bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomized controlled trial of GnRH antagonist monotherapy versus GnRH agonist plus bicalutamide (CAB) for patients with metastatic hormone-sensitive prostate cancer (mHSPC) (KYUCOG-1401).
Authors: Yokomizo Akira , Morokuma Futoshi , Eto Masatoshi , Shiota Masaki , Matsuyama Hideyasu , Matsumoto Hiroaki , Kamoto Toshiyuki , Terada Naoki , Kawahara Kazuya , Enokida Hideki , Tatarano Shuichi , Fujimoto Naohiro , Higasijima Katsuyoshi , Sakai Hideki , Hakariya Tomoaki , Igawa Tsukasa , Suekane Shigetaka , Kamba Tomomi , Sugiyama Yutaka , Naito Seiji 
Published: February 2022

99 Background: To investigate a clinical response of GnRH antagonist monotherapy against CAB therapy for mHSPC. Methods: Histopathological confirmed mHSPC patients were randomly assigned to GnRH antagonist monotherapy group (Group A) and CAB group (Group B). A deferred CAB therapy by adding bicalutamide to GnRH antagonist was performed in Group A after PSA progression. The primary endpoint was PSA progression free survival (PSA-PFS). The secondary endpoints were time to CAB treatment failure (CAB-TTF), radiographic progression free survival (rPFS), overall survival (OS), change of PSA, effect on hormone dynamics, change of bone metabolic markers, effect on lipid metabolism, adverse events (AE). This trial was registered with UMIN-CTR (UMIN000014243). Results: A total of 200 patients (101 patients in Group A and 99 in Group B) were registered from June 2014 to June 2017. The PSA-PFS was significantly better in Group B (HR (95% CI) =1.40 (1.01-1.95), p=0.041) as shown in the table. Time to CAB treatment failure (TTF) tended to be better in Group A, but there was no statistically significant difference in CAB-TTF between two groups (Table). rPFS and OS were also not statistically significant difference (Table). Time to PSA nadir was significantly shorter in Group B (HR (95% CI) = 0.72 (0.54 - 0.97), p = 0.028). The proportion of patients whose serum testosterone did not reach or maintain the castration level was more frequent in Group A (significant difference at 60 weeks, p = 0.046). There was no significant difference in the effect of bone metabolic markers and lipid metabolism between two groups. In terms of AE, injection-site-reaction was more frequent in Group A. Conclusions: LH-RH agonist CAB therapy (Group B) prolonged PSA-PFS compared to LH-RH antagonist monotherapy (Group A), probably due to the higher frequency of insufficient achievement of castration level in Group A. However, a deferred CAB therapy by adding bicalutamide to GnRH antagonist resulted in no difference in CAB-TTF, rPFS and OS. Clinical trial information: UMIN000014243.[Table: see text]
Overall survival (OS) in patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC) treated with enzalutamide (ENZA) + androgen deprivation therapy (ADT) by high or low disease volume and progression to mHSPC (M0 at diagnosis) or de novo mHSPC (M1 at diagnosis): Post hoc analysis of the phase 3 ARCHES trial.
Authors: Armstrong Andrew J. , Iguchi Taro , Azad Arun , Szmulewitz Russell Zelig , Holzbeierlein Jeffrey , Villers Arnauld , Alcaraz Antonio , Alexeev Boris , Shore Neal D. , Gomez-Veiga Francisco , Rosbrook Brad , Zohren Fabian , Yamada Shunsuke , Haas Gabriel P. , Stenzl Arnulf 
Published: February 2022

115 Background: In ARCHES (NCT02677896), ENZA + ADT improved radiographic progression-free survival, OS, and other key secondary endpoints vs placebo (PBO) + ADT for pts with mHSPC (also known as metastatic castration-sensitive prostate cancer). Final OS results confirmed a long-term survival benefit with ENZA + ADT (hazard ratio [HR] 0.66; 95% confidence interval [CI] 0.53, 0.81; p<0.0001). We present post hoc analyses of OS by disease volume and progression to M1 HSPC after initial diagnosis with localized disease (M0) or presentation of de novo mHSPC at initial diagnosis (M1). Methods: Pts with mHSPC (N=1150) were randomized 1:1 to ENZA (160 mg/day) + ADT (n=574) or PBO + ADT (n=576), stratified by disease volume and prior docetaxel use. After unblinding, 180 (31.3%) PBO + ADT-treated pts crossed over to open-label ENZA + ADT. High disease volume was defined per CHAARTED criteria. Medical profiles of pts assessed as MX/unknown metastasis at initial diagnosis (n=213) were further reviewed centrally and adjudicated as having either M0 or M1 disease. Median OS and HRs were estimated by Kaplan-Meier methods and Cox proportional hazards, respectively. Results: Median treatment duration was 40.2 months (mo) for ENZA + ADT and 13.8 mo for PBO + ADT. Inclusive of crossover, 401 (69.6%) PBO + ADT pts had subsequent life-prolonging therapy. OS benefits with ENZA + ADT were seen in all disease volume and M0/M1 populations at a similar magnitude to the overall population (Table). Median OS was not reached in most populations except PBO + ADT pts with high disease volume (45.9 mo; 95% CI 40.1, not estimable [NE]) or high disease volume and M1 disease (43.4 mo; 95% CI 36.4, 49.7) and ENZA + ADT pts with high disease volume and M0 disease (54.2 mo; 95% CI 54.2, NE). Conclusions: Our post hoc analysis demonstrates consistent long-term survival benefit with ENZA + ADT vs PBO + ADT across pts with mHSPC with high and low disease volumes and M0 or M1 disease at initial diagnosis, despite substantial treatment crossover and subsequent therapy use in PBO + ADT pts.[Table: see text]
Association of changing bone metastatic (mets) patterns with dynamics of circulating tumor DNA (ctDNA) in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Conteduca Vincenza , Scarpi Emanuela , Rossi Alice , Ferroni Fabio , Gurioli Giorgia , Bleve Sara , Gianni Caterina , Schepisi Giuseppe , Brighi Nicole , Lolli Cristian , Cursano Maria Concetta , Virga Alessandra , Casadei Chiara , Altavilla Amelia , Farolfi Alberto , Ulivi Paola , Barone Domenico , Matteucci Federica , Paganelli Giovanni , De Giorgi Ugo 
Published: February 2022

152 Background: Accurate monitoring response of bone mets to treatment is an active need for mCRPC patients (pts). Recently, ctDNA has been showed as an early biomarker efficacy of androgen receptor signaling inhibitor (ARSI) therapy for mCRPC ( Conteduca, Br J Cancer 2020). In this study, we aimed to reveal if ctDNA analysis can permit more reliable prediction of bone mets burden and radiographic progression disease (PD). Methods: In a biomarker study (REC 2192/2013), targeted next generation sequencing was performed to assess ctDNA fraction. Radiographic evidence of bone disease was documented by conventional imaging according to PCWG3 criteria ( Scher, J Clin Oncol 2018), and was classified on the basis of mets number (≤5, 6 -19, ≥20) in oligometastatic (O), diffuse (D), and widespread (W), respectively. Associations were explored both through uni/multivariate logistic regressions. Results: Serial plasma samples and radiographic scans on ARSI treatment were prospectively collected from 73 CRPC with bone mets. Median age was 74 years [interquartile range (IQR) 69-79]. Bone mets patterns were significantly associated with median baseline ctDNA level (O = 0.16, D = 0.33, and W = 0.46, p 0.0003). Similar results were reported on treatment and at PD (p 0.0003 and p 0.0007, respectively). In 24 pts with a progressive worsening of bone mets pattern (O→D→W) compared to pts with no change in bone mets pattern on ARSI, we observed an early meaningful ctDNA rise with a % ctDNA variation from baseline to 3 month therapy of 150.6% (IQR 104.9-210.7) vs 11.1% (IQR 0-36.6), p < 0.0001. Univariate analysis showed that early ctDNA rise was significantly associated with radiographic progression free/overall survival (rPFS/OS): hazard ratio (HR) 2.06, 95% confidence interval (CI) 1.30-3.27, p 0.002, and HR 1.82, 95% CI 1.15-2.88, p 0.01, respectively]. In multivariable analyses including ctDNA variation, changing bone mets pattern, age, performance status, and presence of concomitant visceral mets, ctDNA change at 3 month ARSI resulted the only independent predictor of both rPFS/OS (HR 2.27, 95% CI 1.04-4.94, p 0.027 and HR 2.98, 95% CI 1.31-6.81, p 0.033, respectively). Visceral mets were associated with only OS (HR 3.87, 95% CI 1.76-8.51, p 0.0008). Conclusions: Early ctDNA variation may reflect changes in bone mets pattern on ARSI allowing to track pattern of bone progression and predict outcome. Further studies to validate these findings are warranted.
Molecular testing for prostate cancer in Greek patients.
Authors: Liontos Michael , Kunadis Elena , Svarna Anna , Skafida Efthymia , Fiste Oraianthi , Markellos Christos , Zakopoulou Roubini , Papatheodoridi Alkistis , Andrikopoulou Angeliki , Kaparelou Maria , Koutsoukos Konstantinos , Zagouri Flora , Dimopoulos Meletios A. 
Published: February 2022

170 Background: Molecular testing for mutations in genes related to homologous recombination repair (HRR) and microsatellite instability (MSI) is suggested for patients with advanced prostate cancer by international guidelines. Recently, olaparib has been approved for patients with metastatic castration resistant prostate cancer patients that bear mutations in BRCA1/2 genes in Europe. In Greece, molecular testing for prostate cancer patients is not reimbursed. In this setting we describe our experience from investigating the molecular profile of patients with advanced/metastatic disease. Methods: We retrospectively collected clinicopathological data of patients treated in our center for advanced/metastatic prostate cancer whose tumours were subjected to whole exome sequencing analysis for a panel of 58 genes including BRCA1/2. All patients provided written informed consent and the study was approved by the local ethics committee. Results: Tumor samples from 37 patients with advanced or metastatic prostate cancer were analyzed. Median age of the patients was 60.2 years (25th-75th percentile 54.4-63.9 years) and most of them (19/37, 51.4%) were presented with de novo metastatic disease. Clinicopathological characteristics of the patients are presented in the table. Eight samples (21.6%) were evaluated as inadequate to perform further analysis. In the remaining 29 cases, no BRCA1/2 mutations were detected. Instead, 7 patients had mutations in HRR-related genes, including 3 patients with ATM mutations, two in CHEK2, one in CHEK1 and one in RAD50. TP53 mutations were found in 8 patients (21.6%) and PTEN mutations in 2 (5.4%). Newer Hormonal Treatments were used as first-line treatment in mCRPC in 24 patients (64.9%), while 6 received docetaxel. Median PFS in first-line mCRPC was 12.0 months (95% CI 9.7-14.3) in the whole population and did not differ significantly in patients with HRD mutations (11.8 months) or TP53 mutations (11.8 months). Two patients with ATM mutations received olaparib as fourth and fifth line of treatment respectively with stable disease as best response. Conclusions: Biomarker driven targeted therapies are currently available for mCRPC patients. In our cohort, molecular testing was negatively affected by the poor quality of archival tissues in a significant percentage of patients. However, mutations in HRR-related genes were found in almost 20% of patients with possible therapeutic implications. Therefore, it is necessary to have a reimbursed molecular testing for prostate cancer patients in Greece.[Table: see text]
Identification of homologous recombination and repair (HRR) deficiency using circulating tumor DNA (ctDNA) in advanced prostate cancer (aPC).
Authors: Bucheit Leslie A. , Yen Jennifer , Drusbosky Leylah , Barbacioru Catalin , Gnerre Sante , Wang Hao , Artyomenko Alexander , Yabolonovitch Arielle , Fu Yu , Lee Che-Yu , Maliska Max , Helman Elena , Dorshner Michael , Lefterova Martina 
Published: February 2022

180 Background: ctDNA testing is a non-invasive means to identify genomic alterations in patients with aPC, including BRCA1/2 and other HRR gene alterations, which are targetable by PARP inhibitors (PARPi). However, classes of HRR inactivating mutations, such as copy number loss and large genomic rearrangements (LGRs) are challenging to detect by ctDNA. Here we describe a CLIA-validated plasma-based ctDNA test that identifies copy number loss and LGRs, in addition to SNV and Indels, in HRR genes. We report the landscape of HRR deficiency (HRD) in a clinical population of > 2,000 patients with aPC. Methods: 2932 samples from patients with aPC previously tested as part of clinical care using an 83-gene cfDNA NGS assay (Guardant360) within an 11-month period were reanalyzed for presence of HRD. HRD alterations were defined as copy number loss, LGR (i.e. intergenic or intragenic gene rearrangements) and deleterious SNV/Indel in 7 clinically focused HRR genes ( ATM, BRCA1, BRCA2, CDK12, CHEK2, PALB2, RAD51D). Clinical information, when available, was obtained from test requisition forms. Results: The median age of the analyzed cohort was 73 years (range: 31-100); when known, the majority of patients were tested at disease progression (81%, 2242/2750). In total, an inactivating BRCA1/2 variant was was identified in 26% (605/2932) of reanalyzed patients, comprising BRCA1/2 loss of heterozygosity (LOH) (13.4% of patients), deleterious SNV or Indels (5.5%), homozygous deletions (3.3%) and LGRs (1.1%). The prevalence of patients with any inactivating HRR alteration increased to 38.5% with the expanded 7 gene set. Overall, prevalence of loss-of-function mutations (SNV/Indel, homozygous deletion or LGR) in BRCA2 was 4.5X frequent than in BRCA1 and comparable to previously described prostate cohorts (8.4% and 1.8% compared to 8.6% and 1.1% in tissue, respectively). Conclusions: Genomic profiling by ctDNA identified an HRR alteration landscape comparable to previously characterized tissue cohorts, with enrichment in BRCA2 over BRCA1 inactivating mutations and frequent BRCA1/2 LOH. Patients with aPC may benefit from PARPi eligibility determination using rapid and reliable ctDNA assessment, particularly at progression. Future studies should assess PARPi outcomes for this population.
Efficacy and safety outcomes of darolutamide in patients with nonmetastatic castration-resistant prostate cancer with comorbidities and concomitant medications from ARAMIS.
Authors: Fizazi Karim , Shore Neal D. , Smith Matthew Raymond , Ramos Rodrigo , Jones Robert J. , Niegisch Guenter , Vjaters Egils , Ortiz Jorge A. , Liang Steve , Wang Yuan , Srinivasan Shankar , Sarapohja Toni , Verholen Frank 
Published: February 2022

256 Background: Patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC) are primarily older, have comorbidities, and take concomitant medications. Darolutamide (DARO), a structurally distinct and highly potent androgen receptor inhibitor, significantly reduced the risk of metastasis by ̃2 years and the risk of death by 31% versus placebo (PBO) and demonstrated favorable safety and tolerability in the phase 3 ARAMIS trial. DARO also has low potential for drug−drug interactions. This post hoc analysis of ARAMIS evaluated overall survival (OS) and safety in pts with ongoing comorbidities and concomitant medications. Methods: Pts with nmCRPC were randomized 2:1 to DARO (n=955) or PBO (n=554) while continuing androgen-deprivation therapy. At the final data cutoff (Nov 15, 2019), OS and adverse events (AEs) were evaluated in pts with a median of ≤ and >6 comorbidities or ≤ and >10 concomitant medications in the double-blind period. HRs (95% CIs) were determined from univariate analysis using Cox regression. Results: The majority of pts had ≥6 comorbidities (53%; 795/1509) or received ≥10 concomitant medications (54%; 813/1509). For pts with ≤6 and >6 comorbidities, DARO prolonged OS vs PBO (HR 0.65 and 0.73, respectively). OS benefit of DARO vs PBO was consistent for pts with metabolic, cardiovascular (CV), and other comorbid disorders (HR range: 0.39–0.88). For pts receiving ≤10 and >10 concomitant medications, OS was prolonged with DARO vs PBO (HR 0.76 and 0.66, respectively). Subgroups of pts receiving concomitant medications for gastrointestinal/metabolic disorders, CV disease, urologic disorders, and pain/inflammation achieved similar OS benefit with DARO vs PBO (HR range: 0.45–0.80). Incidence of AEs and AEs leading to treatment discontinuation with DARO was comparable to PBO across subgroups by number of comorbidities and concomitant medications (Table). Conclusions: The OS benefit and safety of DARO remained consistent with that observed in the overall ARAMIS population, even in patients with a high number of comorbidities or concomitant medications. Clinical trial information: NCT02200614. [Table: see text]
Implementation of PSMA-PET in focal dose-escalated radiotherapy of primary prostate cancer patients: Results of a planned safety analysis of a phase II trial.
Authors: Spohn Simon K.B. , Gainey Mark , Kamps Marius , Mix Michael , Ruf Juri , Benndorf Matthias , Zschaeck Sebastian , Ghadjar Pirus , Baltas Dimos , Grosu Anca L. , Zamboglou Constantinos 
Published: February 2022

260 Background: Positron emission tomography targeting prostate specific membrane antigen (PSMA-PET) changes treatment management of primary prostate cancer (PCa) patients and might improve focal dose escalation in radiotherapy (RT) due to superior coverage of intraprostatic tumour burden. The 2-armed, non-randomized HypoFocal phase II trial investigates the safety of implementation of PSMA-PET-based focal therapy planning in external beam radiotherapy (EBRT) and high-dose-rate brachytherapy (HDR-BT). Here we present results from the planned safety analysis after 6 months of follow-up (FU). Methods: Intermediate- and high risk PCa Patients with cN0 and cM0 staged by mpMRI and PSMA PET were included. EBRT was delivered in 20 fractions with 60 Gy to the prostate and up to 75 Gy to mpMRI- and PSMA-PET defined boost volumes (arm A). HDR-BT was delivered with 15 Gy to the prostate and a boost of up to 19 Gy, followed by EBRT with 44Gy in 20 fractions (arm B). 36% of patients received androgen deprivation therapy. Volumes, treatment plans, gastrointestinal (GI) and genitourinary (GU) toxicities according to CTCAE v5.0 and Quality of Life (QoL) was assessed. Results: 25 patients were enrolled in each study arm in two centers (Freiburg and Berlin). Clinical T stage was significantly different between mpMRI and PSMA-PET (p=0.007) with upstaging towards ≥ cT2c stages in PET. GTV-PET and GTV-Union were significantly larger than GTV-MRI, resulting in large boost volumes (see table). Boost volumes received a median mean dose of 70 Gy in EBRT and a median D90 of 19 Gy in HDR-BT At 6 months FU, prevalence of ≥ grade 2 GU and GI toxicity was 4% and 0% for arm A and 12 and 4% for arm B. Two patients experienced grade 3 GI toxicitiy 9 and 12 months after RT, related to biopsy. No signification change of QoL was observed after 6 months of FU. cT stages and target volumes. Conclusions: Implementation of PSMA-PET in primary PCa patients relevantly alters cT-stage and RT treatment management with significantly larger GTVs and subsequent boost volumes. Still, boost delivery was feasible with acceptable acute toxicities and good QoL. Putative oncological benefits should be evaluated in larger cohorts. Clinical trial information: DRKS00017570. [Table: see text]
Impact of lymph node yield at prostatectomy on outcomes in NRG/RTOG 9601.
Authors: Chan Emily , Pugh Stephanie L. , Simko Jeff , Feng Felix Y , Shipley William U. , Lukka Himanshu , Bahary Jean-Paul , Pisansky Thomas Michael , Zeitzer Kenneth Lee , Lawton Colleen Anne , Efstathiou Jason A. , Rosenthal Seth A. , Balogh Alexander G. , Lovett Richard Dana , Wong Anthony C. , Dess Robert Timothy , McGinnis Scott , Kuettel Michael R. , Demora Lyudmila , Sandler Howard M. 
Published: February 2022

265 Background: A recent study ( Fossati et al, 2018) found that higher lymph node count at radical prostatectomy was associated with improved outcomes in patients treated with salvage radiation for elevated prostate-specific antigen (PSA) after surgery. We sought to validate these results in NRG/RTOG 9601, a randomized controlled trial of men with pT2/T3 disease who underwent either radiation (RT) alone or RT+antiandrogen (bicalutamide) therapy for PSA elevation following radical prostatectomy from 1998-2003. Methods: We reviewed available pathology reports for all patients in NRG/RTOG 9601 to determine the nodal count at radical prostatectomy. Clinical data was as of 11/5/2015, same as the primary endpoint for the trial. Cox proportional hazards models were used to assess the effect of number of positive lymph nodes, treatment arm (RT alone or RT+bicalutamide), Gleason score, positive margins, and seminal vesicle invasion on the following endpoints: times to local and distant failure and overall and disease specific survival. Results: Out of the 760 patients originally eligible in the trial, 552 (73%, 276 in each arm) had complete data available. Median node count in the entire cohort was 6 (range 0-33, Q1-Q3 3-9). There were no significant differences between treatment arms in terms of patient demographic or clinical characteristics, including total lymph nodes removed in either arm (RT alone vs RT+bicalutamide median 5 vs 6, p = 0.11). There was no significant association between total lymph nodes and overall survival with both arms combined (HR = 1.00, 95% CI:0.97-1.03, p = 0.87) or in the individual arms alone (RT+Casodex: HR = 1.01, 95% CI:0.97-1.05, p = 0.65; RT+Placebo: HR = 0.98, 95% CI: 0.94-1.03, p = 0.45). There was also no significant association between total lymph nodes and disease-specific survival with both arms combined (HR = 1.00, 95% CI:0.95-1.04, p = 0.84) and in the arms alone (RT+Casodex: HR = 1.00, 95% CI:0.95-1.05, p = 0.92; RT+Placebo: HR = 0.99, 95% CI: 0.92-1.07, p = 0.86). In multivariable analysis performed on the two arms, Gleason score was the only feature associated with worse overall and disease-specific survival, seen only in the RT alone arm. Similar findings were seen when evaluating times to local and distant failure. Conclusions: Lymph node yield in NRG/RTOG 9601 did not show any association with adverse outcomes in the entire cohort, or in either treatment arm alone. The therapeutic benefit of an extensive lymph node dissection in this population remains uncertain. Clinical trial information: NCT00002874.