bluuebunny/crossref_metadata_2025 huggingface dataset:
Biomarker patterns of localized and metastatic prostate cancer.
Authors: Feldman Rebecca , Reddy Sandeep K. , Gatalica Zoran , Mahanes Joanne R. , Myers Charles E.
Published: February 2017

192

Background: Presence or absence of metastases is a determining factor for prostate cancer prognosis. Common sites of metastasis include bone (B), lymph nodes (LN) or visceral organs (V). We sought to determine theranostic biomarker differences between primary (P) and metastatic (M) specimens, with subset analysis for differences between metastatic sites. Methods: 497 prostate cancer cases referred to Caris Life Sciences between 2009 thru 2014 were evaluated. Specific testing was performed and included a multiplatform approach: sequencing (Sanger, NGS), protein expression (IHC) and gene amplification (CISH/FISH). Results: 58% (287/497) were M specimens, of which 23% (66), 24% (68) and 52% (149) were from B, LN and V, respectively. Significant differences for EGFR amplification/overexpression, low MGMT expression, TOPO1/2A overexpression and higher PTEN mutation rate were found in the M subgroup. These alterations indicate a role for EGFR/PTEN in progression of prostate cancer, and potential role of MAPK/PAM-targeted therapies, alkylating agents and topoisomerase inhibitors in M disease. Mutational profiles of the M subgroup are more genetically unstable exhibiting mutations in 60% of genes tested (notable events include APC & β-Catenin, PTEN, TP53 and BRCA1/2) vs. 30% observed in the P subgroup (p=0.0067). In the subset analysis, EGFR amplification was higher in B (29%) and V (24%) compared to LN (13%); (not significant). Low TS expression was more frequent in B vs. LN (p=0.004), TOPO2A overexpression was higher in V vs. B (p=0.0001) and there was a trend for PD1 positive infiltrating lymphocytes being more abundant in LN vs B (p=0.09). Interestingly, cMET overexpression (7/230) and amplification (1/162) were rarely observed across the cohort, providing support for the surprising failure of cabozantinib in castration-resistant prostate cancer. Conclusions: Our data indicate a role for multiplatform profiling to identify therapeutic options that are appropriate for subsets of patients. Molecular changes associated with M disease including EGFR, PTEN, MGMT and TOPO1/2A, present opportunities for developing therapeutic strategies which may include a combination of targeted therapies, as well as traditional cytotoxic chemotherapies.
Tracking clonal diversity in metastatic prostate cancer progression.
Authors: Hovens Christopher , Hong Matthew , Macintyre Geoff , Wedge David , Van Loo Peter , LunkePhD Sebastian , Alexandrov Ludmil , Slogget Clare , Cmero Marek , Mangiola Steafano , Lonie Andrew , Naeem Haroon , Sapre Nikhil , Phal Pramit , Kerger Michael , Pedersen John , Ryan Andrew , Haviv Izhak , Costello Anthony , Corcoran Niall
Published: February 2017

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Background: Genomic heterogeneity has been observed in a number of tumor types including prostate cancer. However, how subclonal tumor diversity changes during metastasis and progression to lethality remains unexplored. Large scale genomic analyses have reported the most prevalent somatic aberrations associated with the dominant clone of the tumor without permitting an analysis of subclonal complexity or how this complexity impinges on metastatic potential or resistance to treatment. Methods: To understand and track the evolution of lethal prostate cancer from initial therapy to end stage metastases, we performed longitudinal and multiregional sampling of tumors from 7 patients with lethal prostate cancer. We performed whole-genome sequencing, RNA sequencing, and SNP profiling. Computational approaches were used to reconstruct the genetic relationships and evolution of the tumors. These evolutionary tree reconstructions allowed us to observe the dynamics of chromoplexy and mutational processes along specific branches of tumor evolution. To refine the genetic landscape and spatial connections between subclones, we employed deep, targeted re-sequencing of variant loci in the original sequenced samples, in additional FFPE sites sampled from the organ confined tumors, and from blood. Results: We show that while all primary and metastatic prostate tumors share a single ancestral clone, metastases arise from subclones present at minor frequencies in the primary tumor. We reveal that individual metastases comprise mixtures of subclones indicative of intra-metastatic heterogeneity. We provide evidence for cross-metastatic site seeding and dynamic remolding of subclonal mixtures in response to therapy suggesting a distinct metastatic hierarchy. Ultra-deep sequencing of end-stage blood reveals the presence of diverse subclones with metastatic potential derived from various stages in the evolution of the tumor. Conclusions: Our results demonstrate unexpected complexity in the origins of both primary and metastatic prostate cancer, with distinct implications for treatment of advanced disease.
Clinical outcomes and safety in men ≥ 75 and < 75 years with metastatic castration-resistant prostate cancer (mCRPC) treated with enzalutamide in the phase 3 PREVAIL trial.
Authors: Graff Julie Nicole , Baciarello Giulia , Armstrong Andrew J. , Higano Celestia S. , Iversen Peter , Forer David , Mansbach Harry H. , Phung De , Tombal Bertrand F. , Beer Tomasz M. , Sternberg Cora N.
Published: February 2017

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Background: In the phase 3 PREVAIL trial, enzalutamide (ENZA), an androgen receptor inhibitor, improved overall survival (OS) and radiographic progression-free survival (rPFS) relative to placebo (PBO) in chemotherapy-naïve men with mCRPC. Methods: PREVAIL randomized 1,717 patients (pts) with asymptomatic or minimally symptomatic chemotherapy-naïve mCRPC 1:1 to ENZA 160 mg daily or PBO. Coprimary endpoints were OS and rPFS. This prespecified analysis evaluated the impact of age (≥ 75 vs < 75 years) on efficacy and safety. Results: In PREVAIL, 609 (35%) pts were aged ≥ 75 years. This older subset had several poorer baseline prognostics relative to those aged < 75 years: worse ECOG performance status (ECOG 1: 45.0% vs 24.7%), higher prostate-specific antigen (PSA; 73.3 vs 37.3 ng/mL) and more cardiovascular disease (26.9% vs 16.5%). In both older and younger pts, ENZA improved OS, rPFS and time to PSA progression (Table). Pts aged ≥ 75 years in both the ENZA and PBO groups combined had a higher rate of grade ≥ 3 adverse events (46% vs 37% in younger pts) and among enzalutamide-treated men more older pts reported falls (any grade; ENZA 19% and PBO 8%) than younger pts (ENZA 7% and PBO 4%). Fewer pts ≥ 75 years received subsequent antineoplastic therapies. Conclusions: In PREVAIL, efficacy outcomes in elderly (≥ 75 years) and younger (< 75 years) pts with chemotherapy-naïve mCRPC were comparable and pts consistently benefited from ENZA treatment. Safety with ENZA was similar in both age groups, although older pts reported a higher incidence of falls and received fewer subsequent antineoplastic therapies. Clinical trial information: NCT01212991. [Table: see text]
Effects of radium-223 dichloride (Ra-223) with docetaxel (D) versus D on prostate-specific antigen (PSA) and bone alkaline phosphatase (bALP) in patients (pts) with castration-resistant prostate cancer (CRPC) and bone metastases (mets): A phase 1/2a clinical trial.
Authors: Morris Michael J. , Higano Celestia S. , Scher Howard I. , Sweeney Christopher , Antonarakis Emmanuel S. , Shevrin Daniel H. , Ryan Charles J. , Loriot Yohann , Fizazi Karim , Pandit-Taskar Neeta , Garcia-Vargas Jose E. , Lyseng Kari , Bloma Marianne , Aksnes Anne-Kirsti , Carrasquillo Jorge A.
Published: February 2017

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Background: Ra-223 is an approved α-emitter prolonging survival in CRPC with symptomatic bone mets. We conducted a phase 1/2a study examining the safety and antitumor effects of Ra-223 + D vs D alone, and previously presented data showing that Ra-223 + D is safe and well tolerated (ESMO 2014). Here we report the effect of Ra-223 + D vs D on bALP and PSA dynamics. Methods: D-eligible pts with progressing CRPC and ≥ 2 bone mets were randomized 2:1 to Ra-223 (50 kBq/kg q 6 wk × 5) + D (60 mg/m2 q 3 wk × 10) vs D (75 mg/m2 q 3 wk with step-down option to 60 mg/m2). bALP and PSA were recorded q 3 wk during first 6-wk cycle, then q 6 wk and q 3 wk, respectively, and analyzed at a central laboratory. Changes in both markers are described by the % of pts who achieved ≥ 30%, > 50%, and > 80% declines between baseline and the safety follow-up visit (3 wk post last D injection) as their best response; pts with elevated baseline bALP (≥ 21 µg/L) levels were included for the bALP analysis. bALP to below the upper limit of normal (ULN) was also recorded, regardless of % decline. Results: 46 pts (33 Ra-223 + D vs 13 D alone) were enrolled. As of October 2014, 21 (Ra-223 + D) vs 5 (D) pts had received all planned study treatment. Median (range) baseline PSA was 99 µg/L (3-1000) for Ra-223 + D pts and 43 µg/L (4-1042) for D pts. Maximal changes in PSA and bALP levels between baseline and safety follow-up are shown in Table. No pt had a bALP increase. Conclusions: Ra-223 + D appears to favorably impact posttreatment PSA and bALP declines. Ra-223 + D appears particularly effective at normalizing bALP levels vs D alone. The clinical benefits of such changes in serum markers will require validation in larger prospective studies. Clinical trial information: NCT01106352. [Table: see text]
Bone scan index as a biomarker to predict outcome in real-life mCRPC patients on abiraterone acetate: A multicenter study.
Authors: Reza Mariana , Ohlsson Mattias , Kaboteh Reza , Anand Aseem , Franck Lissbrant Ingela , Damber Jan-Erik , Budäus Lars , Eichenauer Till , Wollmer Per , Edenbrandt Lars , Tragardh Elin , Bjartell Anders
Published: February 2017

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Background: Bone Scan Index (BSI) is a quantitative measurement that reflects the tumor burden in bone calculated from bone scintigraphy. It also represents a prognostic marker in patients (pts) with metastatic castration resistant prostate cancer (mCRPC). Abiraterone acetate (AA) has showed to prolong survival before and after chemotherapy in this group of pts. In this study we evaluated the predictive value of BSI change as a biomarker of response in mCRPC patients on treatment with AA. Methods: We retrospectively studied 62 mCRPC pats who received AA following disease progression after chemotherapy at 3 different academic hospitals. Automated baseline and follow-up BSI data was obtained from images of whole-body bone scintigraphies performed before and during AA treatment. Data on clinical overall survival (OS), blood levels of prostate-specific antigen (PSA), alkaline phosphatase (ALP) and haemoglobin (Hb) at the time of baseline and upon follow-up was collected from medical records. The association between changes in these parameters at follow-up and survival was evaluated using Cox proportional-hazards regression models and Kaplan-Meier estimates of the survival function. Discrimination between prognostic variables was assessed using the concordance index (C-index). Results: Pts with an increase in BSI of > 0.3 (n=31) had 13% one year-survival rate compared to 42% for pts with improvement or stable disease according to BSI change at follow-up (BSI change < 0.3; n=31) (p< 0.001). Among all parameters evaluated (BSI, PSA, ALP, Hb) in a univariate Cox analysis, BSI change from baseline to follow-up presented the highest and strongest association with OS (C-index=0.7, Hazard ratio= 1.3 and p=0.0001). Conclusions: Increase in BSI of ≥ 0.3 is significantly associated with reduced survival in mCRPC pts under AA treatment following disease progression in a post-chemotherapy setting. BSI is a candidate biomarker to evaluate response and survival in this group, and change in BSI could be a valuable tool in monitoring pts with mCRPC on second-line therapies. BSI could then serve as a decision making tool supporting physicians to continue current treatment or to consider alternative therapies.
Impact of skeletal-related events on survival in patients with prostate cancer metastatic to bones.
Authors: McDougall Jean A. , Goulart Bernardo Haddock Lobo , Sullivan Sean D , McCune Jeannine S. , Bansal Aasthaa , Karnopp Andrew , Fedorenko Catherine R. , Valderrama Adriana , Seal Brian S. , Ramsey Scott David
Published: February 2017

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Background: Skeletal related events (SREs), defined as pathological fracture, spinal cord compression, surgery or radiotherapy to the bone, occur in nearly half of men diagnosed with metastatic prostate cancer. Accurate assessment of the risk of death associated with SREs is important to making decisions about the use of recently approved treatments, which have been shown to decrease the frequency of skeletal events, yet estimating the impact of SREs on survival presents several methodological challenges given the recurrent time-dependent nature of exposure. Methods: A cohort of men >65years of age, diagnosed with prostate cancer and bone metastasis between January 1, 2004 and December 31, 2009 was identified from the Surveillance Epidemiology and End Results (SEER) registries were linked to Medicare Parts A and B claims. The outcome of interest, death from any cause, was ascertained from SEER and survival time was calculated from the date of metastatic prostate cancer diagnosis. Multivariable Cox proportional hazards models treating the occurrence of an SRE as a time-dependent exposure were used to estimate the hazard ratios (HR) and corresponding 95% confidence intervals (CI) for the association between SRE occurrence, number, and type, and death. Results: Among 3,297 men with metastatic prostate cancer, 40% experienced ≥1 SRE during the observational follow-up period (median 19 months). Compared to men who remained SRE-free, cohort members who had ≥1 SREs had a two-fold higher risk of death (HR 2.2, 95% CI 2.0-2.4). Those whose first SRE was a pathological fracture had a 2.7-fold higher risk of death (HR 2.7, 95% CI 2.3-3.1), followed by spinal cord compression (HR 2.1, 95% CI 1.8-2.5), surgery (HR 1.8, 95% CI 1.5-2.2) and radiotherapy (HR 2.2, 95% CI 1.9-2.4). Compared to those experiencing only one SRE, men who experienced a second SRE of any type had double the risk of death (HR 2.2, 95% CI 1.9-2.6). Conclusions: SREs were associated with ≥50% reduction in overall survival. This finding is consistent across different types of SREs and supports using therapies to prevent or treat SREs in patients with prostate cancer metastatic to the bones.
Efficacy of a novel cytotoxic polybisphosphonate for treatment of bone metastasis in castration-resistant prostate cancer (CRPC).
Authors: Nilsson Sten , Lindberg Henriette , Thellenberg-Karlsson Camilla , Nyman Claes , Marquez Marcela , Lennartsson Lena , Blom René , Castellanos Enrique , Holmberg Anders R
Published: February 2017

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Background: A cytostatic polybisphosphonate was developed for Tx of mCRPC. It has a) anti-resorptive effects, osteoclast inhib., b) tum. cell spec./tox, confirmed in in-vivo models. Tox. study shows high tolerability. Animal PK study has shown T½ < 3 hrs; principal accumulation in liver, spleen, kidneys. Methods: Clin phase I/IIa (clinicaltrials.gov NCT01595087): Prim obj: to define MTD of ODX given every 3rd week. Sec. obj: OS, bone metab. and resp. markers, PSA, QoL and PK. Explorative in vitrostudies (basis for rand. phase IIb trial in pts. with docetax-res. mCRPC). A docetax-resist. cell-line was developed from DU145 in escalating conc. of docetax, then continuous growth in docetax 500 µg/ml. Cells subj. to cytotox. exp. with ODX (iCELLigence system and fluorom microculture cytotox assay). Results: Clin Phase I/IIa first-in-man trial (clinicaltrials.gov NCT01595087): 17/28 patients rec. 4-7 doses every 3rd week. No DLTs; max dose adm.: 3.0 mg/kg: no drug-related SAEs. Tx was well tolerated. Efficacy and QoL data w. considerable variability as to be expected in this population of pts. w. mCRPC. Max blood conc. ODX: 110-160 fmol/mL; 85-90 % cleared within first 1 hr. Efficacy of ODX in docetax-res DU145TR: A dose-dependent cytotox effect seen when adding ODX in “sub-clin.” doses. All cells were apparently killed in the clin. relevant dose 6 uM. Conclusions: ODX is a novel drug cand. w. high cytotox. efficacy in vivo and in vitro, even in highly docetax-res. cells. Animal studies and Phase I trial show excellent tolerability. Studies now ongoing to elucidate whether short-term treatment is as efficacious as continuous treatment and whether some cells de facto may develop resistance also to this new treatment concept. A multicenter rand. double-blind pbo. controlled trial (EudraCT 2014-002054-39) starts Q4 2014 in mCRPC pts failing docetax and/or cabazitaxel AND abiraterone and/or enzalutamide. Clinical trial information: NCT01595087.
Evaluation of 3 T pelvic MRI imaging in prostate cancer patients receiving postprostatectomy IMRT.
Authors: Verma Vivek , Gay Hiram Alberto , Chen Ling , Michalski Jeff M. , Grubb Robert L.
Published: February 2017

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Background: The purpose of the study was to evaluate the utility of a 3 T pelvic magnetic resonance imaging (MRI) in detecting a local recurrence in post-prostatectomy prostate cancer patients prior to receiving adjuvant or salvage intensity-modulated radiation therapy (IMRT). Methods: Ninety prostate cancer patients status post-prostatectomy with rising prostate-specific antigen (PSA) had a 3 T pelvic MRI prior to IMRT. The following variables were analyzed for predicting positive findings on MRI: initial presenting and initial post-op PSA, PSA at the time of imaging, PSA velocity, surgical margins, Gleason score, pathological stage, pre-RT digital rectal examination, and type of surgical prostatectomy. Results: The only significant variable predictive of a positive MRI was positive margins. Specifically, 15 of 46 (33 %) patients with positive margins had a positive MRI, while 5 of 44 (11 %) patients with negative margins had a positive MRI. In the MRI positive group, the location of the positive findings on MRI corresponded with the pathology report in 9 of 12 (75 %) cases. Conclusions: Post-prostatectomy patients with pathologic positive margins are three times more likely to have positive findings on a 3 T MRI. [Table: see text]
Prior and concurrent use of abiraterone and enzalutamide with Ra-223 in an expanded access setting.
Authors: Sartor A. Oliver , Fernandez Daniel Celestino , Morris Michael J. , Iagaru Andrei , Brown Alan , Almeida Fabio , Sweeney Christopher , Smith Matthew Raymond , Dicker Adam , Wong Yu-Ning , Shore Neal D. , Gratt Jeremy , Petrenciuc Oana , Vogelzang Nicholas J.
Published: February 2017

253

Background: The aim of this prospective early-access program (EAP) was to monitor acute and long-term safety of Ra-223 CL2. The ALSYMPCA RA-223 phase III trial was completed prior to abiraterone (Abi) and enzalutamide (Enza) approval. Herein we provide experience with RA-223 in relationship to Abi and Enza. Methods: Symptomatic bone metastatic CRPC pts in the US who were ineligible for or had prior docetaxel were enrolled. Treatment included Ra-223 50 kBq/kg IV q4weeks for 6 cycles concomitant with standard of care medications. Analyses were conducted to assess safety and overall survival (OS) in pts with prior and concurrent Abi and Enza. Results: Of 184 treated, 120 (65%) had prior and 35 (19%) pts had concurrent Abi; 59 (32%) had prior and 25 (14%) pts had concurrent Enza. Baseline characteristics were generally balanced in the overall and across prior and concurrent groups. Pts with no concurrent Abi or Enza had a similar OS to the overall group (Abi 16m, Enza 17m, overall 17m). Due to a small number of events (7 Abi, 6 Enza), a median value was not calculated for the concurrent groups. 8 deaths occurred during treatment none were related to RA-223. The rate of Grade 3-5 AEs was similar across concurrent (Abi 37%, Enza 36%) and prior groups (Abi 43%, Enza 42%) vs overall 41%. Most frequently occurring Gr 3-4 events were anemia (Abi 17%, Enza 8%, overall 11%), thrombocytopenia (Abi 6%, overall 3%), and back pain (Enza 8%, overall 4%). Conclusions: In this EAP, Ra-223 concurrently administered with either abiraterone or enzalutamide was safe and well tolerated adding important information on concurrent use of RA-223 and hormonal agents. Clinical trial information: NCT01516762. [Table: see text]
Effect of radium-223 dichloride (Ra-223) on risk for and duration of hospitalization in ALSYMPCA by docetaxel (D) subgroup.
Authors: Cislo Paul , Reuning-Scherer Jonathan D.
Published: February 2017

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Background: In ALSYMPCA, the first-in-class alpha-emitting radiopharmaceutical Ra-223 significantly improved overall survival vs placebo (pbo) and was well tolerated in patients (pts) with castration-resistant prostate cancer (CRPC) with symptomatic bone metastases and no visceral metastases regardless of prior D use. To understand whether treatment (tx) benefit in prior and no prior D subgroups relates to differences in health care resource utilization, hospitalization and other resource use were evaluated. Methods: Hospitalization, nursing home visit, home health care and adult day care services use, and physician visit data were captured. To account for differences in observation time due to differing survival, resource use was annualized for each pt. Mean number and duration of encounters/year were compared using t-tests. To compare tx groups based on rate of use/year, incidence rates and ratios were calculated using a generalized estimating equation regression model with covariates. Results: For prior D pts, hospitalization incidence rates for Ra-223 vs pbo were 1.18 vs 1.70 (incidence rate ratio = 0.69; 95% CI, 0.53-0.90; P = 0.006) and mean hospitalization days/year were 8.53 vs 16.51 (P = 0.001). Among prior D pts with ≥1 hospitalization, mean hospitalization days/year for Ra-223 vs pbo were 19.65 vs 33.02 (P = 0.003). For no prior D pts, hospitalization incidence rates for Ra-223 vs pbo were 1.02 vs 1.10 (incidence rate ratio = 0.92; 95% CI, 0.66-1.29; P = 0.643) and mean hospitalization days/year were 7.53 vs 12.11 (P = 0.027). Among no prior D pts with ≥1 hospitalization, mean hospitalization days/year for Ra-223 vs pbo pts were 19.12 vs 26.61 (P = 0.063). The only other tx differences were nursing home days/year and day care services/year in the no prior D subgroup, but t-test and regression results were inconsistent. Conclusions: In the prior D subgroup, Ra-223 pts experienced 8.0 fewer hospitalization days/pt/year, driven by a 31% reduction in hospitalization and shorter duration among pts hospitalized. In the no prior D subgroup, Ra-223 pts experienced 4.6 fewer hospitalization days/pt/year, primarily driven by a shorter duration among pts hospitalized. Clinical trial information: NCT00699751.
Effect of lipid nanoparticle siRNA delivery systems on silencing clusterin and progression in enzalutamide resistant prostate cancer in vivo.
Authors: Yamamoto Yoshiaki , Lin Paulo JC , Zhang Fan , Kawai Yoshihisa , Beraldi Eliana , Leong Jeffrey , Matsuyama Hideyasu , Cullis Pieter R , Gleave Martin Edwin
Published: February 2017

256

Background: Clusterin (CLU) is induced by androgen receptor (AR) pathway inhibition and its overexpression confers treatment resistance. Lipid nanoparticle (LNP) facilitates tumor uptake and intracellular processing through an enhanced permeation and retention effect (EPR), currently with multiple products undergoing clinical evaluation. Gene silencing using small interfering RNA (siRNA) is a promising approach but in vivo delivery remains a major barrier. In our study, we investigated the efficacy siRNA tumor delivery using LNP systems in enzalutamide-resistant (ENZ-R) castration-resistant prostate cancer (CRPC) model. Methods: To validate the effect of LNP siRNA tumor delivery in vivo, gene silencing of a reporter gene, luciferase (LUC), in PC3-M-luc stable cell line was treated with LNP LUC-siRNA and examined for Luc activity by the IVIS imaging system. Next, we investigated the efficacy of LNP CLU-siRNA tumor delivery and LNP CLU-siRNA sensitized AR knockdown activity in ENZ-R CRPC LNCaP in vitro and in vivo models. Results: LNP LUC-siRNA exhibited LUC silencing effects in PC-3M-luc xenograft and metastatic models. LNP CLU-siRNA suppressed PSA and decreased AKT and ERK phosphorylation in ENZ-R LNCaP cells in vitro. LNP CLU-siRNA sensitized AR antisense oligonucleotides (ASO) activity, more potently inhibiting ENZ-R cell growth rates and increased apoptosis when compared to AR-ASO monotherapy. In vivo,combinatory treatment of LNP CLU-siRNA and AR-ASO significantly suppressed tumor growth and serum PSA levels compared to LNP LUC -siRNA (control) and AR-ASO in ENZ-R LNCaP xenografts. Conclusions: The LNP CLU-siRNA systems sensitized AR knockdown resulting in inhibition of ENZ-R LNCaP cell growth, providing pre-clinical proof-of-principle as a promising AR co-targeting approach in ENZ-R CRPC.
Bone metabolism biomarkers in men with advanced prostate cancer (PC) and bone metastases treated with denosumab versus zoledronic acid (ZA).
Authors: Smith Matthew Raymond , Brown Janet Elizabeth , Fizazi Karim , Klotz Laurence , Marx Gavin M. , Wang Huei , Warner Douglas , Lipton Allan
Published: February 2017

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Background: Denosumab, compared with ZA, has recently demonstrated significant benefits in preventing skeletal-related events (SREs) in a double-blind phase 3 study of men with castration-resistant PC and bone metastases (N=1901). This post hoc analysis was performed to determine if key bone metabolism biomarker levels correlated with time-to-first SRE. Methods: Time-to-Grade ≥2 increase in total serum alkaline phosphatase (ALP) was assessed for correlation with time-to-first SRE. Levels of urinary N-telopeptide (uNTX) and serum bone-specific alkaline phosphatase (BSAP) markers were measured at baseline and study week 13, and correlations with time-to-first SRE were assessed. Covariate analyses were performed using a Cox proportional hazards model, stratified by treatment group or (for baseline analyses) with treatment group as the independent variable. Results: Analysis of the relationship between time-to-Grade ≥2 increase in total ALP and time-to-first SRE demonstrated that Grade ≥2 increases in ALP of PC patients were associated with a higher risk of first SRE (hazard ratio [HR] 1.838, 95% confidence interval [CI] 1.559, 2.167; P<0.0001). In dichotomized analyses (< vs ≥ median), a higher level of uNTX and BSAP (at baseline or week 13) was correlated with an increased risk of first SRE (Table). In baseline covariate analyses, treatment benefit for denosumab was maintained after adjusting for either baseline uNTX (HR 0.818, 95% CI 0.703, 0.951; P=0.0091) or BSAP (HR 0.813, 95% CI 0.700, 0.943; P=0.0061). Conclusions: Higher levels of uNTX or BSAP at baseline or week 13 were associated with worse SRE outcomes in men with advanced PC and bone metastases. Denosumab was more efficacious for preventing or delaying SREs compared with ZA, regardless of bone-related biomarker levels. Relationship of covariate to time-to-first SRE Clinical trial information: NCT00321620. [Table: see text]
Drug-drug interactions in patients with castration-resistant prostate cancer undergoing abiraterone therapy: Characterizing the scale of the problem.
Authors: Jamani Rehana , Lee Esther K. , Berry Scott R. , DeAngelis Carlo , Giotis Angie , Emmenegger Urban
Published: February 2017

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Background: Abiraterone acetate (AA), used to treat CRPC, inhibits androgen biosynthesis by blocking cytochrome P450 (CYP) 17. It also inhibits other cytochromes involved in the metabolism of various widely-used medications (strong inhibition of CYP1A2, CYP2D6, and CYP2C8; moderate inhibition of CYP2C9, CYP2C19 and CYP3A4/5). Hence, there is presumably a high potential for drug-drug interactions (DDI) that can either diminish the efficacy of AA or concurrent medications, or increase the risk of DDI-related adverse events (AE); however, the scale of AA-associated DDI is currently unknown. Methods: We conducted a retrospective review of pharmacy records and electronic pt charts to retrieve individual drug histories, comorbidities, and AE of CRPC pts beginning AA treatment between Jan 2010 and Apr 2014. Individual drug histories were analyzed for DDI using two commercial databases, Lexicomp and Micromedex. Results: 91 informative pts were identified. Using Lexicomp, the most common drugs flagged for potential DDI of high clinical significance (i.e., “avoid combination”, or “consider therapy modification”) with AA were dexamethasone, metoprolol, clopidogrel, oxycodone, and citalopram. They were administered to 12 (13%), 10 (11%), 6 (7%), 4 (4%), and 4 (4%) pts respectively. Micromedex assigned a major risk of DDI to oxycodone and a moderate risk to metoprolol. At least 1 potentially significant DDI was found in 38/91 pts (42%) with Lexicomp, and in 42/91 pts (46%) with Micromedex. Most common AE were fluid retention seen in 19 pts (21%), fatigue in 15 (16%), liver-function test abnormalities in 13 (14%), hypertension in 13 (14%), and pain in 11 (12%), all corresponding to AE typically associated with the use of AA. We did not find unequivocal evidence for DDI-related AE. Conclusions: The use of commercial DDI databases reveals a substantial risk of potentially consequential DDI in CRPC pts undergoing AA therapy, although some of the flagged DDI (e.g., between AA and dexamethasone) may be of theoretical rather than practical concern. Further investigation with larger patient populations is required to better establish the clinical relevance of these DDI.
IND 205B: A phase II study of the PI3K inhibitor PX-866 and continued abiraterone/prednisone in patients with recurrent or metastatic castration resistant prostate cancer (CRPC) with PSA progression on abiraterone/prednisone.
Authors: Hotte Sebastien J. , Joshua Anthony M. , Torri Vamsee , Macfarlane Robyn Jane , Basappa Naveen S. , Powers Jean , Winquist Eric , Mukherjee Som , Gregg Richard William , Kollmannsberger Christian K. , Finch Daygen L. , Xu Hao , Hausman Diana Felice , Seymour Lesley , Eisenhauer Elizabeth A. , Chi Kim N.
Published: February 2017

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Background: PX-866 is an irreversible, pan-isoform inhibitor of Class I PI-3K. In part A of this study, PX-866 as a single agent was well tolerated and showed modest activity in CRPC but did not meet a priori benchmarks as a single agent in unselected patients (pts). As androgen receptor inhibition promotes PI3K activity in PTEN-loss PC models, the addition of PX-866 in patients whose PSA is rising on abiraterone acetate plus prednisone (AA+P) may reverse resistance and phase B of the study tested this hypothesis clinically. Methods: In this multicentre, phase II study, CRPC pts with PSA progression on AA+P received PX-866, 8mg daily on a 6-week cycle while continuing AA+P. Primary endpoint was lack of progression at 12 weeks (PCWG2 criteria). Secondary endpoints included PSA and objective response rates. PX-866 would be deemed worthy of further study if at least four of 25 pts were progression free at 12 weeks. Results: 25 pts were accrued and all are evaluable for toxicity and PSA response. Eleven pts had measurable disease of which 11 are evaluable for objective response. Median age was 72, ECOG PS was 0/1 in 10/15 pts. Eighteen pts received prior chemotherapy. Median number of cycles was 2 (range 1–3). 52% of pts received at least 90% of planned dose of PX-866. Most common adverse events (AEs) were fatigue (21 patients), diarrhea, (18), nausea (13), vomiting (11) and anorexia (12); one patient discontinued because of protocol therapy toxicity (grade 3 anemia). Other grade 3 AEs (one patient for each) were diarrhea, vomiting, fatigue, AST and ALT elevation and lymphocyte and platelet changes. Six pts were progression free at 12 weeks. No objective or PSA responses were seen. Of the pts with measurable disease, best objective response was stable disease in six (2.3-3.6m) and best PSA response was non-response in eight pts. Conclusions: The addition of PX-866 to AA+P in unselected pts progressing on AA+P shows no evidence of antitumour effects. Strategies to combine PI3K inhibition with AR targeted therapies should consider initiation earlier in the disease course and/or recruiting a selected population. Clinical trial information: NCT01331083.
Impact of dose-escalated radiation on overall survival in men with nonmetastatic prostate cancer.
Authors: Kalbasi Anusha , Li Jiaqi , Berman Abigail T. , Swisher-McClure Samuel , Smaldone Marc C. , Small Dylan , Mitra Nandita , Bekelman Justin E.
Published: February 2017

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Background: Infive publishedRCTs, dose-escalated external beam radiation therapy (EBRT) for prostate cancer resulted in improved biochemical and local control. However, the question of whether dose escalation improves overall survival (OS) remains unanswered. We examined OS among men with non-metastatic prostate cancer undergoing EBRT in the modern era. Methods: Using the National Cancer Database (NCDB), we conducted non-randomized comparative effectiveness studies of dose-escalated versus standard-dose EBRT in men diagnosed from 2004-2006 in three analytic cohorts defined by NCCN risk category: low- (N=12,848), intermediate- (N=14,966) or high-risk (N=14,587) prostate cancer. We categorized patients in each risk cohort into 2 treatment groups: standard-dose (68.4 Gy to <75.6 Gy) or dose-escalated (≥75.6 Gy to 90 Gy) EBRT. The primary outcome was time to death from any cause, measured from diagnosis to NCDB date of death or end of follow-up (December 31, 2011). We compared OS between treatment groups in the three analytic cohorts using Cox proportional hazard models. Inverse probability weighted propensity score methods were used to balance differences between treatment groups in age, race, year of diagnosis, AJCC T- and N-stage, PSA, Gleason score, androgen deprivation therapy, IMRT use, comorbid disease, income, insurance, urban/rural location, facility type and facility volume. In secondary analyses, we evaluated dose response for survival by categorizing dose in approximately 2 Gy increments. Results: Median follow up for survivors was between 73 and 74 months in all three risk cohorts. Dose-escalated EBRT was associated with improved survival in the intermediate-risk (adjusted HR 0.81, 95% CI 0.77 and 0.85, p<0.0001) and high-risk groups (aHR 0.85, 95% CI 0.81 and 0.89, p<0.0001), but not the low-risk group (aHR 0.99, 95% CI 0.92-1.06, p=0.803). For every incremental ~2Gy increase in dose, there was a 9% (95% CI 6% – 11%, p<0.0001) and 7% (95% CI 3% - 10%, p=0.004) reduction in the hazard of death for intermediate- and high-risk patients, respectively. Conclusions: Dose-escalated EBRT is associated with improved survival in men with intermediate- and high-risk, but not low-risk, prostate cancer.
A retrospective analysis of clinical factors influencing response to treatment with cabazitaxel in patients with metastatic castration resistant prostate cancer.
Authors: Yokom Daniel , Alimohamed Nimira S. , Winquist Eric , Berry Scott R. , Hubay Stacey , Lattouf Jean-Baptiste , Leonard Helene , Girolametto Carla , Saad Fred , Sridhar Srikala S.
Published: February 2017

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Background: The TROPIC trial demonstrated that cabazitaxel improves overall survival (OS) in mCRPC patients progressing on or after docetaxel; a setting where both abiraterone and enzalutamide are also approved. We evaluated baseline factors that may help predict prostate specific antigen (PSA) response or PSA progression defined as per the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria and OS in mCRPC patients treated with cabazitaxel. Methods: Forty patients from five centres participated in an early access program and were retrospectively reviewed to capture baseline characteristics, disease history, prior and subsequent treatments, PSA response, and OS. The influence of selected variables on PSA response and OS were evaluated by univariate and multivariate stepwise regression analysis. Results: At cabazitaxel initiation, median age was 65, ECOG 0-1 (90%), median PSA was 216 ng/mL, 25% had visceral disease and 70% had pain. Median number of prior docetaxel cycles was 9 and median time from treatment was 9.6 months (5-14.2). Median number of cabazitaxel cycles was 7 (1-27). Fourteen patients received abiraterone before cabazitaxel. In patients with prior abiraterone treatment there was no impact on PSA response compared to patients with no prior abiraterone. In the multivariate regression analysis, presence of visceral disease, low albumin (≤40g/L), low hemoglobin (<100 g/L) and longer time between last docetaxel dose and start of cabazitaxel were correlated with PSA response to cabazitaxel (p<0.10). Age < 65, BMI ≥ 30kg/m2 and presence of pain were linked to an increased likelihood of PSA progression. None of the factors selected were significantly associated with OS. Conclusions: In routine clinical practice, this study suggests that mCRPC patients with visceral disease and a longer time elapsed between last docetaxel dose and start of cabazitaxel may experience a greater PSA response with cabazitaxel.
Clonal heterogeneity in platinum-resistant metastatic urothelial cancer.
Authors: Faltas Bishoy , Beltran Himisha , Eng Kenneth , Pauli Chantal , Robinson Brian D. , Mosquera Juan Miguel , Nanus David M. , Tagawa Scott T. , Elemento Olivier , Rubin Mark A.
Published: February 2017

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Background: Beyond platinum-based chemotherapy, there are currently no approved therapies for advanced PRUC. Our objective was to generate the first detailed genomic profile of metastatic PRUC to identify molecular changes critical to platinum-resistance and metastasis development. Methods: Following informed consent, we collected 50 urothelial cancer (UC) tissue samples, from 23 patients. Metastatic tumor samples were obtained from biopsies or metastatectomy. Germline samples were prospectively collected and matched archival formalin-fixed paraffin-embedded primary tumors from the same patients were retrieved. Our cohort comprises 23 metastatic samples, 37 PRUC samples and 18 trios of matched primary, metastatic and germline samples including 2 rapid autopsies yielding tumor samples from multiple sites. We performed whole exome sequencing of all tumor and germline samples followed by integrated analysis of somatic single nucleotide variants and copy-number alterations and to analyze clonality. We utilized DAVID bioinformatic tool for pathway analysis. Results: Advanced PRUC samples were enriched for several molecular alterations, we identified 414 recurrently mutated genes including common genes such as TP53 (45%) as well as actionable alterations in PIK3CA (11%) and TSC1 (19%). We also identified frequent alterations in novel genes such as DPCR1 (38%) and NIN (28%). Frequent copy number alterations included CDKN2A deletion (33%), E2F3 amplification (10%) and ERBB2 amplification (7%). Pathway analysis showed enrichment of mutations in the apoptosis (p=1.0E-7) and cell cycle regulation (p=1.6E-2) pathways compared to TCGA primary UC dataset. We reconstructed phylogenetic trees from matched primary, metastatic and germline trios. Variant allele frequencies of certain shared mutations increased from primary tumors to lymph node and visceral metastases revealing clonal selection of mutations present in primary tumors. Conclusions: This study generates a detailed profile of the genomic landscape of advanced PRUC revealing extensive heterogeneity and clonal selection underlying platinum-resistance and metastatic spread.
Phase II study of pazopanib with weekly paclitaxel in refractory urothelial cancer.
Authors: Srinivas Sandy , Narayanan Sujata , Harshman Lauren Christine , Pachynski Russell Kent , Lam Anthony P. , Fan Alice C. , Poushnejad Shermeen , Haas Denise , Vaishampayan Ulka N.
Published: February 2017

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Background: Currently, there are no standard treatments for relapsed or refractory urothelial carcinoma (UC). Discouraging results have been observed in trials evaluating established chemotherapeutics as single agents or in combination regimens. Paclitaxel has moderate activity when used alone and in combination in UC. Pazopanib is active in other solid tumors secondary to its potent anti-angiogenic effects. We report the results of a multi-center phase II study evaluating the combination of paclitaxel with pazopanib in refractory UC. Methods: Eligible patients (pts) had histologically confirmed UC, with disease that progressed on upto 2 chemotherapeutic regimens. Pazopanib (800 mg) was administered daily, with weekly paclitaxel (80mg/m2) for 3 weeks in a 28 day cycle. Treatment was continued until disease progression or unacceptable toxicity. The primary endpoint of the study was response-rate (RR) based on RECISTv 1.1 criteria. Secondary endpoints included safety, and progression free-survival (PFS). Results: From April 2010 to September 2014, 32 patients were enrolled. Median age was 67 years (29-89) and median ECOG performance status was 1 (0-2). 17 pts (54%) had UC of the upper urinary tract disease and 15(47%) had primary bladder tumors. All pts had multiple metastatic sites, including 9 (28%) with liver metastases. Median number of prior cytotoxic regimens was 2, and 50% were considered cisplatin responsive. Objective responses were observed in 58% with 3 (12%) complete responses (CR), and 12 pts (46%) with partial responses (PR). Another 9 (35%) acheived stable disease (SD). High grade toxicities included grade 3 hypertension (n=2), grade 3 fatigue (n=4), grade 3 thrombosis (n=2) and grade 4 neutropenia (n=2). Nearly half of the patients( n= 14 ) required growth factor support. Conclusions: Our phase II study combining paclitaxel and pazopanib demonstratedsignificant anti-tumor activity in relapsed/refractory UC. This combination is safe, effective and is worthy of evaluation in randomized phase 3 study. Clinical trial information: NCT01108055.
PDL1 status in muscle-invasive urothelial carcinoma in the context of neoadjuvant cisplatin-based chemotherapy.
Authors: Liu Jen-Jane , Baras Alexander S , Gandhi Nilay M , Guner Gunes , Munari Enrico , Faraj Sheila , Taube Janis M. , Schoenberg Mark , Hahn Noah M. , Drake Charles G. , Netto George J. , Bivalacqua Trinity
Published: February 2017

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Background: Although complete and partial response rates to cisplatin-based neoadjuvant chemotherapy (cNAC) are 40-50% in patients with muscle-invasive urothelial carcinoma (MIUC), post-cystectomy cancer specific survival (CSS) for patients who fail to respond to cNAC is poor (5-y CSS = 27%). Therefore, up to half of MIUC could be amenable to alternative systemic therapies. Anti-programmed death ligand (PDL1) has shown promising results in tumors with proven PDL1 expression, including advanced stage MIUC. We evaluated PDL1 expression in MIUC in a cohort categorized by pathologic response to cNAC to test the hypothesis that anti-PDL1 therapy is a rational therapeutic option for patients non-responsive to cNAC. Methods: We studied 150 patients who received cNAC followed by open radical cystectomy (RC) from 2000-2013. Pathologic response (<pT1 N0 at RC) and CSS were compared to patients who had RC without cNAC. Tissue microarrays of MIUC specimens representing patients with and without response to cNAC were stained with PD-L1 (Cell-Signaling, E1L3N, 1:100) and FOXP3 (eBioscience, 236A/E7, 1:250). The degree of tumoral PDL1 and tumoral lymphocyte FOXP3 staining was manually scored. Tumors with 5% and >15/hpf staining were considered positive for PDL1 and FOXP3, respectively. Percentage of non-responders to cNAC staining positive for PDL1 was the primary outcome of our study. Results: The rate of PDL1 positivity in MIUC cNAC non-responders was 47% which was similar to the 43% rate in responders. There was a strong positive correlation of tumoral PDL1 staining with tumoral lymphocytes FOXP3 staining, Goodman-Kruskal gamma=0.71 (p<0.0001), which was independent of cNAC responder status (Table). Conclusions: Patients with MIUC that are non-responders to cNAC have poor long term CSS. Our results demonstrate that cNAC non-responders exhibit frequent PDL1 tumoral staining, suggesting that neoadjuvant or adjuvant anti-PDL1 therapy represents an attractive therapy worthy of prospective clinical trial testing in MIUC patients whose tumors do not respond to or in patients who cannot tolerate cisplatin based chemotherapy. [Table: see text]
Incidence, predictors, and cost implications of gastrointestinal complications following intensity-modulated radiation therapy for prostate cancer.
Authors: Wood Monica J. , Reznor Gally , Trinh Quoc-Dien , Nguyen Paul Linh
Published: February 2017

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Background: The objective of this study was to examine the incidence and predictors of gastrointestinal (GI) complications following intensity-modulated radiation therapy (IMRT) for prostate cancer and their impact on national healthcare expenditure. Methods: Using Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked data, we identified 11,781 men diagnosed with non-metastatic prostate cancer from 2002 to 2006 who underwent definitive IMRT, had no pre-existing GI toxicity, and had at least 36 months of follow-up after IMRT initiation. Annual incremental spending was defined as the difference between the total Medicare payments in the year after the development of the first GI complication and the total Medicare payments in the year preceding prostate cancer diagnosis, excluding prostate cancer treatment-related costs. We used multivariate logistic regression to evaluate the odds ratio of developing IMRT-related GI toxicity, and quantile regression to compare the annual incremental costs between groups. All analyses were done using SAS 9.3. Results: Over the 36-month follow-up period, the incidence of post-IMRT GI complications was 26.5% (n=3,118). Patients on anti-coagulation therapy or receiving brachytherapy boost were more likely to develop IMRT-related GI toxicities (OR 1.11, 95% CI 1.01-1.22 (p=0.029) and OR 1.18, 95% CI 1.08-1.30 (p<0.001), respectively). The median Medicare annual incremental cost per patient associated with post-IMRT GI complications was $3,375 in 2014 dollars (95% CI $3,222-3,529, p<0.0001). Among patients with post-IMRT GI complications, the presence of diabetes was associated with an additional $610 (95% CI $206-1,014, p=0.003) per patient in Medicare spending. Conclusions: Medicare spending associated with post-IMRT GI complications is considerable, often in excess of 10% of IMRT cost. Quantifying these expenditures may better frame the potential for cost savings of emerging technologies that aim to reduce the incidence and severity of IMRT-related GI toxicities.