bluuebunny/crossref_metadata_2025_split huggingface dataset:
KEYNOTE-365 cohort B updated results: Pembrolizumab (pembro) plus docetaxel and prednisone in abiraterone (abi) or enzalutamide (enza)-pretreated patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Kolinsky Michael Paul , Gravis Gwenaelle , Mourey Loic , Piulats Josep M. , Sridhar Srikala S. , Romano Emanuela , Berry William R. , Gurney Howard , Retz Margitta , Appleman Leonard Joseph , Boegemann Martin , De Bono Johann S. , Joshua Anthony M. , Emmenegger Urban , Conter Henry Jacob , Laguerre Brigitte , Wu Helen , Schloss Charles , Poehlein Christian Heinrich , Yu Evan Y. 
Published: February 2020

103 Background: KEYNOTE-365 (NCT02861573) is a phase 1b/2 study to evaluate pembro in combination with other agents in mCRPC. Here we report updated results from cohort B (pembro + docetaxel and prednisone). Methods: Cohort B enrolled pts who failed or were intolerant to ≥4 wk of abi or enza in the prechemotherapy mCRPC state and whose disease progressed within 6 mo of screening as determined by PSA progression or radiologic bone/soft tissue progression. Pts received pembro 200 mg IV + docetaxel 75 mg/m2 IV Q3W and prednisone 5 mg orally twice daily. Primary end points were safety, PSA response rate (confirmed PSA decrease >50%), and ORR per blinded independent central review (BICR). Results: Of 104 treated pts, 72 discontinued, primarily due to progression (55%). Median age was 68 y (range 50-86), 24% were PD-L1+, 25% had visceral disease, and 50% had measurable disease. Median follow-up was 13 mo for all pts (n=104) and 19 mo for pts who had ≥27 wk of follow up (n=72). See table for efficacy outcomes. Treatment-related AEs occurred in 100 pts (96%); most frequent (≥30%) were alopecia, diarrhea, and fatigue (39% each). Grade 3-5 treatment-related AEs occurred in 42 pts (40%). Five pts died of AEs; 2 deaths were from treatment-related AEs (pneumonitis). Conclusions: With additional follow-up, pembro + docetaxel and prednisone continued to show activity in pts with mCRPC who failed previous antihormonal therapy. Safety of the combination was consistent with the known profiles of the individual agents and will be further evaluated in a phase 3 study (KEYNOTE-921). Clinical trial information: NCT02861573. [Table: see text]
PSA progression compared to radiographic or clinical progression in metastatic castration-resistant prostate cancer patients treated with enzalutamide.
Authors: Gandhy Shruti U. , Karzai Fatima , Marte Jennifer L. , Bilusic Marijo , McMahon Sheri , Strauss Julius , Couvillon Anna , Williams Monique , Hankin Amy , Steinberg Seth M. , Figg William Douglas , Arlen Philip M. , Dahut William L. , Gulley James L. , Madan Ravi Amrit 
Published: February 2020

105 Background: Enzalutamideis ahighly effective treatment in patients with metastatic castration resistant prostate cancer (mCRPC). Although Prostate Cancer Working Group Guidelines (PCWG) recommend continuing treatment until radiographic progression of disease (rPD) or clinical progression (cPD), many patients discontinue therapy for rising PSA alone. Methods: We conducted an open label, randomized phase 2 clinical trial in mCRPC patients (on testosterone suppression therapy) previously untreated with docetaxel, abiraterone, or enzalutamide, comparing enzalutamide alone or in combination with PROSTVAC, a therapeutic cancer vaccine designed to induce an anti-tumor immune response. The study discontinued accrual after a planned interim analysis indicated no difference in progression between the two arms. Patients were followed beyond PSA progression (first of three confirmed PSA rises, evaluated monthly) until rPD per PCWG (scans done every 3 months per protocol). Results: A total of 57 patients were enrolled with a median follow up time of 55.4 months. Of those, 47 (82%) patients were Caucasian and seven (12%) patients were African American. The median age of patients on enrollment was 67.2 years. 49/57 (86%) patients had PSA progression and the median time to first PSA rise for all 57 patients combined was 6.4 months (95% CI: 3.7-11.0 months) after starting enzalutamide. 38/57 (67%) patients experienced progressive disease (majority with rPD and 1/38 (3%) with cPD), with the median time to progression for all 57 patients of 23.3 months (95% CI: 16.1-27.8 months). Conclusions: Consistent with PCWG recommendations, these data suggest that a rising PSA may not be a warning of near-term clinically significant disease progression in mCRPC patients given the nearly 17-month difference between the first rise in PSA and ultimate rPD or cPD seen in this analysis. These data highlight the need to continue to educate patients and providers on PCWG criteria for progression, which were also used in original trials that led to the FDA approval of enzalutamide, so as not to substantially limit the potential efficacy of mCRPC therapies such as enzalutamide. Clinical trial information: NCT01867333.
PROfound: Efficacy of olaparib (ola) by prior taxane use in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations.
Authors: De Bono Johann S. , Fizazi Karim , Saad Fred , Shore Neal D. , Roubaud Guilhem , Ozguroglu Mustafa , Penel Nicolas , Matsubara Nobuaki , Mehra Niven , Procopio Giuseppe , Kolinsky Michael Paul , Nishimura Kazuo , Feyerabend Susan , Joung Jae Young , Vogelzang Nicholas J. , Carducci Michael Anthony , Kang Jinyu , Poehlein Christian Heinrich , Wu Wenting , Hussain Maha H. A. 
Published: February 2020

134 Background: Optimal sequencing of therapies for mCRPC is not established. In the Phase III PROfound study (NCT02987543), ola significantly prolonged radiographic progression-free survival (rPFS) vs physician’s choice of new hormonal agent (pcNHA) in pts with mCRPC and an alteration in genes with a direct or indirect role in HRR. We report exploratory subgroup analyses by prior taxane (yes vs no). Methods: Men with mCRPC that had progressed on prior NHA were randomized to ola (tablets; 300 mg bid) or pcNHA (enzalutamide or abiraterone). Pts had alterations in BRCA1, BRCA2 or ATM (Cohort A) or ≥1 of 12 other prespecified genes with a direct or indirect role in HRR (Cohort B). Stratification factors were prior taxane use and measurable disease. rPFS was assessed by blinded independent central review with RECIST v1.1 + PCWG3. Results: Subgroup analyses of rPFS and overall survival (OS) favored ola vs pcNHA irrespective of prior taxane in Cohort A, Cohorts A+B and pts with a BRCA1 and/or BRCA2 or CDK12 alteration (Table). In the ATM subgroup hazard ratio (HR) point estimates for rPFS and OS were lower in pts who had received prior taxane vs pts who had not, but 95% CIs overlapped and pt numbers were small so data should be interpreted with caution. Conclusions: The benefit of ola over pcNHA in pts with mCRPC and HRR gene alterations was generally independent of prior taxane status in the overall study population. Clinical trial information: NCT02987543. [Table: see text]
Pembrolizumab (pembro) plus enzalutamide (enza) for enza-resistant metastatic castration-resistant prostate cancer (mCRPC): KEYNOTE-199 cohorts 4-5.
Authors: Graff Julie Nicole , Antonarakis Emmanuel S. , Hoimes Christopher J. , Tagawa Scott T. , Hwang Clara , Kilari Deepak , Ten Tije AJ , Omlin Aurelius Gabriel , McDermott Raymond S. , Vaishampayan Ulka N. , Elliott Anthony , Wu Helen , Kim Jeri , Schloss Charles , De Bono Johann S. 
Published: February 2020

15 Background: KEYNOTE-199 (NCT02787005) is a multicohort phase 2 study. Cohort (C)4 (RECIST-measurable disease) and C5 (bone-predominant disease) consist of chemotherapy-naive patients (pts) with mCRPC treated with enza + pembro after progression with enza. Results for C4 and C5 presented. Methods: Pts with or without prior abiraterone had clinically meaningful response/benefit to enza followed by disease progression. Pts received pembro 200 mg Q3W with continuation of enza for up to 35 cycles or until progression/intolerable toxicity. Primary end point: ORR, blinded independent central review (C4). Secondary end points: DCR, PSA response rate (≥50% reduction), rPFS, OS, and safety (C4, C5); DOR (C4). Results: Of 126 pts (C4, 81; C5, 45), 107 discontinued, primarily due to progression. Median follow-up: 13.7 mo (C4, 11.8; C5, 18.6). ORR (95% CI) for pts with measurable disease was 12% (6-22) in C4; DCR for all pts: 51% (39-62) in C4 and 51% (36-66) in C5 (Table). Any grade/grade 3-5 treatment-related AEs occurred in 75%/26% pts in C4 and 69%/24% in C5. Two pts in C4 died of immune-related AEs (Miller Fisher syndrome and myasthenia gravis). Incidence of any grade/grade 3-4 rash (regardless of treatment relatedness) was higher than previously reported for individual agents (33%/6%). All except one pt (grade 3 treated with IV steroids) were treated with oral/topical steroids or had no intervention. Conclusions: Addition of pembro to enza following enza resistance showed modest antitumor activity in pts with RECIST-measurable and bone-predominant mCRPC. Combination had manageable safety and is being evaluated in a phase 3 trial. Clinical trial information: NCT02787005. [Table: see text]
Improving data accessibility: New strategies towards implementation of a genomic data portal.
Authors: McNair Christopher , Knudsen Karen E. 
Published: February 2020

159 Background: It is now standard practice to utilize genomic profiling as a mechanism to navigate cancer patients to more effective therapies and clinical trials. Despite routine use, there is no single solution to perform these tests at most institutions, neither in-house nor external. As such, a myriad of options continue to be utilized for molecular diagnostic purposes. Significantly, lack of standardization in testing results in difficulty developing consistent mechanisms for ingesting, organizing, and accessing the data resulting from these tests. Ultimately, the result is a substantial gap in the types of studies researchers are able to perform simply due to lack of data accessibility. Methods: Typical workflows for genomic profiling do not involve a data repository such as the EMR or data warehouse for reasons including: lack of EMR ability to store genomic data, no processes for genomic profiling results to be integrated. The SKCC Cancer Informatics team at Jefferson has utilized the open source cBioPortal platform as a means of organizing, visualizing, and increasing overall access to Jefferson patient-specific genomic data at SKCC, termed the Genomic Data Portal (GDP). Results: We have developed processes for ingesting and transforming test results from multiple sources including in-house and external vendors. Once ingested, results are integrated with patient-specific clinical information from the EMR and tumor registry in order to increase the power of the data. The GDP currently houses over 1200 samples, including over 80 samples from advanced prostate cancer patients, with these numbers growing as more patients receive testing. Genomic results for each patient include gene mutation, fusion, and CNV, in addition to TMB and MSI. Clinical information drawn from the EMR and tumor registry includes demographics, overall survival, as well as disease specific information such as Gleason Score. Conclusions: The GDP has shown utility for multiple purposes including translational research studies and clinical trial feasibility and design. Importantly, this workflow can be adopted by institutions with varying technical expertise and resources, further enabling the research community.
The effect of deep AR suppression with enzalutamide or apalutamide on endogenous glucocorticoids: Implications for adverse effects and development of combination therapies.
Authors: Sharifi Nima , Alyamani Mohammad , Li Jianbo , Patel Mona , Berk Michael , Taylor Susan , Przybycin Christopher , Posadas Edwin M. , Madan Ravi Amrit , Gulley James L. , Rini Brian I. , Garcia Jorge A. , Klein Eric A. 
Published: February 2020

17 Background: Metabolic consequences of potent AR suppression with enzalutamide and apalutamide are unresolved. Endocrine perturbations induced by potent AR antagonists may promote adverse effects and impinge on the potential efficacy of combination therapies, including for example, immunotherapies. We hypothesized that enzalutamide and apalutamide will block 11β-HSD2, the major enzyme that inactivates cortisol in peripheral tissues and results in increased systemic exposure to endogenous active glucocorticoids. We further hypothesized that AR is co-expressed with 11β-HSD2, suggesting a mechanism of suppression. Methods: Cortisol and cortisol/cortisone ratio (substrate/product of 11β-HSD2) were measured in serum using mass spectrometry before and on-treatment in 3 clinical trials: 1) neoadjuvant apalutamide + leuprolide 2) enzalutamide +/- PROSTVAC for metastatic castration-resistant prostate cancer 3) enzalutamide +/- PROSTVAC for non-metastatic castration-sensitive prostate cancer. AR and 11β-HSD2 expression were assessed in kidneys of 13 men and 9 women. Results: A rise in cortisol concentration and cortisol/cortisone ratio occurs uniformly across all 3 trials of potent AR antagonists. For example, a rise in cortisol/cortisone ratio occurred in 23/25 (92%) patients (p<0.001), 30/38 (79%) patients (p=0.051), and 36/64 (67%) patients (p<0.001), in the 3 respective trials. AR is only expressed alongside 11β-HSD2 in the kidneys of men but not women. Conclusions: Treatment with enzalutamide or apalutamide increases systemic exposure to active glucocorticoids. This effect is likely mediated by AR suppression of 11β-HSD2 in the kidney. These findings have potential consequences for immune suppression, the efficacy of treatment combinations using next-generation AR antagonists, and adverse effects of these drugs.
Impact of baseline serum IL-8 on metastatic hormone-sensitive (mHSPC) prostate cancer outcomes in the phase III CHAARTED trial (E3805).
Authors: Harshman Lauren Christine , Wang Xin Victoria , Yamamoto Hidemi S. , Hamid Anis , Drake Charles G. , Carducci Michael Anthony , DiPaola Robert S. , Fichorova Raina N. , Sweeney Christopher 
Published: February 2020

171 Background: IL-8 (CXCL-8) is a cytokine produced by leukocytes and tumor cells, which promotes inflammation, angiogenesis, anti-apoptosis, and metastasis. Our published training set identified serum IL-8 levels drawn within 28 days of androgen deprivation therapy (ADT) initiation as prognostic for shorter overall survival (OS). We sought to validate this finding using samples from CHAARTED patients treated with ADT +/- docetaxel for mHSPC. Methods: We assayed serum samples drawn ≤28 days from ADT initiation from 233 patients using the same Mesoscale multiplex ELISA assay as the training set. Multivariable Cox proportional hazards models adjusted for ECOG performance status, disease volume, and prior local therapy (radiation/prostatectomy vs. none) with IL-8 as continuous and binary variables. The training median 9.3 pg/mL was the a priori binary cutpoint. Fixed-effects meta-analysis of the training and validation sets was performed. Results: Higher IL-8 levels were prognostic for shorter OS and time to CRPC for ADT alone and ADT + docetaxel (Table) and were independent of disease volume or docetaxel use. Meta-analysis of binary IL-8 levels >9.3pg/mL from patients treated with ADT alone (training + validation cohorts) was prognostic for poorer OS (HR 1.8, 95% CI: 1.2-2.7, p= 0.007) and shorter time to CRPC (HR: 1.4, 95%CI: 0.99-1.9, p=0.057). The validation cohort’s baseline median IL-8 level was similar at 10 pg/mL. Conclusions: Higher IL-8 is prognostic for shorter time to CRPC and OS independent of docetaxel use, disease volume and presentation with metachronous or de novo metastatic disease. These findings support targeting IL-8 as a strategy to improve mHSPC outcomes.[Table: see text]
Plasma cell-free DNA (cfDNA) profiling of copy number variation (CNV) to identify poor prognostic biomarkers in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Kwan Edmond Michael , Fettke Heidi , Bukczynska Patricia , Ng Nicole , Hauser Christine , Graham Lisa-Jane K. , Mahon Kate Lynette , Dai Chao , Xie Feng , Wang Xiaohong , Zhao Zhixin , Zhou Kemin , Du Peter , Yu Jianjun , Jia Shidong , Tan Winston , Horvath Lisa , Kohli Manish , Azad Arun 
Published: February 2020

176 Background: Multiple tumour tissue studies have demonstrated the prognostic utility of CNVs in mCRPC. However, accurate assessment of CNVs in plasma cfDNA remains challenging, and prognostic significance has not been well characterized. Using a large customized panel, we correlated plasma CNVs with clinical outcomes in a contemporary cohort of mCRPC patients. Methods: Deep targeted sequencing was performed using a 180-gene cfDNA panel (Predicine) in 56 patients commencing AR pathway inhibitors (enzalutamide or abiraterone; n = 34) or taxane chemotherapy (n = 22) at two Australian institutions. Kaplan-Meier estimates and Cox proportional-hazards models were used to correlate CNVs with progression-free survival (PFS) and overall survival (OS). Significant results were validated in an independent cohort (Mayo Clinic, n = 144). Results: Median follow-up was 19.4 months (mo; IQR 11.3-31.9). The most common CNVs in the Australian cohort are shown (Table). OS was significantly decreased in patients with PI3KCA gain (median 21.7 mo vs 6.6 mo, p < 0.0001), PTEN loss (24.8 mo vs 11.7 mo, p = 0.0019) and AR gain (21.7 mo vs 12.0 mo, p = 0.0083). Furthermore, all three alterations independently predicted for poor survival in multivariable analyses (MVA; Table). Findings in the independent cohort showed similar OS results in MVA: PIK3CA gain (HR 2.0, p = 0.07), PTEN loss (HR 1.7, p = 0.08) and AR gain (HR 1.7, p = 0.03). Conclusions: Sequencing of plasma cfDNA revealed that PTEN loss, and PIK3CA and AR gain are associated with inferior clinical outcomes in patients commencing contemporary systemic treatment. These data support therapeutic strategies co-targeting the PI3K and AR pathways in mCRPC.[Table: see text]
Copy number amplification of androgen receptor in cell-free DNA is a potential prognostic factor in patients with CRPC.
Authors: Hamano Itsuto , Hatakeyama Shingo , Yoneyama Tohru , Suzuki Yuichiro , Yamamoto Hayato , Imai Atsushi , Yoneyama Takahiro , Hashimoto Yasuhiro , Ohyama Chikara 
Published: February 2020

180 Background: A circulating cell-free DNA (cfDNA) has been suggested as a potential biomarker for castration-resistant prostate cancer (CRPC). However, clinical implication of the parameters in cfDNA remains unclear. We aimed to investigate the impact of copy number variation (CNV) of androgen-receptor amplification (AR-amp) in cfDNA on prognosis in patients with CRPC. Methods: We retrospectively evaluated AR-amp in cfDNA in 154 patients with prostate cancer between April 2018 and September 2019. We compared AR-amp between the patients with CRPC and non-CRPC. An optimal cutoff point was defined using receiver operating characteristic (ROC) curve. The effect of AR-amp on prognosis was evaluated between the CRPC patients with AR-amp high and low. Results: The median age and initial PSA was 75 years and 34 ng/mL, respectively. The number of patients with abiraterone acetate, enzalutamide, docetaxel, cabazitaxel was 24, 15, 21, and 2, respectively. No significant association was observed between the AR-amp and serum prostate-specific antigen (PSA) level at AR-amp measurement. Of 154, 73 (47%) patients developed to CRPC. The AR-amp was significantly higher in the patients with CRPC than that in the non-CRPC (1.07 vs. 0.97, respectively, P<0.001). The cutoff value of AR-amp was defined 1.16 with area under the ROC curve of 0.672. Overall survival was significantly shorter in the patients with AR-amp low (≤1.16, n=46) than that with AR-amp high (>1.16, n=27) (8.9 vs. 9.6 months, respectively, P < 0.001). The AR-amp was not significantly different between the pre- and post-docetaxel status in patients with CRPC. Conclusions: AR-amp in cfDNA might be a potential biomarker for poor prognosis in patients with CRPC who were treated with life-prolonging therapies.
Efficacy of cabazitaxel second-line and beyond.
Authors: Vengalil Salil , Nolan Emma , Sultana Nasira , Joseph Shibu , Bhana Rajanee , El-Helw Loaie 
Published: February 2020

226 Background: Prostate cancer accounts for the 2nd most common cause of cancer deaths in males in the UK. Cabazitaxel (CBZ) is a third generation taxane with activity demonstrated even in docetaxel resistant cases. Results of the TROPIC study established survival benefit for CBZ in metastatic castrate resistant prostate cancer (mCRPC) patients but there was also a higher incidence of febrile neutropenia (FN) reported. We studied the efficacy of CBZ in mCRPC patients treated in our centre and assessed FN rates with the use primary granulocyte colony stimulating factor (GCSF) support. Methods: We conducted a retrospective audit of mCRPC patients treated with CBZ from January 2016 – January 2019. We analysed treatment outcomes, FN rates and potential prognostic factors. Results: There were 42 patients in total with a median age of 70 years (range; 54-91). The median follow up was 9.5 months (range; 2-34 months). Most of our patients had extensive disease, with bone and visceral metastases seen in 88% and 31% respectively. CBZ was given as second line treatment in 15 (35.7%) patients on progression following docetaxel and as third line in 27 (64.3%) patients. Majority of our patients (95%) had WHO PS of either 0 or 1. Median number of cycles of CBZ administered was 6 and 31% of patients completed 10 cycles of treatment. Median biochemical progression free survival (PFS) for patients who received at least 3 or more cycles of CBZ was 6 months and median overall survival (OS) was 11 months. Median OS for patients who received CBZ as 2nd line and 3rd line treatments were 9 and 13 months respectively. Patients with visceral metastases had a median OS of 9 months. Median OS for patients with Haemoglobin (Hb) ≥12gm/dl and lower Hb were 19 and 9 months respectively (p = 0.004). Patients in favourable prognostic group (Normal Hb, Normal albumin and no visceral metastases) had a median OS of 24 months compared to 10 months for those in less favourable group. There were no episodes of FN reported in our group with the use of primary GCSF prophylaxis. Conclusions: CBZ is effective as a 2nd or 3rd line treatment option in patients with mCRPC. Neutropenic complications can be significantly reduced with the use of primary GCSF prophylaxis. Low pre-treatment Hb seems to be a predictor for poor overall survival.