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PubMed | McKesson, Health-U, Sanofi S.A., Texas Oncology Baylor Charles mmons Cancer Center and 5 more.
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2017

79 Background: Following docetaxel (D), treatment options for mCRPC include cabazitaxel (CBZ), abiraterone acetate (AA), and enzalutamide. With the introduction of new agents, optimal sequencing is undefined. We evaluated the prevalence of sequencing of AA and CBZ following D in a large community-based cohort to develop a hypothesis for the most optimal sequence.A retrospective analysis of treatment patterns using the MSH iKnowMed EHR was conducted. Post-D mCRPC patients receiving CBZ and/or AA at full EHR sites with 2 visits were included; clinical trial patients excluded. CBZ utilization between Jun10 and May12 and sequencing of CBZ or/and AA from Apr11 and May12 (when both drugs were available) were examined. OS, time to treatment failure (TTF), and demographics analyses are ongoing.667 evaluable patients were identified. Overall CBZ (n=359 pts/2 y) utilization declined between Jun10-May11 (n=232) and Jun11-May12 (n=127). From Apr11 to May12: overall AA (n=465 pts/y) utilization increased between Mar-May11 (n=73) to Jun-Aug11 (n=164) and subsequently decreased (n=57) from Mar-May12. Between Apr11-May12, 130 patients received both CBZ and AA. More men (P<0.001) received DCBZAA (n=88, 67.7%) compared with DAACBZ (n=42, 32.3%). Median age of patients receiving both CBZ and AA was 67 (44-89) y and their median baseline PSA (111 evaluable) was 84.3 (0.4-7672.2) ng/mL.AA was administered more frequently than CBZ in post-D mCRPC patients. However, the sequence of DCBZAA was more prevalent than DAACBZ in this large community-based cohort. Until predictive biomarkers and outcomes with respective sequences are identified, delivery of all active agents according to patient-specific clinical factors should probably be considered. [Table: see text].


Scher H.I.,Sloan Kettering Cancer Center | Fizazi K.,University Paris - Sud | Saad F.,University of Montréal | Taplin M.-E.,Dana-Farber Cancer Institute | And 16 more authors.
New England Journal of Medicine | Year: 2012

BACKGROUND: Enzalutamide (formerly called MDV3100) targets multiple steps in the androgen-receptor-signaling pathway, the major driver of prostate-cancer growth. We aimed to evaluate whether enzalutamide prolongs survival in men with castration-resistant prostate cancer after chemotherapy. METHODS: In our phase 3, double-blind, placebo-controlled trial, we stratified 1199 men with castration-resistant prostate cancer after chemotherapy according to the Eastern Cooperative Oncology Group performance-status score and pain intensity. We randomly assigned them, in a 2:1 ratio, to receive oral enzalutamide at a dose of 160 mg per day (800 patients) or placebo (399 patients). The primary end point was overall survival. RESULTS: The study was stopped after a planned interim analysis at the time of 520 deaths. The median overall survival was 18.4 months (95% confidence interval [CI], 17.3 to not yet reached) in the enzalutamide group versus 13.6 months (95% CI, 11.3 to 15.8) in the placebo group (hazard ratio for death in the enzalutamide group, 0.63; 95% CI, 0.53 to 0.75; P<0.001). The superiority of enzalutamide over placebo was shown with respect to all secondary end points: the proportion of patients with a reduction in the prostate-specific antigen (PSA) level by 50% or more (54% vs. 2%, P<0.001), the soft-tissue response rate (29% vs. 4%, P<0.001), the quality-of-life response rate (43% vs. 18%, P<0.001), the time to PSA progression (8.3 vs. 3.0 months; hazard ratio, 0.25; P<0.001), radiographic progression-free survival (8.3 vs. 2.9 months; hazard ratio, 0.40; P<0.001), and the time to the first skeletal-related event (16.7 vs. 13.3 months; hazard ratio, 0.69; P<0.001). Rates of fatigue, diarrhea, and hot flashes were higher in the enzalutamide group. Seizures were reported in five patients (0.6%) receiving enzalutamide. CONCLUSIONS: Enzalutamide significantly prolonged the survival of men with metastatic castrationresistant prostate cancer after chemotherapy. (Funded by Medivation and Astellas Pharma Global Development; AFFIRM ClinicalTrials.gov number, NCT00974311.) Copyright © 2012 Massachusetts Medical Society.


PubMed | MedStar Washington Hospital Center, US Marine Corps, Genentech, Health ResearchTx LLC and 2 more.
Type: Journal Article | Journal: Breast cancer research and treatment | Year: 2016

Trastuzumab reduces the risk of relapse in women with HER2-positive non-metastatic breast cancer, but little information exists on the timing of trastuzumab initiation. The study investigated the impact of delaying the initiation of adjuvant trastuzumab therapy for >6months after the breast cancer diagnosis on time to relapse, overall survival (OS), and relapse-free survival (RFS) among patients with non-metastatic breast cancer. Adult women with non-metastatic breast cancer who initiated trastuzumab adjuvant therapy without receiving any neoadjuvant therapy were selected from the US Department of Defense health claims database from 01/2003 to 12/2012. Two study cohorts were defined based on the time from breast cancer diagnosis to trastuzumab initiation: >6months and 6months. The impact of delaying trastuzumab initiation on time to relapse, OS, and RFS was estimated using Cox regression models adjusted for potential confounders. Of 2749 women in the study sample, 79.9% initiated adjuvant trastuzumab within 6months of diagnosis and 20.1% initiated adjuvant trastuzumab >6months after diagnosis. After adjusting for confounders, patients who initiated trastuzumab >6months after the breast cancer diagnosis had a higher risk of relapse, death, or relapse/death than those who initiated trastuzumab within 6months of diagnosis (hazard ratios [95% CIs]: 1.51 [1.22-1.87], 1.54 [1.12-2.12], and 1.43 [1.16-1.75]; respectively). The results of this population-based study suggest that delays of >6months in the initiation of trastuzumab among HER2-positive non-metastatic breast cancer patients are associated with a higher risk of relapse and shorter OS and RFS.


Sonpavde G.,Texas Oncology And Us Oncology Research | Matveev V.,Russian Academy of Medical Sciences | Burke J.M.,Rocky Mountain Cancer Centers | Caton J.R.,Willamette Valley Cancer Center | And 9 more authors.
Annals of Oncology | Year: 2012

Background: AT-101 (A), a small molecule oral inhibitor of the Bcl-2 family, has activity alone and in combination with docetaxel (Taxotere) and prednisone (DP) in metastatic castration-resistant prostate cancer (mCRPC). A randomized, double-blind, placebo-controlled phase II trial compared DP combined with either AT-101 (A) or placebo in chemonaive mCRPC.Patients and methods: Men with progressive mCRPC despite androgen deprivation were eligible and randomized 1 1. Patients received docetaxel (75 mg/m 2 day 1) and prednisone 5 mg orally twice daily every 21 days with either AT-101 (40 mg) or placebo twice daily orally on days 1-3. The primary end point was overall survival (OS).Results: Two hundred and twenty-one patients were randomly assigned. Median OS for AT-101 plus docetaxel-prednisone (ADP) and placebo-DP was 18.1 versus 17.8 months [hazard ratio (HR) 1.07, 95% confidence interval 0.72-1.55, P = 0.63]. Secondary end points were also not statistically different. Grade 3/4 toxic effects for ADP versus placebo-DP were cardiac events (5% versus 2%), lymphopenia (23% versus 16%), neutropenia (47% versus 40%), ileus (2% versus 0%) and pulmonary embolism (6% versus 2%). In a subgroup of high-risk mCRPC (n = 34), outcomes appeared to favor ADP (median OS 19 versus 14 months).Conclusions: AT-101 was tolerable but did not extend OS when combined with DP in mCRPC; a potential benefit was observed in high-risk patients. © The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


With an upcoming publication in the Worldwide Leaders in Healthcare, Robin Minskoff-Pollack, RN, joins the prestigious ranks of the International Nurses Association. Robin is a registered nurse with 45 years of experience in her field, and an extensive expertise in all facets of nursing, especially oncology nursing. Robin is currently serving patients at the Virginia Oncology Associates in Norfolk, Virginia, where she acts as triage nurse and HIPAA/Compliance/Safety Officer. Robin attended Prince George’s Community College and received her Associate degree in Nursing in 1977. She credits her success in nursing to being in a challenging and rewarding career, in which she continuously learns new things. The patients, their families, and her peers are all very appreciative of what she does, which greatly contributes to her thriving career. In her spare time, Robin enjoys sewing, handcrafts, and her dogs. Learn more about Robin here: https://www.linkedin.com/in/robin-minskoff-pollack-23675293 and read her upcoming publication in the Worldwide Leaders in Healthcare. To find a Doctor by Specialty and Zip Code, please visit www.findatopdoc.com and book your appointment online instantly.


PubMed | Eastern Virginia Medical School, Princess Anne High School, Virginia Oncology Associates, Jefferson Lab and 3 more.
Type: | Journal: EBioMedicine | Year: 2016

Metastatic breast cancer exhibits diverse and rapidly evolving intra- and inter-tumor heterogeneity. Patients with similar clinical presentations often display distinct tumor responses to standard of care (SOC) therapies. Genome landscape studies indicate that EGFR/HER2/RAS pathway activation is highly prevalent in malignant breast cancers. The identification of therapy-responsive and prognostic biomarkers is paramount important to stratify patients and guide therapies in clinical oncology and personalized medicine.In this study, we analyzed matched pairs of tumor specimens collected from 182 patients who received neoadjuvant systemic therapies (NST). Statistical analyses were conducted to determine whether EGFR/HER2/RAS pathway biomarkers and clinicopathological predictors, alone and in combination, are prognostic in breast cancer.SIAH and EGFR outperform ER, PR, HER2 and Ki67 as two logical, sensitive and prognostic biomarkers in metastatic breast cancer. We found that increased SIAH and EGFR expression correlated with advanced pathological stage and aggressive molecular subtypes. Both SIAH expression post-NST and NST-induced changes in EGFR expression in invasive mammary tumors are associated with tumor regression and increased survival, whereas ER, PR, and HER2 were not. These results suggest that SIAH and EGFR are two prognostic biomarkers in breast cancer with lymph node metastases.The discovery of incorporating tumor heterogeneity-independent and growth-sensitive RAS pathway biomarkers, SIAH and EGFR, whose altered expression can be used to estimate therapeutic efficacy, detect emergence of resistant clones, forecast tumor regression, differentiate among partial responders, and predict patient survival in the neoadjuvant setting, has a clear clinical implication in personalizing breast cancer therapy.This work was supported by the Dorothy G. Hoefer Foundation for Breast Cancer Research (A.H. Tang); Center for Innovative Technology (CIT)-Commonwealth Research Commercialization Fund (CRCF) (MF14S-009-LS to A.H. Tang), and National Cancer Institute (CA140550 to A.H. Tang).


PubMed | Sloan Kettering Cancer Center, Astellas Pharma Inc., Virginia Oncology Associates and Medivation Inc.
Type: Journal Article | Journal: Clinical cancer research : an official journal of the American Association for Cancer Research | Year: 2016

Preclinical evidence suggests that both docetaxel and enzalutamide target androgen receptor translocation and signaling. This phase Ib study assessed the safety, tolerability, and pharmacokinetics of docetaxel when administered with enzalutamide as first-line systemic chemotherapy in men with metastatic castration-resistant prostate cancer (mCRPC).Docetaxel-nave patients received 21-day cycles of docetaxel (75 mg/m(2)). Enzalutamide (160 mg/day) was administered daily starting on day 2 of cycle 1. Patients were allowed to stop and restart docetaxel at any time following cycle 2. Treatment continued indefinitely until unacceptable toxicity or discontinuation due to investigator or patient preference.A total of 22 patients received docetaxel, of whom 21 also received enzalutamide. Docetaxel was administered for a median of 5.0 cycles and enzalutamide for a median of 12.0 months. With concomitant treatment, geometric mean docetaxel exposure decreased by 11.8%, whereas peak concentrations decreased by 3.7% relative to docetaxel alone. The most common toxicities observed during the period of concomitant therapy were neutropenia (86.4%) and fatigue (77.3%). Common toxicities observed with post-docetaxel enzalutamide were constipation (23.8%), decreased appetite (19.0%), fatigue (19.0%), and musculoskeletal pain (19.0%). Treatment with enzalutamide and docetaxel resulted in prostate-specific antigen decreases in almost all patients based on exploratory analysis of available baseline and on-study prostate-specific antigen data.The combination of docetaxel and enzalutamide is feasible, although higher rates of neutropenia and neutropenic fever than anticipated were observed. Reductions in docetaxel exposure with enzalutamide coadministration were not considered clinically meaningful. This combination warrants further study in a larger mCRPC population. Clin Cancer Res; 22(15); 3774-81. 2016 AACR.


Chang D.Z.,Virginia Oncology Associates
OncoImmunology | Year: 2012

Using in vivo models of pancreatic ductal adenocarcinoma (PDAC), we demonstrated that mast cells migrate to the tumor site and provide a microenvironment that allows for tumor progression. These results indicate that targeting mast cells may be a promising novel therapy for PDAC. ©2012 Landes Bioscience.


PubMed | Duke University, Virginia Oncology Associates and Duke Cancer Institute
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2017

105 Background: PTEN loss is common in advanced prostate cancer, leading to constitutive activation of the PI3 Kinase pathway. Temsirolimus blocks mTOR/TORC1, a key signaling node in this pathway; its activity in men with advanced castration-resistant metastatic prostate cancer is unknown.We conducted a single arm trial of weekly IV temsirolimus in men with chemorefractory metastatic CRPC who had >=5 circulating tumor cells (CTCs) at baseline (Cellsearch). The primary endpoint was change in CTCs at 8 weeks; secondary endpoints were composite progression-free survival (excluding PSA), PSA and radiographic response rates, safety, and survival. At PSA/CTC progression, an anti-androgen could be added while continuing temsirolimus.Eleven patients were accrued out of a planned 20; the trial was stopped prematurely due to lack of efficacy/feasibility. Median age was 61, with 55% African-Americans and 36% Caucasians. Median baseline PSA was 390 ng/dl, median baseline CTC was 14 cells, 50% had significant pain, and 63% had >2 prior chemotherapy regimens. The median decline in CTC enumeration at week 8 was 48% and three patients experienced a decline in CTCs to <5. However, 73% of men had persistently unfavorable CTCs (>=5) over time and only 1 patient had a >=30% PSA decline. Median PFS was 1.9 months (95% CI 0.9-3.1) and median OS was 8.8 months (95% CI 3.1-15.6). Toxicities included grade 4 hypophosphatemia and grade 4 CNS hemorrhage, and frequent grade 3 fatigue, anemia, stomatitis, hypokalemia, weakness, and hyperglycemia. Persistently high N-cadherin expression on longitudinal CTC analysis was observed as a marker of epithelial plasticity and treatment resistance.Temsirolimus lacked sufficient clinical activity in men with metastatic CRPC, despite transient CTC improvements in some men. Future studies should focus on combination approaches or novel PI3K pathway inhibitors.NCT00887640.


PubMed | Brown University, Comprehensive Cancer Centers Of Nevada And Us Oncology Research, Dana-Farber Cancer Institute, Progenics Pharmaceuticals Inc. and 2 more.
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2017

119 Background: The abundant expression of prostate specific membrane antigen (PSMA) on prostate cancer cells provides a rationale for antibody therapy. PSMA ADC, a fully human antibody to PSMA linked to the microtubule disrupting agent monomethyl auristatin E (MMAE), binds PSMA and is internalized within the prostate cancer cell where cleavage by lysosomal enzymes release free MMAE, causing cell cycle arrest and apoptosis. We have completed a phase 1 dose escalation study of PSMA ADC in subjects with taxane-refractory mCRPC.Eligibility requirements include progressive mCRPC following taxane-containing chemotherapy and ECOG status of 0 or 1. PSMA ADC was administered by IV infusion Q3W for up to 4 cycles. Safety, pharmacokinetics (PK), PSA, circulating tumor cells (CTC), clinical disease progression and immunogenicity to PSMA ADC were assessed. Serum PSMA ADC and total antibody were measured by ELISA, and free MMAE was measured by LC/MS/MS.The dosing cohorts ranged from 0.4 mg/kg to 2.8 mg/kg.52 subjects with mCRPC were dosed in nine dose levels. All subjects received prior docetaxel, 5 also received cabazitaxel and 3 subjects also received paclitaxel. PSMA ADC was generally well tolerated with the most commonly seen adverse events being anorexia and fatigue. Peripheral neuropathy was reported by 7 subjects after repeated doses. Two were grade 3. Dose limiting toxicities (DLT) seen at 2.8 mg/kg were neutropenia (one death) and reversible liver function tests (LFTs) elevations. Antitumor activity was manifested as reductions either in PSA or CTCs at 1.8 mg/kg PSMA ADC in approximately 50% of patients. Exposure to PSMA ADC increased with dose and was ~1,000-fold greater than MMAE exposure and no accumulation was observed.PSMA ADC in this study was generally well tolerated in doses up to 2.8 mg/kg every three weeks in subjects with mCRPC, previously treated with taxane. Antitumor activity was seen at higher dose levels. DLTs were neutropenia and reversible LFT abnormalities. The maximum tolerated dose of PSMA ADC was determined to be 2.5 mg/kg. A phase 2 trial in taxane refractory mCRPC has been initiated.NCT01414283.

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