. , Frizzell Bart , Harrison Michael Roger , Zhang Tian , Lee W. Robert , Wu Yuan , Koontz Bridget F. 
Published: March 2019

29 Background: Salvage external beam radiotherapy (RT) and hormonal therapy improves survival over RT alone in men with non-metastatic hormone naïve PC and PSA recurrence after radical prostatectomy (RP). We investigated the safety/efficacy of enzalutamide with salvage RT and ADT in this setting. Methods: This was a 3 center prospective phase 2 single arm clinical trial in the Dept of Defense Prostate Cancer Clinical Trials Consortium. Eligibility: Gleason 7-10 PC and PSA recurrence within 4 years (yrs) of RP, PSA 0.2-4.0, no prior hormonal therapy, and no metastases on CT/Bone Scan imaging. Men received 6 months (mos) of ADT with 160 mg/d enzalutamide and 66 Gy RT to the prostate bed. Primary endpoint was 2 yr PFS with testosterone (T) recovery to >100 ng/dl. Secondary objectives included PSA nadir, 3 yr PFS, safety and patient reported quality-of-life over time. This trial was designed with 84% power to detect a 20% improvement in 2 yr PFS vs historic data and a 1-sided alpha of 0.05. Results: We enrolled 38 men (90% white, 8% black, 2% Asian); 37 (97%) completed therapy and were evaluable with T recovery at 2 yrs. Median age was 64 yrs; 47% Gleason 8-10, 79% T3/T4 disease, 21% had resected N+ PC; median PSA was 0.4 (0.19-4.19). Median follow-up is 29.5 mo. Treatment was well tolerated with 11 patients (29%) experiencing G3 toxicities (including 4 HTN, 2 urinary retention, 2 CV events); no G4-5 or unexpected toxicities were observed. T recovery occurred in 35 (95%) at 12 mos. The primary endpoint of 2 yr PFS was 65% (95% CI: 47%-78% vs. historic controls with 51% 2 yr PFS rate) among the 37 patients with T recovery. PSA remained at undetectable levels in 69% at 2 yrs. The 3 yr PFS was 53% (95% CI: 36%, 68%). QOL data over time suggest short term reductions in urinary and sexual function with recovery by 12-24 mo in most men. Conclusions: Salvage enzalutamide and ADT for 6 months with RT following RP for men with PSA recurrent high risk PC is safe, and demonstrates encouraging efficacy at 2 and 3 years. Most men have testosterone recovery at 1 year. These data warrant prospective controlled phase 3 trials to assess the impact of potent AR inhibition in this curative intent setting. Clinical trial information: NCT02057939.
Drug-drug interaction (DDI) of darolutamide with cytochrome P450 (CYP) and P-glycoprotein (P-gp) substrates: Results from clinical and in vitro studies.
Authors: Zurth Christian , Graudenz Kristina , Denner Karsten , Korjamo Timo , Fricke Robert , Wilkinson Gary , Seitz Friedeborg , Prien Olaf 
Published: March 2019

297 Background: Maintaining quality of survival, by delaying disease progression and minimizing therapy burden, is critical for patients and has been evaluated in the pivotal phase III ARAMIS study in patients with non-metastatic castration-resistant prostate cancer. Due to comorbidity, elderly men often receive multiple comedications, including CYP and P-gp substrates, eg, simvastatin and digoxin. Enzalutamide and apalutamide, approved androgen receptor (AR) inhibitors, are strong CYP3A4 inducers and thus have potential for CYP-mediated DDIs. The effect of darolutamide, a structurally unique AR antagonist, on CYP activity ( in vitro and in vivo) and P-gp activity ( in vivo) was assessed. Methods: Inhibition of CYP isoforms by Daro was investigated in human liver microsomes using standard substrates. In addition, CYP and P-gp activity during darolutamide treatment was studied in a phase I trial of 15 healthy men who received 75 mg dabigatran etexilate (DABE, P-gp substrate) + 1 mg midazolam (MDZ, CYP3A4 substrate) once followed by 600 mg darolutamide (two 300 mg tablets) twice daily (BID) given with food for 9 days. On day 9, darolutamide was concomitantly administered with a single dose of 75 mg DABE + 1 mg MDZ. Results: Based on in vitro data, no clinically relevant inhibition of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4 by darolutamide is expected. In 13 evaluable subjects in the phase I study, concomitant darolutamide reduced MDZ Cmax by ~32% and AUC by ~29% vs MDZ alone. Concomitant darolutamide reduced non-conjugated dabigatran Cmax by 16% and AUC by 9% vs DABE alone. The observed treatment-emergent adverse events were consistent with the known safety profile of darolutamide. No new safety risks were revealed by co-administration of darolutamide and DABE or MDZ. Safety data for patients in ARAMIS who received darolutamide, including those with concomitant CYP or P-gp substrates, will be presented. Conclusions: Darolutamide showed only weak effects or none on P-gp, CYP3A4, or any other relevant CYP enzyme. Thus, darolutamide is not expected to cause any clinically relevant DDI with CYP or P-gp substrates, minimizing complications of polypharmacy. Clinical trial information: NCT03237416.
Timing of docetaxel chemotherapy and impact on outcomes in metastatic castrate-resistant prostate cancer (MCRPC).
Authors: Thomson Alastair , Pollard Adam , Mark Frances May 
Published: March 2019

298 Background: Docetaxel use has led to a significant prolongation in overall survival (OS) in metastatic prostate cancer after castrate resistance, with a more substantial OS gain when used in combination with initial androgen deprivation therapy (ADT). There is however limited information on outcomes in patients who initially do not receive chemotherapy, perhaps through patient choice or impaired performance status, who become suitable for docetaxel, comparing earlier with later docetaxel treatment. Methods: We retrospectively reviewed patients’ electronic clinical and prescribing records diagnosed with MCRPC and treated with docetaxel from 01/01/2006 to 24/11/2016 in a single centre in the UK. Data was reviewed for number of individual treatments received pre and post chemotherapy, including initial ADT, enzalutamide, abiraterone, docetaxel, cabazitaxel, mitoxantrone, radium 223, single agent steroids and diethylstilboestrol. Prostate specific antigen (PSA) response, number of cycles and dosing of docetaxel and OS were also reviewed. Results: 168 consecutive patients with MCRPC receiving docetaxel were reviewed. Median Gleason grade across the three groups was 8. 48 patients (29%) received docetaxel after 1 or 2 previous treatments, 105 (63%) after 3 or 4 previous treatments and 15 (9%) after 5 or 6. PSA response rates were superior in the earlier treated group (61%, p=0.003), compared with 30% and 31% respectively in the later groups. Median number of cycles was 5.5 overall, with a mean weighted dose received of 396mg/m2, 373mg/m2 and 301mg/m2 in the after 1 or 2 treatments, after 3 or 4 treatments and after 5 or 6 treatment groups. Median OS from castrate resistance for the earlier group was 29 months, not significantly less (p=0.1) than the 35 months for an intermediate number of prior treatments and 42 months for the later treated group. Conclusions: In this group of patients in routine clinical practice who do not receive docetaxel with initial ADT, PSA response rates are significantly improved and overall dose received is higher with subsequent earlier use. However, overall survival is not significantly different between the early and later docetaxel treated patients.
SABR in high-risk prostate cancer: Outcomes from two prospective clinical trials with and without elective nodal irradiation.
Authors: Alayed Yasir , Cheung Patrick , Vesprini Danny , Liu Stanley K. , Chu William , Chung Hans T. , Musunuru Hima Bindu , Davidson Melanie , Ravi Ananth , Ho Ling , Deabreu Andrea , D'alimonte Laura , Bhounr Zeeba , Zhang Liying , Commisso Kristina , Loblaw Andrew 
Published: March 2019

3 Background: There is limited data on SABR in high-risk prostate cancer (PCa) especially regarding the role of elective nodal irradiation (ENI). This study compares two prospective phase II trials using SABR in high-risk prostate cancer, with and without ENI. Methods: Both trials enrolled patients with high-risk PCa only. Trial1 (pHART8) patients received 40Gy/5 to the prostate and 30Gy/5 to the seminal vesicles. Trial2 (SATURN) patients received 40Gy/5 to the prostate and 25Gy/5 to the pelvis and seminal vesicles. CTCAE and RTOG toxicities were collected. Biochemical failure (BF) was defined as nadir+2 and 4-year PSA response rate (4yPSARR) was < 0.4 ng/ml. Results: 60 patients were included (pHART8, n=30; SATURN, n=30). Median follow-up was 5.6y and 4.0y. Median nPSA was 0.02ng/ml for both. Six patients had BF, all from pHART8; four were managed with ADT and two are being observed. The BF rate was 14.6% at 5y in pHART8 and 0% in SATURN. All six biochemical failures were associated with a PSA of ≥ 0.4 ng/ml at 4y. 63% of patients in pHART8 and 93% in SATURN had a 4yPSARR. BF probability at 5y was 0% for those achieving a 4yPSARR, and 35.1% if not (p = p < 0.0001). Two patients died in pHART8, one from metastatic disease. One patient in SATURN died from other causes. No other patients developed metastatic disease, and one patient in pHART8 had CRPC. OS at 5y was 93.2% and 96.7% (p=0.86). There was significantly worse late GI and sexual toxicity in pHART8, but no difference in late GU toxicity between the two trials. Conclusions: SABR in high-risk prostate cancer yields biochemical control rates that are comparable to other radiotherapy modalities. ENI using SABR is feasible and led to a significant improvement in biochemical control as well as in 4yPSARR which proved to be a predictor of biochemical control, without an increase in late GI or GU toxicity. Longer follow-up would provide a better assessment of biochemical control. Clinical trial information: NCT01505075 and NCT01953055.
Abiraterone acetate plus prednisone/prednisolone compared with enzalutamide in metastatic castration resistant prostate cancer before or after chemotherapy: A retrospective study of real-world data (ACES).
Authors: Das Prantik , Price James , Jones Michael , Martin-Fernandez Cristina , Ali Akram , Mugunthan Thangrarajh , Mallick Chandrani 
Published: March 2019

303 Background: Abiraterone acetate (a prodrug of abiraterone, which is a selective inhibitor of androgen biosynthesis) combined with prednisone/prednisolone (AA+P) and enzalutamide (ENZ) (an androgen-receptor–signalling inhibitor) have proven survival benefit in men with metastatic castration resistant prostate cancer (mCRPC) in chemo naïve and prior chemo patients. There have been no studies directly comparing the effectiveness of ENZ to AA+P in mCRPC patients. Methods: A retrospective, survival analysis study of 143 real world mCRPC patients (90 in AA+P and 53 in ENZ group) was conducted. Patients who started their treatment between 1st February 2012 and 31st May 2016 were included. The primary endpoint was biochemical progression free survival (PFS). Secondary end points were radiographic progression free survival (rPFS) and overall survival (OS). Data was analysed using Cox proportional hazards models, adjusting for covariates: prior radical or palliative treatment; Gleason score; baseline PSA; age; and chemo naïve or not. Results: After median follow up of 15 months (IQR 7 to 23) 112 events of biochemical progression were observed (71 in AA+P and 41 in ENZ). 41%in AA+P group and 30% patients in ENZ group received prior chemo. The chance of biochemical progression was significantly lower among ENZ patients than AA+P patients, when adjusting for all covariates in the Cox PH model (Hazard Ratio 0.54, 95% CI 0.35 to 0.82, p=0.004. There was a trend implying the chance of rPFS could be higher among ENZ patients than AA+P patients (HR 1.24, 95% CI 0.76 to 2.02, p=0.4). OS is lower among ENZ patients than AA+P patients, when adjusting for all covariates in the Cox PH model (HR 0.91, 95% CI 0.59 to 1.41, p=0.7). 38% of ENZ patients reported fatigue compared to 16% of AA+P patients while hypertension was reported slightly more in AA+P patients than in ENZ patients. Conclusions: This study showed a statistically significant difference in biochemical progression-free survival, favouring ENZ, but no significant difference in radiographic progression-free survival or overall survival.
Intermittent bicalutamide in recurrent non-metastatic castrate sensitive prostate cancer: A single institution experience.
Authors: Prentice Mark , Davda Reena , Durno Kimberley , Payne Heather Ann 
Published: March 2019

307 Background: Despite radical treatment, a proportion of men with prostate cancer will develop localized recurrence. Intermittent LHRH analogue (LHRHa) therapy has shown equivalence to long-term hormone manipulation with reduced toxicity. The non-steroidal competitive androgen receptor antagonist, bicalutamide, offers disease control with a further reduced toxicity profile. We report our institution’s experience of intermittent bicalutamide therapy (IBT) in recurrent non-metastatic castrate sensitive disease. Methods: Patients with biochemical recurrence and non-metastatic status on conventional imaging treated with IBT April 2016-November 2017 are reported. Previous LHRHa in the radical setting was allowed if testosterone recovery had occurred. For inclusion, one full course of IBT therapy had to be completed and treatment break commenced. Dose was 150mg with all other treatment decisions were at clinician discretion. Results: 103 men were identified with 4 were excluded due to insufficient data or failure to start treatment break. Mean age at initial diagnosis was 64.5yrs and, at commencement of IBT, 71.7. Mean overall time on IBT was 47months (20 and 27 months on and off treatment respectively). The longest recorded time on IBT was 153 months. 1 patient completed 8cycles of IBT. Mean number of cycles was 2.8 (range 1-8). Mean length of treatment break reduced with successive cycles of therapy measuring less than time on treatment after cycle 4. Of 39 patients with follow up therapies recorded, 77% received continuous bicalutamide as second line therapy. Conclusions: IBT offers a valid alternative to intermittent LHRHa therapy in recurrent non-metastatic castrate sensitive prostate cancer with the advantage of an improved toxicity profile benefiting patients. Further work to assess long-term outcomes in this patient population is warranted.[Table: see text]
Patients with an extremely high prostate-specific antigen at prostate cancer diagnosis: A single institution analysis.
Authors: Qin Qian , Bikkasani Krishna , Oh William K. , Liaw Bobby Chi-Hung , Galsky Matt D. , Tsao Che-Kai 
Published: March 2019

309 Background: High prostate specific antigen (PSA) at diagnosis is associated with worse outcomes in patients (pt) with prostate cancer. However, treatment selection and clinical outcome in those diagnosed with an extremely high PSA (> 500 ng/ml) are not well characterized, and we aim to better study this unique pt population. Methods: Using the Mount Sinai Genitourinary (GU) Cancer Biorepository, an IRB approved database containing all consented GU cancer pts seen between 2010-2018, we identified 23 pts with a PSA >500 at prostate cancer diagnosis. Descriptive analysis was performed to capture clinical characteristics, treatment selection and response, and outcomes in this cohort. Results: The median age and PSA at diagnosis were 64 (54-85) and 1057 ng/ml (528-11,418). At presentation, 1 pt had localized versus 22 pts had metastatic disease, 3 were asymptomatic, and sites of metastasis included lymph nodes (LN) only (n=3), bone only (n=8), or LNs and bone (n=11). Pts were initiated on either first line androgen deprivation (ADT) or ADT plus docetaxel if seen after 2015 (1 refused). All pts had >90% PSA response to first line therapy, with median PSA nadir 4.38 ng/ml (0.06-153), duration of response 6 months (1-33), and time to castration-resistant prostate cancer (CRPC) 14.5 months (5-99). There are differences in treatment selection and outcomes for pts treated with ADT vs. ADT plus docetaxel first line (see table). Conclusions: In pts with PSA >500 at prostate cancer diagnosis, we have observed significant heterogeneity in clinical presentation and response to treatment. In pts treated with first line ADT plus docetaxel, we observed 2 of 7 pts with extended treatment response (> 42 months). Differences in disease biology may account for this observation, and molecular characterization will be needed to better understand this subset. [Table: see text]
PRINT: Prostate cancer intensive, non-cross reactive therapy for CRPC—Early observations of feasibility and efficacy.
Authors: Liaw Bobby Chi-Hung , Tsao Che-Kai , Galsky Matt D. , Bakst Richard Lorne , Stewart Robert , Stock Richard , Oh William K. 
Published: March 2019

310 Background: Optimal sequencing of approved therapeutic agents in mCRPC is not known. The standard approach, is to treat until resistance then switch. The PRINT trial explores the efficacy of treating mCRPC with a rapidly-cycling, non-cross reactive regimen as a way to more effectively treat an intrinsically heterogeneous disease, to delay or prevent drug resistance, and minimize treatment toxicity. Methods: Patients were treated with 3 consecutive treatment modules, each of 12 weeks' duration: 1. abiraterone acetate 1000 mg PO daily and prednisone 5 mg PO BID; 2. cabazitaxel 20 mg/m2 IV and carboplatin AUC 4 IV q3 weeks; 3. enzalutamide 160 mg PO daily and radium-223 50 kBq/kg IV q4 weeks (in those with bone metastases). After completion of this 9 month regimen, patients are followed on ADT alone. Primary endpoint is PSA or radiographic time to disease progression. Results: From 3/2017 to 10/2018, 28 of 40 planned men with mCRPC were enrolled, 19 (67.9%) with bone metastases. PSA response rates ( > 90%/ > 50%), compared to baseline, following each treatment module: 1. 50%/78.6%; 2. 50%/92.7%; 3. 64.39%/92.7%. Currently, 14 patients have completed the study regimen with median follow up of 3.6 months, 8 of whom continue without any additional therapy. Of the patients evaluable for primary endpoint, median time to PSA progression is 96+ days (95% CI 82-110+ days). The regiment was well tolerated, grade 3/4 adverse effects include: hyperglycemia (17.9%), diarrhea (7.1%), anemia (3.6%), fatigue (3.6%), neutropenia (3.6%), thrombocytopenia (3.6%). Measurable response and molecular correlate data will be presented. Conclusions: Treatment of mCRPC with a rapidly-cycling non-cross reactive regimen is feasible, demonstrates significant antitumor benefits, and is well tolerated. Further follow up will determine if PRINT delays progression compared with standard approaches. Clinical trial information: NCT02903160.
Protection of prostate cancer cells from GSK-3β-induced oxidative stress by Il-8 through activating the mTOR signaling pathway.
Authors: Sun Yi , Yang Lu , Wei Qiang 
Published: March 2019

311 Background: Both oxidative stress and inflammation play important roles in prostate cancer cell apoptosis or proliferation. However, the mechanisms underlying these processes remain unclear. Thus, we chose IL-8 as the bridge between inflammation and cancer cell oxidative stress-induced death and confirmed its connection with mTOR and GSK-3beta. Methods: We overexpressed GSK-3beta and observed the effect of GSK-3beta on reactive oxygen species (ROS) and cell death induced by oxidative stress. Then, IL-8 was upregulated or downregulated to determine its impact on preventing cells from damage by GSK-3beta-induced oxidative stress. In addition, we confirmed the role of mTOR in this process through its overexpression or knockdown. Real-time PCR, Western blotting, transcription, Cell Counting Kit 8, flow cytometry and other techniques were used. Results: IL-8 promotes prostate cancer cell proliferation and decreases apoptosis, while GSK-3beta induces cell death by oxidative stress through the activation of the caspase-3 signaling pathway by increasing ROS. In addition, mTOR can also decrease the activation of the caspase-3 signaling pathway by inhibiting GSK--3beta and thus decreasing ROS production. Moreover, the inhibitory effect of IL-8 on GSK-3beta occurs through the regulation of mTOR. Conclusions: The results of this study highlight the importance of GSK-3beta, which increases the production of ROS and then induces oxidative stress in tumor cells, while IL-8 and mTOR attenuate the oxidative stress to protect prostate cancer cells through the inhibitor GSK-3beta.