bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic and phenotypic evidence for prostate cancer osteomimicry in circulating tumor cells from men with metastatic castration resistant prostate cancer (mCRPC) treated with radium-223.
Authors: Armstrong Andrew J. , Gupta Santosh , Healy Patrick , Kemeny Gabor , Leith Lauren Beth , Zalutsky Michael , Spritzer Charles , Davies Catrin , Ware Katie , Somarelli Jason , Wood Kris , Glover Wayne , Hsu Shiaowen David , Gerber Drew , Rothwell Colin , Mundy Kelly , Anand Monika , Gregory Simon , Halabi Susan , George Daniel J.
Published: February 2018

160

Background: Radium-223 is a targeted alpha therapy that improves survival in men with mCRPC. The biologic basis for radium-223 efficacy is not completely understood. We hypothesized that PC osteomimicry, a form of epithelial plasticity leading to an osteoblastic phenotype, may contribute to the intralesional deposition of radium-223 and subsequent irradiation of the tumor microenvironment. Methods: We conducted a pharmacodynamic study of radium-223 in men with bone predominant mCRPC to investigate genomic and phenotypic alterations in circulating tumor cells (CTCs), ctDNA, and metastases. Prior to radium and 3 and 6 months after radium, liquid and metastatic biopsies were collected, including CTCs for phenotypic characterization and CTC/ctDNA genomic analysis. The primary objective was to describe the prevalence of CTC bone alkaline phosphatase (BAP) over time. We measured radium-223 decay products in tumor and surrounding normal bone during treatment. Results: We enrolled 20 men with heavily pre-treated symptomatic bone predominant mCRPC and treated with radium-223 over a median of 6 doses. 55% had elevated serum BAP. PFS was 5.5 mo; OS was 13.3 mo; 10% had unfavorable (≥5) to favorable ( < 5) Cellsearch CTC conversion; 5% had ≥30% PSA decline. We found evidence of persistent CTC BAP expression in both EpCAM+ and EpCAM- CTCs in the majority of men over time during radium treatment. We identified genomic gain of key osteomimicry regions in CTC DNA, including loci for BAP, osteopontin, and OB-cadherin. Radium-223 uptake was observed in tumor to a greater degree than surrounding normal bone. CTC DNA and matched ctDNA and CTC cultures suggested persistence of CTCs with aggressive genomic alterations such as AR, FOXA1, and MYC gain and PTEN and RB1 loss. We established multiple CTC cultures and one CTC PDX; cells exhibited evidence of epithelial plasticity with BAP expression. Conclusions: Osteomimicry may contribute to the uptake of Radium-223 within bone metastases and may thereby enhance the therapeutic benefit of radium-223. We found genomic and phenotypic evidence of osteomimicry in CTCs and CTC cultures from men with mCRPC. Clinical trial information: NCT02204943.
SPARTAN, a phase 3 double-blind, randomized study of apalutamide (APA) versus placebo (PBO) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC).
Authors: Small Eric Jay , Saad Fred , Chowdhury Simon , Hadaschik Boris A. , Graff Julie Nicole , Olmos David , Mainwaring Paul N. , Uemura Hiroji , Lopez-Gitlitz Angela , Trudel Geralyn Carol , Espina Byron M. , Shu Youyi , Park Youn C. , Rackoff Wayne R. , Yu Margaret K. , Smith Matthew Raymond ,   On Behalf of the SPARTAN investigators
Published: February 2018

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Background: Pts with nmCRPC are at risk for developing metastatic disease and cancer-specific mortality. There are no approved treatments for nmCRPC. APA is an orally administered next-generation androgen receptor inhibitor with antitumor activity in CRPC. SPARTAN evaluated the effects of APA on metastasis-free survival (MFS) in men with nmCRPC. Methods: Pts with nmCRPC and prostate-specific antigen doubling time (PSADT) of ≤ 10 mos were randomized 2:1 to APA (240 mg QD) or PBO. The primary end point was MFS, defined as the time from randomization to first radiographic distant metastasis (per blinded central review) or death. Secondary end points included time to metastasis (TTM), progression-free survival (PFS), time to symptomatic progression (SymProg), and overall survival (OS). Pts were eligible to receive study-provided abiraterone acetate plus prednisone after developing distant metastases. Second progression-free survival (PFS2, the time from randomization to disease progression or death after first treatment for metastatic CRPC) was also evaluated. Results: 1207 pts were randomized. Baseline PSADT was < 5 mos in both groups. APA decreased the risk of distant metastasis or death by 72% (HR = 0.28; 95% CI, 0.23-0.35; p < 0.0001), with a median MFS of 40.5 vs 16.2 mos in the PBO group. Secondary end points (TTM, PFS, and SymProg) were all significantly improved. At an interim analysis for OS, there was a trend favoring APA. At a median follow-up of 20.3 mos, 61% of APA and 30% of PBO pts were still on treatment. Rates of discontinuation due to adverse events were low in both groups (10.7% APA, 6.3% PBO). Mean baseline health-related quality of life scores were maintained with treatment, with no difference between groups over time. Of those whose disease progressed, 80% of PBO and 56% of APA pts received therapy for metastatic CRPC. PFS2 was significantly longer for APA vs PBO. Conclusions: APA significantly improved median MFS by 2 years in men with nmCRPC. APA also significantly increased TTM, PFS, SymProg, and PFS2. APA was associated with improved OS. These results support the addition of APA to androgen deprivation therapy in men with nmCRPC. Clinical trial information: NCT01946204.
Addition of docetaxel to first-line long-term hormone therapy in prostate cancer (STAMPEDE): Long-term survival, quality-adjusted survival, and cost-effectiveness analysis.
Authors: James Nicholas , Woods Beth , Sideris Eleftherios , Spears Melissa Ruth , Dearnaley David P. , Mason Malcolm , Clarke Noel , Parmar Mahesh K B , Sydes Matthew Robert , Sculpher Mark ,   STAMPEDE Investigators
Published: February 2018

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Background: Results from large randomised controlled trials have shown that adding docetaxel to standard of care (SOC) in men initiating hormone therapy for prostate cancer prolongs survival for those with metastatic disease and prolongs time to treatment failure for those without metastatic disease. We report on the impact of docetaxel on health related quality of life (HRQoL), resource use and cost-effectiveness for men treated in the STAMPEDE trial. Methods: Health outcomes and costs in the UK NHS were modelled using EuroQol (EQ-5D)and resource use data collected within the STAMPEDE trial (STAMPEDE enrolled men advanced prostate cancer starting first line hormone therapy. SOC was hormone therapy for ≥2 years and radiotherapy in some patients. Docetaxel (75 mg/m2) was administered alongside SOC for six 3-weekly cycles with prednisolone 10 mg daily. Lifetime predictions of costs, changes in predicted survival duration, quality adjusted life years (QALYs), and incremental cost effectiveness ratios (ICERs) were calculated. Results: Compared to patients allocated SOC, docetaxel was estimated to extend predicted survival by an average of 0.89 years for M1 patients and 0.78 years for M0 patients. Docetaxel was estimated to extend discounted QALYs by 0.51 years in M1 patients and 0.39 years in M0 patients. QALY gains in M0 patients were driven by the beneficial effect of delayed and reduced relapse. Docetaxel was cost-effective both in M1 patients (ICER = £5,514/QALY vs. SOC) and M0 patients (higher QALYs, lower costs vs. SOC). The probabilistic sensitivity analysis indicated a very high probability ( > 99%) that docetaxel is cost-effective in both M0 and M1 patients. Docetaxel remained cost effective in M0 patients even when no survival advantage was assumed due to reductions and delays in relapse. Conclusions: Docetaxel improves overall HRQoL, delays time to, and reduces the need for, subsequent therapy, and is cost-effective, amongst patients with both non-metastatic and metastatic disease. Clinicians should consider whether the evidence is now sufficiently compelling to support docetaxel use in non-metastatic patients. Clinical trial information: ISRCTN78818544.
Comparative assessment of abiraterone or enzalutamide activity in the PROREPAIR-B study.
Authors: Lozano Rebeca , Romero-Laorden Nuria , del Pozo Angela , Medina Ana , Mendez Maria Jose , Morales Barrera Rafael , Gonzalez del Alba Aranzazu Aranzazu , Rodriguez-Vida Alejo , Hernandez Amaia , Silla-Castro Juan Carlos , Vazquez Sergio , Gonzalez Belen , Pinto Alvaro , Perez Gracia Jose Luis , Querol Rosa , Cañadilla Vanessa , Domenech Montserrat , Pritchard Colin , Castro Elena , Olmos David
Published: February 2018

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Background: Germline mutations in DNA repair genes have been associated with poor prostate cancer outcomes in retrospectives studies. Such defects have been identified in 12% of mCRPC patients. Several studies are ongoing to assess the benefit of these patients from platinum-based chemotherapy and PARP inhibitors, but no conclusive data are available with regards to currently approved therapies for mCRPC, as Abiraterone or Enzalutamide. Methods: PROREPAIR-B (NCT03075735) is a prospective multicentre observational cohort study. Patients diagnosed with mCRPC, with unknown mutational status at study entry and who were going to start a first-line treatment for mCRPC were eligible. For this sub-analysis patients who received Abiraterone or Enzalutamide as first androgen receptor targeted therapy (ART) were selected. The endpoints of this sub-analysis included to assess the impact of BRCA1, BRCA2, ATM, PALB2 and other germline mutations in DNA repair genes on cause-specific survival (CSS), progression-free survival (PFS), time to PSA progression (bPFS) and response to the first ART received as 1st or 2nd line therapy. Results: 337 patients were eligible for this analysis. CSS from mCRPC was not significantly different between gDDR carriers and non-carriers. However, CSS from mCRPC in BRCA2 carriers was significantly shorter than in non-carriers (23.3 Vs 34.6 months, p = 0.02). CSS from first ART, PFS and response-rates were not significantly different between both groups. However, the bPFS was significantly shorter in patients harbouring gDDR mutations (7.3 Vs 3.8 months, p = 0.04), especially in BRCA2 carriers (7.3 Vs 3.0 months, p = 0.03). Conclusions: This is the first study to prospectively follow-up DNA repair germline mutations to determine the outcome on standard treatment for mCRPC. The results suggest that different gDDR defects may have different impact on mCRPC outcomes. Clinical trial information: NCT03075735.
Incidence and severity of prostate cancer (PCa) in 792 hypogonadal men with and without long-term testosterone therapy (TTh): Results from a controlled registry study.
Authors: Haider Ahmad , Haider Karim Sultan
Published: February 2018

167

Background: There is no evidence that TTh in hypogonadal men increases PCa incidence or severity. A US-Scandinavian group recently found that men receiving TTh had lower risk of aggressive PCa (Loeb S et al., J Clin Oncol 2017; 35:1430-6). Methods: 412 men with testosterone ≤350 ng/dL and symptoms received testosterone undecanoate 1000 mg every 3 months for up to 12 years. 380 hypogonadal men (57-74) opted against TTh. Median follow-up: 9 years. Total observation time covered approximately 6,400 patient-years. Prostate volume (PV) and PSA were measured and digital rectal examination/transrectal ultrasound performed before treatment/observation initiation and then every 3-6 months (T-group) or once or twice per year (CTRL). Biopsies were performed when indicated according to EAU guidelines. Results: In the T-group, 11 men (2.7%) were diagnosed with PCa. In CTRL, 34 (8.9%) were diagnosed with PCa. The incidence per 10,000 years was 33 in the T-group and 108 in CTRL. The mean baseline age of PCa patients was 65.2 years in the T-group and 64.3 in CTRL. All PCa diagnoses in the T-group were made within the first 18 months of treatment initiation. In CTRL, PCa was diagnosed at any time during the observation time. In the T-group, radical prostatectomy was performed in all men. All but 1 patient had a Gleason score (GS) ≤6, and all but 1 a predominant GS of 3. Tumor grade was G2 in all 11 (100%), tumor stage T2a in 7 (64%), T2b in 3 (27%), and T2c in 1 (9%) patient(s). In CTRL, radical prostatectomy was performed in all but 6 patients. GS was > 6 in all 34 patients. 7 men had a GS of 7, 17 a GS of 8, and 10 a GS of 9. 2 men had a predominant Gleason score of 3, 22 had 4, and 10 had 5. Tumor grade was G2 in 6 (17.6%) and G3 in 28 (82.4%) patients, tumor stage T2c in 1 (0.3%), T3a in 3 (8.8%), T3b in 13 (38.2%) and T3c in 17 (50%) patients. In CTRL, biochemical recurrence occurred in 8 (23.5%) patients. These patients received androgen deprivation therapy (ADT). 10 (29.4%) patients died of whom 5 were on ADT. In the T-group, there were no biochemical recurrences or deaths during the observation time. Conclusions: In hypogonadal men, TTh may decrease PCa incidence compared to CTRL. PCa was less severe in the T-group.
Glypican-1 as a novel immunotherapeutic target in prostate cancer.
Authors: Zaslavsky Alexander , Adams Mackenzie , Wissmueller Sandra , Campbell Douglas , Klingemann Hans , Walsh Brad , Palapattu Ganesh S.
Published: February 2018

174

Background: New effective therapies for men with prostate cancer are desperately needed. Recently, cancer immunotherapy has emerged as an important new treatment strategy for prostate cancer and for castrate resistant prostate cancer (CRPC). Multiple studies have identified the heparan sulfate proteoglycan-1 Glypican 1 (GPC-1) as being overexpressed in different cancers, and also as being a possible marker of poor prognosis in several solid tumor cancers. GPC-1 has been recently identified as a potential marker for prostate cancer. The MIL-38 monoclonal antibody detects GPC-1 and an IgG1 chimeric version of this antibody has been developed for preclinical studies. Here we sought to examine MIL-38 binding to a panel of prostate cancer cell lines and examine its feasibility as a novel immunotherapeutic agent targeting GPC-1 in prostate cancer Methods: Expression of GPC-1 in CRPC cell lines was examined by Flow cytometry and Western Blotting using MIL-38 as the detector antibody. The competency of GPC-1 as an immunotherapeutic target was assessed via chimeric MIL-38 induced Antibody Dependent Cell Cytotoxicity (ADCC) using high affinity Natural Killer cells (haNKs) in vitro . Results: Flow cytometry and Western blot assessments of normal prostatic epithelial cells (i.e. RWPE-1) and cells from prostate cancer cell lines (i.e. PC-3, 22RV1, DU-145, VCaP, LNCaP, CWR-R1, and LAPC-4) revealed that only cancer cells expressed GPC-1. Enzalutamide resistant cell lines demonstrated higher expression of GPC-1 than their respective parental line. ADCC assays demonstrated enhanced haNK – prostate cancer cell cytotoxicity in the presence of chimeric MIL-38 anti-GPC-1 antibody, while the IgG1 isotype control had no effect. Conclusions: GPC-1 protein was expressed by most prostate cancer cell lines, including enhanced expression by enzalutamide resistant cells. Preliminary in vitro ADCC assay results revealed the potential utility of GPC-1 as an immunotherapeutic target in prostate cancer.
Extended radical prostatectomy following neoadjuvant chemohormononal therapy (low dose estrmustine + LHRH agonist/antagonist) contributes to good cancer control for patients with high risk localized prostate cancer.
Authors: Enokida Hideki , Yoshino Hirofumi , Nakagawa Masayuki
Published: February 2018

185

Background: Patients with high-risk prostate cancer (PCa) according to D’Amico risk categories are prone to a pathological diagnosis of positive margins or lymph node invasion and biochemical recurrence, despite having undergone radical prostatectomy (RP). Therefore, it is controversial whether RP should be done for high risk PC patients. Methods: 87 high-risk PCa patients prospectively underwent ‘extended’ RP following neoadjuvant chemohormonal therapy (NAC); primarily 6 months of estramustine phosphate 280 mg bid, along with a LH-RH agonist/antagonist. Our surgical technique was developed to reduce the rates of positive surgical margins. The goal is to approach the muscle layer of the rectum by dissecting the mesorectal fascia and continuing the dissection through the mesorectum until the muscle layer of the rectum is exposed. The procedure was safely performed as a result of good recognition of the structure between the perineal body and the rectal surface. We also performed extended lymphadenectomy if the patients meet two or more of D’Amico risk categories Results: More than 1 year had elapsed after surgery in 69 of the 87 patients with the median follow-up period of 36.2 months. Among those 69 patients, 18 (26.1%) experienced PSA failure. Kaplan-Meier analyses revealed that significant poorer PSA progression-free survival were observed in patients with higher positive biopsy core ratio, lymph node metastasis, and higher pathological stage (pT3a/b). Multivariate Cox-regression analysis revealed that higher pathological stage (pT3a/b) was the only independent valuable for predicting PSA progression failure. These 18 cases received salvage androgen deprivation therapy followed-by external beam radiotherapy and showed no progression after the salvage therapies (median follow-up period, 34.6 months after PSA progression). Conclusions: NAC concordant with extended RP is feasible and contributes to negative surgical margins that might provide good cancer control for patients with high-risk PCa.
Efficacy of ferumoxytol as a lymphatic contrast agent in prostate cancer.
Authors: Dattoli Michael J. , Bravo Stephen M , Kaplon Daniel , Hayes Matt , Osorio Alexandria , Dycus Patricia M , Bostwick David G. , Kaminski Joseph
Published: February 2018

186

Background: Ferumoxytol (Feraheme) is a ferromagnetic nanoparticle with lymphotrophic biokinetics, delivered to lymph nodes by normal macrophages. MRI suppresses normal lymph nodes containing Feraheme. Objective is to validate safety and efficacy in finding lymph node positivity in prostate cancer (PCa). Methods: Nonrandomized prospective evaluation of 178 consecutive PCa patients (pts) at high risk for lymph node spread enrolled 2/13-3/15. All received IV Feraheme. 177 received 6/mg/kg over 20 min. One pt received 3 mg/kg infusion. T2 MEDIC and T2* sequence imaging of abdomen and pelvis, given 24 hours later. Images reviewed by 2 board certified radiologists with same interpretations, blinded to clinical and histo-path info (pre-MRI TNM stage/PSA/Gleason). Nodes were deemed abnormal if they did not suppress after Feraheme infusion (group 1, 94 patients). Nodes were deemed suspicious if suppressed and met usual size criteria with high signal intensity on DWI and decreased ADC map values and morphologic features (group 2, 84 pts). 83 group 1 pts had CT biopsies (77 pelvis, 6 retroperitoneum);11 pts had open PLND. 382 lymph nodes sampled. 76 group 2 patients had CT biopsies (73 pelvis, 3 retroperitoneum); 9 pts had open PLND. 340 lymph nodes sampled. Rad-path correlation was performed. Nodes were stained; reviewed by a single pathologist with no knowledge of MRI findings. Histo-path results for each node were cataloged for later MRI comparison. Results: 90 group 1 pts (96%) proved metastatic PCa; 4 pts (4%) were normal. 68 group 1 pts (77%) had malignant lymph nodes not meeting usual imaging criteria. 39 group 2 pts (47%) showed metastatic PCa; 46 pts (53%) were normal. One group 2 pt had an allergic reaction with hives; infusion ceased at 3mg/kg; pt treated to full resolution with 50 mg IV Benadryl. Conclusions: Feraheme can evaluate lymphatic dissemination of metastatic disease in PCa patients, with a lower limit of resolution of focal lymph node metastases of 2-3 mm. Better resolution gives implications for therapeutic radiation planning of newly diagnosed or recurrent/metastatic PCa. Toxicity was very acceptable at 6mg/kg. Feraheme may play a significant role as a lymphatic contrast agent in the early dissemination of lymphatic metastatic disease.
Local ablative radiotherapy: A means to revert low volume castration-resistant prostate cancer into a hormone-sensitive status?
Authors: HÃ¶lscher Tobias , Lohaus Fabian , Zoephel Klaus , Wirth Manfred , Baumann Michael , Troost Esther
Published: February 2018

188

Background: (Stereotactic) Ablative radiotherapy (aRT) in patients with oligometastatic prostate cancer is safe, achieves high local control rates and its clinical benefit is currently being addressed in clinical trials. However, the selection of patients benefitting most from aRT remains unclear. Moreover, the highly specific and sensitive multimodality functional imaging modality, 68Ga-PSMA-PET-CT/-MR, is widely available. Therefore, we retrospectively evaluated the efficacy of PSMA-PET guided local aRT in low volume oligometastatic castration resistant prostate cancer (CRPC) patients. Methods: Fifteen patients with metachronous oligometastatic CRPC as diagnosed on PSMA-PET were treated with local aRT. Nine patients were treated with a conventionally fractionated regime (25 x 2 Gy) and six with stereotactic hypofractionated RT (3 x 10 Gy), while in all androgen deprivation was continued. The time to PSA-progression, i.e. PSA-nadir + 2 ng/ml (PSA+2) was estimated with the Kaplan-Meier method and compared to an individually estimated time to PSA+2 according to the individually calculated pre-RT PSA doubling time (PSA-DT). Results: At staging PSMA-PET, the median PSA was 3.4 ng/ml (range 1.3 -14.5) and the median PSA-DT was 3.2 months (range 0.6 - 15.3). In four patients no PSA-response after aRT was observed. The responding eleven patients (73%) had a mean decrease in PSA-level of 80% from baseline. The mean time to PSA-nadir was 10.7 months (range 4.5 - 11.5). The mean time to PSA+2 or last follow-up was 15.6 months [95%CI: 9.7 - 21.4] compared to 3.3 months [95%CI: 1.5 - 5.1] estimated PSA-DT without local aRT (p < 0.001). Conclusions: A relevant subset of patients with 68Ga PSMA-PET-detected oligometastatic low volume CRPC had a meaningful PSA-response with aRT. They were reverted into an earlier stage of their disease again. A prospective clinical trial on this clinically highly relevant question is being prepared.
Niclosamide in combination with abiraterone and prednisone in men with castration-resistant prostate cancer (CRPC): initial results from a phase Ib/II trial.
Authors: Pan Chong-xian , Lara Primo , Evans Christopher P. , Parikh Mamta , Dall'era Marc , Liu Chengfei , Robles Daniel , Gao Allen
Published: February 2018

192

Background: Prostate cancer is driven by androgen receptor (AR) signaling. The variant AR-V7 lacks the ligand binding domain, constitutively activates the AR pathway, and confers resistance to Abiraterone (Abi) and enzalutamide (Enza). We discovered that the anti-helminthic drug niclosamide targets AR-V7 and sensitizes resistant CRPC to Enza and Abi. We hypothesize that niclosamide/PDMX1001 potentiates the efficacy of Abi against CRPC. Here we report the initial results of this ongoing investigator-initiated phase Ib/II trial. Methods: Eligible patients (pts) have progressive CRPC with serum testosterone < 50 ng/dl. No prior Abi was allowed. In the Phase Ib cohort, pts received Abi 1000 mg PO qd, prednisone 5 mg PO bid, with intrapatient dose-escalation of niclosamide/PDMX1001 from 400 mg PO bid to 1600 mg PO tid. Trough niclosamide/PDMX1001 levels were measured. The Phase II cohort will enroll 27 patients with detectable AR-V7 in the peripheral blood. Co-primary endpoints include toxicity and response as determined by the Prostate Cancer Working Group 2 criteria. Results: Of 6 pts (age 74-83) in the Phase Ib cohort, five pts tolerated a niclosamide/PDMX1001 dose of 1,600 mg po tid without dose limiting toxicity; per protocol, this is the recommended Phase II dose. Niclosamide/PDMX1001 trough level was 0.305 and 0.496 µM in the two pts analyzed thus far, higher than the target level of 0.1µM required for anti-cancer activity. Of 6 pts, two pts achieved complete PSA response ( < 0.01 ng/ml), compared to historical control 0/30 pts treated with Abi alone; two with partial PSA response (≥50% decrease). Of the remaining two pts, one was prematurely taken off from the study after one cycle because of rising PSA, and the other had PSA decrease of 17.1%, but biopsy of the only enlarged lymph node showed all necrotic tissue. The only toxicity was Grade 1 nausea and diarrhea. The Phase II cohort will now enroll. Molecular correlative studies will be presented. Conclusions: The combination of niclosamide/PDMX1001, Abi and prednisone is well tolerated with promising safety and efficacy data. Targeted serum trough levels of niclosamide are clinically achievable. Clinical trial information: NCT02807805.
Visceral metastases on abiraterone vs. placebo: A post-hoc analysis of mode of radiographic progression in COU-AA-302.
Authors: Teply Benjamin A. , Qiu Fang , Antonarakis Emmanuel S. , Carducci Michael Anthony , Denmeade Samuel R.
Published: February 2018

194

Background: Abiraterone prolongs survival in patients with prostate cancer due to its potent inhibition of androgen synthesis. We previously observed increased rates of visceral metastatic disease at the time of progression on abiraterone compared to baseline, a poor prognostic feature associated with non-AR dependent prostate cancer. We hypothesized that the rate of development of visceral disease was increased with abiraterone compared to other treatments without potent androgen signaling inhibition. In order to test this, we examined time to visceral disease among patients treated with abiraterone vs placebo on the COU-AA-302 trial. Methods: We performed a post-hoc analysis of radiographic progression data for the phase 3 study of abiraterone vs placebo, via a data sharing agreement through the Yale Open Data Access Project. Data were censored at end of study treatment. The distribution of cumulative incidence for visceral metastases was calculated by the Kaplan-Meier method and compared with log-rank testing. Multivariable cox regression analysis was performed to assess for independent association of study treatment (abiraterone vs placebo) with the development of visceral metastases. Results: Median follow-up was 12.5mo, and 84 of 1088 patients developed visceral metastases. Univariate log-rank testing showed no difference in time to visceral metastasis between groups (p = 0.97). 1- and 3-yr cumulative incidence of visceral metastases were estimated at 6.4% and 15.6% for abiraterone and 4.6% and 17.0% for placebo, respectively. Study treatment was not a significant predictor for the development of visceral metastasis (HR 0.76; 95% CI 0.47-1.21) after adjustment for baseline metastatic disease burden (soft tissue and bone) and LDH. Conclusions: Abiraterone was not associated with increased visceral metastases at progression compared to placebo. These data give more confidence to oncologists that abiraterone is not driving prostate cancer to an aggressive phenotype characterized by visceral metastases - a finding that is particularly important as abiraterone is increasingly used in early disease states.
Indirect treatment comparison (ITC) of abiraterone acetate (AA) plus prednisone (P) and docetaxel (DOC) on patient-reported outcomes (PROs) in metastatic castration-naïve prostate cancer (mCNPC).
Authors: Feyerabend Susan , Saad Fred , Li Tracy , Ito Tetsuro , Diels Joris , Van Sanden Suzy , De Porre Peter , Abogunrin Seye , Koufopoulou Maria , Fizazi Karim
Published: February 2018

200

Background: AA + P added to androgen deprivation therapy (ADT) improved overall survival among newly diagnosed mCNPC patients (pts) with high-risk disease (HRD) vs placebos (PBOs) + ADT in the phase 3 LATITUDE study. Although ADT with or without chemotherapy is recommended in clinical guidelines as the mainstay of management for mCNPC, adding DOC to ADT does not consistently improve health-related quality of life (HRQoL). We performed an ITC to understand the relative impact of AA + P vs DOC on PROs in mCNPC pts. Methods: PROs were assessed using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) and Brief Pain Inventory (BPI). Mean change from baseline (BL) was based on differences in FACT-P and BPI scores between active vs control arms in LATITUDE (intention-to-treat [ITT] population) and CHAARTED (available data included mCNPC pts with high-volume disease [HVD] and low-volume disease [LVD]). Higher FACT-P score indicates better outcome/function; lower BPI score indicates better outcome/less pain. The probability of AA + P being better than DOC at 3, 6, 9, and 12 mos after treatment was based on fixed-effects Bayesian network meta-analysis. Results: Benefits in PROs with AA + P vs DOC were observed from 3 mos and sustained at least 1 year after treatment. Bayesian probability of AA + P being the better treatment for PROs ranged from 92.3% to 100%. Conclusions: Results from a Bayesian ITC suggest that AA + P was superior to DOC in improving PROs for at least 1 year after initiating treatment in men with mCNPC. In the absence of head-to-head trials, these analyses can provide useful insights on the relative impact of treatment options on HRQoL in mCNPC pts. Clinical trial information: NCT01715285. [Table: see text]
Impact of new systemic therapies on overall survival (OS) of patients (pts) with metastatic castration resistant prostate cancer (mCRPC) in a hospital-based registry.
Authors: Francini Edoardo , Gray Kathryn P. , Shaw Grace , Evan Carolyn , Hamid Anis , Perry Caitlin E , Kantoff Philip W. , Taplin Mary-Ellen , Sweeney Christopher
Published: February 2018

203

Background: From 2004 to 2009, mCRPC treatment options were limited to docetaxel (D), mitoxantrone, first generation anti-androgens (AA), estrogens, steroids, and ketoconazole, with only D showing OS benefit. Since 2010, five new therapies prolonged OS and were approved for mCRPC: sipuleucel-T, cabazitaxel, abiraterone acetate, enzalutamide, and radium 223. We sought to assess the aggregate impact of new therapies on OS. Methods: We used the DFCI CRIS database to identify cohorts of pts who developed mCRPC between 2004-2007 (cohort A) and 2010-2013 (cohort B). Therapies for mCRPC in each cohort were annotated. Given the median follow-up (FU) was 10.6 years (yrs) in cohort A and 4.6 yrs in cohort B, we evaluated OS, defined as time from mCRPC per PCWG3 criteria to death from all causes or last follow-up visit within 5 yrs (truncated OS). Kaplan-Meier method estimated the time to events distribution with median (95% CI). Cox proportional hazards model evaluated effects of treatment groups on disease outcomes with estimates of hazard ratio (95% CI). Results: Of the 583 pts identified, 317 (54%) were in cohort A and 266 (46%) in cohort B. Pts in cohort B had a significantly longer median OS (p<0.001), a 5-yr OS of 26% vs. 10%, and a 31% reduced risk of death compared to cohort A (HR=0.69; 95% CI, 0.57-0.83) (see Table). On multivariable analysis, adjusting for prior local Rx, ECOG PS, and the number of agents received, longer OS is confirmed associated with cohort B vs. A and also with ECOG PS status 0 vs. 1, number of agents received 5-12 vs. ≤3. Conclusions: Using the DFCI prostate cancer database, therapies approved for mCRPC since 2010 showed a modest impact on OS, with a median improvement of 6 months. There was a more substantial effect on long term survivors with 2.6 fold increase of 5-yr OS. [Table: see text]
Onset and maintenance of testosterone suppression in four pivotal trials of subcutaneously administered leuprolide acetate formulated with in-situ forming polymeric delivery technology.
Authors: Twardowski Przemyslaw , McLane John A. , Atkinson Stuart , Boldt-Houle Debbie , Sartor A. Oliver
Published: February 2018

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Background: Subcutaneously administered leuprolide acetate (SC-LA) formulated with in-situ forming polymeric delivery technology has demonstrated efficacy in suppressing testosterone (T) levels to achieve and maintain medical castration in patients with advanced prostate cancer (PCa). Increasing evidence suggests that reaching and sustaining the lowest T possible is desirable and correlated with disease specific survival. Data was pooled from four pivotal trials to determine the onset and maintenance of T levels at or lower than castration with SC-LA treatment. Methods: Eugonadal PCa patients received either 7.5 (6 doses), 22.5, 30, 45 mg (2 doses each) injections of SC-LA lasting 1, 3, 4, or 6 months, respectively, in 4 open-label, fixed-dose, pivotal trials. Serum T levels were assessed at screening, baseline (Day 0), and at least once per week throughout the studies. Target T levels were 50, 20, and 10ng/dL. The time when T crossed target level was extrapolated using the following formula: (target T – post-target T) / (pre-target T – post-target T) x (post-target date – pre-target date) = estimated days between crossing target T and post-target measurement Results: In the pooled population (N=437), median onset of T ≤50, ≤20, and ≤10ng/dL were 21 days, 28 days, and 35 days, respectively. Once the target T level was achieved, the mean proportion of time that patients maintained T suppression below each target level was 100% for T≤50 ng/dL, 94-99% for T≤20ng/dL, and 66-85% for T≤10ng/dL (Table). Conclusions: SC-LA achieved rapid onset of T≤50ng/dL in 3 weeks, T≤20ng/dL in 4 weeks, and T≤10ng/dL in 5 weeks. SC-LA maintained consistently low T levels, with over 66%, 95%, and 100% of the treatment period remaining below 10, 20, and 50 ng/dL respectively. This T suppression profile may have relevance for improved patient survival and extended time to disease progression. [Table: see text]
Safety and efficacy of abiraterone acetate (AA) in patients aged 75 or more with metastatic castration-resistant prostate cancer (mCRPC) in both pre-chemotherapy or post-chemotherapy settings: Real-life experience from thirteen Italian centers.
Authors: Sirotova Zuzana , Courthod Giulia , Tartarone Alfredo , Caffo Orazio , Maines Francesca , Bertuccelli Maurizio , Morelli Franco , Numico Gianmauro , Guglielmini Pamela , Fornarini Giuseppe , Prati Veronica , Palesandro Erica , Ortega Cinzia , Mosca Alessandra , Miraglia Stefania , Perrone Valentina , Fea Elena , Allegrini Giacomo , Mozzicafreddo Alessandro , Schena Marina
Published: February 2018

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Background: Prostate cancer affects mainly elderly patients (pts) that have different comorbidities. AA is a selective androgen synthesis inhibitor that showed the efficacy in either chemotherapy (CT) naive pts or those pretreated with docetaxel. Its oral administration and good tolerability make it a manegeable treatment for elderly mCRPC pts. Methods: We collected retrospectively data regarding mCRPC pts aged ≥75 years treated with AA in 13 Italian Centers since April 2013. The median age was 79 years (r. 75-90) with 48% of pts being octagerians. Post CT pts had more extensive disease, higher baseline PSA and ECOG PS. Nearly all the pts had comorbidities, the most frequent being hypertension present in 146 pts (58%), 43 pts (17%) had diabetes type II. We evaluated duration of the AA treatment, overall response rate (ORR), 50% PSA decline, time to progression (TTP) and overall survival (OS). We reported all toxicities observed. Results: A total of 252 pts ,147 pre treated with docetaxel and 105 chemo naive, were included. Median duration of treatment with AA was 8,6 months in post CT and 11,5 in CT naive pts. ORR was 35,3% in pre docetaxel and 27,4% in post docetaxel group. 64 pts (65%) and 51 pts (46%) obtained 50% PSA reduction in pre and post docetaxel group, respectively. Median TTP was 8,6 in post docetaxel and 11,9 in CT naive pts. We observed a median OS of 13,8 months in post CT group while for CT naive pts data were not yet mature. AA was well tolerated with only 8 pts (3,2%) who discontinued treatment due to toxicity, while in 4 pts (1,6%) temporary dose reductions were performed. The most frequent G3 toxicities were hypertension and liver toxicity with 4 pts (1,6%) and 5 pts (2%), respectively. After progressing on AA, 85 pts (34%) received at least one subsequent treatment. 40 pts (15,9%) are still on treatment with AA. Conclusions: Even if almost all the pts reported comorbidities at AA start and 72 pts (28,6%) had PS ECOG 2, only a small proportion of them discontinued the treatment due to toxicity confirming that AA is well tolerated and efficient treatment also for elderly patients.
Functional outcome and quality of life in patients undergoing salvage radical prostatectomy (SRPE).
Authors: Pfister David , Pullankavumkal Jasmin , Haidl Friederike , Zugor Vahudin , Kohl Tobias , Porres-Knoblauch Daniel , Heidenreich Axel
Published: February 2018

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Background: Salvage radical prostatectomy is one option for patients with locally recurrent disease with proven long term oncologic control. There are concerns about worse functional results due to fibrotic tissue after radiotherapy and patients are treated with palliative systemic androgendreptivation. We retrospectively analyzed continence and quality of life in patients undergoing SRPE. Methods: After biopsy proven local recurrent prostate cancer 138 patients were offered SRPE and extended lymphadenectomy. Continence and quality of life had been collected before 6 and 12 months after surgery. Validated questionaires with ICIQ and EORTC qlq 30 had been used. Results: Präoperatively at 6 monts and 12 months the feed back was available in 93, 84 and 82 patients respectively. Präoperatively there was no or mild incontinence in 38(40.8%), moderate in 33 (35.5%) and strong incontinence in 22 (23.7%) of the patients. There is a significant decrease in the rate of continence after 6 and 12 months to no or mild in 19 (23.1%), moderate in 19 (23.2%) and strong incontinence in 44 (53.7%) of the patients. In 5 patients an artifitial sphinkter was implanted. Quality of life did not change significantly before and 12 months after surgery. Median value of Question 30 was 6 and five respectively. Conclusions: Patients need to be informed about a worse functional outcome and the potential need for further surgical interventions as artificial sphinkter implantion compared to primary radical prostatectomy. Quality of life seems to be affected only moderatly. Nevertheless there is already a rather high rate of any incontinence before surgery that needs to be taken into account.
68-Ga-PSMA-PET in the diagnosis of local recurrent disease after radiotherapy in patients with prostate cancer.
Authors: Pfister David , Schmidt Matthias , Kohl Tobias , Porres-Knoblauch Daniel , Heidenreich Axel
Published: February 2018

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Background: For planning salvage procedures in recurrent prostate cancer accurate diagnostic tools are needed. Till now in patients suspicious for isolated local recurrent cancer invasive biopsy was needed. 68-Ga-PSMA-PET is frequently used to identify even small metastatic deposits. We analyzed the diagnostic value to identify local recurrence in patients after radiotherapy undergoing salvage radical prostatectomy, sRPE. Methods: We retrospectively reviewed patients undergoing sRPE with 68-Ga-PSMA-PET as preoperative staging. All patients underwent sRPE and extended lymph node dissection. Sensitivity, Specificity, pos and neg predictive value had been calculated per patient and per prostate lobe. Results: 37 patients with preoperative 68-Ga-PSMA-PEt could be identified. In all but one at least in one lobe PSMA staining could be identified. Mean tumor volume per prostate lobe was 6.22 (0.1-24)ml. Sensitivity, Specificity, neg and pos predictive value per lobe is 80%, 75%, 32% and 96%. Sensitivity to identify cancer recurrence per person irrespective of the side is 95% with a pos predictive value of 100%. Conclusions: 68-Ga-PSMA-PET seems to have a very high diagnistic value to identify local recurrence after radiotherapy. After validation of our experience an invasive biopsy to proof cancer recurrence might be spared.
Myeloid and plasmacytoid dendritic cell vaccinations for castration-resistant prostate cancer patients.
Authors: Westdorp Harm , van Oort Inge M. , Creemers Jeroen H.A. , Schreibelt Gerty , Mehra Niven , de Goede Anna L. , Hulsbergen-Van De Kaa Christina , Figdor Carl G. , Witjes Alfred , Aarntzen Erik H.J.G. , Mus Roel D.M. , Gotthardt Martin , Barentsz Jelle O. , De Vries Jolanda , Gerritsen Winald R.
Published: February 2018

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Background: Immunotherapy has limited applicability in the treatment for CRPC patients (pts). An advantageous effect of immune stimulation in CRPC pts was shown by sipuleucel-T, a dendritic cell (DC)-based vaccine. Vaccination (Vac) strategies using myeloid and plasmacytoid DC (mDC and pDC) may improve immunological and clinical outcome of CRPC pts. Methods: In this randomised phase II trial, 21 HLA-A*02.01 positive chemo-naive CRPC pts received maximally 3 cycles of 3 Vac consisting of mDC, pDC or combined mDC + pDC, loaded with tumour-associated antigens (MUC1, NY-ESO-1, and MAGE-C2). Radiological responses were assessed on 68Ga-PSMA PET-CT scan for RECIST 1.1, iron oxide-enhanced MRI scan of lymph nodes and MRI bones. Primary endpoint is the immunological response after DC Vac. Secondary endpoints are safety, feasibility, PSA responses, radiological PFS and OS. Results: All vaccine types were well tolerated, 14 out of 21 pts had grade 1-2 toxicity. There was no grade 3-4 toxicity observed. After 6 months, no radiological disease progression was observed in 62% (13 out of 21 pts). At 12 months follow-up, 45% of patients (5 out of 11) showed stable disease. Mean radiological PFS was 6.1 months (95% CI: 3.7-8.6). No difference between the groups was observed. One patient had a partial radiological response and a significant drop in PSA level from 120 ng/ml to 3.4 ng/ml. Radiological stable pts showed preVac a PSA doubling time of 6.9 months (95% CI: 3.8-10.1), at 6 months after randomisation this was 13.1 months (95% CI: 4.9-21.2). Over a median follow-up period of 12.0 months, median OS was not reached. Primary immunological outcome will be presented. Conclusions: Myeloid and plasmacytoid DC Vac is feasible and safe in early CRPC pts, with preliminary results hinting at possible clinical efficacy. This warrants further study. Clinical trial information: NCT02692976.
Detection of germline deleterious mutations in prostate cancer patients with use of a validated 30-gene sequencing assay.
Authors: Vlachostergios Panagiotis J. , Molina Ana M. , Beltran Himisha , Nanus David M. , Tagawa Scott T.
Published: February 2018

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Background: Germline DNA repair gene alterations in men with metastatic prostate cancer (PC) unselected for family history of malignancy occur in a greater frequency compared to localized PC and the general population. We hypothesized that assessing heritable alterations in a broader panel of high-susceptibility genes, may be relevant for detecting familial associations with other cancers in PC patients. Methods: We examined a cohort of 52 PC patients (median age 60, range 45-80) with histologically confirmed PC (17 localized, 35 metastatic). Germline DNA was isolated from blood lymphocytes or buccal swabs, and targeted next-generation sequencing was conducted with use of a previously validated panel of 30 genes associated with an elevated risk for common cancers (Color Genomics). As a reference for gene aberration frequencies we used the Exome Aggregation Consortium (ExAC) database. Results: The majority of patients (48/52, 92%) had a positive family history of cancer in any relative. Nine deleterious pathogenic mutations were identified in germline DNA samples from 8/52 (15%) patients, affecting the following genes: APC (n = 2, 3.8%), BRCA2 (n = 2, 3.8%), CHEK2 (n = 3, 5.7%), ATM (n = 1, 1.9%), RAD51D (n = 1, 1.9%). APC mutations were significantly more frequent in our cohort compared to the ExAC database (0.3%, p < 0.001). The frequency of DNA repair gene alterations (7/52, 13.5%) was also significantly higher compared to the ExAC database (0.3%, p < 0.001). The median overall survival (OS) between patients with and without germline gene alterations was similar (81.5 versus 74 months, respectively). The presence of heritable gene alterations from the 30-gene panel was significantly more frequent in patients with a positive family history of any cancer (p < 0.001) or prostate, breast, ovarian cancer (p = 0.001) in a first degree relative. Conclusions: The use of a targeted panel of high-susceptibility cancer-associated genes in PC not only confirms the enrichment of germline mutations in men with PC. It can also reveal associations of PC with other cancers which may portend implications for treatment and prognosis.
Dexamethasone in pretreated men with metastatic castration-resistant prostate cancer (mCRPC): A prospective study.
Authors: Baciarello Giulia , Hamilou Zineb , Chebib Ralph , Albiges Laurence , Fuerea Alina , Loriot Yohann , Massard Christophe , Colomba Emeline , Di Palma Mario , Escudier Bernard , Fizazi Karim
Published: February 2018

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Background: Corticosteroids have demonstrated activity in men with mCRPC. Previous data suggested that dexamethasone (D) can induce PSA responses when introduced after progression in mCRPC men receiving AR axis targeted drugs and/or prednisone (P). Methods: We prospectively tested P to D switch or D addition at PSA progression in 43 men with mCRPC with PSA progression and stable clinical disease. Baseline characteristics of the patients, time to castration resistance (TTCRPC), response to previous treatment, PSA response during D 0.5 mg/day and biochemical progression-free-survival (bPFS) after D initiation were recorded. Results were assessed using the Fisher’s exact test to compare variables. Results: Data from 43 patients were prospectively collected: 29 (67%) had been treated with abiraterone (AA) + P, 11 (26%) with enzalutamide (ENZ) and 3 (7%) with other treatments. At progression, 27 patients (63%) switched from P to D while continuing AA, 9 (21%) stopped their treatment and began D alone and 7 (21%) received D added to ENZ. Median age was 75 (70-79.5) and median bPFS with previous treatment was 17 months (6.75-22.25). After D initiation, 28% of patients had a PSA decrease ≥ 30% and the median bPFS was 4 months (2-6). The median bPFS was non-statistically different in patients with previous response to AR axis targeted drugs ≥ 6 months (4 [2-6] vs 1 [1-2] months; p-value = 1) and in those with TTCRPC ≥12 months (4 months [2-7.5] vs. 2 [1.5-2]; p-value = 0.3). Eleven patients (26%) had a bPFS ≥ 6 months and 5 (12%) had a bPFS ≥ 12 months. All long D responders (bPFS ≥ 6 months) had a TTCRPC ≥ 12 months, 10/11 patients had a previous PFS ≥ 6 months on AA or ENZ. None of the 2 patients (4.6%) with primary resistance to AA, responded to switch from P to D. Conclusions: D alone or in combination with previous AR axis targeted agents has activity in mCRPC men, with long responders observed amongst those with previous long response to ADT or to next generation AR axis targeting.
Overall survival and immune responses with sipuleucel-T and enzalutamide: STRIDE study.
Authors: Petrylak Daniel Peter , Drake Charles G. , Pieczonka Christopher Michael , Corman John M. , Garcia Jorge A. , Dunshee Curtis , Van Mouwerik Tim , Tyler Robert C. , Chang Nancy N. , Quinn David
Published: February 2018

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Background: STRIDE (NCT01981122) is the first study comparing concurrent (con) vs sequential (seq) enzalutamide (enz) with sipuleucel-T (sip-T) in patients (pts) with metastatic castration-resistant prostate cancer. Pts were followed until death or for 3 years. Methods: Fifty-two pts were randomized 1:1 to 3 sip-T infusions and enz started 2 wks before (n = 25, con) or 10 wks after (n = 27, seq) sip-T. Enz was continued for 52 wks or until disease progression (DP)/toxicity. Time to clinical outcomes was estimated by Kaplan-Meier analysis. Results: Median age (years): con 66; seq 72 (p = 0.01). Baseline characteristics and laboratory values were similar between arms. K-M estimated median follow up: 40.2 months. Clinical trial information: NCT01981122. Conclusions: Long-term follow-up suggests sip-T+enz is well-tolerated with no new safety concerns. Though not powered for such, con vs seq rx did not result in differences in OS or DP; differences in PSA responses cannot be excluded. Larger studies could better evaluate the clinical impact of combining immunotherapy with hormonal agents.[Table: see text]