bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of androgen receptor (AR) gene status in plasma DNA with outcome on enzalutamide in chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC): Exploratory results from the PREMIERE trial—On behalf of SOGUG.
Authors: Grande Enrique , Font Pous Albert , Fernández Núñez Natalia , Gonzalez del Alba Aranzazu , Mellado Begoña , Fernandez Calvo Ovidio , Mendez Maria Jose , Climent Miguel Ángel , Duran Ignacio , Gallardo Enrique , Rodriguez Sanchez Angel , Santander Carmen , Sáez M Isabel , Puente Javier , Fernandez Perez Maria Piedad , Conteduca Vincenza , Wetterskog Daniel , Attard Gerhardt , Castellano Daniel , Gonzalez-Billalabeitia Enrique 
Published: September 2018

5016 Background: Building on previous discoveries studying AR status in plasma (Carreira S, Sci Transl Med 2014, Romanel A, Sci Transl Med 2015) and following a road-map for biomarker development, we aimed to clinically qualify AR status in chemotherapy-naïve mCRPC using an optimized multiplex droplet digital PCR (ddPCR) assay (Condeduca et al.;ASCO2017;Abstract#). Methods: Between February and November 2015, 98 asymptomatic or oligo-symptomatic chemotherapy-naïve mCRPC patients were recruited in 16 Spanish hospitals. Tissue and blood samples were required at study entry. Although initially designed to study the predictive value of TMPRSS2-ETS, data emerging after the trial was initiated led the group to prioritize alternative predefined exploratory biomarkers, including plasma ARand CTC characterization (Grande E. ESMO 2016 & Font A. et al; ASCO2017; Abstract #). Outcome measures included PSA-progression-free survival (sPFS), radiographic progression-free survival (rPFS) and overall survival (OS). Cox regression was used for survival analyses and Fisher’s exact test for PSA response. Results: Ninety-four patients had plasma DNA available for analysis. At baseline, AR gain was present in 11 pts (12%) and CTCs in 35 (37%). AR gain in CTC-positive and negative patients was 20% and 7%, respectively. At first interim analysis and with a median follow-up of 10.6 months, detection of AR gain was associated with worse sPFS (median, 3.60 versus 15.5 m, HR, 4.33; 95% CI 1.94-9.68; P < 0.001), rPFS (median, 3.90 m versus not reached HR, 8.06; 95% CI, 3.26-19.93; P < 0.001) and OS (medians not reached, HR, 11.08; 95% CI, 2.16-56.95; P = 0.004). These results were independently associated in multivariate analysis including cfDNA and CTCs for all described endpoints. AR gain patients were less likely to have a ≥50% decline in PSA (OR, 4.93; 95% CI, 1.30-18.75; P = 0.025). Conclusions: Detection of AR gain in plasma using a robust multiplex ddPCR method predicts an adverse outcome in chemotherapy-naïve mCRPC. Further prospective randomized studies are warranted. Clinical trial information: NCT02288936.
A randomized phase II study of pelareorep (REO) plus docetaxel vs. docetaxel alone in patients with metastatic castration resistant prostate cancer (mCRPC): Canadian Cancer Trials Group study IND 209.
Authors: Eigl Bernhard J. , Winquist Eric , Tu Dongsheng , Hotte Sebastien J. , Canil Christina M. , Gregg Richard William , Zulfiqar Muhammad , North Scott A. , Ellard Susan , Ruether Joseph D. , Le Lyly H. , Kakumanu Ankineedu Saranya , Theis Ashley , Booth Christopher M. , Potvin Kylea R. , Chi Kim N. , Seymour Lesley 
Published: September 2018

5021 Background: Pelareorep (REO) is an oncolytic virus with in vitro and in vivo activity in many cancers, including prostate. It has in vitro synergism with microtubule targeted agents especially taxanes. We undertook a clinical trial to evaluate REO in mCRPC patients (pts) receiving docetaxel. Methods: In this randomized, open-label multicenter phase II study, pts received docetaxel 75mg/m2 on day 1 of a 21-day cycle in combination with REO given as 3x1010 TCID50 IV daily on days 1-5 (arm A), or alone (arm B). The primary endpoint was 12-week lack of disease progression (LPD) rate. Secondary endpoints included objective response rate; survival; circulating tumor cell (CTC) enumeration at 0, 6 and 12 weeks; PSA response rate and biomarkers. Results: Eighty-five pts were randomized. Median age was 69, ECOG performance status (PS) was 0/1/2 in 31%/66%/3% of pts. Bone/regional lymph node/liver metastases were present in 98%/24%/6% of pts. More pts in arm A had poor prognostic factors for survival at baseline (median prognostic index 1.44 vs. 1.29). The median number of cycles delivered for arms A/B was 7/9 (range 1-10 and 1-13). In arm A, 51%/68% of pts received ≥90% of planned dose intensity of docetaxel/REO respectively, vs. 76% of pts for docetaxel in arm B. Adverse events (AE) were as expected for docetaxel therapy but more prevalent in arm A (grade 3 or higher all AEs 80 vs. 74%). A higher rate of grade 4 febrile neutropenia was noted in arm A (7 vs. 0%) but may represent virus related fevers. The 12-week LPD rate was 61% and 52.4% in A/B respectively (p = 0.51). OS was worse in arm A vs. B (HR 1.95; 95% CI 0.94-4.06; p = 0.07 after adjusting for age, PS and baseline prognostic score). There was no difference between arms in CTC favourable status at any timepoint. No survival benefit of REO with D was found in any subset from the biomarker analysis. Conclusions: While the combination of REO with D for patients with mCRPC was tolerable and LPD rate was comparable in both arms, docetaxel dose intensity and survival were inferior and so this combination, as tested, does not merit further study. Clinical trial information: NCT01619813.
Prognostic value of free testosterone (FT) levels during chemotherapy with carboplatin plus weekly docetaxel in metastatic castration- and docetaxel-resistant prostate cancer (mDRPC).
Authors: Reuter Christoph , Morgan Michael A. , Ivanyi Philipp , Grünwald Viktor , Merseburger Axel S. , von Klot Christoph A. J. 
Published: September 2018

5039 Background: Carboplatin plus docetaxel (DC) may be effective in mDRPC. Platinum(II)-complexes interfere with steroid biosynthesis lowering testosterone levels by inhibiting the cholesterol side chain cleavage enzyme (CYP11A1), 3β-hydroxysteroid dehydrogenase (HSD3B1,2) and 17α hydroxylase/C17,20-lyase (CYP17A1). Methods: Docetaxel failure/resistance was defined according to the Prostate Cancer Working Group (PCWG2 2007) criteria. Treatment consisted of at least two cycles of carboplatin AUC5 iv for 30 min on day 1 every 4 weeks (q4w), docetaxel at a dose of 35 mg/m2 iv for one hour on days 1, 8, (15) plus prednisone 2x5mg/day orally after receiving informed consent until disease progression or occurrence of intolerable adverse effects. Efficacy measures were done following PCWG2 recommendations. Free testosterone levels were measured before (n = 77) and during DC chemotherapy (n = 69). Results: Of the 100 pts. treated since February 2005, 96% had bone metastases, 45% had lymph node, 27% liver and 21% lung involvement. At the time of the current analysis, the median follow-up was 13.6 months, 93 pts. had died and 97 had progressive disease. The objective response rate was 36.5% in the 63 pts. with measureable disease. Response of prostate-specific antigen (≥50%) was observed in 50% of patients. Median progression-free survival (PFS) for all patients was 6.9 months (CI 95% 5.5, 8.3) and median OS was 15.4 months (CI 95% 11.5, 19.4). The most common reversible grade 3/4 toxicity was leukopenia/ neutropenia (40/32%). Median free testosterone levels were 0.61 pg/ml before and < 0.18 pg/ml during carboplatin/docetaxel treatment (nadir levels, p < 0.001; detection limit < 0.18 pg/ml). Median serum androgene levels (T+DHT) were 0.1 ng/ml before and below the detection limit of < 0.05 ng/ml during DC treatment. In multivariate analyses, LDH, PSA response, free testosterone nadir levels below the detection limit ( < 0.18 pg/mL) during DC treatment were associated with longer OS (p < 0.05). Conclusions: These data suggest that carboplatin plus weekly docetaxel may be an important salvage treatment option for DRPC patients.
Clinical activity and safety of ASN001, a selective CYP17 lyase inhibitor, administered without prednisone in men with metastatic castration-resistant prostate cancer (mCRPC): A phase 1/2 clinical trial.
Authors: Garcia Jorge A. , Dreicer Robert , Pantuck Allan J. , Haas Naomi B. , Vaishampayan Ulka N. , Rao Niranjan Sathyanarayana , Denis Louis J. , Tolcher Anthony W. 
Published: September 2018

5041 Background: ASN001 is a novel, non-steroidal, potent inhibitor of CYP17 lyase that selectively inhibits synthesis of testosterone over cortisol in the adrenals to avoid the need for co-administration of prednisone. ASN001 also exhibits high oral bioavailability and low potential for drug-drug interaction. Methods: This Phase (Ph) 1/2 clinical trial in men with progressive mCRPC evaluates once-daily, oral ASN001 at escalating doses of 50, 100, 200, 300 and 400 mg (NCT02349139). While Ph 1 also allowed enrollment of pretreated patients, no prior enzalutamide (ENZA) or abiraterone (ABI) is permitted in Ph 2. Endpoints include maximum dose (MTD) and dose limiting toxicities, recommended Ph 2 dose, PK, effect on steroid hormone biosynthesis and clinical efficacy (PSA and imaging). Results: To date, 26 mCRPC pts have been enrolled. No prednisone was administered and no mineralocorticoid excess has been reported. Overall, ASN001 was well tolerated. Most drug-related adverse events were Gr 1/2 and included fatigue, constipation and nausea. At 400mg, two pts experienced asymptomatic, reversible Gr 3 ALT/AST elevation, but no recurrence when retreated at 300mg. Enrollment of ABI/ENZA naïve patients continues at lower doses to further evaluate safety and efficacy. Testosterone decrease to below quantifiable limits and DHEA decrease of up to 80% was observed. Systemic exposure was high (Cmax, AUC and T1/2 at 300 mg QD were 6.7 µM, 80 µM.h and 21.5 h, respectively). Stable disease up to 18+ months has been observed despite prior ABI and ENZA exposure. PSA decline of > 50% (up to 93% decline) and up to 37+ wks duration was observed in 3 of 4 ABI/ENZA naïve patients at starting doses of 300/400mg. Conclusions: Overall, ASN001 was safe and well tolerated. Prednisone co-administration was not needed. Encouraging preliminary evidence of efficacy is reflected by PSA declines in evaluable mCRPC pts not pretreated with ABI or ENZA and by durable disease stabilization in refractory disease. Enrollment is ongoing at doses below 400mg QD in ABI/ENZA naïve mCRPC pts. Updated and detailed results will be presented at the meeting. Clinical trial information: NCT02349139.
Trop-2 expression on treatment resistant cancer cells in castrate-resistant prostate cancer (CRPC) as a predictive biomarker for targeted therapy.
Authors: Ku Kimberly Peihsi , Lang Joshua Michael , Sperger Jamie , Dehm Scott , Kohli Manish , Wang Liguo , Wang Liewei , Tagawa Scott T. , Scher Howard I. 
Published: September 2018

5045 Background: Trophoblastic cell-surface antigen (Trop-2) is a transmembrane glycoprotein that is highly expressed in many solid tumors. Sacituzumab govitecan (IMMU-132) is an antibody-drug conjugate of an anti-Trop-2 humanized antibody with SN-38. Early clinical trials have shown high response rates in a broad range of diseases including triple negative breast and urothelial cancers. We evaluated Trop-2 expression in tumor biopsies and circulating tumor cells (CTCs) from men with mCRPC (metastatic castrate-resistant prostate cancer). Methods: Trop-2 expression was evaluated from mCRPC biopsies from patients (Pts) treated with abiraterone acetate (AA) on the PROMOTE clinical trial, CTCs from a separate cohort treated with either enzalutamide or AA. Trop-2 CTCs were compared with EpCAM captured CTCs using a microscale technology termed the VERSA (Vertical Exclusion-based Rare Sample Analysis) platform to compare protein and gene expression signatures of resistance to these agents. Results: RNA sequencing identified Trop-2 gene expression in > 70% of metastatic biopsies. The AR splice variant V7 was found in 48 biopsies that also expressed Trop-2. Trop-2 expression was not altered by treatment with AA at 12 weeks. The number of CTCs captured from 25 pts with Trop-2 or EpCAM were closely correlated (R2= 0.84). Gene expression analysis showed similar patterns of expression for the TROP-2 and EPCAM captured cells. AR splice variant expression (AR-V7, AR-V9) in Trop-2 and EpCAM CTCs was detected in 33% of patients. Expression of neuroendocrine markers was identified in 40% of Trop-2 CTCs. Conclusions: Trop-2 is frequently expressed in mCRPC and co-expressed in tumors that express AR splice variants. Trop-2 CTCs are detected in CRPC pts previously treated with AA or Enzalutamide that also express multiple AR splice variants and neuroendocrine markers. The results support Trop-2 expression as predictive biomarker of sensitivity to targeted therapies tumors resistant to AA or Enzalutamide. Men with mCRPC are being enrolled on a Phase I trial with IMMU-132, and multi-site Phase II clinical trial in men who have progressed on AA or Enzalutamide is being finalized.
The immunomodulatory protein Dickkopf-1 (DKK1) defines a non-neuroendocrine subtype of metastatic castration-resistant prostate cancer (mCRPC) with low AR and low PSA expression.
Authors: Wise David , Armenia Joshua , Chen Yu , Nelson Peter , Schultz Nikolaus , Sawyers Charles L. , Scher Howard I. 
Published: September 2018

5054 Background: Advanced stagemCRPC can manifest AR-signaling independent growth typified by loss of AR and/or PSA expression in the absence of neuroendocrine (NE) features on biopsy. We sought to identify therapeutically relevant biomarkers of this highly resistant prostate cancer subtype. Methods: An unbiased differential gene expression analysis of non-neuroendocrine mCRPC biopsies was carried out comparing patients with ARlow to patients with ARhigh disease in a discovery cohort (SU2C/PCF, 18 pts: 8 ARlow, 10 ARhigh) and validation cohort (Fred Hutchinson, 76 pts: 12 ARlow, 64 ARhigh). The AR and NE status of the biopsies were defined by AR and PSA mRNA expression and gene signatures representative of AR activity and NE lineage. An RNA sequencing-based signature of immune cell subsets was calculated using the Cibersort algorithm. Results: Differential gene expression analysis identified the secreted Wnt antagonist, DKK1, as significantly upregulated in ARlow cases compared to ARhigh cases (11.2 RPKM vs. 0.28 RPKM, p < 0.03) in our discovery cohort and confirmed in our validation cohort (9.2 FPKM vs. 0.99 FPKM, p < 0.001). DKK1 protein was also found to be increased in non-neuroendocrine ARlow relative to ARhigh prostate cancer in vitro cell and organoid models (858 pg/mg total protein vs. 2 pg/mg total protein, p < 0.05) and patient-derived xenografts (28.6 FPKM vs. 0.78 FPKM, p < 0.0001). Consistent with the role of DKK1 as a negative modulator of anti-tumor immunity, patient biopsies with the highest quartile of DKK1 expression showed an RNA signature consistent with lower levels of active NK cells (0.2% vs. 1.8%, p < 0.005), and lower levels of CD8+ T cells (3.7% vs. 9.7%, p< 0.005) compared to those with the lowest quartile of DKK1 expression. Conclusions: DKK1 represents a secreted biomarker that is disproportionately enriched in non-neuroendocrine mCRPCs that lack AR expression. Because DKK1 has been implicated as a suppressor of anti-tumor immunity and is a target of an existing neutralizing antibody, our results support the clinical evaluation of the role of DKK1 blockade in DKK1-positive AR-negative prostate cancer.
Baseline CTC subtype to predict outcomes on mCRPC patients (pts) receiving enzalutamide (E) compared to abiraterone (A).
Authors: Scher Howard I. , Jendrisak Adam , Schreiber Nicole A. , McLaughlin Brigit , Graf Ryon P , Rodriguez Angel , Fleisher Martin , Lee Jerry , Kelvin James , Wang Yipeng , Landers Mark Andrew , Dittamore Ryan Vance 
Published: September 2018

5070 Background: Prior response to A or E does not predict sensitivity to E following A or A following E. The detection of AR-V7 predicts insensitivity to either drug, but identifies only a portion of non-responders. We previously identified 15 CTC subtypes based on unique phenotypic features in mCRPC pts, each with unique biology and different degree of likelihood of predicting resistance to either drug. Here we explored the relationship between individual subtypes and sensitivity to A vs. E, but not both. Methods: 107 pre-treatment blood samples from mCRPC pts starting A (n = 47) or E (n = 60) as a 1st or 2nd line of Tx were analyzed for CTCs utilizing the Epic Sciences platform. Samples were assayed for CTC subtypes based upon 15 pre-defined phenotypic CTC classifiers (Type A-O). Treatment outcomes were assessed by serial PSA changes and landmarked percent time of therapy progression on radiographs, and overall survival following either A or E. Cell type prevalence was also analyzed in relation to clinical outcomes, and subsets of the CTC subtypes subject to single cell NGS to ascertain genomic drivers common to each subtype. Results: CTCs were identified in 94% (101/107) of pt samples. One, cell Type K, found in 25% (27/107) of pts, was associated with a statistically significant inferior outcomes on E for all measures. Whereas similar outcomes were seen between K+ & K- pts treated with A. The distinct features of Cell Type K include a large nucleus, high nuclear entropy and high Nuclear/cytoplasmic AR terminal ratio; and a unique genomic profile enriched for cell cycle and DNA repair alterations relative to other CTC subtypes. Conclusions: The presence of specific CTC subtypes in pre-Rx phlebotomy samples associated with outcomes on A or E. A CTC subtype (Cell Type K) helped to identify pts with poor outcomes on E but not A vs. those without the cell type. Further biologic interrogation of K cells and ongoing clincial validation of the CTC subtype is planned. [Table: see text]
Indentification of a CTC-based gene expression signature predicting resistance to abiraterone and enzalutamide in mCRPC.
Authors: Morgan Todd Matthew , Chung Jae-Seung , Wang Yugang , Henderson James , Singhal Udit , Qiao Yuanyuan , Zaslavsky Alexander , Hovelson Daniel H , Alva Ajjai Shivaram , Feng Felix Yi-Chung , Palapattu Ganesh S. , Taichman Russell S. , Chinnaiyan Arul M. , Tomlins Scott A. 
Published: September 2018

5072 Background: Circulating tumor cell (CTC)-based detection of AR-V7 has been shown to be one potential marker for predicting response to 2nd generation androgen receptor (AR) therapies. However, the apparent rarity of AR-V7 positivity is indicative of the importance of other drivers of resistance in this setting. We sought to utilize a multiplex gene expression platform for assessing CTCs in order to determine other predictive biomarkers of response. Methods: Whole blood (~5mL) was obtained from 37 patients with mCRPC starting enzalutamide (n=16) or abiraterone (n=21). CTCs were isolated using anti-EpCAM-conjugated magnetic beads. Following cell lysis, mRNA was extracted followed by multiplex qRT-PCR for 92 prostate cancer-related genes. Samples were considered CTC-positive based on a previously established set of epithelial markers. We identified genes associated with PSA and radioclinical progression free survival (PFS) using Cox regression analysis. Muli-gene models were tested using ROC analysis. Results: We identified 20 patients (54%) with detectable CTCs, and patients were followed for a median of 10 months (IQR 3.9-19.4 months). Seven genes were associated with both PSA PFS and radioclinical PFS in the Cox analyses (Table). Combing the 7 genes into a single model gave AUC values of 0.88 for PSA PFS and 0.89 for radioclinical PFS. In comparison, the AR-V7-only model resulted in AUC values of 0.65 and 0.66. Conclusions: We identified seven prostate cancer-related genes that can be determined from CTCs and appear to predict short time to progression in men with mCRPC being treated with 2nd generation hormonal therapies. While this is a small cohort and prospective validation is needed, these findings highlight the potential role for this approach in helping guide therapy choice. [Table: see text]
Neoadjuvant randomized trial of degarelix (Deg) ± cyclophosphamide/GVAX (Cy/GVAX) in men with high-risk prostate cancer (PCa) undergoing radical prostatectomy (RP).
Authors: Antonarakis Emmanuel S. , Zahurak Marianna , Schaeffer Edward M. , Partin Alan W. , Ross Ashley , Allaf Mohamad , Tosoian Jeffrey , Nirschl Thomas , Chapman Carolyn , O'Neal Tanya Skelton , Cao Haiyi , Durham Jennifer N. , Guner Gunes , Del Valle Javier Baena , Ertunc Onur , Demarzo Angelo , Drake Charles G. 
Published: September 2018

5077 Background: GVAX-Prostate is a GM-CSF–secreting allogeneic cellular vaccine, whose immunogenicity may be enhanced by androgen ablation as well as low-dose Cy. We conducted a neoadjuvant immunologic study comparing Deg vs. Cy/GVAX→Deg. Methods: Men with high-risk PCa (T1c–3b N0 M0, Gleason 7–10) were randomized 1:1 to Deg(240 mg SQ) vs. Cy(200 mg/m2 IV)/GVAX(2.5×108 PC3 cells, 1.6×108 LNCaP cells) given 2 wk before Deg; all pts then had RP 2 wk after Deg. CD8+ T cell and Treg densities in the primary tumor were quantified by IHC (cells/mm2). Clinical endpoints were time-to-PSA-relapse, time-to-next-therapy, and time-to-metastasis. The study was powered (α = 0.05, β = 0.18) to show a 2-fold increase in mean CD8+ density with Cy/GVAX→Deg (Arm B) vs. Deg (Arm A). Results: 28 men were enrolled (Arm A = 15, Arm B = 13). A concurrent control group (N = 20) who did not receive neoadjuvant therapy provided untreated RP tumor samples. Baseline variables were balanced across study arms: 64% had Gleason ≥8, 56% were pT3b, 18% were pN1. There were nonsignificant increases in CD8+ and Treg densities in Arm B vs. A, and statistically significant increases in CD8+ and Treg densities in both arms (A, B) compared to group C (TABLE). CD8+ and Treg densities were strongly correlated. Outcomes were numerically better in Arm B vs A with respect to time-to-PSA-relapse (HR 0.42, 95%CI 0.13–1.38, P= 0.15) and time-to-next-therapy (HR 0.43, 95%CI 0.13–1.39, P= 0.16), although not statistically significant. Conclusions: Intratumoral immune infiltrates were marginally augmented by Cy/GVAX→Deg vs. Deg alone, while CD8+ and Treg densities were significantly greater in both study arms vs. control, supporting the immunogenic effects of androgen ablation. CD8+ / Treg ratios were remarkably consistent across groups. Clinical trial information: NCT01696877. [Table: see text]