bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical activity and safety of ASN001, a selective CYP17 lyase inhibitor, administered without prednisone in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Garcia Jorge A. , Dreicer Robert , Pantuck Allan J. , Haas Naomi B. , Vaishampayan Ulka N. , Rasco Drew W. , Tyler Allison Janine , Rao Niranjan Sathyanarayana , Bristow Penelope J. , Reddy Sanjeeva , Denis Louis J. , Tolcher Anthony W. 
Published: March 2017

240 Background: ASN001 is a novel, non-steroidal, potent inhibitor of CYP17 lyase. It selectively inhibits synthesis of testosterone over cortisol in the adrenals to avoid the need for co-administration of prednisone. ASN001 also exhibits high oral bioavailability and low potential for drug-drug interaction supporting its use in future combination trials. Methods: This Phase 1/2 clinical trial in men with progressive mCRPC evaluates once-daily, oral ASN001 at escalating doses of 50, 100, 200, 300 and 400 mg (NCT02349139). While the Phase 1 also allowed enrollment of pretreated patients, no prior enzalutamide (ENZA) or abiraterone (ABI) is permitted in Phase 2. Endpoints included maximum dose (MTD) and dose limiting toxicities, recommended Phase 2 dose, pharmacokinetics, effect on steroid hormone biosynthesis and clinical efficacy (PSA and imaging). Results: To date, 23 mCRPC pts have been enrolled. No prednisone was administered and no mineralocorticoid excess has been reported. Overall, ASN001 was well tolerated. Most drug-related adverse events were Gr 1/2 and included fatigue, nausea and dizziness. At 400mg, two pts experienced asymptomatic, reversible Gr 3 elevation of ALT/AST, but no recurrence when retreated at a lower dose (300mg). Testosterone decreased to below quantifiable limits and DHEA decrease of up to 80% was observed in ABI/ENZA naïve patients. Systemic exposure was high (Cmax, AUC and T1/2 at 300 mg QD was 6.7 µm, 80 µm.h and 21.5h, respectively). RECIST defined Stable Disease up to 15+ months has been observed at the 100mg cohort despite prior ABI and ENZA exposure. PSA decline of > 50% (51%-70%) was observed in 3 of 3 ABI/ENZA naïve patients at doses of 300/400mg. Conclusions: Overall, ASN001 was safe and well tolerated without need for prednisone co-administration. Encouraging preliminary evidence of efficacy is based on the PSA decline observed in evaluable mCRPC pts not pretreated with ABI or ENZA and based on durable disease stabilization after progression on ABI and ENZA. Enrollment is ongoing at doses below 400mg QD in ABI/ENZA naïve mCRPC pts. Updated and detailed results will be presented at the meeting. Clinical trial information: NCT02349139.
The role of cytoreductive radical prostatectomy (cRP) in men with hormone-sensitive, metastatic prostate cancer (mPCA).
Authors: Heidenreich Axel , Fossati Nicola , Suardi Nazareno , Montorsi Francesco , Karnes Jeffrey , Shariat Shahrokh F. , Gandaglia Giorgio , Briganti Alberto 
Published: March 2017

241 Background: Androgen deprivation represents the standard treatment for PCA with osseous metastases. We explored the role of cRP in the largest cohort of contemporary patients with mPCA treated in 4 tertiary referral centres. Methods: A total of 114 patients with mPCA, lymph node, osseous or visceral metastases underwent cRP. Surgery related complications (Clavien-Dindo classification) and functional outcome were analysed. Oncologic outcome parameters such as cancer specific & overall survival as well as biochemical and clinical-free survival were evaluated using descriptive statistical analysis. Results: Mean patient age was 61 (42-69) years. Mean and median follow-up was 39.7 months (7-75) and 47 months (28-96), resp. 93 (81.6%) and 21 (18.4%) patients had low volume and high volume mets, resp.,. 80(70.2%) pts underwent neoadjuvant ADT with LHRH analogues. Surgical approach was open retropubic RP in 104 (92%) pts and 2 (1.8%), 10 (8.8%) and 101 (89.4%) pts underwent no, limited or extended pelvic LAD, resp. Adjuvant therapy was delivered in 99 (86.8%) pts. Pathohistology revealed significant vital PCA in 100% of cases: n = 16 (14.0%) exhibited pT4a, n = 21 (18.4%) had pT2 and the remainder had pT3a/b PCA. Positive lymph nodes or positive surgical margins were identified in 61.6% and 36.8%, resp.. 110 (96.5%) are alive and 66.7% are relapse-free. 74 (64.9%) pts did not experience any surgery related complications; 15 (13.1%) pts experienced Clavien Dindo grade IIIb/IV complications and underwent reintervention. Low versus high volume (32.2% vs 50%, p = 0.03), PSA at cRP < 1ng/ml vs PSA > 4 ng/ml, (18.9% vs 45.6%, p = 0.02) were associated with relapse. Low vs high volume disease (7.1% vs 32.1%), PSA < 4ng/ml vs PSA > 4 ng/ml (6.1% vs 47.8%) and neoadjuvant vs no neoadjuvant therapy (8.75% vs 24.2%) were associated with Clavien-Dindo IIIB complications (p < 0.05). Conclusions: cRP is feasible in men with mPCA independent on the extent of disease with a low rate of significant complications and good functional outcome. About two thirds of the patients remain relapse-free after a median follow-up of close to 4 years. cRP might be an individualized treatment option in the multimodality management of mPCA.
Telemedicine-enabled clinical trial of metformin in patients (pts) with biochemically-recurrent prostate cancer (PCa).
Authors: Galsky Matt D. , Shahin Mohamed , Olson Ashley , Shaffer David R. , Gimpel-Tetra Kiev , Tsao Che-Kai , Baker Charles , Leiter Amanda , Holland John , Sablinski Tomasz , Mehrazin Reza , Sfakianos John , Acon Patricia , Oh William K. 
Published: March 2017

243 Background: Clinical trials are critical to informing cancer care but are hampered by slow accrual and suboptimal generalizability, both contributed to by poor geographic accessibility. We previously reported that > 50% of the US population resides > 1 hour from the nearest PCa clinical trial site (Galsky, JAMA Int Med, 2015). We sought to test the feasibility of replacing on-site study visits with telemedicine visits in a prospective clinical trial. Methods: Castration-naïve non-metastatic pts with PCa and a rising PSA after local therapy were eligible. Pts required a single on-site visit for enrollment. Treatment consisted of metformin 850 mg QD x 1 month followed by 850 mg BID x 5 months. Telemedicine visits were conducted monthly using a HIPAA-compliant smartphone application. The primary objective was to determine feasibility defined as completion of all eligible telemedicine visits by > 2/3 enrolled pts; pts were ineligible for future telemedicine visits if treatment discontinued early for toxicity or disease progression. Secondary objectives included safety, % patients with ≤ 20% PSA rise at 6 months, quality of life, and patient satisfaction. Results: 15 pts were enrolled, median age 68 (range, 57, 83), one-way driving time 1.3 hours (range, 0.2-2.8), Gleason score 7 (range, 6, 9), and pre-study PSA 4.1 (range, 0.52, 31.7). The 6 month course of metformin was completed by 11/15 (73%) pts; 2 discontinued early due to rising PSA, 1 due to adverse event (AE), and 1 remains on study. Excluding 1 pt still on study, 14/14 (100%; 95% CI 76, 100) pts completed all 78 eligible telemedicine visits. The most common AEs were diarrhea (grade 1 = 60%) and fatigue (grade 1 = 20%); 1 pt experienced grade ≥ 3 AE (dehydration). The 6-month PSA was ≤ 20% baseline in 1 pt; median % PSA change at last televisit was +52.8% (range, -3.0, +318.8). Quality of life and pt satisfaction will be reported at the meeting. Conclusions: To our knowledge, this is the first ever interventional oncology clinical trial conducted via telemedicine. Telemedicine-enabled trials are feasible and may overcome barriers to trial participation. Metformin was generally well tolerated but associated with minimal anti-PCa activity as measured by PSA. Clinical trial information: NCT02376166.
A phase II study of muscadine grape skin extract in men with biochemically recurrent prostate cancer.
Authors: Paller Channing Judith , Heath Elisabeth I. , Taplin Mary-Ellen , Stein Mark N. , Bubley Glenn J. , Pili Roberto , Mayer Tina M. , Zhou Xian Chong , Hudson Tamaro , Abbas Muneer , Anders Nicole , Dowling Donna , KIng Serina , Drake Charles G. , Antonarakis Emmanuel S. , Eisenberger Mario A. , Denmeade Samuel R. , Rudek Michelle A. , Rosner Gary L. , Carducci Michael Anthony 
Published: March 2017

248 Background: Pulverized muscadine grape ( Vitis rotundifolia) skin (MPX) is a potential therapeutic option for men with biochemically recurrent (BCR) prostate cancer (PCa) wishing to defer androgen deprivation therapy. MPX demonstrated antitumor effects in PCa through antioxidant activity of its principal polyphenol components, ellagic acid, quercetin, and resveratrol. A Phase I trial demonstrated safety of MPX in doses up to 4000 mg/day. Methods: This is a 12-month, multi-center, placebo-controlled, two-dose, double-blinded trial of MPX (manufactured by Muscadine Naturals Inc. in Warsaw, NC) in 125 men with BCR PCa. Participants were stratified by baseline PSADT and Gleason score, with no restrictions for PSADT and no upper limit PSA value. Patients were randomly assigned 2:2:1 to receive 4000 mg (8 capsules) of MPX, 500 mg (1 capsule) of MPX plus 7 capsules of placebo, or 8 capsules of placebo. PSA levels were obtained every 3 months The trial was powered to detect a statistically significant between-group difference of around 6 months (low dose) and 12 months (high dose) in PSADT relative to placebo. Results: The intention to treat (ITT) population included 116 patients, of which 97% were treated for up to 6 and 58% were treated for up to 12 months. This ITT population was 79% white, with median age 68 years, 47% with Gleason score ≤ 6 or 3+4, and 12% with ECOG status of 1. Median PSADT in the ITT population lengthened from 7.5 months at baseline (range 1.4 to 74.6) to 9.8 months after treatment (range 2.3 to 151.5) (p < 0.001). There was no significant treatment difference in PSADT between the control and the treatment groups (p = 0.84). Eighteen percent (21/116) of men had a post-baseline PSADT of more than 200% of baseline. No clinically significant toxicities were seen. Conclusions: These data suggest that both 500 and 4000 mg of MPX are safe. The lengthening PSADT in patients treated with MPX is not significantly greater than that provided by placebo. A subgroup analysis of patients more likely to benefit (those with the AA genotype of MnSOD) is ongoing. Clinical trial information: NCT01317199.
Patient NCCN risk classification based on combined clinical cell cycle risk (CCR) score.
Authors: Stone Steven , Reid Julia E. , Brawer Michael K. 
Published: March 2017

249 Background: Improved prognostic tools for newly diagnosed prostate cancer are needed to more appropriately match treatment to a patient’s risk of progression. The cell cycle progression (CCP) score is a highly validated prognostic RNA expression signature which has been combined with CAPRA (CCR, combined clinical cell cycle risk score) to generate an estimate of prostate cancer mortality (PCM) within 10-years of diagnosis. Here, we evaluate how the prognostic information from CCR can reclassify patients compared to their initial assignment to an NCCN risk category based on clinicopathologic features alone. Methods: The CCR score was previously validated and is calculated as a linear combination of CAPRA and CCP score (0.39 x CAPRA + 0.57 x CCP). A risk reclassification scheme was applied to patients tested by the Myriad Genetics commercial laboratory (N = 16,442). First, PCM risk was assigned based on the patient’s CCR score. Next, patients whose PCM risks were outside the interquartile range (IQR) of their NCCN risk category were reclassified according to whether their PCM risks fell within the IQR of another NCCN risk category. Finally, patients whose PCM risks were below (or above) the IQR of the NCCN low (or high) category were reclassified as low (or high). Results: Based on clinicopathologic features alone the commercial cohort was classified according to NCCN Guidelines as low (N = 8,695), favorable intermediate (N = 3,347), intermediate (N = 3,086), or high risk (N = 1,224). After calculating patient risk of PCM based on CCR, 25% of the NCCN low risk men were reclassified to favorable intermediate or intermediate risk; 47% of the NCCN favorable intermediate risk men were reclassified (24% lower and 23% higher); 49% of the NCCN intermediate risk men were reclassified (24% lower and 25% higher); and 25% of the NCCN high risk were reclassified to favorable intermediate or intermediate risk. There is no outcome data associated with commercial samples. Conclusions: The prognostic information in the CCR score results in significant amounts of risk reclassification for all patients with localized disease when compared to stratification based only on NCCN risk categories.
Cost-effectiveness analysis of magnetic resonance imaging-ultrasound fusion biopsy versus systematic transrectal ultrasound-guided biopsy in diagnosing prostate cancer.
Authors: Ingham Matthew , Mossanen Matthew , Wang Ye , Chang Steven Lee 
Published: March 2017

25 Background: We sought to determine if the reported improved performance of magnetic resonance imaging-ultrasound (MRI-US) fusion biopsy over systematic transrectal ultrasound-guided biopsy (TRUS) in the detection of prostate cancer justifies the added cost of the MR imaging. Methods: A decision-analytic Markov model with a lifetime horizon of 10 years was developed to evaluate diagnostic accuracy, long-term health outcomes, costs, and quality-of-life of two strategies (i.e., TRUS versus MRI-US fusion biopsy [prostate MRI followed potentially by MRI-US fusion biopsy]) as the initial diagnostic test in men with elevated prostate-specific antigen ( > 4 ng/ml) without prior evaluation. Probabilities of clinical events were obtained from published literature. Direct medical costs, including diagnostic and treatment-related costs, were derived from the Premier Hospital Database. Costs were inflated to 2015 US dollars and discounted at an annual rate of 3%. Health outcomes were measured in quality-adjusted life years (QALYs), which were determined based on published literature and expert opinion. We calculated the incremental cost-effectiveness ratio and performed sensitivity analyses to assess uncertainty. Results: The MRI-US fusion biopsy strategy yielded a lower average discounted cost ($5,358 versus $6,372) and higher total QALYs-gained (7.21 versus 7.19) than TRUS. The reduced expenditures associated with MRI-US fusion biopsy was primarily due to avoiding intervention for clinically insignificant prostate cancer. The results were robust with the sensitivity analyses. Conclusions: For men in the United States with an elevated PSA, the use of MRI-US fusion biopsy in the evaluation for prostate cancer represents a greater value than TRUS, the standard of care option. Widespread adoption of MRI-US fusion biopsy may serve to reduce the economic burden of prostate cancer.
Liver metastases in mCRPC patients post-therapy with abiraterone (Abi) and/or abiraterone/enzalutamide (Enza).
Authors: Ranasinghe Lahiru , Cotogno Patrick , Ledet Elisa M. , Steinberger Allie E. , Feibus Allison H. , Degeyter Kyle , Bordlee Bruce , Sartor Oliver 
Published: March 2017

250 Background: Liver metastases (mets) are a particularly poor prognostic group among mCRPC patients. The objective of this study is to characterize mCRPC patients who have had treatment with Abi or Enza to identify risk factors that may be associated with subsequent development of liver mets. Methods: A sample of 67 patients (n = 17 liver mets and 50 non-liver met patients matched by treatment history) seen at Tulane Cancer Center were selected for analysis. All patients had prior Abi and or Abi/Enza. Race, age at PCa diagnosis and Gleason Score at PCa diagnosis were assessed. For patients with liver mets, total liver metastatic volume was measured using CT scans and correlated against PSA, LDH and AST values at the time of the scan. Wilcoxon rank sum tests were run analyzing PSA, LDH and AST at the start of Abi treatment, end of Abi treatment as well the duration of Abi treatment, and the nadir PSA for these patients. Results: Patients were predominantly Caucasian, had a median Gleason Score of 8 at diagnosis and were at a median age of 57 for those with liver mets and 62 for non-liver met at PCa diagnosis. Pearson correlation analysis of the total liver lesion volume and lab values revealed a significant correlation for LDH (R = 0.491, < 0.01) and AST (R = 0.368, p < 0.05), but not for PSA. Further evaluation of PSA and AST values at the start and end of Abi treatment as well as at nadir PSA revealed no statistically significant differences between liver met patients and non-liver met patients. However, there was a significant difference (p = 0.015) between LDH levels at the end of Abi treatment with a median of 347 U/L for liver met and 238 U/L for non-liver met patients. Conclusions: LDH and AST levels correlate with extent of liver metastases. Additionally, elevated LDH at the end of Abi treatment is indicative of an increased risk for developing liver metastases. Larger sample sizes and molecular characterization of these tumors are required to gain more insights into this important patient population.
AR amplification eradication with high-dose testosterone (T) in patients with heavily pretreated mCRPC.
Authors: Cotogno Patrick , Ledet Elisa M. , Schiff Joshua , Manogue Charlotte , Lewis Brian E. , Sartor Oliver 
Published: March 2017

251 Background: Patients (Pts) with mCRPC resistant to novel hormones (abi/enza) and taxanes pose a challenge for clinicians. Typically, once these agents are exhausted, clinical trials represent the best therapeutic option; however, many pts are not appropriate for clinical trials due to marrow suppression and/or extensive pre-treatments. Herein we present limited experience with three pts treated with high dose T when therapeutic clinical trial options were not available. Methods: Data was retrospectively collected at Tulane Cancer Center for pt treatment history, laboratory parameters, and circulating free-DNA genomic testing. High dose testosterone was used at a dose of 87.5-100 mg given daily as a 1% testosterone gel applied to the skin. Results: All the mCRPC patients were pre-treated with abi, enza, taxanes, & radium-223. All pts had RBC transfusions due to marrow suppression. All patients were previously treated on clinical trials. After starting high dose T, pt 1 demonstrated a clinical improvement in energy and appetite with a PSA decline from 530 to 45.8 ng/ml (-91.4%) over 30 days. At baseline, cfDNA analyses measured 15.9X AR amplification and 3.7X MYC amplification. The cfDNA also contained 9.8% of P53R273H mutation. Post high-dose T (serum T from castrate to 1462 ng/dL), both of the cfDNA measured amplifications returned to normal and P53 mutation declined to 0.5%. The PSA nadir occurred 30 days after T start; T was stopped 96 days after starting because of PSA rise to 280 ng/ml. The pt then restarted abi, despite prior resistance, and PSA declined from 280 to 65 ng/ml (-76.6%). The 2 other patients had PSA increases and clinical deterioration and high dose T was stopped after 2-3 weeks. Conclusions: Response to high dose T has been reported in occasional case reports going back over 60 years ago (see Brendler H et al. Arch Surg 1950;61:433–40). The frequency of favorable responses is unknown. In one case, a reversal of AR and MYC amplification was observed. The responding patient then was re-sensitized to abi, a drug to which he was previously resistant. Further research, such as the TRANSFORMER trial, is needed to understand the molecular changes and treatment options for this population.
Validation of the total illness burden index for prostate cancer (TIBI-CaP) in men with castration-resistant prostate cancer (CRPC): Data from TRUMPET.
Authors: Flanders Scott , Wilson Samuel D. , Kim Janet , Greenfield Sheldon , Kaplan Sherrie H. , Billimek John , Barlev Arie , Wong Elaine , Lin Daniel W. , Karsh Lawrence Ivan , Quinn David I. , Shevrin Daniel H. , Shore Neal D. , Symanowski James Thomas , Penson David F. 
Published: March 2017

256 Background: The TRUMPET registry is a prospective, observational cohort study of patients (pts) with CRPC designed to evaluate treatment patterns and health-related quality of life (HRQoL) outcomes associated with CRPC and its management in a real-world setting. Comorbidities may influence how physicians approach CRPC treatment; therefore, evaluation of comorbidity presence and severity is important. The TIBI-CaP questionnaire measures comorbidity, with the aim of this analysis to validate TIBI-CaP in CRPC. Methods: Data were collected from 302 enrolled CRPC pts treated in academic and community-based sites under routine care. Baseline data collected included clinical history and self-reported demographics, comorbidities, and HRQoL. TIBI-CaP scores were analyzed based on correlation analysis and analysis of variance (ANOVA). Estimated correlations were used to verify the association of TIBI-CaP scores to scores on the SF-12v2 and FACT-P questionnaires. ANOVA models were run with SF-12v2 and FACT-P as response and quartile ranges for TIBI-CaP scores as predictor. Results: Mean age was 73.7 years. 84.7% were white; 13.9% were black. 87.8% had M1 CRPC at study entry. Mean (SD) TIBI-CaP score was 5.3 (2.72) [range 0-13], with 42.4% of CRPC pts presenting with moderate/severe comorbidity burden (higher scores). TIBI-CaP scores had statistically significant (p value < 0.0002) negative correlations with all SF-12v2 composite and domain scores. Correlation estimates for physical condition and mental condition scores were -0.46 and -0.23, respectively. TIBI-CaP scores also had statistically significant (p value < 0.02) negative correlations with FACT-P total scores and all subscales. FACT-P total scores had a -0.44 correlation estimate. F-tests showed significant differences across the four quartiles of TIBI-CaP scores and SF-12v2 and FACT-P (all p values < 0.05). Conclusions: At baseline, TIBI-CaP scores were negatively correlated with CRPC pts baseline functional status as measured by the SF-12v2 and FACT-P questionnaires. TIBI-CaP was strongly associated with HRQoL physical subscales. This analysis demonstrates validity of TIBI-CaP in CRPC pts.