bluuebunny/crossref_metadata_2025_split huggingface dataset:
Keynote-365 cohort a: Pembrolizumab (pembro) plus olaparib in docetaxel-pretreated patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Yu Evan Y. , Massard Christophe , Retz Margitta , Tafreshi Ali , Carles Galceran Joan , Hammerer Peter , Fong Peter C.C. , Shore Neal D. , Joshua Anthony , Linch Mark David , Gurney Howard , Romano Emanuela , Augustin Marinela , Piulats Josep M. , Wu Haiyan , Schloss Charles , Poehlein Christian Heinrich , De Bono Johann S. 
Published: March 2019

145 Background: Activity with pembro or olaparib has been observed in mCRPC pts who progressed on 2nd-generation hormonal therapy (HT) and chemotherapy. From KEYNOTE-365 (NCT02861573), a phase 1b/2 umbrella study testing combinations in mCRPC, we report early results from cohort A combining pembro + olaparib. Methods: Pts with mCRPC were eligible if they progressed within 6 months prior to screening determined by either PSA progression or radiologic progression in bone or soft tissue. Pts were docetaxel-pretreated for mCRPC, may have received 1 other chemotherapy, and had ≤2 2nd-generation HT. Pts received pembro 200 mg IV Q3W + olaparib 400 mg orally twice daily. Primary end points: safety and PSA response rate (confirmed PSA decline ≥50%). Key secondary end points: ORR RECIST v1.1 (investigator review), disease control rate (DCR: CR+PR+SD ≥6 mo), time to PSA progression, composite response rate (ORR RECIST v1.1, confirmed PSA response, or confirmed decrease in circulating tumor cell count from ≥5 to <5 cells/7.5 mL blood), rPFS, and OS. Results: Median follow-up was 11 mo. 41 initiated treatment (median age 69 years; PD-L1+ 27%; visceral disease 42%; RECIST-measurable 68%; homologous recombination repair mutation [HRR] 0%). See efficacy in table below. Treatment-related AEs occurred in 39 (95%) pts. Most frequent (≥30%) were anemia (37%), fatigue (34%), and nausea (34%). Grade 3-5 treatment-related AEs were in 21 (51%) pts. There were 2 deaths; only 1 was treatment-related (cause unknown). Conclusions: Combination of pembro + olaparib has activity in pts previously treated with docetaxel and ≤2 2nd-generation HT for mCRPC and who are HRR wild type. Observed safety profile for the combination is consistent with individual profiles of pembro and olaparib. Clinical trial information: NCT02861573. [Table: see text]
Late administration of luteinizing hormone-releasing hormone (LHRH) agonists and the impact on testosterone suppression in the real-world management of prostate cancer.
Authors: Twardowski Przemyslaw , Sartor A. Oliver , McLane John A. , Boldt-Houle Debbie , Atkinson Stuart , Tagawa Scott T. 
Published: March 2019

149 Background: LHRH agonists are standard for androgen deprivation therapy (ADT) for advanced prostate cancer (PCa). Increasing evidence suggests maintaining very low testosterone (T) levels is desirable and correlate with disease-specific survival. However, T levels may rise above castrate level between administrations, especially if the next dose is delayed. A previous publication showed that subcutaneously-administered leuprolide acetate (LA) provided a longer duration of action than intramuscularly-administered LA past the dosing interval. This study evaluated the timeliness of LHRH agonist administrations and subsequent rate of T breakthroughs in PCa patients. Methods: A retrospective review of electronic medical records from 1/1/07-6/30/16 of 85,030 LHRH agonist administrations for PCa treatment was conducted to evaluate the percentage of late subsequent administrations and T tests with T > 50 ng/dL. A late administration was defined as occurring on or after day 33 (1 mo formulation), 98 (3 mo), 129 (4 mo), or 195 (6 mo). Descriptive statistics were used. Results: 26.9% of all subsequent LHRH agonist administrations were late: 14.4% were ≤ 1 week late, 3.1% were between 1 and 2 weeks late, and 9.4% were > 2 weeks late. 21% of T tests demonstrated T > 50 ng/dL when administrations were late, in contrast to only 4% of measured T levels exceeded 50 ng/dL when LHRH agonists were administered early or on time. Conclusions: Across LHRH agonists, greater than a quarter of subsequent administrations were defined as late. Among late administrations, about half were > 1 week late, and more than a third were > 2 weeks late. Late administrations were correlated with inadequate castration over 20% of the time. Considering the clinical benefits of maintaining effective T suppression during ADT, clinicians should administer treatments within approved dosing instructions, include routine monitoring of T levels, and consider prescribing treatments with proven prolonged effect through the dosing period to achieve T suppression to castrate levels.
Prospective head-to-head comparison of 18F-fluciclovine and 68Ga-PSMA-11 PET/CT for localization of prostate cancer biochemical recurrence after primary prostatectomy.
Authors: Calais Jeremie , Ceci Francesco , Nguyen Kathleen , Gartmann Jeannine , Eiber Matthias , Reiter Robert Evan , Kishan Amar Upadhyaya , Jadvar Hossein , Fendler Wolfgang P , Czernin Johannes 
Published: March 2019

15 Background: 18F-Fluciclovine PET/CT (FACBC) is standard-of-care in US for localization of prostate cancer (PCa) biochemical recurrence (BCR) after definitive therapy. 68Ga-PSMA-11 PET/CT (PSMA) detects PCa BCR even at low prostate-specific antigen (PSA) levels (<2.0 ng/mL). We conducted a single-center prospective head-to-head comparison of these 2 PET/CT imaging tracers for localizing PCa BCR after radical prostatectomy (RP) in patients with PSA < 2.0 ng/ml. Methods: Patients with PCa BCR after RP and PSA levels ranging from ≥0.2 to ≤2.0 ng/mL without any prior salvage therapy were eligible. All patients underwent FACBC and PSMA scans within ≤15 days. Images analysis was performed a) by on-site clinical reading and b) by 3 blinded international expert readers for each modality. Detection rates on per-patient and per-region based analysis served as primary study endpoints. Based on literature data we hypothesized a detection rate difference of 22% in favor of PSMA. A power analysis determined a sample size of 50 patients. Results: The 50 patients were enrolled from March to September 2018. Median PSA level was 0.50 ng/ml. Median time interval between the 2 scans was 6 days. We present here the preliminary results from the non-blinded clinical reads. Detection rate on a per-patient basis was 69% for PSMA and 34% for FACBC. Concordant findings were observed in 30/49 patients (61%): 16/49 (32%) with both positive scans and 14/49 (29%) with both negative scans. Discordant findings were observed in 19/49 patients (39%): 18/49 (37%) had a positive PSMA but a negative FACBC scan while 1/49 (2%) had a positive FACBC with a negative PSMA (local recurrence). Detection rates were consistently lower for FACBC than for PSMA for all regions: Prostate bed (12% vs 20%), pelvic nodes (14% vs 37%), extra-pelvic nodes (2% vs 8%), skeleton (2% vs 8%) and visceral organs (2% vs 6%). Conclusions: This preliminary analysis from the non-blinded on-site clinical reads demonstrates prospectively that PSMA detection rates is more than double the FACBC detection rate in patients with PCa BCR after RP and with PSA ≤2.0 ng/ml. Clinical trial information: NCT03515577.
Efficacy of docetaxel and androgen receptor axis-targeted agents in castration-resistant prostate cancer patients with intraductal carcinoma of the prostate.
Authors: Yamamoto Akiyuki , Kato Masashi , Tsuzuki Toyonori , Gotoh Momokazu 
Published: March 2019

150 Background: This study aimed to investigate the efficacy of docetaxel and androgen receptor axis-targeted (ARAT) agents in castration-resistant prostate cancer (CRPC) patients with intraductal carcinoma of the prostate (IDC-P). Methods: We retrospectively identified 311 CRPC patients from June 2002 to February 2016. All patients were initially administered with androgen deprivation therapy (ADT), followed by docetaxel or ARAT (abiraterone or enzalutamide) after progressing to CRPC. The primary outcome of interest was overall survival (OS) from the time of CRPC diagnosis and progression-free survival (PFS) from the time of administration of docetaxel or ARAT. Results: IDC-P was found in 180 of 311 patients. The median OS was 33.4 and 64.0 months with and without IDC-P, respectively (hazards ratio [HR], 2.14; P < 0.001). For the first treatment for CRPC, docetaxel was administered to 71 and 50 patients with and without IDC-P, respectively, with a median OS of 30.4 and 64.0 months, respectively (HR, 2.62; P < 0.001). ARAT was administered to 109 and 81 patients with and without IDC-P, respectively, with a median OS of 45.0 and 69.9 months, respectively (HR, 1.84; P = 0.017). Regarding patients with IDC-P, the OS in patients who were administered with ARAT was longer than that in those administered with docetaxel (HR, 0.58; P = 0.008). The median PFS was 7.5 and 12.1 months with and without IDC-P, respectively (HR, 1.36; P = 0.03). Multivariate analysis showed that the prognostic factors for OS were the presence of IDC-P (HR, 1.91; P < 0.001), and administration of ARAT (HR, 0.66; P = 0.02). Conclusions: The presence of IDC-P is an independent prognostic factor for OS and PFS in CRPC patients. ARAT may prolong OS in CRPC patients with IDC-P.
Quality of life differences for LHRH-antagonist versus LHRH-agonist in special patient groups with cardiovascular comorbidities and higher tumor burden in patients with hormone-sensitive prostate cancer (hsPCa).
Authors: Lehmann Jan , Flesch Markus , Gedamke Michael 
Published: March 2019

153 Background: ADT with LHRH-agonists or LHRH-antagonists (degarelix, D) is the standard of care in advanced hsPCa. An analysis of ProComD from 2018 showed that D was more frequently used in patients with cardiac and peripheral arterial disease. Methods: In the ProComD, a two-arm, prospective non-interventional study, potential differences in comorbidity and other parameters such as baseline PSA and metastatic status on patient reported outcome between D and LHRH-agonists treatment were investigated. Results: Data on patients with a minimum follow-up period of one year (n = 285, D = 179, LHRH-agonist = 106) up to three years (n = 62, D = 40, LHRH-agonist = 22) were documented. Baseline criteria were generally similar except for disease T-stage (p = 0.0238), metastatic status (p = 0.0419) and PSA (p = 0.0041). The average age of patients was 74.1 years. Stage distribution: D vs LHRH-agonists, pT2 25.7/24.5%, pT3 24.1/34.9%, pT4 6.1/2.8%, unknown. 44.1/37.7%, cNX 49.7/44.3%, cN0 32.4/42.5%, cN+ 17.9/12.3%, cMX 27.4/25.5%, cM0 34.1/49.1%, cM1 38.6/25.5%. Global health status (EORTC) did not change over 12 months neither for D nor for LHRH-agonists. Differences in subscales between D and LHRH-agonists were observed for role functioning, cognitive functioning and, while QoL was unchanged under D, LHRH-agonists sig. reduced QoL (p = 0.073, p = 0.0368). Pain (marginal sig.) p = 0.0621) as well as analgesics (17.3% vs 1.1% at 3 months vs baseline) were reduced by D. Since baseline PSA differed sig., we specifically evaluated the subgroup of patients with a PSA > 50 ng/ml, where Global Health Status was found to be different between D and LHRH-agonists already at month 6 and at month 12 (p = 0.0331, p = 0.0232), favoring D. Conclusions: Our results indicate that Degarelix, with a different mode of action, is used in a different patient group (CVD and higher tumor stage as well as metastatic patients) compared to LHRH-agonists treatment. EORTC Global Health is similar to LHRH-agonists, but differences occur in subscales (role and cognitive functioning) as well as in subgroups (PSA > 50 ng/ml) in favour of the LHRH-antagonist. Clinical trial information: NCT02234089.
The effect of VERU-111, a novel oral inhibitor of α and β tubulin, on tumor growth in the human castration-resistant, AR-variant prostate cancer (PCa) model 22Rv1.
Authors: Markowski Mark Christopher , Getzenberg Robert H. , Steiner Mitchell S. , Azad Nilofer Saba , Eisenberger Mario A. , Antonarakis Emmanuel S. 
Published: March 2019

167 Background: VERU-111 is a novel, oral α and β tubulin inhibitor that blocks tubulin polymerization and is not a substrate for multi-drug resistance. In xenograft mouse models of taxane responsive and resistant cancers, VERU-111 results in tumor inhibition at ≤20 mg/kg orally dosed infrequently as 1/week. VERU-111 and docetaxel were tested in the human PCa model, 22Rv1, which expresses androgen receptor splice variants, including AR-V7, and is resistant to abiraterone and enzalutamide. Methods: Human 22Rv1 cells were implanted into SCID mice. When tumors reached 150-200 mm , the animals were randomized into 4 groups (n = 10 per group): PO vehicle; PO VERU-111 5 or 20 mg/kg; or IP docetaxel 10 mg/kg 3X per week. Animal weights and tumor volumes were measured 2X week and at study end. Animals were removed from study when the tumor volume exceeded 2000 mm or upon treatment for 28 days. Results: VERU-111 (PO 5 and 20 mg/kg) 3X/week significantly reduced tumors by 31% (p = 0.049) and 49% (p = 0.010), respectively, compared to vehicle. Administration of 10 mg/kg docetaxel IP had a nonsignificant reduction in tumor size. With respect to toxicity, mice treated with oral VERU-111 either significantly gained (5 mg/kg) or maintained their weight (20 mg/kg), whereas the docetaxel treated mice lost weight (p = 0.013). There was a significantly greater weight in mice treated with VERU-111 versus docetaxel (p = 0.014). Conclusions: VERU-111, a next generation, orally α and β tubulin inhibitor, has significant anti-tumor activity against PCa and other tumors. In the human PCa model 22Rv1, VERU-111 had a statistically significant reduction in tumor growth and was well tolerated. In contrast, IP docetaxel did not significantly reduce tumor growth and had greater toxicity. A phase 1/2 trial evaluating VERU-111 in men with metastatic castration and novel androgen blocking agent (abiraterone or enzalutamide) resistant prostate cancer is in progress. [Table: see text]
Genomic validation of three-tiered sub-classification of high-risk prostate cancer.
Authors: Muralidhar Vinayak , Zhang Jingbin , Spratt Daniel Eidelberg , Feng Felix Y , Davicioni Elai , Yousefi Kasra , Wang Natalie , Choeurng Voleak , Nguyen Paul L. 
Published: March 2019

17 Background: Recent data and National Comprehensive Cancer Network (NCCN) guidelines suggest that high-risk prostate cancer (cT3-4, Gleason score ≥ 8, or prostate-specific antigen [PSA] > 20 ng/mL) is a heterogenous group in terms of long-term patient outcomes. We sought to determine whether sub-classification of high-risk prostate cancer based on clinical factors correlates with genomic markers of risk. Methods: We identified 3,220 patients with NCCN unfavorable intermediate-risk (n=2,000) or high-risk (n=1,220) prostate cancer. We defined the following sub-classification of high-risk prostate cancer based on previously published data: favorable high-risk (cT1c, Gleason 6, and PSA > 20 ng/mL or cT1c, Gleason 4+4=8, PSA < 10 ng/mL); very high-risk (cT3b-T4 or primary Gleason pattern 5); and standard high-risk (all others with cT3a, Gleason score ≥ 8, or PSA > 20 ng/mL). We used a set of 37 previously published genomic classifiers, including the 22-gene Decipher assay, to determine whether high-risk genomic features correlated with the clinical sub-classification of high-risk prostate cancer. Results: Among those with favorable high-risk, standard high-risk, and very high-risk prostate cancer, 50.4%, 64.2%, 81.6% had a high-risk Decipher score, respectively (p < 0.001). Among 36 other genomic signatures, 33 had a similar increasing trend across the three sub-classes of high-risk (p < 0.05 after correction for multiple hypothesis testing). Patients in the three sub-classes of high-risk disease were positive for a median number of 5, 7, and 14 high-risk signatures. Under a novel clinical-genomic risk group classification (Spratt et al., 2017), 27.5%, 19.7%, and 7.0% of patients with favorable, standard, or very high-risk disease would be re-classified as intermediate-risk, respectively. In comparison, among those with unfavorable intermediate-risk prostate cancer, 38.2% had a high-risk Decipher score and would be re-classified as clinical-genomic high-risk. Conclusions: Genomic markers of risk correlate with the clinical sub-classification of high-risk prostate cancer into favorable high-risk, standard high-risk, and very high-risk disease, validating the prognostic utility of this stratification.
A phase I and randomized phase II study of cabozantinib plus docetaxel and prednisone (C+DP) versus docetaxel and prednisone (DP) alone in metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Al Harthy Munjid , Madan Ravi Amrit , Karzai Fatima , Petrylak Daniel Peter , Kim Joseph W. , Arlen Philip M. , Theoret Marc Robert , Marte Jenn , Bilusic Marijo , Couvillon Anna , Chun Guinevere , Owens Helen , Hankin Amy , Cordes Lisa M. , Figg William Douglas , Gulley James L. , Dahut William L. 
Published: March 2019

173 Background: A phase I study of Cabozantinib (C) in combination with docetaxel (D) and prednisone (P) in patients (pts) with mCRPC determined that 40 mg daily was the maximum tolerated dose of C in combination with D and P (C+DP). We report a pooled analysis of the phase I and randomized phase II study comparing C+DP to DP alone. Methods: Eligible pts had mCRPC without prior chemotherapy in the castrate setting. All pts received a fixed dose of D (75 mg/m2IV day one of each 21 day cycle) and P (5 mg PO twice daily), and in the C+DP group, C at three escalating dose levels: 20 mg, 40 mg, or 60 mg in the phase I cohort (all PO daily) and 40 mg daily in the phase II cohort. Results: A total of 32 pts received C+DP (19 pts in phase I and 13 pts in the phase II cohort). 12 pts received DP alone. Baseline characteristics for C+DP vs DP included median age 69 (45 – 84) vs 69 (50-83) and median PSA 74.8 ng/ml (0.01-4093.7) vs 309.5 ng/ml (94.6 – 2649) respectively. Clinical trial information: NCT01683994. 18/32 C+DP pts had previous enzalutamide or abiraterone, with a median PFS of 13.6 months (95% CI: 5.2 – 21.0). 23/32 pts (72%) treated with C+DP required dose reduction or discontinuation of C, and 10/32 (31%) required C discontinuation. 2/32 patients (6%) in the C+DP group died on protocol, possibly related to study drug (sudden death NOS/venous thromboembolism). Grade 4 adverse events (AEs) in the C+DP group included: neutropenia (28%), leukopenia (6%), pulmonary embolism (3%), and mucositis (3%) and in DP: hyperglycemia (8%). Grade 3 AEs (>10%) in C+DP included: neutropenia (31%), febrile neutropenia (16%), leukopenia (13%), hypophosphatemia (13%) and in DP: anemia (17%). Conclusions: In pts with mCRPC, C+DP is associated with a greater PFS and PSA responses compared to DP alone. Toxicities with the combination were manageable. Further study is required to better define the potential benefits of C+DP in mCRPC.[Table: see text]
In geriatric evaluation, some iadl (Katz) scale items are more predictive of efficacy and toxicity than ADL (Lawton) scale or Charlson Comorbidity Index in metastasic castration-resistant protate cancer (mCRPC) patients treated with cabazitaxel in a weekly schedule.
Authors: Climent Duran Miguel Angel , Pérez-Valderrama Begoña , Mellado Begona , Fernandez Parra Eva , Fernandez Calvo Ovidio , Anido Herranz Urbano , Domenech Montserrat , Hernando Polo Susana , Arranz Jose Angel , Caballero Diaz Cristina , Juan Fita María José , Castellano Daniel E. , ochoa De Olza Maria 
Published: March 2019

176 Background: Cabazitaxel (CBZ) improves overall survival in mCRPC that progresses during or after docetaxel treatment. CABASEM is a phase II study to evaluate the efficacy and safety of a weekly schedule of CBZ for 'unfit' (ECOG2, previous neutropenic fever with docetaxel, or radiotherapy to <25% of areas of bone marrow reserve) mCRPC patients after docetaxel failure. Fragility scales were performed to patients included before treatment and results are described. Methods: All 70 patients were treated with CBZ 10 mg/m2/wk 4 administration every 5 weeks. Geriatric fragility scales performed were Lawton daily day activities (ADL), BPI score, Katz instrumental daily day activities (IADL) and Charlson index. General and specific items have been analyzed in relation with toxicity and efficacy (clinical benefit (OR+SD), PSA response, composite PFS, PSA-PFS, and overall survival) in all patients and in older than 70 years. Results: Median age 73 (range 54-85). Charlson index and ADL scale had not relationship with any toxicity observed and any efficacy outcome in the whole group nor in older than 70. IADL independence grade was related to survival in the whole group (p=0,025) and older than 70 (p=0,02). In the whole group, some IADL items were associated with PSA response (buying, p=0.003; cooking, p=0.06; and IADL independence grade p=0.01), PSA PFS (telephone use, p=0.01; handle finances, p=0.06), composite PFS (telephone use, p=0.013; housekeeping, p=0.03; handle finances, p=0,06) and OS (telephone use p=0.001; laundry, p=0.008; handle finances, p=0.02 and IADL dependence grade, p=0.003). Only any grade diarrhea and grade 2 neutropenia was associate with buying (p=0.025) and cooking (p=0.05) IADL items respectively, in patients older than 70 years. Conclusions: IADL scale and items seem to be more related to efficacy (OS, PSA response, PFS, clinical benefit and PSA PFS) than ADL and Charlson scales in mCRPC older than 70 years treated with weekly cabazitaxel. No clear association of scales and items with toxicity were observed in this group of patients. Clinical trial information: NCT01518283.
Age-related variation in gene alteration frequency in metastatic prostate cancer.
Authors: Chalmers Zachary Rockow , Frampton Garrett Michael , Ross Jeffrey S. , Hussain Maha H. A. , Abdulkadir Sarki 
Published: March 2019

178 Background: Despite advances in therapy, metastatic prostate cancer (mPCA) remains lethal. Younger men with mPCA have a significantly greater risk of mPCA-related death compared to men diagnosed later in life. This suggests that early-onset mPCA is a uniquely aggressive subtype of disease, however, the genomic drivers have not been explored. Here, we analyze data from 2,196 mPCA specimens profiled as part of routine clinical care. Methods: Comprehensive genomic profiling was performed by hybridization capture of exonic regions from either 236, 315 or 324 cancer-related genes and select introns from 19 genes commonly rearranged in cancer. Libraries were sequenced to high, uniform coverage and assessed for all classes of genomic alterations. Tumor mutational burden (TMB) was determined from 1.1 Mb of sequence and microsatellite instability (MSI) from 114 loci. Results: 336 (15.3%) men were < 60 years old (yo), and 1,860 (84.7%) were ≥60 yo at time of biopsy. Lymph node, liver, and bone were the three most common metastatic sites in both groups, accounting for 75% of all specimens. Patients < 60 yo harbored significantly fewer AR and PTEN point mutations when compared to patients ≥60 yo (OR = 0.48, p < 0.001; OR = 0.51, p = 0.01). Copy number alterations in PTEN and CDKN2A/B were significantly more common among young patients (OR = 1.46, p = 0.003; OR = 1.91, p = 0.04). AR copy number alterations were significantly less common among young patients (OR = 0.57, p < 0.001). Although uncommon in mPCA, markers of genomic instability including MSH2 mutations and MSI were both significantly less common among patients < 60 yo (0.00% vs. 1.29%, p = 0.04; 0.89% vs. 3.06%, p = 0.03). There were no significant differences in the frequency of TP53, APC, BRCA2, ATM, and CDK12 point mutations, MYC copy number alterations, or TMPRSS2-ERG fusions. The average TMB was not significantly different between young and old patients, with 3.26 and 5.79 mutations per Mb, respectively (p = 0.19). Conclusions: Younger men with mPCA appear to represent a genomically distinct disease subtype. To better define this population, we are prospectively investigating the genomic, genetic, and environmental risk factors through an ongoing PCF funded clinical trial.