bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic value of chromogranin-a (CGA) compared to circulating tumor cells (CTCs) in metastatic castration resistant prostate cancer (mCRPC).
Authors: Giridhar Karthik , Sanhueza Cristobal T. , Hillman David W. , Alkhateeb Hassan , Carlson Rachel , Tan Winston , Quevedo Fernando , Pagliaro Lance C. , Costello Brian Addis , Kohli Manish
Published: February 2018

249

Background: Serum CGA has been identified as a candidate prognostic biomarker for mCRPC. In a two cohort study, we compared the prognostic value of serum CGA with a validated CTC assay. Methods: In the discovery cohort (DC), blood samples were collected from 256 men with mCRPC. In an independent validation cohort (VC), 92 men with mCRPC were enrolled in a biospecimen collection study. In both cohorts, men receiving proton pump inhibitors and those with non-castrate levels of testosterone ( > 50ng/dl) were excluded. Serum CGA was measured in a homogeneous automated immunofluorescent assay using time-resolved amplified cryptate emission. In the VC, CTC enumeration was performed using the FDA cleared CELLSEARCH CTC test prior to treatment with abiraterone acetate/ prednisone. Cox proportional hazard regression and Kaplan-Meier analysis were performed for associations with elevated CGA (above reference range), unfavorable (≥ 5) CTCs, and overall survival (OS). Results: In the DC, 200 men were eligible for analysis. The median age was 72 years (yrs), 81/200 pts had a Gleason score (GS) ≥ 8, 34/200 had an elevated CGA. At a median follow up of 2.2 yrs, 156/200 were deceased. In the subset of men with GS ≥ 8, elevated CGA was associated with shorter OS [hazard ratio (HR) 2.19, p = 0.017]. In the VC, 71 men were eligible for analysis. The median age was 71 yrs, 36/71 tumors were GS ≥ 8, 31/71 pts had an elevated CGA, 26/66 had unfavorable CTCs (≥ 5). At a median follow up of 1.8 yrs, 31/71 were deceased. Elevated CGA (HR 1.91, p = 0.043) and unfavorable CTC counts (HR 2.97, p = 0.0012) were adversely associated with OS. In the high GS group, both CTCs and CGA had the same area under the curve (AUC) of 0.72. Pts with elevated CTC and CGA had the poorest OS (HR 3.76, p = 0.008). Conclusions: Elevated serum CGA was negatively associated with OS in men with mCRPC. Serum CGA represents a prognostic biomarker that may complement CTC enumeration. Clinical trial information: NCT#01953640.
Continuous infusion fluorouracil (5FU) in heavily pre-treated mCRPC patients.
Authors: Manogue Charlotte , Moses Marcus Marie , Lewis Brian E. , Sartor A. Oliver
Published: February 2018

257

Background: Pts with mCRPC resistant to novel hormones (abi/enza), and taxane chemotherapy are challenging. Extensive pre-treatment typically poses an issue for clinical trials, and there is no consensus regarding how to manage patients who no longer respond to conventional therapies but maintain a good performance status. Methods: 13 mCRPC pts were treated with 5FU at 200mg/m2 continuous infusion as a novel treatment option for those with heavily pretreated mCRPC. Data was retrospectively collected at Tulane Cancer Center for patient treatment history, and laboratory parameters. Results: All treated patients had prior exposure to an average of 8.7 lines of treatment. 5FU was used as median 8th line therapy. All pts had extensive bony disease and 6 had liver involvement. Median PSA at start of treatment was 356 ng/dL. 5 pts progressed within a month of initiation of therapy, and 2 pts did not respond. 8 (61%) patients had treatment for >1 month with 6 having >30% PSA reduction, 4 with a >50% PSA reduction and 2 with a >90% PSA reduction (Table). Median time on therapy was 4.5 months with 2 patients remaining on treatment for >6 months despite multiple pretreatments and far advanced disease. 5FU was well tolerated with improvement in both performance status and symptoms in several patients. Conclusions: Continuous 5FU is active in select highly pretreated pts and targets folate metabolism via inhibition of thymidylate synthase. It is one of the few chemotherapies that can be administered with little myelosuppression, an important issue in far-advanced pts. Prostate specific membrane antigen (PSMA) expression is upregulated in CRPC, especially after abi/enza treatment. PSMA hydrolyzes polyglutamated folates and functions as a folate transporter; its over-expression stimulates both folate transport and prostate cancer cell line growth. We hypothesize that 5FU, functioning as an anti-folate, antagonizes the downstream effects of PSMA over-expression. PSA data for pts on treatment > 1 month. [Table: see text]
Effect of β-hydroxy-β-methylbutyrate (HMB) on muscle strength in older men with prostate cancer (Pca) started on androgen deprivation therapy (ADT): Preliminary results of an open-label, randomized trial.
Authors: Bylow Kathryn A. , Kilari Deepak , Riese Matthew John , Burfeind John , Stolley Melinda , Prost Robert W , Musto Kaylinn , Neilson Raquel , Szabo Aniko , Thomas James P. , Ng Alexander V.
Published: February 2018

258

Background: ADT causes muscle weakness and wasting within 3 months (mo), causing older men on ADT to experience functional impairments and falls. HMB, a leucine metabolite which decreases muscle protein breakdown, improves strength, fat-free mass and function in older patients when given with arginine (A) and glutamine (G). Use of HMB +AG in older men with PCa starting on ADT to improve muscle loss and function has not been reported. Methods: Men age ≥ 60 with Pca starting on ADT were eligible. 42 men to date have been randomized to receive HMB + AG (Juven) twice daily for 3 mo vs no supplement. Physical performance measures using the Short Physical Performance Battery (SPPB) and hand dynamometer measurements were done at baseline and 3 mo. Both of these validated tests predict morbidity and mortality in older patients. Information on primary outcome, body composition, will be reported in the future according to study plan. Interim results are reported here to describe functional geriatric outcomes. Results: 42 men (mean age 70.2) with Pca (42.4% localized, 27.3% biochemical recurrence, 30.3% metastatic) have enrolled to date. Change in SPPB score favored HMB group: 12.6% of HMB vs 23.1% of controls had decline of ≥ 1point (pt) and 56.3% of HMB vs 15.4% of controls had increase of ≥ 1 pt (p = 0.045). The change in timed chair stand portion of SPPB (measures quadriceps strength) trended in favor of HMB group: -1.5 ± 2.9 seconds (sec) for HMB vs +0.4 ± 2.5 sec for controls, p = 0.073. 41.2% of HMB vs 15.4% of controls experienced an improvement in chair stand score. Change in hand grip strength also favored HMB group: 52.9% of HMB vs 84.6% of controls lost strength and 29.4% of HMB vs 0 controls gained strength, p = 0.047. No significant side effects were reported in HMB group. Conclusions: These are preliminary results of an ongoing trial. HMB is well tolerated in men with PCa on ADT. There is a trend in all measures of muscle function in favor of the HMB group. A much higher than expected % of men on HMB experienced improvement in measures of muscle function despite being on ADT. Further studies are ongoing to clarify the role of HMB in older men on ADT. Clinical trial information: NCT01607879.
Cosegregation of cfDNA AR amplifications and mutations in relation to BRAF and MYC in CRPC.
Authors: Christensen Bryce Raymon , Ledet Elisa , Moses Marcus Marie , Chapman Lynne , Steinwald Peter , Shahbandi Ashkan , Cotogno Patrick , Schiff Joshua , Layton Jodi Lyn , Lewis Brian E. , Sartor A. Oliver
Published: February 2018

261

Background: cfDNA can be utilized to evaluate androgen receptor (AR) alterations in metastatic castrate resistant prostate cancer (mCRPC) patients. Given the role of androgen receptors in the pathophysiology of PC, mutations in the AR gene can have important implications regarding prognosis and treatment. The goal of this research was to evaluate associations between certain PC treatments and AR mutations. Methods: Treatment and demographic data from 121 patients diagnosed with PC was collected including genetic data derived from the Guardant360 test (Guardant Health, Redwood City, CA). AR alterations were compared among race, treatment history, and other somatic alterations. Results: 52.9% (n = 64) of the mCRPC pts evaluated had an AR alteration. Of the pts with AR alterations, 43.8% (n = 28) had AR amplification (amps), 37.5% (n = 24) had AR mutations (muts), and 18.8% (n = 12) had both. AR muts included: T878A (n = 15), H875Y (n = 8), W742C (n = 11), AR L702H (n = 7), and others. AR alterations comprised on average about 7% of tumoral cfDNA. To better understand the relationship between AR alterations and other commonly detected cfDNA aberrations, associations between BRAF (27.3%), TP53 (44.6%), and MYC (19.0%) and AR were assessed. Among these genes, P53 alterations were all Muts. MYC (n = 21) and BRAF (n = 27) alterations were predominantly amps though muts were also detected in MYC (n = 3) and BRAF (n = 9). P53 muts were not significantly associated with AR alterations. BRAF and MYC alterations significantly associated with AR alterations (p = 0.0012 and p = 0.0223). Pts were re-tested upon disease progression; among these patients, 52.2% (n = 24) had an increase in overall mut burden. Conclusions: AR alterations in cfDNA impact both disease progression and response to therapy. Co-segregation of AR, BRAF, and MYC alterations may also have significant prognostic and therapeutic implications. Further research, a larger sample size, and longitudinal assessment are needed to further elucidate associations between disease progression and treatment response to the development of somatic alterations over time in mCRPC.
Incidence, patterns of treatment, and survival among men newly diagnosed with advanced prostate cancer: An analysis of SEER-Medicare data.
Authors: Beebe-Dimmer Jennifer Lynn , Ruterbusch Julie J. , Cooney Kathleen A. , Schwartz Kendra L. , Bolton Adam , Heath Elisabeth I.
Published: February 2018

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Background: About 5% of men are newly-diagnosed with advanced stage prostate cancer (PCa) and experience far poorer survival compared to men diagnosed with local or regionally-advanced disease. PCa mortality is higher in African Americans (AA) compared to non-Hispanic whites (NHW), with a marginally higher proportion of AA men first diagnosed with advanced disease. Thus, we sought to describe recent trends in incidence, survival and patterns of treatment among men diagnosed with de novo AJCC stage IV PCa. Methods: SEER*Stat software was used to calculate age-adjusted rates and annual percent changes for PCa stratified by AJCC stage and race/ethnicity for men age 66 or older diagnosed 2004-2014. We then used the Surveillance, Epidemiology and End Results database linked to Medicare Claims files to identify men diagnosed with advanced PCa during same time period. We examined patterns of treatment among all eligible patients and by race/ethnicity. Results: Rates for AJCC stage I-III PCa among elderly men have significantly declined in recent years for both NHW and AA men (-5.8% APC, p<0.001 for both), while rates for AJCC stage IV increased for NHW men (+1.5% APC, p=0.011) and decreased for NHB men (-1.8% APC, p=0.008). Of the 8,828 eligible patients identified from the SEER-Medicare database, 13% were AA, with a median survival of 32 months among all patients and survival significantly poorer among AA (p < 0.0001). AA patients were also more likely to go without treatment (p < 0.0001) compared to NHW patients, even after accounting for early mortality and TNM stage. The frequency of nearly all forms of treatment was lower among AA patients with the exception of orchiectomy, which was significantly higher (10.1% vs. 6.1%), and among Medicare Part D enrollees, the progesterone Megace (24.6% vs. 15.0%). Conclusions: Results from this study of Medicare patients diagnosed with advanced stage PCa suggest less aggressive treatment may contribute to the poorer survival observed in AA men. Understanding drivers of treatment-related decisions are critical in reducing racial disparities in survival among men with advanced PCa.
Evaluating changes in circulating tumor cell count in prostate cancer patients during androgen deprivation plus chemotherapy by using AxonDx enumeration device.
Authors: Brobey Reynolds , Amato Robert J. , Smith Jeff , Dehghani Mehdi , Murphy Kent , Wang Yue
Published: February 2018

266

Background: Circulating tumor cell (CTC) counts have clinical utility as a prognostic marker in cancer. For prostate cancer (PCa), CTC counts ≥5 CTC/7.5 ml using the FDA-approved CellSearch system convey a negative prognosis with respect to overall survival, but the significance of changes in CTC count during treatment is not fully understood. To determine whether longitudinal CTC counts can be used as a prognostic and/or predictive marker of clinical outcome in PCa patients undergoing androgen deprivation therapy (ADT) plus chemotherapy, we used the AxonDx nCyte non-enrichment-based CTC detection and enumeration system to evaluate CTC counts at baseline, during, and after therapy in 18 patients for up to 11 months. Methods: Whole blood was drawn from PCa patients on clinical trials for ADT plus chemotherapy at PSA evaluation (±radiographic reevaluation) into vacutainers containing K3-EDTA and processed within 6 hr. PBMC containing nucleated cells harvested from 6 ml of whole blood were fixed, permeabilized and blocked with BSA buffer, and stained using a proprietary antibody cocktail containing DAPI, an anti-cytokeratin mixture, the pan-leukocyte marker CD45, and markers selective for granulocytes and lymphocytes. Stained cells were drawn onto 1.2 µm pore filters, washed, placed on counting slides, and analyzed. CTCs are identified as cytokeratin-positive, nucleus-positive and leukocyte marker-negative. Results: CTCs were obtained from 12 patients for 2-9 months at 2-7 time points; from 2 patients for 11 months at 5-7 time points, and from 4 patients for 1 month at 1 time point. We detected time-dependent changes in CTC counts following treatment that did not necessarily correlate with patient’s local prostate specific antigen (PSA) levels but were early indicators of subsequent increase in tumor burden. Conclusions: The AxonDx nCyte system can reliably detect CTCs from PCa patient samples that trend along with other signs of disease progression. CTCs can be used longitudinally for clinical monitoring of patients with PCa prior to signs of progression via tumor markers or scans during ADT plus chemotherapy, providing a reliable biomarker for PCa.
Association of prostate-specific antigen (PSA) trajectories with risk for metastasis and mortality in non-metastatic castration-resistant prostate cancer (nmCRPC).
Authors: Li Sophia , Ding Zhijie , Lin Jennifer H , Behl Ajay S. , Pericone Chris , Macomson Brian , Shore Neal D.
Published: February 2018

27

Background: Currently there is insufficient guidance for the management of nmCRPC. This study assessed patient risk of developing metastases and death based on their PSA levels over time. Methods: This was a retrospective study using the Optum electronic health record database (1/1/2007 – 4/30/2016) in men ≥18 years. nmCRPC was defined as a PC diagnosis, 2 rising PSA levels ≥1 week apart, testosterone < 50 ng/dL (post-PC diagnosis), and no ICD-9/10 code or therapy indicating metastasis. Patients were required to have ≥1 PSA record per 3-month period for 9 months following nmCRPC diagnosis. Group Based Trajectory Modeling (GBTM) was used to group patients based on similar PSA trends over 9 months. The association of these PSA groups with metastasis/mortality risk was measured using multivariate Cox proportional hazard regression models. An overall trend for metastasis and mortality across the groups was also tested. Results: From a total of 729 patients included, 4 distinct groups were identified: Group 1 (49% of patients), 2 (32%), 3 (14%) and 4 (5%). Group 1 had the lowest PSA (7 ng/mL) at nmCRPC diagnosis and steady PSA during the 9-month follow-up. In contrast, Groups 2, 3 and 4 had higher PSA at nmCRPC diagnosis (17, 61, 513 ng/mL respectively) and rising PSA during follow-up. There was a trend of increasing metastasis and mortality risk (p < 0.001 for both trends) with the higher PSA groups. For metastasis, Hazard Ratios (HRs) and 95% confidence intervals (CIs) were 1.7 (1.3-2.2), 3.5 (2.5-5.0), 1.8 (0.7-4.7) in Groups 2, 3 and 4, respectively, vs. Group 1. For mortality, HRs (95% CIs) were 1.9 (1.4-2.5), 2.6 (1.8-3.7), 4.5 (2.4-8.4) in Groups 2, 3 and 4, respectively, vs. Group 1. Metastasis-free survival (MFS) independently predicted mortality risk. Patients developing metastasis within 1 year had 4.4-fold greater risk for mortality (95% CI = 2.2-8.8) than those who remained MFS at year 3. Conclusions: A large proportion of nmCRPC patients with PSA increases during the follow-up period had significantly increased risk for metastasis and mortality, with MFS predicting mortality risk. Periodic measurement of PSA may better inform management of nmCRPC.
Novel method for rapid enrichment of high purity circulating tumor cells (CTCs) for prostate cancer (PCa) gene expression profiling.
Authors: Morrison Gareth , Jojo Nita , Cunha Alexander , Xu Yucheng , Robinson Peggy S. , Dorff Tanya B. , Quinn David I. , Goldkorn Amir
Published: February 2018

271

Background: CTC RNA analysis currently involves single cell recovery that is laborious and expensive, or alternatively lysis of preserved whole blood which yields RNA predominantly from leukocytes which vastly outnumber CTCs. To effectively characterize gene expression in large patient cohorts, new enrichment methodologies are needed that yield high purity CTC populations while preserving RNA integrity. Here we describe a simple yet robust method for enrichment of prostate CTCs for gene expression analysis. Methods: Blood was drawn with informed consent under an IRB-approved protocol. For initial optimization, CFSE-stained PCa cells were spiked into healthy blood and recovered using various combinations of 2 methods: microfluidic enrichment (Parsortix™ system) and CD45 depletion. For assay qualification, a prostate-specific multiplexed qRT-PCR gene expression panel was developed. Enrichment and gene expression were tested initially using PCa cell lines spiked into healthy blood, then metastatic castrate resistant prostate cancer (mCRPC) blood samples in parallel with CellSearch enumeration. Results: Optimal enrichment of live cells was achieved with CD45 depletion followed by microfluidic enrichment, resulting in an average spiked cell recovery of 30% and approximately 100 contaminating background leukocytes. Using this enrichment method, prostate specific genes were detectable by multiplexed qRT-PCR down to 25 cells spiked into 7.5 ml whole blood, and transcripts were not measurable in matched healthy blood controls. When applied to mCRPC patient blood containing CTCs by CellSearch, multiplexed qRT-PCR successfully detected prostate specific genes in all samples. Conclusions: We developed a novel enrichment method capable of rapidly and efficiently recovering live CTCs with high purity, free of magnetic beads and with very few background leukocytes. Captured cells yielded high-quality RNA with high sensitivity and specificity for prostate-specific transcripts. This approach is applicable to high throughput gene expression profiling assays and offers an alternative to laborious single cell recovery or non-cancer-specific whole blood fixation.
Validation of nuclear-localized AR-V7 on circulating tumor cells (CTC) as a treatment-selection biomarker for managing metastatic castration-resistant prostate cancer (mCRPC).
Authors: Scher Howard I. , Graf Ryon P , Schreiber Nicole A. , Winquist Eric , McLaughlin Brigit , Lu David , Orr Sarah , Fleisher Martin , Lowes Lori , Anderson Amanda K. L. , Wang Yipeng , Dittamore Ryan Vance , Allan Alison L , Attard Gerhardt , Heller Glenn
Published: February 2018

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Background: A previous analysis of 161 patients (pts) tested for nuclear-localized AR-V7(+) CTCs showed a therapy interaction between AR-V7 positivity and improved overall survival (OS) on taxane chemotherapy vs. androgen receptor signaling inhibitors (ARSI). To validate the use of the biomarker result for physician decision making, we prospectively analyzed an independent, multicenter, blinded, cross-sectional cohort (n = 225) to confirm a therapy interaction with AR-V7. We corrected for possible pt selection bias by the treating physician by analyzing the association of therapy to OS in low and high risk groups defined by the test cohort. Methods: Two analyses were performed: (1) the validation of a therapy interaction between AR-V7 positivity and superior OS benefit for pts treated with taxanes in the context of use for 2nd+ line pts; and (2) as the choice between ARSI or taxanes was at the discretion of the attending physician, pt risk was incorporated into the predictive biomarker assessment. A pt-specific risk score was developed from line of therapy and other covariates to stratify pts as low and high risk, and the association of AR-V7 status and OS was performed within each risk group to correct for physician decision making and address possible confounding with treatment assignment. Results: (1) A therapy interaction between AR-V7(+) pts and lower risk of death on taxanes vs. ARSI (HR: 0.23, p = 0.003, 95% CI: 0.09 – 0.61) was validated. (2) In the validation cohort, high risk AR-V7(+) pts had an OS benefit when treated with taxanes (p = 0.02) and the AR-V7(-) pts had an improved OS with ARSI therapy (p = 0.02). AR-V7 incidence was low in the low risk pts, precluding the analysis for this sub-cohort. Conclusions: The results validate that the nuclear-localized AR-V7(+) biomarker has an interaction with therapy and improved survival on taxanes. Further, when adjusting for pt risk, the biomarker is predictive of OS in the high risk group. Nuclear-localized AR-V7 protein in CTCs can aid in the decision between ARSI and taxane chemotherapy in the 2nd or greater line of therapy for mCRPC.
Multi-parametric liquid biopsy analysis of circulating tumor cells (CTCs), cell-free DNA (cfDNA), and cell-free RNA (cfRNA) in metastatic castrate resistant prostate cancer (mCRPC).
Authors: Hodara Emmanuelle , Zainfeld Daniel , Morrison Gareth , Cunha Alexander , Xu Yucheng , Carpten John D. , Danenberg Peter V. , Dempsey Paul W. , Usher Joshua , DANENBERG KATHLEEN , Bischoff Farideh Z. , Khurana Aditi , Cotter Philip D. , Moore Mathew , Gunn Shelly , Dorff Tanya B. , Quinn David I. , Goldkorn Amir
Published: February 2018

274

Background: Molecular profiling of prostate cancer using liquid biopsies such as CTC capture and cell-free nucleic acid analysis yield informative yet distinct datasets. Additional insights may be gained by simultaneously interrogating multiple liquid biopsy components to construct a more comprehensive molecular disease profile. We have conducted an initial proof of principle study aimed at piloting this multi-parametric approach. Methods: Blood was drawn under an IRB-approved protocol from 20 mCRPC patients. Samples were analyzed simultaneously for the following: CTC enumeration and single CTC and matched white blood cell capture for whole genome amplification and low-pass copy number variation; CTC DNA and matched cfDNA for somatic single nucleotide variant analysis; plasma cfRNA extraction and qRT-PCR for AR, AR-V7, and PCA3. When available, liquid biopsies were compared with matched tumor profiles. Results: Fifteen of 20 patients (75%) had detectable CTCs by CellSearch (range: 1-692/7.5mL, median: 16.5/7.5mL). Thirteen of 20 patients (65%) had detectable SSNVs in CTC DNA and/or matched cfDNA, including mutations in TP53, PIK3CA, HRAS, and EGFR. Matched CTC DNA and cfDNA demonstrated both shared and distinct SSNVs. Copy number analysis of single CTCs was performed in 2 patients, and both had CNVs in multiple cancer relevant genes. A majority of CNVs were present in matched solid tumor profiles, but some were exclusive to the liquid biopsies. Plasma PCA3 and AR transcripts were detected in 18/20 (90%) and AR-V7 in 4/20 (20%) cfRNA samples. Unique SSNVs were detected at second time points at disease progression (more are being collected). Conclusions: In this pilot cohort, simultaneous multi-parametric profiling was feasible for CTC DNA mutations and CNVs, and matched plasma cfDNA mutations and cfRNA gene expression. These disease-specific molecular profiles were often concordant with tumor tissues but also contained new, potentially actionable alterations unique to CTC DNA or cfDNA. Expanded studies will build upon this approach to optimally leverage liquid biopsies for molecularly directed patient management.
Enzalutamide and metformin combination therapy to overcome autophagy resistance in castration resistant prostate cancer (CRPC): Current results from a phase I study.
Authors: Parikh Mamta , Hyunh Jasmine C , Lara Primo , Pan Chong-xian , Robles Daniel , Evans Christopher P.
Published: February 2018

281

Background: Preclinical models have shown that autophagy is a resistance mechanism of enzalutamide (enza), a small molecule suppressing the androgen pathway approved for treatment of CRPC. Metformin, an autophagy inhibitor, enhances preclinical therapeutic responses when combined with Enza, thus prompting a Phase I clinical trial evaluating the combination. We present results to date. Methods: Eligible patients (pts) had established CRPC, ECOG 0-2, adequate hematologic and organ function, and ≤ 2 prior treatments for CRPC. Major exclusion criteria included prior enza or metformin treatment, presence of brain metastases, history of DM2 or seizures. An initial cohort of 3 pts were treated with enza 160 mg PO qdaily and metformin 500 mg PO bid (DL1), with metformin dose escalated to 1000 mg PO bid (DL2) in subsequent 3 pts if dose-limiting toxicity (DLT) was observed in ≤1 pt in DL1. Primary objective was to establish the maximum tolerated dose (MTD), with secondary objectives of evaluating PSA response of ≥ 50%, PSA progression, and safety. Results: A total of 12 pts have been enrolled to date; mean age was 77 (range 60-95). No DLTs were observed at DL1; 1 DLT due to Grade 3 abdominal pain was observed at DL2, with an additional 6 pts subsequently enrolled in expansion. The only adverse effects ≥ Grade 3 were: syncope (1/12), hallucinations (1/12), and abdominal pain (2/12). One pt withdrew consent, 2 required dose reduction of metformin, and 1 died of progressive disease. Of 10 evaluable pts, PSA response was seen in 8 pts. Conclusions: The combination of enza 160 mg qdaily and metformin 1000 mg PO bid is safe and well-tolerated. Efficacy results to date support continued study of the combination in pts with CRPC. Clinical trial information: NCT02339168.
Efficacy and safety of abiraterone acetate (AA) and low-dose prednisone (P) in Japanese patients with newly diagnosed, metastatic, hormone-naïve prostate cancer (mHNPC): Subgroup analysis of LATITUDE trial.
Authors: Fukasawa Satoshi , Suzuki Hiroyoshi , Sato Fuminori , Hashine Katsuyoshi , Hasumi Hisashi , Matsumoto Hiroaki , Tsuchiya Tomohiro , Uemura Hirotsugu , Oya Mototsugu , Kanayama Hiroomi , Kawaguchi Kazushiro , Noguchi Hidehisa , Enjo Kentaro , Tran Namphuong , Todd Mary Beth , Fizazi Karim , Matsubara Nobuaki
Published: February 2018

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Background: Patients with high-risk mHNPC have a poor prognosis. In Japan, mHNPC accounts for approximately 10% of newly diagnosed prostate cancers. AAP was approved for the treatment of castration-resistant prostate cancer in Japan in July 2014. We now report the clinical benefit of AAP with ADT in Japanese patients with newly diagnosed, high-risk mHNPC. Methods: Interim analysis of the multinational, randomized, double-blind, placebo-controlled, phase 3 study, LATITUDE, was previously reported at ASCO2017. We evaluated the superiority of AA 1g + P 5 mg + ADT (AAP group) to ADT+PBOs of AA and P (P group) in mHNPC with ≥ 2 of 3 risk factors (Gleason ≥ 8, ≥ 3 bone lesions, measurable visceral metastases) for the subgroup of Japanese patients. Results: Of 1199 total patients in LATITUDE trial, 70 patients were Japanese (AAP group, n = 35; P group, n = 35). The hazard ratio (HR) for overall survival in the AAP group versus the P group was 0.635 (95% confidence interval [CI], 0.152 to 2.659) and HR for radiographic progression-free survival was 0.219 (95%CI, 0.086 to 0.560). The incidence of adverse events (AE) was 97% (34/35) in both groups. AEs that occurred in the AAP group at a frequency ≥10% compared with the P group included hypertension, hypokalemia, rib fracture, hematuria and hyperbilirubinemia. The incidence of Grade 3 and 4 AEs was 66% in the AAP group and 20% in the P group. As a whole, efficacy and safety of Japanese patients in LATITUDE were shown to be consistent with those of overall population. Conclusions: AAP has shown a favorable risk/benefit balance and may serve as a new treatment option to improve the prognosis of Japanese mHNPC patients with high-risk prognostic factors. Clinical trial information: NCT01715285.
Survival outcomes of pre-metastatic castration-resistant prostate cancer and the burden of developing metastasis: A systematic literature review.
Authors: Shore Neal D. , Rai Gershwinder , Fizazi Karim , Wilson Laura , Zhan Lin
Published: February 2018

293

Background: Surgical or medical castration is an important component of prostate cancer treatment. However, resistance develops in almost all men and poor prognosis has been established once the disease metastasizes. A systematic literature review (SLR) was conducted to explore the treatment options and survival outcomes associated with non-metastatic castration-resistant prostate cancer (CRPC) and to understand the humanistic and economic impact of developing metastasis. Methods: The SLR was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement guidelines and guidance from the National Institute of Health and Care Excellence, Centre for Reviews and Dissemination and Institute for Quality and Efficiency in Healthcare. The search designed to identify clinical and humanistic evidence from all countries and epidemiology, guidelines and economic evidence in Brazil, China, France, Germany, Japan, UK, and US. Results: Median overall survival for non-metastatic CRPC patients ranged from 44 to 74 months; median progression-free survival from 9 to 22 months; and median metastasis-free survival from 16 to 53 months. The most common form of metastasis was bone metastasis, which was associated with an increased risk of skeletal-related events (SREs). Quality-of-life was widely reported to decrease upon metastasis, driven by increased pain and SREs. Higher healthcare costs associated with metastatic CRPC were attributable to physician visits and treating bone-metastasis-related complications. Conclusions: Currently, there is a lack of approved therapies specifically for non-metastatic CRPC patients, who will invariably develop metastases with associated adverse clinical and economic implications. Delaying the onset of metastasis is an unmet clinical need for improved patient outcomes and couldl also lead to economic benefits for healthcare delivery systems.
Weekly cabazitaxel in elderly patients (EP) with metastatic castration resistant prostate cancer (mCRPC) progressing after docetaxel treatment: WeCabE, a phase II study.
Authors: Castagneto Bruno , Stevani Ilaria , Bortolus Roberto , Bearz Alessandra , Buosi Roberta , Chimienti Emanuela , Guglielmi Alessandra , Guglielmini Pamela , Santarossa Sandra , Fratino Lucia
Published: February 2018

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Background: Docetaxel (Doc) and Cabazitaxel (Cab) every 3 weeks with daily prednisone are standard first and second line chemotherapies in mCRPC. In daily practice, many mCRPC pts are aged > 65 years and around 20% are aged > 75years. MATuRITY registry shows that taxanes therapy provides EP with increased chances of surviving even in case of frailty. EP unfit due to their comorbidities are at risk of AE related to the chemo-treatment, so an appropriate adjustment of the dosage and schedule should be take into account. According to SIOG guidelines, G-8 Screening Tool represents a key tool to identify a suitable subset of EP able to receive cab. Methods: WeCabE enrolled mCRPC EP ≥ 70 and < 85 years, G8 Score 8-14, PS 0-2. Cab was administered at a dose of 8mg /m2 (10mg/m2 if well tolerated) for 4 out 5 weeks Use of G-CSF was allowed. Median PFS, primary endpoint, was evaluated according to PCWG-2. Secondary endpoints were: PSA Response, ORR, OS, Safety, Geriatric assessment (Minimal Data Set according with Elderly Task Force EORTC) on outcomes. PSA response, safety, impact of the treatment on pain and G8 score pre and post cab were analysed. Results: At time of this analysis 14 EP enrolled in WeCabE were analysed. Median age was 78 years, 35.7% of pts were 80-85 years. Median number of cycles received, in pts who ended treatment was 4. Overall 55.6% of pts reached a PSA response while 33.3% achieved a stability. 42.8% of pts ended therapy without a worsening/rising of symptoms, 42.8% and 14.4% showed, respectively, mild and severe pain at end of cab. G8 best score improvement during treatment was 1.28 (median). The most common AE G 3-4 was fatigue (20%) while G1-2 toxicities were diarrhea (40%) and fatigue (60%). Only one pt experienced neutropenia and anemia G3-4. Conclusions: These preliminary results confirm the usefulness of G8 tool to identify elderly mCRPC pts suitable to receive chemotherapy. It suggests that weekly cabazitaxel, in elderly mCRPC, is effective including in very old pts ( > 80 ), with a manageable safety profile. Additional results will be presented at ASCO GU meeting. Trial partially supported by Sanofi Genzyme Clinical trial information: 2014-001647-20.
Treatment patterns for metastatic hormone-sensitive prostate cancer (mHSPC) progressing after up-front docetaxel in combination with androgen deprivation therapy (D-ADT).
Authors: Barata Pedro C. , Emamekhoo Hamid , Mendiratta Prateek , Gopalakrishnan Dharmesh , Koshkin Vadim S. , Tyler Allison Janine , Ornstein Moshe Chaim , Grivas Petros , Gilligan Timothy D. , Rini Brian I. , Kyriakopoulos Christos , Garcia Jorge A.
Published: February 2018

305

Background: D-ADT increases overall survival (OS) in men with mHSPC. All patients (pts) however progress and develop castration-resistant prostate cancer (CRPC). Little is known about response to subsequent therapy and outcomes in this setting. Methods: Retrospective analysis of consecutive mHSPC pts treated with ≥3 cycles of D-ADT at Cleveland Clinic and University of Wisconsin-Madison. We aimed to describe baseline, progression characteristics, treatment choices, sequence and outcome of subsequent therapy. Results: A total of 146 mHSPC pts were treated with D-ADT (6% 1-2 cycles; 94% ≥3 cycles). Final analysis included 136 pts, median age 65 (range 35-86), 65% GS≥8, 79% high-volume disease. Median number of D cycles was 6 (1-6). PSA declined to “0” at 12 and 24 months in 32% and 25% of pts, respectively. Median time to CRPC (biochemical, clinical or radiographic) was 19.6 months (95% CI, 16.6-22.6). 57 pts (42%) received ≥1 subsequent treatment after CRPC [46 hormonal therapy (HT) (21 abiraterone acetate, 19 enzalutamide, 6 ASN-001); 4 Sipuleucel-T; 4 radium-223, 5 chemotherapy (2 carboplatin-based, 2 cabazitaxel, 1 D); 3 temsirolimus/bevacizumab]. Treatment response was independent from time to CRPC (≥12 months, p = 0.264). Pts receiving HT as the first subsequent treatment had a median rPFS of 13.3 months (95% CI, 10.1-16.5) compared with 3.1 months (95% CI, 0-15.8) for non-HT (p = 0.332). Treatment choice was independent of GS (p = 0.513), visceral disease (p = 0.374) and time to CRPC (p = 0.500). Most CRPC pts treated with ≥2 lines of therapy received one HT (n = 21) followed by a different HT (43%), chemo (38%), radium-223 (14%) or olaparib (10%). 57% of pts were alive at 2 years. Longer OS correlated with time to CRPC (p = 0.010) and first subsequent treatment with HT (p = 0.009) but not with visceral disease (p = 0.258), GS (p = 0.599) or sequence of therapies received (HT/HT vs HT/non-HT, p = 0.836). Conclusions: Prior D-ADT did not preclude subsequent treatment response in CRPC pts, independent of time to CRPC. The choice of first-line treatment for CRPC may impact survival in favor of those who start HT.
Tracking of long-term B-cell memory responses using B-cell receptor (BCR) sequencing in prostate cancer (PC) patients (pts) treated with sipuleucel-T (sip-T).
Authors: Zhang Li , Kandadi Harini , Paciorek Alan , Chang Nancy N. , Sheikh Nadeem Anwar , Fong Lawrence
Published: February 2018

309

Background: Sip-T is an autologous cellular immunotherapy for asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). Sip-T’s induction of B-cell responses to PAP and other antigens correlates with improved survival (Sheikh 2013, GuhaThakurta 2015). Cancer vaccine-induced changes to BCR repertoire are unknown. To assess changes in BCR repertoire upon booster treatment, we compared patients retreated with sip-T (P10-1) to treatment-naïve patients (STRIDE). Methods: STRIDE pts (N = 52) received sip-T with concurrent or sequential enzalutamide for mCRPC (Petrylak 2015). P10-1 pts (N = 8) previously treated with sip-T for androgen-dependent PC were retreated with a booster course for mCRPC, after a median of 8.9 years (Beer 2017). Blood samples were collected at baseline (wk 0) and during (wk 2, 4)/post-sip-T (wk 6, 26, 52). Deep sequencing was performed using the ImmunoSEQ assay (Adaptive Biotechnologies). BCR diversity was assessed by clonality, and BCR dynamics by fold-change analysis (Zhang 2017). Results: BCR repertoire had significantly higher clonality in P10-1 vs STRIDE (wk 0: p = 0.003, wk 2: p < 0.001, wk 4: p < 0.001), suggestive of a more focused BCR repertoire. P10-1 also showed increased clonality from wk 0 to 4 (p = 0.063), whereas STRIDE showed a significant increase in clonality from wk 0 to 6 (p = 0.039), suggesting that BCR repertoire focused earlier in P10-1. Starting at wk 2, more clones remained in the repertoire in P10-1, indicating that sip-T stimulated immunologic memory early, after 1st retreatment (p < 0.05). There was less change over time (clonal shuffling) within the 100 most abundant baseline clones in P10-1 (p = 0.080), suggesting more relevant clones preexisted at baseline and enriched over time. After the first two sip-T infusions, more clones contracted in P10-1 (p = 0.027, p = 0.014), whereas more new clones were generated in STRIDE (p = 0.083, p = 0.003). Conclusions: Sip-T induces long-lasting changes in the BCR repertoire. Sip-T retreatment leads to quicker focusing of BCR repertoire than initial treatment. These results are consistent with sip-T inducing durable immunologic memory.
Comprehensive analysis of AR alterations in cell free DNA from prostate cancer patients.
Authors: Ledet Elisa , Lilly Michael B. , Sonpavde Guru , Agarwal Neeraj , Nagy Rebecca J , Sartor A. Oliver
Published: February 2018

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Background: Somatic alterations identified in cfDNA may be associated with prognosis. Select AR alterations are associated with abiraterone/enzalutamide resistance in PCa. The goal was to characterize AR amplifications (amps) and somatic point mutations (muts) detected in cfDNA from PCa patients and to relate those changes to non-AR alterations detected in the cfDNA landscape. Methods: cfDNA data was obtained from a heterogeneous group of unique PCa pts who underwent Guardant360 testing (Guardant Health, Redwood City, CA). This assay includes next generation sequencing for full exonic coverage of 73 genes and amplifications in 18 genes. The AR amps/muts detected in cfDNA testing were reported. Results: Over 6,800 genomic alterations including AR amps/muts were identified in 892 PCa patients. Pts were a median age of 70 (range = 41-93) at testing. 49% (n = 436) had AR amp only, 32% (n = 283) had nonsynonymous (NS)-muts only, 18% (n = 165) had both amp and NS-muts; < 1% (n = 8) had synonymous AR muts only. AR amps had a mean absolute copy number of 3.3 (range = 1.2-165.2). Many patients had multiple AR muts; a total of 112 unique muts were identified in the AR gene, some of which are poorly characterized. The most prevalent AR muts were L702H (n = 220), T878A (n = 129), H875Y (n = 102), W742C (n = 75), W742L (n = 34), F877L (n = 19), and T878S (n = 14). The AR muts with the highest mutant allele fraction were H875Y, T878A, and L702H. Aside from AR, among these selected pts, amps/muts were identified in 74 other genes including TP53 50% (n = 449), MYC 34% (n = 301), BRAF 32% (n = 287), PIK3CA 29% (n = 259), MET 25% (n = 224), CDK6 26% (n = 229), EGFR 24% (n = 219), FGFR1 21% (n = 189), and APC 12% (n = 112). DNA repair gene alterations were detected in combination with AR alterations, BRCA2 8% (n = 69), BRCA1 5% (n = 42), and ATM 3% (n = 28). Conclusions: To our knowledge, this is the largest dataset ever reporting AR alterations in cfDNA. Both amps and muts, were frequently found in cfDNA from PCa pts. The common AR muts were L702H, T878A, H875Y and W742C/L, which are linked to resistance to abiraterone, enzalutamide or bicalutamide. Determining the association with other somatic cfDNA alterations and clinical outcomes may be critical for conceiving optimal treatment strategies.
A phase 1/2a trial of docetaxel plus ribavirin for reprogramming efficacy in patients with progressive metastatic castration resistant prostate cancer who have previously received docetaxel alone: DRREEM trial.
Authors: Kosaka Takeo , Shinojima Toshiaki , Kikuchi Kayoko , Hagiwara Sachiko , Kojima Shin-ichiro , Hongo Hiroshi , Ueda Koji , Miyake Shinji , Oya Mototsugu
Published: February 2018

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Background: We previously reported a novel cell reprogramming approach, termed drug efficacy reprogramming, as a new model for identifying candidate antitumor drugs targeting the cancer stemness-related gene network, and identified ribavirin as a candidate drug for overcoming docetaxel-resistant castration-resistant prostate cancer (CRPC). We conducted this phase 1/2a trial of docetaxel plus ribavirin for reprogramming efficacy in patients with progressive metastatic castration resistant prostate cancer who have previously received docetaxel alone. (DRREEM trial) Methods: In this clinical study, patients received intravenous docetaxel at 60-75 mg/m2is intravenously administered on Cycle1-Day1 in combination with the investigational drug (ribavirin). Docetaxel is administered at 3-week intervals (1 cycle) (total: 3 cycles). During administration, the dose may be reduced based on the subject’s condition if necessary. The primary endpoint was safety. Accessory evaluation items included prostate-specific antigen (PSA) response, objective response rate, health-related quality of lifel. Exploratory items included changes in CTC count, cfDNA, and exosome. Patients with progressive CRPC based on PSA and/or radiographic criteria, performance status (PS) 0–1, and normal renal and hepatic function were eligible. Results: Six patients were enrolled in this study; average age was 71.7±4.2. Average serum PSA concentration was 100.1±128.0 ng/ml (range: 3.0-336.8). The median cycle of docetaxel received before the study was 6 cycles. Safety: Grade 3/4 adverse events requiring dose modification were not observed. Two patients showed PSA reduction. Three patients showed stable disease. Changes in the blood concentrations of ribavirin, docetaxel, and prednisolone were within normal range. Conclusions: This combination of ribavirin with docetaxel was well tolerated with a promising response rate that justifies further investigations in docetaxel-resistant CRPC. This clinical study provides a useful drug re-positioning model in the area of translational medicine. Clinical trial information: UMIN000021107.
Frequency of liver test increases on abiraterone acetate in men with castrate-resistant prostate cancer (CRPC): Natural history, management, and outcome.
Authors: Colomba Emeline , Marret Grégoire , Baciarello Giulia , Massard Christophe , Loriot Yohann , Albiges Laurence , Carton Edith , Alexandre Jerome , Huillard Olivier , Culine Stephane , Fizazi Karim
Published: February 2018

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Background: Abiraterone acetate (abiraterone) in combination with prednisone is a standard of care for patients with metastatic CRPC. Abiraterone is seldom associated with liver toxicity and systematic monitoring of ALT and AST is required. Clinical management and outcome of these patients have not been described. Methods: We retrospectively identified 22 men with mCRPC with liver tests disorder occurring during abiraterone therapy from December 2009 to September 2017 from three oncology centers in France. Results: Thirty nine liver disorder events occurred in 22 patients during abiraterone therapy. The median age was 62 (50-80) years. Only one patient had liver metastasis. No patient had a history of chronic alcoholism. Accountability of the liver tests increase to abiraterone was doubtful in two patients who were receiving antibiotics when the event occurred. The incidence of AST increase (19 events) and that of ALT (20 events) were similar. Liver toxicity was of grade 1, 2, and 3 (CTCAEv4) in 5 (22.7%), 5 (22.7%), and 9 (40.9%) patients for ALT, and in 9 (40.9%), 6 (27.3%), and 5 (22.7%) for AST, respectively. The median time from abiraterone initiation to the detection of liver toxicity was 15.8 (4-95) weeks. The median time from highest ALT/AST increase to normalization was 7.7 (2-15) weeks. Normalization of liver test was observed in 19 (86.4%) patients, and 3 patients died of cancer progression before their liver tests had normalized. In 12 patients (54.4%), liver tests spontaneously returned to baseline values, while abiraterone was continued at full dose. Abiraterone was discontinued in 6 patients (27.7%) due to liver test increase. It was reintroduced after a break in four patients and then discontinued in two for a subsequent liver disorder event. No patient reported symptoms clearly related to liver test increase. Conclusions: Liver tests increase is a quite rare event that typically occurs within the first 4 months on abiraterone, though it can also happen up to 20 months later. It is typically asymptomatic and most patients experience normalization of tests, either spontaneously or after dose reduction/discontinuation.
Novel nomograms for castration-resistant prostate cancer and survival outcome in patients with de novo bone-metastatic prostate cancer.
Authors: Zhao Jinge , Sun Guangxi , Liao Banghua , Zhang Xingming , Shen Pengfei , Chen Junru , Liu Jiandong , Zeng Hao
Published: February 2018

336

Background: Treatments for de novo metastatic prostate cancer (mPCa) are evolving. However predictive models for this subset of the population are still lacking. The aim of this study is to develop nomograms to predict the incidence of castration resistant PCa (CRPC) and overall survival (OS) for de novo mPCa patients. Methods: Data from 449 de novo mPCa patients were retrospectively analyzed. Patients were randomly divided into either the training or the validation cohort. Predictive factors were selected by Cox-proportional model and further used for building predictive models. The outcomes were incidence of CRPC and OS. Results: Predictive parameters included: Gleason Score (GS), intraductal carcinoma of the prostate (IDC-P), ECOG status, alkaline phosphatase (ALP), hemoglobin (HGB) and prostate specific antigen (PSA). IDC-P and GS were the strongest prognosticators for both the incidence of CRPC and OS. Nomograms for predicting CRPC and OS had an internal validated C-index of 0.762 and 0.723, respectively. Based on the beta-coefficients of the final model, risk classification systems were constructed. For those with favorable-, intermediate- and poor-prognosis, the median time to CRPC was 62.6, 28.0 and 13.0 months (P<0.001), and the median OS was not reached, 55.0 and 33.0 months, respectively (P<0.001). Conclusions: We developed two novel nomograms to predict the incidence of CRPC and OS for de novo mPCa patients. These tools may assist physicians’ decision-making and design of clinical trials.