bluuebunny/crossref_metadata_2025 huggingface dataset:
A treatment planning comparison of proton therapy and intensity-modulated radiotherapy (IMRT) for prostate cancer using the normal tissue complication probability (NTCP).
Authors: Fischer-Valuck Benjamin Walker , Olsen Lindsey , Mazur Thomas , Altman Michael , Bottani Beth , Gay Hiram Alberto , Michalski Jeff M.
Published: February 2017

153

Background: The volume of rectum receiving high-dose (i.e. > or = 60 Gy) is consistently associated with the risk of Grade > or = 2 rectal toxicity or rectal bleeding based on common terminology criteria for adverse events (CTCAE). Our goal was to compare intensity-modulated photon radiotherapy (IMRT) with proton radiotherapy in regard to the rectal dose using the normal tissue complication probability (NTCP). Methods: Between July 2014 and September 2015 the first 10 consecutive low or intermediate risk prostate cancer patients were treated with proton therapy at our institution. All 10 patients were planned with three-dimensional conformal proton therapy (3D-CPT) using two parallel opposed fields as well as comparison IMRT plans. A rectal balloon filled with water was used in all patients treated. Prescribed dose to the prostate was 79.2 Gy or cobalt Gy equivalent (CBE) for protons. Dose-volume histograms were compared. The Lyman-Kutcher-Burman model (n = 0.09, m = 0.13, and TD50 = 76.9 Gy) was used to generate NTCP estimates for both IMRT and proton plans. Results: At least 95% of the planning target volume received the prescription dose for both proton and IMRT plans. Dose constraints placed on the rectum included volume receiving 65 Gy (V65) less than 17% and V40 less than 35%. The mean dose to the rectum was 24.5 Gy (range, 19.5-30.1 Gy) and 31.7 Gy (range, 23.7-39.4 Gy) for the proton and IMRT plans, respectively. The V65 constraint was unachievable in 3 of the proton plans and 3 of the IMRT plans. The mean V70 and V75 for proton plans was 8.4% and 5.4% compared to 7.5% and 4.8% for the IMRT plans. The mean NTCP for proton treatment plans was 7.72% (range, 2.7-11.7%) and 7.92% (range, 1.7-15.3%) for IMRT (P = 0.45). After median follow-up of 6 months, no grade 2 or higher toxicity has been reported. Conclusions: Utilizing NTCP estimations, proton therapy and IMRT have similar predicted rates of rectal toxicity. Currently, a Phase III randomized clinical trial is underway comparing proton therapy and IMRT with regards to rectal toxicity and quality of life.
Magnetic resonance image-guided radiation therapy (MR-IGRT) for the treatment of prostate cancer: Initial clinical experience and patient selection.
Authors: Fischer-Valuck Benjamin Walker , Michalski Jeff M.
Published: February 2017

156

Background: Magnetic resonance image-guided radiation therapy (MR-IGRT) has been implemented at our institution since 2014. We report on the initial clinical experience and patient selection in treating prostate cancer utilizing the first commercially-implemented MR-IGRT system. Methods: A total of 13 patients with prostate cancer have been treated with intensity-modulated radiation therapy (IMRT) using an MR-IGRT system. Of those treated, 6 patients received definitive radiation therapy (RT) for low, intermediate or high risk prostate cancer, 5 patients were treated with salvage RT after biochemical failure following surgery, and 1 patient was treated for the boost portion of definitive RT. Results: Patients were selected for MR-IGRT based on various clinical decisions. Four patients had co-morbidities requiring anticoagulation for which fiducial marker placement was contraindicated and soft tissue visualization via MR imaging was thought to be beneficial for daily set-up. Three patients were referred from outside institutions with concerns of radiation dose to the small bowel, and daily MR monitoring of bowel anatomy could be performed with plans for treatment adaptation if anatomy changed. One patient had received prior RT for rectal cancer and dose to organs at risk was of concern. The remainder of patients were post-operative salvage cases selected based on physician concern of accurate and reproducible daily localization with fiducial markers alone. Daily volumetric MR was monitored with the ability for treatment adaptation should small bowel dose increase, and no treatment changes were required. For all cases, onboard sagittal cine MR was visually monitored for bladder and target motion, and qualitative evaluation demonstrated no significant intra-fraction motion. Conclusions: MR-IGRT provides unique advantages when fiducial markers are contraindicated or when daily visualization of dose to the small bowel or other organs at risk is required to monitor and potentially prevent normal tissue toxicity. Clinical trials are in development to formally evaluate MR-IGRT for the treatment of intact and salvage prostate cancer.
Phase II clinical study of radium-223 chloride (BAY 88-8223) in Japanese patients with symptomatic castration-resistant prostate cancer (CRPC) with bone metastases.
Authors: Uemura Hiroji , Nagamori Satoshi , Wakumoto Yoshiaki , Uemura Hirotsugu , Kimura Go , Yokomizo Akira , Kikukawa Hiroaki , Mizokami Atsushi , Kosaka Takeo , Masumori Naoya , Kawasaki Yoshihide , Yonese Junji , Nasu Yasutomo , Fukasawa Satoshi , Sugiyama Takayuki , Uemura Motohide , Yamaguchi Iku , Tsutsui Hirokazu , Matsunaga Eisuke , Matsubara Nobuaki
Published: February 2017

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Background: The ALSYMPCA study was conducted to evaluate the alpha-emitting radiopharmaceutical Radium-223 Chloride (BAY 88-8223) in patients with symptomatic bone metastases in Castration resistant prostate cancer (CRPC). This trial met its primary endpoint of overall survival at the time of pre-planned interim analysis. Post hoc analysis showed a reduction from baseline in total ALP at 12 weeks (32% reduction in the BAY 88-8223 arm vs. 37% increase in placebo arm, P < 0.001) (Sartor et al. ASCO 2013). We are reporting here a single-arm, open-label, multicenter, phase II clinical study of BAY 88-8223 in Japanese patients with symptomatic CRPC with bone metastases. Methods: Eligible patients had progressive, symptomatic CRPC with at least 2 bone metastases on bone scintigraphy and no known visceral metastases; were receiving Best Standard of Care; and either had previously received docetaxel, were docetaxel ineligible, or had refused docetaxel. Patients received 6 injections of radium-223 (50 kBq/kg IV) every 4 weeks. The primary endpoint was percentage of change in total ALP from baseline at 12 weeks. Secondary endpoints included overall survival, time to symptomatic skeletal event, percentage of change in bone ALP/PSA/biomarkers, and safety. Results: A total of 67 subjects were enrolled; 18 were screening failures, and 49 were received to the study treatment and received at least one administration from September 2013 to May 2014. The mean percent change in total ALP from baseline at 12 weeks was -19.3% (95%CI: -28.0% to -10.7%). The results of secondary endpoints will be presented. The safety and tolerability profile for BAY 88-8223 were highly favorable and only 1 subject (2.0%) experienced lymphocyte count decreased as a Grade 4 adverse event, and there was no death during the study treatment and within 30 days after the last injection of study treatment. Conclusions: The reduction from baseline in total ALP at 12 weeks seen in this phase II study is consistent with the results shown in ALSYMPCA study. Overall, BAY 88-8223 was well tolerated in Japanese patients with CRPC and bone metastases. Clinical trial information: NCT01929655.
Gleason score and the risk of cause-specific and overall mortality following radiation with or without 6 months of androgen deprivation therapy for men with unfavorable-risk prostate cancer.
Authors: Warren Laura Elizabeth , Chen Ming-Hui , Denham James William , Steigler Allison , Renshaw Andrew A. , Loffredo Marian J. , Kantoff Philip W. , D'Amico Anthony V.
Published: February 2017

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Background: We evaluated whether a differential impact of adding 6 months of androgen deprivation (ADT) to radiation therapy (RT) on all-cause, prostate cancer-specific, and other-cause mortality (ACM, PCSM, OCM) in men with unfavorable-risk PC exists within Gleason score (GS) subgroups. Methods: Individual patient data from 743 men with unfavorable-risk PC from two randomized ADT trials were utilized. Competing risks and Cox regression were used to determine whether adding 6 months of ADT to RT significantly impacted PCSM, OCM and ACM within GS subgroups. Results: Men with GS 9,10 versus ≤ 8 were significantly more likely to be over 75 (23.3% versus 12.7%;p = 0.03). At a median follow-up of 11.9 and 11.8 years in the 683 and 60 patients with GS ≤ 8 and GS 9,10, 315 (46.1%) and 44 had died (73.1%), respectively. ADT in men with GS ≤ 8 was associated with significantly decreased ACM (Adjusted hazard ratio (AHR) 0.66; 95% confidence interval (CI): 0.52-0.82; p < 0.001) and PCSM (0.43; 0.28-0.66; p < 0.001) but was not associated with OCM (0.90; 0.68-1.17; p = 0.43). Among men with GS 9,10 PC, ADT significantly reduced PCSM (0.33; 0.11-0.99; p = 0.048) but not ACM (0.79; 0.38-1.61; p = 0.51) and increased OCM (2.16; 0.81-5.79; p = 0.12) resulting in opposite effects of ADT on OCM by GS subgroup (Table) such that the relative AHR of OCM in GS 9,10 versus ≤ 8 was nearly significantly increased (2.42; 0.87-6.71; p = 0.09). Conclusions: While ADT reduced PCSM for all men, survival was not prolonged in men with GS 9,10 due to ADT-driven increased OCM. This supports the hypothesis that older men with significant comorbidity may not experience prolonged survival when ADT is added to RT. [Table: see text]
OLIGOPELVIS – GETUG P07, a multicentre phase II trial of combined salvage radiotherapy and hormone therapy in oligometastatic pelvic node relapses of prostate cancer: Preplanned analysis of acute toxicity.
Authors: Supiot Stephane , Crehange Gilles , Buthaud Xavier , Pasquier David , Hasbini Ali , De Laroche Guy , Pommier Pascal , Loos Genevieve , Beckendorf Veronique , Sargos Paul , Rio Emmanuel , Campion Loic
Published: February 2017

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Background: We explored the role of salvage pelvic radiotherapy combined with LH-RH agonists in pelvic oligometastatic patients (pts) detected by 18F-choline positron-emission tomography (FCH-PET) imaging in biochemically relapsing prostate cancer patients following radical therapy. We report a preplanned analysis of acute toxicity and quality of life after the first 20 pts. Methods: Biochemically relapsing prostate cancer pts with 1-5 FCH-PET positive oligometastatic pelvic lymph nodes received high-dose image-guided intensity-modulated radiation therapy (RT: pelvic lymph nodes 54 Gy, 30 f; FCH-PET-positive lymph nodes 66 Gy, 30 f; prostate bed 66 Gy, 33 f; if FCH-PET-positive prostate bed relapse 72 Gy, 36 f) combined with 6 months LH-RH agonists. Primary objective was biochemical-clinical failure-free survival. After the first 20 pts, a preplanned analysis of toxicity at 1 months after RT completion was conducted. Stopping criteria were more than 10 or 2 pts experiencing grade 2 or 3 toxicity respectively. Changes in toxicity (NCI-CTC AE v4), and quality of life (EORTC QLQ-C30 and PR25 questionnaires) over time were analyzed by the Wilcoxon signed-rank test. Results: 20 pts (median age 62) presenting oligometastatic pelvic lymph nodes (mean 1.7) received RT to lymph nodes in all pts and to the prostate bed in 8 pts with a boost to a local relapse in 2 pts. Grade 2 gastrointestinal and genitourinary toxicity was noted in 4/20 and 0/20 pts respectively during radiotherapy that resolved completely in all pts one month after treatment. No grade 3 toxicity was noted. At 1 month, significant worsening was reported by pts for 4/21 QoL items but the worsening was clinically relevant ( > 10 points) for 2 items only: fatigue and dyspnea. However, there was significant - but clinically non-relevant ( < 10 points) - worsening of physical functioning and hormonal-treatment related symptoms. Conclusions: High-dose RT to the pelvis and oligometastatic lymph nodes did not increase acute toxicity. As per protocol, the study resumed and is now recruiting 50 more patients. Clinical trial information: NCT02274779.
Dynamic correlation of serum C-reactive protein (CRP) levels with serum prostate-specific antigen (PSA) levels in patients with prostate cancer (PCa) on androgen deprivation therapy (ADT).
Authors: Kucuk Omer , Balci Bengi , Liu Yuan , Zhang Chao , Yilmaz Bahiddin , Atag Elif , Karaoglu Aziz , Jani Ashesh B. , Harris Wayne , Carthon Bradley Curtis , Rossi Peter John , Master Viraj A. , Alemozaffar Mehrdad , Filson Christopher Paul , Sanda Martin George
Published: February 2017

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Background: CRP, a marker of inflammation, has been associated with disease extent and prognosis in urologic cancers (Huang J, et al. Mol Aspects Med, 2015). In this study we wanted to see whether CRP is dynamically correlated with PSA in patients with PCa when they were on ADT. Methods: 83 patients on ADT were included in this analysis. Their CRP and PSA were recorded longitudinally and the range of length of follow up time is from 3 to 47 (median 16) months. All patients had at least 3 pairs of CRP and PSA measurements available. Statistical analysis was conducted using Dynamic Correlation (Dubin JA, Muller H-G. J Am Stat Assoc, 2005) package ‘dynCorr’ in R 3.1.2, and SAS Version 9.4. Significance levels were set at 0.05. We calculated dynamical correlation as function of time lag between CRP and PSA measurements along with 95% bootstrap confidence intervals and p value. Results: See below table. Conclusions: We found that at lag = 30 days (CRP leads PSA by 30 days), the correlation is significant at level of < 0.05, which means any increase or decrease of CRP at a given time point will lead to about same change in PSA 30 days later. Though these findings must be verified in a larger setting, our results support, in the setting of ADT use, the role of CRP as an early marker of PCa progression and treatment response. [Table: see text]
Do we need daily corticosteroid combined with docetaxel when treating against castration-resistant prostate cancer?
Authors: Shimomura Tatsuya
Published: February 2017

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Background: Depend on the result of TAX 327, docetaxel are usually used with daily corticosteroid (prednisone) against castration resistant prostate cancer (CRPC). However there is no evidence that combination of daily corticosteroid itself with docetaxel improve survival rate. In this study we investigated whether daily corticosteroid have survival benefit in our docetaxel treatment cohort. Methods: Total of 120 CRPC cases were treated with docetaxel in our department between 2011 and 2014. We compared the group 1 (with daily corticosteroid) and group 2 (without daily corticosteroid) and evaluated their clinical outcome. In group 2, there was no case using estramustine or any estrogen medicine. Results: Group 1 was 104 cases and group 2 was 11 cases in this study. In terms of clinical and pathological demographics at diagnosis of prostate cancer and at starting docetaxel, almost all of the factors did not have significant difference between group1 and 2 other than white blood cell count(mean 7142 and 5664, respectively. p = 0.0449). About the treatment outcome, there were no significant difference in overall survival (p = 0.8696) , PSA response rate (39.2% vs 52.0%, p = 0.2348), PSA decline ³a50% (38.4% vs 45.5%,p = 0.651), PSA decline ³a90% (14.4% vs 36.4%, p = 0.062) and number of cycles (Mean 7.19 vs 8.33, p = 0.174) between group 1 and 2. Conclusions: Although this study was retrospective and the cohort was small, we did not find the difference of outcome among the 2 groups. At least, we could say that there was no survival benefit in the daily corticosteroid groups. And there is a possibility that we do not need to combine daily corticosteroid with docetaxel. We will need prospective randomized trial to prove this hypothesis.
Comprehensive genomic profiling of neuroendocrine carcinoma of the prostate.
Authors: Pal Sumanta K. , Milowsky Matthew I. , Elvin Julia Andrea , Ali Siraj Mahamed , Hoffman-Censits Jean H. , Vergilio Jo-Anne , Suh James , Mian Badar , Fisher Hugh A.G. , Nazeer Tipu , Miller Vincent A. , Stephens Philip J. , Ross Jeffrey S.
Published: February 2017

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Background: Neuroendocrine carcinoma of the prostate (NCAP) is an aggressive high grade malignancy that often presents as metastatic disease. Current treatments of this tumor have only modest benefit leading investigators to query whether comprehensive genomic profiling (CGP) would have potential to discover novel targets of therapy. Methods: DNA was extracted from 40 microns of FFPE sections from 37 consecutive cases of relapsed/metastatic NCAP. CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of 583X for up to 315 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. Genomic alterations (GA) included base substitutions (SUB), INDELs, copy number alterations (CNA) and fusions/rearrangements. Clinically relevant GA (CRGA) were defined as GA linked to drugs on the market or under evaluation in mechanism driven clinical trials. Results: The median age of the men in this study was 65.1 years (range 43 to 83 years). All (100%) cases were positive for neuroendocrine markers on immunohistochemical staining and were Stage IV at the time of CGP. Samples used for sequencing were obtained from the primary tumor in 9 (24%) of NCAP and from metastatic sites in 28 (76%) of NCAP (12 liver, 6 LN, 2 each from bladder, pelvis and soft tissue, and 1 each from rectum, bone, urethra and ureter. There were 213 total GA (5.8 GA/sample) and 47 CRGA (1.3 CRGA/sample). The most frequent GA were non-CRGA mutations in TP53 (68%) and RB1 (51%). TMPRSS:ERG fusions were identified in 32% of cases whereas AR was altered in 8% (1 mutation and 2 amplifications). The most frequent CRGA involved PTEN (32%), BRCA2 (14%), FGFR1 (5%), PIK3CA (5%) and AKT2 (3%). No alterations in BRAF were identified. Clinical responses to MTOR inhibitors in patients with MTOR pathway alterations will be presented. Conclusions: NCAP has distinctive genomic alterations from classic acinar CAP including reduced frequencies of alterations in TMPRSS:ERG and AR and frequent RB1 mutations. Multiple alterations in the MTOR pathway identified in this infrequent tumor type suggest that these patients may be candidates for MTOR inhibitors and other targeted therapies.
Real-world experience of therapeutic sequencing and time to first anticancer intervention (ACI) following sipuleucel-T (sip-T): Initial data from the PROCEED registry.
Authors: Sartor A. Oliver , Cooperberg Matthew R. , Armstrong Andrew J. , Vogelzang Nicholas J. , Vacirca Jeffrey L. , Scholz Mark C. , Dakhil Shaker R. , Nordquist Luke T. , Heath Elisabeth I. , Chang Nancy N. , LIll Jennifer Susan , Higano Celestia S.
Published: February 2017

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Background: Sip-T is an autologous immunotherapy approved for asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC).Many therapeutic agents have been approved in a short time frame, and their optimal sequencing in mCRPC is under investigation. The sequencing of agents post–sip-T treatment on PROCEED (NCT01306890) and factors associated with a shorter time to first ACI (tACI) are described. Methods: The number of unique and most common sequences and sequence trends were analyzed. Post–sip-T ACIs evaluated were abiraterone (abi), enzalutamide (enz), docetaxel (D), and cabazitaxel (cbz), excluding radium-223 due to its late approval relative to PROCEED initiation. The tACI and factors associated with shorter tACI were assessed. Results: 1902 pts received ≥1 sip-T infusion, and an estimated 37.0% and 21.2%had not received an ACI at 1 and 2 y, respectively, post–sip-T. 1331 (70%) pts received abi, enz, D, or cbz after sip-T. 47 therapy sequences were recorded post–sip-T, with the most used therapies in order of prevalence: abi alone, enz alone, D alone, abi → enz, abi → D, D → enz, and D → abi. The most common post–sip-T sequences beginning with abi, enz, or D are below (Table). Only 25 pts received cbz as the first ACI post–sip-T. Pts who received abi prior to sip-T had a shorter median tACI (4.6 mos) compared with all pts (8.3 mos) or pts with D prior to sip-T (7.3 mos). Higher baseline alkaline phosphatase, lower hemoglobin, and prior radical prostatectomy were associated with shorter tACI. Conclusions: In the evolving mCRPC space, 47 unique ACI sequences were recorded post-sip-T. The most common sequences post–sip-T were abi, enz, and D as single agents. Prior abi was associated with a shorter tACI post–sip-T, which warrants longer follow-up. While many pts received subsequent therapy, ~20% had not received an ACI at 2 y post–sip-T. Clinical trial information: NCT01306890. [Table: see text]
Circulating tumor cell (CTC) detection, N-terminal androgen (AR) characterization, and PTEN loss in metastatic or advanced castration resistant prostate cancer (CRPC).
Authors: Jia Shidong , Baird Sarah , Anderson Amanda K. L. , Werner Shannon L. , Petersen Jane , Huw Ling , Marrinucci Dena C. , Patel Premal H.
Published: February 2017

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Background: Detection and characterization of CTCs offers a minimally invasive mechanism for understanding patient response to therapy and disease evolution. Here we describe a proprietary technology platform to examine CTC incidence, N-terminal AR expression, and PTEN loss in metastatic or advanced CRPC patient samples from a phase II clinical trial (GO27983) testing the combination of the AKT inhibitor ipatasertib and abiraterone. Methods: Blood samples from CRPC patients (n = 283) were collected at screening and shipped to Epic Sciences. Upon receipt, the nucleated cells were plated onto microscope slides and stored at -80C. Two slides were thawed per patient and analyzed with an N-terminal AR CTC assay. CTCs were detected using a combination of CD45 exclusion, CK and N-terminal AR expression, and morphologic criteria. Traditional (CD45-, CK+, DAPI+) and Non-Traditional (CD45-/CK- with distinct morphology or CD45-/CK+ with fragmented nuclei) CTCs were enumerated and N-terminal AR expression was quantified for each CTC. Samples with > 2 Traditional CTCs enumerated per slide were further evaluated for PTEN loss by FISH (n = 170). Results: Traditional CTCs were detected ( ≥ 1 cell/ml) in 86% (242 of 283) of samples. Non-traditional CTCs were detected in 93% (263 of 283) of patients. N-terminal AR positivity was detected ( ≥ 1 AR+ cell/ml) in 53% (128 of 242) of Traditional CTC-positive samples, with the % positivity ranging from 0.4-100%. PTEN status was determined for 66% (160 of 243) of patients with Traditional CTCs detected. Patients with homozygous (HO) PTEN loss had a significantly higher mean CTC/mL (p = 0.0013) and AR+ CTC/mL value (p = 0.0014) than patients with PTEN non-deleted status. Conclusions: The ability of the Epic Sciences platform to detect AR+ CTCs and PTEN loss at screening provides a non-invasive approach to characterizing and monitoring CTCs identified in advanced CRPC patients. The study is ongoing to monitor longitudinal changes in CTC incidence and AR expression in relation to PTEN status. Clinical trial information: NCT01485861.
Cardiovascular safety profile of VT-464 in patients (pts) with castrate-resistant prostate cancer (CRPC).
Authors: Kurman Michael R , Sager Philip , Rudoltz Marc S. , Eisner Joel , Goodman Daniel , Heyman Eugene , Salvail Daniel , Bell Caroline , Moore William R.
Published: February 2017

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Background: VT-464 is a dual selective inhibitor of CYP17,20 lyase and an androgen receptor antagonist in development for the treatment of CRPC. In early clinical testing, several pts receiving VT-464 in 28-day cycles were noted to have syncopal, pre-syncopal or vaso-vagal episodes with typical prodromes. To further evaluate these events, Holter monitoring (HM) was performed in pts enrolled in two clinical studies. Methods: Continuous HM was performed at Screening, after the first dose of VT-464 C1D8, and C2D1 for study INO-VT-464-CL-001; and at Screening, after the first dose of VT-464, and C2D1 for study INO-VT-464-CL-004. The Screening visit HM data was considered the baseline. Plasma levels of VT-464 (in selected pts) and 12-lead ECGs of 10-seconds duration were extracted in triplicate for each pt from the HM data at Baseline, Day 1 and C2D1 at multiple time points. Results: 57 pt screened for VT-464 treatment, underwent HM. Nonsustained ventricular tachycardia (NSVT) was seen in 6 pts (11%) prior to VT-464, providing a background estimate in this population. 37 pts were treated with VT-464 and had > 1 post-screen HM; 4 pts (11%; all with cardiac disorders) had post-treatment NSVT (all < 5 beats); no episodes of sustained VT were seen. 28 pts had ECG data extracted from HMs that coincided with peak plasma levels of VT-464. There was no QTcF or QRS prolongation; increases in the HR (mean 13.1-19.5 BPM but with a non-significant VT-464 concentration/HR relationship) and small PR increases (mean 32.9 ms; partially driven by several pts) without second degree AV block were observed. Conclusions: VT -464 did not prolong QTcF or QRS intervals and the lack of a significant exposure response HR analysis suggests that the HR increases may not be drug related. The PR prolongation is unlikely to be clinical significance. HM showed a frequency of NSVT consistent with background frequency for this pt population.A detailed examination of study pts experiencing syncope or presyncope revealed these to likely be vasovagal in nature, consistent with the increased vagal tone observed in nonclinical testing. There does not appear to be a pro-arrhythmogenic potential of VT-464 based on data from both nonclinical and clinical assessments. Clinical trial information: NCT02361086.
A randomized, double-blind, placebo-controlled phase II study of maintenance therapy with tasquinimod (TASQ) in patients (pts) with mCRPC responsive to or stabilized during first-line docetaxel chemotherapy.
Authors: Fizazi Karim , Ulys Albertas , Sengeløv Lisa , Moe Mette , Ladoire Sylvain , Thiery- Vuillemin Antoine , Flechon Aude , Sabbatini Roberto , Bellmunt Joaquim , Climent Miguel Angel , Chowdhury Simon , Dumez Herlinde , Matouskova Michaela , Penel Nicolas , Liutkauskiene Sigita , Stachurski Lech , Sternberg Cora N. , Baton Frederique , Germann Nathalie , Daugaard Gedske
Published: February 2017

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Background: TASQ is an oral immunomodulatory, antiangiogenic and antimetastatic agent that targets the tumor microenvironment. In a phase 2 trial in mCRPC, TASQ increased PFS in chemotherapy-naive pts vs placebo (PBO) (Pili et al. JCO 2011), but there was no OS benefit in a recent phase 3 trial (NCT01234311). This study assessed whether TASQ maintenance therapy improved disease control duration in mCRPC pts with response or stabilization on first-line docetaxel (NCT01732549). Methods: Pts with mCRPC not progressing after docetaxel (min. 6 cycles; RECIST criteria; no PSA rise for last 3 tests) were assigned (1:1) to receive within 6 wks of last docetaxel administration: oral TASQ qd (0.25 mg/d rising to 1.0 mg/d over 4 wks, if tolerated) or PBO, until progression or toxicity. Randomization was stratified by visceral metastases and opioid analgesic use. Primary endpoint: radiographic PFS (rPFS) per RECIST 1.1 and PCWG 2 criteria, assessed locally. Planned sample size: 140 pts to achieve 80% power to detect an rPFS hazard ratio (HR) of 0.588 with a 1-sided α error of 0.05. Secondary endpoints: other clinical outcome measures, OS and safety. Results: From Jan 2013 to Oct 2014, 144 pts were randomized (TASQ: n = 71; PBO: n = 73) at 44 sites in 11 countries. Baseline characteristics were similar in both groups – median age: 70 yrs; visceral metastases: 23%; ECOG PS 0–1: 97%; opioid use: 15%. Median follow up: 59 wks for TASQ; 53 wks for PBO. Median rPFS (locally assessed) was 31.7 wks [90% CI 24.3–53.7] with TASQ; 22.7 wks [90% CI 16.1–25.9] with PBO (HR 0.6 [90% CI 0.4–0.9]; p = 0.0162). OS data are immature (14 deaths). Median time to next anticancer therapy: 42.3 wks [90% CI 32.0–58.0] for TASQ; 29.0 wks [90% CI 23.1–39.1] for PBO (HR 0.7 [90% CI 0.5–1.0]). TEAEs ( ≥ Grade 3): TASQ (51%); PBO (26%). TEAEs with TASQ (all grades; > 20%): decreased appetite (37%), constipation (32%), fatigue (28%), nausea (27%), arthralgia (25%), asthenia (24%) and back pain (21%). Conclusions: We believe this is the first completed trial of a maintenance strategy with a novel agent in mCRPC, an appealing concept in pts not progressing after docetaxel therapy. Clinical trial information: NCT01732549.
Prognostic value of neutrophil-to-lymphocyte ratio (NLR) in metastatic castration-resistant prostate cancer (mCRPC) pts receiving a new agent (NA)-based third line treatment: Preliminary results from a multicenter Italian study.
Authors: Caffo Orazio , De Giorgi Ugo , Alesini Daniele , Fratino Lucia , Ortega Cinzia , Tucci Marcello , Scagliarini Sarah , Zagonel Vittorina , Zucali Paolo Andrea , Morelli Franco , Sartori Donata , Sabbatini Roberto , D'Angelo Alessandro , Donini Maddalena , Barni Sandro , Procopio Giuseppe , Sirotova Zuzana , Sava Teodoro , Conteduca Vincenza , Galligioni Enzo
Published: February 2017

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Background: The NLR is a marker of systemic inflammatory response: several studies investigated its prognostic relevance in mCRPC but to date no information is available concerning this issue in pts treated in third line therapy. The present study is aimed to assess the possible relationship between third line clinical outcome and NLR in a large series of mCRPC pts treated with a NA [abiraterone acetate (AA), cabazitaxel (CABA), or enzalutamide (ENZ)] after the failure of docetaxel (DOC) and another NA. Methods: We collected data of pts who received sequentially two NAs after DOC in 38 Italian hospitals. For each pt we recorded the clinical outcome of all treatments received after DOC. Cox regression analysis was used to assess the independent prognostic value of a series of pretreatment covariates, in terms of overall survival (OS), comprising NLR. Results: A consecutive series of 291 mCRPC pts with bone (88%), nodal (53%) or visceral (18%) mets, was collected. All pts received a NA-based third line: 90 received AA, 123 CABA and 78 ENZ. At the time of this analysis, data on NLR were available for 198 pts (68%): AA 68 (75%) – CABA 80 (65%) – ENZ 50 (64%): the median value was 3.1 (IQR 2.2-4.7). In the univariate analyses, the NLR as a discrete variable using the median value of 3.1 as threshold, was significantly associated with both OS and progression free survival (PFS), calculated from the third line start (p < 0.0001 and p = 0.001, respectively). No association was observed with either biochemical or objective response. These results were confirmed at the multivariate analysis. In Kaplan-Meier analysis, the median OS from the start of third-line was higher (18.2 vs 8.1 mos) in pts with NLR ≤ 3.1 compared to those with NLR > 3.1 (log-rank; P < 0.0001). Similarly, the median PFS was 6.3 and 3.5 in pts with NLR ≤ 3.1 and > 3.1, respectively. Conclusions: At the best of our knowledge, this is the first report on the NLR value in mCRPC third line treatment. From our preliminary data, it appears that NLR may be a prognostic and predictive factor in mCRPC pts, treated with NA-based third line.
Clinical and immunologic impact of short course enzalutamide without androgen deprivation therapy for biochemically recurrent prostate cancer.
Authors: Madan Ravi Amrit , Donahue Renee Nicole , Singh Harpreet , Karzai Fatima , Theoret Marc Robert , Heery Christopher Ryan , Strauss Julius , Harold Nancy , Couvillon Anna , Marte Jennifer L. , Hankin Amy , Grenga Italia , Chun Guinevere , Rosner Inger L. , McLeod David G. , Cordes Lisa M , Figg William Douglas , Dahut William L. , Schlom Jeffrey , Gulley James L.
Published: February 2017

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Background: Enzalutamide (enz) is FDA approved for advanced prostate cancer, but studies are evaluating enz in earlier stages of disease. We have conducted a clinical trial (NCT01875250) of enz ± a therapeutic vaccine in biochemically recurrent prostate cancer. Methods: Eligible patients (pts) had a PSA between 2.0-20.0 ng/ml, no metastatic disease and normal testosterone (T). Treatment for all pts included enz 160 mg daily for 84 days (D), but no T lowering therapy was permitted. This analysis evaluated all pts for the impact of enz on PSA and T regardless of randomization. Pts treated with Enz alone were evaluated for immune responses.The impact of the vaccine will be evaluated after protocol-defined requisite follow-up. Results: Median age for all pts (n = 34) was 66 years (range: 52-87), with a median on-study baseline PSA of 4.55 ng/ml (2.02-19.43). Common adverse events included fatigue and breast tenderness, but no pts discontinued enz for toxicity. The median PSA decline was 99% (range: 52% to > 99%) with 11/34 pts having undetectable nadirs. Median time to first PSA rise after 84 D course of enz was 29 D (13-70) and median recovery to baseline PSA in 25 evaluable pts was 190 D (84-469). T increased above normal limits in 18/34 pts (median Tmax = 802 ng/dl). Immune analysis (n = 12) indicated enz alone increased naïve T-cells and NK cells, and decreased several subsets of myeloid derived suppressor cells with a highly suppressive phenotype. Conclusions: The preliminary findings from this study suggest that short-course enz is well tolerated, leads to prolonged PSA suppression and enhanced immune responses in patients with biochemically recurrent prostate cancer. These immune studies provide the rationale for the use of enz in combination with immunotherapeutics in this and other malignancies. Clinical trial information: NCT01875250.
SOCS3 immunohistochemical expression to support the 2005 International Society of Urological Pathology (ISUP) modified Gleason grading system.
Authors: Petrone Gian Luigi , Pierconti Francesco , Martini Maurizio , Cenci Tonia , Larocca Luigi Maria
Published: February 2017

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Background: In the 2005 International Society of Urological Pathology (ISUP) Consensus Conference, a modified Gleason grading system for prostate cancer was proposed. (Epstein JI et al. Am J Surg Pathol 2005; 29:1228-1242) Afterwards an interobserver study among experts in genitourinary pathology proposed some modifications and refinements to the 2005 ISUP modified grading system concerning the cribriform pattern carcinoma that it should never be diagnosed as Gleason pattern 3, assigning Gleason pattern 4 to cribriform glands (Latour M et al. Am J Surg Pathol 2008; 32: 1532-1539; Epstein J I Journal of Urology 2010: 183:433-440). Methods: The study population consisted of 80 patients undergoing biopsies at the Institute of Urology of our hospital, between February 2012 and January 2013 stratified into 3 different categories on the basis of histologic pattern: 1) 20 patients with classical and modified Gleason score 3+3 = 6; 2) 30 patients with classical Gleason score 3+3 = 6 upgraded to Gleason score 7 according to the ISUP modified grading system; and 3) 30 patients with classical and modified Gleason score 3+4 = 7. We evaluate the immunohistochemical protein expression of the suppressor of cytokine signaling (SOCS) proteins 3 (SOCS3) in these three different group of prostatic cancer biopsies. Results: We found that the SOCS3 pattern staining negative (-) or with SOCS3 negative staining with weak intensity staining in less than 50% of neoplastic glands (+/-) increases progressively in concomitance with the rise of Gleason score and SOCS3 positivity (+), correlates with classical or modified Gleason score 6 (P = 0,0004 Fisher’s exact tests) and with classical Gleason score 3+3 = 6 upgraded to Gleason score 7 (P = 0,0010 Fisher’s exact tests). Conclusions: In conclusion our data seem to support from a molecular point of view the modified criteria by 2005 International Society of Urological Pathology (ISUP) Consensus Conference as well as the hypothesis that the diagnosis of Gleason cribriform pattern 3 virtually does not exist and cribriform glands-regardless of their size-are nearly always considered pattern 4.
Randomized phase II trial of docetaxel plus prednisolone with or without androgen deprivation treatment in castration-resistant prostate cancer.
Authors: Jeong Jae Ho , Hyun Hyejung , Jeong In Gab , Hong Jun Hyuk , Ahn Hanjong , Lee Jae-Lyun
Published: February 2017

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Background: Androgen deprivation therapy (ADT) has been the main treatment option for patients with locally advanced or metastatic prostate carcinoma. However, the impact of continued ADT on clinical outcomes in castration-resistant prostate cancer (CRPC) patients treated with cytotoxic chemotherapy is controversial. We conducted a randomized phase II study to assess the impact of continued ADT in patients with CRPC receiving docetaxel plus prednisolone chemotherapy. Methods: Patients with CRPC were randomly assigned (in a 1:1 ratio) to receive docetaxel (75mg/m2 every 3 weeks) plus prednisolone (5mg twice daily on days 1-21) with ADT (leuprolide 11.25 mg long-acting depo every 12 weeks, ADT group) and docetaxel plus prednisolone without ADT (No-ADT group). For patients in the No-ADT group, ADT was resumed at the end of chemotherapy. The primary endpoint was time to PSA progression. Secondary objectives included PSA response rates, progression-free survival (PFS), and overall survival (OS). Suspension of leuprolide support prevented the attainment of our original goal of enrolling 80 men. Results: Between April 2011 and July 2014, 45 patients were enrolled in this study; 23 patients were randomly assigned to the ADT group and 22 to the No-ADT group. The median age was 68 years (range = 49-81) and median baseline serum PSA was 60.3 ng/mL (interquartile range = 14.7-157.3). Time to PSA progression was 6.5 months in ADT group and 4.3 months in No-ADT group, respectively (P = 0.673). PSA response rates were 55.2% and 44.8% in the ADT group and the No-ADT group, respectively (P = 0.463). The median PFS and OS were 5.3 months and 19.4 months for ADT patients and 4.3 months and 20.8 months for No-ADT patients, respectively (P = 0.608, P = 0.635). The testosterone level rose to more than the castrate level in 5 (22.7%) patients of the No-ADT group. Conclusions: Clinical outcomes were not signiﬁcantly different when patients with CRPC received concurrent ADT, or were not so treated, when receiving docetaxel plus prednisolone chemotherapy. Clinical trial information: NCT01487902 Clinical trial information: NCT01487902.
ODM-204, a novel dual inhibitor of CYP17A1 and androgen receptor for the treatment of castration-resistant prostate cancer.
Authors: Kallio Pekka , Oksala Riikka , Moilanen Anu , Riikonen Reetta , Rummakko Petteri , Malmström Chira , Mustonen Mika VJ
Published: February 2017

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Background: Castration-resistant prostate cancer (CRPC) is characterized by high androgen receptor (AR) expression and persistent activation of AR signaling axis by residual tissue androgens. Inhibiting AR and androgen biosynthesis together may be more effective than inhibiting either alone to treat CRPC. ODM-204 is a potent, orally administered investigational non-steroidal dual inhibitor of CYP17A1 and AR. In vivo, ODM-204 shows favourable pharmacokinetic/ pharmacodynamics (PK/PD) properties in intact mature male monkeys and strong antitumor activity in VCaP xenograft. Methods: The inhibition of CYP17A1 by ODM-204 was studied by using human testicular microsomes and adrenal cortex cell line. Potency to human AR was demonstrated in cells stably transfected with the full-length AR and androgen-responsive reporter gene constructs. PK/PD relationships were evaluated in intact male mature monkeys after single and multiple doses of ODM-204 (10-30 mg/kg/day) by measuring plasma PK after several time points and serum testosterone (T), dehydroepiandrosterone (DHEA), luteinizing hormone (LH), aldosterone, and cortisol 5 hours after the daily dose. Efficacy was further studied in VCaP xenograft in intact male nude mice treated with ODM-204, enzalutamide (enza), abiraterone (abi), or enza+abi-combination for 28 days. Results: ODM-204 binds to AR with a high affinity (Ki47 nM) and selectivity, and has a high potency towards CYP17A1 (IC5022 nM). In intact monkeys, ODM-204 was well tolerated and showed good oral bioavailability with linear and dose proportional pharmacokinetics. Already after a single oral dose of ODM-204, serum T and DHEA were markedly suppressed. After multiple days of dosing, LH was increased, however, changes in cortisol and aldosterone were only minimal. In VCaP xenograft model, ODM-204 showed significant antitumor activity, better than single agent enza or abi, or their combination. Conclusions: ODM-204 is a novel, dual CYP17A1 and AR inhibitor for the treatment of CRPC. A clinical phase 1/2 dose-escalation trial (NCT02344017) is ongoing in patients with mCRPC to determine PK, PD, safety and anti-tumor activity of ODM-204.
Observation of CNS events in real-world use of enzalutamide (ENZ) and bicalutamide (BIC).
Authors: Behl Ajay , Ellis Lorie , Pilon Dominic , Lefebvre Patrick , Dawson Nancy Ann
Published: February 2017

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Background: TERRAIN, a randomized, double-blind, multi-center, phase II trial compared efficacy and safety of ENZ to BIC in men with mCRPC. Although ENZ and BIC fall within the same drug classification, rates of seizure and other central nervous system (CNS) events, observed in non-clinical trial populations have not been explored. The objective of this study was to compare rates of real world CNS events in patients treated with ENZ or BIC. Methods: Retrospective claims from Truven Health MarketScan database were used to identify patients with a PC diagnosis; ≥1 claim for ENZ or BIC (index date) after 9/1/2012; > 6 months of continuous eligibility prior to index date (baseline period) and no use of ENZ or BIC prior to index. Patients were followed until 12/2014 or loss to follow-up. Patients were excluded if they had a CNS condition or another cancer diagnosis during the baseline period. CNS conditions were defined as a diagnosis for amnesia or memory impairment, anxiety, ataxia, cognitive disorders, confusion, convulsions, disturbance in attention, dizziness, falls, fatigue/asthenia, hallucinations, headaches, insomnia, pain, paresthesia, seizures, weakness, or other CNS disorders. Kaplan-Meier (KM) survival curves were used to compare the KM rates of developing any CNS conditions between patients who initiated ENZ relative to patients who initiated BIC. A subgroup analysis of patients with metastatic disease was performed. Results: The table below compares the development of CNS conditions between ENZ and BIC patients. Conclusions: This study shows that rates of CNS events are significantly higher in patients initiating ENZ as compared to BIC, even when controlling for metastatic status. [Table: see text]
Effect of local therapy on the systemic anti-tumor response in prostate cancer.
Authors: Ross Ashley , Benzon Benjamin , Glavaris Stephanie , Simons Brian , Hughes Robert , Mullane Patrick , Miller Rebecca , Nugent Katriana , Shinder Brian , Blosser Richard , Tran Phuoc T. , Hurley Paula , Vuica-Ross Milena , Schaeffer Edward M. , Drake Charles G.
Published: February 2017

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Background: The genomic complexities and adaptability of aggressive cancer implies that it may only be eradicated by equally adaptable systems. Immune checkpoint blockade (such as that targeting PD−1 or CTLA−4) has shown dramatic and durable efficacy in immunogenic malignancies, but little or no benefit in less immunogenic cancers such as prostate cancer. Here we use a mouse model of prostate cancer to investigate whether local therapy can mount or augment an immune response to distant tumors. Methods: Immuno−competent FVB mice were bilaterally implanted with Myc−CAP cells to form isogenic grafts. Two weeks after tumor introduction, ablative therapies including radiation (stereotactically as a single 10 Gy fraction), cryoablation (two freeze−thaw cycles of less than −40 degree Celsius), whole tumor cauterization, or excision were applied to the larger graft in the presence of checkpoint blockade (intra−peritoneal anti−CTLA−4 or anti−PD1) or control injection (hamster anti−mouse IgG). Tumor sizes and mouse survival was recorded as was lymphocytic infiltrates which were characterized histologically and by flow cytometry. Results: Ablative therapies of cautery or cryoablation, but not excision or radiation caused a statistically significant delay in the growth of distant untreated tumors (P < 0.05 for both). Flow cytometric analysis demonstrated concurrent increases in the CD8+IFNgamma+ T cell population in the lymph nodes draining the untreated distant tumor. Flow also demonstrated an increase in CD4+FoxP3+ cells (P < 0.05 for each). Low dose anti−CTLA−4 therapy (1mg/kg) synergized with all local therapies to greatly increase survival and delay distant untreated tumor growth. This corresponded to an increase in activated T cells within distant tumors. Anti−PD−1 therapy did not synergize with local therapies. Conclusions: Some ablative local therapies (cautery, cryoablation) alone may incite an immune response in distant tumors. Checkpoint inhibition with low dose CTLA−4 blockade synergizes with all local therapies to incite a systemic anti−tumor response. PD−1 blockade has minimal effectiveness when combined with local therapies and may require combinatorial drug use for effectiveness in prostate cancer.
Characterization of plasma-derived and urinary exosomal microRNA from metastatic CRPC patients.
Authors: Ledet Elisa M. , Miller Patrick J. , Gambhira Ratish , Dotiwala Aryeneesh , Sartor A. Oliver
Published: February 2017

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Background: Exosomes are nano-sized (50-100nm) vesicles derived from normal and tumor cells that function in cell-cell communication. These vesicles and their nucleic acid cargo may potentially serve as biomarkers for assessment of risk stratification and therapeutic response. The goal of this study was to characterize exosome derived microRNA (miRNA) isolated from plasma (pExos) and urine (uExos) of metastatic CRPC patients. Methods: Plasma samples were obtained from 18 mCRPC patients and 1 normal control. Following exosome isolation, RNA extraction and library prep, paired-end sequencing was performed using Illumina Hi-Seq 2000. A bioinformatics pipeline was used for data processing including alignment, duplicate removal, normalization, and variant calling. Visualization and differential analyses were performed with SNP & Variation Suite v8.x. RNA derived from uExos was amplified using whole transcriptome amplification and interrogated with Prostate Cancer (PCa) miScript miRNA PCR Array. Results: Exosomes from both plasma and urine had similar amounts of miRNA/total RNA with average 34% miRNA (range 19%-51%). pExos had larger RNA fragments (range 10-333 nt) while uExos were more highly fragmented (range 10-60 nt). The amount of miRNA and fragmentation pattern was highly variable amongst patients. In pExos, RNA from PDPK1, USP9X, MAGI2, HMGA2 and PTGFR were present and previously shown in PCa. Also in pExos, miR941-2, miR4454, miR1302-2, miR143HG and miR22HG were annotated in prostate cancer patients; these miRNA have previously been identified in cancer. In uExos miR-16-5p and miR-375 were present and are shown to be differentially regulated in prostate cancer. Expression analyses will be presented. PCR validation is ongoing. Conclusions: The identification of cancer associated miRNA in pExos and uExos may potentially serve as biomarkers in mCRPC patients. The abundance and stability of miRNA contained in exosomes may provide insight into tumor evolution and disease progression. Additional studies evaluating the clinical relevance and prognostic value of exosomal miRNA are warranted.