bluuebunny/crossref_metadata_2025_split huggingface dataset:
A multicentric phase II randomized trial of docetaxel (D) plus enzalutamide (E) versus docetaxel (D) as first-line chemotherapy for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): CHEIRON study.
Authors: Caffo Orazio , Palesandro Erica , Nole Franco , Gasparro Donatello , Mucciarini Claudia , Aieta Michele , Zagonel Vittorina , Iacovelli Roberto , De Giorgi Ugo , Rossetti Sabrina , Fratino Lucia , Sacco Cosimo , Nicodemo Maurizio , Giordano Monica , Sartori Donata , Scapoli Daniela , Verri Elena , Kinspergher Stefania , Pappagallo Giovanni L. , Aglietta Massimo 
Published: March 2019

148 Background: D and E demonstrated to be efficacious in the treatment of mCRPC pts. Due to different antitumor mechanism of action of these agents, it could be postulated that their combination can improve disease control. CHEIRON study tried to demonstrate the candidate efficacy of chemo-hormonal combination D+E versus D in mCRPC first-line. Methods: Eligibility criteria included untreated mCRPC diagnosis, ECOG PS ≤ 2, adequate renal, hepatic and hematological functions. Pts were randomized to receive D 75 mg/m2 IV d1 q3w plus prednisone 5 mg PO BID for 8 courses alone or plus E 160 mg PO daily for 24 weeks. Stratification criteria were presence of pain and visceral metastases. The primary endpoint of the study was the rate of pts without disease progression (according to PCWG2) at 6 mos after randomization. Results: Between 09/2014 and 10/2017, 246 pts (median age 70 years, range 44-88, pain reported by 54 pts, visceral metastases present in 50 pts) were randomized to DE (120) or D (126). The rate of pts without disease progression at 6 mos was significantly higher in DE arm compared to D arm [87.3% (CI95% 64-80) vs 72.6% (CI95% 80-92); p = 0.006). Similarly, a higher proportion of DE pts achieved a PSA reduction ≥ 50% compared to the baseline values compared to the D pts [92.2%(CI95% 61-77) vs 70.0%(CI95% 86-96); p < 0.0001). No differences were observed in terms of objective response rate. Major haematological toxicities consisted of grade 3-4 anemia (3 pts DE – 1 pt D) and grade 3-4 neutropenia (23 pts DE – 19 pts D); febrile neutropenia was observed in 10 DE pts and in 5 D pts. At a median follow-up of 20 mos, the median progression free survival was 11.3 mos (CI95% 10.0-12.7) and 9.1 mos (CI95% 8.9-9.2) in DE and D arm, respectively (p = 0.004). In D arm the median overall survival was 30.5 mos (CI95% 24.1-36.8) compared to 28.7 mos (CI95% 20.7-36.6) of the experimental arm (p NS). Conclusions: From the present study, the first phase II randomized trial testing the addition of a new generation hormone agent to D, DE improved the 6-mo disease control with a prolongation of PFS compared to the standard chemotherapy. Clinical trial information: NCT02453009.
Response to PARP inhibitor therapy in metastatic castrate-resistant prostate cancer (mCRPC) patients with BRCA1/2 versus ATM mutations.
Authors: Marshall Catherine Handy , McNatty Andrea , Eisenberger Mario A. , Bryce Alan Haruo , Antonarakis Emmanuel S. 
Published: March 2019

154 Background: Poly ADP-ribose polymerase inhibitors (PARPi) are being studied as a treatment option for men with mCRPC and deficient homologous recombination DNA repair. While the FDA has granted “breakthrough” designation status to olaparib for use in mCRPC patients with either BRCA1/2 or ATM mutations, it is not known if responsiveness to PARPi may be influenced by the mutation type. Because ATM functions as a sensor of DNA damage rather than a mediator of DNA repair, we hypothesized that patients with ATM mutations may not show robust responses to PARPi therapy compared to those with BRCA1/2 mutations. Methods: We conducted a retrospective analysis of mCRPC patients treated with off-label olaparib at Johns Hopkins Hospital and Mayo Clinic Scottsdale who had somatic or germline mutations in BRCA1/ 2 or ATM. The primary endpoint was PSA50 response. Secondary endpoints included overall survival (OS) and radiographic/clinical progression-free survival (PFS). Results: 40 men received olaparib for mCRPC of which 17 had pathogenic mutations (5 ATM-mutant, 12 BRCA1/2-mutant). Eleven (65%) had germline and 6 (35%) had somatic alterations. Five (29%) had Gleason sum ≤7 at diagnosis, 4 (24%) had Gleason sum 8, and 8 (47%) had Gleason sum ≥9. Three (18%) had metastatic disease at diagnosis. Mean age at start of olaparib therapy was 65.6 (range, 52-76) years. Prior chemotherapy was received by 59% of men, and prior abiraterone/enzalutamide by 88% of men. Eleven (65%) had extra-osseous metastases at start of therapy. PSA50 responses were achieved by 10/12 men (83%) with BRCA1/2 mutations and 0/5 men (0%) with ATM mutations (Fisher’s exact test, P= 0.003). Men with BRCA1/2 mutations had a median PFS of 12.3 mo versus 3.3 mo for those with ATM mutations (HR 0.14, 95%CI 0.03-0.60; P= 0.008). There was no difference in OS (HR 0.24, 95%CI 0.03-1.173; P= 0.16). Conclusions: Men with mCRPC harboring mutations in BRCA1/2 appear to have better PSA responses and longer PFS with olaparib compared to men with ATM mutations. ATM-mutant mCRPC patients may require alternative therapies ( e.g. chemotherapy, ATR inhibitors). Larger prospective studies are needed to confirm or refute these preliminary findings.
Predictors of germline DNA damage repair gene mutations (gDDRm) in patients (pts) with metastatic castration-resistant prostate cancer (CRPC).
Authors: Yip Steven , Sunderland Katherine , Beigi Arshia , Angeles Arkhjamil , Khalaf Daniel , Warner Evan W , Vandekerkhove Gillian , Sun Sophie , Annala Matti , Wyatt Alexander William , Chi Kim N. 
Published: March 2019

159 Background: gDDRm are present in 6-12% of pts with CRPC and have implications for prognosis, treatment outcomes and familial screening. This study's aim was to identify clinical/pathologic characteristics associated with a higher risk of a pt harboring a gDDRm. Methods: 631 consecutive pts with metastatic prostate cancer were screened for germline mutations in 22 DNA repair genes (including ATM, BRCA1/2, MSH2/6, FANC/ERCC members). Clinical/pathologic characteristics (age at diagnosis, visceral metastases (mets) at time of CRPC, Gleason score, intraductal/cribriform histology (I/C) at diagnosis, family history (FHx) of prostate, breast, ovarian, or pancreatic cancer, time from androgen deprivation therapy initiation to CRPC) were compared between gDDRm+ and gDDRm- cases. A multivariate logistic model of gDDRm status was constructed using purposeful selection of covariates where clinical judgement was employed in addition to statistical significance. A weighted scoring system was created by multiplying each risk factor (RF) by its estimated β coefficient. A pt’s total score was calculated by the sum of each weighted RF. Results: gDDRm+ were identified in 38/631 pts (6.0%, BRCA2 = 28, ATM = 4, BRCA1 = 2, PALB2 = 2, MSH2 = 1, ERCC3 = 1). 29 gDDRm+ and 128 gDDRm- cases with complete clinical/pathologic information were included in the model. Multivariate modeling revealed that visceral mets, FHx and I/C were statistically significantly associated with gDDRm+; age ≤ 65 was included in the model because it was considered clinically relevant (Table). Based on the model results, the weights of each RF are: visceral mets (2), FHx (1), I/C (2), age ≤ 65 (1). Using a total score cut-off ≥ 1, the model achieves a sensitivity, specificity, positive predictive value, and negative predictive value of 97%, 31%, 24%, and 98%, respectively. Conclusions: In this cohort, visceral mets, FHx and I/C were independently associated with a higher risk of harboring a gDDRm. The predictive model may aid in selecting pts for gDDRm screening. Model validation is required. [Table: see text]
Experience with sipuleucel-T in metastatic castration-resistant prostate cancer (mCRPC) with visceral spread from PROCEED.
Authors: Vogelzang Nicholas J. , Kantoff Philip W. , Scholz Mark C. , Vacirca Jeffrey L. , Dakhil Shaker R. , Goel Sanjay , Harmon Matthew , Tang Hong , Brown Bruce , Armstrong Andrew J. 
Published: March 2019

174 Background: Trials of approved agents in mCRPC have reported shorter overall survival (OS) in men with visceral metastases (mets). The phase 3 IMPACT trial evaluated sipuleucel-T, an autologous cellular immunotherapy, in mCRPC but excluded visceral mets. PROCEED, a registry of mCRPC patients receiving sipuleucel-T, offers the first description of sipuleucel-T in patients with visceral mets. Methods: PROCEED enrolled men with mCRPC treated with sipuleucel-T biweekly x 3. Dose adjustment for organ dysfunction was unnecessary. Men were followed until death, study withdrawal, or a minimum of 3 years. OS is reported in this post-hoc subgroup analysis. Results: 1902 men received ≥1 sipuleucel-T infusion between 2011-2014. Visceral mets (n = 90) included liver (n=21), lung (n=61), and brain (n=2) involvement. Compared to patients without visceral mets (Table), men with visceral mets had poorer performance status (PS) and higher baseline prostate-specific antigen (PSA). Median OS was 20.5 and 31.2 mo in those with and without visceral mets. Patients with liver and lung mets had a median OS of 16.3 and 21.0 mo, respectively. Activation of antigen-presenting cells, a measure of immune activation and product potency, was similar in those with and without visceral mets. Conclusions: Initial observations suggest that patients with mCRPC and visceral spread can activate their immune cells to produce sipuleucel-T, but have a shorter OS than those with bone and/or lymph node spread. (NCT01306890). Clinical trial information: NCT00065442. [Table: see text]
Real-world PROCEED registry data: Sipuleucel-T in elderly men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Armstrong Andrew J. , Olsson Carl A , Schnadig Ian D. , Concepcion Raoul S , Vacirca Jeffrey L. , Tutrone Ronald F , Dakhil Shaker R. , Chang Nancy N. , Tang Hong , Brown Bruce , Vogelzang Nicholas J. 
Published: March 2019

177 Background: Managing patients ≥ 80 years old (yo) with mCRPC is challenging, given the high prevalence of comorbidities, polypharmacy, organ dysfunction, and reduced performance status (PS). Balancing treatment benefit with safety and quality of life is particularly germane for this group. Sipuleucel-T, an autologous cellular immunotherapy for mCRPC, is generally well-tolerated. Prior analyses from PROCEED, a large registry for sipuleucel-T in men with mCRPC, demonstrated that upregulation of immune cells in these elderly patients is similar to that of younger men. Here, we report on this clinical experience. Methods: PROCEED enrolled men with mCRPC treated with sipuleucel-T given every 2 weeks x 3, with no dose adjustment for organ dysfunction or drug interactions. The elderly cohort included those ≥ 80 yo. Men were followed until death, study withdrawal, or a minimum of 3 years. Results: Of 1902 patients who received ≥1 sipuleucel-T infusion, 374 (19.7%) were ≥ 80 yo. Compared to men < 80 yo (Table), this cohort was 14 years older, had worse Eastern Cooperative Oncology Group (ECOG) PS and higher prostate-specific antigen (PSA) at baseline. All grade (16.3% elderly v. 13.7% younger) and grade 3-5 (10.7% elderly v. 9.9% younger) serious adverse events were comparable between groups. However, the median overall survival (OS) of elderly men was 10.7 mo shorter than that of younger men (< 80 yo). Conclusions: Sipuleucel-T was generally well-tolerated in those ≥ 80 yo in a real-world setting and may be considered a first-line option for the elderly with asymptomatic or minimally symptomatic mCRPC. As expected, OS was shorter than in younger patients. Clinical trial information: NCT01306890. [Table: see text]
A noninvasive prognostic biomarker for metastatic castration-resistant prostate cancer: Very small nuclear circulating tumor cells.
Authors: Chen Pin-Jung , Jan Yu Jen , Teng Pai-Chi , Chen Jie-Fu , Cheng Shirley , Yao Nu , Reis-Sobreiro Mariana , Lozano Amber , Gomez Amy , Freeman Michael , Tseng Hsian-Rong , Posadas Edwin M. 
Published: March 2019

179 Background: Circulating tumor cells (CTCs) have arisen as a contemporary biomarker for prostate cancer (PC). A subgroup of PC CTCs, with particularly small nuclei ( < 8.54 μm), were found to be correlated with poor prognosis and the emergence of visceral metastases (VM). This subgroup was named very-small nuclear CTCs (vsnCTCs). The findings led us to explore vsnCTCs as an aggressive biomarker in metastatic castration-resistant PC (mCRPC). We also explored a biological pathway that potentially drives this morphologic phenomenon. Studies showed that the disruption of the linker of nucleoskeleton and cytoskeleton (LINC) complex proteins, such as emerin, results in nuclear envelope instability and drives cancer cells to an amoeboid phenotype with increasing capacity of migration and invasion. We hypothesized that emerin mislocalization is associated with vsnCTC formation and may be a critical step of metastasis. Methods: Using our NanoVelcro CTC assay, we are able to capture and enumerate CTCs from patients' blood and correlate this data with clinical outcomes. We collected samples from 35 mCRPC patients who failed first-line androgen deprivation therapy and started treatment with abiraterone, enzalutamide, or taxane-based chemotherapy. Survival analyses were performed to exam the correlation between vsnCTC counts and patients’ prognosis. Concurrently, emerin staining was performed and the distribution and expression levels were analyzed in selected vsnCTC samples. Results: The presence of one or more vsnCTCs correlated with worse overall survival (P = 0.00013), progression free survival (PSA progression: P = 0.012; radiographic progression: P = 0.0015), and faster time to VM (P = 0.024). We also observed lower emerin content in vsnCTCs compared to WBC, and more prominent emerin mislocalization in vsnCTCs compared to CTCs with larger nuclei. Conclusions: Our study demonstrated the importance of morphologic characterization of CTCs and suggested that vsnCTCs is a putative biomarker for prediction of worse outcome. Additionally, our findings of emerin mislocalization in vsnCTCs suggested a potential biological pathway behind this nuclear morphologic phenomenon.
Treatment efficacy of abiraterone (abi), enzalutamide (enza) or cabazitaxel (caba) in metastasic castration-resistant prostate cancer patients (mCRPC) after progression to docetaxel plus androgen deprivation therapy (ADT) in hormone sensible disease.
Authors: Climent Duran Miguel Angel , Sáez M Isabel , Piulats Josep M. , Montesa A. , Chirivella Isabel , gonzalez Forastero Alejandro , Caballero Diaz Cristina , Heras Lucia , Mellado Begona , Vazquez-Estevez Sergio , Olmos David , Duran Ignacio , Juan Fita María José 
Published: March 2019

198 Background: Different treatments efficacy for mCRPC when progression after docetaxel x 6 cycles + ADT (as CHAARTED scheme) are unknown as all pivotal trials where performed in patients who progressed to mCPRC after ADT. Methods: A retrospective analysis of 175 mCRPC patients of 10 spanish hospitals who were treated with docetaxel + ADT as first line treatment was performed. Patients characteristics at diagnosis (age, gleason) and at progression to mCRPC were analyzed (PSA, presence of visceral mets, type of progression). As efficacy endpoints, clinical and objective response, and survival from progression to mCRPC were analyzed. Results: Median age at diagnosis 65.2 years old (range 44-84). Metastatic at diagnosis 173. Bone metastasis 155 (88,5%), visceral 31 (17.7%), gleason >7 130 (74,3%), number docetaxel cycles: 6 (80%), 5 (5,7%), <5 (14,3 %). Median survival from diagnosis: 35 months. Progression to CRPC 78pts (44.5%) Type of progression: PSA 74/78 (94,9%), clinical 45/78 (57.7%), radiological 59/78 (75.6%). Median survival from progression to CRPC: 10.3 months. Treatments frequency, clinical benefit (RP/EE) and median survival: abi 30 (38.4%)/ 7(23.3%)/ 15.7 m; enza 12 (15.4%)/ 4 (33.3%)/ 10.4 m, caba 14(17.9%)/ 3(21.4%)/ 6.4m; Other treatments frequency: Ra223 4 (5.1%), docetaxel 4 (5.1%), others/no treatment/BSC 14 (17.8%). Clinical and radiological progression before treatment was 36.7%/63.3% in abi patients, 58.3%/63.7% in enza and 93.9%/93.9% in caba pts. Visceral (mostly hepatic) metastasis were more frequent in caba (57.1%) than in abi (11.8%) or enza (0%) pts. Median PSA value abi 375/ caba 1633. Conclusions: Although AA seems be more effective than cabazitaxel in mCRPC progressed after docetaxel + ADT in HSPC, patients treated with caba are of worse prognosis.
MiCheck performance: Comparator trial of MiCheck with PHI, % free PSA and PSA—The impact on decision making for prostate biopsy.
Authors: Shore Neal D. , Saltzstein Daniel R. , Pieczonka Christopher Michael , Beebe-Dimmer Jennifer Lynn , Ruterbusch Julie J. , Campbell Douglas , Walsh Brad 
Published: March 2019

199 Background: A more accurate diagnostic test is still needed to enhance decision-making regarding prostate biopsy. MiCheck is a triage test to assist in a decision to proceed to prostate biopsy. It measures multiple cancer related proteins in blood while combining this information with clinical factors. It has been optimised to differentiate between aggressive (AgCaP) and non-aggressive (non-AgCaP) prostate cancer. The MiCheck-01 clinical trial collected samples from patients who proceeded to biopsy on the basis of an elevated age adjusted PSA. The performance of MiCheck was compared with PSA, %free PSA and PHI. Methods: Serum samples were tested according to the MiCheck manufacturer’s instructions. Patient samples were also tested using a standard PSA assay and additionally underwent PHI and % free PSA measurement. A range of different MiCheck cutpoints were examined for test performance and one chosen following consultation with Urologists and Clinical Chemists. This algorithm was applied to all evaluable patients from the trial and the outputs used for the development of a health economic model. The net cost impact of using MiCheck was assessed. Results: The best performing MiCheck algorithm demonstrated a high AUC when differentiating AgCaP from non-AgCaP. MiCheck demonstrated a higher AUC than PSA, %free PSA and PHI in this population. Furthermore, the algorithm was superior to the other tests in PSA 4-10ng/ml range. The derived algorithm was applied to patients from the trial using a high sensitivity cutpoint. At this cutpoint, 25% of biopsies were avoided while only 5 (4%) AgCaP patients underwent a later diagnosis. A diagnostic workflow model of how the test might be employed by the clinician was constructed. This was applied to a health economic analysis demonstrating significant cost savings (between $2,744 and 5,047 per patient in year one) when incorporating MiCheck to standard of care. Conclusions: The MiCheck test demonstrates a superior ability to discriminate between AgCaP and non-AgCaP in comparison to PSA,PHI, and % free PSA. Use of the MiCheck test would assist clinicians in assessing the need for a prostate biopsy and provide significant healthcare cost savings.
Metastasis-free survival as a predictor of overall survival in non-metastatic castration-resistant prostate cancer.
Authors: Gagnon Richard , Alimohamed Nimira S. , Batuyong Eugene , Chow Alyssa , Lee-Ying Richard M. 
Published: March 2019

201 Background: Recent trials have shown that apalutamide and enzalutamide can improve metastasis free survival (MFS) in advanced non-metastatic (M0) castrate-resistant prostate cancer (CRPC). MFS is a novel clinical endpoint, demonstrated to be a strong predictor of overall survival (OS) for localized prostate cancer, yet it is unknown if this is also true for M0 CRPC. Our aim was to determine how strongly MFS in M0 CRPC correlates with OS in a real world population. Secondary analyses evaluated whether a rapid PSA-doubling time (PSADT), of ≤10 months, impacts outcomes. Methods: We performed an analysis of patients diagnosed with advanced prostate cancer, followed at the Tom Baker Cancer Centre, in Calgary, Alberta from 2001-2017. Patients were excluded if they did not develop M0 CRPC. MFS and OS were measured using the Kaplan-Meier method and the log-rank test was used to compare outcomes based on PSADT. Correlation between OS and MFS was determined using Pearson Correlation and Kendall’s Tau-B. Results: A total of 1310 patients were identified with advanced prostate cancer, of which 87 developed M0 CRPC. The median age of diagnosis of M0 CRPC was 72 years, with a median Gleason score of 7.0, initial PSA of 10.4, and PSADT of 5.1 months. Only 6 patients were treated with second-generation anti-androgens or chemotherapy. Median MFS and OS after M0 CRPC diagnosis were 44.1 and 83.7 months, respectively. Pearson Correlation between MFS and OS was strong with a coefficient of 0.850 (p < 0.001); with non-parametric Kendall’s Tau, correlation was also strong with a coefficient of 0.632 (p < 0.001). PSADT ≤10 months was identified in 70 patients, and associated with a significantly shorter MFS, compared to a PSADT > 10 months (40.2 vs. 90.4 months; p = 0.001), as well as shorter OS (76.2 vs. 104.3 months; p = 0.008). Conclusions: MFS for M0 CRPC is strongly correlated with OS in a real world population. PSADT of ≤10 months seems to be a useful prognostic tool in estimating MFS and OS in patients with M0 CRPC. MFS was better than expected even in patients with a PSADT of ≤10 months, which may due to our adherence to the biochemical definition of castration-resistant disease, as well as lack of standard imaging intervals in the real world.
The efficacy of enzalutamide for castration-resistant prostate cancer (CRPC) patients with intraductal carcinoma of the prostate (IDC-P).
Authors: Kawanishi Hideji , Kato Masashi , Yamamoto Akiyuki , Tsuzuki Toyonori 
Published: March 2019

209 Background: Enzalutamide (ENZ) was approved to prolong survival for castration-resistant prostate cancer (CRPC) patients before and after chemotherapy. No factor was identified to predict the effectiveness of ENZ so far. .Intraductal carcinoma of the prostate (IDC-P) was newly recognized on 2017 EAU guideline and considering as a poor prognostic factor、although there has been no reports to predict the therapeutic effects of ENZ according to the presence of IDC-P. In this study, we evaluated the efficacy of ENZ for CRPC patients with or without IDC-P. Methods: We retrospectively identified 199 CRPC patients treated with ENZ from 2014 to 2018 in author-affiliated hospitals. All needle biopsy slides were reviewed by a single genitourinary pathologist and IDC-P was defined according to the criteria of McNeal at initial biopsy. Endpoint is overall survival (OS) from the time of CRPC diagnosis and time to treatment failure of ENZ. PSA response is defined as over 50% PSA decline from baseline. Results: The median patient age was 71 (range, 49–90) years. The median initial PSA was 154 ng/ml (range, 3.9–24736 ng/ml). The patients who received docetaxel were 42/199 (21%). IDC-P was detected in 98 patients (49%) at initial prostate biopsy. PSA response was 70.5% in patients without IDC-P and 53.9% in patients with IDC-P. The median OS from the time of CRPC was 37.9 and 71.5 months with and without IDC-P, respectively (P=0.013). There was no significant difference on OS in CRPC patients with IDC-P between before and after docetaxel (P=0.941). Same result was observed in CRPC patients without IDC-P (P=0.86). In time to treatment failure by ENZ, patients with IDC-P showed worse prognosis than patients without IDC-P after docetaxel (P=0.068). On the other hand, the difference disappeared before docetaxel regardless the presence of IDC-P (P=0.94). Conclusions: IDC-P is a poor prognostic factor for CRPC patients treated with ENZ. ENZ may be most effective for CRPC patients with IDC-P before chemotherapy.