bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting reciprocal feedback inhibition: Apalutamide and everolimus in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Rathkopf Dana E. , Slovin Susan F. , Morris Michael J. , Danila Daniel Costin , Delacruz Anthony , Shelkey Gregory , DeNunzio Mia , McLaughlin Brigit , Scher Howard I. 
Published: March 2017

204 Background: Studies in xenograft CRPC and PTEN-deficient prostate cancer models have shown synergistic anti-tumor activity of next-generation anti-androgens such as apalutamide when combined with PI3K/mTOR inhibitors such as everolimus. (Carver B et al., Cancer Cell 2011) The primary hypothesis of this study was that the combination of apalutamide with everolimus would overcome resistance to prior hormonal therapy with abiraterone acetate and prednisone (AAP). Methods: The primary endpoint in mCRPC patients with prior AAP was to evaluate the safety, pharmacokinetics (PK), and recommended phase 2 dose (RP2D) of fixed dose apalutamide 240 mg po qd when combined with everolimus 5 mg po qd (cohort 1, n = 3) and everolimus 10 mg po qd (cohort 2, n = 6). The plan was to expand to treat 40 patients at the RP2D. Results: Nine patients were enrolled in phase 1. The PK for the combination was consistent with historical data of either drug given as monotherapy. The most common treatment related adverse events were < = grade 2 fatigue (67%), diarrhea (56%), and anorexia (56%). In cohort 2, 1 patient had a DLT of grade 3 rash. The median time on treatment was 17 weeks (range 7-51+). The best response was SD in all 9 patients. Patients came off study for: progression (n = 3), investigator choice (n = 3) and toxicity unrelated to treatment (n = 2). Seven patients had detectable CTCs at baseline (EPIC Sciences). One patient had a rise in CTC number that then converted to undetectable and remained on study 37 weeks. One out of 6 evaluable patients had PTEN loss in tissue at baseline (MSK IMPACT) and remained on study 12 weeks. One patient with prior AAP and enzalutamide exposure has remained on study 51+ weeks with a > 50% decline in PSA (PTEN pending). Conclusions: Although the combination of apalutamide and everolimus was safe and well tolerated, the treatment response was similar to historical data of AAP followed by apalutamide alone. (Rathkopf D et al., ASCO 2014) We elected to close this study before expansion in favor of evaluating novel AR/PI3K pathway combinations in patients who have not yet been exposed to AAP. Drug provided by Janssen and Novartis. Trial support: PCF and MSK Experimental Therapeutics Center. Clinical trial information: NCT02106507.
Real-world outcomes in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) receiving second-line (2L) chemotherapy (CT) vs alternative androgen receptor-targeted agents (ARTA) after lack of response to first-line (1L) ARTA in US community oncology practices.
Authors: Oh William K. , Cheng Wendy Y. , Miao Raymond , Vekeman Francis , Gauthier-Loiselle Marjolaine , Duh Mei Sheng , Drea Edward , Szatrowski Ted P. 
Published: March 2017

214 Background: The relationship between treatment sequence and mCRPC outcomes is unclear. This retrospective study assessed if 2L CT vs alternative ARTA is associated with improved outcomes in pts with lack of response to 1L ARTA in the US community oncology setting. Methods: Using Altos electronic medical records, we identified 345 mCRPC pts with lack of response to 1L ARTA (abiraterone or enzalutamide) who received 2L docetaxel or cabazitaxel (CT cohort N = 147), or alternative ARTA (ARTA cohort N = 198) from May 2011 to Oct 2014. Outcomes were evaluated from start of 2L therapy and compared for 2L CT vs ARTA cohorts using one-sided tests. Prostate-specific antigen (PSA) response ( ≥ 50% reduction) and overall survival (OS) were assessed using logistic and Cox proportional hazard regression models adjusted for year, age, metastases, opioid use, ECOG performance score, PSA, hemoglobin (Hb), alkaline phosphatase (ALP), lactate dehydrogenase (LDH) and albumin (Alb) levels. Results: At start of 2L therapy, pts receiving CT vs ARTA were younger (median age, 74 vs 79 yr) and had a worse prognosis: higher mean PSA (439 vs 231 ng/mL), LDH (344 vs 234 U/L) and ALP (241 vs 166 U/L), lower mean Hb (11 vs 12 g/dL), higher mean Halabi risk score (159 vs 137; JCO 2014:32;671–7), increased opioid use (42 vs 22%), and more pts had Alb < lower limit of normal (LLN; 25 vs 15%); all p < 0.01. More pts in the CT vs ARTA cohort had a PSA response (adjusted odds ratio = 2.27, p = 0.005) and there was a non-statistically significant trend toward improved OS for 2L CT vs ARTA (adjusted hazard ratio [aHR] = 0.81, p = 0.148). Among pts with poor prognostic features, those in the CT cohort had significantly improved OS (Halabi intermediate–high risk score: aHR = 0.55 p = 0.009; Hb < 11 g/dL: aHR = 0.41 p = 0.002; LDH > upper limit of normal: aHR = 0.18 p = 0.014; Alb < LLN: aHR = 0.42 p = 0.020), compared with those in the ARTA cohort. Conclusions: Treatment with 2L CT, vs 2L ARTA, may be more suitable for pts with a lack of response to 1L ARTA, particularly in pts with a poor prognosis. Funding: Sanofi Genzyme.
The use of five-alpha reductase inhibitors and their association with reclassification and pathologic outcomes in the Canary Prostate Active Surveillance Study (PASS).
Authors: Kearns James T , Faino Anna V , Newcomb Lisa F , Brooks James D. , Carroll Peter , Dash Atreya , Ellis William J , Fabrizio Michael , Gleave Martin , Morgan Todd Matthew , Nelson Peter S , Thompson Ian Murchie , Wagner Andrew , Zheng Yingye , Lin Daniel W. 
Published: March 2017

22 Background: The outcomes of patients who enroll in active surveillance (AS) programs for prostate cancer (PCa) while currently taking five-alpha reductase inhibitors (5-ARIs) have not been well defined. Previous studies suggest that the initiation of 5-ARIs after enrolling in AS decreases the rate of reclassification and/or treatment for PCa, but there is still an FDA black box warning about the risk of grade risk prostate cancer while on 5-ARI. The objective of this study was to evaluate the safety of remaining on a 5-ARI after initiating AS for PCa. Methods: All men were enrolled in PASS. Inclusion criteria were current or never 5-ARI user, Gleason 3+3 or 3+4 PCa at diagnosis, ≤ 34% core ratio at diagnosis and ≥ 1 surveillance biopsy. Reclassification was defined as an increase in Gleason score and/or ratio of biopsy cores positive for cancer to ≥ 34%. Results: 1045 men were included in this study, 938 who had never used a 5-ARI and 107 5-ARI users. 5-ARI users had larger prostate volume (51 cc vs 40 cc, p < 0.01), a higher rate of BPH (77% vs 29%, p < 0.01) and older age (65 vs 62 years, p < 0.01). All other clinical parameters, including serum PSA, were statistically similar. Kaplan Meier analysis of any reclassification is shown in the figure. There was no significant difference in any reclassification (p = 0.12). The use of 5-ARI at diagnosis was significantly protective for reclassification in a proportional hazards model (HR 0.68, p = 0.03); this difference was not significant after accounting for serum PSA, BMI, prostate size and positive cores ratio at diagnosis (HR 0.78, p = 0.18). There was no significant effect on adjusted analysis when evaluating for disease upgrading. 171 patients underwent radical prostatectomy (RP), 158 never 5-ARI users and 13 5-ARI users. There were no statistically significant differences when evaluating for Gleason grade or adverse pathology. 5-ARI users had a longer median time to RP (3.6 vs 2.1 years, p = 0.045). Conclusions: There is no association between 5-ARI use at diagnosis and reclassification on AS for men in the Canary PASS cohort. 5-ARI users have a longer median time to RP and do not have more severe PCa at RP.
Randomized phase II trial of sipuleucel-T immunotherapy preceded by sensitizing radiation therapy and sipuleucel-t alone in patients with metastatic castrate resistant prostate cancer.
Authors: Twardowski Przemyslaw , Wong Jeffrey Y.C. , Pal Sumanta K. , Frankel Paul Henry , Franklin Kelly , Junqueira Maribel , Prajapati Manisha R. , Harwood Deborah , Agarwal Neeraj 
Published: March 2017

222 Background: Sipuleucel-T (sip-T) is an autologous cellular vaccine indicated for patients (pts) with asymptomatic or minimally symptomatic metastatic castration resistant prostate cancer (mCRPC). Since radiation therapy (RT) can suppress the bone marrow function and immune response, previous studies evaluating sip-T excluded pts who received RT less than or equal to 28 days prior to sip-T therapy. Recent evidence suggests that RT may act synergistically with immunotherapy to enhance and broaden antitumor immune response. Methods: Pts who met standard criteria for sip-T were randomized to receive sip-T alone (Arm A) or sip-T initiated 1 week after completing sensitizing RT to single metastatic site (Arm B). RT was delivered at 300cGy/day to 3000 cGy total. The primary endpoint was the ability to safely combine sip-T preceded by RT and generate sip-T product with adequate immune activation parameters. Secondary endpoints included the measurement of immune responses to prostatic acid phosphatase (PAP) and PA20204 (recombinant fusion protein utilized in the generation of sip-T). Results: 51 pts were enrolled, 2 did not receive any sip-T because of vascular access problems and were excluded. 24 were treated on Arm A, 25 on Arm B. 47/49 pts received all 3 sip-T infusions. Median age was 66 yrs (range 45-90). Sip-T product parameters including: total nucleated cell (TNC) count, antigen presenting cell (APC) count and APC activation were similar in both groups. 2 pts on Arm A demonstrated PSA response. Median progression free survival (PFS) was 3.0 months on Arm A and 4.6 months on Arm B (p = 0.19). Both arms showed similar increases in humoral responses to PA2024 and PAP. IFN-ƴ ELISPOT T-cell activation responses to PA20204 were observed in both arms, but were more robust in the Arm A (p = 0.04). Both arms were well-tolerated, with fatigue as the most common grade 2 adverse event (1 pt in Arm A and 3 pts in Arm B). Conclusions: Sensitizing RT completed 1 week before generation of sip-T did not affect product parameters and the ability to deliver sip-T therapy. RT did not enhance the humoral and cellular responses associated with sip-T therapy. Clinical trial information: NCT01807065.
Comprehensive genomic sequencing of prostate sarcomatoid carcinoma tumors identifies differences in genomic alterations compared to prostate adenocarcinoma tumors.
Authors: Millis Sherri Z. , Stephens Philip J. , Ross Jeffrey S. , Miller Vincent A. , Ali Siraj Mahamed , Wang Jue 
Published: March 2017

226 Background: Sarcomatoid carcinoma of the prostate is a rare variant of prostatic cancer and has a significantly worse prognosis. The genomic features underpinning this rare subtype of malignancy are not well understood, and at present, there are no effective therapies. Methods: Tissue from 1417 prostate cancer patients was assayed by hybrid-capture based comprehensive genomic profiling (CGP) in the course of clinical care to evaluate genomic alterations (GA: base substitutions, indels, amplifications, copy number alterations, fusions/rearrangements) and targeted therapy opportunities. Tumor mutational burden (TMB) was calculated from a minimum of 1.11 Mb sequenced DNA and reported as mutations/Mb. Results: Profiling identified different patterns in GAs between prostate adenocarcinoma (1409) and prostate sarcomatoid carcinoma (8) (table), most notably in the commonly identified alterations in prostate cancers: TP53, RB1, and TMPRSS2-ERG. Additionally, the PI3K/mTOR pathway was altered in 50% of the sarcomatoid carcinoma cohort. None of the sarcomatoid carcinoma patients had a high TMB, while 4% of the prostate adenocarcinomas had TMB greater than 19 mutations/Mb. The sarcomatoid carcinoma cohort also had on average 8 GAs, while the prostate adenocarcinoma cohort had an average of 13 GAs. Conclusions: Genomic profiles of tumors from patients with prostate cancers reveal that those with sarcomatoid carcinoma features are more likely to have genomic alterations in TP53, RB1, and TMPRSS2 but fewer overall GA’s. Based on rearrangements and the sarcoma profile, utilization of a broad CGP panel that includes analysis of a larger panel of rearrangements identifies more commonly rearranged genes that would not be identified in non-comprehensive panels that do not evaluate these rearrangements. These findings may contribute to a better understanding of the oncogenesis of sarcomatoid prostate carcinoma and for defining novel systemic treatment options. [Table: see text]
Predictors of long-term response to abiraterone acetate with prednisone and cabazitaxel after first-line docetaxel in patients with metastastic castration-resistant prostate cancer (mCRPC): Subgroup analysis of a prospective observational study.
Authors: Sala Nuria , Méndez-Vidal María José , Pinto Alvaro , Puente Javier , Rodriguez Sanchez Angel , Cuevas Sanz Jose Miguel , Vazquez-Estevez Sergio , Muñoz del Toro Jacobo , Ruiz Pedro , Garcia Angela , Gonzalez del Alba Aranzazu 
Published: March 2017

227 Background: Recently treatment options for mCRPC have increased considerably. It remains unclear if there is any predictive factor to recognize which patients (pts) could obtain the most benefit in second line (2L) mCRPC. Recent data have been published addressing long-term predictive factors in a retrospective cohort in 2L1. We aim to reproduce it in this prospective study. Methods: The CAPRO study is a prospective multicenter national observational descriptive study. The primary endpoint was to describe the management in 2L mCRPC pts after DOC in routine clinical practice. To characterize which factors are associated with a better response in 2L mCRPC, we performed a multivariant analysis in the subgroup of pts with a long-term response (long-term responders (LTR): pts receiving abiraterone acetate + prednisone (AA) or Cabazitaxel (CB) for > 12 mo). Results: 150 patients were recruited (Jul 2013-Jan 2015). We identified 36 LTR (29/100 with AA: (29%) and 7/44 (15.9 %) with CB as 2L. No statistical differences in the number of LTR treated with AA vs CB (p = 0.095) were observed. LTR group (before starting 2L): median age 77.2 (51-87) median PSA 56.7 ng/dL (5.3-2627 ng/dL), alkaline phosphatase 92.5 IU/L (44-630 IU/L) and LDH 221.5 IU/L (147-445 IU/L). At median follow-up of 7.8 mo (IQR 4.2- 12.8), median PFS (clinical and/or radiological) was significantly longer in LTR AA group (not yet reached) vs LTR CB group 18.14 [95% CI 12.67-23.6]; HR 0·29 [95% CI 0,092 – 0,918; p = 0.025]. In a multivariate analysis two factors were significantly associated with LTR in 2L mCRPC: Gleason score < 7 (OR: 0.22 95% CI 0.065-0.745, p = 0.015) and normal LDH ( < 250 IU/L) (OR: 0.235, 95% CI 0.093-0.595, p = 0.002). No differences in safety profile between LTR vs non LTR of AA group and CB group were found. Conclusions: In this final subgroup analysis we observed Gleason score < 7 and LDH < 250 IU/L are predictors of long term response in 2L mCRPC. Median PFS in LTR treated with AA was significantly longer than LTR treated with CB. These findings need to be validated in further larger prospective studies.
Assessment of urologists experience with abiraterone acetate and with a real-world trial: Results obtained from a Canadian Observational Study in Metastatic Cancer of the Prostate (COSMiC).
Authors: Feifer Andrew , Fradet Vincent , Drachenberg Darrel , Gotto Geoffrey , Rendon Ricardo A. , Sabbagh Robert , Shayegan Bobby , Danielson Brita Lavender , Casey Richard , Zardan Anousheh , Camacho Fernando , Hew Huong 
Published: March 2017

238 Background: Abiraterone Acetate (AA) is a selective inhibitor of the androgen biosynthesis and has significantly improved OS for mCRPC patients. Canadian Observational Study in Metastatic Cancer of the Prostate (COSMiC) is a Non-Interventional Observational Study pPhase IV clinical trial; NCT02364531) specifically designed to (1) collect real-world drug-specific outcomes (clinical and patient reported outcomes) and (2) assess urologists experience with incorporation of AA in their practice. Here we report data collected from COSMiC trial on the success of AA integration into the urology practice and physicians experience in participating in the trial. Methods: (1) A comprehensive questionnaire was developed to assess urologists experience with (a) integration and usage of AA in their practice and (b) COSMiC trial. (2) Questionnaire was sent to the active trial sites (47 sites) and collected data from 30 sites is summarized here. Results: 93.3% of participants in COSMiC trial were urologists (63.3% community vs. 30% academic). The ease of use and success in integration of AA in urology practice was rated easy by 50% of the participants, easy once they overcame few barriers by 46.7% and challenging by 3.3%. Drug-related barriers identified included time involvement (50%), resource issues such as nursing support (23.3%), and lack of appropriate infrastructure (33.3%). 90% of the active sites indicated that treating mCRPC patients with AA will be part of their practice post-trial. As part of this report we also assessed and identified physicians barriers in participating in COSMiC trial. 86.7% of the sites reported that trials such as COSMiC will add value to the therapeutic area and 93.3% of the sites reported interest in participating in trials of this nature in future. Conclusions: This report indicates that integration of AA in urology practices is considered easy and manageable for most urologists, in some cases after overcoming few initial barriers. There is high interest in participating in future real-world trials of this nature among urologists and such studies add value to the therapeutic area. Clinical trial information: NCT02364531.
National, centralised hospital datasets can inform clinical trial outcomes in prostate cancer: A pilot study in the STAMPEDE trial.
Authors: Mintz Harriet Paige , Evison Felicity , Parsons Helen M , Sydes Matthew Robert , Spears Melissa Ruth , Patel Prashant , James Nicholas D. ,   The STAMPEDE Trial Group
Published: March 2017

257 Background: Hospital Episode Statistics (HES) are routinely collected data describing National Health Service (NHS) hospital visits in England, with procedure & disease codes. This study, embedded in STAMPEDE, aimed to build a model using HES, linked to primary medical records & trial case report forms (CRFs) to identify progressive disease events (PDEs), including skeletal-related events (SREs). Methods: Analysis of 5 STAMPEDE patients (pts) in 2 stages (data to Jul 16). 1: Detailed manual note review of 3 pts’ PDEs were compared to HES & CRFs to build model. 2: Used model to use HES to identify possible PDEs in 2 pts, verified by note review & compared to CRFs. Created algorithm rules to identify PDEs per 8 week interval plus further analysis of HES coding to find SREs. Results: Prostate cancer PDEs coincided with clustering of HES events. HES found 4 PDEs omitted from CRFs but missed 2 (total PDEs: HES 10, CRFs 8). HES found a false positive CRF PDE. Compared with note review HES missed 4 PDEs (false negatives), with 2 missed & 2 upgraded to PDEs post-standard query procedures, plus HES found 3 false positives (1 STAMPEDE treatment & 2 delayed treatments post-PDE). Hence HES found 71% of PDEs in note review (HES 10, note review 14).CRFs found 57% of PDEs compared to note review (CRFs 8, note review 14). Hence HES found 14% more PDEs than were recorded in CRFs compared to note review. HES identified 4 additional SREs not recorded in CRFs but missed 2. Conclusions: Hospital record review revealed site staff may miss reporting major clinical efficacy outcome events on CRFs, especially nearer end-of-life. HES successfully identified most PDEs (often found as a cluster of SREs), plus additional trial events not reported on CRFs compared to note review and as predicted HES & CRFs found less PDEs. PDEs & SREs missed from CRF recording can be identified in HES.This confirmed use of HES to detect PDEs is feasible. HES-identified events have potential as a primary data source when subsequently verified by standard data queries. Future work will test this model prospectively in the forthcoming BladderPath trial. It may offer a superior, cost-effective method of primary data collection compared to traditional CRF recording.
An update on clinical outcome data for a phase II randomized study comparing androgen deprivation therapy plus docetaxel versus androgen deprivation therapy alone in men with locally advanced/metastatic hormone sensitive prostate cancer.
Authors: Hassani Adam , Frew John A. , McMenemin Rhona Margaret , Azzabi Ashraf S. , Pedley Ian D. 
Published: March 2017

259 Background: Androgen deprivation therapy has been the standard of care for advanced prostate cancer for many years. However recent studies have reported a survival benefit for upfront docetaxel chemotherapy in men with hormone sensitive prostate cancer. The GenTax trial was a single institution phase II study investigating clinical outcome and gene profiling for patients with treatment naïve prostate cancer treated with either docetaxel chemotherapy plus androgen deprivation therapy (D+ADT) or androgen deprivation therapy alone (ADT). We report on updated clinical outcome data for this trial. Methods: Patients with newly diagnosed T3/T4, PSA ≥ 50ng/ml or Gleason score ≥ 8, or metastatic disease were enrolled. Patients were randomised to ADT or D+ADT (docetaxel 75mg/m2 q21 days for 6 cycles). Data were analysed for overall survival, toxicities, time to second line treatment and number of subsequent treatments. Results: 30 patients were randomly assigned to ADT (n = 15) or D+ADT (n = 15) between 10/13/2005 and 12/02/2009. 7 patients in each arm had metastatic disease. Grade 3-4 toxicities were infrequent in D+ADT arm and were not noted in the ADT arm. There were no significant differences between treatment arms for overall survival (log rank p = 0.977) or time to second line treatment (log rank p = 0.954). Median overall survival was 98 months (95% CI 72.3 - 123.7) for ADT and 87 months (95% CI 71.5 - 102.5) for D+ADT. Median time to second line treatment was 45 months (95% CI 13.4 - 76.6) for ADT and 46 months (95% CI 13.2 – 78.8) for D+ADT. Number of subsequent treatments ranged from 0-6 (mean 2.40) for ADT-only and 0-5 (mean 2.13) for D+ADT. Conclusions: The combination of docetaxel and ADT in the hormone sensitive setting is well tolerated, as previously reported. This study was not sufficiently powered to detect statistically significant differences in survival. Patients proceeded to receive a number of subsequent lines of therapy although the order in which these were given was variable. There is a need to establish optimal sequencing of treatments in the upfront docetaxel era. Clinical trial information: 2004-004874-96.