bluuebunny/crossref_metadata_2025 huggingface dataset:
Redefining postprostatectomy biochemical progression: The significance of a PSA cutoff below 0.2 ng/ml—Results from two retrospective series with and without salvage radiotherapy.
Authors: Budäus Lars , Schiffmann Jonas , Tennstedt Pierre , Bottke Dirk , Heinzer Hans , Graefen Markus , Moser Lutz , Bartkowiak Detlef , Wiegel Thomas
Published: February 2017

153

Background: Biochemical recurrence (BCR) after radical prostatectomy (RP) is usually defined at a PSA >0.2 ng/ml. BCR may precede clinical progression by years. Though salvage radiotherapy (SRT) is recommend to be initiated at PSA <0.5 ng/ml, its efficiency at PSA <0.2 ng/ml is not well documented. Methods: We relied on two independent post-RP cohorts. Cohort 1 (n=311, Hamburg) comprised men whose post-RP PSA levels had risen to 0.1-0.2 ng/ml. Further biochemical and clinical progression were recorded during follow-up. Cohort 2 (n=198, Berlin) were patients with BCR who received SRT (66/72 Gy) at a PSA <0.5 ng/ml. The median follow-up was 6.9 years. Post-SRT progression and overall survival were addressed by Kaplan-Meier analysis and Cox regression modelling. Results: In cohort 1, 299 (96%) men experienced further PSA progression (>0.2 ng/ml) within a median time of 7 months. Subsequent PSA rise to >0.3, >0.4, and >0.6 ng/ml was recorded in 174 (58%), 123 (41%), and 24 (8%) men, respectively. Twenty-four (8%) men developed metastases. In cohort 2, 112 men received SRT at PSA between 0.03 and 0.2 ng/ml, and 86 at 0.2-0.499 ng/ml. The latter group, had a poorer 10-years BCR-free Kaplan-Meier rate, 43% vs. 66% (p=0.051). Together with pT<3, Gleason Score <7, and post-RP PSA <0.03 ng/ml, SRT at PSA <0.2 ng/ml was an independent favorable predictor of freedom from BCR (OR=0.60, p<0.05). Ultimately, 14 patients died. However, overall survival did not significantly correlate with the pre-SRT PSA. Conclusions: The vast majority of patients with a PSA >0.1 ng/ml after RP will subsequently progress to PSA >0.2 ng/ml. Improved progression free survival can be achieved, if SRT is administered at a PSA <0.2 ng/ml. Therefore the contemporary PSA threshold for defining BCR after RP needs to be reconsidered and early sRT should be contemplated on a individual basis for optimizing oncological outcomes.
Genomic analysis of circulating cell-free DNA (cfDNA) to investigate mechanisms of resistance to enzalutamide (ENZ) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts).
Authors: Azad Arun , Wyatt Alexander , Volik Stanislav , Haegert Anne , Le Bihan Stephane , Bell Robert H , Anderson Shawn A , McConeghy Brian , Shukin Robert , Gleave Martin Edwin , Collins Colin , Chi Kim N.
Published: February 2017

157

Background: Factors driving clinical resistance to ENZ are poorly understood. Genomic analysis of cfDNA is a promising and minimally invasive approach for investigating mechanisms of therapeutic resistance in mCRPC. Methods: Baseline plasma samples were collected from 53 mCRPC pts commencing ENZ. In 31 of these pts, 12-week and treatment cessation samples were also obtained. DNA was extracted and subjected to array Comparative Genomic Hybridization (aCGH) for chromosome copy number (CN) analysis and androgen receptor (AR) gene sequencing (MiSeq) for mutation analysis. Endpoints were i) PSA50 or PSA30 response rates (RR) (PSA decline ≥ 50% or 30% for ≥ 3 weeks); and ii) radiographic/clinical progression-free survival (PFS). Results: CN changes on baseline aCGH included 8p loss (26%), 8q gain (32%), MYC gain (28%), CCND1 gain/amplification (amp) (11%), MET gain (13%), RB1 loss (21%) and AR gain/amp (30%). Correlation of clinical and genomic data showed multiple links between AR CN status and outcomes on ENZ. Firstly, compared to no AR gain/amp, pts with pre-treatment AR gain/amp had lower PSA50 (41% vs. 19%, P=0.12; Χ2) and PSA30 RR (54% vs. 25%, P=0.051; Χ2) and shorter median PFS (4.6 vs. 2.3 months, P<0.001; log-rank). Secondly, on multivariate analysis, pre-treatment AR gain/amp (HR 3.42, P=0.002) together with prior abiraterone (HR 4.72, P=0.001) was confirmed as an independent prognostic factor for PFS. Thirdly, in pts with serial plasma samples, 16% (5/31) had a change in AR CN status from baseline with 3 pts converting from no AR gain to AR gain and 2 pts from AR gain to AR amp. Of note, median PFS in these 5 pts was only 2.8 months. Finally, AR gain/amp at baseline or emergence of AR gain/amp on-treatment was associated with decreased median PFS compared with no AR CN increase at any timepoint (2.3 months vs. 6.5 months, P<0.001; log-rank). Conclusions: Detection of AR gain/amp in pre- or on-treatment cfDNA samples correlated with adverse outcomes on ENZ. These data indicate that AR gain/amp may be a biomarker of primary and acquired resistance to ENZ in mCRPC pts. Updated data including AR gene sequencing will be presented.
A genome-wide linkage study of lethal prostate cancer predisposition gene in a set of high-risk pedigrees.
Authors: Cannon-Albright Lisa A , Teerlink Craig , Alex Anitha , Albright Frederick S. , Stephenson Robert A , Agarwal Neeraj
Published: February 2017

159

Background: Using the unique Utah genealogical resource that links 12 generations of genealogy data to a statewide cancer registry from 1966 and statewide death certificates from 1904 we have identified a set of high-risk prostate cancer pedigrees with multiple cases having died from prostate cancer. Methods: Clusters of prostate cancer cases descended from a common ancestor, among whose descendants is observed a statistical excess of prostate cancer (high-risk prostate cancer pedigrees) were recruited and sampled. Pedigrees with 4 or more cases dying from prostate cancer (as evidenced by inclusion as a cause of death on a Utah death certificate) were genotyped with 720k high-density SNPs across the genome. Linkage analysis with markers not in linkage disequilibrium was performed to identify regions hypothesized to contain a prostate cancer predisposition gene. Results: A single extended Utah high-risk prostate cancer pedigree including 6 distantly related sampled prostate cancer cases who went on to die as a result of their cancer showed significant evidence for linkage at chromosome arm 4q24 (LOD score = +3.28), with 5 of the 6 cases having inherited the same region of chromosome 4 from a common ancestor. Conclusions: The inability of association studies to identify prostate cancer predisposition genes has returned focus to linkage studies of highly informative high-risk pedigrees, which provide power for identifying and localizing regions of interest for predisposition genes. A focus on only those cases who are members of high-risk prostate cancer pedigrees, who also went on to die as a result of their prostate cancer, has resulted in the identification of evidence for a prostate cancer predisposition gene on chromosome arm 4q24, confirming a previous GWAS that reported association with prostate-cancer-specific-survival (Pomerantz MM et al., 2011) in this region harboring TET2 (a tumor suppressor gene involved in pathogenesis of acute myeloid leukemia, myelodysplastic syndrome, and myeloproliferative neoplasms), and PP2A (implicated in androgen receptor regulation in prostate cancer cell lines).
Prostate-specific antigen velocity as a predictive biomarker in a prospective prostate cancer screening study (IMPACT study).
Authors: Mikropoulos Christos , Selkirk Christina , Saya Sibel , Bancroft Elizabeth , Dadaev Tokhir , Brendler Charles , Saunders Edward , Leongamornlert Daniel , Page Elizabeth , Borrella Clara Cieza , study Collaborators And Steering Group The IMPACT , Moss Sue , Kote-Jarai Zsofia , Helfand Brian , Eeles Ros A.
Published: February 2017

16

Background: We retrospectively assessed the clinical application of Prostate Specific Antigen Velocity (PSA V) in the IMPACT study (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in men at higher genetic risk and controls). This is a case-control prostate cancer (PrCa) screening study for men with a known genetic predisposition to PrCa; participants with a single PSA reading above 3ng/ml are offered diagnostic TRUS prostate biopsies (PB). Methods: We calculated PSA velocity (PSA V) using all three validated methods, including the arithmetic mean, the linear regression and the first and last readings equations. Pearson chi-square test was used to compare PSA V between four genetic groups: BRCA1 carriers and BRCA1 negative controls and BRCA2 carriers and BRCA2 negative controls. Results: PSA V data were evaluated in 191 men who underwent a PB with a total of 57 PrCas diagnosed. PSA V using both a threshold of 0ng/ml/year and 0.75ng/ml/year in any of the three methods was not predictive of PrCa diagnosis in BRCA1/2 controls and BRCA1 carriers. Conversely, BRCA2 carriers with a PSA V over 0.75ng/ml/year (by linear regression) were 5 times more likely to be diagnosed with PrCa [95%CI=1.5-14; p=0.003]. Interestingly PSA V using linear regression was predictive of clinically significant tumours as defined by Gleason Score (GS) >= 7. Regardless of their genetic status, men with a PSA V over 0.75/ng/ml/year were 3 times more likely to have a clinically significant PrCa [95% CI: 1.006-11.107; p=0.045] whereas men with a BRCA2 mutation were 12 times more likely [95%CI: 1.1-98; p=0.039]. Conclusions: PSA V is an important tool for identifying which men with a BRCA2 mutation would benefit from a prostatic biopsy and could be incorporated into a predictive model, along with the total PSA value. PSA V also predicts for tumour aggressiveness regardless of genetic predisposition, but more so for those with a known high risk gene mutation. Clinical trial information: NCT00261456.
Germ line predictors of response to androgen deprivation therapy in men with advanced prostate cancer.
Authors: Agarwal Neeraj , Buckley Tyler Howard , Farnham Jim M. , Patel Shiven B. , Alex Anitha , Teerlink Craig , Albright Frederick S. , Stephenson Robert A , Cannon-Albright Lisa A
Published: February 2017

162

Background: Germline variations in genes involved in androgen biosynthesis and metabolic pathways may predict time to response to androgen deprivation therapy (ADT) in advanced prostate cancer, serve as prognostic and predictive biomarkers, and guide towards more individualized upfront therapy. Methods: 47 polymorphisms (PMs) in 22 genes involved in the androgen metabolic pathway were investigated using tagging SNPs for association with time to onset of castration resistance in 144 Caucasian men diagnosed with advanced prostate cancer undergoing ADT. Linear regression was employed using Gleason score as a covariate and assessing each SNP under one of three genetic models: 1) an additive model in which the number of minor alleles contributes increasing risk (or protection), 2) a dominant model in which the presence of 1 or 2 minor alleles have the same effect, and 3) a recessive model in which the presence of 2 minor alleles are necessary. Results: PMs in 3 genes (CYP1A1, HSD17B3, and HSD17B12) were significantly associated with time to prostate cancer recurrence after medical castration while controlling for Gleason Score. Table summarizes the genes found to be significantly associated with time to recurrence and the modes of inheritance considered. (Only SNPs found to be nominally significant (p < .05) either with or without controlling for Gleason score in at least one model are shown.) Conclusions: In this preliminary report of ongoing work, germ line variations in multiple genes in the sex steroid hormone metabolic pathway predicted time to response to ADT, and warrant further validation to define their role as prognostic and predictive markers in this setting. [Table: see text]
Tumor-directed PET imaging of metastases in metastatic castration-resistant prostate cancer (mCRPC) using Zr-89 labeled antiprostate-specific membrane antigen (PSMA) antibody J591.
Authors: Feldman Jarett L. , Morris Michael J. , Tagawa Scott T. , Nanus David M. , Solomon Stephen Barnett , Carrasquillo Jorge A. , Reuter Victor E. , Lewis Jason Stuart , O' Donoghue Joseph A. , Martinez Danny F. , Slovin Susan F. , Rathkopf Dana E. , Gonen Mithat , Beylergil Volkan , Durack Jeremy C. , Cheal Sarah M. , Bander Neil Harrison , Scher Howard I. , Larson Steven M. , Pandit-Taskar Neeta
Published: February 2017

164

Background: There is no standard imaging (SI) modality that specifically and accurately images prostate cancer (PC) metastases, hampering prognostication and response assessment. J591 is a humanized antibody that targets the external domain of PSMA. We have previously reported on the feasibility, PK and biodistribution properties of 89Zr-J591 in 10 patients (pts) (Pandit-Taskar et al, Eur J Nuc Med Img 2014). We now report on the targeting/accuracy in 50 pts with mCRPC. Methods: Following standard CT/MRI, bone scan (BS), and FDG PET imaging, 5 mCi of 89Zr-J591 was administered IV. 89Zr-J591 was imaged 6-8 days after injection. Positive (pos) scan findings were confirmed, where possible, with biopsies (bxs) in the following preference: concordant 89Zr-J591 and FDG pos, 89Zr-J591 and FDG mismatch, and a mismatch between SI and any PET. Results: Imaging: A total of 703 lesions in 50 pts were identified using all imaging modalities. Bone:538 total bone lesions were detected. 491(91%) lesions were present on J591 of which 99 were only evident by J591. BS identified 339 (63%), CT 301 (56%), and FDG 207 (38%). Soft Tissue: 165 total soft tissue lesions were detected. 90 (55%) were seen on J591 of which 17 were only evident by J591. CT identified 124 (75%) and FDG 88 (53%). Pathology:46 bx’s were evaluable (21 bone, 25 soft tissue) in 34 pts. Of the unique J591 lesions biopsied (bx’d), 5/7 were pos for PC. Bone: We bx’d 19 J591 pos lesions and 2 J591 neg sites. Overall, path concordance with J591 was: 89% true pos, 100% true neg, 11% false pos, and 0% false neg. Soft tissue: We bx’d 16 J591 pos lesions and 9 J591 neg sites. Of these, we found 88% true pos, 11% true neg, 13% false pos, and 89% false neg. Conclusions: J591 PET identifies additional disease in bone not seen using other imaging modalities. These lesions are highly likely to correspond to disease by bx. However, the tracer performed less well in soft tissue, with a high false neg rate. Clinical trial information: NCT01543659.
Effect of metastatic site biopsy on circulating tumor cell (CTC) count in castrate resistant prostate cancer (CRPC) stage.
Authors: Kohli Manish , Eiken Patrick W , McMenomy Brendan P , Atwell Thomas D , Tan Winston , Qin Rui , Carlson Rachel , Campion Michael B , Wang Liewei , Costello Brian Addis , Pitot Henry Clement , Quevedo Fernando , Scheel Elizabeth A , Ho Thai Huu , Bryce Alan Haruo , Paz-Fumagalli Ricardo , Moynihan Timothy J. , Dronca Roxana Stefania , Liu Minetta C.
Published: February 2017

190

Background: It is not known if biopsy of CRPC stage metastases alters CTC results. We evaluated pre & post biopsy CTC counts in a prospective cohort undergoing pre-chemotherapy abiraterone acetate/prednisone (AA/P). Methods: CTC enumeration was performed on 7.5mL blood using the FDA cleared immunomagnetic/immunofluorescence assay (CellSearch). Time of blood draw for CTC counts pre/post biopsy was recorded for each biopsy. Biopsies were performed using 11/13 gauge core biopsy device for bone lesions and 18 gauge core needle biopsy device for soft tissue/nodal metastases. All patients (pts) underwent two serial biopsies 3 months apart. Change in CTC counts pre/post biopsy for visits 1 and 2 were evaluated using Wilcoxon signed rank test (significance at p<0.05). Differences in CTC count change (visit1) pre/post biopsy based on metastatic site (skeletal vs. non-skeletal) was compared using Wilcoxon rank-sum test. Results: Median age of the cohort was 74 years (IQR: 68-78); median PSA at V1 was 16.4 ng/ml (IQR: 6.4-87.6); at V2 was 11.5 ng/ml (IQR: 1.8-23.7). Of 59 pts undergoing biopsies 42 were in bone and 17 in nodal/soft tissue masses. At V1, pre/post biopsy CTC counts were measured on 50 and 49 pts, respectively; at V2, pre/post CTC counts were measured on 43 and 36 pts. High volume metastatic disease at V1 was observed in 67.8 % of all pts. Table lists CTC counts and time of collection pre/post biopsy for both visits. Mean change in pre/post biopsy CTC counts for skeletal sites was 0.7 (range: -12 to 64) compared to 12.1 (range: -21 to 13) for non-skeletal sites (p=0.23). Conclusions: An increase in mean CTC counts after biopsy of CRPC metastases was observed. No significant differences in change of CTC counts based on site biopsied (skeletal versus non-skeletal) was noted. Correlation with clinical outcomes is on-going. Clinical trial information: NCT# 01953640. [Table: see text]
Testosterone levels in metastatic castration-resistant prostate cancer (mCRPC).
Authors: von Klot Christoph A. J. , Boeker Alena , Herrmann Thomas R. W. , Kramer Mario W. , Kuczyk Markus A. , Merseburger Axel S.
Published: February 2017

191

Background: It is common practice to continue anti-androgen therapy in terms of androgendeprivation when performing chemotherapy or androgendeprivation with new second generation therapeutic agents such as enzalutamide or abiraterone acetate. Clinical Studies aiming at the question whether continuation of conventional ADT is necessary in this setting are currently recruiting. In this study we analyzed androgen deprivation in patients with mCRPC under chemotherapy and second generation androgen suppression. Methods: Out of 620 screened patients a total of 36 patients with continuous testosterone monitoring and mCRPC underwent therapy with docetaxel, abiraterone acetate, enzalutamide, carboplatin, carbozantinib or cabazitaxel and were evaluated. Data were gathered from our center over a median follow up period of 27.8 (0.6 - 65.1) month. A cutoff of 0.5 ng/dL was used to discriminate patients according to testosterone castration levels. Statistical evaluation was performed applying Kaplan Meier survival estimates, Cox regression and log rank test. Results: Median follow up was 26.2 month (range 1.4 - 64.8 month). Mean patient age was 70.9 years (range 51 - 86 years). The mean testosterone concentration in our cohort was 0.5 ng/dL. Serum testosterone levels varied greatly: ranging from 0 to 16 ng/dL. A total of 18 patients died during follow up. Median survival over all patients according to Kaplan-Meier survival estimation was 38.7 month (95% CI: 31 - NA month). Median survival for patients with testosterone levels below and above 0.5 ng/dL were 48.67 and 18.13 month respectively (log rank test: p = 0.0029). In Cox regression analysis, the hazard ratio for risk of death for patients with testosterone concentrations > 0.5ng/dL was 6.03 (95% CI: 1.5 - 25, p - 0.0132). For the covariates PSA velocity, patient age and primary Gleason score there was no significant effect on risk of death (p = 0.0597, 0.5006, 0.7354). Conclusions: In patients with mCRPC i.e rising PSA or progression under androgen deprivation, conventional suppression of testosterone levels still represents a vital factor for overall survival even at the mCRPC stage and under therapy with second line anti hormonal therapeutic medication and chemotherapy.
Effect of prostate-specific membrane antigen (PSMA) radioimmunotherapy on circulating tumor cell (CTC) count.
Authors: Karir Beerinder S , Batra Jaspreet S , Date Pravin R. , Hodes Gillian , Christos Paul J. , Beltran Himisha , Nanus David M. , Bander Neil Harrison , Tagawa Scott T.
Published: February 2017

199

Background: CTC counts with CellSearch methodology are prognostic; changes following therapy may be associated with improved outcomes. Since FDA clearance, baseline and follow up CTC counts were included in studies of radiolabeled J591. The effect of J591 alone (without an effector molecule) is unknown. Methods: Our phase II single-dose 177Lu-J591 (Cohort 3), phase I fractionated dose 177Lu-J591 (expansion cohorts), and phase I fractionated 177Lu-J591 + docetaxel (all pts) trials were analyzed. Any pt with baseline and at least 1 follow-up CTC count (CellSearch) was included in the analysis. A retrospective subset of patients undergoing J591-based imaging without an effector molecule attached was also analyzed. Results: 48 pts received 177Lu-J591 with prospectively measured CTC counts with median age of 73.7 years. 26 of 48 (54.2%) had unfavorable (≥5 CTCs/7.5 mL blood) baseline CTCs (median 29, range 5-449 CTCs/7.5 mL). Of the 23 with ≥5 baseline CTCs and available 4-6 wk post-treatment counts, 22 (95.6%) had declines of 15-100%, with 12 (52.2%) converting to favorable counts. Of the 18 with ≥5 baseline CTCs and available 12-14 wk post-treatment counts, 10 (55.5%) had declines of 8-100%, with 7 (38.9%) converting to favorable counts. Of the 22 of 48 (45.8%) with baseline CTC counts <5, 1 became unfavorable at 4-6 wks, later re-converting to favorable (early control rate of 95.5%) and 1 became unfavorable at 12-14 wks (sustained control rate of 95.5%). 7 men with unfavorable counts underwent imaging with 20 mg of J591 without an attached effector molecule; 4 (57%) demonstrated decline in CTCs following the imaging dose, with 1 stable and 2 continued to increase prior to subsequent therapy. Conclusions: In addition to the favorable PSA declines previously reported, radiolabeled J591 results in frequent favorable changes in CTC counts, with >90% of men with baseline unfavorable counts receiving 177Lu-J591 demonstrating CTC count decline or control in pts with baseline favorable counts. A small retrospective subset suggests that CTC counts may also be controlled with naked (unlabeled) anti-PSMA monoclonal antibody and a prospective study investigating this phenomenon will begin enrollment. Clinical trial information: NCT00195039 , NCT00538668 , NCT00916123 .
Project data sphere (PDS) in prostate cancer: A first look including concomitant medication use.
Authors: Gill Bethany , Khoja Leila , Li Zhu Juan , Hamilton Robert James , Koritzinsky Marianne , Penn Linda , Abdallah Kald , Pintilie Melania , Joshua Anthony M.
Published: February 2017

204

Background: PDS enables patient-level analyses of control arms of cancer trials. The interface (www.projectdatasphere.org) allows for both web-based and download-based analyses. We aimed to validate established prostate cancer prognostic models and explore the effect of concomitant medications on survival in mCRPC. Methods: Data was obtained for 2,747 control subjects with mCRPC from 7 Phase III clinical trials with 1962 subjects available for OS analyses from 5 studies. Overall survival was estimated using the Kaplan-Meier Method. Cox-proportional hazards models, stratified by trial, were used to estimate hazard ratios. Results: Metastatic site was significant for overall survival (Median: Node only 23.69m, Bone 18.17m, Lung 14.72m, Liver 9.43m; p < 0.001). Of the 23 types of medication examined, after adjusting for metastatic site, patients taking proton pump inhibitors (HR: 1.155, p=0.017) and Erythropoietin (HR: 1.49, p-value<.001) had worse overall survival whilst patients taking fish oil (HR:0.68, p-value=0.033) and non-lipophilic statins (HR:0.69, p=.00277) had improved overall survival. Within the limits of available data, we validated the prognostic models for overall survival proposed by Templeton et al. and Sonpavde et al individually and after inclusion of concomitant medication where patients taking metformin (HR=0.729, p=.0082) and Cox 2 inhibitors (HR=0.708, p=.015) had improved OS whilst those taking low molecular weight heparin (HR=1.352, p=.004) had worse OS. Conclusions: As a first project utilizing open-source PDS data in prostate cancer, we validated two prostate cancer prognostic models and illuminated the ability to undertake novel analyses such as the association of concomitant medications with outcome. Limitations of the data relate to incomplete and inconsistent data entry. Future expansion of patient trials and numbers will help to facilitate future analyses.
Effect of cabazitaxel on the growth of human castration-refractory prostate cancer cells in vitro compared to docetaxel and on the anti-tumor properties of the angio-inhibitor PEDF in vivo.
Authors: Nelius Thomas , Jarvis Courtney , Martinez-Marin Dalia , Filleur Stephanie
Published: February 2017

205

Background: Docetaxel/DTX and cabazitaxel/CBZ have shown promise in the treatment of metastatic Castration-Refractory Prostate Cancer/mCPRC however, comparative studies are missing. Toxicities of these drugs are significant, urging the need to modify taxane regimens. Recently, low-dose metronomic/LDM treatments using conventional chemotherapeutic drugs have shown benefits in CPRC in improving the effect of anti-angiogenic agents. Previously, we have demonstrated that LDM-DTX in combination with PEDF curbs significantly CRPC growth, limits metastases formation and prolongs survival in vivo. In this study, we intended to compare the cytotoxic effect of CBZ and DTX on CRPC cells in vitro and CL1 tumors in vivo. Methods: PC3, DU145 cell lines were from ATCC.CL1 cells were obtained from androgen-deprived LNCaP cells. Cell proliferation was assessed by crystal violet staining and cell cycle analyses. In vitro cytotoxicity assays were performed on CL1 cells/RAW264.7 macrophages co-cultures treated with PEDF and increasing doses of taxanes. For the in vivo studies, CL1 cells were engineered to stably express the DsRed Express protein +/- PEDF. PEDF anti-tumor effects were assessed on s.c. xenografts treated with DTX (5mg/kg ip ev. 4 day) as reference, CBZ (5mg/kg ip ev. 4 days, 1mg/kg for 10 days, 0.5mg/kg q.a.d. and 0.1mg/kg daily) or placebo. Results: CBZ limits cell proliferation with a greater efficacy than DTX in all CRPC cell lines tested. DU145 presented the largest difference. High doses of taxane blocked tumor cells in mitosis, whereas LDM increased the SubG1 population. This effect was significantly higher in DU145 cells treated with CBZ. In vivo, 5mg/kg CBZ delayed tumor growth more efficiently than 5mg/kg DTX. PEDF/5mg/kg CBZ markedly delayed tumor growth compared to all treatments. Finally, engulfment of tumor cells by macrophages was higher in combined treatments suggesting an inflammation-related process. Conclusions: CBZ is more efficient than DTX both in vitro and in vivo.The data also reinforce PEDF as a promising anti-neoplasic agent in combination with LDM taxane chemotherapies.
Primary resistance to abiraterone acetate (AA) after docetaxel treatment in metastatic castration-resistant prostate cancer (mCRPC): A multicenter retrospective analysis.
Authors: Maruzzo Marco , Basso Umberto , Diminutto Alberto , De Giorgi Ugo , Fratino Lucia , Lo Re Giovanni , D'Angelo Alessandro , Donini Maddalena , Verderame Francesco , Ratta Raffaele , Procopio Giuseppe , Campadelli Enrico , Massari Francesco , Gasparro Donatello , Macrini Sveva , Messina Caterina , Giordano Monica , Maines Francesca , Zagonel Vittorina , Caffo Orazio
Published: February 2017

206

Background: AA improves survival in mCRPC patients pre-treated with docetaxel. All patients eventually become resistant at different interval times, but some of them show an early progression and should be considered as primary resistant (PRES). To date, no factors have been identified as predictive of primary resistance. Methods: The clinical outcomes of a consecutive series of patients treated with AA after docetaxel failure in 19 Italian Hospitals within a Named Patient Program (NPP) was previously reported (BJU 2014). In the present analysis, we focus on patients who achieved an investigator-assessed PFS ≤ 3 months (PRES) and those with PFS ≥ 12 months (long term responders, LR). The main aim is to determine clinical characteristics associated with primary resistance. Results: Among the 265 patients enrolled in the NPP, we identified 97 PRES (37%) and 71 LP (27%). Poor performance status, visceral metastases, presence of pain, low baseline haemoglobin level, increased LDH and ALP levels, and short time from diagnosis to AA therapy were significantly associated with early progression (Table). Conclusions: Several clinical parameters appear to correlate with early progression under AA. Their role as potential predictive factors of resistance deserve further exploration in order to develop alternative treatment strategies. [Table: see text]
Exploring the effects of abiraterone/enzalutamide failure prior to the initiation of radium-223 dichloride in men with metastatic castrate-resistant prostate cancer.
Authors: Cotogno Patrick , Ledet Elisa M. , Steinberger Allie E. , Chowdry Rajasree Pia , Stolten Michael , Sartor Oliver
Published: February 2017

214

Background: FDA approval of three life-prolonging agents for metastatic castrate resistant prostate cancer (mCRPC) has occurred since April 2011. Two agents, abiraterone (abi) and enzalutamide (enza), disrupt androgen signaling. The third, radium-223 dichloride (Ra-223), targets bone metastases via alpha radiation. We sought to explore associations between prior abi/enza progression, number of Ra-223 cycles, prognostic factors, and overall survival (OS). Methods: Forty-two mCRPC patients (pts) treated with Ra-223 were identified. The sample was stratified based on progression (or not) on abi or enza prior to starting Ra-223. Number of Ra-223 doses administered, prognostic variables before Ra-223 treatment, and Kaplan-Meier estimates of overall survival (OS) were compared. Results: A strong association (p = 0.016) was demonstrated between prior abi/enza failure and number of Ra-223 doses administered. Patients without prior abi/enza failure were more likely to receive ≥ 4 doses of Ra-223 (94.12% vs 60.0%; odds ratio [OR] = 10.667; 95% CI, 1.214 – 93.699; p = 0.033). In comparison, those not receiving at least 4 doses of Ra-223 had a negative predictor in OS (p = .001) with a median survival of 89 days (n = 10; 95% CI, 44.064 – 133.936) compared to 303 days (n=15; 95% CI, 170.452 – 435.548). Patients initiating Ra-223 treatment after abi/enza progression had a higher median PSA (207.5 vs 49.2 ng/mL, p = 0.001), LDH (315 vs 253.5 U/L, p = 0.007) and alkaline phosphatase (ALP) (191 vs 106 U/L, p = 0.004). Conclusions: Our retrospective single institution analysis indicates that mCPRC patients who previously failed abi/enza are significantly less likely to complete 4 or more Ra-223 doses. These patients had significantly worse prostate cancer by a variety of standard prognostic variables. More information is needed from larger data sets to better understand this patient population and to best determine the optimal timing of Ra-223 administration.
Association between PSA declines at 4 weeks and OS in patients treated with abiraterone acetate (AA) for metastatic castration resistant prostate cancer (mCRPC) after docetaxel.
Authors: Rescigno Pasquale , Lorente David , Ferraldeschi Roberta , Bianchini Diletta , Sideris Spyridon , Zafeiriou Zafeiris , Smith Alan David , Mehra Niven , Grist Emily , Jayaram Anuradha , Kolinsky Michael Paul , Perez Lopez Raquel , Mateo Joaquin , Parker Chris , Dearnaley David Paul , Hall Emma , Tunariu Nina , Attard Gerhardt , De Bono Johann Sebastian
Published: February 2017

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Background: Falls in prostate specific antigen (PSA) levels by 50% from the baseline at 12 weeks are currently used to assess response to treatment for mCRPC (Scher et al, 2008). However PSA decline algorithms do not provide robust intermediate endpoints of overall survival (OS) benefit in mCRPC. We evaluated the association between PSA decline at 4 weeks and OS. Methods: We identified mCRPC patients who had received treatment with abiraterone acetate (AA) plus prednisolone post-docetaxel at the Royal Marsden (London, UK) between 01.01.2006 and 30.04.14. Patients were eligible for this analysis if they had PSA levels assessed at baseline, after 4 weeks and 12 weeks of treatment. PSA response at 4 weeks was defined as a ≥30% (PSA4w30) and ≥50% (PSA4w50) decline from baseline (PSABL). Association with outcome was analyzed using multivariate Cox regression and log-rank analyses. A significant p-value of 0.0167 was pre-specified to account for multiple testing. Demographics and clinical data were retrospectively collected from the hospital electronic patient record system (EPR). Results: We identified 124 patients who had received AA post-docetaxel and were eligible for this analysis. PSA4w30 was associated with longer OS (median OS 11.1 vs. 6.8 months; HR 0.50; 95% CI 0.32-0.80; p=.004). PSA4w50 was not associated with OS. A ≥50% PSA decline at 12 weeks (PSA12w50), the standard response measure, was also associated with OS (median OS 9.3 vs. 8.2; HR 0.49; 95% CI 0.29-0.80; p=.005). PSA4w30 was significantly associated with PSA12w50 (p<.001). Lack of a PSA response at 4 weeks correlated with a lack of response at 12 weeks (p=0.000), with a sensitivity of 84.9% [95% CI 75-91.4] and a specificity of 86.5% [95%CI 72–94.1]). PSA4w30 remained significantly correlated with OS (P<.001) in multivariate analyses including other established prognostic factors in mCRPC (ECOG PS, albumin, PSABL, ALP, LDH, Hemoglobin). Conclusions: Further studies to identify mCRPC patients not responding to treatment as early as possible are warranted; PSA4w30 may be useful to help identify patients unlikely to benefit from AA.
ODM-204: A novel dual inhibitor of CYP17A1 and androgen receptor for the treatment of castration-resistant prostate cancer—Preclinical data.
Authors: Oksala Riikka , Moilanen Anu , Riikonen Reetta , Rummakko Petteri , Huhtaniemi Riikka , Kallio Pekka
Published: February 2017

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Background: Castration-resistant prostate cancer (CRPC) is characterized by high androgen receptor (AR) expression and persistent activation of AR signaling axis by residual tissue/tumor androgens. Targeting AR and androgen biosynthesis together may be more effective than either alone. ODM-204 is a novel, non-steroidal dual inhibitor of CYP17A1 and AR, which has shown promising results in preclinical studies. Methods: The binding affinity of ODM-204 to wild type AR was determined in rat prostate cytosolic lysates. The potency and functional activity of ODM-204 to human AR were demonstrated in cells stably transfected with the full-length AR and androgen-responsive reporter gene constructs. In addition, assays for AR nuclear translocation and the transactivation of human AR mutants T877A, W741L, and F876L were conducted. The effects of ODM-204 on the growth of androgen-dependent VCaP and LNCaP cells in vitro and subcutaneously grafted VCaP cells in vivo with the oral dose of 50 mg/kg/day were studied. The inhibition of CYP17A1 by ODM-204 was studied in vitro by using human and rat testicular microsomes and a human adrenal cortex cell line, and in vivo in male rats coadministered with luteinizing hormone releasing hormone agonist leuprolide acetate to mimic clinical situation. Results: ODM-204 is a potent inhibitor of both AR and CYP17A1. It binds to AR with a high affinity (Ki=47 nM) and selectivity and has a high potency towards CYP17A1 (IC50=22 nM). In addition, ODM-204 inhibited testosterone-mediated nuclear translocation of AR and the mutant ARs (IC50 values for AR(T877A), AR(W741L), and AR(F876L) were 95, 277, and 6 nM, respectively), and suppressed androgen-induced cell proliferation of LNCaP (IC50=170 nM) and VCaP (IC50=280 nM) cells. In a VCaP xenograft model, ODM-204 showed significant antitumor activity (tumor growth inhibition=66%). In rats, inhibitory effects of leuprolide acetate on testosterone production and androgen-sensitive organ weights were potentiated by ODM-204. Conclusions: ODM-204 is a promising new dual CYP17A1 and AR inhibitor for the treatment of CRPC. Clinical trials in patients with mCRPC will be started in early 2015.
Multivariable analysis of predictors of side effects of cabazitaxel in the Italian Expanded Access Program.
Authors: di Lorenzo Giuseppe , Buonerba Carlo , Bracarda Sergio , Gasparro Donatello , Gernone Angela , Messina Caterina , Zagonel Vittorina , Puglia Livio , Bosso Davide , De Placido Sabino
Published: February 2017

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Background: Cabazitaxel-based chemotherapy provides a survival benefit after docetaxel failure in patients with prostate cancer. Grade 3-4 neutropenia and febrile neutropenia were relatively frequent in the registrative trial, but their incidence in clinical practice is likely to be lower, as shown by data collected in the Expanded Access Program (EAP). While cumulative doses of docetaxel are associated to neuropathy, the effect of cumulative doses of cabazitaxel is unknown. In this study, we assessed 'per cycle' incidence and predictors of toxicity in the Italian cohort of the EAP, with a focus on the effect of cumulative doses of cabazitaxel. Methods: The study population consisted of 218 Italian patients enrolled in the cabazitaxel EAP. The influence of selected variables on the most relevant side effects identified was assessed using a Generalised Estimating Equations (GEE) model at univariate and multivariate analysis. Multivariate logistic regression analysis was performed using a backward selection procedure. Variables with a p value ⩽0.1 were kept in the final model. Results: Per cycle incidence of grade 3-4 neutropenia was 8.7%, while febrile neutropenia occurred only in 0.9% of cycles and was an early event, occurring during the first three cycles only. Multivariate logistic regression analysis showed that the odds of having grade 3 – 4 neutropenia, febrile neutropenia and anemia were statistically significantly reduced by 10, 48 and 7%, respectively, every 10 mg/m2 increase of total prior dose of cabazitaxel. Interestingly, a body surface area > 2 m2 was associated to increased odds of having grade 3-4 neutropenia. In this regard, it must be noted that all patients with body surface area > 2 m2 had their total dose capped to 50 mg, with a mean (95% CI) and median (IQR) dose reduction of 7.1 (7.58-6.69) and 5.9 (2.76-10.27) % with respect to planned dose. Conclusions: Cumulative doses of cabazitaxel are associated to decreased risk of bone marrow toxicity. Patients with body surface area >2 m2 are at increased risk of bone marrow toxicity and dose capping should be considered. These data indicate that cabazitaxel should not be arbitrarily suspended because of concerns of cumulative toxicity.
Phase 1/2a, open-label, dose-escalation and safety study of APC-100 in men with advanced prostate cancer.
Authors: Kyriakopoulos Christos , Heath Elisabeth I. , Eickhoff Jens C. , Kolesar Jill , Yayehyirad Mulusew , Moll Thomas , Liu Glenn
Published: February 2017

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Background: Normal human prostate epithelium and prostate carcinoma exhibit high levels of oxidative stress, which is thought to play a role in the pathogenesis of prostate cancer. APC-100 (2,2,5,7,8-Pentamethyl-6-chromanol) is an oxidative stress modulator that reduces reactive oxygen species (ROS) in prostate cancer cells and inhibits growth of cultured androgen-dependent and independent human prostate cancer cells. We aimed to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), adverse events (AEs), clinical activity and pharmacokinetic (PK) parameters of APC-100 in men with castrate-resistant prostate cancer (CRPC). Methods: This open label phase 1/2a study utilizes a time-to-event reassessment method (TITE-CRM) design. Patients (pts) in cohorts of 3 were treated with escalating doses of APC-100 (900mg-2400mg) orally once daily continuously in 150 mg capsules. Cycles were 28 days. All patients were evaluable with PSAs and imaging studies. Results: Twenty pts (median age 72 [range 54-87]) with metastatic and non-metastatic CRPC were enrolled in the dose escalation cohort. Pts remained on study for a median of 12 weeks (range 4-36) and received therapy for a median of 3 cycles (range 1-9). One possible DLT (elevated ALT) was seen at dose level 1 and the patient was taken off study. No other DLTs at least possibly related to therapy were seen and no dose reductions were required. Most frequent AEs at least possibly related to therapy included nausea (grade 1 in 6 pts) and elevated transaminases (grade 1-3 in 5 patients). After enrolment of 20 pts the MTD was not reached, however the maximal feasible dose was exceeded due to the number of capsules required. Five of the 20 patients had stable disease per PSA and/or RECIST 1.1 as their best response. The median progression free survival (PFS) for the cohort was 2.8 months (range 1-8). Conclusions: APC-100 appears to be well tolerated with the MTD not reached. Limited PK assessment supports the need for alternative formulation to allow dose escalation to doses necessary to achieve exposures required for response. Once MTD is established, future studies will explore the activity of APC-100 as a therapeutic and chemopreventive intervention. Clinical trial information: NCT01436214.
A multicenter phase I study of cabazitaxel (Cbz), mitoxantrone (Mito), and prednisone (Pred) (CAMP) for chemotherapy-naïve patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Aggarwal Rahul Raj , Bryce Alan H. , Weinberg Vivian K. , Ryan Charles J. , Derleth Christina Louise , Harzstark Andrea , Lee Mina , Small Eric Jay
Published: February 2017

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Background: Cbz/pred extends survival in mCRPC patients (pts) following docetaxel and first-line studies comparing Cbz to docetaxel are ongoing. Mito/pred also has anti-tumor activity in mCRPC and a non-overlapping mechanism of action and toxicity profile with Cbz. A multicenter phase 1 trial was initiated through the DOD PCCTC to establish the maximally tolerated dose (MTD) and recommended phase 2 dose (RP2D) of the combination of Cbz, Mito, and Pred (CAMP). Methods: Chemotherapy (chemo)-naïve pts with mCRPC were enrolled in an accelerated titration design. The primary objective was to determine the MTD and RP2D of CAMP; secondary objectives included PSA response rate and duration of response. Cbz 20 and 25 mg/m2 were each evaluated in combination with escalating doses of Mito (starting dose 4 mg/m2), both administered on day 1 of a 21-day cycle. Pred 5 mg BID and pegfilgrastim were given with each cycle. Results: 20 pts were enrolled. The median age was 66 (range 51-78) and the median baseline PSA was 62.5 (range 3.0-791.2). There were 2 DLTs observed at the dose level of Cbz 25 mg/m2 + Mito 10 mg/m2 (sepsis and febrile neutropenia). No DLTs were observed with Cbz 20 mg/m2 (N = 10), establishing Cbz 20 mg/m2 + Mito 12 mg/m2 as the MTD and RP2D. The most common grade ≥ 3 related adverse events were hematologic (neutropenia, n = 8; thrombocytopenia, n = 3; febrile neutropenia, n = 2). No cardiac adverse events were observed. The median number of treatment cycles was 9 (range 2-16), and 5 pts remain on study. Greater than 50% maximal PSA declines from baseline were observed in 8 of 18 evaluable pts (44%). Objective tumor responses have been observed in 2 of 4 pts (50%) with measurable disease, with evaluation ongoing. The median duration of response has not been reached (range 4.9-10.0+ months). Conclusions: The approved single-agent dose of Mito (12 mg/m2) was safely combined with Cbz 20 mg/m2, a dose with demonstrated activity in mCRPC and potentially less hematologic toxicity than 25 mg/m2. Preliminary efficacy data are encouraging with durable responses observed in a subset of pts. Further study of the treatment combination is warranted. Clinical trial information: NCT01594918.
Effect of combined sequential treatment of sipuleucel-T followed by enzalutamide in metastatic chemo-naïve castration-resistant prostate cancer: Results of single center of large urology group.
Authors: Mouraviev Vladimir , Pieczonka Christopher Michael , Telonis Dimitios , Albala David
Published: February 2017

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Background: The timing and sequencing of combination therapy is becoming of outmost importance for the treatment of mCRPC patients. As a result our hypothesis has been to layer on enzalutamide very quickly after the completion of sipuleucel-T. Methods: We collected the data of 84 patients with chemo-naïve mCRPC treated with sipuleucel-T at our practice from September 2011 to January 2014. Prior to the initiation of treatment the baseline status was recorded in all patients. We then selected and analyzed outcomes of 19 patients who received sequential enzalutamide treatment after completion of sipuleucel-T. The average timing for the initiation of enzalutamide was 2.5±1.6 months after completion of the immune therapy. We believe this to be a very unique cohort as all of these patients were treated with enzalutamide off label (i.e. pre-chemo). Results: The median time of enzalutamide therapy was 5.4 months (range: 1-13). In our cohort of 19 patients: 1 case showed radiographic full regression of metastatic lesions in bone, lung and lymph nodes. Another case showed radiographic full regression of bony metastatic lesions. 2 other cases – showed a partial regression radiographically of bony metastatic disease. 13 cases showed stable disease according to RECIST-criteria. The remaining 2 patients were deceased due to progression of mCRPC. The patients with full and partial response were in the lowest quartile of our cohort as defined as a PSA ≤ 3.87 ng/ml. On the contrary, all cases of progression and death were documented in highest (last) quartile as defined by a PSA level more than 84 ng/ml. Conclusions: Our experience demonstrates a promising effect using sequential sipuleucel-T immunotherapy followed by enzalutamide for mCRPC. To our knowledge this will be the first case of complete radiographic regression of lung, bone, and extensive lymph node disease. Currently there are studies undergoing that will hopefully validate our experience with using enzalutamide at the initiation of sipuleucel-T.
Trends in prescribing preferences (PPrefs) of U.S.-based oncologists for patients (Pts) with metastatic castrate-resistant prostate cancer (mCRPC) following docetaxel (DO).
Authors: Ryan Charles J. , Kim Won , Buettner Arden , Britton Susan Lynne , Lankford Maria L. , Neely Doug B. , Green Mark R.
Published: February 2017

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Background: PPrefs of 467 US-based medical oncologists (MOs) in post-DO mCRPC pts were studied prospectively. A validated, proprietary, live, case-based market research tool was utilized with a core case scenario and 4 distinct treatment (Rx) outcomes following chemotherapy (CTx). Data were acquired using blinded audience response technology. Research support sources were double blinded. Methods: Core case: 59 y/o status post (s/p) radical prostatectomy with PSA failure after 15 months (mo), s/p salvage pelvic radiation (RT) → presents with rise in PSA and 3.5cm pelvic lymph node 16mo following RT→ progresses through multiple Rx over the next 42mo, including combined androgen blockade, anti-androgen withdrawal, sipuleucel-T and abiraterone (ABI). Now starting DO CTx due to increasing bone metastases and bone pain (BP). PPrefs for 4 variant scenarios of DO CTx were probed: (1) DO 75 mg/m2Q3wk x 6 cycles (cy) →Resolution of BP/PSA response → DO held due to cumulative myelosuppression/fatigue. Pt more active off CTx, ECOG PS 1. 3mo later →asymptomatic 30% rise in PSA. (2) DO x 4 cy → decrease in PSA, BP, node size. Prior to cy 6, has asymptomatic PSA progression. (3) DO x 4 cy→ decrease in PSA, BP, node size. Prior to cy 6, has both PSA and BP progression. (4) DO x 2 cy → progression with increased BP, PSA, and pelvic nodal disease. Results: See Table. Conclusions: PPrefs after DO CTx were outcome-dependent. In the absence of BP, ENZ is the most common PPref, even in this ABI-refractory pt. PPref for R223 over 2nd line CTx in the acquired symptomatic resistance setting is notable. PPref for 2nd line CTx increases with rapid, symptomatic disease progression. [Table: see text]